Gonorrhea Drug Choices Dwindling, but Trend May Be Slowed

Troy Brown

June 10, 2013

The last antibiotics effective against Neisseria gonorrhea are losing their strength, but certain prescribing practices may slow that trend, according to an analysis of data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in the United Kingdom.

Catherine A. Ison, PhD, from the Sexually Transmitted Bacteria Reference Unit, Microbiological Services at Public Health England, London, United Kingdom, and colleagues report their findings online June 10 in the Lancet.

"Disturbingly, no obvious reserve treatments are available for gonorrhea after the cephalosporins, no new agents have been licensed, and no alternative drugs exist to which resistance has not been noted," the authors write.

The researchers collected 7378 N gonorrhoeae isolates from patients attending 26 genitourinary medicine clinics and 24 laboratories in England and Wales between 2007 and 2011. They had information on antimicrobial susceptibility for 6176 (83.7%) of the isolates. A total of 547 (8.9%) isolates had decreased susceptibility to cefixime (minimum inhibitory concentrations [MIC], ≥0.25 mg/L). During the first part of the study period, reduced susceptibility became more common, going from 1.5% in 2007 to 17.1% in 2010 (P < .0001). However, the researchers saw a subsequent decline in the frequency of reduced susceptibility to 10.8% in 2011 (P < .0001).

The researchers observed a bimodal distribution in MIC of cefixime between 2009 and 2011, with peaks of 0.008 mg/L and 0.125 mg/L. This suggested the circulation of a discrete group of resistant organisms when there had been no such clear stratification earlier.

Most isolates with decreased susceptibility to cefixime were also less susceptible to ceftriaxone and ciprofloxacin (MIC, ≥1.0 mg/L for 545 [99.6%] of 547 isolates). The geometric mean MIC of ceftriaxone increased between 2007 and 2010, going from 3.9 × 10−3 mg/L to 5.2 × 10−3 mg/L (P = .001), but decreased significantly in 2011 to 4.3 × 10−3 mg/L (P = .001).

The only years in which the MIC for ceftriaxone was 0.125 mg/L or greater were 2008 (5 isolates) and 2009 (4 isolates). Azithromycin resistance (≥1 mg/L) was lower than 5% each year.

The researchers conducted multivariable analyses to identify factors associated with reduced susceptibility, adjusting for male sex, year of isolation, ethnic origin, and concurrent chlamydia infection. Gonorrhea among men who have sex with men (odds ratio [OR], 5.47, 95% confidence interval [CI], 3.99 - 7.48; P < .0001) and year of isolation (2008: OR, 1.97 [95% CI, 1.02 - 3.81; P = .04]; 2009: OR, 7.79 [95% CI, 4.42 - 13.7; P < .0001]; 2010: OR, 13.08 [95% CI, 7.49 - 22.8; P < .0001]; 2011: OR, 6.72 [95% CI, 3.8 - 11.9; P < .0001]) were significantly associated with lessened cefixime susceptibility in the multivariable analysis.

In multivariate analyses, gonorrhea in women (OR, 0.49; 95% CI, 0.29 - 0.81; P = .006), people of black ethnic origin (OR, 0.54; 95% CI, 0.36 - 0.79; P = .002), and individuals with concurrent chlamydia infection (OR, 0.71; 95% CI, 0.54 - 0.92; P = .011) remained inversely associated with decreased cefixime susceptibility.

No other factors identified in univariate analyses were linked with decreased antimicrobial susceptibility in the multivariable analysis.

Treatment use changed dramatically between 2009 and 2011. Cefixime was prescribed to 789 (61%) of 1298 patients in 2009, 568 (50%) of 1145 patients in 2010, and only 55 (5%) of 1194 patients in 2011. At the same time, ceftriaxone use increased gradually from 2008 to 2011. Azithromycin was prescribed together with ceftriaxone to 947 (79%) of 1194 patients in 2011 compared with only 287 (25%) of 1145 patients in 2010. Another 135 (11%) were prescribed doxycycline with ceftriaxone.

The Gonococcal Resistance to Antimicrobials Surveillance Programme "recommended an increased dose of 500 mg [ceftriaxone] to ensure coverage against isolates with high MICs. Coadministration of 1 g of oral azithromycin was advocated, for all patients, to treat any concomitant chlamydia infection and as dual cover against gonorrhoea," the authors write.

"This change in practice has been followed by a substantial fall in the number of gonococcal isolates showing decreased susceptibility to cefixime (MIC ≥0.125 mg/L) between 2010 and 2011, and no isolates have shown decreased susceptibility to ceftriaxone since 2009," the authors write.

In an accompanying editorial, David J.M. Wright, PhD, and Berge Azadian, MD, from the Department of Microbiology at Chelsea and Westminster Hospital in London, United Kingdom, comment on the study. "The combination of azithromycin and ceftriaxone is only additive and no synergistic action exists between them. Finally, rifamides might be a possible treatment for gonorrhoea, although when rifampicin is given alone, up to two-thirds of isolates show intermediate rifampicin resistance," Dr. Wright and Dr. Azadian write.

One coauthor consults for several pharmaceutical and diagnostic companies, including Achaogen, Adenium, Allecra, Astellas, AstraZeneca, Bayer, Basilea, bioMerieux, Cubist, Curetis, Discuvra, GlaxoSmithKline, Merck, Meiji Seika, Pfizer, Roche, Tetraphase, and Wockhardt; holds grants from Basilea, Cubist, Meiji Seika, and Merck; has received lecture honoraria or travel reimbursement from AstraZeneca, Curetis, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Pfizer, and Tetraphase; and holds shares in Dechra, Eco Animal Health, GlaxoSmithKline, Merck, and Pfizer, collectively amounting to less than 10% of portfolio value. Dr. Ison has received funding from Merck for testing alternative antimicrobial agents. The other authors and the editorialists have disclosed no relevant financial relationships.

Lancet. Published online June 10, 2013.

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