Practical Therapeutics Drugs5: 144-153 (1973)
Venereal Disease: Diagnosis and Treatment W.M. Platts Christchurch Hospital, Christchurch
After being nearly beaten by penicillin in the early 50s, the sexually transmitted diseases have staged a phenomenal comeback, and are now epidemic or pandemic in most countries of the western world. The reasons for this are social, not medical; popularisation of pre- and extramarital sex, a proportion of which is always promiscuous, has facilitated the spread of the organisms concerned, which have overwhelmed the epidemiological defences in many countries. This is especially true of gonorrhoea which, with its short incubation period and large carrier reservoir in women, is still increasing, even in countries like England despite its excellent system of venereal disease control. In USA, where 80 % of cases are seen by private doctors, it is quite out of control, the yearly incidence being about 1 % of the total population. Sweden's rate is about half of this, New Zealand's (estimated) under a third, and England's under a quarter. A new phenomenon is the youth of those involved, the majority, except in countries where prostitution is legal, being teenagers. With syphilis, the position is a little better although its rapid spread is causing great concern in USA. Its long incubation period facilitates contact tracing and thus epidemiological control. Despite this, its incidence has risen in practically all countries, but the position in China is apparently an outstanding exception to the above trends . Apart from this classical pair which head the list of the five official venereal diseases, the biggest problem now is nonspecific urethritis (NSU; or nongonococcal urethritis, NGU). Increasing even more quickly than gonorrhoea, its incidence in New Zealand (as in England) is almost double that of male gonorrhoea. Its cause, supposedly Viral, remains undiscovered, and its remarkable
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incidence pattern - i.e. cases being sporadic and unconnected , and women being clinically uninvolved as well as 'non-infective' to other males - almost suggests an allergy of the mucous lining of the male urethra to the vaginal content of a particular female. However, tetracyclines abolish urethral discharge in 80 % of cases, proving that an infective agent (or agents) is involved. This being so, one can only postulate that it is widely distributed in commensal form amongst the sexually active, and is activated by a particular intercourse by circumstances yet unknown. The main problem with nonspecific urethritis is its tendency to recur sometimes years later and frequently in multiple fashion. Finally, the seven sexually transmitted diseases (STD), the transmiss ion of which is linked to sexual contact but not confined to it , have all become common again. These comprise two vaginitides (trichomoniasis and candidiasis) ; three viral infections (herpes progenitalis, genital warts and mollusca contagiosa); and two parasitic infestations (pubic lice and scabies). The incidence rate in New Zealand of the five more common members of this group, which frequently occur in comb ination, or associated with gonorrhoea, is between 10 and 20 % of that of gonorrhoea. Previously, many of these were remarkable only in times of social unrest or war.
1. Diagnosis 1.1 Gonorrhoea Diagnosis of gonorrhoea, especially in females, was revolutionised by Thayer and Martin's (T-M) introduction in 1964 of a selective growth medium which contains a vancomycin, colistin and nystatin supplement to suppress the faster growing commensals of the female genital tract (Proteus overgrowth can be controlled by the further addition of trimethoprim to this mixture). It should be noted that T-M medium must be fresh and should be used within 5 days of pouring if its excellent reliability is to be retained [1] . Stuart's transport medium, with its long shelf-life if kept in a refrigerator, enables specimens to be sent long distances, although overnight delay in plating out results in a small but definite loss of viable organisms. The more recent 'Transgrow' transport medium [2] which is in use in many parts of USA is very efficient for long delay transport, e.g. 48 hours, but needing carbon dioxide as it does, and losing efficiency with age (its formula is the same as T-M growth medium) it lacks the simplicity and reliability of Stuart's. If cases are not to be missed, two swabs should be taken from females at an intervai of less than 48 hours and cultured. A recent American series showed that 8.6 % of positives [3] were picked up on their second culture. In our own series of 266 positive cases, 98 % were picked up on this first culture, but one
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Table 1. Numbers of positive and negative cultures from different sites in 247 female patients with gonorrhoea
Positive at 4 routine different sites Negative at 4 routine different sites
Positive at single site
Vagina
Cervix
Urethra
218 29
209 38
53 75
185 62
247
247
128
247
12
7
2
1
Anus
was not positive until the fourth culture (and then at the anal site only), which stresses the importance of continuing cultures in those strongly suspected of having gonorrhoea. It must be remembered, however, that many males and some females escape infection after a single exposure to a positive case. Swabbing sites are all-important . The endocervix yields the highest number of positives with the urethra close behind (see table I). The anal culture, taken inch into the anal canal, is positive, we have by inserting the swab about found, in about 40 % of cases of female genital gonorrhoea, and is being used routinely in increasing numbers of clinics in USA. In a small proportion of females it may be the only positive site. The vaginal swab is used for culture of Trichomonas and Candida spp. It should never be relied on to diagnose gonorrhoea if only one site is used. Males are diagnosed on the spot by Gram-stained smear of the urethral discharge which should be routinely cultured not only for confirmation but also as a laboratory efficiency control in culture technique. The oxidase test sugar reactions and the sensitivity to penicillin should be tested routinely on all strains that grow from both males and females. A recent useful development in diagnostics is the use of a stiff, short bacterial loop to take an urethral 'scrape' from the lateral wall of the fossa navicularis about inch from the orifice in males with little or no discharge. This procedure has been made more important by the small, but increasing numbers of symptomless male gonorrhoea carriers being seen. Such patients should also be given a slide so they can take a morning smear before urinating . Serological diagnosis of gonorrhoea is unreliable, for the antigens at present available lack sensitivity and specificity, but from the work being done on this, a reliable antigen may well appear during the next few years [4] . Fluorescent antibidy tests (FA) using a fluorescein tagged antibody on a dried smear is also regarded as lacking necessary sensitivity for routine use, but can be used in two areas: as an adjunct to culture in smears from conjunctivae, joint fluids or skin lesions (in gonococcal septicaemia) when partial therapy may have destroyed
*
*
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cultural recovery of organisms, and as a confirmatory test for organisms grown on T·M medium [5]. In male patients with no epidemiological likelihood of gonorrhoea and no urethral discharge who ask 'have I got VD?' , the two-glass test, in which the first 50 ml or so (the first catch) of urine is passed into one glass, and then some into a second glass, is always used. If both glasses are crystal clear after the addition of a few drops of dilute acetic acid to dissolve carbonates and phosphates, there is no likelihood of gonorrhoea or NSU. This test is also used routinely on all surveillances, the diminution of the number of 'threads' in the first glass indicating the progress towards cure. The patient should be seen weekly until both glasses are clear. In females, surveillance in New Zealand consists of two repeat sets of cultures a week apart.
1.2 Syphilis In infectious syphilis the dark ground microscopic examination of serum squeezed from the suspected chancre, or any moist lesion, is the first effecive diagnostic measure to be undertaken. Pitfalls are lack of familiarity with the technique' of setting up a dark ground microscope or preparing a proper darkground slide, and the positive identification of Treponema pallidum from the commensal varieties that are often present. Determinations from dark ground examination of mouth lesions are especially unreliable. A fairly recent introduction has been a fluorescent antibody test using a thin unfixed dried smear (made like a blood smear) of the serum suspected to contain treponemes, the technique being a reversal of that used in the FTA-ABS test, using a known high antibody serum. Any laboratory doing the FTA-ABS test can do this fluorescent antibody test for which the smear may be sent by mail. Serology, however, is the most important tool. The FTA-ABS becomes positive usually within a week of the appearance of the primary sore [6] . The
Abbreviations Used
=Venereal Disease Research Laboratory VORL =Cardiolipin Wassennann Reaction CWR FTA-ABS = Fluorescent treponema! antibody absorption TPHA = Treponema pal/idum haemaggiutination test =Treponema pallidum immobilisation TPI RPCF = Reiter-protein complement fixation
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Treponema pallidum Haemagglutination Test (TPHA) of Rathgen appears to have all the qualities of the FTA-ABS and behaves similarly. The VDRL and RPCF tests become positive close behind these, followed by the CWR and lastly the TPI, so in any case of suspected early syphilis the whole battery of tests, except the TPI, is asked for. If it is late in the primary stage, or the case is a secondary one, there is no problem - all tests will be strongly positive. In latent and tertiary cases the reagin tests, VORL and CWR, can be variable, so reliance is placed on the antitreponemal group, the FTA-ABS and the TPHA, the TPI being the final court of appeal. This group is also used to exclude biological false positive reagin results which are common. Reagin tests are valuable in two special areas: as screening tests because of their cheapness and simplicity, and in surveillance of treated cases for which they are quantitated, the antitreponemal group being too sensitive for this. Recently, in some laboratories in London, the TPHA, which is easily performed and automated although not yet cheap, has been adopted for routine use together with the traditional VDRL as a screening test. 1.3 Nonspecific Urethritis Nonspecific urethritis is diagnosed by exclusion. It varies in intensity from slight crusting of the meatus in the morning with a few threads in the first urine glass (see section 1.1) to a frank profuse yellow discharge resembling classical gonorrhoea. If the urethral discharge is pale, flocculent, mild or mucoid it is usually NSU. The long incubation period of 6 days to 3 weeks or up to several months is an important differentiating point. 50 % of NSU cases recur, sometimes years later, usually after intercourse; in these cases the discharge can reappear the following day.
