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. 2014 Feb;58(2):1127–1135. doi: 10.1128/AAC.01242-13

In Vitro and In Vivo Antibacterial Activities of Omadacycline, a Novel Aminomethylcycline

A B Macone a, B K Caruso a, R G Leahy a, J Donatelli a, S Weir b, M P Draper a, S K Tanaka a,✉, S B Levy a
PMCID: PMC3910882  PMID: 24295985

Abstract

Omadacycline is the first intravenous and oral 9-aminomethylcycline in clinical development for use against multiple infectious diseases including acute bacterial skin and skin structure infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). The comparative in vitro activity of omadacycline was determined against a broad panel of Gram-positive clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Lancefield groups A and B beta-hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae (PRSP), and Haemophilus influenzae (H. influenzae). The omadacycline MIC90s for MRSA, VRE, and beta-hemolytic streptococci were 1.0 μg/ml, 0.25 μg/ml, and 0.5 μg/ml, respectively, and the omadacycline MIC90s for PRSP and H. influenzae were 0.25 μg/ml and 2.0 μg/ml, respectively. Omadacycline was active against organisms demonstrating the two major mechanisms of resistance, ribosomal protection and active tetracycline efflux. In vivo efficacy of omadacycline was demonstrated using an intraperitoneal infection model in mice. A single intravenous dose of omadacycline exhibited 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 ranged from 0.30 mg/kg to 1.74 mg/kg, and the ED50 for Escherichia coli was 2.02 mg/kg. These results demonstrate potent in vivo efficacy including activity against strains containing common resistance determinants. Omadacycline demonstrated in vitro activity against a broad range of Gram-positive and select Gram-negative pathogens, including resistance determinant-containing strains, and this activity translated to potent efficacy in vivo.

INTRODUCTION

Widespread resistance to antibiotics, including resistance to the older tetracyclines (tetracycline, doxycycline, and minocycline), has limited their usefulness in recent years (1, 2). New tetracycline derivatives that inhibit resistant organisms have been approved or are in development, including the glycylcyclines and specifically tigecycline, and fluorocyclines, including eravacycline (TP-434), and both tigecycline and eravacycline have potent Gram-positive and Gram-negative in vitro activity (3–6). The discovery of the 9-aminomethyl class of tetracyclines has led to the identification of omadacycline (PTK 0796) that is poised to begin phase 3 clinical trials in acute bacterial skin and skin structure infections (ABSSSI), community-acquired (CA) bacterial pneumonia (CABP), and urinary tract infections (UTI) with both an intravenous (i.v.) and oral tablet formulation. Omadacycline, (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9{[(2,2-dimethylpropyl)amino]methyl}-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, contains a four-ring carbocyclic skeleton and is a semisynthetic compound prepared by chemical modification of minocycline (Fig. 1) (7, 8).

FIG 1.

FIG 1

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Chemical structure of omadacycline.

Omadacycline is distinct from older tetracyclines because it demonstrates in vitro activity against a relatively broad spectrum of organisms, including Gram-positive, Gram-negative, anaerobic, and atypical pathogens, and demonstrates similar in vitro activity against pathogens that express not only tetracycline resistance but resistance to other antibiotics, including methicillin, vancomycin, erythromycin, and ciprofloxacin (9–20). This broad in vitro activity has been confirmed in various in vivo models of infection (21–24). Omadacycline is bioavailable in humans by both oral and intravenous routes and does not demonstrate significant gastrointestinal side effects (25–28). The targeted indications encompass acute bacterial infections where a broad-spectrum antibiotic with activity against the most prevalent community-acquired multidrug-resistant organisms is desired. This report is the initial description of the in vitro spectrum and in vivo efficacy of omadacycline. The in vitro activity of omadacycline translates into potent in vivo efficacy in a lethal infection model, suggesting that the pharmacodynamic requirements necessary for human clinical trial investigation can be achieved.

MATERIALS AND METHODS

Bacterial strains.

Routine clinical isolates were obtained from the following sources: Children's Hospital, Boston, MA; Channing Laboratories, Boston, MA; Clinical Microbiology Institute, Wilsonville, OR; Glaxo Smith Kline, Collegeville, PA; Tufts Medical Center, Boston, MA; University of California at Los Angeles Medical Center, Los Angeles, CA; University of Wisconsin Hospitals and Clinics, Madison, WI. For testing, isolates were chosen randomly so that all sites would be represented. All isolates were stored frozen at −80°C in tryptic soy broth or Mueller-Hinton broth (Northeast Laboratories, Waterville, ME) plus 20% glycerol (Becton, Dickinson, Sparks MD). Horse or sheep blood supplementation was used for fastidious organisms. Isolates were subcultured twice onto appropriate solid medium (tryptic soy agar with 5% sheep blood or chocolate agar; Becton, Dickinson, Sparks MD) prior to MIC testing. Quality-control isolates were obtained from the American Type Culture Collection (ATCC, Manassas, VA).

For the in vivo experiments, the bacterial strains Streptococcus pneumoniae 700905 and Staphylococcus aureus 29213 and the clinical isolate S. aureus USA300 were obtained from the American Type Culture Collection (ATCC 700905, ATCC 29213, and CA USA300 FPR3757/ATCCBAA 1556, respectively) (ATCC, Manassas, VA). Tetracycline-sensitive S. pneumoniae PBS1339 (GSK1629) was obtained from GlaxoSmithKline, Philadelphia, PA. S. pneumoniae 157E-2 was derived from passing S. pneumoniae 157E (originally called GSK157E and obtained from GlaxoSmithKline) twice through mice. S. aureus USA400 is a clinical isolate (CA USA400 REF 571) obtained from Paul Fey, University of Nebraska Medical Center, Omaha, NE. S. aureus MRSA5 (where MRSA is methicillin-resistant S. aureus) was obtained from the University of Maryland, College Park, MD. Escherichia coli PBS1478 (also referred to as SC8294) was originally obtained from Bristol Meyers Squibb, Fort Devens, MA.

