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
Pharmacology
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
Microbiology
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
Table: Clinical Trials Summary3-6,13,14 |
|||||
Trial |
Patient Population |
Intervention |
Outcomes |
Results |
Comments |
|
O’Riordan, et al, 2018 (OASIS-1 trial) Phase III, randomized, double-blind, multicenter study Clinical trial NCT02378480 |
N = 655 adult patients with ABSSSI Cellulitis (38%), wound infection (33%), major abscess (29%) Mean age 47 years Male (65%) White (92%) Mean BMI 28.1 kg/m2 |
Omadacycline 100 mg IV BID x 2 doses, then 100 mg IV once daily vs. linezolid 600 mg IV BID Duration: 7-14 days Could switch to oral after minimum 3 days |
Primary end point:
|
Early clinical response in omadacycline (84.8%) vs. linezolid (85.5%) 95% CI [-6.3 to 4.9] in mITT population* Clinical success in omadacycline (86.1%) vs. linezolid (83.6%) 95% CI [-3.2 to 8.2] in mITT population Success rates in S. aureus, MRSA, S. anginosus, and mixed infections similar in both groups in microbiologically mITT population Efficacy and safety similar in the following subgroups: CKD, higher BMI, IV drug use history, hepatitis C Trend toward higher clinical success in DM2 subgroup for omadacycline |
|
|
2018 (OASIS-2 trial) Phase III, randomized, double-blind, multicenter study Clinical Trial: NCT02877927 |
N = 735 adult patients with ABSSSI Excluded: immune compromised, ESRD on dialysis, septic shock, allergy to tetracyclines or linezolid Wound infection (58%), cellulitis (24%), major abscess (18%) Mean age 44 years Male (63%) White (91%) Mean BMI 27.9 kg/m2 |
Omadacycline 450 mg/d on days 1 and 2, then 200 mg daily or linezolid 600 mg BID Duration: 7-14 days |
Primary end point:
|
Early clinical response in omadacycline (87.3%) vs. linezolid (82.2) 95% CI [-2.0 to 10.5] Clinical success in omadacycline (83.9%) vs. linezolid (80.5%) 95% CI [-2.3 to 9.1] in mITT population |
Omadacycline met 10% noninferiority margin compared to linezolid |
|
Stets R, et al, 2017 (OPTIC study) Phase III, randomized, double-blind, multicenter, noninferiority study Clinical Trial: NCT02531438 |
N = 774 adult patients with CABP Excluded: known or suspected HAP, immune compromised, allergy to tetracycline or fluoroquinolone Mean age 62 years > 75 years (20.4%) |
Omadacycline 100 mg IV every 12 hr x 2 doses, then 100 mg IV daily vs. moxifloxacin 400 mg IV daily Minimum 3 days IV, then option to switch to oral (omadacycline 300 mg daily or moxifloxacin 400 mg daily) Total duration: 7-14 days |
Primary end point:
Secondary end point:
|
Early clinical response in omadacycline (81.1%) vs. moxifloxacin (82.7%) 95% CI [-7.1 to 3.8] Clinical success in omadacycline (87.6%) vs. moxifloxacin (85.1%) 95% CI [-2.4 to 7.4] Clinical success in clinically evaluable cohort for omadacycline (92.9%) vs. moxifloxacin (90.4%) 95% CI [-1.7 to 6.8] |
Omadacycline met 10% noninferiority margin compared to moxifloxacin Eight patients with S. pneumoniae resistant to tetracycline still responded to omadacycline (continued) |
|
Adaptive Phase II, randomized, double-blind, multicenter, noninferiority study |
Est. N = 200 female adults uncomplicated urinary tract infections/cystitis |
Omadacycline oral vs. nitrofurantoin Total duration: 14 days |
|
N/A — study still recruiting and not yet complete |
|
|
Adaptive Phase II, randomized, double-blind, multicenter, noninferiority study |
Est. N = 200 female adults acute pyelonephritis |
Omadacycline IV or IV/oral vs. IV/oral levofloxacin |
Investigator assessment of clinical response post-treatment evaluation |
N/A — study still recruiting and not yet complete |
|
|
*Patients without a potentially causative monomicrobial gram-negative infection |
|||||
Pharmacokinetics
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
Pharmacodynamics
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
Table: Dosage and Administration2 |
||
Indication |
Dose |
Treatment Duration |
|
Adult CABP |