1.4 The Sexually Transmitted Diseases(STD) Diagnosis of the STD group needs some comment. Any generalised acutely itchy polymorphic rash in a non-eczematous young person is probably scabies. Demonstration of the mite is difficult, and a therapeutic trial with gammexane cream or benzylbenzoate emulsion may be the best approach to diagnosis. Pediculosis pubis is usually self evident, but on occasions tends to be missed by both doctor and patient, unless a thorough search in good light is made for nits and adults which are semi-transparent and very variable in size. The vaginitides are poorly handled by private doctors, the tendency being to prescribe one of the broad-spectrum pessaries for any vaginal discharge without attempting differentiation. Trichomoniasis and candidiasis account for
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practically all the marked and mild degrees of vaginitis. A Stuart's medium vaginal swab plated onto Sabouraud's and a special Trichomonas medium, together with a wet smear if a microscope is available, will diagnose the great majority of cases of true vaginitis! . A pale, cloudy or mucoid vaginal discharge without a vaginitis is common, and is due to an overproduction of cervical mucus - mucorrhoea. It is hormonally controlled and therefore a normal variation, so should be treated by reassurance and not pessaries. The 'Pill' is often the cause. The odd nonspecific vaginitides do not fit into these categories and are difficult to deal with, but are usually mild, and can occasionally be due to a severe cervical erosion or infection with Corynebacterium vagina/e. The few cases of female gonorrhoea presenting with a vaginal discharge show a purulent endocervicitis, not a vaginitis. Genital warts require careful searching for in the female . They are pale, with a cauliflower-like surface, and occur most commonly in the vestibule near the fourchette, but may be profuse and in any moist area. The sexual partner should also be examined. Genital herpes, commencing as typical vesicles, eventually forms multiple ulcers which can progress to deep erosive sores in the female . They are very painful and there is an inguinal adenitis. The umbilicated pearly papules of molluscum contagiosum on the lower abdomen or flanks are easy to diagnose and cure by mild chemical cautery, or by lifting out the 'mollusc body' with a needle .
2. Treatment 2.1 Gonorrhoea The key to gonorrhoea control is casefinding . Close to this in importance is effective treatment. Only by ensuring that the cure rate approaches 100 % can the all-important relative sensitivity of the gonococcus to penicillin be kept high enough to prevent escalation of the dose needed for cure. This has so far been achieved in New Zealand (where 408 strains were tested in 1972), as it has in England and Scandinavia (see fig. 1). However, the worldwide picture is not so encouraging; inefficient treatment is overall increasing the resistance of the gonococcus to penicillin [5]. To try and reverse this trend, the US Public Health Service (USPHS) increased penicillin dosage schedules in March 1972 to a single 4.8 mega units dose of soluble
1 See also Practical Therapeutics article 'Vaginitis : Diagnosis and Treatment', Drugs 4: 419 (1972).
--
Venereal Disease: Diagnosisand Treatment
UK
london Norway
NewZeeland Canedo
USA
150
Australia Ugenda
Fer Eest 10
20
30
40
50
60
70
80
Percentage of the gonococcus
Fig. 1. Penicillin sensitivity of the gonococcus. Solid bars showing percentage of more resistant strains (MIC > 0.12 j.lg/ml). After Willcox (1972).
