Looking across the Northern border it is clear that CDC Guidelines are not universally followed even in North America. Public Health Canada still recommends cefixime for uncomplicated gonorrhea (GC), albeit at the high single oral dose of 800 mg [1]. In the US, CDC has opted for combination treatment with ceftriaxone plus azithromycin, with several alternatives, one of which includes cefixime at the more conventional dose of 400 mg. It made cefixime a 2nd line option mainly because of treatment failures abroad and a rising resistance trend for cefixime between 2006 and 2011 when MICs of 0.25 μg/mL were recorded in 1.3% of isolates. Of interest, there are 18 isolates with MIC of 0.5 μg/mL and 1 isolate with an MIC of 1.0 μg/mL in the GISP database [2].
Less known is the fact that since 2011 the feared increase in cefixime resistance actually reversed: in 2013, only 0.4% of isolates had MICs in the 0.25 μg/mL category (down from 1.3% in 2011) and there also were significantly fewer isolates with MICs of 0.5 μg/mL. So, for practical purposes, cefixime at a single dose of 400 mg PO should still work just as well as before the Guideline change.
That is good news but should not be interpreted to mean that our treatment options for GC are what they were.
Moran et al. from CDC published an article in 1995 in which they mention that “thirty regimens comprising 21 antimicrobial drugs have been shown to be highly effective for rectal and urogenital infections; the agents involved are cefixime, cefodizime, cefotaxime, cefoxitin, ceftizoxime, ceftriaxone, cefuroxime, cefuroxime axetil, ciprofloxacin, fleroxacin, norfloxacin, ofloxacin, pefloxacin, temafloxacin, azithromycin, aztreonam, netilmicin, rifampin plus erythromycin stearate, sisomicin, and spectinomycin.”[3]
At first blush it seems we have used up a good number of drugs in the past 20 years but that is not really the case. Many quinolones on the list have become resistant to GC in lock-step with ciprofloxacin. Temafloxacin is gone because of a unique side effect (hemorrhagic uremic syndrome). Spectinomycin, a very atypical aminoglycoside, is no longer available in the US (abandoned by Pfizer around 2007) but still has adequate activity and could be resurrected if need be. Siso- and netilmycin have never seen much use in the US but the recent CDC Guideline mentions that gentamicin at a single IV dose of 240 mg may be an option for special cases. Of the macrolide class, erythromycin is out but azithromycin at the 1 g PO dose (in conjunction with ceftriaxone IM) or as a single drug regimen (2 gm PO of the extended-release form) has retained a solid place in the treatment option line-up.
Many of the beta-lactams have been decimated, however ceftriaxone experienced a marvelous come-back. Why has this drug beaten the odds and remains as active as ever? Well, if you look at the CDC data you get a bit concerned: in 2013, an increase in high-MIC level pathogens (MIC = 2) can be observed in 0.4% of isolates, a 3-4 fold increase over previous years. An ominous fact or just a blip?
Who knows. A single number does not make a trend, but Dr. Neisser’s gonococcus is a wily organism. Hence, it is good to see that FDA has bestowed QIDP status on several drugs now in development specifically for GC. In an upcoming blog I will discuss the 3 candidates: solithromycin (CEM-101), AZ-0914, and delafloxacin. Stay tuned.
NOTE: Updated STD Guidelines were published in MMWR June 5, 2015,
with the following recommendations:
Abbreviations:
GISP = Gonococcal Isolates Surveillance Project
References:
[1] http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/section-5-6-eng.php#toc361210467
[2] http://www.cdc.gov/std/gisp2013/table1.htm
[3] J Moran Clin Infect Dis 1995;20 (Suppl 1): S47
