Efficacy of Human-Simulated Exposures of Ceftolozane-Tazobactam Alone and in Combination with Amikacin or Colistin against Multidrug-Resistant Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model

Abstract

Combination therapy is an attractive option for the treatment of multidrug-resistant (MDR) infections; however, limited data are available on combinations with ceftolozane-tazobactam (C-T). The pharmacodynamic chemostat model was employed to compare human-simulated exposures of C-T at 3 g every 8 h alone or in combination with amikacin at 25 mg/kg of body weight daily or colistin at 360 mg daily against four MDR isolates. C-T alone resulted in 24-h changes in the number of CFU of -0.02 ± 0.21, -1.81 ± 0.55, -1.44 ± 0.40, and +0.62 ± 0.05 log CFU/ml against isolates with C-T MICs of 4, 4, 8, and 16 μg/ml, respectively. Amikacin and colistin monotherapy displayed various results. The addition of amikacin to C-T resulted in -2.00 ± 0.23 ( < 0.001, additive)-, -1.50 ± 0.83 ( = 0.687, indifferent)-, -2.84 ± 0.08 ( = 0.079, indifferent)-, and -2.67 ± 0.54 ( < 0.001, synergy)-log CFU/ml reductions, respectively. The addition of colistin to C-T resulted in -3.02 ± 0.22 ( < 0.001, additive)-, -3.21 ± 0.24 ( > 0.05, indifferent)-, -4.6 ± 0.11 ( = 0.002, synergy)-, and -3.01 ± 0.28 ( < 0.001, synergy)-log CFU/ml reductions, respectively, against the MDR isolates with these MICs. Greater overall reductions in bacterial burden, including additive or synergistic interactions at 24 h, with C-T plus amikacin or colistin were observed against 3 out of 4 MDR strains tested, particularly those strains that were intermediate or resistant to C-T. Further studies assessing combination regimens containing C-T against MDR are warranted.

Efficacy of Ceftolozane-Tazobactam in Combination with Colistin against Extensively Drug-Resistant Pseudomonas aeruginosa, Including High-Risk Clones, in an In Vitro Pharmacodynamic Model

“…Time-kill curves were generated to evaluate the effects of C/T and colistin alone and in combination in all of the isolates. Colistin showed a similar pattern across the isolates (initial 3-to 5-log reduction in bacterial growth after 2 h, followed by regrowth in all cases), supporting previous reports (24).…”

“…In 11 isolates (ST111 , ST175 [10][11][12][13][14][15][16][17][18][19][20][21][22][23] All isolates treated with the C/T plus colistin combination showed an initial 2-to 5-log 10 CFU/ml reduction followed by a plateau. The combination had bactericidal effect in all cases, a synergistic effect at 24 . In this last case, the results were similar to those observed for C/T and colistin as monotherapy.…”

“…Monogue and Nicolau (27) published the first study assessing synergy of C/T against Gram-negative microorganisms and demonstrated synergistic effects for C/T combined with colistin or fosfomycin using time-kill curves. Rico Caballero et al (24) further added to this body of knowledge in an in vitro pharmacodynamic study that showed greater overall reductions in bacterial burden and additive or synergistic effects for C/T combined with amikacin or colistin.…”

“…Several studies have recommended antibiotic therapy combining an antipseudomonal ␤-lactam and an aminoglycoside or fluoroquinolone (16)(17)(18)(19)(20). Data on combinations containing C/T, however, are scarce (21)(22)(23)(24). Combination regimens featuring colistin are more common and were recently recommended in the IDSA guidelines for the treatment of critically ill patients with ventilator-associated pneumonia due to the high prevalence of MDR/XDR microorganisms (25).…”

Colistin Use and Its Resistance in Kingdom of Saudi Arabia: A Narrative Review

“…Intrathecal colistin-based therapy was also highly recommended Acinetobacter baumannii [14]. Favourable synergistic clinical value of combining colistin with ceftolozane-tazobactamhas also been suggested for treatment of infections caused by MDR Pseudomonas aeruginosa [15].…”