Effect of Different Piperacillin-Tazobactam Dosage Regimens on Synergy of the Combination with Tobramycin against Pseudomonas aeruginosa for the Pharmacokinetics of Critically Ill Patients in a Dynamic Infection Model

Abstract

We evaluated piperacillin-tazobactam and tobramycin regimens against Pseudomonas aeruginosa isolates from critically ill patients. Static-concentration time-kill studies (SCTK) assessed piperacillin-tazobactam and tobramycin monotherapies and combinations against four isolates over 72 h. A 120 h-dynamic in vitro infection model (IVM) investigated isolates Pa1281 (MICpiperacillin 4 mg/L, MICtobramycin 0.5 mg/L) and CR380 (MICpiperacillin 32 mg/L, MICtobramycin 1 mg/L), simulating the pharmacokinetics of: (A) tobramycin 7 mg/kg q24 h (0.5 h-infusions, t1/2 = 3.1 h); (B) piperacillin 4 g q4 h (0.5 h-infusions, t1/2 = 1.5 h); (C) piperacillin 24 g/day, continuous infusion; A + B; A + C. Total and less-susceptible bacteria were determined. SCTK demonstrated synergy of the combination for all isolates. In the IVM, regimens A and B provided initial killing, followed by extensive regrowth by 72 h for both isolates. C provided >4 log10 CFU/mL killing, followed by regrowth close to initial inoculum by 96 h for Pa1281, and suppressed growth to <4 log10 CFU/mL for CR380. A and A + B initially suppressed counts of both isolates to <1 log10 CFU/mL, before regrowth to control or starting inoculum and resistance emergence by 72 h. Overall, the combination including intermittent piperacillin-tazobactam did not provide a benefit over tobramycin monotherapy. A + C, the combination regimen with continuous infusion of piperacillin-tazobactam, provided synergistic killing (counts <1 log10 CFU/mL) of Pa1281 and CR380, and suppressed regrowth to <2 and <4 log10 CFU/mL, respectively, and resistance emergence over 120 h. The shape of the concentration–time curve was important for synergy of the combination.

Guanidinylated Amphiphilic Tobramycin Derivatives Synergize with β-Lactam/β-Lactamase Inhibitor Combinations against Pseudomonas aeruginosa

“…Mechanism-based modeling experiments revealed that tobramycin disrupts the OM and consequently increases accumulation of the partner BL at the target site . It is also in part caused by both BL and tobramycin eliciting their antibacterial action by inhibiting cell wall and protein synthesis, respectively. , Meanwhile, the guanidinylated amphiphilic derivatives 5 and 8 , which are devoid of antibacterial activity, selectively permeabilize the OM.…”

“…Studies have also displayed the effectiveness of tobramycin with piperacillin/tazobactam and in vitro synergy with ceftazidime/avibactam . The synergistic interaction is presumed to arise from the ability of the aminoglycosides to disrupt the outer membrane (OM) and enhance the periplasmic concentration of the BL antibiotic. , The inclusion of an OM permeabilizing adjuvant based on membrane-acting agents such as aminoglycosides − and polymyxins has also been investigated. OM permeabilizers in the form of tobramycin conjugates have been reported to synergize with BL antibiotics such as piperacillin, aztreonam, cephalosporins, and carbapenems. ,,, These hybrid molecules consist of a secondary domain linked to tobramycin via an alkyl tether and lack ribosomal binding activity with the C -5 position used as a point of attachment.…”

“…18 The synergistic interaction is presumed to arise from the ability of the aminoglycosides to disrupt the outer membrane (OM) and enhance the periplasmic concentration of the BL antibiotic. 19,20 The inclusion of an OM permeabilizing adjuvant based on membrane-acting agents such as aminoglycosides 21−23 and polymyxins 24 has also been investigated. OM permeabilizers in the form of tobramycin conjugates have been reported to synergize with BL antibiotics such as piperacillin, aztreonam, cephalosporins, and carbape-nems.…”

A mnemonic for managing acute exacerbations of chronic obstructive pulmonary disease

“…15 Piperacillin and tazobactam combination covers P. aeruginosa and H. influenzae. 16 Treatment success with antibiotics can be defined as a reduction in dyspnea and sputum purulence. 2 The GOLD guidelines developers recommend amoxicillin with clavulanic acid as a first-line option.…”

“…S. pneumoniae and H. influenzae are sensitive to amoxicillin 15. Piperacillin and tazobactam combination covers P. aeruginosa and H. influenzae 16. Treatment success with antibiotics can be defined as a reduction in dyspnea and sputum purulence 2…”