Pharmacodynamics of NOSO-502 studied in vitro and in vivo: determination of the dominant pharmacodynamic index driver.

Background: NOSO-5O2 is the first clinical candidate of a new antimicrobial class-the odilorhabdins. The pharmacodynamics of NOSO-502 were studied in vitro and in vivo to establish the pharmacodynamic index (PDI) driver.

Methods: A dilutional pharmacokinetic system was used for in vitro experiments.

Exposure of Escherichia coli to antibiotic-efflux pump inhibitor combinations in a pharmacokinetic model: impact on bacterial clearance and drug resistance.

Background: Efflux pump inhibitors (EPIs) offer an attractive therapeutic option when combined with existing classes. However, their optimal dosing strategies are unknown.

Methods: MICs of ciprofloxacin (CIP)+/-chlorpromazine, phenylalanine-arginine β naphthylamide (PAβN) and a developmental molecule MBX-4191 were determined and the pharmacodynamics (PD) was studied in an in vitro model employing Escherichia coli MG1655 and its isogenic MarR mutant (I1147).

Antibacterial effect of seven days exposure to ceftolozane-tazobactam as monotherapy and in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa with ceftolozane-tazobactam MICs at or above 4 mg/l in an in vitro pharmacokinetic model.

Objectives: To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MIC ≥ 4 mg/L).

Methods: An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h.

Results: Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.

Comparative bactericidal activity of representative β-lactams against Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa.

Background: There is surprisingly little comparative published data on the bactericidal action of different sub-classes of β-lactams against aerobic Gram-negative rods, and the assumption is that all behave in the same way.

Objectives: To describe a systematic investigation of a representative penicillin, cephalosporin, monobactam and carbapenem against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.

Methods: Concentration-time-kill curves (TKC) were determined for three strains each of E.

Lessons from isavuconazole therapeutic drug monitoring at a United Kingdom Reference Center.

We determined isavuconazole serum concentrations for 150 UK patients receiving standard isavuconazole dosing regimens, including serial therapeutic drug monitoring for several patients on prolonged therapy. Mean trough isavuconazole concentrations in these patients were virtually identical to those reported previously from clinical trials, although greater variability was seen in patients below 18 years of age. Serial monitoring in patients receiving prolonged therapy suggested gradual, near-linear accumulation of the drug over many weeks.

Pharmacodynamics of plazomicin and a comparator aminoglycoside, amikacin, studied in an in vitro pharmacokinetic model of infection.

The new aminoglycoside plazomicin shows in vitro potency against multidrug-resistant Enterobacteriales. The exposure-response relationship of plazomicin and the comparator aminoglycoside amikacin was determined for Escherichia coli, while for Klebsiella pneumoniae only plazomicin was tested. An in vitro pharmacokinetic model was used.

Antibacterial effect of imipenem/relebactam on aerobic Gram-negative bacilli: in vitro simulations of 7 or 14 day human exposures.

Objectives: We assessed the antibacterial effect of human simulations of dosing with imipenem/relebactam (with or without amikacin) on Enterobacteriaceae or Pseudomonas aeruginosa over 7 or 14 day antibiotic exposures.

Methods: An in vitro pharmacokinetic model was used to assess changes in bacterial load and population profiles.

Results: Imipenem/relebactam produced an initial >4 log drop in viable counts followed by suppression for 7 days for Enterobacteriaceae whether the strain was WT, produced KPC enzymes or produced an AmpC enzyme with porin loss.

Antibacterial effect of ceftolozane/tazobactam in combination with amikacin against aerobic Gram-negative bacilli studied in an in vitro pharmacokinetic model of infection.

Objectives: To use a pre-clinical infection model to assess the antibacterial effect of human simulations of dosing with ceftolozane/tazobactam (with or without amikacin) or meropenem against Enterobacteriaceae and Pseudomonas aeruginosa.

Methods: An in vitro pharmacokinetic model was used to assess changes in bacterial load and profiles after exposure to mean human serum concentrations over 168 h. Changes in area under the bacterial kill curve (AUBKC; log cfu/mL·h) and growth on 4 × MIC recovery plates were the co-primary outcome measures.

Pharmacodynamics of inhaled amikacin (BAY 41-6551) studied in an in vitro pharmacokinetic model of infection.

Background: The pharmacodynamics of inhaled antimicrobials are poorly studied. Amikacin is being developed for inhalational therapy as BAY 41-6551.

Objectives: We employed an in vitro pharmacokinetic model to study the pharmacokinetics/pharmacodynamics of amikacin.

Differences in the pharmacodynamics of ceftaroline against different species of Enterobacteriaceae studied in an in vitro pharmacokinetic model of infection.

Objectives: Dose-ranging experiments were performed to study the pharmacodynamics of ceftaroline against Enterobacteriaceae.

Methods: A range of fT>MIC values (0%-100%) were simulated over 96 h using a single-compartment dilutional in vitro pharmacokinetic model using Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Citrobacter koseri and Serratia marcescens (n = 16). Antibacterial effect was assessed by change in viable count and population profiles by growth on ceftaroline MIC ×2, ×4 and ×8 agar plates.

Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection.

