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Time for change
Standards for the management of gonorrhoea need to encompass relief of symptoms, rapid eradication of Neisseria gonorrhoeae from all sites, action to ensure that sexual partners are treated, and sexual health education to promote risk reduction in future sexual interaction. Many antimicrobial regimens have in the past demonstrated the capacity to eradicate N gonorrhoeae from genital sites.1 Efficacy in clinical trials has been shown to correlate with the length of time a particular antimicrobial regimen provides a blood level of four times the MIC90.1,2 Sensitivity and pharmacokinetics are therefore key factors, together with data from clinical trials and toxicity, in determining treatment recommendations. Weighing these factors is particularly relevant to the choice of recommended cephalosporins.3 The prevalence of gonococcal resistance to antimicrobials is variable and can change dramatically. Pharmacokinetics can differ significantly within and between classes of antimicrobials. It is therefore not surprising that antimicrobial regimens differ in clinical efficacy, particularly when eradication from non-genital sites is considered. What worked in treating gonorrhoea yesterday or even today will not necessarily continue to be an effective treatment.
While all guidelines need regular review, the British Association of Sexual Health and HIV (BASHH)/National guideline on gonorrhoea4 has needed a significant change in recommended therapy in response to data from the Gonococcal Resistance to Antimicrobial Programme (GRASP), which has shown a dramatic rise in high level quinolone resistance in England and Wales during the past 2 years.5,6 In 2001, the majority of people with gonorrhoea attending genitourinary medicine clinics in the United Kingdom received a quinolone antibiotic, consistent with the former guideline.7 Quinolone therapy alone would now result in failure to resolve symptoms or eradicate N gonorrhoeae in more than 10% of unselected cases in some regions, although clinical failures have been uncommon because treatment for gonorrhoea is frequently combined with a tetracycline or macrolide to manage possible co-incidental chlamydial infection. When a patient is identified to have gonorrhoea in the United Kingdom, it can now be anticipated that resistance to penicillins, tetracyclines, and quinolones will all exceed 5%.5
Options are now limited to achieve a minimum of 95% cure of unselected cases of anogenital gonorrhoea with single dose antimicrobial therapy at initial presentation. Treatment trials for gonorrhoea have been few in recent years and the revised 2004 recommendation to use a long acting third generation cephalosporin, notably ceftriaxone or cefixime, is based on historical efficacy from clinical trials, the known pharmacokinetics of these antimicrobials, in vitro resistance data (GRASP), and extensive worldwide clinical experience with these agents in settings where resistance to quinolones is common. No other antimicrobials can surpass these cephalosporins in terms of the evidence base, clinical effectiveness, or favourable pharmacokinetics with respect to selection of resistance and therapeutic reserve.3 Some may question whether the adoption of cephalosporins might be a step too far when the utility of other classes of antimicrobials is not exhausted, particularly in localities where the prevalence of resistance is relatively low. The clinical care of the individual patient involves integrating the judicious use of best available evidence with clinical expertise. The revised guideline is not prescriptive but specifically acknowledges situations where use of other antibiotics may be appropriate, notably when the antimicrobial sensitivity of an isolate is known before treatment or local surveillance data suggest low prevalence of resistance to a chosen antibiotic. The oral macrolide azithromycin is specifically not recommended as a single agent treatment for gonorrhoea. Studies using a single 1 g dose report unpredictable treatment failures and resistance can develop during treatment.8,9 Unlike other antimicrobials recommended for the treatment of gonorrhoea, azithromycin MICs do not provide a reliable guide to treatment outcome and treatment failures have been reported for “susceptible” isolates.10
Other elements of the guideline were also reconsidered in the light of developing technology and changing clinical practice. The 2004 guideline includes reference to detection of N gonorrhoeae by nucleic acid amplification tests (NAATS) and removal of the recommendation for a test of cure to routinely form part of post-treatment assessment. These changes may seem a significant shift from the traditional care pathway. The specialty must use its stretched resources in diagnostics, staff, and facilities to maximum effectiveness. Routine tests of cure need justification in terms of benefit to the patient or public health. Judgment on such benefits will inevitably be opinion based. Failure with recommended treatments for gonorrhoea is rare.11 There is no compelling need to prove pathogen eradication in most infections and test of cure is not recommended after treatment for genital tract chlamydial infection.
Patients with gonorrhoea deserve only to be treated according to those guidelines that reliably eradicate the infection, minimise the opportunity for the development of resistance, and meet public health needs. Any change in patient care is associated with potential benefits, risks, and costs. Realisation of the benefits of change to the guideline requires ownership and implementation by the membership of BASHH. The open debate that the revised guideline has generated has been helpful and welcomed by me and the Clinical Effectiveness Group. Guidelines are, after all, drafted from evidence filtered through opinion and clinical experience.
Time for change