title: Might real-time pharmacokinetic/pharmacodynamic optimisation of high-dose continuous-infusion meropenem improve clinical cure in infections caused by KPC-producing Klebsiella pneumoniae?
abstract: The effect of real-time pharmacokinetic/pharmacodynamic (PK/PD) optimisation of high-dose continuous-infusion meropenem on the clinical outcome of patients receiving combination antimicrobial therapy for treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections was retrospectively assessed. Data for all patients with KPC-Kp-related infections who received antimicrobial combination therapy containing high-dose continuous-infusion meropenem optimised by means of therapeutic drug monitoring (TDM) were retrieved. Optimal PK/PD exposure was considered a steady-state concentration to minimum inhibitory concentration ratio (Css/MIC) of 1-4. Univariate binary logistic regression analysis was performed to identify independent predictors of clinical outcome. Among the 30 eligible patients, 53.3% had infections caused by meropenem-resistant KPC-Kp (MIC ≥ 16 mg/L). Tigecycline and colistin were the two antimicrobials most frequently combined with meropenem. Mean doses of continuous-infusion meropenem ranged from 1.7 to 13.2 g/daily. The Css/MIC ratio was ≥1 in 73.3% of cases and ≥4 in 50.0%. Clinical outcome was successful in 73.3% of cases after a median treatment length of 14.0 days. In univariate analysis, a significant correlation with successful clinical outcome was found for a Css/MIC ratio ≥1 (OR = 10.556, 95% CI 1.612-69.122; P = 0.014), a Css/MIC ratio ≥4 (OR = 12.250, 95% CI 1.268-118.361; P = 0.030) and a Charlson co-morbidity index of ≥4 (OR = 0.158, 95% CI 0.025-0.999; P = 0.05). High-dose continuous-infusion meropenem optimised by means of real-time TDM may represent a valuable tool in improving clinical outcome when dealing with the treatment of infections caused by KPC-Kp with a meropenem MIC ≤ 64 mg/L.
authors.affiliation: Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital, Udine, Italy; Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy. Electronic address: federico.pea@asuiud.sanita.fvg.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Pea
authors.affiliation: Infectious Diseases Clinic, Santa Maria della Misericordia University Hospital, Udine, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Della Siega
authors.affiliation: Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital, Udine, Italy; Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Cojutti
authors.affiliation: Microbiology Laboratory Unit, Santa Maria della Misericordia University Hospital, Udine, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Sartor
authors.affiliation: Infectious Diseases Clinic, Santa Maria della Misericordia University Hospital, Udine, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Crapis
authors.affiliation: Microbiology Laboratory Unit, Santa Maria della Misericordia University Hospital, Udine, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Scarparo
authors.affiliation: Infectious Diseases Clinic, Santa Maria della Misericordia University Hospital, Udine, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bassetti
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003091:Colistin / Q000008:administration & dosage / Q000493:pharmacokinetics; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D007710:Klebsiella Infections / Q000188:drug therapy*; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008911:Minocycline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D012189:Retrospective Studies; D013845:Thienamycins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000078304:Tigecycline; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000078304:Tigecycline; D000077731:Meropenem; D008911:Minocycline; D003091:Colistin
keywords: Continuous infusion; KPC-producing Klebsiella pneumoniae; Meropenem; Pharmacokinetics/pharmacodynamics