Ceftolozane plus tazobactam is an antipseudomonal cephalosporin combined with tazobactam, an established beta-lactamase inhibitor, and has in vitro potency against a range of clinically important β-lactamase-producing bacteria, including most extended-spectrum-β-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of β-lactam-β-lactamase inhibitor combinations presents a number of theoretical and practical challenges, including modeling different half-lives of the compounds. In this study, we studied the pharmacodynamics of ceftolozane plus tazobactam against Escherichia coli and Pseudomonas aeruginosa using an in vitro pharmacokinetic model of infection.

Pharmacodynamics of ceftaroline against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection.

An in vitro single-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]).

Pharmacodynamics of the antibacterial effect of and emergence of resistance to doripenem in Pseudomonas aeruginosa and Acinetobacter baumannii in an in vitro pharmacokinetic model.

An in vitro dilutional pharmacokinetic model of infection was used to study the pharmacodynamics of doripenem in terms of the ability to kill Pseudomonas aeruginosa or Acinetobacter baumannii and also changes in their population profiles. In dose-ranging studies, the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T(MIC)s) required for doripenem to produce a 24-h bacteriostatic effect and a -2-log-unit reduction in viable count were 25% ± 11% and 35% ± 13%, respectively, for P. aeruginosa (MIC range, 0.

Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model.

Objectives: Therapeutic options in Clostridium difficile infection (CDI) are limited. We examined linezolid activity in vitro and potential therapeutic efficacy using a gut model of CDI.

Methods: MICs were determined by agar incorporation for 118 diverse C.

Pharmacodynamics of telavancin studied in an in vitro pharmacokinetic model of infection.

The antibacterial effects of telavancin, vancomycin, and teicoplanin against six Staphylococcus aureus strains (1 methicillin-susceptible S. aureus [MSSA] strain, 4 methicillin-resistant S. aureus [MRSA] strains, and 1 vancomycin-intermediate S.

Bacterial strain-to-strain variation in pharmacodynamic index magnitude, a hitherto unconsidered factor in establishing antibiotic clinical breakpoints.

Antibiotic pharmacodynamic modeling allows variations in pathogen susceptibility and human pharmacokinetics to be accounted for when considering antibiotic doses, potential bacterial pathogen targets for therapy, and clinical susceptibility breakpoints. Variation in the pharmacodynamic index (area-under-the-concentration curve to 24 h [AUC(24)]/MIC; maximum serum concentration of drug in the serum/MIC; time the serum concentration remains higher than the MIC [T > MIC]) is not usually considered. In an in vitro pharmacokinetic model of infection using a dose-ranging design, we established the relationship between AUC(24)/MIC and the antibacterial effect for moxifloxacin against 10 strains of Staphylococcus aureus.

Comparative antibacterial effects of daptomycin, vancomycin and teicoplanin studied in an in vitro pharmacokinetic model of infection.

Objectives: To compare the antibacterial effects (ABEs) of the free (f) drugs daptomycin, vancomycin and teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), using high and low inocula in a pharmacokinetic in vitro model. To determine the daptomycin fAUC/MIC ratio for a static effect and 3 log reduction in viable count and relate this target to the clinical breakpoint.

Pharmacodynamics of minocycline against Staphylococcus aureus in an in vitro pharmacokinetic model.

Free drug serum concentrations of minocycline associated with the doses given to humans (100 mg every 12 hours for 24 hours) were simulated in an in vitro hollow-fiber pharmacokinetic model. Four strains of methicillin (meticillin)-resistant Staphylococcus aureus (MRSA), United Kingdom EMRSA 15 and 16 plus a pair of blood culture isolates before and after long-term minocycline treatment, were employed. The minocycline MICs for these four strains were 0.

Pharmacodynamics of the antibacterial effect and emergence of resistance to tomopenem, formerly RO4908463/CS-023, in an in vitro pharmacokinetic model of Staphylococcus aureus infection.

The antibacterial effects (ABE) of tomopenem (formerly RO4908463/CS-023) against seven Staphylococcus aureus strains (methicillin-resistant S. aureus [MRSA] strain tomopenem MICs, 0.5 to 16 mg/liter; methicillin-sensitive S.

Pharmacodynamics of dalbavancin studied in an in vitro pharmacokinetic system.

Objectives: The antibacterial effect of dalbavancin was studied against Staphylococcus aureus using stepwise declining concentrations designed to model a range of free drug concentrations observed in human serum.

Methods: Initial concentrations ranged from 0.6 to 21 mg/L and experiments were conducted over 240 h.

Pharmacodynamics of moxifloxacin against anaerobes studied in an in vitro pharmacokinetic model.

The antibacterial effects of moxifloxacin against Bacteroides fragilis, Clostridium perfringens, and gram-positive anaerobic cocci (GPAC) were studied in an in vitro pharmacokinetic model. Initially, a dose-ranging study with area under the concentration-time curve (AUC)/MIC ratios of 6.7 to 890 was used to investigate the effect of anaerobic conditions on the AUC/MIC antibacterial effect (ABE) relationship with Escherichia coli.

Pharmacodynamics of ceftazidime plus the serine beta-lactamase inhibitor AM-112 against Escherichia coli containing TEM-1 and CTX-M-1 beta-lactamases.

A strain of Escherichia coli containing TEM-1 and CTX-M-1 was tested in an in vitro pharmacokinetic model against ceftazidime with and without AM-112, a serine beta-lactamase inhibitor. Ceftazidime alone was less effective than ceftazidime plus AM-112, and a single dose was more effective than three fractionated doses.