Assessment of pharmacokinetics-pharmacodynamics to support omadacycline dosing regimens for the treatment of patients with acute bacterial skin and skin structure infections.

Pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy were evaluated using data from omadacycline-treated patients with acute bacterial skin and skin structure infections (ABSSSI) enrolled in two phase 3 studies. Patients received omadacycline 100 mg intravenously (IV) every 12 hours for two doses, followed by 100 mg IV every 24 hours (q24h), with the option to switch to 300 mg oral (PO) q24h after 3 days or 450 mg PO q24h for two doses, followed by 300 mg PO q24h for a total duration of 7-14 days. Clinical response was evaluated at 48-72 hours [early clinical response (ECR)], end of treatment (EOT), and 7-14 days after EOT.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses Evaluating Omadacycline Dosing Regimens for the Treatment of Patients with Community-Acquired Bacterial Pneumonia Arising from Streptococcus pneumoniae and Haemophilus influenzae.

Omadacycline, a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and Haemophilus influenzae, is approved in the United States to treat patients with community-acquired bacterial pneumonia (CABP). Using nonclinical pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy and surveillance data for omadacycline against S. pneumoniae and H.

Omadacycline vs moxifloxacin in adults with community-acquired bacterial pneumonia.

Objective: Community-acquired bacterial pneumonia (CABP) is a major clinical burden worldwide. In the phase III OPTIC study (NCT02531438) in CABP, omadacycline was found to be non-inferior to moxifloxacin for investigator-assessed clinical response (IACR) at post-treatment evaluation (PTE, 5-10 days after last dose). This article reports the efficacy findings, as specified in the European Medicines Agency (EMA) guidance.

Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data.

Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously developed population pharmacokinetic (PK) model based on phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 phase 1 studies used to develop the previous model were pooled with data from three additional phase 1 studies, a phase 1b uncomplicated urinary tract infection study, one phase 3 CABP study, and two phase 3 ABSSSI studies.

Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against Haemophilus influenzae Using a One-Compartment Infection Model.

Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including , which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five isolates.

Once-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial.

Background: Pathogen resistance and safety concerns limit oral antibiotic options for the treatment of acute bacterial skin and skin structure infections (ABSSSI). We aimed to compare the efficacy and safety of once-daily oral omadacycline, an aminomethylcycline antibiotic, versus twice-daily oral linezolid for treatment of ABSSSI.

Methods: In this phase 3, double-blind, randomised, non-inferiority study, eligible adults with ABSSSI at 33 sites in the USA were randomly assigned (1:1) to receive omadacycline (450 mg orally every 24 h over the first 48 h then 300 mg orally every 24 h) or linezolid (600 mg orally every 12 h) for 7-14 days.

Omadacycline for Community-Acquired Bacterial Pneumonia.

Background: Omadacycline, a new once-daily aminomethylcycline antibiotic agent that can be administered intravenously or orally, reaches high concentrations in pulmonary tissues and is active against common pathogens that cause community-acquired bacterial pneumonia.

Methods: In a double-blind trial, we randomly assigned (in a 1:1 ratio) adults with community-acquired bacterial pneumonia (Pneumonia Severity Index risk class II, III, or IV) to receive omadacycline (100 mg intravenously every 12 hours for two doses, then 100 mg intravenously every 24 hours), or moxifloxacin (400 mg intravenously every 24 hours). A transition to oral omadacycline (300 mg every 24 hours) or moxifloxacin (400 mg every 24 hours), respectively, was allowed after 3 days; the total treatment duration was 7 to 14 days.

Omadacycline for Acute Bacterial Skin and Skin-Structure Infections.

Background: Acute bacterial skin and skin-structure infections are associated with substantial morbidity and health care costs. Omadacycline, an aminomethylcycline antibiotic that can be administered once daily either orally or intravenously, is active against pathogens that commonly cause such infections, including antibiotic-resistant strains.

