Infectious Disease Alert Updates
September 1, 2022
- Cumulative Estrogen Exposure Linked to Lower Stroke Risk
- Wider Access to SNAP Benefits Could Improve Healthcare Outcomes Among Children
- For Older Americans, More Steps Lead to Better Cardiovascular Health
- Chlorthalidone vs. Hydrochlorothiazide: Which Is Superior for Treating Hypertension?
- Resistance of SARS-CoV-2 Variants to Monoclonal Antibodies
By Carol A. Kemper, MD, FACP
Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center
Questions in Gonorrhea Management
SOURCE: Barbee LA, St Cyr SB. Management of Neisseria gonorrhoeae in the United States: Summary of evidence from the development of the 2020 Gonorrhea Treatment Recommendations and the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infection Treatment Guidelines. Clin Infect Dis 2022;74(Suppl 2):S95-S111.
A group of subject matter experts convened to discuss key questions and concerns in the management of gonorrhea in adolescents and adults in the United States. More than 2,200 abstracts and 248 articles available between 2013 and 2019 were reviewed, and the discussion focused on several main topics, as follows:
1. Optimal treatment for gonorrhea at all anatomic sites.
Ceftriaxone (CFTX) remains the mainstay of therapy for gonorrhea (GC) at all anatomic sites. Ongoing data from the Gonococcal Isolate Surveillance Project (GISP) shows relatively stable minimum inhibitory concentrations (MICs) to CFTX, with 0.21% of all isolates having CFTX MICs ≥ 0.125 mcg/mL and < 0.1% demonstrating “high alert” MICs > 0.25. Most of these resistant isolates have been found in the Northeast and West, and none have been found in the Midwest. However, given concerns about the inevitable upward trend in MIC, the current 2021 sexually transmitted disease (STD) treatment guidelines recommended increasing the treatment dose for uncomplicated GC for all anatomic sites to CFTX 500 mg intramuscular (IM) single dose; and for individuals weighing more than 150 kg, 1 gram IM single dose. If chlamydia has not been ruled out, then add doxycycline 100 mg orally BID for seven days. While treatment failures, especially at extragenital sites, occur, none have yet been associated with laboratory-confirmed resistance to CFTX.
Since the publication of the previous Centers for Disease Control (CDC) STD treatment guidelines in 2015, there has been a disappointing and rapid decline in susceptibility to azithromycin, with 5% of isolates demonstrated MIC ≥ 2 mcg/mL in 2018.
Unfortunately, no single agent meets the World Health Organization (WHO) and CDC recommended goal of reliably achieving > 95% cure for extragenital sites, including CFTX, which generally provides > 99% effectiveness for urogenital infection but variously reported diminished effectiveness against rectal GC (88.5% to 99.9%) and pharyngeal GC (91.4% to 97.9%).
Cefixime monotherapy (either 400 mg or 800 mg orally) was effective in urogenital infection but much less effective in rectal (90%) or pharyngeal (64%) infection.
Gentamicin 240 mg remains effective for most cases of urogenital infection but was not adequate for rectal (90%) or pharyngal (84%) infection. When combined with azithromycin 2 grams, the effectiveness was much better for all anatomic sites — but this effect may be eroded by the increasing loss of azithromycin susceptibility, and therefore no longer is recommended. Even higher doses of gentamicin (360 mg) IM were not sufficiently effective and may be associated with an increased risk of ototoxicity/nephrotoxicity, and therefore this combination is not recommended for first-line therapy.
2. What treatment alternatives are there for GC?
Treatment in patients with severe penicillin and cephalosporin allergy remains a challenge. Primary care providers first must determine the likelihood of a true (severe) penicillin allergy — which really only affects < 1% of the population. Cross reaction with cephalosporins is unlikely.
If a true penicillin or cephalosporin allergy cannot be ruled out, and susceptibility testing for ciprofloxacin is available to verify susceptibility, then ciprofloxacin 500 mg orally single dose therapy is recommended. Treatment with ciprofloxacin is not recommended for pregnant or nursing women. Otherwise, gentamicin 240 mg IM plus azithromycin 2 grams orally should be given. While these agents may be effective for urogenital infection, none of these treatments is guaranteed to be effective in pharyngeal infection.
3. Is test of cure still recommended?
Based on available evidence, test of cure is not recommended for urogenital and rectal infection. However, test of cure is required for pharyngeal infection in all patients, regardless of which treatment they received.
It is recommended that both cultures and nucleic acid amplification test (NAAT) be obtained in such cases, so that susceptibility testing can be obtained if needed. Follow-up testing should occur > 7 days and < 14 days following initial treatment. If only NAAT testing is done and is found to be positive, it is strongly recommended that culture/susceptibility be obtained before further treatment is given.
4. Is immediate partner treatment still appropriate?
Yes. Available data continue to strongly support recommendations for immediate referral of all sexual partners for testing and treatment with CFTX.
