THE 10URNAL OF INFECTIOUS DISEASES • VOL. 133, NO.5· © 1976 by the University of Chicago. All rights reserved.

MAY 1976

The Lack of Effect of Ampicillin plus Probenecid Given for Genital Infections with Neisseria gonorrhoeae on Associated Infections with Chlamydia trachomatis From the Departments of Genito-Urinary Medicine and Microbiology, University College Hospital, and the Department of Bacteriology, University College Hospital Medical School. London, England

J. D. Oriel, G. L. Ridgway, P. Reeve, D. C. Beckingham, and Jean Owen

Penicillin has been the drug of choice in the treatment of gonorrhea for three decades. Within the last few years, oral ampicillin has also been found to be effective; it is usually given in a single dose combined with probenecid. In Britain and western Europe, ampicillin (2 g) combined with probenecid (1 g) has cured > 90% of patients with uncomplicated gonorrhea [1, 2]. Genital infections with Neisseria gonorrhoeae are often accompanied by infection with Chlamydia subgroup A (Chlamydia trachomatis ). This

organism, which is an important cause of nongonococcal urethritis (NGU) [3, 4], has been recovered from 25%-30% of men with gonococcal urethritis and from 35%-60% of women with gonococcal cervicitis [5-8]. There is evidence that penicillin, in a dosage sufficient to cure gonococcal urethritis in men, may not eradicate an associated chlamydial infection; such men later develop postgonococcal urethritis (PGU), a disease analogous to NGU [5] (and quoted from J. D. VaughanJackson in [9]). No data are available concerning the results of penicillin therapy of C. trachoma tis infection associated with gonococcal infection in women or concerning the effect on the organism of ampicillin in a dosage appropriate for the therapy of gonorrhea. We report herein the effect of a single oral dose of ampicillin (2 g) plus probenecid (1 g) on C. trachomatis associated with infections with N. gonorrhoeae in both men and women. Cell culture for C. trachomatis was performed before and after

Received for publication September 18, 1976. This work was supported by a grant from the Medical Research Council of Great Britain. We are grateful to Dr. E. Joan Stokes for kindly providing laboratory facilities and to Ms. Lam Po Tang for technical assistance. Please address requests for reprints to Dr. J. D. Oriel, Department of Genito-Urinary Medicine. University College Hospital, Gower Street, London WCIE 6AU, England.

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Forty-six men were successfully treated with a single oral dose of ampicillin (2 g) plus probenecid (l g) for urethral infections with Neisseria gonorrhoeae. Chlamydia trachomatis was isolated from cultures of cells obtained from 11 of these men both before and after treatment; C. trachomatis was isolated from one man before but not after treatment and from three men after but not before treatment. No isolates were obtained from the remaining 31 men either before or after treatment. Of the 15 patients whose cultures yielded C. trachomatis, 12 developed postgonococcal urethritis; of the 31 patients from whose cultures no isolate was obtained, five developed postgonococcal urethritis. Of 44 women successfully treated with ampicillin plus probenecid for cervical infections with N. gonorrhoeae, 18 had C. trachomatis isolated from the cervix both before and after treatment. C. trachomatis was isolated from five women before but not after treatment and from two women after but not before treatment. No isolates were obtained from the remaining 19 women either before or after treatment. Thus ampicillin plus probenecid in the dosage used rarely eliminated C. trachomatis from the genital tract of either men or women. Whereas men with a persisting chlamydial infection will probably develop postgonococcal urethritis and thus receive appropriate treatment, such an infection in women is not likely to be suspected unless attempts are made to isolate C. trachomatis.

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Ampicillin-Probenecid and C. trachomatis

therapy in all cases, and the development of PGU was assessed in both the Chlamydia-positive and the Chlamydia-negative men. Materials and Methods

Results

Men. Patients whose cultures for C. trachomatis before or after therapy were contaminated or whose gonococcal infection required further treatment because of relapse or reinfection were excluded from the study. Results were available for 46 men with confirmed gonococcal urethritis; 43 of these men were heterosexual and three homosexual. C. trachomatis was recovered from 12 of the 46 men (26 %) on first examination and from another three men during follow-up study, for an overall isolation rate of 33% (table 1). Isolates of C. trachomatis were obtained from 11 patients both before and after therapy with ampicillin plus probenecid (group 1). The intervals between isolations were one week for four men, Table 1. Effect of a single oral dose of ampicillin (2 g) plus probenecid (1 g) on the frequency of isolation of Chlamydia trachomatis and on the development of postgonococcal urethritis (POD) in 46 men with gonococcal urethritis. Isolate obtained Group no.

