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Review
Will targeting oropharyngeal gonorrhoea delay the further emergence of drug-resistant Neisseria gonorrhoeae strains?
  1. D A Lewis1,2
  1. 1Western Sydney Sexual Health Centre, Parramatta, New South Wales, Australia
  2. 2Centre for Infectious Diseases and Microbiology & Marie Bashir Institute for Infectious Diseases and Biosecurity, Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
  1. Correspondence to Professor David A Lewis, Western Sydney Sexual Health Centre, Level 4 Jeffrey House, 162 Marsden Street, Parramatta, NSW 2150, Australia; david.lewis2{at}sydney.edu.au

Abstract

Gonorrhoea is an important sexually transmitted infection associated with serious complications and enhanced HIV transmission. Oropharyngeal infections are often asymptomatic and will only be detected by screening. Gonococcal culture has low sensitivity (<50%) for detecting oropharyngeal gonorrhoea, and, although not yet approved commercially, nucleic acid amplification tests (NAAT) are the assay of choice. Screening for oropharyngeal gonorrhoea should be performed in high-risk populations, such as men-who-have-sex-with-men(MSM). NAATs have a poor positive predictive value when used in low-prevalence populations. Gonococci have repeatedly thwarted gonorrhoea control efforts since the first antimicrobial agents were introduced. The oropharyngeal niche provides an enabling environment for horizontal transfer of genetic material from commensal Neisseria and other bacterial species to Neisseria gonorrhoeae. This has been the mechanism responsible for the generation of mosaic penA genes, which are responsible for most of the observed cases of resistance to extended-spectrum cephalosporins (ESC). As antimicrobial-resistant gonorrhoea is now an urgent public health threat, requiring improved antibiotic stewardship, laboratory-guided recycling of older antibiotics may help reduce ESC use. Future trials of antimicrobial agents for gonorrhoea should be powered to test their efficacy at the oropharynx as this is the anatomical site where treatment failure is most likely to occur. It remains to be determined whether a combination of frequent screening of high-risk individuals and/or laboratory-directed fluoroquinolone therapy of oropharyngeal gonorrhoea will delay the further emergence of drug-resistant N. gonorrhoeae strains.

  • NEISSERIA GONORRHOEA
  • GONORRHOEA
  • ORAL SEX

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Introduction

Neisseria gonorrhoeae, the pathogen responsible for gonorrhoea, spreads very efficiently through unprotected sexual intercourse and may initially infect the mucous membranes of the urethra, endocervix, anal crypts, oropharynx and conjunctiva. Gonorrhoea is an important sexually transmitted infection and untreated genital infection is associated with a number of serious complications as well as enhanced transmission of HIV.1 ,2 In contrast, oropharyngeal infections are often asymptomatic and rarely cause any morbidity. This poses a challenge for public health control of gonorrhoea, and diagnosis of oropharyngeal gonorrhoea typically relies on screening efforts in high-risk populations, such as men-who-have-sex-with-men (MSM) and commercial sex workers (CSW).

Gonococci have repeatedly thwarted gonorrhoea control efforts since the demise of sulphonamides in the early 1940s.2 Subsequently, resistance has emerged against penicillins, tetracyclines, fluoroquinolones, macrolides and, most recently, extended-spectrum cephalosporins (ESC).2 Multidrug- and extensively drug-resistant gonorrhoea is an urgent public health threat, particularly given the lack of alternative drugs in the therapeutic pipeline and the absence of a gonococcal vaccine.3 ,4

The emergence and initial spread of antimicrobial resistance has been associated with certain key populations, such as MSM, CSW and male partners of sex workers.5 Oro-penile transmission of gonococci within these populations enhances transmission of gonorrhoea within their sexual networks, and oropharyngeal infections may also drive the emergence and propagation of antimicrobial-resistant N. gonorrhoeae strains.6 The latter has been highlighted through the molecular analysis of mosaic penA genes, responsible for reduced susceptibility and resistance to ESCs.7–9

This review will highlight several aspects of oropharyngeal gonorrhoea that are relevant for ongoing control efforts, describe the importance of the oropharyngeal niche in respect of acquisition of antimicrobial resistance determinants and treatment failure, and, finally, discuss whether or not targeting oropharyngeal gonorrhoea might delay the emergence of further drug-resistant N. gonorrhoeae strains.

