Seth T. Housman

Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers

ABSTRACT This study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC0–24) for ELF and AM relative to the free AUC0–24 (fAUC0–24) in plasma. The half-life and volume of distribution in plasma were 9.23 ± 2.04 h and 108.25 ± 20.53 liters (means ± standard deviations), respectively. Total AUC0–24 in plasma was 25.13 ± 5.78 μg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a mean fAUC0–24 of 2.65 ± 0.72 μg · h/ml in plasma. Mean concentrations (μg/ml) at 2, 6, 12, and 24 h were 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 in ELF and 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.

Efficacies of Ceftazidime-Avibactam and Ceftazidime against Pseudomonas aeruginosa in a Murine Lung Infection Model

ABSTRACT This study aimed to determine the efficacy of human-simulated plasma exposures of 2 g ceftazidime plus 0.5 g avibactam every 8 h administered as a 2-h infusion or a ceftazidime regimen that produced a specific epithelial lining fluid (ELF) percentage of the dosing interval in which serum free drug concentrations remain above the MIC (fT>MIC) against 28 Pseudomonas aeruginosa isolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. The fT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28 P. aeruginosa strains used, the ceftazidime-avibactam MICs were 4 to 64 μg/ml, and those of ceftazidime were 8 to >128 μg/ml. The change in log10 CFU after 24 h of treatment was analyzed relative to that of 0-h controls. Pharmacokinetic studies in serum and ELF were conducted using ceftazidime-avibactam in infected and uninfected mice. Humanized ceftazidime-avibactam doses resulted in significant exposures in the lung, producing reductions of >1 log10 CFU against P. aeruginosa with ceftazidime-avibactam MICs of ≤32 μg/ml (ELF upper 95% confidence limit for fT>MIC [ELF fT>MIC] of ≥19%), except for one isolate with a ceftazidime-avibactam MIC of 16 μg/ml. No efficacy was observed against the isolate with a ceftazidime-avibactam MIC of 64 μg/ml (ELF fT>MIC of 0%). Bacterial reductions were observed with ceftazidime against isolates with ceftazidime MICs of 32 μg/ml (ELF fT>MIC of ≥12%), variable efficacy at ceftazidime MICs of 64 μg/ml (ELF fT>MIC of ≥0%), and no activity at a ceftazidime MIC of 128 μg/ml, where the ELF fT>MIC was 0%. ELF fT>MICs were similar between infected and uninfected mice. Ceftazidime-avibactam was effective against P. aeruginosa, with MICs of up to 32 μg/ml with an ELF fT>MIC of ≥19%. The data suggest the potential utility of ceftazidime-avibactam for treatment of lung infections caused by P. aeruginosa.

In Vitro Pharmacodynamics of Polymyxin B and Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii

ABSTRACT Carbapenem-resistant Acinetobacter baumannii is increasing in prevalence. Polymyxin B and tigecycline are among the most active antibiotics used against this pathogen in vitro. Past in vitro studies, however, neglected the importance of simulating exposures observed in humans to determine their antibacterial effects. In this study, four carbapenem-resistant A. baumannii isolates were evaluated using an in vitro pharmacodynamic model. Free-drug exposures using 1 mg/kg of body weight of polymyxin B every 12 h (q12h), 100 and 200 mg tigecycline q12h, and the combination of these regimens were simulated. The microbiological responses to these treatments were measured by the change in log10 CFU/ml over 24 h and the area under the bacterial killing and regrowth curve (AUBC). Resistance was assessed by a population analysis profile (PAP) conducted after 24 h of treatment. Polymyxin B achieved a reduction on the order of −2.05 ± 0.68 log10 CFU/ml against these A. baumannii isolates, while all isolates grew to control levels with tigecycline monotherapy. Combination therapy with polymyxin B plus 200 mg tigecycline q12h achieved a greater reduction in bacterial density than did therapy with polymyxin B alone (−3.31 ± 0.71 versus −2.05 ± 0.68 log10 CFU/ml, P < 0.001) but not significantly different than combination therapy with 100 mg tigecycline q12h (−2.45 ± 1.00 log10 CFU/ml, P = 0.370). Likewise, combination therapy with polymyxin B plus 200 mg tigecycline q12h significantly reduced the AUBC compared to that with polymyxin B alone (62.8 ± 8.9 versus 79.4 ± 10.5 log10 CFU/ml, P < 0.05). No changes in the PAP from baseline were observed for either antibiotic alone. In this study, combination therapy with simulated exposures of polymyxin B and tigecycline at an aggressive dose of 200 mg q12h produced synergistic or additive effects on humans against these multidrug-resistant A. baumannii strains.

