Overview of Current Treatment Options for MRSA-Induced Pneumonia

Pneumonia Caused by MRSA and Its Treatment

MRSA is the causative agent in 9% of community-acquired pneumonias (CAP), 23% of nosocomial pneumonias (HAP), and 15% of pneumonias arising in association with ventilation support (VAP). Mortality in these infections reaches up to 50%. S. aureus, including MRSA, can also cause secondary pneumonia in patients with COVID-19.

Antibiotics used to treat MRSA-induced pneumonia vary significantly in terms of class, indication (CAP, HAP, VAP), pharmacodynamics/pharmacokinetics, available form, antibacterial spectrum (beyond MRSA), and toxicity profile, necessitating careful individual selection of a specific drug for each patient. Additionally, other agents effective against MRSA are in clinical development and may offer interesting or adjunctive treatment options in the future.

Ceftaroline Fosamil

Ceftaroline fosamil, a 5th generation cephalosporin in an i.v. form, shows in vitro activity against MRSA and is approved by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) for the treatment of CAP. However, randomized controlled trials (RCTs) with this drug did not include patients with MRSA infection, so we must rely on observational studies, whose meta-analysis shows a clinical success rate of 72% for ceftaroline fosamil. Tolerance is good, with mild gastrointestinal (GI) symptoms being the most common.

Ceftobiprole Medocaril

Another i.v. 5th generation cephalosporin with in vitro activity against MRSA is ceftobiprole medocaril. It is approved in some European countries for the treatment of CAP and HAP based on non-inferiority demonstrated in RCTs compared with ceftriaxone for CAP and ceftazidime for HAP. In the subset of patients with MRSA, it showed better results in terms of rapid improvement. Tolerance is good, with GI issues and injection site reactions being the most common side effects. Ceftobiprole medocaril is currently not approved for use in the Czech Republic.

Linezolid

Linezolid is an oxazolidinone available in p.o. and i.v. forms with excellent penetration into the fluid covering the respiratory epithelium. It is approved for the treatment of CAP, HAP, and VAP and has maintained its efficacy against MRSA for 15 years of clinical use, with resistance rarely reported. Meta-analyses of RCTs with patients suffering from MRSA pneumonia consistently show at least a trend towards higher efficacy, with varying statistical significance. In comparisons with vancomycin, a meta-analysis of 4 RCTs did not show a greater benefit for linezolid, but a subsequent meta-analysis of 6 RCTs did (a 19% higher chance of clinical recovery). Another RCT showed linezolid's superiority and lower nephrotoxicity compared to vancomycin. The most frequently reported side effects are myelosuppression and GI symptoms.

Delafloxacin

Delafloxacin is a new fluoroquinolone with in vitro activity against MRSA resistant to other fluoroquinolones. It is approved in p.o. and i.v. forms for the treatment of CAP. In an RCT, it demonstrated non-inferiority compared to moxifloxacin in terms of clinical response in patients with CAP, though only 2 patients in the study had MRSA infection, both in the delafloxacin group. There are no available results from observational studies with delafloxacin in treating MRSA CAP. Delafloxacin has lower neurotoxicity than other fluoroquinolones, and no severe phototoxicity or QT interval prolongation has been reported. Mild dysglycemia appears as a side effect.

Lefamulin

The semi-synthetic pleuromutilin lefamulin, recently approved for the treatment of CAP, shows in vitro activity against G⁺ and G⁻ bacteria including MRSA. Its noninferiority to moxifloxacin in the treatment of CAP has been confirmed by 2 RCTs. In the first study, both drugs were administered in an i.v. form, with linezolid added in the moxifloxacin arm for patients suspected of MRSA infection, and in the second study, both drugs were administered p.o. Lefamulin showed good tolerance, with nausea, insomnia, hypokalemia, and diarrhea (in p.o. form) being the most common side effects. Lefamulin can prolong the QT interval.

Omadacycline

Omadacycline belongs to aminomethylcyclines and is effective in vitro against various G⁺ and G⁻ bacteria including MRSA. The FDA approved its i.v. and p.o. forms, but the EMA did not grant registration due to a mortality difference unfavorable to omadacycline compared to moxifloxacin. Omadacycline demonstrated noninferiority to moxifloxacin in patients with CAP, though only one had MRSA positivity. The most common side effects are GI, and there are no observational study results available.

Other Medications

Current recommendations list vancomycin among the first-choice drugs for CAP, HAP, and VAP with suspected MRSA etiology based on its noninferiority in some comparative studies. However, its nephrotoxicity is a limitation. The use of telavancin in treating pneumonia is limited by a higher incidence of adverse effects compared to vancomycin, including nephrotoxicity.

Teicoplanin shows low lung penetration, and we have limited knowledge from RCTs in treating pneumonia. The lack of data from controlled studies in the pneumonia indication is also a limitation for trimethoprim-sulfamethoxazole, minocycline, doxycycline, and clindamycin, which can show in vitro activity against MRSA isolates. Regarding adding rifampicin as adjunctive therapy for MRSA pneumonia, there is no evidence of its benefit, and potential drug interactions and toxicity must be considered.

Conclusion

The availability of various drugs for treating MRSA-induced pneumonia allows for individualized treatment based on the severity of the condition, the onset of infection, specific patient risks, drug toxicity, potential drug interactions, and the route of administration.

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Source: Bassetti M., Labate L., Melchio M. et al. Current pharmacotherapy for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Expert Opin Pharmacother 2022 Feb; 23 (3): 361–375, doi: 10.1080/14656566.2021.2010706.