44 0. IDS0E, T. GUTHE, & R. R. WILLCOX mercury, or with small penicillin doses (Heyman et may reduce fever, they have been considered not al., 1952). The majority of clinicians therefore also capable of preventing the Jarisch-Herxheimer reac- initiate treatment of late syphilis with normal peni- tion (Bien & Suchanek, 1969) and the benefits they cillin doses. Only in cases in which the potential provide may be outweighed by the risks involved risk of increased local damage is more than normally (Viegas et al., 1969). serious (primary optic atrophy or nerve deafness) is Few instances of therapeutic paradox-i.e., clinical initial treatment with very small doses of penicillin, progression in spite of " biological " cure due to or with steroid cover, believed justified (Huriez & rapid replacement of organic tissue by fibrotic scar Agache, 1958; Huriez & Vanoverschelde, 1965). tissue-have been reported following penicillin Corticosteroids have been reported to exert some treatment of late syphilis (Reynolds, 1948; Mohr & effect on the Jarisch-Herxheimer reaction in general Hahn, 1952), and in some of them the worsened (Gudjonsson & Skog, 1968; Arfouilloux, 1969; condition may have been due to inadequate treat- Viegas et al., 1969). However, while corticosteroids ment (Mohr & Hahn, 1952).

THERAPY OF SYPHILIS WITH ANTIBIOTICS OTHER THAN PENICILLIN

GENERAL invisible binding to the proteins takes place, is a constituent of the penicillin nucleus as well as of the Penicillin should not be used for treatment of cephalosporin nucleus, 7-aminocephalosporanic acid syphilis in persons known to be actual or potential (see Fig. 1 and 2) (Feinberg, 1970). There are reports penicillin reactors. Cross-sensitivity occurs in per- of anaphylactic reactions to the initial injection of sons sensitized to this antibiotic regardless of the cephaloridine in patients previously allergic to peni- type of penicillin, since the basic immunological cillin (Thobum et al., 1966; Rothschild & Doty, mechanism in penicillin allergy relates to the anti- 1966; Pedersen-Bjergaard, 1967). Also, skin-sensitiz- genicity of protein-hapten combinations with ing antibodies to cephalothin, cephaloridine, and derivatives of the penicillin G nucleus, 6-aminopeni- 7-aminocephalosporanic acid have been demonstrat- cillanic acid. Although therapy of early syphilis with ed in a patient 5 months after anaphylactic reaction a-aminobenzylpenicillin (ampicillin) has shown clini- to orally administered penicillin (Grieco, 1967). cal and serological results almost comparable to Furthermore, sensitivity to cephaloridine has been those obtained with benzylpenicillin (Cannata, 1965; acquired by handling cephaloridine preparations, Argenziano & Montagnani, 1967), this drug offers with anaphylactic shock after one injection of the no alternative for the treatment of benzylpenicillin- drug (Kaplan & Weinstein, 1967). Apparently, sensitized patients. Also it appears that skin rashes 7-aminocephalosporanic acid derivatives, e.g., ce- occur more frequently after treatment with ampi- phaloridine, cephalosporin C, cephalothin, cephalex- cillin than with other penicillins (Kronig & Dennig, in, and cephaloglycin, are not completely safe 1970). This is possibly due to an ampicillin-specific substitutes for penicillin in allergic patients (J. Amer. allergenic effect of the side-chain component of med. Ass., 1967). Above all, they should not be used ampicillin (Lancet, 1969). Clemizole penicillin in patients who have previously had reactions of an (Muckter et al., 1954, 1957) requires daily injections anaphylactic nature to penicillin. It is probable that of 800 000-1 000 000 IU for the maintenance of similar immunologic mechanisms are also associated effective penicillin concentrations in serum and tissue with the use of synnematin B, the structure of which (Walter & Heilmeyer, 1965), but has insignificant closely resembles that of penicillin. effect in preventing immediate penicillin reactions in Metals are not attractive substitutes for penicillin sensitized persons (Rosenthal, 1958; Sciple et al., in view of their toxicity, the chronic suppressive 1959; Calnan, 1964; Green, 1970). nature of their action, the inconvenient mode of Experimental and clinical evidence shows cross- administration, and the need for application over a sensitivity between conventional penicillins and the long period of time. Effective antibiotics other than cephalosporins (Brandriss et al., 1964; Batchelor et penicillin must be considered a more desirable alter- al., 1966; Mashimo et al., 1967). This is mainly due native. to the fact that the ,B-lactam ring, through which Many antibiotics have been shown to have anti- PENICILLIN IN THE TREATMENT OF SYPHILIS 45 treponemal effect in laboratory experiments, e.g., tinomycin, and derivatives ofthe cephalosporins, e.g., aspergillic acid, gliotoxin, neomycin, polymyxin B, cephaloridine and synnematin B, all of which have bacitracin (Eagle & Fleischmann, 1948), and novo- antitreponemal effects and have undergone (or are biocin (Edelson, 1957; Garson & McLeod, 1957). undergoing) clinical trials in human treponematoses. Because of the scarcity or toxicity of these anti- However, few of the studies undertaken are on a biotics further clinical trials in man have often not large scale. They compare in no way with those been justified. The antifungal antibiotic griseo- undertaken in the early penicillin years. fulvin produced by Penicillium griseofulvum has The broad-spectrum antibiotics are usually bacte- shown some treponemicidal effect (Hasegawa, 1966). riostatic. They interfere with the synthesis of DNA Inactive against T. pallidum in doses given for and RNA, inhibiting the vital processes of the gonorrhoea are kanamycin (Wilkinson et al., 1967), microorganisms and enabling the defence mechan- rifampicin or rimactane (Fuga & Gentili, 1968), and ism of the host to kill them (Lancet, 1967). This the combination of trimethoprim and sulfonamides may explain the weaker effect in vitro of the broad- (neither of which are antibiotics) (Csonka, un- spectrum antibodies as compared to that observed published report to WHO, 1969). in vivo in animal and human syphilis. In contrast, Streptomycin, obtained from Streptomyces griseus, the penicillins and the related cephalosporins are was investigated in the treatment of early syphilis bacteriocidal, acting primarily on the cell wall. in 1945 (Herrell & Nichols, 1945). Following doses of 5.3-16.3 mg per kg of bodyweight per day, the Tetracyclines patients showed initial improvement but subsequent- Chlortetracycline. This compound, produced by ly relapsed. Animal studies indicate that treponemi- a strain of Streptomyces aureofaciens (Duggar, 1948), cidal doses in humans, estimated at some 182 mg was reported in 1948 to give satisfactory initial per kg of bodyweight, would greatly exceed safety results in the treatment of early syphilis (O'Leary et margins in regard to toxicity (Brown, unpublished al., 1948), late cutaneous syphilis, and neurosyphilis; report to WHO, 1959). In practice, therefore, daily doses of 3 g over 15 days, totalling 45 g, were streptomycin is not acceptable for the treatment of suggested in early syphilis. By 1952 one worker and syphilis (Stauber & Kajzer, 1963). Normal doses in his colleagues had treated over 100 cases of syphilis the treatment of gonorrhoea, ranging from 3.0 to with a total dose of 70 g over approximately 11 days 15 mg per kg of bodyweight, would have little or and followed them for up to 2 years (Rodriquez et no treponemicidal effect and are thus unlikely to al., 1952). Satisfactory results were found in 80% modify the course of a concomitantly acquired syphi- of cases of early syphilis and improvement was litic infection (Willcox, 1964a), although they will observed in neurosyphilis. In addition, excellent do so when given in repeated doses (Willcox, 1950a). results were recorded in the treatment of syphilitic Gentamycin belongs to the streptomycin-neo- pregnant women. It was concluded that chlortetra- mycin group and contains the streptamin nucleus cycline in the doses given had a therapeutic effect that is common to these compounds. Gentamycin comparable to 4.8 million IU of penicillin G. Later is useful in systemic treatment of bacterial infections reports have confirmed the effectiveness of chlor- and has proved effective against Pseudomonas aeru- tetracyclines in all stages of syphilis (Taggart et al., ginosa (Weinstein et al., 1964). Laboratory experi- 1952; Montgomery & Knox, 1959a; Gamier, 1963; ments (Holzmann et al., 1969) and clinical observa- Merklen & Renoux, 1966). However, a high inci- tions (Luger, 1969) seem to indicate that genta- dence of gastrointestinal and vitamin B disturbances mycin has no antitreponemal effect when applied in was reported by most of the investigators (Knox & the usual therapeutic doses (40 mg 3 times daily, Moore, 1963). Recommended total doses for treat- intramuscularly). ment of early syphilis are 30-40 g given over 10-15 days, and of late syphilis 36-45 g over 10- 15 days. CHARACTERISTICS OF ANTIBIOTICS OTHER THAN PENICILLIN USED IN SYPHILIS THERAPY Oxytetracycline. Derived from Streptomyces rimosus, oxytetracycline became available in 1950 The following appraisal includes the tetracyclines (Finlay et al., 1950) and was soon used in the treat- (chlortetracycline, oxytetracycline, demethylchlor- ment of syphilis (Hendricks et al., 1950; Schoch & tetracycline and N-(pyrrolidinomethyl)tetracycline), Alexander, 1950). Oral total doses of 4.2-10.5 g chloramphenicol, erythromycin, spiramycin, spec- over 6-8 days gave satisfactory short-term results in 46 0. IDS0E, T. GUTHE, & R. R. WILLCOX early syphilis. As the incidence of early symptomatic of tetracycline, and excretion is more than 40 % syphilis at that time was low, cases for clinical trial slower (Barber & Garrod, 1963). A smaller dose than became scarce. A few reports with limited numbers used in the other tetracyclines will therefore main- of patients treated with total doses of 30-50 g over tain comparable blood concentrations. Furthermore, 15 days indicated therapeutic effects similar to in vitro and in vivo experiments have shown that chlortetracycline (Robinson & Robinson, 1951; demethylchlortetracycline has somewhat stronger Irgang & Alexander, 1953). Oxytetracycline was also treponemicidal effects than other tetracyclines used intramuscularly in doses of 200 mg twice daily (Siegenthaler et al., 1960; Fegeler & Knauer, 1963). over 10 days for treatment of early syphilis (Baler, In oral doses of 150-250 mg four times a day over 1956). More than 30% relapses were reported after 10-15 days, satisfactory clinical results have been 8 months' follow-up. Recently, oxytetracycline achieved in early syphilis (Siegenthaler et al., 1960; administered parenterally has attracted new interest. Fegeler & Knauer, 1963; Kimmig, 1966; Nolting, In one study, a long-acting preparation was adminis- 1966). However, in cases of renal disturbance there tered intramuscularly in primary and secondary is a danger of blood and tissue accumulation of the syphilis (Garnier et al., 1965). Daily application of antibiotic because of its slow rate of excretion 250-500 mg for 10 days gave results equal to those (Walter & Heilmeyer, 1965). Also, demethylchlor- achieved with penicillin treatment. The patients tetracycline is more likely than other tetracyclines to frequently experienced pain at the injection site. induce photosensitibity skin reactions. Similar good results were reported in early syphilis N-(pyrrolidinomethyl)tetracycline. This is highly with oxytetracycline given intravenously (Bosse, soluble and provides a neutral aqueous solution. 1966; Steppert, 1966). Four cases of primary sero- It is therefore easily administered parenterally, reactive syphilis and 2 cases of secondary syphilis resulting in high blood and tissue levels (Knothe & were reported as treated with parenterally adminis- Mahler, 1959). Its toxicity (mainly liver damage) tered oxytetracycline (Luger, 1968). In one case the may exceed that of other tetracyclines (Lundsgaard- intramuscular treatment with a repository compound Hansen et al., 1960). N-(pyrrolidinomethyl)tetra- was discontinued because of pain at the injection cycline passes the placental barrier (Spittel et al., site and fever (but treatment continued with oral 1961). In vitro and in vivo experiments indicate that oxytetracycline), while intravenous injections in its antitreponemal effect is less than that of demethyl- 5 cases caused no side effects. The clinical and sero- chlortetracycline and chlortetracycline (Fegeler & logical responses were satisfactory. The recom- Knauer, 1963). Satisfactory results were obtained mended total doses for early syphilis are 30-40 g with intravenous N-(pyrrolidinomethyl)tetracycline orally over a period of 10-15 days, intramuscularly treatment in cases of early and late syphilis followed 250 mg every 6 hours for 10 days, and intravenously for more than 4 years after treatment (Kiihl, 1965; 250 mg twice a day for 20 days. Matanic, 1965, 1966). Excellent results were also Tetracycline. This antibiotic was introduced in observed after venous administration in primary and 1953 (Conover et