Br J Vener Dis: first published as 10.1136/sti.27.1.38 on 1 March 1951. Downloaded from

CHEMOTHERAPY OF VENEREAL DISEASES ITS USES AND ABUSES BY S. M. LAIRD Ipswich For centuries the man of medicine practised the therefore, to provide an effective tissue level of the relief of symptoms, his power to influence the drug at the site of infection and to maintain this processes of disease being strictly limited; the art level until the infective agent has been eliminated. of medicine was largely confined to providing When the organism is sensitive and the drug is circumstances favourable for the vis medicatrix bactericidal this period may be very short, but where naturae to function to the best advantage. When, the action of the drug is merely bacteriostatic it however, Pasteur, Lister, and Koch turned the must be administered over longer periods so that spot-light of science on the bacterial battlefield, the natural defence mechanisms of the host may knowledge of the biology of infections began to have time to overcome the infection. Three grow. The biochemical search for specific remedies important factors are thus concerned: the efficacy and the birth of chemotherapy during the last of the drug; the virulence of the organism; and half-century were inevitable developments. Sal- the natural defensive powers of the patient. varsan and the later arsphenamine preparations, the bismuth compounds, the sulphonamides, and Efficacy of the Drug.-This depends on the the antibiotics are all potent weapons in the fight sensitivity of the organism and on the tissue level against the bacterial enemies of man; their use which can be established and maintained at the site involves relatively new and fundamental principles. of infection. The tissue level is usually lower than As in modern warfare, the discoveries of the the blood level of the drug but if the site of infection http://sti.bmj.com/ " backroom boys " must undergo carefully studied is vascular enough these levels will approximate field trials, and the lessons learnt from such trials closely to one another. The persistence of the must then be assimilated by those who will play tissue concentration at a higher level than that of their part in the front line. Otherwise the new the blood concentration after administration of the weapons may not be used to full advantage and drug has ceased, is an important practical obser- disaster may overtake those that abuse them. vation. The blood level achieved depends on the

frequency of administration and on the rate of on October 1, 2021 by guest. Protected copyright. absorption and excretion of the drug used. In the Application of Chemotherapy case of crystalline penicillin G in aqueous solution, The mode of action of chemotherapeutic agents both absorption and excretion are rapid, and 3- on bacteria is not yet known in detail; there is hourly administration of 40,000 units is required to evidence, however, that the drugs may interfere with maintain an effective therapeutic level; even an the surface structure of the bacterial cell and with individual dose of 500,000 units must be repeated the enzyme actions necessary for its normal after only 8 hours. Attempts to delay excretion metabolism. We are all familiar with the morpho- are open to objection, and more practical progress logical and tintorial changes which the gonococcus has followed the use of absorption-delaying may manifest under the influence of sulphonamides, vehicles. Of these preparations, procaine penicillin and the electron microscope has shown aberrant in oil with 2 per cent. aluminium monostearate forms and division of the Nichols strain of T. (300,000 u/ml.), alone or reinforced with crystal- pallidum in contact with penicillin. The important line penicillin G (100,000 u/ml.), gives adequate result of these intrinsic effects is that in practice the results when injected every 24 or even 48 hours chemotherapeutic agent may be bacteriostatic, or in 2-ml. doses. More recently, aqueous procaine bactericidal, or both. The aim of chemotherapy is, penicillin preparations have become available, 38 Br J Vener Dis: first published as 10.1136/sti.27.1.38 on 1 March 1951. Downloaded from

