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Neisseria gonorrhoeae with Reduced Susceptibility to Azithromycin --- San Diego County, California, 2009

A single 2 g dose of azithromycin effectively treats genitourinary infections caused by susceptible Neisseria gonorrhoeae and has been used to treat uncomplicated gonorrhea in persons with cephalosporin allergy. However, azithromycin is not recommended as monotherapy because of concern over the emergence of resistance. Instead, a 1 g dose of azithromycin is recommended as a component of dual therapy for gonorrhea, in conjunction with a cephalosporin (i.e., 250 mg of ceftriaxone or 400 mg of cefixime, if ceftriaxone is not an option). During January 1992--July 2009, of 87,566 N. gonorrhoeae isolates tested for azithromycin susceptibility by CDC's national Gonoccoccal Isolate Surveillance Project (GISP), only 39 (0.04%) had minimum inhibitory concentrations (MICs) ≥8 µg/mL (including 25 with 8 µg/mL and 14 with 16 µg/mL), indicating reduced susceptibility; none of the isolates were collected in San Diego County, California (CDC, unpublished data, 2011). During August--October 2009, five of 55 (9.1%) N. gonorrhoeae isolates obtained from men with symptomatic urethritis tested at San Diego County's main municipal sexually transmitted disease (STD) clinic had high azithromycin MICs: three with 8 µg/mL and two with 16 µg/mL. This report summarizes the laboratory and epidemiologic findings associated with this reduced susceptibility to azithromycin. In San Diego County, clinicians treating cephalosporin-allergic patients with a 2 g dose of azithromycin for uncomplicated gonorrhea are advised to obtain tests of cure 3 weeks after treatment and to recommend sexual abstinence until a negative test result for gonorrhea is achieved. Continued surveillance for antibiotic resistance and effective control efforts are critical for gonorrhea prevention.

GISP conducts susceptibility testing of urethral N. gonorrhoeae isolates obtained from men with symptomatic urethritis seeking care at 29 U.S. STD clinics, including San Diego County's main municipal STD clinic. MICs to eight antibiotics, including azithromycin, are determined by agar dilution (1). Additionally, in San Diego County, nucleic acid amplification tests (NAATs) are used to test for urethral, pharyngeal, and rectal gonorrhea and chlamydia infections at the county's public health laboratory. Patients are interviewed and asked to inform their recent sex partners (i.e., preceding 3 months) of their infections or bring them in for treatment.

Case Reports

During August--October 2009, five cases of urethral gonorrhea with high MICs to azithromycin (three with 8 µg/mL and two with 16 µg/mL) were diagnosed by Gram stain and confirmed by NAAT at San Diego County's main municipal STD clinic. The five N. gonorrhoeae isolates with high MICs (9.1%) obtained from the five patients were among 55 N. gonorrhoeae isolates obtained from men with symptomatic urethritis tested during the 3-month period. All five patients were men who have sex with men (MSM). Four were human immunodeficiency virus (HIV)-negative by self-report and one had an HIV-negative test result.

Three of the five patients were non-Hispanic white men, one was non-Hispanic black, and one was Hispanic. Four were San Diego County residents, and one was a resident of a Midwestern state. Median age was 29 years (range: 19--31 years). None had traveled internationally within 3 months of receiving their gonorrhea diagnosis. In accordance with CDC recommendations in effect at the time of diagnosis (2), all five were treated with 125 mg of ceftriaxone for uncomplicated gonorrhea and were given a 1 g dose of azithromycin for presumptive treatment of chlamydia infection (subsequently, the recommended dosage for ceftriaxone was increased to 250 mg [3]).

