Penicillinase-producing N gonorrhoeae

The first penicillinase-producing N gonorrhoeae (PPNG) was isolated from a woman with pelvic inflammatory disease attending a STI clinic in the UK in 1976.6 Further PPNG cases were identified at this London-based clinic, which managed 11% of all the UK's PPNG cases up to 1983, and for the first 7 years, the majority of PPNG cases were imported, mainly from Nigeria and Ghana. Almost all these early PPNG cases were heterosexually-acquired and approximately a third of men named either female sex workers or casual female sexual partners as their source of infection. In the same year that the first PPNG isolate was reported from London, an outbreak of PPNG infection occurred in Liverpool.7 Most PPNG were acquired by young black men living in the inner city from women frequenting local nightclubs. Once this PPNG outbreak had been controlled, most of PPNG cases diagnosed at the Liverpool STI clinic were either in female sex workers or their male clients, many of whom were seamen at the local docks. Within the UK, a smaller PPNG outbreak, again linked to female sex work, was described in Cardiff between October 1980 and July 1981.8

In the Netherlands, surveillance for PPNG strains commenced in 1977 and the majority of the first infections were acquired from untraceable female sex workers in the Far East or in West Africa.9 By 1978, however, more than 80% of PPNG infections were acquired in the country's main cities of Amsterdam, Rotterdam and The Hague with approximately half of the cases being diagnosed in foreign labourers.

The first PPNG case documented in the USA occurred in a 25-year-old man who had recently returned from South-East Asia.10 The first major USA-based PPNG outbreak occurred in Los Angeles County (California) in 1980 and reached an average of 50 cases per month until March 1981.11 Sex workers were yet again the key population linked to enhanced transmission. The expanded prevention programme implemented in March 1981 by the County of Los Angeles Department of Health Services involved culturing specimens from individuals in high-risk groups, particularly sex workers, for N gonorrhoeae at a number of locations including the county jail.

Two further US-based PPNG outbreaks are worthy of mention as they highlight the involvement of different core groups. First, a large outbreak of 2455 PPNG cases was reported from Dade County (Florida) in 1985.12 Geospatial mapping using zip codes identified a geospatial core that accounted for approximately a third of all the PPNG cases. A retrospective analysis indicated that men infected with PPNG were more likely to have self-medicated through illicit over-the-counter purchases of antimicrobial agents. In contrast to the previous reports, acquisition of PPNG was not associated with sex work. A second PPNG outbreak was identified in Colorado Springs (Colorado) in April 1990. An investigation identified 56 cases of PPNG from December 1989 through to March 1991.13 Until 1990, only sporadic cases of PPNG had occurred in Colorado Springs, mostly among military personnel returning from South-East Asia. Investigation revealed that 39 (70%) of the 56 PPNG cases occurred in young men and women with social ties to street gangs. Network analysis characterised the sexual and social connections of those with PPNG infections. Investigations revealed that many network members reported frequent sexual encounters and multiple sexual partners. In addition, some young women reported exchange of sex for crack cocaine and heavy use of crack cocaine.

In Canada, a heterosexually-acquired PPNG outbreak was reported that spanned several Canadian cities and two provinces in 1984.14 This outbreak was defined by gonococci containing a new 4.9 kb ‘Toronto’ plasmid encoding for β-lactamase production. Although definitive epidemiological links between most cases could not be established, it was reported that female sex workers in the Toronto area were involved in the outbreak.

Chromosomally-mediated penicillin resistant N gonorrhoeae

In terms of β-lactamase negative chromosomally-mediated penicillin-resistant N gonorrhoeae (CMRNG), a community-based outbreak within the USA was reported in Durham (North Carolina) in 1983.15 Phenotypical typing methods suggested that this outbreak had arisen from the introduction of a penicillin-resistant N gonorrhoeae isolate which was then transmitted at high frequency within the community. Epidemiological investigation highlighted the involvement of female sex workers and their male clients in the initial phase of the outbreak.16 In 1987, Hook et al17 reported that patients infected with CMRNG in Baltimore (Maryland) were typically older, reported more previous episodes of gonorrhoea and reported greater numbers of recent and new sexual partners. They also noted that patients with CMRNG had a non-significant increased likelihood to having contact with sex workers, using parenteral drugs or being sexual partners of drug users.

Tetracycline resistant N gonorrhoeae

The first 12 cases of high-level tetracycline-resistant N gonorrhoeae (TRNG) were identified in the USA in 1985.18 These infections were reported in Atlanta (Georgia) and Philadelphia (Pennsylvania) and the patients were heterogeneous in nature, although MSM were represented. A retrospective review of laboratory records at the Centers for Disease Control and Prevention identified an earlier TRNG isolate that had been cultured from a MSM post-treatment with tetracycline in New Hampshire in 1983.18

In the spring of 1985, a microepidemic of 12 cases of β-lactamase positive TRNG was also reported in the Netherlands, mainly in The Hague.19 By 1989, 40% of the country's PPNG harboured the TetM-expressing plasmid and these PPNG/TRNG isolates were detected more frequently in men. It was also demonstrated that men reporting sexual contact with sex workers had an increased risk of PPNG/TRNG acquisition in The Hague and Rotterdam.19

Fluoroquinolone resistant N gonorrhoeae

Fluoroquinolone-resistant N gonorrhoeae (QRNG) first emerged and then spread rapidly within the Western Pacific Region from the early 1990s onwards.20 As with the emergence and spread of penicillin and tetracycline-resistant gonococci, sex workers and MSM were linked to the emergence of fluoroquinolone resistance in several countries. For example, a rapid emergence and rise in the prevalence of QRNG was observed among female sex workers in the Philippines in the mid-1990s and in Indonesia in 2004.21 ,22 Within Australia, the first cases of QRNG were imported and linked to sexual exposure to female sex workers in the Philippines.23 Subsequently, QRNG became concentrated in MSM in New South Wales and Victoria.24 A high QRNG prevalence was also reported on the Indian subcontinent in the late 1990s among sex workers.25

Within the UK, the drift in gonococcal susceptibility to ciprofloxacin and the emergence of therapeutic failure was well documented in London from 1989 to 1997.26 During this period, isolates with reduced susceptibility to ciprofloxacin (minimum inhibitory concentration (MIC)>0.12 mg/L) were mostly acquired abroad and imported into the UK. The proportion of QRNG among patients attending London's STI clinics increased from 0.9% to 7.9% over a 4 year period (2000–2003).27 Martin et al reported that the proportion of QRNG isolates acquired abroad, mainly from the Far East and Europe, had approximately halved by 2002. In 2000, most QRNG isolates were heterosexually-acquired and many had unique sequence types (STs) by N gonorrhoeae multiantigen sequence typing (NG-MAST). From 2001 onwards, QRNG were more frequently isolated from MSM and found to occur in clusters defined by unique STs. Although MSM have continued to be the key population group most strongly associated with QRNG transmission within the UK, an outbreak of QRNG in North-West England was associated with female sex workers from late 1999 until February 2000.28

The emergence and spread of QRNG within the USA also evolved from sporadic imported cases to endemic transmission among MSM and heterosexuals. An increase in QRNG was first described in Hawaii in 1999. A retrospective review of medical records identified recent foreign travel or a sexual partner with recent foreign travel, as well as recent use of antimicrobial agents, as key risk factors.29 In California, Bauer et al30 reported several independent risk factors for QRNG acquisition that included recent antibiotic use, race/ethnicity and MSM orientation. A multivariate model for MSM demonstrated that antibiotic use and HIV seropositivity were significantly associated with QRNG acquisition. Increases of QRNG among MSM were subsequently reported in Massachusetts, New York City and the 30 sites surveyed by the Gonococcal Isolate Surveillance Project (GISP) during 2003.31 In contrast with the US experience, Ota et al32 reported that heterosexual men and patients older than 30 years were the main demographic risk factors associated with QRNG infection in Ontario, Canada.

