Gonorrhea Resistant to Cefixime Found in North America

Jenni Laidman

January 08, 2013

Growing global resistance by Neisseria gonorrhoeae to cefixime, the last oral antibiotic used against it, has been documented in North America with a Canadian study that showed a nearly 7% treatment failure rate, according to research published in the January 8 issue of JAMA.

In a retrospective cohort study of patients attending an Ontario clinic, Vanessa G. Allen, MD, MPH, medical microbiologist, Public Health Ontario, Toronto, Canada, and colleagues reviewed records of 291 individuals treated with the cephalosporin cefixime after culturing positive for gonorrhea between May 1, 2010, and April 30, 2011. Of the 133 people who returned after treatment for test of cure, 13 cultured positive for gonorrhea; 9 (6.77%; 95% confidence interval [CI], 3.14% - 12.45%) of those patients were determined to have failed treatment. Four of the 9 patients who failed treatment were asymptomatic.

"This study presents the first series of clinical failures of gonorrhea associated with the use of cefixime in North America, identified by the concurrent strategies of routine test-of-cure and culture-based testing for N gonorrhoeae," the authors write. Failure was defined as the isolation of N gonorrhoeae identified by molecular typing as identical to the isolate taken at diagnosis. The patient also had to deny re-exposure after treatment.

In an accompanying editorial, Robert D. Kirkcaldy, MD, MPH, medical epidemiologist, Division of STD Prevention, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, and colleagues said the results of this study, although grave, were not surprising.

"Deeply Troubling"

"Although this milestone was expected, its arrival is deeply troubling; clinicians now face the emergence of cephalosporin-resistant N gonorrhoeae without any well-studied, effective backup treatment options," the editorial authors write.

The CDC last year updated its gonorrhea treatment recommendations and no longer considers cefixime part of a first-line regimen. It instead recommends the dual therapy of 250 mg intramuscular ceftriaxone with either azithromycin or doxycycline.

In the Canadian study, the rate of failure associated strongly with a cefixime minimum inhibitory concentration (MIC) of 0.12 μg/mL or more, with a 25.0% treatment failure rate (95% CI, 10.69% - 44.87%; 7/28 patients). In comparison, the clinical failure rate for infections with a cefixime MIC of less than 0.12 μg/mL was 1.90% (95% CI, 0.23% - 6.71%; 2/105 patients). The relative risk for treatment failure of MICs of 0.12 μg/mL or more compared with less than 0.12 μg/mL was 13.13 (95% CI, 2.88 - 59.72; P < .001).

Clinical failure occurred in 4 of 76 urethral infections (5.26%), 2 of 7 pharyngeal infections (28.6%), and 3 of 39 rectal infections (7.69%). "Seven of the 9 isolates had a cefixime MIC of at least 0.12 μg/mL, and the remaining 2 isolates had MICs of less than 0.12 μg/mL," the authors note.

Four of the 13 cases that cultured positive were not classified as treatment failure because patient records included no explicit denial of sexual re-exposure between diagnosis and retesting.

All 9 patients in the Canadian study were eventually cleared of infection. Six patients were treated with 250 mg intramuscular ceftriaxone, and the remaining 3 patients were treated with 800 mg cefixime.

As the authors explain, cephalosporin MICs were first found to be increasing in Asia in the late 1990s, and resistance has been seen in the United States and Canada since 2000. "The CDC's Gonococcal Isolate Surveillance Project (GISP) analyzed isolates from 2000-2010; isolates with cefixime MICs 0.25 μg/mL or greater increased from 0.2% to 1.4% and isolates with ceftriaxone MICs 0.12 μg/mL or greater increased from 0.1% to 0.3%," the authors write.

Pipeline Running Dry

There are an estimated 106.1 million cases of gonorrhea worldwide each year, according to the editorialists. A disease that was once treated with a single dose of an oral antibiotic has steadily defeated each new treatment against it, they add. In the 1940s it was sulfonamides, in the 1970s and 1980s it was penicillins and tetracyclines, and by 2007, it was fluoroquinolones. "Since then, cephalosporins have been the only antibiotic recommended for treatment. However, gonococcal susceptibility to oral cephalosporins is declining, and the effectiveness of these drugs is threatened," the editorialists write.

Unfortunately, there is nothing in the pipeline to quickly take its place.

"A clinical trial sponsored by the National Institute of Allergy and Infectious Diseases examining novel combinations of existing drugs just completed enrollment, and a small study of a new oral agent is ongoing," the editorial authors write. "But the antibiotic pipeline is running dry: continued investment in antibiotic development is critical. Meanwhile, the gonococcus has continued to develop the capability to defeat each new antibiotic used. The threat of drug-resistant gonorrhea is increasing and has reached North America. Clinicians, drug developers, and public health professionals must act now."

The authors and editorialists have disclosed no relevant financial relationships.

JAMA. 2013;309:163-170, 185-187. Article abstract, Editorial extract

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