Pharmacodynamics of carbapenems for the treatment of Pseudomonas aeruginosa ventilator-associated pneumonia: associations with clinical outcome and recurrence.
This study was designed to evaluate the pharmacodynamics of doripenem, imipenem and meropenem as a predictor of clinical success, mortality, 28 day recurrence and development of resistance in patients treated for Pseudomonas aeruginosa ventilator-associated pneumonia (VAP).



Previously published demographic and outcome data derived from patients treated for P. aeruginosa VAP with doripenem, imipenem or meropenem were utilized. Patient-specific data were used in conjunction with published population pharmacokinetic models to construct concentration-time profiles for each patient. Etest MICs were used to determine pharmacodynamic profiles. Classification and regression tree (CART) analysis was utilized to partition pharmacodynamics based on outcomes with P values of 0.05.



Eighty-six patients were included in the analysis. Initial carbapenem MICs ranged from 0.03 to 32 mg/L. VAP recurred in 28 patients; of these, 17 patients were initially infected with susceptible organisms, and 14 of them developed resistance. CART fT>MIC partitions identified for clinical success and survival were 19.2% (P = 0.016) and 47.9% (P < 0.001), respectively. No statistically significant partitions for fT>MIC were identified for recurrence or resistance development.



We identified fT>MIC cut-offs for positive clinical outcomes in patients with P. aeruginosa VAP that were similar to those observed in animal models of infection for stasis (∼20%) and 1 log decreases in cfu (∼40%). Although in vitro studies have suggested a link between drug exposure and development of resistance, we were unable to identify such a relationship clinically.
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
Jared L
JL
Crandon
Sorbonne Universités, UPMC Université Paris 06, INSERM, UMRS_1166-ICAN Institute of Cardiometabolism and Nutrition, Paris, France.
Charles-Edouard
CE
Luyt
Service de Bactériologie-Hygiène, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Alexandra
A
Aubry
Sorbonne Universités, UPMC Université Paris 06, INSERM, UMRS_1166-ICAN Institute of Cardiometabolism and Nutrition, Paris, France.
Jean
J
Chastre
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA david.nicolau@hhchealth.org.
David P
DP
Nicolau
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D052978:Disk Diffusion Antimicrobial Tests; D000077726:Doripenem; D005260:Female; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy*; D011446:Prospective Studies; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D012008:Recurrence; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D015378:Imipenem; D000077726:Doripenem; D000077731:Meropenem