The importance of core groups in the emergence and early transmission of QRNG isolates within major cites is further illustrated with examples from South America and sub-Saharan Africa. The first reported QRNG case in South America was in a male contact of a female sex worker in Buenos Aires, Argentina.33 Likewise, the first case of clinical failure due to QRNG in sub-Saharan Africa occurred in an 18-year-old male contact of a female sex worker who presented with urethral discharge to a clinic in Kwa-Zulu Natal province, South Africa.34 Duncan et al35 reported that QRNG were present at a prevalence of approximately 70% among high-risk MSM in coastal Kenya, many of who report participation in transactional sex. Importantly, as many of these MSM have female sexual partners, they act as bridging populations for the transmission of QRNG into the general population. Vandepitte et al36 reported a QRNG prevalence of 80% among female sex workers in Kampala in 2008–2009, when ciprofloxacin was still first-line therapy for presumptive gonorrhoea within the country. This observed QRNG prevalence in sex workers far exceeded the 37% reported in a contemporary survey conducted among male STI clinic patients within Uganda.37

SPECTINOMYCIN-RESISTANT N gonorrhoeae

Spectinomycin was first used to treat gonococcal infections in US military personnel in 1981 on account of the high prevalence of PPNG in Korea. Within 3 years, gonococci exhibiting resistance to spectinomycin were reported.38 The first spectinomycin-resistant PPNG case was reported from the Philippines in a 20-year-old military man who developed a penile discharge following recent sex with three Philippine women.39 Boslego et al38 highlighted the core nature of some military personnel stationed abroad in terms of exposure to antimicrobial-resistant gonococci and their bridging role in terms of importation of these resistant strains to their own countries. This is well illustrated by the early cases of spectinomycin-resistant N gonorrhoeae infections reported in the USA. For example, 10 heterosexually-acquired cases of spectinomycin-resistant gonorrhoea were diagnosed in six states in 1985–1986.40 Five of these cases occurred in military staff and civilians who had acquired their gonorrhoea from sexual contacts, including sex workers, in Korea. The remaining five individuals with locally-acquired spectinomycin-resistant gonorrhoea included one female sex worker who reported multiple sexual contacts with military staff.

AZITHROMYCIN-RESISTANT N gonorrhoeae

Most cases of azithromycin resistance have been geographically scattered. The first azithromycin-resistant isolate (MIC 2 mg/L) was identified in the USA through GISP in 1993. The isolate was cultured from the urethra of a 29-year-old heterosexual man who fitted the core group definition in that he had reported two previous episodes of gonorrhoea in the past 12 months.41 An outbreak due to a cluster of 33 gonococci with decreased susceptibility to azithromycin (MIC≥1 mg/L) was reported in Kansas City (Missouri) in 1999–2000.42 Although two auxovars were represented among this gonococcal population, all 33 isolates had the same serovar (IB-3), the same Lip subtype (17c) and the same mtrR gene mutation. A case-control study identified that cases were 10 years older than the controls and seven times more likely to report sexual contact with a female sex worker.

The first gonococcal isolate to demonstrate high level resistance to azithromycin (AzHLR, MIC>256 mg/L) was isolated in Buenos Aires, Argentina in 2001.43 Although well characterised microbiologically, epidemiological information regarding the index case and sexual contacts are lacking.43 High-level azithromycin-resistant N gonorrhoeae isolates emerged and subsequently spread among heterosexual men and women within Scotland in 2004.44 As the most successful NG-MAST STs associated with AzHLR (ST470 and ST649) were transmitted among young heterosexuals, it was hypothesised that widespread use of 1 g single-dose azithromycin as a treatment for chlamydial infection contributed to the emergence of AzHLR strains. Subsequently, a cluster of six heterosexually-acquired AzHLR isolates, also typed as ST649 by NG-MAST, was identified within the UK in Liverpool and Cardiff.45

Cephalosporin resistant N gonorrhoeae

Documented gonorrhoea treatment failures to oral third-generation extended spectrum cephalosporins (ESCs) were first reported in Japan as early as 2000 and, as with the fluoroquinolones, oral ESC resistance was preceded by evidence of elevated MIC distributions for these antimicrobial agents.46 Since 2000, there has been a rapid spread of ESC-resistant gonococci within Japan which have been well described microbiologically but frequently lack key information on behavioural risk factors for their acquisition.47 ,48 Yokoi et al49 reported four gonorrhoea treatment failures, using a regimen of cefixime 200 mg 12 h for 3 days, and did note that each index patient reported sexual contact with a female sex worker in central Japan.

