EARLY SYPHILIS ITS TREATMENT WITH SOME EVALUATIONS
M.P. Vora, M.B.B.S., D.V.D
St.George’s Hospital, Bombay
Exploring ancient and modern medical learning
Vol.1, No.1 of October 1961; Pages: 15-22.
By early syphilis is meant the primary syphilis (sero-negative and sero-positive) and early secondary stage together with early asymptomatic syphilis.
Importance of prompt and accurate diagnosis and treatment of syphilis cannot be overstressed. It must be remembered that in a case of syphilis each day’s delay in making a positive diagnosis lessens the patient’s chances of a permanent cure and may make all the difference to his ultimate state. It is, therefore, essential that every effort is made to diagnose syphilis by finding the Tr.pallidum before the blood gives a positive serologic test for syphilis or the late clinical signs appear.
The objects of treatment of early syphilis are (1) to make the patient rapidly non-infectious thus preventing immediate or remote risk to others, (2) to effect complete eradication of the infection in the shortest possible time (3) to avoid the dangers of late tertiary manifestations.
Early stage is the most appropriate stage for starting treatment: there is overwhelming evidence to show that adequate treatment at this stage will cure all cases of syphilis, the criteria of cure being:- (1) absence of subsequent clinical or serological signs and symptoms of disease (2) non-infection of the partner (3) procreation of healthy progeny, and (4) finally the cause of death, in no way attributable to the antecedent syphilis. On the other hand there is evidence to show that inadequate and irregular treatment in the early stage of syphilis, predisposes to the later crippling cardiovascular and nervous complications.
Treatment of early syphilis may be considered under the following headings:-
1. General 2. Local 3. Specific.
General: It is of utmost importance to maintain the general health of the patient - especially when very young or old. Life should be carefully regulated. Skin conditions such as seborrhoea, eczema and conditions of the mouth and teeth should be attended. Sexual contacts and alcohol should be prohibited.
Local treatment : When a sore is under investigation, no antiseptic or antibiotic should be applied to the lesion. Normal saline application helps to heal and does not prevent the demonstration of the Tr.pallidum. In case there is added secondary infection, it is advisable to prescribe sulpha drugs by mouth. They have no effect on spirochaetes and rapidly control sepsis. Once the diagnosis of syphilis is established antisyphilitic treatment should be instituted at once.
Specific treatment : the drugs used in the treatment of syphilis are:-
How these can be best used can only be decided after considering important factors such as age, sex, weight, race, the severity of the disease, the condition of the patient and the response to drugs. The extremes of age demand caution. In the very young, intravenous therapy is not practicable. Hence penicillin, bismuth and intramuscular arsenic are the drugs of choice. The aged on the other hand present a different aspect. They need less intensive but prolonged treatment with more rest intervals. They cannot tolerate arsenicals so well as do the young. Hence penicillin and bismuth, and arsenic with great caution, are the drugs usually employed. The young adult in the prime of life who is the victim of early syphilis should be given the most thorough and intensive course designed to eradicate the infection. Hence arsenic, bismuth and penicillin may all be given. Mercurials and iodides have no place in the treatment of early syphilis.
Penicillin alone as the therapeutic agent : In penicillin we have the most valuable antisyphilitic drug and all cases of early syphilis should be given its benefit. Various preparations of penicillin are available for the treatment of syphilis; penicillin G in pure crystalline form, procaine penicillin G, procaine penicillin G with 2% aluminum monostearate (P.A.M.), Benzathine penicillin and Benethamine penicillin. However, the latest preparations have distinct advantage over older preparations including P.A.M. They can be injected with ease, they maintain effective blood levels for longer periods and there is no question of including penicillin sensitivity or resistance in a person. Oily preparations are difficult to inject, they leave a lump at the site of injection, require 16 to 18 gauge needle for aspiration and injection and make the syringe difficult to clean. Though P.A.M. is strongly recommended by W.H.O. it is not the preparation of choice. Newer aqueous preparations of penicillin are long acting and suitable.
Penicillin as a single curative agent for early syphilis has yet to be fully proved. Though the unit dosage and the time interval between doses to produce an effect on Tr. pallidum are known, information on the statistical basis is lacking and covers periods of only 6 to 24 months. Many failures noted may be re-infections. A patient who is apparently cured by rapid treatment may be re-infected rapidly. This state of affairs was not met with the older methods of treatment. Penicillin is excellent from the aspect of public health; but it has not been universally accepted as good enough for the individual case as the more prolonged treatment previously used. Penicillin alone is not capable of curing all cases of syphilis. The incidence of early relapse is great. With experience in the therapeutics of syphilis, the conservative-minded, would like to go in for a combination which has the virtues of a rapid method using penicillin with a share of the older non-intensive treatment with arsenic and bismuth. The superiority of this mixed treatment has been confirmed to a certain extent. This combined treatment reduces the incidence of early infectious relapse. The incidence of complications with newer arsenoxides is very small indeed as compared to the older arsenical preparations.
At present, therefore, a mixed treatment is perhaps the judicious one although penicillin alone may prove completely successful for the majority of patients in early syphilis. The post-treatment period of observation ought to be controlled by full clinical, C.N.S. and cardiovascular system check-ups, serological tests and examination of cerebrospinal fluid. Such observations should last for at least two years after the completion of treatment.
Experience shows that patients with sero-negative stage have decidedly a better prognosis than those with sero-positive or secondary syphilis, requiring a graded dosage for each of these three forms or stages. If the treatment is standardized at the level of secondary stage, it will be easy from the point of administration.
In using penicillin, it is necessary to maintain an effective and continuous blood level over a period of about 8 to 10 days.
If patients are unlikely to attend regularly for follow-ups for 2 years, penicillin by itself is not recommended as a routine except in certain special circumstances such as in an expectant mother with syphilis late in pregnancy, hepatic disorders, chronic skin diseases and marked arsenical sensitivity.
Mixed treatment : Penicillin-Arsenic-Bismuth
At present it is accepted that a penicillin course is the equivalent of at atleast 2-10 weeks’ courses of arsenic and bismuth. The standard treatment adopted in the British Army involves the use of penicillin with one full course of arsenic and bismuth over ten weeks’ period. In France, arsenic is completely dropped and penicillin and bismuth only are given. There is some evidence to suggest that arsenic, bismuth and penicillin, when administered concurrently, are synergistic and enhance the effectiveness of one another. It is already shown that a regime where penicillin is combined with more prolonged treatment with arsenic and bismuth is more successful than one of short period. The current trend in treatment is therefore to give therapeutic doses of penicillin and to combine this therapy with arseno-bismuth therapy.
It is better to commence treatment with procaine penicillin G. 600,000 daily for 10 days and during the same period to commence arsenic and bismuth completing 0.6 to 1.0 gm. of Oxophenarsine hydrochloride and 2 gm. of bismuth in 10 weeks period. Dosages suggested for an average adult are: vide infra.
Oxophenarsine hydrochloride is the drug of choice in the treatment of syphilis. Dose varies from 0.04 to 0.06 gm. i.v. once or twice a week. Its toxic reactions are less frequent than those of arsphenamines. Dose of Oxophenarsine tartrate is 0.06 to 0.09 gm. i.v. These preparations dissolve very quickly and are not rapidly oxidized. Since only 1/10 of the dose of arsphenamines is given, severe ill-effects from its use are less frequent. Full clinical examination of every patient is necessary before treatment with arsenic or bismuth is commenced and before each subsequent injection, the skin, conjunctivae, urine, etc. should be inspected and examined.
Prior to injection patient should have fasted for about 3 hours and should abstain from food for at least 3 hours after the injection. It is good to give glucose 1 oz. and Sodium bicarb 15 gr. And fresh lime juice 4 oz. by mouth about one hour before the injection. Urine should be examined for presence of bile and albumen; weight of the patient should be taken at each visit, inquiry should be made about drug tolerance before each subsequent dose.
Stage of syphilis
(1) Sero-negative Primary
4.8 M.U.*in 8 days
One unit course of Arseno-Bismuth
(2) Sero-positive Primary
6 M.U.*in 10 days
One unit course of Arseno-Bismuth
(3) Early Secondary
6 M.U.*in 10 days
Two unit courses of Arseno-Bismuth
*(one million units = 1 M.U.)
Technic of injection : - There is a real need to develop good technic of i.v. injections. It is important that during the injection the needle point should be properly in the vein. If the patient complains of pain or if any suggestion of swelling at the point of the needle is noticed, the injection stopped at once and the piston of the needle investigated by suction or by detachment of the syringe from the needle. If there is no free flow of blood, the needle-point is not in the vein.
Bismuth : - Bismuth preparations take the second place in the treatment os syphilis. They are given by only i.m. route and have less rapid but prolonged action than that of arsenicals. In general water soluble and oil soluble salts are rapidly absorbed and excreted, while metal suspensions or colloids and insoluble salts are more slowly absorbed and excreted.
Prior to administration, care should be taken to ensure an even distribution of the insoluble suspension by shaking the container thoroughly. Every precaution should be taken to prevent bacterial contamination either of the needle, syringe or the drug. Preparation is drawn into the syringe through a wide bore needle and a separate needle is used for actual injection. If proper care is taken, toxic reactions are seldom. It is important that before each injection is given, the patient’s teeth, gums and oral mucosa and urine are examined. The dosage for adults is calculated in terms of bismuth metal and is from 0.074 to 0.148 gm. of water soluble bismuth, and for suspension of metallic bismuth and insoluble salts 0.2 gm. to 0.4 gm. per week.