NAATs revealed concurrent pharyngeal chlamydia and rectal gonorrhea in one of the five men and rectal gonorrhea in another. One man had had exposure to azithromycin when he had been treated 113 days earlier with 125 mg of ceftriaxone for gonorrhea and 1 g of azithromycin for presumptive chlamydia. Isolates from all five men were susceptible to ceftriaxone, cefixime, penicillin, tetracycline, ciprofloxacin, and cefpodoxime. Of the five patients, three were treated and did not return to the clinic, one was treated successfully based on test of cure, and one was treated, reinfected within 3 months, and retreated successfully based on test of cure.

The five men reported a total of 13 male partners with whom they had had oral or anal sex (range: 1--4 partners). None of the men named partners in common. County health workers attempted to contact sex partners to encourage testing and treatment. Three of five sex partners with known contact information went to the STD clinic for treatment and testing. Two had asymptomatic pharyngeal gonorrhea; the third contact did not have gonorrhea but had rectal chlamydia and newly diagnosed HIV infection. Of the two contacts with pharyngeal gonorrhea, one was treated and did not return to the clinic. The other contact, who reported penicillin allergy, was treated with 2 g azithromycin and returned to the clinic for test of cure, which was positive for pharyngeal gonorrhea. The patient was desensitized and treated with ceftriaxone under supervision at a hospital. The patient then declined to return for test of cure.

Three patients and two contacts were available for extended interviews. Four reported no recreational drug use; one acknowledged using mushrooms during the preceding 12 months. Venues for meeting sex partners included a website (one interviewee), a gay nightclub (two), and through friends (two).

Molecular Study Results

Typing was performed on the five isolates with high MICs to azithromycin by using N. gonorrhoeae multiantigen sequence typing (NG-MAST), in which polymerase chain reaction (PCR)--based methods are used to sequence portions of the highly polymorphic outer-membrane genes por and tbpB (4). NG-MAST assigns a number to each unique por and tbpB allele sequence on the basis of identified polymorphisms, and assigns a sequence type to the isolate on the basis of the combination of allele numbers.

For the first four isolates obtained, PCR-based methods also were used to sequence two genes associated with N. gonorrhoeae azithromycin resistance: the gene encoding the 23S ribosomal (rRNA) subunit (5), for which four alleles per genome exist, and the coding and promoter regions of the mtrR gene (6), for which one allele per genome exists.

NG-MAST showed one isolate with por allele 1808 and tbpB allele 29, which is sequence type 2992. Four isolates had por allele 2577, which shares >99% homology with por allele 1808, and tbpB allele 29; these four isolates were assigned a novel sequence type, 4198 (Table). DNA sequencing analysis of the 23S rRNA gene revealed the C2611T, a resistance-associated mutation, and analysis of the mtrR gene revealed the G115A mutation and G131A, a novel mutation (Table).

Subsequent Isolates with High MICs

During November 2009--December 2010, of 229 new isolates obtained from MSM who were examined at the STD clinic and tested through GISP, four (1.7%) had high MICs to azithromycin: three with 8 µg/mL and one with 16 µg/mL. These isolates were not molecularly characterized. Subsequently, in February and September 2010, San Diego County alerted local clinicians that N. gonorrhoeae infections with high MICs to azithromycin had been identified and reminded clinicians to treat uncomplicated gonorrhea only with recommended agents. Through December 2010, no treatment failures had been reported.

Reported by

Kenneth A. Katz, MD, Elaine F. Pierce, MD, Heidi Aiem, Philip Henderson, Health and Human Svcs Agency, County of San Diego; Mark Pandori, PhD, Abel Wu, Sean Buono, San Francisco Dept of Public Health Laboratory; Pennan M. Barry, MD, STD Prevention and Control Svcs, San Francisco Dept of Public Health; Michael Samuel, DrPH, Carol Kong, MPH, STD Control Br, California Dept of Public Health. Paula Dixon, Univ of Alabama Regional Gonoccoccal Isolate Surveillance Project Laboratory. Gail Bolan, MD, Hillard S. Weinstock, MD, Eileen L. Yee, MD, Robert D. Kirkcaldy, MD, Div of Sexually Transmitted Diseases Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention; Christina B. Khaokham, MSN, MPH, EIS Officer, CDC. Corresponding contributor: Christina B. Khaokham, CDC, ckhaokham@cdc.gov, 619-692-5571.