Antibiotics and in vitro susceptibility testing.

Omadacycline was synthesized at Paratek Pharmaceuticals, Inc. Antibiotic comparators used for the in vitro studies were obtained from Sigma-Aldrich, St. Louis, MO. For the in vivo studies, tigecycline was obtained from Bosche Scientific, New Brunswick, NJ. Doxycycline was obtained from Hovione, East Windsor, NJ. Linezolid and levofloxacin were purchased from Sequoia Research, Pangbourne, United Kingdom. Vancomycin HCl and ceftriaxone were purchased from Sigma, Atlanta, GA. Daptomycin was obtained from Cubist Pharmaceuticals, Inc., Lexington, MA. Microdilution broth MICs were performed according to CLSI (formerly NCCLS) guidelines (18).

PCR for detection and identification of tetracycline resistance genes.

The presence of the efflux genes tet(K) and tet(L), as well as tet(A), tet(B), and genes of the ribosomal protection (RP) family [tet(M), tet(O), and tet(S)] was assessed by multiplex PCR (29).

Systemic i.p. challenge model.

Six-week-old, specific-pathogen-free, male CD-1 mice, weighing 18 to 30 g (Charles River, Wilmington, MA), were used for all experiments. Animals were acclimated for 1 week following delivery. Mice were allowed food and water ad libitum and kept in a constant 12-h light/dark cycle. Bacterial cultures were grown by either streaking frozen colonies onto tryptic soy agar II plates with 5% sheep's blood (Northeast Laboratories, Waterville, ME) and incubating them overnight in a CO2 enriched environment at 37°C (S. pneumoniae) or growing frozen isolates in a 37°C shaker at 180 rpm in Mueller-Hinton broth (Northeast Labs, Waterville, ME) (for S. aureus and E. coli). For S. pneumoniae, following the overnight incubation, the colonies were aseptically collected from two to three agar plates and resuspended in 3 ml of sterile phosphate-buffered saline (PBS) (Fisher Scientific, Boston, MA) for a final concentration of approximately 1 × 109 CFU/ml. For S. aureus and E. coli strains, an overnight broth was grown to a concentration of approximately 1 × 109 CFU/ml. Serial dilutions of all bacterial suspensions were performed in sterile PBS to obtain the infectious dose used for individual experiments. Infectious doses used in each experiment were confirmed by plating serial dilutions on tryptic soy agar II plates with 5% sheep's blood and incubating plates overnight (in a CO2 enriched environment for S. pneumoniae) at 37°C, after which bacterial colonies were then enumerated. Septicemia was induced by infecting mice intraperitoneally (i.p.) with 500 μl containing (6.85 ± 1.58) × 102 CFU (mean ± standard deviation) of S. pneumoniae PBS1339, (1.07 ± 1.15) × 106 CFU of S. pneumoniae 700905, (1.02 ± 1.22) × 105 CFU of S. pneumoniae 157E-2, (7.13 ± 3.31) × 107 CFU of S. aureus USA300, (6.40 ± 1.53) × 106 CFU of S. aureus 29213, (1.08 ± 0.43) × 103/ml CFU of S. aureus USA400, (1.06 ± 0.56) × 108 CFU of S. aureus MRSA5, and (6.60 ± 2.34) × 106 CFU of E. coli PBS1478 in an autoclaved 4.5% bacteriological mucin (VWR Scientific, Pittsburg, PA) suspension. Mice were infected using a 3-ml lock-top sterile syringe with a sterile 25-gauge, 5/8-in. needle (Becton, Dickinson, Franklin Lakes, NJ). 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. All animal protocols were critically reviewed and approved by the Paratek Pharmaceuticals, Inc., Institutional Animal Care and Use Committee.

RESULTS

MICs of omadacycline, tetracycline, and doxycycline on characterized tetracycline-resistant Gram-positive and Gram-negative bacteria.

Omadacycline demonstrated activity against the Gram-positive pathogens S. aureus, Enterococcus faecalis, Enterococcus faecium, S. pneumoniae, and beta-hemolytic streptococci carrying ribosomal protection [tet(M), tet(O), and tet(S)] and efflux [tet(K) and tet(L)] tetracycline resistance genes (Table 1). The concentration of omadacycline required to inhibit growth of several strains of E. coli carrying efflux genes [tet(A)] was also reduced compared to conventional tetracyclines.

TABLE 1.

In vitro activity of omadacycline against tetracycline-resistant and -susceptible bacteria

Organism(s) Tetracycline resistance gene(s) No. of isolates MIC range (μg/ml)a
Omadacycline Tetracycline Doxycycline
Staphylococcus aureus tet(M) 19 0.125–1 32->64 2–16
tet(K) 5 0.125–0.25 16–32 1–4
35 ≤0.06–0.5 ≤0.06–0.25 ≤0.06–0.125
Enterococcus faecalis tet(M) 14 0.125–0.5 32–64 4–8
tet(L) 1 0.25 64 16
tet(M), tet(L) 3 0.5 >64 16
tet(S) 1 0.25 32 2
11 0.25–0.5 ≤0.06–0.25 ≤0.06–0.125
Enterococcus faecium tet(M) 13 0.125–0.5 32–64 2–8
tet(M), tet(L) 2 0.25 >64 8–16
tet(K) 1 0.12 32 4
tet(O) 1 0.12 32 4
8 0.125–0.5 0.125–0.25 ≤0.06
Streptococcus pneumoniae tet(M) 22 ≤0.06 4–64 2–4
18 ≤0.06–0.25 ≤0.06–0.25 ≤0.06–0.25
Beta-hemolytic streptococcib tet(M) 17 ≤0.06–0.5 4–64 2–16
tet(O) 4 ≤0.06–0.25 32–64 8
26 ≤0.06–0.5 ≤0.06–0.125 ≤0.06
Escherichia coli tet(A) 4 2 64->64 16
17 0.5–2 0.5–2 0.5–1
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a

Commercial-grade tigecycline was not available at the time of in vitro testing.

b

S. pyogenes and S. agalactiae.

Omadacycline demonstrates in vitro activity against a broad panel of clinically relevant Gram-positive and Gram-negative bacterial strains.

