377

CHEMOTHERAPY AND THE VENEREAL DISEASESR, R. WILLCOX, M.D.

Consultant Senior Assistant, Venereal Diseases Department, St. Mary's Hospital, London; Physician-in-Charge,Venereal Diseases Clinic, King Edward VII Hospital, Windsor

G. M. Findlay'°, in the preface to his authori-tative Recent Advances in Chemotherapy, quotesthe story in the Book of Tobit of the AngelRaphael who banished an evil spirit from Sara bymeans of a foul-smelling concoction. This, hestates, was one of the earliest examples of theuse of chemotherapeutic aerosols! Certainlychemotherapy has been employed for a very longtime in the treatment of venereal disorders: forcenturies mercury was used, sometimes even byinhalation, for the treatment of syphilis. Indeed,the first great advance towards modem methodsfollowed Ehrlich's discovery of arsphenaminewhich, in an improved form in conjunction withbismuth, was for 30 years a most striking exampleof what could be achieved by chemotherapy.When the sulphonamides were introduced in

1936, and obtained similar excellent results forgonorrhoea, the chemotherapeutic era for thevenereal diseases was almost completely estab-lished. However, as a number of strains of thegonococcus were originally unresponsive, andothers were made so by small doses of sulphon-amides given for'often trivial complaints, theresistant strains gradually became predominant.After only six or seven years in some places, e.g.Italy5, gonorrhoea again became almost as great aproblem as in pre-sulphonamide times. Then in1943 came penicillin, and with it the simplest,safest and most effective treatment of gonorrhoeayet discovered and, with its application to thetreatment of syphilis, this too became a safe andless time-consuming procedure.During these early days it was thought that

perhaps other potent antibiotics remained to bediscovered and the research laboratories of theU.S.A. engaged teams of experts to find and testthese as they were isolated. As the months wentby and the new discoveries proved either too toxicor less effective, opinion swung the other waytowards the view that penicillin was the mosteffective antibiotic, which by chance was also thefirst to be unearthed. Then came streptomycin,

which was lethal to organisms previously un-touched by penicillin. Since that time new anti-biotics have appeared in bewildering profusion andone, chloramphenicol, has been synthesized.Those applicable to venereology are: penicillinfrom Penicillium notatum, streptomycin fromActinomyces griseus, aureomycin from 'Strepto-myces aureofaciens, chloromycetin (chlorampheni-col) from Streptomyces venezuelae, and terramycinfrom Streptomyces rimosus.Although it is likely that this small group of

drugs can cure all of the venereal diseases, thesulphonamides, bismuth, and to a lesser extent thearsphenamines, are still being employed in theirtreatment; partly because the newer antibioticsare expensive and in short supply, and partlybecause many clinicians have been unwilling toplunge into the unknown without retaining a life-line connecting with tried experience. With thisoverall picture in mind the most important of thevenereal diseases will be considered separately.Gonorrhoea

This disease is readily cured by penicillin,streptomycin, aureomycin, chloramphenicol andterramycin. Uncomplicated gonorrhoea, there-fore, is no longer a therapeutic problem.The general aim with all of the antibiotics is to

maintain an effective serum level for six to eighthours. With less than this time there is the riskof failure and the possibility of breeding drug-faststrains, while with a longer time there is thetheoretical danger of masking syphilis (i.e. shouldthe patient contract syphilis at the same time asthe gonorrhoea, the small dose of antibiotic givenfor the treatment of the latter disease might beinsufficient for the syphilis and result in itsappearance, perhaps in perverted form, after thepatient is no longer under surveillance). Peni-cillin, aureomycin, chloramphenicol, and terra-mycin are all potent against T. pallidum, and thedanger, therefore, exists with all. It is least withstreptomycin but, even so, is not absent. The

