Mycoplasma genitalium: A formidable foe in need of new treatment, diagnostic options
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As an infectious diseases pharmacist who works in a hospital setting, I do not often encounter patients with Mycoplasma genitalium.
However, I was recently asked about obtaining lefamulin for an outpatient with a persistent M. genitalium infection despite a couple of courses of standard treatment.
M. genitalium has been an established cause of sexually transmitted infections in both men and women since it was first identified in the early 1980s. The true incidence of M. genitalium in the United States isn’t actually known because it’s not a reportable infection, and few epidemiological studies have been done in the general population. However, a recent meta-analysis reported a worldwide prevalence of 1.3% to 3.9%, with countries with lower levels of development having the highest rates. The incidence in high-risk groups such as patients screened in sexual health clinics has been as high as 35%, especially in men with nongonococcal urethritis.
M. genitalium is primarily associated with nongonococcal, nonchlamydial urethritis in men and cervicitis in women. More serious complications such as pelvic inflammatory disease, spontaneous abortions and infertility have also been associated with M. genitalium infections in women. It is a very slow-growing fastidious organism that complicates both diagnostic techniques and obtaining susceptibility information. Because M. genitalium cultures can take up to 6 months, nonculture diagnostics such as nucleic acid amplification tests are the primary mechanism for diagnosis. Unfortunately, molecular tests to detect antimicrobial resistance markers are not commercially available in the U.S. at this time. The lack of available resistance testing, along with the limited number of antibiotics available for managing M. genitalium infections, creates a significant problem when trying to treat patients with this infection, especially those with recurrent or persistent infection.
Increasing resistance
Antibiotic resistance is an increasing problem for STIs, and M. genitalium is no exception. The prevalence of macrolide resistance with M. genitalium is high and continues to increase in many parts of the world, with most countries reporting more than 40% resistance. Treatment with azithromycin alone can select for resistance during therapy for macrolide-susceptible strains and is not recommended. This is why two-stage therapy is recommended in the CDC’s new STI treatment guideline (Table). Initiating treatment with doxycycline reduces the organism burden, facilitates clearance and can help reduce the risk for developing resistance. A recent study enrolled men with urethritis symptoms at six STD clinics and found that among those treated with azithromycin-based therapy alone, persistent symptoms were reported by 25.8% of patients with a macrolide-resistant M. genitalium infection, whereas 13% of those without macrolide resistance reported ongoing symptoms.
Fluroquinolone resistance has also emerged because of mutations in the quinolone resistance determining regions of the parC gene. The prevalence of this mutation in the U.S. has been reported to be as high as 15%. This resistance is of clinical significance because studies have demonstrated a significant decline in clinical cure rates following treatment with moxifloxacin from 100% before 2010 to 89% in later studies.
Promising treatments
Lefamulin is a pleuromutilin that inhibits bacterial protein synthesis by binding to the 50S subunit at the peptidyl transferase center, which prevents peptide bond formation. It has a novel mechanism of action by a unique induced-fit mechanism to close the binding pocket within the ribosome, which ensures tight binding of the drug to the target site. Because of this mechanism, cross-resistance with other antibiotic classes is low. It has potent in vitro activity against many gram-negative and gram-positive bacteria.
Although published clinical studies are lacking, in vitro data suggest lefamulin has potent activity against pathogens that commonly cause STIs, including multidrug-resistant Neisseria gonorrhoeae and M. genitalium. Lefamulin penetrates genitourinary tissues, including the prostate and pelvic tissues, making it an attractive agent for treatment of STIs, especially in populations with high rates of macrolide or fluoroquinolone resistance, and in those for whom treatment with standard-of-care antibiotic regimens has failed.
Lefamulin is available in both IV and oral formulations. Unfortunately, the cost of lefamulin can certainly be a barrier, in addition to obtaining insurance authorization, which can be difficult. Lefamulin oral dosage is 600 mg twice per day, with a current average wholesale cost of approximately $330 per day of treatment. A patient assistance program is available, along with other patient access resources that may be helpful in obtaining the agent for patients.
Solithromycin is another promising agent that is not FDA approved but has potent activity against M. genitalium. However, solithromycin was found to be inferior to ceftriaxone plus azithromycin for treatment of uncomplicated genital gonorrhea in the SOLITAIRE-U trial.
Emerging resistance and limited treatment options for those with resistant or recurrent M. genitalium infections present significant challenges in managing these infections. When faced with symptomatic treatment failure or positive test of cure after standard regimens, the CDC guidelines recommend expert consultation to help guide treatment options. Clearly, new treatment options are needed. More importantly, improved diagnostic testing is needed to quickly identify those infected with M. genitalium while concurrently identifying antimicrobial resistance so treatments can be optimized to improve patient outcomes. Continuing to treat M. genitalium infections without knowing the resistance profile may actually be making our resistance issues worse with this infection by increasing treatment failures and increasing the risk of transmitting to others.
- References:
- Bachmann LH, et al. Clin Infect Dis. 2020;doi:10.1093/cid/ciaa293.
- Baumann L, et al. Sex Transm Infect. 2018;doi:10.1136/sextrans-2017-053384.
- Bradshaw C, et al. J Infect Dis. 2017;doi:10.1093/infdis/jix132.
- Chen MY, et al. Lancet Infect Dis. 2019;doi:10.1016/S1473-3099(19)30116-1.
- Gnanadurai R, Fifer H. Microbiology. 2020;doi:10.1099/mic.0.000830.
- Li, Y, et al. Int J STD AIDS. 2017;doi:10.1177/0956462416688562.
- Paukner S, et al. Antimicrob Agents Chemother. 2018;doi:10.1128/AAC.02380-17.
- Veve M, Wagner JL. Pharmacotherapy. 2018;doi:10.1002/phar.2166.
- Workowski KA, et al. MMWR Recomm Rep. 2021;doi:10.15585/mmwr.rr7004a1.
- For more information:
- Jeff Brock, PharmD, MBA, BCPS AQ-ID, is an Infectious Disease News Editorial Board Member and an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at: jbrock@mercydesmoines.org.
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