Nongonococcal Urethritis
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H. H. HANDSFIELD and W. R . BOWIE The nongonococcal urethritis (NGU) syndrome is a group of sexually transmitted infections that together exceed the frequency of gonorrhea in men in most urban areas of Europe and the United States, and probably in much of the remainder of the world. “Nongonococcal” is preferred to the term “non-specific” urethritis because the latter is less precise and carries the inaccurate implication that the causes are unknown and perhaps unknowable. Key Words: Urethritis; Sexually transmissible disease.
ETIOLOGY
Although long suspected to be a cause of NGU,the role of Chlamydia trachomatis was not firmly established until reproducible techniques for isolating the organism became available in 1965 [14]. C. trachomatis has been isolated from 35% to 50% of cases of NGU, [9, 24, 34, 381 and its etiologic role has been confirmed by low isolation rates (55%) in controls matched for sexual experience [9, 241, by seroconversion [9, 241, and by differential responses of patients to antimicrobial agents with and without activity against C. trachomatis [5]. The chlamydiae, formerly classified as viruses or Bedsoniae, are obligately intracellular bacteria that require viral isolation techniques. Immunotype variants of C. trachomatis cause lymphogranuloma venereum and endemic trachoma, as well as NGU and related syndromes (Table 1). The term “TRIC agent” (for TRachoma-Znclusion Conjuncticitis) is discouraged because of confusion caused by the common use of “trich” as verbal shorthand for Trichomonas vaginalis. The role of Ureaplasma urealyticum (formerly “T-stain mycoplasma’ ’) in NGU is controversial 1311. Early studies showed higher urethral isolation rates from men with NGU than from men without urethritis, but these studies failed to control for sexual experience. It has subsequently been shown that 50% to 60% of sexually experienced men harbor U . urealyticum without signs or symptoms of urethritis [24, 29, 321 and studies of patients and controls who had similar levels of sexual activity demonstrated no difference in isolation rates of U . urealyticum [24,29]. Still more recently, however, Bowie et al. [9], studying men with their first episodes of NGU, showed a greater isolation rate in patients than in matched controls and found higher concentrations of U . urealyticum in C. trachomatis-negative NGU patients than in C. trachomatispositive NGU patients or in controls with positive cultures for U . urealyticum. In addiAccepted August 6, 1979. Presented at the First Pan American Congress of Andrology, Caracas, Venezuela, March 13-16, 1979. From the Seattle-King County Department of Public Health and the Department of Medicine, University of Washington, Seattle, WA, USA, and the Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Address requests for reprints to: H. H. Handsfield, 1102 Public Safety Building, Seattle, WA 98104, USA.
321 0 Elsevier North Holland, Inc.. ARCHIVES OF ANDROLOGY, 3, 321-327 (1979)
014&5016/79/080321-07$02.25
322 H. H. Handsfield and W. R. Bowie TABLE 1 Classification and Characteristics of Chlamydia Causing Infection in Man -~
~
INHIBITION BY IODINE SYNONYMSSULFONAMIDESTAINING
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SPECIES
DISEASES
Chlnmydici psittur,i
Subgroup B Chlamydia
No
No
Psittacosis
Chlnmydiu rrachorrmris
TRIC agent"
Yes
Yes
Nongonococcal urethritis and related syndromes (primarily serotypes D-K)
Subgroup A Chlamydia
Endemic trachoma (Primarily serotypes A, B, Ba, C) Lymphogranuloma venereum (serotypes L, , L,, and L3) 'I
TRIC
=
TRachoma and Inclusion Conjunctivitis.
tion, spectinomycin, which is active against U . urealyticum but not against C. trachomritis , cured NGU associated with U . urealyticurn but not chlamydia1 urethritis, whereas treatment with sulfisoxazole, to which C . trachornatis but not U . urealyticurn is susceptible, had the opposite clinical effect [ 5 ] .Thus, U . urealyticurn may cause 30%to 40% of first episodes of NGU. The high prevalence of U . urealyticum carriage in sexually experienced men without urethritis is unexplained; it is possible that some strains are more pathogenic than others. The etiology of NGU in the 10% to 30% of cases caused by neither C. trachomatis nor U. tcrealytic.um is unknown. Both Corynebacterium genitalium type 1 [13] and Closrridium dijiic.de [I61 have been isolated more frequently from NGU patients than from men without urethritis, but in neither case were the controls matched with patients for sexual experience, and the roles of these organisms remain problematical. NGU is caused infrequently by T . vaginalis or Herpes simplex [9, 24, 481; cell wall deficient Neissrria gonorrhoeue , Hemophilus vaginalis , cytomegalovirus, Candida sp. , and the aerobic and anaerobic commensal bacteria of the urethra, vagina, and perineum rarely, if ever, cause NGU [ 8 , 9 , 241. There are no objective data to implicate alcohol, caffeine, highly spiced foods, allergy, physical strain, or increased or decreased sexual activity per se as causes of NGU, despite much folklore to the contrary. Such face-saving explanations evolved to avoid the social stigmata associated with venereal disease. EPIDEMIOLOGY
In the United Kingdom, NGU is at least twice as frequent as gonorrhea, and its incidence continues to rise while that of gonorrhea is stable or decreasing [45, 461. Although no other reliable nationwide data are available, a similar pattern has been observed in several clinics in the United States and elsewhere [38,44,45]. This situation is probably due in part to the frequency of mildly symptomatic and asymptomatic
Nongonococcal Urethritis 323 TABLE 2 Clinical Characteristics of Gonococcal and Nongonococcal Urethritis
NON-
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CLINICAL CHARACTERISTIC
GONOCOCCAL URETHRITIS
GONOCOCCAL
URETHRITIS
Incubation period
2-8 Days
10-20 Days
Onset
Abrupt
Gradual
Dysuria
Prominent (Occasionally absent)
Variable (Often absent)
Urethral discharge“ Purulent White Clear
(Percent of 41) 73% 27% 0
(Percent of 77) 36% 55% 9%
a
Based on author’s unpublished data.
