Relationship between Ceftolozane-Tazobactam Exposure and Selection for Pseudomonas aeruginosa Resistance in a Hollow-Fiber Infection Model

Abstract

dIt is important to understand the relationship between antibiotic exposure and the selection of drug resistance in the context of therapy exposure. We sought to identify the ceftolozane-tazobactam exposure necessary to prevent the amplification of drugresistant bacterial subpopulations in a hollow-fiber infection model. Two Pseudomonas aeruginosa challenge isolates were selected for study, a wild-type ATCC strain (ceftolozane-tazobactam MIC, 0.5 mg/liter) and a clinical isolate (ceftolozane-tazobactam MIC, 4 mg/liter). The experiment duration was 10 days, and the ceftolozane-tazobactam dose ratio (2:1) and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The studied ceftolozane-tazobactam dosing regimens ranged from 62.5/31.25 to 2,000/1,000 mg per dose in step fold dilutions. Negative-control arms included no treatment and tazobactam at 500 mg every 8 h. Positive-control arms included ceftolozane at 1 g every 8 h and piperacillin-tazobactam dosed at 4.5 g every 6 h. For the wild-type ATCC strain, resistance was not selected by any ceftolozane-tazobactam regimen evaluated. For the clinical isolate, an inverted-U-shaped function best described the relationship between the amplification of a drug-resistant subpopulation and drug exposure. The least (62.5/31.25 mg) and most (2,000/1,000 mg) intensive ceftolozane-tazobactam dosing regimens did not select for drug resistance. Drug resistance selection was observed with intermediately intensive dosing regimens (125/62.5 through 1,000/500 mg). For the intermediately intensive ceftolozane-tazobactam dosing regimens, the duration until the selection for drug resistance increased with dose regimen intensity. These data support the selection of ceftolozanetazobactam dosing regimens that minimize the potential for on-therapy drug resistance selection.

Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined β-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of β-Lactam–β-Lactamase Inhibitor Combinations

“…While these results are promising, our time-kill studies utilized static concentrations of ceftolozane-tazobactam, making the extrapolation of our results into the clinical setting difficult. To the best of our knowledge, only two studies, by VanScoy et al (10,37), have looked at ceftolozane-tazobactam in a hollow-fiber infection model. Further studies evaluating the performance of the combination regimen against other pathogens containing ␤-lactamase enzymes are needed to completely understand the niche of ceftolozane-tazobactam among other ␤-lactams.…”

Relationship between Fosfomycin Exposure and Amplification of Escherichia coli Subpopulations with Reduced Susceptibility in a Hollow-Fiber Infection Model

“…Those patient populations at risk for the development of antibiotic-resistant Enterobacteriaceae infections include but are not limited to those with prolonged hospitalization, immunocompromised status, and a neurological diagnosis (1). One way to reduce the likelihood of the emergence of on-therapy antibiotic resistance is to utilize dosing regimens that result in exposures sufficient to prevent the amplification of bacterial subpopulations with reduced susceptibility.The hollow-fiber infection model has been utilized to characterize the relationship between drug exposure and resistance amplification over time (2,3,4). For ceftolozane-tazobactam, the relationship between drug exposure and resistance amplification of CTX-M-15-producing Escherichia coli resembled an inverted-U-shape function (3).…”

“…The hollow-fiber infection model has been utilized to characterize the relationship between drug exposure and resistance amplification over time (2,3,4). For ceftolozane-tazobactam, the relationship between drug exposure and resistance amplification of CTX-M-15-producing Escherichia coli resembled an inverted-U-shape function (3).…”

Dose optimization of ceftriaxone-vancomycin combination using fractional inhibitory concentration kinetics in resistant bacteria

“…The exposure-response relationships help in evaluating the PK/PD indices [8,9] and further identifying the efficacy drivers for understanding the potential activity of antibacterial agents. The three PK/PD indices that are routinely used for explaining the therapeutic efficacy in terms of achieving MIC and mechanism based action of antibiotics include: 1) % T>MIC time (% time for which the levels of antibiotic in serum/plasma exceed the MIC); 2) Area under the concentration-time curve (AUC)/MIC ratio; 3) Peak plasma concentration (C max )/MIC ratio [10][11][12]. Maximum literature for these kinds of PK/PD studies is available for single antibacterial agents [13,14]; the effect of combination therapy on the PK and PD, and subsequently on PK/PD indices is very limited [15].…”