Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients

Stein, Gary E.; Smith, Curtis; Scharmen, Amy; Kidd, James M.; Cooper, Christopher; Kuti, Joseph L.; Mitra, Subhashis; Nicolau, David P.; Havlichek, Daniel H.

doi:10.1089/sur.2018.141

Cited by 42 publications

(34 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Drug penetration is a consideration for central nervous system (CNS) infections, resulting in different breakpoints for CNS and non‐CNS infections for β‐lactams, and it would seem that this may also apply to other sites of infection. However, to what extent this is clinically relevant has not been completely explored, and most pharmacokinetic/pharmacodynamic models recommend targets based on serum concentrations . In our case, using an estimate of 30% ceftazidime penetration into the ELF and assuming 10% protein binding, the patient achieved an estimated 20% f T > 4×MIC over the dosing interval while receiving CAZ‐AVI 2.5 g every 8 hours and CVVHDF.…”

Section: Discussionmentioning

confidence: 97%

“…The broader and more general question most clinically relevant to our specific patient is how current recommended dosages relate to critically ill patients and whether or not serum drug concentrations should serve as a surrogate for the drug concentration achieved at the site of infection. Another study raised several important concerns in dosing CAZ‐AVI in critically ill patients, such as alterations in volume of distribution and protein binding. By using Monte Carlo simulation with 5000 patient iterations, these authors concluded that 2.5 g every 8 hours should suffice for dosing critically ill patients with isolates with a CAZ‐AVI MIC of 8 μg/ml or lower and creatinine clearance values more than 50 ml/minute.…”

Section: Discussionmentioning

confidence: 99%

“…In critically ill patients, some experts support a target of 100% f T > 4×MIC to maximize efficacy and minimize the potential for resistance . Predictive pharmacokinetic/pharmacodynamic indices for avibactam include both f T > MIC and ratio of free drug area under the concentration‐time curve (AUC) to MIC for the pathogen ( f AUC:MIC), with the prevailing recommendation for a free avibactam concentration more than 1 μg/ml for at least 50% of the dosing interval . According to Clinical and Laboratory Standards Institute (CLSI) M100‐S28, Enterobacteriaceae and P. aeruginosa are susceptible to CAZ‐AVI when the ceftazidime MIC is 8 µg/ml or lower .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Steady‐State Ceftazidime‐Avibactam Serum Concentrations and Dosing Recommendations in a Critically Ill Patient Being Treated for Pseudomonas aeruginosa Pneumonia and Undergoing Continuous Venovenous Hemodiafiltration

et al. 2019

View full text Add to dashboard Cite

Ceftazidime-avibactam (CAZ-AVI) is a novel intravenous b-lactam/b-lactamase inhibitor combination used in the treatment of multidrug-resistant (MDR) gram-negative infections. Although renal dosing recommendations exist for the medication, limited data are available for dosing in patients receiving continuous renal replacement therapy. In this report, we describe a case in which CAZ-AVI 2.5 g was administered as a 2-hour infusion every 8 hours to a 50-year-old critically ill patient with MDR Pseudomonas aeruginosa (CAZ-AVI minimum inhibitory concentration [MIC] 8 lg/ml) pneumonia who was also receiving continuous venovenous hemodiafiltration (CVVHDF). Total serum concentrations of both ceftazidime and avibactam were measured at~0.5, 2, 4, and 6 hours after completion of the 2hour infusion of the 11th dose of CAZ-AVI. Ceftazidime pharmacokinetic parameters were as follows: maximum serum concentration (C max ) 152.39 lg/ml, half-life 5.17 hours, volume of distribution at steady state (Vd ss ) 11.51 L, clearance 1.54 L/hour, and area under the concentration-time curve (AUC) 1295.38 hour•lg/ml. This regimen achieved free ceftazidime serum concentrations more than 4 times the MIC for 100% of the dosing interval. Avibactam pharmacokinetic parameters were as follows: C max 35.83 lg/ml, half-life 5.92 hours, Vd ss 12.44 L, clearance 1.45 L/hour, and AUC 343.44 hour•lg/ml, which achieved free avibactam concentrations above 1 lg/ml for 100% of the dosing interval. Higher Institutional review board and funding source: For this work, a medication approved by the Food and Drug Administration was used in the course of routine medical care and was considered exempted research (https://www.hhs.gov/ohrp/regulationsand-policy/decision-charts/index.html#c1). Drug concentrations were not used to alter medical management of the patient and were not reported until after the patient was discharged from our facility. Drug concentrations were paid for by a pharmacy department research and education fund and were not charged to the patient.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Steady‐State Ceftazidime‐Avibactam Serum Concentrations and Dosing Recommendations in a Critically Ill Patient Being Treated for Pseudomonas aeruginosa Pneumonia and Undergoing Continuous Venovenous Hemodiafiltration

et al. 2019

View full text Add to dashboard Cite

show abstract

“…All pharmacokinetic parameters obtained from published studies of ceftazidime and avibactam among critically ill patients were collected. 29 The concentration versus time curve was generated using a one-compartment model for CAZ and AVI. The targeted PK and PD indexes of ceftazidime were represented as the percentage of free drug time exceeding MIC (% f Time>MIC), and the target value was 50 and 100%.…”

