After the widespread use of oral expanded-spectrum cephalosporins for the treatment of gonorrhea, initial reports of gonococci with reduced susceptibility and cases of treatment failure (TF) have been reported globally. A recent publication reported that the rate of clinical failures after treatment of Neisseria gonorrhoeae infections with cefixime was relatively high and was associated with elevated minimum inhibitory concentration (MIC).1 The rising cefixime MIC values have prompted treatment guideline changes in the United States, Canada, and Europe.2–4 Pharyngeal gonorrhea is symptomatic in fewer than 10% of infected individuals but can serve as an asymptomatic reservoir for the emergence of resistance through genetic exchange with other Neisseria spp. and facilitate ongoing transmission through high-risk groups such as men who have sex with men (MSM) and sex workers but also increasingly among heterosexual persons.5,6 After anecdotal reports of increasing TFs of pharyngeal gonorrhea in our region, we sought to review characteristics associated with TFs.
Individuals attending 2 Alberta sexually transmitted infection (STI) clinics from 2008 to 2011 were asked about their participation in receptive fellatio as part of the routine sexual history. Those reporting this behavior with a male partner had pharyngeal cultures for N. gonorrhoeae collected. Specimens were plated at the bedside on selective media (Thayer Martin) with daily transportation of specimens to the Provincial Laboratory for Public Health. Identification of N. gonorrhoeae was undertaken using the AccuProbe assay (Gen-Probe, San Diego, CA). The MIC for 6 antibiotics was performed by E-test (Biomerieux, France); MIC interpretation was based on Clinical and Laboratory Standards Institute guidelines.7 Molecular genotyping of the isolates was done using the N. gonorrhoeae multiantigen sequence typing.8 Identification of genetic polymorphisms associated with increased MICs to β-lactams and cephalosporins (penA, ponA, mtrCDE), insertions/deletions in mtr promoter, pilQ, and bla TEM-1, was carried out by polymerase chain reaction, Sanger sequencing, and sequence analysis.9
Provincial STI treatment guidelines at the time included cefixime 400 mg orally as a single dose (SD) or SD ceftriaxone 125 mg intramuscular (IM), with cotreatment of chlamydia, unless a negative result was available. All pharyngeal cases were informed of the need for a test of cure (TOC) 7 days after treatment. Treatment failures (TF) were defined as a positive follow-up culture, no sexual exposure since treatment, and identical sequence types (STs) before and after treatment. Patients reporting sexual exposure between treatment and TOC were considered a reexposure and not included in this analysis.
Comparisons of demographics and clinical findings between patients who had completed a TOC with and without TF were conducted using χ 2 or Fisher exact test for proportions (excluding missing data) and Mann-Whitney U test for continuous variables. Linear-by-linear association was used to assess trends over time. Data were analyzed using IBM SPSS Statistics Version 19.0 (IBM, Armonk, NY). Ethics approval was obtained from the University of Alberta’s Health Research Ethics Board.
Three hundred fifty cases of pharyngeal gonorrhea were identified, with 44.6% (n = 156) of cases being identified in the pharynx alone and only 10.9% (n = 38) reporting pharyngeal-related symptoms. Nearly one half (n = 160; 45.7%; 95% confidence interval [CI], 40.5%–51.0%) of patients underwent TOC (within 7–34 days after treatment), with a TF rate of 13.1% (n = 21; 95% CI, 7.8%–18.4%). There was no significant difference in sex, age, sexual partnering, or being symptomatic for those who did and did not return for a TOC. Men with pharyngeal infection alone (53.6%) were more likely to return for a TOC than men infected in multiple sites (34.2%, P = 0.005).
Among the 160 patients who returned for a TOC, there were no differences in sex, age, sexual partnering, or trends over time for those who failed treatment and those who did not (Table 1). Cefixime MIC values were available for 124 (77.5%) of the patients who underwent a TOC; MIC values ranged from 0.016 μg/mL or less to 0.25 μg/mL, with 6.4% (n = 8) of these isolates having a MIC value of at least 0.12 μg/mL. There was no significant difference in elevated MIC values (≥0.12 μg/mL) between MSM (7.7%; n = 6) and heterosexual patients (4.3%; n = 2, P = 0.71). The remaining 36 pharyngeal cases without an MIC value had an E-test performed on isolates collected from a different site on the same day. Only 1 (2.8%) of these isolates had a cefixime MIC value of 0.12 μg/mL, and none was in the TF group.
Men who were infected in the pharynx alone (25.0%) were more likely to have a TF than men infected in multiple sites (2.5%, P = 0.002), and a higher proportion of TFs were reported among patients who were asymptomatic (P = 0.02). Treatment failure rates for cases receiving cefixime 400 mg monotherapy was 27.7% compared with 3.0% for cefixime 400 mg and azithromycin 1 g. There was no association between MIC values and cefixime treatment regimes (Table 2).
