Nafithromycin in community-acquired bacterial pneumonia: a focused systematic review of the human clinical development program

Nafithromycin is a novel lactone ketolide being developed as a short-course oral treatment for community-acquired bacterial pneumonia (CABP). Its clinical development program includes early pharmacokinetic studies in healthy adults and later-phase efficacy trials in patients with CABP. This systematic review aimed to synthesize the available human clinical evidence on its pharmacology, safety, and efficacy. This systematic review was conducted in accordance with PRISMA 2020 and registered in PROSPERO (CRD420261367133). PubMed/MEDLINE, Embase, Scopus, CENTRAL, ClinicalTrials.gov, and the Clinical Trials Registry - India were searched from inception to 12 April 2026. Clinical studies evaluating nafithromycin in humans at any stage of development were eligible. Study selection and data extraction were performed independently by two reviewers. Given heterogeneity in study phase, design, population, and outcomes, findings were synthesized narratively. Four studies were included: two Phase 1 studies in healthy adults, one Phase 2 randomized comparative study, and one Phase 3 randomized non-inferiority trial in adults with CABP. Early-phase studies suggested that nafithromycin was generally well tolerated in the short term and had pharmacokinetic properties supportive of once-daily dosing, including high pulmonary exposure in epithelial lining fluid and alveolar macrophages. In the Phase 2 study, early clinical response rates were high with both 3-day and 5-day nafithromycin regimens. In the Phase 3 trial conducted in India, a 3-day oral nafithromycin regimen was non-inferior to 7-day moxifloxacin for early clinical response at Day 4, with no severe TEAEs, serious TEAEs, or deaths reported in either treatment arm. However, the evidence base remains limited in size and geographic diversity, and data in older adults, patients with renal or hepatic impairment, and microbiologically confirmed macrolide-resistant pneumococcal disease were sparse. Nafithromycin is a short-course oral candidate for CABP with supportive early clinical and pharmacokinetic data, but the current evidence base remains limited. Further evidence is needed to clarify its generalisability, rare or delayed safety profile, and effectiveness in microbiologically confirmed macrolide-resistant pneumococcal disease.