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By Denise Kwong, PharmD, BCPS
Clinical Pharmacist, Stanford University School of Medicine
Dr. Kwong reports no financial relationships relevant to this field of study.
Omadacycline is a next-generation semisynthetic tetracycline derivative (aminomethylcycline) with broad spectrum in vitro activity against gram-positive and gram-negative aerobic organisms, anaerobes, atypicals, and other organisms such as Yersinia pestis and Bacillus anthraxis.1 The drug was approved on Oct. 3, 2018, by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).2
In the OASIS-1 Phase III, double-blind, randomized, controlled trial, patients with cellulitis were treated with either intravenous omadacycline or linezolid with the option to switch to oral antibiotics after three days. The total treatment duration was seven to 14 days. The patient population and study design were similar in OASIS-2, with the intervention arms consisting of strictly oral omadacycline vs. oral linezolid. The primary end point was early clinical response and survival with at least 20% reduction of ABSSSI lesion size within 48-72 hours. In both trials, omadacycline met 10% noninferiority margin compared to linezolid.3,4
The Optic study was a Phase III double-blind, randomized, noninferiority controlled trial comparing omadacycline with moxifloxacin in patients with CABP. Omadacycline met noninferiority criteria with the primary end point of early clinical response in omadacycline (81.1%) vs. moxifloxacin (82.7%), 95% confidence interval (CI), -7.1 to 3.8.5 Currently, omadacycline is being evaluated for use in treating other infections, including cystitis and acute pyelonephritis.1
Omadacycline is a semisynthetic tetracycline derivative (aminomethylcycline) that binds the 30s-ribosomal subunit to block protein synthesis. The chemical structure includes an aminomethyl group at the C9 position, which helps improve binding affinity and antimicrobial potency compared to tetracycline. Omadacycline has similar binding affinity as glycylcycline tetracyclines such as tigecycline and eravacycline.7-9
Omadacycline demonstrates in vitro activity against several tetracycline-resistant strains. Some examples include gram-positive bacteria expressing tetracycline resistance (tetK, tetL, tetM) and Enterobacteriaceae expressing efflux gene (tetB). Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae with macrolide resistance (erm A, B, and/or C) and ciprofloxacin resistance genes (gyrA and parC) also were susceptible to omadacycline in vitro.2
Some notable gram-positive organisms with in vitro susceptibility data from the 2017 SENTRY Antimicrobial Surveillance Program include S. aureus (MRSA and MSSA) and Enterococcus faecalis with MIC50/90 0.12/0.25 mg/mL ABSSSI breakpoints. E. faecium isolates had MIC50/90 0.06/0.12 mg/L ABSSSI breakpoints. Enterococcus species tested included VRE isolates. For Streptococcus, FDA-identified susceptibility ABSSSI and CABP breakpoints for omadacycline are ≤ 0.12 mcg/mL with isolates of MIC 0.25 and ≥ 0.5 conferring intermediate susceptibility and resistance, respectively.10 FDA-identified MSSA CABP breakpoints for omadacycline are ≤ 0.25 mcg/mL with isolates of MIC 0.5 and ≥ 0.1 conferring intermediate susceptibility and resistance, respectively.11
Some notable gram-negative organisms with in vitro susceptibility data from the 2017 SENTRY Antimicrobial Surveillance Program include Acinetobacter baumannii and Stenotrophomonas maltophilia with MIC50/90 4/8 mg/L. Pseudomonas was not susceptible to omadacycline.10 FDA-identified susceptibility ABSSSI breakpoints for omadacycline against Enterobacteriaceae are ≤ 4 mcg/mL with isolates of MIC 8 and ≥ 16 conferring intermediate susceptibility and resistance, respectively. Of note, omadacycline is not active in vitro against Morganella, Proteus, and Providencia. FDA-identified susceptibility CABP breakpoints for omadacycline against Haemophilus are ≤ 2 mcg/mL with isolates of MIC 4 and ≥ 8 conferring intermediate susceptibility and resistance, respectively.11
Omadacycline has a broad spectrum that includes in vitro activity against anaerobes such as Bacteroides fragilis with MIC90 4 mcg/mL and Clostridioides difficile with MIC 90 0.25 mcg/mL. Omadacycline also has in vitro activity against Mycobacterium species, including M. abscessus (MIC90 2 mcg/mL), M. fortuitum (MIC90 0.5 mcg/mL), and M. chelonae (MIC90 0.25 mcg/mL).1,10
Omadacycline comes in oral and intravenous formulations, with 34.5% bioavailability of the oral formulation. Absorption is affected by food and divalent cations, with max concentrations and AUC decreasing by 42% and 63%, respectively, when a high-fat meal with dairy is administered two hours prior to omadacycline dosing. Omadacycline is not metabolized by the liver. It is excreted primarily in the urine unchanged with the intravenous formulation and in the feces with the oral formulation. Compared to tigecycline, omadacycline has higher lung penetration compared to plasma AUC.2
Qtc prolongation was not appreciable in Phase III clinical trials compared to moxifloxacin. Transient tachycardia was observed in Phase I studies.2
Omadacycline does not require renal or hepatic dose adjustment. The oral formulation should be taken with water on an empty stomach fasting four hours prior to administration. Avoid concurrent dairy products, antacids, or multivitamins two hours before or four hours after administration. The intravenous formulation is infused in a dedicated IV line over 30-60 minutes and flushed with 0.9% sodium chloride or 5% dextrose before and after medication administration.2,12
Use of omadacycline is contraindicated in patients who have known hypersensitivity to omadacycline or to the tetracycline class of antibacterial medications.2
In the CABP clinical trial, there were eight deaths among patients with community-acquired bacterial pneumonia treated with omadacycline (2%) compared to four deaths (1%) with moxifloxacin. Deaths occurred in patients > 65 years of age with multiple comorbidities. Although this mortality imbalance was noted in the clinical trial, the cause and clinical significance were not defined.2 Pregnancy was excluded in the clinical trials, although tetracyclines as a class can cause tooth discoloration, enamel hypoplasia, and inhibition of bone growth during the second and third trimesters of pregnancy.2
Common (> 2%) adverse effects include nausea, vomiting, infusion site reactions, ALT/AST/GGT increase, hypertension, headache, diarrhea, insomnia, and constipation.2
Omadacycline absorption is impaired by antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron. No notable antagonistic interactions with other antimicrobials were identified.2
Omadacycline is a synthetic tetracycline derivative that shows promise with overcoming tetracycline resistance. This medication is FDA-approved for CABP and ABSSSI. There are new Phase II clinical trials in recruitment for cystitis and pyelonephritis. Its place in therapy is still being established.
Financial Disclosure: Peer Reviewer Patrick Joseph, MD, is a consultant for Genomic Health Reference Laboratory, Siemens Clinical Laboratory, and CareDx Clinical Laboratory. Infectious Disease Alert’s Editor Stan Deresinski, MD, FACP, FIDSA, Updates Author Carol A. Kemper, MD, FACP, Peer Reviewer Kiran Gajurel, MD, Executive Editor Shelly Morrow Mark, Editor Jonathan Springston, and Editorial Group Manager Leslie Coplin report no financial relationships to this field of study.