Phase I, Open-Label, Safety and Pharmacokinetic Study To Assess Bronchopulmonary Disposition of Intravenous Eravacycline in Healthy Men and Women

ABSTRACT This study evaluated the pulmonary disposition of eravacycline in 20 healthy adult volunteers receiving 1.0 mg of eravacycline/kg intravenously every 12 h for a total of seven doses over 4 days. Plasma samples were collected at 0, 1, 2, 4, 6, and 12 h on day 4, with each subject randomized to undergo a single bronchoalveolar lavage (BAL) at 2, 4, 6, or 12 h. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry, and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods. Penetration for ELF and AM was calculated by using a ratio of the area under the concentration time curve (AUC0–12) for each respective parameter against free drug AUC (fAUC0–12) in plasma. The total AUC0–12 in plasma was 4.56 ± 0.94 μg·h/ml with a mean fAUC0–12 of 0.77 ± 0.14 μg·h/ml. The eravacycline concentrations in ELF and AM at 2, 4, 6, and 12 h were means ± the standard deviations (μg/ml) of 0.70 ± 0.30, 0.57 ± 0.20, 0.34 ± 0.16, and 0.25 ± 0.13 with a penetration ratio of 6.44 and 8.25 ± 4.55, 5.15 ± 1.25, 1.77 ± 0.64, and 1.42 ± 1.45 with a penetration ratio of 51.63, respectively. The eravacycline concentrations in the ELF and AM achieved greater levels than plasma by 6- and 50-fold, respectively, supporting further study of eravacycline for patients with respiratory infections.

Pharmacodynamic profile of commonly utilised parenteral therapies against meticillin-susceptible and meticillin-resistant Staphylococcus aureus collected from US hospitals.

Staphylococcus aureus is a well-recognised pathogen with an evolving phenotypic profile often limiting conventional β-lactam use. In vitro potency and pharmacodynamic profile of commonly utilised agents against 1238 meticillin-susceptible S. aureus (MSSA) and 1259 meticillin-resistant S. aureus (MRSA) from clinical specimens at 42 hospitals were assessed. Non-duplicate, non-urine isolates were tested by broth microdilution against cefazolin, ceftaroline, ceftriaxone, daptomycin, linezolid, nafcillin, tigecycline and vancomycin. Monte Carlo simulations were conducted using pharmacokinetic profiles from patients or volunteers to generate the probability of target attainment and determine the cumulative fraction of response (CFR), a modelling-based prediction tool of achieving pharmacokinetic/pharmacodynamic endpoints, for commonly used regimens. Of isolates tested, 62 MSSA (5.0%) were ceftriaxone-non-susceptible and 4 (0.3%) and 2 (0.2%) MRSA were ceftaroline- and daptomycin-non-susceptible, respectively. Against MSSA, cefazolin 1000 mg q8h and nafcillin 2000 mg q4h produced CFRs ≥90%. For ceftriaxone, only 2000 mg q12h produced a CFR ≥90%. Against MSSA and MRSA, ceftaroline, daptomycin, linezolid and tigecycline provided CFRs ≥90%. Vancomycin produced similar CFRs against MSSA and MRSA. Vancomycin 1000 mg and 15 mg/kg q8h produced CFRs of 91% and 93%, respectively, whilst q12h doses were <90%. Against respiratory and blood isolates or ICU isolates, only vancomycin q8h produced desired CFRs, where the MIC90 was 2 μg/mL. These data suggest cefazolin and nafcillin produce high CFRs against MSSA, whilst ceftriaxone at common doses may no longer be suitable. Vancomycin q8h is needed to optimise CFRs. Ceftaroline, daptomycin, tigecycline and linezolid produced sufficiently high CFRs against MSSA and MRSA utilising approved regimens.

Comparative Pharmacokinetics, Pharmacodynamics, and Tolerability of Ertapenem 1 Gram/Day Administered as a Rapid 5-Minute Infusion versus the Standard 30-Minute Infusion in Healthy Adult Volunteers

To compare ertapenem pharmacokinetics, pharmacodynamics, and tolerability when administered as a rapid 5‐minute infusion to the standard 30‐minute infusion.

Tissue Pharmacokinetics of Cefazolin in Patients with Lower Limb Infections

ABSTRACT Cefazolin, a first-generation cephalosporin with activity against methicillin-susceptible Staphylococcus aureus and streptococci, is often used to treat lower limb infections caused by these pathogens. Antimicrobial penetration is often limited in these patients due to compromised vasculature. Therefore, we sought to evaluate the exposure profile of cefazolin in serum and tissue in patients with lower limb infections. An in vivo microdialysis catheter was inserted into the tissue near the margin of the wound and constantly perfused with lactated Ringers solution. Steady-state serum and tissue samples were simultaneously collected over a dosing interval. Serum protein binding was also assessed. Serum concentrations were analyzed by noncompartmental analysis. Tissue concentrations were corrected for percent in vivo recovery by using the retrodialysis technique. Seven patients with a mean weight of 95.45 ± 18.51 kg and a mean age of 54 ± 19 years were enrolled. Six patients received 1 g every 8 h, and one patient received 2 g every 24 h due to acute kidney injury. The free area under the curve from 0 to 8 h (fAUC0–8) values for serum and wound were 48.0 ± 18.66 and 56.35 ± 41.17 μg · h/ml, respectively, for the patients receiving 1 g every 8 h. The fAUC0–24 values for serum and wound were 1,326.1 and 253.9 μg · h/ml, respectively, for the single patient receiving 2 g every 24 h. The mean tissue penetration ratio (tissue/serum fAUC ratio) was 1.06. These data suggest that the amount of time that free-drug concentrations remain above the MIC (fT>MIC) for cefazolin in wound tissue is adequate to treat patients with lower limb infections.