Oropharyngeal gonorrhoea: coloniser or pathogen?

It is widely believed that most oropharyngeal N. gonorrhoeae infections are transient and reflect self-limited colonisation. Wallin and Siegel reported on 17 patients with oropharyngeal gonorrhoea who were left untreated and followed up for 12 weeks.10 At 6 weeks, seven (41%) patients were still culture-positive whereas all cultures were negative at 12 weeks. Hutt and Judson repeated cultures for N. gonorrhoeae at 2–7 days in 60 patients before they received antimicrobial therapy.11 Among their cohort, four (44%) of nine patients again tested positive for N. gonorrhoeae by culture after an internal of 7 days from their first positive gonococcal culture test.

In terms of transmission, gonococci are readily detected in expectorated saliva, and this is important for sexual transmission.11 Gonorrhoea may be transmitted from the mouth to the male urethra (fellatio), the female urethra and lower genital tract (cunnilingus) and to the anorectum (anilingus). The rate of genital–oral transmission is higher with fellatio than with cunnilingus. It has also been reported that gonorrhoea may be transmitted by kissing.12

Detection of oropharyngeal gonorrhoea

Traditionally, culture has been the ‘gold standard’ for the diagnosis of gonorrhoea on account of its high specificity, although performance may be affected by specimen-collection technique and transport conditions.13 Culture has a high sensitivity for detecting N. gonorrhoeae in men with urethral discharge, but a much lower sensitivity at oropharyngeal site. Mitchell et al14 reported that more widespread swabbing to cover an adequate area within the oropharynx improves N. gonorrhoeae isolation rates.

Although commercial N. gonorrhoeae assays are not yet licensed to test oropharyngeal specimens, studies consistently report that nucleic acid amplification tests (NAAT) are approximately twice as sensitive as culture at this anatomical site.15 ,16 The disadvantage of NAATs, particularly when they are used for testing oropharyngeal specimens in low-prevalence populations, is that they are prone to generating false-positive results due to primer binding to DNA sequences in non-gonococcal Neisseria spp.17 However, not all bacteria of a given Neisseria sp cross-react with gonococcal NAAT targets and cross-reactions depend on the target itself as the rate of genetic exchange is gene-dependent.17 In many cases, specificity can be improved by performing a second confirmatory NAAT targeting a different DNA sequence.17

The prevalence and incidence of oropharyngeal gonorrhoea in MSM

The contribution of oropharyngeal N. gonorrhoeae infection to the spread of gonorrhoea among MSM has yet to be determined; however, it is biologically plausible that an anatomical site with high frequency of mucosal contact during sex would also be a key site for propagating onward transmission of gonococcal infection, and in particular, antimicrobial-resistant gonorrhoea.18

The prevalence of oropharyngeal N. gonorrhoeae infection among MSM varies by facility, but typically ranges from 3% to 7%.19–21 At anonymous HIV counselling and testing sites in San Francisco, the reported prevalence of oropharyngeal gonorrhoea in MSM (4.7%) far exceeded that of heterosexual men (0.4%) and women (0.1%).22 The prevalence and incidence of oropharyngeal gonorrhoea in MSM has perhaps been best described within the context of the EXPLORE study, which was a multi-site randomised controlled trial of an HIV behavioural intervention for MSM.20 A longitudinal oropharyngeal gonorrhoea ancillary study, conducted in San Francisco, determined the prevalence and incidence of oropharyngeal gonococcal infection as 5.5% (136/2475 tests) and 11.2 cases per 100 person-years, respectively.20 The authors reported that younger age and number of insertive oral sex partners in the past 3 months were predictors of oropharyngeal gonorrhoea.