Editorial Note

The five N. gonorrhoeae infections with high MICs to azithromycin identified in MSM during a 3-month period in 2010 in San Diego County amount to an unusually large cluster. One man had recent exposure to azithromycin, which might be a risk factor for development of N. gonorrhoeae azithromycin resistance (7). The lack of any reported sex partners in common among the five men and the later discovery of four new isolates with high MICs to azithromycin, also in MSM, suggest that azithromycin-resistant strains might be circulating among MSM in San Diego County.

In 1999, GISP identified a cluster of N. gonorrhoeae infections with reduced azithromycin susceptibility (MIC range: 1--4 µg/mL) among 12 men examined at a Kansas City, Missouri, STD clinic (8). The 12 said they had not had sex with men; six reported contact with a female commercial sex worker. The high MICs to azithromycin observed in the San Diego County cluster are consistent with those reported since 2001 from England and Wales (9) and Argentina (10), where strains with MICs ≥8 µg/mL to 2,048 µg/mL have been identified. The England and Wales isolates were recovered from three females and three males, all heterosexual. No demographic or behavioral characteristics were available from Argentina.

NG-MAST findings in San Diego County indicated that the five isolates are associated with two closely related N. gonorrhoeae strains. Sequencing of the 23S rRNA and mtrR coding regions of the four sequenced isolates, which demonstrated identical mutations, further supports the isolates' relatedness. The 23S rRNA gene encodes a component of the 50S ribosome, where bacterial protein synthesis occurs. The C2611T mutation produces a 50S ribosome to which macrolides cannot bind, preventing them from exerting a bacteriostatic effect (4). The mtrR gene encodes a repressor of a bacterial efflux pump that exports antibiotics, including macrolides, out of the bacteria. In the mtrR gene, deletions in the promoter region, observed in one sequenced isolate, and missense mutations in the coding region, identified in all four sequenced isolates, can lead to decreased efflux pump repression, increased export of macrolides, and ultimately, decreased ability of azithromycin to inhibit bacterial protein synthesis (5). Although the G115A mutation in the mtrR coding region has been reported previously (6), the G131A mutation is novel.

The association between azithromycin MICs in N. gonorrhoeae and treatment outcomes is not well-understood. For surveillance purposes, GISP defines reduced susceptibility of N. gonorrhoeae to azithromycin as MICs ≥2 µg/mL (1). CDC does not recommend azithromycin as monotherapy for routine treatment of gonorrhea because of concerns regarding emerging resistance. Dual therapy with a cephalosporin (i.e., ceftriaxone or cefixime, if ceftriaxone is not an option) and either azithromycin or doxycyline is recommended by CDC for uncomplicated rectal and urogenital gonorrhea; for pharyngeal gonorrhea, ceftriaxone is the recommended cephalosporin (with either azithromycin or doxycycline) (3).

The potential for the emergence of cephalosporin and azithromycin resistance in N. gonorrhoeae poses challenges to clinicians and public health agencies. Continued surveillance for antibiotic resistance by using culture and susceptibility testing is essential for detecting resistance and guiding treatment. Additionally, development of new diagnostic and treatment strategies and effective antibiotics will be critical to gonorrhea prevention and control.

