Research Article: Estimating the fitness cost and benefit of cefixime resistance in Neisseria gonorrhoeae to inform prescription policy: A modelling study

Date Published: October 31, 2017

Publisher: Public Library of Science

Author(s): Lilith K. Whittles, Peter J. White, Xavier Didelot, Nicola Low

Abstract: BackgroundGonorrhoea is one of the most common bacterial sexually transmitted infections in England. Over 41,000 cases were recorded in 2015, more than half of which occurred in men who have sex with men (MSM). As the bacterium has developed resistance to each first-line antibiotic in turn, we need an improved understanding of fitness benefits and costs of antibiotic resistance to inform control policy and planning. Cefixime was recommended as a single-dose treatment for gonorrhoea from 2005 to 2010, during which time resistance increased, and subsequently declined.Methods and findingsWe developed a stochastic compartmental model representing the natural history and transmission of cefixime-sensitive and cefixime-resistant strains of Neisseria gonorrhoeae in MSM in England, which was applied to data on diagnoses and prescriptions between 2008 and 2015. We estimated that asymptomatic carriers play a crucial role in overall transmission dynamics, with 37% (95% credible interval CrI 24%–52%) of infections remaining asymptomatic and untreated, accounting for 89% (95% CrI 82%–93%) of onward transmission. The fitness cost of cefixime resistance in the absence of cefixime usage was estimated to be such that the number of secondary infections caused by resistant strains is only about half as much as for the susceptible strains, which is insufficient to maintain persistence. However, we estimated that treatment of cefixime-resistant strains with cefixime was unsuccessful in 83% (95% CrI 53%–99%) of cases, representing a fitness benefit of resistance. This benefit was large enough to counterbalance the fitness cost when 31% (95% CrI 26%–36%) of cases were treated with cefixime, and when more than 55% (95% CrI 44%–66%) of cases were treated with cefixime, the resistant strain had a net fitness advantage over the susceptible strain. Limitations include sparse data leading to large intervals on key model parameters and necessary assumptions in the modelling of a complex epidemiological process.ConclusionsOur study provides, to our knowledge, the first estimates of the fitness cost and benefit associated with resistance of the gonococcus to a clinically relevant antibiotic. Our findings have important implications for antibiotic stewardship and public health policies and, in particular, suggest that a previously abandoned antibiotic could be used again to treat a minority of gonorrhoea cases without raising resistance levels.

Partial Text: Gonorrhoea, caused by the bacterial pathogen N. gonorrhoeae, is one of the most common sexually transmitted infections in England. Incidence has increased year on year since 2008, culminating in over 41,000 cases in 2015 [1]. Around 22,000 of these cases were found in men who have sex with men (MSM), constituting a 20% annual increase. The greatest cause for concern, however, is the rapid growth in antimicrobial resistance. The bacterium has quickly developed resistance to each first-line antibiotic in turn, from penicillin to cephalosporins, such as cefixime and ceftriaxone [2, 3]. Treatment with ceftriaxone is the last remaining single-drug option in most settings worldwide; however, diminishing susceptibility led England and many other countries to recommend treatment of gonorrhoea with a dual therapy of ceftriaxone and azithromycin [4–6]. Ceftriaxone resistance has been detected only sporadically in England; however, azithromycin resistance is easily selected for and was prevalent in a recent outbreak [7]. Resistance to azithromycin effectively reduces the current treatment to a monotherapy, making resistance trends increasingly important to monitor against the threat of potentially untreatable gonorrhoea.



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