Critically ill patients receiving beta-lactam antibiotics may benefit from dosing guided by measured drug levels, according to new recommendations from an international expert panel. The panel conditionally endorsed the approach as a way to improve treatment success, while acknowledging the need for more evidence.
The guidance, published in Pharmacotherapy, defines individualized dosing as using drug levels measured in each patient to guide treatment, rather than relying only on standard dosing based on factors such as weight or kidney function. According to the report, drug levels can vary by as much as 10- to 30-fold between patients.
“Historically, we’ve used population-level approaches to how we dose and monitor antimicrobials, specifically beta-lactam antibiotics,” first author Erin Frazee Barreto, PharmD, PhD, FCCM, FASN, of the department of pharmacy at Mayo Clinic in Rochester, Minn., said in an interview. “Advances in technology now allow us to measure drug concentrations in the serum, and, in some cases, directly at the site of infection, which has revealed that we’re not doing a very good job of being accurate and precise with how we dose beta-lactams.”
Dr. Barreto and colleagues convened a 19-member international panel of experts in infectious diseases, critical care, pharmacy, laboratory medicine, pediatrics and drug dosing. The panel developed 13 clinical questions and conducted a systematic review of several research databases and clinical trial registries, with two reviewers independently screening studies and extracting data. When enough evidence was available, the panel combined results from multiple studies and rated the strength of the evidence using a standard approach. When evidence was insufficient, it relied on expert consensus to develop best-practice statements.
The resulting guidance was endorsed by the American College of Clinical Pharmacy, the Infectious Diseases Society of America and several international organizations specializing in infectious diseases, critical care and therapeutic drug monitoring.
For patient outcomes, 11 studies, including four randomized trials and seven observational studies, compared individualized beta-lactam dosing with usual care. Across nine studies that reported clinical cure, patients receiving individualized dosing had nearly twice the odds of being cured. This finding remained consistent across additional analyses. However, the evidence was rated as low certainty because studies used different definitions of clinical cure.
The findings for mortality were less clear. Across 11 studies, individualized dosing was linked to lower mortality, but the difference was not statistically significant. The benefit was even smaller when researchers looked only at randomized trials. Individualized dosing also did not significantly improve microbiologic eradication or shorten hospital or intensive care unit stays.
The panel conditionally recommended keeping free beta-lactam drug levels above the minimum concentration needed to stop the pathogen from growing throughout the dosing period, with the goal of improving clinical cure. Loading doses and longer infusions may help achieve these levels. However, there was not enough evidence to recommend specific drug-level targets for reducing mortality, clearing the infection or shortening hospital stays.
The panel supported prioritizing individualized dosing for critically ill patients and those with altered kidney function, including acute kidney injury, chronic kidney disease, kidney replacement therapy or unusually rapid drug clearance. Individualized dosing may also be considered for patients with liver failure or cirrhosis, low blood protein levels, difficult-to-treat infections, suspected drug toxicity or other conditions that may alter how the body processes medications.
The safety evidence remains unclear. Very high beta-lactam levels may increase the risk of side effects, but the available studies had several limitations, including the effects of kidney dysfunction, varying definitions of high drug levels and inconsistent safety monitoring. The panel particularly recommended watching for harmful effects on the nervous system.
The authors noted several limitations, including few randomized trials, differences in how studies defined outcomes, uncertainty in the results and limited access to rapid drug-level testing and dosing software. They stressed that individualized dosing is not required for every patient and that clinicians should use their clinical judgment when deciding whether to use it.
The ACCP Foundation Ltd. supported the recommendations with an unrestricted grant. The authors disclosed panel members’ potential conflicts of interest and reported no health care industry funding or influence.
Expert analysis
Dr. Barreto spoke with this news organization about what the guidance means for clinical practice.
In your opinion, what are the top two to three best practice statements from this review?
Dr. Barreto: A key item is the recommendation in favor of beta-lactam individualization to improve treatment outcomes. That’s the first recommendation out of the gate in the paper. This is one of the first large-scale, systematic reviews and meta-analyses to rigorously evaluate the impact of individualized beta-lactam dosing on patient outcomes. It demonstrated that individualized beta-lactam dosing improves treatment outcomes, particularly clinical cure, with signals of benefit across other endpoints as well.
I think another strength of this consensus document is that it recognizes that implementing this approach is not straightforward for everyone. It requires substantial resources, support, and commitment to implement. We acknowledge and attend to the fact that not everyone practices in a highly specialized referral center. There are significant constraints on how care is delivered in the current healthcare environment, particularly financial limitations.
The consensus statement aimed to acknowledge this and balance the evidence of benefit with what is realistically feasible in clinical practice. We provide a lot of information, references, and resources about implementation considerations that clinicians can use as they seek to translate this into care.
As you and your coauthors put together this update, was there a topic, or perhaps more than one, that caused more deliberation than usual?
Dr. Barreto: One of the more complex areas was the discussion around safety. Studies suggest that individualized beta-lactam dosing can help reduce exposure to excessively high drug concentrations, which have been associated with adverse effects, particularly neurotoxicity. However, clinical trials have not systematically demonstrated that individualized dosing consistently improves patient safety, in part because these adverse effects are relatively uncommon and not fully understood. As a result, the available evidence was insufficient to make a recommendation regarding the impact of beta-lactam dose individualization on safety. This could be misinterpreted as suggesting that safety is unimportant, when the real issue is simply that the evidence remains limited. We still provide a best-practice statement including close scrutiny of patients for these side effects.
Is there anything else you’d like to say about this work?
Dr. Barreto: I think clinicians tend to get hung up on the challenges of implementation, sometimes allowing those barriers to overshadow a critical appraisal of the evidence. They may acknowledge that individualized dosing is beneficial but question whether the difficulty of putting it into practice makes it worthwhile. Having spent several years dealing with the hurdles of implementing beta-lactam dose individualization, I can appreciate the struggle, but those challenges should not prevent continued progress.
