Doxycycline post exposure prophylaxis could select for cross-resistance to other antimicrobials in various pathogens: An in silico analysis

Abstract

Background A number of randomized controlled trials have found that doxycycline post exposure prophylaxis (PEP) can reduce the incidence of gonorrhoea, chlamydia and syphilis in men who have sex with men (MSM). If tetracycline resistance is associated with resistance to other antimicrobials in a range of bacterial species, then doxycycline PEP could have the unintended effect of selecting for resistance to other antimicrobials in these bacterial species. Methods Antimicrobial susceptibility data were retrieved from two sources: pubMLST ( https://pubmlst.org/ ) and Pathogenwatch ( https://pathogen.watch/ ) for the following bacterial pathogens: Klebsiella pneumoniae, Salmonella enterica subsp. Enterica serovar Typhi , Campylobacter jejuni, Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes. We assessed if tetracycline resistance was associated with resistance to six relevant antimicrobials. Results We found evidence of cross resistance to various antimicrobials in all six bacterial species assessed. Cross resistance was found in 4 of 5 antimicrobials for K. pneumoniae, 1 of 2 for C. jejuni, 3 of 5 for S. enterica subsp. Enterica serovar Typhi, 5 of 5 for S. aureus, 5 of 6 for S. pneumoniae and 2 of 3 for S. pyogenes. These associations include a higher prevalence of methicillin resistance in tetracycline resistant S. aureus, penicillin resistance in S. pneumoniae, macrolide and clindamycin resistance in S. pyogenes, fluoroquinolone resistance in S. enterica subsp. Enterica serovar Typhi and third-generation cephalosporin resistance in K. pneumoniae. Conclusion These results suggest that studies evaluating the effects of doxycycline PEP should include the effects of doxycycline on resistance not only to doxycycline but also to other antimicrobials and in a broader array of bacterial species than has been included in doxycycline PEP studies thus far.

Sexual behaviour and incidence of sexually transmitted infections among men who have sex with men (MSM) using daily and event-driven pre-exposure prophylaxis (PrEP): Four-year follow-up of the Amsterdam PrEP (AMPrEP) demonstration project cohort

“…Post-exposure prophylaxis using doxycycline can effectively prevent bacterial STIs [ 40 ], and could, in the future, be considered for specific PrEP users. This is currently being adopted in some countries (e.g., the United States [ 41 ]), but not in the Netherlands, and long-term effects on antimicrobial resistance remain unknown [ 42 , 43 ].…”

Modelling of doxycycline-based prevention of bacterial sexually transmitted infections in comparison to condom-based and test-based prevention

“…However, the remaining uncertainties regarding the quantitative dimension of doxycycline prevention-associated resistance selection may leave a feeling of uneasiness when filling-in the prescription in spite of the above-mentioned EACS recommendation. Evidence of doxycycline prevention-induced resistance selection has been shown in laboratory experiments [ 36 ], even selection-based cross-resistance spread was confirmed [ 37 ] and the loss of doxycycline as an option for the therapy of difficult-to-cure diseases like pelvic inflammatory disease would be challenging to compensate. Antibiotic therapy of traveler's diarrhea with partly doxycycline-containing schemes has been associated with increased selection of ESBL- (extended spectrum beta-lactamase-) expressing Enterobacterales in the travelers' gut [ 38 ].…”

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

“…Recent studies have provided evidence of this association between tetracyclines and antimicrobials such as cephalosporins, macrolides, fluoroquinolones, aminoglycosides and lincomycins for a range of pathogens, including N. gonorrhoeae, S. aureus, S. pneumoniae, Shigella spp., Salmonella spp. and Klebsiella pneumoniae ( Gestels et al, 2023 ; Mortimer et al, 2023 ; Whiley et al, 2023 ). Considering that doxycycline PEP would result in a 26–90-fold increase in doxycycline consumption in a typical PrEP cohort, it is possible that this could select for resistance to tetracyclines and other antimicrobials in this list of priority pathogens ( Gestels et al, 2023 ; Whiley et al, 2023 ; Vanbaelen et al, 2023e ).…”

“…and Klebsiella pneumoniae ( Gestels et al, 2023 ; Mortimer et al, 2023 ; Whiley et al, 2023 ). Considering that doxycycline PEP would result in a 26–90-fold increase in doxycycline consumption in a typical PrEP cohort, it is possible that this could select for resistance to tetracyclines and other antimicrobials in this list of priority pathogens ( Gestels et al, 2023 ; Whiley et al, 2023 ; Vanbaelen et al, 2023e ). These considerations imply that studies need to include assessing the effect of doxycycline PEP on a broader range of bacteria-antimicrobial combinations before concluding that it is safe.…”