US Pharm. 2024;49(11):40-44.
ABSTRACT: Antimicrobial stewardship is an essential part of patient care in an era of overutilized antimicrobials and inadequate development of new antimicrobials. The World Health Organization has deemed antimicrobial resistance a threat to human safety on a global level. While the development of new antimicrobials to combat antimicrobial resistance takes time, there are three antibiotics that were recently approved by the FDA. Pharmacists play a unique role in the fight against antimicrobial resistance by being experts in medications, evidence-based medicine, and knowledge of pharmacokinetics and pharmacodynamics.
The Society of Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance in Hospitals has defined the stewardship of antimicrobials as activities that help optimize antimicrobial therapy, ensuring the best clinical outcome for the patient while lowering the risk of subsequent development of antimicrobial resistance.1 As such, antimicrobial stewardship is a fundamental practice in the community and acute care settings, including the ICU. Antimicrobial stewardship programs have been created to help prioritize and promote the appropriate utilization of antimicrobials to combat ongoing antimicrobial resistance.2
Unfortunately, the overuse and misuse of antimicrobials have led to an antimicrobial resistance crisis and threaten human safety on a global level; therefore antimicrobial stewardship has become a priority for the World Health Organization (WHO).2 The overuse of antibiotics in humans, animals, and plants is the main driver for the development of antimicrobial resistance, according to the WHO. The antimicrobial resistance collaborators estimate that bacterial antimicrobial resistance was directly responsible for 1.27 million global deaths in 2019 and overall contributed to 4.95 million deaths.3 Unfortunately, there has been inadequate research and development for new antimicrobials despite increasing resistance and urgent need for new antimicrobials. Given this, acute care settings should prioritize antimicrobial stewardship.
Antimicrobial Stewardship
In the ICU, 30% to 60% of antibiotics either are not indicated and inappropriately broad or are inappropriately narrow.4 Hospital use and provider prescribing habits are of utmost importance in appropriate utilization of antimicrobials. The ICU is a prime place for pharmacists and providers to hone antimicrobial stewardship skills. Several ways to do so include knowing national guidelines and local resistance patterns, evaluating patient-specific factors, and shortening the time to diagnosis.5 Antimicrobial resistance varies from country to country as well as hospital to hospital. Given this, pharmacists should be aware of their local community and hospital antibiograms to help guide appropriate antimicrobial selection. Interestingly, when European and U.S. hospital-acquired pneumonia and ventilator-associated pneumonia guidelines are compared, differences in empirical antimicrobials can be seen owing to the differences in resistance patterns worldwide.6
When selecting appropriate antimicrobials, it is essential to evaluate patient-specific factors that may necessitate the need of broadened therapy. Pharmacists can utilize tools to their advantage to help determine risk factors for multidrug-resistant organisms. As such, the extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBLE) clinical risk score has been shown to decrease the use of carbapenem. The clinical scoring tool assesses for outpatient procedures within 1 month, prior infections or colonization with ESBLE within 12 months, and number of prior courses of β-lactams and/or fluoroquinolones used within 3 months. A score of ≥3 indicated high risk, providing a negative predictive value of 97%.7 This is just one of the clinical tools that can be employed to help ensure appropriate antimicrobial selection for empirical utilization. Other methods of improving antimicrobial stewardship lie in the use of shortening the time to diagnosis. Institutions frequently utilize rapid molecular tests. Within hours of a positive test result, molecular diagnostics, such as polymerase chain reaction, microarray technology, fluorescent in situ hybridization, or matrix-assisted laser desorption/ionization time of flight mass spectrometry, can identify an organism and test its susceptibility to an antibiotic by looking for known genetic resistant determinants, such as methicillin-resistant Staphylococcus aureus.8 As such, broad-spectrum antibiotics can be narrowed and altered appropriately based on these results, limiting the unnecessary use of antibiotics. Additionally, following national guidelines for when to utilize broad-spectrum antimicrobials, as well as limiting durations to appropriate lengths of time, may also help with antimicrobial resistance.
In addition to the above, pharmacists play a unique role in helping select the appropriate antimicrobial doses and administration modalities given their expertise in pharmacokinetic-pharmacodynamic properties. Pharmacists have the knowledge base to distinguish antimicrobials by their pharmacodynamic property, meaning the concentration or time-dependent killing mechanism. Knowing this allows for the appropriate determination of dosing for critically ill patients who might be volume-overloaded with increased volumes of distribution, poor renal function and thus clearance, and altered protein binding. Antibiotic dosing regimens for ICU patients derived from other patient groups are likely to be suboptimal, owing to the changes noted above.4 Additionally, critically ill patients may require organ support, such as extracorporeal membrane oxygenation or renal replacement therapy, which additionally alters the pharmacokinetic profile. In a retrospective study conducted at 64 hospitals worldwide, 16% did not achieve the appropriate pharmacokinetic profile, and these patients were 32% less likely to have a positive clinical outcome (odds ratio, 0.68; P = .009).9 Thus, a paradigm shift to more personalized antibiotic dosing in the critically ill patient is needed. The appropriate dosing of antimicrobials is paramount for antimicrobial stewardship, and pharmacists are primed for this role.
New Antimicrobials
Knowledge of newly approved antimicrobials and their place in therapy may help mitigate inappropriate use that could further perpetuate the development of antimicrobial resistance. Accordingly, it is important to keep abreast of the antimicrobial pipeline. Three antibiotics recently approved by the FDA include ceftobiprole, pivmecillinam, and sulbactam-durlobactam.
