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Selecting the dosage of ceftazidime–avibactam in the perfect storm of nosocomial pneumonia
- Source :
- European Journal of Clinical Pharmacology
- Publication Year :
- 2019
- Publisher :
- Springer Berlin Heidelberg, 2019.
-
Abstract
- Purpose Ceftazidime–avibactam is a novel β-lactam/β-lactamase inhibitor combination recently approved in Europe and the USA for the treatment of adults with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), among other indications. In the phase III REPROVE trial (NCT01808092), ceftazidime–avibactam demonstrated non-inferiority to meropenem for the treatment of patients with nosocomial pneumonia (NP), including VAP. As ceftazidime–avibactam was not studied in patients with NP prior to REPROVE, selecting an appropriate dosage regimen in the “perfect storm” of NP required careful consideration of potential determinants and confounders of response specific to the NP patient population. Methods This review describes the series of preclinical studies and pharmacokinetic/pharmacodynamic (PK/PD) analyses that supported ceftazidime–avibactam dosage selection for patients with NP/VAP (2000/500 mg by 2-h intravenous infusion every 8 h, adjusted for renal function). In parallel, important considerations for antibiotic dosage selection in patients with NP are highlighted, including adequate drug penetration into the lungs, the suitability of murine-derived plasma PK/PD targets, evaluation of MIC distributions against clinical bacterial isolates from patients with NP, and consideration of PK in patients with NP, who are often critically ill. These analyses also supported the European approval of ceftazidime–avibactam for adults with HAP, including VAP, before the completion of REPROVE. Conclusions This work serves as a successful practical example of dosage design for a new antibacterial drug therapy in the indication of NP, including VAP, where previous drug therapies have failed, possibly as a result of evaluation of too few variables, thereby limiting the accuracy of pharmacodynamic predictions.
- Subjects :
- Drug
Nosocomial pneumonia
medicine.medical_specialty
medicine.drug_class
media_common.quotation_subject
Antibiotics
Review
Meropenem
Ceftazidime
Ceftazidime–avibactam
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
Internal medicine
Dosage selection
medicine
Animals
Humans
Pharmacology (medical)
030212 general & internal medicine
media_common
Pharmacology
0303 health sciences
Dose-Response Relationship, Drug
030306 microbiology
business.industry
Healthcare-Associated Pneumonia
Pneumonia, Ventilator-Associated
General Medicine
Antibiotic therapy
medicine.disease
Ceftazidime/avibactam
Anti-Bacterial Agents
Europe
Pneumonia
Regimen
Drug Combinations
Pharmacodynamics
business
Azabicyclo Compounds
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 14321041 and 00316970
- Volume :
- 76
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- European Journal of Clinical Pharmacology
- Accession number :
- edsair.doi.dedup.....8cfd6d0af91ba2501e02dcfc86a13444