The efficacy and safety of omadacycline plus β-lactam versus moxifloxacin plus β-lactam for the treatment of severe community-acquired pneumonia: study protocol of a multicenter, prospective, randomized controlled non-inferiority trial.

BACKGROUND: Severe community-acquired pneumonia (sCAP) is associated with high morbidity and mortality. Current empirical antimicrobial regimens are increasingly challenged by rising antimicrobial resistance and safety concerns (e.g., fluoroquinolone-related adverse events). Omadacycline, a novel aminomethylcycline antibiotic, has demonstrated broad-spectrum activity against common respiratory pathogens (including drug-resistant strains) and a favorable safety profile. However, direct comparative evidence to support its use in combination with β-lactams in this setting is lacking. Therefore, the primary objective of this trial is to evaluate whether omadacycline combined with a β-lactam is non-inferior to the standard β-lactam plus moxifloxacin regimen for the treatment of sCAP in adults. METHODS: This is a multicenter, prospective, randomized, open-label, active-controlled, non-inferiority trial conducted across 8 tertiary hospitals in China. Eligible participants are adult patients (≥ 18 years old) who meet the IDSA/ATS 2019 diagnostic criteria for sCAP, with no contraindications to the study drugs (omadacycline, β-lactams, or moxifloxacin) and able to complete follow-up. A total of 248 patients will be recruited and randomized in a 1:1 allocation ratio to either of the two arms. The experimental arm will receive omadacycline (200 mg iv once daily for the first day, then 100 mg iv q24h) plus β-lactam therapy (piperacillin-tazobactam 4.5 g iv q8h or meropenem 1 g iv q8h). The control arm will receive moxifloxacin (400 mg iv q24h) plus the same β-lactam regimen. The treatment duration for both groups will be 7-14 days, adjusted based on clinical response. The primary endpoint is early clinical response at 72-96 h (defined as improvement in ≥ 2 major clinical symptoms/signs of pneumonia without worsening of any other major symptom/sign). Secondary endpoints include clinical cure at the end of treatment, 28-day all-cause mortality, epidemiology of pathogens of severe CAP, time to clinical stability, incidence of adverse events, and length of hospital stay. This trial has obtained ethical approval from the Ethics Committee of the leading center (Approval Number: [KY-2025-8-167-1]). The study protocol has been filed with the Ethics Committees of all other participating hospitals in accordance with relevant regulatory requirements, and all patients will provide written informed consent prior to enrollment. DISCUSSION: This trial aims to evaluate the non-inferiority of the omadacycline-plus-β-lactam regimen versus the standard fluoroquinolone-based combination in patients with severe CAP. If non-inferiority is demonstrated, this novel regimen could offer a safer alternative that reduces fluoroquinolone-associated adverse events, preserves the utility of existing antibiotic classes, and may provide a potential option for addressing multidrug-resistant pathogens. These findings would directly inform empirical antibiotic selection and antimicrobial stewardship strategies across both general wards and intensive care units. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2500109407. Registered on 17 September 2025. (https//www.chictr.org.cn/showproj.html? proj=286992).