Omadacycline: a novel aminomethylcycline

Figures & data

Table 1 In vitro antimicrobial activity of omadacycline against organisms in different studies

Organism	N	MIC50, µg/mL	MIC90, µg/mL	MIC Range, µg/mL	Reference
Staphylococcus aureus	18,577	0.12	0.25	0.015–4	^Citation14
Staphylococcus aureus	51	0.125	0.5	≤0.06–1	^Citation11
Staphylococcus aureus, methicillin susceptible	10,836	0.12	0.25	0.015–2	^Citation14
Staphylococcus aureus, methicillin susceptible	16	0.125	0.125	≤0.06–0.25	^Citation11
Staphylococcus aureus, methicillin resistant	7,741	0.12	0.25	0.015–4	^Citation14
Staphylococcus aureus, methicillin resistant	39	0.25	0.5	0.125–1	^Citation11
Staphylococcus aureus, multidrug- and methicillin resistant	10	0.5	0.5	0.25–0.5	^Citation11
Staphylococcus aureus, methicillin resistant, North America	2708	0.12	0.5	0.03–4	^Citation14
Staphylococcus aureus, methicillin resistant, Europe	952	0.12	0.25	0.03–4	^Citation14
Staphylococcus aureus, methicillin resistant, HA in North America	598	0.12	0.5	0.06–4	^Citation14
Staphylococcus aureus, methicillin resistant, HA in Europe	486	0.12	0.25	0.03–2	^Citation14
Staphylococcus aureus, methicillin resistant, CA in North America	1861	0.12	0.25	0.03–4	^Citation14
Staphylococcus aureus, methicillin resistant, CA in Europe	424	0.12	0.25	0.03–1	^Citation14
Staphylococci, coagulase negative	2,992	0.25	1	0.015–2	^Citation14
Staphylococci, coagulase negative, methicillin susceptible	837	0.12	0.5	0.015–2	^Citation14
Staphylococci, coagulase negative, methicillin resistant	2,155	0.25	1	0.015–2	^Citation14
Enterococcus spp.	5,519	0.06	0.25	0.015–4	^Citation14
Enterococcus spp., vancomycin susceptible	4,456	0.12	0.25	0.015–4	^Citation14
Enterococcus spp., vancomycin resistant	1,063	0.06	0.25	0.015–1	^Citation14
Enterococcus faecalis	3,346	0.12	0.25	0.015–4	^Citation14
Enterococcus faecalis	31	0.25	0.5	0.125–0.5	^Citation11
Enterococcus faecalis, vancomycin susceptible	3,254	0.12	0.25	0.015–4	^Citation14
Enterococcus faecalis, vancomycin resistant	92	0.12	0.25	0.015–1	^Citation14
Enterococcus faecalis, multidrug resistant	3	0.25	0.5	0.25–0.5	^Citation11
Enterococcus faecium	1,955	0.06	0.12	0.015–1	^Citation14
Enterococcus faecium	24	0.25	0.5	0.125–0.5	^Citation11
Enterococcus faecium, vancomycin susceptible	1,019	0.06	0.12	0.015–1	^Citation14
Enterococcus faecium, vancomycin resistant	936	0.06	0.25	0.015–1	^Citation14
Enterococcus faecium, vancomycin resistant	19	0.25	0.5	0.125–0.5	^Citation11
Enterococcus faecium, multidrug- and vancomycin resistant	12	0.25	0.5	0.125–0.5	^Citation11
Streptococcus pneumoniae	6,253	0.06	0.06	0.015–0.5	^Citation14
Streptococcus pneumoniae	41	≤0.06	0.125	≤0.06–0.25	11
Streptococcus pneumoniae, penicillin resistant	1,466	0.06	0.12	0.015–0.5	^Citation14
Streptococcus pneumoniae, penicillin resistant	23	≤0.06	≤0.06	≤0.06	^Citation11
Streptococcus pneumoniae, multidrug- and penicillin resistant	18	≤0.06	≤0.06	≤0.06	^Citation11
Streptococci, viridans group	1,538	0.06	0.12	0.015–0.5	^Citation14
Streptococci, beta-hemolytic	3,196	0.06	0.12	0.015–0.5	^Citation14
Streptococcus pyogenes	1,576	0.06	0.06	0.015–0.5	^Citation14
Streptococcus pyogenes	30	0.125	0.25	≤0.06–0.5	^Citation11
Streptococcus agalatiae	1,570	0.06	0.12	0.015–0.5	^Citation14
Streptococcus agalatiae	18	0.125	0.125	≤0.06–0.25	^Citation11
Enterobacteriaceae	20,305	2	8	0.06–>32	^Citation14
Escherichia coli	8,519	0.5	2	0.12–32	^Citation14
Escherichia coli	12	1	2	0.5–2	^Citation11
Escherichia coli, ESBL phenotype	1,947	1	4	0.12–32	^Citation14
Klebsiella pneumoniae	4,181	2	8	0.12–>32	^Citation14
Klebsiella pneumoniae	14	2	4	1–8	^Citation11
Klebsiella pneumoniae, ESBL phenotype	1,475	2	8	0.25–>32	^Citation14
Klebsiella oxytoca	762	1	4	0.5–32	^Citation14
Haemophilus influenzae	3,383	1	1	0.06–8	^Citation14
Haemophilus influenzae	53	1	2	0.5–8	^Citation11
Haemophilus influenzae, beta-lactamase positive	736	1	1	0.25–4	^Citation14
Moraxella catarrhalis	1,226	0.12	0.25	0.06–1	^Citation14

