Curr Opin Infect Dis. 2014;27(1):62-67.
Abstract and Introduction
Abstract
Purpose of review Neisseria gonorrhoeae has demonstrated a remarkable genetic capacity to acquire antimicrobial resistance (AMR) determinants. This review focuses on the recent developments in respect of third generation extended spectrum cephalosporin (ESC)-resistant gonorrhoea and the search for future treatment options.
Recent findings The estimated incidence of new gonorrhoea cases is increasing, and the antimicrobial resistance profile of N. gonorrhoeae is worsening. The most significant recent finding has been the emergence of extensively drug-resistant (XDR) N. gonorrhoeae characterized by very high ceftriaxone minimum inhibitory concentrations. A national switch from cefixime to high-dose ceftriaxone as first-line antigonococcal therapy in England and Wales, as well as parts of Japan, has been accompanied by a reduction in the prevalence of oral ESC-resistant gonococci. Azithromycin given in combination with either gentamicin or gemifloxacin has been shown to be an effective alternative antigonococcal therapy. Both ertapenem and solithromycin have good in-vitro activity against ESC-resistant N. gonorrhoeae strains.
Summary Current strategies to control gonococcal AMR should focus on the use of higher doses of ceftriaxone given as part of dual therapy and further evaluation of alternative drug combinations. The emergence of XDR gonorrhoea argues for enhanced efforts to develop novel antimicrobial agents and a gonococcal vaccine.
Introduction
Neisseria gonorrhoeae, a Gram-negative diplococcus, is the aetiological agent responsible for gonorrhoea. Although gonorrhoea is mostly acquired through sexual intercourse, it may be transmitted by direct inoculation to the eye of both neonates and adults. Untreated gonorrhoea may result in several complications, such as pelvic inflammatory disease, infertility, ectopic pregnancy, epididymo-orchitis and disseminated gonococcal infection. The most recent 2008 WHO estimates have documented a 21% global increase in the total number of new cases of gonorrhoea in adults compared with 2005, with an estimated 106 million adults being infected with N. gonorrhoeae in 2008.[1]
Since the first introduction of sulphonamides to treat gonorrhoea in the 1930s, the gonococcus has shown a remarkable genetic capacity to develop antimicrobial resistance (AMR) to sequential antimicrobial agents introduced for the treatment of gonorrhoea.[2] Importantly, N. gonorrhoeae is naturally competent for the uptake of extracellular DNA, which enables the bacterium to acquire resistance determinants through transformation. AMR may be divided into chromosomally mediated and plasmid-mediated resistance. Chromosomal mutations typically affect drug-target interactions or the functioning of the multidrug-resistance efflux pump.[3] Plasmids may contain resistance determinants and be passed from one gonococcus to another through conjugation. For N. gonorrhoeae, plasmid-mediated resistance has been described for penicillin and tetracycline.[3]
With rising rates of AMR, we are running out of available treatment options for gonorrhoea. This review will first briefly review the key historical milestones in the development of AMR to earlier therapies and then summarize recent literature in the past 1–2 years (2011–2013) with particular focus on resistance to the third generation extended spectrum cephalosporins (ESCs) and potential options for the future.
Gonococcal Resistance to Penicillins and Tetracyclines
Following the early demise of sulphonamides and the contemporary introduction of penicillin in the early 1940s, penicillin became established as the mainstay of therapy for gonorrhoea.[3] Increasing curative doses were required to combat the rise in penicillin minimum inhibitory concentrations (MICs) that were observed from the 1950s onwards. Chromosomally mediated penicillin resistance, due to a combination of mutations in several genes (e.g. penA, penB, mtrR and its promoter), was reported in many parts of the world during the 1960s.[3] In the mid-1970s, plasmid-mediated penicillinase-producing N. gonorrhoeae (PPNG) strains emerged. By the late 1970s, penicillin was no longer effective as a treatment for gonorrhoea in many regions of the world.
Decreased susceptibility to tetracycline, and eventual emergence of chromosomal resistance due to multiple genetic mutations (e.g. rpsJ, penB, mtrR and its promoter), followed a similar course to penicillin. In the 1980s, gonococci were detected with high-level tetracycline resistance due to plasmid-mediated expression of the TetM determinant. Tetracycline-resistant N. gonorrhoeae strains rapidly spread globally, and the TetM-encoding plasmid was frequently found in PPNG strains.
