Single- and Multiple-Dose Study To Determine the Safety, Tolerability, Pharmacokinetics, and Food Effect of Oral MRX-I versus Linezolid in Healthy Adult Subjects.

A multipart phase 1 study was conducted to determine the safety, tolerability, pharmacokinetics, and food effect of the novel oral oxazolidinone, MRX-I, in healthy adults, as well as the tolerability of longer-term exposure of both oral MRX-I and linezolid. Thirty subjects in part 1 received single ascending doses of MRX-I or placebo under fasting or fed condition in a double-blind crossover design. Twelve subjects in part 2 received MRX-I at 800 mg every 12 h (q12h) for 14 days in a double-blind, placebo-controlled design.

Ceftaroline versus ceftriaxone in a highly penicillin-resistant pneumococcal pneumonia rabbit model using simulated human dosing.

Ceftaroline (CPT) is a new cephalosporin exhibiting bactericidal activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), as well as common Gram-negative pathogens. This study investigated the in vivo efficacy of a 48-hour simulated human dose regimen of CPT compared with ceftriaxone (CRO) against isolates of S. pneumoniae with different susceptibilities to penicillin in a rabbit pneumonia model.

In vitro activity of CXA-101 plus tazobactam (CXA-201) against CTX-M-14- and CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae.

CXA-101, a novel cephalosporin with good antipseudomonal activity, was evaluated against a consecutive and polyclonal collection of extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli (n = 149) and Klebsiella pneumoniae (n = 20), mainly CTX-M-15- (69%) or CTX-M-14 producing (22%). A total of 41% of the E. coli isolates belonged to the international clone O25b-ST131.

Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus beta-lactamase-producing Enterobacteriaceae.

Background: The developmental oxyimino-cephalosporin CXA-101 (FR264205) is notable for having greater antipseudomonal activity than ceftazidime. It is active against Enterobacteriaceae too, but is compromised by extended-spectrum, AmpC and carbapenem-hydrolysing beta-lactamases. We investigated the tazobactam concentrations needed to potentiate this cephalosporin against strains with these mechanisms.

Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa.

CXA-101, previously designated FR264205, is a new antipseudomonal cephalosporin. The objective of this study was to determine the penicillin-binding protein (PBP) inhibition profile of CXA-101 compared to that of ceftazidime (PBP3 inhibitor) and imipenem (PBP2 inhibitor). Killing kinetics, the induction of AmpC expression, and associated changes on cell morphology were also investigated.

Efficacy of the new cephalosporin ceftaroline in the treatment of experimental methicillin-resistant Staphylococcus aureus acute osteomyelitis.

Objectives: To evaluate the activity of a new cephalosporin, ceftaroline, in comparison with other antistaphylococcal drugs (linezolid and vancomycin) at projected human therapeutic doses against methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains.

Methods: Using a rabbit experimental model of acute osteomyelitis, efficacy was assessed following 4 days of treatment by colony counts of infected bone tissues (joint fluid, femoral bone marrow and bone).

Pharmacokinetics and safety of CXA-101, a new antipseudomonal cephalosporin, in healthy adult male and female subjects receiving single- and multiple-dose intravenous infusions.

CXA-101 is a novel, broad-spectrum cephalosporin with excellent antipseudomonal activity. A Phase 1 study was performed to determine the safety, tolerability, and pharmacokinetics of CXA-101 after single- and multiple-dose intravenous administration over 1 h to healthy male and female subjects. In part 1 of the study, five cohorts of eight subjects each (six receiving CXA-101 and two receiving a placebo) received single ascending doses of 250, 500, 1,000, 1,500, and 2,000 mg.

Anti-biofilm and resistance suppression activities of CXA-101 against chronic respiratory infection phenotypes of Pseudomonas aeruginosa strain PAO1.

Objectives: Biofilm growth, mucoid phenotype and proficient resistance development by hypermutable strains dramatically limit the efficacy of current therapies for Pseudomonas aeruginosa chronic respiratory infection (CRI) in cystic fibrosis (CF) patients. We evaluated the activity of the new cephalosporin CXA-101, ceftazidime, meropenem and ciprofloxacin against biofilms of wild-type PAO1 and its mucoid (mucA), hypermutable (mutS) and mucoid-hypermutable derivatives, and analysed the capacity of these strains to develop resistance during planktonic and biofilm growth.