Before therapy

After therapy

1 2 3 4

Yes Yes No No

Yes No Yes No

No. of patients developing POU/no. with isolation pattern 10/11 1/1 1/3 5/31

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All of the patients were seen in the Department of Genito-Urinary Medicine, University College Hospital, London, between March 1 and July 31, 1975. After general and local examination, specimens were collected as follows. Specimen collection from men. A specimen of urethral secretion was taken with a disposable plastic loop and spread on a slide for gram staining and microscopic examination. A second specimen was inoculated onto a culture plate for detection of N. gonorrhoeae. A wire-mounted endourethral swab (Medical Wire & Equipment Co., Ltd., Potley, Corsham, Wiltshire, England) was then passed 4-5 em into the urethra and inserted into a 2-ml bottle of transport medium for Chlamydia, and the wire was cut off with sterilized cutters. A two-glass urine test and a serologic test for syphilis were also performed. Specimen collection from women. Patients were examined in the lithotomy position; a Cusco speculum was used to expose the cervix. Specimens for microscopic examination and culture for N. gonorrhoeae were taken from the urethra and cervix with plastic loops, and a vaginal specimen was taken for microscopic study and culture for Trichomonas vaginalis. The cervix was cleaned with cotton wool, and a specimen for culture for C. trachomatis was collected with a cotton-wool swab, which was inserted into the cervical canal and rotated. The swab was then broken into a 2-ml bottle of chlamydia transport medium. Rectal specimens for culture for N. gonorrhoeae were taken in some cases, but rectal specimens were not examined for Chlamydia. Serological tests for syphilis were performed. Once the diagnosis of gonorrhea had been made, both men and women were given a single oral dose of 2 g of ampicillin plus 1 g of probenecid. Follow-up examinations were normally performed three to four days, seven days, and 14 days after therapy, although there was some individual variation in these intervals. Some patients were observed for up to three months. Each time a patient attended the clinic, the diagnostic tests

described above were performed, but culture for C. trachomatis was not repeated less than one week after therapy. Patients were advised not to resume intercourse until tests for cure (three negative cultures for N. gonorrhoeae) had been performed (a period of not less than two to three weeks in the majority of cases). Assessment of PGU. PGU was defined as the presence of ~ 20 polymorphonuclear leukocytes in a gram-stained urethral smear examined at a magnification of X900. The procedure has been described in detail elsewhere [6]. Laboratory methods. N. gonorrhoeae was cultured on a selective medium [10]. Cell culture for C. trachomatis was performed by centrifugation of specimens onto McCoy cells pretreated with with idoxuridine followed by incubation and examination for chlamydial inclusions [11].

Oriel et al.

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Tabie 2.

Effect of a single oral dose of ampicillin

(2 g) plus probenecid (1 g) on the frequency of iso-

lation of Chlamydia trachomatis from the cervix of 44 women with gonorrhea. Isolate obtained Group no.

Before therapy

After therapy

5 6 7 8

Yes Yes No No

Yes No Yes No

No. of patients 18 5 2

19

(with an interval between isolation attempts of two weeks for both). Finally, C. trachomatis was not isolated from 19 patients (group 8) before or after therapy, with intervals of one week (six women), two weeks (seven women), three weeks (three women), four weeks (one woman), five weeks (one woman) , and seven weeks (one woman) between isolation attempts. Discussion

These results indicate that a single dose of ampicillin and probenecid, although known to be an effective treatment for gonorrhea, rarely eliminates C. trachomatis from the genital tract of men or women. There is now evidence that four antimicrobial agents that have been used for the treatment of gonorrhea (penicillin, ampicillin, kanamycin, and gentamicin) may, in clinical dosage, fail to eradicate an associated chlamydial infection [5, 6, 9]. C. trachomatis can be demonstrated in the genital tract in approximately one-quarter of men and one-half of women infected with N. gonorrhoeae. In the case of men with gonococcal urethritis, persistence of C. trachomatis after therapy will probably (as was confirmed here) result in PGU, which will be diagnosed either on routine follow-up examination or because the patient develops symptoms; appropriate treatment with a tetracycline can then be instituted. However, women with persisting chlamydial infection are unlikely to be diagnosed unless isolation of C. trachomatis is attempted, since such infection presents no distinctive symptoms or signs [7, 8]. The possibility clearly exists that many women successfully treated for gonorrhea may be discharged as cured despite having a continuing and undiagnosed infection with C. trachomatis. Since this organism is now regarded as of major importance in the etiology of NGU, the epidemiological implications are disquieting. The management of patients simultaneously infected with N. gonorrhoeae and C. trachomatis thus poses definite therapeutic problems. It is suggested that, when existing treatment schedules for gonorrhea are revised or new ones introduced, the activity of antimicrobial agents against C. trachomatis, as well as against N. gonorrhoeae, be as-

