Tetracycline; protein synthesis of bacteria; Bacterial 30S ribosomal subunit (binds to the A site of the 30S subunit, inhibiting protein synthesis) [1][2][3]

- Antibacterial spectrum and activity: Omadacycline exhibited potent activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentrations (MIC90) of 0.25-1 μg/mL, Streptococcus pneumoniae (MIC90 0.06-0.25 μg/mL), and vancomycin-resistant Enterococcus (VRE, MIC90 0.5-2 μg/mL). It also showed activity against some Gram-negative bacteria such as Haemophilus influenzae (MIC90 2 μg/mL) and Moraxella catarrhalis (MIC90 0.25 μg/mL). The drug retained activity against tetracycline-resistant strains due to resistance to efflux pumps and ribosomal protection proteins [2][3]
- Time-kill kinetics: Against S. aureus (including MRSA) and S. pneumoniae, Omadacycline displayed concentration-dependent bactericidal activity at 2-4 times the MIC, achieving ≥3 log10 CFU/mL reduction in bacterial counts within 24 hours [2]
- Post-antibiotic effect (PAE): For S. aureus and S. pneumoniae, Omadacycline exhibited a PAE of 1.5-3 hours at 2-4 times the MIC [2]

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Omadacycline is a novel, aminomethyl tetracycline antibiotic being developed for oral and intravenous (IV) administration to treat community-acquired bacterial infections such as acute bacterial skin and skin structure infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). In vitro, omadacycline has activity against Gram-positive and Gram-negative aerobes, anaerobes, and atypical pathogens including Legionella and Chlamydia spp. Omadacycline offers once daily oral and IV dosing and a clinical tolerability and safety profile that compares favorably with contemporary antibiotics used across serious community-acquired infections where resistance has rendered many less effective. In studies in patients with complicated skin and skin structure infections, including those with MRSA infections, omadacycline exhibited an efficacy and tolerability profile that was comparable to linezolid. Ongoing and planned clinical studies are evaluating omadacycline as monotherapy for treating serious community-acquired bacterial infections including Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and Community-Acquired Bacterial Pneumonia (CABP). This review provides an overview of the discovery, microbiology, nonclinical data, and available clinical safety and efficacy data for omadacycline, with reference to other contemporary tetracycline-derived antibiotics.

- Efficacy in murine infection models: In a murine thigh infection model with S. aureus (including MRSA) and S. pneumoniae, Omadacycline administered subcutaneously (10-80 mg/kg) dose-dependently reduced bacterial counts (≥3 log10 CFU reduction at higher doses). In a murine pneumonia model with S. pneumoniae, intravenous administration (20-60 mg/kg) significantly reduced lung bacterial burden and improved survival rates [2]
- Efficacy in clinical trials: In phase 3 trials for acute bacterial skin and skin structure infections (ABSSSI), Omadacycline (intravenous followed by oral) showed non-inferiority to linezolid, with clinical success rates of 87.5% vs. 85.1% (p=0.44). For community-acquired bacterial pneumonia (CABP), it was non-inferior to moxifloxacin, with clinical success rates of 81.1% vs. 82.7% (p=0.66) [1][3][4]

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In vivo efficacy of omadacycline is demonstrated using an intraperitoneal infection model in mice. A single intravenous dose of omadacycline exhibits efficacy against Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus, including tet (M) and tet (K) efflux-containing strains and MRSA strains. The 50% effective doses (ED50s) for Streptococcus pneumoniae obtained ranged from 0.45 mg/kg to 3.39 mg/kg, the ED50s for Staphylococcus aureus obtained ranges from 0.30 mg/kg to 1.74 mg/kg, and the ED50 for Escherichia coli is 2.02 mg/kg.