The comparative in vitro activity of omadacycline was assessed against a broad panel of clinically significant Gram-positive and Gram-negative bacteria. Omadacycline was as active as comparators against susceptible S. aureus and was more active than most comparators against MRSA strains, most of which were resistant to more than one comparator antibiotic (Table 2). These results indicate that omadacycline specifically overcomes the problem of tetracycline, doxycycline, and minocycline resistance in S. aureus.

TABLE 2.

In vitro activity against Gram-positive organisms

Organism name or group No. of isolates Antibiotica MIC range (μg/ml) MIC50 (μg/ml) MIC90 (μg/ml)
S. aureus 55 Omadacycline ≤0.06–1 0.125 0.5
Tetracycline ≤0.06–64 0.125 64
Minocycline ≤0.06–16 0.125 8
Cefotaxime 1–>64 32 >64
Vancomycin 0.25–2 0.5 1
Levofloxacin ≤0.06–>64 4 32
Linezolid 0.5–2 2 2
Azithromycin 0.25–>64 >64 >64
Clindamycin ≤0.06–>64 0.125 >64
Doxycycline ≤0.06–8 ≤0.06 8
Methicillin-resistant S. aureus 39 Omadacycline 0.125–1 0.25 0.5
Tetracycline ≤0.06–64 0.25 64
Minocycline ≤0.06–16 0.25 8
Cefotaxime 4–>64 >64 >64
Vancomycin 0.25–2 0.5 1
Levofloxacin 0.5–>64 8 32
Linezolid 0.5–2 2 2
Azithromycin 0.5–>64 >64 >64
Clindamycin ≤0.06–>64 >64 >64
Doxycycline ≤0.06–8 0.125 8
Methicillin-sensitive S. aureus 16 Omadacycline ≤0.06–0.25 0.125 0.125
Tetracycline ≤0.06–16 ≤0.06 0.125
Minocycline ≤0.06–0.125 ≤0.06 0.125
Cefotaxime 1–2 2 2
Vancomycin 0.25–0.5 0.5 0.5
Levofloxacin ≤0.06–4 0.125 0.125
Linezolid 1–2 1 2
Azithromycin 0.25–32 0.5 0.5
Clindamycin ≤0.06–0.125 ≤0.06 0.125
Doxycycline ≤0.06–1 ≤0.06 ≤0.06
Multidrug- and methicillin-resistant S. aureus 10 Omadacycline 0.25–0.5 0.5 0.5
Tetracycline 32–>64 >64 >64
Minocycline 2–16 8 8
Cefotaxime 32–64 >64 >64
Vancomycin 0.5–1 1 1
Levofloxacin 8–32 8 32
Linezolid 0.5–2 1 2
Azithromycin >64 >64 >64
Clindamycin >64 >64 >64
Doxycycline 2–8 8 8
E. faecalis 31 Omadacycline 0.125–0.5 0.25 0.5
Tetracycline 0.125–>64 32 64
Minocycline 0.125–16 8 16
Vancomycin 0.5–8 1 2
Levofloxacin 0.5–64 1 32
Linezolid 1–4 1 2
Azithromycin 1–>64 8 >64
Clindamycin 2–>64 32 >64
Doxycycline ≤0.06–16 4 16
Multidrug-resistant E. faecalis 3 Omadacycline 0.25–0.5 0.25 0.5
Tetracycline 32–64 32 64
Minocycline 8–16 8 16
Vancomycin 0.5–8 0.5 8
Levofloxacin 16–64 32 64
Linezolid 1 1 1
Azithromycin >64 >64 >64
Clindamycin >64 >64 >64
Doxycycline 4 4 4
E. faecium 24 Omadacycline 0.125–0.5 0.25 0.5
Tetracycline 0.125–>64 32 64
Minocycline 0.125–32 8 16
Vancomycin 0.5–>64 >64 >64
Levofloxacin 1–>64 64 >64
Linezolid 0.5–4 2 2
Azithromycin 4–>64 >64 >64
Clindamycin ≤0.06–>64 >64 >64
Doxycycline ≤0.06–16 2 8
Vancomycin-resistant E. faecium 19 Omadacycline 0.125–0.5 0.25 0.5
Tetracycline 0.125–>64 32 64
Minocycline 0.25–32 8 16
Vancomycin 64–>64 >64 >64
Levofloxacin 1–>64 64 >64
Linezolid 0.5–4 2 2
Azithromycin >64 >64 >64
Clindamycin >64 >64 >64
Doxycycline ≤0.06–8 2 4
Multidrug- and vancomycin-resistant E. faecium 12 Omadacycline 0.125–0.5 0.25 0.5
Tetracycline 32–>64 32 >64
Minocycline 4–16 8 16
Vancomycin >64 >64 >64
Levofloxacin 8–>64 32 >64
Linezolid 0.5–2 1 2
Azithromycin >64 >64 >64
Clindamycin >64 >64 >64
Doxycycline 2–8 2 4
S. pneumoniae 41 Omadacycline ≤0.06–0.25 ≤0.06 0.125
Tetracycline ≤0.06–64 16 32
Minocycline ≤0.06–8 2 8
Cefotaxime ≤0.06–8 1 2
Vancomycin ≤0.06–0.5 0.25 0.25
Levofloxacin 0.25–1 0.5 1
Penicillin ≤0.06–8 2 4
Linezolid 0.25–2 1 1
Azithromycin ≤0.06–>64 2 >64
Clindamycin ≤0.06–>64 ≤0.06 >64
Doxycycline ≤0.06–4 2 4
Penicillin-resistant S. pneumoniae 23 Omadacycline ≤0.06 ≤0.06 ≤0.06
Tetracycline ≤0.06–64 32 32
Minocycline 0.125–8 8 8
Cefotaxime 0.5–8 1 8
Vancomycin 0.125–0.25 0.25 0.25
Levofloxacin 0.5–1 0.5 1
Penicillin 2–8 4 8
Linezolid 0.5–2 1 1
Azithromycin ≤0.06–>64 4 >64
Clindamycin ≤0.06–>64 ≤0.06 >64
Doxycycline ≤0.06–4 4 4
Multidrug- and penicillin-resistant S. pneumoniae 18 Omadacycline ≤0.06 ≤0.06 ≤0.06
Tetracycline 16–64 32 32
Minocycline 4–8 8 8
Cefotaxime 0.5–8 1 8
Vancomycin 0.125–0.25 0.125 0.25
Levofloxacin 0.5–1 0.5 1
Penicillin 2–8 4 8
Linezolid 0.5–1 1 1
Azithromycin 2–>64 >64 >64
Clindamycin ≤0.06–>64 >64 >64
Doxycycline 2–4 4 4
S. pyogenes 30 Omadacycline ≤0.06–0.5 0.125 0.25
Tetracycline ≤0.06–64 ≤0.06 64
Minocycline 0.125–8 0.25 8
Cefotaxime ≤0.06 ≤0.06 ≤0.06
Vancomycin 0.25 0.25 0.25
Levofloxacin 0.25–1 0.25 1
Linezolid 0.5–1 1 1
Azithromycin ≤0.06–>64 ≤0.06 8
Clindamycin ≤0.06–>64 ≤0.06 ≤0.06
Doxycycline ≤0.06–8 ≤0.06 8
S. agalactiae 18 Omadacycline ≤0.06–0.25 0.125 0.125
Tetracycline ≤0.06–64 32 64
Minocycline 0.125–32 16 16
Cefotaxime ≤0.06 ≤0.06 ≤0.06
Vancomycin 0.125–0.5 0.25 0.5
Levofloxacin 0.125–0.5 0.5 0.5
Linezolid 1–1 1 1
Azithromycin ≤0.06–8 ≤0.06 0.125
Clindamycin ≤0.06 ≤0.06 ≤0.06
Doxycycline ≤0.06–16 8 8
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a