infection, and to the fact that efforts usually are not made to locate and treat sexual contacts. Relative to gonorrhea, NGU occurs somewhat more frequently in men who have attained a higher socioeconomic standing, in students, in men who are less sexually active (as measured by age of first intercourse, numbers of sexual partners, and histories of prior sexually transmitted infections), in slightly older men, and in Caucasians [lo, 24, 451. Homosexual men appear to be less likely to acquire NGU than heterosexuals [lo, 451. CLINICAL MANIFESTATIONS
Table 2 illustrates the clinical features of symptomatic NGU compared to gonococcal urethritis, The symptoms and signs are usually less florid than in gonorrhea, but there is sufficient overlap that differentiation cannot be made accurately on clinical grounds alone [27, 421 and the duration of the incubation period is difficult to assess in most patients. Although the relative incidences of asymptomatic and symptomatic NGU are unknown, asymptomatic NGU is common; its prevalence approaches 20% of men attending sexually transmitted disease clinics for reasons other than urethritis [43]. The female counterpart of NGU is variable. Most contacts of infected men have no genito-urinary symptoms, or have subtle symptoms that may not bring them to medical attention [21, 331. C. trachomatis is a common cause of mucopurulent cervicitis and the “urethral syndrome” in sexually active women, and has been implicated in nongonococcal pelvic inflammatory disease [21, 22, 30, 331. Postgonococcal urethritis occurs in 36% [35] to 64% [23] of heterosexual men with urethral gonorrhea who are treated with penicillin, ampicillin, or spectinomycin, and infrequently in men treated with tetracycline [23, 261. This syndrome is the result of coincident gonorrhea and NGU, the latter unmasked when gonorrhea is treated with drugs that are not effective for NGU [24, 351. C. rrachomatis has been isolated from 19% [24] to 34% [35] of men with gonorrhea, and postgonococcal urethritis develops in virtually all of these if they are treated with drugs other than the tetracyclines [35].
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324
H. H. Handsfield and W. R. Bowie
C. truchomatis is the major cause of acute epididymitis in men under 35 years of age [2], inclusion conjunctivitis of the newborn [20] and a distinctive neonatal pneumonia [ 1,201, has been implicated in pelvic inflammatory disease [30] and is frequently isolated from men with Reiter’s Syndrome [28]. Unpublished data have also implicated C . truchomutis as a cause of midtrimester abortion [22]. U . urecilyticum has been associated with low birth weights in newborns, impaired fertility, and puerperal sepsis [31]. Accordingly, the common attitude that NGU is a clinically unimportant entity that is more an inconvenience than a serious threat to health is inappropriate. DIAGNOSIS
The diagnosis of nongonococcal urethritis involves ( 1 ) documentation of urethritis, and ( 2 ) establishing the absence of gonococcal infection. In the sexually active young adult. urethritis can be reliably diagnosed when a purulent or mucopurulent urethral discharge is observed. The presence of polymorphonuclear leukocytes (PMNs) on microscopical examination is confirmatory. Patients should be examined after 4 to 8 hr of holding their urine; under these conditions, the majority of symptomatic men have an easily expressible discharge [3, 431. In asymptomatic men and in men with symptoms of urethritis who have either no discharge or a clear mucoid discharge, urethritis may be diagnosed by semiquantitation of PMNs on a Gram stained urethral smear, as described independently by Bowie [3] and by Swartz et al. [43]. A calcium alginate tipped urethrogenital swab (Calgiswab, Inolex) is passed 2-3 cm into the urethra, a smear is prepared by rolling the swab on a microscope slide over a 1-2 cm2 area, and stained. The area of maximum concentration of cellular material is identified on low power and then examined with the oil immersion objective ( 9 7 0 ~ )an ; average of 2 5 PMNs/970x field is diagnostic of urethritis [3, 431. This method is less cumbersome and equally sensitive as microscopical examination of a centrifuged specimen of the initial 10-15 ml of voided urine, which is considered abnormal if there are 220 leukocytes per 400x field [3, 9, 241. The relative sensitivities of these techniques compared to macroscopic examination of voided urine for “threads” of mucus or inflammatory exudate are unknown. Examination of Gram stained smears prepared from urethral scrapings obtained with a sterile bacteriological loop is widely used, but semiquantitation of PMNs has not