In Taiwan, Wong et al50 analysed gonococci isolated from patients in Taipei. Through use of NG-MAST, they identified three major clusters (ST547, ST835 and ST2180) which were significantly associated with MSM and a positive HIV serostatus. While ST547 isolates were fully susceptible to ESCs, those isolates belonging to ST835 and ST2180 were highly resistant to ESCs.

Within England and Wales, Chisholm et al analysed 96 N gonorrhoeae isolates with elevated cefixime MICs (≥0.125 mg/L). Almost 90% of these isolates were from men and, for those cases where sexual orientation data were available, two-thirds were cultured from MSM. The majority of these isolates belonged to NG-MAST ST1407 (74%) or to a closely related ST with a similar tbpB but different por allele (21%). Gonococci of ST1407 or related STs that share the tbpB allele, which belong to the multilocus ST (MLST) ST1901 and possess the type XXXIV mosaic penA allele, have been reported elsewhere in Europe, in Japan and North America.51 Similar elevations in the ESC MICs for N gonorrhoeae isolated from MSM have been reported elsewhere in Europe.52

The first N gonorrhoeae strains reported in the USA with elevated cefixime MICs (0.25–0.5 mg/L) were cultured from three heterosexual patients in Hawaii in 2001.53 One of two male patients reported sex with two female sexual partners from Japan, one of whom was the third case. In 2010, GISP reported 1.4% and 0.3% of gonococci to have elevated MICs to cefixime (MIC ≥ 0.25 mg/L) and ceftriaxone (MIC ≥ 0.125 mg/L), respectively.54 However, the prevalence of elevated MICs to both antimicrobials was substantially higher among the MSM population (cefixime, 4.0%; ceftriaxone, 0.9%). Further analysis of these GISP data revealed some of the core group behaviours associated with MSM who acquire gonorrhoea, specifically a history of previous gonococcal infections, recent antimicrobial use, HIV coinfection and recent travel.55

The first two verified cases of oral ESC-resistant N gonorrhoeae urethral infection within Africa were recently reported in two MSM in Johannesburg.56 The gonococci from both men contained the type XXXIV penA mosaic allele and they were indistinguishable by NG-MAST (ST4822) and multilocus ST (ST1901). NG-MAST ST4822 is closely related to NG-MAST ST1407 and so these South African MSM-associated gonococci may have evolved from the ST1407 clone circulating in Europe, Japan and North America. Since this initial report, two further N gonorrhoeae isolates with identical antibiograms and NG-MAST profiles have been isolated from MSM in other South African cities (D Lewis, unpublished data).

Finally, extensively drug-resistant N gonorrhoeae isolates have recently been reported from the Western Pacific region and Europe and are emerging within classical core groups. The first case involved a 31-year-old female sex worker, who was screened for gonorrhoea in Kyoto in early 2011.57 Her pharyngeal culture grew N gonorrhoeae for which the ceftriaxone MIC was 2 mg/L. This strain (H041), which was typed as ST1407 by NG-MAST, had a novel penA mosaic allele that was closely related to penA mosaic allele X responsible for prior cefixime treatment failures in Japan.58 The second extensively drug-resistant N gonorrhoeae isolate (F89) was cultured from the urethra of a 50-year-old MSM in Quimper, France in mid-2010.59 The F89 strain had a novel penA mosaic allele which consisted of a type XXXIV penA mosaic allele with an additional A501P mutation. The importance of the MSM core group was further highlighted with the isolation of identical N gonorrhoeae isolates from two sexually-related MSM in Catalonia, Spain.60 Both these isolates were resistant to ceftriaxone (MIC 1.5 mg/L) and possessed the same NG-MAST and penA allele genotypes as the French F89 strain.