Commercial-grade tigecycline was not available at the time of in vitro testing.

One of the more difficult to treat pathogens, and the pathogen that has been the most problematic in terms of resistance to antibiotics, is the genus Enterococcus, including both Enterococcus faecalis and Enterococcus faecium. Isolates of both species have acquired mechanisms of resistance to vancomycin, and such strains present a difficult therapeutic challenge. Omadacycline is active against both species and is equally active against vancomycin-susceptible and -resistant isolates (Table 2). Omadacycline is also equally active against tetracycline-resistant and -susceptible isolates of E. faecalis and E. faecium.

S. pneumoniae is an important respiratory pathogen in the hospital and community. Of particular concern in the community are isolates resistant to accepted oral antibiotics, particularly penicillins and cephalosporins, macrolides, and tetracyclines. Omadacycline exhibits activity against all S. pneumoniae isolates tested, regardless of resistance to these agents and even when isolates are resistant to multiple antibiotics (tetracycline plus penicillin plus azithromycin) (Table 2).

Omadacycline also exhibits in vitro activity against other streptococci. Streptococcus pyogenes (Lancefield group A, beta-hemolytic streptococcus) and Streptococcus agalactiae (Lancefield group B, beta-hemolytic streptococcus) are susceptible to omadacycline (Table 2).

Finally, omadacycline exhibits activity in vitro against some Gram-negative bacteria including E. coli, Klebsiella pneumoniae, and Haemophilus influenzae (Table 3).

TABLE 3.

In vitro activity against Gram-negative organisms

Organism No. of isolates Antibiotica MIC range (μg/ml) MIC50 (μg/ml) MIC90 (μg/ml)
E. coli 23 Omadacycline 0.5–2 1 2
Tetracycline 0.5–>64 2 >64
Cefotaxime ≤0.06–0.5 ≤0.06 0.125
Levofloxacin ≤0.06–16 ≤0.06 4
Minocycline 0.5–16 1 8
Ampicillin 2–>64 >64 >64
Gentamicin 0.25–64 1 8
Ciprofloxacin ≤0.06–32 ≤0.06 8
Doxycycline 0.5–64 1 64
K. pneumoniae 14 Omadacycline 1–8 2 4
Tetracycline 0.5–>64 2 >64
Cefotaxime ≤0.06–>64 ≤0.06 32
Levofloxacin ≤0.06–64 ≤0.06 32
Minocycline 2–>64 2 64
Gentamicin 0.5–32 0.5 32
Ciprofloxacin ≤0.06–>64 ≤0.06 >64
Doxycycline 1–64 2 32
H. influenzae 53 Omadacycline 0.5–8 1 2
Tetracycline 0.125–64 2 32
Cefotaxime ≤0.06–1 ≤0.06 ≤0.06
Levofloxacin ≤0.06 ≤0.06 ≤0.06
Ampicillin ≤0.06–>64 64 >64
Azithromycin 0.25–4 1 2
Doxycycline 0.125–8 0.5 4
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a

Commercial-grade tigecycline was not available at the time of in vitro testing.

Comparative efficacy studies in the in vivo systemic infection model.

The efficacy of omadacycline was tested in a systemic infection model to determine if omadacycline has potential as a clinical therapy in humans. The i.p. challenge model is a standard in vivo model of systemic infection commonly used as a basic screening tool to evaluate the antibiotic potential of novel therapies (30).

