Neisseria gonorrhoeae With High-Level Resistance to Azithromycin: Case Report of the First Isolate Identified in the United States

Katz, Alan R.; Komeya, Alan Y; Soge, Olusegun O.; Kiaha, Mandy; Lee, Maria Veneranda C.; Wasserman, Glenn M.; Maningas, Eloisa V.; Whelen, A. Christian; Kirkcaldy, Robert D.; Shapiro, Steven J.; Bolan, Gail; Holmes, King K.

doi:10.1093/cid/cir929

Cited by 92 publications

(53 citation statements)

References 16 publications

(19 reference statements)

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“…Sporadic infections with highly azithromycin-resistant N. gonorrhoeae isolates have been reported since 2001 in Argentina [7], in Scotland (2004) [8], in Wales (2007) [9], in Italy (2007) [10], in the United States (2011) [11] and in Sweden in 2013 [12]. Here we described the first isolate identified and presumably acquired in France.…”

Section: Discussionmentioning

confidence: 85%

“…Here we described the first isolate identified and presumably acquired in France. In previous publications [7,9,11,12], high-level azithromycin resistance was shown to result from the accumulation of mutations in the four rrl alleles at positions 2143 (G instead of A) or 2599 (T instead of C) in the domain V of the 23S rRNA involved in the binding site of azithromycin (NG numbering). In this report, our isolate harboured the C2599T mutation in the four rrl alleles.…”

Section: Discussionmentioning

confidence: 99%

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High-level azithromycin-resistant Neisseria gonorrhoeae clinical isolate in France, March 2014

et al. 2014

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We report the first case in France of a high-level azithromycin-resistant Neisseria gonorrhoeae (minimum inhibitory concentration (MIC) = 96 mg/L) assigned to MLST7363 (NG-MAST ST6360), also resistant to ciprofloxacin and tetracycline but susceptible to ceftriaxone. The patient was a 51 year-old heterosexual man who returned following 1g azithromycin monotherapy. Mechanisms of azithromycin resistance were a C2599T mutation in the four copies of the rrl gene and a novel mutation in the promoter of the mtrR gene.The surveillance of Neisseria gonorrhoeae (NG) susceptibility to antibiotics in France is based on a voluntary sentinel network of laboratories [1]. In March 2014, the first NG strain showing a high level of azithromycin resistance was isolated from the urine of a 51 year-old man living in the south of France. He had a history of a Chlamydia trachomatis infection 20 years ago. The patient was heterosexual and declared having sex with only two regular female partners (last sexual contact four and ten days before symptoms). Case descriptionAt the first visit, the patient presented with mild symptoms of urethritis. He was in good general state of health and his HIV test was negative. No microbiological analyses were performed and the patient was treated empirically with a single dose of azithromycin (1 g orally) for suspected C. trachomatis infection. The patient presented again with persisting symptoms 48 hours later. At that time, he was treated empirically with a single dose of spectinomycin (2 g intramuscularly) and bacteriological examination was performed with direct microscopic examination and culture. Culture results indicated the presence of an azithromycin-resistant NG isolate. The absence of C. trachomatis infection was determined retrospectively by negative nucleic acid amplification test. At a third visit, one week later the patient was successfully cured and free of clinical symptoms.In France, the first-line treatment of uncomplicated urogenital gonorrhoea is ceftriaxone (500 mg intramuscularly), whereas spectinomycin is used in cases of contraindication to beta-lactams. For our patient, the clinician chose spectinomycin because of his own prescribing practices. Infection with the azithromycinresistant-strain was presumably acquired in France since neither the patient nor his sexual contacts had travelled in the past six months or had other known sexual contacts. In addition, they had not received any antibiotic treatment in the preceding six months.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

High-level azithromycin-resistant Neisseria gonorrhoeae clinical isolate in France, March 2014

et al. 2014

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“…Investigation of factors contributing to the development and transmission of azithromycin resistance in N. gonorrhoeae is needed. Although multiple isolates with high-level azithromycin resistance have been detected in different countries (26,(30)(31)(32)(33)(34)(35), international susceptibility data do not clearly indicate emerging gonococcal azithromycin resistance. The pooled prevalence of reduced azithromycin susceptibility (defined as MICs of Ն2.0 g/ml) increased in Latin America from 0% in 1999 to 25.8% in 2008 and then fell to 1.0% by 2010 (36).…”

Section: Resultsmentioning

confidence: 99%

“…Isolates with high azithromycin MICs have been sporadically detected in the United States, and resistant strains have been detected following azithromycin monotherapy in the United States and elsewhere, suggesting the possibility of within-host selection for azithromycin resistance (15,23,24,33). Thus, gonorrhea treatment with azithromycin monotherapy is discouraged.…”

Section: Gonococcal Azithromycin Mics Changed Little In the Unitedmentioning

confidence: 99%

Analysis of Neisseria gonorrhoeae Azithromycin Susceptibility in the United States by the Gonococcal Isolate Surveillance Project, 2005 to 2013

Kirkcaldy

Soge

Papp

et al. 2015

Antimicrob Agents Chemother

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e Azithromycin, administered with ceftriaxone, is recommended by the CDC for the treatment of gonorrhea. Many experts have expressed concern about the ease with which Neisseria gonorrhoeae can acquire macrolide resistance. We sought to describe gonococcal azithromycin susceptibility in the United States and to determine whether azithromycin susceptibility has changed over time. We analyzed data from 2005 to 2013 from the Gonococcal Isolate Surveillance Project, a CDC-supported sentinel surveillance network that monitors gonococcal antimicrobial susceptibility. A total of 44,144 N. gonorrhoeae isolates were tested for azithromycin susceptibility by agar dilution methods. The overall azithromycin MIC 50 was 0.25 g/ml, and the MIC 90 was 0.5 g/ml. There were no overall temporal trends in geometric means. Isolates from men who had sex with men had significantly higher geometric mean MICs than isolates from men who had sex exclusively with women. The overall prevalence of reduced azithromycin susceptibility (MIC, >2 g/ml) was 0.4% and varied by year from 0.3% (2006 and 2009) to 0.6% (2013). We did not find a clear temporal trend in gonococcal azithromycin MICs in the United States, and the prevalence of reduced azithromycin susceptibility remains low. These findings support the continued use of azithromycin in a combination therapy regimen for gonorrhea.

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“…Case reports of AZM-resistant N. gonorrhoeae have been described in many countries, including Canada and the United States (10)(11)(12)(13)(14)(15)(16)(17)(18), but only rarely has AZM-resistant N. gonorrhoeae been reported to be associated with concurrent reduced susceptibility to 3GC (16,17). In Canada, AZM-resistant N. gonorrhoeae was first identified in 1997, and the first AZM-resistant isolates were identified in Ontario in 1998 (10).…”

mentioning

confidence: 99%

Azithromycin Resistance Is Coevolving with Reduced Susceptibility to Cephalosporins in Neisseria gonorrhoeae in Ontario, Canada

Allen

Seah

Martín

et al. 2014

Antimicrob Agents Chemother

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d Azithromycin (AZM) is routinely recommended as a component of dual therapy for gonorrhea in combination with third-generation cephalosporins (3GC). In this study, we examined the prevalence of AZM-resistant (AZM r ) Neisseria gonorrhoeae from July 2010 to February 2013, assessed the rate of concurrent cephalosporin resistance under the current treatment recommendations, and analyzed the clonal distribution of AZM r isolates in Ontario, Canada. Nineteen AZM r clinical isolates (one per patient; MIC, >2 g/ml) were included in the study. Susceptibility profiles of these isolates to 11 antibiotics, molecular typing, characterization of macrolide resistance mechanisms, and penicillin-binding protein 2 (PBP2) patterns were determined for all the isolates. Two groups were defined based on AZM r level; group A isolates displayed high-level resistance (MIC, >2,048 g/ml) due to mutations (A2143G) in the four copies of the 23S rRNA rrl gene, and group B isolates had moderate resistance to AZM (MICs, 2 to 8 g/ml, C2599T mutation in the rrl gene), with a subgroup belonging to sequence type 3158 (ST3158) (n ‫؍‬ 8), which also showed reduced susceptibility to 3GC (MICs, 0.12 to 0.25 g/ml, PBP2 pattern XXXIV). This AZM r phenotype was not observed in previous provincial surveillance in 2008 (the ST3158 clone was found, with AZM MICs of 0.25 to 0.5 g/ml associated with mtrR mutations). We hypothesized that the AZM mutant prevention concentration (MPC) in the ST3158 subpopulation we found in 2008 was higher than the MPC in wild-type isolates (AZM MIC, <0.031 g/ml), increasing the chances of additional selection of AZM r mutations. Full AZM resistance is now emerging in this clone together with reduced susceptibility to 3GC, threatening the future efficacy of these antibiotics as therapeutic options for treatment of gonorrhea.

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Neisseria gonorrhoeae With High-Level Resistance to Azithromycin: Case Report of the First Isolate Identified in the United States

Cited by 92 publications

References 16 publications

High-level azithromycin-resistant Neisseria gonorrhoeae clinical isolate in France, March 2014

High-level azithromycin-resistant Neisseria gonorrhoeae clinical isolate in France, March 2014

Analysis of Neisseria gonorrhoeae Azithromycin Susceptibility in the United States by the Gonococcal Isolate Surveillance Project, 2005 to 2013

Azithromycin Resistance Is Coevolving with Reduced Susceptibility to Cephalosporins in Neisseria gonorrhoeae in Ontario, Canada

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