Despite a Lack of US Guidelines, Implementing β-Lactam Therapeutic Drug Monitoring Remains Key

As the benefits of β-lactam therapeutic drug monitoring (TDM) have become better recognized, international guidelines were published with the service becoming more available globally. However, there are no guidelines yet in the United States, and many centers do not have established β-lactam TDM programs.

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Despite a lack of US guidelines for implementation, it remains necessary to follow certain steps for establishing β-lactam TDM programs. Additionally, many of the steps involved may need to be completed simultaneously to ensure the program is established and implemented as efficiently as possible.

Step 1. Identify the patient groups and antibiotics to target

Although not exhaustive, the following is a list of patient-specific conditions that may warrant performing β-lactam TDM:

• critical illness;

• cystic fibrosis;

• pediatrics;

• lack of response despite receipt of an active antibiotic;

• infection with organisms with higher minimum inhibitory concentrations; and

• drug toxicities presumed to be due to supratherapeutic β-lactam concentrations.

For thorough overviews of target patient populations and summaries of studies, articles such as those by Fratoni et al, Cusumano et al, and Venugopalan et al can be helpful resources.^1-3

Furthermore, although it may be wise to start with a smaller list of antibiotics or select units (eg, a medical intensive care unit) and expand as the institution gains more experience, it would be reasonable to select antibiotics that are used more commonly, especially in the special patient groups mentioned previously who likely would benefit from β-lactam TDMs.

Depending on which patient population or antibiotics are targeted, it can be important to develop a multidisciplinary workforce group to discuss the program. Some of the key stakeholders to include in the group may include representatives of the infectious diseases, pharmacy, critical care, clinical laboratory, and inpatient finance teams.

Step 2. Evaluate and discuss options with the clinical laboratory

Once the target patient population(s) and the β-lactam(s) to be monitored are established, it is important to then evaluate the TDM options available.

• Step 2a. Find a clinical laboratory champion.

° Some ideal champions include a pharmacist with specialized training in laboratory sciences working in that setting or a laboratory director/supervisor.

• Step 2b. Evaluate available resources.

° Collaborate with a laboratory champion to evaluate options. If in a large health system or in an academic medical center, the clinical laboratory may be able to run in-house assays, validate to perform drug concentration testing, or have access to a research laboratory that can offer such services. If such a process is not already set up but the institution has the infrastructure for it, it may be an option to discuss these services with the lab contact person. However, if an internal option is not possible, there are several commercial laboratories, such as ARUP Laboratories, that may already have agreements/contracts that offer levels for some common β-lactams (eg, meropenem and piperacillin). Other options are to establish a new partnership with a commercial company, such as Atlantic Diagnostic Laboratories, that performs β-lactam concentrations (eg, cefepime, meropenem, piperacillin, and tazobactam) or sends concentrations as needed to an academic/research center such as the Infectious Disease Pharmacokinetics Laboratory at the University of Florida.

• Step 2c. Consider specific factors that will impact feasibility.

° Costs and turnaround time: The laboratory cost (approximately $75-$200 per concentration) and turnaround time (time to draw labs, assay performance, travel time [if sent-out labs]) may affect implementation of the service. Discuss how the costs will be covered and/or billed or who will be responsible (ie, department, patient-level).

° Other factors to consider include: specimen types (most labs perform concentrations only on serum), if the company/center offers consultative services that may or may not be included in the charge, and how the concentrations will be reported (ie, whether results will be reported via the electronic medical record [EMR] and how/when information technology should be involved; most labs will report total concentrations and will need to estimate unbound/free concentration of the drug based on drug information resources).

Step 3. Develop a protocol in collaboration with key stakeholders

With the multidisciplinary workforce group, begin drafting a protocol. A few centers such as the University of Florida have built a robust β-lactam TDM program that can serve as a template.³ Some important aspects that should be addressed in the protocol include the following:

• Will this be a pharmacist-led program? It is important to establish whether the program will involve working through a collaborative practice agreement or whether the pharmacist will work closely with physicians.

• Who will respond to the concentrations and when? Establish when the service will be available and how recommendations will be communicated (eg, EMR note template). Additionally, it is important to manage expectations for response time.

• How many concentrations will be obtained? As many as 3 concentrations (peak, midpoint level, and trough) or as few as 1 (trough) may be warranted, so consideration of different patient scenarios may be helpful.¹

• Will concentrations be obtained at steady state? This is a key point to establish among all stakeholders for program-wide consistency.

• What target parameter will be used to evaluate the concentrations? For example, it is important to decide what the concentration parameters will be set at (50%-70% T > MIC, 100% free (ƒ) T > MIC, or 100% ƒT > 4xMIC). Further, consideration of site of infection may also affect the target desired. For this reason, it is valuable to include estimated free unbound concentrations in the protocol.

• How will dosages be adjusted? For dose adjustment, first-order kinetic equations can be used. There are also software programs that utilize Bayesian modeling that the institution may already be using that can assist with β-lactam monitoring (eg, DoseMeRx, PrecisePK, Optimum Dosing Strategies, and InsightRx).

Step 4. Publish/share the experience

Since we can all benefit from each other’s experiences, the last step in the process is to share results of β-lactam TDM program implementation with the health care community. Through publication of results, it is possible to enter the scientific discourse and support future US guidelines for β-lactam TDM program implementation across the country.

References

1. Fratoni AJ, Nicolau DP, Kuti JL. A guide to therapeutic drug monitoring of β-lactam antibiotics. Pharmacotherapy. 2021;41(2):220-233. doi:10.1002/phar.2505

2. Cusumano JA, Klinker K, Huttner A, Luther MK, Roberts JA, LaPlante KL. Towards precision medicine: therapeutic drug-monitoring-guided dosing of vancomycin and β-lactam antibiotics to maximize effectiveness and minimize toxicity. Am J Health-Syst Pharm. 2020;77(14):1104-1112. doi:10.1093/ajhp/zxaa128

3. Venugopalan V, Hamza M, Santevecchi B, et al. Implementation of a β-lactam t herapeutic drug monitoring program: experience from a large academic medical center. Am J Health-Syst Pharm. 2022;79(18):1586-1591. doi:10.1093/ajhp/zxac171

About the Authors

Patricia Saunders-Hao, PharmD, BCIDP, BCPS, is a clinical pharmacy specialist practicing in the area of infectious diseases and antimicrobial stewardship at North Shore University Hospital in Manhasset, New York.

Esther Bae, PharmD, BCIDP, is a clinical pharmacy specialist in OPAT/Ambulatory Stewardship at the University of Texas Southwestern Medical Center in Dallas, Texas.