New International Guidelines on Prolonged Infusion Beta-Lactams

By David R. Ha, PharmD, BCIDP

Infectious Diseases and Antimicrobial Stewardship Pharmacist; Manager, Stanford Antimicrobial Safety and Sustainability Program, Stanford Health Care; Lecturer, Stanford University School of Medicine, Division of Infectious Diseases and Geographic Medicine; Program Coordinator, PGY2 Infectious Diseases Pharmacy Residency Program, Stanford Healthcare

SYNOPSIS: The largest randomized clinical trial of prolonged vs. intermittent beta-lactam antibiotic (meropenem) infusion in septic intensive care unit patients found no benefit in mortality or emergence of antibiotic resistance. Unfortunately, this trial has numerous flaws that ultimately limit its generalizability.

SOURCE: Hong LT, Downes KJ, FakhriRavari A, et al. International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists. Pharmacotherapy 2023;43:740-777.

Hong et al have published the first-ever international consensus guidelines on the use of prolonged-infusion (PI) beta-lactams. These guidelines have been endorsed by several U.S. and European professional societies, including the Infectious Diseases Society of America, Society of Infectious Diseases Pharmacists, and Society of Critical Care Medicine.

The authors included representatives from the endorsing societies and were divided into five working groups to focus on pharmacokinetics/pharmacodynamics (PK/PD), clinical outcomes, therapeutic drug monitoring, stability and special populations (obesity, pediatrics), and populations with altered renal clearance (augmented renal clearance of critical illness or cystic fibrosis and those undergoing renal replacement therapy). PI was defined as infusion over three to 24 hours in a 24-hour period and standard infusion (SI) was defined as infusion over one hour or less. Infusions between one and three hours were not classified.

The work groups developed PICO (Population, Intervention, Comparator, and Outcome) questions and performed systematic reviews and grading of evidence using GRADE criteria. Meta-analyses also were performed if sufficient randomized controlled trial (RCT) data existed for a particular PICO question.

The authors had several notable findings and recommendations:

• The microbiologic benefits of PI include: enhanced bacterial killing in vitro, particularly of gram-negative pathogens and possibly suppression of the development of resistance, depending on agent, species, minimum inhibitory concentration (MIC), and inoculum.

• Performing therapeutic drug monitoring (TDM) of beta-lactams could not be recommended for or against because of limited evidence but could be considered by clinicians.

- If performing TDM for PI beta-lactams, the authors recommended plasma free drug levels should exceed the MIC by at least 50% to 70% of a dosing interval.

- For continuous infusion (CI) beta-lactams, the authors recommended plasma free drug levels should exceed at least four times the MIC for 100% of the dosing interval.

• The authors recommended to consider PI over SI beta-lactams in severely ill adult patients with gram-negative infections to reduce mortality and improve clinical cure. This was a conditional recommendation with very low certainty of evidence.

• The authors recommended to use a loading dose for CI beta-lactam antibiotics but could not recommend for or against a loading dose for extended infusion (EI) beta-lactam antibiotics.

• The authors could not recommend for or against PI over SI beta-lactams in the following cases because of inadequate supportive evidence:

- non-severely ill adult patients to reduce mortality or improve clinical cure;

- pediatric patients to improve efficacy;

- obese patients to improve efficacy;

- to provide a safety advantage and reduce adverse events.

COMMENTARY

While PI beta-lactam antibiotics have been widely promoted and used in clinical practice, Hong and colleagues have published the first-ever international consensus guidelines on their use. The authors provided a contemporary systematic approach to important clinical questions regarding PI beta-lactams.

What some clinicians initially may find surprising is the overall low quality of evidence found in their PICO question-directed systematic reviews and meta-analyses. While this may douse enthusiasm for PI beta-lactams for some, it should be noted that conditional recommendations with low-quality evidence is typical in infectious diseases treatment guidelines, and in a field dominated by non-inferiority approaches, the search for superiority is a challenging one.¹

The strongest (still conditional) recommendation for PI over SI beta-lactam antibiotics in these guidelines is made for severely ill adult patients with gram-negative infections to reduce mortality and increase clinical cure. The authors arrived at this conclusion based on meta-analysis of 14 randomized trials showing benefit in clinical cure. Mortality benefit, however, has mainly been limited to retrospective observational studies, particularly in Pseudomonas aeruginosa infections.

A notable omission from these guidelines, because of the timing of publication, is the recently published MERCY randomized trial, the largest trial to date assessing CI vs. SI beta-lactams for critically ill patients with sepsis and/or septic shock.² The MERCY trial did not show any difference in its composite outcome of mortality or subsequent recovery of multidrug-resistant organisms with CI vs. SI meropenem. One could argue that had the MERCY trial been included in this meta-analysis, the authors may have downgraded their level of recommendation for severely ill adults to one of equipoise. However, the MERCY trial had major flaws limiting its interpretation for this PICO question, since it included many patients with gram-positive infections as well as infections where the pathogen was unknown. A sizeable portion of included patients received concomitant gram-positive- and non-meropenem gram-negative-directed therapy. Due to these major limitations and others, it certainly can be argued that the MERCY trial, despite a strong design, did not ultimately have the appropriate patient population to be able to adequately answer the question specifically in gram-negative infections that this PICO question focuses on.

Aside from severely ill adult patients, no recommendation could be made for or against PI over SI in any other assessed population. For non-severely ill adult patients, the authors’ meta-analysis of six RCTs found no difference in outcomes between PI and SI beta-lactam antibiotics. This may have been because none of these trials was adequately powered. Certain non-severely ill populations, like neutropenic patients or those with augmented renal clearance or on renal replacement therapy, may benefit more than others, although data are limited. If institutions have concerns about PI beta-lactams negatively affecting nursing workload, line compatibility, or quality-of-life measures, it may be reasonable to forgo PI administration in non-severely ill patients.

Additionally, the authors could not provide a recommendation for or against PI over SI beta-lactams in pediatric patients. This may be because of the overall more antibiotic-susceptible infections as well as innately better outcomes children tend to have compared with adult patients for the same type of infection. The authors suggested that future study be conducted in severely ill children or those with multidrug-resistant infections to elucidate populations that may benefit. The authors also could not provide a recommendation for obese adults, largely because of limited comparative studies published to date.

The authors provided no recommendation for or against TDM of beta-lactam antibiotics. Three RCTs exist in this space and were enriched for patients theoretically more likely to benefit from TDM (e.g., burn patients, augmented renal clearance). All three demonstrated improvements in attainment of target PK/PD indices; however, none of them demonstrated clinical benefit. It should be noted that these trials were powered for achievement of PK/PD indices and not clinical outcomes, a major limitation. Thus, the authors still suggested that TDM may be pursued on a case-by-case basis in selected patients, like critical illness, augmented renal clearance, or cystic fibrosis.

Some clinicians posit that PI beta-lactams may provide a safety advantage since frequently the total daily dose of antibiotic, and, therefore exposure, required is lower. That said, the authors could not identify evidence to support this sentiment in adult or pediatric patients among eight trials. This may be because beta-lactams generally are well-tolerated drugs, and certain common adverse drug reactions, including rash, kidney injury, and transaminitis (many of which have a hypersensitivity mechanism), and diarrhea (including C. difficile diarrhea), may not be strongly dose-dependent. The authors also noted that no trials were designed with safety as a primary outcome measure.

These first international consensus guidelines on PI beta-lactam antibiotic use published by Hong et al are a welcome addition to the literature because they provide a contemporary systematic assessment of the existing literature in this space and are endorsed by numerous relevant organizations and societies. While few patient populations existed where recommendations could be made favoring PI beta-lactam antibiotics, the authors exposed well the limitations in existing published data and provided myriad targets for future research.

REFERENCES

1. Miles KE, Rodriguez R, Gross AE, Kalil AC. Strength of recommendation and quality of evidence for recommendations in current Infectious Diseases Society of America Guidelines. Open Forum Infect Dis 2021;8:ofab033.
2. Monti G, Bradić N, Marzaroli M, et al. Continuous vs intermittent meropenem administration in critically ill patients with sepsis: The MERCY randomized clinical trial. JAMA 2023;330:141-151.