EditorialPublication Exclusive

Managing the threat of untreatable gonorrhea

Gonorrhea is a sexually transmitted infection that can lead to serious reproductive tract morbidity if untreated and may facilitate HIV transmission. With an estimated 106 million new cases diagnosed in 2008 globally, the ongoing emergence of resistance to antimicrobials used to treat gonorrhea is therefore a global public health concern. Gonorrhea is now at risk of becoming an untreatable disease. In the absence of any effective vaccine, strategies that prolong and maximize the effectiveness of available antimicrobials are crucial for controlling this infection.

Treatment of gonorrhea is empirical, based on national and/or international guidelines. WHO recommends that any empirical therapy for gonorrhea should achieve at least 95% cure rate, requiring resistance rates below 5% in the gonococcal population. With penicillin, tetracycline and ciprofloxacin resistance rates as high as 100% in some countries, particularly from the Southeast Asia Western Pacific region, these are no longer treatment options.

Origin of resistance

The causes of antimicrobial resistance in gonorrhea are multifactorial, but three factors are critical. First, the causative organism, Neisseria gonorrhoeae, not only mutates at random, but has a remarkable propensity to acquire extrageneous genetic material from other Neisseria spp. The potential to acquire new resistance mechanisms is therefore high. Second, repeated widespread empirical use of a monotherapy, followed by a new monotherapy when resistance and treatment failures emerge, creates a selection pressure for resistance. Third, gonorrhea is probably underdiagnosed, particularly in asymptomatic cases, potentially allowing unrestricted dissemination of resistant strains. This was especially true before the introduction of more sensitive nucleic acid amplification tests (GC-NAATs) in many countries.

When treatment guidelines changed in many developed countries in response to widespread emergence of ciprofloxacin resistance, most guidelines recommended an oral third-generation cephalosporin, usually cefixime (Suprax, Lupin). It was recognized that treatment of gonorrhea was approaching a critical stage, with few alternative therapeutic options available. Despite this, additional factors created an environment that accelerated the emergence of resistance.

Stephanie Chisholm

Gwenda A. Hughes

First, use of oral third-generation cephalosporins less potent than cefixime may have led to inadequate treatment, creation of a selection pressure and onward transmission of less susceptible strains. Second, cefixime achieves poor eradication rates in pharyngeal infection. As pharyngeal infection is typically asymptomatic and may remain undetected, the potential for infection to persist and facilitate genetic exchange with other commensal Neisseria spp. is high. Furthermore, suboptimal concentrations of an antimicrobial achieved while treating other infected sites may select for resistant strains in the pharynx.

Inevitably, gonococcal populations began to show increasing minimum inhibitory concentrations for cefixime, eventually reaching levels predicted to result in treatment failure (≥0.25 mg/L). Around this time, sporadic reports of treatment failure emerged. Although cefixime treatment remained effective in most patients, it was evident that the utility of this antimicrobial was diminishing. The contribution of a mosaic form of the penA gene, encoding penicillin binding protein 2, to cefixime resistance is well established. The mosaic gene shows evidence of recombination with other Neisseria spp. Cefixime resistance thus most likely developed at pharyngeal sites, which harbor numerous other commensal Neisseria spp., highlighting the importance of diagnosis and effective treatment of gonorrhea at all infected sites.

Renewed vigor for antimicrobial stewardship

One positive outcome of the emergence of cefixime resistance was a renewed approach to antimicrobial stewardship. Across the globe, treatment guidelines were rapidly revised before widespread treatment failure emerged and, for the first time, recommended dual therapy, typically 250 mg to 500 mg of ceftriaxone (administered parenterally) and an oral dose of 1 g to 2 g azithromycin. In theory, this more aggressive regimen should slow the development of resistance, as the likelihood of a strain simultaneously acquiring resistance mechanisms to both antimicrobials is lower. Whether this is too little, too late remains to be seen, but early data are encouraging.

In England and Wales, as in many countries, the sharp decline in prevalence of cefixime resistance after the guideline change to dual therapy hinted at the effective treatment and reduced transmission of a predominantly clonal group of organisms exhibiting cephalosporin resistance (NG-MAST sequence type 1407 and related types).

Kevin A. Fenton

There is no room for complacency, however, as the potential for current therapies to be compromised by resistance remains. The most imminent threat to dual therapy is high-level azithromycin resistance (AziHR). Azithromycin is rarely used alone to treat gonorrhea, but MICs at this level (≥128 mg/L) almost certainly would result in treatment failure. To date, AziHR occurs sporadically, and has not been documented in combination with raised ceftriaxone MICs. However, some gonococcal strains sensitive to azithromycin can quickly recombine under selection pressure in vitro to develop high-level resistance. Although dual therapy to treat gonorrhea is unlikely to create that selection pressure, there are other clinical situations that could (eg, use of 1 g azithromycin to treat non-gonococcal urethritis before culture or GC-NAAT results are available). Additionally, ceftriaxone MICs as high as 2 mg/L and pharyngeal treatment failures with ceftriaxone monotherapy are documented. Fortunately, acquisition of extended-spectrum beta-lactamases is not.

Search for a new approach

Antimicrobial resistance is a clear and present threat to the management and control of gonorrhea that has required the scientific and medical community to rethink traditional approaches to treatment strategies. While we await the development and availability of new treatment agents, effective antimicrobial stewardship will be key in retaining gonorrhea as a treatable infection. This must be informed by robust surveillance systems and the maintenance of culture to ensure novel emerging resistance patterns can be identified. Treatment guidelines should be reviewed in response to emerging evidence on antimicrobial resistance and treatment failures and promoted by clinicians and professional groups for rapid and effective implementation.

References:

Bala M. Sex Transm Infect. 2013;89 Suppl 4:iv28-35.
Chisholm SA. Antimicrob Agents Chemother. 2010;54:3812-3816.
Chisholm SA. J Antimicrob Chemother. 2010;65:2141-2148.
Ison CA. Lancet Infect Dis. 2013;13:762-768.

WHO. Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae. 2012; ISBN 978 92 4 150350 1.

For more information:
Stephanie Chisholm is the molecular epidemiology and surveillance section head in the Sexually Transmitted Bacteria Reference Unit, Microbiology Services, Public Health England. She can be reached at Stephanie.Chisholm@phe.gov.uk.
Gwenda Hughes, BA(Hons), PhD, FFPH, is consultant scientist (epidemiology) and head of the STI Section in the Department of HIV and STIs, Centre for Infectious Disease Surveillance and Control, Public Health England.
Kevin A. Fenton, MD, PhD, FFPH, is National Director of the Health and Wellbeing at Public Health England and a member of the Infectious Disease News Editorial Board.
Disclosures: The authors report no relevant financial disclosures.

Gonorrhea is a sexually transmitted infection that can lead to serious reproductive tract morbidity if untreated and may facilitate HIV transmission. With an estimated 106 million new cases diagnosed in 2008 globally, the ongoing emergence of resistance to antimicrobials used to treat gonorrhea is therefore a global public health concern. Gonorrhea is now at risk of becoming an untreatable disease. In the absence of any effective vaccine, strategies that prolong and maximize the effectiveness of available antimicrobials are crucial for controlling this infection.

Treatment of gonorrhea is empirical, based on national and/or international guidelines. WHO recommends that any empirical therapy for gonorrhea should achieve at least 95% cure rate, requiring resistance rates below 5% in the gonococcal population. With penicillin, tetracycline and ciprofloxacin resistance rates as high as 100% in some countries, particularly from the Southeast Asia Western Pacific region, these are no longer treatment options.

Origin of resistance

The causes of antimicrobial resistance in gonorrhea are multifactorial, but three factors are critical. First, the causative organism, Neisseria gonorrhoeae, not only mutates at random, but has a remarkable propensity to acquire extrageneous genetic material from other Neisseria spp. The potential to acquire new resistance mechanisms is therefore high. Second, repeated widespread empirical use of a monotherapy, followed by a new monotherapy when resistance and treatment failures emerge, creates a selection pressure for resistance. Third, gonorrhea is probably underdiagnosed, particularly in asymptomatic cases, potentially allowing unrestricted dissemination of resistant strains. This was especially true before the introduction of more sensitive nucleic acid amplification tests (GC-NAATs) in many countries.

When treatment guidelines changed in many developed countries in response to widespread emergence of ciprofloxacin resistance, most guidelines recommended an oral third-generation cephalosporin, usually cefixime (Suprax, Lupin). It was recognized that treatment of gonorrhea was approaching a critical stage, with few alternative therapeutic options available. Despite this, additional factors created an environment that accelerated the emergence of resistance.

Stephanie Chisholm

Gwenda A. Hughes

First, use of oral third-generation cephalosporins less potent than cefixime may have led to inadequate treatment, creation of a selection pressure and onward transmission of less susceptible strains. Second, cefixime achieves poor eradication rates in pharyngeal infection. As pharyngeal infection is typically asymptomatic and may remain undetected, the potential for infection to persist and facilitate genetic exchange with other commensal Neisseria spp. is high. Furthermore, suboptimal concentrations of an antimicrobial achieved while treating other infected sites may select for resistant strains in the pharynx.

Inevitably, gonococcal populations began to show increasing minimum inhibitory concentrations for cefixime, eventually reaching levels predicted to result in treatment failure (≥0.25 mg/L). Around this time, sporadic reports of treatment failure emerged. Although cefixime treatment remained effective in most patients, it was evident that the utility of this antimicrobial was diminishing. The contribution of a mosaic form of the penA gene, encoding penicillin binding protein 2, to cefixime resistance is well established. The mosaic gene shows evidence of recombination with other Neisseria spp. Cefixime resistance thus most likely developed at pharyngeal sites, which harbor numerous other commensal Neisseria spp., highlighting the importance of diagnosis and effective treatment of gonorrhea at all infected sites.

Renewed vigor for antimicrobial stewardship

One positive outcome of the emergence of cefixime resistance was a renewed approach to antimicrobial stewardship. Across the globe, treatment guidelines were rapidly revised before widespread treatment failure emerged and, for the first time, recommended dual therapy, typically 250 mg to 500 mg of ceftriaxone (administered parenterally) and an oral dose of 1 g to 2 g azithromycin. In theory, this more aggressive regimen should slow the development of resistance, as the likelihood of a strain simultaneously acquiring resistance mechanisms to both antimicrobials is lower. Whether this is too little, too late remains to be seen, but early data are encouraging.

In England and Wales, as in many countries, the sharp decline in prevalence of cefixime resistance after the guideline change to dual therapy hinted at the effective treatment and reduced transmission of a predominantly clonal group of organisms exhibiting cephalosporin resistance (NG-MAST sequence type 1407 and related types).

Kevin A. Fenton

There is no room for complacency, however, as the potential for current therapies to be compromised by resistance remains. The most imminent threat to dual therapy is high-level azithromycin resistance (AziHR). Azithromycin is rarely used alone to treat gonorrhea, but MICs at this level (≥128 mg/L) almost certainly would result in treatment failure. To date, AziHR occurs sporadically, and has not been documented in combination with raised ceftriaxone MICs. However, some gonococcal strains sensitive to azithromycin can quickly recombine under selection pressure in vitro to develop high-level resistance. Although dual therapy to treat gonorrhea is unlikely to create that selection pressure, there are other clinical situations that could (eg, use of 1 g azithromycin to treat non-gonococcal urethritis before culture or GC-NAAT results are available). Additionally, ceftriaxone MICs as high as 2 mg/L and pharyngeal treatment failures with ceftriaxone monotherapy are documented. Fortunately, acquisition of extended-spectrum beta-lactamases is not.

Search for a new approach

Antimicrobial resistance is a clear and present threat to the management and control of gonorrhea that has required the scientific and medical community to rethink traditional approaches to treatment strategies. While we await the development and availability of new treatment agents, effective antimicrobial stewardship will be key in retaining gonorrhea as a treatable infection. This must be informed by robust surveillance systems and the maintenance of culture to ensure novel emerging resistance patterns can be identified. Treatment guidelines should be reviewed in response to emerging evidence on antimicrobial resistance and treatment failures and promoted by clinicians and professional groups for rapid and effective implementation.

References:

Bala M. Sex Transm Infect. 2013;89 Suppl 4:iv28-35.
Chisholm SA. Antimicrob Agents Chemother. 2010;54:3812-3816.
Chisholm SA. J Antimicrob Chemother. 2010;65:2141-2148.
Ison CA. Lancet Infect Dis. 2013;13:762-768.

WHO. Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae. 2012; ISBN 978 92 4 150350 1.

For more information:
Stephanie Chisholm is the molecular epidemiology and surveillance section head in the Sexually Transmitted Bacteria Reference Unit, Microbiology Services, Public Health England. She can be reached at Stephanie.Chisholm@phe.gov.uk.
Gwenda Hughes, BA(Hons), PhD, FFPH, is consultant scientist (epidemiology) and head of the STI Section in the Department of HIV and STIs, Centre for Infectious Disease Surveillance and Control, Public Health England.
Kevin A. Fenton, MD, PhD, FFPH, is National Director of the Health and Wellbeing at Public Health England and a member of the Infectious Disease News Editorial Board.
Disclosures: The authors report no relevant financial disclosures.