Abbreviations: MIC, minimum inhibitory concentration; HA, hospital-acquired; CA, community-acquired; ESBL, extended-spectrum beta-lactamase.

Table 2 Pharmacokinetic parameters of omadacycline in healthy adult subjects

Parameters	Intravenous 100 mg		Oral 300 mg		Oral 450 mg
	Single-dose	Steady-state	Single-dose	Steady-state	Single-dose	Steady-state
Cmax (μg/mL)	1.507 (38.6)	2.120 (32.0)	0.548 (26.7)	0.952 (44.2)	0.874 (26.6)	1.077 (25.0)
AUC (μg•h/mL)	9.358 (22.1)	12.140 (26.6)	9.399 (27.2)	11.156 (44.9)	8.977 (26.6)	13.367 (26.0)
Tmax (h)	0.55 (0.25–0.68)	0.50 (0–1)	2.50 (1–4.05)	2.50 (0–8)	2.50 (1.5–3)	2.50 (1.5–4)
V or V/F (L)	256 (25.6)	190 (27.7)	794 (23.6)	ND	ND	ND
CL or CL/F (L/h)	11.24 (23.8)	8.8 (25.2)	34.6 (30.9)	ND	ND	ND
t1/2 (h)	16.2 (14.7)	16.0 (21.7)	14.96 (16.5)	15.5 (10.7)	13.45 (12.9)	16.83 (8.1)

Notes: Parameters are presented as mean (% coefficient of variation) except for T_max which is presented as median (minimum, maximum). Adapted from Nuzyra (Omadacycline) [Package Insert]. Boston, MA: Paratek Pharmaceuticals, Inc.; December2018. Available from https://www.nuzyra.com/nuzyra-pi.pdf.⁶

Abbreviations: C_max, maximum plasma concentration; AUC, area under the concentration-time curve; T_max, time to C_max; V (for intravenous) or V/F (for oral), apparent volume of distribution; F, bioavailability (assumed to be 1 in this table); CL (for intravenous) or CL/F (for oral), apparent systemic clearance; t_1/2, elimination half-life; ND, not determined.

Figure 1 Mean±SD plasma concentration-time curve of omadacycline after administration of 300 mg oral dose (open triangles) and 100 mg intravenous dose (closed circles) in healthy subjects.Note: Data from Sun et al.²³

Figure 2 Mean±SD area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of omadacycline following oral administration of a 300 mg oral dose under fasting condition (solid black bar), when a standard high-fat non-dairy meal was ingested 4 hours pre-dose (solid gray bar), when a standard high-fat non-dairy meal was ingested 2 hours pre-dose (crossed line bar), and when a standard high-fat meal including dairy was ingested 2 hours pre-dose (confetti bar).Note: Data from Tzanis et al.²⁹

Figure 3 Mean±SD unbound plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) concentration-time curve of omadacycline, eravacycline, and tigecycline after multiple intravenous doses of 100 mg, 1 mg/kg, and 50 mg, respectively. Note that the duration of time represents the dosing interval of 24 hours for omadacycline and 12 hours for eravacycline and tigecycline.Note: Data from these studies^30,35

Table 3 Plasma AUC_0–24/MIC ratios associated with net stasis and kill endpoints

	MIC (μg/mL)	Stasis	1-log10 Kill	2-log10 Kill
Streptococcus pneumonia strains^a
ATCC 10813, PCN-susceptible	0.0625	15.79	19.66	25.05
140, PCN-susceptible	0.125	NC	6.06	18.65
1293, PCN-resistant	0.0625	19.83	179.98	NA
ATCC 49619, PCN-resistant	0.03125	NC	15.21	56.20
Staphylococcus aureus strains^b
ATCC 25923, MSSA	0.25	22.71	61.63	ND
ATCC 29213, MSSA	0.25	29.64	58.83	ND
SMITH, MSSA	0.25	51.13	302.51	ND
6538P, MSSA	0.25	22.05	48.95	ND
MW2, MRSA	0.5	23.12	52.49	ND
R2527, MRSA	0.5	21.68	62.06	ND
ATCC 33591, MRSA	0.5	16.19	56.61	ND
WIS-1, MRSA	0.5	13.8	42.48	ND
LSI 1848, MRSA	0.5	20.41	62.86	ND
307109, MRSA	0.5	16.52	32.17	ND

Notes: ^aPharmacodynamic evaluation in neutropenic murine pneumonia model. ^bPharmacodynamic evaluation in neutropenic murine thigh infection model. Lepak AJ, Zhao M, Marchillo K, VanHecker J, Andes DR. In vivo pharmacodynamic evaluation of omadacycline (PTK 0796) against Streptococcus pneumoniae in the murine pneumonia model. Antimicrob Agents Chemother. 2017;61(5):e02368–16. doi:10.1128/AAC.02368-16. Amended with permission from American Society for Microbiology.⁴¹ Adapted from Lepak AJ, Zhao M, Marchillo K, VanHecker JDA. In Vivo Pharmacodynamic Evaluation of Omadacycline (PTK 0796) against Staphylococcus Aureus (SA) in the Murine Thigh Infection Model. San Diege, CA, USA: IDWeek; 2017:1531.⁴²

Abbreviations: PCN, penicillin; MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus; NC, not calculated; NA, endpoint not achieved; ND, not determined.

Table 4 Primary and select secondary endpoints in the OASIS-1 study, a phase 3 clinical trial comparing non-inferiority of omadacycline vs linezolid for acute bacterial skin and skin-structure infections

	Efficacy endpoints	OASIS-1 study			OASIS-2 study
		Omadacycline (n=316)	Linezolid (n=311)	Difference in percentage points (95% CI)	Omadacycline (n=360)	Linezolid (n=360)	Difference in percentage points (95% CI)
US Food and Drug Administration Primary Endpoint	Early clinical response in MITT, % (n)	84.8% (268)	85.5% (266)	−0.7 (−6.3–4.9)	87.5% (325)	82.5% (297)	5 (−0.2–10.3)
	Early clinical response in cPP, % (n/N)	92.6% (276/298)	94.6% (278/294)	−1.9 (−6.1–2.1)	NR	NR	NR
	Early clinical response in MITT, cellulitis or erysipelas, % (n/N)	78.9 (97/123)	83.9 (99/118)	−5.0 (−14.9–4.9)	NR	NR	NR
	Early clinical response in MITT, wound infection, % (n/N)	89.2% (91/102)	88.5% (92/104)	0.8 (−8.2–9.7)	NR	NR	NR
	Early clinical response in MITT, major abscess, % (n/N)	87.9% (80/91)	84.3% (75/89)	3.6 (−6.7–14.2)	NR	NR	NR
European Medicines Agency Co-Primary Endpoints	Investigator-assessed clinical response at PTE in MITT, % (n)	86.1% (272)	83.6% (260)	2.5 (−3.2–8.2)	84.2% (303)	80.8% (291)	3.3 (−2.2–9.0)
Investigator-assessed clinical response at PTE in cPP, % (n/N)	96.3% (259/269)	93.5% (243/260)	2.8 (−1.0–6.9)	97.9% (278/284)	95.5% (279/292)	2.3 (−0.5–5.8)
	Investigator-assessed clinical response at PTE in MITT, cellulitis or erysipelas, % (n/N)	91.1% (112/123)	84.7% (100/118)	6.3 (−2.0–15.0)	88.4% (76/86)	92.9% (78/84)	−4.5 (NR)
	Investigator-assessed clinical response at PTE in MITT, wound infection, % (n/N)	81.4% (83/102)	80.8% (84/104)	0.6 (−10.3–11.4)	82.4% (173/210)	76.6% (164/214)	5.7 (NR)
	Investigator-assessed clinical response at PTE in MITT, major abscess, % (n/N)	84.6% (77/91)	85.4% (76/89)	−0.8 (−11.5–10.0)	84.4% (54/64)	79.0% (49/62)	5.3 (NR)
	Investigator-assessed clinical responses at PTE by pathogen at baseline, m-MITT	N=228	N=227		N=276	N=287
	Staphylococcus aureus, % (n/N)	83% (130/156)	83% (126/151)		82.7% (182/220)	79.8% (186/233)
	Methicillin-susceptible S. aureus, % (n/N)	84% (74/88)	82% (84/102)		80.8% (97/120)	79.2% (103/130)
	Methicillin-resistant S. aureus, % (n/N)	83% (57/69)	86% (43/50)		85.6% (89/104)	79.4% (85/107)
	Streptococcus anginosus group, % (n/N)	74% (35/47)	70% (26/37)		86.0% (49/57)	73.3% (33/45)
	Streptococcus constellatus, % (n/N)	64% (16/25)	64% (9/14)		NR	NR
	Streptococcus intermedius, % (n/N)	83% (10/12)	78% (14/18)		78.3% (18/23)	66.7% (16/24)
	Streptococcus pyogenes, % (n/N)	73% (8/11)	89% (16/18)		69.0% (20/29)	56.3% (9/16)
	Enterococcus faecalis, vancomycin susceptible % (n/N)	90% (9/10)	92% (12/13)		100.0% (7/7)	70.0% (7/10)

Notes: Data from these studies.^49,50,63

Abbreviations: 95% CI, 95% confidence interval; MITT, modified intent-to-treat; cPP, clinical per-protocol; PTE, post-treatment evaluation; m-MITT, microbiologic-MITT; NR, not reported.

Table 5 Primary and select secondary endpoints in the OPTIC study, a phase 3 clinical trial comparing non-inferiority of omadacycline vs moxifloxacin for community-acquired bacterial pneumonia

