Piercing Through: Lefamulin Treatment of an Antibiotic-Resistant Mycoplasma Genitalium Urethritis

Abstract

Multidrug-resistant (MDR) Mycoplasma genitalium (M. genitalium) presents a significant risk of treatment failure in many sexually transmitted infections (STIs) and can result in persistent and recurrent urethritis or cervicitis. This case report describes a recurrent M. genitalium urethritis resistant to sulfamethoxazole-trimethoprim (TMP-SMX), doxycycline, and moxifloxacin. The infection was ultimately cured after both the removal of a nidus of infection and through the use of Lefamulin. Lefamulin is a novel agent approved for use in community-acquired bacterial pneumonia and bacterial skin infections that may be useful in difficult sexually transmitted infections. Background/Objectives: Deciding whether or not to treat M. genitalium can be challenging as it can be a colonizer, or present with a symptomatic pathogen, and even if it is causing symptoms, it can be drug-resistant. Our objective here is to highlight important considerations on whether or not to treat and, if so, what options exist. Conclusions: In a world of increasing drug-resistant STIs, this case highlights the challenges of managing MDR M. genitalium and how foreign bodies can allow reoccurrence. Also highlighted in this case, Lefamulin appears to be a viable alternative line of treatment of MDR M. genitalium that defies other first-line antibiotics.

1. Introduction

Mycoplasma genitalium is an emerging pathogen STI that was first identified in the early 1980s. This small, cell wall-deficient bacterium has been associated with a variety of urogenital conditions, including urethritis in men and cervicitis and pelvic inflammatory disease in women [1]. The bacterium, similar to many others, mainly causes urethritis in men largely due to the longer male urethra, which provides a higher surface area for the bacterium to adhere to and colonize [2].

A key distinction in the pathogenicity of M. genitalium is between colonizing and infecting pathogens. Colonizing M. genitalium bacteria are present on mucosal surfaces, but do not cause symptoms in the host. An infecting M. genitalium bacterium is characterized by the active invasion of tissues, triggering an immune response and symptomatic disease. It is important to note that a colonizing M. genitalium is harder to identify and treat as it is not being actively attacked by the host’s immune system [1]. The distinction between the two different roles that M. genitalium can play is crucial for understanding the clinical impact and the responsible management of the pathogen in order to prevent the creation of further MDR M. genitalium.

Despite its clinical significance, routine testing for M. genitalium is not widespread, primarily due to several challenges and limitations. In fact, due to the high incidence of colonization, many experts feel that M. genitalium should not be included in the initial diagnostic workup until other pathogens are ruled out and symptoms persist [3]. At our institution, testing for M. genitalium is recommended only after other pathogens are ruled out and the patient has failed treatment for nongonococcal urethritis (typically doxycycline). Furthermore, NAAT testing for M. genitalium takes ~2 weeks to produce a result, while results for gonorrhea and chlamydia are returned in ~2 days, which can lead to empiric prescribing. Once identified, we strive to follow CDC guidelines [3], with first-line therapy being 7 days of doxycycline, followed by azithromycin, and if macrolide resistance is known, then doxycycline is used, followed by moxifloxacin. One major hurdle is the lack of standardized, FDA-approved diagnostic tests, which hinders the consistent detection of this pathogen in clinical settings, although Nucleic Acid Amplification Tests (NAATs) for M. genitalium are available [4]. Furthermore, M. genitalium is difficult to culture properly, limiting its reproduction to only labs with sophisticated cell culture apparatuses [5].

2. Case

The patient is a 25-year-old cisgender male who has sexual intercourse with men (MSM), with a history of well-controlled, suppressed human immunodeficiency virus (HIV). He presented with intermittent dysuria and pelvic pain for 6 months, as well as clear urethral discharge. Upon physical exam, he has a genital piercing at the penile tip which has been there for more than 3 years.

He initially received sulfamethoxazole-trimethoprim 800/160 mg twice daily for seven days due to cellulitis of genital piercing or suspected urinary tract infection (UTI). His symptoms did not resolve. The patient then underwent M. genitalium testing, received a subsequent positive result, and doxycycline 100 mg was initiated twice daily for another seven days of therapy. Symptoms improved but recurred after approximately one month. Mycoplasma testing was repeatedly positive, and a treatment of moxifloxacin 400 mg daily for seven days was initiated, leading to symptom improvement and a negative test of cure.

