SYPHILIS SYPHILIS 
A collection of articles reprinted, 
with permission, from the American Journal of The Medical Sciences, 
\ 
The Journal of the American Medical Association and 
The War Department Technical Bulletin 
by The United States,Office of War Information 
1945 SYPHILIS 
THE TREATMENT OF EARLY AND LATENT SYPHILIS 1 
John H. Stokes, M.D., Herman Beerman, M.D. and Virgene 
Scherer Wammock, M.D. The American Journal of the Medical 
Sciences, Vol. 206, No. 4, October 1943. 
THE TREATMENT OF EARLY SYPHILIS WITH PENICILLIN 26 
A Preliminary Report of 1,418 Cases 
Joseph Earle Moore, M.D., Baltimore, J. F. Mahoney, M.D., 
Medical Director, U. S. Public Health SeiVice, Stapleton, Staten 
Island, N. Y., Commander Walter Schwartz (MCI, U.S.N., 
Lieutenant Colonel Thomas Sternberg, Medical Corps, Army of 
the United States and W. Barry Wood, M.D., St. Louis. The 
Journal of the American Medical Association, Vol. 126, No. 2, 
September 9, 1944. 
PENICILLIN TREATMENT OF SYPHILIS 32 
War Department Technical Bulletin 106, 11 October 1944. 
THE ACTION OF PENICILLIN IN LATE SYPHILIS 37 
Including Neurosyphilis, Benign Late Syphilis and Late Congenital Syphilis: Preliminary Report 
John H. Stokes, M.D., Philadelphia, Lieutenant Colonel Thomas 
H. Sternberg, Medical Corps, Army of the United States, Com- 
mander Walter H. Schwartz (MC), U.S.N., John F. Mahoney, 
M.D., Senior Surgeon, U. S. Public Health Service, Stapleton, 
Staten Island, N. Y., J. E. Moore, M.D., Baltimore and W. Barry 
Wood, Jr., M.D., St. Louis. The Journal of the American Medical 
Association, Vol. 126, No. 2, September 9, 1944 
PENICILLIN IN THE PREVENTION AND TREATMENT OF CONGENITAL SYPHILIS 45 
Report on Experience with the Treatment of Fourteen Pregnant Women with Early Syphilis and Nine Infants 
with Congenital Syphilis 
J. W. Lentz, M.D., Norman R. Ingraham, Jr., M.D., Herman 
Beerman, M.D. and John H. Stokes, M.D., Philadelphia. The 
Journal of the American Medical Association, Vol. 126, No. 7, 
October 14. 1944. SYPHILIS 
THE TREATMENT OF EARLY AND LATENT SYPHILIS 
Bv John H. Storks, M.D. 
Herman Beerman, M.D. 
AND 
I 
Virgene Scherer Wammock, M.D. 
The best approach to the modern treatment of early syphilis is a series 
of short, and to some extent disputable statements indicating landmarks 
in the progress of the past 35 years. This summary is substituted for 
the narrative type of historical perspective in this review. 
The Mercurial Era. Syphilis therapy up to 1912 left the disease to 
pursue its physiopathologic course comparatively little influenced at least 
by the milder and hence most popular forms of medication—the therapy 
per on of the widely copied French school. PAen mercury intramuscularly 
except as the water-soluble salts, and the violently reaction-producing 
calomel veneered the surface of a syphilitic infection rather than attacked 
its roots. 
The Early Arsphenamine Era. The “therapia sterilisans” period oi- 
l-dose cure era promised by Ehrlich’s theorization slowly changed under 
the impact of criticism from older observers of the course of syphilis under 
treatment. The belief that something radical, time-saving and treatment- 
shortening had been accomplished by “606” died hard. One dose was 
succeeded by successive doses as experience grew. Relatively new con- 
ceptions of “cure by stage” came into existence with curious incompre- 
hensible offshoots such as the doctrine of chancre-excision. “Abortive 
cure,” essentially the systematic speculative underestimation of the amount 
of treatment required by the seronegative primary stage, dates back to 
this era. From 1916 to 1919 the “course” conceptions of syphilis treat- 
ment established themselves, together with a combined theoretical and 
speculative discussion of the necessity for and the appropriate use of 
arsphenamine and heavy metal. 
The Early Evaluative Period. From 1919 to 1922, an extensive litera- 
ture, unfortunately not too familiar to some claimants for priorities, con- 
stituted the initial “shake-down” of an accumulating experiential tradi- 
1 tiom While limited to the serologic effects of treatment and the occur- 
rence of grossly visible forms of relapse as criteria for determining effects, 
many of the outlines along which the new era has developed were fore- 
shadowed by the reports of Gennerich,17 the German Dermatological 
Society (Rost, 1921,40 Almkvist,1 Bering,4 Boas,7 Hoffmann,21 Bruck,9 
Jadassohn,24 Ullmann,47 Eicke,15 Hoffmann-Mergelsberg,22 Miillern-Aspe- 
gren,33 Haxthausen,20 Rasch,38 Scholtz[Silberstein42], Satke,41 Mutschler,34 
Zieler,50 Bruns,10 Riecke,39 Bernard,5 Harrison19 and others). The stage- 
of-beginning treatment conception received more or less precise delinea- 
tion towards the latter part of 1922. A type of foreshortened intensified 
therapy, that of Scholtz, was reported by Silberstein42 in 1923, before any 
American contributions were in the field. When American studies did 
appear, however, they rapidly established a series of important con- 
ceptions, beginning with Moore and Kemp’s31 demonstration based on 
Keidel’s30 foresighted Johns Hopkins system, of the importance of con- 
tinuity in treatment, and S. WT. Becker’s2 demonstration at the Mayo 
Clinic of the value of massing or intensification of arsenical therapy at 
the moment treatment is begun. Familiar to Americans during this period 
are the Pollitzer-Ormsby35,37 variation on the Scholtz technic and other 
types of intermittent systems which lost ground after the League of 
Nations confirmation28 46 of the substantial superiority of continuous 
treatment. 
The League of Nations Syphilis Commission Evaluations.* Begun 
on a massive scale in 1928 with conclusions and recommendations stated 
in 1935, this world-wide survey of technical methods in the treatment of 
early syphilis provides the basis for what may now be spoken of as the 
conservative or prolonged method for the treatment of early and latent 
syphilis. Under the terms of the cooperative agreement among the 
nations participating, each was individually encouraged to make the most 
of his own material in addition to contributing to the general pool. This 
rapidly brought American material into the foreground, and the contribu- 
tions of the Cooperative Clinical Group13 working under the aegis and 
with the statistical cooperation of the United States Public Health Service, 
express today what might be called the basic formula of American practice. 
From the League of Nations evaluation for which Martenstein supervised 
the interpretations,28 two general systems of treating early syphilis emerged 
—the British-Scandinavian intermittent and the American continuous 
systems. A certain amount of argument has inevitably arisen over the 
suitability of the material for deciding the question of intermittence versus 
continuity, but on the whole the Commission’s findings seemed to justify 
the belief that the intermittence of the recommended intermittent system 
is more'formal than actual and that its intensity especially in simultaneous 
arsenical and heavy metal administration, causes its effects to be sub- 
stantially those of a somewhat less intensive but continuous technic. 
Enthusiasm for the newer foreshortened procedures (see below) should 
not be allowed to dim the significance of this great evaluative accomplish- 
ment, and the syphilologist of today may without hesitation subscribe to 
either of the announced conservative systems as the equal in curative 
* Under the direction of the League of Nations Health Organization, the following 
countries participated: Denmark, France, Germany, Great Britain, United States of 
America. The membership in 1928 included Jadassohn (Breslau), Chairman, Madsen 
(Copenhagen), Colonel Harrison (London), Queyrat (Paris), Stokes (Philadelphia), 
Rasch (Copenhagen); Gougerot replaced Queyrat, Lomholt replaced Rasch in 1935. 
Statistical consultant, Westergaard (Copenhagen). Evaluation and report by Marten- 
stein (Dresden). 
2 effect of the more recent “ hurry-up” systems of procedure with a sub- 
stantially greater margin of safety. 
Since the League of Nations evaluation has established such substantial 
landmarks, it may wrell be used as a milestone at which to summarize the 
high points of the progress of syphilotherapy since the close of the mer- 
curial age. The following fundamental principles have emerged from a 
quarter century of revolutionary progress: 
1. Early and not late syphilis is the domain of systems. Bad effects follow' 
haphazardness, short courses, low dosage and lapse from treatment in 
early syphilis. 
2. The “stage at which treatment is begun” principle is established with 
trustworthy evidence that seronegative primary syphilis is the most easily 
cured of all stages of the disease, seropositive primary syphilis the most 
uncertain or resistant and secondary syphilis midw'ay between the two. 
3. Relapse follows short treatment, especially arsenical, producing delayed 
secondaries, neurorecurrence, infectious mucosal lesions, serologic relapse 
and fastness. 
4. Single drug treatment is inferior to combined treatment and a heavy 
metal improves arsenical results and compensates shortcomings. 
5. Prolongation—more injections, longer courses—gives superior results 
in systems dominated by the calendar interval of 1 week. Prolongation 
and increased mass through individual and total dosage were, of course, 
attempts to meet the resistance of the 30% relapsing group among early 
syphilitics at large. 
6. Dosage theory was spotted with empiricism. The concept of lower 
drug tolerance of the female as compared wdth the male; the large versus 
small dose school; the crowding or time-dose problems represented by the 
so-called intensive method; the toxicity fears (simultaneous versus alternate 
administration of arsenical and heavy metal); the idiosyncrasy and tech- 
nical error factors in reaction interpretation which held down dosage, 
while reports of relapse and resistance raised it. 
7. Calendar servitude or the domination of the 7-day interval on a purely 
empirical unevaluated basis was general. Few ventured to think in terms 
of shorter intervals or would admit their practicality or desirability. 
8. Rising appreciation of scheduling. It became clear that schedules 
or systems critically examined by large syphilologic centers and expert 
experience were the sound basis for treatment methods rather than the 
results of blood serologic tests, thus slowly displacing the serologism of 
the 1920’s. 
9. The vital comprehension of toxicity and therapeutic efficiency relations 
was dominated by the laboratory and rested on the insecure foundation 
of trypanosomiasis in mice rather than syphilis in man or animals. This 
group of conceptions, though expressed by impressive numerical indices 
was essentially vague and inadequate. A true experimental basis for 
syphilotherapeusis did not yet exist. 
10. Despite these strictures on the knowledge of the day, the work of indi- 
vidual investigators plus the League of Nations evaluations established 
the following facts: 
(а) An arsphenamine alone can “ cure ” early syphilis in a large percentage 
of cases.27 
(б) Heavy metal is a potent augmenting force, particularly true of bismuth; 
a fact recently “re-discovered” by recent workers with intensive methods. 
(c) Arsenical therapy can be “crowded” or “foreshortened” without fatal 
effect and with good results (Scholtz-Silberstein massive divided dose 
system). 
3 (d) Continuity and calendar regularity are vitally important to the con- 
servative or prolonged systems evaluated by the League of Nations. “ A 
little treatment continuously given is twice as effective as the same amount 
of treatment intermittently given.” 
(e) Prolongation of treatment (in the weekly calendar or conservative 
systems) irons out most complications, relapse and resistance.3 
(/) Some important League of Nations and Cooperative Clinical Group 
principles: 
(1) The curative outlook is one-third better when treatment is begun 
in the seronegative primary stage than in other stages of early and 
and latent syphilis. 
(2) The good results obtained by prolonging continuous treatment 
longer than 1 year more than double those obtained by the same 
kind of treatment carried through less than a year. 
(3) Intermittent and irregular treatment are the principal sources of 
delayed reversal of the blood serologic reaction. 
(4) Prolongation and intensification of treatment, using much 
arsphenamine and heavy metal, but especially much arsphena- 
mine in the first 3 months promotes good results. 
(5) Satisfactory results may occur with little treatment, but much 
treatment and over prolonged periods is twice as effective as little 
treatment if continuously applied, and 5 times as effective as 
treatment intermittently applied. 
(6) Arsphenamine is the chief factor in relapse prevention, and this 
applies specifically to the incidence of neurosyphilis (note impor- 
tance of this principle in foreshortened intensive methods). 
(7) Serologic irreversibility becomes the more marked the later in 
early syphilis treatment is begun, and the more frequently lapse 
from continuity occurs whether in the form of rest intervals or 
otherwise. 
(8) A weak positive serologic reaction interrupting a series of nega- 
tives in early syphilis is a distinct warning of the possibility of 
relapse. 
Much of the effectiveness of the foreshortened intensive treatment 
methods was predicted by Martenstein’s conclusions from the general 
League of Nations material that the employment of a comparatively 
heavy individual dosage of the arsenical and of bismuth or mercury with 
administration in rapid succession at the outset of treatment, leads to 
superior results. Furthermore, approximately the same amount of treat- 
ment should be administered to primary as to secondary cases. 
(g) Large dosage is preferable to small; should follow a weight standard, 
and be without sex differentiation. 
(h) Many of the most serious complications of treatment are due to back- 
ground causes (idiosyncratic-allergic, intercurrent infections, and technical 
factors rather than the drugs as such alone). In particular, the combina- 
tion of arsenic and bismuth is as safe as arsenic alone. 
(i) To date, no claims for the use of a heavy metal alone in the treatment 
of early syphilis have withstood critical evaluation. An arsenical is essen- 
tial as a controller of infectiousness. The effect is augmented by bismuth, 
and also though probably less so, by mercury. Twenty full doses each of 
arsenical and heavy metal approximate a minimal amount of treatment 
for infection control (so-called 20-20 standard). 
(j) The controversies over the individual merits of arsenicals (606, 914 and 
so forth) have been largely submerged by the overwhelming popularity of 
4 mapharsen in American practice, due largely to its low toxicity, combined 
with high spirillicidal value. This has been overwhelmingly demonstrated 
in the 5-day massive dose arsenotherapy (5-day drip) and its therapeutic 
efficacy when intensively employed has also been demonstrated by the 
Eagle-Hogan animal experiments. 
Additional Basic Principles for Present and Future Emphasis. 1. The 
Boeck11 material underlies the principle that syphilis “cures” itself in 40% 
of cases. 
2. A little treatment in early syphilis36 raises the percentage of cure 
another 20 % to 30 %. 
3. Intensification and prolongation (or repetition in the case of intensive 
foreshortened methods) directed at the resistant 30% bags another 15% 
to 25%, depending on stage-of-beginning-treatment, for cure. 
4. The remaining 5% to 15% represents the irreducible residue of 
resistance (deficient defense, special strains and so forth) that nothing 
save time, therapeutic repetition and variation, and fever, if anything, will 
cure. 
5. Non-specific agents (fever) have important re-enforcing and curative 
effects in early as well as late syphilis—chiefly by enhancing the effective- 
ness of arsenicals faster than it increases their toxicity.6 
6. The spinal fluid examination is an indispensable evaluative and cura- 
tive check procedure more important ultimately than blood serology. 
7. As to observation and discharge as cured, all patients who have had an 
entirely non-relapsing course while receiving ideal treatment should be 
informed that a cardiovascular reexamination in the 5- to 10-year period 
is necessary. 
8. The syphilitic pregnant woman or the woman who has had syphilis 
and is believed to be cured should have her status reviewed with every 
pregnancy and safety-first requires her treatment for protection of the 
child during each pregnancy whether seronegative or seropositive. 
9. Unsatisfactory results (non-cure) are usually reviewed by the 5th year 
of observation and Padget found no less satisfactory results in any case 
after 10 or more years of observation. 
Principles Established by the Clinical and Experimental Study of Fore- 
shortened Intensive Methods. The past decade of work with intensive 
treatment methods has contributed a number of additional important 
principles to our understanding of syphilotherapy. 
1. Hyman, and his co-workers16 have demonstrated that an approxima- 
tion to the total curative dose of an arsenical can he administered to a human 
being by an intravenous infusion method (drip) without necessarily dis- 
astrous effects with a controllable though increased toxicity and with 
satisfactory results. 
2. A toxicity-therapeutic efficacy relationship has been worked out by 
Eagle and Hogan1416 on the basis of animal, and more recently human 
clinical results. Syphilis can be cured in 80% to 100% of cases (stage- 
of-beginning-treatment factor) by a total dose of 20 to 30 mg. per kilo 
body weight of an arsenoxide (mapharsen) alone. 
3. The toxicity of such a dose is inversely proportional to the time in which 
this dose is given. 
4. Any combination of toxicity and time relationship (that is, any margin 
of safety) that practical considerations may dictate is theoretically possible, 
the mortality rising with the shortening of the time in which the total 
dose is delivered. 
5. The addition of bismuth (“re-discovery”) greatly enhances the effect of 
5 all foreshortened intensive arsenotherapy (informally estimated by Eagle 
as 8 times better effect with bismuth than without). 
6. Serologic signs and symptoms under foreshortened procedure disappear 
gradually on a now well-recognized gradient to which a quantitative 
serologic procedure is essential in interpretation. 
7. A wide variety of time and technical variations (5-day intravenous drip 
versus 10-day multiple injection, versus 10 to 12 weeks of 2 to 3 injections 
weekly, versus 26-week schedules) with graded morbidity and mortality 
but substantially identical therapeutic outcome can be employed as forms 
of “foreshortened intensive” systems in the name of various types of 
exigency or expediency. 
8. The mortality of the 5-day drip is currently estimated at 1:200 to 
1:300. Any schedule completed in 20 days or less will have a mortality 
greater than 1:1000 (Eagle-Hogan); 10- to 12-week systems have a mor- 
tality of approximately 1:1500. The mortality of 20- and 26-week sys- 
tems is not yet definitely known. That of reasonably good performance 
of the standard conservative prolonged systems is estimated by Hahn18 
(Johns Hopkins Hospital) at 1:1950; with optimum experience at 1:2800. 
It must be recalled that the mortality of conservative treatment is com- 
puted from arsphenamine and not mapharsen-treated cases. The toxicity 
of mapharsen is so low (1 death in 3938 patients16), that a material drop 
in mortality should follow its use in the conservative systems. Levine 
and Keddie estimate the mapharsen death rate to be \ that from neo- 
arsphenamine. 
9. The foreshortened intensive procedures (up to 12 weeks) greatly reduce 
the incidence of neurosyphilis. 
10. The justification of the foreshortened procedures except for their 
apparent efficacy in the prevention of neurosyphilis (spinal fluid abnor- 
mality) is in the main still one of emergency and expediency. The ultimate 
results are obtainable by the older slower methods with less risk of life. 
What effect this will have on their post-war use remains to be seen. 
In a discussion of the basic principles of system evaluation applicable 
to foreshortened intensive methods, Stokes436 wrote as follows: 
“ Any new systems proposed should be judged basically by their ability 
(a) to equal or surpass the ‘curative’ expectancy of the old ones; (6) to 
lead to less infectious relapse; (c) to reduce the incidence of cardiovascular 
and neurosyphilis, and (d) by their relative risks to the patient. 
“For the evaluation of a system, time and observation are necessary to 
establish reduction of, or absence of relapse and progression. For the 
former, 2 to 4 years; for the latter, up to 10 years is a reasonable observa- 
tional requirement. For decision on relapse the patient must be repeat- 
edly and frequently observed, for it is a come and go affair. For the 
evaluation of ‘ cure,’ from a decade to a lifetime, the longer the better, is 
required. ■ 
“A system which under such scrutiny has shown itself at least equal 
to its predecessors may then proceed to claim additional advantage and 
support for a variety of reasons, including cheapness, rapidity, controlla- 
bility of the lapse factor because the whole job is finished in a short time, 
aid in the widening of availability of treatment by making possible the 
treatment of more persons*per unit of time, personnel and equipment. 
Such considerations are in the main secondary to those of control of infec- 
tiousness and real curative power. 
“ If the new system equals the old or surpasses it in all these particulars 
it has but one more hurdle to make before achieving priority. While 
6 yrimum non nocere is losing some of its meaning in a war-torn world, there 
are still arch conservatives who are inclined to examine critically the bad 
effects, the complications of a system. Of real importance to the victim 
are the risks involved, the chances of damage or of death from treatment 
in the case of a disease which with none or very little treatment gives the 
victim at the outset a 40 to 70% chance of escape from serious conse- 
quences. If an equal chance of escape with an older method offering less 
risk exists, only the most cogent reasons and a free choice by the patient 
of the more dangerous method justify its election.” 
The Conservative or Prolonged Standards of Treatment for Early, Early 
Latent and Late Latent Syphilis. It is now in order to summarize wrhat 
may be called the “official” or most widely authenticated and accepted 
systems for use in that phase of the disease which permits of systematiza- 
tion in procedure. While it is impossible, with the rapid changes taking 
place in syphiiotherapy, to predict how long such systems will have a 
following, it should be clearly understood that they are effective, and will 
do all that the foreshortened systems will, with a very much greater 
margin of safety. To the British-Scandinavian intermittent system8 
(which must be exactly followed, diagram in hand) and a slight but now', 
for American practice, “official” modification of the American continuous 
(League of Nations) system, the “ 30-60-03,1,43 is added the as yet un- 
proved and unevaluated but rational “Army Plan” recommended to the 
Surgeons General by the National Research Council and publicized in 
Circular Letter No. 74. The conservative systems are still, we believe, 
the backbone of modern practice, the basis of much of our present knowl- 
edge of mechanism and effects, and likely to be displaced completely only 
by certain radical changes in the whole chemotherapeutic attack on the 
disease such as are affecting the pyogenic infections, gonorrhea, etc. (the 
sulfonamides, penicillin). 
The British-Scandinavian {League of Nations) System: Plan of Courses 
of Inject ion. 
A course consists of 8 weekly injections of neoarsphenamine (0.6 to 0.75 gin. 
each) or arsphenamine (0.4 to 0.5 gm. each) given simultaneously with 8 weekly 
injections of an insoluble bismuth compound (0.2 to 0.24 gm. bismuth metal each) 
and followed by 2 more weekly injections of bismuth compound. An equivalent 
amount of a mercury preparation may be substituted for the bismuth (inunctions 
for 40 days at 3 gm. of unguentum hydrargyri or injections of 70 mg. of mild 
mercurous chloride or 120 mg. of mercuric salicylate, etc., suspended in a suitable 
base). It is recommended that: 
(а) In cases wdiich remain or become serologically negative during or by the end 
of the first course, 4 such courses be administered, with intervals of 3 to 5 weeks 
between any 2 courses. 
(б) In cases which have not become seronegative by the end of the first course, 
in addition to the amount of treatment showm in (o), further courses should be 
administered until the patient has received as a minimum 3 beyond that which 
has ended with negative serum reactions. At the option of the individual clinician, 
this treatment may be prolonged as may be considered necessary. 
(c) Cases presenting signs of clinical relapse of an early type should be dealt 
with on principles similar to those enunciated in (b). 
For non-pregnant females, treatment should be administered on the plan out- 
lined for men, with the exception that the single dose of neoarsphenamine should 
be reduced by 0.15 gm. and that of arsphenamine by 0.1 gm. 
In the event of any reduction in the amount of treatment being indicated, it is 
recommended that this be effected by reducing the number of arsenical injections 
rather than by reducing the individual dose or increasing the intervals. 
7 The American Continuous System: The “30-60-03” “Official” Modifi- 
cation, Circular Letter No. 18 of the Surgeon General’s Office, U. S. Army. 
The published work of the United States Public Health Service and the 
Cooperative Clinical Group in the United States has indicated that con- 
tinuous treatment with an effective arsenical alternating with bismuth on 
a definitely defined schedule with calendar regularity and without rest 
periods during the arsenical phase is the optimum conservative technic 
for the treatment of seronegative and seropositive primary syphilis, 
secondary syphilis, and early latency (within the first 4 years of the 
infection when the duration is known). An essentially similar standard 
of treatment employing 606, parallel with an acceptable intermittent 
(British-Scandinavian) system of treatment employing neoarsphenamine, 
has been recommended by the Commission on Syphilis and Cognate Sub- 
jects of the League of Nations as a result of an extended study of an inter- 
national statistical material. It may therefore, it is believed, be accepted 
as having the support of authority. 
For mnemonic convenience, the designation, “30-60-03” is suggested, 
for the standard system for early and early latent syphilis;43 the “30” 
representing the number of arsenical injections; the “60” representing 
the number of weeks of bismuth therapy, equivalent to 60 injections of 
bismuth subsalicylate, and the “0” and “3” representing respectively, 
no rest periods, and 3 years of combined treatment observation. By 
“treatment observation” is meant the total elapsed time from the institu- 
tion of treatment in accordance with this schedule until the patient is 
discharged from observation as presumptively cured. 
Since the sequence of various types of treatment in this system, the pre- 
vention of relapse by overlapping of heavy metal and arsenical therapy, 
the serologic controls, the spinal fluid examination, all are integral parts 
of the treatment system, the following diagram is offered as presenting 
these various relationships. 
The “30-60-03" for Early Syphilis. 
30 neoarsphenamine or mapharsen injections, 60 weeks of bismuth injections. 
NO rest intervals in the arsenical phase, 3 years of treatment observation. 
0 = neoarsphenamine or mapharsen; x = bismuth subsalicylate; weekly intervals. 
xxxxxxxxxx 8 weeks rest (and continue this intermittently to a total of 60 bismuth 
injections). 
A = first 3 injections compressible into 10 to 14 days. Some risk of increased re- 
activity. 
B = average case seronegative, 16th week. 
C = Examine spinal fluid if blood is still positive, 24th week. 
D = Always insist on spinal fluid examination before rest period. 
1 = if blood test has become negative, suspect low resistance. 
2, 3,4,5 = if weak positives appear among negatives, suspect relapse, neurosyphilis. 
The “30-60-03” schedule as thus presented can be drawn up in “vertical” as 
distinguished from the above “horizontal” arrangement, week by week, for printing 
directly on record forms. 
The published observation of the USPHS-CCG group on the treatment of early 
syphilis indicated that the “30 60-03” schedule could be most effectively applied 
to seronegative primary syphilis and fully developed secondary syphilis. In the 
case of seropositive primary syphilis, whose status should be confirmed in the 
seronegative cases by a repetition of the blood test on the day following the first 
8 arsenical injection, there were definite indications that the seropositive primary 
phase of the disease, lacking the development of a full-fledged immunity reaction 
on the part of the body was the most resistant to cure, and the most prone to 
relapse of the 3 groups of cases included under the designation, “early syphilis.” 
It has accordingly been proposed that in seropositive primary syphilis and initially 
negative primary syphilis which becomes seropositive on the blood immediately 
following the institution of treatment, a “40-80-04” system be employed, meaning 
thereby an additional 10 arsenical injections and 20 bismuth injections and another 
year of observation over and above the standards proposed as generally applicable 
to early and early latent syphilis. This extension of the arsenical phase of treat- 
ment can take the form of 5 courses of the arsenical of 8 injections each, in place 
of the 3 courses of 8 and 1 course of 6 injections in the “30-60-03” system. The 
bismuth therapy may follow the usual 2-injection overlap, plus 4 additional injec- 
tions in the arsenical intermission that is employed in the “30-60-03”; the remain- 
ing bismuth injections to complete the 80-week standard, being continued in 
10-injection intermittent courses after the completion of the arsenical phase of 
treatment. 
The 26-Week Army System. The diagram is adapted from Circular Letter 
No. 74, Surgeon General’s Office, U. S. Army. 