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author has shown that syphilitic chancres will losetheir spirochaetes after the administration of only1.5-6.0 g. of this drug45, although such will notoccur after single doses of o.6 g.52On the other hand, this danger is probably over-

rated. In order to avoid it altogether, it has forsome years been the practice in this country tofollow up for a period of six months all patientswith gonorrhoea who are treated with penicillin,instead of the three months which was usual withthe sulphonamides, which drugs have no maskingaction upon syphilis. Few cases have in fact beenrevealed in which the usual incubation period ofsyphilis has been open to question and, as rela-tively few patients actually attend for six monthsanyway, the usefulness of this procedure is mini-mized. In fact Macfarlane24, after an analysis of2,600 cases of gonorrhoea treated with penicillin,considers that a surveillance of three months isprobably sufficient. Bauer2 states that there waslittle evidence of masked syphilis amongst demobi-lized American troops treated in the Forces forgonorrhoea. Willcox42 has examined the V.D.statistics of this country and by 1948 could findno evidence that syphilis was being masked but,to the contrary, that it was probably actually beingcured during the incubation period. If the latteris once proven then it would be logical to treatgonorrhoea with larger doses of penicillin than weare using today. At present we adopt a kind of'all or none' rule. As a routine we employ assmall a dose as is necessary to cure the infectionbut, if complications dictate the giving of a higherdose, then it is logical to increase it sufficiently(e.g. to 2.4 mega units or more) so as a minimalcurative dose for syphilis is given.Adequate doses of the various drugs are, there-

fore, 300,000 units of procaine penicillin with orwithout z per cent. aluminium monostearate,0.5-1.0 g. of streptomycin or dihydrostreptomycin,all by single injections. If the oral antibioticsare employed for those persons who fear the needlethen 500,000 units of penicillin in buffered tabletsmay be given in a single dose, or the newerpreparations, aureomycin, chloramphenicol andterramycin, may be employed. Although Greaveset al.2 had 48 cured'of 50 patients given singledoses of 750 mg. of chloramphenicol, the resultsobtained with single doses of i gm. of aureomycin(56 cures in 7027), and terramycin (3 cures in 628),have not been so satisfying. The method advo-cated by Hendricks et al.l6 for terramycin mightwell be applied to all three of these drugs. Thatis to give two doses each of i gm. at an intervalof six hours.At the present stage of our knowledge penicillin

is the best antibiotic to choose for routine pur-poses, except for those patients who dislike injec-

tions and who may be given the orally administereddrugs, and also for those patients in whom therisk of developing syphilis is higher than average.These latter include patients with acute gonorrhoeaand phimosis in whom the sub-preputial conditioncannot be adequately inspected, those with undiag-nosed sores under observation, those with sus-picious inguinal adenitis, and those with a historyof intercourse with an infectious syphilitic. Thesepatients should receive sulphonamides while thedark field and serum tests are being performed:

*$should this treatment be unsuccessful, as was thecase in 176 of 205 patients treated in London byDunlop in I9498, then streptomycin in a singledose of 0.5 g. may be used.There is no great advantage in giving strepto-

mycin instead of penicillin as a routine, as thesomewhat smaller risk of masking syphilis isoffset by the possibility of encouraging drug-faststrains which may so easily be fostered with thisdrug. In addition, an injection of streptomycin issomewhat more painful than penicillin. If used,however, the results are satisfactory. For ex-ample, Taggart et al.32 had 95 of 104 cured with aslittle as o.2-0.4 g. of dihydrostreptomycin.Granuloma InguinaleThis world-wide disease, which has been

described as the -enfant terrible of the SouthernUnited States, is a chronic debilitating conditionproducing genital or near genital granulomatousulceration, often a similar condition in the groinsarising from lesions below the skin (pseudo-buboes), and occasional metastatic spread. Thecausative organism is Donovania granulomatis,which may be seen in scrapings from the lesionsand resemble closed safety-pins, being found inthe large mononuclear cells. The disease is en-countered in Great Britain extremely rarely.