Methods: In this double-blind trial, we randomly assigned adults with acute bacterial skin and skin-structure infections (in a 1:1 ratio) to receive omadacycline (100 mg given intravenously every 12 hours for two doses, then 100 mg given intravenously every 24 hours) or linezolid (600 mg given intravenously every 12 hours).

In vitro pharmacodynamic evaluation of ceftolozane/tazobactam against β-lactamase-producing Escherichia coli in a hollow-fibre infection model.

The proliferation of multidrug-resistant Gram-negative pathogens has been exacerbated by a lack of novel agents in current development by pharmaceutical companies. Ceftolozane/tazobactam was recently approved by the FDA for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. In the present study, the activity of ceftolozane/tazobactam against four isogenic Escherichia coli strains was investigated in a hollow-fibre infection model simulating various clinical dosing regimens.

Outcomes of high-dose levofloxacin therapy remain bound to the levofloxacin minimum inhibitory concentration in complicated urinary tract infections.

Background: Fluoroquinolones are a guideline-recommended therapy for complicated urinary tract infections, including pyelonephritis. Elevated drug concentrations of fluoroquinolones in the urine and therapy with high-dose levofloxacin are believed to overcome resistance and effectively treat infections caused by resistant bacteria. The ASPECT-cUTI phase 3 clinical trial (ClinicalTrials.

The Novel Aminomethylcycline Omadacycline Has High Specificity for the Primary Tetracycline-Binding Site on the Bacterial Ribosome.

Omadacycline is an aminomethylcycline antibiotic with potent activity against many Gram-positive and Gram-negative pathogens, including strains carrying the major efflux and ribosome protection resistance determinants. This makes it a promising candidate for therapy of severe infectious diseases. Omadacycline inhibits bacterial protein biosynthesis and competes with tetracycline for binding to the ribosome.

Characteristics and Outcomes of Complicated Intra-abdominal Infections Involving Pseudomonas aeruginosa from a Randomized, Double-Blind, Phase 3 Ceftolozane-Tazobactam Study.

Ceftolozane-tazobactam is active against Gram-negative pathogens, including multidrug-resistant Pseudomonas aeruginosa In a subgroup analysis of patients with complicated intra-abdominal infections (cIAIs) involving P. aeruginosa from a phase 3 program, ceftolozane-tazobactam demonstrated potent in vitro activity against P. aeruginosa Clinical cure in the microbiologically evaluable population was 100% (26/26) for ceftolozane-tazobactam plus metronidazole and 93.

Efficacy of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTIs) caused by levofloxacin-resistant pathogens: results from the ASPECT-cUTI trial.

Objectives: Empirical fluoroquinolone therapy is widely used in treating complicated urinary tract infections (cUTIs), even in areas of high fluoroquinolone resistance. While it is believed that high antibiotic concentrations in urine might be sufficient to overcome and effectively treat infections caused by resistant bacteria, clinical trial data validating this assumption are limited. This post hoc analysis evaluated the efficacy of ceftolozane/tazobactam versus levofloxacin in the subgroup of patients with cUTIs caused by levofloxacin-resistant pathogens in a randomized, controlled trial (NCT01345929/NCT01345955).

Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an In Vitro Infection Model.

We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (%time>threshold). Using anin vitroinfection model and the same isogenic CTX-M-15-producingEscherichia colitriplet set genetically engineered to transcribe different levels ofblaCTX-M-15, herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different β-lactam agent, or differentblaCTX-M-15transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128, >256, and >256 μg/ml for the low-, moderate-, and high-level CTX-M-15-producingE.

Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined β-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of β-Lactam-β-Lactamase Inhibitor Combinations.

