Two cases of multidrug-resistant genitourinary Mycoplasma genitalium infection successfully eradicated with minocycline

Introduction

Mycoplasma genitalium (MG) causes up to 25% of nongonococcal urethritis (NGU) cases. ¹ The macrolide azithromycin is still used for NGU treatment in many areas of the world. However, with emergence of MG strains carrying macrolide-associated resistance gene mutations (MRMs), the azithromycin cure rate for MG infections has declined. ² Three successive randomized controlled trials of azithromycin versus doxycycline (a tetracycline) for NGU reported azithromycin cure rates for MG falling from 87% to 40% and doxycycline being essentially ineffective (<50% cure rate). ² The fluoroquinolone moxifloxacin, previously effective against MG infections not cured by azithromycin, is now less efficacious (with cure rates <90% in several studies ³ ) as strains with quinolone-associated resistance mutations (QRMs) have emerged. ⁴

In some areas of the world, including the U.S., there are no other antibiotics with proven efficacy against MG infections with MRMs and QRMs that have failed azithromycin and moxifloxacin. There are sparse data supporting the use of the tetracycline minocycline in these cases. ⁵ Here, we report two cases of resistant MG NGU in HIV-negative men who have sex with men (MSM) that presented in 2017 and were cured with an extended course of minocycline.

Case report

Patient 1 was a 31-year-old MSM with complaints of dysuria and penile discharge. His genitourinary examination was unremarkable, except for shoddy inguinal adenopathy. He had a negative urine gonorrhea and chlamydia nucleic acid amplification test (NAAT) and a positive urine MG NAAT (BioReference Laboratories, New Jersey, USA). Rectal NAAT was not performed given the lack of clinical exposure and symptoms. His urinary symptoms persisted and MG NAAT remained positive over a five-month period despite these treatments: azithromycin 1 g, moxifloxacin 400 mg once daily for 7 days, doxycycline 100 mg twice daily for 14 days, azithromycin 1 g weekly for four weeks, and moxifloxacin for four weeks. He then received a six-week course of both doxycycline and moxifloxacin, with temporary symptom improvement, but his dysuria eventually recurred. The patient was in a non-monogamous relationship. His primary partner tested MG negative twice (by urine and anal NAAT) and was empirically treated on two occasions with azithromycin 1 g and subsequently a one-week course of moxifloxacin.

After failing the dual treatment regimen, the patient was confirmed to have persisting MG infection by real-time PCR ⁶ and his urine sample was evaluated for MRMs and QRMs. Sequencing of the amplicon revealed a MRM in 23S rRNA at A2072G (E. coli numbering 2059). ⁷ A QRM in parC was also identified (G248T, which causes the amino acid change S83I [E. coli numbering 80]), ⁸ as was a point mutation in gyrA (G295A [D99N]) with unknown function. The patient was treated with a 14-day course of minocycline 100 mg twice daily and his symptoms resolved. Urine MG NAAT four weeks after completion of treatment was negative.

Patient 2 was a 32-year-old monogamous MSM complaining of dysuria and urethral discharge. His genitourinary examination was unremarkable. He had a negative urine gonorrhea and chlamydia NAAT and a positive urine MG NAAT (BioReference Laboratories). Rectal NAAT was not performed given the lack of clinical exposure and symptoms. His positive urine MG NAAT and symptoms persisted over a four-month period despite these treatments: azithromycin for 5 days (500 mg day 1, 250 mg days 2–5), moxifloxacin 400 mg once daily for 7 days, followed by moxifloxacin for four weeks with doxycycline (started at the tail end and expanded for another 10 days). His partner tested MG negative by urine and anal NAAT.

After failing the dual treatment regimen, persisting MG infection was confirmed by real-time PCR and sequencing revealed the A2072G 23S rRNA MRM and the G248T parC QRM. He was treated with minocycline 100 mg twice daily for 14 days with complete symptom resolution. NAATs from urine and urethral swab were MG negative six weeks after treatment completion.

Discussion

MG treatment has become more challenging due to the emergence of MG strains with both MRMs and QRMs, and detection of these strains may be becoming more widespread. A study of 140 MG-infected persons in Melbourne, Australia, reported that 8.6% had strains with both MRMs and QRMs, ⁴ and a study of 25 HIV-infected MSM with MG infection in Alabama, USA, reported these strains in 24%. ⁹

Despite doxycycline’s poor efficacy against MG, ² for which the responsible mechanism is not understood (tetracycline resistance-associated mutations have not been identified ¹⁰ ), men with MG NGU in our case report and in another case report ⁵ were treated successfully with an extended minocycline course despite failing multiple other treatments (including doxycycline). Minocycline is a drug within the tetracycline class. Minimum inhibitory concentrations of minocycline for reference and clinical MG strains seem slightly lower than those of doxycycline and structural differences between the two antibiotics likely affect how well the drug works in vivo. ¹¹ The most common side effects of minocycline are nausea and diarrhea; however, other notable side effects include dizziness, headache, and fatigue.

There are limited alternative antibiotic options with efficacy against MG strains with MRMs and QRMs, including the streptogramin pristinamycin, the ketolide solithromycin, and the fluoroquinolone sitafloxacin ¹⁰ ; however, they are not available in many parts of the world, including the U.S. For these areas, minocycline may be a reasonable treatment option for resistant MG strains that have failed macrolides and fluoroquinolones until other treatments become available.