Managing Multidrug-Resistant Organisms in ICU

 

Managing Multidrug-Resistant Organisms (MDROs) in ICU: Current Approaches

Dr Neeraj Manikath ,Claude.ai

Abstract

Multidrug-resistant organisms (MDROs) represent a significant challenge in intensive care units (ICUs) globally, contributing to increased morbidity, mortality, and healthcare costs. This review examines current strategies for managing MDROs in ICU settings, with particular focus on novel antimicrobial agents such as cefiderocol and ceftazidime-avibactam, as well as infection control bundles and environmental hygiene measures. We also discuss the role of surveillance systems, particularly the WHO Global Antimicrobial Resistance Surveillance System (GLASS), in monitoring and guiding responses to antimicrobial resistance. Evidence suggests that a multifaceted approach combining appropriate antimicrobial therapy, comprehensive infection control measures, and active surveillance is essential for effective MDRO management in critical care environments.

Keywords: multidrug-resistant organisms, intensive care unit, antimicrobial resistance, cefiderocol, ceftazidime-avibactam, infection control bundles, environmental hygiene, WHO GLASS

Introduction

Antimicrobial resistance (AMR) represents one of the most pressing challenges to global public health, with particular impact in intensive care units where vulnerable patients are exposed to multiple risk factors for acquiring multidrug-resistant organisms (MDROs).^1^ The World Health Organization has identified AMR as one of the top ten global public health threats facing humanity, with projections suggesting that by 2050, AMR could cause 10 million deaths annually if left unchecked.^2^

ICUs serve as epicenters for MDRO emergence and transmission due to several factors: high antimicrobial use, critically ill patients with compromised immune systems, frequent use of invasive devices, and close proximity of patients.^3^ Common MDROs encountered in ICUs include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum β-lactamase (ESBL)-producing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), multidrug-resistant Pseudomonas aeruginosa, and Acinetobacter baumannii.^4^

This review examines current approaches to managing MDROs in ICU settings, focusing on newer antimicrobial agents, infection control bundles, environmental hygiene strategies, and the role of surveillance systems in guiding clinicians and policymakers.

Novel Antimicrobial Agents

Cefiderocol

Cefiderocol represents a significant advancement in the fight against MDROs, particularly gram-negative pathogens. As a siderophore cephalosporin, cefiderocol employs a unique "Trojan horse" strategy to penetrate bacterial cells by binding to iron and utilizing bacterial iron transport systems to enhance cellular entry.^5^

Mechanism of Action and Spectrum of Activity

Cefiderocol binds to penicillin-binding proteins (PBPs), inhibiting cell wall synthesis. Its distinctive structure provides stability against various β-lactamases, including extended-spectrum β-lactamases, AmpC β-lactamases, and both serine and metallo-carbapenemases.^6^ Cefiderocol demonstrates potent activity against a broad spectrum of gram-negative pathogens, including carbapenem-resistant Enterobacterales, multidrug-resistant Pseudomonas aeruginosa, and Acinetobacter baumannii.^7^

Clinical Evidence in ICU Settings

The CREDIBLE-CR study evaluated cefiderocol versus best available therapy for serious infections caused by carbapenem-resistant gram-negative bacteria. In this study, clinical cure rates were comparable between cefiderocol and best available therapy (52.5% vs. 50.0%), though mortality was numerically higher in the cefiderocol arm.^8^ The APEKS-NP trial demonstrated non-inferiority of cefiderocol compared to meropenem for hospital-acquired pneumonia, including ventilator-associated pneumonia, with comparable clinical cure rates and safety profiles.^9^

Dosing Considerations in Critical Care

For patients with normal renal function, the standard dosage is 2g administered intravenously every 8 hours, with dose adjustments required for patients with renal impairment. Therapeutic drug monitoring may be beneficial in critically ill patients due to pharmacokinetic variability.^10^

Ceftazidime-Avibactam

Ceftazidime-avibactam combines a third-generation cephalosporin with a novel non-β-lactam β-lactamase inhibitor that extends its activity against many resistant gram-negative organisms.