5. Are current GC surveillance recommendations appropriate?
Routine surveillance for GC infection of all anatomic sites should be performed every three months for all high-risk men who have sex with men (MSM), including those on pre-exposure prophylaxis (PreEP). MSM at lower risk, along with other male adolescents and adults at lesser risk, can be screened every six to 12 months. All sexually active women at risk for GC should be screened at least annually for urogenital infection, or more often as necessary (this was broken down by age, new sex partner, number of partners, number of partners of the new sex partner, etc.). Generally, women are not at risk for pharyngeal and rectal infection, and such screening is not required, with the exception of female sex workers, who have a higher risk of pharyngeal infection. (Author’s note: Since sexual histories often are less than accurate, more liberal screening may be appropriate for some patients.)
Re-infection is common, and it is recommended that both men and women with a diagnosis of GC be retested at three months.
6. Diagnostic testing, including that for disseminated GC infection (DGI).
For patients at risk who are being surveilled more frequently, it is reasonable to educate patients on home self-collection of specimens for all anatomic sites.
While agar dilution is considered the gold standard for susceptibility testing, gradient strips are an acceptable alternative.
For DGI cases, it is strongly recommended that specimens be obtained simultaneously from any available site (e.g., skin, synovial fluid, blood, and central nervous system), as well as both urogenital and extragenital sites, for both NAAT and culture. Even then, the diagnosis may be difficult to confirm.
Ertapenem Non-Inferior to Ceftriaxone in Gonorrhea
SOURCE: de Vries HJC, de Laat M, Jongen VW, et al. Efficacy of ertapenem, gentamicin, fosfomycin, and ceftriaxone for the treatment of anogenital gonorrhea (NABOGO): A randomized, non-inferiority trial. Lancet Infect Dis 2022;22:706-717.
Four different therapeutic agents were compared for the treatment of urogenital and/or anorectal gonorrhea (GC) in this randomized, double-blinded non-inferiority trial, conducted between 2017 and 2020 in the Netherlands. A total of 346 adults 18 years of age or older with confirmed or suspected urogenital and/or anorectal GC were randomized in a 1:1:1:1 fashion to receive either ceftriaxone 500 mg intramuscular (IM) (the control group), ertapenem 1,000 mg IM, gentamicin 5 mg/kg IM (maximum dose 400 mg), or oral fosfomycin 6 grams. A secondary analysis examined the effectiveness of treatment in pharyngeal infection. All of the patients returned for follow-up for test of cure testing between seven and 28 days. Fosfomycin was chosen based on earlier study data demonstrating 97% effectiveness in male urethritis using 3 grams orally on three days (days 1, 3, and 5).
Both ceftriaxone and ertapenem were highly effective in both urogenital/anorectal infection, with a 93/93 (100%) cure with ceftriaxone and 86/87 (98.8%) cure demonstrated for ertapenem. Gentamicin was effective in 79/85 subjects (93%), considered below the 95% World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) treatment goal for GC.
The fosfomycin arm was terminated prematurely when, during interim analysis, only 4/33 (12%) participants had achieved cure. This was a real disappointment because it was the only potential oral treatment option for GC.
In the secondary analysis, the efficacy of the four agents for pharyngeal disease was 90% for ceftriaxone, 88% for ertapenem, 26% for gentamicin, and 0% for fosfomycin. Adverse reactions occurred in 23% of patients receiving ceftriaxone, 56% of patients receiving ertapenem, and 95% of those receiving fosfomycin — almost all due to diarrhea associated with the higher dose. Most of these adverse reactions had resolved by the time of the follow-up visit. Fourteen patients in the gentamicin arm (16.5%) had diminished renal function, although none with glomerular filtration rates < 50 mL/min.
There was no apparent difference in minimum inhibitory concentrations (MICs) to ceftriaxone, ertapenem, gentamicin — or even fosfomycin — comparing patients with microbiologic cure vs. treatment failure. Isolates from all sites were compared by Multi-Antigen Sequence Typing (NG-MAST), and for each patient with more than one site of infection, the same isolate was identified.
Only ertapenem proved non-inferior to ceftriaxone in the treatment of urogenital/anogenital GC in this double-blind, randomized, clinical treatment trial. This is good news for patients with severe cephalosporin allergy, or those with extended spectrum drug resistance to cephalosporins, where ertapenem still may retain activity. However, its effectiveness in pharyngeal GC (88%) was similar to ceftriaxone (90%), and neither met the WHO/CDC goal of > 95% efficacy for this anatomic site. More generalized use of ertapenem probably is not going to occur, based on the potential contribution to emerging carbapenem resistance in gram-negative pathogens.
Questions in Gonorrhea Management; Ertapenem Non-Inferior to Ceftriaxone in Gonorrhea
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