Christina A. Sutherland

Optimal dosing of piperacillin-tazobactam for the treatment of Pseudomonas aeruginosa infections: prolonged or continuous infusion?

Study Objective. To compare conventional intermittent dosing regimens of piperacillin‐tazobactam with prolonged and continuous infusions to determine the optimal dosing scheme against a local Pseudomonas aeruginosa population.

Comparison of 2 Blood Culture Media Shows Significant Differences in Bacterial Recovery for Patients on Antimicrobial Therapy

BACKGROUND Antimicrobial removal devices in blood culture media are designed to remove antibiotics from the blood culture solution, thereby facilitating bacterial growth. How well these devices function clinically has not been established. METHODS All blood drawn for culture from adult inpatients and emergency department visitors in a level I trauma center was placed in paired BACTEC Plus and BacT/Alert FAN culture media and studied simultaneously, consecutively, and prospectively between 1 February and 30 September 2011. All cultures were processed per standard laboratory protocols. RESULTS Of 9395 total cultures collected, 1219 (13%) were positive, 831 were included, and 524 (33%) contained pathogens. BACTEC had a 4.5-hour faster detection time (P < .0001), and isolated exclusively 182 of 524 (35%; P < .001) pathogens, 136 of 345 (39%) of the gram-positive cocci (P < .001), 48 of 175 (27%; P = .02) of the gram-negative rods, 101 of 195 (52%) of Staphylococcus aureus (P < .001), and 59 of 120 (49%; P = .004) septic events. If active antibiotics had been dosed 0-4 or 4-48 hours prior to culture collection, the odds of that culture growing in BACTEC were 4.8- and 5.2-fold greater, respectively, than of growing in BacT/Alert (P < .0001). Both were equivalent in the recovery of yeast and when no antimicrobials were dosed. CONCLUSIONS BACTEC media has faster time to detection and increased bacterial recovery over the BacT/Alert media in the following categories: overall growth, pathogens, septic events, gram-positive cocci, gram-negative rods, Staphylococcus aureus, and cultures where antimicrobials were dosed up to 48 hours before culture collection.

Pharmacokinetics of meropenem 0.5 and 2 g every 8 hours as a 3-hour infusion.

Study Objective. To assess the pharmacokinetics of meropenem administered as a 3‐hour infusion.

In Vivo Microdialysis Study of the Penetration of Daptomycin into Soft Tissues in Diabetic versus Healthy Volunteers

ABSTRACT Daptomycin is approved for the treatment of complicated skin and soft tissue infections, including diabetic wounds of the lower extremities, at a dose of 4 mg/kg of body weight once daily. For such localized tissue infections, drug concentrations in the interstitial space are an important determinant of successful therapy. In the diabetic population, peripheral arterial disease may limit antibiotic penetration into the target tissue. The objective of this study was to describe and compare the pharmacokinetic profiles of daptomycin in the interstitial fluid of soft tissues in diabetic and healthy volunteers by using in vivo microdialysis. Twelve subjects (six diabetic and six healthy) received a single 4-mg/kg dose of daptomycin intravenously. Samples of plasma and tissue were simultaneously collected over 24 h. Diabetic and healthy groups were matched in mean age (±10 years), gender ratio, mean weight (±10 kg), and creatinine clearance rate (±20 ml/min/1.73 m2). Pharmacokinetic parameters for plasma were similar between groups (P > 0.05). The mean peak drug concentrations ± standard deviations in tissue were 4.3 ± 3.3 μg/ml and 3.8 ± 1.4 μg/ml for diabetic and healthy subjects, respectively. The degree of tissue penetration, defined as the ratio of the area under the free drug concentration-time curve for tissue to that for plasma, was 0.93 ± 0.61 for diabetic subjects and 0.74 ± 0.09 for healthy subjects (P = 0.46). Daptomycin at 4 mg/kg penetrated well into the soft tissue, reaching concentrations approximately 70 to 90% of those of the free drug in plasma. Moreover, these free, bioactive concentrations in tissue exceeded the MICs for staphylococci and streptococci over the 24-h dosing interval.

