Gonorrhea drifting toward cephalosporin resistance

Neisseria gonorrhea strains are showing a worrisome drift in susceptibility to cephalosporins, causing experts to warn that the bacterium is only a step away from acquiring high-level resistance that would render ineffective the current first-line antimicrobials.

That development could have disastrous consequences since cephalosporins are the last remaining class of antimicrobial agents that are highly effective against N. gonorrhoeae.

“The challenge is to maintain gonorrhea as a treatable infection.”

Because Neisseria gonorrhoeae is highly versatile, that task won’t be easy. The bacterium has a solid track record of acquiring and developing resistance. Since sulfomide was introduced for the treatment of gonorrhea in the 1930s, N. gonorrhoeae has developed different mechanisms for evading each new first-line antimicrobial agent. Penicillins, tetracyclines, quinolones, and azithromycin have all fallen by the wayside.

“We should never underestimate the gonococcus. Those of us who’ve spent our lives working with it know that it always comes up with surprises,” observed the director of sexually transmitted bacteria reference laboratory at the UK Health Protection Agency, London.

The case of ciprofloxacin is a good example of how quickly and relentlessly high-level resistance can occur and how slow national and international infectious disease treatment guideline panels often are to respond.

Ciprofloxacin was recommended as a highly effective first-line agent for gonorrhea beginning in about 1990. However, by 2004, when the European Gonoccal Antimicrobial Surveillance Program (Euro-GASP) was initiated, the mean resistance to Ciprofloxacin among N. gonorrhoeae isolates from 17 participating countries was already at 31%. In 2006 it rose to 42%, climbing further to 53% in 2007 and 63% in 2009.

To put these resistance figures into context, the World Health Organization recommends considering switching to a different first line agent when the prevalence  of resistant organisms reaches 5% in order to maintain therapeutic success rates in excess of 95%. By the middle of the past decade resistance rate in Europe exceeded that standard by 8- to 10-fold. Yet European gonorrhea treatment guidelines finally got around to recommending replacement of ciprofloxacin by cephalosporins as first-line agents only a few months ago.

Resistance to the oral cephalosporin cefixime (Suprax) now stands at an average of about 5% across Europe. Monitoring by Euro-GASP Prevention and Control, indicates five European countries — Austria, Italy, Denmark, Belgium, and Slovenia — already have rates in excess of 5%. Gonorrhea treatment failures with cefixime have been reported.

Mechanism is attributed to penA mosaic. The microorganism will need to acquire additional mechanism in order for full resistance to occur but that’s just a matter of time.

As for ceftriaxone, an injectable first-line cephalosporin, the Euro-GASP data for 2004-2009 show a drift in minimum inhibitory concentrations towards the more resistance end of the spectrum over time. There have been occasional reports of treatment failures. The resistance mechanism appears to differ from that for cefixime.

How does this resistance on the part of N.gonorrhoeae happen? The culprits are misuse or overuse of antimicrobials due to an inadequate or incomplete course, the over-the-counter availability existing in some countries, and long-term use of a single agent.

For the effectiveness of cefixime and ceftriaxone to be maintained as long as possible, it’s going to be necessary to think outside the box.

“We’re already testing new agents, and retesting old agents as well. We’ve started testing gentamicin as a possibility, for example.” “And we’re going  to think about increasing the dose and using multiple dosing — that’s obviously not something STI physicians want to do, but it may be something they’ll have to do. We may also have to instigate enhanced surveillance of targeted high-risk groups where we lower the threshold for changing therapy.”

The Centers for Disease Control and Prevention is already moving in this direction with its recommendation that in selected high-risk groups the cutoff for changing therapy should be lowered from the 5% suggested by the WHO to 3%.

“If we put all of these things together and we act quickly, then we hopefully can retain gonorrhea as a treatable infection.”