title: Impact of bacterial load on pharmacodynamics and susceptibility breakpoints for tigecycline and Klebsiella pneumoniae.
abstract: In the absence of other therapeutic options, tigecycline is used to treat bloodstream infections and pneumonia caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp). In this study, the standard and high tigecycline dosing regimens were simulated and tested against different inocula of CP-Kp isolates in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model.
  
  
  
  Four susceptible isolates (EUCAST MICs of 0.125-1 mg/L) and two intermediately susceptible CP-Kp clinical isolates (MICs of 2 mg/L) were tested at three different inocula (107, 105and 103cfu/mL), simulating tigecycline serum and lung fCmaxconcentrations of 0.15 and 1.5 mg/L, respectively, of 50 mg tigecycline every 12 h for 48 h. The exposure-effect relationships were described and the probability of target attainment was calculated for each inoculum in order to determine PK/PD susceptibility breakpoints.
  
  
  
  No cfu reduction was observed at serum concentrations. At lung concentrations and low inocula, a bacteriostatic and killing effect was found for isolates with MICs of 0.25 and 0.125 mg/L, respectively. The fAUC0-24/MIC (tAUC0-24/MIC) associated with half-maximal activity was 16 (150) with 103cfu/mL, 28 (239) with 105cfu/mL and 79 (590) with 107cfu/mL. A PK/PD susceptibility breakpoint of ≤0.06 and ≤0.125 mg/L for bacteraemia with ≤101cfu/mL and ≤0.25 and ≤0.5 mg/L for pneumonia with ≤103cfu/g was determined for the standard tigecycline dose of 50 mg and the higher dose of 100 mg, respectively.
  
  
  
  Tigecycline monotherapy with either 50 or 100 mg would not be sufficient for most patients with bacteraemia, though the higher dose of 100 mg could be effective for patients with pneumonia with low bacterial load.
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Marilena
authors.initials: M
authors.lastname: Tsala
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Sophia
authors.initials: S
authors.lastname: Vourli
authors.affiliation: First Department of Propaedeutic Medicine, Laikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: George L
authors.initials: GL
authors.lastname: Daikos
authors.affiliation: Department of Microbiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Tsakris
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Loukia
authors.initials: L
authors.lastname: Zerva
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece jmeletiadis@med.uoa.gr.|Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D058491:Bacterial Load; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008962:Models, Theoretical; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000382:microbiology; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline