Targeted benefits of prolonged-infusion piperacillin-tazobactam in an in vitro infection model of Pseudomonas aeruginosa

Abstract

Given the inconsistent clinical findings, our goal was to characterize the pharmacodynamics (PDs) of prolonged-infusion piperacillin-tazobactam (TZP) in an in vitro pharmacodynamic model of Pseudomonas aeruginosa. Specifically, the study was designed to investigate the influence of MIC on the activity of prolonged-infusion TZP using pharmacokinetics (PKs) consistent with a non-critically ill patient population. There was no benefit with prolonged- compared with standard-infusion TZP against isolates with susceptible MICs of 8 or 16 mg/L. However, prolonged-infusion TZP produced more than two times the final bacterial kill against less susceptible isolates with an intermediate MIC of 32 mg/L. The PDs of TZP were well described by a sigmoid Emax model (r(2) = 0.84) where %ƒT>MIC thresholds of 27 and 75% were associated with bacteriostatic and bactericidal effects, respectively. However, the well-established PD relationship with %ƒT>MIC was not observed with prolonged-infusion TZP. In conclusion, this study characterizes the targeted benefits of prolong-infusion TZP based on pathogen MIC, and supports the assertion that the benefits are selective and most likely observed in patients with less susceptible pathogens or altered PKs.

Optimal infusion rate in antimicrobial therapy: explosion of evidence in the last five years

“…Zelenitsky et al 39 characterized the pharmacodynamics of prolonged-infusion piperacillin/tazobactam in an in vitro pharmacodynamic model of P aeruginosa . The benefits of prolonged infusion were selective and most likely observed in patients with less susceptible pathogens, ie, prolonged infusion had no advantages over standard infusion against isolates with susceptible MICs of 8 or 16 mg/L, whereas it produced more than twice the final bacterial kill against less susceptible isolates with an intermediate MIC of 32 mg/L.…”

Combinatorial Drug Therapy for Controlling Pseudomonas aeruginosa and Its Association With Chronic Condition of Diabetic Foot Ulcer

“…Enhanced drug efficacy of piperacillin-tazobactam in combination with amikacin and vancomycin (78% susceptibility) showed better results against various empirical infections 115 and critically ill patients. 116 A pharmacodynamic and prolonged infusion study 117 showed the efficiency of piperacillin-tazobactam against AmpC βlactamase, showing effectiveness against multiple drug-resistant isolates. 118 Inability to cross the biofilm barrier is the most general phenomenon that inhibits the activity of microbes, and clinical isolates of Pseudomonas grown at different time interval have shown the inefficiency of antibiotics.…”

Limitations of ceftriaxone compared with cefazolin against MSSA: an integrated pharmacodynamic analysis

“…A one-compartment model, described previously, was used to simulate infection in an immunocompromised host. [9][10][11] The central compartment, containing 250 mL of Mueller-Hinton broth with 25 mg/L calcium and 12.5 mg/L magnesium (Mueller-Hinton II broth, Becton Dickinson & Company, Sparks, MD, USA), was continuously stirred and maintained at 37 C. A computerized pump (Masterflex, Cole-Parmer, Chicago, IL, USA) delivered fresh broth from a reservoir flask through the central compartment to produce the desired elimination t1 =2 . Five clinical MSSA isolates were tested in the IPDM studies.…”

“…The antibiotic concentrations (within 15% of target) in the central compartment were confirmed with antibiotic bioassays using Bacillus subtilis ATCC 6633. 9,16 The PK parameters were verified using linear regression analysis. Experiments were conducted in triplicate on separate occasions.…”