Week 
Arsenoxide 
Week Bismuth 
2 
1 ' 
2 
2 
Bismuth subsalicylate 
3 
3 
intramuscularly once 
4 
Arsenoxide intravenously 
4 
a week, 5 injections 
5 
twice a week; total 20 
5 
6 
injections 
6 
Omit bismuth subsalicyl- 
7 
7 
ate 5 weeks 
8 
8 
9 
9 
10 
10 
11 
11 
12 
12 
13 
Omit arsenoxide 6 weeks 
13 
Bismuth subsalicylate 
14 
14 
once a week, 6 injec- 
15 
15 
tions 
16 
16 
17 
17 
18 
18 
Omit bismuth subsalicyl- 
19 
19 
ate 5 weeks 
20 
Arsenoxide as in first 
20 
21 
course twice a week; 
21 
22 
total, 20 injections 
22 
23 
23 
Bismuth subsalicylate 
24 
24 
once a week, 5 injec- 
25 
25 
tions 
26 
26 
Dosage. Arsenoxide, 0.05 to 0.07 gm., based on patient’s weight. Bismuth 
subsalicylate, 0.2 gm. (Forty injections arsenoxide—16 bismuth subsalicylate.) 
Serologic Control of Treatment. In patients with early syphilis treated with the 
Army system, a serologic test will be done at the beginning and end of the schedule 
of treatment outlined but treatment may be stopped whether the serologic reac- 
tion for syphilis is positive or negative. After the completion of treatment the 
serologic tests should be repeated 3 and 6 months later. If the reaction is negative 
after 6 months, the case may be classified as “result satisfactory” and the Syphilis 
Register may be closed. If the test is positive after 6 months, the patient should 
be referred to a station or general hospital. 
In patients with latent syphilis the serologic tests should be repeated at the 
completion of the treatment outlined, but the Syphilis Register may be closed when 
this treatment is completed, regardless of the result of the serologic test. 
Spinal fluid examination should be performed In a hospital in patients with early 
syphilis at the end of the course of treatment outlined, or as soon as possible there- 
9 after, but in any event before the Syphilis Register is closed. In apparent latent 
syphilis, spinal fluid examination should be performed in a hospital before treat- 
ment or as soon as possible thereafter, but in any event before the Syphilis Register 
is closed. 
A System of Treatment for Latency—“ plus." Before defining 
a system by which adequate treatment of latency may be judged, it must 
be reemphasized here that the latency implied is “ monosymptomatic 
seropositive latency” in which absolutely no clinical evidence of syphilis 
can be identified on complete physical examination except the positive 
and confirmed—and confirmable—blood-serologic reaction for the disease. 
An adequate examination of the spinal fluid is necessary to establish the 
fact that a seeming latency is not complicated by asymptomatic neuro- 
syphilis. A patient who has been adequately treated for an early syph- 
ilitic infection but who still remains seropositive on the blood in order to 
be considered as in monosymptomatic seropositive latency (serologically 
fast) should have had a negative spinal fluid 1 year after the close of his 
treatment for early syphilis, and if more than a year has elapsed since the 
cessation of such treatment, a repetition of the spinal fluid examination is 
desirable. A long series of negative spinal fluids is not necessary to the 
establishment of the status of monosymptomatic seropositive latency, for 
according to USPHS-CCG observation, more than 1 or 2 repetitions of a 
negative fluid in the absence of any developing clinical signs is unnecessary. 
The latency of a syphilitic infection is divided arbitrarily into an early 
and a late period, partly because of the greater risk of infectious relapse 
and other types of recurrence in early latency, and partly because of the 
presumed better outlook for complete arrest if not cure in the earlier years 
of the latent period. The dividing line between early and late latency 
has tended in American practice to be the fourth year of the disease. This 
is an arbitrary setting which may in the judgment of an expert, be varied 
one way or the other. A young and robust person whose infection is of 
5 or even 6 years presumed duration may be advised to accept the standard 
for an early infection in his treatment. On the other hand most genuine 
latency, after the 4th year, shows relatively little tendency to progression, 
and may be treated by a standard substantially lower than that proposed 
for the radical cure of early infection. 
The treatment of early latency (first 4 years of the disease) is that of 
early syphilis—the “30-60-03” system. 
The Cooperative Clinical Group’s13 experience has indicated that for 
the treatment of late latency (after the 4th year) 3 courses of 8 injections 
each of an effective arsenical given in continuity and alternation with 
10 injections of bismuth subsalicylate, without overlap and with con- 
tinuity extending only through the arsenical phase, constitute an adequate 
beginning. The continuous treatment with arsenical and heavy metal 
is then followed by an intermittent and prolonged treatment with bismuth 
alone which should total, including the three 10-injection bismuth courses 
given with the arsenical phase, not less than 60 weeks of bismuth therapy. 
Further treatment with bismuth to the extent of 80 weeks, or even 100 
weeks, or on the basis of 80 weeks, plus “ a course a year” for several years, 
was found to increase appreciably the good results by the criteria em- 
ployed. It is not necessary, however, in judging candidates for admission 
to the services, to insist on prolongation of the heavy metal phase beyond 
the 60th week. Approximately 70% of monosymptomatic seropositive 
latency may be expected to reverse to negative on the blood for an indefi- 
10 nite period following a 24-60 course, and the failure of the remaining 30 % 
to reverse may be regarded as no bar to eligibility. 
As a general principle, late latent cases remaining seropositive after a 
24-60 course should be observed at intervals of a year or two with physical 
examination and appropriate tests for evidence of cardiovascular progres- 
sion and ultimate neurosyphilitic involvement. 
It should be emphasized that late latency is usually much overtreated 
on the basis of fluctuating positive blood serologic reactions alone, or be- 
cause of conflicts between the results of various laboratories (“serologic 
discord”). 
Massive Dose, Foreshortened Chemotherapy of Eealy Syphilis, Description 
of Procedure, Indications and Contraindications. All methods of intensive 
therapy are intended for patients with early syphilis (primary, secondary, 
relapsing secondary, and early latency) who have received little or no 
previous therapy, who are robust young people, especially men, reason- 
ably free from serious visceral disease, particularly hepatitis, myocarditis, 
severe hypertension, nephritis, excessive alcoholism, blood dyscrasias, 
active pulmonary tuberculosis, and history of previous serious arsenical 
reaction. Although it is safe to administer sulfonamides simultaneously 
with conservative prolonged therapy and even with the 12-week system, 
it is unsafe to give sulfonamide therapy for gonorrhea or other conditions 
to patients receiving 5- to 10-day intensive therapy. 
Pre-treatment Routine (All Methods of Intensive Chemotherapy) (after Leifer, 
194016). The routine examination consists of the following: 1. Daily urinalysis, 
including determination of urobilin. 
2. Determination of the urea nitrogen content of the blood and the icterus index. 
3. Complete blood count, including that of the platelets. 
4. Complete physical examination on admission. 
5. Serologic examinations made in 3 different laboratories (these include the 
Kolmer, Kline diagnostic, Kline exclusion, Kahn standard and titered Wassermann 
tests). 
6. Dark-field examination of material from all open sores. 
7. Estimation of renal function by determination of the specific gravity of the 
urine. 
8. Special tests of hepatic function by the bilirubin method. 
9. Studies of the excretion of arsenic in the urine and in the stool and its con- 
centration in the blood (optional; for study purposes). 
Technic of 5-Day Intravenous Drip (Chargin, Hyman, Leifer16) (after Committee 
on Massive Drip Intravenous Therapy, 1940). Materials* 1. Needle—deep injec- 
tion type, No. 20, 1$ inch length. 
2. Diluent—5% dextrose solution. 
3. Drug—mapharsen (arsenoxide), ampoules 0.04, 0.06, and 0.06 gm. 
4. Glass gravity cylinder, 300 cc. capacity with attached rubber tubing, glass 
drip chamber, adapter for needle. Vacoliter or similar container may be used 
instead of apparatus described (L. W. Shaffer). 
5. Adhesive or Scotch tape (5 inch width). 
Dosage of Mapharsen: 1. Total dosage for the 5-day treatment period is deter- 
mined by the stripped weight of the patient. In patients weighing less than 
70 kg. (155 pounds) the total dose is 1000 mg. (1 gm.); in those weighing 70 kg. 
or more, the total dose of mapharsen is 1200 mg. (1.2 gm.). 
2. The daily dose is 200 mg. (0.2 gm.) for patients receiving a total of 1000 mg. 
(1 gm.). 
3. The daily dose is 240 mg. (0.24 gm.) for patients receiving a total of 1200 mg. 
(1.2 gm.). 
4. If a patient receives less than the intended daily dose (this will most often 
occur on the first day of therapy), the deficiency in dosage may then be spread over 
the remaining days of treatment. Thus, if the patient receives 120 mg. (0.12 gm.) 
11 the first day instead of the intended total daily dosage of 240 mg. (0.24 gm.) he 
may be given 30 mg. (0.03 gm.) additional on each of the succeeding 4 days of treat- 
ment. 
Procedure: Site of Election for Insertion of Needle. After cleansing of forearm 
and application of a tourniquet above the elbow to distend the veins, the needle 
is attached to a 2 cc. Luer type syringe and inserted in a vein on the forearm, 
usually anterior or outer aspect, between elbow and wrist, to allow movement at 
these articulations. Needle should be inserted Into vein up to the hub, a gauze 
sponge placed beneath the needle hub, and the needle fixed in place with adhesive 
(or Scotch) tape. Alternate arms used on succeeding days. 
The adapter of the intravenous set is attached to the needle (after the adapter 
has been freed of air bubbles) after the removal of the tourniquet, and the solution 
is allowed to flow rapidly until 10 to 15 cc. have entered. Should any swelling 
or infiltration be noted about the needle point, the flow should be stopped; the 
needle removed, and reintroduced into a different vein in the same or opposite 
forearm. The rate of flow is regulated by the fine adjustment clamp so that solu- 
tion enters at a speed of about 50 to 60 drops per minute; thus, the entire quantity 
of 2000 cc. will require 8 to 12 hours for introduction. 
Addition of Bismuth to Massive Dose Technic. Since July, 1941, L. W. Shaffer 
has been using bismuth concurrently with the arsenical. It may be used as follows: 
Dosage of Bismuth With Intravenous Drip Method: 1. Suspension of bismuth 
subsalicylate in oil is employed. 
2. The patient should receive 0.2 gm. bismuth subsalicylate (0.13 gm. bismuth 
metal) intramuscularly as soon as the diagnosis of early syphilis has been confirmed. 
3. The second dose of 0.2 gm, should be given on the 3d day of treatment, the 
third dose of 0.2 gm. on the 6th day and a fourth dose of 0.2 gm. on the 9th day, 
before discharge. 
Method of Preparing Arsenoxide Solutions. Mapharsen (arsenoxide), 0.01 gm., 
is dissolved in 100 cc. of 5% dextrose solution. Usual procedure is to prepare 
500 cc. of such solution, containing 0.06 gm. mapharsen—this is enough for 3 hours 
of treatment. 
When the Vacoliter containing 2000 cc. of 5% dextrose is used, the total daily 
dose of 0.24 gm. mapharsen (arsenoxide) is prepared the first thing in the morning 
and the solution allowed to run in, in the 10 to 12 hour treatment period. 
This has been the practice in one institution. The preparation of the drug for 
the 10 to 12 hour period all at once has simplified the technic to a great extent. 
Variants in Usual Procedure: 1. Primary fever on the 1st day (Herxheimer) — 
therapy is stopped if temperature reaches 101.4° F. or more. This usually happens 
between the 6th and 8th hour; by the time patient may only have received from 
0.12 to 0.16 gm. mapharsen. The practice has been to compensate for this insuffi- 
cient dose in the following manner: 1st day—0.12 gm. mapharsen (arsenoxide); 
2d day—0.28 gm. mapharsen (arsenoxide); 3d day—0.28 gm. mapharsen (arsen- 
oxide); 4th day—0.28 gm. mapharsen (arsenoxide); 5th day—0.24 gm. mapharsen 
(arsenoxide). 
2. Clinical jaundice—when this appears in the course of treatment, the procedure 
should be interrupted. It has only been seen once in all cases studied (Com- 
mittee report). 
General Medical Care During 5-Day Intravenous Drip. Routine soapsuds 
enema should be given the night before treatment is begun, to obviate the need 
for bedpan, and whenever thereafter indicated. According to Leifer’s (1940) 
description: “The nursing problem during the period of treatment consists of 
the preparation of fresh solution for each patient at the end of 2 or 3 hours and the 
refilling of the gravity flask. Meals are served on the ordinary bed tray. Patients 
can feed themselves. They are also capable of handling the urinal but, naturally, 
must be assisted somewhat in the use of the bedpan. The latter disturbance may 
be prevented by having the patient evacuate or have an enema during the evening, 
when treatment has been discontinued. 
“The patients are given a high calory diet, rich in starches and carbohydrates. 
The majority of the patients read, listen to the radio, or play cards during the day 
In the evening, after discontinuance of therapy, they may get out of bed. They 
12 suffer little or no discomfort. Many of them register a gain in weight of as much 
as 10 pounds (4.5 kg.). This gain in weight is not due to any appreciable edema 
but may be explained by the fact that most of these patients otherwise under- 
nourished, are so well treated with regard to food and nursing care.” 
Technic of 10-Day Multiple Injection Intensive Therapy for Syphilis.16 With 
this treatment system patients need not be confined to bed, but they should be 
treated in the hospital and observed for at least 2 days after the last injection of 
mapharsen (arsenoxide). Routine ward diet may be employed. 
Two injections of mapharsen (arsenoxide) are given daily for a 10-day period. 
The injections are given in the morning and evening of each day, 10, or preferably, 
12, hours apart. Schoch, however, has given single injections of 100 to 120 mg. 
daily as an ambulatory procedure. Dosage is governed roughly by weight. 
Patients weighing 50-70 kg. (110 to 154 pounds) should receive 0.05 gm. of maphar- 
sen twice daily for 10 days. Patients weighing between 70 and 90 kg. (155 to 
200 pounds) should receive 0.06 gm. of mapharsen twice daily for 10 days. The 
dosage may be increased to 0.070 gm. in each injection for patients weighing over 
90 kg. (200 pounds). Each dose of mapharsen (arsenoxide) should be dissolved in 
from 8 to 10 cc. of distilled water. The solution should he aerated and rapidly 
injected, intravenously, promptly after preparation. In cases where solutions are 
made in bulk, individual doses should be given within at least a 2-hour period 
after preparation. 
On the 1st, Jfh, 8th and 12th days, 0.2 gm. of bismuth subsalicylate in oil should 
be injected deeply into alternate gluteal muscles. 
Thomas and his associates of Bellevue Hospital combine fever therapy with the 
intensive multiple syringe technic (1941, 1943). The risk of serious cerebral 
accidents with this method increases with the amount of arsenoxide (mapharsen) 
given. The addition of fever does not prevent cerebral reactions but lessens their 
frequency by necessitating a lower dosage of arsenical. 
Reactions from 5- to 10-Day Intensive Therapy and Their Management. 
Minor Reactions: 1. Pain in the arm: cold wet dressings, ice-bag, aspirin, 
codeine only if pain is severe. 
2. Mild headache: aspirin or codeine usually gives prompt relief. If 
headache is severe, increasing and persistent, consider this as possible 
prodrome of toxic encephalopathy. 
3. Nausea and vomiting: give only fluids by mouth, and sedation if 
necessary. If persistent, discontinue treatment temporarily. May give 
5% or 10% dextrose solution alone intravenously. 
4. Primary fever: sharp rise in temperature occurs on the 1st day of 
treatment especially with intravenous drip. It is usually almost normal 
by evening, and normal by the next day. If the temperature goes above 
101.4° F. discontinue drip for the day.' Next day, drip may be rein- 
stituted, practically always without recurrence of fever; this early fever 
need not cause omission of the second dose when multiple syringe method 
is used. Primary fever is usually accompanied by a flare-up of the syph- 
ilitic lesions (Herxheimer reaction, therapeutic shock). Symptomatic 
treatment may be used if necessary. 
5. Secondary fever: secondary rises of temperature in excess of 101 ° F. 
at any time after the first day of treatment are an indication for interrupt- 
ing therapy because secondary fever is sometimes associated with a mild 
toxicoderma- Most often in the 5-day treatment the fever occurs on 
the last evening of therapy. Mapharsen should not be given again until 
the temperature is normal. If fever recurs when treatment is reinstituted, 
efforts at intensive therapy should be abandoned entirely. 
If the patient has received at least a total of 800 mg. (0.8 gm.) of maphar- 
sen (arsenoxide) before the appearance of fever, intensive arsenotherapy 
by any system should not be reinstituted. In this case all further arsenical 
13 therapy may be omitted, but the patient should receive a total of at least 
12 weekly intramuscular injections of bismuth subsalicylate before all 
treatment is stopped. 
Symptomatic treatment for this reaction may be used, if necessary. 
6. Toxicoderma: usually appears in the post-treatment period on the 
7th day, and is often preceded by and accompanied with fever. The type 
is most commonly morbilliform, scarlatiniform, or urticarial, and there is 
no exfoliation. This is not arsenical exfoliative dermatitis, and is not a 
serious sensitizing reaction. The rash usually fades in 1 to 4 days without 
therapy. Symptomatic treatment may be used, when indicated. 
Since this reaction does not usually occur with the intravenous drip 
method until all treatment has been completed, it has no bearing on inter- 
ruption of such treatment. When the 10-day multiple injection system 
is used, the occurrence of this “9th-day erythema” is an indication for 
interrupting treatment. This reaction may be associated (rarely) with 
toxic encephalopathy, and continued treatment may increase the risk. 
7. Renal damage: usually insignificant, consisting of minor traces of 
albumin, occasional red and white blood cells. No treatment is needed. 
Marked albuminuria or hematuria is a signal for discontinuing treatment. 
8. Peripheral neuritis: rarely encountered, and only in the post-treat- 
ment period. Usually manifested only by subjective symptoms, most 
often paresthesias. Objective changes are rarely encountered, and only 
sensory in type, never motor. The process disappears spontaneously. 
This reaction was common in the cases treated early by the 5-day method, 
probably because of immobility of the arm and the use of a drug too toxic 
(neoarsphenamine) for such a method. 
9. Nitritoid reaction: rarely observed with multiple injections or with 
the intravenous drip procedure, unless the rate of flow of the latter is 
inordinately fast (mapharsen [arsenoxide] is well known to produce this 
reaction only rarely). 
10. Precordial oppression (Falk and Rattner, 1942; Prats, Veras and 
Haraszti, 1942): this occurs occasionally with 5-day treatment. Discon- 
certing but not frequent or serious. 
Major Reactions: 1. Severe headache: especially towards the 4th or 
5th day of treatment, the occurrence of severe, persistent and increasing 
headache not readily relieved by aspirin or codeine should be viewed as 
of possible serious import (prodrome of toxic encephalopathy). It is best 
to discontinue intensive therapy and after a rest interval from all arsenical 
therapy of at least 4 weeks (this rest period to be occupied with weekly 
bismuth injections) to place the patient on the standard or 26-week treat- 
ment schedule, the duration of which may be shortened to the extent of the 
mapharsen dosage before the reaction occurred (e. g., if the patient received 
a total of 400 mg. mapharsen before the reaction, 1200 mg. additional 
should be given by injections twice weekly with bismuth added as in the 
standard schedule). 
2. Jaundice: this is an uncommon complication and calls for discon- 
tinuance of intensive therapy. No instance of acute yellow atrophy has 
occurred although Rattner and Falk (1942) observed a case of severe 
hepatitis with other visceral damage (see below). For the treatment of 
this reaction, the patient may be given intravenous 10% dextrose solution, 
high carbohydrate-low fat diet, and injections of liver extract therapeuti- 
cally. Intestinal elimination should be encouraged with saline catharsis. 
14 3. Blood dyscrasias (especially purpura or bleeding from any part of the 
body): rarely encountered, but necessitating permanent discontinuance 
of all arsenotherapy, Treatment usually consists in blood transfusions. 
4. Exfoliative dermatitis: rarely, if ever, encountered. Requires per- 
manent discontinuance of all arsenotherapy. Symptomatic treatment, 
dextrose intravenously, and liver extract. 
5. Encephalopathy: women are especially susceptible. This reaction 
may be manifested by severe headache, vertigo, tremor, fever, unusually 
severe nausea and vomiting, mental confusion, disorientation, and apathy; 
by single or repeated convulsive seizures, and by prolonged chorea. In 
serious instances hyperthermia usually supervenes and death may result. 
Mpy occur on the 3th to 5th day of treatment, or not until the 6th or 
7th day; rarely thereafter. Often preceded by headache of increasing 
severity (see above). There is no means of anticipating this reaction 
(Thomas, Wexler and Dattner, 1942). In mild cases, the suspicion of 
toxic encephalopathy should be checked by examination of the spinal 
fluid for cells, globulin or increased protein. If such tests are positive, 
further treatment with arsenical drugs should be abandoned. If the spinal 
fluid is normal, treatment may be resumed if the symptoms have com- 
pletely disappeared and the temperature is normal. 
Treatment of this serious reaction is of uncertain value but the prog- 
nosis is not as bad as is usually assumed (Chargin, 1940). Suggested 
procedures include (1) repeated drainage of spinal fluid (20 to 40 cc.) in 
repeated taps daily; (2) dehydration by use of intravenous 50% sucrose 
solution, 50 to 200 cc.; (3) sedation is of value in all cases. Where symp- 
toms are mild, any of the barbiturates may be used by mouth. If convul- 
sions occur, sodium amytal 0.24 grn. (3f gr.) may be given intravenously 
or intramuscularly (this dose may be repeated every 2 to 3 hours for 
several doses if convulsions occur or the patient is restless; (4) adrenalin. 
Oxygen inhalations may also be given. Sodium thiosulfate is of no value 
(Chargin, 1940). 
6. Severe renal injury (rare); Thomas and his colleagues (1943) have 
reported acute nephrosis in patients receiving short arsenical and pro- 
longed fever treatment but no particular renal damage occurs in their 
patients treated with the multiple injection method (10- or 6-day). Ratt- 
ner and Falk (1942) reported a severe case with acute glomerulonephritis, 
anuria, uremia, hepatitis, ileus and pericarditis in a patient treated by the 
5-day method. This is rare. 
Post-treatment Routine After 5 to 10 Day Intensive Therapy (to be carried out 
before discharge from hospital). (1) Complete physical examination. (2) Labora- 
tory studies, (a) Titered blood serologic test for syphilis. (6) Complete urine 
analysis, (c) Complete blood count (hemoglobin, red blood cell and white blood 
cell count and differential), (d) Other laboratory procedures (icterus index,'serum 
bilirubin, urobilinogen, non-protein nitrogen where indicated). 
Outline of Proposed 12-Week Schedule of Modified Intensive Treatment 
(Eagle, 1943). Patients are to be treated with mapharsen (arsenoxide) 
3 times weekly (Monday, Wednesday, and Friday; or Tuesday, Thursday, 
and Saturday) at the following dosage scale: less than 120 pounds (55 kg.), 
50 mg.; 120 to 155 pounds (55 to 70 kg.), 60 mg.; greater than 155 pounds, 
70 mg. Treatment is to continue for 12 weeks or to a total of 36 injections. 
Hospitalization is not necessary, and patients are to be treated on “duty 
status.” Patients are to receive intramuscular injections of bismuth 
15 subsalicylate (0.2 gm., equivalent to 0.13 gm. of metallic bismuth) once 
weekly throughout the course of mapharsen (arsenoxide) treatment, to a 
total of 12 injections. 
Follow-up Observation After All Methods of Intensive Chemotherapy. 1. Patient 
should be reexamined at monthly intervals for 6 months. 
2. This reexamination should include a complete physical examination with 
special attention to the mucous membranes of the mouth and throat, the genitals 
and the perianal region for easily overlooked evidences of infectious relapse. 
3. Quantitative blood serologic tests for syphilis should be performed monthly 
for 6 months, and then at the 9th and 12th month. (The blood serologic reactions 
usually become negative at the 12th to 16th week after the start of treatment). 
4. Examination of the spinal fluid should be done, if feasible, sometime between 
the 6th and 12th month. 
5. The patient should not receive any further anti-syphilitic therapy, except as 
specifically set forth under “management of the unsatisfactory case.” 
Management of the Unsatisfactory Case. A patient who has become clinically 
“cured” and- serologically negative and remained so until the 12th month of 
observation, and in whom the spinal fluid is negative, may be discharged from 
observation as a “satisfactory result.” Should such a person return at a later 
date with a new dark-field positive lesion, this may be considered as a new infec- 
tion and the patient may be re-treated in the original manner (Schoch, 1943; 
Moore, 1943; L. W. Shaffer, 1943). A case must be considered as unsatisfactory 
or a treatment failure, if: (a) There is definite objective evidence of infectious 
relapse, corroborated by a positive blood serologic reaction- for syphilis, and if 
possible by positive dark-field examination. (6) There is incontrovertible evidence 
of serologic relapse without clinical relapse, i. e., the patient’s blood serologic 
reaction has dropped to negative or near negative and then to persistently strongly 
positive (this is best interpreted by a quantitative procedure), (c) Reagin fast- 
ness, i. e., where the blood serologic reaction for syphilis has never reverted to 
negative but remains persistently positive (preferably determined by a constant 
titer of quantitative tests) for a 6 months period after treatment. 
The unsatisfactory case (infectious relapse, serologic relapse, seroresistance, and 
the new infection) may be re-treated by intensive therapy except in the event of 
serious reaction from the original treatment. The results of intensive re-treatment 
of the unsatisfactory case have not been fully evaluated, but appear to be less 
satisfactory than original treatment. 
Special Considerations Concerning Early Syphilis Treatment. Criteria 
of Adequacy of Treatment for Syphilis. The answer to this question 
depends fundamentally upon the definition of “adequacy.” If by ade- 
quacy is meant the securing of a condition of non-infectiousness in an 
infectious case, one kind of answer will be appropriate; if adequacy is to 
be interpreted in terms of clinical or of radical cure, another answer will 
be appropriate; if adequacy means the placing of an infected individual at 
one or another type or stage of involvement in syphilis on asymptomatic 
status that will permit of full or limited service in the armed forces, still 
another answer is necessary. The subject is dealt with under each of 
these three heads briefly as follows: 
Treatment of Non-infectiousness. The immediate infectiousness of sur- 
face lesions of syphilis is controlled in all but the rare treatment-resistant 
or arsenic-fast case, it will be recalled, by the first one, or at most two, 
injections of an effective trivalent arsenical, provided the dose is adequate 
(0.3 to 0.5 gm. arsphenamine 606; 0.4 to 0.6 gm. neoarsphenamine; 40 to 
60 mg. mapharsen). The duration of this effect of 1 or 2 injections is 
not precisely known, but is estimated roughly as approximately 30 to 
90 days. Failure to continue treatment does not necessarily, but may in a 
percentage of cases ranging from 0% to 64%, lead to infectious relapse. 
16 A useful tabulation from the Cooperative Clinical Group and the Uni- 
versity of Pennsylvania material is herewith presented: 
Arsenical treatment 
Infectious 
Additional 
Infectious 
alone, number of 
relapse 
(%) 
heavy metal 
relapse 
injections 
injections 
(%) 
1- 4 
64 
20| 
45 0 
5- 9 
14 
20 
9.0 
10-19 
20 
4.0 
20-29 
20 
3.6 
28.8* 
30-40 
28.2 or more 
“appropriate” 
0 
1.2 
From this tabulation it will be apparent that the critical point at which 
sharp reduction in the probability of recurrent infectiousness takes place 
is between the 5th and 9th injections of the arsenical (14% relapse without 
and 9 % with heavy metal); and that the so-called 20-20 standard, often 
quoted as adequate for treatment to non-infectiousness, reduces the risk 
of infectious relapse to 4%, beyond which a slow reduction to 0% to 
1.2% is secured by prolonging treatment beyond 20 arsenical injections 
with 30 or more injections of heavy metal. 
