Pharmacodynamics of Ceftolozane Combined with Tazobactam against Enterobacteriaceae in a Neutropenic Mouse Thigh Model.
Ceftolozane is a new broad-spectrum cephalosporin and is combined with tazobactam to broaden the activity of ceftolozane against strains producing extended-spectrum beta-lactamases (ESBLs). We determined the pharmacodynamics (PD) of the combination in the neutropenic mouse thigh model to determine the optimal exposure of tazobactam. Treatment of CD-1 neutropenic mice was started 2 h after infection with ceftolozane every 2 h (q2h) alone or in combination with tazobactam at different dosing frequencies for 24 h, and the number of CFU in the thighs was determined before and after treatment. The maximum effect model was fit to the dose-response and the pharmacokinetic/PD index (PDI)-response to determine the PDI values for ceftolozane alone and ceftolozane in combination with tazobactam resulting in a static effect and a 1-log kill. The effect of tazobactam was dependent on the percentage of time that the free drug concentration remained above the concentration threshold (percent [Formula: see text]), whereby dosing q2h was more efficacious than dosing every 8 h (q8h), reducing the tazobactam daily dose by a factor 6.9 to 59.0 (n = 3 strains) to obtain a static effect. Using R2as an indicator of the best fit of the percent [Formula: see text]-response relationships, the concentration threshold best correlating with the response varied from 0.5 to 2 mg/liter, depending on the strain. A similar result was obtained when the q2h and q8h regimens were analyzed. For all isolates tested, the mean [Formula: see text] for 0.5 mg/liter tazobactam was 28.2% (range, 17.5 to 45.8%) and 44.4% (range, 26.6 to 54.7%) for a static effect and a 1-log kill, respectively, at ceftolozane exposures that produced a ceftolozane concentration of 4 mg/liter (a concentration greater than the MIC) for 33.9 to 63.3% of a 24-h period under steady-state pharmacokinetic conditions. The main PDI that correlated with the effect of tazobactam was the [Formula: see text] achieved with a CTof 0.5 mg/liter tazobactam.
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
M J
MJ
Melchers
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.|Transplantation-Oncology Infectious Disease Program, Division of Infectious Diseases, Weill Cornell Medicine, New York, New York, USA.
E
E
Mavridou
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.|Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
A C
AC
van Mil
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
C
C
Lagarde
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands jwmouton@gmail.com.|Department of Medical Microbiology & Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
J W
0000-0001-6736-4149
JW
Mouton
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002511:Cephalosporins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D029968:Escherichia coli Proteins / Q000235:genetics; D005260:Female; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D051379:Mice; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000078142:Tazobactam; D001618:beta-Lactamases / Q000235:genetics
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D029968:Escherichia coli Proteins; C519491:ceftolozane; D010397:Penicillanic Acid; D001618:beta-Lactamases; C000602253:beta-lactamase CTX-M, E coli; D000078142:Tazobactam
Antimicrob Agents Chemother. 2015 Nov 02;60(1):368-75
26525790
Antimicrob Agents Chemother. 2015;59(6):3373-6
25824214
Antimicrob Agents Chemother. 1999 Oct;43(10):2473-8
10508027
Antimicrob Agents Chemother. 2013 Jun;57(6):2809-14
23629705
Antimicrob Agents Chemother. 2012 Jan;56(1):544-9
22064538
J Antimicrob Chemother. 2007 May;59(5):926-33
17395686
Microb Drug Resist. 2015 Feb;21(1):7-16
25188329
Ann N Y Acad Sci. 2013 Jan;1277:84-90
23346859
Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6197-202
19339491
Antimicrob Agents Chemother. 2013 Dec;57(12):5924-30
24041895
J Antimicrob Chemother. 2010 Sep;65(9):1972-4
20595207
Clin Infect Dis. 2015 May 1;60(9):1389-97
25595742
Clin Microbiol Rev. 2001 Oct;14(4):933-51, table of contents
11585791
Antimicrob Agents Chemother. 2015 Aug;59(8):4521-5
25987635
Antimicrob Agents Chemother. 2015 Feb;59(2):790-5
25403667
Antimicrob Agents Chemother. 2013 Apr;57(4):1577-82
23274659
Clin Microbiol Infect. 2008 Jan;14 Suppl 1:194-7
18154547
BMC Infect Dis. 2006 Mar 17;6:55
16545113