Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions

Abstract

Summary Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in sub-optimal outcomes. In this paper, we review the patient- and pathogen-related challenges that contribute to inadequate antibiotic dosing and discuss how a process for individualised antibiotic therapy, that increases the accuracy of dosing, can be implemented to further optimise care for the critically ill patient. The process for optimised antibiotic dosing firstly requires determination of the physiological derangements in the patient that can alter antibiotic concentrations including altered fluid status, microvascular failure, serum albumin concentrations as well as altered renal and hepatic function. Secondly, knowledge of the susceptibility of the infecting pathogen should be determined through liaison with the microbiology laboratory. The patient and pathogen challenges can then be solved by combining susceptibility data with measured antibiotic concentration data (where possible) into a clinical dosing software. Such software uses pharmacokinetic-pharmacodynamic (PK/PD) models from critically ill patients to accurately predict the dosing requirements for the individual patient with the aim of optimising antibiotic exposure and maximising effectiveness.

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

“…This is especially important for critically ill patients, as they are most at risk for high morbidity and mortality (52).…”

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

“…A catalyst for using beta-lactam TDM is the apparent advancement in computer software that enables clinicians to use drug concentration data to the greatest benefits possible, without exhaustive pre-vious training. Using Bayesian or nonlinear regression, one can use the patient's own data for adjusting beta-lactam dosage, and some programs allow even the incorporation of population pharmacokinetic data, including local data, to optimize performance (11,141). Notably, interpretation of levels produced by the laboratory should be by collaboration with clinicians knowledgeable in PD concepts and, ideally, with consideration of the MIC.…”

“…Since beta-lactam concentrations are typically referenced to the MIC of the drug needed to inhibit bacteria, understanding the precise MIC, and in some scenarios the genotypic presence of resistance mechanisms, for each beta-lactam will be paramount (10). Once a target threshold and MIC are established, some confidence in the patient's specific pharmacokinetic profile is required to design an optimal and targeted dose (11). Unlike the case for vancomycin and some aminoglycosides, however, the availability of assays to clinically test for beta-lactam concentrations is limited.…”

Bacterial sepsis

“…Dosage recommendations and microbiologic determination of the susceptibility of a bacterial strain to particular antibiotics are based on the assumption that the pharmacokinetics of the drug correspond to those of a "normal patient. " However, the distribution and elimination capacity of various antibiotic groups is highly variable in sepsis patents, and difficult to predict [189][190][191][192][193][194][195][196]. Although specialist societies such as the Paul Ehrlich Gesellschaft (PEG) or IDSA allow for this in their recommendations [153,178,183], these facts are still paid too little attention in clinical routine-with the effect of increased mortality in seriously ill patients [104,[197][198][199][200].…”

“…The fT>MIC is lower for carbapenems because a more pronounced post-antibiotic effect is assumed for this substance class than for other substances [198]. These recommendations are derived from animal experiments; clinical investigations underscore the fact that in sepsis patients, an fT>MIC of 100% elicits a more effective anti-infective effect, and is thus relevant for outcome [190,[201][202][203]. Especially on the basis of striving to achieve adequate tissue concentrations even in deep-lying compartments (pneumonia; bone infections; infections of the central nervous system, CNS)-frequently in the context of disturbed microcirculation in sepsis patients [204][205][206] and also wishing to avoid development of resistance [207,208]-many experts recommend aiming for a concentration of β-lactam antibiotics in the primary compartment (serum/plasma) that exceeds the MIC by 4-times (up to 6-times) for 60-100% of the dosing interval [209].…”