Omadacycline has demonstrated favorable pharmacokinetics intravenously in multiple species and has demonstrated good intravenous and oral bioavailability in humans (27, 28, 31). Omadacycline is currently being developed as both an intravenous and oral broad-spectrum clinical therapy (25, 26, 32). However, the oral bioavailability of omadacycline in rodents is significantly lower, as demonstrated by pharmacokinetic evaluation and subsequent efficacy studies (data not shown). Because murine omadacycline bioavailability is particularly poor compared to the good oral bioavailability previously observed in other nonrodent species and humans, in vivo efficacy studies in mice were conducted by administering omadacycline intravenously.

A single i.v. dose of omadacycline demonstrated potent efficacy against tetracycline-sensitive and tetracycline-resistant strains of S. pneumoniae and S. aureus, as well as proving efficacious against the common Gram-negative pathogen E. coli, in the murine systemic i.p. challenge model (Table 4). Efficacy was evaluated by determining the ED50s for omadacycline and each comparator antibiotic. Against the highly virulent, mucoid, tetracycline-sensitive S. pneumoniae PBS1339 strain, the ED50 of 3.34 mg/kg for omadacycline was similar to that of the glycycline, tigecycline (4.13 mg/kg). Omadacycline was over 4 to 5 times more efficacious than doxycycline, vancomycin, and levofloxacin and over 7 times more efficacious than linezolid (with ED50s of 14.23 mg/kg, 15.7 mg/kg, 19.35 mg/kg, and 24.47 mg/kg, respectively). Ceftriaxone and daptomycin were slightly more potent than omadacycline (1.10 mg/kg and 1.43 mg/kg, respectively).

TABLE 4.

In vivo efficacy of omadacycline versus clinically used antibiotic comparators in a murine i.p. challenge model

Strain (mean CFU/mouse) and compound MIC (μg/ml) ED50 (mg/kg [95% CI])a
S. pneumoniae PBS1339 (6.85 × 102)
    Omadacycline 0.125 3.34 ± 1.56
    Ceftriaxone 0.015 1.1 (1.08–1.12)
    Daptomycin 0.125 1.43 (1.24–1.62)
    Doxycycline ≤0.06 14.23 (11.72–16.74)
    Levofloxacin 0.25 19.35 (9.15–29.56)
    Linezolid 1 24.47 (13.70–35.23)
    Tigecycline 0.125 4.13 (2.46–5.79)
    Vancomycin 0.5 15.70 (9.26–22.14)
S. pneumoniae 700905 (1.07 × 106)
    Omadacycline ≤0.06 0.45 (0.32–0.58)
    Vancomycin 0.25 0.91 (0.73–1.09)
    Doxycycline 4 >54
    Tigecycline 0.125 1.72 (0.6–2.82)
    Linezolid 0.5 13.88 (3.20–24.56)
S. pneumoniae 157E-2 (1.02 × 105)
    Omadacycline ≤0.06 1.10 (1.08–1.12)
    Vancomycin 1 12.32 (6.83–17.81)
    Doxycycline ≤0.06 1.55 (0.85–2.25)
    Tigecycline ≤0.06 1.72 (0.06–3.37)
    Linezolid 0.5 >27
S. aureus 29213 (6.40 × 106)
    Omadacycline 0.25 1.74 (0.91–2.58)
    Vancomycin 1 6.09 (3.62–8.56)
    Doxycycline 0.125 0.91 (0.89–0.92)
    Tigecycline 0.125 0.73 (0.69–0.76)
    Linezolid 2 9.91 (7.94–11.87)
S. aureus USA300 (7.13 × 107)
    Omadacycline 0.25 0.90 (0.33–1.46)
    Vancomycin 0.5 >18
    Doxycycline 1 4.13 (3.88–4.38)
    Tigecycline 0.125 0.58 (0.40–0.75)
    Linezolid 1 8.18 (8.05–8.31)
S. aureus USA400 (1.08 × 108)
    Omadacycline 0.5 0.45 (0.43–0.48)
    Vancomycin 0.5 3.29 (0.42–6.16)
    Doxycycline ≤0.06 1.12 (0.88–1.35)
    Tigecycline ≤0.06 1.09 (0.49–1.69)
    Linezolid 2 8.12 (3.07–13.17)
S. aureus MRSA5 (1.06 × 108)
    Omadacycline 0.25 0.30 (0.295–0.305)
    Vancomycin 1 >18
    Doxycycline 8 >54
    Tigecycline ≤0.06 1.74 (0.91–2.57)
    Linezolid 1 24.53 (16.13–32.94)
E. coli PBS1478 (6.60 × 106)
    Omadacycline 1 2.02 (1.09–2.96)
    Ciprofloxacin ≤0.06 0.07 (0.05–0.09)
    Doxycycline 1 17.46 (13.51–21.42)
    Tigecycline ≤0.06 1.75 (1.12–2.38)
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a

Values are means of seven independent in vivo experiments ± standard deviations. CI, confidence interval.

Against the tetracycline-resistant, azithromycin-resistant Tet M S. pneumoniae 700905 strain, the ED50 for omadacycline (0.45 mg/kg) was lower than that of all the other comparators tested. Omadacycline was over 30 times more active than linezolid (13.88 mg/kg) and slightly more efficacious than vancomycin (0.91 mg/kg) and tigecycline (1.72 mg/kg). Doxycycline failed to demonstrate any efficacy even at the highest dose tested (54 mg/kg); thus, an ED50 value could not be calculated.

The ED50 of 1.10 mg/kg for omadacycline was lower than that of all the other antibiotics tested against the tetracycline-sensitive S. pneumoniae 157E-2 strain. The efficacy of omadacycline was similar to that of doxycycline (1.55 mg/kg) and tigecycline (1.72 mg/kg), but omadacycline was over 11 times more active than vancomycin (12.32 mg/kg). Linezolid failed to protect the mice at the highest dose tested (27 mg/kg); thus, an ED50 value could not be calculated.

