Incubating syphilis and contact treatment

34 0. IDS0E, T. GUTHE, & R. R. WILLCOX Clinical manifestations that late congenital syphilis (of more than 2 years' duration) has in common with acquired syphilis in adults react similarly to penicillin treatment and patients should be subjected to the same follow-up measures. Tabes dorsalis is encountered less frequently than in the adult (US Department of Health, Education and Welfare, 1968) and cardiovascular syphilis is only occasionally encountered (McCulloch, 1930; Bonugli, 1961). Reservations must be made as to the effect of penicillin in complications peculiar to congenital syphilis. In eighth-nerve deafness penicillin can to some extent arrest progression of the pathological changes, but reduced hearing will be only insignifi- cantly restored (Tomanek & Horak, 1964). This is in contrast to eighth-nerve deafness associated with early syphilis in adults, where penicillin can certainly improve and sometimes completely restore hearing. This emphasizes again the necessity for early diag- nosis and treatment. Interstitial keratitis is not dramatically affected by penicillin, nor can recurrences or extension to the other eye be prevented (Klauder, 1947; London & Noojin, 1948). Clutton's joints do not respond well to penicillin (US Department of Health, Education and Welfare, 1968). The rather poor achievements of penicillin alone in the treatment of these complica- tions may be caused by delayed hypersensitivity phenomena concerned in their pathogenesis. This would explain the observed beneficial effect of additional corticosteroids in interstitial keratitis (Home, 1951; de Graciansky & Grupper, 1957; Nunziata et al., 1964; Rasmussen, 1969), in eighth- nerve deafness (Hahn et al., 1962; Hahn, 1964; Morrison, 1969), and in Clutton's joints (US Department of Health, Education and Welfare, 1968). In eighth-nerve deafness, the addition of large doses of prednisone has been particularly recommended (Hahn, 1964; Patterson, 1968; Morri- son, 1969). The pathogenesis of interstitial keratitis should be considered in the light of the finding of treponemes in the aqueous humour of the eye in affected patients (Goldman & Girard, 1967; Dunlop et al., 1968), although the meaning of this observa- tion is as yet unclear. Virulent treponemes sensitive to penicillin have recently been recovered from the aqueous humour after apparently adequate penicillin treatment of a syphilitic infant (Hardy et al., 1970), perhaps indicating too low a level of the antibiotic in this fluid. INCUBATING SYPHILIS AND CONTACT TREATMENT TERMINOLOGY The terms " prophylaxis " and " prevention " are often used synonymously. " Prophylactic treatment" generally signifies treatment aiming at protecting individuals from developing disease by using an effective drug either prior to (preventive) or after (abortive) exposure to contagion. Since the spread of disease in the community will be prevented by this procedure, the effect will also be epidemiological. Prophylactic treatment of symptomless contacts in venereal disease control programmes is therefore often termed epidemiological treatment. ABORTIVE TREATMENT Eagle (1949) showed that the treponemicidal effect of penicillin is directly dependent on the number of treponemes in the host. Inoculation of animals in the incubation period demonstrated that (a) the penicillinaemia required to prevent the development of manifest symptoms must be prolonged with increasing numbers of inoculated treponemes, and (b) the later in the incubation period penicillin treat- ment was commenced, the longer penicillinaemia had to be extended to be efficacious. A similar pattern is discenible in man. The observations made raised practical questions on the abortive treatment of incubating syphilis in sex contacts of persons with infectious syphilis, particularly as regards total dosages required and the duration of post-treatment control. In some instances doses of 100 000 IU of PAM given intramuscularly for acute gonorrhoea do not cure a concomitantly acquired syphilis infection (Ids0e, 1947). On the other hand, 300 000 IU of PAM in one injection proved sufficient to cure most cases of early seronegative syphilis (Wright et al., 1950). It is therefore probable that in incubating syphilis the failures with this dose are progressively fewer, the earlier in the incubation period the treat- ment is instituted. On the other hand, if the doses are increased the results will be better. Thus as PENICILLIN IN THE TREATMENT OF SYPHILIS PROPHYLACTIC TREATMENT OF ACQUIRED SYPHILIS (EPIDEMIOLOGICAL TREATMENT) PREVENTIVE TREATMENT Adequate penicillinaemia to prevent inoculation of trepo- nemes at the time of exposure (pre-exposure treatment) ABORTIVE TREATMENT Adequate penicillinaemia to destroy the treponemes dur- ing the incubation period (post-exposure treatment) PROPHYLACTIC TREATMENT OF CONGENITAL SYPHILIS (PRENATAL TREATMENT) before 4th month of pregnancy PREVENTIVE TREATMENT prevention of foetal infection early as 1949 it was shown in a series of 256 persons who had been exposed to infectious syphilis that 900 000 IU of POB gave practically full protection against the development of manifest infection, while two-thirds of a control group who did not receive abortive treatment after exposure developed syphilis (Alexander et al., 1949). In another series in which 600 000 IU of POB was used, only about 4% of the treated contacts developed syphilis compared to 25% of untreated contacts (Plotke et al., 1949). Epidemiological treatment was 100% effective when 748 clinically and serologically nonreactive contacts were given 2.4 million IU of benzathine penicillin at one session (Moore, 1964). Intramuscular injections of 600 000 IU of benzathine penicillin or of aqueous procaine penicillin G and an intramuscular tetra- cycline preparation given in a dosage of 500 mg on two successive days gave very unsatisfactory results. Fourteen of 161 patients (or a 9% cumulative rate after 4th month of pregnancy ABORTIVE TREATMENT If cure of infected foetus based on numbers observed for varying periods) developed syphilis when a placebo was used. In practice it is often difficult and sometimes impossible to define accurately the date of exposure to infection. Moreover, the incubation period may have individual variations. There is also the possi- bility that the presence of a primary chancre may be overlooked or concealed or that it may not develop (syphilis d'emblee). Immunologically speaking the patient may or may not be in the incubation period and a safety margin is therefore desirable. Abortive treatment schedules should take this into account, adhering to the minimum requirements for curative penicillin treatment of clinical primary-secondary syphilis, i.e., a total of 4.8 million IU of PAM or 2.4 million IU of benzathine penicillin G (Garson, 1965; Allison, 1965). In communities where the prevalence of syphilis is low and infectious cases are encountered only sporadically, abortive treatment is 35 0. IDS0E, T. GUTHE, & R. R. WILLCOX usually limited to patients where a definite source of infection can be identified and where the exposure date can be determined, e.g., in cases where " ping- pong" syphilis is likely to result. In such cases treatment may be initiated very early in the incuba- tion period, making its distinction from preventive treatment difficult. Reduction of the dosages used is then considered justified. Absolute indications for prophylactic treatment are transfusion syphilis and treatment of infants born of untreated or inadequate- ly treated syphilitic mothers (Wolff, 1966). PREVENTIVE TREATMENT If there is already a treponemicidal penicillin con- centration in the blood and tissues of a previously noninfeCted contact at the moment of treponeme transmission, these will be killed provided the peni- cillinaemia is of sufficiently long duration after exposure (Eagle, 1949). Hence long-acting repository preparations provide possibilities for the true pre- ventive or pre-exposure use of penicillin. A single dose of 600 000 IU of PAM produces an effective prophylactic blood-level duration for 5-6 days. However, under conditions of repeated sexual expo- sure repeated injections of PAM are required in most cases where preventive treatment is desired, in order to maintain an adequate penicillinaemia over a " practical " period of time (weeks). Experience shows that in organized brothels maintenance doses of PAM in prostitutes at calculated intervals repre- sent an effective epidemiological weapon (Edmund- son, 1953; Durel, 1958; Guthe, 1958; MacCabe, 1961; De Reus, 1970). Such prophylactic use of PAM requires knowledge of the necessary peni- cillinaemia so as to reduce to a minimum the amount of repository penicillin needed in medical supervision of prostitutes. With benzathine penicillin G in aqueous suspen- sion or in oil (BOM) a treponemicidal penicillinaemia can be maintained for a longer period than with PAM after single injections; thus with 2.4 million IU administered intramuscularly, adequate penicillin- aemia will persist for 2-3 weeks. This has facilitated prophylactic treatment of prostitutes (Hill, un- published report to WHO, 1969). To what extent such preventive prophylactic penicillin injections are currently used is difficult to estimate. The peni- cillinaemia at the time of and following exposure is uncertain with peroral penicillin, since there are greater individual variations in the resorption and excretion of perorally than of parenterally used penicillin. Routine peroral preventive application of penicillin in syphilis is therefore not advised. How- ever, in pleasure houses and similar places in many countries, tetracycline tablets and other antibiotics are widely used for prophylaxis of syphilis and gonorrhoea. The continued use of intramuscular penicillin injections to maintain treponemicidal blood levels for preventive purposes may result in side effects, e.g., sensitization to penicillin, and the development of penicillin-resistant micro-organisms, e.g., the gonococcus, in the host. It has therefore been discontinued in some areas. Regular preventive application of penicillin should be limited to indi- viduals under medical supervision. Studies have been carried out among bar girls in Japan of the preventive effect of vaginal foam tablets that also include small doses of penicillin G, chloramphenicol or oxytetracycline (Ohno et al., 1958). It was shown that effective antibiotic vaginal concentrations can be maintained by continued use of the tablets, apparently with little systemic absorption, and that they are effective in the prophylaxis of both gonor- rhoea and syphilis. Further critical observation of the long-term effect of such tablets seems necessary, including the possible inducement of allergy to penicillin. A study for this purpose