Until recently it was treated with antimonialson a regime reminiscent of the older treatments ofsyphilis. This was fairly effective, althoughresistant cases were not infrequently encounteredand a considerable proportion relapsed. Thesituation was upchanged by the introduction ofboth the sulphonamides and penicillin, althoughthe latter has been found useful in clearing thesecondary infection in patients with super-addedfuso-spirochetosis.

Greenblatt and his group'3 have perhaps thegreatest experience of the treatment of granulomainguinale with antibiotics. Their published seriesnow exceeds 142 cases treated with streptomycin,46 with aureomycin, while 23 cases have beentreated with chloramphenicol. Streptomycin givenas 4 g. daily for five days has proved most suc-cessful, as the author can testify, having employedit on a number of patients in Southern Rhodesia.43

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The principal disadvantage of treatment withstreptomycin is that admission to hospital isnecessary. Aureomycin in doses of z g. daily foro1 to 15 days is also most effective and may begiven to out-patients, although gastro-intestinalside-effects and those of vitamin-B deficiencymay occur. Greenblatt13 considers that chloram-phenicol in the same dosage is less toxic thanaureomycin and recommends its priority for out-patients.Lymphogranuloma Venereum

This virus disorder, characterized by buboes inthe male and by proctitis and rectal stricture inthe female, is seldom seen in Great Britain exceptoccasionally in the sea ports. In the past it hasbeen fairly well controlled by the sulphonamides,although the virus has been shown to persist inpatients showing apparent clinical cure. In 1948Wright et al.63 demonstrated that aureomycin waseffective in this condition, and this has been sup-ported on small numbers of cases by variousauthors4 44. Recent more critical examination, how-ever, on larger series of cases29 36 has not been soencouraging. Greenblatt and his group13 con-sider that aureomycin is relatively ineffective inearly cases but useful in large doses in late,usually female, cases with proctitis. The sameworkers consider that chloramphenicol is even lessuseful. Streptomycin is not effective althoughpenicillin in large doses may be so in the earlycase with climatic bubo.38At the present time the recommended treatment

consists of sulphonamides given over a period ofat least one week. Those cases which do notrespond may be given oral aureomycin 2 g. dailyfor io to I5 days.Non-specific UrethritisAs gonorrhoea is now cured so easily, and the

incidence of syphilis in Britain is declining, non-specific urethritis is in many respects the mosttroublesome condition seen in the male venerealdiseases clinic. Whereas in pre-chemotherapeutictimes the physician commiserated with the patientwhen gonococci were found in his urethral smear,summarily dismissing him when they were not,the reverse is almost true today. Now the patientmay be congratulated on the discovery of thegonococcus so rapid is the cure, but with a non-gonococcal urethritis the prognosis is moreguarded.The causes of non-gonococcal urethritis are

legion. Harkness (I950)15 is to be praised for soably presenting them in his monograph. Apartfrom those cases caused by definite specific causes,perhaps the major number are those of abacterialurethritis, in which virus inclusion bodies and/or

pleuro-pneumonia-like organisms may be foundin scrapings from the urethra. Exactly the rela-tionship between these two with each other, ifany, or indeed with the urethritis itself, is not yetcompletely understood although there are goodreasons to believe that the commoner cause is thatof a virus.Many chemotherapeutic substances have been

used in the treatment of this condition. Coutts7favours neo-arsphenamine for those cases, oftenaccompanied by so-called abacterial pyuria, inwhich a spirochaete has been found. This varietyappears to be relatively uncommon in GreatBritain and, in any event, the arsphenamines arebest avoided when possible now that less toxicdrugs are available. The sulphonamides are fairlysuccessful and deserve a trial, although theyseldom cause a non-gonococcal discharge to dryup in the same sudden and complete manner asan acute gonorrhoea; Penicillin is usually in-effective.The results of treatment with streptomycin are

often better although the numbers of publishedcases are small,2 39 and these are not whollysatisfying. Aureomycin,52 chloramphenicol6 andterramycinl are more effective and doubtless,when these now expensive drugs are more readilyavailable, they will become the drugs of choice.The recommended dose of streptomycin is

i gm. once or preferably twice daily for five days.With the oral antibiotics two 250 mg. capsulestaken four times daily for two days, followed byone capsule four times daily for four days (total8 gm.) is a satisfactory course.Two warnings should, however, be given:

