title: Evaluation of once-daily vancomycin against methicillin-resistant Staphylococcus aureus in a hollow-fiber infection model.
abstract: For methicillin-resistant Staphylococcus aureus (MRSA) infections, data suggest that the clinical response is significantly better if the total vancomycin area under the concentration-time curve (AUC)/MIC ratio is ≥400. While the AUC/MIC ratio is the accepted pharmacokinetic/pharmacodynamic (PK/PD) index for vancomycin, this target has been achieved using multiple daily doses. We are unaware of a systematically designed dose fractionation study to compare the bactericidal activity of once-daily administration to that of traditional twice-daily administration. A dose fractionation study was performed with vancomycin in an in vitro hollow-fiber infection model against an MRSA USA300 strain (MIC of 0.75 μg/ml) using an inoculum of ∼10(6) CFU/ml. The three vancomycin regimens evaluated for 168 h were 2 g every 24 h (q24h) as a 1-h infusion, 1 g q12h as a 1-h infusion, and 2 g q24h as a continuous infusion. Free steady-state concentrations (assuming 45% binding) for a total daily AUC/MIC ratio of ≥400 were simulated for all regimens. A validated liquid chromatography-tandem mass spectrometry method was used to determine vancomycin concentrations. Although once-daily and twice-daily dosage regimens exhibited total trough concentrations of <15 μg/ml, all regimens achieved similar bactericidal activities between 24 and 168 h and suppressed the amplification of nonsusceptible subpopulations. No colonies were found on agar plates with 3× MIC for any of the treatment arms. Overall, the results suggest that once-daily vancomycin administration is feasible from a PK/PD perspective and merits further inquiry in the clinical arena.
authors.affiliation: Albany College of Pharmacy & Health Sciences, Albany, New York, USA. Anthony.nicasio@acphs.edu
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Nicasio
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Lodise
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: D'Hondt
authors.forename: Robert
authors.initials: R
authors.lastname: Kulawy
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D015169:Colony Count, Microbial; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D014640:Vancomycin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin
references.citation: Expert Opin Investig Drugs. 1999 Aug;8(8):1223-38
references.pmid: 15992147
references.citation: Antimicrob Agents Chemother. 2000 Nov;44(11):2948-53
references.pmid: 11036005
references.citation: Antimicrob Agents Chemother. 2009 Sep;53(9):3894-901
references.pmid: 19596879
references.citation: Antimicrob Agents Chemother. 1988 Jun;32(6):848-52
references.pmid: 3415206
references.citation: Am J Med. 2006 Jun;119(6 Suppl 1):S37-44; discussion S62-70
references.pmid: 16735150
references.citation: Clin Infect Dis. 2011 Apr 15;52(8):969-74
references.pmid: 21460308
references.citation: Clin Perform Qual Health Care. 1996 Jul-Sep;4(3):148-53
references.pmid: 10159303
references.citation: Infect Dis Clin North Am. 2003 Sep;17(3):479-501
references.pmid: 14711073
references.citation: Am J Health Syst Pharm. 2009 Jan 1;66(1):82-98
references.pmid: 19106348
references.citation: Antimicrob Agents Chemother. 1997 Nov;41(11):2497-501
references.pmid: 9371356
references.citation: Antimicrob Agents Chemother. 2007 Nov;51(11):3988-4000
references.pmid: 17846144
references.citation: Ther Drug Monit. 1989;11(3):269-75
references.pmid: 2728085
references.citation: J Infect Dis. 2005 Aug 1;192(3):420-8
references.pmid: 15995955
references.citation: Clin Pharmacokinet. 2004;43(13):925-42
references.pmid: 15509186
references.citation: J Antimicrob Chemother. 2002 Jan;49(1):155-60
references.pmid: 11751780
references.citation: Antimicrob Agents Chemother. 1999 Jul;43(7):1549-55
references.pmid: 10390201
references.citation: Clin Infect Dis. 2009 Aug 15;49(4):507-14
references.pmid: 19586413
references.citation: Antimicrob Agents Chemother. 2008 Jun;52(6):2156-62
references.pmid: 18411321
references.citation: J Antimicrob Chemother. 2008 Nov;62(5):1065-9
references.pmid: 18635520
references.citation: Int J Antimicrob Agents. 2011 Apr;37(4):332-8
references.pmid: 21388792
references.citation: Am J Med. 1990 Jul;89(1):58-66
references.pmid: 2195890
references.citation: Antimicrob Agents Chemother. 2011 Sep;55(9):4277-82
references.pmid: 21670191
references.citation: Clin Infect Dis. 1998 Jan;26(1):1-10; quiz 11-2
references.pmid: 9455502
references.citation: Clin Infect Dis. 2006 Jan 1;42 Suppl 1:S35-9
references.pmid: 16323118