al., 1953). It can be produced secondary syphilis (Luger, 1968). The dosage semisynthetically from chlortetracycline. Rajam et recommended is 275 mg twice daily intravenously al. (1956) reported four cases of early syphilis treated for 15-20 days. To prevent Jarisch-Herxheimer with a total dose of 24 g of this drug over 12 days. reactions, 25 mg prednisolone sodium succinate has The short-term results were satisfactory. Two also been added to the first one or two injections pregnant syphilitic mothers delivered nonsyphilitic (Luger, 1968). children. Satisfactory serological response in latent Other new tetracyclines. These include limecycline, syphilis was also reported (Urabe et al., 1961). No methacycline, clomocycline, doxycycline, and a failures were observed in 52 patients in different triple mixture of tetracycline, chlortetracycline, and stages of syphilis treated with a total of 30 mg of demethylchlortetracycline, but there is as yet little tetracycline (Lucas & Price, 1967). Similar oral information on their use in syphilis. Doxycycline is dosages to those usually recommended for oxy- a semisynthetic derivative of oxytetracycline. Be- tetracycline (Skog, 1966) should be given. cause of its fast and almost complete absorption Demethylchlortetracycline. This substance, struc- after oral application and its slow renal elimination, turally very similar to chlortetracycline, appeared prolonged blood-levels are obtained (Dimmling, in 1960 (Finland & Garrod, 1960). It has a high 1967; Winkler & Weih, 1967; Meyer-Rohn, 1968). degree of stability. Its absorption is better than that Possible side reactions resemble those of other PENICILLIN IN THE TREATMENT OF SYPHILIS 47

tetracyclines, although intestinal disorders appear to 1963; Walter & Heilmeyer, 1965). It was soon found be less frequent. Preliminary good results have been that treponemes were susceptible to erythromycin achieved in a limited number of patients with early (Keller & Morton, 1953). In 1954 the first cases of syphilis treated with doxycycline in dosages of symptomatic early syphilis were treated with the 200 mg daily for 10-20 days (Alexander & Schoch, drug (Alexander & Schoch, 1954), using 200 mg 1966; Steppert, 1968; Wodniansky et al., 1969). orally 4 times a day for 8 days. The initial results compared well with those observed after therapy Chloramphenicol with broad-spectrum antibiotics. Subsequent clinical The first broad-spectrum antibiotic to be dis- studies have confirmed these findings (Montero, covered, chloramphenicol was obtained from Strepto- 1956; Montgomery & Knox, 1959b; Lebedeva, 1965; myces venezuelae (Ehrlich et al., 1947). The crystal- Wojtkiewiczowa & Toruniowa, 1965). The absorp- line antibiotic was named chloromycetin. Later, tion of erythromycin given orally is somewhat when it became the first to be synthetically produced irregular due to acid lability. Coated tablets have (1949), it was renamed chloramphenicol. It is easily therefore to be used. Erythromycin stearate and and completely resorbed by oral administration and notably the propionyl ester of erythromycin (erythro- peak blood-levels are reached in 2-4 hours. It mycin estolate) are acid-fast, better absorbed and diffuses in therapeutic concentrations into the spinal will give higher blood-levels than the erythromycin fluid as well as into the placental circulation. base with comparable doses (Barber & Garrod, Preparations for parenteral administration are avail- 1963; Walter & Heilmeyer, 1965). The highest levels able, of which the water-soluble chloramphenicol have been obtained with lauryl sulfate of erythro- succinate is particularly suitable. In contrast to the mycin estolate (Griffith & Black, 1962; Luger, 1968). tetracyclines chloramphenicol rarely causes gastro- Erythromycin stearate and erythromycin estolate are intestinal disturbances by oral application. It there- therefore at present the erythromycin preparations fore appeared to be attractive for experimental and of choice (Braun-Falco, 1970; Towpik, 1970). clinical trials in syphilis. Reports appearing between Satisfactory results have been achieved in early 1949 and 1954 indicated that chloramphenicol syphilis (Gertler, 1961; Montgomery et al., 1961; administered orally and parenterally was as effective Brown et al., 1963; Knox & Moore, 1963; Fernando as the tetracyclines in all stages of syphilis (Robinson 1969). Both preparations are