Introduction
Beta-lactam antibiotics are the backbone of the treatment of all major infectious syndromes in acutely ill patients. Estimates indicate that up to 70% of hospitalized patients treated with an antibiotic receive a beta-lactam. Reference Liu, Fielding-Singh and Greene1 As hydrophilic small molecules, changes to volumes of distribution with resuscitation, altered host physiology, and dynamic end organ function each contribute to substantial variability in observed beta-lactam drug concentrations. Reference Roberts, Paul and Akova2 As time-dependent antimicrobials, subtherapeutic beta-lactam levels can decrease clinical and microbiologic cure and contribute to development of antimicrobial resistance. Reference Roberts, Paul and Akova2 In rare circumstances, supratherapeutic levels can increase the risk for dose-dependent adverse effects such as neurotoxicity. Reference Barreto, Webb, Pais, Rule, Jannetto and Scheetz3
Therapeutic drug monitoring (TDM) is one strategy used to individualize doses, thereby improving effectiveness and safety. Use of beta-lactam TDM to individualize therapy is increasing in popularity worldwide, albeit only used rarely in the United States. Reference Chen, Seabury and Steele4 Data on the benefits of TDM-guided beta-lactam dose optimization are promising, but at times conflicting. A meta-analysis of TDM-guided beta-lactam dosing in critically ill patients revealed 85% higher target attainment, 17% greater clinical cure, 14% greater microbiological cure, and 21% reduction in treatment failure. Reference Pai Mangalore, Ashok and Lee5 Despite improved pharmacokinetic/pharmacodynamic (PK/PD) target attainment, recently conducted randomized controlled trials have failed to show improved clinical outcomes or decreased mortality. Reference Abdulla, Ewoldt and Hunfeld6–Reference Roggeveen, Guo and Fleuren8 Some study limitations that may have contributed to reduced observed benefit of beta-lactam TDM include delays in time to sampling, heterogeneous patient populations, and variability in PK/PD targets. Generally, three different PK/PD targets have been variably tested for beta-lactams to optimize clinical effectiveness: 40–60% ƒT > MIC, 100% ƒT > MIC, and 100% ƒT > 4xMIC, making comparisons across studies challenging. Reference Barreto, Webb, Pais, Rule, Jannetto and Scheetz3 Safety thresholds for beta-lactams are less clear. There does appear to be an exposure response relationship between beta-lactams and neurotoxicity and cytopenias. Reference Barreto, Webb, Pais, Rule, Jannetto and Scheetz3,Reference Legg, Carmichael and Chai9 Other adverse effects appear more idiosyncratic (e.g., nephrotoxicity and hepatotoxicity). TDM may be useful to minimize beta-lactam associated toxicities, but these are relatively rare and hard to systematically evaluate. The majority of evidence describing the impact and implementation of beta-lactam TDM is based in the acute hospital setting. Beta-lactam antibiotics are also used in the outpatient setting, including as part of outpatient parenteral antimicrobial therapy (OPAT) programs.
OPAT, defined as the administration of parenteral antimicrobial therapy for at least 2 doses on different days without an intervening hospitalization, has been shown to be clinically efficient and cost-effective. Reference Norris, Shrestha and Allison10 Nearly 250,000 patients in the US receive OPAT annually. Reference Norris, Shrestha and Allison10 Prolonged courses of antibiotics over weeks to months predominate in OPAT due to difficult to treat sources of infection (e.g. bone/joint infections and endocarditis) and/or resistant organisms. The prolonged exposure to antibiotics can lead to more opportunities for adverse events (AEs). Approximately 20–30% of patients treated with OPAT experience at least one AE. Reference Keller, Williams and Gavgani11,Reference Billmeyer, Ross, Hirsch, Evans, Kline and Galdys12 To optimize the pharmacokinetics and pharmacodynamics of treatment regimens and decrease the risk for AEs, TDM may be considered.
TDM in OPAT is commonplace for vancomycin or aminoglycosides, but rare for beta-lactam antibiotics due to clinical and logistical nuances. At our centers, beta-lactam TDM has been used in select patients involved with the OPAT program. This concise communication aimed to illustrate the potential of beta-lactam TDM in OPAT through a patient case, characterize key challenges and opportunities associated with beta-lactam TDM in OPAT, and provide a framework for others who aim to implement beta-lactam TDM in the OPAT setting.
Clinical application
To illustrate the potential for beta-lactam TDM in the OPAT setting, we first describe the case of an individual with suspected dose-dependent beta-lactam toxicity who benefited from TDM:
A 76-year-old man needed OPAT with piperacillin/tazobactam for a Pseudomonas aeruginosa lung abscess. The initially planned three-week course was prolonged to two months based on laboratory features, imaging, and clinical signs and symptoms. During therapy, the patient experienced new-onset confusion which prompted an emergency department visit and neurologic workup. Laboratory and imaging findings, including a head CT, were unrevealing. The patient was dismissed back to the care of the OPAT team who ordered a piperacillin/tazobactam concentration. At the time of the drug concentration, the patient was treated with 13.5 grams/day of piperacillin/tazobactam via continuous intravenous infusion (weight 41 kg, serum creatinine 0.6 mg/dL, estimated creatinine clearance 61 mL/min). The steady-state piperacillin serum concentration was 83.6 mg/L. Using first-order kinetics, the dose was proportionally reduced to 9 g/day to achieve a target closer to 16 to 64 mg/L (to achieve approximately 1–4x the P.aeruginosa isolate MIC). The patient’s mental status improved, and he completed the antimicrobial course without further interruption or intervention.