(i) The oral antibiotics are also effective againstgonorrhoea and, if they are employed indis-criminately in all cases of urethral discharge, willusually effectively cure both diseases. Althoughgonorrhoea in the adult male is nearly alwaysvenereally acquired, there are a number of casesin which this cannot be fairly said for non-specificurethritis: and the venereologist never knowswhen he may be called to give evidence in thedivorce court. If, therefore, the practitionerintends to treat the patient himself, or give pre-liminary treatment prior to reference to a clinicwhich may be open only once or twice a week,he should first take a urethral smear. Should thepatient be referred to hospital for post-treatmenttests then the smear may be sent with him. (2) Anoccasional cause of non-specific urethritis is intra-urethral chancre. The diagnosis is nearly alwaysbetrayed by the characteristic enlargement of theinguinal glands, although it is surprising how oftenthese comparatively uncommon cases are missedowing to the omission of the elementary precautionof dropping the trousers at the time of examina-

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tion. As these drugs all have a potent actionupon syphilis, the perhaps inadequate doses givenfor urethritis might have serious later conse-quences if this condition was due to intra-urethral chancre.

All cases of non-specific urethritis treated withthe antibiotics should have the same follow-up aspatients with gonorrhoea.Soft Sore (Chancroid)

This complaint, due to H. ducreyi, respondsto the sulphonamides, penicillin, streptomycin,aureomycin, chloramphenicol and terramycin.

Sulphonamides, in doses of 4-5 g. daily forfive to seven days, are definitely preferred, as theyhave no effect upon a syphilitic infection whichmay mimic chancroid or accompany it. As theapproach to this condition is to exclude syphilisby three daily dark-field examinations of materialfrom the sores, followed by serum tests once amonth for three months, with the object of beingable positively to assure the patient at the end ofthis time that he is not suffering from the moreserious disease, none of the antibiotics are recom-mended as a routine as they would influence asyphilitic infection if present. If they are used,then the patient should have the full follow-up fortwo years, with repeated serum tests and a cerebro-spinal fluid examination at the end of this time,just in case the condition was syphilitic after all.Such a prolonged inconvenience is to be avoidedfor a relatively trivial condition as chancroid.

Soft sore may be accompanied by inguinalbuboes which may break down and result in chan-croidal ulceration in the groins, or it may becomplicated by phagedoena in which case theremay be gross tissue destruction. In those cases,therefore, in which threatened loss of the memberexceeds the risks of masking syphilis, the anti-biotics should be used.

It is interesting to observe that Wetherbee etal.37 tried a number of antibiotics againstH. ducreyi in vitro and came to the conclusion thatstreptomycin, previously successfully tried inman,17 was the only one likely to be effective.This has since been disproved. The writer46 47 48performed inoculation experiments on some 227volunteers, inoculating some of them with virulentbubo fluid from untreated persons, treating themwith various drugs, and noting whether the experi-mental infection was or was not produced at thesite of inoculation. In another group of patientswith chancroidal buboes, fluid from which wasproved to be virulent by inoculation into untreatedcontrols, the fluid was again aspirated and inocu-lated into others 24 hours and more after treat-ment with one of the drugs had commenced. Bythese means it was shown that sulphonamides,

streptomycin, penicillin in high doses, aureomycinand chloramphenicol were all effective, whileneoarsphenamine, bismuth and antimony were not.

