omadacycline and Diabetes-Mellitus

Recent understanding of antimicrobial chemotherapy has expanded to appreciate significant impacts on the host-pathogen relationship by antibiotics. Omadacycline statistically outperformed linezolid in treating acute bacterial skin and skin structure infections in patients with diabetes mellitus in a recent post-hoc analysis of the OASIS-1 and OASIS-2 clinical trials. This difference may speak directly or indirectly to neutrophil dysfunction in diabetes. Neutrophil dysfunction increases the likelihood of Gram-negative bacterial infection, whereby diabetics may benefit from the broader spectrum of omadacycline compared with linezolid. Indirectly, oxazolidinones like linezolid have been shown to be dependent on neutrophil function, potentially compromising the potency of this drug class in diabetics. Finally, tetracyclines like omadacycline have collateral anti-inflammatory properties that have not been seen in other antibiotic drug classes. These differences may impact clinical outcomes in the treatment of infections that are not predicted by their antimicrobial activities alone, as measured in standard susceptibility testing assays.

Topics: Anti-Bacterial Agents; Diabetes Mellitus; Humans; Linezolid; Skin Diseases, Bacterial; Soft Tissue Infections; Tetracyclines

We assessed the plasma and soft-tissue pharmacokinetic exposure of omadacycline in infected patients with diabetic foot infection (DFI) and healthy volunteers using in vivo microdialysis.. Eight patients and six healthy volunteers were enrolled and received an omadacycline IV loading dose (200 mg) followed by two oral doses (300 mg) every 24 h. Microdialysis catheters were placed in the soft tissue near the infected diabetic foot wound (patients) or thigh (healthy volunteers). Plasma and dialysate fluid samples were collected, starting immediately prior to the third dose and continued for 24 h post-dose. Protein binding was determined by ultracentrifugation.. The mean ± SD omadacycline pharmacokinetic parameters in plasma for infected patients and healthy volunteers were: Cmax, 0.57 ± 0.15 and 1.14 ± 0.26 mg/L; t½, 16.19 ± 5.06 and 25.34 ± 12.92 h; and total omadacycline AUC0-24, 6.27 ± 1.38 and 14.06 ± 3.40 mg·h/L, respectively. The omadacycline mean plasma free fraction was 0.21 and 0.20 for patients and healthy volunteers, corresponding to free plasma AUC0-24 of 1.13 ± 0.37 and 2.78 ± 0.55 mg·h/L, respectively. Omadacycline tissue AUC0-24 was 0.82 ± 0.38 and 1.37 ± 0.48 mg·h/L for patients and volunteers, respectively.. The present study describes the plasma and soft-tissue exposure of omadacycline in patients with DFI and healthy volunteers. Integrating these data with the microbiological, pharmacokinetic/pharmacodynamic and clinical efficacy data is foundational to support clinical assessments of omadacycline efficacy specifically for DFI. This, coupled with the once-daily oral administration, suggests omadacycline could be an advantageous translational therapy for the hospital and outpatient setting.

Topics: Anti-Bacterial Agents; Area Under Curve; Diabetes Mellitus; Diabetic Foot; Healthy Volunteers; Humans; Microdialysis; Tetracyclines; Wound Infection

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.. 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.. 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.. 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.

Topics: Adult; Anti-Bacterial Agents; Body Mass Index; Diabetes Mellitus; Humans; Skin Diseases, Bacterial; Tetracyclines