CHEMOTHERAPY OF VENEREAL DISEASES 39 and these are reported to be more convenient that any treatment schedule for any infection will to administer and, on in vitro testing, to be have its failures or relapses. as effective as the oily procaine penicillin. The peak level achieved by these delayed-absorption General Principles preparations is much lower than that of crystalline The fundamentals considered above provide penicillin in aqueous solution, and, in acute infection certain principles which must be observed faithfully or where the organism is relatively insensitive, in the use of chemotherapy. there is a danger that effective use may be sacrificed (1) The infective agent must be identified bac- to the convenience of administration. The more teriologically and its sensitivity to chemotherapeutic rapid absorption in ambulant patients as compared agents determined, either by direct laboratory with the bed-patient must also be remembered. investigation or in the light of past clinical Penicillin can be given by mouth, but its oral use experience. is wasteful, less certain than parenteral admini- stration, and more open to abuse. Instillation into (2) Having considered which chemotherapeutic the conjunctival sac and the use of penicillin agent to employ, the best method of administration ointment for blepharitis and other eye conditions must be chosen with reference to route, individual are justifiable exceptions to the rule that penicillin and total dosage, frequency, and duration. The should only be given by injection. The widespread biology and location of the infection, the resultant prescription of penicillin ointment for local appli- tissue pathology, and possible toxic reactions to cation to surface lesions, often not infective in treatment must all receive attention. origin, is an outstanding abuse of chemotherapy, (3) The patient's general condition must receive which daily causes danger and acute distress, from all necessary care to promote the highest possible sensitization, to hundreds of patients. level of well-being and encourage his natural powers of resistance; such attention may need to embrace Virulence ofInfecting Organism.-The strength of psychological and social factors. the infection and its sensitivity to chemotherapeutic drugs are fundamentally important. Drug-sensi- (4) Where the infection may be contagious, as tivity, or conversely drug resistance, is usually with the venereal diseases, epidemiological investi- relative rather than absolute. Most of us have had gation of intimate contacts and the prevention of first hand experience of the development of drug- re-infection are often necessary. resistance in connexion with the sulphonamide (5) As chemotherapy is not invariably successful, treatment of gonorrhoea. This phenomenon has the patient must receive adequate observation to probably resulted from the steady elimination of establish cure or to detect relapse or failure without http://sti.bmj.com/ sensitive strains from the human population, and delay. from the encouragement of the gonococcus to Practical Application develop drug-resistance by irregular and inadequate Observance of these principles constitutes the dosage arising from attempts at self-treatment or proper use of chemotherapy; their non-observance, prophylaxis and, ifthe truth is told, from uninformed means its abuse. Their practical application to medical prescribing. There is little sign so far, of certain particular venereal diseases may be briefly the gonococcus or T. pallidum becoming resistant to outlined as follows: on October 1, 2021 by guest. Protected copyright. penicillin, but the demonstration of strains of staphylococci and other bacteria developing such Gonorrhoea.-Diagnosis must never be based resistance should serve as a warning of this solely on clinical findings; smears and, certainly in the female, cultures are essential for pre-treatment dangerous possibility. diagnosis and post-treatment follow-up. One in- Natural Defence.-The third fundamental in jection of 1 ml. (400,000 units) procaine penicillin chemotherapy comprises the natural defensive power reinforced with crystalline penicillin G is effective in of the patient. This factor is vital where the drug uncomplicated infection in the male. For the action is wholly or largely bacteriostatic. I believe female I prefer one dose of 800,000 units. When that sometimes insufficient attention is given to it complications are present, more than one such in the assessment of the results obtained with a injection may be required combined with local particular treatment schedule. We have all seen treatment and I believe this to be particularly true the case of early syphilis cured with minimum of salpingitis. treatment while other patients fail to respond to The higher initial blood level achieved by the much more adequate therapy. I believe that such reinforcement of procaine penicillin with the instances arise from variation between individuals crystalline penicillin G is of especial value in in their natural powers of recovery, and moreover gonorrhoea. In all cases I think it valuable to Br J Vener Dis: first published as 10.1136/sti.27.1.38 on 1 March 1951. Downloaded from

40 BRITISH JOURNAL OF VENEREAL DISEASES combine the penicillin with " Sulphatriad ", 4 g. achieve as much as one injection ofneoarsphenamine daily for five days, partly because the latter is often with less danger of toxic reaction. I still prefer to more effective than penicillin against secondary admit to hospital all cases ofearly syphilis, especially organisms, and partly because the combination of where pregnancy co-exists. To such patients I give two or more chemotherapeutic agents is thought to 100 injections crystalline penicillin G in aqueous reduce greatly the possibility of development of solution (total 4 mega units), and at the same time I drug-resistant strains. begin a course often weekly injections 0*2 g. bismuth In non-gonococcal urethritis in the male I use oxychloride. After discharge from hospital the streptomycin only after penicillin and Sulphatriad patient is given ten weekly injections of 600,000 have failed, giving 1 g. daily for not more than three units procaine penicillin so that the whole schedule days. In my experience, gonococcal rheumatism takes about 12 weeks to complete. If the patient and Reiter's disease still require artificial fever and is unable to come into hospital he is given 600,000 meticulous management ofthe genito-urinary focus; units of procaine penicillin daily for 15 days and here chemotherapy, including chloromycetin and then ten weekly injections. In pregnant women aureomycin, has proved disappointing. treatment should be maintained up to the time of confinement. Syphilis.-My early experience of the treatment of The value of penicillin in neurosyphilis and optic primary and secondary syphilis with sixty injections atrophy seems very considerable, and I have also amorphous penicillin (total 2-4 mega units in 71 thought it of benefit in cardiovascular syphilis. days) with a relapse rate of some 12 to 14 per cent. Preliminary preparation with bismuth is essential to quickly led me to combine penicillin with arsenic reduce Herxheimer reactions and prevent a thera- and bismuth. From 1945 to 1948 my treatment of peutic paradox and I can think of no case of late early syphilis comprised 100 injections penicillin (4 syphilis of such urgency that this important mega units) combined with one course of ten weekly preliminary to penicillin is precluded. injections of neoarsphenamine and bismuth. This schedule gave excellent results in 97 per cent. of I began my remarks with a reference to the vis patients, the failures (less than 3 per cent.) all medicatrix naturae and its all important role in the arising in examples of late secondary syphilis. From patient's recovery. It is still vital but now we can May, 1948, such cases of late secondary syphilis assist it greatly by the intelligent use of chemo- have been given two courses of metal chemotherapy therapy. These drugs have eased the patient's with improved results. Towards the end of 1949 an burden immensely but their proper usage in assisting increasingly reassuring follow-up of my own cases his recovery has placed an added responsibility on and mounting experience reported from the U.S.A. his doctor which was unknown to the practitioner http://sti.bmj.com/ led me to abandon the use of the arsenicals in the of earlier days. Let us abuse neither the respon- belief that 600,000 units procaine penicillin can sibility nor the drugs. on October 1, 2021 by guest. Protected copyright.