All but 2 patients with TF returned for a TOC after additional treatment; all had negative results. Final treatment for most patients with TF (n = 19; 90.5%) included SD ceftriaxone IM, with doses ranging from 125 mg to 1 g. A patient in 2008 failed treatment with cefixime 400 mg and was successfully treated with SD oral ciprofloxacin 500 mg (ciprofloxacin MIC, 0.002 μg/mL). The remaining patient with TF was initially treated with SD oral azithromycin 2 g because of a penicillin allergy (azithromycin MIC, 0.012 μg/mL) but subsequently received SD oral cefixime 400 mg with no reaction.
Sequence types were heterogeneous with 12 unique ST identified; the most common STs were ST-3935 (n = 3), ST-225 (n = 2), ST-210 (n = 2), and ST-1407 (n = 2). Single-nucleotide polymorphisms (SNPs) in penA (312M, 316T, 545S) were associated with increased MICs (≥0.12 μg/mL) to cefixime (P = 0.005). All isolates with cefixime MICs of at least 0.12 μg/mL (n = 2) had penA SNPs 312M, 316T, and 545S and also had the ponA SNP 421P and an A-deletion at the mtr promoter. These isolates also had wild-type mtrCDE residues A39, G45, and A39/R44. All isolates with cefixime MICs less than 0.12 μg/mL (n = 19) had wild-type residues in penA at I312, V316, and G545. Half (52.6%; n = 10) of these isolates were wild-type L421, and 47.4% (n = 9) had a 421P SNP in ponA. Nearly three quarters of these isolates (73.7 %; n = 14) were wild-type A39, G45, and A39/R44, and the remaining 26.3% (n = 5) had SNPs 39T, 45D, and 39T/44H in mtrCDE. More than one half (57.95%; n = 11) of these isolates had an A-deletion, and 15.8% (n = 3) had a T insertion in the mtr promoter.
Our data show a 13.1% TF rate in those returning for TOC for pharyngeal gonorrhea, exceeding the 5% threshold for TF recommended by the World Health Organization10 and higher than the 9.0% rate of TF among MSM reported by Ota et al.11 Although the absolute number of pharyngeal TF increased from 4 per year between 2008 and 2010 to 9 cases in 2011, the proportion of pharyngeal TF remained stable over time (range, 10.8%–14.8%; P = 0.82), thus refuting the anecdotal reports of increasing pharyngeal TF in our region over time. We were not able to demonstrate that reduced susceptibility to cefixime was the explanation for the high TF rates in our region to date. Polymorphisms in penA in 2 isolates were associated with cefixime MICs of 0.12 μg/mL or greater; both were ST-1407, types previously linked to reduced susceptibility to expanded-spectrum cephalosporins.12
It has been recognized for some time that treatment of pharyngeal gonorrhea is associated with lower treatment success rates, especially with SD oral regimens.6 In clinical trials, the cefixime 400-mg dose cured 92.3% of pharyngeal gonococcal infections (95% CI, 74.9%–99.1%).13,14 However, in our study, SD oral cefixime 400 mg monotherapy resulted in a much higher (31.6%) TF rate. The lower TF rate (4.2%) when using cefixime in conjunction with azithromycin is supported by findings in both the United Kingdom and the Unites States.15,16 These TFs are probably related to reduced drug concentrations of oral cephalosporins in the pharynx compared with other sites.5,17
Recently, both the Centers for Disease Control and Prevention and the Public Health Agency of Canada issued revised treatment guidelines for pharyngeal infection with both agencies now recommending dual therapy with SD ceftriaxone 250 mg IM plus oral azithromycin 1 g.2,3 The Canadian guidelines also recommend SD oral cefixime 800 mg plus azithromycin 1 g as an alternate therapy. The higher dose of cefixime was based on pharmacokinetic modeling suggesting a modest benefit from this increased dose.17,18 Our treatment success rate of 97% with dual therapy using SD oral cefixime 400 mg plus azithromycin 1 g has been found by others to be as effective as ceftriaxone-based regimes, raising the intriguing possibility that this may be a viable alternate when ceftriaxone is not available or when oral therapies would be preferred such as for expedited partner therapy.16 It is unknown at this time if the higher dose of cefixime (800 mg) plus azithromycin 1 g SD will be more effective.
Our study is limited by the retrospective nature of our data, small numbers of TFs, and possible bias in the return of clients for TOC who were more likely to return if they were infected in the pharynx alone or because of other unknown characteristics. Our cases were screened using culture, which may underestimate the number of pharyngeal cases detected owing to its lower sensitivity than nucleic acid amplification tests; however, in Canada, there are no nucleic acid amplification tests licensed for use in extragenital sites.
In summary, our data confirm that cefixime monotherapy is inadequate for the treatment of pharyngeal gonorrhea but that dual therapy with oral cefixime and azithromycin may be an effective alternate therapy. These findings should ideally be confirmed by prospective clinical trials. In addition, continued surveillance of TFs for gonorrhea as well as research into the mechanisms of TF at different anatomical sites is essential.
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