Gonococcal Resistance to Fluoroquinolones
The introduction of fluoroquinolones in the early 1980s was initially greeted with the same enthusiasm as penicillin in the 1940s. Although not suitable for pregnant women, fluoroquinolones such as ciprofloxacin showed great promise as a single-dose treatment against N. gonorrhoeae with little or no side-effects. However, treatment failures to both the low dose (250 mg) and higher dose (500 mg) regimens were reported in the early 1990s as a result of mutations in the quinolone resistance determining regions of the gyrA and parC genes.[3] Like resistance to penicillin and tetracycline, fluoroquinolone resistance spread rapidly across the world, initially within the Asia-Pacific region in the 1990s, in Europe and North America at the turn of the century, and most recently in Africa and South America.[3]
Gonococcal Resistance to Extended Spectrum Cephalosporins
With the demise of fluoroquinolones, most countries moved to the use of third-generation ESCs as first-line therapy for gonorrhoea. Many regard ESC as the last antimicrobial agent class suitable for widespread single-dose single-agent therapy. Among the oral ESCs, only cefixime has met the criterion on the lower bound of the 95% confidence interval (CI) for effective treatment of pharyngeal gonorrhoea as defined by the WHO recommended cure rate of 95% or greater.[3]
In 2001, following the widespread use of oral ESCs in Japan, gonococci with reduced susceptibility to these agents emerged in Japan and were associated with cefixime treatment failures.[4–6] It was noted early on that, while these early strains were generally resistant to fluoroquinolones and penicillin, they remained susceptible to intramuscular ceftriaxone, albeit with raised ceftriaxone MICs compared with fully susceptible strains.[4]
Mechanisms of Gonococcal Resistance to Extended Spectrum Cephalosporins
In general, gonococci with reduced susceptibility/resistant to oral ESCs have multiple chromosomal mutations in the penA gene, which encodes for penicillin-binding protein 2 (PBP-2), the principal target of ESCs. The reduced susceptibility of these gonococci to ESCs appears to be due to conformational alteration of the β-lactam-binding pocket of PBP-2.[7] These mosaic penA genes are thought to result from the acquisition of substantial parts of the penA gene of commensal Neisseria species, which share the same anatomical niche as the gonococcus. In support of this view, molecular characterization of gonococcal mosaic penA genes has revealed considerable homology with the penA gene of other Neisseria species.[8,9] Given that commensal Neisseria species are more abundant in oro-pharyngeal than urethral/endocervical niches, it has also been hypothesized that horizontal transfer and recombination between these bacteria and the gonococcus is more likely to occur in the oro-pharynx. This concept highlights the importance of key populations, such as commercial sex workers (CSW) and men-who-have-sex-with-men (MSM), in the generation and transmission ESC-resistant N. gonorrhoeae.
There are several variations in mosaic PBP-2 structure and some gonococcal strains, which possess a mosaic penA gene, remain susceptible to ESCs.[8] Accordingly, researchers have looked for other genetic mutations that may account for the observed alterations in ESC susceptibility. Mutations in the gonococcal PBP-2 at amino acid position 501 (e.g. A501 V, A501T and A501P), which have not been found in commensal Neisseria species, appear to preferentially reduce susceptibility to ceftriaxone.[7,10,11]
Emergence of Multidrug Resistant and Extensively Drug Resistant Gonorrhoea
Nonsusceptible gonococci with elevated ESC MICs are now being identified at increasing prevalence in many other countries and regions of the world.[2,11,12–14,15–18,19,20] As noted above, these gonococci are typically multidrug-resistant (MDR) strains exhibiting additional resistance to fluoroquinolones as well as older drugs.[4,12,21]
More worrying has been the recent emergence of XDR N. gonorrhoeae strains among CSW and MSM populations, which are characterized by high ceftriaxone MICs.[11,14,22] The first such gonococcal strain (H041) possessed a ceftriaxone MIC of 2–4 mg/l and was isolated from the oropharynx of a Japanese female CSW in Kyoto in 2009.[22] Following the identification of this XDR strain, an intensified surveillance activity was undertaken in both Kyoto and Osaka (2010–2012) in order to determine the extent of spread of this strain.[23] It has been reassuring to note that all 193 N. gonorrhoeae isolates tested were classified as susceptible in vitro to both cefixime and ceftriaxone (MIC ≤ 0.25 mg/l). These data suggest that the H041 strain has not spread further within the local community and raise the intriguing possibility that the H041 strain may be less fit than ceftriaxone-susceptible strains. Subsequent to identification of the H041 strain, gonococci with substantially elevated ceftriaxone MICs were isolated from the urethra of an MSM patient in France (strain F89, ceftriaxone MIC 2 mg/l) and from the urethral and rectal samples of two sexually related male partners in Spain (ceftriaxone MIC 1.5 mg/l).[11,14] These three European isolates appear to be related as they share the same N. gonorrhoeae multiantigen sequence typing (NG-MAST) sequence type (ST 1407) but are unrelated to the Japanese H041 strain (NG-MAST ST 4220).[11,14,22] These three NG-MAST ST 1407 isolates also belong to the same multilocus sequence typing-based ST 1901 superclone that is presently circulating internationally.[2,12,13,24–27]
A number of verified ceftriaxone-associated oro-pharyngeal gonorrhoea treatment failures have also been recently reported.[15,22,28,29] The ceftriaxone MICs for these strains varied from 0.016 mg/l to 2–4 mg/l and, for those isolates with lower MICs, it is likely that pharmacodynamic factors were important in the failure of ceftriaxone to eradicate N. gonorrhoeae from the oropharynx.[2]
Alternative Single-Dose Options for Treating Gonorrhoea
Spectinomycin, gentamicin and azithromycin have been considered as alternative monotherapeutic options to treat or prevent further spread of ESC-resistant gonorrhoea. However, there are limitations to the use of each of these three antimicrobial agents.
Spectinomycin is not available in several countries and is a costly drug. In addition, spectinomycin has a low cure rate for oro-pharyngeal gonorrhoea, which means it is of limited use in treating MSM and CSWs. Furthermore, resistance to spectinomycin rapidly emerged, as a result of a single nucleotide polymorphism in the 16S rRNA gene, when it was introduced as a first-line treatment for gonorrhoea in the Republic of Korea in 1981.[30] A novel mechanism of high-level spectinomycin resistance has been recently reported in a Norwegian strain due to mutations in the gonococcal gene encoding ribsosomal protein S5.[31]
Single-dose intramuscular gentamicin (240 mg) has been used in Malawi for approximately 20 years as national first-line therapy to treat presumptive gonorrhoea as part of the syndromic management of genital discharges. There are limited in-vitro data to suggest that it has remained effective, at least up to 2007.[32] However, carefully designed clinical studies are still required to assess the safety and efficacy of gentamicin monotherapy for gonorrhoea.[33] A recent study of over 1300 European gonococcal isolates reported high susceptibility to gentamicin.[34] In contrast, a recent meta-analysis reported that single-dose gentamicin resulted in an unacceptable pooled cure rate of 91.5% (95% CIs, 88.1–94.0%).[35] Importantly, few data exist for the effectiveness of gentamicin in treating oropharyngeal gonorrhoea, and more studies are required in this regard.[33]
Single-dose oral azithromycin has been shown to be effective in treating gonorrhoea in clinical trials undertaken in an era of full susceptibility to ESCs.[36] Gonococci that are nonsusceptible to ESCs also tend to exhibit reduced susceptibility or resistance to azithromycin, which will limit the usefulness of this drug as a single first-line agent.[12,37] Importantly, strains with high-level resistance to azithromycin have already been described, and there also have been a number of reports of the development of azithromycin resistance during therapy.[2,3,37,38]
Extended Spectrum Cephalosporin Strategies to Slow Down the Spread of Multidrug Resistant/Extensively Drug Resistant Neisseria gonorrhoeae
Two ESC-based strategies are currently receiving attention as a means to slow down the spread of MDR and the further emergence of XDR N. gonorrhoeae strains. Firstly, there is growing evidence from Japan as well as England and Wales that a national change in recommended first-line therapy for gonorrhoea from oral cefixime to injectable high-dose ceftriaxone is slowing down the transmission of N. gonorrhoeae with reduced susceptibility/resistance to oral ESCs.[19,23] Given this observation, there is a growing consensus that the use of oral ESCs should be abandoned in favour of injectable ceftriaxone.