used orally, since et al., 1949; Romansky et al., 1949; Willcox, 1950b; intramuscular injections are irritating and painful Olansky et al., 1953). Later clinical studies have (American Medical Association, 1966). A cooper- confirmed this view (Rajam et al., 1955; Gertler, ative assessment of the results of treatment with 1961; Lejman & Burzynski, 1961; Roy & Ghosh, erythromycin in the USA (Lucas & Price, 1967) 1963; Capinski et al., 1968; Lebioda et al., 1968). showed a cumulative failure rate of 27.4% when Pregnant syphilitic women have also been treated 20 gm was given over 10 days. The proposed dosage (Rangiah, 1964). Among 23 such patients treated scheme in early syphilis was 30 gm over 10 days with a total of 20 g chloramphenicol satisfactory (three 250 mg tablets 4 times a day). However, clinical and serological results were found in both higher total doses are necessary (up to 60 g) in mothers and babies followed up for 2 years. How- neurosyphilis and in prenatal syphilis, since erythro- ever, further clinical studies of chloramphenicol in mycin diffuses less easily into the spinal fluid and the treatment of syphilis have been discouraged the foetal circulation than the tetracyclines and because of reported side effects, notably aplastic chloramphenicol (South et al., 1964; Walter & anaemias. The dosages of chloramphenicol in syphi- Heilmayer, 1965). Nevertheless, in the few cases of lis are similar to those with tetracyclines. neurosyphilis and prenatal syphilis that have been treated with adequate dosages, results have been The macrolide group reported to be comparable to those obtained with Erythromycin. This substance was isolated in 1952 penicillin treatment when followed for up to 2 years from a strain of Streptomyces erythreus (McGuire after treatment (Montgomery et al., 1961). et al., 1952). It belongs to a group of closely related Carbomycin (magnamycin). Derived from Strepto- antibiotics (oleandomycin, carbomycin, spiramycin) myces halstedii in 1952, carbomycin has been shown with a macrocyclic lactone ring (macrolides). They to have an antitreponemal effect approaching that have a limited bacteriological spectrum comprising of erythromycin. It has also been used in a few mainly Gram-positive bacteria (Barber & Garrod, cases of early and late syphilis with satisfactory 48 0. IDS0E, T. GUTHE, & R. R. WILLCOX short-term results (Buckinger et al., 1955; Hookings experimental syphilis cephaloridine has shown a & Graves, 1956). However, it is irregularly absorbed more marked antitreponemal effect in vitro and in from the digestive tract and has been withdrawn vivo than the tetracyclines and chloramphenicol, from commercial production (Barber, 1965; Walter although lower than penicillin G (Galla et al., & Heilmeyer, 1965). 1965). Clinical studies also have demonstrated good Spiramycin. Spiramycin, obtained in 1954 from immediate results in the treatment of early syphilis Streptomyces ambofaciens, has a similar bactericidal (Flarer et al., 1965; Seftel, 1965; Seftel et al., 1966; spectrum to that of penicillin, and approximately Flarer, 1967; Gonzales-Ochoa & Moreno, 1967; equal bactericidal effect (Walter & Heilmeyer, 1965). Oller, 1967; Glicksman et al., 1968) although It attracted interest in the therapy of syphilis follow- follow-up periods are too short for final assessment. ing reports of good initial results in the early disease In the few cases of prenatal syphilis treated, the as observed up to 48 months after treatment (De babies have been serologically and clinically negative Barros & Belda, 1965). The treatment schedules after 3 months' observation (Oller, 1967). Since used so far have been: orally, 250-500 mg every there are indications that the diffusion of cephalori- 6 hours for 8 days; intramuscularly, 250 mg every dine from blood to the spinal fluid is poor (Mur- 12 hours for 6 days; intravenously, 250 mg daily for doch, 1965; Walter & Heilmeyer, 1965), its effect 6 days. Spiramycin has also been used as an adjuvant in the treatment of neurosyphilis needs clarification. in early syphilis, followed by penicillin treatment Most cephalosporins (an exception is cephaloglysin) (Merklen & Renoux, 1966). are poorly absorbed in oral administration and are The pharmacological properties of spiramycin therefore given parenterally. Satisfactory blood have not yet been clarified (Kuehne & Benson, 1965) levels are maintained by intramuscular doses of although animal experiments indicate that high 250-500 mg every 8-12 hours for 10 days (Oller, concentrations persist for some time in the tissues 1967). The total adequate dose has yet to be and bones following a rapid fall in blood-level established. (Barber, 1965; Pellerat et al., 1961). Synnematin B (cephalosporin N) is closely related to penicillin chemically since it possesses the 6-amino- The cephalosporins penicillanic acid nucleus and resembles it in some of The cephalosporins were derived naturally from its pharmacological properties (Gottshall et al., 1951). Cephalosporium acremonium, a mould found in a It has been shown to have good antitreponemal sewage outlet in Sardinia (Brotzu, 1948). Later effect in vitro and in rabbits in vivo (Wheeler et al., several antibiotics were isolated from this mould 1957). In a few cases of early syphilis, treatment (Burton & Abraham, 1951). One of them was with total doses of 2.0-3.6 million IU intramuscularly cephalosporin N, which was shown to be identical yielded satisfactory clinical and serological results with synnematin B, isolated from Cephalosporium (Wheeler et al., 1957; Schwimmer & Henderson, salmosynnematum (Gottshall et al., 1951) and is in 1959). Because of its cross-reactivity with the peni- fact a penicillin (penicillin N). Since the isolation of cillins, it is not an alternative in patients allergic to the cephalosporin nucleus (Abraham & Newton, penicillin. 1961) several semisynthetic derivatives have been defined, among them cephalosporin C, cephalothin, Spectinomycin cephaloridine, cephalexin and cephaloglycin (Hodg- Spectinomycin was obtained in 1961 from the kin & Maslen, 1961). The cephalosporins have mould Streptomyces spectabilis (Mason et al., 1962). biological and chemical relationships with the peni- It has been found to give results in rabbit syphilis cillins inasmuch as the cephalosporin nucleus, comparable unit-for-unit to those obtained with 7-aminocephalosporanic acid, contains a /3-lactam penicillin G (Clark & Yobs, 1963, 1966; US Depart- ring identical to that of the penicillin nucleus fused ment of Health, Education and Welfare, 1965a). to a sulfur-containing ring (Fig. 2). This similarity A comprehensive evaluation of spectinomycin treat- in structure accounts for the immunochemical cross- ment of patients with early syphilis to be observed reactivity between these two antibiotics, and for a for a posttreatment period of 2 years is currently similar type of action on the bacterial cell wall being undertaken by the US Public Health Service. (Chang & Weinstein, 1964; Stewart, 1965; Abraham A cumulative failure rate of 29.0% in one year was & Newton, 1967; Stewart, 1967; Jones, 1970; found in 43 patients treated with 4 gm spectinomycin Stewart et al., 1970b; Sweet & Dahl, 1970). In daily for 8 days (Lucas & Price, 1967). Spectino- PENICILLIN IN THE TREATMENT OF SYPHILIS 49

mycin is not absorbed after oral medication, but biotics (except cephaloridine and synnematin B), as high serum levels are achieved shortly following other investigators have observed (Keller & Morton, parenteral administration (Walter & Heilmeyer, 1953). More exact experimental animal evidence 1965). from the WHO International Treponematosis It should be noted that the tetracyclines, chlor- Laboratory Center (Turner & Hollander, 1957) ranks amphenicol, spiramycin, spectinomycin and cephalo- the antibiotics investigated for antitreponemal effect ridine are also effective in gonorrhoea. Although the in the following order: (1) penicillin; (2) erythro- dosages employed for treatment of this disease may mycin and Magnamycin; (3) chlortetracycline and not modify the course of concomitantly acquired oxytetracycline; (4) chloramphenicol; and (5) strepto- syphilis, a serological check should be made monthly mycin. Later observations indicate that cephalori- for 3 months following treatment (Clark & Yobs, dine and synnematin B, which are chemically and 1963; Durel, 1963; Willcox, 1963; Oller, 1967). structurally related to penicillin, kill treponemes of surface lesions almost as rapidly as penicillin (Greaves, 1962). Clinical experience so far has RESULTS OF TREATMENT OF EARLY SYPHILIS shown that darkfield findings of primary and WITH ANTIBIOTICS OTHER THAN PENICILLIN secondary syphilis remain positive markedly longer Table 14 summarizes 1 435 cases of early syphilis after spectinomycin treatment than