been studied with this technique, and has not been compared with specimens obtained with swabs. Absence of Gram negative diplococci on smear rules out gonorrhea with 90%-95% reliability [25], depending in part on the experience of the microscopist. A smear that is negative for Gram negative diplococci should usually be confirmed with a culture for Neisseria gonorrhoeue [ 2 5 , 271. A culture should always be performed on men without objective evidence of an abnormal urethral discharge, since the Gram stained smear has a sensitivity of 570% in men with asymptomatic urethral gonorrhea [19]. When available, cultures for C. truchomutis or U . nreulyticum and/or microimmunofluorescence serology for C. truchomatis may be useful, but most clinicians do not presently have access to these tests. TREATMENT
The tetracyclines are the drugs of choice for NGU, and have been studied more extensively than any other antimicrobial agents [4]. Treatment with tetracycline hydro-
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Nongonococcal Urethritis 325 chloride in a dose of 500 mg orally four times daily for seven days results in clinical resolution of NGU in approximately 90% of patients [4, 15, 181, and C. trachomatis is always eradicated [9, 18, 241. Persistent urethritis at the completion of treatment often is correlated with the presence of tetracycline-resistant U . urealyticum [22]. During the next six weeks after completion of therapy, however, NGU persists or recurs in approximately 30% of patients (up to 17% of patients with chlamydial urethritis and up to 47% of patients with nonchlamydial NGU) [4, 181. Regardless of the initial culture results, recurrences within 6 weeks are always chlamydia-negative [ 181. Minocycline is the most active tetracycline against C . trachomatis in vitro [7, 361. Bowie et al. [6] therefore treated 21 1 men with NGU with minocycline in a randomized, double-blind study. The four minocycline regimens included 100 mg daily for 7 days (58 patients), 100 mg twice daily for 7 days (54 patients), 100 mg daily for 21 days (48 patients), and 100 mg twice daily for 21 days (48 patients). Eight percent of patients had persistent NGU at the completion of treatment, regardless of the daily dose or the duration of therapy. Moreover, the combined persistence and recurrence rate was 30.3%, without statistically significant differences between the four regimens [6]. These figures are virtually identical to those obtained in a separate study in the same clinic using the standard one week tetracycline regimen [ 181. Twenty-three percent of men treated with 200 mg minocycline daily developed dizziness, lightheadedness, or ataxia, compared to 13% of men taking 100 mg daily [6]. It was concluded that minocycline gives results that are comparable to those obtained with tetracycline HC1, and that the optimal regimen of minocycline is 100 mg daily for 7 days [6]. Where low cost is important, tetracycline HCl 500 mg four times daily for 7 days remains the treatment of choice, but minocycline has the important advantage of once daily therapy. On the basis of pharmokinetics and the in vitro susceptibilities of C. trachomatis [7, 361 and U . urealyticum [40], it might be anticipated that doxycycline 100 mg daily for 7 days would be effective, and would eliminate the problem of vestibular toxicity, but this regimen has not been studied. Other tetracyclines have no important advantages. When a tetracycline cannot be given, erythromycin is usually prescribed in a dose of 500 mg four times daily, and has been reported to be moderately successful in limited studies in which neither chlamydial nor ureplasmal cultures were done [47]. C. trachomatis is susceptible to erythromycin, [7, 361 but U . urealyticum shows variable susceptibility [40]. The sulfonamides are effective in no more than 50% of patients with NGU [4,5] probably reflecting the susceptibility of C . trachomatis and the resistance of U . urealyticum [4]. Sulfamethoxazole-trimethoprim is probably no more effective than a sulfonamide alone. The aminocyclitol antibiotics, such as streptomycin and spectinomycin, to which U . urealyticum is susceptible but C . trachomatis is resistant, are effective only in nonchlamydial NGU [4, 51. The penicillins, the cephalosporins, and metronidazole are not effective. It is probable that failure to treat female sex partners has contributed to the rising incidence of NGU, and uncontrolled experience suggests that such treatment reduces the rate of recurrence [ 17, 371. Although adequately controlled studies are lacking, routine treatment of female sex partners is probably warranted to break the chain of transmission, to reduce the risk of recurrence of NGU in the patient, and to reduce the risk of potential complications of chlamydial or ureaplasmal infection in his partners. Sexual intercourse should be proscribed until both the patient and his partner have
