Experimental design and modelling approach to evaluate efficacy of β-lactam/β-lactamase inhibitor combinations

Sy, Sherwin K. B.; Derendorf, Hartmut

doi:10.1016/j.cmi.2017.07.020

Cited by 17 publications

(15 citation statements)

References 31 publications

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“…Other investigators have started to develop mechanistic-based modeling approaches, including for the ceftazidime-avibactam combination. [48][49][50] In conclusion, PopPK models of ceftazidime and avibactam incorporating phase III data from patients with cIAI, cUTI, and NP, found several covariates influence variability in exposure to both agents. However, CrCL was the only covariate with a sufficiently large effect to warrant dose adjustments.…”

Section: Discussionmentioning

confidence: 82%

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Ceftazidime‐Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups

Lovern²,

Green³

et al. 2018

Clinical Translational Sci

113

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Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady-state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure-microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime-avibactam dosage regimens (2000-500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).

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Section: Discussionmentioning

confidence: 82%

“…Our approach involved defining fixed joint PK/PD targets that were conservative with respect to the exposure levels assumed to be required for clinical efficacy. Other investigators have started to develop mechanistic‐based modeling approaches, including for the ceftazidime‐avibactam combination …”

Section: Discussionmentioning

confidence: 99%

Ceftazidime‐Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups

Lovern²,

Green³

et al. 2018

Clinical Translational Sci

113

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“…In the present model, the bacterial counts impacted on ATM degradation according to an exponential function instead of an E max model. The prevention of degradation by AVI was modeled according to a fractional inhibitory E max model, as described elsewhere . Very low AVI concentrations were sufficient to prevent ATM degradation, as shown by the low estimated IC 50 values ( Table ).…”

Section: Resultsmentioning

confidence: 99%

“…The in vitro constant‐concentration time‐kill studies included a growth control, AVI alone, ATM alone, and ATM‐AVI combinations. The concentrations of ATM alone and in combination were based on its respective MIC values at selected AVI concentrations (ranging from 0−8 mg/L), consisting of 0.25–4 times the MIC in twofold increment . In the experiments performed with AVI as monotherapy, AVI concentrations were chosen to cover the concentrations used in combination plus onefold and twofold its MIC, ranging from 0.004−64 mg/L.…”

Section: Methodsmentioning

confidence: 99%

“…The concentrations of ATM alone and in combination were based on its respective MIC values at selected AVI concentrations (ranging from 0−8 mg/L), consisting of 0.25-4 times the MIC in twofold increment. 8 In the experiments performed with AVI as monotherapy, AVI concentrations were chosen to cover the concentrations used in combination plus onefold and twofold its MIC, ranging from 0.004−64 mg/L. In sum, 32 static time-kill assays were conducted for each strain, including 1 control, 6 levels of AVI alone, 5 levels of ATM alone, and 20 ATM-AVI combinations.…”

Section: Static Time-kill Studiesmentioning

confidence: 99%

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Semimechanistic Pharmacodynamic Modeling of Aztreonam‐Avibactam Combination to Understand Its Antimicrobial Activity Against Multidrug‐Resistant Gram‐Negative Bacteria

Chauzy

Torres

Buyck

et al. 2019

CPT Pharmacom & Syst Pharma

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Aztreonam‐avibactam (ATM‐AVI) is a promising combination to treat serious infections caused by multidrug‐resistant (MDR) pathogens. Three distinct mechanisms of action have been previously characterized for AVI: inhibition of ATM degradation by β‐lactamases, proper bactericidal effect, and enhancement of ATM bactericidal activity. The aim of this study was to quantify the individual contribution of each of the three AVI effects. In vitro static time‐kill studies were performed on four MDR Enterobacteriaceae with different β‐lactamase profiles. β‐Lactamase activity was characterized by measuring ATM concentrations over 27 hours. Data were analyzed by a semimechanistic pharmacodynamics modeling approach. Surprisingly, even though AVI prevented ATM degradation, the combined bactericidal activity was mostly explained by the enhancement of ATM effect within clinical range of ATM (5–125 mg/L) and AVI concentrations (0.9–22.5 mg/L). Therefore, when selecting a β‐lactamase inhibitor for combination with a β‐lactam, its capability to enhance the β‐lactam activity should be considered in addition to the spectrum of β‐lactamases inhibited.

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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Experimental design and modelling approach to evaluate efficacy of β-lactam/β-lactamase inhibitor combinations

Cited by 17 publications

References 31 publications

Ceftazidime‐Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups

Ceftazidime‐Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups

Semimechanistic Pharmacodynamic Modeling of Aztreonam‐Avibactam Combination to Understand Its Antimicrobial Activity Against Multidrug‐Resistant Gram‐Negative Bacteria

Medicinal Chemistry of β‐Lactam Antibiotics

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