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: Survival with at least 20% reduction of ABSSSI lesion size within 48-72 hours
  • Investigator assessment of clinical success: Survival, resolution, and improvement at post-treatment evaluation visit 7-14 days after last day of therapy
  • Secondary end point:
  • Safety and tolerability (AE, vital signs, ECG, labs from 0 -37 days)

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: Survival with at least 20% reduction of ABSSSI lesion size within 48-72 hours
  • Investigator assessment of clinical success: Survival, resolution, and improvement at post-treatment evaluation visit 7-14 days after last day of therapy

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:

  • Early clinical response: Survival, no rescue antibiotic given, symptom improvement within 72-120 hours after first dose
  • Investigator assessment of clinical success: Survival, resolution, and improvement at post-treatment evaluation visit 5-10 days after last dose

Secondary end point:

  • Clinical success at post-treatment evaluation

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

  • Clinical success defined by resolution of cystitis symptoms
  • Investigator assessment of clinical response post-treatment evaluation

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
Maintenance: 100 mg IV daily or 300 mg oral daily

7-14 days

Adult ABSSSI

Load: 200 mg IV x 1 or 100 mg IV BID on day 1
Maintenance: 100 mg IV daily or 300 mg oral daily

7-14 days

Adult ABSSSI (tablets only)

Load: 450 mg oral daily on day 1 and day 2
Maintenance: 300 mg oral daily

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

  1. 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].
  2. 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.
  3. 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.
  4. Oral omadacycline vs. oral linezolid for the treatment of ABSSSI. Available at: https://clinicaltrials.gov/ct2/show/results/NCT02877927. Accessed May 9, 2019.
  5. 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.
  6. Stets R, Popescu M, Gonong JR, et al. Omadacycline for community-acquired bacterial pneumonia. N Engl J Med 2019;380:517-527.
  7. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019; May 3, 2019.
  8. 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.
  9. Draper MP, Weir S, Macone A, et al. Mechanism of action of the novel aminomethylcycline antibiotic omadacycline. Antimicrob Agents Chemother 2014;58:1279-1283.
  10. 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].
  11. 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.
  12. 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.
  13. Oral omadacycline vs. oral nitrofurantoin for the treatment of cystitis. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT03425396. Accessed May 16, 2019.
  14. 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.