In the tetracycline-sensitive S. aureus 29213 i.p. challenge model, omadacycline was more than 3 to 5 times more potent than vancomycin and linezolid (1.74 mg/kg versus 6.09 mg/kg and 9.91 mg/kg, respectively) but was slightly less effective than doxycycline and tigecycline (0.91 mg/kg and 0.73 mg/kg, respectively).

Against the clinical MRSA Tet K, Tet 38 S. aureus USA300 strain, omadacycline had an ED50 of 0.90 mg/kg and was over 9 times more active than linezolid (8.18 mg/kg). Omadacycline was over 4 times more potent than doxycycline (4.13 mg/kg) but slightly less potent than tigecycline (0.58 mg/kg). Vancomycin failed at all the doses tested including 18 mg/kg; thus, an ED50 could not be accurately calculated.

A single i.v. dose of omadacycline resulted in an ED50 of 0.45 mg/kg against the tetracycline-sensitive clinical S. aureus USA400 strain. Omadacycline was more efficacious than any of the other comparators tested. Omadacycline was twice as active as doxycycline and tigecycline (1.12 mg/kg and 1.09 mg/kg, respectively) and 7 and 18 times more effective, respectively, than vancomycin and linezolid (3.29 mg/kg and 8.12 mg/kg, respectively).

Omadacycline also had a lower ED50 than any of the other comparators tested against the MRSA Tet M S. aureus MRSA5 strain. With an ED50 of 0.30 mg/kg, omadacycline was over 5 times more efficacious than tigecycline (1.74 mg/kg) and over 80 times more active than linezolid (24.53 mg/kg). Neither vancomycin nor doxycycline demonstrated efficacy at the highest doses tested (18 mg/kg and 54 mg/kg, respectively).

With an ED50 of 2.02 mg/kg, omadacycline also demonstrated in vivo efficacy against the Gram-negative bacteria, tetracycline-sensitive E. coli PBS1478. Although omadacycline was not as potent as ciprofloxacin (0.07 mg/kg), a single i.v. dose of omadacycline demonstrated similar efficacy as tigecycline (1.75 mg/kg) and was over 8 times more effective than doxycycline (17.46 mg/kg).

DISCUSSION

Omadacycline demonstrates in vitro activity against staphylococci, including methicillin-resistant S. aureus strains also resistant to conventional tetracyclines (tetracycline, doxycycline or minocycline), macrolides (azithromycin), or lincosamides (clindamycin). The in vitro activity of omadacycline was also superior to doxycycline, minocycline, clindamycin, linezolid, or vancomycin against enterococcus, including vancomycin-resistant E. faecalis or E. faecium, and S. pneumoniae strains including penicillin- and multiresistant strains. Commercial-grade tigecycline was not available when these in vitro studies were conducted. Like other new tetracyclines, omadacycline MICs were minimally affected by the presence of tetracycline ribosomal protection or major efflux determinants in Gram-positive or Gram-negative bacteria (6, 33, 34). Omadacycline exhibited in vitro activity against specific Gram-negative bacteria including E. coli, H. influenzae, and K. pneumoniae. Other new tetracyclines, including the previously approved tigecycline and eravacycline (TP-434), which is currently in development, have demonstrated excellent Gram-positive in vitro activity and clinical efficacy (tigecycline) and more potent in vitro Gram-negative activity (eravacycline and tigecycline) (6, 35). The excellent broad-spectrum activity of these new tetracyclines accounts in part for the pursuance of development and approval pathways for several serious Gram-positive (for ABSSSI and CABP, tigecycline and omadacycline) and Gram-negative disease indications (complicated intra-abdominal infection [cIAI], tigecycline; for cIAI and complicated UTI [cUTI], eravacycline (6, 35).

The in vitro activity of omadacycline was demonstrated in an in vivo systemic infection model. A single intravenous dose of omadacycline exhibited efficacy against a variety of clinically relevant strains of S. aureus and S. pneumoniae, as well as E. coli, in a lethal i.p. challenge model, indicating that omadacycline was comparable or more efficacious than other currently available antibiotics.

Omadacycline is metabolically stable and has demonstrated low protein binding across all concentrations and species tested (36). In a phase 1 oral absorption, distribution, metabolism, and excretion (ADME) study, no metabolites of omadacycline were isolated, and balanced elimination via the gut and urinary systems and a high concentration of omadacycline were detected in urine (27). These data support further consideration of clinical trial testing in patients with urinary tract infections. In a phase 2 study of patients with complicated skin and soft tissue infections, oral and i.v. omadacycline was well tolerated, with efficacy demonstrating comparability with the comparator linezolid. These data support further clinical trial investigation in skin and soft tissue infections (37).

Antimicrobial resistance continues to grow while the remaining effective antibiotic arsenal continues to diminish. Staphylococci including methicillin-resistant S. aureus, enterococcus including vancomycin-resistant E. faecalis and E. faecium, and pneumococcus including penicillin and multidrug-resistant S. pneumoniae remain problems in the community and the hospital, with limited treatment options (38–43). Omadacycline is capable of overcoming multiple mechanisms of tetracycline resistance as well as of maintaining efficacy against the tetracycline-susceptible strains, as demonstrated both in vitro and in vivo. Omadacycline may be an important and desirable treatment alternative for patients with community-acquired infections where the epidemiology suggests a problematic prevalence of resistant pathogens. Our data support the clinical evaluation of intravenous and oral treatment with omadacycline for multiple infectious disease indications.

ACKNOWLEDGMENTS

We received financial support from Paratek Pharmaceuticals, Inc.

A.B.M., B.K.C., R.G.L., M.P.D., S.K.T., and S.B.L. are employees of Paratek Pharmaceuticals. J.D. and S.W. were employees of Paratek Pharmaceuticals during the conduct of this study.

