Doxycycline Post-Exposure Prophylaxis Could Induce Cross-Resistance to Other Classes of Antimicrobials in Commensal Neisseria Species: An Analysis of Commensal Neisseria spp. in Japan

Objectives: We aimed to, for the first time, characterize the antimicrobial susceptibilities of commensal Neisseria species in the general population in Japan. We assessed if the tetracycline MICs of these isolates where changing over time and given the recent interest in doxycycline post exposure prophylaxis if the tetracycline MICs were associated with those of the other antimicrobials. Methods: Neisseria spp. were isolated from 1,679 patients visiting dental clinics in Japan, between 2018-2023. The MICs of tetracycline, ceftriaxone, cefixime, penicillin, azithromycin and ciprofloxacin against Neisseria spp. were determined using agar dilution. Linear regression was used to assess if there was an association between MIC and the year the isolate was obtained from, controlling for species identity. Results: Neisseria spp. were detected in 424 of 1,679 individuals sampled. Of these, 417 (98.3%) were identified as Neisseria subflava, and the remaining 7 (1.7%) as Neisseria mucosa. The median tetracycline MIC was 0.5 mg/L (IQR 0.5-1 mg/L). The MICs of penicillin, cefixime, ceftriaxone and ciprofloxacin were lower in N. mucosa than N. subflava. The tetracycline MICs of Neisseria spp. were positively correlated with penicillin, azithromycin and ciprofloxacin. No significant correlations were found with cefixime or ceftriaxone. Conclusions: Our results suggest that the intensive use of doxycycline in populations could select for Neisseria spp. with higher tetracycline MICs and in so doing select for higher penicillin, azithromycin and ciprofloxacin MICs. This could in turn increase the probability of resistance associated mutations being passed on to the pathogenic Neisseria spp.