has been started by the International Union against the Venereal Diseases and Treponematoses (World Health Orga- nization, 1969). EPI:DEMIOLOGICAL TREATMENT The need for epidemiological treatment of con- tacts of patients suffering from yaws and endemic syphilis became evident early in the WHO-assisted mass campaigns against endemic treponematoses (Grin, 1953; Guthe et al., 1953). The widening use of prophylactic or epidemiological treatment as an important part of venereal disease control, particu- larly in the USA (Brown, 1964; J. Amer. med. Ass., 1964; Garson, 1965), has attracted wide interest. The principles of epidemiological treatment are rapid location and examination of contacts of infectious syphilitics, and treatment of those who have symptoms as well as those who are still clinically and serologically nonreactive on initial examination. Studies indicate that in contagion-exposed social strata 5-20% of such contacts subsequently develop syphilis within 3 months if not treated (US Depart- ment of Health, Education and Welfare, 1969). The method is particularly applicable in local outbreaks 36 PENICILLIN IN THE TREATMENT OF SYPHILIS of infectious syphilis, in which study reports indicate that good results have been obtained (Brown, 1964; Allison, 1965). An evaluation begun in 1963 by the US Public Health Service of the epidemiological treatment of clinically and serologically negative contacts was completed in 1965 (US Department of Health, Education and Welfare, 1965b). It covered 1 652 cases, with 78% observed for a minimum period of 60 days. One group was given penicillin, the other a placebo, and the epidemiological effect was compared. Altogether 10.9% of the 393 contacts who were given a placebo developed syphilis. Epi- demiological treatment with benzathine penicillin G in total dosages of 2.4 million IU was 100% effective, while 1.2 million IU of PAM was found to be 95% effective. In the USSR, using a full course of penicillin (gtejnluht et al., 1967), no cases of syphilis occurred in 388 treated contacts. Epidemiological treatment is thus useful in the control of disease in groups where exposure dates are unlikely to be defined and where there is considerable likelihood that infection has occurred (US Department of Health, Education and Welfare, 1968). Acceptance of epidemiological treatment for the prevention of syphilis has been slower in some areas than in others, particularly in Europe, and has been the subject of prolonged and controversial debate (King, 1954, 1968; Willcox, 1954, 1968; Ormea, 1967). However, as far back as 1955, a WHO survey of port clinics in different countries showed that treatment of all or selected contacts was practised in approximately one-third of them. The proportion was highest (60.9%) in Central and South America and lowest (17%) in European clinics (Willcox & Guthe, 1957). The effectiveness of the mass use of penicillin in a prison population has also been described (Smith, 1965). In many cases, differentiation between prophylac- tic treatment on epidemiological indications and therapeutic treatment of manifest infection may not be possible. Patients treated before the appearance of clinical symptoms and serological reactivity should in any case be subsequently controlled as if already treated for early syphilis. Although in some instances this may prove difficult in practice, it has gradually become accepted that the epidemiological benefits justify the small risks of individuals failing to undergo post-treatment control (J. Amer. med. Ass., 1964; gtejnluht et al., 1967). PROPHYLACTIC EFFECT OF PENICILLIN ALREADY PRESENT IN THE BODY On exposure to or after recent infection with T. pallidum, many persons unknowingly have trepo- nemicidal blood and tissue levels of penicillin result- ing from treatment with penicillin for conditions other than syphilis. Some will also have had established syphilis without knowing it, and the treatment given may be sufficient to modify, but not to cure, the disease. In the USA in the 5-year period 1951-55, for example, when the consumption of penicillin exceeded 350 tonnes, a general and immeasurable penicilHinization of the adult popula- tion at large must have taken place. The same mechanism has undoubtedly been at work in other countries too. This "happenstance " penicillin is thought by several investigators to have played a part in interrupting the transmission of unrecognized infections with T. pallidunm and consequently in the decrease in the incidence of new cases of early syphilis that took place between 1948 and 1956 in many countries of the world (Danehower & Schamberg, 1963). On the other hand, since 1956 an increasing number of infections other than syphilis have been treated with broad-spectrum antibiotics in dosages ineffective in the treatment of incubating syphilis. Also, gonorrhoea is now treated much more frequently with drugs other than penicillin. Some antibiotics are less effective against syphilis, e.g., kanamycin and rifampicin. The preventive effect on concomitant syphilis of penicillin treatment of gonorrhoea has thus been considerably lessened. Lastly, the occurrence of penicillin reactions, which some years ago tended to weaken confidence in penicillin as a safe drug, has contributed to a tightening-up of the previous general use-and mis- use-of penicillin, thus reducing its broad pro- phylactic effect in the general population. 37