β-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill

Abstract

Objectives To determine the β-lactam exposure associated with positive clinical outcomes for Gram-negative blood stream infection (BSI) in critically ill patients. Patients and methods Pooled data of critically ill patients with mono-microbial Gram-negative BSI treated with β-lactams were collected from two databases. Free minimum concentrations (fCmin) of aztreonam, cefepime, ceftazidime, ceftriaxone, piperacillin (co-administered with tazobactam) and meropenem were interpreted in relation to the measured MIC for targeted bacteria (fCmin/MIC). A positive clinical outcome was defined as completion of the treatment course or de-escalation, without other change of antibiotic therapy, and with no additional antibiotics commenced within 48 h of cessation. Drug exposure breakpoints associated with positive clinical outcome were determined by classification and regression tree (CART) analysis. Results Data from 98 patients were included. Meropenem (46.9%) and piperacillin/tazobactam (36.7%) were the most commonly prescribed antibiotics. The most common pathogens were Escherichia coli (28.6%), Pseudomonas aeruginosa (19.4%) and Klebsiella pneumoniae (13.3%). In all patients, 87.8% and 71.4% achieved fCmin/MIC ≥1 and fCmin/MIC >5, respectively. Seventy-eight patients (79.6%) achieved positive clinical outcome. Two drug exposure breakpoints were identified: fCmin/MIC >1.3 for all β-lactams (predicted difference in positive outcome 84.5% versus 15.5%, P < 0.05) and fCmin/MIC >4.95 for meropenem, aztreonam or ceftriaxone (predicted difference in positive outcome 97.7% versus 2.3%, P < 0.05). Conclusions A β-lactam fCmin/MIC >1.3 was a significant predictor of a positive clinical outcome in critically ill patients with Gram-negative BSI and could be considered an antibiotic dosing target.

Evaluation of Meropenem‐Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance

“…However, the unbound minimum concentration to MIC ratios (fC min /MIC) for these two intermittent regimens (0.0128 to 0.0256, respectively) were substantially below the fC min /MIC of ~ 2-6 that has been associated with suppression of resistance emergence for meropenem against P. aeruginosa in the HFIM 31 ; they were also below the fC min /MIC of > 1.3 reported as a significant predictor of a positive clinical outcome in critically ill patients with Gram-negative bloodstream infections. 32 For both meropenem intermittent regimens, treatment failure may be attributed to amplification of less-susceptible bacteria. Indeed, compared with the control arm there was a > 700,000-fold increase in meropenem less-susceptible bacteria when Pa1280 was exposed to regimens of 1 or 2 g q8h.…”

Therapeutisches Drug Monitoring (TDM) in der antiinfektiven Therapie – von der Theorie zur Praxis

“…B. mit einer TDM-Strategie für Aminoglykoside bereits vor vielen Jahren in einem Allgemeinpatientenkollektiv zeigen, dass die Krankenhaus-Aufenthaltsdauer signifikant sinkt (20,3 vs. 26,3 Tage, p < 0,045) [40]. Aktuelle klinische Daten geben auch erste Hinweise für β-Lactam-Antibiotika, dass eine freie Wirkstoffkonzentration von 100 % des Dosisintervalls fT > 1x MHK < 4x MHK mit einem besseren Outcome verbunden ist [41,42]. [43].…”

“…Gerade vor dem Hintergrund des Erreichens adäquater Gewebekonzentration auch in tiefen Kompartimenten (z. B. Pneumonie) [27,47] und dem Vermeiden einer Resistenzentwicklung [32], empfehlen zahlreiche Experten als Ziel im primären Kompartiment Serum/Plasma, 60-100 % der Zeit eines Dosierungsintervalls, das 4-6-Fache der MHK bei β-Lactam-Antibiotika anzustreben [7,8,11,22,41,42].…”

Optimisation of alternative antibiotic dosing regimens for maximal antibacterial activity and suppression of emergence of resistance

“…However, a MERINO sub-study observed no difference in mortality between PTZ and meropenem patients for isolates with a PTZ minimum inhibitory concentration (MIC) of <8 mg/L (291). This importance of pathogen MIC as a determinant of PTZ therapy supports investigation of different approaches to PTZ dosing to maximise bacterial killing and potentially improve patient outcomes (304).…”

“…Trough beta-lactam antibiotic concentrations of 2.5 to 4-fold the pathogen MIC has been associated with enhanced bacterial killing and the suppression of emergence of resistance in in vitro studies using intermittent infusion dosing regimens (30,287). These exposure targets have been supported by observational data where patient mortality was reduced when an unbound (free) beta-lactam concentration exceeds the pathogen minimum inhibitory concentration (MIC) throughout the dosing interval (100% fT>MIC) (89,304).…”