Load: 200 mg IV x 1 or 100 mg IV BID on day 1 |
7-14 days |
|
Adult ABSSSI |
Load: 200 mg IV x 1 or 100 mg IV BID on day 1 |
7-14 days |
|
Adult ABSSSI (tablets only) |
Load: 450 mg oral daily on day 1 and day 2 |
7-14 days |
|
CABP = community-acquired bacterial pneumonia; ABSSSI = acute bacterial skin and skin structure infection |
||
Table: Cost7 |
||||
Drug Name |
How Supplied |
Average Wholesale Price |
Cost Per Day (maintenance dose) |
Cost Per 7-Day Course |
|
Omadacycline for injection |
100 mg single-dose vial |
$414.00 |
$414.00 |
$3,312 |
|
Omadacycline tablet |
150 mg tablet |
$237.00 |
$474.00 |
$3,792 |
Contraindications
Use of omadacycline is contraindicated in patients who have known hypersensitivity to omadacycline or to the tetracycline class of antibacterial medications.2
Warnings/Precautions
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
Adverse Effects
Common (> 2%) adverse effects include nausea, vomiting, infusion site reactions, ALT/AST/GGT increase, hypertension, headache, diarrhea, insomnia, and constipation.2
Significant Drug Interactions
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
Conclusion
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.
REFERENCES
- Watkins RR, Deresinski S. Omadacycline: A novel tetracycline derivative with oral and intravenous formulations. Clin Infect Dis 2019. doi:10.1093/cid/ciz242. [Epub ahead of print].
- Paratek Pharmaceuticals. NUZYRA (omadacycline injection, powder, lyophilized, for solution) NUZYRA (omadacycline tablet, film coated) [package insert]. Boston, MA: Oct. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209816_209817lbl.pdf.
- O’Riordan W, Green S, Overcash JS, et al. Omadacycline for acute bacterial skin and skin-structure infections. N Engl J Med 2019;380:
528-538. - Oral omadacycline vs. oral linezolid for the treatment of ABSSSI. Available at: https://clinicaltrials.gov/ct2/show/results/NCT02877927. Accessed May 9, 2019.
- Stets R, Popescu M, Gonong J, et al. A Phase 3 randomized, double-blind, multi-center study to compare the safety and efficacy of IV to oral omadacycline to moxifloxacin for the treatment of adult subjects with CABP (The OPTIC Study). Open Forum Infect Dis 2017;4(Suppl1):S543-S544.
- Stets R, Popescu M, Gonong JR, et al. Omadacycline for community-acquired bacterial pneumonia. N Engl J Med 2019;380:517-527.
- Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019; May 3, 2019.
- Heidrich CG, Mitova S, Schedlbauer A, et al. The novel aminomethylcycline omadacycline has high specificity for the primary tetracycline-binding site on the bacterial ribosome. Antibiotics (Basel) 2016;5. doi: 10.3390/antibiotics5040032.
- Draper MP, Weir S, Macone A, et al. Mechanism of action of the novel aminomethylcycline antibiotic omadacycline. Antimicrob Agents Chemother 2014;58:1279-1283.
- Huband MD, Pfaller MA, Shortridge D, Flamm RK. Surveillance of omadacycline activity tested against clinical isolates from the United States and Europe: Results from the SENTRY Antimicrobial Surveillance Programme, 2017. J Glob Antimicrob Resist 2019. doi: 10.1016/j.jgar.2019.02.017. [Epub ahead of print].
- U.S. Food and Drug Administration. Omadacycline injection and oral products. Available at: https://www.fda.gov/drugs/development-resources/omadacycline-injection-and-oral-products. Accessed May 9, 2019.
- Berg JK, Tzanis E, Garrity-Ryan L, et al. Pharmacokinetics and safety of omadacycline in subjects with impaired renal function. Antimicrob Agents Chemother 2018;62. Doi: 10.1128/AAC.02057-17.
- Oral omadacycline vs. oral nitrofurantoin for the treatment of cystitis. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT03425396. Accessed May 16, 2019.
- IV or IV/PO omadacycline vs. IV/PO levofloxacin for the treatment of acute pyelonephritis. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT03757234. Accessed May 16, 2019.
Omadacycline was approved in 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).
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