Footnotes

Published ahead of print 2 December 2013

REFERENCES

  • 1.Levy SB, McMurry LM, Barbosa TM, Burdett V, Courvalin P, Hillen W, Roberts MC, Rood JI, Taylor DE. 1999. Nomenclature for new tetracycline resistance determinants. Antimicrob. Agents Chemother. 43:1523–1524 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Chopra I, Roberts M. 2001. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol. Mol. Biol. Rev. 65:232–260. 10.1128/MMBR.65.2.232-260.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Cai Y, Wang R, Liang B, Bai N, Liu Y. 2011. Systematic review and meta-analysis of the effectiveness and safety of tigecycline for treatment of infectious disease. Antimicrob. Agents Chemother. 55:1162–1172. 10.1128/AAC.01402-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Chopra I. 2001. Glycylcyclines: third-generation tetracycline antibiotics. Curr. Opin. Pharmacol. 1:464–469. 10.1016/S1471-4892(01)00081-9 [DOI] [PubMed] [Google Scholar]
  • 5.Petersen PJ, Jacobus NV, Weiss WJ, Sum PE, Testa RT. 1999. In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Antimicrob. Agents Chemother. 43:738–744 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Sutcliffe JA, O'Brien W, Fyfe C, Grossman TH. 2013. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob. Agents Chemother. 57:5548–5558. 10.1128/AAC.01288-13 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Nelson ML, Ismail MY. 2007. The Antibiotic and Nonantibiotic Tetracyclines, p 597–617 In Taylor JB, Triggle DJ. (ed), Comprehensive medicinal chemistry II, vol 7 Therapeutic areas II: cancer infectious diseases, inflammation and immunology and dermatology; Elsevier, Oxford, United Kingdom [Google Scholar]
  • 8.Bhatia B, Bowser T, Chen J, Ismail M, McIntyre L, Mechiche R, Nelson M, Ohemeng K, Verma A, Jones G, Fallon M. 2003. PTK 0796 and other novel tetracycline derivatives exhibiting potent in vitro and in vivo activities against antibiotic resistant gram-positive bacteria, abstr 2420, poster F-755. Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 9.Biedenbach DJ, Mendes RE, Sader HS, Jones RN. 2010. In vitro evaluation of PTK796 activity tested against Staphylococcus aureus, including hospital- and community-associated MRSA strains from the U. S. A. and Europe, abstr E-1569. Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 10.Dubois J, Tanaka SK. 2006. In vitro activity of MK-2764/PTK 0796 against Legionella spp., abstr 1846, poster F1-1974. Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 11.Macone A, Donatelli J, Dumont T, Levy SB, Tanaka SK. 2003. In vitro activity of PTK 0796 against gram-positive and gram-negative organisms, abstr 2439, poster F-754 Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 12.Macone AB, Arbeit RD, Hait HI, Draper MP, Tanaka SK. 2010. Identification and susceptibility of pathogens isolated from patients with complicated skin and skin structure infections (cSSSI): results of a PTK796 (PTK) phase 2 clinical trial, abstr 3178, poster L1-1760 Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 13.Sader HS, Mendes RE, Biedenbach DJ, Jones RN. 2010. Antimicrobial activity of PTK796 tested against gram-positive organisms causing bloodstream infections in 2009, abstr E-1588 Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 14.Smith K, Tanaka SK, Appelbaum PC. 2006. Antistaphylococcal activity of MK-2764/PTK 0796 compared to other agents, abstr 1860, poster F1-1971. Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 15.Traczewski MM, Brown SD. 2003. PTK 0796: In vitro potency and spectrum of activity compared to ten other antimicrobial compounds, abstr 2458, poster F-753 Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 16.Weir S, Macone A, Donatelli J, Trieber C, Taylor DE, Tanaka SK, Levy SB. 2003. The mechanism of action of PTK 0796, abstr 2473, poster F-751 Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 17.Weir S, Macone A, Donatelli J, Trieber C, Taylor DE, Tanaka SK, Levy SB. 2003. The activity of PTK 0796 against tetracycline resistance, abstr 2611, poster F-752 Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 18.Clinical and Laboratory Standards Institute 2000. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M07-A05. Clinical and Laboratory Standards Institute, Wayne, PA [Google Scholar]
  • 19.Flamm RK, Farrell DJ, Sader HS, Jones RN. 2012. Antimicrobial activity of PTK 0796 (omadacycline) and comparator agents against contemporary pathogens commonly associated with community acquired respiratory tract infections collected during 2011 from the European Union, abstr P01449, p 383–384 Abstr. 22nd Eur. Congr. Clin. Microbiol. Infect. Dis. European Society of Clinical Microbiology and Infectious Diseases, Basel, Switzerland. [Google Scholar]
  • 20.Sader HS, Flamm RK, Jones RN. 2012. Antimicrobial activity of PTK 0796 (Omadacycline) tested against gram-positive organisms isolated from European Hospitals in 2011, abstr P1450, p 384 Abstr. 22nd Eur. Congr. Clin. Microbiol. Infect. Dis. European Society of Clinical Microbiology and Infectious Diseases, Basel, Switzerland [Google Scholar]
  • 21.Craig WA, Andes D, Odinecs A. 2006. In vivo pharmacodynamics of MK-2764/PTK 0796 against various gram-positive and gram-negative bacteria in the thighs of neutropenic and normal mice, abstr 1875, poster F1-1974 Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC. [Google Scholar]
  • 22.Leahy RG, Hanley B, Macone AB, Draper MP, Tanaka SK. 2011. Comparative efficacy of omadacycline (PTK796) in lethal Streptococcus pneumoniae and Staphylococcus aureus pneumoniae models, abstr 3059, p 1074 Abstr. 21st Eur. Congr. Clin. Microbiol. Infect. Dis., Milan, Italy, 7 to 10 May 2011 [Google Scholar]