Heavy metal, in the statistical table presented above, is taken to repre- 
sent 0.2 gm. of an insoluble bismuth salt of not less than 57 % metallic 
content, or 1 week of mercurial inunctions, or its intramuscular equivalent 
in a water-soluble or insoluble mercurial salt. 
It will presently be apparent therefore that the best treatment to secure 
non-infectiousness is practically identical with the optimum treatment 
for the securing of “satisfactory results” or “cure.” 
The Influence of the Development of Secondaries on Relapse. An 
interesting and seemingly paradoxical situation was revealed in the com- 
parison of serological with clinical relapse under treatment—a relation of 
particular importance because it might well form the basis for polemic 
discussion. The stage of syphilis at which treatment is begun influences 
the incidence of mucocutaneous relapse in a different way from that in 
which it affects all other forms of relapse. The first Cooperative Clinical 
Group survey of mucocutaneous relapse as such44 indicated that it occurs 
in 10% of patients beginning treatment in the seronegative primary stage; 
8.6% of those beginning treatment in the seropositive primary stage; and 
only 4.2 % in those who began treatment after their secondaries had fully 
developed, t Relapse incidence of the mucocutaneous type was therefore 
markedly less if the patient was allowed to develop his full cutaneous 
secondary reaction to the disease, the difference amounting to as much as 
58% reduction in probability as the patient passed from a seronegative 
primary to the florid secondary phase. On the other hand, the existence 
of a distinct relapsing type was foreshadowed by the fact that patients 
who began treatment with late or recurrent secondaries relapsed in 22.3 % 
of cases. Serologic relapse, on the other hand, occurred in 12 % of patients 
whose treatment was begun in seronegative primary syphilis; 15.1 % under 
the same circumstances in early secondary syphilis (1st year); and 20% 
if treatment was not begun until delayed secondaries after the 1st year. 
It appears, therefore, that to begin the treatment of a patient in the sero- 
* University of Pennsylvania figures; all others are C. C. G. 
f One week of mercurial inunctions equals 1 injection. 
J The percentages estimated on the basis of 3244 cases observed and treated for 
six months or over were seronegative primary 16.4%, seropositive primary 20.2%, secon- 
dary (first year) 9.5%, secondary delayed 9.2%. The principle illustrated is the same 
in both. 
17 negative stage of primary syphilis, while it has already been shown defi- 
nitely to increase the prospect of complete cure, nonetheless subjects him 
to a definite slight risk of mucocutaneous recurrence and therefore of more 
prolonged infectiousness. The probable explanation, of course, is that 
the skin and mucous membranes have never been given the opportunity 
to develop what might be thought of as a local tissue immunity by full 
reaction to the disease. 
It must, of course, be appreciated that the reduced incidence of relapse 
and progression in patients who have had secondaries arises simply from 
the fact that in reaching that stage they have automatically, so to speak, 
set behind them that much of the life history of the disease. It must, 
too, remain for further study to decide whether the increased risk of infec- 
tious recurrence after early treatment justifies postponement until the 
patient has developed secondaries. At the present time the higher pro- 
portion of curative results seems to justify immediate treatment rather 
than postponement. The increased risk of infectiousness through recur- 
rence can hardly be greater than the risk of infectiousness represented by a 
patient who is allowed to live at large in the community without benefit 
of the arsphenamines until his secondary eruption has fully developed. 
In any event, the application of such a principle demands universal hospi- 
talization for the patient between the primary stage and the full develop- 
ment of secondaries, an obvious impracticability at this time. Until the 
proponents of postponement (as for example, Bernard) can advance in- 
dubitable evidence that there is other than merely mucocutaneous protec- 
tive value in permitting a patient to go on to secondaries, the postponement 
of treatment until secondaries develop is not only against the interests of 
the public health but against that of the individual patient who above all 
things, desires the greatest possibility of personal cure. 
Jadassohn, from an international questionnaire,24 has reported that the 
effect of arsphenamine in controlling the infectiousness of syphilis had led 
to an estimated reduction in incidence of new cases of the disease of 75 % 
to 80% in Belgium, Sweden, and Holland; 60% in Finland; 50% in Den- 
mark; 50% to 80% in Switzerland; 30% to 60% in Italy and Czecho- 
slovakia; and 25% in Norway . 
Rules for Preventing Infectious Relapse. The prevention of infectious 
recurrence and the reduction of relapse to the lowest possible terms 
requires of the practitioner, then, an unhesitating acceptance of the follow- 
ing rules: (1) The concept of abortive cure by short courses should be 
abandoned, no matter how early the patient may come under treatment. 
(2) Not less than 20 injections of an arsphenamine, and more if possible, 
preferably in 1 or 2 courses, and an equivalent amount of heavy metal 
without rest intervals, should be given in an early case to control infec- 
tiousness. (3) Treatment should be continuous rather than intermittent 
or intensive, there being no time, at least within the first year or more, 
that the patient is not under the influence of one or another effective mode 
of treatment for syphilis with an arsphenamine or heavy metal. (4) 
Treatment should be massed well to the fore—that is, within the first 
3 months, for this is the period in which mass as distinguished from pro- 
longation, reaches its greatest effectiveness in preventing relapse. (Cf. 
Massive dose arsenotherapy.) 
Stokes, Miller and Beerman46 in their study of bismuth arsphenamine sulfonate 
observed a similar phenomenon. The proportion of relapse in continuous treated 
eases was 9.1% and in those allowed rest intervals 14.3%. Of the continuously 
treated cases 60% had comparatively little treatment (20 injections or less) while 
18 86% of the intermittently treated patients who had the higher incidence of relapse 
had had comparatively heavy courses of 21 injections or more (40% had over 
40 injections). It appeared that a small amount of treatment continuously applied 
yielded fewer relapses of all kinds than a larger amount with rest periods or lapses. 
With so much emphasis placed on the seriousness of lapse in the promo- 
tion of infectious recurrence, it is proper to emphasize as the 5th rule for 
the physician, his responsibility in educating his patient and in holding 
him to a sufficiently prolonged course and in utilizing follow-up assistance 
if and when it is available. (6) He should understand, too, that infectious 
relapse is detected by actual physical examination with special emphasis 
on the mouth, anus, and genitalia rather than by serologic tests. One 
should examine especially the lips, penis, scrotum and vulva. (7) Positive 
serologic tests may warn of infectious relapse and confirm the diagnosis, 
but since they cannot be frequently applied, physical examination and 
instruction of the patient himself in the recognition of infectious lesions 
are the more important approaches. (8) Serologic tests and stripped 
physical examinations, to be of value in detecting relapse, should, if any- 
thing, be more frequently made after treatment is completed and the 
patient is put on observation than during treatment itself. The opposite 
is corhmon practice, and this applies especially to the first 2 or 3 years of 
the disease. (9) Negative serologic reactions, as has been repeatedly 
emphasized, are not proof of non-infectiousness, immediate or future. 
A negative serologic reaction should not deceive the physician or patient into 
relaxing precautions. (10) Treatment and time are the chief preventives 
of infectiousness. (11) Since potentially infectious relapses occur over- 
whelmingly in the first 2 years of early syphilis, sexual relations and inti- 
mate contact without absolute protection should be allowed only while the 
patient is under actual arsenical treatment. The duration of non-infectious- 
ness when treatment is stopped before the 12th injection of arsphenamine 
may not, apparently, exceed 1 month. 
Adequacy With Respect to “Cure” or “Satisfactory Results.” Infor- 
mation on this subject is based on case material observed for not less than 
2, and upward to 20, years since the onset of the infection or the institution 
of treatment. Material of less than 2 years of observational control is 
fundamentally weak in its demonstration of the possibility of relapse, 
since the first 2 years of infection are overwhelmingly those of relapse 
predisposition. On adequacy in the sense of “satisfactory results,” 
5 groups of data will be quoted; (a) Cooperative Clinical Group results 
in the treatment of early syphilis by a continuous alternating use of 
arsenical and heavy metal without rest period, through 65 weeks of 
treatment observation; (6) Padget’s36 Johns Hopkins Hospital Syphilis 
Clinic report on 551 patients completely reexamined 5 years or more after 
the termination of their original treatment for early syphilis; (c) optimal 
treatment for early syphilis, 1 to 20 years observation;12 (d) a shortened 
20-week system, Hood23 reporting on Johns Hopkins Hospital material; 
(e) the 5-day intensive intravenous drip arsenotherapy of syphilis (without 
the use of heavy metal), Leifer, Chargin and Hyman (1941) and Elliott, 
Baehr, Shaffer, Usher and Lough (1941).16 
It is not possible at this time to offer more than speculative estimates 
on 10-day multiple syringe and 10- to 12-week intensive mapharsen- 
bismuth16 systems which are under study. 
The Cooperative Clinical Group’s standard treatment system experience indi- 
cates that for satisfactory results, treatment must be continuous and not inter- 
19 mittent or irregular, and must combine the alternate use of an effective arsenical 
(mapharsen is not represented in this material) and a bismuth. Striking reductions 
in effectiveness with occurrence of infectious relapse, progression of syphilitic 
manifestations, serologic relapse and seroresistance occur in all phases of early 
syphilis in which intermittence or irregularity is allowed to occur. Disregarding 
the precise system of administration, the highest proportion of satisfactory results 
in seronegative primary syphilis was obtained with 10 to 19 injections of arsphena- 
mine with accompanying heavy metal; in seropositive primary syphilis, with 25 
to 35 injections; in early secondary syphilis (seen in the 1st year) 20 to 29 injections. 
Higher rather than lower dosage of the arsphenamine is recommended. Failure 
to secure a satisfactory result by 20 injections or less may be met by 10 additional 
injections, plus heavy metal, which may double the proportion of unsatisfactory 
outcomes reclaimed. The irreducible margin of failure in the treatment of early 
syphilis by older standards ranges from 4% to 27%, depending on method, stage 
at which treatment is begun, adequacy of treatment during the first 2 years of 
infection. 
The Johns Hopkins Syphilis Clinic material36 is particularly valuable because of 
the length of observation (over 10 years in half of the patients), and shows clearly 
the importance to adequacy of the treatment results of the stage at which treatment 
is begun (82% cure in seronegative primary syphilis, 68.8% in secondary syphilis, 
58.7% in early latent syphilis). The poorest results, as in the Cooperative Clinical 
Group series were observed among patients whose treatment was begun in the sero- 
positive primary stage. Cure was obtained by 83.4% of the patients whose treat- 
ment during the first 6 months was by a continuous system, and is increased to 
90.4% if treatment during the next 6 months was likewise continuous. It was 
shown that the final or “adequate outcome” depended in a directly quantitative 
fashion not only on the number of doses of the arsphenamine received, but also 
inversely, upon the time span during which it was given. In other words, the more 
injections in the shorter time, the better the results. The development of early 
or intermediate relapse was found to be of grave prognostic significance. 
Cannon found in a series of some 600 patients treated with 3 standard arsphena- 
mines, that arsphenamine 606 was incontestably superior to neoarsphenamine or 
silver arsphenamine, and that 1 year of regular and continuous treatment with the 
arsenical injections closely spaced (2- and 3-day intervals in the first 3 to 5 weeks 
and at intervals of not less than 1 week thereafter) gave the highest proportion of 
satisfactory results. The difference between seronegative primary, seropositive 
primary and secondary syphilis was not more than 6%. 
The 20-20 Arsenical-Bismuth Simultaneous Injection Course (Hood). This 
shortened system, not comparable because of longer intervals (weekly) with the 
26-week system of Circular Letter No. 74, utilizes weekly injections of mapharsen 
and simultaneous weekly intramuscular injections of an oil-suspended bismuth salt. 
The maximum period of observation (33 months) was only sufficient to indicate 
that the proportion of unsatisfactory results in the form of seroresistance, sero- 
relapse, clinical relapse and involvement of the central nervous system, amounting 
to 13.6% of the observed series, was approximately that of unsatisfactory results 
obtained in early syphilis treated with other arsenical drugs and treatment systems. 
If confirmed by longer observation, such a treatment system should show how little 
rather than how much treatment is necessary to produce the average or so-called 
“standard” results which are so strikingly uniform throughout the entire range 
from 5-day intravenous drip to 65-week continuous combined therapy. 
Massive Dose Arsenotherapy {“5-Day Drip”). The 2 series, Leifer et al., and 
Elliott et al., the former with of course the longer series of observed cases, illustrates 
the following principles regarding adequacy: (a) Curative results can be obtained 
with a trivalent arsenical alone (neoarsphenamine, mapharsen). (b) Of the two, 
mapharsen because of its low reactivity is the drug of choice, and 1200 mg. admin- 
istered in 5 days, the optimum dose, (c) In seronegative primary syphilis, 90 
to 100% pursue a satisfactory and uneventful course; without reference to type 
of drug or stage of disease, an aggregate of 81% secured a satisfactory result in one 
5-day course, and one re-treatment in 15 cases raised the result to approximately 
20 88% for the entire series (Leifer et al.). Elliott and co-workers estimated their 
curative results at at least 85% of all cases with early syphilis. 
Adequacy of Treatment From the Standpoint of Service in the Armed 
Forces. A tentative basis for evaluation proposed for admission of registrants 
with syphilis to the United States Army is as follows: 
Registrants with (1) confirmed positive serologic tests for syphilis and no clinical 
manifestations of the disease; or (2) with convincing histories of a trustworthy 
diagnosis of syphilis; or (3) of treatment for the disease on serologic or clinical 
grounds even though such evidence may possibly have been inadequate, may be 
considered for unlimited military service: (a) Provided that a negative spinal 
fluid since treatment was begun has been reported from a trustworthy source; 
and (b) provided that in infections estimated to be of less than 4 years duration, 
at least 30 to 40 arsenical and 40 to 60 insoluble bismuth injections or its equivalent 
with a minimum total of 75 injections have been given, with approximate con- 
tinuity (no rest periods or lapses) during the first 30 weeks of treatment; and (c) 
provided that except as further qualified below in infections estimated to be over 
4 years duration, at least 20 arsenical injections or its equivalent with a minimum 
total of 60 injections have been given in alternating courses; rest periods between 
consecutive courses not exceeding 8 weeks, being allowable. 
Evidence of duration of the infection shall be weighed by the examiner with due 
regard for the age, general venereal history and medical guidance of the registrant. 
In infections of unknown duration it shall be presumed for classification purposes 
that those of registrants under 26 years of age are of less than 4 years duration, and 
over 26 years of age, of more than 4 years duration. 
In congenital infections and in acquired infections of more than 10 years known 
duration, in which no clinical progression occurred since treatment was begun; 
and in which a normal spinal fluid has been recorded at some time after treatment 
was begun and negative physical examination is recorded not less than 2 years 
after treatment was terminated, the infection shall be regarded as “quiescent,” 
and the registrant eligible for unlimited military service; provided the treatment 
in question shall have included 20 arsenical and 20 heavy metal injections. 
For the determination of treatment, the signed statements of acceptable treat- 
ment sources administering it with total number of doses of each drug and approxi- 
mate calendar dates of administration and available laboratory and clinical data 
shall be required as evidence. 
The Prognostic Significance of Secondary and Serologic Relapse. The follow- 
ing principles, based in the main upon the groups of material cited in connection with 
the criteria of adequacy of treatment for syphilis, are widely accepted. Early 
evidence of potentially unfavorable or relapsing course in an early syphilitic infec- 
tion can be found in (a) failure of the primary or secondary lesions to heal under an 
arsenical therapy; (b) continued presence of Sp. pallida in the lesions after the 
employment of a known effective trivalent arsenical (these 2 groups constitute 
treatment resistance in syphilis;30 (c) prematurely early reversal of a positive 
serologic reaction on the blood to negative (4th to 7th week in seropositive primary 
or secondary syphilis); (d) failure of a positive serologic reaction on the blood to 
reverse to negative after the 16th week (in the intensive or 5-day drip system 
reversal is ordinarily expected by quantitative tests between the 10th and 18th 
weeks after the institution of treatment but late secondaries may not reverse for 
many months even though “cured”). 
Cooperative Clinical Group results13 (observation period too short) showed a 
relapse expectancy of 19.7% including all forms, of which, when observed for more 
than 6 months, 12.1% was mucocutaneous, 3.4% asymptomatic neurosyphilis, 
4.1% symptomatic neurosyphilis, and 0.9% cardiovascular syphilis. 
The unfavorable prognostic significance of early and intermediate relapse was 
well brought out in Padget’s series in which “cure” was achieved in 73.2% of 
456 patients in whom no relapse was observed, whereas only 28.2% of those sus- 
taining an intermediate relapse achieved “cure”. Persistent seropositive reactions 
on the blood, however, occurred in 16% of those who sustained no relapse, and in 
10.3% of those who underwent intermediate relapse. Late benign syphilis devel- 
oped 8 times as frequently in relapsers as in non-relapsers, cardiovascular syphilis 3.5 times as frequently; neurosyphilis 6 times as frequently; multiple late manifes- 
tations 7.5 times as frequently in relapsers as in non-relapsers. The occurrence of 
weak positive serologic reactions on the blood appearing in the course of a series of 
negatives in treated early syphilis have been emphasized as of relapse significance 
by certain authors. 
Significance of Seropositivity After Treatment Which Was Begun During 
Early Syphilis. Broadly speaking, Padget’s experience indicated that a 
residue 6f 14.9% persistent serologic positiveness would appear in a series 
of early syphilitics on whom the satisfactory results he described had been 
secured. In these cases there would be no manifestations such as abnor- 
mal spinal fluid, cardiovascular disease, visceral disease and so forth to 
accompany the persistent seropositiveness. The inclination would be, 
therefore, to rate it in these cases as without significance. In general, 
however, persistence of a positive serologic reaction on the blood of early 
syphilitics under treatment by the older standard continuous systems 
was an indication of presence of asymptomatic neurosyphilis, and called 
for an examination of the spinal fluid immediately.26,48 The more inten- 
sive foreshortened treatment systems seem so materially to have reduced 
the likelihood of the occurrence of asymptomatic neurosyphilis that the 
neurosyphilitic significance of persistent seropositivity will probably be 
greatly reduced by their use. In addition, to asymptomatic neurosyphilis, 
syphilis of the cardiovascular system, often coming to recognition 5 or 
more years after the cessation of treatment, may be included in the prog- 
nostic significance of seropositiveness of a persistent type in early syphilis. 
The Prevention of Cardiovascular Syphilis. This is still the terra incog- 
nita of modern syphilology and the studies thus far summarized have 
thrown relatively little light upon it. Langer26 and others have attributed 
the increase in the incidence of aortitis since 1912 to the use of arsphena- 
mine in the treatment of syphilis, but our experience with this drug in 
early syphilis fails to substantiate this belief, the incidence of recognizable 
aortic lesions not increasing materially in the period studied. It is, of 
course, true that our study does not extend forward into the period of 
maximum recognition of this form of syphilis. Moore, Danglade and 
Reisinger29 in considering Langer’s contention, believed that the apparent 
increase coincident with the use of arsphenamine in treatment is due 
rather to more accurate pathologic study with increasing knowledge of 
microscopic appearance of aortic syphilis. Progression of cardiovascular 
syphilis in spite of various methods of treatment occurred in 0.8% to 
1.2% of our patients. Warthin’s49 observation, which placed the inci- 
dence of aortic syphilis in syphilitic adults between 1909 and 1919 at 
97.6%, and between 1919 and 1929 at 86.3%, further supports the view 
that arsphenamine is not responsible for the apparently increasing inci- 
dence observed by Langer. 
Moore and Padget32 in their analysis of seroresistant syphilis (early) 
emphasize the seriousness of seroresistance in early syphilis and its rela- 
tively lesser significance in late syphilis. Twenty-three per cent of their 
seroresistant group sustained infectious relapse as against 5 % who secured 
prompt serologic reversal. Neurosyphilis occurs in 31% of the sero- 
resistant cases, but in only 18 % of those who sustain prompt reversal. 
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Prats, G. F., Infante Varas, L., Simon, K. T., and Harazsti, E.: Rev. Argent, der 
matosif., 26, 65, 1942. 
Body, E. F., Haraszti, E., and Giacamon, J.: Rev. Argent, dermatosif., 26, 92, 1942 
Brun, J. F., Ramirez, D., and Roman, A.: Rev. med. veracruzana, 22, 3691, 1942 
Goodman, H.: Urol, and Cutan. Rev., 46, 379, 1942. 
Sadusk, J. F., Jr., Craige, B., Jr., Brookens, N., Poole, A. K., and Strauss, M. J. 
Yale J. Biol, and Med., 14, 333, 1942. 
Marin, A.: L’Union med. du Canada, 71, 342, 1942. 
Schoch, A. G., and Alexander, L. J.: Arch. Dermat. and Syph., 46, 128, 1942. 
24 Wallis, S. R.: Hawaii Med. J., 1, 363, 1942. 
Editorial: Am. J. Syph., Gonor. and Yen. Dis., 26, 510, 1942. 
Geiger, A. J., Craige, B., Jr., and Sadusk, J. F., Jr.: Yale J. Biol, and Med., 14, 357, 
1942. 
Falk, A. B., and Rattner, H.: Arch. Dermat. and Syph., 46, 283, 1942. 
Thomas, E. W., Wexler, G., and Dattner, B.: Am. J. Syph., Gonor. and Yen. Dis., 
26, 529, 1942. 
Pelzman, I. A., and Greenwald, E.: Am. J. Syph., Gonor. and Yen. Dis., 26, 637, 
1942. 
Nelson, E. E.: Internal. Med. Digest., 41, 182, 1942. 
Levin, E. A., and Keddie, F.: J. Am. Med. Assn., 118, 368, 1942. 
Roemer, M. I.: J. Med. Soc. New Jersey, 39, 498, 1942. 
Siegel, J , Goldstein, D. H., and Goldwater, L. J.: Arch. Dermat. and Syph., 46, 
783, 1942. 
Levin, I. M., Hoffman, S. J., Koransky, D. S , Richter, I. B., and Gumbiner; 
J. Am. Med. Assn., 120, 1373, 1942. 
Kvittingen, J.: Brit. Med. J., 1, 69, 1943. 
Arnold, H. L., Jr.: Proc. Staff Meet. Clinic Honolulu, 9, 1, 1943. 
Eagle, H., and Hogan, R. B.: Yen. Dis. Inform., 24, 33, 69 and 159, 1943. 
Schoch, A. G., and Alexander, L. J.: Am. J. Syph., Gonor. and Yen. Dis., 27,15,1943. 
Editorial: (J. E. M.) Ibid., p. 108. 
Shaffer, L. W.: Yen. Dis. Inform., 24, 108, 1943; Ibid., p. 113. 
Schwind, J. L.: Proc. Soc. Exper. Biol, and Med., 52, 128, 1943. 
Thomas, E. W., and Wexler, G.: Arch. Dermat. and Syph., 47, 563, 1943. 
Hood, B. J.: Am. J. Syph., Gonor. and Yen. Dis., 27, 267, 1943. 
Thomas, E. W., Wexler, G., Schur, M., and Goldring, W., with technical assistance 
of Eggleston, N.: J. Am. Med. Assn., 122, 807, 1943. 
Bowman, G. W., and Huber, C. P.: Monthly Bull. Indiana State Board of Health, 
46, 86, 1943. 
Rattner, H.: J. Am. Med. Assn., 122, 986, 1943. 
Harris, H. L., and Sorensen, R. M.: Iowa State Med. J., 33, 254, 1943. 
(17.) Gennerich, W.: Die Syphilis des Zentralnervensystems, Berlin, Julius Springer, 
1922. (18.) Hahn, R. D.: Am. J. Syph., Gonor. and Yen. Dis., 25, 659, 1941. (19.) 
Harrison, L. W.: (a) Practitioner, 126, 193, 1931; (5) Med. Research Council, Spec. 
Report, No. 132, 1929; (c) The Diagnosis and Treatment of Venereal Diseases in General 
Practice, Oxford, p. 427, 1931. (20.) Haxthausen, H.; Ugesk. f. Lseger, 81, 217, 1919. 
(21.) Hoffmann, E.: Therap. d. Gegenw., 63,11,1922. (22.) Hoffmann, E., and Mergels- 
berg, O.: Dermat. Ztschr., 35, 1, 1921. (23.) Hood, B.: Am. J. Syph., Gonor. and 
Yen. Dis., 27, 267, 1943. (24.) Jadassohn, J.: (a) Ztschr. f. arztl. Fortbild., 23, 749, 
1926; (6) KJin. Wchnschr., 1, 1193, 1243, 1922; (c) Ibid., 5, 2248, 1926. (25.) Kemp, 
J. E., and Menninger, W. C.: Bull. Johns Hopkins Hosp., 58, 24, 1936. (26.) Langer, 
E.: Mlinchen. med. Wchnschr., 73, 1782, 1926. (27.) Leredde, E.: (a) La sterilisation 
de la syphilis, Paris, A. Maloine, 1912; (b) Paris med., 7, 153, 1917. (28.) Martenstein, 
H.: Quart. Bull. Health Organ, League of Nations, 4, 129, 1935; see also J. Am. Med. 
Assn., 104, 1329, 1935. (29.) Moore, J. E., Danglade, J. H., and Reisinger, J. C.: 
Arch. Int. Med., 49, 753, 1932. (30.) Moore, J. E., and Keidel, A.: Bull. Johns Hopkins 
Hospital, 39, 1, 1926. (31.) Moore, J. E., and Kemp, J. E.: Bull. Johns Hopkins Hosp., 
39, 16, 36, 1926. (32.) Moore, J. E., and Padget, P.: J. Am. Med. Assn., 110, 96, 1938. 
(33.) Miillern-Aspegren: Acta Dermat-Vener., 3, 572, 1922. (34.) Mutschler, R.: 
Arch. f. derm. u. syph., 147, 107, 1924. 
(35.) Ormsby, C. S.: J. Am. Med. Assn., 56, 504, 1911, and 75, 1, 1920. (36.) Padget, 
P.: Am. J. Syph., Gonor. and Yen. Dis., 24, 692, 1940. (37.) Pollitzer, S.: J. Cutan. 
Dis., 34, 633, 1916. (33.) Rasch, C.: Nordisk. Bibliotek for Therapi, pr 10, 1922. 
(39.) Riecke: Miinchen. med. Wchnschr., 66, 969, 1919. (40.) Rost: Arch. f. Derm, 
u. Syph., 138,89,1922. (41.) Satke, V.: Dermat. Ztschr., 39, 349,1923. (42.) Silberstein, 
S.: Arch. f. derm. u. syph., 143, 334, 1923. (43.) Stokes, J. H.: (a) Yen. Dis. Inform., 
17, 315, 1936; (b) J. Connecticut State Med., 2, 172, 1938; (c) J. Am. Med. Assn., 120, 
1093, 1942. (44.) Stokes, J. E., Besancon, J. H., and Schoch, A. G.: J. Am. Med. Assn., 
96, 344, 1931. (45.) Stokes, J. H., Miller, T. H., and Beerman, H.: Arch. Derm, and 
Syph., 23, 624, 1931. (46.) Stokes, J. H., and Usilton, L. J.: Yen. Dis. Inform., 18, 
66, 1937; Arch. Dermat. and Syph., 35, 377, 1937. (47.) Ullmann, K,: Wien. Klin. 