Comparison of the Activity of a Human Simulated, High-Dose, Prolonged Infusion of Meropenem against Klebsiella pneumoniae Producing the KPC Carbapenemase versus That against Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model

ABSTRACT We have previously demonstrated that a high-dose, prolonged-infusion meropenem regimen (2 g every 8 h [q8h]; 3-hour infusion) can achieve 40% free drug concentration above the MIC against Pseudomonas aeruginosa with MICs of ≤16 μg/ml. The objective of this experiment was to compare the efficacy of this high-dose, prolonged-infusion regimen against carbapenemase-producing Klebsiella pneumoniae isolates with the efficacy against P. aeruginosa isolates having similar meropenem MICs. An in vitro pharmacodynamic model was used to simulate human serum concentrations. Eleven genotypically confirmed K. pneumoniae carbapenemase (KPC)-producing isolates and six clinical P. aeruginosa isolates were tested for 24 h, and time-kill curves were constructed. High-performance liquid chromatography (HPLC) was used to verify meropenem concentrations in each experiment. Meropenem achieved a rapid ≥3 log CFU reduction against all KPC isolates within 6 h, followed by regrowth in all but two isolates. The targeted %fT>MIC (percent time that free drug concentrations remain above the MIC) exposure was achieved against both of these KPC isolates (100% fT>MIC versus MIC = 2 μg/ml, 75% fT>MIC versus MIC = 8 μg/ml). Against KPC isolates with MICs of 8 and 16 μg/ml that did regrow, actual meropenem exposures were significantly lower than targeted due to rapid in vitro hydrolysis, whereby targeted %fT>MIC was reduced with each subsequent dosing. In contrast, a ≥3 log CFU reduction was maintained over 24 h for all Pseudomonas isolates with meropenem MICs of 8 and 16 μg/ml. Although KPC and P. aeruginosa isolates may share similar meropenem MICs, the differing resistance mechanisms produce discordant responses to a high-dose, prolonged infusion of meropenem. Thus, predicting the efficacy of an antimicrobial regimen based on MIC may not be a valid assumption for KPC-producing organisms.

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.

Tissue Penetration and Pharmacokinetics of Tigecycline in Diabetic Patients with Chronic Wound Infections Described by Using In Vivo Microdialysis

ABSTRACT Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent in vivo recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 ± 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC0-24) were 2.65 ± 0.33, 2.52 ± 1.15, and 2.60 ± 1.02 μg·h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (P = 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 ± 0.02 μg/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue fAUC/plasma fAUC) were 99% in the thigh and 100% in the wound (P = 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity.

Serum Bactericidal Activities of High-Dose Daptomycin with and without Coadministration of Gentamicin against Isolates of Staphylococcus aureus and Enterococcus species

