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Research Letter

We need to consider collateral damage to resistomes when we decide how frequently to screen for chlamydia/gonorrhoea in preexposure prophylaxis cohorts

Kenyon, Chris

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doi: 10.1097/QAD.0000000000002020
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Abstract

A number of HIV preexposure prophylaxis (PrEP) guidelines now recommend STI screening 3 monthly in MSM [1–3]. The Belgian national guidelines are one of a number that explicitly advocate 3-monthly, 3-site (pharynx, urethra and rectum) Neisseria gonorrhoeae/Chlamydia trachomatis testing – henceforth termed 3 × 3 testing [4]. An under examined impact of this strategy is the adverse effect on the microbiome and resistomes of PrEP recipients. A range of studies have established that antimicrobial consumption rates are the major determinants of antimicrobial resistance (AMR) [5–7].

High rates of antimicrobial consumption is, thus, one mechanism to explain the repeated emergence of AMR to a range of antimicrobials in range of bacterial species (N. gonorrhoeae, Treponema pallidum, Mycoplasma genitalium, Shigella soneii, Staphylococcus aureus) in MSM [8]. As the combined prevalence of C. trachomatis/N. gonorrhoeae is around 15–20% in PrEP cohorts [2], 3 × 3 screening could lead to high antimicrobial exposure. We, therefore conducted a review of cumulative N. gonorrhoeae/C. trachomatis incidence in PrEP studies that performed 3 × 3 screening and estimated antimicrobial consumption in these studies. We then compared these estimated antimicrobial consumption rates with rates from two studies where an association was found between antimicrobial consumption and resistance to evaluate if 3 × 3 screening may be inducing AMR. The two studies selected were one international and one intranational comparative study. The international study compared antimicrobial consumption in all 26 European countries with available data and correlated this with AMR prevalence estimates from various sources [7]. The other study was a nationwide surveillance study of antimicrobial consumption and resistance in Streptococcus pneumoniae in 13 Spanish provinces [9].

In June 2018, we conducted a literature review with the MeSH terms ‘PREP’ OR ‘PREEXPOSURE PROPHYLAXIS’ OR ‘PRE EXPOSURE PROPHYLAXIS’ AND ‘CHLAMYDIA’ OR ‘GONORRHOEA’ OR ‘SYPHILIS’ using PubMed as a search platform. Eighty-one studies were identified. We restricted studies to only those that conducted 3 × 3 testing using nucleic acid amplification testing for N. gonorrhoeae/C. trachomatis and reported N. gonorrhoeae /C. trachomatis incidence rates.

We then calculated the rate of antimicrobial consumption for these studies based on the assumption that all detected STIs (N. gonorrhoeae, C. trachomatis and syphilis) were treated. Consumption estimates were calculated separately according to European IUSTI (International Union Against STIs) [10,11] or United States (USA) Centers for Disease Control and Prevention (CDC) treatment guidelines [12]. In the case of C. trachomatis, we assumed all cases were treated with azithromycin and as far as syphilis was concerned, we made the simplifying assumption that all cases were treated with 2.4 mU benzathine penicillin G intramuscular injection (IMI). Consumption is reported in defined daily dosing per 1000 persons daily (DID) following standard WHO methodology [13].

Three studies met our entry criteria (Table 1). The combined incidence of the three STIs varied between 83.5 and 107.7/100 person-years between the studies. This translated into medium-to-high consumption rates for benzathine penicillin G (0.2–0.3 DID), azithromycin (USA guidelines: 6.3–8.3 DID, Europe guidelines: 8.9–12.2 DID) and ceftriaxone (USA: 0.2–0.3 DID, Europe: 0.6–0.7 DID).

Table 1
Table 1:
Preexposure prophylaxis study characteristics, incidence of chlamydia and gonorrhoea and calculated antimicrobial consumption based on these incidence rates.