	Omadacycline (n=386)	Moxifloxacin (n=388)	Difference in percentage points (95% CI)
Early clinical response in ITT, % (n)	81.1% (313)	82.7% (321)	−1.6 (−7.1–3.8)
Early clinical response in cPP, % (n/N)	86.5% (308/356)	87.2 (314/360)	−0.7 (−5.7–4.3)
Early clinical response in ITT, PSI risk class III, % (n/N)	84.1 (191/227)	86.6 (187/216)	−2.4 (−9.1–4.2)
Early clinical response in ITT, PSI risk class IV, % (n/N)	77.5% (79/102)	80.2% (93/116)	−2.7 (−13.8–8.1)
Investigator-assessed clinical response at PTE in ITT, % (n)	87.6% (338)	85.1% (330)	2.5 (−2.4–7.4)
Investigator-assessed clinical response at PTE in cPP, % (n/N)	92.9% (316/340)	90.4% (312/345)	2.5 (−1.7–6.8)
Investigator-assessed clinical response at PTE in ITT, PSI risk class III, % (n/N)	90.7% (206/227)	88.0% (190/216)	2.8 (−3.0–8.7)
Investigator-assessed clinical response at PTE in ITT, PSI risk class IV, % (n/N)	83.3% (85/102)	80.2% (93/116)	3.2 (−7.4–13.4)
Investigator-assessed clinical responses at PTE by pathogen at baseline, MITT	N=204	N=182
Gram-positive bacteria, % (n/N)	85% (52/61)	88% (49/56)
Streptococcus pneumoniae, % (n/N)	86% (37/43)	91% (31/34)
S. pneumoniae, penicillin-susceptible, % (n/N)	88% (23/26)	95% (21/22)
S. pneumoniae, macrolide-resistant, % (n/N)	100% (10/10)	100% (5/5)
S. pneumoniae, tetracycline-resistant, % (n/N)	88% (14/16)	76% (13/17)
Staphylococcus aureus, % (n/N)	73% (8/11)	82% (9/11)
Gram-negative bacteria, % (n/N)	85% (67/79)	81% (56/69)
Haemophilus influenzae, % (n/N)	81% (26/32)	100% (16/16)
Haemophilus parainfluenzae, % (n/N)	83% (15/18)	76% (13/17)
Klebsiella pneumoniae, % (n/N)	77% (10/13)	85% (11/13)
Atypical bacteria, % (n/N)	90% (66/73)	91% (58/64)
Mycoplasma pneumoniae, % (n/N)	89% (31/35)	86% (25/29)
Legionella pneumophila, % (n/N)	93% (27/29)	96% (27/28)
Chlamydia pneumoniae, % (n/N)	93% (14/15)	93% (13/14)

Note: From The New England Journal of Medicine, Stets R, Popescu M, Gonong JR, et al, Omadacycline for community-acquired bacterial pneumonia. N Engl J Med. 380:517–527. Copyright © (2019)  Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society⁵¹

Abbreviations: 95% CI, 95% confidence interval; ITT, intent-to-treat; cPP, clinical per-protocol; PTE, post-treatment evaluation; m-ITT, microbiologic-ITT; PSI, pneumonia severity index.

Table 6 United States food and drug administration identified breakpoints for omadacycline

Infection type	Pathogens	Minimum inhibitory concentrations (µg/mL)			Disk diffusion zone diameter (mm)
		S	I	R	S	I	R
Acute Bacterial Skin and Skin Structure Infections	Enterobacteriaceae: Klebsiella pneumoniae, Enterobacter cloacae (excluding Morganella spp., Proteus spp., and Providencia spp.)	≤4	8	≥16	≥18	16–17	≤15
	Staphylococcus aureus (including methicillin‑resistant isolates)	≤0.5	1.0	≥2.0	≥21	10–20	<18
	Staphylococcus lugdunensis	≤0.12	0.25	≥0.5	≥20	26–28	≤25
	Enterococcus faecalis	≤0.25	0.5	≥1.0	≥18	16–17	≤15
	Streptococcus anginosus group: S. anginosus S. intermedius S. constellatus	≤0.12	0.25	≥0.5	≥24	18–23	≤17
Community-Acquired Bacterial Pneumonia	Enterobacteriaceae: Klebsiella pneumoniae (excluding Morganella spp., Proteus spp., and Providencia spp.)	≤4	8	≥16	≥18	16–17	≤15
	Staphylococcus aureus (including methicillin‑susceptible isolates only)	≤0.25	0.5	≥1.0	≥23	21–22	≤20
	Haemophilus spp.: H. influenzae H. parainfluenzae	≤2	4	≥8	≥20	17–19	≤16
	Streptococcus pneumoniae	≤0.12	0.25	≥0.5	≥20	17–19	≤16

Note: Adapted from U.S. Food and Drug Administration. Omadacycline injection and oral products: FDA identified breakpoints. Available from: https://www.fda.gov/drugs/development-resources/omadacycline-injection-and-oral-products.⁵⁴

Abbreviations: S, susceptible; I, intermediate; R, resistant.

