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A Case of Persistent and Possibly Treatment Resistant Pharyngeal Gonorrhea

Levy, Vivian MD; Pandori, Mark PhD; Berrada, Zenda L. PhD; Relucio, Karen I. MD; Lopez, Teresa P. BA; Samuel, Michael C. DrPH; Park, Ina U. MD, MS

Sexually Transmitted Diseases: April 2016 - Volume 43 - Issue 4 - p 258–259
doi: 10.1097/OLQ.0000000000000430
Case Report

An HIV-negative man with pharyngeal gonorrhea had a positive test-of-cure (nucleic acid amplification test) result 7 days after treatment with ceftriaxone/azithromycin. Neisseria gonorrhoeae Multi-Antigen Sequencing Type 1407 and mosaic pen A (XXXIV) gene were identified in the test-of-cure specimen, and culture was negative. Retreatment with ceftriaxone 500 mg intramuscularly plus azithromycin 2 g orally yielded a negative test-of-cure result.

An HIV-negative man with pharyngeal gonorrhea had a positive nucleic acid amplification test result 7 days after treatment with an isolate possessing Neisseria gonorrhoeae Multi-Antigen Sequencing Type 1407 and mosaic pen A (XXXIV) gene.

From the *San Mateo County Health System, San Mateo, CA; †Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA; ‡San Francisco Department of Public Health, San Francisco, CA; and Departments of §Obstetrics, Gynecology and Reproductive Sciences and ¶Family and Community Medicine, University of California, San Francisco, San Francisco, CA

The authors thank the Edison Clinic nursing staff Lowell Hylden, RN; Girley Macaraeg, RN; Mariejane Madayag-Santos, RN; and Maritza Sandoval, MA, of the San Mateo County Health System for assistance implementing the test-of-cure study that gave rise to this case. They alsothank Dr David Hess from Santa Clara University Biotechnology Laboratory for assistance with resistance assays and Jennifer Monroe Zakaras, MPH, for assistance in manuscript preparation.

Conflict of interest: The authors declare that there are no conflicts of interest.

Financial support: None.

Correspondence: Vivian Levy, MD, San Mateo County Health System, Edison Clinic, 222 West 39th Avenue, San Mateo, CA 94403. E-mail:

Received for publication October 20, 2015, and accepted December 20, 2015.

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A 23-year-old asymptomatic, HIV-negative man who had sex with men (MSM) and women presented with an asymptomatic pharyngeal Neisseria gonorrhoeae (NG) infection identified by nucleic acid amplification test (NAAT; Aptima Combo 2; Hologic, Bedford, MA) and a urethral Chlamydia trachomatis infection. The patient reported 1 female sexual partner and 3 male partners in the 2 months before presentation. The female partner and 2 of the male partners were from northern California, and the third male partner was a European male tourist who was the patient's last sexual partner before the initial sexually transmitted disease screening. The patient reported unprotected vaginal and oral sex with the female partner and oral sex with all 3 male partners. After his positive screening results, the patient was recalled and was treated 1 week after the initial positive screening NAAT result with ceftriaxone 250 mg intramuscularly and azithromycin 1 g orally by directly observed therapy. As part of standard clinical care, screening was performed with NAAT alone, and neither NAAT nor culture was performed on the day of treatment. As part of a pilot to conduct test-of-cure (TOC) for NG infections which was ongoing at the time, the patient was recalled for a pharyngeal TOC 7 days later, which was performed with culture and NAAT. Cultures were obtained bedside using Jembec-style Modified Thayer Martin media, which was immediately placed in a zippered plastic bag with a CO2 tablet (Hardy Diagnostics, Santa Maria, CA) following the manufacturer's instructions to maintain appropriate CO2 levels before submission to the laboratory.

At 7 days after treatment, the participant had a persistently positive pharyngeal NG NAAT and a negative NG culture. The patient denied any interim sexual activity.

Laboratory analyses of the initial screening pharyngeal NAAT specimen yielded NG Multi-Antigen Sequencing Type (MAST) 1407 and presence of mosaic penA (XXXIV) gene, which was independently verified by both the San Francisco Department of Public Health Laboratory and the Santa Clara University Biotechnology Laboratory. Analysis of the TOC NAAT specimen also identified NG MAST type 1407.

The patient returned for repeat treatment 6 days after the TOC (postdiagnosis day 20) when he was retreated with ceftriaxone 500 mg intramuscularly and azithromycin 2 g orally by directly observed therapy, which was consistent with local guidelines for suspected treatment failure at the time. The patient was briefly lost to follow-up, and a second TOC was not performed until 14 days after retreatment (postdiagnosis day 34), which was NAAT negative; culture was not repeated.

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The pharynx is an important reservoir for NG infection and transmission among MSM, and screening of extragenital sites including the pharynx and rectum is routinely recommended in MSM.1 Screening is crucial to the identification of pharyngeal NG infections because these infections are common among MSM and the majority are asymptomatic.2 We report a case with a persistently positive pharyngeal NG NAAT 7 days after recommended dual therapy, identified as NG MAST 1407 and possessing the mosaic penA (XXXIV) gene. NG MAST type 1407 strains often possess higher minimum inhibitory concentrations (MICs) to third-generation cephalosporins and have been associated with treatment failures globally.3 Isolates with the mosaic penA (XXXIV) gene, a mutation that modifies the affinity of penicillin-binding proteins to β-lactam antibiotics, have been shown to possess a reduced susceptibility to oral extended spectrum cephalosporins.4 These are well-identified mechanisms of chromosomally mediated cephalosporin resistance for NG.

Pharyngeal NG infection may be relevant to NG resistance due to the asymptomatic nature of pharyngeal infection, poorer antibiotic penetration into pharyngeal tissue, and potential genetic reassortment between NG and commensal Neisseria species allowing transfer of antibiotic resistance.5 Centers for Disease Control and Prevention guidelines at the time of our case identification recommended a TOC interval of 7 days after treatment, which was recently extended for pharyngeal NG up to 14 days due to the possible persistence of NG DNA/RNA posttreatment at the pharynx.1,2 We found that performance of a TOC 7 days after treatment yielded a residual positive result, and it is unclear whether this result was truly representative of a treatment failure versus a delayed clearance of nonviable NG. In a prior study including 100 patients with pharyngeal gonorrhea, positivity of NG DNA using real-time polymerase chain reaction assays targeting the opa gene and porA pseudogene occurred in 13% at a 7-day TOC and 8% at a 14-day TOC. NG persistence on TOCs in this study was associated with elevated MICs to ceftriaxone and azithromycin.6 The persistence of DNA seen at TOCs could reflect a slower kill rate of NG or reinfection. Although culture was negative in the case of our patient, prior studies of pharyngeal NG culture have demonstrated poor sensitivity (50%) compared with NAAT, and thus, a negative culture should not exclude treatment failure.6 More recent studies estimate the sensitivity of NG culture at 86.2%, although only 2 (0.3%) of 768 specimens in this study were pharyngeal samples; thus, generalizability to our study is limited.7

Molecular testing in this case revealed characteristics of the NG strain (NG MAST 1407 and mosaic penA gene) that would be concerning for treatment failure, and this case raises issues regarding the use of NAAT and molecular methods such as NG MAST to identify treatment failures, especially at extragenital sites where culture demonstrates lower sensitivity than at the urethral site. Although pretreatment and posttreatment cultures would be the gold standard in verifying treatment failure, most clinicians only have ready access to NAAT, particularly for the initial screening specimen. Even in the circumstances where culture can be obtained on the follow-up specimen, the challenge for specimens with NAAT-positive/culture-negative results lies in determining whether the NAAT is falsely positive or the culture is falsely negative. Better data on the time to clearance of GC nucleic acid from pharyngeal sites with commercially available NAATs would facilitate this determination. In addition, culture-independent molecular markers of antibiotic resistance are also needed; these could be reported to clinicians to provide information on genotypic markers of resistance rather than relying on the antibiotic susceptibility testing of live isolates.

This case highlights the challenges of determining NG treatment failure in an asymptomatic patient in the era of NAAT diagnostics. Pretreatment and posttreatment culture isolates were not available for our case patient to allow the determination of phenotypic resistance, but both the pretreatment and posttreatment specimens were NG MAST type 1407 with the absence of sexual exposure between the first treatment date and the 7-day TOC. It is unclear whether the positive day 7 NAAT posttreatment with a negative culture was due to residual NG nucleic acid or a true treatment failure with poor pharyngeal culture sensitivity. In addition, the patient's eventual conversion to a negative NAAT result after retreatment has reflected the natural course of pharyngeal NG clearance. In one small series of 17 patients with pharyngeal gonorrhea, 80% had negative pharyngeal cultures at 4 weeks with no treatment and all had negative cultures by 12 weeks with no treatment.2 In the United States, cephalosporin-resistant NG poses a significant threat in the western US and among MSM,8 a pattern that mirrors previous quinolone resistance that first occurred throughout Asia and then in the United States.9 Although cephalosporin treatment failures have not been documented yet in the United States, treatment failures have been documented in Japan, Europe, and Canada.10,11 Given the potentially significant role played by pharyngeal NG infection in cephalosporin-resistant NG, augmenting US surveillance systems to include pharyngeal isolates should be considered, as surveillance of urethral NG alone may underestimate the prevalence of NG antibiotic resistance.12 Although one recent study at 5 sentinel US sites found no difference in the proportion of NG isolates with elevated ceftriaxone, cefixime, or azithromycin MICs by anatomic site,13 all verified NG treatment failures to date after ceftriaxone treatment have been pharyngeal infections.6 Further investigations into culture-independent molecular methods for determining antibiotic resistance and treatment failure are also greatly needed.

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