title: Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox?
abstract: The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.
authors.affiliation: a Clinica Malattie Infettive, DIPMI, DISSAL, IRCCS AOU San Martino-IST, Università di Genova , Genova , Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Del Bono
authors.affiliation: a Clinica Malattie Infettive, DIPMI, DISSAL, IRCCS AOU San Martino-IST, Università di Genova , Genova , Italy.
authors.forename: Daniele Roberto
authors.initials: DR
authors.lastname: Giacobbe
authors.affiliation: b Unità di Microbiologia, DIPSE, DISC, IRCCS AOU San Martino-IST, Università di Genova , Genova , Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Marchese
authors.affiliation: c Centro ortopedico di Quadrante, Ospedale Madonna del Popolo , Omegna , Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Parisini
authors.affiliation: d Unità di Farmacologia Clinica e Tossicologia, DIMI, Università di Genova , Genova , Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fucile
authors.affiliation: b Unità di Microbiologia, DIPSE, DISC, IRCCS AOU San Martino-IST, Università di Genova , Genova , Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Coppo
authors.affiliation: d Unità di Farmacologia Clinica e Tossicologia, DIMI, Università di Genova , Genova , Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Marini
authors.affiliation: e U.O. Anestesia e Rianimazione, DIPEA, IRCCS AOU San Martino-IST , Genova , Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Arena
authors.affiliation: f U.O. Anestesia e Terapia Intensiva, DIPEA, IRCCS AOU San Martino-IST , Genova , Italy.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Molin
authors.affiliation: d Unità di Farmacologia Clinica e Tossicologia, DIMI, Università di Genova , Genova , Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Martelli
authors.affiliation: e U.O. Anestesia e Rianimazione, DIPEA, IRCCS AOU San Martino-IST , Genova , Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Gratarola
authors.affiliation: a Clinica Malattie Infettive, DIPMI, DISSAL, IRCCS AOU San Martino-IST, Università di Genova , Genova , Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Viscoli
authors.affiliation: f U.O. Anestesia e Terapia Intensiva, DIPEA, IRCCS AOU San Martino-IST , Genova , Italy.|g Anestesia e Terapia Intensiva, DISC, Università di Genova , Genova , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pelosi
authors.affiliation: d Unità di Farmacologia Clinica e Tossicologia, DIMI, Università di Genova , Genova , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mattioli
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy*; D001426:Bacterial Proteins / Q000096:biosynthesis; D003091:Colistin / Q000097:blood / Q000627:therapeutic use; D016638:Critical Illness; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005839:Gentamicins / Q000097:blood / Q000627:therapeutic use; D006801:Humans; D007710:Klebsiella Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000201:enzymology / Q000472:pathogenicity; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008911:Minocycline / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use; D013845:Thienamycins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000078304:Tigecycline; D001618:beta-Lactamases / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005839:Gentamicins; D013845:Thienamycins; D000078304:Tigecycline; D001618:beta-Lactamases; C063912:carbapenemase; D000077731:Meropenem; D008911:Minocycline; D003091:Colistin
keywords: KPC; Klebsiella pneumoniae; PK/PD; bloodstream infections; carbapenemases; meropenem MICs; treatment