title: Pharmacological and patient-specific response determinants in patients with hospital-acquired pneumonia treated with tigecycline.
abstract: Pharmacokinetic and clinical data from tigecycline-treated patients with hospital-acquired pneumonia (HAP) who were enrolled in a phase 3 clinical trial were integrated in order to evaluate pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy. Univariable and multivariable analyses were conducted to identify factors associated with clinical and microbiological responses, based on data from 61 evaluable HAP patients who received tigecycline intravenously as a 100-mg loading dose followed by 50 mg every 12 h for a minimum of 7 days and for whom there were adequate clinical, pharmacokinetic, and response data. The final multivariable logistic regression model for clinical response contained albumin and the ratio of the free-drug area under the concentration-time curve from 0 to 24 h (fAUC(0-24)) to the MIC (fAUC(0-24):MIC ratio). The odds of clinical success were 13.0 times higher for every 1-g/dl increase in albumin (P < 0.001) and 8.42 times higher for patients with fAUC(0-24):MIC ratios of ≥0.9 compared to patients with fAUC(0-24):MIC ratios of <0.9 (P = 0.008). Average model-estimated probabilities of clinical success for the albumin/fAUC(0-24):MIC ratio combinations of <2.6/<0.9, <2.6/≥0.9, ≥2.6/<0.9, and ≥2.6/≥0.9 were 0.21, 0.57, 0.64, and 0.93, respectively. For microbiological response, the final model contained albumin and ventilator-associated pneumonia (VAP) status. The odds of microbiological success were 21.0 times higher for every 1-g/dl increase in albumin (P < 0.001) and 8.59 times higher for patients without VAP compared to those with VAP (P = 0.003). Among the remaining variables evaluated, the MIC had the greatest statistical significance, an observation which was not surprising given the differences in MIC distributions between VAP and non-VAP patients (MIC(50)and MIC(90) values of 0.5 and 0.25 mg/liter versus 16 and 1 mg/liter for VAP versus non-VAP patients, respectively; P = 0.006). These findings demonstrated the impact of pharmacological and patient-specific factors on the clinical and microbiological responses.
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA. SBhavnani@ICPD.com
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rubino
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Hammel
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dartois
authors.forename: C Angel
authors.initials: CA
authors.lastname: Cooper
authors.forename: Joan
authors.initials: J
authors.lastname: Korth-Bradley
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D003428:Cross Infection / Q000188:drug therapy* / Q000382:microbiology; D004311:Double-Blind Method; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008911:Minocycline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification; D000078304:Tigecycline; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline