A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients

Abstract

f De-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when antibiotics are switched are rarely considered. The primary objective of this study was to compare the fractional target attainments of contemporary dosing of empirical broad-spectrum ␤-lactam antibiotics and narrower-spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment. We performed a simulation study using published population pharmacokinetic (PK) studies in critically ill patients for a number of broad-spectrum ␤-lactam antibiotics and narrower-spectrum antibiotics. Simulations were undertaken using a data set obtained from critically ill patients with sepsis without absolute renal failure (n ‫؍‬ 49). The probability of target attainment of antibiotic therapy for different microorganisms for which de-escalation was applied was analyzed. EUCAST MIC distribution data were used to calculate fractional target attainment. The probability that therapeutic exposure will be achieved was lower for the narrower-spectrum antibiotics with conventional dosing than for the broad-spectrum alternatives and could drastically be improved with higher dosages and different modes of administrations. For a selection of microorganisms, the probability that therapeutic exposure will be achieved was overall lower for the narrower-spectrum antibiotics using conventional dosing than for the broad-spectrum antibiotics. P rovision of antibiotic therapy that is timely and of an appropriate spectrum is one of the mainstays of treatment (1, 2). This has led to the widespread use of broad-spectrum antibiotic therapy for the empirical treatment of infections. After identification of the causative microorganism, antibiotic therapy is typically adapted to the susceptibility profile of the microorganism, with a preference to change therapy to narrower-spectrum agents in order to decrease selective pressure for resistant pathogens. This process is called antibiotic de-escalation and is considered an important element in antibiotic stewardship programs (3-5).Although the timing and adequacy of the antibiotic therapy remain crucial, recent data hint at the importance of antibiotic dosing and exposure on clinical outcome (6). Changes in the physiology of the critically ill alter the pharmacokinetics (PKs) of ␤-lactam antibiotics, with many patients being at risk of being underdosed (7,8). Attainment of PK/pharmacodynamic (PD) targets associated with efficacy is also dependent on the susceptibility of the pathogen and varies across antibiotic classes, an element that is rarely considered (8).Although de-escalation of antibiotic therapy is a key element in many antibiotic stewardship programs, the possible change in PK/PD target attainment in de-escalation has not yet been considered. De-escalation has been associated with improved outcomes in ...

What’s new in multidrug-resistant pathogens in the ICU?

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Probability of pharmacological target attainment with flucloxacillin in Staphylococcus aureus bloodstream infection: a prospective cohort study of unbound plasma and individual MICs

“… 7 , 8 However, data on target attainment of unbound flucloxacillin in plasma are scarce. Simulation studies based on a small number of patients with MSSA-BSI have demonstrated flucloxacillin underdosing 9 , 10 and high variability of the unbound flucloxacillin fraction, particularly in critically ill patients. 5 , 11 In these studies, the MSSA oxacillin standard epidemiological cut-off value (ECOFF; 2 mg/L) and not the strain-specific flucloxacillin MIC value was used to calculate target attainment.…”

Safety of antimicrobial de-escalation for culture-negative severe pneumonia

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