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Drug Resistant Gonorrhea Makes its Way into North America

The first documented failure of oral treatment for gonorrhea in North America has been reported in Toronto. The article, Neisseria gonorrhoeae Treatment Failure and Susceptibility to Cefexime in Toronto, Canada, published in the January 9, 2013, Journal of the American Medical Association, provides support for growing concern surrounding the second most prevalent bacterial sexually transmitted infection in the world.

This news comes on the heels of a decision by the Centers for Disease Control and Prevention (CDC), made in August of last year, to release new treatment recommendations in response to the increasing threat of antibiotic resistance.   Cephalosporins -- the class of antibiotics recommended for treatment of gonorrhea since 2007 -- are the last line of defense in a growing list of drugs that are no longer effective against N gonorrhoeae.

Previously, a 400 mg dose of oral cefixime (Suprax) was prescribed, often in conjunction with azithromycin (Zithromax) or doxycycline. The new recommendations replace cefixime with ceftriaxone (Rocephin), which is given as an intramuscular injection.

This change appears to have been an apt move.

The Toronto study followed 291 patients identified between May 2010 and April 2011 who were asked to return to a sexual health clinic for testing to determine if they were cured 2 to 4 weeks after being treated with 400 mg oral cefixime.

Results

• Of the 133 individuals who returned for testing, 13 had a positive culture with an isolate identical to that found pretreatment.
• 9 patients were determined to have experienced cefixime treatment failure, representing a 6.8% treatment failure rate.
• All 9 patients were successfully re-treated using either a higher (800 mg) dose of cefixime or 250 mg ceftriaxone.
• N gonorrhoeaeisolates with higher cefixime minimum inhibitory concentrations (MICs) were associated with higher failure rates.
• Treatment failure reached 25.0% for MICs of 0.12 mcg/mL or greater, compared with 1.9% for lower MICs.
• Pharyngeal (throat) infections had the highest treatment failure rate, at 28.6%, compared with 7.7% for rectal and 5.3% for urethral infections.

In analyzing the results, the researchers acknowledged some limitations. The data relies on participants' self-reported denial of sexual re-exposure between treatment and test of cure. Although coupled with a test to determine if the isolate was identical, people would be expected to get the same isolate again if re-infected by the same partner. 

Another complication is that 6 of the 9 patients who patients who experienced treatment failure had been given combination therapy with azithromycin or doxycycline, which may have compounded the actual rate of clinical failure. A third factor is that less than half of the initially treated patients returned for follow-up testing. If it is assumed that those who did not return were successfully cured, the actual treatment failure rate would fall to 3.09% -- below the World Health Organization’s 95% threshold for acceptable efficacy. 

News of the study has reverberated through the public health world. "The development and spread of cephalosporin resistance in N gonorrhoeae, particularly ceftriaxone resistance, would greatly complicate treatment of gonorrhea," CDC officials warned. To date, no comparable study has been released in the U.S.

The Toronto report is only a piece in what is becoming an international puzzle.  Cephalosporin resistance has been detected since the early 2000s in East Asia, and in January 2009 a Kyoto commercial sex worker was found to be positive for pharyngeal gonorrhea. She was treated with ceftriaxone multiple times before testing negative 4 months later. Ceftriaxone-resistant isolates have also been identified in France and Spain. 

In many cases gonorrhea is self-limiting. Half of pharyngeal cases detected by culture spontaneously remit within a week. However, untreated urethral and vaginal infections can cause epididymitis and pelvic inflammatory disease. Gonorrhea also increases susceptibility to HIV infection, as well as being associated with increased HIV viral load. 

Within the U.S. there has been some promising work towards developing a gonorrhea vaccine. Gail Bolan, director of the CDC's Division of STD Prevention, said that ultimately a vaccine is "the key to prevention and control," but that it is a "distant goal." In the meantime, the CDC hopes that the latest recommendations will delay the development of completely antibiotic-resistant gonorrhea until a new treatment method is found. 

2/20/13

References

VG Allen, L Mitterni, C Seah, et al. Neisseria gonorrhoeae Treatment Failure and Susceptibility to Cefixime in Toronto, Canada. Journal of the American Medical Association 309(2):163-170. January 9, 2013.

RD Kirkcaldy, GA Bolan, and JN Wasserheit. Cephalosporin-Resistant Gonorrhea in North America (Editorial). Journal of the American Medical Association 309(2):185-187. January 9, 2013.

E Hook, W Shafer, C Deal, et al. CDC Grand Rounds: The Growing Threat of Multidrug-Resistant Gonorrhea. Morbidity and Mortality Weekly Report 62(06):103-106. February 15, 2013.