In vitro stability and drug–drug interaction potential of omadacycline[6]
The stability of omadacycline (4.8 and 48 μM) was assessed in human microsomes and hepatocytes. After 30 min incubation of omadacycline in human microsomes, >90% of omadacycline was recovered intact. Similarly, after incubation of omadacycline up to 24 h in human hepatocytes, >86% was recovered intact. These results indicate that omadacycline is not metabolized to any significant extent.The potential for drug-drug-interactions with omadacycline was assessed using either pooled human liver microsome preparations, S9, liver cytosol, or recombinant flavin monooxygenases (FMO1, FMO3, FMO5). Induction of CYP450 isozymes was evaluated in primary human hepatocytes incubated with omadacycline 1–100 μM and a substrate probe for 24 and 48 h. Inhibition of CYP450 isozymes was evaluated with pooled human microsomes at omadacycline concentrations of 1–50 μM and isozyme specific substrates at concentrations approximating the Km of each substrate. Isozymes evaluated included CYP 1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, and 3A4/5.Omadacycline did not induce CYP isozymes, and no or minimal (<40% of maximal positive control response) induction of their mRNAs was observed. Omadacycline demonstrated no significant inhibition of CYP isozyme activity. In addition, there was no time-dependent inhibition of omadacycline or its possible metabolites for CYP1A2 2C9, 2D6 or 3A4/5.

- MIC determination: Broth microdilution assays were performed according to CLSI guidelines. Bacterial strains were inoculated into cation-adjusted Mueller-Hinton broth containing serial dilutions of Omadacycline (0.015-128 μg/mL) and incubated at 35°C for 18-24 hours. The MIC was defined as the lowest concentration inhibiting visible growth [2]
- Time-kill assay: Bacterial cultures (10^6 CFU/mL) were exposed to Omadacycline at concentrations of 0.5×, 1×, 2×, and 4× MIC. Aliquots were taken at 0, 4, 8, 12, and 24 hours, plated on agar, and colony-forming units (CFU) were counted after incubation [2]

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Omadacycline MIC90s for MRSA, VRE, and beta-hemolytic streptococci are 1.0 μg/mL, 0.25 μg/mL, and 0.5 μg/mL, correspondingly. For PRSP and H. influenzae, the corresponding omadacycline MIC90s are 0.25 μg/ml and 2.0 μg/mL. Omadacycline exhibits efficacy against organisms that exhibit both ribosomal protection and active tetracycline efflux, the two main mechanisms of resistance[1]. Omadacycline has little effect on the synthesis of DNA, RNA, or peptidoglycans, but it inhibits the synthesis of proteins. Furthermore, omadacycline exhibits enhanced binding, comparable to tigecycline, to the tetracycline binding site on the 30S subunit of the bacterial ribosome due to additional molecular interactions.

- Murine thigh infection model: Immunocompromised mice were inoculated intramuscularly with S. aureus or S. pneumoniae (10^6-10^7 CFU). Omadacycline was administered subcutaneously at 0, 4, and 8 hours post-inoculation (doses 10-80 mg/kg). Thighs were harvested 24 hours post-inoculation, homogenized, and bacterial counts were determined by plating [2]
- Murine pneumonia model: Mice were inoculated intranasally with S. pneumoniae (10^7 CFU). Omadacycline was administered intravenously at 6 and 24 hours post-inoculation (doses 20-60 mg/kg). Lungs were collected 48 hours post-inoculation for bacterial enumeration and histopathological analysis [2]

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Systemic i.p. challenge model. Six-week-old, specific-pathogen-free, male CD-1 mice, weighing 18 to 30 g were used for all experiments. At 1 h postinfection (p.i.), mice were dosed intravenously (i.v.) with omadacycline or comparator compounds of interest, dissolved in sterile saline for injection at a volume of 10 ml/kg. All drug doses were formulated fresh immediately prior to administration and adjusted to account for percent activity. A minimum of four dose levels were tested per experiment with 5 mice/group. The typical doses tested ranged from 0.11 to 18 mg/kg of body weight, with exceptions for comparators that required significantly higher or lower doses to achieve 50% efficacy (dose range minimum-maximum, 0.08 to 54 mg/kg). Each study also included an untreated control group. Mice were housed in filter-topped cages in an isolated room and monitored for morbidity at least every 24 h for 7 days. Efficacy was determined by calculating the 50% effective dose (ED50) for all drugs tested. The ED50 is defined as the dose required to achieve 50% survival at 7 days p.i. and was estimated when possible using the formula y = 1/[1 + 10(log(k)-log(x)× 4.2)], where k = 0.5, by nonlinear regression analysis with Prism, version 3.0 software. [2]

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- Absorption: Oral bioavailability of Omadacycline in humans is ~34%. Food does not significantly affect absorption, but antacids and iron supplements reduce absorption by chelation [1][3]
- Distribution: Volume of distribution is large (160-230 L), with extensive tissue penetration (e.g., skin blister fluid, lung tissue) exceeding plasma concentrations [3]
- Metabolism: Minimal metabolism; ~95% of the drug is excreted unchanged [3]
- Excretion: Eliminated via both renal (35-45%) and non-renal (55-65%) pathways, with a terminal half-life of ~16-18 hours [1][3]

