#PharmToExamTable: Are we correctly dosing β-lactam antibiotics?

A #PharmToExamTable question about antibiotic treatment, answered by Jeremy Tigh, PharmD, an ID pharmacy resident at UNMC

(Reviewed by Andrew Watkins, PharmD)

In a recent popular publication, Crass et al. ask the question: are we jumping the gun on renal dosing of antibiotics? In this review I expand upon Crass’s question, with a focus on β-lactams.

β-lactams, Dosing Strategies, and Clinical Trials

β-lactams are one of the most commonly prescribed antibiotic drug classes with numerous clinical indications for gram-positive and gram-negative infections. Penicillins, cephalosporins, and carbapenems all share common s structural aspects that bind to penicillin binding proteins, inhibiting the cross linking of peptides in the bacterial cell wall, resulting in bactericidal action. Efficacy parameters are described as the percentage of time of the dosing interval in which the free serum antibiotic concentration remains above the minimum inhibitory concentration (MIC). The value needed for bactericidal activity varies, but generally the goal is 40-70%; however, clinical data suggests that optimal rates of clinical cure and bacteriological eradication (protects against regrowth and subsequent development of resistance) are achieved with time above MIC of 100% (1).

Early Antibiotic Therapy and Acute Kidney Injury

Acute kidney injury (AKI) is common in patients presenting with infectious diseases resulting in dosage adjustment per drug labeling for many first line antibiotics. Crass et al. hypothesized that this dosage reduction is likely unnecessary in many patients as AKI can be transient and that by dose-adjusting so early in therapy, important patient outcomes may be impacted due to decreased drug exposure (3). In their retrospective study looking at more than 18,500 patient encounters they were able to provide evidence to support their hypothesis. AKI was common with an overall rate of approximately 1 in 5 of their population. When they restricted their analysis to patients with clinically meaningful renal dysfunction (likely warranting dose adjustment) up to 38% of those cases may have qualified. Additionally, they showed that 57% of those patients had resolution of their kidney injury by 48 hours and that there was a higher probability that patients with AKI on admission would have recovery rather than persistence of the AKI (3). One possible explanation for this dynamic renal function may be due to inaccuracies in the way that we measure and estimate a patient’s clearance, as serum creatinine is dynamic and variable. The authors suggest that delaying dose adjustment on initiation of therapy for β-lactam antibiotics may enhance meeting pharmacodynamic targets during crucial early therapy, but this must be balanced with the risk of toxicity. Limitations of their study include that antibiotic dosing and patient outcomes were not evaluated, making it difficult to know whether or not this actually affects patient outcomes.

Critically Ill Patients

Intensive care unit (ICU) patients are usually excluded from dose finding studies as pharmacokinetics and drug exposure are often significantly altered in this population (4). Because of this, utilizing standard dosing regimens for β-lactams may make it difficult to achieve optimal exposure. A recently published study by Abdulla et al. looked at patients treated with a variety of β-lactams and subsequent drug levels and attainment of pharmacodynamics goals (.4) The study included 147 patients, of which 63.3% met a goal of time above MIC at 100%. When analyzing time above 4 times the MIC (a suggested optimal concentration), only 36.7% met the goal. They identified male gender, a high BMI, and an eGFR >90 ml/min as risk factors for not obtaining goal PD parameters. Another study performed by Wong et al. support these findings (5) In a similar population they analyzed the same PD goals, but also analyzed time that drug concentration was 10 times above MIC, a subjective surrogate for toxicity. Out of 330 patients analyzed, a similar number of patients met PD goals as compared to Abdulla et al., but 17.3% of patients were indicated to have dosage reductions with measured high levels, emphasizing the risk of excessive drug exposure. Failure to obtain target values was not independently associated with negative clinical outcomes, making it difficult to support the hypothesis that non-target obtainment would lead to worse clinical outcomes. The complexity and dynamic nature of ICU patients makes associating clinical variables and risk of not obtaining target PK/PD goals difficult to apply without therapeutic drug monitoring. Currently, therapeutic drug monitoring for β-lactams is not widely used in clinical practice. Lack of guidelines, long turnaround times, and limited laboratory access are barriers to its implementation (4,5).

Conclusions

It is important to consider the limitations of estimating renal function and applying renal dosage adjustment to dynamic patients. Prospective studies are needed to establish causal links between antibiotic doses, renal dysfunction and enhancement (ARC), and patient outcomes in both acute and critically ill patients before therapeutic drug monitoring of β-lactams will be accepted as a useful tool in optimizing therapy.

References

1. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1-10; quiz 11-12.
2. Zhang L, Xu N, Xiao S, et al. Regulatory perspectives on designing pharmacokinetic studies and optimizing labeling recommendations for patients with chronic kidney disease. Journal of clinical pharmacology. 2012;52(1 Suppl):79s-90s.
3. Crass RL, Rodvold KA, Mueller BA, Pai MP. Renal Dosing of Antibiotics: Are We Jumping the Gun? Clin Infect Dis. 2019;68(9):1596-1602.
4. Abdulla A, Dijkstra A, Hunfeld NGM, et al. Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT). Critical care (London, England). 2020;24(1):558.
5. Wong G, Briscoe S, McWhinney B, et al. Therapeutic drug monitoring of β-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures. Journal of Antimicrobial Chemotherapy. 2018;73(11):3087-3094.
6. Boschung-Pasquier L, Atkinson A, Kastner LK, et al. Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2020;26(3):333-339.