Wchnschr., 35, 455, 479, 502, 951, 1922. (48.) Vonderlehr, R. A., and Usilton, L. J.: 
Reprint No. 99, from Yen. Dis. Inform., 19, 396, 1938. (49.) Warthin, A. S.: South. 
Med. J., 24, 273, 1931. (50.) Zieler, K.: Deutsch. med. Wchnschr., 52, 49, 1926. 
25 SYPHILIS 
THE TREATMENT OF EARLY SYPHILIS 
WITH PENICILLIN 
A PRELIMINARY REPORT OF 1,418 CASES 
JOSEPH EARLE MOORE, M.D. 
BALTIMORE 
J. F. MAHONEY, M.D. 
Medical Director, U. S. Public Health Service 
STAPLETON, STATEN ISLAND, N. Y. 
COMMANDER WALTER SCHWARTZ (MC), U.S.N. 
LIEUTENANT COLONEL THOMAS STERNBERG 
MEDICAL CORPS, ARMY OF THE UNITED STATES 
AND 
W. BARRY WOOD, M.D. 
ST. LOUIS 
In December 1943 Mahoney, Arnold and Harris 1 
reported briefly on the effect of pencillin in experimental 
syphilis of rabbits and in 4 human patients wflth sero- 
positive primary syphilis. As a result of these obser- 
vations and of further experimental studies carried out 
in the laboratories of Mahoney 2 and Eagle 3 there was 
organized, about Sept. 1, 1943, under the general 
auspices of the Committee on Medical Research of the 
Office of Scientific Research and Development and 
under the specific direction of the Subcommittee on 
Venereal Diseases, National Research Council, a 
cooperative study of the effect of penicillin in syphilis 
in human beings. A Penicillin Panel was appointed by 
this subcommittee, with membership including the 
authors of this paper.4 Because of the special problems 
confronting the armed forces, particular emphasis has 
been laid on early syphilis and on neurosyphilis, though 
other forms of late syphilis have also been studied. 
The preliminary results obtained to date are here pre- 
sented in two papers, this dealing with early syphilis; 
the other, with Stokes as spokesman for the group, with 
late syphilis. 
The penicillin employed has been derived from Army, 
Navy, Public Health Service, and Office of Scientific 
Research and Development sources. Only the sodium 
salt has been employed in these studies. Penicillin 
allocated to the Office of Scientific Research and Devel- 
opment for research purposes has been distributed by 
the Committee on Chemotherapeutic and Other Agents, 
National Research Council, Dr. Chester Keefer, chair- 
man. This committee has allocated gradually increas- 
ing amounts of the drug to the Subcommittee on 
Venereal Diseases, which in turn has apportioned it 
among those civilian clinics selected for participation 
in the study. 
Early syphilis is at present under investigation in 
twenty-three clinics or research centers. These, with 
the names of the responsible investigators, are as 
follows: U. S. Army (Fort Bragg, North Carolina, 
Capt. William Leifer, Camp Howze, Texas, Major 
Franklin Grauer), U. S. Navy (Naval Medical Center, 
Bethesda, Md., Lieut. Comdr. E. C. Barksdale), United 
The authors are members of the Penicillin Panel of the Subcom- 
mittee on Venereal Diseases, National Research Council. 
The work described in this paper was done under several contracts 
recommended by the Committee on Medical Research of the Office of 
Scientific Research and Development. 
Read in a panel discussion on “Penicillin in the Treatment of 
Syphilis” before the Section on Dermatology and Syphilology at the 
Ninety-Fourth Annual Session of the American Medical Association, 
Chicago, June 15, 1944. 
1. Mahoney, J. F.; Arnold, D. C., and Harris, A.: Penicillin Treat- 
ment of Early Syphilis; A Preliminary Report, Yen. Dis. Inform. 34: 
355, 1943. 
2. Mahoney, J. F., and others: Unpublished data. 
3. Eagle, H.: Unpublished data. 
4. Dr. J. R. Heller Jr., medical director in charge Venereal Disease 
Division, United States Public Health Service, was later added to the 
membership of the panel. 
26 States Public Health Service (Marine Hospital, Staple- 
ton, S. I., Dr. J. F. Mahoney), Massachusetts Memorial 
Hospital, Boston (Dr. Oscar Cox), Bellevue Hospital, 
New York (Dr. Evan Thomas), Chicago Intensive 
Treatment Center (Dr. S. W. Becker), Cleveland City 
Hospital and University Hospitals (Dr. Harold Cole), 
University of Pennsylvania Hospital (Dr. J. H. 
Stokes), University of Texas (Dr. Chester Frazier), 
Washington University, St. Louis (Dr. W. Barry 
Wood Jr.), Yale University (Dr. Francis Blake), 
Dallas Venereal Disease Clinic (Dr. Arthur Schoch), 
Leland Stanford Jr. University Hospital (Dr. C. W. 
Barnett), Duke University Hospital (Dr. C. L. Callo- 
way), Vanderbilt University Hospital (Dr. R. H. 
Kampmeier), Johns Hopkins Hospital (Drs. J. E. 
uniform manner. The immediate results of treatment 
were to be reported to the Penicillin Panel on specially 
devised forms (figs. 1 and 2), susceptible of coding, 
punch carding and machine statistical analysis. 
Table 1.—Four Treatment Schedules 
Duration 
Interval 
Route of 
No. of 
of Treat- 
Between 
Adminis- 
Single 
Injec- 
Total 
ment 
Injections 
tration 
Dose 
tions 
Dose 
?!/& days 
3 hours 
Intramuscular 
1,000 units 
60 
60,000 units 
7hi days 
3 hours 
Intramuscular 
5,000 units 
60 
300,000 units 
7% days 
3 hours 
Intramuscular 
10,000 units 
60 
600,000 units 
7% days 
3 hours 
Intramuscular 
20,000 units 
60 1,200,000 units 
On the basis of the very preliminary studies of 
Mahoney and his associates, there appeared to be five 
variables requiring study. These were (1) the route 
of administration, originally chosen 1 as intramuscular 
for the sake of slightly delayed absorption and excre- 
tion as compared to the intravenous route; (2) the 
interval between injections, at first selected 1 as every 
three hours day and night on the basis of known data 
as to the rate of absorption and excretion; (3) the 
duration of treatment, originally arbitrarily selected as 
eight days;1 (4) the total dosage, again arbitrarily 
selected as 1,200,000 units,1 and (5) possible combina- 
tions of penicillin with other drugs, e. g. mapharsen. 
At the outset it was decided by the Penicillin Panel 
to hold the first three of these variables constant; i. e., 
all cases were to be treated by the intramuscular route 
every three hours day and night to a total of sixty 
injections given in seven and one-half days. The first 
effort was to be to define the minimum effective dose 
so given within this time period. Four treatment 
schedules were accordingly drawn up (table 1). 
These covered a twenty fold dosage range up to 
and including the original maximum arbitrarily chosen 
by Mahoney and his co-workers. In addition there 
were originally planned (but subsequently temporarily 
dropped) two other groups, to test the combined effect 
of penicillin plus mapharsen. These two groups com- 
prised a total penicillin dosage of 60,000 and 300,000 
units respectively plus a total of 320 mg. of mapharsen 
given in eight divided doses of 40 mg. each daily for 
eight days. This mapharsen dosage was deliberately 
selected as a relatively safe and known subcurative dose 
from which a high rate of relapse might be expected. 
Later, as material accumulated, the variable of time 
was brought under study, and three additional treat- 
ment groups were established with a total dosage of 
penicillin of 300,000, 600,000 and 1,200,000 units 
respectively given in thirty intramuscular injections 
every three hours day and night over a four day period. 
The latter groups have been so recently started as not 
Fig. 1.—Obverse of form for reporting early syphilis by participating 
clinics. 
Moore and C. F. Mohr), Tulane University (Dr. R. V. 
Platon), Presbyterian Hospital, New York (Dr. A. B. 
Cannon), University of Virginia Hospital (Dr. D. C. 
Smith), New York Hospital (Dr. Walsh McDermott) 
and the Detroit Health Department (Dr. Loren 
Shaffer). This report is based on the work of these 
investigators and of many of their associates and assis- 
tants, too numerous to name.5 
These clinics and centers agreed (1) to treat patients 
with early syphilis on assigned treatment schedules in 
an effort to define as promptly as possible the all impor- 
tant time-dose relationship and (2) to pool their results 
under the Penicillin Panel of the Subcommittee on 
Venereal Diseases. Only those patients in whom the 
diagnosis of early syphilis was indubitable, on the basis 
of actual demonstration of treponemes, were to be 
acceptable. All patients were to be originally examined 
and subsequently followed in as nearly as possible a 
Table 2.—Duration of Follow-Up from Start of Treatment 
in 1,418 Patients with Early Syphilis (June 1, 1944) 
Duration of Follow-Up, 
No. of Patients 
Weeks 
Followed 
1 to 4 
671 
5 to 8 
307 
9 to 16 
327 
17 to 24 
25 to 48 
6 
to justify consideration in this paper, which is devoted 
entirely to the eight day treatment schedule. The only 
exception to the statement lies in 25 cases treated by the 
intravenous route before the present organized study 
began; in them the dosage was variable and the duration 
of treatment four to eight days. 
5. The statistical data have been prepared by Miss Gwendolyn Futcher. 
27 For the purposes of this report, the books of the 
Penicillin Panel have been temporarily closed as of 
May 25, 1944. To that date there had been received 
1,587 case reports of early syphilis, of which 1,418 were 
suitable for analysis as to various points. Of these 177 
had seronegative primary, 379 seropositive primary, 
698 uncomplicated and 67 complicated 6 early secondary 
syphilis and 97 various types of recurrent (usually 
previously treated) secondary syphilis. Of the patients 
461 were white, 950 Negro and 7 of other races; 791 
were male and 627 female, of whom 58 were pregnant 
at the time of treatment. 
The preliminary nature of this report is indicated by 
table 2, in which the duration of follow-up after treat- 
ment is shown. The majority of patients have so far 
been observed for less than two months; only 113 of the 
entire number for four months or longer. This fact 
must be repeatedly emphasized as a matter of caution; 
the results here presented are subject to major revision 
after further observation. It is planned 
to report further information as it devel- 
ops at three to six month intervals. 
THE IMMEDIATE RESULTS OF 
TREATMENT 
Disappearance Time of Treponema 
Pallidum from Open Lesions.—Data are 
available on this point from 663 cases 
treated with penicillin alone (excluding 
those cases treated with penicillin plus 
mapharsen). 
Regardless of the single or total dose 
of penicillin, organisms have promptly 
disappeared from open lesions in every 
case within a range of six to sixty hours. 
At the two extremes of dosage, 1,000 
and 40,000 units, the average disappear- 
ance time varied only from twenty-one 
to fourteen hours. Whether the apparent 
trend toward shortening of disappear- 
ance time is significant is open to ques- 
tion because of the varying intervals at 
which dark field examinations were done 
in the several clinics. Not shown in the 
table is the fact that the intravenous holds no advantage 
over the intramuscular route in this respect. 
Healing of Lesions.—This is difficult to measure in 
statistical terms. There has been no observed instance 
of failure of lesions to heal, regardless of the single or 
total dose. With a total dosage of 60,000 units in eight 
days, healing is less prompt than with arsenical therapy; 
with larger total dosage, 300,000 units and up, it is as' 
rapid as with standard chemotherapy or more so. 
Serologic Response.—In figure 3 is shown the median 
blood serologic response,7 in terms of quantitative titer, 
of four groups of patients treated with penicillin alone 
(excluding those treated with penicillin plus maphar- 
sen). Included are both seropositive primary and 
secondary syphilis. Regardless of the total dosage, 
whether 60,000, 300,000, 600,000 or 1,200,000 units, 
there is apparent a trend toward serologic reversal 
within a period of about twenty days after the start 
of treatment. Within the range of 300,000 to 1,200,000 
units this trend is approximately uniform, regardless of 
dosage; with 60,000 units it is a little slower and less 
pronounced. Parenthetically, this rate of serologic 
reversal is identical with that observed after arsenical 
chemotherapy, whether with an arsphenamine at weekly 
Table 3.—Average Disappearance Time of Treponema Pallidum 
from Open Lesions of Early Syphilis After Varying 
Treatment Schedules (June 1, 1944) 
Size of Individual Dose 
Given Every Three 
Hours, Units 
Cases 
Average Disappearance 
Time of Treponema 
Pallidum, Hours 
1,000 
52 
21 
5,000 
201 
20 
10,000 
237 
19 
20,000 
135 
13 
40,000 
38 
14 
intervals or mapharsen given by various intensive 
methods. 
Further data are shown in tables 4 and 5. In table 4 
is summarized the blood serologic response of 48 
NAME.. 
ObtPerjod STS Uniu 
No. Days after Clinical Status (technique Quant, titer 
start of Rx employed) 
1 0-7 IZIIIIZ^IZIIIZZIIIIZZZZZZIZIZZIIIZZIIZI'ZZZIIIZI 
2 8-14 
3 15-21 _ 
4 22-28 • 
5 29-42 
6__ 43-56 • ’ 
7 57-84 
8 85-112 
9 113-140 
10 141-168 
11 169-224 * 
12 225-280 
13 281-336 
14 337-392 
15. 393-476 
16 477-560 
17 I 560 I || 
Time required from ortset of treatment to seronegativity (first) (permanent) 
Final Classi- 
fication 
Follow-up Observation (not to be filled in by clinic) 
Final outcome pregnancy: Cerebro-spinal Fluid (Follow-up examination) 
Delivery (days after start Dale Celia Tot. Prut. fixaDon (amallest Colloidal olh^ 
0f ' mgm. amt, giving pos. result) 
• JL 
Clinical and serologic 2. i 
status child:— 
3. | 
4. i 
_5. • 
6. 
, 
Fig. 2.—Reverse of form. for reporting early syphilis by participating clinics. 
patients with seronegative primary syphilis observed 
for nine or more weeks after the start of treatment. 
These are not broken down by total dosage since, 
regardless of the range of 60,000 to 1,200,000 units, 
the response was identical. In 28 patients the sero- 
logic test for syphilis, originally negative, remained so 
Table 4.—Blood Serologic Response in Seronegative Primary 
Syphilis, Patients Followed More Than Nine Weeks from 
Start of Treatment, All Treatment Schedules Combined 
(June 1, 1944) 
Serologic Test for Syphilis 
Negative, 
Remained 
Negative 
28 
Negative, 
Became Positive, 
Later Negative 
18 
Serologic 
Relapse 
2 
Oases Followed 
'48 
throughout the period of observation; in 18 it became 
temporarily positive, then reverted to negative, and in 
2 only there was a subsequent serologic relapse. From 
the serologic standpoint, therefore, and during the very 
brief observation period so far available, the results may 
be said to be satisfactory in 95.8 per cent of the cases. 
6. Complicated by asymptomatic neurosyphilis, syphilitic meningitis or 
ocular, osseous or visceral lesions. 
7. This has been determined by a statistical device which assign® to 
the initial quantitative titer, regardless of the actual number of units, 
the numerical value of 100. All subsequent observations are expressed 
in terms of per cent of the original titer. 
28 In seropositive early syphilis (combining seropositive 
primary and secondary syphilis) the results, now broken 
down by treatment schedule, are shown in table 5 
(limited to patients observed for nine or more weeks 
after the start of treatment). Here there is a direct 
relationship between “satisfactory” and “unsatisfactory” 
immediate serologic results and total dosage of peni- 
cillin ; the larger the dose, the better the result. The 
only and perhaps a major exception to this is in the 
group of patients who received 300,000 units of peni- 
cillin plus 320 mg. of mapharsen in seven and one-half 
days. This group shows as good initial results as were 
shown by patients receiving four times as much peni- 
cillin without mapharsen. 
So far it is clear that the minimum effective dose of 
penicillin in early syphilis in man cannot be determined 
on the bases of disappearance time of surface organisms, 
healing of lesions or (except very roughly) serologic 
relapse or apparently reinfection, has been classified as 
clinical relapse. Serologic relapse includes not only 
those who, originally seronegative or rendered so by 
treatment, subsequently became seropositive but also 
those who, still seropositive in low titer, subsequently 
develop high titer tests.8 An effort has been made to 
Table 6.—Incidence of Relapse in Seronegative Primary Syphi- 
lis Treated by Varying Schedules in Eight Days, Patients 
Observed for More Than Thirty-Eight Days (June 1, 1944) 
Treatment Schedule, 
Oases 
f 
Relapse 
Total 
Total Dose, Units 
Followed Clinical 
Serologic Number 
% 
60,000 
1 
200,000 
600,000 
14 
i 
i 
7.2 
600,000 
i 
1 2 
9.5 
1,200,000 
52 
... 
Intravenous (see text) 
4 
.. 
Total 
92 
2 
1 3 
3.2 
observe all patients clinically and serologically at weekly 
intervals for the first two months, every two weeks for 
another two to three months and at least monthly 
thereafter. 
The number of relapses reported in this paper is 
minimal and less than the number which have actually 
occurred. This is due to (1) an inevitable lag in report- 
ing from the individual clinic to the Penicillin Panel 
and (2) delay in defining apparent serologic relapse 
on the basis of a single observation until confirmed by 
subsequent tests (for the sake of avoiding laboratory 
error). 
Days of observation after start of treatment 
Fig. 3.—Median serologic response of seropositive early syphilis to penicillin with four treatment schedules ranging from 60,000 to 1,200,000 
units total dose in eight days; June 1, 1944. 
response since, regardless of total dose, within the range 
employed the drug is effective in all of these respects. 
The only available criterion lies, therefore, in the inci- 
dence of relapse. 
The method of statistical reporting here adopted is 
recognizedly inaccurate in that the incidence of relapse 
is related to the total number of patients observed for 
a period of time greater than that of the earliest 
observed relapse. In the tables to follow all patients 
are included who were observed for thirty-eight days 
or longer after the start of treatment, since this was 
the shortest interval at which relapse was observed. 
The brief interval available for study prevents the adop- 
tion of the statistical method used by Eagle,9 which will, 
however, be utilized in later more definitive analyses. 
Preliminary rough test of this method of appraisal 
suggests that the eventual incidence of relapse will 
probably be from four to five times as great as that 
reported here. In table 6 is shown the incidence of 
relapse, clinical and serologic, in 92 patients with sero- 
Table 5.—Blood Serologic Response in Seropositive Early 
Syphilis According to Treatment Schedule, Patients Fol- 
loived More Than Nine Weeks from Start of Treatment 
(June 1, 1944) 
Serologic Test for Syphilis Response' 
r 
Satisfactory 
Unsatisfactory 
(Reversed, or 
(No Significant 
Treatment Schedule, 
Cases 
Titer Falling), 
Change, or 
Units 
Followed 
% 
Relapse), % 
60,000 
38 
57.8 
42.1 
60,000 + mapharsen 
26 
76.9 
23.0 
300,000 
79 
82.1 
17.7 
300,000 + mapharsen 
24 
91.0 
8.3 
600,000 
109 
88.0 
12.0 
1,200,000 
02 
90.3 
9.0 
Relapse After Penicillin Treatment.—In this mate- 
rial, relapse has been rigidly defined. Any subsequent 
clinical manifestation of the disease, whether obviously 
8. Not yet classified as relapse or “unsatisfactory result” are those 
patients whose serologic tests have shown no improvement. Twelve 
months after treatment will be allowed to elapse before such patients are 
classified as seroresistant. 
9. Eagle, H.; The Treatment of Early and Latent Syphilis in Nine 
to Twelve Weeks with Triweekly Injections of Mapharsen; A Pre- 
liminary Analysis of the First 4,823 Cases, to be published. 
29 negative primary syphilis. The numbers, broken down 
by treatment schedule, are too small to be significant, 
though the total observed relapse rate, 3.2 per cent, 
is low. 
Similar data for seropositive primary syphilis are 
shown in table 7 and for secondary syphilis in table 8. 
the time of starting treatment and the incidence of 
relapse. The proportions in patients treated with peni- 
cillin alone are 3.2 per cent for seronegative primary, 
5.0 per cent for seropositive primary and nearly 10 per 
cent for early secondary syphilis. 
Table 11 shows the average and extreme intervals 
between the start of treatment and observed relapse. 
Here there is no direct correlation as to total dose. 
Relapses have occurred as early as thirty-eight days 
and as late as two hundred and ninety-four days after 
the start of treatment. Considering the short periods of 
observation so far available for all groups treated, 
further relapses in all may be confidently anticipated. 
The Optimum Time-Dose Relationship for Penicillin 
in Early Syphilis.—The available data indicate that 
within the twentyfold dosage range employed in a 
period of seven and one-half days penicillin has a pro- 
found immediate effect in terms of disappearance of 
surface organisms, healing of lesions and serologic 
reversal. In seronegative primary syphilis no state- 
ments as to minimum effective dose are as yet justi- 
fiable. In seropositive primary and early secondary 
syphilis any dose less than 600,000 units in seven and 
one-half days is clearly ineffective. A total dose of 
600.000 units provides a minimum relapse rate of nearly 
5 per cent, of 1,200,000 units a rate of 2 per cent, within 
the short period for which such patients have so far 
been followed. The intravenous route appears to be 
less effective, even in large doses, than the intra- 
muscular. 
The possibility that even 1,200,000 units in a four to 
eight day period will prove to be inefficacious after 
further observation has led the Penicillin Panel to 
inaugurate the study of two additional treatment groups 
Table 7.—Incidence of Relapse in Seropositive Primary Syphi- 
lis, Treated by Varying Schedules in Eight Days, Patients 
Observed for More Than Thirty-Eight Days (June 1, 1944) 
Relapse 
Treatment Schedule, 
Cases 
' 
Total 
Total Dose, Units 
Followed Clinical 
Serologic 
Number 
% 
60,000 
8 
2 
2 
25.0 
200,000 
3 
300,000 
30 
2 
i 
3 
10.0 
600,000 
37 
1,200,000 
75 
i 
i 
2 
2.6 
Intravenous (see text)— 
5 
1 
-• 
1 
20.0 
Total 
6 
2 
8 
5.0 
Table 8.—Incidence of Relapse in Secondary Syphilis Treated 
by Varying Schedides in Eight Days, Patients Followed for 
More Than Thirty-Eight Days (June 1, 1944) 
Treatment Schedule, 
Total Dose, Units 
Cases 
Followed Clinical 
Relapse 
X 
Total 
Serologic Number 
% 
60,000 
37 
9 
2 
11 
29.6 
200,000 
3 
2 
37.5 
300,000 
6 
4 
10 
10.6 
600,000 
4 
3 
7 
5.0 
1,200,000 
64 
2 
2 
3.1 
Intravenous (see text).... 
.. , 16 
i 
1 
a 
12.5 
Total 
.. 355 
23 
12 
35 
9.8 
These relate to patients treated with penicillin alone 
(excluding the combined penicillin with mapharsen 
groups). Here there is obvious a direct correlation 
between total dose and relapse incidence. 
The data of tables 6, 7 and 8 are combined in table 9 
for all patients with early syphilis; and here is added 
information concerning the patients treated with penicil- 
lin plus 320 mg. of mapharsen (two groups, 60,000 and 
300.000 units respectively) and also concerning a small 
group of patients (25 in number) treated by the intra- 
venous route before the present organized study was 
begun. In patients treated with penicillin by the intra- 
muscular route the incidence of relapse, even in the brief 
observation period available, is in direct proportion to 
total dosage (nearly 30 per cent with 60,000 units, only 
2 per cent with 1,200,000 units). In the small group 
who received large doses intravenously, ranging from 
600.000 to 1,200,000 units, and whether by multiple 
injections or continuous drip, the observed relapses are 
five to six times as great as in patients treated with 
comparable doses by the intramuscular route, suggest- 
ing that the intravenous route not only holds no advan- 
tage over the intramuscular route but is actually less 
effective. 
In table 10 the incidence of relapse is related to the 
stage of disease at the start of treatment in patients 
treated with penicillin alone (omitting the groups com- 
bined with mapharsen, among which only 1 relapse has 
so far occurred) and without regard to total dosage. 
In conformity with Eagle’s report9 as to semi-intensive 
arsenotherapy, and in contrast to the older Cooperative 
Clinical Group and other data 10 as to “standard” pro- 
longed arsenical chemotherapy, there seems to be here a 
direct relationship between the stage of the disease at 
Table 9.—Incidence of Relapse in All Types of Early Syphilis 
Treated by Varying Schedules, Patients Observed for More 
Than Thirty-Eight Days (June 1, 1944) 
Treatment Schedule, 
Relapse 
Total Dose, Units 
Cases 
-A 
(Route Intramuscular 
Fol- 
Clin- 
Sero- 
Total 
Unless Specified) 
lowed 
ical 
logic 
Number 
% 
60,000 
46 
11 
2 
13 
28.2 
60,000 + 320 mg. mapharsen 
26 
200,000 
11 
3 
3 
27.2 
300,000 
138 
9 
5 
14 
10.1 
300,000 + 320 mg. mapharsen 
68 
1 
1 
1.4 
600,000 
194 
6 
4 
9 
4.6 
1,200,000 
191 
1 
3 
4 
2.0 
Various intravenous schedules *... 
25 
2 
1 
3 
12.0 
* Dosage range 600,000 to 1,200,000 (all but 3 eases 1 million +), 
, single 
intravenous injections, intravenous drip or both. 
in 4 to 8 days. 
Table 10.—Incidence of Relapse by Stage of Disease, All Treat- 
ment Schedules * Combined, Patients Followed More Than 
Thirty-Eight Days (June 1, 1944) 
Relapse 
! K 
Cases Total 
Stage of Disease 
Followed Clinical Serologic Number 
% 
Primary seronegative 
92 2 1 3 
3.2 
Primary seropositive 
.. 158 6 2 8 
5.0 
Secondary 
.. 355 23 12 35 
9.8 
* Omitting 94 patients 
treated with penicillin + mapharsen. 
given a total of 2,400,000 units in thirty and sixty 
intramuscular injections in four and seven and one-half 
days respectively. These patients are being treated in 
the United States Army and eight selected United 
States Public Health Service rapid treatment centers. 
The results obtained to date in the two small groups 
of patients given 60,000 and 300,000 units of penicillin 
respectively, in each case plus the known subcurative 
10. Stokes, J.- H., and others: Cooperative Clinical Studies in the 
Treatment of Syphilis: Early Syphilis, Ven. Dis. Inform. 13; 165, 207 
and 253, 1932. 
30 total dose of 320 mg. of mapharsen in eight days, are 
worth emphasizing. In 94 such patients followed for 
thirty-eight days or more only one relapse has occurred. 
It is perhaps to be expected that certain patients with 
early syphilis will prove to be resistant to penicillin 
exactly as a relatively standard proportion of 5 to 15 per 
cent of patients has proved to be resistant to arsenic 
heavy metal chemotherapy. But, in view of what is 
already known concerning the probable modes of action 
of penicillin and of arsenic and bismuth in syphilis (con- 
siderations too lengthy for discussion here) it is possible 
that those patients resistant to penicillin will not be the 
same ones resistant to metal chemotherapy and that a 
combination of the two forms of treatment will eventu- 
ally prove to be more effective than any method of use 
of either one alone. 