penicillin G (sodium or potassium benzylpenicillin) preceded by 1 g of oral probenecid, or 3.5 g ampicillin in one oral dose also given with probenecid [8]. It is paramount that penicillin, with its enormous safety factor, its cheapness, and not least its treponemacidal effect be retained as the standard treatment for gonorrhoea. Significant advances in penicillin therapy have been : 1) Realisation that the short, high blood peak given by aqueous solutions of the pure crystalline salt alone, or mixed with the slower acting procaine penicillin suspension is superior to the longer, lower blood level curve given by procaine penicillin alone. The procaine fraction of this preparation is a vasoconstrictor and delays absorption [5]; absorption also varies with the particle size, and therefore the brand used. A third variable with the procaine penicillin suspension alone, is that the higher the concenttation, the slower is the rate of absorption [9]. 2) The concomitant use of probenecid has in most cases doubled or tripled the serum concentration of penicillin. Because over half the penicillin is protein bound and the intracellular penicillin concentration is half that in the extracellular fluid, high in vivo concentrations are necessary [5] . Two 0.5 g probenecid tablets (1 g) 30 minutes before the injection is probably all that is required, but in New Zealand, 3 further doses of 0.5 g are given 6 hours apart. This regimen, together with a single injection of a mixture of 1.2 mega units of procaine penicillin G with 1.0 mega units of aqueous penicillin ('Gonopen') has given a 99 % cure rate at the Christchurch clinic in 1,100 cases involving both sexes.
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Single shot parenteral treatment is regarded as the ideal because of its guarantee of absorption and therefore an approximately predictable and reproducible serum concentration. Second preference is single dose oral treatment, despite considerable individual variation in gastric absorption. A course of oral treatment is often defeated by failure of the patient to take the remedy. The only single dose oral regimen approaching parenteral penicillin in efficacy is one using ampicillin together with 2 tablets of probenecid, taken at the same time; 5 X 0.5 g ampicillin capsules (2.5 g) in one dose is adequate in New Zealand, although more resistant Australian strains may need the 3.5 g dose recommended by the USPHS [8] . Gastric upset is uncommon . Those who are allergic to penicillin cannot be given ampicillin, and cephalosporins are inadvisable because of the possibility of cross allergy. In any case, cephaloridine [10], cephalothin [5] and cephalexin [16] do not give acceptable cure rates. Oral tetracyclines are used widely and give acceptable cure rates in a 4 day schedule of 500 mg 6-hourly. In cases involving resistant strains, a loading dose of up to 1.5 g can be used. Equivalent regimens of the new tetracycline analogues are equally effective but more expensive - doxycycline ('Vibramycin') and minocycline ('Minocin') as a single dose of 3 capsules have, in some hands, given cure rates in the mid 90 %s [11] , but a 4 day regimen using a dose comparable to that recommended for tetracycline is preferable, as vomiting sometimes occurs with the single dose regimen and gastric absorption is variable [5] . The chief problem with the tetracyclines and analogues is the resistance which develops much more quickly than to penicillin. In addition , infective or transferrable resistance develops. All Neisseria gonorrhoeae isolates resistant to 0.5 units/rnl of penicillin are also resistant to 1 mg/ml of tetracycline [5] . Such isolates also have increased resistance to chloramphenicol, erythromycin, kanamycin, gentamicin, spiramycin, rifampicin and the semisynthetic penicillins and also, to a small extent, to spectinomycin . Spectinomycin ('Trobicin') given as a single treatment, in an intramuscular dose of 2 g for males and 4 g (2 g into each buttock) for females is now recommended by the USPHS as the drug of choice when penicillin and ampicillin are contra-indicated [8] . A small series of 38 mates and 20 females using this dosage with full surveillance was tried at Christchurch Hospital in 1970, with only one failure in each group [13]. Subsequent trials involving larger numbers of patients have confirmed its effectiveness [12] . Side-effects are minimal and the injection is much less painful than penicillin. Whether absolute resistance will develop, as for streptomycin, is not yet known. Thiamphenicol ('Urfamycin'), a chloramphenicol derivative developed in Italy, should be mentioned . It is given as a single dose of 2.5 g by mouth, and in"
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a large French series of several thousands, mainly males, gave a failure rate of 1.6 % [14] , but it has not yet been evaluated outside of Europe . Other remedies sometimes employed are co-trimoxazole (trimethoprimsulphamethoxazole) or spiramycin, but neither achieves an acceptable cure rate. Kanamycin by single injection is somewhat better, but needs re-evaluation in the light of the changing antibacterial status of the gonococcus.
2.2 Syphilis Penicillin is still the drug of choice, and in contrast to the gonococcus no increased resistance of the treponeme has been proved. A serum level of only 0.03 units/ml is treponemacidal but it must be continuous, and must extend over a period of 10 to 14 days in infectious syphilis, and 21 days in all late and latent cases. This can be achieved in two ways; either by weekly injections of 2.4 (or 3.0 in late cases) mega units of benzathine penicillin, or daily injections of 600,000 units (or 1 mega unit) of procaine penicillin suspension. The procaine penicillin regimen is preferred in neurosyphilis as benzathine penicillin passes the blood brain barrier poorly. In congenital syphilis, a total dose of 450 ,000 units of procaine penicillin/kg body weight is divided by 10 and given in 10 daily doses, or else a single injection of benzathine penicillin in a dose of 100,000 units/kg body weight [IS] . Tetracyclines are the next choice, 30 to 40 g over a period of IS to 20 days in early syphilis, and 60 to 80 g in late syphilis. Tetracyclines should not be used in pregnant women because of the risk of hepatotoxicity, or in children under the age of 6 or 7 because of the risk of tooth discolouration. Erythromycin estolate is effective in a 30 g dose given over 15 days in infectious syphilis, and in appropriate doses it can be given to infants. It is not yet evaluated in late syphilis. It must be realised that tetracyclines and erythromycin estolate, as alternatives to penicillin, are much less efficient antitreponemal drugs and should only be used where penicillin is fully contra-indicated. The cephalosporins have not yet been evaluated in syphilis treatment [15] . Surveillance of treated infectious syphilis consists of serological studies monthly for 6 months, 3-monthly for 6 months, and again a year later. Seroreversal takes 6 to 12 months if the case is treated in the infectious stage. In late syphilis, seropositivity usually remains despite successful treatment. The cerebrospinal fluid serology is done only on cases treated in the latent and late phase, either when first seen, or at the end of surveillance.
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2.3 Nonspecific Urethritis This increasingly common condition which infects males only, is diagnosed by exclusion of the gonococcus from the urethral discharge. Its cause and mode of transmission are still unknown. Tetracyclines, followed closely by erythromycin, are the best remedies for this condition; which appears to be suppressed rather than fully cured in about half the cases treated. Abstinence from intercourse and alcohol are essential if cure is to be hoped for. A minimum course should be 6 days on full dosage (500 mg 6-hourly), the maximum being 3 weeks, but in those in whom symptoms present when intercourse is unavoidable, e.g. within a marriage, a long-term (e.g. I or 2 months) maintenance course of tetracycline 250 mg 3 times a day often prevents recurrences. The sexual partner in a stable relationship is usually treated empirically, but there is no proof of the efficacy of drug treatment in preventing recurrences in the male.
References 2
CIwrles, A.G.; Cohen, S.; Kass, M.B. et al.: Arner. J. Obstet. Gynec.108: 595-599 (1970) . Martin. I.E. and Lester,A.: HSMHAHlth. Rep. 86:
9
Johnson, D. w.; Kvak, P.A.; A/abk, V.L.et al.: New
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Nystrom, B. andMolin,L.: Wid. Hlth. Org. Circular
Engl.J .Med.281:
30-33(1971). 3 4
Johnson, D.W.; Holmes, K.K.; Kvate, P.P. et aL: Arner. J. Epidem. 90: 438-448 (1969) . Willcox, R.R.: Abstr. of Hygiene 46: 913-944 (1971) .
5 6 7 8
Schroeter, A.L. and Lucas,I.B.: Obstet. and Gynec. 39: 275-285 (1972) . Gamer, M.P. : Broadsheet No.2, Laboratory Diagnosls ofSyphllis, Coll. Path. of Aust. WiUcox, R.R.: Brit. J. rener , Dis. 48: 163 (1972). US Department of Health, Education and Welfare, Recommended Treatment Schedules (March 1972).
11 12 13 14 15 16
1~(1970).
WHO/VDT71: 375. Thatcher, Pazin, G. and Domescik, G.: Publ. lllth.Rep.(Wash.)85: 160-162(1970). Peterson, A.H.; Wiemer, P.J.;Holmes, K.K. etal.: J. Arner. med. Ass. 220: 205-208 (1972) . PIDus, WM.: Med. J. Aust. 2: 500-501 (1970) . Siboulet,A.: Wid. Hlth. Org. Circular WHO/VDT72: 377. Sparling, P.F.: New Engl. J. Med. 284: 642~53 (1971) . WiUcox, R.R. and Woodcock, K.S.: Postgrad. med. J. 46 (suppl.) : 103 (Oct. 1970).
w.;
Author's address : Dr W.M Platts, Christchurch Hospital, Christchurch (New Zealand)