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326 H. H. Handsfield and W. R. Bowie
completed treatment or, if they are likely to continue sexual activity, their treatment should coincide. Minocycline, which is associated with significantly greater frequency and degree of vestibular toxicity in women than in men [6,48] should not be used to treat female sex partners; tetracycline HCl, 500 mg four times daily for 7 days is preferable. A small proportion of men with NGU suffers repeated recurrences despite sexual abstinence or prolonged treatment of the patient and all partners. Such individuals should be evaluated for trichomoniasis (and perhaps given a trial of therapy with metronidazole), bacterial and nonbacterial prostatitis, upper urinary tract infection, urethral stricture, foreign bodies, and urethral trauma. In the absence of these conditions, all that can be offered is repeated short courses of a tetracycline when urethritis recurs. REFERENCES 1. Beem MO, Saxon EM (1977): Respiratory tract
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colonization and a distinctive pneumonia syndrome in infants infected with Chlamydia rrachomaris. N Engl J Med 296: 306-310 Berger RE, Alexander ER, Monda GD, Ansell J, McCormick G, Holmes KK (1978): Chlamydia trarhomaris as a cause of acute “idiopathic” epididymitis. N Eng J Med 298: 301-304 Bowie WR (1978): Comparison of Gram stain and first-voided urine sediment in the diagnosis of urethritis. Sex Transm Dis 5: 39-42 Bowie WR (1978): Etiology and treatment of nongonococcal urethritis. Sex Transm Dis 5: 27-33 Bowie WR, Alexander ER, Floyd JF, Holmes J. Miller Y, Holmes KK (1976): Differential response of chlamydia1 and Ureaplasmu-associated urethritis to sulfafurazole (sulfisoxazole) and aminocyclitols. Lancet ii: 1276- 1278 Bowie WR, Floyd JF, Stimson JB, Alexander ER, Holmes KK (1977): Double-blind comparison of two doses and two durations of minocycline therapy for nongonococcal urethritis (abstract). Tenth International Congress of Chemotherapy, Zurich, September 18-22, 1977 Bowie WR, Lee CK, Alexander ER (1978): Prediction of efficacy of antimicrobial agents in treatment of infections due to Chlamydia rrachomark. J Infect Dis 138: 655-659 Bowie WR, Pollock HM, Forsyth PS, Floyd JF, Alexander ER, Wang SP, Holmes KK (1977): Bacteriology of the urethra in normal men and men with nongonococcal urethritis. J Clin Microbiol 6: 482-488 Bowie WR, Wang SP, Alexander ER, Floyd J, Forsyth PS, Pollock HM, Lin JL, Buchanan TM, Holmes KK (1977): Etiology of nongonococcal urethritis: Evidence for Chlamydia trachomutis and Ureplrcsma ureolyticum. J Clin Invest 59: 735-742 Dans PE (1974): The establishment of a universitybased venereal disease clinic. I: Description of
the clinic and its population. J Am Vener Dis Assoc 1: 70-78 1 I . Fanning WL, Gump DW, Sofferman RA (1977): Side effects of minocycline: A double-blind study. Antimicrob AgentsChemother 11: 712-717 12. Ford DK, DuVernet M (1963): Genital strains of human pleuropneumonia like organisms. Br J Vener Dis 39: 18-20 13. Furness G, Evangelista AT, Kaminsky Z (1977): Corynebacterium ganiralium (nonspecific urethritis corynebacteria): Biologic reactions differentiating commensals of the urogenital tract from the pathogens responsible for urethritis. Invest Urol 15: 23-27 14. Gordon FB, Quan AL (1965): Isolation of the trachoma agent in cell culture. Proc SOC Exp Biol (NY) 118: 354-359 15. Grimble AS, Amarasuriya KL (1975): Nonspecific urethritis and the tetracyclines. Br J Vener Dis 51: 198-204 16. Hafiz S, McEntegart MG, Morton RS, Waitkins SA (1975): CIostridium difcile in the urogenital tract of males and females. Lancet i: 420-421 17. Handsfield HH (1978): Gonorrhea and nongonococcal urethritis: Recent advances. Med Clin N Am 62: 925-943 18. Handsfield HH, Alexander ER, Wang AP, Pedersen AHB, Holmes KK (1976): Differences in the therapeutic response of chlamydia-positive and chlamydia-negative forms of nongonococcal urethritis. J Am Vener Dis Assoc 2: 5-9 19. Handsfield HH, Lipman TO, Harnisch JP, Tronca E, Holmes KK (1974): Asymptomatic gonorrhea in men: Diagnosis, natural course, prevalence, and significance. N Engl 3 Med 290: 117-123 20. Harrison HR, English MG, Lee CK, Alexander ER (1978): Chlamydia rrachornatis infant pneumonitis: Comparison with matched controls and other infant pneumonitis. N Engl J Med 298: 702- 708 21. Hilton AL, Richmond SJ, Milne JD, Hindley F,