Challenges and opportunities
Several factors impede the integration of beta-lactam TDM in OPAT. Sample collection and interpretation are uniquely challenging when beta-lactam TDM is performed in the OPAT setting relative to the hospital. Distinct from other monitorable medications in OPAT (e.g., vancomycin), two beta-lactam serum concentrations are needed to determine an individual pharmacokinetic profile for a patient treated with intermittent infusion beta-lactams (over ≤ 3 hours). Reference Ausman, Moreland-Head and Abu Saleh13
Intravenous access and resource constraints for sample collection (e.g., nursing, phlebotomy) are less reliable in the OPAT setting than in the hospital. Insurance and/or the home health agency staffing may limit the number of home visits in a single day. Patients could present to a facility for blood sampling, but travel and wait time between sample collections (i.e., at least one drug half-life) may be prohibitive. A single sample may be sufficient if drawn as a “true trough” (immediately prior to the next dose) or during continuous infusion therapy, yet continuous infusion therapy is not suitable for all patients due to preference, availability of specialized equipment, and drug stability concerns. Similar to other monitored medications in OPAT, interpretation of resulted beta-lactam levels depends on a detailed understanding of the timing of samples relative to dose administration. Unlike in the hospital, Medication Administration Records (MARs) are rarely available for patients in OPAT. Insurance coverage for beta-lactam TDM in OPAT may also vary. Electronic devices have been successfully used to assess medication adherence; similarly, there may be a future role for digital tracking platforms to record timing of medication administration to assist clinicians interpret concentrations with greater accuracy. Reference Mason, Cho and Rayo14 The lack of awareness and education among healthcare providers regarding the benefits of beta-lactam TDM in OPAT may also present a significant barrier to implementation. Many clinicians may not be familiar with the principles of TDM or its relevance to beta-lactam therapy, leading to underutilization. Addressing the knowledge gap through targeted educational initiatives can enhance healthcare providers’ understanding of beta-lactam TDM benefits.
While there are challenges for beta-lactam TDM in the OPAT setting, there are also advantages. In the hospital, beta-lactam dosing and monitoring is managed by a vast array of primary and consultative services, which makes implementation of a TDM program challenging. Reference Ausman, Moreland-Head and Abu Saleh13,Reference Venugopalan, Hamza and Santevecchi15 The small multidisciplinary contingent of infectious diseases experts in OPAT is ideal for TDM training and implementation. Reference Mahoney, Childs-Kean, Khan, Rivera, Stevens and Ryan16,Reference Rivera, Mara, Mahoney and Ryan17 These individuals are familiar with adjusting antibiotics based on laboratory values. OPAT clinicians also routinely navigate challenges with outpatient blood sample collection, and have extensive experience interpreting TDM without MARs. Home health staff education on appropriate sample timing can be provided via durable materials or in-services. The majority of beta-lactam assays are performed by reference laboratories, leading to a 1–3 day delay in results reporting. In hospitalized patients, rapidly changing pharmacokinetics, microbiology, and clinical status may render these delayed results clinically uninformative. OPAT treatment plans are usually definitive (i.e., based on resultant microbiology, imaging), average durations are 2–8 weeks, and patients are clinically stable. Reference Mahoney, Childs-Kean, Khan, Rivera, Stevens and Ryan16 These features make the delay in results reporting less consequential in the OPAT setting and the TDM results, when properly obtained, more informative toward the ongoing treatment plan.
Given the unique considerations associated with beta-lactam TDM in the OPAT setting, we propose a general framework of the key factors for OPAT program leadership to consider (Table 1). Key decisions necessary to develop an OPAT beta-lactam TDM program include patient selection, pharmacokinetic/pharmacodynamic targets, and the process map with responsible parties. Legacy workflows of antibiotic TDM in OPAT (e.g., vancomycin) may be adapted for beta-lactams, accounting for unique considerations like the need for multiple samples and send out laboratory testing. Shared decision making between OPAT clinicians and patients is encouraged to discuss the potential benefits of beta-lactam TDM alongside the potential treatment burden (e.g., time, travel, and cost).
Table 1. OPAT specific considerations for beta-lactam TDM
OPAT: outpatient parenteral antimicrobial therapy, EMR: electronic medical record, TDM: therapeutic drug monitoring
Conclusion
The scope of precision medicine with beta-lactam TDM should not be limited to hospitalized patients. The potential for beta-lactam TDM in the OPAT setting to improve drug effectiveness and safety is considerable. Thoughtful beta-lactam TDM program development and implementation by a multidisciplinary OPAT team is necessary to overcome clinical and logistical challenges unique to this environment.
Acknowledgements
None.
Financial support
This project was supported in part by the National Institutes of Health under Award Number K23AI143882 (PI; EFB). The funding source had no role in study design; data collection, analysis, or interpretation; writing the report; or the decision to submit the report for publication. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Competing interests
All authors report no conflicts of interest relevant to this article.
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