One month after the negative test result, the patient re-presented with similar symptoms, as well as urine NAAT positive for chlamydia and mycoplasma. Upon recommendation, the patient temporarily removed his genital piercing, doxycycline was re-initiated because the chlamydia test came back well before the mycoplasma test and there was a negative test of cure to both organisms after three weeks. The patient reapplied his genital piercing after the resolution of symptoms from this encounter. Based on the patient’s reported sexual history, no additional partners were identified during the course of illness. The patient’s current partner’s mycoplasma repeat testing was positive and chlamydia negative, at which point mycoplasma resistance testing revealed mutations in the 23S rRNA gene consistent with macrolide resistance, and the patient concurrently saw urology in consultation. Urology recommended a course of doxycycline 100 mg twice daily for fourteen days to both the patient and their partner.

After initial treatment with TMP-SMX, doxycycline, and moxifloxacin, and a negative mycoplasma test from the partner, the patient received Lefamulin 600 mg twice daily for 14 days with the aim of improving symptoms and was recommended to temporarily remove the piercing. The partner never tested positive for M. genitalium. Symptoms initially improved, but two months after the trial of Lefamulin, the patient reapplied their genital piercing and symptoms recurred, after which Lefamulin was re-trialed (see Figure 1, time course) and the patient was willing to finally permanently remove the piercing after the three previous temporary removals. The removed piercing was not sampled and tested as the patient was now asymptomatic following the final trial of Lefamulin. Since the piercing was removed, the patient has been asymptomatic for 30 months, no further mycoplasma testing has been performed; regular anal swabs, and urine Nucleic Acid Amplification testing for chlamydia and gonorrhea have been negative.

3. Discussion

M. genitalium infects the human genital tract much less commonly than, for example, chlamydia, but approximately ~1–2% of people have M. genitalium in their urogenital tract as either pathogen or colonizer [6]. Sometimes, M. genitalium occurs in the presence of other organisms that also may colonize or cause pathology in the human urogenital tract. Distinguishing when M. genitalium should be tested for, and whether or not it is playing a pathogenic role, is not always straightforward, and controversy persists [7]. Currently, the CDC recommends against routine screening. The only exceptions are current sex partners of individuals treated for symptomatic M. genitalium infection and persistent or recurrent urethritis or cervicitis or PID in the absence of gonorrhea or chlamydia and with persistent symptoms despite therapy [8].

M. genitalium’s pathogenesis is linked to its infectious ability and particular structures that allow it to latch on to the epithelial cells of the host. For example, two of its surface proteins, MgpB and MgpC, are considered virulence factors. MgpB attaches the pathogen to the urogenital tract epithelial cells while MgpC cements this bond, so adherence is sustained for future colonization. In addition, these proteins exert antigenic variation to enhance immune evasion, as this cementing over time keeps the organism under the radar of the immune system long enough that immune clearance is ineffective [6]. Furthermore, M. genitalium promotes tissue damage for an immune response via inflammation; it activates Toll-like receptors which drive the upregulation of production and the secretion of pro-inflammatory cytokines, which worsen tissue damage and symptoms [6]. However, asymptomatic colonization is also a possible outcome of M. genitalium infection, perhaps even the most common outcome [8].

As antimicrobial resistance has increased, treatment for M. genitalium infection has become more complicated. The recommended first line of treatment in the United States per the CDC is doxycycline for 7 days, followed by either moxifloxacin or azithromycin [8,9,10]. The use of doxycycline first can lower the overall bacterial burden such that resistance emerges less frequently. Unfortunately, because of macrolide resistance due to mutations in the 23S rRNA gene, failure is common [6]. Should treatment fail or macrolide resistance be found, the second line of drug therapy is fluoroquinolones, with moxifloxacin being the drug of choice. Unfortunately, due to mutations in the parC and gyrA genes, resistance to fluoroquinolones is also increasing, compounding options [7]. At this point, the literature suggests high resistance rates of doxycycline and macrolides (50–70%) [11,12,13,14,15,16] and growing moderate resistance to quinolones (20–30%) [17,18,19].

AMR in M. genitalium represents a critical clinical and public health issue. Currently, increased resistance is noted with this mycoplasma due to rapid mutation, allowing for more frequent treatment failure and difficult clinical presentation for the clinician. However, with increasing susceptibility testing and the possibility of new antimicrobials, there is hope for the definitive treatment of this infection in the future [7]. In some regions of the world, older antibiotics such as pristamycin have been made available by health authorities. While more data is needed before this becomes routine, some experts have noted that minocycline MICs are slightly lower than those of doxycycline, so perhaps they offer an advantage [20]. A recent trial of minocycline and metronidazole supports this approach [21].

