Rebecca A. Keel

In Vivo Comparison of CXA-101 (FR264205) with and without Tazobactam versus Piperacillin-Tazobactam Using Human Simulated Exposures against Phenotypically Diverse Gram-Negative Organisms

ABSTRACT CXA-101 is a novel antipseudomonal cephalosporin with enhanced activity against Gram-negative organisms displaying various resistance mechanisms. This study evaluates the efficacy of exposures approximating human percent free time above the MIC (%fT > MIC) of CXA-101 with or without tazobactam and piperacillin-tazobactam (TZP) against target Gram-negative organisms, including those expressing extended-spectrum β-lactamases (ESBLs). Sixteen clinical Gram-negative isolates (6 Pseudomonas aeruginosa isolates [piperacillin-tazobactam MIC range, 8 to 64 μg/ml], 4 Escherichia coli isolates (2 ESBL and 2 non-ESBL expressing), and 4 Klebsiella pneumoniae isolates (3 ESBL and 1 non-ESBL expressing) were used in an immunocompetent murine thigh infection model. After infection, groups of mice were administered doses of CXA-101 with or without tazobactam (2:1) designed to approximate the %fT > MIC observed in humans given 1 g of CXA-101 with or without tazobactam every 8 h as a 1-h infusion. As a comparison, groups of mice were administered piperacillin-tazobactam doses designed to approximate the %fT > MIC observed in humans given 4.5 g piperacillin-tazobactam every 6 h as a 30-min infusion. Predicted piperacillin-tazobactam %fT > MIC exposures of greater than 40% resulted in static to >1 log decreases in CFU in non-ESBL-expressing organisms with MICs of ≤32 μg/ml after 24 h of therapy. Predicted CXA-101 with or without tazobactam %fT > MIC exposures of ≥37.5% resulted in 1- to 3-log-unit decreases in CFU in non-ESBL-expressing organisms, with MICs of ≤16 μg/ml after 24 h of therapy. With regard to the ESBL-expressing organisms, the inhibitor combinations showed enhanced CFU decreases versus CXA-101 alone. Due to enhanced in vitro potency and resultant increased in vivo exposure, CXA-101 produced statistically significant reductions in CFU in 9 isolates compared with piperacillin-tazobactam. The addition of tazobactam to CXA-101 produced significant reductions in CFU for 7 isolates compared with piperacillin-tazobactam. Overall, human simulated exposures of CXA-101 with or without tazobactam demonstrated improved efficacy versus piperacillin-tazobactam.

Efficacy of Human Simulated Exposures of Ceftaroline Administered at 600 Milligrams Every 12 Hours against Phenotypically Diverse Staphylococcus aureus Isolates

ABSTRACT Ceftaroline exhibits bactericidal activity against Gram-positive pathogens, including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, as well as common Gram-negative pathogens. This study evaluated the efficacy of human simulated exposures of ceftaroline against S. aureus in both the neutropenic and immunocompetent mouse thigh infection models. Twenty-six S. aureus isolates (4 MSSA, 22 MRSA) with ceftaroline MICs ranging from 0.125 to 4 μg/ml were collected. All isolates were tested in the neutropenic model and a subset of 13 MRSA isolates were tested in the immunocompetent model. Two hours after inoculation, a ceftaroline regimen that simulated the percentage of the dosing interval that free-drug concentrations remained above the MIC of the infecting organism (fT>MIC) of humans administered ceftaroline at 600 mg every 12 h (q12h) infused over 1 h was given. The change in log10 CFU/ml after 24 h of treatment was analyzed relative to the 0- and 24-h controls for neutropenic and immunocompetent mice, respectively. The human simulated regimen resulted in efficacy against all isolates tested in both infection models. In the neutropenic model, a 0.95 to 3.28 log10 CFU/ml reduction was observed when compared with the 0-h control, whereas for the immunocompetent model, all isolates obtained a >1 log10 CFU/ml reduction (log10 CFU/ml reduction range: 1.06 to 2.43) in bacterial density. Irrespective of immune competency, a reduction in bacterial density was observed at the highest MIC of 4 μg/ml (fT>MIC of 27.5%). Human simulated exposures of ceftaroline 600 mg q12h provided predictable efficacy against all tested S. aureus isolates in the mouse thigh model independent of immune status. These data support the clinical utility of ceftaroline against S. aureus, including MRSA, with MICs of ≤4 μg/ml.