It should also be emphasized that penicillin, as so far 
employed in early syphilis, is not suitable for mass 
application. Injections every three hours day and night 
over whatever period of time demand hospitalization 
and trained nursing or professional care. However 
available these may be for the armed forces, facilities 
are inadequate in civilian practice to meet the enormous 
demand. The eventual general use of the drug depends 
Treatment Resistant Early Syphilis.—Eight patients, 
most of them with dark field positive psoriasiform syph- 
ilids, persisting in spite of or recurring during metal 
chemotherapy, have been treated with penicillin, with 
prompt healing in all and with subsequent serologic 
behavior similar to that of previously untreated early 
syphilis. 
Infantile Congenital Syphilis.—Not included in the 
tabular presentations are some 20 infants with early 
congenital syphilis. The majority of them have been 
treated with a total dose of penicillin of 20,000 units 
per kilogram of body weight, corresponding to a total 
dose of 1,200,000 units in the adult. Their behavior 
in terms of symptomatic improvement and serologic 
response is analogous to that of early acquired syphilis 
in the adult. 
The Outcome of Pregnancy.—Though 58 pregnant 
women with early syphilis have so far been treated, it 
is too early to speak of any results as to the outcome 
in the child. 
REACTIONS TO PENICILLIN 
Herxheirner Reactions.—Of 1,418 patients treated. 
846 (59 per cent) have had Herxheirner reactions 
within the first twenty-four hours. This consists 
usually of fever alone (685 cases) ; in the others, 
exacerbation of secondary skin lesions with or without 
fever. The fever is usually mild (less than 102 F.), 
though in 174 cases (12 per cent) the febrile rise has 
been higher than this level. In no case has the reaction 
been alarming, nor has it interfered with subsequent 
treatment. 
Other Reactions.—Only 59 patients (41 per cent of 
the total treated) have had other reactions attributable 
to penicillin. In 15 there were cutaneous eruptions 
(8 urticaria, 7 other types of skin rashes, none severe). 
Seven had mild gastrointestinal reactions, 33 secondary 
fever. 2 abscessed buttocks and 2 miscellaneous mild 
disturbances. In no case has penicillin treatment had 
to be suspended because of reactions from the drug. 
SUMMARY 
1. An organized study of the effect of penicillin in 
early syphilis is in progress in an effort to determine the 
optimum method of use of the drug. The results so far 
available are preliminary. 
2. Penicillin has a profound immediate effect in early 
syphilis in terms of (a) disappearance of surface organ- 
isms from open lesions, (b) healing of lesions and (c) 
a trend toward serologic reversal. 
3. These immediate effects are in general identical 
within a twentyfold dosage range of 60,000 to 1,200,000 
units administered by the intramuscular route every 
three hours day and night to a total of sixty injections 
in seven and one-half days. 
4. The same immediate effects are apparent within 
the dosage range of 300,000 to 1,200,000 units given 
by the intramuscular route every three hours day and 
night to a total of thirty injections in four days. 
5. These immediate effects cannot be utilized to deter- 
mine the optimum time-dose relationship, which, in 
man, depends on the incidence of relapse. 
6. The incidence of relapse, when penicillin is admin- 
istered alone, is in direct relationship to the total dosage 
given by the intramuscular route in a seven and one-half 
day period, greatest with 60,000 units and least with 
1,200,000 units. 
7. Relapse appears to be more frequent after intra- 
venous than after intramuscular administration of com- 
parable doses. 
Table 11.—Average and Extreme Intervals from Start of 
Treatment to Relapse According to Treatment Schedule 
(June 1, 1944) 
Average Interval, Extreme Intervals, 
Treatment Schedule, Units 
Days 
Days 
60,000 
104 
64 to 154 
60,000 + mapharseu 
No relapses observed 
200,000 
116 
83 to 135 
300,000 
90 
38 to 166 
300,000 + mapharsen 
53* 
600,000 
98 
73 to 113 
1,200,000 
132 
63 to 294 
Intravenous 
74 
56 to 126 
* One relapse only. 
on the development of methods which will permit its 
administration on an ambulatory basis. 
As with arsenical chemotherapy, it is probable that 
the optimum time-dose relationship for the treatment 
of early syphilis in man with penicillin alone and its 
relative efficacy when administered alone or in combi- 
nation with other forms of treatment will be guided by 
data from the experimental laboratory not as yet avail- 
able but shortly to be expected. 
In man, further immediate studies should be directed 
to (1) determination of the relative effectiveness of 
1,200,000 units versus much larger doses in four and 
eight days respectively, (2) variation of the time inter- 
val between individual dosage within the range of three 
to twenty-four hours, (3) more exact definition of the 
merits of intravenous versus intramuscular administra- 
tion and (4) an expansion of the combinations peni- 
cillin plus arsenic and penicillin plus bismuth. 
Results of Treatment of Special Forms of Early 
Syphilis.—Thirteen patients with early syphilis in this 
series had positive spinal fluids before treatment (11 of 
them group 2, 2 group 3). Of these, the fluid abnor- 
malities disappeared or improved under penicillin treat- 
ment alone in 10 within time period ranging from ten 
to fifty days; 3 were unimproved. 
Acute Syphilitic Meningitis.—Ten patients with this 
complication of early syphilis have been treated, the 
majority with 1,200,000 units in seven and one-half 
days. Symptomatic relief has been dramatically prompt 
in all and, in the majority, spinal fluid abnormalities 
have disappeared or are rapidly improving. 
31 8. The lowest incidence of relapse—and the most 
favorable serologic response—was in small groups of 
patients treated with 60,000 and 300,000 units respec- 
tively of penicillin plus a known subcurative dose of 
mapharsen. 
9. Penicillin has a favorable effect in early asymp- 
tomatic neurosyphilis, acute syphilitic meningitis, early 
syphilis treatment resistant to arsenic and bismuth and 
infantile congenital syphilis. 
10. No opinion can be as yet expressed as to the 
effect of penicillin in the prevention of prenatal syphilis. 
11. The optimum time-dose relationship of penicillin 
in early syphilis is not yet established. Certainly the 
minimum dose, especially in secondary syphilis, should 
not be less than 1,200,000 units; probably it should 
be more. 
12. Herxheimer reactions after the penicillin treat- 
ment of early syphilis are frequent but not serious; 
other reactions, due to penicillin itself, are negligible. 
13. Further avenues of study are suggested. 
SYPHILIS 
PENICILLIN TREATMENT OF SYPHILIS. 
1. PURPOSE. The purpose of this bulletin is 
to introduce penicillin treatment of syphilis in 
the Army and to outline the administrative and 
professional details involved. When penicillin 
is not obtainable through normal supply chan- 
nels the system of treatment recommended in 
S. G. O. Circular Letter No. 74, 25 July 1942, 
subject, “Diagnosis and treatment of the ve- 
nereal diseases,” will be used. 
2. INDICATIONS FOR PENICILLIN 
TREATMENT OF SYPHILIS. Penicillin 
will be used in the treatment of the following 
types of syphilis: 
a. Untreated primary and secondary syphilis. 
(Mapharsen-bismuth treatment has not been 
initiated.) 
b. Untreated latent syphilis. (Mapharsen- 
bismuth treatment has not been initiated.) It is 
essential that a preliminary spinal fluid exami- 
nation be made in all cases of presumed latent 
syphilis. If the spinal fluid is abnormal as de- 
fined in paragraph 4a (2), TB MED 48, 31 May 
1944, the case must be classified as asymptoma- 
tic neurosyphilis and be managed according to 
that directive. 
c. Treated primary and secondary syphilis 
which has failed to respond to mapharsen-his- 
muth therapy, This includes— 
(1) Clinical relapse, such as mucocutaneous, 
ocular, osseous, or visceral. 
(2) Treatment-resistance, a rare condition 
manifested by failure of the primary and 
secondary lesions to respond to adequate ma- 
pharsen-bismuth therapy, usually accompanied 
by the presence of living treponemes in the 
lesions. 
(3) Serologic relapse as evidenced by reversal 
of a negative STS (serologic test for syphilis) 
at the conclusion of mapharsen-bismuth 
therapy to positive during the 6 months post- 
treatment observation period. Criteria of sero- 
logic relapse are discussed in paragraph 7b. 
(4) Serum-fastness as evidenced by a per- 
sistent positive STS at the end of mapharsen- 
bismuth therapy. 
d. Treated primary secondary, and latent 
syphilis intolerant or sensitive to mapharsen- 
32 bisrrmth therapy. This group includes indivi- 
duals who have had a serious reaction to arsenic 
that contraindicates its further use. Jaundice, 
exfoliative dermatitis, a blood dyscrasia 
(thrombocytopenic purpura, agranulocytosis, 
aplastic anemia) and encephalopathy are ex- 
amples of such reactions. Patients who mani- 
fest persistent intolerance of less serious char- 
acter, such as severe headaches, nausea, vomit- 
ing, and diarrhea, even with reduced doses of 
mapharsen, may also be included. 
3. TECHNIC OF PENICILLIN TREAT- 
MENT OF SYPHILIS, a. Facilities and per- 
sonnel. Penicillin therapy requires hospitaliza- 
tion of approximately 10 days, including 7y2 
days of therapy, and time consumed for pre- 
therapeutic diagnostic procedures and adminis- 
trative details. It is the responsibility of the 
medical officer in charge to see that adequate 
supplies of the drug are on hand before actual 
treatment of the patient is started. 
b. Dosage and technic of administration of 
penicillin. Uniform dosage and technic will be 
used in all cases. The total dosage will be 
2,400,000 units of penicillin, given in 60 con- 
secutive intramuscular injections of 40,000 units 
(2 cc of penicillin solution) at 3-hour intervals 
day and night for 7y2 days. Any convenient 
time schedule may be adopted, but in most 
Army hospitals the most suitable schedule is 
0200, 0500, 0800, 1100, 1400, 1700, 2000, and 
2300. The solution should be injected intra- 
muscularly into the upper outer quadrant of 
alternate buttocks. The needle should be 2 
inches to %y2 inches in length, preferably 20- 
gauge, in order to insure intramuscular injec- 
tion rather than injection into fat. No addi- 
tional antisyphilitic therapy is to be given 
during or after the completion of the course 
of penicillin except in the ccLse of penicillin 
treatment failures discussed in paragraphs 7 
and 8 below. 
c. Noninterruption of penicillin treatment. 
Treatment should continue without interrup- 
tion after its initiation. On the first day of 
treatment, commonly, and during the course 
of treatment less frequently, minor reactions 
may be encountered. None of these is indica- 
tion for the discontinuance or interruption of 
therapy. There have been no instances so far 
in which it has been necessary to discontinue or 
interrupt the treatment schedule. 
4. REACTIONS OBSERVED IN PENICIL- 
LIN TREATMENT OF SYPHILIS, a. 
Herxheimer reactions. These occur frequently 
in cases of primary and secondary syphilis, less 
commonly in cases of latent syphilis, and rarely 
in cases that have already received some anti- 
syphilitic therapy. The manifestations may be 
focal or systemic and are ascribed to the 
massive destruction of treponemes in the 
syphilitic lesions and in the blood stream. 
These reactions may therefore be considered of 
favorable significance. Both the focal and 
systemic Herxheimer reactions are encountered 
on the first day of treatment only. They begin 
usually some 3 to 6 hours after the first peni- 
cillin injection, gradually become worse and 
reach a peak, after which they slowly and 
progressively subside, disappearing within an 
average of 24 hours. No specific therapy is 
required although such drugs as aspirin and 
codeine may be given for relief of symptoms. 
It must be emphasized that these symptoms 
disappear spontaneously in spite of the con- 
tinued, regular administration of penicillin, 
and are not justification for discontinuance of 
therapy. 
(1) The focal Herxheimer reaction consists of 
an aggravation of the existing syphilitic lesions. 
There may be increased swelling of the chancre, 
further enlargement of already enlarged re- 
gional lymph nodes accompanied by pain, and 
exaggeration of the secondary eruption. A 
pallid, sparse, macular eruption often becomes 
extremely profuse and vividly red, and may re- 
semble measles or scarlet fever. 
(2) The systemic Herxheimer reaction may be 
manifested by a variety of symptoms, such as 
headache, malaise, nausea, occasionally vomit- 
ing, abdominal cramps, and weakness, but its 
most characteristic features are chilly sensa- 
tions and fever. Peak temperatures of 105.4° 
F. have been recorded, although generally 
lower grades of fever prevail. 
b. Other reactions due to 'penicillin. Other 
reactions caused by penicillin have been ex- 
tremely rare and trivial in the dosages recom- 
33 mended in this bulletin. Most patients will 
complain of more or less local muscle soreness 
at the site of the injections, but usually this 
has not been objectionable. The most common 
late systemic reactions have been secondary 
fever occurring toward the end of treatment 
and terminating immediately on its cessation; 
urticaria or other minor skin eruptions; gener- 
alized pruritus; herpes labialis and progeni- 
talis; and mild gastro-intestinal symptoms such 
as abdominal cramps, nausea, and occasionally 
vomiting. 
5. POST-TREATMENT OBSERVATION 
OF PATIENTS TREATED FOR SYPH- 
ILIS WITH PENICILLIN, a. Serologic and 
clinical follow-up, All syphilis cases treated 
with penicillin will have a monthly inspection 
and quantitative STS for a period of 12 months. 
In theaters of operation suitable alterations of 
this plan may be adopted. 
(!) Laboratory technic. In patients treated for 
syphilis with penicillin laboratory procedures 
will be performed in the local Army laboratory 
wherever possible. In those situations where no 
Army serologic laboratory is locally available, 
blood serum and spinal fluid will be shipped to a 
service command laboratory. The service com- 
mand laboratory will provide on request special 
merthiolated tubes for the shipment of speci- 
mens of blood serum and spinal fluid. 
(2) Quantitative serologic tests for syphilis. 
On each specimen of blood the laboratory should 
be requested by the medical officer to perform 
the authorized quantitative STS, described in 
TM 8-227, and to report the result in units. 
b. Spinal fluid. (1) In primary and second- 
ary syphilis the spinal fluid will be examined as 
soon after the completion of 6 months of obser- 
vation as feasible. In no case will the syphilis 
register be closed until this examination has 
been accomplished. 
(2) Spinal fluid tests to be performed. Cell 
count; Pandy or Nonne-Apelt qualitative tests 
for protein; quantitative estimation of total 
protein; complement fixation (Wassermann) 
test, or, if this is not feasible, a flocculation test; 
and colloidal gold test. The cell count and Pan- 
dy or Nonne-Apelt test should be performed at 
the local laboratory within 30 minutes after the 
spinal fluid is withdrawn. 
c. Special administrative features of penicil- 
lin treatment. (1) Preparation of the Syphilis 
Register (W. D., A. G. O. Form No. 8-114) 
(formerly W. D., M. D. Form No. 78). This 
will be filled in completely in the usual manner 
and a brief note describing the treatment pro- 
cedure will be made in the register. A sample 
note reads as follows: 
Soldier received intensive penicillin ther- 
apy from 20 June 1944 to 27 June 1944 
consisting of 60 consecutive intramuscu- 
lar injections of 40,000 units at 3-hour in- 
tervals for a total dose of 2,400,000 units. 
There was a febrile Herxheimer reaction 
the first day with peak fever of 102.4° F. 
Lesions were healed when therapy was 
completed. 
Notation will also be made in the register that 
patient is to be managed in accordance with TB 
MED 106. 
(2) Preparation of W. D., M. D. Form No. 78a 
(Patient’s Record of Syphilis Treatment). 
This will be prepared as a personal record for 
the soldier. A brief account of the treatment 
status of the patient will be entered. This can 
be done simply by repeating the note made in 
the syphilis register, described in (1) above. 
An additional statement will be made to the 
effect that no further treatment is required, ex- 
cept in the event of clinical or serological re- 
lapse, but that the patient will have a regular 
monthly physical examination and blood test. 
This form can be used as a record of follow-up 
and a reminder for the soldier by inscribing at 
each visit the date set for the next examination. 
(3) Closure of the syphilis register. (a) Pri- 
mary and secondary syphilis. The syphilis reg- 
ister will be closed in primary and secondary 
syphilis and transmitted to The Surgeon Gen- 
eral after 12 months of observation in all pa- 
tients who have become and remained serolog- 
ically negative; who have had no evidence of 
clinical relapse; and who have had a negative 
spinal fluid between the completion of 6 months 
of observation and the time of closing of the 
register. 
(b) Latent syphilis. The syphilis register 
will be closed in latent syphilis and transmitted 
to The Surgeon General after 12 months of 
observation if there has been no clinical or sero- 
34 logic relapse even though the serologic tests 
have remained persistently positive. It is 
anticipated that serum-fastness will not be un- 
common in cases that receive penicillin therapy 
in the latent stage of syphilis. 
6. CLINICAL AND SEROLOGIC POST- 
TREATMENT COURSE OF FAVORABLY 
RESPONDING PENICILLIN TREATED 
SYPHILIS, a. Primary and secondary syph- 
ilis. (1) Clinical course. The rate of healing 
of primary and secondary syphilitic lesions var- 
ies, depending principally upon the type of le- 
sion. Ordinarily, simple nonulcerated chancres 
of small size, mucous patches, and macular erup- 
tions are healed by the time the treatment course 
is completed. Large ulcerated chancres, deeply 
infiltrated papular eruptions, and large condy- 
lomata lata may not heal completely for 1 to 3 
weeks after treatment is concluded. Presence 
of such lesions, unless physically incapacitating, 
or requiring extensive local treatment, will not 
be cause for prolonged hospitalization. 
(2) Serologic course. The titre of the STS de- 
clines gradually from positive to negative in the 
post-treatment period, the negative phase being 
achieved in a variable time. The majority of 
cases become negative between the second and 
fourth post-treatment months, although earlier 
and later reversals occur. In general, the high- 
er the initial titre of the quantitative STS the 
longer the test will take to become negative, and 
the lower the initial titre the sooner the test 
will become negative. 
(3) Critical relapse period. The critical period 
for relapse, both clinical and serologic, appears 
on the basis of present information to lie be- 
tween the third and sixth post-treatment 
months, although relapses have occasionally 
been observed at earlier and later periods. 
h. Latent syphilis. (1) Clinical course. Since 
these patients have no visible syphilitic lesions, 
no observations as to healing can be made. 
(2) Serologic course. The serologic curve may 
take the same course as that observed in primary 
and secondary syphilis. This is especially true 
of cases of very early latent syphilis, notably 
those which have only recently passed from the 
secondary phase into the phase of latency. On 
the other hand, individuals with older latent 
syphilis are likely to exhibit serologic refractor- 
iness, the STS showing either no tendency or 
little tendency to lose strength. This results in 
the case having to be classified eventually as 
serum-fast. 
7. DEFINITION OF PENICILLIN FAIL- 
URE. Care should be exercised in the determi- 
nation of failure since patients may develop 
intercurrent skin eruptions of nonsyphilitic 
character. Intercurrent infections and smallpox 
vaccination may produce a temporary elevation 
of the titre of the quantitative STS. All forms 
of clinical relapse are generally accompanied by 
serologic relapse, or by persistently high sero- 
logic titres. Treatment failures may be divided 
into nine categories. 
a. Mucous <md/or cutaneous relapse is mani- 
fested by the appearance of syphilitic lesions of 
the mouth, genitals, and skin, the latter espe- 
cially in the anogenital region. There may be 
lesions of both skin and mucous membranes 
(mucocutaneous relapse), or of either surface 
alone. Darkfield examinations should be per- 
formed to corroborate the diagnosis. If dark- 
field examination is negative, repeated quanti- 
tative STS should be performed which will 
reveal a progressively rising titre. In doubtful 
cases, consultation is desirable. 
b. Serologic relapse is manifested by a rising 
titre of the quantitative STS after the test has 
become negative or has manifested a previously 
falling trend. When a serologic relapse is sus- 
pected, the patient should be thoroughly and 
frequently examined, since serologic relapse is 
usually accompanied or shortly followed by 
mucocutaneous or some other clinical relapse. 
Since the titre of the quantitative STS may 
vary from time to time, as a result of labora- 
tory technic, and in different laboratories, it is 
not sufficient to accept minor fluctuations in 
the titre as evidence of serologic relapse. 
Serologic relapse should be diagnosed only 
when a series of consecutive tests, performed 
preferably in the same laboratory, shows per- 
sistently increasing titres over a period of 3 to 
4 weeks. In the event that a titred test is not 
available, a change from a doubtful or negative 
reaction to a persistently positive reaction will 
be accepted as adequate evidence of serologic 
35 relapse. It should be noted that the titre char- 
acteristically rises during, and for a brief 
period after penicillin therapy. This eleva- 
tion is temporary and is not to be considered 
evidence of serologic relapse. 
c. Serum-fastness in primary and secondary 
syphilis is manifested by a failure of the quan- 
titative STS to show a marked decline within 
an arbitrary period of 6 months after com- 
pletion of therapy. Mihor fluctuations in the 
titre may be observed, and also a drop to a 
lower sustained level, but there is no consistent, 
gradual, and maintained fall to negative. This 
condition will be uncommon in primary and 
secondary syphilis, where it will be considered 
a treatment failure when present 6 months af- 
ter completion of therapy. It will not he un- 
common in latent syphilis, in which it will not 
he considered a treatment failure. 
d. Neurologic relapse (neurorecurrence) may 
occur as acute syphilitic meningitis, with head- 
ache, dizzy spells, fever, and rigidity of the 
neck. In fulminant cases, coma may supervene 
rather rapidly. Less commonly relapse in the 
nervous system may appear as an isolated cra- 
nial nerve palsy or paralysis of one or more 
extremities. Diagnosis should be confirmed by 
spinal fluid examination. In these cases the 
neurologist should be consulted for diagnostic 
assistance. 
e. Asymptomatic neurosyphilis is manifested 
only by an abnormal spinal fluid. 
f. Ocular relapse may be manifested by iritis, 
usually unilateral, or optic neuritis, or neuroret- 
initis, which may be unilateral or bilateral 
The latter conditions may be accompanied by 
headache, and blurring and progressive failure 
of vision. In these cases the ophthalmologist 
should be consulted for diagnostic assistance. 
g. Osseous relapse is manifested by severe 
pain, often nocturnal, in the long bones, most 
often the tibias, or severe headache when cra- 
nial bones are affected. Local tenderness over 
the affected bone is often very acute. Roent- 
genograms may assist in the diagnosis. 
h. An extremely rare case may occur (none 
so far observed in 3,000 cases) that is treat- 
ment-resistant to penicillin, where lesions fail 
to heal and living treponemes are present after 
completion of the treatment course. 
i. Other forms of visceral relapse such as 
hepatitis have so far not been observed but 
should be watched for. 
8. MANAGEMENT O F PENICILLIN 
FAILURES, a. Cases of neurologic relapse 
and asymptomatic neurosyphilis will be man- 
aged in accordance with TB MED No. 48, 
31 May 1944. 
h. All other forms of treatment failure after 
the 2,400,000-unit course of penicillin will re- 
ceive a second course of the drug. This will 
consist of 4,000,000 units of penicillin, given in 
80 consecutive intramuscular injections of 50,- 
000 units at 3-hour intervals day and night for 
10 days. These patients will be followed dur- 
ing the post-treatment period as described in 
paragraph 5. Treatment failures after the 
second course of penicillin will be transferred 
to one of the general hospitals designated as a 
neurosyphilis center in section I, War Depart- 
ment Circular No. 347, 1944, for further evalu- 
ation and treatment. In theaters of operations, 
suitable arrangements should be provided for 
expert consultation in these cases. 
9. TREATMENT OF CERTAIN ARMY 
AIR FORCE PERSONNEL. Personnel of 
the Army Air Forces required to participate 
in frequent and regular aerial flights may be 
treated with penicillin, as provided herein, un- 
der conditions prescribed by the Commanding 
General, Army Air Forces. 
[A. G. 300.5 ( 29 Sep 4).] 
By order of the Secretary of War : 
G. C. MARSHALL, 
Chief of Staff. 
Official: 
J. A. ULIO, 
Major General, 
The Adjutant General. 
36 is so striking and complete that it seems unnecessary 
to collect further cases merely to demonstrate it as 
such. In ocular syphilis, simple inflammatory processes 
respond; later and more complicated lesions such as 
the optic neuritides and interstitial keratitis recover, 
relapse, present resistance and residues proportional to 
damage already done. This statement is probably true 
of visceral syphilis and of special localized processes and 
eighth nerve involvement. 
These categorical statements are based on a material 
collected from 182 cases, observed for periods ranging 
from eight to two hundred and fourteen days after the 
institution of treatment. The preliminary conclusions 
are sharply limited by qualifications involving not only 
duration of observation and small numbers in indi- 
vidual breakdown items but by wide variation in time- 
dosage relationships and little uniformity as to time 
and type of test and recheck procedure. No precedents 
existing, each investigator groped his way into his 
problem. A considerable part of the material collected 
from nonuniform records was of such short observation 
and so “mixed” in therapeutic procedure that it fur- 
nished little evaluative worth. The distribution by 
source, duration of observation and diagnosis is given 
in table 1. Paresis, a crucial tester of therapeutic effect, 
heads the list (56 cases) and neurosyphilis totals 122 
cases. Observation of sixty days or more was main- 
tained in 44 Pennsylvania, 20 Johns Hopkins, 11 Mayo, 
1 Bellevue. 5 New York Hospital and 1 Michigan case, 
a total of 82 cases. 
Notwithstanding the limitations described, the mate- 
rial furnished the basis for demonstrating by both 
symptoms and laboratory tests (quantitative serologic, 
spinal fluid examination) the incontestable reality of the 
effect of penicillin treatment in syphilis. It permits an 
exploratory breakdown into grades of treatment effect 
as such, in relation to previous standard treatment; 
by at least two grades of intensity of penicillin treat- 
ment—low intensity (type A) 600,000 to 1,200,000 
units of the sodium salt at 10,000 to 25,OCX) units 
intramuscularly every three to four hours and high 
intensity (type B) 2,400,000 to 4,000,000 units at 25,000 
to 50,000 units intramuscularly every two to four hours. 
It was not possible from this material to estimate the 
difference in effect of hourly variations or unit dose 
variations, or of intravenous or intraspinal medication. 
EFFECT OF PENICILLIN ON THE REAGIN TITER 
OF THE BLOOD 
Irrespective of the system used and in all types of 
late (excluding latent) syphilis, penicillin causes 
improvement (reduction) of reagin titer in from about 
50 to 60 per cent of 96 late cases in which such data 
were available (table 2). An initial Herxheimer-like 
rise or “provocative” effect is observable in about 20 
per cent of late cases. Within the period of observation 
10 per cent of late cases became completely negative. 
In 5 cases of seroresistant syphilis, 1 became negative 
(low titer to start with) and 4 improved. Herx- 
heimer effect occurred in 1. 
In 32 cases of general paresis, disregarding treatment 
system employed, 16 were serologically improved, 2 
reduced to negative. 
EFFECT OF PENICILLIN ON THE SPINAL FLUID 
IN NEUROSYPHILIS 
This furnishes probably the most graphic demonstra- 
tion of the effect of penicillin, because of its multiple 
quantitative approach. Seven grades of change were 
SYPHILIS 
THE ACTION OF PENICILLIN IN 
LATE SYPHILIS 
INCLUDING NEUROSYPHILIS, BENIGN LATE SYPHILIS 
AND LATE CONGENITAL SYPHILIS: 
PRELIMINARY REPORT 
JOHN H. STOKES, M.D. 