Mycoplasma species lack a cell wall and are inherently resistant to antimicrobials that act at this site, but are often treated with macrolides and tetracyclines, which target the 50S and 30S ribosomal subunits, respectively [22].

Pleuromutilins are an emerging class of antibiotics in approaching the challenge of MDR organisms. Lefamulin is a newer agent in the class and is currently FDA-approved for community-acquired bacterial pneumonia due to the common respiratory pathogens, as well as mycoplasma species that are macrolide-resistant. The mechanism of action of Lefamulin involves binding to the central component of bacterial 23S rRNA through multiple molecular interactions, including hydrophobic, van der Waals, and hydrogen bonds. This is a novel mechanism that does not appear to be compromised by resistance to other agents that also act on protein synthesis.

The class of chemically related molecules that act in this way are collectively called pleuromutilins. In comparison to other pleuromutilins, Lefamulin contains a C-14 side chain that provides increased protection against mutations and resistance, as it can bind more hydrogen bonds to its target and induce the clearance of the pathogen. Other agents in the class, including tiamulin and retapamulin, do not possess this additional hydroxyl group, but instead include side chains with a nitrogen-containing moiety [4].

In an in vitro study quantifying minimum inhibitor concentrations (MICs) of organisms implicated in STIs, Lefamulin exhibited MICs between 0.002 and 0.063 for M. genitalium, compared to 0.5 to 1 for doxycycline and 0.125 to >16 for moxifloxacin [23]. Investigators in this study identified lefamulin as a potential first-line treatment for this organism due to rising rates of resistance.

With increasing rates of resistance in MDR M. genitalium against common first-line agents, lefamulin is an agent with increasing potential for providing effective treatment of infection with this pathogen. While lefamulin is not yet considered in guidelines for STIs, it provides an option for patients with resistant infections that do not meet resolution after initial treatment. Lefamulin has the potential to overcome resistance mechanisms present in MDR M. genitalium and possibly other sexually transmitted infections. A recent study of lab strains and 49 clinical isolates of M. genitalium including multiple MDR isolates, with 28% being resistant to quinolones, 57% resistant to macrolides, and many resistant to both, demonstrated 100% susceptibility to Lefamulin at or below 0.064 ug/mL [24]. There is also in vitro data to support using Lefamulin for N gonorrhea infection, another situation where MDR is common and few options exist [25]. As this is a single case report and the molecular typing of the M. genitalium was not available, it is hard to definitively determine that this was a single recurrent infection, perhaps facilitated by the piercing foreign body. Nevertheless, it provides some anecdotal data that may aid in atypical recurrent cases.

While the decision making in this case was made without the benefit of clinical data with Lefamulin, just recently a small trial of Lefamulin was published suggesting benefit in some cases, though not all cases were resolved [26]. In brief, 28 heavily antibiotic-exposed MG-infected patients received either Lefamulin monotherapy or a variety of Lefamulin/doxycycline combinations. Lefamulin was well tolerated and likely contributed to clearance in about half of the cases, but failed to eradicate many infections.

4. Conclusions

This case highlights the growing challenge of managing MDR M. genitalium. The patient’s persistent symptoms despite treatments with first- and second-line antibiotics underscore the challenging nature of MDR M. genitalium management. The successful treatment of this recurrent infection with Lefamulin indicates its potential as a promising treatment for MDR M. genitalium. Lefamulin’s unique mechanism of action and high efficacy against resistant pathogens suggests that it may play a pivotal role in addressing drug-resistant infections as a whole.

Moreover, this case demonstrates the importance of comprehensive patient management, including the identification and removal of infection inducers such as genital piercings, to achieve successful treatment outcomes. It also underscores the need for further research into resistance mechanisms, alternative therapies, and the inclusion of novel agents like Lefamulin in treatment guidelines.

Finally, with the increasing prevalence of STIs and the widespread adoption of prevention strategies such as DoxyPEP, there is an urgent need to balance preventive measures with antimicrobial stewardship to prevent the emergence of further resistance. While Lefamulin has been taken off the market, there remains a need for novel agents like it or others may still be needed given how common antibiotic-resistant STIs have become.