Despite a dearth of new agents currently being developed to combat multidrug-resistant Gram-negative pathogens, the combination of ceftolozane and tazobactam was recently approved by the Food and Drug Administration to treat complicated intra-abdominal and urinary tract infections. To characterize the activity of the combination product, time-kill studies were conducted against 4 strains ofEscherichia colithat differed in the type of β-lactamase they expressed. The four investigational strains included 2805 (no β-lactamase), 2890 (AmpC β-lactamase), 2842 (CMY-10 β-lactamase), and 2807 (CTX-M-15 β-lactamase), with MICs to ceftolozane of 0.

In Vitro Activity of Ceftolozane-Tazobactam against Anaerobic Organisms Identified during the ASPECT-cIAI Study.

The in vitro activities of ceftolozane-tazobactam, meropenem, and metronidazole were determined against anaerobic organisms isolated from patients with complicated intraabdominal infections (cIAI) in global phase III studies. Ceftolozane-tazobactam activity was highly variable among different species of the Bacteroides fragilis group, with MIC90 values ranging from 2 to 64 μg/ml. More-potent in vitro activity was observed against selected Gram-positive anaerobic organisms; however, small numbers of isolates were available, and, therefore, the clinical significance of these results is unknown.

Relationship between ceftolozane-tazobactam exposure and selection for Pseudomonas aeruginosa resistance in a hollow-fiber infection model.

It is important to understand the relationship between antibiotic exposure and the selection of drug resistance in the context of therapy exposure. We sought to identify the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. Two Pseudomonas aeruginosa challenge isolates were selected for study, a wild-type ATCC strain (ceftolozane-tazobactam MIC, 0.

Pharmacological basis of β-lactamase inhibitor therapeutics: tazobactam in combination with Ceftolozane.

We recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of blaCTX-M-15. The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level.

Pharmacokinetics-pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model.

Despite β-lactamase inhibitors being available for clinical use for nearly 30 years, a paucity of data exists describing the pharmacokinetic-pharmacodynamic (PK-PD) determinants of efficacy for these agents. Herein, we describe dose fractionation studies designed to determine the exposure measure most predictive of tazobactam efficacy in combination with ceftolozane and the magnitude of this measure necessary for efficacy in a PK-PD in vitro infection model. The challenge organism panel was comprised of an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of bla(CTX-M-15).

Outcomes with daptomycin in the treatment of Staphylococcus aureus infections with a range of vancomycin MICs.

Objectives: Recent recommendations by the Infectious Diseases Society of America for the treatment of Staphylococcus aureus suggest the use of alternative agents when vancomycin MIC values are >or=2 mg/L. This study examines the outcome of patients treated with daptomycin for S. aureus infections with documented vancomycin MICs.

Effects of daptomycin in combination with other antimicrobial agents: a review of in vitro and animal model studies.

This review summarizes the in vitro and animal model data available on antibiotic combinations with daptomycin. The majority of studies focus on the clinically relevant combinations of daptomycin with rifampicin or with gentamicin. These studies demonstrate that daptomycin does not adversely affect the activity of other antimicrobial agents that may be administered concomitantly.

Susceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions.

The decrease in vancomycin treatment efficacy that is accompanying increases in vancomycin minimum inhibitory concentration (MIC) within the susceptible range (so-called MIC creep) has led to the suggestion that vancomycin is losing its potency in treating serious Staphylococcus aureus infections. Understanding the clinical importance of the microbiological effects of glycopeptides on bacterial lipopeptides and lipoglycopeptides will be crucial in treating serious meticillin-resistant S aureus infections. We review the observed effects of reduced glycopeptide susceptibility on the activities of daptomycin in S aureus in vitro and in vivo.

Evidence for daptomycin Etest lot-related MIC elevations for Staphylococcus aureus.

MIC testing was performed simultaneously by Etest and broth microdilution (BMD) on 587 Staphylococcus aureus isolates submitted by local laboratories to a reference laboratory for confirmatory testing (May 2005 to July 2008). Testing bias was assessed for Etest to BMD MIC ratios. Categoric and essential agreement, very major (BMD nonsusceptible, Etest susceptible), and major (BMD susceptible, Etest nonsusceptible) errors were evaluated.