Early syphilis

PENICILLIN IN THE TREATMENT OF SYPHILIS 13 atypical chancres, syphilis d'emble, abnormal clini- cal forms, polymorphism, milder signs and symp- toms, and prolonged incubations have all been described as being more frequent than before. These aspects were studied in a survey undertaken among members of the WHO Expert Advisory Panel on Venereal Infections and Treponematoses in 1965. Fifty-five per cent of the panel experts did not find that the initial manifestations had changed, although occasional atypical manifestations occurred. EARLY SYPHILIS TREATMENT RESULTS During the first decade following the introduc- tion of penicillin, its efficacy in early syphilis was ap- praised in relatively short-term observation studies in a number of countries (Willcox et al., 1954), notably the USA (Moore, 1948; Bauer & Price, 1949; and others), Austria (Gumpesberger, 1953), France (Jame et al., 1952; Gougerot, 1953), Switzerland (Mayer & Herkenhoff, 1951; Miescher & Brenn, 1952), Yugoslavia (Grin, 1953), Norway (Danbolt, 1954), India (Rangiah, 1950), and Turkey (Ceriboglu, 1950). In these early studies and-surprisingly enough-also in later investigations, very few reports of the results of penicillin treatment complete- ly satisfy the criteria and methods of analysis well outlined by Iskrant et al. (1951); an important exception is the Blue Star study in the USA (1945) (Bauer, 1951; Shafer et al., 1954). Moreover, there are differences in definition concerning stages of disease in relation to characteristics at the start of therapy, the nature ofpenicillin preparations, dosages and treatment schedules in relation to time/dose considerations, follow-up observations after treat- ment, criteria of cure, etc. We have analysed the voluminous medical litera- ture on the effect of the use of penicillin in the treatment of early syphilis since 1943. Only 5 640 patients have been retained as meeting generally the appraisal requirements (Tables 2, 3 and 4). Even in these patients the stages of the disease are not always fully defined. In the present study a number of patients have therefore been grouped as " early syphilis not defined ", and the category " early latents " has been retained where the penicillin effect in relation to the immunological state at the onset of treatment could not be assessed. Primary syphilis Table 2 shows the treatment results as observed in Austria, France, Poland, Singapore, Switzerland, the United Kingdom, and Yugoslavia. In 1 381 cases of serologically nonreactive primary syphilis treated with 2.4-24.0 million IU of penicillin and followed for 2-10 years, clinical (and serological) normality was the outcome. In one group of 211 patients (Jefferiss & Willcox, 1963) retreatment was required in 3.2% of the 186 cases followed, this being attri- buted in most cases to reinfection. Among 1 030 patients treated for seroreactive primary syphilis, 93-100% obtained serological nonreactivity, as determined by lipoidal antigen tests. Some reinfec- tions were described in these patients also (Jefferiss & Willcox, 1963; Tramier & Oddoze, 1965). Secondary syphilis Table 3 includes 783 patients with secondary syphilis who were treated on the basis of the same dose/time relationship schedules as those for primary syphilis, or in some cases (Capinski et al., 1969) with somewhat higher total doses. Among these patients 98-100% serological nonreactivity (using lipoidal antigen tests) was achieved. No relapses were observed, but in another group of 196 patients there was a 3.2% rate of recurrence among the 158 cases followed, the majority thought to be reinfections (Jefferiss & Willcox, 1963). "Early syphilis " and " early latents" Table 4 includes 2 458 patients with " early syphi- lis not defined " or " early latent syphilis " treated on the basis of similar dose/time schedules in Denmark, the Federal Republic of Germany, France, Poland, Sweden, the United Kingdom, the USA, and the USSR and followed for 2-11 years. In a group of 50 patients described as early latents, the retreat- ment rate was 8.7% of the 46 cases followed (Jefferiss & Willcox, 1963), the great majority being attributed to reinfections. In a group of 146 patients with " early syphilis " there was one clinical relapse and 12 reinfections (Degos & Ebrard, 1957) and serological nonreactivity was achieved in 78 %. In a parallel survey of 103 early syphilis patients treated with the same penicillin schedules plus bismuth in courses lasting 2-4 years, the investigators found 95 % serological nonreactivity and one relapse but 0. IDS0E, T. GUTHE, & R. R. 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The earlier adequate penicillin treatment is applied in the course of serologically reactive infection, the earlier and more frequently will nonreactivity be achieved (Jefferiss & Willcox, 1963; Luger & Ebner, 1963); reinfections are then more likely (Thomas, 1949). Also, reinfections are unlikely during chronic suppressive bismuth treatment that may act as prophylaxis over a period of time. Finally, re- infections are also less probable in patients having repeated treatments with penicillin for subsequent gonococcal infections. It has already been ascer- tained that differences in patients' social groups, sexual activity and behavioural patterns will affect the likelihood of re-exposure to contagion (Tramier & Oddoze, 1965), giving rise to different reinfection rates in different patient series. Most patients in Tables 3 and 4 became serologically nonreactive within 10 months and all of them within 2 years (to reagin tests). It is notable that in cases where the treponemal immobilization (TPI) test was reported reactive before treatment (Perdrup, 1960) only 50- 70% reverted to nonreactivity within the observation period-a finding to be discussed subsequently. Late complications Among a group of 956 patients with "early syphilis" (Table 4), one person developed sympto- matic neurosyphilis 5 years after treatment (Smith & Price, 1960). In this case the treatment was considered to have been inadequate by the investiga- tors. In the studies in Tables 2, 3 and 4 this was the only case in which late complications occurred. In England, 1 379 patients who were followed up and underwent spinal fluid examination at least one year after penicillin treatment for early syphilis all showed normal findings (Jefferiss, 1963). Of 231 patients treated with penicillin for early syphilis only 3 had inconsequential spinal fluid abnormalities (Fernando, 1968). PENICILLIN PREPARATIONS AND TOTAL DOSES Smith & Price (1960) pointed out that many patients had been treated either with outmoded types of penicillin or with lesser dosages than were subsequently considered adequate. Other investiga- tors saw no significant difference in treatment results with different penicillin preparations although the general trend was towards the use of repository 15 0 0 C.) 0. 