Secondly, the use of dual antimicrobial therapy to treat gonorrhoea has already been instituted in some countries in order to curtail the rise in prevalence of gonococci with reduced susceptibility/resistance to ESCs.[19,39] It has been argued that a more proactive approach to antimicrobial therapy for gonorrhoea is required, with preemptive changes in national first-line therapy occurring before the prevalence of treatment failure exceeds the 5% threshold.[19] The United Kingdom currently favours a single dose of intramuscular ceftriaxone (500 mg) given in combination with a single dose of oral azithromycin (1 g).[19,40] In contrast, the US Centers for Disease Control and Prevention (CDC) currently recommends a lower dose of intramuscular ceftriaxone (250 mg) that should be given as dual therapy with either single-dose oral azithromycin (1 g) or with a 7 days' course of oral doxycycline (100 mg, 12 hourly).[39]
The National Institute for Allergy and Infectious Diseases, in collaboration with the CDC, have conducted a randomized multicentre clinical trial to evaluate the efficacy and safety of single-dose oral azithromycin (2 g) given as dual therapy with either single-dose intramuscular gentamicin (240 mg) or single-dose oral gemifloxacin (320 mg).[41] Preliminary results indicate that the azithromycin/gentamicin combination was 100% effective, whereas the azithromycin/gemifloxacin combination was 99.5% effective, in curing urogenital gonorrhoea.[41]
Novel Antimicrobial Treatment Options
Both ertapenem and solithromycin (CEM-101) appear to have reasonable in-vitro activity against ESC-resistant N. gonorrhoeae isolates.[42,43] However, the ertapenem MIC does increase in the presence of ESC-resistance-associated mutations.[42] This observation raises the possibility that further mutations in the penA gene could easily render this antimicrobial agent ineffective.[2] In addition, the fact that ertapenem is a parenteral 1-β-methyl-carbapenem makes it rather unsuitable for gonorrhoea treatment. Single-dose oral solithromycin, a fluoroketolide, is currently undergoing phase 2 safety and efficacy evaluation in patients with uncomplicated urogenital gonorrhoea. Solithromycin may be less prone to generate in-vivo resistance compared with other macrolides.[43,44] However, the presently circulating high-level macrolide resistant gonococci will be unlikely to respond to solithromycin. Tigecycline, a parenteral glycylcycline with activity against ESC-susceptible gonococci, has yet to be evaluated against ESC-resistant N. gonorrhoeae strains.[2]
Antimicrobial Treatment Options in Development
Despite the need for new antimicrobial treatment options, no such agents are in the late development stage. Pleuromutilins, novel inhibitors of bacterial topoisomerases and efflux pumps, FabI inhibitors and LpxC inhibitors are among compounds that may potentially be exploited to improve the management of MDR/XDR gonorrhoea in the future.[2]
Containment of Neisseria gonorrhoeae Antimicrobial Resistance
The WHO has recommended a public health containment and surveillance approach to contain AMR.[45] In respect of antimicrobial agents, key areas for attention include the regulatory framework, drug procurement, drug quality and management of the drug supply.[21] Equally important to the containment of AMR is a reduction in gonorrhoea burden, better diagnostics, improvement in prescribers' behaviour, more rational consumer expectations and increased consumer adherence.[21] The WHO recently published a global action plan, which included a number of public health recommendations to contain the emergence and spread of ESC-resistant gonococci.[46] A number of national and regional response plans have also been published.[47–49]
Conclusion
The lack of quality regional surveillance AMR data means it is presently impossible to estimate the global burden of MDR and XDR gonorrhoea. However, it is clear that control of gonorrhoea is failing at the global level, and we are seeing both increases in the incidence of new gonorrhoea cases and a worsening of the AMR profile of N. gonorrhoeae. Current strategies to control gonococcal AMR should include, where possible, the use of higher doses of ceftriaxone given as dual therapy with an effective second antimicrobial agent and continued evaluation of alternative drug combinations for both urogenital as well as rectal and oropharyngeal gonorrhoea. The recent emergence of the XDR gonococcal 'superbug' strongly argues the case for investment in research and development for both novel antimicrobial agents and, most importantly of all, a gonococcal vaccine.
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* Article described a novel spectinomycin-resistance mechanism in gonococci.
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* Article discusses in-vitro activity and potential use of ertapenem to treat ESC resistant and MDR gonorrhoea.
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* Article discusses in-vitro activity and potential use of solithromycin to treat ESC resistant and MDR gonorrhoea.
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** WHO action plan to combat the emergence and spread of ESC-resistant gonorrhoea with several key public health recommendations.
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