Differences in suppression of regrowth and resistance despite similar initial bacterial killing for meropenem and piperacillin/tazobactam against Pseudomonas aeruginosa and Escherichia coli.

We described bacterial killing and resistance emergence at various fixed concentrations of meropenem and piperacillin/tazobactam against Pseudomonas aeruginosa and Escherichia coli. Time-kill studies were conducted utilizing nine isolates and a large range of concentrations. Within each strain and antibiotic, initial killing was similar, with concentrations ≥2×MIC. At many (strain-specific) concentrations causing substantial initial killing, regrowth occurred at 24-48h. For remaining concentrations, growth typically remained suppressed (<5-log10 cfu/mL). The concentrations of meropenem required to suppress regrowth ranged from 2-8×MIC for P. aeruginosa and 2-64×MIC for E. coli. For piperacillin/tazobactam, the equivalent concentrations ranged from 8-16×MIC for P. aeruginosa and 4-16×MIC for E. coli. The number of less-susceptible bacteria increased with rising concentrations before decreasing at even higher concentrations. Suppression of regrowth and resistance was substantially improved with higher concentrations (typically ≥8×MIC), suggesting a benefit of higher ß-lactam concentrations beyond those required for maximum initial killing.

Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MICmeropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼107.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log10). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function (fT>5×MIC = 56 and 69%, fCmin/MIC < 2); the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT>5×MIC ≥ 82%, fCmin/MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.

Effect of different renal function on antibacterial effects of piperacillin against Pseudomonas aeruginosa evaluated via the hollow-fibre infection model and mechanism-based modelling.

BACKGROUND: Pathophysiological changes in critically ill patients can cause severely altered pharmacokinetics and widely varying antibiotic exposures. The impact of altered pharmacokinetics on bacterial killing and resistance has not been characterized in the dynamic hollow-fibre in vitro infection model (HFIM). METHODS: A clinical Pseudomonas aeruginosa isolate (piperacillin MIC 4 mg/L) was studied in the HFIM (inoculum ∼10(7) cfu/mL). Pharmacokinetic profiles of three piperacillin dosing regimens (4 g 8-, 6- and 4-hourly, 30 min intravenous infusion) as observed in critically ill patients with augmented renal clearance (ARC), normal renal function or impaired renal function (creatinine clearances of 250, 110 or 30 mL/min, respectively) were simulated over 7 days. The time courses of total and less-susceptible populations and MICs were determined. Mechanism-based modelling was performed in S-ADAPT. RESULTS: For all regimens with ARC and regimens with 8- or 6-hourly dosing with normal renal function, initial killing of ≤∼2 log10 was followed by regrowth to 10(8)-10(9) cfu/mL at 48 h. For 8- and 6-hourly dosing at normal renal function, the proportion of less-susceptible colonies increased ∼10-100-fold above those in ARC and control arms. Regimens achieving an fCmin of ≥5× MIC resulted in bacterial killing of 3-4 log10 without regrowth and suppressed less-susceptible populations to ≤∼2 log10. The mechanism-based model successfully quantified the time course of bacterial growth, killing and regrowth. CONCLUSIONS: Only high piperacillin concentrations prevented regrowth of P. aeruginosa. Individualized dosing regimens that account for altered pharmacokinetics and aim for higher-than-standard antibiotic exposures to achieve an fCmin of ≥5× MIC were required to maximize bacterial killing and suppress emergence of resistance.

Aberrant P53 expression lacks prognostic or predictive significance in colorectal cancer: results from the VICTOR trial.

AIM: Biomarkers with prognostic and predictive value can help stratify patients with colorectal cancer (CRC) into appropriate treatment groups. We sought to evaluate the clinical utility of P53 protein expression as a biomarker in VICTOR, a large phase III trial of rofecoxib in stage II and III CRC. PATIENTS AND METHODS: Tissue micro arrays were constructed from 884 tumors and the expression of P53 was examined by immunohistochemistry. Tumors were dichotomised as either P53-positive (nuclear expression in >10% of cells or the 'absent' pattern, both representing TP53 mutation) or P53-negative (nuclear expression in <10% of cells). RESULTS: Aberrant P53 expression was found in 65% (482/740) of patients. It was associated with distal location (p<0.001) and stage III disease (p<0.001). No effect was observed on disease-free or overall survival, and there was no interaction with chemotherapy or radiotherapy. CONCLUSION: Analysis of P53 expression in the patients recruited to the VICTOR trial confirmed that P53 expression is associated with site and stage of CRC. However, independently, this biomarker has neither prognostic nor predictive utility in this cohort of patients.