Abandoned gonorrhoea treatments may again be effective

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A previously recommended treatment for gonorrhoea, cefixime, may be an effective alternative to current treatments as clinicians battle outbreaks and emergence of antimicrobial resistance (AMR), according to a study published this week by Xavier Didelot of Imperial College London, UK, and colleagues.

Gonorrhoea, caused by the bacteria N. gonorrhoeae, is one of the most common sexually transmitted infections in England, and incidence has increased in recent years, particularly among men who have sex with men (MSM). Treating gonorrhoea is complicated by the rapid development of antimicrobial resistance (AMR). The cephalosporin antibiotic cefixime was a recommended first-line treatment for gonorrhoea before increasing prevalence of cefixime-resistant strains of N. gonorrhoeae was observed around 2010, leading to the removal of cefixime from treatment guidelines. While the currently recommended dual therapy of ceftriaxone-azithromycin remains effective, emerging ceftriaxone resistance has led to fears that this regimen may in turn become inadequate.

To determine whether re-introduction of cefixime treatment in a minority of cases might provide an effective alternative and help prevent emergence of resistance to ceftriaxone-azithromycin, the researchers developed a mathematical model of the dynamics of cefixime resistance observed between 2008 and 2015. The model includes a fitness benefit of cefixime resistance in N. gonorrhoeae during periods of wide use of the antibiotic (explaining the increase in resistant strains up to 2010) and a fitness cost of resistance (explaining the decrease in cefixime resistance after 2010). The model estimates treating cefixime-resistant gonorrhoea with cefixime to be unsuccessful in 83% (95% credible interval [CrI] 53%–99%) of cases, representing a fitness benefit of resistance large enough to counterbalance the fitness cost to N. gonorrhoeae when more than 31% (95% CrI 26%–36%) of cases are treated with cefixime. The authors therefore suggest that cefixime could be used to treat up to 25% of gonorrhoea cases without risk of cefixime resistance re-emerging.

The authors note that epidemiological data for their model is restricted to MSM, the population in which the cefixime-resistant outbreak of gonorrhoea was concentrated, and that assumptions made to keep the model simple and generalisable may impact predictions.

In an accompanying Perspective, Magnus Unemo of Örebro University Hospital, Örebro, Sweden, and Christian Althaus of the University of Bern, Switzerland, discuss the value of modelling studies to inform AMR management. They also note the limitations of the current evidence base informing such models, highlight the need for studies measuring the many factors that affect transmissibility of resistant strains, and suggest caution before widely reintroducing antimicrobials such as cefixime.

Abstract
Background: Gonorrhoea 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 findings: We 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.
Conclusions: Our 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.

Authors
Lilith K Whittles, Peter J White, Xavier Didelot

PLOS material
PLOS Medicine abstract
PLOS Medicine perspective


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