  • 23.Tessier PR, Fan HW, Tanaka SK, Nicolau DP. 2006. Pharmacokinetic/pharmacodynamic profile of MK-2764/PTK 0796 against S. pneumoniae in a murine pneumonia model, abstr 1888, poster F1-1973 Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 24.Yu D, Kelley KA, Osborn MN, Trzasko A, Pettiford S, McKenney D, Bradford PA. 2010. Efficacy of PTK796 in a rat MRSA infective endocarditis (IE) model, abstr B-069 Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 25.Arbeit RD, Roberts JA, Forsythe AR, Johnston SM, Seyedi F, Pukshansky M, Tanaka SK. 2008. Safety and efficacy of PTK 0796: Results of the phase 2 study in complicated skin and skin structure infections following IV and oral step down therapy, abstr L-1515b Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 26.Noel GJ, Draper M, Hait H, Tanaka SK. 2012. Safety and efficacy of PTK 0796 (Omadacycline) as treatment of complicated skin and soft tissue infection (cSSTI), abstr P694, p 123–124 Abstr. 22nd Eur. Congr. Clin. Microbiol. Infect. Dis. European Society of Clinical Microbiology and Infectious Diseases, Basel, Switzerland [Google Scholar]
  • 27.Sun H, Ting L, Maietta R, Machineni S, Praestgaard J, Kuemmell A, Stein DS, Sunkara G, Kovacs SJ, Draper MP. 2012. A single-dose study to evaluate the pharmacokinetics, safety, and tolerability of multiple formulations of PTK 0796 in healthy subjects, abstr P1423, p 374–375 Abstr. 22nd Eur. Congr. Clin. Microbiol. Infect. Dis. European Society of Clinical Microbiology and Infectious Diseases, Basel, Switzerland [Google Scholar]
  • 28.Ting L, Sun H, Kovacs SJ, Klausner K, Tanaka SK. 2010. Pharmacokinetics of intravenous and oral PTK796, a new aminomethylcycline antibiotic, abstr K-124. Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 29.Ng LK, Martin I, Alfa M, Mulvey M. 2001. Multiplex PCR for the detection of tetracycline resistant genes. Mol. Cell. Probes 15:209–215. 10.1006/mcpr.2001.0363 [DOI] [PubMed] [Google Scholar]
  • 30.Frimodt-Moller N, Knudsen JD, Espersen F. 1999. Chapter 14: The mouse peritonitis/sepsis model, p 127–136 In Zak O, Sande MA. (ed), Handbook of animal models of infection. Academic Press, London, United Kingdom [Google Scholar]
  • 31.Cannon EP, White NM, Chaturvedi P, Esposito C, Koroma J, Tanaka SK. 2003. Phamacokinetics of PTK 0796 in mouse, rat and cynomolgus monkey, abstr 2655, poster F-759. Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC. [Google Scholar]
  • 32.Hait H, Arbeit R, Molnar D, Noel GJ, Tanaka SK. 2011. In a phase 2 complicated skin and soft tissue infections (cSSTI) trial outcomes assessed early in the course of therapy were consistent with outcomes assessed 10–17 days after completing therapy for patients treated with either omadacycline (OMC; PTK796) or linezolid, abstr P1528. Abstr. 21st Eur. Congr. Clin. Microbiol. Infect. Dis., Milan, Italy, 7 to 10 May 2011 [Google Scholar]
  • 33.Peterson LR. 2005. Antimicrobial activity and pharmacokinetics/pharmacodynamics of the novel glycylcycline, tigecycline. Diagn. Microbiol. Infect. Dis. 52:163–164. 10.1016/j.diagmicrobio.2005.06.011 [DOI] [PubMed] [Google Scholar]
  • 34.Peterson LR. 2008. A review of tigecycline–the first glycylcycline. Int. J. Antimicrob. Agents 32(Suppl 4):S215–S222. 10.1016/S0924-8579(09)70005-6 [DOI] [PubMed] [Google Scholar]
  • 35.Bradford PA, Weaver-Sands DT, Petersen PJ. 2005. In vitro activity of tigecycline against isolates from patients enrolled in phase 3 clinical trials of treatment for complicated skin and skin-structure infections and complicated intra-abdominal infections. Clin. Infect. Dis. 41(Suppl 5):S315–S332. 10.1086/431673 [DOI] [PubMed] [Google Scholar]
  • 36.Chaturvedi P, Esposito C, Koroma J, Cannon EP, Tanaka SK. 2003. In vitro assessment of plasma protein binding and metabolic stability of PTK 0796, abstr 2675, poster F-760. Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC [Google Scholar]
  • 37.Noel GJ, Draper MP, Hait H, Tanaka SK, Arbeit RD. 2012. A randomized, evaluator-blind, phase 2 study comparing the safety and efficacy of omadacycline to those of linezolid for treatment of complicated skin and skin structure infections. Antimicrob. Agents Chemother. 56:5650–5654. 10.1128/AAC.00948-12 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Appelbaum PC. 2002. Resistance among Streptococcus pneumoniae: Implications for drug selection. Clin. Infect. Dis. 34:1613–1620. 10.1086/340400 [DOI] [PubMed] [Google Scholar]
  • 39.Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J. 2009. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin. Infect. Dis. 48:1–12. 10.1086/595011 [DOI] [PubMed] [Google Scholar]
  • 40.Devasahayam G, Scheld WM, Hoffman PS. 2010. Newer antibacterial drugs for a new century. Expert Opin. Investig. Drugs 19:215–234. 10.1517/13543780903505092 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, Fridkin SK. 2008. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007. Infect. Control Hosp. Epidemiol. 29:996–1011. 10.1086/591861 [DOI] [PubMed] [Google Scholar]
  • 42.Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK. 2007. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298:1763–1771. 10.1001/jama.298.15.1763 [DOI] [PubMed] [Google Scholar]
  • 43.Palmer KL, Kos VN, Gilmore MS. 2010. Horizontal gene transfer and the genomics of enterococcal antibiotic resistance. Curr. Opin. Microbiol. 13:632–639. 10.1016/j.mib.2010.08.004 [DOI] [PMC free article] [PubMed] [Google Scholar]

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