Thursday, May 23, 2013

A History of Gonococcal Resistance: Are We Screwed?

Gonococcal infection is a growing public health problem that continues to remain of concern in the United States. Infection can occur in a number of anatomical sites, including the urethra, rectum, oropharynx, eye, and endocervical canal. Complications of untreated infection may lead to damage of reproductive organs, which may include pelvic inflammatory disease, infertility, and ectopic pregnancy in females, as well as disseminated gonococcal infection and conjunctivitis in neonates. With all of these potential complications, it is especially important to be able to recognize signs and symptoms of infection and treat patients with empiric antimicrobial therapy if there is a high index of suspicion.

A few weeks ago, I saw this tweet in my Twitter feed, which prompted my attention and piqued my interest:


The evolution of antimicrobial agents that have been used to treat this infection over the past century is quite fascinating, but somewhat disheartening at the same time. With the discovery of penicillin and sulfonamide in the early part of the 20th century, these two agents were hailed as the "go-to" treatments of this infection. Fast forward a few decades and after discoveries were made regarding the growing resistance patterns of gonococcal strains to these agents as well as tetracyclines, adjustments to treatment strategies for this infection had to be made relatively quickly. This also prompted the implementation of the Gonococcal Isolate Surveillance System (GISP) in the mid 1980s, which was designed by the Centers for Disease Control and Prevention (CDC) as a surveillance tool of susceptibility patterns of gonorrhea among cultures obtained from infected men at participating clinics. This would allow for recognition of early resistance to allow for prompt recommendations to be made for alternative therapies.

Fluoroquinolones and spectinomycin then came on the scene and were used along with both oral and parenteral cephalosporins (namely cefixime and ceftriaxone, respectively) in the 1990s and 2000s. However, in the early 2000s, a number of strains emerged in California and Hawaii that demonstrated increasing resistance to fluoroquinolones, particularly among infected homosexual males, and these strains eventually made their way into the heterosexual population. This led to modification of the treatment recommendations for gonococcal infection by the CDC in 2007 to remove fluoroquinolone therapy as a treatment option for this disease state. At this point in time, spectinomycin had already been removed from the United States market for a year as well. This further limited our treatment options to cephalosporins and...cephalosporins (oral and parenteral).

Even the last two years have been huge for the cephalosporins used to treat gonorrhea. In 2011, the CDC recommended higher doses of ceftriaxone to be used for gonococcal infection (250 mg from 125 mg) due to treatment failures, decreased in vitro susceptibility, and greater demonstrated efficacy for pharyngeal infection. The CDC has also recently recognized the growing number of isolates of gonorrhea that exhibited elevated minimum inhibitory concentrations (MICs) to cefixime, which increased by 17-fold from 2006 through 2011. This had already been a problem across the EU and Asia, and eventually made its way to the United States, particularly among men in the western part of the United States and the homosexual population. With the fear that this may contribute to resistance, the CDC made a statement this past August of no longer recommending cefixime or other oral cephalosporins as first-line therapy for the treatment of gonorrhea.

So where does this leave us? It is difficult to predict how successful the 10 by '20 campaign for the discovery and development of new antimicrobial agents will be. There is one ongoing trial that is evaluating a new treatment option (solithromycin [CEM-101], a macrolide antibiotic) for uncomplicated gonococcal infection. There is another trial that is currently evaluating the efficacy of azithromycin as a combination with either gemifloxacin or gentamicin for the treatment of gonorrhea. However, until these trials are completed, our best option for now is to increase public awareness of this situation and ensure that patients and their partners are adequately and effectively treated in order to minimize complications secondary to infection as a means of decreasing disease burden and health care costs. In addition, the CDC has developed a response plan for public health awareness of cephalosporin-resistant strains of gonorrhea.

The importance of reporting of patterns of resistance to the appropriate channels for epidemiological purposes and public awareness cannot be emphasized further. The history of gonococcal resistance should serve as a lesson to all of us on how quickly antimicrobial resistance can evolve and develop and highlight the therapeutic challenges that we may potentially be faced with as this continues to inevitably occur with other infectious diseases.

References:
MMWR Recomm Rep 2010; 59(RR-12):1-110.
MMWR Morb Mortal Wkly Rep 2007; 56:332-336.
MMWR Morb Mortal Wkly Rep 2011; 60:873-877.
MMWR Morb Mortal Wkly Rep 2012; 61:590-594.
MMWR Morb Mortal Wkly Rep 2013; 62:103-106.