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Gonorrhea: Treatment and prevention of the sexually transmitted superbug
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Neisseria gonorrhea is the second most commonly reported notifiable disease in the United States, only to be outdone by Chlamydia trachomatis. In 2012, there were 334,826 new cases of gonorrhea reported in the United States, but it is estimated that the true number of new gonorrhea cases is close to double that due to underdiagnosis and underreporting. Reporting of gonorrhea began in 1941, with the lowest recorded rate in history being in 2009; however, the rate has steadily been climbing since then. Also on the rise is the rate of gonorrhea resistance to each of the antibiotics that is used for treatment. Due to the rise in antibiotic-resistant gonorrhea, the CDC revised its treatment recommendations numerous times. Recently, a couple of new combination regimens have been discovered using pre-existing antibiotics that are promising in treating gonorrhea in this era of increasing antibiotic resistance.
Trends in resistance
Sulfonamide antibiotics were the first to be used in treatment of gonorrhea in the 1930s. However, resistance quickly developed after 2 years. When penicillin was developed, it was the next antibiotic used for gonorrhea treatment. It also fell victim to gonorrhea through the additive effects of chromosomal mutations resulting in multiple resistance mechanisms. Tetracycline was another important early treatment option for gonorrhea. However, it too saw increasing rates of gonorrhea resistance.
In the 1990s, both fluoroquinolones and cephalosporins were the recommended treatment options for gonorrhea, but by the late 1990s, resistance to ciprofloxacin had been detected. By 2006, nearly 14% of isolates in the United States were resistant to ciprofloxacin. These resistant isolates were found all over the country in both homosexual and heterosexual populations. This prevalence of ciprofloxacin resistance led the CDC to stop recommending fluoroquinolones as an empiric treatment option for gonorrhea. Susceptibility to cephalosporins has declined as well, which resulted in further revisions of the CDC’s recommended treatment options.
Kati Shihadeh
Mechanisms of resistance
Penicillin and cephalosporins: Initially, N. gonorrhoeae was very sensitive to penicillin; only 150,000 units were needed to treat an infection. As resistance increased, higher doses of penicillin were used and temporarily overcame the resistance, but eventually a large number of treatment failures were reported with high-dose penicillin. Penicillin and cephalosporins work by inhibiting bacterial cell wall synthesis by binding to penicillin-binding proteins. Chromosomal changes over several years led to alterations in penicillin-binding proteins, so there was a decreased affinity of penicillin and early generation cephalosporins for their binding sites and subsequently decreased susceptibility. N. gonorrhoeae also produces beta-lactamases that hydrolyze the beta-lactam ring, rendering penicillin and some cephalosporins ineffective. Genes that encode for beta-lactamases are plasmid mediated and easily transferable from one strain of gonorrhea to another, which can quickly lead to high level resistance.
Fluoroquinolones: This class of antibiotics works by binding to topoisomerases, including DNA gyrase to exert a bactericidal effect. One mechanism of gonorrhea resistance is by altering fluoroquinolones-binding sites on these enzymes. Another mechanism of resistance is decreased access of fluoroquinolones to these binding sites by changes in cell permeability and possibly by efflux mechanisms.
CDC recommendations
With the rise in antibiotic resistance to gonorrhea, the CDC has amended its recommended treatment options accordingly. With the rise in fluoroquinolone resistance, the CDC stopped recommending fluoroquinolones as a viable treatment option in 2007. Resistance to cephalosporins was on the rise as well, to the point in which, in 2010, the CDC increased the recommended dose of ceftriaxone from 125 mg intramuscularly to 250 mg intramuscularly as a single dose and recommended combination therapy with either 250 mg intramuscular ceftriaxone or cefixime (Suprax, Lupin Pharmaceuticals) 400 mg orally plus either azithromycin 1 g orally as a single dose or doxycycline 100 mg daily for 7 days. The rate of cefixime resistance continued to rise, so the CDC revised the 2010 guidelines in 2012 to no longer recommend cefixime as a first-line option. The CDC currently recommends ceftriaxone 250 mg intramuscularly as a single dose plus either a single dose of azithromycin 1 g orally or 7 days of oral doxycycline. There are two alternatives for patients who are unable to receive ceftriaxone. Cefixime 400 mg orally could be substituted for ceftriaxone. In the case of severe penicillin allergy, a single dose of azithromycin 2 g orally is recommended.
New combination regimens
A study conducted by the CDC and NIH was completed in 2013 and found two new promising regimens for the treatment of gonorrhea. The study was conducted in five cities in the United States. Patients received gentamicin 240 mg intramuscularly one time if they weighed more than 45 kg or 5 mg/kg intramuscularly one time if they weighed 45 kg or less, plus azithromycin 2 g by mouth one time, or patients received gemifloxacin (Factive, Cornerstone Therapeutics) 320 mg by mouth one time, plus azithromycin 2 g by mouth one time. Approximately 400 patients completed the study; about 200 in each arm. Microbiological efficacy of gentamicin plus azithromycin was 100%. The microbiological efficacy of gemifloxacin plus azithromycin was 99.5%. Neither regimen was associated with any severe adverse events. Adverse effects of diarrhea, nausea and vomiting were more prevalent in the gemifloxacin group.
Gonorrhea is one of the most common STDs in the United States. Without proper treatment, this infection can lead to serious problems, including chronic pelvic pain, life-threatening ectopic pregnancy, infertility and facilitation of HIV transmission. Gonorrhea was once highly susceptible to many antibiotics, but in time it has developed resistance through various mechanisms to several classes of antibiotics. Ceftriaxone combined with azithromycin or doxycycline is the preferred and highly effective treatment option.
The two new combination regimens of gentamicin plus azithromycin and gemifloxacin plus azithromycin are promising and should be considered by providers when ceftriaxone cannot be used.
CDC. MMWR. 2012; 61:590-594.
CDC. MMWR. 2010;59:1-110.
National Institute of Allergy and Infectious Diseases (NIAID). Randomized Clinical Trial Evaluating the Efficacy of Gentamicin/Azithromycin and Gemifloxacin/Azithromycin Combination Therapies as an Alternative Regimen for Uncomplicated Urogenital Gonorrhea. 2014. Available at: http://clinicaltrials.gov/show/NCT00926796. Updated July 16, 2014. Accessed August 6, 2014.
Patel AL. J Med Res. 2011;134:419-431.
Disclosure: Shihadeh reports no relevant financial disclosures.