Section: Methodsmentioning

confidence: 99%

The Potential Use of Ceftazidime-Avibactam Against Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates Harboring Different Carbapenemase Types in a Thai University Hospital

Nasomsong

Nulsopapon

Changpradub

et al. 2021

DDDT

View full text Add to dashboard Cite

Purpose: MBL and OXA-48 genes in carbapenem-resistant Enterobacterales (CRE) have emerged as a major public health problem worldwide, including Thailand. Due to the lack of susceptibility data and dosing regimens of ceftazidime-avibactam (CZA) against CRE in Thailand, especially in colistin-resistant era, we aimed to demonstrate in vitro susceptibility data of CZA and optimal dose based on Monte Carlo simulation of CZA to expand the treatment options. Patients and Methods: We collected 49 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients at Phramongkutklao Hospital (June-October 2020). CZA disk diffusion and E-test testing were performed to obtain minimum inhibitory concentration (MIC). Each drug regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). Results: The most common genotypes of CRKP were bla OXA-48 (53.1%) and bla OXA-48 +bla NDM (42.8%). CZA showed 47.7% and 90.5% susceptible rate against all genotypes of carbapenemases and OXA-48 type CRKP isolates. The MIC 50 and MIC 90 of CZA against CRKP were 2 and >256 µg/mL. The categorical agreement (CA) between disk diffusion and E-test testing of CZA against CRKP was 95.4%. The CZA dosing regimens of 2.5 g infused 2-3 h every 8 h achieved ≥90% of the target of free ceftazidime plasma concentration over MIC (%fTime >MIC) ≥50% and 100% against isolates MICs of ≤8 and ≤8 µg/mL, respectively. The avibactam regimens also provided 100%fTime at 0.5 µg/mL. Based on CFR ≥90%, no CZA regimens were effective against all of the studied CRKP isolates except CRKP carrying OXA-48. Conclusion: CZA exhibited a fairly susceptible rate among the OXA-48-positive isolates in Thailand. The current suggested dose of CZA with prolonged infusion appears appropriate to achieve the pharmacokinetic/pharmacodynamic targets of ceftazidime and avibactam against CRKP carrying bla OXA-48 .

show abstract

“…The covariates that affected the VD of both ceftazidime and avibactam were body weight, and mechanical ventilated patients when treated for nosocomial pneumonia, and treatment indication (40). Another PK study was carried out in 10 critically ill patients receiving ceftazidimeavibactam to once again evaluate adequacy of proposed standard dosage regimens (41). Both studies showed that standard dosage regimens resulted in a >90% probability of attaining the PD of 8 mg/L during >50% of the time for a relatively heterogenous patient population.…”

Section: Ceftzidime-avibactammentioning

confidence: 99%

Minireview on Novel Anti-infectious Treatment Options and Optimized Drug Regimens for Sepsis

Hites

2021

Front. Med.

View full text Add to dashboard Cite

Sepsis, a life-threatening organ dysfunction caused by a dysregulated response to infection is a major public health concern, as it is a leading cause of mortality and critical illness worldwide. Antibiotics are one of the cornerstones of the treatment of sepsis; administering appropriate antibiotics in a rapid fashion to obtain adequate drug concentrations at the site of the infection can improve survival of patients. Nevertheless, it is a challenge for clinicians to do so. Indeed, clinicians today are regularly confronted with infections due to very resistant pathogens, and standard dosage regimens of antibiotics often do not provide adequate antibiotic concentrations at the site of the infection. We provide a narrative minireview of different anti-infectious treatments currently available and suggestions on how to deliver optimized dosage regimens to septic patients. Particular emphasis will be made on newly available anti-infectious therapies.

show abstract

Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients

Cited by 42 publications

References 27 publications

Steady‐State Ceftazidime‐Avibactam Serum Concentrations and Dosing Recommendations in a Critically Ill Patient Being Treated for Pseudomonas aeruginosa Pneumonia and Undergoing Continuous Venovenous Hemodiafiltration

Steady‐State Ceftazidime‐Avibactam Serum Concentrations and Dosing Recommendations in a Critically Ill Patient Being Treated for Pseudomonas aeruginosa Pneumonia and Undergoing Continuous Venovenous Hemodiafiltration

The Potential Use of Ceftazidime-Avibactam Against Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates Harboring Different Carbapenemase Types in a Thai University Hospital

Minireview on Novel Anti-infectious Treatment Options and Optimized Drug Regimens for Sepsis

Contact Info

Product

Resources

About