If the antibiotics are used, streptomycin is theone least likely to mask syphilis, although theauthor noted the healing of lesions with dis-appearance of treponemata in three cases of earlysyphilis given only I.5-6.0 g. of streptomycinover two to three days.46 The dose recommendedis that given for granuloma venereum, or evensmaller amounts, as i gm. twice daily for sevendays, may be sufficient. If the oral antibioticsare employed the course recommended for non-specific urethritis is adequate.

Patients treated with sulphonamides should befollowed up with serum tests once a month forthree months. The period of surveillance shouldbe extended to six months for those patientstreated with antibiotics. The insistence on such afollow-up is only feasible in well-developed com-munities. In places where it is not feasible,e.g. tropical Africa, where diagnostic facilities areoften absent, it is justifiable to treat all patientswith penile sore as for syphilis, adding sulphon-amides for the few cases which prove refractory.For this purpose a single injection of 2.4 megaunits of procaine penicillin G with 2 per cent.aluminium monostearate is most suitable.49

SyphilisThe older drugs used in the treatment of

syphilis, iodides, mercury, bismuth and thearsphenamines, have all had their day and arenow fading from the scene. France, particularly,releases them less readily and the French influenceis felt in many parts of the world, especially theNear East as in Turkey, Lebanon, Syria andEgypt.

Penicillin is the best agent yet discovered. Thenewer antibiotics,. aureomycin,l 25 41 chloram-phenicol,31 40 and terramycin,16 have all beenshown capable of healing the -lesions of earlysyphilis and of reversing the serum reaction.Aureomycin has also been shown capable ofhealing gummata21 and of reversing abnormalspinal fluids.22 Even so, the treatment of syphiliswith these drugs is only in the experimental stageand, at present, they should not be used otherthan experimentally. Their final position in thescheme of things, as a sole or adjuvant treatment,or in relationship with each other, has yet to bedecided. In this paper, therefore, only penicillinwill be considered.

Early SyphilisTowards the end of the mercury era, with its

alternation of too much and too little treatment(usually too much), it was usual to treat the

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patient with appropriate rest periods for at leastone year. The same practice was followed witharsenic and bismuth once it was realized thatEhrlich's dream of curing syphilis with a singledose was not to be realized. Indeed, the French35have defined the treatment of syphilis as: (i) Theperiod of attack for one year; (2) the period ofconsolidation for two to three years; and (3) theperiod of insurance treatment for three to fouryears, followed by observation for life. Thus, insome circumstances, the treatment of syphilishas been sometimes almost as bad as the diseaseitself.

However, the older regimes did at least ensurethat more than go per cent. of those that com-pleted it were cured. Thus Thompson andSmith,33 analysing the results of 77I cases afterI6 to 29 years, found 90.4 per cent. were free ofthe disease. Few cases, however, completed theirtreatment, while with penicillin practically allpatients obtain the essential part. With penicillinthe period of attack is reduced to only eight days,although the period of surveillance remains thesame. It is the period of consolidation which isopen to dispute.Although penicillin was discovered in Britain

its exploitation has been more successfully pursuedin the U.S.A. The first schedule to be employedfor syphilis consisted of 2.4 mega units given over7i days, but the varying and equivocal resultslater obtained led to the realization that penicillincontained a number of fractions (G, F, X and K),of which the G fraction is the most potent againstsyphilis.

In a short time crystalline penicillin G waspurified and used as a routine in the treatment ofsyphilis with greatly improved results. Theoriginal method of giving the injections every twoto four hours was replaced by single daily injec-tions of a delayed-absorption preparation such aspenicillin in oil-beeswax (POB-Romansky for-mula30). The standard course of penicillin thenconsisted of eight daily injections of penicillin inoil-beeswax, although this substance was notalways easy to administer. It has now beenreplaced by procaine penicillin G with 2 per cent.aluminium monostearate (PAM). It was foundthat procaine and penicillin combined together toform a substance which was more slowly absorbed.When procaine penicillin is suspended in arachisoil and gelled with 2 per cent. aluminium mono-stearate even more prolonged serum levels can beobtained, and eight daily injections of 600,000units of PAM are now widely employed for earlysyphilis.