Mechanism of Action and Spectrum of Activity

Avibactam is a diazabicyclooctane β-lactamase inhibitor that covalently binds to serine β-lactamases, including extended-spectrum β-lactamases (ESBLs), AmpC enzymes, and some carbapenemases (KPC). This combination effectively restores ceftazidime's activity against many resistant gram-negative bacteria.^11^ Ceftazidime-avibactam shows activity against most Enterobacterales, including ESBL and KPC carbapenemase producers, as well as P. aeruginosa, but has limited activity against Acinetobacter species and organisms producing metallo-β-lactamases (MBLs).^12^

Clinical Evidence in ICU Settings

The REPRISE trial demonstrated efficacy of ceftazidime-avibactam against ceftazidime-resistant Enterobacterales and P. aeruginosa infections, with clinical cure rates of 91% for ceftazidime-avibactam versus 71% for best available therapy.^13^ A meta-analysis of observational studies showed improved survival with ceftazidime-avibactam compared to colistin-based regimens for carbapenem-resistant Enterobacterales infections (OR 0.37, 95% CI 0.21-0.66).^14^

Dosing and Combination Strategies

The standard dose is 2.5g (2g ceftazidime + 0.5g avibactam) administered intravenously every 8 hours for patients with normal renal function, with dose adjustments for renal impairment. In severe infections caused by highly resistant pathogens, combination therapy may be considered, often with aminoglycosides or polymyxins.^15^

Other Promising Agents

Meropenem-Vaborbactam

This combination of carbapenem and boronic acid-based β-lactamase inhibitor demonstrates activity against KPC-producing Enterobacterales. The TANGO II trial showed superiority over best available therapy for CRE infections with higher clinical cure rates (65.6% vs. 33.3%) and lower nephrotoxicity.^16^

Imipenem-Relebactam

Combining imipenem with the novel β-lactamase inhibitor relebactam extends activity against many carbapenem-resistant gram-negative pathogens. Clinical trials have demonstrated non-inferiority to imipenem-cilastatin for hospital-acquired and ventilator-associated pneumonia.^17^

Plazomicin

This next-generation aminoglycoside was designed to overcome common aminoglycoside resistance mechanisms. The CARE trial demonstrated efficacy in carbapenem-resistant Enterobacterales infections, though limited by a small sample size.^18^

Infection Control Bundles

Definition and Components

Infection control bundles represent coordinated sets of evidence-based interventions that, when implemented together, achieve better outcomes than when implemented individually. These bundles typically include several key components:

1. Hand hygiene protocols: Implementation of the WHO's "Five Moments for Hand Hygiene" with regular compliance monitoring.^19^
2. Contact precautions: Including appropriate use of personal protective equipment (PPE) such as gloves and gowns.
3. Patient isolation or cohorting: Physical separation of MDRO-colonized or infected patients.
4. Active surveillance cultures: Targeted or universal screening to identify asymptomatic carriers.
5. Antimicrobial stewardship: Optimizing antimicrobial use through appropriate selection, dosing, and duration.
6. Healthcare worker education: Regular training on MDRO transmission and prevention.

Evidence of Effectiveness

Multiple studies have demonstrated the effectiveness of comprehensive infection control bundles in reducing MDRO transmission and infection rates in ICU settings. A systematic review by Tomczyk et al. found that multimodal interventions reduced the acquisition of MDROs by 37% in acute care settings.^20^

The REDUCE MRSA trial, a cluster-randomized study involving 43 hospitals, demonstrated that a bundle including universal decolonization reduced MRSA clinical isolates by 36.5% and bloodstream infections from any pathogen by 44%.^21^ Similarly, a quasi-experimental study in Greek ICUs demonstrated that implementation of a comprehensive bundle reduced carbapenem-resistant A. baumannii infections by 58% over a two-year period.^22^

Implementation Challenges

Despite proven effectiveness, implementation challenges include:

1. Resource constraints: Limited personnel, time, and financial resources.
2. Compliance issues: Difficulty maintaining sustained adherence to all bundle elements.
3. Cultural barriers: Resistance to changing established practices.
4. Monitoring burden: Challenges in measuring compliance and outcomes.

