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Morbidity and Mortality Weekly Report
Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections

<p>CDC Staff</p>

August 10, 2012

Gonorrhea is a major cause of serious reproductive complications in women and can facilitate human immunodeficiency virus (HIV) transmission (1). Effective treatment is a cornerstone of U.S. gonorrhea control efforts, but treatment of gonorrhea has been complicated by the ability of Neisseria gonorrhoeae to develop antimicrobial resistance. This report, using data from CDC's Gonococcal Isolate Surveillance Project (GISP), describes laboratory evidence of declining cefixime susceptibility among urethral N. gonorrhoeae isolates collected in the United States during 2006–2011 and updates CDC's current recommendations for treatment of gonorrhea (2). Based on GISP data, CDC recommends combination therapy with ceftriaxone 250 mg intramuscularly and either azithromycin 1 g orally as a single dose or doxycycline 100 mg orally twice daily for 7 days as the most reliably effective treatment for uncomplicated gonorrhea. CDC no longer recommends cefixime at any dose as a first-line regimen for treatment of gonococcal infections. If cefixime is used as an alternative agent, then the patient should return in 1 week for a test-of-cure at the site of infection.

Infection with N. gonorrhoeae is a major cause of pelvic inflammatory disease, ectopic pregnancy, and infertility, and can facilitate HIV transmission (1). In the United States, gonorrhea is the second most commonly reported notifiable infection, with >300,000 cases reported during 2011. Gonorrhea treatment has been complicated by the ability of N. gonorrhoeae to develop resistance to antimicrobials used for treatment. During the 1990s and 2000s, fluoroquinolone resistance in N. gonorrhoeae emerged in the United States, becoming prevalent in Hawaii and California and among men who have sex with men (MSM) before spreading throughout the United States. In 2007, emergence of fluoroquinolone-resistant N. gonorrhoeae in the United States prompted CDC to no longer recommend fluoroquinolones for treatment of gonorrhea, leaving cephalosporins as the only remaining recommended antimicrobial class (3). To ensure treatment of co-occurring pathogens (e.g., Chlamydia trachomatis) and reflecting concern about emerging gonococcal resistance, CDC's 2010 sexually transmitted diseases (STDs) treatment guidelines recommended combination therapy for gonorrhea with a cephalosporin (ceftriaxone 250 mg intramuscularly or cefixime 400 mg orally) plus either azithromycin orally or doxycycline orally, even if nucleic acid amplification testing (NAAT) for C. trachomatis was negative at the time of treatment (2). From 2006 to 2010, the minimum concentrations of cefixime needed to inhibit the growth in vitro of N. gonorrhoeae strains circulating in the United States and many other countries increased, suggesting that the effectiveness of cefixime might be waning (4). Reports from Europe recently have described patients with uncomplicated gonorrhea infection not cured by treatment with cefixime 400 mg orally (5–8).

GISP is a CDC-supported sentinel surveillance system that has monitored N. gonorrhoeae antimicrobial susceptibilities since 1986, and is the only source in the United States of national and regional N. gonorrhoeae antimicrobial susceptibility data. During September–December 2011, CDC and five external GISP principal investigators, each with N. gonorrhoeae–specific expertise in surveillance, antimicrobial resistance, treatment, and antimicrobial susceptibility testing, reviewed antimicrobial susceptibility trends in GISP through August 2011 to determine whether to update CDC's current recommendations (2) for treatment of uncomplicated gonorrhea. Each month, the first 25 gonococcal urethral isolates collected from men attending participating STD clinics (approximately 6,000 isolates each year) were submitted for antimicrobial susceptibility testing. The minimum inhibitory concentration (MIC), the lowest antimicrobial concentration that inhibits visible bacterial growth in the laboratory, is used to assess antimicrobial susceptibility. Cefixime susceptibilities were not determined during 2007–2008 because cefixime temporarily was unavailable in the United States at that time. Criteria for resistance to cefixime and ceftriaxone have not been defined by the Clinical Laboratory Standards Institute (CLSI). However, CLSI does consider isolates with cefixime or ceftriaxone MICs ≥0.5 µg/mL to have "decreased susceptibility" to these drugs (9). During 2006–2011, 15 (0.1%) isolates had decreased susceptibility to cefixime (all had MICs = 0.5 µg/mL), including nine (0.2%) in 2010 and one (0.03%) during January–August 2011; 12 of 15 were from MSM, and 12 were from the West and three from the Midwest.* No isolates exhibited decreased susceptibility to ceftriaxone. Because increasing MICs can predict the emergence of resistance, lower cephalosporin MIC breakpoints were established by GISP for surveillance purposes to provide greater sensitivity in detecting declining gonococcal susceptibility than breakpoints defined by CLSI. Cefixime MICs ≥0.25 µg/mL and ceftriaxone MICs ≥0.125 µg/mL were defined as "elevated MICs." CLSI does not define azithromycin resistance criteria; CDC defines decreased azithromycin susceptibility as ≥2.0 µg/mL.

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