References

  1. CDC. Gonococcal Isolate Surveillance Project protocol. Atlanta, GA: US Department of Health and Human Services, CDC; 2007. Available at http://www.cdc.gov/std/gisp/protocol2006_web_version_rev12_2007.pdf. Accessed May 6, 2011.
  2. CDC. Sexually transmitted diseases treatment guidelines, 2006. MMWR 2006;59(No. RR-11).
  3. CDC. Sexually transmitted diseases treatment guidelines, 2010. MMWR 2010;59(No. RR-12).
  4. Martin IM, Ison CA, Aanensen DM, Fenton KA, Spratt BG. Rapid sequence-based identification of gonococcal transmission clusters in a large metropolitan area. J Infect Dis 2004;189:1497--505.
  5. Chisholm SA, Dave J, Ison CA. High-level azithromycin resistance occurs in Neisseria gonorrhoeae as a result of a single point mutation in the 23S rRNA genes. Antimicrob Agents Chemother 2010;54:3812--6.
  6. Warner DM, Shafer WM, Jerse AE. Clinically relevant mutations that cause derepression of the Neisseria gonorrhoeae mtrC-mtrD-mtrE efflux pump system confer different levels of antimicrobial resistance and in vivo fitness. Mol Microbiol 2008;70:462--78.
  7. Young H, Moyes A, McMillan A. Azithromycin and erythromycin resistant Neisseria gonorrhoeae following treatment with azithromycin. Int J STD AIDS 1997;8:299--302.
  8. CDC. Fluoroquinolone-resistance in Neisseria gonorrhoeae, Hawaii, 1999, and decreased susceptibility to azithromycin in N. gonorrhoeae, Missouri, 1999. MMWR 2000;49:833--7.
  9. Chisholm SA, Neal TJ, Alawattegama AB, Birley HD, Howe RA, Ison CA. Emergence of high-level azithromycin resistance in Neisseria gonorrhoeae in England and Wales. J Antimicrob Chemother 2009;64:353--8.
  10. Galarza PG, Alcala B, Salcedo C, et al. Emergence of high level azithromycin-
    resistant Neisseria gonorrhoeae strain isolated in Argentina. Sex Transm Dis 2009;36:787--8.

What is already known on this topic?

Neisseria gonorrhoeae isolates with high minimal inhibitory concentrations (MICs) to azithromycin, defined as MIC ≥8 µg/mL, have been reported worldwide, including in the United States. High MICs have been associated with mutations in the 23S rRNA gene or the mtrR gene.

What is added by this report?

Three N. gonorrhoeae isolates with MICs to azithromycin 8 µg/mL and two with MICs 16 µg/mL were collected during August--October 2009 from men who have sex with men in San Diego County, California. Four of these five isolates had a novel NG-MAST sequence type, and all four isolates sequenced had a novel combination of mutations involving the 23S rRNA gene and the coding region of the mtrR gene associated with N. gonorrhoeae azithromycin resistance.

What are the implications for public health practice?

Continued surveillance for antimicrobial resistance in N. gonorrhoeae is essential for effective disease prevention and control. Treatment of gonorrhea with monotherapy is not recommended because of concern over the emergence of antibiotic resistance. Clinicians should treat uncomplicated gonorrhea with the recommended dual therapy and maintain vigilance for treatment failure.


TABLE. Minimum inhibitory concentrations (MICs) to azithromycin, results of Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST), and results of DNA sequencing analyses for five N. gonorrhoeae isolates --- San Diego County, California, 2009

Isolate

MIC (µg/mL)

NG-MAST results

23S rRNA gene

mtrR gene

por

tbpB

Sequence type

Allele 1

Allele 2

Allele 3

Allele 4

Promoter region

Coding region

1

16

1808

29

2992

C2611T

C2611T

C2611T

C2611T

A deletion*

G115A, G131A

2

16

2577

29

4198

C2611T

C2611T

C2611T

C2611T

WT

G115A, G131A

3

8

2577

29

4198

C2611T

C2611T

C2611T

C2611T

WT

G115A, G131A

4

8

2577

29

4198

C2611T

C2611T

C2611T

C2611T

WT

G115A, G131A

5

8

2577

29

4198

NA

NA

NA

NA

NA

NA

Abbreviations: A = adenine; C = cytosine; T = thymine; G = guanine; WT = wild type; NA = not available.

* Single base-pair deletion in the 13-bp inverted repeat in the mtrR promoter region.



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