Treatment of multidrug-resistant Pseudomonas aeruginosa with ceftolozane/tazobactam in a critically ill patient receiving continuous venovenous haemodiafiltration

Kuti, Joseph L.; Ghazi, Islam M.; Quintiliani, Richard; Shore, Eric

doi:10.1016/j.ijantimicag.2016.06.005

Cited by 35 publications

(41 citation statements)

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“…This continuous infusion regimen achieved a median steady-state concentration of 36 mg/liter, which is just below the 10ϫ MIC cutoff point. In previous case reports, no ceftolozane-related adverse effects were observed at equivalent or higher concentrations (11,13,19). Thus, clinicians may choose to use continuous infusion if there is a particular clinical concern with increased peak concentrations during intermittent infusion.…”

Section: Discussionmentioning

confidence: 89%

A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

Sime

Lassig-Smith

Starr

et al. 2019

Antimicrob Agents Chemother

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The aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for ceftolozane-tazobactam and CVVHDF. Unbound drug concentrations were measured from serial prefilter blood, postfilter blood, and ultrafiltrate samples by a chromatographic assay. Population pharmacokinetic modeling and dosing simulations were performed using Pmetrics. A four-compartment pharmacokinetic model adequately described the data from six patients. The mean (± standard deviation [SD]) extraction ratios for ceftolozane and tazobactam were 0.76 ± 0.08 and 0.73 ± 0.1, respectively. The mean ± SD sieving coefficients were 0.94 ± 0.24 and 1.08 ± 0.30, respectively. Model-estimated CVVHDF clearance rates were 2.7 ± 0.8 and 3.0 ± 0.6 liters/h, respectively. Residual non-CVVHDF clearance rates were 0.6 ± 0.5 and 3.3 ± 0.9 liters/h, respectively. In the initial 24 h, doses as low as 0.75 g every 8 h enabled cumulative fractional response of ≥85% for empirical coverage against Pseudomonas aeruginosa, considering a 40% fT>MIC (percentage of time the free drug concentration was above the MIC) target. For 100% fT>MIC, doses of at least 1.5 g every 8 h were required. The median (interquartile range) steady-state trough ceftolozane concentrations for simulated regimens of 1.5 g and 3.0 g every 8 h were 28 (21 to 42) and 56 (42 to 84) mg/liter, respectively. The corresponding tazobactam concentrations were 6.1 (5.5 to 6.7) and 12.1 (11.0 to 13.4) mg/liter, respectively. We suggest a front-loaded regimen with a single 3.0-g loading dose followed by 0.75 g every 8 h for critically ill patients undergoing CVVHDF with study blood and dialysate flow rates.

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Section: Discussionmentioning

confidence: 89%

A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

Sime

Lassig-Smith

Starr

et al. 2019

Antimicrob Agents Chemother

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“…C-T is approved for the treatment of complicated intra-abdominal and urinary tract infections, including acute pyelonephritis, at a dose of 1.5 g every 8 h (q8h); furthermore, clinical trials of C-T for hospital-acquired bacterial pneumonia are under way using a higher dose of 3 g every 8 h (10). As a result of its in vitro potency and to preserve its future effectiveness, C-T is often reserved by hospitals for use against MDR or extensively drug resistant (XDR) P. aeruginosa infections (14)(15)(16)(17)(18).…”

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confidence: 99%

“…Studies addressing the benefits of combination therapy have rarely found a clinical benefit, as long as at least one antibiotic with activity was prescribed; however, only a few studies with MDR P. aeruginosa have been conducted, and none have included newer, potent antibiotics, such as C-T (19,20). Nonetheless, many patients described in case series and isolated reports receive combination therapy (14)(15)(16)(17), presumably because this reduces the trepidation associated with using a newer agent when few other options remain. Munita and colleagues (16) presented retrospective data on 35 patients treated with C-T for carbapenem-resistant P. aeruginosa infections.…”

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confidence: 99%

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

Caballero

Abuhussain

Kuti

et al. 2018

Antimicrob Agents Chemother

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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.

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“…The pharmacokinetics of C/T in patients receiving continuous venovenous hemodiafiltration (CVVHDF) was described in two different case reports [54,55]. In both cases C/T was administered at 2000/1000 mg every 8h.…”

Section: Pharmacokinetics In Special Patient Populationsmentioning

confidence: 99%

Ceftolozane/tazobactam: place in therapy

Giacobbe

Bassetti

Rosa

et al. 2018

Expert Review of Anti-infective Therapy

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Ceftolozane/tazobactam (C/T) is a new antibiotic resulting from the combination of a novel cephalosporin, structurally similar to ceftazidime, with tazobactam, a well-known beta-lactamase inhibitor. C/T remains active against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and multi-drug resistant (MDR) P. aeruginosa, and has been recently approved for the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). A trial on hospital-acquired pneumonia is ongoing. Areas covered: The place in therapy of C/T is delineated by addressing the following main topics: (i) antimicrobial properties; (ii) pharmacological properties; (iii) results of clinical studies. Expert commentary: C/T is approved for cIAI and cUTI. However, the drug has a special value for clinicians in any kind of infectious localization for two main reasons. The first is that C/T is especially valuable in suspected or documented severe infections due to MDR P. aeruginosa, which is not a rare occurrence in many countries. The second is that C/T may provide an alternative to carbapenems for the treatment of infections caused by ESBL-producers, thus allowing a carbapenem-sparing strategy. Reporting of off-label use is mandatory to increase the body of evidence and the clinicians' confidence in using it for indications other than cIAI and cUTI.

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Treatment of multidrug-resistant Pseudomonas aeruginosa with ceftolozane/tazobactam in a critically ill patient receiving continuous venovenous haemodiafiltration

Cited by 35 publications

References 5 publications

A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

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

Ceftolozane/tazobactam: place in therapy

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