The importance of the oropharyngeal niche for generation of antimicrobial resistance

The oropharynx is an ideal niche for genetic exchange between related bacterial species. The effect of antibiotic therapy on oral commensal flora may be prolonged and enables such flora to serve as a reservoir of antimicrobial resistance determinants for other pathogenic bacteria. For example, it has been demonstrated that use of single courses of macrolides can increase the carriage of the ermB macrolide resistance genes by oral streptococci and that this may last for 180 days or more.23 Likewise, the use of clarithromycin to eradicate Helicobacter pylori resulted in an immediate rise in the prevalence of macrolide-resistant oral streptococci that remained for 1 year after treatment.24

Non-gonococcal Neisseria spp account for <1% of Neisseria spp isolated from the urogenital tract, but have a higher prevalence in oropharynx.25 In the case of N. lactamica, individuals may be colonised for at least 12 weeks after experimental inoculation, although some individuals appear to be resistant to carriage.26 It is postulated that oral commensal Neisseria spp may acquire resistance mutations as a result of repeated exposure to antimicrobial agents, and these species may, in turn, transfer resistance to pathogenic Neisseria spp. As an example, the development of sulphonamide resistance in N. meningitidis is thought to have occurred as a result of horizontal DNA transfer from commensal Neisseria possessing mutations in the dihydropteroate synthase gene.27 Similarly, the acquisition by gonococci of penA DNA sequences from commensal Neisseria spp (N. perflava, N. cinerea, N. flavescens) as well as N. meningitidis is thought to be the main mechanism of ESC resistance.7–9

Features of N. gonorrhoeae that facilitate the emergence of antimicrobial resistance

Gonococci are naturally competent for DNA transformation, which, along with plasmid transfer, is a key mechanism whereby antimicrobial resistance determinants are acquired. The process of DNA donation is poorly understood, but it is thought to be mainly due to release of DNA after cell death. Some N. gonorrhoeae isolates can also secrete single-stranded DNA via a type IV secretion system encoded on a gonococcal genetic island.28 Transforming DNA contains a unique 10 base pair DNA uptake sequence that is recognised by a receptor on the gonococcal outer membrane.29

Mucosal surfaces capable of being infected by N. gonorrhoeae also vary with respect to the presence, nature and concentration of inhibitory hydrophobic molecules. The host environment may select gonococci with certain outer membrane phenotypes, which, in turn, may result in altered antimicrobial susceptibility. Morse et al30 demonstrated that N. gonorrhoeae isolated from the urethra or anorectum of MSM are frequently chromosomally resistant to penicillin and erythromycin compared with gonococci isolated from heterosexual men or women; this was shown to be due to mutations in the multiple transferable resistance (mtr) efflux operon (Mtr phenotype). Gonococci with the Mtr phenotype were more resistant to growth inhibition by faecal lipids, suggesting that these strains have a fitness advantage in the hydrophobic environment of the rectum. Given that N. gonorrhoeae may move between anorectal and oropharyngeal sites, either directly or indirectly, through intermediate urethral exposure, gonococci at the oropharynx will likely have similar phenotypes to rectal isolates. While it has been suggested that gonococcal strains infecting the pharynx may also be less susceptible to antimicrobial agents, evidence to support this hypothesis is lacking.31 ,32

Rationale for ensuring effective treatment of oropharyngeal gonorrhoea

There have always been good reasons to treat oropharyngeal N. gonorrhoeae infections. First, the condition is a risk factor for urethral gonorrhoea; second, pharyngitis and tonsillitis may ensue if oropharyngeal gonorrhoea is left untreated; and third, oropharynx may be a source for disseminated gonococcal infection.25 ,33 With the emergence of ESC-resistant N. gonorrhoeae strains, it is now more important than ever to detect and treat oropharyngeal gonorrhoea effectively.

Efficacy of antimicrobial agents at the oropharyngeal site

Most clinical trials to assess the efficacy of existing or new antimicrobial agents have focused on cure of N. gonorrhoeae residing in the urethra or endocervix, yet oropharyngeal gonorrhoea is less easy to cure.31 ,34 In a systematic review of 144 reports of therapeutic trials, assessing microbiological cure of 16 737 uncomplicated gonococcal infections through use of 87 antimicrobial regimens, Moran reported that 96.4% of all gonococcal infections were cured overall.31 However, when these data were analysed by anatomical site of infection, it was clearly demonstrated that the cure rates were significantly lower in the oropharynx of both males (79.2%) and females (83.7%) compared with those observed at the urethra, cervix or rectum. These differences remained significant after stratifying by treatment regimen.

Why are antimicrobial agents less effective at the oropharynx?

