Safety and efficacy of omadacycline by BMI categories and diabetes history in two Phase III randomized studies of patients with acute bacterial skin and skin structure infections

Manjunath P Pai, Mark H Wilcox, Surya Chitra, Paul C McGovern, Manjunath P Pai, Mark H Wilcox, Surya Chitra, Paul C McGovern

Abstract

Objectives: The objectives of this post-hoc analysis were to examine the safety and efficacy of omadacycline by BMI categories and diabetes history in adults with acute bacterial skin and skin structure infections (ABSSSI) from two pivotal Phase III studies.

Patients and methods: OASIS-1 (ClinicalTrials.gov identifier NCT02378480): patients were randomized 1:1 to IV omadacycline or linezolid for 7-14 days, with optional transition to oral medication. OASIS-2 (ClinicalTrials.gov identifier NCT02877927): patients received once-daily oral omadacycline or twice-daily oral linezolid for 7-14 days. Early clinical response (ECR) was defined as ≥20% reduction in lesion size 48-72 h after the first dose. Clinical success at post-treatment evaluation (PTE; 7-14 days after the last dose) was defined as symptom resolution such that antibacterial therapy was unnecessary. Safety was assessed by treatment-emergent adverse events and laboratory measures. Between-treatment comparisons were made with regard to WHO BMI categories and diabetes history.

Results: Patients were evenly distributed among healthy weight, overweight and obese groups. Clinical success for omadacycline-treated patients at ECR and PTE was similar across BMI categories. Outcomes by diabetes status were similar in omadacycline- and linezolid-treated patients: at ECR, clinical success rates were lower for those with diabetes; at PTE, clinical success was similar between treatment groups regardless of diabetes history. The safety of omadacycline and linezolid was largely similar across BMI groups and by diabetes history.

Conclusions: Omadacycline efficacy in patients with higher BMI and in patients with diabetes was consistent with results from two pivotal Phase III ABSSSI trials. Fixed-dose omadacycline is an appropriate treatment for ABSSSI in adults regardless of BMI.

© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Figures

Figure 1.
Figure 1.
Clinical success at ECR was consistent across BMI categories for patients receiving omadacycline and comparable to outcomes for those receiving linezolid (mITT population). The table shows outcomes by subclasses of the obese group: obese class I, BMI 30 to 2; obese class II, BMI 35 to <40 kg/m2; and obese class III, BMI ≥40 kg/m2.
Figure 2.
Figure 2.
Clinical success at PTE was largely similar across BMI categories for patients treated with omadacycline or linezolid. The table shows outcomes by subclasses of the obese group: obese class I, BMI 30 to 2; obese class II, BMI 35 to <40 kg/m2; and obese class III, BMI ≥40 kg/m2.
Figure 3.
Figure 3.
Tipping-point analysis for clinical success at (a) ECR and (b) PTE showed no body weight at which the clinical success of either omadacycline or linezolid was substantially negatively affected. The solid lines represent the difference in probability of clinical success above and below the body weight cut-point and the shaded areas represent the associated 95% CI.
Figure 4.
Figure 4.
Clinical success was generally similar at (a) ECR and (b) PTE for patients who did and those who did not have a history of diabetes in the omadacycline and linezolid treatment groups.

References

    1. Kaye KS, Petty LA, Shorr AF. et al. Current epidemiology, etiology, and burden of acute skin infections in the United States. Clin Infect Dis 2019; 68 Suppl 3: S193–9.
    1. WHO. Obesity and Overweight. 2020. .
    1. Hales CM, Carroll MD, Fryar CD. et al. Prevalence of Obesity Among Adults and Youth: United States, 2015–2016. NCHS Data Brief, No. 288. National Center for Health Statistics, 2017.
    1. Ghilotti F, Bellocco R, Ye W. et al. Obesity and risk of infections: results from men and women in the Swedish National March Cohort. Int J Epidemiol 2019; 48: 1783–94.
    1. Winter-Jensen M, Afzal S, Jess T. et al. Body mass index and risk of infections: a Mendelian randomization study of 101,447 individuals. Eur J Epidemiol 2020; 35: 347–54.
    1. Ward ZJ, Bleich SN, Cradock AL. et al. Projected U.S. state-level prevalence of adult obesity and severe obesity. N Engl J Med 2019; 381: 2440–50.
    1. Longo C, Bartlet G, MacGibbon B. et al. The effect of obesity on antibiotic treatment failure: a historical cohort study. Pharmacoepidemiol Drug Saf 2013; 22: 970–6.
    1. Pai MP, Bearden DT.. Antimicrobial dosing considerations in obese adult patients: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2007; 27: 1081–91.
    1. Meng L, Mui E, Holubar MK. et al. Comprehensive guidance for antibiotic dosing in obese adults. Pharmacotherapy 2017; 37: 1415–31.
    1. Cantú TG, Yamanaka-Yuen NA, Lietman PS.. Serum vancomycin concentrations: reappraisal of their clinical value. Clin Infect Dis 1994; 18: 533–43.
    1. Pai MP, Neely M, Rodvold KA. et al. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev 2014; 77: 50–7.
    1. Chung EK, Cheatham SC, Fleming MR. et al. Population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese and nonobese patients. J Clin Pharmacol 2015; 55: 899–908.
    1. Hall RG 2nd, Pasipanodya JG, Meek C. et al. Fractal geometry-based decrease in trimethoprim-sulfamethoxazole concentrations in overweight and obese people. CPT Pharmacometrics Syst Pharmacol 2016; 5: 674–81.
    1. O’Riordan W, Green S, Overcash JS. et al. Omadacycline for acute bacterial skin and skin-structure infections. N Engl J Med 2019; 380: 528–38.
    1. O’Riordan W, Cardenas C, Shin E. et al. Once-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial. Lancet Infect Dis 2019; 19: 1080–90.
    1. Abrahamian FM, Sakoulas G, Tzanis E. et al. Omadacycline for acute bacterial skin and skin structure infections. Clin Infect Dis 2019; 69 Suppl 1: S23–32.
    1. Abu-Ashour W, Twells LK, Valcour JE. et al. Diabetes and the occurrence of infection in primary care: a matched cohort study. BMC Infect Dis 2018; 18: 67.
    1. Carey IM, Critchley JA, DeWilde S. et al. Risk of infection in type 1 and type 2 diabetes compared with the general population: a matched cohort study. Diabetes Care 2018; 41: 513–21.
    1. Golan Y. Current treatment options for acute skin and skin-structure infections. Clin Infect Dis 2019; 68 Suppl 3: S206–12.
    1. Xie F, Mantzarlis K, Malliotakis P. et al. Pharmacokinetic evaluation of linezolid administered intravenously in obese patients with pneumonia. J Antimicrob Chemother 2019; 74: 667–74.
    1. Opal S, File TMJ, van der Poll T. et al. An integrated safety summary of omadacycline, a novel aminomethylcycline antibiotic. Clin Infect Dis 2019; 69 Suppl 1: S40–7.
    1. Lakota EA, Van Wart SA, Tzanis E. et al. Population pharmacokinetic analyses of omadacycline using Phase 1 and 3 data. ASM Microbe, Atlanta, GA, USA, 2018. Poster Sat628.
    1. Lakota EA, Friedrich L, Steenbergen JN. et al. Omadacycline pharmacokinetics: impact of comorbidities. Twenty-Ninth European Congress of Clinical Microbiology and Infectious Diseases, Amsterdam, The Netherlands, 2019. P1943.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren