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Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent

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Abstract

Omadacycline is a novel aminomethylcycline antibiotic developed as a once-daily, intravenous and oral treatment for acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP). Omadacycline, a derivative of minocycline, has a chemical structure similar to tigecycline with an alkylaminomethyl group replacing the glycylamido group at the C-9 position of the D-ring of the tetracycline core. Similar to other tetracyclines, omadacycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Omadacycline possesses broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical bacteria. Omadacycline remains active against bacterial isolates possessing common tetracycline resistance mechanisms such as efflux pumps (e.g., TetK) and ribosomal protection proteins (e.g., TetM) as well as in the presence of resistance mechanisms to other antibiotic classes. The pharmacokinetics of omadacycline are best described by a linear, three-compartment model following a zero-order intravenous infusion or first-order oral administration with transit compartments to account for delayed absorption. Omadacycline has a volume of distribution (Vd) ranging from 190 to 204 L, a terminal elimination half-life (t½) of 13.5–17.1 h, total clearance (CLT) of 8.8–10.6 L/h, and protein binding of 21.3% in healthy subjects. Oral bioavailability of omadacycline is estimated to be 34.5%. A single oral dose of 300 mg (bioequivalent to 100 mg IV) of omadacycline administered to fasted subjects achieved a maximum plasma concentration (Cmax) of 0.5–0.6 mg/L and an area under the plasma concentration-time curve from 0 to infinity (AUC0–∞) of 9.6–11.9 mg h/L. The free plasma area under concentration–time curve divided by the minimum inhibitory concentration (i.e., fAUC24h/MIC), has been established as the pharmacodynamic parameter predictive of omadacycline antibacterial efficacy. Several animal models including neutropenic murine lung infection, thigh infection, and intraperitoneal challenge model have documented the in vivo antibacterial efficacy of omadacycline. A phase II clinical trial on complicated skin and skin structure infection (cSSSI) and three phase III clinical trials on ABSSSI and CABP demonstrated the safety and efficacy of omadacycline. The phase III trials, OASIS-1 (ABSSSI), OASIS-2 (ABSSSI), and OPTIC (CABP), established non-inferiority of omadacycline to linezolid (OASIS-1, OASIS-2) and moxifloxacin (OPTIC), respectively. Omadacycline is currently approved by the FDA for use in treatment of ABSSSI and CABP. Phase II clinical trials involving patients with acute cystitis and acute pyelonephritis are in progress. Mild, transient gastrointestinal events are the predominant adverse effects associated with use of omadacycline. Based on clinical trial data to date, the adverse effect profile of omadacycline is similar to studied comparators, linezolid and moxifloxacin. Unlike tigecycline and eravacycline, omadacycline has an oral formulation that allows for step-down therapy from the intravenous formulation, potentially facilitating earlier hospital discharge, outpatient therapy, and cost savings. Omadacycline has a potential role as part of an antimicrobial stewardship program in the treatment of patients with infections caused by antibiotic-resistant and multidrug-resistant Gram-positive [including methicillin-resistant Staphylococcus aureus (MRSA)] and Gram-negative pathogens.

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Fig. 1
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(adapted from Refs. [1, 10, 12])

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Authors and Affiliations

  1. Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    George G. Zhanel, Heather J. Adam, Alyssa Golden, Rachel Hink, Frank Schweizer, Michael A. Zhanel, Denice Bay, Philippe R. S. Lagacé-Wiens, Andrew J. Walkty & James A. Karlowsky

  2. College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    Jenine Esquivel, Sheryl Zelenitsky & Courtney K. Lawrence

  3. Diagnostic Services, Shared Health, Winnipeg, MB, Canada

    Heather J. Adam, Philippe R. S. Lagacé-Wiens, Andrew J. Walkty & James A. Karlowsky

  4. Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB, Canada

    Liam Berry & Frank Schweizer

  5. Division of Pulmonary, Critical Care, Allergy and Clinical Immunology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Joseph P. Lynch III

  6. Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, MB, R3A 1R9, Canada

    George G. Zhanel

Authors
  1. George G. Zhanel
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  2. Jenine Esquivel
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  3. Sheryl Zelenitsky
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  4. Courtney K. Lawrence
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  5. Heather J. Adam
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  6. Alyssa Golden
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  7. Rachel Hink
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  8. Liam Berry
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  9. Frank Schweizer
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  10. Michael A. Zhanel
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  11. Denice Bay
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  12. Philippe R. S. Lagacé-Wiens
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  15. James A. Karlowsky
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Contributions

JE (involved in design and concept of entire manuscript and drafting all sections), SZ (involved in design and concept of entire manuscript and drafting pharmacokinetic and pharmacodynamics sections), CKL (involved in design and concept of entire manuscript and drafting pharmacokinetic and pharmacodynamics sections), HJA (involved in design and concept of entire manuscript and drafting all sections), AG (involved in design and concept of entire manuscript and drafting mechanisms of action and resistance sections), RH (involved in design and concept of entire manuscript and drafting mechanisms of action and resistance and microbiology sections), LB (involved in design and concept of entire manuscript and drafting chemistry and microbiology sections), FS (involved in design and concept of entire manuscript and drafting chemistry and microbiology sections), MAZ (involved in design and concept of entire manuscript and drafting introduction, mechanisms of action/resistance, chemistry and microbiology sections), DB (involved in design and concept of entire manuscript and drafting introduction, mechanisms of action/resistance, chemistry and drug interaction sections), PRSL-W (involved in design and concept of entire manuscript and drafting animal models section), AJW (involved in design and concept of entire manuscript and drafting clinical trials, adverse effects and place in therapy sections), JPL (involved in design and concept of entire manuscript and drafting clinical trials and place in therapy sections), JAK (involved in design and concept of entire manuscript and drafting all sections), GGZ (involved in design and concept of entire manuscript and drafting all sections, senior and corresponding author).

Corresponding author

Correspondence to George G. Zhanel.

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Conflict of interest

No conflicts are declared for Jenine Esquivel, Sheryl Zelenitsky, Courtney K. Lawrence, Heather J. Adam, Alyssa Golden, Rachel Hink, Liam Berry, Frank Schweizer, Michael A. Zhanel, Denice Bay, Philippe R. S. Lagacé-Wiens, Andrew J. Walkty, Joseph P. Lynch III and James A. Karlowsky. Dr Zhanel has received research grants from Paratek Pharmaceuticals (omadacycline), Pfizer (tigecycline), and Tetraphase (eravacycline).

Funding

The authors are grateful to Paratek Pharmaceuticals for their assistance with literature retrieval and an unrestricted research grant to aid in funding Jenine Esquivel.

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Zhanel, G.G., Esquivel, J., Zelenitsky, S. et al. Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent. Drugs 80, 285–313 (2020). https://doi.org/10.1007/s40265-020-01257-4

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  • DOI: https://doi.org/10.1007/s40265-020-01257-4

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