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two weeks for four men, three weeks for one man, and four weeks for two men. C. trachomatis was isolated from one patient before treatment but not two weeks later (group 2). C. trachomatis was not isolated from three patients (group 3) before therapy but was isolated subsequently (after one week for one man and two weeks for two men). C. trachomatis was not isolated from 31 patients (group 4) either before or one week (11 men), two weeks (13 men), three weeks (four men), four weeks (one man), five weeks (one man), or six weeks (one man) after therapy. After treatment with ampicillin and probenecid, 17 of the 46 patients (37%) developed PGU. Of the 15 patients who yielded C. trachomatis before or after therapy, 12 (80%) developed PGU; of the 31 patients who were isolation-negative throughout the study, five (16%) developed PGU. Women. Results were available from 44 female patients (table 2). Of the 44 women with confirmed gonorrhea, 23. (52%) yielded C. trachomatis from the cervix on first examination, and another two women had similar cultures during follow-up study, for an overall isolation rate of 57%. C. trachomatis was isolated from 18 patients both before and after therapy (group 5). The intervals between isolations were one week for three women, two weeks for six women, three weeks for four women, five weeks for two women, eight weeks for one woman, nine weeks for one woman, and 12 weeks for one woman. C. trachomatis was isolated from five patients (group 6) before therapy but not one week (three women), three weeks (one woman), or four weeks (one woman) afterward. C. trachomatis was not isolated from two patients (group 7) before therapy but was isolated subsequently

Ampicillin-Probenecid and C. trachomatis

sessed. It may in the future be possible to devise therapy that is equally effective against both of these commonly occurring organisms.

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6.

References

7.

8.

9.

10.

11.

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1. Eriksson, G. Oral ampicillin in uncomplicated gonorrhoea. 1. Treatment of gonococcal urethritis in men. Acta Derm. Venereol. (Stockh.) 50:451454, 1970. 2. Willcox, R. R., Woodcock, K. R., Latto, D., John, J., Redmond, A., Parker, R. R, Rees, G. D., Cobbold, R. J. C. Treatment of gonorrhoea with single doses of ampicillin plus probenecid. I. Comparison with procaine penicillin. II. Comparison of results in London and Wales. Br, J. Vener. Dis. 49:263-270, 1973. 3. Holmes, K. K., Handsfield, H. H., Wang, S. P., Wentworth, B. B., Turck, M. Anderson, J. B., Alexander, E. R. Etiology of nongonococcal urethritis. N. Eng!. J. Med. 292: 1199-1205, 1975. 4. Dunlop, E. M. C., Vaughan-Jackson, J. D., Darougar, S., Jones, B. R. Chlamydial infection. Incidence in 'non-specific' urethritis. Br. J. Vener. Dis. 48:425-428, 1972. 5. Richmond, S. J., Hilton, A. L., Clarke, S. K. R. Chlamydial infection. Role of Chlamydia sub-

group A in non-gonococcal and post-gonococcal urethritis. Br. J. Vener. Dis. 48:437-444, 1972. Oriel, J. D., Reeve, P., Thomas, B. J., Nicol, C. S. Infection with Chlamydia group A in men with urethritis due to Neisseria gonorrhoeae. J. Infect. Dis. 131:376-382, 1975. Hilton, A. L., Richmond, S. J., Milne, J. D., Hindley, F., Clarke, S. K. R. Chlamydia A in the female genital tract. Hr. J. Vener. Dis. 50: 1-10, 1974. Oriel, J. D., Powis, P. A., Reeve, P., Miller, A., Nicol, C. S. Chlamydial infections of the cervix. Br. J. Vener. Dis. 50: 11-16, 1974. Dunlop, E. M. C. Non-specific genital infection; laboratory aspects. In R. S. Morton and J. R. W. Harris [ed.]. Recent advances in sexually transmitted diseases. Churchill Livingstone, Edinburgh, 1975, p. 284. Philips, I., Humphrey, D., Middleton, A., Nicol, C. S. Diagnosis of gonorrhoea by culture on a selective medium containing vancomycin, colistin, nystatin and trimethoprim (VeNT). A comparison with gramstaining and immunofluorescence. Br. J. Vener. Dis. 48:287-292, 1972. Reeve, P., Owen, J., Oriel, J. D. Laboratory procedures for the isolation of Chlamydia trachomatis from the human genital tract. J. Clin. Pathol, 28: 910-914, 1975.

The lack of effect of ampicillin plus probenecid given for genital infections with Neisseria gonorrhoeae on associated infections with Chlamydia trachomatis.

THE 10URNAL OF INFECTIOUS DISEASES • VOL. 133, NO.5· © 1976 by the University of Chicago. All rights reserved. MAY 1976 The Lack of Effect of Ampici...
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