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Clarke SKR (1974): Chlamydia A in the female genital tract. Br J Vener Dis 50: 1-10 Holmes KK: Personal communication. Holmes KK, Johnson DW, Floyd TM, Kvale PA, (1967): Studies of venereal disease: 11. Observations on the incidence, etiology, and treatment of the postgonococcal urethritis syndrome. JAMA 202: 467-473 Holmes KK, Handsfield HH, Wang SP, Wentworth BB, Turck M, Anderson JA, Alexander ER (1975): Etiology of nongonococcal urethritis. Jacobs NF, Kraus SJ (1975): Gonococcal and nongonococcal urethritis in men: clinical and laboratory differentiation. Ann Intern Med 82: 7-12 Karney WW, Pedersen AHB, Nelson M, (1977): Spectinomycin versus tetracycline for the treatment of gonorrhea. N Engl J Med 296: 889-894 Kaufmann RE, Wiesner PJ (1974): Nonspecific urethritis. N Engl J Med 291: 1175-1177 Kousa M, Saikku P, Richmond S, Lassus A (1978): Frequent association of chlamydial infection with Reiter’s syndrome. Sex Transm Dis 5: 57-61 Lee YH, Tam PI, Schumacher JR, Rosner B, Alpert S , McCormack WM (1976): Reevaluation of the role of T-mycoplasmas in nongonococcal urethritis. J Am Vener Dis Assoc 3: 25-28 M5rdh PA, Ripa T, Svensson L, Westrom L (1977): Chlamydia trachomatis infection in patients with acute salpingitis. N Engl J Med 296: 1370- 1379 McCormack WM, Braun P, Lee YH, Klein JO, Kass EH (1973): The genital mycoplasmas. N Engl J Med 288: 78-89 McCormack WM, Lee YH, Zinner SH (1973): Sexual experience and urethral colonization with genital rnycoplasmas. Ann Intern Med 78: 696-698 Oriel JD, Johnson AL, Barlow D, Thomas BJ, Nayyar K, Reeve P (1978): Infection of the uterine cervix with Chlamydia trachomatis. J infect Dis 137: 443-451 Oriel JD, Reeve P, Thomas BJ, Miller A, Nicol CS (1972): Chlamydial infection: Isolation of Chlamydia from patients with non-specific genital infection. Br J Vener Dis 48: 429-436 Oriel JD, Reeve P, Thomas BJ, Nicol CS (1975): Infection with Chlamydia group A in men with urethritis due to Neisseria gonorrhoeae. J Infect Dis 131: 376-382
36. Ridgway GL, Owen JM, Oriel JD (1978): The antimicrobial susceptibility of Chlamydia trachomatis in cell culture. Br J Vener Dis 54: 103- 106 37. Schachter J (1978): Chlamydia1 infections. N Engl I Med 298: 428-435, 490-495, 540-549 38. Schachter J, Hanna L , Hill EC, Massad S , Sheppard CW, Conte JE, Jr, Cohen SN, Meyer K F (1975): Are chlamydial infections the most prevalent venereal disease? JAMA 231: 12521255 39. Shepard MC (1970): Nongonococcal urethritis associated with human strains of “T” niycoplasmas. JAMA 211: 1335-1340 40. Apaepen MS, Kundsin RB (1977): Simple, direct broth-disk method for antibiotic susceptibility testing of Ureaplasrna urealyticum . Antimicrob Agents Chemother 11: 267-270 41. Sueltmann S, Allen V, inhorn SL, et a!. (1971): Study of mycoplasma in university students with non-gonococcal urethritis. Health Lab Sci 8: 62-66 42. Swartz SL (1977): Diagnosis of nongonococcal urethritis. in: Nongonococcal Urethritis and Related Infections, American Society for Microbiology. Hobson D, Holmes KK (Ed). Washington, DC, pp 15-17 43. Swartz SL, Kraus SJ, Herrmann KL, Stargel MD, Brown WJ, Allen SD (1978): Diagnosis and etiology of nongonococcal urethritis. J Infect Dis 138: 445-454 44. Volk J, Kraus SJ (1974): Nongonococcal urethritis: A venereal disease as prevalent as epidemic gonorrhea. Arch Intern Med 134: 511-514 45. Wiesner PJ (1977): Selected aspects of the epidemiology of nongonococcal urethritis. In: Nongonococcal Urethritis and Related infections, American Society for Microbiology, Hobson D, Holmes KK (Eds). Washington, DC, pp 9- 14 46. Willcox RR (1977): How suitable are available pharmaceuticals for the treatment of sexually transmitted diseases? 1 : Conditions presenting as genital discharges. Br J Vener Dis 53: 314-323 47. Willcox RR (1972): “Triple tetracycline” in the treatment of nongonococcal urethritis in males. Br J Vener Dis 48: 137- 140 48. Wong JL, Hines PA, Brasher MD, Schachter J (1977): The etiology of nongonococcal urethritis in men attending a venereal disease clinic. Sex Transm Dis 4: 4-8
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H. H. HANDSFIELD and W. R . BOWIE The nongonococcal urethritis (NGU) syndrome is a group of sexually transmitted infections that together exceed the frequency of gonorrhea in men in most urban areas of Europe and the United States, and probably in much of the remainder of the world. “Nongonococcal” is preferred to the term “non-specific” urethritis because the latter is less precise and carries the inaccurate implication that the causes are unknown and perhaps unknowable. Key Words: Urethritis; Sexually transmissible disease.