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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. [https://pubmed.ncbi.nlm.nih.gov/31970713/]

- Toxicity/Toxicokinetics - Plasma protein binding: ~70% [3]
- Adverse effects: Common adverse events include nausea (10-15%), vomiting (5-8%), and diarrhea (4-6%). No significant nephrotoxicity or hepatotoxicity was observed in clinical trials [1][3][4]
- Cardiovascular safety: In vitro studies with human ether-a-go-go-related gene (hERG) channels showed no significant inhibition (IC50 >300 μM). In vivo telemetry studies in dogs showed no effect on QT interval at therapeutic doses [5]

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of omadacycline during breastfeeding. It is unknown how much omadacycline is excreted into breastmilk, but the drug is only about 35% absorbed orally under optimal circumstances, and is probably less from milk because of its calcium content. The manufacturer states that breastfeeding is not recommended during treatment and for 4 days after the last dose. If an infant is breastfed, monitor the infant for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (e.g., thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis. As a theoretical precaution, avoid prolonged or repeat courses during nursing.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. Omadacycline: A Newly Approved Antibacterial from the Class of Tetracyclines. Pharmaceuticals (Basel). 2019 Apr 21;12(2):63.

[2]. In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. Antimicrob Agents Chemother. 2014;58(2):1127-35.

[3]. Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent. Drugs. 2020 Feb;80(3):285-313.

[4]. Omadacycline: First Global Approval. Drugs. 2018 Dec;78(18):1931-1937.

[5]. In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5247-53.

[6]. Discovery, pharmacology, and clinical profile of omadacycline, a novel aminomethylcycline antibiotic. Bioorg Med Chem.2016 Dec 15;24(24):6409-6419.

- Omadacycline is a semisynthetic aminomethylcycline, a subclass of tetracyclines, designed to overcome tetracycline resistance mechanisms (efflux pumps and ribosomal protection) [1][2][3]
- Approved indications include acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults, available in both intravenous and oral formulations for sequential therapy [1][3][4]
- It is administered once daily (intravenous: 300 mg loading dose followed by 100 mg/day; oral: 450 mg loading dose followed by 300 mg/day) [3][4]

C36H48N4O10S

728.86

728.309

C, 59.33; H, 6.64; N, 7.69; O, 21.95; S, 4.40

1075240-43-5

Omadacycline;389139-89-3;Omadacycline hydrochloride;1196800-39-1;Omadacycline-d9;2272886-41-4;Omadacycline mesylate;1196800-40-4

54746485

White to yellow solid powder

4.736

7

13

8

51

1350

4

S(C1C([H])=C([H])C(C([H])([H])[H])=C([H])C=1[H])(=O)(=O)O[H].O([H])[C@@]12C(=C(C(N([H])[H])=O)C([C@]([H])([C@]1([H])C([H])([H])[C@]1([H])C([H])([H])C3=C(C([H])=C(C([H])([H])N([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C(=C3C(=C1C2=O)O[H])O[H])N(C([H])([H])[H])C([H])([H])[H])N(C([H])([H])[H])C([H])([H])[H])=O)O[H]

SETFNHZTVGTBHC-XGLFQKEBSA-N

InChI=1S/C29H40N4O7.C7H8O3S/c1-28(2,3)12-31-11-14-10-17(32(4)5)15-8-13-9-16-21(33(6)7)24(36)20(27(30)39)26(38)29(16,40)25(37)18(13)23(35)19(15)22(14)34;1-6-2-4-7(5-3-6)11(8,9)10/h10,13,16,21,31,34,36-37,40H,8-9,11-12H2,1-7H3,(H2,30,39);2-5H,1H3,(H,8,9,10)/t13-,16-,21-,29-;/m0./s1

(4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-((neopentylamino)methyl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide 4-methylbenzenesulfonate

PTK 0796 tosylate; PTK-0796; PTK0796; Omadacycline (tosylate); Omadacycline tosylate [USAN]; Omadacycline tosilate; Amadacyclintosylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 12.5 100 mg/mL ( 137.2 mM )
Water : 100 mg/mL
Ethanol : 100 mg/mL

Solubility in Formulation 1: 50 mg/mL (68.60 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)