Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Versus Man

Abstract

Beta-lactams remain a critical member of our antibiotic armamentarium and are among the most commonly prescribed antibiotic classes in the inpatient setting. For these agents, the percentage of time that the free concentration remains above the minimum inhibitory concentration (%fT > MIC) of the pathogen has been shown to be the best predictor of antibacterial killing effects. However, debate remains about the quantity of fT > MIC exposure needed for successful clinical response. While pre-clinical animal based studies, such as the neutropenic thigh infection model, have been widely used to support dosing regimen selection for clinical development and susceptibility breakpoint evaluation, pharmacodynamic based studies in human patients are used validate exposures needed in the clinic and for guidance during therapeutic drug monitoring (TDM). For the majority of studied beta-lactams, pre-clinical animal studies routinely demonstrated the fT > MIC should exceed approximately 40–70% fT > MIC to achieve 1 log reductions in colony forming units. In contrast, clinical studies tend to suggest higher exposures may be needed, but tremendous variability exists study to study. Herein, we will review and critique pre-clinical versus human-based pharmacodynamic studies aimed at determining beta-lactam exposure thresholds, so as to determine which targets may be best suited for optimal dosage selection, TDM, and for susceptibility breakpoint determination. Based on our review of murine and clinical literature on beta-lactam pharmacodynamic thresholds, murine based targets specific to each antibiotic are most useful during dosage regimen development and susceptibility breakpoint assessment, while a range of exposures between 50 and 100% fT > MIC are reasonable to define the beta-lactam TDM therapeutic window for most infections.

Pharmacokinetics, Pharmacodynamics, and Dosing Considerations of Novel β-Lactams and β-Lactam/β-Lactamase Inhibitors in Critically Ill Adult Patients: Focus on Obesity, Augmented Renal Clearance, Renal Replacement Therapies, and Extracorporeal Membrane Oxygenation

“…Pharmacodynamically, like conventional β-lactams, the %ƒT > MIC has been described as the optimal PK/PD index associated with the efficacy of NBLA. However, the optimal percentage to target is still controversial [ 29 ]. Preclinical studies of conventional β-lactams suggested that approximately 1–2 log 10 reductions of colony-forming units (CFU) can be achieved with <100%ƒT > MIC, depending on the used antimicrobial (i.e., 40%, 50–60%, and 50–70%ƒT > MIC for carbapenems, penicillins, and cephalosporins respectively) [ 30 ].…”

“…Although the utilization of conventional PD thresholds (i.e., 40–60%ƒT > MIC) could be argued for NBLA, especially when considering the concentrations of BLIs, for the most part, BLIs by their own are inactive against invading pathogens [ 30 ]. The PD targets of such inhibitors (i.e., threshold of concentration (C T ) for avibactam/tazobactam and 24 h area under the free concentration–time curve ( f AUC 24 /MIC) for vaborbactam/relebactam) reflect the required concentrations to restore β-lactam activity, thus leaving PD targets of β-lactam backbone consistent with the PD targets described above for the severely sick population [ 29 , 35 ].…”

MIC Discrepancies between Parenteral and Oral Anti-Staphylococcal Beta-Lactams among MSSA

“…Most β-lactams are considered to be maximally effective when their free concentration at the site of infection is four times above the MIC (fT > MIC) for at least 40-70% of the dosing interval [19,20]. When these concepts are applied to cephalexin, drug concentrations would need to be at 16 μg/mL for MSSA (4 times the observed median MIC).…”

β-Lactamase Sensitive Probe for Rapid Detection of Antibiotic-Resistant Bacteria with Gas Chromatography–Tandem Mass Spectrometry

“…However, dissemination of antimicrobial resistance around the world has been one of the biggest threats to global public health, with a growing threat from infectious diseases, especially to critically ill infections or immunocompromised patients. − Accordingly, the early qualitative and quantitative detection of drug-resistant bacteria is of great significance for the efficient diagnosis and treatment of drug-resistant bacteria infection. One of the main resistance mechanisms is the production of β-lactamase (Bla).…”