Strategies for Successful Implementation

Successful implementation strategies include:

1. Leadership engagement: Securing support from institutional leadership and clinical champions.
2. Multidisciplinary approach: Involving physicians, nurses, pharmacists, infection preventionists, and environmental services.
3. Regular feedback: Providing performance data to frontline staff.
4. Adaptation to local context: Tailoring interventions to specific institutional needs and resources.
5. Use of implementation science frameworks: Employing structured approaches to translate evidence into practice.^23^

Environmental Hygiene

Importance in MDRO Transmission

Environmental contamination plays a significant role in MDRO transmission within ICUs. Studies have demonstrated that pathogens can persist on environmental surfaces for extended periods, with C. difficile spores surviving for months, and MRSA and VRE surviving for days to weeks.^24^ Patients admitted to rooms previously occupied by MDRO-positive patients have a significantly higher risk of acquiring the same organism, highlighting the importance of effective terminal cleaning.^25^

Evidence-Based Cleaning and Disinfection Practices

Standard Cleaning Protocols

Evidence supports a systematic approach to environmental cleaning in ICUs:

1. Defined responsibility: Clear assignment of cleaning responsibilities for all environmental surfaces and equipment.
2. Appropriate product selection: Use of EPA-registered hospital-grade disinfectants with documented activity against relevant pathogens.
3. Correct application: Adherence to manufacturer recommendations for concentration, contact time, and application method.
4. Frequency: Increased cleaning frequency for high-touch surfaces.

Advanced Disinfection Technologies

Several technologies have emerged to supplement standard cleaning practices:

1. Ultraviolet (UV) light systems: UV-C devices have demonstrated efficacy in reducing environmental bioburden. A multicenter randomized trial showed that adding UV-C disinfection to standard terminal cleaning reduced acquisition of target MDROs by 30%.^26^

2. Hydrogen peroxide vapor/aerosolized hydrogen peroxide: These systems provide enhanced disinfection with studies demonstrating significant reductions in environmental contamination and some showing decreases in MDRO transmission rates.^27^

3. Continuously active disinfectants: Surfaces with persistent antimicrobial activity offer promise for maintaining cleanliness between cleaning cycles.^28^

Monitoring Cleaning Effectiveness

Several methods to evaluate cleaning effectiveness include:

1. Visual inspection: Limited sensitivity but provides immediate feedback.
2. Fluorescent markers: Allow objective assessment of cleaning thoroughness.
3. ATP bioluminescence: Measures organic material remaining on surfaces.
4. Microbial sampling: Direct assessment of microbial contamination through swabs or contact plates.

A multimodal approach incorporating education, feedback using objective monitoring tools, and defined cleaning protocols has been shown to improve cleaning effectiveness and reduce environmental contamination.^29^

WHO Global Antimicrobial Resistance Surveillance System (GLASS)

Overview and Objectives

The WHO Global Antimicrobial Resistance Surveillance System (GLASS), launched in 2015, represents the first global collaborative effort to standardize AMR surveillance. Its primary objectives include:

1. Fostering national AMR surveillance systems
2. Harmonizing global data collection, analysis, and sharing
3. Detecting emerging resistance trends and informing containment strategies
4. Supporting evidence-based policy development^30^

Structure and Implementation

GLASS employs a phased implementation approach focused on:

1. National coordination: Establishing National Coordinating Centers responsible for data collection and quality assurance.
2. Standardized methodologies: Promoting uniform laboratory techniques and interpretive criteria.
3. Priority pathogens: Initially focusing on key bacterial pathogens, with expansion to include fungi, viruses, and parasites.
4. Capacity building: Supporting laboratory infrastructure and training in resource-limited settings.