Actually a ' single' injection of 2.4 mega unitsof PAM (4 ml. in each buttock) will maintain ablood level for a week or more40 54 and the cure

of syphilis by a single injection is possible.Ehrlich's dream is realized. This is not athoroughly satisfactory treatment for the indi-vidual, although only io per cent. of failures werenoted after 15 months in consolidated figures oftheUnited States Public Health Service.8 Its greatestpotentialities, however, are for mass treatmentcampaigns in medically undeveloped areas, inwhich the main object is not to guarantee a curefor the individual but to reduce the incidence ofinfective lesions in the masses. The writer hasused this method with success in Africa, andW.H.O. are employing it in Haiti and Indonesiafor yaws, and in Iraq for bejel. Syphilis ofprimitive races is frequently of the bejel type;non-venereal and spread by close contact, dirt,overcrowding, flies and the communal drinkingbowl. The writer found another variety, thenjovera, in Southern Rhodesia.51 'Single shot'methods are most valuable in such circumstances,60but are not recommended for those countries inwhich the best possible treatment of the individualis practised.. In this country we never abandoned entirelythe use of the more prolonged treatments buteffected the traditional British compromise andcombined one course of neo-arsphenamine andbismuth with 4.o-4.8 mega units of penicillin.

It has been noted that cases in the secondarystage, which comprise about one-third of the malesald two-thirds of the female cases of early syphilis,fare less well than those of primary, especiallysero-negative primary syphilis. The failure ratefor secondary cases at two years with the old 2.4mega units of commercial penicillin alone has beenassessed at 35 per cent.1 With crystalline peni-cillin G it was substantially reduced to I2 percent.3However pleased we have been in this country

with the results of a schedule consisting of 4.8mega units of penicillin over eight days plus5.5-6.0 g. of neoarsphenamine and 2 g. of bismuthover io weeks, the toxic complications of derma-titis, agranulocytosis, and encephalopathy-not toforget the added risk of syringe-transmittedjaundice when intravenous injections are given-caused many clinicians to drop the arsenic andgive only penicillin and bismuth.20 23

Unfortunately we have no central statisticalunit in Great Britain which can produce co-opera-tive figures of our own results. Some co-operative data is, however, forthcoming asa result of the action of the W.H.O. who,rightly concentrating on the results of treat-ment of. secondary syphilis, have obtained andcombined data from two London clinics. It ishoped that in the future we will continue toproduce such figures for ourselves, for this basic

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feature of clinical research has maintained for solong the American lead in venereal disease affairs.The W.H.O. analysis is most interesting and

has been presented by Guthe and Reynolds.l1The British figures concerning penicillin, neo-arsphenamine and bismuth, and penicillin andbismuth only, are contrasted with those of PAMalone in America. The cumulative retreatmentrate at two years is considered to be 14.5 per cent.with penicillin alone, I3.6 per cent. with penicillinand bismuth, and only 5.4 per cent. with peni-cillin, arsenic and bismuth. On the other hand,the percentage of serious reactions was only 0.12with penicillin alone, o.91 with penicillin andbismuth and 9.55 with penicillin, arsenic andbismuth. Moreover, the percentages of patientscompleting treatment with the three groupsrespectively was 96.8, 83.2 and 69.8 per cent.(although it must be admitted that the numberscompleting the penicillin course must have beenapproximately equal in all groups).A statistical examination of the above indicates

that the differences between the toxicity anddefault rates of the different groups are significant.Those between the efficacy of penicillin and bis-muth, and penicillin, arsenic and bismuth, arenot; and one awaits eagerly the collection of moredata. It thus appears that any possible superiorresults of combining arsenic and bismuth withpenicillin are offset by the increased default rateand the added risk of toxic complications. Triadsare now in progress at St. Mary's giving weeklyinjections of 600,000oo-900,ooo units of penicillinfor io weeks following the same penicillin courseof eight daily injections of 600,000 units, and thisprobably represents a good standard treatment forearly syphilis. This is followed by serum testsonce a month for six months, once a quarter for ayear, half-yearly for a further year, with a cerebro-spinal fluid examination at the end of that time.Relapses may be treated as before, perhaps withthe addition of bismuth and/or arsenic.Late Syphilis