PHILADELPHIA 
LIEUTENANT COLONEL THOMAS H. STERNBERG 
MEDICAL CORPS, ARMY OF THE UNITED STATES 
COMMANDER W ALTER H. SCHWARTZ (MC), U.S.N 
JOHN F. MAHONEY, M.D. 
Senior Surgeon, U. S. Public Health Service 
STAPLETON, STATEN ISLAND, N. Y. 
J. E. MOORE, M.D. 
BALTIMORE 
AND 
W. BARRY WOOD Jr., M.D. 
ST. LOUIS 
These cases are drawn from eight clinics at present 
engaged in a study of the effect of penicillin on late 
syphilis, under the general auspices of the Committee 
on Medical Research of the office of Scientific Research 
and*Development. These, with the names of the respon- 
sible investigators, are as follows: University of Penn- 
sylvania (John H. Stokes, M.D.), Cornell University 
(Walsh McDermott, M.D.), Mayo Clinic (Paul A. 
O’Leary, M.D.), Boston Psychopathic Hospital (Harry 
P. Solomon, M.D.), University of Michigan (Udo J. 
Wile, M.D.), Bellevue Hospital (Evan Thomas, M.D.) 
and Johns Hopkins University (J. E. Moore, M.D.). 
Associated with each of them are various co-workers 
and assistants too numerous to mention here, but to 
whom due credit will subsequently be given. 
Penicillin has distinctly beneficial serologic and clin- 
ical effects on neurosyphilis, including early and late 
manifestations, not excepting tabes and paresis, and 
including asymptomatic neurosyphilis. Its action on 
gummatous manifestations of skin, mucosae and bones 
The authors are members of the Penicillin Panel of the Subcom- 
mittee on Venereal Diseases, National Research Council. 
The work described in this paper was done under contract recom- 
mended by the Committee on Medical Research between the Office of 
Scientific Research and Development and several universities. 
Read in a panel discussion on“Penici!lin in the Treatment of Syphilis” 
before the Section on Dermatology and Syphilology at the Ninety-Fourth 
Annual Session of the American Medical Association, Chicago, June 15, 
1944. 
37 considered: worse, no change and five grades of 
improvement as follows: grade 1, reduction in cell 
count or total protein; grade 2, reduction in both cell 
count and total protein; grade 3, reduction of cell count, 
total protein and intensity of colloidal test; grade 4, 
35 definite. The commonest change is a reduction in 
cells and total protein, but grade 4 improvement is 
remarkably common, including all four items of the fluid 
examination. 'This response is, as would be expected, 
evident in a higher proportion (1/4) in asymptomatic 
neurosyphilis than in paresis (1/9). Some of the cases 
rated as “worse” are, we believe, to be regarded as 
Herxheimer or flare effects and would probably 
improve on longer observation. It is interesting that 
4 asymptomatic cases accompanied by gummatous 
benign syphilis were among the 6 asymptomatic cases 
in which the condition became “worse.” 
In order to carry the specific touch of conviction to 
the doubter as to the effect of penicillin on the blood 
and spinal fluid, we reproduce here serial spinal fluid 
and blood observations of 6 patients, 3 with late con- 
Table 1.—Penicillin Investigation: Late and Miscellaneous 
Syphilis; Distribution of Material by Source, Duration of 
Observation and Diagnosis 
Duration of Observation 
Immediate :r 
A 
Less Than 
20-59 
60-99 
100-139 
140-214 
Total 
Diagnosis 
20 Days 
Days 
Days 
Days 
Days 
Cases 
Paresis and taboparesis... 
11 
22 
15 
4 
4 
56 
Tabes, including primary 
optic atrophy 
6 
8 
5 
2 
1 
22 
Meningovascular neuro- 
syphilis 
6 
3 
3 
3 
1 
16 
Asymptomatic neuro- 
syphilis 
2 
13 
8 
1 
4 
28 
Benign late skin and bone 
4 
8 
3 
0 
6 
21 
Interstitial keratitis 
0 
5 
3 
3 
2 
13 
Iritis 
0 
2 
1 
0 
1 
4 
Miscellaneous 
4 
6 
5 
6 
1 
22 
Total 
182 
Clinic sources 
Bellevue 
1 
3 
1 
0 
0 
5 
Boston 
8 
8 
0 
0 
0 
16 
Johns Hopkins 
9 
23 
10 
2 
8 
52 
Mayo 
7 
3 
6 
1 
4 
21 
Michigan 
6 
2 
1 
0 
0 
9 
New York Hospital 
1 
10 
5 
0 
0 
16 
Pennsylvania 
1 
18 
20 
16 
8 
63 
Totals 
33 
67 
43 
19 
20 
182 
Table 4.—Penicillin Treatment• Series 1 in Case 3; Total 
Dose 1,200,000 Units 
Cerebrospinal Fluid 
After 
Penicillin, 
Quantitative 
Kline 
C. S. F. 
Wassermann 
Pays 
(Blood) 
Cells 
(Kolmer) 
Protein 
Mastic 
0 
16 units 
29 
0123 
3 plus 
443221000C 
13 
12 
0012 
2 plus 
2211000000 
76 
2 
10 
0112- 
1 plus 
3211000000 
Table 5.—Penicillin Treatment Series 2 in Case 2; Total 
Additional Dose 1,200,000 Units 
reduction in cells and protein and in intensity of both 
colloidal and complement fixation tests; grade 5, return 
to normal. 
In grouping improvements, grades 1 and 2 together 
were rated as slight, grades 3, 4 and 5 together as 
definite improvement. Improvement as a whole, how- 
ever, included grades 2, 3, 4 and 5. 
Cerebrospinal Fluid 
After 
Quantitative 
' 
C. S. F. 
Penicillin, 
Kline 
Wassermann 
Days 
(Blood) 
Cells 
(Kolmer) 
Protein 
Mastic 
104 
16 units 
ll 
0112 
20 mg. 
2211100000 
164 
Less than 1 
5 
0012 
20 mg. 
2211000000 
Table 6.—Penicillin Treatment Series 1 in Case 5; Total 
Dose 1,200,000 Units 
Table 2.—Blood Serologic Response to Penicillin 
Cerebrospinal Fluid 
After 
Quantitative 
' 
C. S. F. 
Penicillin, 
Kline 
Wassermann 
Days 
(Blood) 
Cells 
(Kolmer) 
Protein 
Mastic 
0 
128 units 
22 
1244 
4 plus 
1333320000 
19 
16 
8 
1244 
3 plus 
4431100000 
55 
32 
4 
0012 
Plus-minus 
2221000000 
86 
64 
3 
0123 
,30 
2221100000 
111 
64 
1 
0124 
50 
2211000000 
Herxheimer 
Improved 
Improve- 
Type of 
or Provoca- 
But Not to 
Reduced to 
ment 
No 
Syphilis 
tive Effect 
Negative 
Negative 
Temporary Change 
Late (96 cases) 
20 
33 
10 
13 
25 
Table 3.—Cerebrospinal Fluid Changes Following Penicillin in 
107 Cases in Which Repeated Spinal Fluid Examinations 
Were Available at Some Time After Treatment 
Slight Improvement 
Definite Improvement 
Diagnosis 
Grade 1 
Cells 
or 
Protein 
Reduced 
Grade 2 
Cells 
and 
Protein 
Reduced 
Grade 3 
Cells 
Protein 
Colloid 
Reduced 
Grade 4 
Cells 
Protein 
Colloid 
and 
Wasser- 
mann 
Reduced 
Grade 5 
Return 
to No 
Normal Change Worse 
Paresis and 
taboparesis 
(42 cases)... 
6 
19 
4 
4 
0 
5 
4 
Tabes and 
meningo- 
vascular 
(25 cases)... 
4 
2 
4 
7 
0 
5 
3 
Asympto- 
matic 
(40 cases)... 
7 
5 
6 
9 
1 
G 
•0 
Total 
(107 cases).. 
17 
20 
14 
20 
1 
16 
13 
genital syphilis and 3 with acquired neurosyphilis. It 
is notable that these effects were secured with low 
intensity (type A) treatment in all but 1 case. 
CASE HISTORIES 
Case 3 (Pennsylvania).—A man aged 38, with acquired syphi- 
lis. Primary optic atrophy in tabes, with euphoria, possible 
taboparesis. Fields (fig. 2) showed sector defect suggesting 
arachnoiditic or retrobulbar neuritic episode. Original spinal 
fluid, cells 122, Kolmer Wassermann reaction 4444, Pandy 
4 plus, mastic 4442110000, improved to cells 29, Kolmer Wasser- 
mann reaction 0123, Pandy 3 plus, mastic 4432210000 by two 
Swift-Ellis treatments. After the first series of treatments 
with penicillin (table 4) the patient began to lose ground 
visually, with slight confusion and increased euphoria. The 
second series of treatments (table 5) resulted in definite improve- 
ment in fields, acuity and mental state. 
Case 5 (Pennsylvania).—A man aged 24 with congenital 
syphilis with typical stigmas, asymptomatic neurosyphilis, pre- 
viously treated with forty arsenical and forty bismuth injec- 
tions, was given the treatment outlined in table 6. He was 
retreated twenty-eight days later with the results shown in 
table 7. 
In a total of 107 cases which had had one or more 
spinal fluid examinations after completion of penicillin 
therapy, it appears that 78 cases showed some degree 
of improvement in spinal fluid findings, 43 slight and 
38 Case 11 (Pennsylvania).—A man aged 18 with congenital 
syphilis discovered at age 6 and treated with thirty neoarsphen- 
amine injections a year for eleven years showed typical 
stigmas, neurologic signs, including Argyll Robertson pupils, 
anisocoria, partial ptosis of the left eyelid, weakness of the 
left seventh nerve and sluggish reflexes. He was given the 
treatment outlined in table 8. The ptosis disappeared under 
penicillin. 
Case 8 (Pennsylvania).—A woman aged 41 with acquired 
asymptomatic neurosyphilis discovered in blood donation, without 
symptoms or previous treatment, was given penicillin with the 
results shown in table 9. 
Case 29 (Pennsylvania).—A woman aged 29 with acquired 
neurosyphilis experienced sudden diminution of vision, advanced 
primary optic atrophy. Previous treatment, 1935-1939, con- 
sisted of eighteen arsphenamine and thirty-six bismuth injec- 
tions. Treatment with penicillin (table 10) resulted in no 
improvement in fields or acuity: right eye 20/400, left eye 
20/300. 
Case 50 (Pennsylvania).—A man aged 25 with congenital 
syphilis, showing typical stigmas and asymptomatic neuro- 
syphilis, had been treated with sixty-two injections of neo- 
100 per cent, the last representing practically complete 
restoration to normality. 
Of 56 cases of paresis and taboparesis, 10 presented 
no adequate classification data. Of the 46 remaining 
cases 30 were classified as simple demented, of which 
Table 9.—Penicillin Treatment Series 1 in Case 8; Total 
Dose 1200,000 Units 
Cerebrospinal Fluid 
After 
Quantitative 
C. S. F. 
Penicillin, 
Kline 
Wassermann 
Days 
(Blood) 
Cells 
(Kolmer) 
Protein 
Mastic 
0 
64 units 
103 
4444 
4 plus 
2444411000 
17 
8 
29 
1244 
2 plus 
2221100000 
46 
32 
11 
0012 
1 plus 
2211000000 
74 
32 
6 
0112 
30 
1111000000 
102 
32 
6 
0112 
40 
2211000000 
129 
8 
4 
0011 
30 
1111000000 
159 
32 
8 
0122 
30 
2211100000 
178 
16 
6 
0012 
30 
2221100000 
Table 7.—Penicillin Retreatment Series 2 in Case 5; Total 
Additional Dose 1200,000 Units 
Table 10.—Penicillin Treatment Series 1 in Case 29; Total 
Dose 1200,000 Units 
Cerebrospinal Fluid 
After 
Quantitative 
C. S. F. 
Penicillin, 
Kline 
Wassermann 
Days 
(Blood) 
Cells 
(Kolmer) Protein 
Mastic 
139 
61 units 
2 
0011 40 
2211000000 
164 
04 
4 
0011 20 
1110000000 
Cerebrospinal Fluid 
After 
Quantitative 
C. S. F. 
Penicillin, 
Kline 
Wassermann 
Days 
(Blood) 
Cells 
(Kolmer) 
Protein 
Mastic 
0 
64 units 
148 
4444 
30 mg. 
3331100000 
9 
64 
16 
1244 
30 mg. 
2221100000 
30 
32 
15 
0012 
30 mg. 
2221000000 
65 
64 
4 
0122 
20 mg. 
1111000000 
119 
32 
0 
0011 
20 mg. 
1111000000 
Table 8.—Penicillin Treatment Series 1 in Case 11; Total 
Dose 1200,000 Units 
Cerebrospinal Fluid 
After 
Quantitative 
C. S. F. 
Penicillin, 
Kline 
Wassermann 
Days 
(Blood) 
Cells 
(Kolmer) 
Protein 
Mastic 
0 
16 units 
32 
1244 
4 plus 
3332210000 
13 
4 
16 
0122 
1 plus 
2111000000 
32 
4 
8 
0011 
Pius-minus 
1111000000 
140 
Less than 1 
1 
0000 
30 mg. 
1110000000 
Table 11.—Penicillin Treatment Series 1 in Case 50; Total 
Dose 1200,000 Units 
Cerebrospinal Fluid 
After 
Quantitative 
C. S. F. 
Penicillin, 
Kline 
Wassermann 
Days 
(Blood) 
Cells 
(Kolmer) 
Protein 
Mastic 
0 
16 units 
96 
4444 
40 mg. 
2455555421 
8 
Negative 
21 
4444 
20 mg. 
4443210000 
36 
32 
12 
0124 
30 mg. 
2221000000 
arsphenamine and 102 injections of bismuth. Results of 
treatment with penicillin are shown in tables 11 and 12. 
Case 64 (Pennsylvania).—A man aged 37 with acquired 
syphilis, early paresis (?), showed sluggish pupils and lower 
cord reflexes and loss of memory. Previous treatment consisted 
of twenty-two mapharsen injections and nineteen bismuth injec- 
tions. 
SYMPTOMATIC RESULTS IN NEUROSYPHILIS 
Since there is a well recognized disparity between 
symptomatic and serologic response in neurosyphilis, 
and the symptomatic often outweighs the serologic 
aspect in importance for the patient, symptomatic 
responses secured by penicillin in neurosyphilis were 
next examined. Here it is important to give warning of 
misinterpretations due to Herxheimer and possibly ther- 
apeutic paradoxical effects from overintense initial treat- 
ment. It is notable that some patients who did badly 
at the start improved later and that top notch sympto- 
matic gains followed a low intensity system in some 
cases. 
Penicillin also has a favorable effect in general pare- 
sis. Three groups were made up from the material 
(conceding the inadequacy from the psychiatric stand- 
point due to record deficiencies) •: simple demented 
paresis (grades 1, 2 3) ; deteriorated paresis (grades 
1, 2, 3) ; progressive paresis (galloping and so on) 
and symptomatic exacerbation suggesting Herxheimer 
effect. Improvement was graded 25, 50 and 75 and 
Table 12.—Penicillin Retreatment Series 2 in Case 50; 
Additional Dose 1,200,000 Units 
Cerebrospinal Fluid 
After 
Quantitative 
C. 8. F. 
Penicillin, 
Kline 
Wassermann 
Days 
(Blood) 
Cells 
(Kolmer) 
Protein 
Mastic 
53 
Negative 
9 
0112 
30 mg. 
2221100000 
84 
16 units 
3 
0000 
20 mg. 
1111000000 
Table 13.—Penicillin Treatment Series 1 in Case 64; Total 
Dose 2,850,000 Units 
Cerebrospinal Fluid 
After 
Quantitative 
C. S. F. 
Penicillin, 
, Kline 
Wassermann 
Days 
(Blood) 
Cells 
(Kolmer) 
Protein 
Mastic 
0 
Less than 1 unit 
72 
4444 
40 mg. 
3555521000 
22 
00 
5 
0011 
20 mg. 
1111000000 
56 
00 
5 
0012 
20 mg. 
1111000000 
only 6 (20 per cent) failed to improve and 1 grew 
worse. Thirteen, or nearly half, improved 50 per cent 
or more, including 8 which improved 75 per cent and 
1 restored symptomatically to normal. Ten cases 
improved only 25 per cent. As might be expected 
39 deteriorated cases (10) made less response, 1 improv- 
ing 50 per cent, 2 75 per cent and 7 showing no change. 
The 1 patient with progressive or galloping paresis in 
Solomon’s service died and 1 of Moore’s simple 
demented patients died thirteen weeks after penicillin. 
We know of no record of spontaneous remission 
under the good effects of hospitalization which can 
3 with lightning pains of unusual severity plus 4 tabo- 
paretic patients with lightning pains who were grouped 
together with respect to this symptom. Of the 14 
tabetic patients 3 improved to the extent of 50 per 
cent or more, and 2 of them with lightning pains were 
relieved completely. Eleven tabetic patients showed 
no change. Of the patients with primary optic atrophy 
none were made worse, and 1 whose visual fields are 
shown (fig. 2) improved slightly but definitely in both 
fields and visual acuity, with concomitant improvement 
in the spinal fluid. There is some question as to whether 
the sector defect in the left field is not a residue of a 
retrobulbar neuritic process. Of the total of 7 patients 
with lightning pains, 2 were completely relieved, 1 
improved 50 per cent, 2 improved 25 per cent, 1 was 
unchanged and 1 became worse. 
Of 16 patients with various forms of meningovascular 
neurosyphilis, 6 presented no data on clinical improve- 
ment. Of the remaining 10, clinical improvements of 
75 per cent were observed in 2, 50 per cent in 2 and 
25 per cent in 2, with 3 showing no change and 1 
becoming worse. 
It is of course difficult to evaluate symptomatology 
into which elements of the subjective and the influence 
of suggestion, rest, practice (as in eye and station and 
gait tests) enter. The intervention of trifling or routine 
medication (as in the eye, for example) with improve- 
ment found to have begun before penicillin, and hence 
Fig. 1.—Improvement in handwriting of a simple demented paretic 
patient approximately six weeks after penicillin treatment. The signature 
before treatment is given above the word “penicillin” (courtesy of George 
D. Gammon, M.D.). 
approach this. The transformations in orientation, 
speech, handwriting and encephalographic findings will 
be more fully presented from the University of Penn- 
sylvania material in objective form by George D. Gam- 
mon, M.D., in a forthcoming paper. From the collected 
records, however, two brief summaries are given: 
A white woman aged 34 with symptomatic paresis, grade 4 
cerebrospinal fluid, could not write or do housework. She 
had auditory hallucinations, personality changes, disorientation, 
tremor of the tongue, hands and mouth, and slurred speech. On 
th’e second day of penicillin therapy she had a Herxheimer 
reaction with right-sided convulsions becoming generalized. 
After twenty-four hours penicillin was reinstituted at half dose 
to a total of 1,200,000 units without untoward effect. By the 
sixteenth day the patient was completely oriented, with memory, 
speech, tremor and electroencephalogram improved. In four 
months the patient was tremor free, speech and writing were 
normal (fig. 1), she was well oriented and hallucination free 
and was satisfactorily performing housework including market- 
ing with points and driving a car. Clinical improvement was 
not accompanied by improvement in the spinal fluid. 
A white man aged 42 with symptomatic paresis developed 
mispronouncing of words, garbled speech, uncertain gait, tremor 
of hands and difficulty in writing in August 1943, when a shell 
exploded near him. Forty-eight arm and hip injections were 
given. He became boastful, speech rambled and tremors were 
more pronounced; handwriting was worse and calculation poor. 
His condition was unimproved during hospitalization after 
50,000 Oxford units per dose of penicillin to a total of 4,000,000 
units. Clinical improvement occurred three weeks after peni- 
cillin with loss of tremors, improved handwriting and speech. 
He passed an examination as a pipe fitter. Improvement in 
the cerebrospinal fluid did not accompany clinical improvement. 
The neurologist considered him mentally improved but not 
to the original level. 
Combining all types of clinically diagnosed paresis 
and taboparesis, exclusive of 10 patients treated with 
intraspinal or intravenous penicillin or malaria and thus 
totaling 46 cases, 15 failed to improve, 12 improved 
25 per cent, 6 improved 50 per cent, 10 improved 75 
per cent, 1 recovered and 2 died. Of 22 patients with 
tabes dorsalis, 14 presented data sufficient for inter- 
pretation, including 7 with primary optic atrophy and 
Fig. 2.—Visual fields in case 3, Pennsylvania Penicillin Series, showing 
improvement with decrease in sector defect. 
perhaps merely spontaneous or progressive, must be 
interpreted by long periods of observation. Symptoma- 
tology which is highly complex and of uncertain origin, 
such as lightning pains, in which the influence of the 
penicillin on other infective backgrounds may play a 
part, must be interpreted at this stage with reserve. 
There seems, however, to be a favorable trend in the 
40 evidence pointing to genuine and indeed rapid good 
effect on the disease process, supported by such objec- 
tive detail as handwriting change, encephalograms, dis- 
appearance of ptosis and of violent headache associated 
with meningitis. Coupled with the objective changes 
in the spinal fluid, such evidence would seem to deserve 
great weight. It is, however, unreasonable to expect 
penicillin to restore degenerations and replace neurons. 
EFFECT OF TREATMENT SYSTEM 
In this material the lack of system in dosage and time 
intervals reduced the number of cases per recognizable 
system below statistically usable levels, especially when 
viewed in relation to duration of observation. Some 
cases were jumbles of methods and had to be discarded. 
There were no blood level determinations, and in 3 
Mayo Clinic cases spinal fluid penicillin determinations 
were repeatedly negative. Accordingly, only a study 
of type A versus type B treatment was attempted, type 
A representing 1,200,000 units or less, usually at 25,000 
units every three to four hours, and type B 2,400,000 
units to 4,000,000 units or more at 25,000 to 50,000 
every two to four hours. Offhand there was no strik- 
spinal fluids and completely achieve them on retreat- 
ment with a similar dosage, a steplike method of 
successive moderate applications of treatment as distin- 
guished from a single massive session would seem to 
deserve further study. Pushing the patient over the 
hump, so to speak, to a partial self cure is a recognized 
principle in dealing with some aspects of late neuro- 
syphilis. 
Serologic response on the blood occurred in 45 per 
cent of the type A or smaller dose treatment cases, and 
in 43 per cent of the larger dose or type B cases. Longer 
observation periods for tbe type B cases would probably 
demonstrate a superior effect. 
PENICILLIN RESPONSE IN RELATION TO 
INFLAMMATORY ACTIVITY 
Using the cell count and the spinal fluid as a guide 
and rating 0 to 20 as low, 21 to 60 as medium and 61 
and above as high cell counts, an attempt was made to 
see whether improvement was greater in cases showing 
a high cell count as an index of definite inflammatory 
activity in comparison to those showing low cell counts. 
With cell counts rated as high, improvement occurred 
Table 14—Effect on Spinal Fluid of Type A (Small Dose) 
Versus Type B (Larger Dose) Treatment 
Grade of Response 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
No Change 
Worse 
Type of Neurosyphilis 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
Paresis and taboparesis 
1 
5 
2 
15 
1 
2 
3 
1 
0 
0 
1 
3 
1 
2 
Tabes 
3 
0 
1 
0 
1 
2 
2 
0 
0 
0 
5 
1 
0 
Meningovascular 
0 
2 
1 
1 
1 
3 
3 
0 
0 < 
0 
0 
0 
0 
1 
Asymptomatic 
6 
2 
3 
1 
5 
4 
5 
1 
0 
3 
3 
6 
0 
Grade totals 
16 
5 
20 
3 
11 
12 
8 
1 
0 
4 
11 
8» 
3 
Total type A 
36 
36 
36 
36 
36 
36 
Total type B 
69 
69 
69 
69 
69 
69 
69 
* Four of these patients 
had benign gummas 
healing 
under 
penicillin 
at a wholly 
inadequate dosage for neurosyphilis 
—less than 
600,000 
units. 
Grade 1 and 2 (slight) improvements occurred 
in 
22 per cent of type A 
and 52 
per cent 
of type B eases. 
Grades 3, 4 and 5 (definite) improvement 
occurred in 
16 of 
36 cases 
(44 per cent) 
on 
type A treatment 
and 19 
of 69 
cases (27.4 
per cent) on 
type B treatment. 
- 
Grades 2, 3, 4 and 5 improvement occurred 
in 
60 per cent 
of the 
type A 
and 56 per cent of 
the type B eases. The periods of 
observation. 
however, were longer in the 
smaller dose treatment 
cases—e. g. 
, paresis. 
over sixty days in type A; 
less than sixty days in all but 5 in type B cases. 
ing difference recognizable between the effect of shorter 
time intervals or larger doses except the induction of 
Herxheimer reactions, which could be avoided by reduc- 
tion in the dosage of the first twenty-four to forty-eight 
hours. The analysis of the case material on which 
treatment information was sufficiently complete for 
classification, comprising 105 cases, is given in tables 
14 and 15. 
It must be clearly recognized that such figures as 
these do not provide for trustworthy therapeutic inter- 
in 11 of 31 cases; with those rated as medium, in 13 of 
28 cases; in those rated as low, in 7 of 45 cases. It 
appears that the proportion of improvement is highest 
in patients with medium and high cell counts in the 
order named and lowest in patients with low cell counts. 
If all cell counts above 20 are rated as high, improve- 
ment occurs in 24 of 59 cases in the higher cell count 
brackets (40.6 per cent) and in 7 of 45 in the low cell 
count bracket (15.5 per cent). Considering the small 
numbers of cases and the arbitrary division lines, the 
figures cannot be more than suggestive that, as has been 
previously indicated, a low cell count has a less favor- 
able prognosis under penicillin treatment than a high 
cell count. 
influence of previous (arsenic, heavy metal) 
TREATMENT ON PENICILLIN RESPONSE 
An analysis of 100 cases of neurosyphilis with data 
on this matter yielded the results shown in table 16. 
The results in this case included grade 1 as well as 
grades 2, 3, 4 and 5. The type of previous treatment 
approximated the captions given, the first numeral rep- 
resenting arsenical, the second heavy metal injections. 
Almost equally good results in the spinal fluid were 
achieved by penicillin after no previous treatment and 
intensive (40-80) routine treatment. There is at least 
no intimation that previous fever therapy prepared the 
Table IS.—Degree of Cerebrospinal Fluid Improvement 
Number 
Moderate to 
Type of 
of 
Slight, 
Definite, 
No Change 
Treatment 
Cases 
Grade 1, 2 
Grades 3, 4, 5 
or Worse 
Type A 
36 
8 (22.2%) 
16 (44.4%) 
12 (33.3%) 
Type B 
68 
35 (51.4%) 
19 (27.9%) 
14 (20.5%) 
pretations. It is particularly in point that the obser- 
vation periods on the type B (larger dose) treated 
cases are shorter than those of type A and that a longer 
observation period may demonstrate a greater efficiency 
of larger dosage. On the other hand, it is also sug- 
gested that in late neurosyphilis good effects may be 
secured by less than the maximum dosage so far 
employed. If patients treated with 1,200,000 units in 
asymptomatic neurosyphilis can achieve almost normal 
41 patients for striking penicillin results. The many qual- 
ifications on such an analysis with regard to selection, 
time of observation and so on must be recalled, but 
there is at least no strong evidence that in the aggregate 
previous standard treatment adds anything to the peni- 
cillin result. 