As of 2023, over 100 countries participate in GLASS, representing more than 70% of the world's population.^31^

Impact on ICU Practice

GLASS data directly impacts ICU practice through:

1. Informing empiric therapy guidelines: Local and regional resistance data guide appropriate initial antimicrobial selection.
2. Alerting to emerging threats: Early detection of novel resistance mechanisms allows proactive containment.
3. Resource allocation: Identification of high-priority pathogens directs infection control resources.
4. Research priorities: Surveillance data highlight knowledge gaps requiring investigation.

Integration with Clinical Decision Support

Integration of GLASS data with clinical decision support systems represents an evolving area with potential to optimize antimicrobial prescribing in ICUs. Studies have demonstrated that incorporating local antibiogram data into electronic prescribing systems can improve appropriate empiric therapy and reduce broad-spectrum antibiotic use.^32^

Practical Implementation Strategies

Multidisciplinary Antimicrobial Stewardship

Effective antimicrobial stewardship programs (ASPs) in ICUs require:

1. Multidisciplinary team: Including infectious disease physicians, clinical pharmacists, microbiologists, and ICU staff.
2. Prospective audit and feedback: Regular review of antimicrobial prescribing with direct feedback to prescribers.
3. Pre-authorization: Requiring approval for certain antimicrobials.
4. Institutional guidelines: Development of evidence-based treatment protocols incorporating local resistance data.
5. Education: Regular training on appropriate antimicrobial use.

A meta-analysis of ASP interventions in ICUs demonstrated reductions in antimicrobial consumption (reduction range: 11-38%) without adversely affecting patient outcomes.^33^

Risk Assessment and Stratification

Identifying high-risk patients allows targeted interventions:

1. Risk factors for MDRO colonization/infection: Previous MDRO history, recent hospitalization, antimicrobial exposure, presence of invasive devices, and comorbidities.
2. Risk-based screening: Focusing surveillance cultures on high-risk populations.
3. Preemptive isolation: Implementing contact precautions for high-risk patients pending screening results.

Staff Education and Engagement

Successful programs emphasize:

1. Regular training: Updated education on current MDRO epidemiology and prevention strategies.
2. Skills development: Hands-on training for proper PPE use and environmental cleaning.
3. Feedback mechanisms: Sharing performance data to motivate improvement.
4. Champion identification: Engaging influential clinicians to model and promote best practices.

Technology and Innovation

Emerging technologies support MDRO management:

1. Rapid diagnostic tests: Molecular methods allowing faster identification of MDROs and resistance determinants.
2. Electronic surveillance systems: Automated alerts for potential outbreaks or high-risk patients.
3. Automated hand hygiene monitoring: Systems providing real-time feedback on compliance.
4. Predictive analytics: Algorithms identifying patients at high risk for MDRO acquisition or infection.

Future Directions

Novel Therapeutic Approaches

Beyond traditional antimicrobials, emerging approaches include:

1. Bacteriophage therapy: Viruses that specifically target bacteria, including MDROs, with early clinical trials showing promise for difficult-to-treat infections.^34^
2. Monoclonal antibodies: Targeting specific bacterial virulence factors or toxins.
3. Microbiome-based interventions: Fecal microbiota transplantation and probiotics to prevent MDRO colonization.
4. Antimicrobial peptides: Natural and synthetic peptides with broad-spectrum activity against MDROs.
5. Anti-virulence strategies: Targeting bacterial virulence without selecting for resistance.

Emerging Surveillance Technologies

Advancements in surveillance include:

1. Whole genome sequencing: Providing detailed understanding of resistance mechanisms and transmission patterns.
2. Metagenomics: Analyzing complex microbial communities directly from clinical samples.
3. Machine learning algorithms: Predicting outbreaks and optimizing control measures.
4. Global data sharing platforms: Enhanced integration of surveillance data across institutions and countries.