Late syphilis consists of late latent syphilis,benign (gummatous) late syphilis, cardiovascularsyphilis and neurosyphilis. Information con-cerning the results of the treatment with penicillinof benign late syphilis and neurosyphilis is tohand, but it is still difficult to evaluate the resultsin late latent and cardiovascular syphilis, asinsufficient time has elapsed as to make thispossible.

In the old days neoarsphenamine and bismuth,given over a period of at least one year, was asatisfactory form of treatment for late syphilis,although in neurosyphilis tryparsamide was oftensubstituted for neoarsphenamine, and fever by

malaria or hypertherm given in addition. Sincepenicillin was introduced it has been the practicein this country after its use to continue treatmentfor six months with arsenic and bismuth; althoughlatterly, in some clinics, a weekly dose of 600,000-9oo,ooo units of procaine penicillin has replacedthe arsenic and sometimes the bismuth also, itbeing felt that there is little that arsenic and bis-muth can accomplish that penicillin cannot dobetter and more safely.

Cardiovascular syphilis may be obvious or itmay be concealed in cases of suspected late latentsyphilis: also it may be present, either recognizedor unrecognized, in neurosyphilis. In all of thesecircumstances there is a danger of a focal Jarisch-Herxheimer reaction in the aorta if competentspirochetocidal drugs (e.g. penicillin, arsphena-mines and oral antibiotics) are suddenly used.Similar focal reactions may occur in other partsof the body in other forms of late syphilis. Forthis reason it has been the practice to commencetreatment giving injections of bismuth, with orwithout iodides, once or twice weekly for four tosix weeks. Late syphilis is seldom a medicalemergency and, after this short course, penicillinmay then be safely given. This perhaps is thestrongest remaining indication for the retention ofbismuth in the treatment of syphilis today. How-ever it is not unlikely that the heavy metal could bereplaced in this respect by the oral antibioticsgiven in increasing doses, but this has yet to beproved.

Incidentally a number of writers consider thatthe danger of therapeutic shock is over-estimated,and at least one group of workers9 have gone sofar as to break a basic rule in the treatment ofaortic syphilis with heart failure, viz., treat theheart failure before the syphilis, and have givenpenicillin and digitalis simultaneously to the pre-viously untreated case without adverse effect.On the other hand, tragedies have indeed fromtime to time been reported and it seems desirablenot to take unnecessary risks even if they areslight.

In the treatment of neurosyphilis malaria andfever have been combined with penicillin in anumber of centres, but the view is now widelyexpressed that there is little to be gained by theaddition of fever, which may, indeed, be dan-gerous in debilitated subjects. There has alsobeen a tendency to increase the dose of penicillinfrom 4.8 million units to 9 million units or more,given over I5 or more consecutive days. Recentassessments by Ingraham et al.,18 however, whoseexperience now extends over 603 cases, some ofwhich have been observed for seven years, stillsuggest that the optimum dose of penicillin is inthe region of 4.0-4.8 million units given over

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eight days. Although no harm can arise fromgiving more than this amount, there is little to begained by doing so: the disease is either cured oris resistant from the outset. The index ofimprovement is the cerebrospinal fluid, which mayshow a spate of abnormalities in neurosyphilis.Clinical signs dependent upon breaks in neuronsare unlikely to change, and the serology in treatedlate syphilis is usually fast.