ABSTRACT The purpose of this experiment was to evaluate the pharmacokinetics and serum bactericidal titers (SBTs) of daptomycin alone and in combination with gentamicin against strains of Staphylococcus aureus and enterococci to determine if there might be any benefit to the addition of the aminoglycoside. A multiple-dose, randomized crossover study was performed in 11 healthy volunteers to evaluate the steady-state pharmacokinetic profile of 6 mg/kg of body weight daptomycin once daily with or without 1 mg/kg gentamicin every 8 h. SBTs were determined against clinical isolates of nosocomial (MRSA 494) and community-acquired (CA-MRSA 44) methicillin-resistant S. aureus, vancomycin-susceptible Enterococcus faecalis (VSEF 49452), vancomycin-resistant Enterococcus faecium (VREF 80), and quality control strains of methicillin-susceptible S. aureus (ATCC 29213) and vancomycin-susceptible E. faecalis (ATCC 29212). Enhancement of bactericidal activity was evaluated by calculating and comparing the areas under the bactericidal curve (AUBC) for each dosing regimen against each isolate. The area under the concentration-time curve from 0 to 24 h and clearance for daptomycin alone were 645 ± 91 μg · h/ml and 9.47 ± 1.4 mg/h/kg, respectively, compared with 642 ± 69 μg · h/ml and 9.45 ± 1.0 mg/h/kg for daptomycin plus gentamicin. Daptomycin alone displayed sustained bactericidal activity against five of the six isolates over the entire 24-h dosing interval; bactericidal activity was maintained for 8 h against VREF 80. Mean AUBCs for daptomycin alone ranged from 935 to 1,263 and 36 to 238 against staphylococcal and enterococcal isolates, respectively, compared with 902 to 972 and 34 to 213 against staphylococci and enterococci when coadministered with gentamicin. The results of this study suggest that the addition of gentamicin does not alter the pharmacokinetic profile or enhance the bactericidal activity of daptomycin against staphylococcal or enterococcal isolates.

Susceptibility Profile of Ceftolozane/Tazobactam and Other Parenteral Antimicrobials Against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa From US Hospitals

PURPOSE Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are frequently isolated pathogens in the hospital setting, and antimicrobial resistance among these organisms is on the rise. In an attempt to meet the challenge of gram-negative resistance, new therapies, including ceftolozane/tazobactam (C/T), were recently approved by the Food and Drug Administration, and others are in late-stage development. The purpose of this study is to describe the in vitro potency of C/T and other parenteral antimicrobials against a geographically diverse population of E coli, K pneumoniae, and P aeruginosa collected in US hospitals. METHODS In 2013 to 2014, 44 hospitals provided nonduplicate, nonurine isolates of E coli (n = 1306), K pneumoniae (n = 1205), and P aeruginosa (n = 1257) from adult inpatients. MICs for C/T and 11 other antimicrobials were determined with broth microdilution methods. FINDINGS The carbapenems, C/T, and colistin displayed the highest percentage of susceptibility and lowest MIC90 against the Enterobacteriaceae, followed by piperacillin/tazobactam (TZP), cefepime, tobramycin, aztreonam, ceftriaxone, and ciprofloxacin. C/T displayed the greatest potency (MIC90 = 2 mg/L) and 97% susceptibility of all compounds against P aeruginosa. In addition, C/T was highly active against P aeruginosa that were nonsusceptible to the carbapenems or TZP or were multidrug resistant and extended-spectrum β-lactamase-producing Enterobacteriaceae. IMPLICATIONS This national survey reported high levels of nonsusceptibility to antimicrobials among both Enterobacteriaceae and P aeruginosa. In contrast, many of these resistant pathogens were susceptible to C/T. These data highlight the enhanced potency of C/T and its potential utility for commonly encountered gram-negative nosocomial pathogens.

Development of HPLC Methods for the Determination of Vancomycin in Human Plasma, Mouse Serum and Bronchoalveolar Lavage Fluid

Two high-performance liquid chromatography methods utilizing a protein precipitation technique were developed to analyze vancomycin in human plasma, mouse serum and bronchoalveolar lavage (BAL) fluid. The mobile phase consisted of ammonium phosphate buffer with acetonitrile. A cross-matrix validation was performed to ensure that the mouse serum was comparable to the original biological matrix of human plasma. Murine BAL samples were run on a saline standard curve. For saline samples, the mobile phase from the human plasma study was used with the addition of 1M sodium hydroxide (0.2%) to avoid interfering peaks. A reversed-phase column was used with an ultraviolet detector set at 240 nm for human plasma and 198 nm for saline to increase peak size. The standard curves were liner over the ranges of 1 to 80 µg/mL for human plasma and 0.1 to 10 µg/mL for saline. These assays are simple, reproducible and accurate. These analytical techniques were successfully applied to analyze vancomycin concentrations in mouse serum and BAL samples.