Methods: MICs and MBCs were determined by microdilution, and mutant frequencies were determined at 4x and 16x the MICs.

Activity of a new cephalosporin, CXA-101 (FR264205), against beta-lactam-resistant Pseudomonas aeruginosa mutants selected in vitro and after antipseudomonal treatment of intensive care unit patients.

CXA-101, previously designated FR264205, is a new antipseudomonal cephalosporin. We evaluated the activity of CXA-101 against a highly challenging collection of beta-lactam-resistant Pseudomonas aeruginosa mutants selected in vitro and after antipseudomonal treatment of intensive care unit (ICU) patients. The in vitro mutants investigated included strains with multiple combinations of mutations leading to several degrees of AmpC overexpression (ampD, ampDh2, ampDh3, and dacB [PBP4]) and porin loss (oprD).

Comparative pharmacokinetics of ceftaroline in rats, rabbits, and monkeys following a single intravenous or intramuscular injection.

This study assessed the pharmacokinetic profiles for intramuscular and intravenous ceftaroline treatment for rats, rabbits, and monkeys. Ceftaroline, a novel cephalosporin with broad-spectrum activity against Gram-positive and Gram-negative pathogens, demonstrated favorable pharmacokinetic profiles following intramuscular administration in all 3 animal species, comparable to the levels for intravenous dosing. The areas under the plasma concentration-time curve obtained after intramuscular administration were increased in rats and similar in rabbits and monkeys, compared with the levels obtained after intravenous dosing (129%, 7.

Activity of a new antipseudomonal cephalosporin, CXA-101 (FR264205), against carbapenem-resistant and multidrug-resistant Pseudomonas aeruginosa clinical strains.

The activity of the new cephalosporin CXA-101 (CXA), previously designated FR264205, was evaluated against a collection of 236 carbapenem-resistant P. aeruginosa isolates, including 165 different clonal types, from a Spanish multicenter (127-hospital) study. The MICs of CXA were compared to the susceptibility results for antipseudomonal penicillins, cephalosporins, carbapenems, aminoglycosides, and fluoroquinolones.

In vivo activity of a novel anti-methicillin-resistant Staphylococcus aureus cephalosporin, ceftaroline, against vancomycin-susceptible and -resistant Enterococcus faecalis strains in a rabbit endocarditis model: a comparative study with linezolid and vancomycin.

We assessed the in vitro and in vivo efficacy of the novel parenteral broad-spectrum cephalosporin ceftaroline against Enterococcus faecalis in time-kill experiments and in a rabbit endocarditis model with simulated human dosing. Ceftaroline was more active than either vancomycin or linezolid against vancomycin-sensitive and -resistant isolates of E. faecalis.

Activity of cephalosporin CXA-101 (FR264205) against Pseudomonas aeruginosa and Burkholderia cepacia group strains and isolates.

Twenty-five years after its introduction, ceftazidime remains the most active cephalosporin against Pseudomonas aeruginosa. Nevertheless, resistance arises by upregulation of AmpC beta-lactamase, by efflux or, less often, via acquisition of additional beta-lactamases. Mutational resistance is especially prevalent among cystic fibrosis (CF) isolates.

Activity of the new cephalosporin ceftaroline against bacteraemia isolates from patients with community-acquired pneumonia.

The activity of ceftaroline, a novel cephalosporin, was evaluated against 1337 isolates from patients with bacteraemic community-acquired pneumonia (CAP) requiring hospitalisation (including 119 Haemophilus influenzae, 9 Moraxella catarrhalis, 164 Staphylococcus aureus, 1007 Streptococcus pneumoniae and 38 Streptococcus pyogenes). Minimum inhibitory concentrations (MICs) were determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines, and susceptibility category assessments were made using CLSI or US Food and Drug Administration (FDA) breakpoints. Ceftaroline MICs were < or = 0.

In vitro evaluation of the antimicrobial activity of ceftaroline against cephalosporin-resistant isolates of Streptococcus pneumoniae.

Increasing pneumococcal resistance to extended-spectrum cephalosporins warrants the search for novel agents with activity against such resistant strains. Ceftaroline, a parenteral cephalosporin currently in phase 3 clinical development, has demonstrated potent in vitro activity against resistant gram-positive organisms, including penicillin-resistant Streptococcus pneumoniae. In this study, the activity of ceftaroline was evaluated against highly cefotaxime-resistant isolates of pneumococci from the Active Bacterial Core surveillance program of the Centers for Disease Control and Prevention and against laboratory-derived cephalosporin-resistant mutants of S.