ETIOLOGY
Although long suspected to be a cause of NGU,the role of Chlamydia trachomatis was not firmly established until reproducible techniques for isolating the organism became available in 1965 [14]. C. trachomatis has been isolated from 35% to 50% of cases of NGU, [9, 24, 34, 381 and its etiologic role has been confirmed by low isolation rates (55%) in controls matched for sexual experience [9, 241, by seroconversion [9, 241, and by differential responses of patients to antimicrobial agents with and without activity against C. trachomatis [5]. The chlamydiae, formerly classified as viruses or Bedsoniae, are obligately intracellular bacteria that require viral isolation techniques. Immunotype variants of C. trachomatis cause lymphogranuloma venereum and endemic trachoma, as well as NGU and related syndromes (Table 1). The term “TRIC agent” (for TRachoma-Znclusion Conjuncticitis) is discouraged because of confusion caused by the common use of “trich” as verbal shorthand for Trichomonas vaginalis. The role of Ureaplasma urealyticum (formerly “T-stain mycoplasma’ ’) in NGU is controversial 1311. Early studies showed higher urethral isolation rates from men with NGU than from men without urethritis, but these studies failed to control for sexual experience. It has subsequently been shown that 50% to 60% of sexually experienced men harbor U . urealyticum without signs or symptoms of urethritis [24, 29, 321 and studies of patients and controls who had similar levels of sexual activity demonstrated no difference in isolation rates of U . urealyticum [24,29]. Still more recently, however, Bowie et al. [9], studying men with their first episodes of NGU, showed a greater isolation rate in patients than in matched controls and found higher concentrations of U . urealyticum in C. trachomatis-negative NGU patients than in C. trachomatispositive NGU patients or in controls with positive cultures for U . urealyticum. In addiAccepted August 6, 1979. Presented at the First Pan American Congress of Andrology, Caracas, Venezuela, March 13-16, 1979. From the Seattle-King County Department of Public Health and the Department of Medicine, University of Washington, Seattle, WA, USA, and the Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Address requests for reprints to: H. H. Handsfield, 1102 Public Safety Building, Seattle, WA 98104, USA.
321 0 Elsevier North Holland, Inc.. ARCHIVES OF ANDROLOGY, 3, 321-327 (1979)
014&5016/79/080321-07$02.25
322 H. H. Handsfield and W. R. Bowie TABLE 1 Classification and Characteristics of Chlamydia Causing Infection in Man -~
~
INHIBITION BY IODINE SYNONYMSSULFONAMIDESTAINING
Syst Biol Reprod Med Downloaded from informahealthcare.com by University of Newcastle on 01/09/15 For personal use only.
SPECIES
DISEASES
Chlnmydici psittur,i
Subgroup B Chlamydia
No
No
Psittacosis
Chlnmydiu rrachorrmris
TRIC agent"
Yes
Yes
Nongonococcal urethritis and related syndromes (primarily serotypes D-K)
Subgroup A Chlamydia
Endemic trachoma (Primarily serotypes A, B, Ba, C) Lymphogranuloma venereum (serotypes L, , L,, and L3) 'I
TRIC
=
TRachoma and Inclusion Conjunctivitis.
tion, spectinomycin, which is active against U . urealyticum but not against C. trachomritis , cured NGU associated with U . urealyticurn but not chlamydia1 urethritis, whereas treatment with sulfisoxazole, to which C . trachornatis but not U . urealyticurn is susceptible, had the opposite clinical effect [ 5 ] .Thus, U . urealyticurn may cause 30%to 40% of first episodes of NGU. The high prevalence of U . urealyticum carriage in sexually experienced men without urethritis is unexplained; it is possible that some strains are more pathogenic than others. The etiology of NGU in the 10% to 30% of cases caused by neither C. trachomatis nor U. tcrealytic.um is unknown. Both Corynebacterium genitalium type 1 [13] and Closrridium dijiic.de [I61 have been isolated more frequently from NGU patients than from men without urethritis, but in neither case were the controls matched with patients for sexual experience, and the roles of these organisms remain problematical. NGU is caused infrequently by T . vaginalis or Herpes simplex [9, 24, 481; cell wall deficient Neissrria gonorrhoeue , Hemophilus vaginalis , cytomegalovirus, Candida sp. , and the aerobic and anaerobic commensal bacteria of the urethra, vagina, and perineum rarely, if ever, cause NGU [ 8 , 9 , 241. There are no objective data to implicate alcohol, caffeine, highly spiced foods, allergy, physical strain, or increased or decreased sexual activity per se as causes of NGU, despite much folklore to the contrary. Such face-saving explanations evolved to avoid the social stigmata associated with venereal disease. EPIDEMIOLOGY
In the United Kingdom, NGU is at least twice as frequent as gonorrhea, and its incidence continues to rise while that of gonorrhea is stable or decreasing [45, 461. Although no other reliable nationwide data are available, a similar pattern has been observed in several clinics in the United States and elsewhere [38,44,45]. This situation is probably due in part to the frequency of mildly symptomatic and asymptomatic
Nongonococcal Urethritis 323 TABLE 2 Clinical Characteristics of Gonococcal and Nongonococcal Urethritis
NON-
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CLINICAL CHARACTERISTIC
GONOCOCCAL URETHRITIS
GONOCOCCAL
URETHRITIS
Incubation period
2-8 Days
10-20 Days
Onset
Abrupt
Gradual
Dysuria
Prominent (Occasionally absent)
Variable (Often absent)
Urethral discharge“ Purulent White Clear
(Percent of 41) 73% 27% 0
(Percent of 77) 36% 55% 9%
a
Based on author’s unpublished data.
