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Infectious Diseases Pharmacotherapy Fellow, Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT
Associate Director, Clinical and Economic Studies, Center for Anti-Infective Research and Development, Hartford Hospital
President, CEO, JMI Laboratories, North Liberty, IA
Director, Center for Anti-Infective Research and Development; Coordinator for Research, Department of Medicine, Division of Infectious Diseases and Pharmacy, Hartford Hospital
Reprints: Dr. Nicolau, Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour St., Hartford, CT 06102, fax 860/545-3992, dnicola{at}harthosp.org
BACKGROUND: Resistance among gram-negative bacteria is increasing within the US.
OBJECTIVE: To determine pharmacodynamic target attainment rates for 10 antimicrobials against selected gram-negative bacilli and compare these results with previous Optimizing Pharmacodynamic Target Attainment Using the MYSTIC Antibiogram (OPTAMA) assessments.
METHODS: A 5000-patient Monte Carlo simulation using data from population pharmacokinetic studies was employed to estimate the pharmacokinetic profiles for standard and/or prolonged infusion (PI) regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, ertapenem, imipenem, levofloxacin, meropenem, piperacillin–tazobactam, and tigecycline. Minimum inhibitory concentration data were obtained from intensive care units of 15 US hospitals participating in the 2006 MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) study for 640 Escherichia coli, 618 Klebsiella spp., and 606 Pseudomonas aeruginosa isolates. Cumulative fraction of response (CFR) was calculated using pharmacodynamic targets for each antibiotic and compared with results from the 2002 and 2004 OPTAMA studies.
RESULTS: Against E. coli, CFRs greater than 92% were maintained for all regimens except the fluoroquinolones (CFR range 69.4–72%), which showed a 7% decrease compared with 2004. The presence of Klebsiella spp. producing KPC-type carbapenemases with associated multidrug resistance resulted in a 7% or greater drop in CFR of standard regimens relative to 2004. Despite these resistant phenotypes, high-dose PI regimens (2 g every 8 hours as 3-hour PI) of cefepime and meropenem achieved CFRs of 97% and 95.8%, respectively. Excluding 3 KPC-harboring hospitals resulted in CFR increases to greater than 98% for carbapenems and cefepime and greater than 88% for all other agents tested, except tigecycline. Against P. aeruginosa, the fluoroquinolones had the lowest CFR (55.8–63.9%), followed by imipenem (74.6–80.4%). The most predictable activity was seen with cefepime 2 g every 12 hours or higher (>90%), ceftazidime 2 g every 8 hours (97.9%), and meropenem 1–2 g every 8 hours (86.7–92.6%). Use of PI for piperacillin–tazobactam and meropenem increased CFRs by 6% and 4%, respectively, over standard infusions.
CONCLUSIONS: Relative to previous years, an increase in resistance was noted among gram-negative bacilli to common antibiotics, resulting in disproportionate decreases in pharmacodynamic target attainment. The use of PI for β-lactams may help to overcome these decreases.
Key Words: Escherichia coli, Klebsiella spp., Monte Carlo simulation, pharmacodynamics, Pseudomonas aeruginosa, prolonged infusion
Published Online, January 27, 2009. www.theannals.com, DOI 10.1345/aph.1L473
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  K. M Shea, S C. Cheatham, D. W Smith, M. F Wack, K. M Sowinski, and M. B Kays Comparative Pharmacodynamics of Intermittent and Prolonged Infusions of Piperacillin/Tazobactam Using Monte Carlo Simulations and Steady-State Pharmacokinetic Data from Hospitalized Patients Ann. Pharmacother., November 1, 2009; 43(11): 1747 - 1754. [Abstract] [Full Text] [PDF]
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