Ceftobiprole (brand-name Zevtera) is a fifth-generation cephalosporin that was approved by the FDA in April 2024 for the treatment of S aureus bloodstream (SAB) infections, including right-sided infective endocarditis, as well as acute bacterial skin and skin structure infections (ABSSSI) in adults. Ceftobiprole was also approved for the treatment of community-acquired bacterial pneumonia (CABP) in adults and pediatric patients aged 3 months and older.10 Its approval for SAB stems from a phase III, noninferiority randomized, controlled trial (RCT) where 387 patients were randomized to receive either ceftobiprole or daptomycin plus optional aztreonam.11 The primary endpoint for this study was overall treatment success—a composite of survival, clearance, symptom improvement, no related complications, and no receipt of other potentially effective antibiotics—at 70 days. Ceftobiprole was found to be noninferior to daptomycin with treatment success rates of 69.8% and 68.7%, respectively (95% CI, –7.1 to 11.1).11 For ABSSSI, it was evaluated in a noninferiority RCT in which 679 were randomized to receive ceftobiprole or vancomycin plus aztreonam.12 The primary endpoint of this study was early clinical response 48 to 72 hours after treatment initiation; ceftobiprole was found to be noninferior with an early clinical success rate of 91.3% compared with 88.1% in the vancomycin and aztreonam arm (95% CI, –1.2 to 7.8).12 For adults with CABP, ceftobiprole was studied in a noninferiority RCT of 706 patients who were randomized to receive either ceftobiprole or ceftriaxone plus optional linezolid.13 Clinical cure rates were assessed in 469 patients and were found to be noninferior—86.6% in the ceftobiprole arm and 87.4% in the comparator arm (95% CI, –6.9 to 5.3); microbiological eradication rates were noninferior as well with rates of 88.2% and 90.8%, respectively (95% CI, –9.3 to 3.6).13 FDA approval for use in pediatric patients was supported by a similar study in 138 patients aged 3 months to 18 years randomized to receive ceftobiprole compared with standard-of-care cephalosporin.14 There was not a significant difference in clinical response rates at Day 4 between ceftobiprole and the standard-of-care group at 95.7% and 93.2%, respectively (95% CI, –5.5 to 14.7).14
Pivmecillinam (brand-name Pivya) is a penicillin that was approved by the FDA in April 2024 for the treatment of adult female patients with uncomplicated urinary tract infections caused by susceptible isolates of Escherichia coli, Proteus mirabilis, and Staphylococcus saprophyticus based upon data from three RCTs.15,16 In the first RCT, three different dosing regimens of pivmecillinam were studied—185 mg three times daily for 7 days, 185 mg two times daily for 7 days, and 370 mg two times daily for 3 days—and compared with placebo.16 The composite endpoint of clinical cure and microbiological response was assessed between Days 8 and 10 and was achieved in 62% of patients in the intervention arms compared with 10% of the placebo arm (95% CI, 41 to 62).16 In the second RCT, pivmecillinam 185 mg three times daily for 3 days was compared with cephalexin 250 mg four times daily for 7 days. This study again looked at a composite outcome of clinical cure and microbiologic response, which was found to have no difference across the groups—72% of patients in the pivmecillinam arm as compared with 76% of patients in the cephalexin arm (95% CI, –16 to 7).16 In the last clinical trial, pivmecillinam 185 mg three times daily for 3 days was compared with ibuprofen 600 mg daily for 3 days, looking at the same aforementioned composite endpoint. Pivmecillinam composite response rate was 66% compared with 22% in the ibuprofen group, which was statistically significant (95% CI, 31 to 57).16 It is important to note that pivmecillinam carries a few warnings and precautions, including risk of hypersensitivity reactions, severe cutaneous adverse reactions, risk of carnitine depletion, and Clostridium difficile–associated diarrhea, and it may also interfere with certain newborn screening tests.16
Sulbactam-durlobactam (brand-name Xacduro) is a β-lactam/β-lactamase combination drug that was approved by the FDA in May 2023 for treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by Acinetobacter baumannii-calcoaceticus complex (ABC) in adults.17 The drug was evaluated in a phase III, noninferiority RCT in which 177 patients with carbapenem-resistant ABC were randomized to receive either sulbactam-durlobactam or colistin; patients in both arms also received concomitant imipenem-cilastatin.18 The primary outcome was 28-day all-cause mortality, which was found to be noninferior, occurring in 19% in the sulbactam-durlobactam group and 32% of the colistin group (95% CI, –30 to 3.5).18 From a safety standpoint, nephrotoxicity was lower in the sulbactam-durlobactam arm compared with colistin—13% versus 38%, respectively. The most common adverse effect reported with sulbactam-durlobactam was abnormal liver function tests, and it is important to note that the drug comes with warning and precautions, including hypersensitivity reactions and risk of C difficile–associated diarrhea.17
Role of the Pharmacist
Pharmacists play an integral role in the management of antimicrobials in all aspects of care. Pharmacists are primed to evaluate literature and make recommendations on antimicrobial selection, dosing, and duration. It is important for pharmacists to be aware of national guidelines, national and local resistance patterns, clinical diagnostic tools, and culture data. Additionally, pharmacists can discuss evidence-based medicine with regard to duration of therapy and risks for multidrug-resistant organisms. Antimicrobial stewardship in the community and hospital settings is of utmost importance for helping combat the antimicrobial resistance crisis.
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