Health System Approaches

Systemic changes to address MDROs include:

1. Value-based incentives: Financial models rewarding infection prevention success.
2. Regional collaboratives: Coordinated approaches across healthcare facilities.
3. One Health approach: Integrating human, animal, and environmental health strategies.
4. Global policy coordination: Harmonized international efforts to combat AMR.

Conclusion

Managing MDROs in ICU settings requires a comprehensive, multifaceted approach. Novel antimicrobials like cefiderocol and ceftazidime-avibactam provide valuable therapeutic options, but must be used judiciously within robust antimicrobial stewardship programs. Infection control bundles and environmental hygiene practices represent essential components of effective MDRO management strategies. The WHO GLASS program provides crucial surveillance data to guide local, national, and global responses.

Future success in combating MDROs will depend on continued innovation in therapeutics, diagnostics, and infection prevention, coupled with strong institutional commitment, interdisciplinary collaboration, and global coordination. By implementing evidence-based strategies and remaining vigilant for emerging threats, healthcare providers can optimize outcomes for critically ill patients while preserving antimicrobial efficacy for future generations.

References

1. Bassetti M, Peghin M, Vena A, Giacobbe DR. Treatment of infections due to MDR gram-negative bacteria. Front Med. 2019;6:74. doi:10.3389/fmed.2019.00074

2. World Health Organization. Global action plan on antimicrobial resistance. Geneva: WHO; 2015.

3. Timsit JF, Bassetti M, Cremer O, et al. Rationalizing antimicrobial therapy in the ICU: a narrative review. Intensive Care Med. 2019;45(2):172-189. doi:10.1007/s00134-019-05520-5

4. Tacconelli E, Carrara E, Savoldi A, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18(3):318-327. doi:10.1016/S1473-3099(17)30753-3

5. Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant gram-negative bacilli. Drugs. 2019;79(3):271-289. doi:10.1007/s40265-019-1055-2

6. Kazmierczak KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible gram-negative bacilli, including serine carbapenemase- and metallo-β-lactamase-producing isolates (SIDERO-WT-2014 Study). Int J Antimicrob Agents. 2019;53(2):177-184. doi:10.1016/j.ijantimicag.2018.10.007

7. Hackel MA, Tsuji M, Yamano Y, et al. In vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 Study). Antimicrob Agents Chemother. 2017;61(9):e00093-17. doi:10.1128/AAC.00093-17

8. Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021;21(2):226-240. doi:10.1016/S1473-3099(20)30796-9

9. Wunderink RG, Matsunaga Y, Ariyasu M, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021;21(2):213-225. doi:10.1016/S1473-3099(20)30731-3

10. Katsube T, Wajima T, Ishibashi T, et al. Pharmacokinetic/pharmacodynamic modeling and simulation of cefiderocol, a parenteral siderophore cephalosporin, for dose adjustment based on renal function. Antimicrob Agents Chemother. 2017;61(1):e01381-16. doi:10.1128/AAC.01381-16

11. Shirley M. Ceftazidime-avibactam: a review in the treatment of serious gram-negative bacterial infections. Drugs. 2018;78(6):675-692. doi:10.1007/s40265-018-0902-x

12. Lagacé-Wiens P, Walkty A, Karlowsky JA. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of gram-negative bacterial infections. Core Evid. 2014;9:13-25. doi:10.2147/CE.S40698

13. Carmeli Y, Armstrong J, Laud PJ, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016;16(6):661-673. doi:10.1016/S1473-3099(16)30004-4

14. Tumbarello M, Trecarichi EM, Corona A, et al. Efficacy of ceftazidime-avibactam salvage therapy in patients with infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Clin Infect Dis. 2019;68(3):355-364. doi:10.1093/cid/ciy492

15. Falcone M, Paterson D. Spotlight on ceftazidime/avibactam: a new option for MDR gram-negative infections. J Antimicrob Chemother. 2016;71(10):2713-2722. doi:10.1093/jac/dkw239

16. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect Dis Ther. 2018;7(4):439-455. doi:10.1007/s40121-018-0214-1