Comparative Efficacies of Human Simulated Exposures of Tedizolid and Linezolid against Staphylococcus aureus in the Murine Thigh Infection Model

ABSTRACT Tedizolid (formally torezolid) is an expanded-spectrum oxazolidinone with enhanced in vitro potency against Gram-positive pathogens, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The efficacies of human simulated exposures of tedizolid and linezolid against S. aureus in an immunocompetent mouse thigh model over 3 days were compared. Four strains of MRSA and one of MSSA with tedizolid and linezolid MICs ranging from 0.25 to 0.5 and from 2 to 4 μg/ml, respectively, were utilized. Tedizolid or linezolid was administered in a regimen simulating a human steady-state 24-h area under the free concentration-time curve of 200 mg every 24 h (Q24) or 600 mg Q12, respectively. Thighs were harvested after 4, 8, 12, 24, 36, 48, and 72 h, and efficacy was determined by the change in bacterial density. The mean bacterial density in control mice increased over the 3-day period. After 24 h of treatment, a reduction in bacterial density of ≥1 log CFU was observed for both the tedizolid and linezolid treatments. Antibacterial activity was enhanced for both agents with a reduction of ≥2.6 log CFU after 72 h of treatment. Any statistically significant differences (P ≤ 0.05) in efficacy between the agents were transient and did not persist throughout the 72-h treatment period. The tedizolid and linezolid regimens demonstrated similar in vivo efficacies against the S. aureus isolates tested. Both agents were bacteriostatic at 24 h and bactericidal on the third day of treatment. These data support the clinical utility of tedizolid for skin and skin structure infections caused by S. aureus, as well as the bactericidal activity of the oxazolidinones after 3 days of treatment.

Comparative In Vivo Efficacies of Epithelial Lining Fluid Exposures of Tedizolid, Linezolid, and Vancomycin for Methicillin-Resistant Staphylococcus aureus in a Mouse Pneumonia Model

ABSTRACT The antibacterial efficacies of tedizolid phosphate (TZD), linezolid, and vancomycin regimens simulating human exposures at the infection site against methicillin-resistant Staphylococcus aureus (MRSA) were compared in an in vivo mouse pneumonia model. Immunocompetent BALB/c mice were orally inoculated with one of three strains of MRSA and subsequently administered 20 mg/kg TZD every 24 hours (q24h), 120 mg/kg linezolid q12h, or 25 mg/kg vancomycin q12h over 24 h. These regimens produced epithelial lining fluid exposures comparable to human exposures observed following intravenous regimens of 200 mg TZD q24h, 600 mg linezolid q12h, and 1 g vancomycin q12h. The differences in CFU after 24 h of treatment were compared between control and treatment groups. Vehicle-dosed control groups increased in bacterial density an average of 1.1 logs. All treatments reduced the bacterial density at 24 h with an average of 1.2, 1.6, and 0.1 logs for TZD, linezolid, and vancomycin, respectively. The efficacy of TZD versus linezolid regimens against the three MRSA isolates was not statistically different (P > 0.05), although both treatments were significantly different from controls. In contrast, the vancomycin regimen was significantly different from TZD against one MRSA isolate and from linezolid against all isolates. The vancomycin regimen was less protective than either the TZD or linezolid regimens, with overall survival of 61.1% versus 94.7% or 89.5%, respectively. At human simulated exposures to epithelial lining fluid, vancomycin resulted in minimal reductions in bacterial counts and higher mortality compared to those of either TZD or linezolid. TZD and linezolid showed similar efficacies in this MRSA pneumonia model.

Pharmacokinetics of intravenous and oral linezolid in adults with cystic fibrosis.

ABSTRACT Linezolid is a treatment option for methicillin-resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients. Little is known, however, about its pharmacokinetics in this population. Eight adults with CF were randomized to receive intravenous (i.v.) and oral linezolid at 600 mg twice daily for 9 doses in a crossover design with a 9-day washout. Plasma samples were collected after the first and ninth doses of each phase. Population pharmacokinetic analyses were performed by nonlinear mixed-effects modeling using a previously described 2-compartment model with time-dependent clearance inhibition. Monte Carlo simulation was performed to assess the activities of the linezolid dosing regimens against 42 contemporary MRSA isolates recovered from CF patients. The following pharmacokinetic parameter estimates were observed for the population: absorption rate constant, 1.91 h−1; clearance, 9.54 liters/h; volume of central compartment, 26.8 liters; volume of peripheral compartment, 17.3 liters; and intercompartmental clearance, 104 liters/h. Linezolid demonstrated nonlinear clearance after 9 doses, which was reduced by a mean of 38.9% (range, 28.8 to 59.9%). Mean bioavailability was 85% (range, 47 to 131%). At steady state, 600 mg given twice daily produced 93.0% and 87.2% probabilities of obtaining the target pharmacodynamic exposure against the MRSA isolates for the i.v. and oral formulations, respectively. Thrice-daily dosing increased the probabilities to 97.0% and 95.6%, respectively. Linezolid pharmacokinetics in these adults with CF were well described by a 2-compartment model with time-dependent clearance inhibition. Standard i.v. and oral dosing regimens should be sufficient to reliably attain pharmacodynamic targets against most MRSA isolates; however, more frequent dosing may be required for isolates with MICs of ≥2 μg/ml.

Correlation between vancomycin and daptomycin MIC values for methicillin-susceptible and methicillin-resistant Staphylococcus aureus by 3 testing methodologies

We examined the potential correlation between vancomycin and daptomycin MIC for 298 Staphylococcus aureus by broth microdilution (BMD), Etest, and MicroScan(®). Etest and BMD identified a significant, albeit poor, correlation between MICs (ρ = 0.29, P < .01, and ρ = 0.15, P = .01, respectively), but no correlation (ρ = 0.08, P = .18) was observed with MicroScan.

Pharmacokinetics and Pulmonary Disposition of Tedizolid and Linezolid in a Murine Pneumonia Model under Variable Conditions

ABSTRACT In vivo pharmacokinetics are often evaluated in only one variation of an infection model, and the resulting exposures are assumed to be similar in each model. We evaluated and compared the effect of lung infection and immune status on the murine pharmacokinetics and pulmonary disposition of tedizolid and linezolid. Both factors resulted in differing blood and pulmonary exposure profiles, with similar trends for tedizolid and linezolid. These data highlight the importance of pharmacokinetic confirmation in each model.

Pharmacodynamic profiling of doripenem, imipenem and meropenem against prevalent Gram-negative organisms in the Asia-Pacific region

Carbapenems are increasingly being utilised owing to the escalating prevalence of antimicrobial-resistant Gram-negative bacteria from community and hospital settings. In this study, pharmacodynamic profiles of doripenem, imipenem and meropenem were evaluated against Gram-negative bacteria isolated from hospitalised patients. MICs for carbapenems were determined for Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii obtained from the COMPACT II programme conducted in the Asia-Pacific region. Monte Carlo simulations were undertaken to assess the pharmacodynamic profile of carbapenems against each of the pathogens. All carbapenem regimens achieved optimal exposures [cumulative fraction of response (CFR) ≥90%] against E. coli and K. pneumoniae. Against P. aeruginosa, doripenem achieved 81.3-95.3% CFR, imipenem achieved 55.2-77.9% CFR and meropenem achieved 71.9-91.3% CFR; only doripenem regimens of 4-h infusion of 1000 mg every 8h (q8h) and 1-h and 4-h infusion of 2000 mg q8h and a meropenem regimen of 3-h infusion of 2000 mg q8h obtained optimal exposures; all carbapenem regimens showed slight (1-7%) improvement in CFRs in favour of isolates collected from ICU sources. Against A. baumannii, CFRs were much lower (25.9-46.7% CFR) and no carbapenem regimens achieved optimal exposure in or outside the ICU. Owing to the high potency of carbapenems against these Enterobacteriaceae populations, standard regimens are likely to perform well in the Asia-Pacific region. However, larger doses combined with prolonged infusions will be required to increase the CFR for these carbapenems against resistant non-fermenting Gram-negatives such as P. aeruginosa and A. baumannii that are prevalent in these countries.