In vitro pharmacodynamics of human-simulated exposures of ampicillin/sulbactam, doripenem and tigecycline alone and in combination against multidrug-resistant Acinetobacter baumannii

OBJECTIVES Multidrug resistance is common among Acinetobacter baumannii, limiting the available options used to treat infections caused by this organism. The objective of this study was to compare monotherapy and combination therapy with ampicillin/sulbactam, doripenem and tigecycline against multidrug-resistant A. baumannii using an in vitro pharmacodynamic model. METHODS Human free-drug concentration profiles of clinically relevant ampicillin/sulbactam, doripenem and tigecycline were simulated alone and in two-drug combinations against four clinical A. baumannii isolates (MICs: ampicillin/sulbactam, 4/2-64/32 mg/L; doripenem, 16 to ≥64 mg/L; and tigecycline, 1-4 mg/L) over 24 h. Microbiological response was measured as log10 cfu/mL and the area under the bactericidal curve (AUBC). RESULTS Control strains grew to 7.11 ± 0.13 log10 cfu/mL. Except for ampicillin/sulbactam-containing regimens against the single ampicillin/sulbactam-susceptible isolate, all A. baumannii demonstrated regrowth to 24 h control levels against all mono and combination regimens. Using AUBC as an endpoint, the most active regimens were 9 g of ampicillin/sulbactam every 8 h (3 h infusion) + 2 g of doripenem every 8 h (4 h infusion; 87.8 ± 21.0), 9 g of ampicillin/sulbactam every 8 h (3 h infusion) + 200 mg of tigecycline every 12 h (30 min infusion; 100.6 ± 33.0) and 9 g of ampicillin/sulbactam every 8 h (3 h infusion) monotherapy (116.7 ± 31.6), followed by 3 g of ampicillin/sulbactam every 6 h (30 min infusion) + 200 mg of tigecycline every 12 h (30 min infusion; 134.0 ± 31.5) and 2 g of doripenem every 8 h (4 h infusion) + 200 mg of tigecycline every 12 h (30 min infusion; 142.7 ± 16.9). CONCLUSIONS Although specific combination regimens displayed additive activity at aggressive doses against these multidrug-resistant A. baumannii, none of the regimens could maintain cfu reductions against the more resistant isolates.

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.

Vancomycin Tissue Pharmacokinetics in Patients with Lower-Limb Infections via In Vivo Microdialysis

BACKGROUND Vancomycin is a common treatment option for skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Given the increasing prevalence of MRSA, vancomycin is widely used as empirical therapy. In patients with lower-limb infections, antimicrobial penetration is often reduced because of decreased vascular perfusion. In this study, we evaluated the tissue concentrations of vancomycin in hospitalized patients with lower-limb infections. METHODS An in vivo microdialysis catheter was inserted near the margin of the wound and was perfused with lactated Ringers solution. Tissue and serum samples were obtained after steady state for one dosing interval. Tissue concentrations were corrected for percentage of in vivo recovery using the retrodialysis technique. RESULTS Nine patients were enrolled (mean ± SD: age, 54 ± 19 years; weight, 105.6 ± 31.5 kg). Patients received a mean of 12.8 mg/kg of vancomycin every 12 hours (n = 7), every 8 hours (n = 1), or every 24 hours (n = 1). Mean ± SD steady-state trough vancomycin concentrations in serum and tissue were 11.1 ± 3.3 and 6.0 ± 2.6 μg/mL. The mean ± SD 24-hour free drug areas under the curve for serum and wound were 283.7 ± 89.4 and 232.8 ± 75.7 μg*h/mL, respectively. The mean ± SD tissue penetration ratio was 0.8 ± 0.2. CONCLUSIONS These data suggest that against MRSA with minimum inhibitory concentrations of 1 μg/mL or less, vancomycin achieved blood pharmacodynamic targets required for the likelihood of success. Reduced concentrations may contribute to poor outcomes and the development of resistance. As other literature suggests, alternative agents may be needed when the pathogen of interest has a minimum inhibitory concentration greater than 1 μg/mL.