infection, and to the fact that efforts usually are not made to locate and treat sexual contacts. Relative to gonorrhea, NGU occurs somewhat more frequently in men who have attained a higher socioeconomic standing, in students, in men who are less sexually active (as measured by age of first intercourse, numbers of sexual partners, and histories of prior sexually transmitted infections), in slightly older men, and in Caucasians [lo, 24, 451. Homosexual men appear to be less likely to acquire NGU than heterosexuals [lo, 451. CLINICAL MANIFESTATIONS
Table 2 illustrates the clinical features of symptomatic NGU compared to gonococcal urethritis, The symptoms and signs are usually less florid than in gonorrhea, but there is sufficient overlap that differentiation cannot be made accurately on clinical grounds alone [27, 421 and the duration of the incubation period is difficult to assess in most patients. Although the relative incidences of asymptomatic and symptomatic NGU are unknown, asymptomatic NGU is common; its prevalence approaches 20% of men attending sexually transmitted disease clinics for reasons other than urethritis [43]. The female counterpart of NGU is variable. Most contacts of infected men have no genito-urinary symptoms, or have subtle symptoms that may not bring them to medical attention [21, 331. C. trachomatis is a common cause of mucopurulent cervicitis and the “urethral syndrome” in sexually active women, and has been implicated in nongonococcal pelvic inflammatory disease [21, 22, 30, 331. Postgonococcal urethritis occurs in 36% [35] to 64% [23] of heterosexual men with urethral gonorrhea who are treated with penicillin, ampicillin, or spectinomycin, and infrequently in men treated with tetracycline [23, 261. This syndrome is the result of coincident gonorrhea and NGU, the latter unmasked when gonorrhea is treated with drugs that are not effective for NGU [24, 351. C. rrachomatis has been isolated from 19% [24] to 34% [35] of men with gonorrhea, and postgonococcal urethritis develops in virtually all of these if they are treated with drugs other than the tetracyclines [35].
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H. H. Handsfield and W. R. Bowie
C. truchomatis is the major cause of acute epididymitis in men under 35 years of age [2], inclusion conjunctivitis of the newborn [20] and a distinctive neonatal pneumonia [ 1,201, has been implicated in pelvic inflammatory disease [30] and is frequently isolated from men with Reiter’s Syndrome [28]. Unpublished data have also implicated C . truchomutis as a cause of midtrimester abortion [22]. U . urecilyticum has been associated with low birth weights in newborns, impaired fertility, and puerperal sepsis [31]. Accordingly, the common attitude that NGU is a clinically unimportant entity that is more an inconvenience than a serious threat to health is inappropriate. DIAGNOSIS
The diagnosis of nongonococcal urethritis involves ( 1 ) documentation of urethritis, and ( 2 ) establishing the absence of gonococcal infection. In the sexually active young adult. urethritis can be reliably diagnosed when a purulent or mucopurulent urethral discharge is observed. The presence of polymorphonuclear leukocytes (PMNs) on microscopical examination is confirmatory. Patients should be examined after 4 to 8 hr of holding their urine; under these conditions, the majority of symptomatic men have an easily expressible discharge [3, 431. In asymptomatic men and in men with symptoms of urethritis who have either no discharge or a clear mucoid discharge, urethritis may be diagnosed by semiquantitation of PMNs on a Gram stained urethral smear, as described independently by Bowie [3] and by Swartz et al. [43]. A calcium alginate tipped urethrogenital swab (Calgiswab, Inolex) is passed 2-3 cm into the urethra, a smear is prepared by rolling the swab on a microscope slide over a 1-2 cm2 area, and stained. The area of maximum concentration of cellular material is identified on low power and then examined with the oil immersion objective ( 9 7 0 ~ )an ; average of 2 5 PMNs/970x field is diagnostic of urethritis [3, 431. This method is less cumbersome and equally sensitive as microscopical examination of a centrifuged specimen of the initial 10-15 ml of voided urine, which is considered abnormal if there are 220 leukocytes per 400x field [3, 9, 241. The relative sensitivities of these techniques compared to macroscopic examination of voided urine for “threads” of mucus or inflammatory exudate are unknown. Examination of Gram stained smears prepared from urethral scrapings obtained with a sterile bacteriological loop is widely used, but semiquantitation of PMNs has not been studied with this technique, and has not been compared with specimens obtained with swabs. Absence of Gram negative diplococci on smear rules out gonorrhea with 90%-95% reliability [25], depending in part on the experience of the microscopist. A smear that is negative for Gram negative diplococci should usually be confirmed with a culture for Neisseria gonorrhoeue [ 2 5 , 271. A culture should always be performed on men without objective evidence of an abnormal urethral discharge, since the Gram stained smear has a sensitivity of 570% in men with asymptomatic urethral gonorrhea [19]. When available, cultures for C. truchomutis or U . nreulyticum and/or microimmunofluorescence serology for C. truchomatis may be useful, but most clinicians do not presently have access to these tests. TREATMENT
