COMMENTARY

The Return of the Gonococcus

Matthew R. Golden MD, MPH, H. Hunter Handsfield, MD

Disclosures

December 26, 2002

Introduction

After years of declining gonorrhea rates, several recent reports have raised concerns that gonorrhea incidence in some parts of the United States is increasing, and that quinolone resistance among gonococci is now established and rising. These developments, coupled with recent changes in gonorrhea testing technologies and the discontinuation of cefixime production, threaten to complicate both the treatment of gonorrhea and public health prevention and control efforts.

Neisseria gonorrhoeae is a common cause of urethritis, cervicitis, and pelvic inflammatory disease. Among men who have sex with men (MSM), gonorrhea is also a common cause of sexually transmitted anorectal infection.[1] In recent years, the control of gonorrhea has taken on new importance since gonorrhea, like other inflammatory sexually transmitted diseases (STDs), is thought to enhance HIV transmission.[2]

Between 1975 and 1997, gonorrhea rates in the United States declined by 74%. Since that time, national rates have plateaued.[3] However, this overall trend masks substantial epidemiologic heterogeneity. The infection remains most common in the industrial Midwest and the South, and disproportionately affects blacks and adolescents. Whereas rates in the South have continued to decline in recent years, rates of reported gonorrhea increased 13.5% in the western United States between 1999 and 2000. Although some of the increase may reflect more widespread testing and use of more sensitive nucleic acid amplification tests, it seems likely that as much of this change represents a true increase in disease incidence that reflects the continued rise in STDs among MSM,[4,5] as well as a new epidemic among heterosexuals.

In late November, the Centers for Disease Control (CDC) reported a rise in the proportion of gonorrhea caused by fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG).[6] For the purpose of this article, fluoroquinolone resistance refers to organisms with minimum inhibitory concentrations to ciprofloxacin of ≥ 1 mcg/mL. Most resistant organisms have MICs > 4, a level of resistance at which approximately half of treated patients fail therapy.[7])

QRNG strains were first recognized as an American problem in the early 1990s when resistant organisms were identified in Hawaii.[8] Since 1997, the proportion of gonorrhea cases in Hawaii caused by QRNG has increased from 1% to 20%. QRNG now accounts for more than 40% of gonorrhea cases detected in parts of Asia. On the basis of these numbers, the 2002 CDC STD treatment guidelines recommend persons reporting sexual exposure to individuals from Hawaii or the Asian Pacific not be treated with quinolones.

Now QRNG has gained a toehold in the continental United States. Among 1311 gonorrhea isolates tested in California in 2001, 2.5% were quinolone resistant. QRNG was more common among Asian/Pacific Islanders than among non-Asian/Pacific Islanders, and was more common in MSM than in heterosexuals in San Diego, though not in other California cities. Among California STD clinic patients with gonorrhea during the first 6 months of 2002, more than 9% had QRNG. As a result of this increase in gonorrhea, CDC and the California Department of Health Services currently recommend that quinolones not be used to treat gonorrhea.

The emergence of QRNG comes at a particularly inopportune time. Gonorrhea is increasingly being diagnosed using nucleic acid amplification tests. As a result, our ability to test for antibiotic resistance, both for clinical and epidemiologic purposes, is eroding. As if this confluence of events isn't bad enough, the manufacturer of cefixime, the primary nonquinolone oral option for gonococcal therapy, recently discontinued production of the drug. If quinolones become an unreliable treatment for gonorrhea throughout the United States -- and the question really is when more than if -- and if cefixime production is permanently discontinued, we will have no reliable oral treatment for gonorrhea. The CDC is currently attempting to negotiate an agreement with the manufacturer to resume the production of cefixime.

In the interim, many clinicians treating patients with gonorrhea will need to alter their testing and treatment practices. On the West Coast of the United States, quinolones should only be used if alternatives such as cefixime (400 mg orally once) or ceftriaxone (125 mg intramuscularly once) are not readily available, or if patients are penicillin allergic. Response to this therapy can be carefully monitored.

Elsewhere in the United States, clinicians treating patients with gonorrhea can continue to use quinolones for patients without a history of exposure to persons from the West Coast or Asia for the time being. However, they should be aware that the days of effective quinolone therapy for gonorrhea are probably numbered. Increased vigilance in detecting and treating for presumed QRNG should be exercised when evaluating MSM, as this population appears to be at particularly high risk of acquiring resistant strains.

Patients with gonorrhea should also be treated for chlamydial infection, both because of the high coinfection rate with gonorrhea and in the hope that at least some resistant organisms may respond to treatment with azithromycin or doxycycline.

Finally, whenever possible, clinicians should continue to perform gonorrhea cultures. Nucleic acid amplification tests offer significant benefits in terms of enhanced sensitivity in testing for Chlamydia trachomatis, but relatively little sensitivity advantage compared with a properly performed gonococcal culture. That advantage is probably dwarfed by the disadvantages inherent in losing the ability to test for antimicrobial resistance.

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