Congenital SyphilisThe optimum time during which to cure con-

genital syphilis is before the child is born. Thismay be done in 95 per cent. of cases by a-courseof eight daily injections of 600,000 units of pro-caine penicillin given during pregnancy. It iscustomary to continue treatment until term, orgive two additional injections of 2.4 mega unitsof PAM once a week during the last two weeks, inorder to insure against a possible relapse in themother being transferred to the child. Penicillinis likewise the drug of choice in the treatment ofearly congenital syphilis, some 400,000 units perkg. of bodyweight being spread over o0 to 15 days.Additional weekly treatment with penicillin,and/or sulpharsphenamine and bismuth which arewell tolerated in the child, may be continued forsix months. The follow-up should be as forearly acquired syphilis in the adult.

Late congenital syphilis offers similar problemsas the treatment of late syphilis in the adult. Inboth a lumbar puncture should be performedbefore treatment to exclude involvement of thecentral nervous system. Penicillin should be

given to all and the treatment continued over aperiod of six months. The complications ofinterstitial keratitis may require fever to bring itto a standstill, but the giving of adequate treat-ment, and even a reversal of the blood to nega-tivity, are no guarantees that the condition maynot affect the other eye after an interval. Corti-sone and ACTH have been shown to exert aprofound effect upon the defence mechanisms ofsyphilis.84 On stopping the drug these mechan-isms revive with added activity and it has beenqueried whether this so-called 'rebound phe-nomenon' may contraindicate their use insyphilis owing to possible dire consequences uponunsuspected aortic and other buried lesions. Itis probable that these drugs will be of great valuein reducing the intense defence mechanisms ininterstitial keratitis, which frequently lead tocomeal opacities and loss of vision. If penicillintreatment precedes, or is given simultaneouslywith cortisone, the 'rebound phenomena' maypossibly be avoided. We must await the resultsof further work.Few cases of syphilis have been reported which

do not respond to penicillin in sufficient doses.Every case of syphilis deserves a course of penicillin.If refractory cases are met we have more peni-cillin, the oral antibiotics and neoarsphenamineand bismuth held in reserve.

SummaryThe indications of the various drugs at present

employed in the treatment of the venereal diseasesmay be summarized as follows:-

Disease. First Choice. Second Choice. Third Choice.

Syphilis Penicillin More penicillin Oral antibioticsNeoarsphenamineBismuth

Gonorrhoea Penicillin Streptomycin AureomycinChloramphenicolTerramycin

Lymphogranuloma venereum Sulphonamides Aureomycin FeverGranuloma inguinale Chloramphenicol Aureomycin Streptomycin

Soft sore (chancroid) Sulphonamides Streptomycin Oral antibioticsPenicillin

Non-specific urethritis Chloramphenicol Streptomycin SulphonamidesTerramycin PenicillinAureomycin

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384 POSTGRADUATE MEDICAL JOURNAL August 1951

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Heinemann, London.52. WILLCOX, R. R., and FINDLAY, G. M. (1949), Brit.

Med. J., 2, 257.53. WRIGHT, L. T., SANDERS, M., HOGAN, M. A., PRIGOT,

A., and,HILL, L. M. (1948), J. Amer. Med. Ass., 138, 408.54. YOUNG, M. Y., ANDREWS, G. W. S., and MONT-

GOMERY, G. M. (1949), Lancet, i, 863.

RUTHIN CASTLE,NORTH WALESA Clinic for the diagnosis and treatment of Internal Diseases (except Mental or Infectious Diseases). The

Clinic is provided with a staff of doctors, technicians and nurses.The surroundings are beautiful. The climate is mild. There is central heating throughout. The annual

rainfall is 30.5 inches, that is, less than the average for England.The Fees are inclusive and vary according to the room occupied.

For particulars apply to THE SECRETARY, Ruthin Castle, North Wales.Telegrams: Castle, Ruthin. Telephone: Ruthin 66.

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