PerspectiveIn the Journals

Efficacy of azithromycin against M. genitalium declines

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August 12, 2015

The efficacy of a single gram of azithromycin for the treatment of Mycoplasma genitalium appears to be decreasing over time, according to the results of a meta-analysis.

“Even though most of the evidence is based on data from observational studies that have considerable variability in sample size and timing of microbial cure, this low efficacy is of concern and is well below the 95% threshold recommended by WHO for STI treatments,” Andrew Lau, of the University of Melbourne, and colleagues wrote in Clinical Infectious Diseases. “However, given that the prevalence of resistance mutations is increasing, it is vital that new treatment regimens for [M. genitalium] are investigated.”

The researchers conducted an online systematic review and meta-analysis of Embase, Medline, PubMed and the Cochrane Central Register of Controlled Trials using search terms such as “M. genitalium” and “azithromycin.” Twenty-one studies, involving 1,490 participants, met inclusion criteria, the researchers wrote. Of these, 16 were observational trials, four were randomized trials and one was a controlled trial.

Based on study results, the random effects pooled microbial cure rate was 77.2% (95% CI, 71.1%-83.4%). The pooled microbial cure was 85.3% (95% CI, 82.3%-88.3%) for the 12 studies completed before 2009, while the pooled microbial cure for the remaining studies conducted since 2009 was 67% (95% CI, 57%-76.9%).

With the prevalence of resistant mutations increasing, it is critical to investigate new treatments for M. genitalium, according to Lau and colleagues.

“A major barrier to improving the management of [M. genitalium] is that the majority of M. genitalium infections are presumptively exposed to 1 g azithromycin during management of associated syndromes,” they wrote. “This raises the broader and more complex issue of whether it is now time to address the presumptive use of azithromycin in [M. genitalium]-associated syndromes.”

In a related editorial, Patrick J. Horner, MD, of the School of Social and Community Medicine, University of Bristol, suggested taking a sensible approach to addressing this issue.

“Given that the lack of widely available commercial test on which to base rational prescribing decisions for treating M. genitalium, we need to be pragmatic until this happens,” he said. “First, do no harm therefore seems a sensible approach.”

According to Horner, one option would be to recommend a regimen of 100 mg doxycycline twice daily for 7 days for the treatment of nongonococcal urethritis or cervicitis. Another option would be prescribing an extended azithromycin regimen of 1.5 g over 5 days, which is “greater than 95% effective and associated with low risk of inducing macrolide antimicrobial resistance, ie, harm is minimized.” – by Colleen Owens

Disclosures: Lau and colleagues report no relevant financial disclosures. Horner reports relationships with Aquarius Population Health, the British Association for Sexual Health and HIV, Cepheid, Crown Prosecution Service, Hologic and Mast Group, as well as a patent for a bacterial vaginosis test.

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Khalil G. Ghanem

Khalil G. Ghanem

Mycoplasma genitalium is an emerging infection that causes urethritis and cervicitis. There are currently no FDA-cleared diagnostic tests for this infection. Many commercial laboratories do offer in-house validated molecular assays to detect this pathogen. These tests, however, are expensive and may not be available in most settings where patients are assessed for sexually transmitted infections. When caring for men with urethritis and women with cervicitis, clinicians are often unaware of the etiologic agent at the time when treatment is prescribed. As such, treatment is often empiric. Occasionally, a Gram stain may be used as a rapid test to detect gonorrhea. A negative Gram stain for Neisseria gonorrhoeae, however, does not ascertain the presence of M. genitalium, while a positive Gram stain does not rule out coinfection with M. genitalium.

The lack of reliable, rapid, and inexpensive tests to diagnose the causes of urethritis and cervicitis preclude clinicians from making informed therapeutic decisions. That lack of reliable point-of-care tests is at the heart of our current dilemma. We have known for a while that the efficacy of a single-gram dose of azithromycin to treat M. genitalium is waning. The meta-analysis by Lau and colleagues confirms this. We also know that a single gram of azithromycin induces the emergence of macrolide-resistant M. genitalium.  Unfortunately, none of the remaining options for the empiric treatment of urethritis and cervicitis are ideal: doxycycline is not an effective agent to treat M. genitalium and is no longer recommended by the CDC as part of the treatment regimen for gonorrhea — 1 g of azithromycin is. The use of a 5-day 1.5 g azithromycin regimen (500 mg on day 1, followed by 250 mg daily for 4 days) may be effective to treat M. genitalium and may reduce the probability of inducing the emergence of macrolide resistance, but data for the treatment of Chlamydia trachomatis with this regimen are limited, and the requirement for multiple doses is less appealing.

Finally, the empiric use of 10 to 14 days of moxifloxacin is expensive and potentially toxic. Currently, the CDC recommends a single gram of azithromycin or a week of doxycycline to treat nongonococcal cervicitis and urethritis. If gonorrhea is not ruled out, they recommend ceftriaxone plus a gram of azithromycin. None of these regimens are adequate to treat M. genitalium.

So what is the best choice? Horner, in his accompanying editorial to the Lau paper, offers some reasonable, but far from perfect, recommendations. Until reliable, inexpensive, rapid tests (or cheap, highly effective, single-dose antibiotics) become available, we will have to live with the consequences of our less-than-ideal therapeutic decisions.

Khalil G. Ghanem, MD, PhD
Associate professor of medicine
Johns Hopkins University School of Medicine

Disclosure: Ghanem reports no relevant financial disclosures.