Doxycycline Post-exposure Prophylaxis and Sexually Transmitted Infections in Italy, 2023

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To the Editor—We read with great interest the review by Hazra et al [1] on doxycycline post-exposure prophylaxis (doxyPEP). We would like to contribute to the ongoing discussion on this topic. First, tetracycline resistance can be even higher than what has been previously reported; most of the diagnoses of gonorrhea have been made by molecular detection and therefore resistance was assessed in a minority of samples. Here we report the minimum inhibitory concentrations (MICs) of Neisseria gonorrhoeae–positive cultures isolated from our sexually transmitted infection (STI) clinic. All consecutive samples were sent for culture, analyzed using the E-test method, and evaluated using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (considering tetracycline resistance if MIC >0.5 mg/L) or the epidemiological cutoff for azithromycin (MIC >1 mg/L). Aggregated data are presented on 154 positive samples, and MIC distributions for ceftriaxone, cefixime, benzylpenicillin, tetracycline, ciprofloxacin, and azithromycin are shown in Figure 1. No resistant strain was observed for ceftriaxone or cefixime, and 3.25% resistance was found for azithromycin, 21.43% for benzylpenicillin, 81.82% for ciprofloxacin, and 97.40% for tetracycline (12.34% high-level resistance with MICs >8 mg/L). This may be relevant since recent reports have shown N. gonorrhoeae strains with decreased susceptibility or resistance to ceftriaxone exhibiting dual resistance to tetracyclines [3]. Genotypic resistance data confirmed such concerns and suggested that there may be a risk that increased use of doxyPEP will select for dual-resistant strains and increased ceftriaxone resistance [4, 5]. Minimal inhibitory concentration (MIC) distribution in isolates of Neisseria gonorrhoeae collected in Turin, Italy, in 2023. Vertical dotted lines represent EUCAST or ECOFF (for azithromycin) thresholds for resistance interpretation: breakpoints for resistance (those with the > symbol) and for susceptibility (those with the < symbol, when available) are shown in each figure [2]. Abbreviations: ECOFF, epidemiological cut-off value; EUCAST, European Committee on Antimicrobial Susceptibility Testing. The second point we would like to emphasize is the paucity of alternative treatments for other STIs. While tetracycline resistance has been rarely reported in Chlamydia trachomatis strains in vivo, it has been shown in animals and in in vitro experiments [6]. Additionally, clinical failures with probable resistance to tetracycline have been reported [7]. Available treatments for Treponema pallidum infections are also limited and highly needed novel options were recently reviewed [8]. Doxycycline is the only oral agent recommended for the treatment of syphilis, but it cannot be used in pregnant women; additionally, both neonatal syphilis and neuro-syphilis require the intravenous administration of penicillin. It should also be emphasized that antimicrobial susceptibility is not routinely studied in chlamydia and syphilis infections due to technical challenges. Despite the significant microbiological differences, the example of Mycoplasma genitalium may be relevant. Resistance-guided treatment is now recommended due to the increased ceftriaxone resistance to macrolides and fluoroquinolones; yet, doxycycline has a lower efficacy and tetracycline-resistant strains have been recently described [9]. We would like to raise a final concern. While doxyPEP is reasonable if the aim is to prevent potential life-threatening or debilitating infections (such as malaria or Lyme disease), the use of this strategy to prevent bacterial STIs, which are easily treated and mostly benign, is probably not fully justified. Despite being controversial in the case of asymptomatic infections, regular screening and prompt treatment might be equally effective, with a potentially lower impact on bacterial resistance [10, 11]. In conclusion, we believe that the use of doxyPEP should be weighed against its potential drawbacks and should probably be considered poorly effective in preventing gonorrhea in Italy. Acknowledgments. The authors thank nurses and health assistants working at the Multidisciplinary Center for Sexual Health (Ce.Mu.S.S.). Author Contributions. A. L.: study concept; A. C. wrote the first draft of the manuscript. S. D. R. and V. G. performed the microbiological analysis. M. T., S. D., D. A., and A. L. collected the samples. All authors read and approved the final version of the manuscript. Data availability. Data are available upon request to the corresponding author. Ethical statement. Ethical approval was not obtained for the study since data are collected as routine surveillance and data are presented as aggregated.

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