Early Research on Gonorrhea: Modern Implications for Asymptomatic Urethral, Extragenital, and Disseminated Gonococcal Infections

The birth of Sexually Transmitted Diseases (initially Journal of the American Venereal Disease Association), the beginning of the modern scientific era of sexually transmitted infections (STIs), and the inception of my academic and public health career were nearly concordant. From 1971 to 1973, I was King Holmes's second research fellow at the University of Washington; we had an article in the inaugural issue of the journal.1 In 1978, I returned to Seattle with a joint appointment on the UW infectious diseases faculty and as director of the Seattle–King County Public Health STD Program, which soon became one of the first fully integrated academic/public health partnerships for STI clinical care, prevention and research—discussed in another commentary in this supplement. Our early research broadened understanding of the clinical spectrum of gonorrhea and impacted subsequent public health prevention strategies. In 1974, we reported what remains the most comprehensive study of asymptomatic urethral gonococcal infection in men.2 Some men had neither symptoms nor signs of urethritis, whereas others were observed to have urethral discharge they did not notice or had ignored. An immediate outcome was reversal of the heretofore common practice of not notifying the male partners of infected women, believing symptoms would bring them to care. Sometimes our study also was misinterpreted as implying a need to screen asymptomatic men for urethral infection. However, the large majority of incident urethral gonococcal infections cause overt discharge and dysuria, and the prevalence of urethral infection is very low in men without overt urethritis, so that screening for urethral Neisseria gonorrhoeae has limited value in gonorrhea prevention—even if some men fail to notice or disregard seemingly obvious symtoms.2 The late 1960s saw a resurgence of disseminated gonococcal infection (DGI) in Seattle, characterized by arthritis, tenosynovitis, pustular dermatitis, and sometimes bacterial endocarditis or meningitis.3 Over the next 3 years, Paul Wiesner, King, and I prospectively evaluated 123 suspected DGI cases, of which 102 were confirmed by isolation of N. gonorrhoeae from blood, synovial fluid, skin lesions, mucosal sites, or patients' sex partners.4 We learned that the causative gonococci were exquisitely sensitive to penicillin and tetracycline,5 and found that oral ampicillin was equally effective treatment as parenteral penicillin. The concordance of the Seattle DGI outbreak and frequent asymptomatic urethral infection soon was explained by novel microbiological characterization of gonococci isolated in our clinical studies. A high proportion of N. gonorrhoeae in the Seattle area had unique nutritional requirements for growth in vitro, specifically for arginine, hypoxanthine, and uracil, the AHU− auxotype. These strains frequently caused asymptomatic urethral infection, were resistant to the innate (non-immune) bactericidal effect of human serum, and often disseminated systemically; and minimal inhibitory concentration (MIC) analysis confirmed the unique antimicrobial susceptibility that we observed in isolates from patients with DGI.6 Not long afterward, in my first article in the renamed journal, we reported additional clinical and epidemiologic associations of AHU− gonococci.7 These strains were found to be rare among men who have sex with men (MSM) even while they comprised the most prevalent auxotype in women and heterosexual men. (Although not reported at the time, few if any of our male DGI patients were MSM.4) We also found that MSM have higher prevalences of relatively antibiotic-resistant gonococci regardless of auxotype.7 This was soon explained by the finding that the rectal environment, including fecal lipids and other toxic compounds, selects for the Mtr gene and other determinants of antibiotic resistance.8 In the same article, we also reported one of the first prospective studies of the anatomic sites of gonococcal infection according to sex and sexual orientation.7 (Back in the day, we accepted patients' stated “sexual preference” without asking the sex of their partners.) Among 85 consecutive MSM STD clinic patients with gonorrhea, N. gonorrhoeae was isolated by culture from the urethra in 54 men (64%), the rectum in 43 (51%), and the pharynx in 16 (19%). Among 162 infected women, the cervix, rectum, and pharynx were infected in 96%, 38%, and 22%, respectively. All 177 heterosexual men had urethral gonorrhea and 11 (6%) also had pharyngeal infection; their rectums were not sampled.7 Thus, in a single publication, we established the rarity of AHU− infection in MSM; confirmed the unique susceptibility of these strains to penicillin and tetracycline; documented that gonococci isolated from MSM are more antibiotic resistant than those infecting women and heterosexual men, independent of auxotype; and reported the prevalences of genital, rectal, and pharyngeal infection according to sex and sexual orientation. Another study published 9 months later reported similar isolation rates of N. gonorrhoeae from the urethra, rectum, and pharynx among MSM.9 Significantly, the site-specific gonococcal infection rates in both studies were almost the same as those reported over the past two decades using nucleic acid amplification testing (NAAT). For N. gonorrhoeae, NAAT is only slightly more sensitive than culture for extragenital and asymptomatic infections. (In contrast, NAAT for Chlamydia trachomatis is substantially more sensitive than culture and has been instrumental in understanding extragenital infection.) Our study7 and the Chicago report9 have rarely been cited in numerous reports documenting extragenital gonorrhea in recent years—as if the discovery of extragenital infection depended on development of NAAT. In reality, many STD clinics were routinely conducting rectal and pharyngeal screening and diagnostic testing for N. gonorrhoeae by culture long before NAATs were developed, based on these and other published studies or their own in-house evaluations. At the time, we considered the data on auxotype and antimicrobial susceptibility paramount and did not fully appreciate the importance of the analysis of infected anatomic sites. The infected sites are not mentioned in the title of either article, and “extragenital” was not used in the text,7,9 undoubtedly limiting recovery of these publications in modern computer-based literature searches. In retrospect, our anatomic site analysis warranted a separate publication with a more specific title and carefully chosen keywords. After a relative paucity of reports and apparently limited interest in DGI following the 1970s, the syndrome has been figuratively rediscovered in the last several years, with case series reports from various countries and California, Georgia, Michigan, and elsewhere in the United States.10 Using today's methods to characterize gonococci, such as N. gonorrhoeae multiantigen sequence typing (NG-MAST), no particular gonococcal strain causes most DGI cases, and no reported outbreaks have involved strains with significant antimicrobial resistance.10 However, published antimicrobial sensitivities have not reported the ranges of antibiotic MIC in the manner of our studies.5–7 NG-MAST and other modern typing methods have not been compared and contrasted to auxotyping, and strains with these nutritional requirements might predispose to DGI across multiple NG-MAST types. Studies comparing auxotyping with the newer gonococcal typing methods would be welcome and might influence clinical management, as would more detailed information on antibiotic susceptibility. Would cefixime or other oral antibiotic treatment be as effective today as ampicillin was in the 1970s? Can surgical drainage of septic joints be replaced by needle aspiration and saline lavage, as in our experience?4 For STI or any other health domain, professionals providing clinical care or devising institutional, regional, or national guidelines and prevention strategies have a natural tendency to preferentially access recently published studies. However, older data—long forgotten, difficult to access, or both—sometimes can provide helpful or even necessary context and guidance. Institutional memory and the perspectives of those who generated such hidden knowledge, however long ago, can help to fill missing gaps.