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Ceftolozane/tazobactam dose regimens in severely/morbidly obese patients with complicated intra-abdominal infection or complicated urinary tract infection.
Int J Antimicrob Agents. 2018 Sep; 52(3):324-330.IJ

Abstract

Ceftolozane/tazobactam is approved for treatment of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) with renal function-based dose adjustment. Given that creatinine clearance, body weight and sex are highly correlated in severely/morbidly obese patients, this study investigated whether approved dosing regimens for ceftolozane/tazobactam are appropriate in severely/morbidly obese patients based on simulated pharmacokinetic/pharmacodynamic target attainment, with confirmation from observed clinical outcomes data from the phase 3 clinical development programme. Using a previously published population pharmacokinetic model, 1000 patients were randomly sampled from an internal pooled database of 201 severely/morbidly obese patients (BMI ≥ 35 kg/m2) and were used for Monte Carlo simulation to test whether the labelled dose regimens can achieve ≥90% probability of a target of 32.2% (1-log kill) time above free ceftolozane concentration against pathogens at an MIC up to 8 mg/L. Clinical outcomes data for severely/morbidly obese patients with cIAI or cUTI from pivotal phase 3 studies were summarised to calculate clinical and composite cure rates as a complimentary support. With the approved renal function-based dosing regimens, >90% target attainment of bactericidal activity was achieved at MICs up to 8 mg/L in the simulated severely/morbidly obese patients with cIAI or cUTI, similar to target attainment in non-obese patients and further confirmed by phase 3 outcomes where cure rates in severely/morbidly obese patients and non-obese patients are similar. Approved dosing regimens of ceftolozane/tazobactam, adjusted according to renal function, can achieve adequate target attainment and high clinical cure rates in severely/morbidly obese patients with cIAI or cUTI.

Authors+Show Affiliations

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07083, USA.Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07083, USA.Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07083, USA.Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07083, USA. Electronic address: luzelena_caro@merck.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29596902

Citation

Xiao, Alan J., et al. "Ceftolozane/tazobactam Dose Regimens in Severely/morbidly Obese Patients With Complicated Intra-abdominal Infection or Complicated Urinary Tract Infection." International Journal of Antimicrobial Agents, vol. 52, no. 3, 2018, pp. 324-330.
Xiao AJ, Huntington JA, Long J, et al. Ceftolozane/tazobactam dose regimens in severely/morbidly obese patients with complicated intra-abdominal infection or complicated urinary tract infection. Int J Antimicrob Agents. 2018;52(3):324-330.
Xiao, A. J., Huntington, J. A., Long, J., & Caro, L. (2018). Ceftolozane/tazobactam dose regimens in severely/morbidly obese patients with complicated intra-abdominal infection or complicated urinary tract infection. International Journal of Antimicrobial Agents, 52(3), 324-330. https://doi.org/10.1016/j.ijantimicag.2018.03.004
Xiao AJ, et al. Ceftolozane/tazobactam Dose Regimens in Severely/morbidly Obese Patients With Complicated Intra-abdominal Infection or Complicated Urinary Tract Infection. Int J Antimicrob Agents. 2018;52(3):324-330. PubMed PMID: 29596902.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ceftolozane/tazobactam dose regimens in severely/morbidly obese patients with complicated intra-abdominal infection or complicated urinary tract infection. AU - Xiao,Alan J, AU - Huntington,Jennifer A, AU - Long,Jianmin, AU - Caro,Luzelena, Y1 - 2018/03/27/ PY - 2017/04/12/received PY - 2018/03/01/revised PY - 2018/03/02/accepted PY - 2018/3/30/pubmed PY - 2019/1/12/medline PY - 2018/3/30/entrez KW - Ceftolozane/tazobactam KW - Infection KW - Monte Carlo simulation KW - Obese KW - Pharmacokinetics KW - Target attainment SP - 324 EP - 330 JF - International journal of antimicrobial agents JO - Int J Antimicrob Agents VL - 52 IS - 3 N2 - Ceftolozane/tazobactam is approved for treatment of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) with renal function-based dose adjustment. Given that creatinine clearance, body weight and sex are highly correlated in severely/morbidly obese patients, this study investigated whether approved dosing regimens for ceftolozane/tazobactam are appropriate in severely/morbidly obese patients based on simulated pharmacokinetic/pharmacodynamic target attainment, with confirmation from observed clinical outcomes data from the phase 3 clinical development programme. Using a previously published population pharmacokinetic model, 1000 patients were randomly sampled from an internal pooled database of 201 severely/morbidly obese patients (BMI ≥ 35 kg/m2) and were used for Monte Carlo simulation to test whether the labelled dose regimens can achieve ≥90% probability of a target of 32.2% (1-log kill) time above free ceftolozane concentration against pathogens at an MIC up to 8 mg/L. Clinical outcomes data for severely/morbidly obese patients with cIAI or cUTI from pivotal phase 3 studies were summarised to calculate clinical and composite cure rates as a complimentary support. With the approved renal function-based dosing regimens, >90% target attainment of bactericidal activity was achieved at MICs up to 8 mg/L in the simulated severely/morbidly obese patients with cIAI or cUTI, similar to target attainment in non-obese patients and further confirmed by phase 3 outcomes where cure rates in severely/morbidly obese patients and non-obese patients are similar. Approved dosing regimens of ceftolozane/tazobactam, adjusted according to renal function, can achieve adequate target attainment and high clinical cure rates in severely/morbidly obese patients with cIAI or cUTI. SN - 1872-7913 UR - https://www.unboundmedicine.com/medline/citation/29596902/Ceftolozane/tazobactam_dose_regimens_in_severely/morbidly_obese_patients_with_complicated_intra_abdominal_infection_or_complicated_urinary_tract_infection_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0924-8579(18)30075-X DB - PRIME DP - Unbound Medicine ER -