Four recent insights suggest the need for more refined methods to assess the resistogenicity of doxycycline post exposure prophylaxis

Abstract

Two recently published randomized trials of doxycycline post exposure prophylaxis (PEP) have concluded that this intervention is highly effective at reducing the incidence of bacterial sexually transmitted infections (STIs) and has little or no risk of promoting the spread of antimicrobial resistance (AMR). In this perspective piece, we review four types of evidence that suggest that the risk of promoting AMR has been inadequately assessed in these studies. 1) The studies have all used proportion resistant as the outcome measure. This is a less sensitive measure of resistogenicity than MIC distribution. 2) These RCTs have not considered population-level pathways of AMR selection. 3) In populations with very high antimicrobial consumption such as PrEP cohorts, the relationship between antimicrobial consumption and resistance may be saturated. 4) Genetic linkage of AMR means that increased tetracycline use may select for AMR to not only tetracyclines but also other antimicrobials in STIs and other bacterial species. We recommend novel study designs to more adequately assess the AMR-inducing risk of doxycycline PEP.

Keywords: AMR; Doxycycline PEP; Gonorrhoea; MIC; PrEP; Proportion resistant; Tetracycline.

Graphical abstract

Fig. 1

Tetracycline MICs of Neisseria gonorrhoeae isolates from the placebo and minocycline PEP arms of the Harrison et al. randomized controlled trial of minocycline PEP conducted in 1979. The MIC distribution curves reveal that the effectiveness of minocycline at preventing infection varied between 0 % and 100 % for high and low tetracycline MIC infections, respectively (P = 0.002; Mann–Whitney test). When this data is transformed into proportion resistant to tetracycline (≥2 mg/L; red shaded area) then 43 % and 66 % are classified as resistant in the placebo and minocycline arms, respectively – a nonsignificant difference, P = 0.168; Chi-square test).

Fig. 2

A schematic illustration of two population-level pathways through which antimicrobial consumption can facilitate the spread of antimicrobial resistance in oral streptococci. 1) Doxycycline reduces the abundance of doxycycline susceptible streptococci in Bill and Rick. This means they are less likely to transmit susceptible streptococci to others, creating a vacant niche that can be colonized by streptococci from contacts at time point two. 2) The use of doxycycline by Ron increases the abundance of doxycycline resistant streptococci at time point two. Ron's resistant streptococci can then colonize the vacant niches of Bill and Rick. By timepoint four, the predominance of doxycycline resistance will reduce the probability that a study will find a positive association between doxycycline use and resistance).