0 E0 0 - '0 ._SC 0 0 cn 00. .) 0 'a n ._ i0 C. 0. cv 0 C 0 E C) C,, 00 0. 0 CO I-- o _- C4N Il, 0 4N 8 _ _0._ Co _0 0 E 1-D0 00 00. = 0 O >- 00~ OC C>.°0o EX 0 OC zDE 2.2 CE- .'- cn 0 C CL 0. O C Z 0 0 0 C- C 0 co0. as0 C) 2 <0.0.L 0. IDS0E, T. GUTHE, & R. R. 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C 0'.CC~~C1 .+ C<2 mr-CE. 0 00U) 0E CE.~ CWOCNN U ) 0-CO0 0 LO a 0 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 0 0~~~~~~~~~~~~~~~~~~U.. 0 (C)co CD .6. co C5 (C0)O4 co U))C5 a I- N~~~~~~~~~~~~~u). 0.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~0( 16 PENICILLIN IN THE TREATMENT OF SYPHILIS 17 penicillin. Nevertheless, it is important that the dose/time relationship requirements within the total dose given were generally met. However, in one group treated with a single injection of either 3.0 million IU of PAM or 2.4 million IU of benza- thine penicillin (de Graciansky & Grupper, 1960), the results were excellent in serologically non- reactive primary syphilis, while in seroreactive primary and in secondary syphilis they were con- sidered inferior to those obtained by prolonged treatment schedules. However, there are indications that total doses above 6 million IU of PAM will not improve the overall results in early syphilis. This is stated in particular by Perdrup (1960), who con- cluded that the final outcome was equally satis- factory using either 6 or 12 million 1U of PAM. In our earlier discussion of the nature and rationale of penicillin therapy in syphilis, it was observed that PAM and DBED are preferred, although aqueous benzyl procaine penicillin G is also used quite extensively in multi-injection treatment regimens. Newer semisynthetic penicillins have also been shown to be treponemicidal in vitro and in vivo (Cottini & Lazzaro, 1964; Cannata, 1965), but the observation time for adequate effect in vivo in early syphilis has as yet been too short for proper evalua- tion. The alternative antibiotic therapy of syphilis in cases of penicillin allergy is discussed elsewhere in this review. COMBINW PENICILLIN-METAL THERAPY Experienced venereologists no longer advocate treatment of early syphilis exclusively with arsenicals or arsenicals combined with bismuth. However, some clinicians, particularly in France (Degos, 1968) and in the USSR (Grobulev, 1966), continue to use bismuth or mercury in addition to penicillin in serologically reactive early syphilis. Only rarely is this procedure based on the view that such combined treatment gives superior results (Garnier, 1963; Huriez et al., 1964; Ciarrocchi, 1968; Degos, 1968). The motive is usually to offer the patient the " benefit of the doubt " or to give an " extra guarantee " of cure. The combined treatment is suggested also for psychological reasons in order to hold cases as long as possible for further observation (Huriez, 1965). While bismuth or mercury is sometimes given initially before penicillin in an attempt to avoid Jarisch- Herxheimer reactions (Nick et al., 1963), the actual curative effect of penicillin cannot, according to some, be expected to be improved by supplementing it with bismuth. Thus Prieto & Jimon (1965) demonstrated that bismuth injections in healthy volunteers did not result in any treponemicidal effect of the serum (TPI procedure). Comparative studies of the results of therapy with penicillin alone and with penicillin combined with arsenic and/or bismuth have shown not only that no advantages are gained by adding these more toxic drugs to penicillin (Willcox et al., 1958) but also that treatment with penicillin alone is much safer. Heller et al. (1948) reported that there were no deaths and 240 (or 0.71 %) treatment reactions in 33 724 patients treated with penicillin alone. In 118 544 patients given penicillin and arsenicals, there were 16 deaths and 1 632 or 1.4% severe reactions. LATE SYPHILIS A year after its introduction in the treatment of early syphilis, penicillin was already being used occasionally in late syphilis (Thomas, 1949). The short-term results compared favourably with those of arsenicals and bismuth, but in contrast to the toxic metals penicillin was well tolerated by the patients even in large doses. However, long-term observations were necessary. The long-term appraisal of results of penicillin therapy in late syphilis must take into account the nature of the tissues and body systems involved, the damage inflicted by the chronic syphilitic inflamma- tion and the functional recovery possible as a result also of supporting therapy and medical care. While these factors apply to late symptomatic syphilis they do not apply to late latent syphilis, since-apart from the presence of detectable serum antibodies- this diagnosis is based on the absence of clinical, radiological, spinal fluid and other findings. The appraisal of the outcome of treatment of late symptomatic syphilis must, under the circumstances, be considerably more qualitative than in early syphilis. In the latter condition the effect of treat- ment on surface pathology is evident and offers, together with the relatively rapid serological changes that occur, definitive criteria for evaluation. In late