Table 7 Safety outcomes of omadacycline and comparators in phase 2 and 3 studies for the treatment of different infections

Type of event % (n)	Phase 2 study in CSSSI^Citation48		OASIS-1 study in ABSSSI^Citation49		OASIS-2 study in ABSSSI^Citation50		OPTIC study in CABP^Citation51
	Omadacycline (N=111)	Linezolid (N=108)	Omadacycline (N=323)	Linezolid (N=322)	Omadacycline (N=368)	Linezolid (N=367)	Omadacycline (N=382)	Moxifloxacin (N=388)
Any AE	41.4% (46)	50.9% (55)	48.3% (156)	45.7% (147)	53.5% (197)	37.3% (137)	41.1% (157)	48.5 (188)
Treatment-related AE	21.6% (24)	30.6% (33)	18.0% (58)	18.3% (59)	NR	NR	10.2% (39)	17.8% (69)
Serious AE	0.9% (1)	1.8% (2)	3.7% (12)	2.5% (8)	1.4% (6)	1.4% (6)	6.0% (23)	6.7% (26)
AE leading treatment to discontinuation	0.9% (1)	1.8% (2)	1.9% (6)	2.2% (7)	1.6% (6)	0.8% (3)	5.5% (21)	7.0% (27)
Death	NR	NR	0.3% (1)	0.6% (2)	NR	NR	2.1% (8)	1.0% (4)
Nausea	11.7% (13)	7.4% (8)	12.4% (40)	9.9% (32)	30.2% (111)	7.6% (28)	2.4% (9)	5.4% (21)
Vomiting	4.5% (5)	3.7% (4)	5.3% (17)	5.0% (16)	16.8% (62)	3.0% (11)	2.6% (10)	1.5% (6)
Diarrhea	2.7% (3)	5.6% (6)	2.2% (7)	3.1% (10)	4.1% (15)	2.7% (10)	1.0% (4)	8.0% (31)
Constipation	4.5% (5)	1.9% (2)	1.2% (4)	1.5% (5)	NR	NR	2.4% (9)	1.5% (6)
Headache	6.3% (7)	8.3% (9)	3.1% (10)	4.0% (13)	3.5% (13)	2.2% (8)	2.1% (8)	1.3% (5)
Rash	4.5% (5)	1.9% (2)	0.9% (3)	0.3% (1)	NR	NR	0.3% (1)	1.3% (5)
ALT elevation	2.7% (3)	6.5% (7)	2.8% (9)	4.3% (14)	5.2% (19)	3.0% (11)	3.7% (14)	4.6% (18)
AST elevation	2.7% (3)	4.6% (5)	2.5% (8)	3.7% (12)	4.6% (17)	3.3% (12)	2.1% (8)	3.6% (14)
Infusion site reactions (≥1)	NR	NR	11% (36)	8.6%(28)			1% (4)	2.5% (10)

Notes: Data from these studies.^48-51

Abbreviations: CSSSI, complicated skin and skin structure infection; ABSSSI, acute bacterial skin and skin structure infection; CABP, community-acquired bacterial pneumonia; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NR, not reported.

Table 8 Dosage of omadacycline for adult patients with ABSSSI and CABP

	ABSSSI (intravenous and oral regimen)	ABSSSI (oral only regimen)	CABP (intravenous and oral regimen)
Loading doses	200 mg by intravenous infusion over 60 minutes on day 1 OR 100 mg by intravenous infusion over 30 minutes, twice on day 1	450 mg orally once a day on day 1 and day 2	200 mg by intravenous infusion over 60 minutes on day 1 OR 100 mg by intravenous infusion over 30 minutes, twice on day 1
Maintenance dose	100 mg by intravenous infusion over 30 minutes once daily OR 300 mg orally once daily	300 mg orally once daily	100 mg by intravenous infusion over 30 minutes once daily OR 300 mg orally once daily
Duration of treatment	7–14 days	7–14 days	7–14 days

Note: Adapted from Nuzyra (Omadacycline) [Package Insert]. Boston, MA: Paratek Pharmaceuticals, Inc.; December2018. Available from https://www.nuzyra.com/nuzyra-pi.pdf.⁶

Abbreviations: ABSSSI, acute bacterial skin and skin structure infections; CABP, community-acquired bacterial pneumonia.

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