after penicillin described in the literature as treated with various treatment (Lucas & Price, 1967). antibiotics other than penicillin: chlortetracycline, oxytetracycline, tetracycline, demethylchlortetracyc- Healing of lesions line, N-(pyrrolidinomethyl)tetracycline, chloramphe- While the broad-spectrum antibiotics assessed in nicol, erythromycin, erythromycin stearate, erythro- the present study apparently possess a lesser capacity mycin propionate, cephaloridine, synnematin B, than penicillin to destroy surface treponemes in early spectinomycin, and spiramycin. All primary and lesions, these lesions heal at least as rapidly as secondary cases showed treponemes in darkfield following penicillin therapy. A healing time of examinations. Only a few of the primary cases were 2-3 days has been described in some cases. It is serologically nonreactive when treatment was ini- possible that a beneficial effect ofthe broad-spectrum tiated. The table includes information on the clinical, antibiotics on microorganisms other than T. palli- serological and other characteristics of the outcome dum present in the lesions might enhance healing of therapy, which are discussed in further detail after the treponemes are killed. However, healing below. time varies quite extensively for the different anti- biotics, i.e., from " promptly 3' to 19 days. Obviously Disappearance time of treponemes the character of the lesions in regard to induration, T. pallidum disappeared " promptly " from lesions depth, size, number, etc.-particularly in relation to of primary syphilis within 5-120 hours using any of the duration of the disease-is of significance in the the broad-spectrum antibiotics included. It is evident healing process. Thus, in some patients treated with therefore that these antibiotics have antitreponemal quite large doses of erythromycin who had indurated effects in man, although weaker than the effect of and pigmented lesions of secondary syphilis, com- penicillin, of which 1.8 g (0.3 million IU) will destroy plete healing required up to 72 days. Such pro- treponemes in surface lesions in 6-26 hours (Moore tracted regression has sometimes been observed also et al., 1944; Greaves, 1962; Suchanek et al., 1967; during treatment with penicillin or metals (Moore Lejman & Starzycki, 1969). No definite conclusion et al., 1944; Stokes et al., 1944). as to the degree of antitreponemal activity of the antibiotics can be drawn on the basis of the data Serological and clinical response ofearly syphilis published. However, the size and duration of lesions Few patients treated with broad-spectrum anti- and an indication of the number of treponemes are biotics for early syphilis have been observed over a possibly of value here. The same is true of relation- sufficient time to fulfil the criteria on which the ships between total doses and period of administra- outcome of penicillin-treated syphilis has been tion on the one hand and the disappearance time of evaluated (Iskrant et al., 1951). This applies particu- treponemes on the other. It is noteworthy, however, larly to the possible development of late complica- that the total dosages of the erythromycin-treated tions. The therapeutic effect of the other antibiotics groups were usually lower than for the other anti- is based-as with penicillin-on intensive, antitrepo- 50 0. IDS0E, T. GUTHE, & R. R. WILLCOX

to coLO to0 0) 0) D - t_ 0 IDCO) C O Cl) LO 0l) E E 0DC) r. .5 .B to I

' eb co c-~o to C~-00to. C- D ctlo C.0 4-1 tox to to) to 0) U)n 0) ._ (A c0) 0 to C C c 0) cU t @o to0

0 0 .t0 a to .0C C 0 W MD 0(A W 0 co to -C 0 to .-t 2' to 0 to4.r .2 E =a oO >2 tooc 0 xLc 0 .0'It=U ._ C0 0 CD cm CD 0 -o to 0 C Q .o tco 0 .70 2'- co ._c .0 0 ._0 C to 4-- ~0 U 0 >to Do0 t CA C. C ~._ .5 C)0 to Co to _ C 0 0 =o 0 OC 0 -0 to toC 0 .0 ._'., .0o *Co 0 0 =._ -o M0 ._Ot U C Eto_ Cl0 Z3 0 0 Q U.@ 0° x W~ U 0 82 0 CD to .0-_E CD CO.to *0cD to mW b. I-i CL CL Cw t o to 4) 0 to Z ~to to 00 tO* 0° CX w ._O 1- to to> 0 CaE r .