PENICILLIN IN OTHER ASPECTS OF LATE SYPHILIS 
Gummatous lesions of skin and bones (21 cases) 
respond so invariably and completely, with 13 results 
rated 100 per cent, 2 at 75 per cent, 4 questionable 
and only 2 failing of improvement (thirty-six and sixty- 
eight days), that little further clinical interest attaches 
to the group beyond speculation as to the part played 
by penicillin in clearing the secondary, usually hemo- 
lytic pyogenic infective invasion as distinguished from 
the syphilis as such. The control of destructive lesions 
of the palate and septum seems satisfactory. The fail- 
ures include one suspected gumma of the orbit, diagnosis 
not established. The dosage required for symptomatic 
improvement ranges about 300,000 units, the time for 
healing from twelve to forty-six days. Carcinoma as 
a complication or a diagnosis must be watched for 
under 1,200,000 units. One of McDermott’s patients, 
a fever failure, received a total of 4,845,000 units in 
two courses without results. Thomas secured improve- 
ment in a case on 4,000,000 units over twenty-five days, 
20,000 units every three hours. Moore has excellent 
serial color photographs of a favorable case. One 
of his cases likewise improved on 3,970,000 units in 
twenty-one days, observed for one hundred and fifty- 
nine days. 
OTHER EYE LESIONS 
Two cases of optic neuritis on 2,000,000 and 3,000,000 
units both showed improvement; O’Leary’s case 
improved 100 per cent on retreatment. Two cases of 
iritis improved 100 per cent, but 1 relapsed and required 
an iridectomy for beginning glaucoma, after failing to 
respond to retreatment. 
EIGHTH NERVE DEAFNESS 
Eighth nerve deafness, beginning in a woman of 
31 with undoubted stigmas of congenital infection, 
improved somewhat though not definitely on 1,200,000 
units. There was a suggestion of Herxheimer-like drop 
in hearing at the outset followed by improvement, but 
the interpretations are complex. Two other cases, 
already far advanced, failed to improve. 
MISCELLANEOUS CASES 
A scattered group of cases, on which information 
is incomplete, includes bone-liver combinations, hepato- 
splenic complexes, seroresistance (Wassermann fast- 
ness) already discussed, Charcot hip and gangrenous 
balanitis in a syphilitic patient. The Charcot hip did 
not improve, and a suspected Charcot ankle is develop- 
ing since penicillin. The gangrenous balanitis healed 
with the loss of less than a third of the corpus spon- 
giosum on 300,000 units at about the rate to be expected 
of a late syphilid. The patient became seronegative. 
The livers of 2 patients undoubtedly enlarged (late 
cases) after treatment and the blood bilirubin increased 
in 1, then subsided, 
REACTIONS TO PENICILLIN 
Penicillin is not a reactionless drug. The disposition 
to pour it about like water in syphilis may lead to 
serious trouble, especially from therapeutic shock and 
possibly also from therapeutic paradoxical effects. The 
former is important under the usual rule that an active 
syphilitic process in a vital structure may be gravely 
and even fatally damaged by the impact of a large dose 
or series of doses at the start of treatment. Most 
Herxheimer effects, however, seem controllable by 
reduction in dosage for the first twenty-four to forty- 
eight hours of an eight day series without loss of 
ultimate effect. There is some question whether there 
are not delayed Herxheimer effects such as are sug- 
gested by spinal fluid and blood serologic curves and 
the initially unfavorable but ultimately favorable course 
of some lesions (eye, nervous system, for example). 
Of 182 cases 43 (24 per cent) had reported reactions 
interpretable as Herxheimer or therapeutic shock 
effects. Of these 23 were fever, highest 105.5 F. The 
blood reagin titer increased definitely and then sub- 
sided in 7 cases. In 4 Pennsylvania cases symptoms 
interpreted as Herxheimer effects in the nervous system 
included transverse myelitic symptoms in 1 case, Jack- 
sonian convulsions lasting twelve hours in another, 
exacerbation of lightning pains, mania and hallucina- 
tions. 
Table 16,.—Spinal Fluid and Clinical Improvement in Neuro- 
syphilis After Penicillin Treatment in Relation to Previous 
Treatment 
Type of 
Previous Treatment 
Clinical Improvement 
Grade 1 and Over 
Occurred in: 
Spinal Fluid 
Grades 1, 2, 3, 4, 5 
Occurred in: 
No treatment 
Little treatment 
20 arsenic, 20 heavy metal. 
40 arsenic, 80 heavy metal. 
Fever therapy 
16 of 32, or 50 per cent 
9 of 23, or 39 per cent 
7 of 16, or 48 per cent 
5 of 16, or 30 per cent 
1 of 13, or 7 per cent 
28 of 32, or 87 per cent 
16 of 23, or 69 per cent 
9 of 16, or 56 per cent 
13 of 16, or 81 per cent 
5 of 13, or 46 per cent 
even if improvement occurs. Concomitant neurosyphi- 
lis was identified in 12 of the 21 cases. Serologic 
improvement (titer reduction) in the blood occurred 
in 14 of 21 cases. 
The paradox of gummatous skin and bone lesions 
healing as the spinal fluid became “worse” (possible 
Herxheimer effect?) was noted in 3 of 10 cases. 
LATE CONGENITAL SYPHILIS 
The interest in this group centers on interstitial kera- 
titis. The neurosyphilitic involvements were reviewed 
with neurosyphilis (see cases 5, 11 and 50). The 
complexity of interstitial keratitis and the eccentricities 
of its behavior are apparent under penicillin as under 
standard treatment. It was difficult to dissuade those 
in charge of some patients to withhold fever and other 
treatment if the patient did not immediately and strik- 
ingly improve. Patients with pronounced corneal and 
other ocular damage were included and too much was 
expected in the way of results. Of 14 cases 6 showed 
improvement, 3 of grade 4 on a scale of 1, 2, 3, 4, 1 of 
grade 3 and 2 of grade 2. Six showed no improvement 
and in 2 the condition was definitely worse. When 
improvement occurred it was apt to be dramatic. One 
patient previously given chemotherapy and fever ener- 
getically without result was given 1,200,000 units in 
eight days. He was relieved of photophobia by the 
third day and returned to work a week after penicillin 
for the first time in many months. He has remained 
well, improvement continuing up to the stage of sta- 
tionary residue. Another improved grade 4 and one 
hundred and four days after penicillin flared and recov- 
ered again without further treatment. A persistently 
seronegative congenital syphilitic patient with character- 
istic stigmas made no response and in fact became worse 
42 Other reactions to penicillin included urticaria (2 
cases) and 1 each of “allergic reaction,” “id” reaction, 
burning of the skin, profuse sweating and phlebitis 
(intravenous injection). Two patients had sharp gas- 
trointestinal reactions. 
SUMMARY 
From a material of 182 cases of late syphilis pre- 
ponderantly neurosyphilis (122 cases) and including 
benign gummatous syphilis, ocular and other forms of 
syphilis and late congenital syphilis, observed from eight 
to two hundred and fourteen days after the penicillin 
therapy was begun on a wide range of time-dosage 
schedules, the following tentative observations are sum- 
marized : 
1. The lesions of benign gummatous syphilis of skin 
and bones heal under a dosage of approximately 300,000 
units in twelve to forty-six days. 
2. Irrespective of the system used, and in all types 
of syphilis, pencillin causes reduction of syphilitic reagin 
titer in the blood in from 50 to 60 per cent of late cases. 
An initial “Herxheimer”-like or provocative rise is 
observed in about 20 per cent of cases. Only 5 sero- 
resistant cases were treated, 1 made negative, 4 
improved. 
3. The abnormal spinal fluid in neurosyphilis is 
improved in 74 per cent to some degree, definitely in 
33 per cent. The commonest change is a drop in cell 
count and total protein (grade 2 improvement on a scale 
of 5) occurring in 67 per cent of cases. One spinal 
fluid was rendered normal within the observation period. 
All four fluid findings improved in 25 per cent of the 
cases of asymptomatic neurosyphilis, 10 per cent in 
paresis and taboparesis. 
4. Symptoms improved in neurosyphilis as follows : 
Simple demented paresis; In 30 cases on which data 
were adequate for classification, 80 per cent improved 
to some degree; nearly half improved 50 per cent or 
more, including 8 who improved 75 per Cent and 1 
restored to normal. Deteriorated paresis: Two of 10 
improved 75 per cent, 1 50 per cent, 7 no change. 
Tabes dorsalis: One fifth of 14 cases improved 50 
per cent or more. Of 7 with lightning pains, 2 were 
completely relieved. 1 improved 50 per cent, 2 improved 
25 per cent, 1 unchanged and 1 worse. Of 7 cases of 
primary (?) optic atrophy, mostly advanced none were 
made worse, 1 improved. In meningovascular neuro- 
syphilis 40 per cent improved 50 to 75 per cent. 
5. Two attempts at statistical evaluation were made: 
One, of the influences of smaller dose as contrasted 
with larger dose treatment and the other, of the response 
under penicillin of spinal fluids with low as contrasted 
with relatively high cell counts, because of small num- 
bers of cases and unavoidable disparities in observation 
period, cannot be accepted as beyond challenge. They 
suggest respectively that in late syphilis, especially 
neurosyphilis, smaller doses, if not grossly inadequate, 
have good effects which may perhaps be improved by 
repetition, as compared with the effects of initial larger 
dosage, the effect being due perhaps to stimulation or 
utilization of the patient’s resistance and defensive 
responses. The figures on response in relation to cell 
count suggest that moderate and high cell count cases 
tend to react somewhat better than cases giving low 
cell counts. 
6. Previous treatment for syphilis by older methods 
in neurosyphilis, including fever therapy, does not 
appear to prepare patients for superior results with 
penicillin. 
7. In late congenital syphilis, interstitial keratitis 
presents rather equivocal though at times dramatically 
favorable results, not as yet interpretable in relation 
to a time-dosage system. Of 14 cases 6 improved, 3 
to 100 per cent, 1 to 75 per cent, 2 to 50 per cent. Two 
were made definitely worse. 
8. Optic neuritis included 2 cases, both improved, 
the second 100 per cent on retreatment. Two cases 
of iritis improved 100 per cent _ at the start, but 1 
relapsed and did not respond to retreatment (glau- 
coma). 
9. Two cases of eighth nerve deafness gave equivocal 
results. 
10. Of miscellaneous cases, Charcot joint was unaf- 
fected (a new one developing) ; gangrenous balanitis 
was cured by low dosage. 
11. Therapeutic shock (Herxheimer) effects are 
undoubted, may be serious in late syphilis and should 
be guarded against by reduced dosage during the first 
twenty-four to forty-eight hours. Severe cerebral and 
cord symptoms may develop in neurosyphilis. 
Reactions to penicillin as such are few and not serious, 
urticaria, itching, allergic skin reactions and a sharp 
gastrointestinal reaction following the course. 
12. It is suggested that, because of the great difficulty 
in developing uniform records for statistical or punch 
machine evaluation in late syphilis, further investigation 
of its behavior under penicillin therapy be committed 
to individual competent investigators who can apply 
the principles of uniformity of treatment and record 
evaluation simultaneously with appropriate individuali- 
zation of the particular case. The durability of the good 
effects thus far observed, the possibility of complica- 
tions from induced allergic response and disturbance 
of the immunity balance of the individual in latent and 
late syphilis remain to be explored by larger experience 
and longer periods of observation. 
ABSTRACT OF DISCUSSION 
ON PAPERS OF DRS. MAHONEY, ARNOLD AND STERNER AND 
MESSRS. HARRIS AND ZWALLY, OF DRS. MOORE AND MAHONEY, 
COMMANDER SCHWARTZ, LIEUTENANT COLONEL STERNBERG 
AND DR. WOOD, AND OF DR. STOKES, LIEUTENANT COLONEL 
STERNBERG, COMMANDER SCHWARTZ AND DRS. MAHONEY, 
MOORE AND WOOD 
Lieutenant Commander E. E. Barksdale, MC-V(S), 
U.S.N.R.: As of June 1, 1944 we have treated 161 cases of 
syphilis with penicillin. Twenty-nine were seronegative, dark 
field positive, primary syphilis, clinically cured and are still 
seronegative to date. Eighty were seropositive, dark field 
positive primaries. Of this group 2 relapsed within approxi- 
mately three weeks after treatment was started. The lesions 
recurred in the same location and again became dark field posi- 
tive. One of this group healed, becoming seronegative, and then 
acquired a new infection with a dark field positive chancre in 
a different location from the previous one. We have treated 
31 cases of secondary syphilis. All the cases were treated on 
a dosage of 1.2 million units intramuscularly, i. e. 20,000 units 
every three hours for sixty injections. By determining quanti- 
tative blood penicillin levels on these patients treated with intra- 
muscular injections every three hours, we found that it was 
impossible to maintain a constant penicillin level, and indeed for 
one third of the time there was no penicillin detected in the 
blood by the test used. This made us think that the continuous 
intravenous drip method might be the procedure of choice. To 
date we have treated 11 cases of syphilis by this method, giving 
a total of 2,080,000 units of penicillin in nine days. With this 
we were able to maintain a more or less constant blood penicil- 
lin level approximately ten times higher than that which could 
be obtained by the intramuscular route. We have had no 
43 relapses, no central nervous system involvement and no case 
has retained a positive serologic reaction as yet beyond the 
fourteenth week. To date we have treated 7 cases of syphilis 
with the usual routine of fever therapy but substituting for 
mapharsen 60,000 units of penicillin intravenously each time 
they were in the fever cabinet. In addition and over the same 
period of time we gave each patient 20,000 units of penicillin 
intramuscularly every three hours until a total of to 4 
million units had been given. It is our impression that this 
method is superior to the one which we had formerly used. I 
am of the opinion at the present time that penicillin is the best 
drug we have ever had for the treatment of syphilis. I think 
that it is possible that the intravenous method of administration 
may be superior. We have had 1 case of primary syphilis 
treated intramuscularly with 1.2 million units, which ended 
fatally ten days after the completion of treatment, of a sub- 
dural hemorrhage which was not related to either the syphilis 
or the treatment. Pathologic examination of body tissues with 
special stains failed to reveal any spirochetes. At autopsy 
therefore this 1 case within ten days after treatment gave no 
pathologic evidence of syphilis. 
Captain William Leifer, M. C., A. U. S.: The experi- 
ence at Fort Bragg now comprises 116 patients treated for 
syphilis with penicillin. One hundred received 1,200,000 units 
and 16 received 2,400,000 units in seven and one-half days 
(technic sixty consecutive intramuscular injections of 20,000 or 
40,000 units at three hour intervals). Reactions were infrequent 
and inconsequential: there were 3 instances of urticaria, 1 of 
erythema multiforme, 2 of generalized pruritus and 7 of herpes 
simplex. Focal and systemic Herxheimer reactions appeared on 
the first day of treatment in 87 per cent of the patients. Only 
those who received 1,200,000 units and who have been followed 
at least three months are being reported. Ten patients began 
treatment in the seronegative primary phase and 12 in the sero- 
positive primary phase. Four have been observed over six 
months, of whom 3 are seronegative, while the fourth has a 
doubtful Kahn reaction. All 4 had negative spinal fluids at 
six months. The remaining 18 patients have been followed 
from three to six months, and all but 1 are seronegative. Thus, 
20 of the 22 cases of primary syphilis have achieved or main- 
tained seronegativity. Twenty-five patients began treatment in 
the secondary stage of syphilis. Two have exceeded six months 
of observation; 1 is seronegative and the other has a'doubtful 
Kahn reaction. Both had negative spinal fluids at six months. 
The remaining 23 patients have been followed between three 
and six months; of these, 11 are seronegative, 9 still have some 
degree of positivity of the blood and 3 are definitive failures. 
Two failures appeared as neurologic relapses (1 with mono- 
plegia, the other with acute syphilitic meningitis) with strongly 
positive spinal fluid; the spinal fluid had been negative in both of 
these immediately before administration of penicillin. The third 
failure was a cutaneous and serologic relapse. Thus, of 25 
cases of secondary syphilis 12 are seronegative, 10 are still 
seropositive and 3 are outright failures. It would seem best to 
use higher doses than might now appear necessary in the treat- 
ment of syphilis. The future may reveal the need not only for 
an increase dosage but also for prolongation of the treatment 
period beyond the present seven and one-half days. Thus far 
the results have been extremely encouraging, but mass treat- 
ment of syphilis with penicillin should be delayed until the 
optimal treatment schedule is determined. 
Commander Frank A. Ellis, Corpus Christi, Texas: I 
should like to give you some of the highlights of the experience 
with penicillin starting in New Zealand in Wellington and 
extending up to Corpus Christi. An enlisted man with acute 
infectious jaundice, after being in the hospital five days, devel- 
oped an acute gonococcic urethritis. His icterus index was 45, 
and we gave him it cured his gonorrhea, and his 
icterus index was brought down to 0.5. Penicillin might cure 
acute jaundice or acute infectious jaundice, as we designate it 
in the Navy. Our results in probably 450 cases of acute gono- 
coccic urethritis have been 100 per cent effective, with this 
exception: We had 2 cases in which acute epididymitis devel- 
oped three days after administration of 100,000 units of penicil- 
lin. On those we immediately repeated the therapy and gave 
them 200,000 units until the smears, urine culture and prostatic 
cultures were negative. My impression is that it certainly 
shortens the course of acute epididymitis. Our results have 
been most disappointing in penicillin therapy for nonspecific 
urethritis. With syphilis I have had no experience whatever 
except this, that I want to caution you about intraurethral 
chancre being masked in acute gonorrhea. If patients are given 
100,000 units, the dosage will be inadequate. 
Colonel Udo J. Wile, U. S. P. H. S.: It is too much to 
expect of penicillin at this time more than has been graphically 
told by the authors. We should accept these facts with the 
possibility that in time the organisms may elaborate for them- 
selves a certain degree of resistance to penicillin. When we 
can speak in terms of thousands instead of terms of hundreds, 
we may have more relapses and more recurrences and possibly 
more reactions. It is, however, a great relief to those of us 
who have for years felt that we were using dangerous drugs 
in the treatment of syphilis to find something at least that 
departs from heavy metals that gives a high index of therapeutic 
effectiveness and apparently a low toxicity. 
Dr. Joseph E. Moore, Baltimore; I close on the same 
restrained note of optimism which has been voiced to you here. 
I don’t think that penicillin is ready for mass application. I 
do feel that our attitude ought to be one of hopefulness, but 
with complete understanding that we are still in the process of 
learning how to use the drug. We don't know yet, and it is 
going to be some time before we are sure. 
SYPHILIS 
44 but this approach to the prevention of congenital syphilis 
is not generally accepted.5 It is relatively toxic and 
must be considered dangerous in routine medical prac- 
tice and a questionable choice even under ideal circum- 
stances. One of the extremely difficult public health 
and social problems in this field has been the post- 
partum observation of the mother for syphilis.6 A drug 
which would be curative during the pregnancy of both 
mother and child is to be wished for. 
3. Although several short series of cases appear in the 
medical literature in which 100 per cent normal infants 
have resulted from adequate arsenotherapy of the syph- 
ilitic pregnant woman,7 larger series show a definite 
residuum of syphilitic infants sometimes in spite of 
ideal therapy.8 This is usually in the neighborhood 
of 5 to 8 per cent diseased infants if the treatment has 
approached accepted adequacy. Particularly difficult 
cases for intravenous arsenotherapy are those in which 
treatment is not commenced until the latter months of 
the pregnancy, particularly if the expectant mother is 
in the early stages of her disease.9 Under such circum- 
stances a very high percentage of infants are syphilitic 
in spite of therapy. This problem is bound to the perme- 
ability of the placenta, to the arsenobenzene derivatives 
and to the effectiveness of the uncertain quantities .of 
the drug which do pass from the mother to the child 
after the fetus in utero has been infected.10 In such 
instances the placental membrane must be traversed 
by a curative dose of the drug if a normal infant is to 
be born. An effective spirillicide which will readily 
traverse the placenta is still to be hoped for. 
4. Three principal factors still complicate the treat- 
ment of infantile congenital syphilis. They are the 
extreme caution with which therapy must be inaugu- 
rated when the disease is manifest,3 the prolonged 
course of treatment essential to cure 11 and again the 
residue of patients who are not cured by arsenotherapy 
and bismuth, a proportion which increases rapidly with 
the age of the infant at the time treatment is begun. 
In addition, the treatment of the syphilitic pregnant 
woman and, more than this, the observation of the 
treated syphilitic woman who subsequently becomes 
pregnant are both critical experiments in the testing 
of the effect of the new drug. Since the fetus is inti- 
mately associated with the mother and is almost uni- 
formly infected if the maternal syphilis is active and 
untreated, these circumstances give the counterpart in 
the human being of the inoculation test of cure in the 
rabbit or other experimental animal. In the woman the 
PENICILLIN IN THE PREVENTION 
AND TREATMENT OF CON- 
GENITAL SYPHILIS 
REPORT ON EXPERIENCE WITH THE TREATMENT OF 
FOURTEEN PREGNANT WOMEN WITH EARLY SYPHILIS 
AND NINE INFANTS WITH CONGENITAL SYPHILIS 
J. W. LENTZ, M.D. 
NORMAN R. INGRAHAM Jr., M.D. 
HERMAN BEERMAN, M.D. 
AND 
JOHN H. STOKES, M.D. 
PHILADELPHIA 
The treatment of the pregnant syphilitic woman and 
of the congenitally syphilitic infant with weekly injec- 
tions of neoarsphenamine or mapharsen supplemented 
by a bismuth preparation, although eminently satis- 
factory from the standpoint of both preventive and 
curative medicine, still has several aspects in which 
improvement may be expected. These facts have led 
us to try penicillin in the treatment of these conditions 
with the hope that it might be possible to eliminate 
some of the deficiencies in present day therapy. 
Included among the factors in the prevention and 
treatment of congenital syphilis which we would like 
to see improved by the discovery and application of 
new drugs and new technics, the following may be 
mentioned: 
1. Arsenotherapy is relatively toxic. Although, 
generally speaking, arsenicals are well tolerated and 
safe to use in the average case,1 reactions do occur 
which interfere with treatment or at times preclude their 
use entirely, and death of the expectant mother has been 
known to result from chemotherapy for syphilis during 
pregnancy.2 A safer drug is accordingly a desideratum. 
2. Antepartum syphilis treatment, as usually adminis- 
tered, is not curative of the mother’s syphilis. For this 
purpose it must be continued for long periods post 
partum and, in order to prevent the birth of syphilitic 
infants, it must usually be repeated in each subsequent 
pregnancy.3 It is true that intensive arsenotherapy 
(five day drip) has been employed successfully for a 
small number of pregnant women with early syphilis,4 
From the Institute for Control of Syphilis, University of Pennsylvania. 
This work was done under a contract between the University of 
Pennsylvania and the Office of Scientific Research and Development, 
recommended by the Committee on Medical Research. 
In addition to the directing investigators whose names appear as 
authors, the following contributed directly to the observations in this 
paper: H. H. Perlman, M.D., chief, Syphilis Clinic, Children’s Hospital; 
Elizabeth Kirk Rose, M.D., representing the pediatric staff, and G. D. 
Gammon, M.D., representing the neurologic staff of the Hospital of the 
University of Pennsylvania; Yirgene Wammock, M.D., and O. M. 
Carrozzino, M.D., representing the staff of the Syphilis Clinic, Philadelphia 
General Hospital. Roentgenographic studies were performed by the 
Department of Roentgenology and Radium Therapy of the Hospital of 
the University of Pennsylvania (E. P. Pendegrass, M.D., director). 
Quantitative titered blood serologic tests for syphilis were carried out 
by Mrs. Verna Mayer Stein, serologist to the Syphilis Clinic, Hospital of 
the University of Pennsylvania. Attendance follow-up after termination 
of penicillin treatment was carried out under the immediate direction of 
Public Health Nurse Dolores Hill Middleton of the staff of the Institute 
for the Control of Syphilis, University of Pennsylvania. 
1. Cole, H. N., and others: Cooperative Clinical Studies in the 
Treatment of Syphilis: Syphilis in Pregnancy, Yen. Dis. Inform. 17: 39 
(Feb.) 1936. 
2. Ingraham, Norman R., Jr.: Complications Due to Arsenical Therapy 
in Syphilitic Pregnant Women: Report of Seven Maternal Deaths, 
J. A. M. A. 113: 1537 (April 22) 1939. Moore, J. E.: Arsenical 
Reactions in Pregnant Women, Am. J. Syph., Conor. & Yen. Dis. 33: 
518 (July) 1939. Arnell, R. E., and Guerriero, W. F.: Arsenical 
Encephalitis During Pregnancy, with Report of 2 Fatal Cases, New 
Orleans M. & S. J. 94 : 482 (April) 1942. 
3. Cole, H. N.; Jeans, P, C., and others: Syphilis in Mother and 
Child, Yen. Dis. Inform, supplement 7, U. S. Gvt. Print. Office, 1940. 
4. Sadusk, J. F., and Shaffer, T. E.: Observations on the Massive 
Dose Arsenotherapy of Early Syphilis by the Intravenous Drip Method: 
III. Pregnancy and Its Outcome, Associated with or by the Treatment of 
Early Syphilis by Massive Arsenotherapy, Yale J. Biol. & Med. 14: 365 
(March) 1942. Rattner, H.: The Treatment of Early Syphilis by the 
Concurrent Administration of Arsenic and Bismuth in a Period of Five 
Days, J. A. M. A. 133:986 (Aug. 7) 1943. 
5. Stokes, J. H.: The Wartime Control of Venereal Disease: Prob- 
lems in the Application of Recent Scientific Discoveries, J. A. M. A. 
130: 1093 (Dec. S) 1942. 
6. Ingraham, N. R., Jr.: The Importance of Treatment in the 
Control of Congenital Syphilis, Yen. Dis. Inform. 19: 124 (May) 1938. 
Ingraham, L. B., and Ingraham, N. R., Jr., and others: The Prevention 
of Congenital Syphilis in the Large Urban Hospital: A Study of Clinic 
Administration, Am. J. Syph., Conor. & Yen. Dis. 35:731 (Nov.) 1941. 
7. Greenlees, J. R. C., cited by Ingraham, N. R., Jr., and Kahler, 
J. E.: The Diagnosis and Treatment of Syphilis Complicating Preg- 
nancy, Am. J. Obst. & Gynec. 37: 134 (Jan.) 1934. Speiser, M. D.: 
Results of Treatment in the Antepartum Syphilis Clinic at Bellevue 
Hospital, ibid. 35:1013 (June) 1938. Moseley, V.; Callaway, J. L., 
and Sharpe, J. S.: A Study of the Incidence of Syphilis in Pregnant 
Women and Some Results of Therapy, ibid. 39:990 (Dec.) 1940. 
8. McKelvey, J. L., and Turner, T. B.: Syphilis and Pregnancy: 
An Analysis of the Outcome of Pregnancy in Relation to Treatment 
in 943 Cases, J. A. M. A. 103:503 (Feb. 17) 1934. Syphilis in 
Pregnancy.1 
9. Ingraham, N. R., Jr.: The Management of Syphilis in the New- 
born and During Early Childhood, Pennsylvania M. J. 43: 950 (May) 
1939. 
10. Eastman, N. J.: The Arsenic Content of the Human Placenta 
Following Arsphenamine Therapy, Am. J. Obst. & Gynec. 31:60 (Jan.) 