In vitro profiling of ceftaroline against a collection of recent bacterial clinical isolates from across the United States.

This study evaluated the in vitro activity of ceftaroline, a novel cephalosporin with broad-spectrum activity against gram-negative and -positive pathogens, against 4,151 recent clinical isolates collected in the United States. Ceftaroline was very potent against bacteria found in community- and hospital-acquired infections, including methicillin-resistant Staphylococcus aureus, multidrug-resistant Streptococcus pneumoniae, and common Enterobacteriaceae spp.

Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections.

Ceftaroline, the bioactive metabolite of ceftaroline fosamil (previously PPI-0903, TAK-599), is a broad-spectrum cephalosporin with potent in vitro activity against multidrug-resistant gram-positive aerobic pathogens, including methicillin-resistant Staphylococcus aureus. A randomized, observer-blinded study to evaluate the safety and efficacy of ceftaroline versus standard therapy in treating complicated skin and skin structure infections (cSSSI) was performed. Adults with cSSSI, including at least one systemic marker of inflammation, were randomized (2:1) to receive intravenous (i.

In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes.

Background: Ceftaroline (PPI-0903M, T-91825) is a novel cephalosporin, administered as an N-phosphono prodrug. We investigated its in vitro activity and resistance selection potential.

Methods: MICs were determined by CLSI agar dilution, but with varied inocula.

Evaluation of PPI-0903M (T91825), a novel cephalosporin: bactericidal activity, effects of modifying in vitro testing parameters and optimization of disc diffusion tests.

Objectives: To evaluate bactericidal activity of PPI-0903M and in vitro testing parameters for this compound.

Methods: A total of 110 strains were tested to determine MIC and MBC values of PPI-0903M. MIC values were determined by reference broth microdilution whereas MBC was assessed by plating the broth from the MIC well and from those wells above the MIC for each organism onto appropriate drug-free growth media.

Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains.

PPI-0903M is a novel N-phosphono-type cephalosporin active against oxacillin-resistant staphylococci and many other gram-positive organisms. This study evaluated the in vitro activity and spectrum of PPI-0903M against 1,478 recent clinical isolates collected from 80 medical centers (22 countries). PPI-0903M demonstrated broader in vitro activity against gram-positive bacteria, particularly against multidrug-resistant staphylococci and streptococci of current clinical concern, than currently available extended-spectrum cephalosporins while maintaining similar activity against gram-negative pathogens.

In vitro activity of doripenem (S-4661) against multidrug-resistant gram-negative bacilli isolated from patients with cystic fibrosis.

Doripenem 50% inhibitory concentrations (MIC50) and 90% inhibitory concentrations (MIC90) for multidrug-resistant strains of mucoid Pseudomonas aeruginosa (n=200 strains), nonmucoid P. aeruginosa (n=200), and Burkholderia cepacia complex (n=200) isolated from patients with cystic fibrosis were 8 and 32, 8 and 64, and 8 and 32 microg/ml, respectively. Doripenem had somewhat better activity than established antimicrobial agents.

Doripenem versus Pseudomonas aeruginosa in vitro: activity against characterized isolates, mutants, and transconjugants and resistance selection potential.

Doripenem is a broad-spectrum parenteral carbapenem under clinical development in Japan and North America. Its activities against (i) Pseudomonas aeruginosa isolates with graded levels of intrinsic efflux-type resistance, (ii) mutants with various combinations of AmpC and OprD expression, (iii) PU21 transconjugants with class A and D beta-lactamases, and (iv) P. aeruginosa isolates with metallo-beta-lactamases were tested by the agar dilution method of the National Committee for Clinical Laboratory Standards.

DNA binding ligands with in vivo efficacy in murine models of bacterial infection: optimization of internal aromatic amino acids.

DNA binding ligands with potent antimicrobial activity against Gram-positive bacteria were further optimized by variation of the internal aromatic amino acids. This modification led to compounds with improved in vivo efficacy in lethal murine models of peritonitis (methicillin-resistant S. aureus, MRSA) and lung infection (S.

In vitro antimicrobial activity of doripenem, a new carbapenem.

The doripenem MICs at which 90% of the tested strains were inhibited ranged from 0.03 to 1 microg/ml for 10 species of Enterobacteriaceae (n = 351), from 0.03 to 0.