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.

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.

New dosing strategies for an old antibiotic: pharmacodynamics of front-loaded regimens of colistin at simulated pharmacokinetics in patients with kidney or liver disease.

Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10(8) CFU/ml) of Pseudomonas aeruginosa.

Pharmacodynamics of early, high-dose linezolid against vancomycin-resistant enterococci with elevated MICs and pre-existing genetic mutations.

Objectives: Vancomycin-resistant enterococci (VRE) have emerged as an important nosocomial pathogen in medical centres worldwide. This study evaluated the impact of front-loading of linezolid on bacterial killing and suppression of resistance against VRE strains with defined genetic mutations.

Methods: Time-killing experiments over 48 h assessed the concentration effect relationship of linezolid against eight strains of vancomycin-resistant Enterococcus faecalis.

Front-loaded linezolid regimens result in increased killing and suppression of the accessory gene regulator system of Staphylococcus aureus.

Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213.

In vitro pharmacodynamics of novel rifamycin ABI-0043 against Staphylococcus aureus.

Objectives: ABI-0043 is a novel benzoxazinorifamycin derivative, which derives its potent bactericidal activity by the specific inhibition of bacterial RNA polymerase. We evaluated the in vitro pharmacodynamics and bactericidal activity of ABI-0043 against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA).

Attenuated vancomycin bactericidal activity against Staphylococcus aureus hemB mutants expressing the small-colony-variant phenotype.

The in vitro bactericidal activities of vancomycin against Staphylococcus aureus hemB mutants displaying the small-colony-variant phenotype and their parental strains were evaluated. Vancomycin killing activities against hemB mutants were markedly attenuated, demonstrating approximately 50% less effect, a result which was well described by a Hill-type pharmacodynamic model.

Pharmacodynamics of cefprozil against Haemophilus influenzae in an in vitro pharmacodynamic model.

An in vitro pharmacodynamic model was used to determine the pharmacokinetic-pharmacodynamic (PK-PD) measure and magnitude most strongly related to cefprozil activity against Haemophilus influenzae. Using 3 clinical isolates of H. influenzae, a series of dose-fractionation studies were conducted, simulating cefprozil pediatric pharmacokinetics.

Application of an in vitro infection model and simulation for reevaluation of fluoroquinolone breakpoints for Salmonella enterica serotype typhi.

Salmonella enterica serotype Typhi and nontyphoidal Salmonella remain major causes of morbidity and mortality worldwide. Ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol no longer provide reliable coverage of Salmonella, and fluoroquinoloes have emerged as first-line treatment options. Due to mounting evidence of decreased in vitro susceptibility and diminished clinical response to fluoroquinolone therapy, it has been suggested that the NCCLS breakpoints for the salmonellae be reevaluated.