1931. Eastman, N. J., and Dippel, A. L.: The Passage of Arsenic 
Through the Human Placenta Following Arsphenamine Therapy, Bull. 
Johns Hopkins Hosp. 53: 288 (Nov.) 1933. Stokes, J. H., and Ingraham, 
N. R., Jr.; Diagnosis and Treatment of Congenital or Prenatal Syphilis, 
M. Clin. North America 38:1575 (Nov.) 1939. 
11. Smith, F. R., Jr.: Congenital Syphilis in Children, Am. J. Syph. 
& Neurol. 13:532 (Oct.) 1935. 
45 ultimate test of cure of her syphilis will always remain 
her ability to give birth to normal children in subse- 
quent pregnancies, even though no further antisyphilitic 
treatment is administered. 
MATERIAL 
The cases used for this report consist of 12 pregnant 
women with symptomatic early syphilis and 2 with early 
latent syphilis and 9 infants with early congenital syph- 
ilis. None had received any type of antisyphilitic ther- 
apy prior to treatment with sodium penicillin. 
The first pregnant woman started treatment on 
Nov. 19, 1943 and was delivered March 20, 1944. 
The maximum period of observation, therefore, at the 
time of writing this paper (June 29, 1944) has been 
for the mother seven and one-half months and for the 
newborn infant three months. Seven of the mothers 
had not delivered at the time this material was analyzed. 
The first infant with congenital syphilis commenced 
his treatment on Feb. 8, 1944, so that in this case the 
maximum period of observation is about four months. 
All patients treated have been included in this report 
in order to evaluate the initial response to therapy and 
the contraindications to treatment, if any. 
The material has been drawn from the clinics and 
wards of several of the Philadelphia hospitals 12 and 
observations were made by members of the University 
of Pennsylvania Penicillin- Panel under the chairman- 
ship of John H. Stokes, M.D. 
RESULTS 
In the Pregnant Syphilitic Woman and Her Child.— 
The clinical response to treatment and the result of 
delivery in each of the 7 pregnant women who have 
reached term is summarized in table 1. This table also 
shows graphically the serologic response to treatment 
of both mother and child. In each instance an appar- 
ently normal infant has resulted at full term except in 
case 76, in which the infant was considered to be pre- 
mature because it weighed only 4 pounds l0l/2 ounces 
(2,112 Gm.) at birth, but it appeared otherwise healthy. 
Dark field examination of the umbilical vein was nega- 
tive in 5 instances and not performed in 2. Roentgeno- 
grams of the long bones during the neonatal period 
performed in 4 cases at birth and repeated at the age of 
6 weeks or later in every instance were all normal. 
Three of the infants had positive cord and neonatal 
blood serologic tests in every case with quantitative 
titers either equal to the mother’s or lower. In case 13, 
the mother’s blood serologic test was 4 Kline units at 
birth and the infant’s y2 unit; in case 25 the mother’s 
titer was 32 units at birth and the infant’s 16 units; 
in case 49 the mother’s and infant’s titers were both 
64 units. 
In each instance in which the infant’s blood serologic 
test was positive at birth it has fallen sharply postnatally 
Table 1.—Summary of Clinical Course of Seven Pregnant 
Women with Early Syphilis Treated with Penicillin # 
Mother 
Infant 
Serologic 
Serologic 
Days 
Test, 
Days 
Test, 
After 
Kline 
After 
Kline 
Clinical Data Penicillin 
Units * 
Delivery 
Units * 
Case 4. B., 17 years. U. of Pa. H. 
0 
256 
10 
256 
Secondary syphilis 
31 
64 
Penicillin started 11/19/43 
74 
64 
Total dose; 1,200,000 units 
95 
8 
105 
64 
Delivered 3/20/44 
115 
8 
0 
Negative 
122 
32 
17 
Negative 
Infant: weight 6 lbs. 1 oz. 
139 
4 
45 
Negative 
175 
32 
53 
Negative 
Dark field umbilical vein nega- 
207 
64 
74 
Negative 
tive, normal physical examina- 
223 
8 
101 
Negative 
tion, roentgenogram of long 
bones normal 
Case 13. B., 29 years. P. G. H. 
Secondary syphilis 
0 
128 
Penicilllin started 12/16/43 
9 
128 
Total dose: 1,200,000 units 
26 
32 
68 
16 
Delivered 3/29/44 
89 
2 
104 
4 
0 
0.5 
Infant: weight 6 lbs. 2% oz. 
124 
16 
20 
Negative 
141 
Negative 
37 
Negative 
Dark field umbilical vein nega- 
159 
Negative 
55 
Negative 
tive, normal physical examina- 
173 
0.5 
69 
Negative 
tion, roentgenogram of long 
83 
Negative 
bones normal 
Case 15. B., 16 years. Pa. Hosp. 
0 
128 
10 
64 
Secondary syphilis 
25 
128 
Penicillin started 12/24/43 
39 
32 
Total dose: 1,200,000 units 
60 
32 
74 
16 
Delivered 5/15/44 
87 
4 
115 
0.5 
Infant: weight 6 lbs. 11 oz. 
122 
Negative 
136 
Negative 
Dark field umbilical vein nega- 
143 
Negative 
0 
Negative 
tive, normal physical examina- 
168 
Negative 
25 
Negative 
tion 
Case 25. B., 18 years. U. of Pa. H. 
0 
128 
16 
64 
Secondary syphilis 
29 
64 
Penicillin started 1/10/44 
53 
64 
Total dose: 1,200,000 units 
63 
16 
79 
32 
Delivered 4/13/44 
94 
32 
0 
16 
103 
32 
9 
4 
Infant: weight 6 lbs. 14% oz. 
114 
Negative 
20 
Negative 
128 
2 
34 
Negative 
Dark field umbilical vein nega- 
148 
4 
54 
Negative 
tive, normal physical examina- 
163 
Negative 
69 
Negative 
tion, roentgenogram of long 
bones normal 
Case 49. B., 21 years. U. of Pa. H. 
Secondary syphilis 
0 
64 
Penicillin started 2/15/44 
8 
64 
Total dose: 2,400,000 units 
21 
128 
36 
64 
Delivered 4/3/44 
48 
64 
0 
64 
49 
1 
16- 
Infant; weight 6 lbs. 5% oz. 
77 
64 
29 
Negative 
98 
32 
50 
Negative 
Dark field umbilical vein nega- 
112 
2 
64 
Negative 
tive, normal physical examina- 
126 
2 
78 
Negative 
tion, roentgenogram of long 
bones normal 
Case 71. B., 22 years. U. of Pa. H. 
Early latent syphilis 
0 
128 
Penicillin started 3/31/44 
14 
64 
Total dose: 1,200,000 units 
33 
128 
46 
32 
Delivered 6/14/44 
60 
32 
76 
64 
0 
Negative 
Infant: weight 5 lbs. % oz. 
77 
1 
0.5 
Normal physical examination 
Case 76. B., 24 years. P. G. H. 
Secondary syphilis 
0 
64 
Penicillin started 4/5/44 
13 
128 
Total dose; 1,200,000 units 
27 
64 
41 
64 
Delivered 6/17/44 
54 
32 
69 
64 
Infant: weight 4 lbs. 10% oz. 
73 
64 
0 
Negative 
Normal physical examination 
12. The Hospital of the University of Pennsylvania supplied 8 cases for 
this study, the Philadelphia General Hospital 11 cases, the Children’s 
Hospital 2 cases, the Pennsylvania Hospital and the St. Luke’s and 
Children’s Medical Center each 1 case. 
FOOTNOTES TO TABLE 
Symptomatic clinical response in the mother in each instance was 
immediate. 
* Given in Kline units for sake of uniformity. Tests were checked 
with quantitative Kolmer Wassermann and Eagle flocculation with 
comparable results. 
# The seven mothers, as of Sept. 28, 1944, have been followed a maxi- 
mum of 286 days post penicillin (average 216 days). All have become 
seronegative except case 4 and case 49 (each less than 1 unit of reagin) 
and case 71, which retains 32 units. All are clinically normal. Each of 
the infants has remained clinically and serologically normal for a maxi- 
mum period of 163 days post partum (average 124 days). One of the 
fourteen pregnant women mentioned in the text, who was treated with 
1,200,000 units of penicillin, developed infectious relapsing lesions just 
prior to delivery, 122 days post penicillin. (Kolmer Wassermann.) 
46 and has become normal in less than one month. In the 
period of observation, none have shown any tendency to 
revert to positive. The remaining 4 infants Were born 
with negative blood serologic tests for syphilis and have 
remained seronegative up to the time these data were 
compiled. In the period of observation, only 3 of the 
mothers have become seronegative: Patient 15 was 
found to be seronegative ninety-five days post penicillin 
and forty-seven days prior to delivery, and patient 39, 
who has not yet reached term, was found to be sero- 
negative seventy-seven days post penicillin and has 
remained so for two months. Patient 25 was found to 
be seronegative sixty-nine days after delivery. 
In the 7 cases in which delivery has occurred peni- 
cillin treatment was started 142, 121, 103, 93, 76, 73 
and 47 days respectively prior to delivery or from the 
fifth to the eighth lunar months of the pregnancy 
respectively. In no instance was treatment instituted 
after the commencement of penicillin treatment. In 
2 cases threatened abortion, as evidenced by spotting 
and by lower abdominal cramps, occurred in 1 instance 
in eighteen hours and in the second case in forty-eight 
hours after the start of penicillin therapy. The drug 
was immediately discontinued but resumed in full dosage 
in twenty-four hours without a recurrence of symp- 
toms. This the only type of reaction that developed in 
any of our pregnant patients could perhaps be con- 
sidered to he a form of therapeutic shock (Herxheimer 
reaction) occurring in a grossly diseased area and 
would possibly fall in the category of placental shock, 
described in the older literature and occasionally seen 
after arsenotherapy administered without preparatory 
treatment to pregnant women with active syphilis. It 
would suggest that, in the present state of our knowl- 
edge at least, it might be best to reduce the penicillin 
dosage by three fourths to one half during the first 
Table 2.—Summary of Case Records'of Five Infants with Early Congenital Syphilis Treated with Penicillin 
Per Pound 
Duration of 
- 
of 
Observation 
Weight on 
Body 
After 
Identifying Data 
Initial Clinical Findings 
Admission 
Total 
Weight 
Penicillin 
Result 
Case 43. P. G. H. 
Race-B. 
D. F. + ; skin lesions, snuffles, 
6 lbs. 3 oz. 
100,000 
16,181 
99 days 
Living; normal physical exam- 
Hex— cT 
enlarged liver; roentgenogram: 
units 
units 
{nation, normal roentgenogram 
Age—42 days 
advanced osteochondritis and 
of long bones, negative serologic 
Treatment started 
periostitis; serologic test posi- 
test since 5/18/44 
2/8/44 
tive, 120 units (Kline) 
Case 47. U. of Pa. 
Race—B. 
Premature snuffles, enlarged 
4 lbs. 7 oz. 
80,000 
18,099 
16 days 
Died 2/27/44; circulatory collapse; 
Sex—cf 
liver; roentgenogram: pro- 
units 
units 
possible congenital heart dis- 
Age—18 days 
nounced osteochrondritis and 
ease; no autopsy 
Treatment started 
periostitis: serologic test posi- 
2/11/44 
tive, 128 units (Kline) 
Case 58. Child. H. 
Race—B. 
Scaling skin lesions most pro- 
12 lbs. 11 oz. 
236,000 
18,373 
79 days 
Normal physical examination; 
Sex—cf 
nounced on palms and soles, 
units 
units 
roentgenogram: periostitis dis- 
Age—4 months 
snuffles; roentgenogram: perios- 
appearing; serologic test, 8 units 
Treatment started 
titis of long bones; serologic 
(Kline) 5/17/44 * 
2/29/44 
test positive, 128 units (Kline) 
Case 63. U. of Pa. H. 
Race—B. 
Malnutrition; dysphagia; sero- 
13 lbs. 
242,000 
18,615 
97 days 
Normal physical examination; 
Sex— cf 
logic test positive, 04 units 
units 
units 
blood serologic test, % unit 
Age—8 months 
(Kline); roentgenogram not 
(Kline) 6/8/44 
Treatment started 
diagnostic 
3/3/44 
Case 112, St. Luke’s 
Race—B. 
Roentgenogram: osteochondritis 
10 lbs. 8 oz. 
111,023 
10,631 
8 days 
Died 6/6/44; temperature eleva- 
Sex— 9 
and periostitis; serologic 
units 
units 
tion to 104 F.; severe diarrhea 
Age—51 days 
test strongly positive; asso- 
and dehydration with weight 
Treatment started 
ciated gonococcic vaginitis 
loss of 3 lbs.; autopsy: gross 
5/29/44 
and microscopic finding of con- 
genital syphilis only 
All of the mothers 
had seropositive latent syphilis and none were 
treated prior to birth of the 
infants given in the table. 
* This patient developed dark field positive skin lesions on Aug. 24, 1944. The infant never became seronegative, and blood titer rose to 32 units 
when relapsing lesions 
appeared. Mother showed no evidence of open 
lesions at the time of relapse in the infant 
and was receiving treatment with 
phcnarsine hydrochloride and bismuth subsalicylate. This 
was considered to be a 
penicillin failure 
and the infant 
was retreated with penicillin. 
prior to the midpoint of the pregnancy or in the month 
immediately preceding term. 
Method of Treating the Syphilitic Pregnant Woman. 
—Each of the pregnant women who have thus far 
reached term had received 1,200,000 Oxford units as 
her total dose of sodium penicillin, with the exception 
of patient 71, who left the hospital without receiving her 
last two four hourly injections and patient 49, who 
received 2,400,000 units. Three additional patients who 
have as yet not reached term also received 2,400,000 
units. The injections were given intramuscularly, each 
dose in approximately 1 cc. of sterile distilled water 
every four hours around the clock for a period of 
approximately eight days. The individual four hourly 
dosage for 10 cases was 25,000 units and for 4 cases 
50,000 units. 
The clinical response of infectious surface lesions to 
treatment of the expectant mother was very rapid. 
Usually, Treponema pallidum disappeared, as deter- 
mined by dark field examination, in less than eight 
hours. In no case did the dark field preparation show 
Treponema pallidum longer than twenty-four hours 
thirty-six to forty-eight hours of treatment of the 
syphilitic pregnant woman. We have followed this 
suggested procedure of reduced dosage during the first 
forty-eight hours for the last 10 pregnant women 
treated and have not had an additional instance of 
threatened abortion. 
In Infantile Congenital Syphilis.—Nine patients with 
early congenital syphilis were treated with sodium 
penicillin. The results in the 3 cases which have been 
followed long enough to make any report possible are 
given in table 2. Two deaths possibly not due to peni- 
cillin treatment which occurred among 9 cases thus far 
treated are also included in this table. The 3 living 
infants followed for 99, 97 and 79 days respectively 
after administration of sodium penicillin all became 
clinically normal to physical examination. 
All 3 infants had relatively high blood serologic titers 
initially, but these dropped sharply to normal in 
1 instance and to relatively low levels in the other 
2 instances {l/2 unit and 8 units respectively) during 
the period of observation. 
47 The 2 infants who showed definite roentgenographic 
changes of syphilitic osteochondritis and periostitis have 
resumed approximately normal bone development, 
as shown in the illustration. 
Dosage Employed in Infantile Congenital Syphilis.— 
In 6 of the 9 cases treated, the total dosage of sodium 
penicillin given every four hours around the clock over 
approximately an eight day period was between 16,000 
and 19,000 units per pound of body weight. This is 
considerably in excess of the dosage given the majority 
of the pregnant women, which except in 4 cases was 
not in excess of 10,000 units per pound of body weight. 
The remaining 3 infants received respectively 2.935, 
10,631 and 11,111 units per pound of body weight. 
The only definite treatment reaction noted among the 
7 infants who are still living was in the first infant 
COMMENT 
Our case material does not permit us to draw sweep- 
ing conclusions either as to the management of the 
syphilitic pregnant woman or with regard to the care 
of the syphilitic infant. We are of the opinion that the 
total dosage of penicillin used, the time dose relation- 
ship or the duration of treatment employed for our 
patients is not the ideal. In fact, we are experimenting 
with other dosage systems. On the other hand, since 
penicillin is now available for general medical use, it 
is felt highly desirable to make such factual information 
as exists available in the medical literature as rapidly 
as possible. 
It is our belief that, as far as it is possible to determine 
with a limited number of cases, a total dosage of sodium 
penicillin in the same magnitude (1,200,000 units) as 
was originally used by Mahoney, Arnold and Harris 13 
in the treatment of early.acquired syphilis in the adult 
is safe to use for the pregnant woman, preferably with 
reduced individual doses for the first thirty-six to forty- 
eight hours. By safe we mean that it clears the mother 
of infective surface lesions; with proper time dose rela- 
tionship it need provoke no after-effects, and it will 
apparently “protect” a good proportion of the offspring 
from early or immediate manifestations of congenital 
syphilis. This is what, plus the danger of other reac- 
tions, we had come to expect of the arsenicals. Peni- 
cillin may therefore perhaps replace them. In view, 
however, of the demonstration of an incompletely cura- 
tive result under 1,200,000 Oxford units in not less 
than 10 per cent of cases of early syphilis and the trend 
to higher dosage (2,400,000 Oxford units) on the part 
of some authorities and competent advisory agencies, 
we believe that such an advance in the total dose of 
penicillin is now proper and presumably safe for the 
pregnant woman in good general condition. By such 
a total dose, using a therapeutic agent with the reaction- 
less record of penicillin, we shall, we hope, approach 
more nearly, if not reach, the cure of the mother with 
the full protection of the child. 
It is net, of course, possible to say whether all the 
infants in the present series have escaped infection, nor 
will it be possible so to state short of several years of 
postnatal observation. It will further not be possible to 
evaluate the effectiveness of treatment of a syphilitic 
pregnant woman to prevent congenital syphilis without 
the analysis of much larger case material observed for 
a much longer time. It must also be pointed out that 
the permeability of the placental membrane to penicillin 
is at present unknown and that cases treated imme- 
diately before delivery or prior to the fifth lunar month 
have not as yet been reported. 
There are indications that penicillin given to the 
mother just prior to delivery (Barksdale) is not 
recoverable from the umbilical vein at birth. Con- 
sidering the fact, however, that untreated pregnant 
women with early syphilis almost uniformly give birth 
to dead or diseased children, we believe that it is 
encouraging, to say the least, that among the 14 women 
treated by us not a single stillbirth or neonatal death 
has occurred. The 7 infants delivered have, moreover, 
remained physically normal and seronegative for days 
of observation numbering 101, 81, 78, 69, 25, 5 and 
1 post partum respectively. 
We realize that a six months or longer period of 
active postnatal observation is desirable to rule out the 
A. Before penicillin. 
B. After penicillin. 
Improvement in syphilitic osteochondritis from penicillin therapy in 
case 43, in which treatment was started when the child was forty-one days 
old. Only the right knee joint is shown, though all the long bones had 
similar involvement. In A, note complete disorganization of distal femoral 
metaphysis and proximal metaphysis of the tibia. This area is approxi- 
mately normal in B, eighty-three days after commencement of penicillin. 
treated (case 43 in table 2). After receiving 19,000 
units of sodium penicillin in the first forty-eight hours 
this patient developed severe dyspnea and cyanosis, 
necessitating supportive treatment and the administra- 
tion of oxygen. His condition remained critical during 
the next eighteen to twenty-four hours, during which 
period penicillin was withheld.. The drug was then 
resumed in full dosage without recrudescence of symp- 
toms and with apparently a favorable outcome. This 
is the only infant that thus after a ninety-nine day 
period has developed a completely negative blood sero- 
logic reaction. 
13. Mahoney, J. R.; Arnold, R. C., and Harris, A.: Penicillin Treat- 
ment of Early Syphilis: A Preliminary Report, Ven. Dis. Inform. 24: 
3SS (Dec.) 1943. Bloomfield, L. A.; Rantz, L. A., and Kirby, W. M. M.: 
The Clinical Use of Penicillin, J. A. M. A. 124:627 (March 4) 1944. 
48 possibility of congenital syphilis. But, if the type of 
medical follow-up evidence which has been found satis- 
factory for pregnant women treated with arsenicals is 
acceptable for those treated with penicillin, then it is 
distinctly exceptional to encounter congenital syphilis 
which is not detectable with the use of roentgenographic 
and blood serologic test procedures by the end of the 
second month. It seems unlikely, therefore, that the 
4 infants who have passed the sixtieth day of postnatal 
observation will develop signs of congenital syphilis in 
the future, though we expect to keep them under obser- 
vation for a matter of years, if possible. 
Infantile Congenital Syphilis.—The present state of 
our knowledge with respect to the ideal treatment of 
infantile congenital syphilis is much less exact than is 
our limited knowledge even of the treatment of the 
syphilitic pregnant woman. Not only are we uncertain 
that we have developed a proper and effective total 
dosage or time-dose relationship for the administration 
of a sodium penicillin to infants with congenital syphilis, 
but we are in addition not certain that the method of 
treatment employed by us is entirely safe for the small 
grossly diseased infant. A word of caution as to the 
possible dangers of indiscriminate experimentation in 
this field is therefore given. 
It is highly possible that the severe reaction (dyspnea, 
cyanosis and so on) observed in case 43 would fall into 
the category of therapeutic shock (Herxheimer reac- 
tion). In this instance, in spite of the severity of infec- 
tion in the infant, little attempt was made to reduce the 
initial dosage for any considerable time, even though 
the first three injections (i. e. the first eight hours of 
treatment) were reduced to one-half the calculated 
dosage. We are likewise not certain that either of the 
two observed deaths resulted from the use of sodium 
penicillin as such. In each instance the death could be 
accounted for from another cause. In case 47 a possible 
congenital heart lesion and in case 112 a severe diarrhea 
with dehydration, uncontrolled by pediatric care, were 
undoubtedly important contributing factors to the deaths 
of the infants. In treating congenitally syphilitic infants 
in the past, however, the reactions caused by injudicious 
treatment have been considered not infrequently a pri- 
mary rather than a secondary cause of death. 
We believe that it may be significant that each of the 
infants in whom severe reaction or death occurred was 
less than 2 months of age. All of the other infants 
treated were older than 2 months at the time treatment 
was started. They therefore had had their infections 
longer, were more fully adjusted to extrauterine exis- 
tence, had presumably built up some individual resis- 
tance and were better able to combat any toxemia 
which might develop from the too rapid treatment of 
overwhelming infected body tissue. We are reminded 
forcefully that the real danger of too energetic arseno- 
therapy of congenital syphilis lies in these first few 
weeks of life when the infection is overwhelming, the 
nutritional state of the infant poor and its resistance to 
disease undeveloped. We cannot fail to remember also 
that for complete safety it has been shown that it is 
necessary to maintain reduced dosage in these cases 
not for a matter of a few days but often for three 
four weeks. Here, then, may be a situation in which 
too rapid treatment with large dosage of penicillin may 
be injurious to the infant even though beneficial for the 
disease itself. 
Since the cases described were treated we have 
observed another infant 2 months old at the inception 
of penicillin therapy but not reported in detail, since 
treatment was completed only on June 5, 1944. This 
infant, which weighed 9 pounds (4.1 Kg.), was given 
a total dosage of 100,000 units of sodium penicillin in 
eight days (approximately 11,000 per pound of body 
weight), but the dosage was kept much reduced from 
the first to the third day. Five per cent of the total 
dosage was given in the first twenty-four hours, 10 per 
cent on the second and third day each and 15 per cent 
on each day thereafter with no untoward reaction. 
In some of the older and heavier infants we have 
also recently given greatly reduced doses for the first 
two or three days of treatment without reaction. In 
spite of this, however, we are not certain that reduced 
dosage carried out for so short a period will be effec- 
tive in preventing reaction in every instance if we are 
here dealing with the type of therapeutic paradox in the 
small severely infected infant which has accompanied 
other types of rapidly effective chemotherapy. One 
necessity for safety certainly stands out with increased 
emphasis. This is the insistence on painstaking and 
experienced general pediatric care as an accompaniment 
to penicillin therapy. 
It is too soon to discuss the proof of “cure” of syphilis 
in women by their ability to hear normal children in 
subsequent pregnancies, since this is a question which 
can be studied only over a period of years. If the appar- 
ently normal infants born of the women with early 
syphilis in this study prove on subsequent observation 
to be nonsyphilitic, then it is a probable but not yet an 
established fact that these women have been cured of 
their disease. The most obvious conceivable exception 
to this supposition would be that the infection was 
suppressed in the mother as a result of treatment for 
the several months of her pregnancy in which she was 
carrying the child to the point where the disease was 
not transmitted, only to have a recrudescence subse- 
quent to delivery. 
It should also be noted that the present report deals 
with early syphilis complicating pregnancy. It is not 
certain that these observations' are necessarily applicable 
to the greatest problem confronting the medical, pro- 
fession in this field, namely latent syphilis of unknown 
duration complicated by pregnancy. It is highly desir- 
able, therefore, that the question of penicillin treatment 
of latent syphilis complicated by pregnancy be studied 
as soon as possible. 
CONCLUSIONS 
1. There are several factors in the medical treatment 
of the syphilitic pregnant woman and the infant with 
congenital syphilis which are in need of further study 
and improvement. 
2. It was with the thought that some solution to these 
problems might be found through the use of penicillin 
that the present study was undertaken. Sodium peni- 
cillin exclusively was employed. Experience with the 
treatment of 14 pregnant women with early syphilis and 
9 infants with congenital syphilis formed the basis for 
this analysis. 
3. The material is reported at "this time, even though 
incomplete, since preliminary observations indicate that 
sodium penicillin has a definitely good effect both on the 
mother and on the child in syphilis in pregnancy and 
on infantile congenital syphilis. Because the drug has 
been released for general distribution, dissemination of 
even our present limited knowledge seems desirable. 
4. The proper total dosage and the time-dose rela- 
tionship has not been worked out to complete satisfac- 
tion either for syphilis and pregnancy or for infantile 
congenital syphilis. 
49 5. The limited existing data would seem to indicate, 
however, that total doses of the magnitude of 1,200,000 
Oxford units and 2,400,000 Oxford units given 
intramuscularly round the clock in approximately eight 
days, as used in the treatment of early syphilis, are 
well tolerated by the pregnant woman, with the pos- 
sible exception that therapeutic or placental shock 
may occur, to be avoided by considerably reducing 
the dose for the first thirty-six to forty-eight hours of 
therapy. The course of expert experience with peni- 
cillin in syphilis in general suggests the desirability 
of the higher dosage (2,400,000 Oxford units). 
6. Preliminary results indicate that “cure” or sup- 
pression of the infection takes place in a number of the 
mothers and that miscarriage, stillbirth and neonatal 
death are averted and the infants are born apparently 
healthy. It must be reiterated, however, that the period 
of observation for either mother or child has not been 
long enough to be certain that they have been cured by 
the dosages employed. The course of the disease has 
nonetheless been profoundly and favorably affected. 
7. Infants with congenital syphilis make a good 
response to dosage of approximately 18,000 units per 
pound of body weight. Grossly infected syphilitic 
infants, however, may be injured by the injudicious use 
of penicillin. In the present state of our knowledge 
their treatment should be approached with extreme cau- 
tion, with reduced dosage and with great emphasis on 
proper general pediatric care. 
SYPHILIS