In comparison, total outpatient antimicrobial consumption in 26 European countries in 2002 varied between 10 and 32 DID [7]. The consumption of penicillin, macrolides and cephalosporins varied between 3.9 and 6.3 DID, 0.3 and 7.8 and 0.03 and 6.7, respectively, between these countries (Table 2) [7]. The results from the Spanish regional study in 1999 were similar (Table 2) [9]. Strong correlations were found between antimicrobial consumption and resistance in various bug–drug combinations in both the 26-country and Spanish studies (Table 2).

Table 2
Table 2:
Range of antimicrobial consumption rates and correlations between antimicrobial consumption and resistance between 26 European countries and 13 Spanish provinces.

Consumption of macrolides in the Liu PrEP study was 28-fold (USA guidelines) to 41-fold (European guidelines) higher than the country with the lowest macrolide consumption (Latvia). In fact, this estimated macrolide consumption was higher than the country/province in the European/Spanish studies with the highest consumption (Tables 1 and 2). This was true regardless of whether CDC or European guidelines were followed. Ceftriaxone consumption in the Liu study was 10-times (USA guidelines) to 20-times (European guidelines) higher than the country with the lowest consumption (Denmark). The estimated consumption of penicillin in the Liu study was, however, five-fold lower than that in the country with the lowest penicillin consumption.

Our analysis is limited by a number of simplifying assumptions including the fact that approximately 20% of N. gonorrhoeae and C. trachomatis infections overlap which, because of overlapping treatment efficacy, means that only treatment of N. gonorrhoeae would be required. In addition, we have not considered the use of alternative treatments of C. trachomatis such as doxycycline [12]. These considerations would lower the antimicrobial consumption estimates. On the other hand, we have not considered the antimicrobial exposures related to screening for other STIs such as M. genitalium that is included in certain PrEP protocols [4]. The analysis is based on extrapolating the effects of antimicrobial consumption intensity on resistance in other studies. No randomized controlled trials (RCTs) have directly assessed the effect of N. gonorrhoeae/C. trachomatis screening on the resistome/microbiome and the risk of AMR. In the absence of these RCTs, this study has provided estimates of macrolide consumption under 3 × 3 screening that are greater than those that have been shown to be strongly associated with AMR for a range of bacterial species [7,14]. Whilst our evidence is indirect, individual-level studies have clearly established the predictable adverse effects of antimicrobials on the resistome/microbiome. A single dose of azithromycin, for example, has been shown to increase the proportion of individuals with macrolide-resistant oral streptococci by 60.4% (compared with placebo) [15]. This adverse effect on the resistome persists for 6/48 months in the oral/colonic microbiomes [15,16]. This combined with the extensive evidence from population-level studies that antimicrobial consumption is the predominant driver of resistance [5–7] suggests that the levels of antimicrobial consumption associated with 3 × 3 screening are likely promoting AMR in MSM [17].

These findings should be considered against a backdrop of recent reports of high-level combined resistance to azithromycin and ceftriaxone in N. gonorrhoeae[18] as well as global estimates of resistant infections resulting in up to 300 million excess deaths by 2050 [19]. One of the key strategies in tackling this AMR-threat is antimicrobial stewardship, which requires limiting antimicrobial usage to situations where benefits clearly outweigh risks [19]. Whilst the rationale for syphilis screening in MSM is strong, the same is not true for N. gonorrhoeae/C. trachomatis screening. No randomized controlled trials have been conducted to assess its efficacy and a systematic review of observational studies found no evidence of a decline in prevalence of N. gonorrhoeae or C. trachomatis with 3 × 3 screening [2]. Until such trials have been conducted, decisions as to how intensively to screen for N. gonorrhoeae/C. trachomatis in PrEP programs should include considerations as to collateral damage to the microbiome and resistome of participants.

Acknowledgements

Author contributions: C.K. conceptualized the study, conducted the literature review and was responsible for the data analysis and writing of the article

Conflicts of interest

There are no conflicts of interest.

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