The tetracyclines are the drugs of choice for NGU, and have been studied more extensively than any other antimicrobial agents [4]. Treatment with tetracycline hydro-
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Nongonococcal Urethritis 325 chloride in a dose of 500 mg orally four times daily for seven days results in clinical resolution of NGU in approximately 90% of patients [4, 15, 181, and C. trachomatis is always eradicated [9, 18, 241. Persistent urethritis at the completion of treatment often is correlated with the presence of tetracycline-resistant U . urealyticum [22]. During the next six weeks after completion of therapy, however, NGU persists or recurs in approximately 30% of patients (up to 17% of patients with chlamydial urethritis and up to 47% of patients with nonchlamydial NGU) [4, 181. Regardless of the initial culture results, recurrences within 6 weeks are always chlamydia-negative [ 181. Minocycline is the most active tetracycline against C . trachomatis in vitro [7, 361. Bowie et al. [6] therefore treated 21 1 men with NGU with minocycline in a randomized, double-blind study. The four minocycline regimens included 100 mg daily for 7 days (58 patients), 100 mg twice daily for 7 days (54 patients), 100 mg daily for 21 days (48 patients), and 100 mg twice daily for 21 days (48 patients). Eight percent of patients had persistent NGU at the completion of treatment, regardless of the daily dose or the duration of therapy. Moreover, the combined persistence and recurrence rate was 30.3%, without statistically significant differences between the four regimens [6]. These figures are virtually identical to those obtained in a separate study in the same clinic using the standard one week tetracycline regimen [ 181. Twenty-three percent of men treated with 200 mg minocycline daily developed dizziness, lightheadedness, or ataxia, compared to 13% of men taking 100 mg daily [6]. It was concluded that minocycline gives results that are comparable to those obtained with tetracycline HC1, and that the optimal regimen of minocycline is 100 mg daily for 7 days [6]. Where low cost is important, tetracycline HCl 500 mg four times daily for 7 days remains the treatment of choice, but minocycline has the important advantage of once daily therapy. On the basis of pharmokinetics and the in vitro susceptibilities of C. trachomatis [7, 361 and U . urealyticum [40], it might be anticipated that doxycycline 100 mg daily for 7 days would be effective, and would eliminate the problem of vestibular toxicity, but this regimen has not been studied. Other tetracyclines have no important advantages. When a tetracycline cannot be given, erythromycin is usually prescribed in a dose of 500 mg four times daily, and has been reported to be moderately successful in limited studies in which neither chlamydial nor ureplasmal cultures were done [47]. C. trachomatis is susceptible to erythromycin, [7, 361 but U . urealyticum shows variable susceptibility [40]. The sulfonamides are effective in no more than 50% of patients with NGU [4,5] probably reflecting the susceptibility of C . trachomatis and the resistance of U . urealyticum [4]. Sulfamethoxazole-trimethoprim is probably no more effective than a sulfonamide alone. The aminocyclitol antibiotics, such as streptomycin and spectinomycin, to which U . urealyticum is susceptible but C . trachomatis is resistant, are effective only in nonchlamydial NGU [4, 51. The penicillins, the cephalosporins, and metronidazole are not effective. It is probable that failure to treat female sex partners has contributed to the rising incidence of NGU, and uncontrolled experience suggests that such treatment reduces the rate of recurrence [ 17, 371. Although adequately controlled studies are lacking, routine treatment of female sex partners is probably warranted to break the chain of transmission, to reduce the risk of recurrence of NGU in the patient, and to reduce the risk of potential complications of chlamydial or ureaplasmal infection in his partners. Sexual intercourse should be proscribed until both the patient and his partner have
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326 H. H. Handsfield and W. R. Bowie
completed treatment or, if they are likely to continue sexual activity, their treatment should coincide. Minocycline, which is associated with significantly greater frequency and degree of vestibular toxicity in women than in men [6,48] should not be used to treat female sex partners; tetracycline HCl, 500 mg four times daily for 7 days is preferable. A small proportion of men with NGU suffers repeated recurrences despite sexual abstinence or prolonged treatment of the patient and all partners. Such individuals should be evaluated for trichomoniasis (and perhaps given a trial of therapy with metronidazole), bacterial and nonbacterial prostatitis, upper urinary tract infection, urethral stricture, foreign bodies, and urethral trauma. In the absence of these conditions, all that can be offered is repeated short courses of a tetracycline when urethritis recurs. REFERENCES 1. Beem MO, Saxon EM (1977): Respiratory tract
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