Technic of I.M. injection: Site generally selected for i.m. injection is the upper and outer gluteal quadrant. Injection may be given with patient lying prone or standing erect. In the latter case, it is important to get the muscles at the site relaxed by asking the patient to turn the toes in and to transfer the body weight on the opposite leg and to bend the knee slightly. A stout i.m. needle 2 to 21/2” long is held by the mount, stabbed smartly at the chosen site. It is proper to wait for a few seconds to make certain that the point has not punctured a blood vessel. After bismuth a little air should be injected to remove the drug from the needle before its withdrawal.
Some Evaluations : The end results of combined penicillin-arseno-bismuth treatment of early syphilis have been evaluated to a certain extent and are substantiated by the following references:-
Curtis 1 while discussing the various acceptable therapeutic plans for the treatment of early syphilis, states that penicillin should be supplemented with arsenoxide and bismuth because the investigations have shown that this therapeutic combination results in a lowered failure rate. Overall response is better with the combined therapy.
Jones 2 reports that penicillin seems effective in the treatment of primary syphilis, but best results are obtained by giving a course of (weekly for 10 weeks) arsenic i.v. and bismuth i.m. with penicillin.
Early diagnosis is important because best results are obtained in sero-negative patients. 87% out of the 323 patients showed a febrile Herxheimer reaction after the start of therapy. The quantitative serologic tests are fairly reliable in predicting success or failure of treatment. Those with a low titre achieved seronegativity earlier and had a better chance of successful treatment than those with high titers.
136 patients were followed for 10 - 35 months to determine the relative merits of penicillin alone and combined therapy with penicillin, arsenic and bismuth. 66 patients were treated with penicillin alone and 17 (26%) required retreatment. 75 were treated with combined therapy and 6 (8.6%) required retreatment. The author concludes that penicillin alone is inadequate for treatment of primary syphilis; addition of arsenic and bismuth gives superior results.
In July 1942, the U.S. Army adopted a new schedule for treatment of early syphilis as a compromise between the more toxic intensive schedule and prolonged treatment schedules. It calls for 40 injections of Oxophenarsine and 16 injections of bismuth over a period of 26 weeks. This schedule has been successfully used in 200,000 patients in the U.S. Army alone and th subsequent satisfactory therapeutic results with low toxicity have confirmed the soundness of its application. It has clinical application at present despite the advent of penicillin.
Sternburg 3 and Leifer 3 have carefully evaluated this form of treatment in 3,000 soldiers with early syphilis. To state briefly, the results appear to be excellent; 95.36% of all patients in all stages of the disease observed for varying periods progressing satisfactorily in all respects:
98.25% in Sero-negative primary
94.48% in Sero-positive primary
84.34% in Secondary
In addition the small percentage 0.64 of abnormal cerebrospinal fluids were found among 2842 examined.
The importance of evaluating results of treatment of early syphilis according to the phase of the disease in which therapy is instituted is stressed. Overall results of any syphilotherapy depend largely on the relative proportion of cases in the sero-negative primary, sero-positive primary and early secondary phases of the disease. No deaths occurred among the 3,000 patients. The probable mortality rate from this schedule of treatment is estimated to be 1 in 33,000 cases. Hence Oxophenarsine hydrochloride remains the arsenical of choice in the treatment of syphilis.
The value of penicillin in syphilotherapy remains uncertain as indicated by several reports, some of which stress the experimental nature of present treatment schedules and the incomplete knowledge of final outcome of syphilis treated with varying schedules of penicillin. Experience with penicillin as an antisyphilitic dates back but a few years during which the nature of penicillin itself has undergone changes. Reports of results in large number of syphilitic cases treated and adequately followed for any prolonged period of time are very limited. Many uncertainties concerning the value of penicillin in syphilis will no doubt be remedied with increased experience or with the use of penicillin in combination with various other antisyphilitic agents. Yet the practitioner has immediate need of a reliable programme for treatment of early syphilis. The committee on Medical Research, U.S. Health Service, and the Food and Drug Administration 4 state “there is both laboratory and clinical evidence that addition of Oxophenarsine in subcuartive dosage to a penicillin treatment schedule enhances the therapeutic effect of each drug. There is also laboratory and clinical evidence to indicate that if bismuth salicylate is added to penicillin or penicillin-arsenic schedule for early syphilis, material reduction in incidence of infectious relapse within the first 6-12 months after treatment may be anticipated.
In a progress report of results obtained from various rapid methods of treatment for early syphilis in 16 rapid treatment centres in the U.S. Public Health Service, Helter 5 observed that among a group of patients having a maximum observation period of 10 months, the combined schedule gave better results than any other schedule employing penicillin. This regimen consists of a combination of arsenic, penicillin and bismuth. Leavitt 6 while studying at the New Mexico Intensive Centre, characterises this combination as the most promising. He says “undoubtedly penicillin alone is the safest of all these methods but the percentage of unsatisfactory results is disappointingly high”.
The advantages of penicillin in treatment of syphilis are that its course may be completed in a short period of time. Disadvantage is the significant incidence of treatment failure. With the newer preparations of penicillin, the need for frequent, injections and hospitalization of the patients can be dispensed with.
The uncertain status of penicillin alone in the treatment of syphilis has been aptly expressed by Stokes, Beerman and Ingraham 7. “From A.D. 1943, it will take a year to guess, two years to intimate, five years to indicate, a decade or more to know what penicillin does in syphilis”.
Considerable confusion currently exists regarding the optimum treatment schedules for patients with early syphilis. Crawford 8 says “from 10 to 20 years are required to evaluate properly the therapeutic results of any approach to syphilis in all respects except immediate effects on fresh infections”. Penicillin therapy has been only of short duration and despite the work done on it, has to withstand the test of time.
Robinson 9 hesitates to accept the glowing reports of the results of penicillin therapy in syphilis. He adds “the syphilitic patient treated with penicillin, must be kept under observation for the remainder of his lifetime”. Eagle 10, Magnuson 10 and Fleischman 10 feel that a synergic action exists between penicillin and arsenic. “That the simultaneous administration of penicillin daily with i.v. injections of Oxophenarsine hydrochloride is more effective than penicillin alone in the treatment of early syphilis of adults to be well substantiated” comments Kolmer 11.
Although penicillin is used in the syphilotherapy for a short time, evidence indicates that it is an antisyphilitic agent of choice. Rise in eminence of penicillin in syphilotherapy does not, however, negate the usefulness of arsenic and bismuth therapy. Many of the more successful treatment schedules include Oxophenarsine and bismuth with injections of penicillin.
Rodriguez 12 and his associates give bismuth, Oxophenarsine, fever, and penicillin to achieve a rate of cure hitherto unattained.
Young 13 concludes that procaine penicillin is the most suitable preparation for clinical use. Its slow absorption and a long lasting therapeutic blood-penicillin level maintenance make it the preparation of choice. It has an additional advantage of administration in an aqueous vehicle rather than in an oil. The fact that penicillin of the repository type can be used either alone or in conjunction with Oxophenarsine and bismuth for the treatment of early syphilis has considerably reduced the need for prolonged treatment of the patient, and the need for prolonged schemes of treatment that ere often difficult for the patient to follow. This treatment has now become more convenient both for the patient and the physician.
Alshuter 14 from his experience of treating 31,000 patients with early syphilis found that the failure rate in early syphilis varied considerably with the stage of infection, the lowest rate occurring with primary sero-negative syphilis and the highest in secondary syphilis.
Since penicillin has been introduced into syphilotherapy, treatment schedules remain tentative. “Like many new therapeutic procedure” says Reynolds 15 “the penicillin treatment of syphilis is passing through the three phases of dubiety, hyperenthusiasm and reaction.” He urges physicians not to lose sight of the fact “that metal chemotherapy is effective”. He points out that if used alone, it gives a cure rate of 95% of patients with early syphilis, though the schedule is leisurely but reactions are minimum. In contrast to arsenicals, penicillin appears to be effective in only about 75 to 80 percent of early cases. “The conclusion seems inescapable” notes Reynolds “that penicillin alone is not the final answer in the treatment of early syphilis”.
Curtis 1 after his numerous studies, comes to the conclusion that penicillin supplemented by both arsenoxide and bismuth salicylates gives better results.
R. Degos and his colleagues L. Vissian and H. Bassett re-examined 2649 cases of syphilis, who had been diagnosed early, treated with curative doses of organic arsenicals and bismuth for one year and with bismuth alone in maintenance doses for three years. The cure rate among these patients 8 to 20 years after treatment, was as high as 99.74% (Ann. De dermat et de syph. Sept. 1950, 497-500). Only with a regular and prolonged scheme of therapy could one obtain this astonishing result.
Conclusions : Inspite of the conflicting nature of evaluations, it can be concluded that penicillin alone is not the final answer in the problem of syphilotherapy. With increased use of penicillin more and more fatal reactions are being reported. The latest evidence shows a distinct rise in the incidence of latent and sub clinical syphilis as the result of penicillin therapy. However, judicious use of penicillin-arsenic and bismuth in one combination or another is still the best available therapy for early syphilis.