The penetration of antimicrobial agents into the oropharyngeal mucosa is a very complex process, for which the presence of inflammation and antibiotic pharmacokinetic properties are important factors. The reasons underlying the well-known differential ability of antimicrobial agents to cure oropharyngeal gonorrhoea may relate to their inability to achieve high extracellular concentrations in tonsillar and other oropharyngeal tissues. As an example of this phenomenon, ceftriaxone given intramuscularly as single 250 mg doses failed to cure oropharyngeal gonorrhoea in two situations where the gonococcal strain's minimum inhibitory concentration (MIC) for ceftriaxone still indicated microbiological susceptibility, albeit reduced (0.016–0.03 μg/mL).35

Several pharmacological studies measuring salivary concentrations of antimicrobial agents, which generally reflect intracellular concentration in oropharyngeal tissues, have demonstrated a limited effect of a number of antimicrobial agents on oropharyngeal commensal flora. Piercy et al36 noted that only minor alterations in the oral flora of participants was observed during treatment with ciprofloxacin, suggesting that the steady-state salivary concentration barely exceeds the reported MIC for commensal oral streptococci or anaerobic bacteria. Likewise, Bergan et al37 reported only minor changes in the salivary flora as a result of a 5-day course of ciprofloxacin, and the main effect noted was a transient suppression of commensal Neisseria species. Najjar et al38 demonstrated that the maximum salivary concentration of cefixime (0.56 µg/mL) was lower than the maximum plasma concentration (2.97 µg/mL). This salivary concentration exceeds the reported MIC values for cefixime-susceptible gonococci, although urethral N. gonorrhoeae isolates failing cefixime therapy have been reported to have MIC values of ≥0.125 µg/mL.39

Will targeting oropharyngeal gonorrhoea delay the emergence of further drug-resistant N. gonorrhoeae strains?

Given the high difficulties of treating oropharyngeal gonorrhoea and the high propensity of the oropharyngeal niche to enable horizontal DNA transfer between N. gonorrhoeae and other bacterial species, it makes sense to prioritise the early detection and successful treatment of oropharyngeal infections in key populations, such as MSM. Given that most oropharyngeal gonorrhoea infections are asymptomatic, any gonorrhoea control strategy will need focus on regular oropharyngeal screening using highly sensitive NAATs. The screening frequency should be determined by a behavioural risk assessment.40 Early detection and treatment of oropharyngeal infections will minimise the time available for horizontal DNA transfer between bacterial species.6 ,7

For the treatment of susceptible N. gonorrhoeae infections, it has been recognised for some time that certain antimicrobial agents, for example ciprofloxacin, have higher efficacy than others, such as spectinomycin or ampicillin, at the oropharyngeal site.11 Accordingly, ciprofloxacin may still have a role to play in treating oropharyngeal gonorrhoea as an ESC-sparing strategy. Real-time molecular assays can rapidly detect characteristic mutations in the fluoroquinolone-resistance determining region of gyrA and could be used to inform clinical practice.41 ,42

It remains to be determined whether a combination of frequent screening of high-risk individuals and/or laboratory-directed fluoroquinolone therapy of oropharyngeal gonorrhoea will delay the further emergence of drug-resistant N. gonorrhoeae strains. However, logic dictates that such an approach will help gonorrhoea control efforts in those countries that can afford to implement these measures.

Key messages

  • Oropharyngeal Neisseria gonorrhoeae infection is generally transient, but is an important driver of gonorrhoea transmission within key populations, particularly men-who-have-sex-with-men.

  • The oropharyngeal niche provides an ideal environment for generating antimicrobial resistance through horizontal transfer of genetic material from commensal Neisseria and other bacterial species to N. gonorrhoeae.

  • Nucleic acid amplification test (NAAT) offers the highest sensitivity for detection of oropharyngeal gonorrhoea; however, NAATs do not provide an organism for antimicrobial susceptibility testing, and false-positivity is a challenge when testing patients for gonorrhoea in low-prevalence populations.

  • Future evaluations of new drugs or novel drug combinations for gonorrhoea should be powered to assess cure in the oropharynx as this is the anatomical site where low efficacy is most likely to be observed.

  • The impact of improved management of oropharyngeal gonorrhoea on the emergence and dissemination of antimicrobial-resistant gonorrhoea requires further study.

References

View Abstract

Footnotes

  • Correction notice This article has been corrected since it was published Online First. The units in the phrase ‘albeit reduced (0.016–0.03 μg/L).35’ have been amended from μg/L to μg/mL.

  • Handling editor Jackie A Cassell

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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