Date Published: May 19, 2016
Publisher: Public Library of Science
Author(s): Stephanie M. Fingerhuth, Sebastian Bonhoeffer, Nicola Low, Christian L. Althaus, Bruce R. Levin.
The sexually transmitted bacterium Neisseria gonorrhoeae has developed resistance to all antibiotic classes that have been used for treatment and strains resistant to multiple antibiotic classes have evolved. In many countries, there is only one antibiotic remaining for empirical N. gonorrhoeae treatment, and antibiotic management to counteract resistance spread is urgently needed. Understanding dynamics and drivers of resistance spread can provide an improved rationale for antibiotic management. In our study, we first used antibiotic resistance surveillance data to estimate the rates at which antibiotic-resistant N. gonorrhoeae spread in two host populations, heterosexual men (HetM) and men who have sex with men (MSM). We found higher rates of spread for MSM (0.86 to 2.38 y−1, mean doubling time: 6 months) compared to HetM (0.24 to 0.86 y−1, mean doubling time: 16 months). We then developed a dynamic transmission model to reproduce the observed dynamics of N. gonorrhoeae transmission in populations of heterosexual men and women (HMW) and MSM. We parameterized the model using sexual behavior data and calibrated it to N. gonorrhoeae prevalence and incidence data. In the model, antibiotic-resistant N. gonorrhoeae spread with a median rate of 0.88 y−1 in HMW and 3.12 y−1 in MSM. These rates correspond to median doubling times of 9 (HMW) and 3 (MSM) months. Assuming no fitness costs, the model shows the difference in the host population’s treatment rate rather than the difference in the number of sexual partners explains the differential spread of resistance. As higher treatment rates result in faster spread of antibiotic resistance, treatment recommendations for N. gonorrhoeae should carefully balance prevention of infection and avoidance of resistance spread.
Antibiotic-resistant Neisseria gonorrhoeae can evolve and spread rapidly . Resistance is commonly observed against the antibiotic classes penicillin, tetracycline and fluoroquinolones [2–4]. Resistance also emerged against cefixime, an oral third generation cephalosporin, in recent years [2, 3]. Since 2010, cefixime is no longer recommended as first-line treatment  following guidelines from the World Health Organization (WHO) that an antibiotic should not be used when more than 5% of N. gonorrhoeae isolates are resistant . Injectable ceftriaxone, in combination with oral azithromycin, is now the last antibiotic remaining as recommended first-line treatment . Although other antibiotics are being tested for their safety and efficacy for N. gonorrhoeae treatment , no new classes of antibiotics are currently available  and management of antibiotics is urgently needed to preserve their efficacy. The current management strategy tries to reduce the overall burden of N. gonorrhoeae infection by expanded screening and treatment of hosts [9, 10], but the outcome of this strategy for resistance is uncertain. Understanding the drivers of resistance spread and anticipating future resistance trends will provide rationales for antibiotic management and help to improve antibiotic treatment strategies.
We fitted a logistic growth model to the proportion of antibiotic-resistant N. gonorrhoeae as observed in the two gonococcal surveillance programs (Fig 2). The proportion of cefixime-resistant N. gonorrhoeae in GRASP appears to increase for both HetM and MSM after 2006. Ciprofloxacin-resistant N. gonorrhoeae in HetM and MSM were spreading in all observed host populations after the year 2000. For a given antibiotic and surveillance program, the rates of resistance spread were consistently higher for MSM than for HetM (Table 4). The average rate of resistance spread was 0.53 y−1 for HetM and 1.46 y−1 for MSM, corresponding to doubling times of 1.3 y (HetM) and 0.5 y (MSM) during the initial exponential growth phase.
In this study, we quantified the rate at which antibiotic-resistant N. gonorrhoeae spread in heterosexual and MSM populations. We used data from two different surveillance programs and estimated that the proportion of ciprofloxacin- and cefixime-resistant N. gonorrhoeae doubles on average every 1.3 y in HetM and 0.5 y in MSM. The faster spread of antibiotic-resistant N. gonorrhoeae in MSM than in heterosexual hosts was corroborated using a dynamic transmission model, which was calibrated to observed prevalence and incidence rates. The model allowed us to identify the higher treatment rates in MSM, compared with heterosexual hosts, as the major driver for the faster spread of antibiotic-resistant N. gonorrhoeae.