Efficacy of Human Simulated Exposures of Ceftaroline against Phenotypically Diverse Enterobacteriaceae Isolates

ABSTRACT Ceftaroline fosamil, a new broad-spectrum cephalosporin, exhibits potent bactericidal activity against common Gram-negative pathogens, including Enterobacteriaceae, and Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The purpose of this study was to evaluate the efficacy of a human simulated dose of ceftaroline fosamil against clinical Enterobacteriaceae in both neutropenic and immunocompetent mouse thigh infection models. Thirty-five Enterobacteriaceae isolates with ceftaroline MICs ranging from 0.25 to 32 μg/ml were selected for the neutropenic model, and five Escherichia coli isolates were also tested in the immunocompetent model. Two hours after inoculation, the ceftaroline fosamil human simulated regimen of 600 mg intravenously (i.v.) every 12 h was administered. The change in log10 CFU after 24 h was compared to that in 0 h controls. The human simulated regimen produced predictable efficacy against 18 of 20 isolates with a MIC of ≤1 μg/ml. Similar efficacy was seen in the immunocompetent model against isolates with a MIC of ≤2 μg/ml, and enhanced efficacy was observed against the isolate with a MIC of 4 μg/ml. Human simulated exposures to ceftaroline fosamil at 600 mg every 12 h provided predictable efficacy against Enterobacteriaceae with MICs of ≤1 μg/ml and enhanced efficacy within the immunocompetent model, supporting the clinical utility of ceftaroline fosamil against these organisms.

Pharmacokinetics of Doripenem in Infected Patients Treated Within and Outside the Intensive Care Unit

BACKGROUND Doripenem often is used in the intensive care unit (ICU) to treat serious infections. However, pharmacokinetics in this population often are altered by various physiologic changes. Current pharmacokinetic data in critically ill patients receiving doripenem are limited. OBJECTIVE To determine the pharmacokinetics of doripenem in patients treated in the ICU versus outside the ICU. METHODS A total of 3–4 serum samples were collected from 25 infected patients receiving doripenem. A 2-compartment model was fit to serum pharmacokinetic data with nonparametric adaptive grid with adaptive γ. In the structural pharmacokinetic model, clearance (Cl) was made proportional to creatinine clearance (CrCl) and an intercept term. Bayesian pharmacokinetic parameters were compared between the 2 populations. A 5000-patient Monte Carlo simulation was performed for various CrCl ranges. The probability of pharmacodynamic target attainment was calculated over a range of minimum inhibitory concentrations (MICs), assuming a target of 35% of the dosing interval that unbound drug concentrations remain above the MIC. RESULTS Mean (range) age, body mass index, and CrCl were 61 (31–90) years, 31.2 (15.1–55.5) kg/m2, and 86 (15–221) mL/min, respectively. After the Bayesian step, r2, bias, and precision were 0.97, 0.04, and 1.44 μg/mL, respectively. Mean (SD) parameters for ICU (n = 13) and non-ICU (n = 12) patients were not significantly different (p > 0.05): volume of central compartment (17.3 [11.2] vs 18.5 [11.7] L), Cl (10.1 [10.2] vs 15.5 [16.9] L/h), k12 (4.7 [4.7] vs 4.7 [4.8] h−1), and k21 (7.1 [5.5] vs 5.7 [5.3] h−1), respectively. Optimal target attainments were obtained for patients with normal renal function up to MICs of 2 μg/mL with a dose of 500 mg every 8 hours as 1-hour and 4-hour infusions. CONCLUSIONS Doripenem pharmacokinetics were similar between ICU and non-ICU patients in this population. Optimal dosing regimens should be selected based on underlying renal function and suspected MIC of the infecting pathogen.