17. Motsch J, Murta de Oliveira C, Stus V, et al. RESTORE-IMI 1: a multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis. 2020;70(9):1799-1808. doi:10.1093/cid/ciz530

18. McKinnell JA, Dwyer JP, Talbot GH, et al. Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae. N Engl J Med. 2019;380(8):791-793. doi:10.1056/NEJMc1807634

19. World Health Organization. WHO guidelines on hand hygiene in health care. Geneva: WHO; 2009.

20. Tomczyk S, Zanichelli V, Grayson ML, et al. Control of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa in healthcare facilities: a systematic review and reanalysis of quasi-experimental studies. Clin Infect Dis. 2019;68(5):873-884. doi:10.1093/cid/ciy752

21. Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med. 2013;368(24):2255-2265. doi:10.1056/NEJMoa1207290

22. Kofteridis DP, Valachis A, Dimopoulou D, et al. Effectiveness of a bundle approach in preventing multidrug-resistant A. baumannii infections in intensive care units. Int J Antimicrob Agents. 2018;52(2):247-252. doi:10.1016/j.ijantimicag.2018.03.019

23. Davey P, Marwick CA, Scott CL, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2017;2(2):CD003543. doi:10.1002/14651858.CD003543.pub4

24. Weber DJ, Anderson D, Rutala WA. The role of the surface environment in healthcare-associated infections. Curr Opin Infect Dis. 2013;26(4):338-344. doi:10.1097/QCO.0b013e3283630f04

25. Mitchell BG, Dancer SJ, Anderson M, Dehn E. Risk of organism acquisition from prior room occupants: a systematic review and meta-analysis. J Hosp Infect. 2015;91(3):211-217. doi:10.1016/j.jhin.2015.08.005

26. Anderson DJ, Chen LF, Weber DJ, et al. Enhanced terminal room disinfection and acquisition and infection caused by multidrug-resistant organisms and Clostridium difficile (the Benefits of Enhanced Terminal Room Disinfection study): a cluster-randomised, multicentre, crossover study. Lancet. 2017;389(10071):805-814. doi:10.1016/S0140-6736(16)31588-4

27. Passaretti CL, Otter JA, Reich NG, et al. An evaluation of environmental decontamination with hydrogen peroxide vapor for reducing the risk of patient acquisition of multidrug-resistant organisms. Clin Infect Dis. 2013;56(1):27-35. doi:10.1093/cid/cis839

28. Rutala WA, Weber DJ. Best practices for disinfection of noncritical environmental surfaces and equipment in health care facilities: a bundle approach. Am J Infect Control. 2019;47S:A96-A105. doi:10.1016/j.ajic.2019.01.014

29. Carling PC, Bartley JM. Evaluating hygienic cleaning in health care settings: what you do not know can harm your patients. Am J Infect Control. 2010;38(5 Suppl 1):S41-50. doi:10.1016/j.ajic.2010.03.004

30. World Health Organization. Global antimicrobial resistance surveillance system (GLASS) report: early implementation 2017-2018. Geneva: WHO; 2019.

31. World Health Organization. Global antimicrobial resistance and use surveillance system (GLASS) report: 2022. Geneva: WHO; 2023.

32. Forrest GN, Van Schooneveld TC, Kullar R, et al. Use of electronic health records and clinical decision support systems for antimicrobial stewardship. Clin Infect Dis. 2014;59(suppl_3):S122-S133. doi:10.1093/cid/ciu565

33. Karanika S, Paudel S, Grigoras C, et al. Systematic review and meta-analysis of clinical and economic outcomes from the implementation of hospital-based antimicrobial stewardship programs. Antimicrob Agents Chemother. 2016;60(8):4840-4852. doi:10.1128/AAC.00825-16

34. Kortright KE, Chan BK, Koff JL, Turner PE. Phage therapy: a renewed approach to combat antibiotic-resistant bacteria. Cell Host Microbe. 2019;25(2):219-232. doi:10.1016/j.chom.2019.01.014