-C co U 0. OC 0 ._.. U 0. to to Q _om>. o.S <:0 0 to tZ aC tCo. 0 to- Ct toc Uo _5 tos to E x to 0 to 0.4D C to C 0 a -6 '._ to 4 z 0 ._ to ._ ._ C ._ ._ to U D _ E C to 0 E WE 0 ED c CL Uc ._LQ PENICILLIN IN THE TREATMENT OF SYPHILIS 51 nemal action of short duration, and-as in penicillin (Montgomery & Knox, 1959b). Results indicate that therapy-the majority of failures are likely to appear erythromycin propionate is more effective dose for within the first year or so after treatment, with dose than erythromycin stearate (Montgomery et al., extremely few after 2 years. Thus the average 1961). Studies of minimum therapeutic dose require- cumulative failure rate among 1 435 cases followed ments of oral erythromycin propionate in early for up to more than 2 years and shown in Table 14 syphilis have been evaluated in the US Public Health was 8.7 %. The failures are in the relapse/rein- Service's venereal disease control programme (US fection group and cannot be further differentiated Department of Health, Education and Welfare, except in some cases on epidemiological grounds. 1965b) using different schedules. A total dosage of Most investigators conclude that the results of 10 g covering a period of 8-10 days proved inade- treatment of early syphilis with antibiotics other than quate, the total cumulative retreatment rate at penicillin now under trial are " satisfactory "; some 12 months being almost 30% in seronegative consider that these results are comparable to those primary syphilis, 17.9% in seropositive primary achieved with penicillin. In the better defined study syphilis, and 12.5% in secondary syphilis. The groups the pattern of serological response is related higher retreatment rates in the primary stage than to the duration of the disease at the start of treatment in the secondary stage indicate that the majority (Montgomery et al., 1961; Lebedeva, 1965), as with of cases requiring retreatment were indeed reinfec- penicillin treatment. tions rather than relapses. The pattern of serological Comparison of the long-term effect of the treat- response of those not retreated, however, did not ment of early syphilis with the various antibiotics in differ significantly from that after the 10 g schedule. the study material is of restricted value because of Very few patients have so far been treated for differences in the duration of infection, doses, prenatal syphilis, congenital syphilis and late syphilis observation periods, etc. In regard to erythromycin, with antibiotics other than penicillin. These cases one group of investigators concludes that the total do not permit conclusions as to long-term results, dose given over 5 days gives inferior results compared although clinically satisfactory responses have been with the same dose given over 10 days, suggesting obtained (O'Leary et al., 1948; Rodriquez et al., that dose/time relationships are also significant in 1952; Willcox, 1952; Rangiah, 1964; Gamier et al., treatment with antibiotics other than penicillin 1965).

SIDE REACTIONS TO ANTIBIOTICS OTHER THAN PENICILLIN

In recent years widespread concern about the safest of the broad-spectrum antibiotics. In recent safety of drugs has been manifested in most coun- years, however, a series of reports has called attention tries. As a result, pharmacological, toxicological, to their affinity to bones and teeth. Administered in and biochemical studies, as well as adequate pre- the neonatal period and in young children, tetra- clinical testing, are now considered essential before cycline may cause retarded growth, malformation of new drugs are marketed (Inman, 1970). Generally bones and teeth, and discoloration of the teeth. acceptable principles and requirements for the evalua- Since tetracyclines pass from mother to child through tion of such trials have been formulated by the the placenta, these adverse effects are also seen in WHO Scientific Group on Principles for the Pre- infants born of mothers treated with tetracyclines in Clinical Testing of Drug Safety (1966). pregnancy (Madison, 1963; J. Amer. dent. Ass., The side reactions to the more important anti- 1964; Kline et al., 1964; Clendenning, 1965; Stauffer, treponemal antibiotics appraised in the present study 1967). Tetracycline therapy has also been associated are summarized in Table 13. Most of the side with acute fatty liver (Dowling & Leper, 1964; reactions to these and other newer antibiotics, includ- Kunelis et al., 1965), and some fatalities have been ing toxic reactions, allergic reactions, and microbio- reported in pregnant women (Horwitz & Marymont, genic effects, have atso been reviewed by Meyler 1964). In all patients the drug had been given (1966). intravenously, and in nearly all cases in high dosages. The tetracyclines were at one time regarded as the Pancreatitis and renal disturbances have also been