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- Antimicrobial resistance
- genitourinary medicine services
- syndrome management
The pattern of antimicrobial resistance in Neisseria gonorrhoeae is depressingly predictable. An antibiotic is chosen and used for a few years but resistance develops, so the dose is increased to maintain efficacy before the drug finally fails irrevocably. For penicillin, this process took a number of decades but with the subsequent use of tetracyclines, macrolides and fluoroquinolones, the cycle has shortened, and the utility of oral cephalosporins is now threatened within a few short years of their introduction as preferred therapy in many countries.1
Following the emergence of N gonorrhoeae strains with decreased susceptibility to oral cephalosporins, clinical treatment failures soon appeared in Japan and Hong Kong;2–4 more recently, similar outcomes have reported from other regions of the world, including Europe. There still exists some debate as to the minimum inhibitory concentration (MIC) breakpoint for oral cephalosporins that correlates with clinical failure. However, data from Deguchi et al suggest that clinical failures may occur with MICs of 0.125 mg/l or higher.3 Pharmacodynamic modelling with Monte Carlo simulations highlighted the fact that, for reliable efficacy, cephalosporins require a free drug level above the MIC for 20–24 h (compared to 7–10 h in the case of penicillin G).5 These analyses predicted that failures with standard doses of cefixime (400 mg) and ceftriaxone (250 mg) become likely around MICs of 0.125 mg/l and 0.25 mg/l respectively. The clinical practice of treating patients with gonorrhoea with an additional agent for presumptive Chlamydia trachomatis infection—particularly azithromycin and, to a lesser extent, doxycycline—may have prevented the appearance of treatment failures in those individuals infected with N gonorrhoeae strains possessing high cephalosporin MICs.
The mechanism of resistance to oral cephalosporins involves changes in the structure and function of a number of key proteins, notably the penA-encoded penicillin binding protein …
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