834. In Vitro Antibacterial Activity of Ceftolozane/Tazobactam (C/T) Alone and in Combination with other Antimicrobial Agents against Multidrug-Resistant (MDR) Pseudomonas aeruginosa (PSA)
Session: Poster Abstract Session: Use of PK/PD to optimize existing antibiotics and antifungals
Thursday, October 5, 2017
Room: Poster Hall CD

Background: Broad spectrum antimicrobial resistance in MDR PSA isolates significantly limits our therapeutic options. C/T has been shown to be highly active against MDR PSA isolates. To assist the clinical decision making process regarding the selection of agents and dosages for this pathogen, we performed time-kill studies assessing various C/T concentrations alone and in combination with other anti-pseudomonal agents.

Methods: Four clinical MDR P. aeruginosa isolates were selected. MICs were determined via broth microdilution methods according to CLSI. Time-kill analyses were performed in duplicate using C/T free concentrations reflective of the peak and trough of a 3g q8h dose (120/25.2 µg/mL,7.5/1.6 µg/mL) and the peak of a 1.5g q8h dose (60/12.6 µg/mL) in humans. The activity of C/T 120, 60, and 7.5 alone and C/T 7.5 in combination with free peak concentrations of FEP, CIP, CST, ATM, MEM, TZP, FOF, or AMK was tested for all isolates. Colony counts were determined at 0, 3, 6, and 24h by serial dilution plating. Synergy was defined at ≥ 2 log10 CFU reduction from the most active agent.

Results: MICs of the 4 MDR P. aeruginosa isolates are in Table 1. As the C/T concentrations increased, bacterial reduction improved, achieving a mean (±SD) log10CFU change from 0h of 0.03 (±0.67), -1.19 (±1.03), -2.59 (±0.86) with C/T 7.5, 60, 120, respectively. C/T 7.5 was synergistic with CST (PSA C8-21, PSA C45-10) and FOF (PSA C28-5, PSA C14-22) in 2 of 4 isolates. No synergy was observed with double β-lactam therapy or CIP. AMK alone achieved maximal bacterial kill; therefore, synergy could not be assessed.  

Conclusion: C/T 3g and 1.5g q8h peak concentrations demonstrate killing against the MDR PSA. CST and FOF were synergistic with C/T in vitro. Our findings aide in identification of novel treatment options and dosing regimens for the treatment of MDR P. aeruginosa.

Table 1. MICs of C/T and comparators against 4 PSA isolates.

Isolate

C/T

FEP

CAZ

CIP

CST

ATM

TZP

MEM

AMK

FOF

PSA C8-21

4

64

128

8

1

128

256

32

8

>64

PSA C28-5

4

64

128

32

1

64

512

32

8

16

PSA C45-10

8

64

128

2

1

128

512

8

2

>64

PSA C14-22

16

32

128

1

2

128

256

16

8

>64

FEP, cefepime; CAZ, ceftazidime; CIP, ciprofloxacin; CST, colistin; ATM, aztreonam; TZP, piperacillin-tazobactam; MEM, meropenem; AMK, amikacin; FOF, fosfomycin

Marguerite Monogue, PharmD, Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, CT and David P. Nicolau, PharmD, FCCP, FIDSA, Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT

Disclosures:

M. Monogue, None

D. P. Nicolau, Merck: Investigator and Speaker's Bureau , Research support

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