From Challenge to Cure: MBL-Producing, Carbapenem-Resistant Gram-Negative Bacterial Infections

Faculty

Teena Chopra, MD, MPH

Professor of Medicine, Division of Infectious Diseases
Wayne State University School of Medicine
Detroit, MI

Keith A. Rodvold, PharmD, FCCP, FIDSA

Distinguished Professor Emeritus
University of Illinois at Chicago
Colleges of Pharmacy and Medicine
Chicago, IL

Andrew Shorr, MD, MPH, MBA, MA

Head, Pulmonary and Critical Care
Director, Medical ICU
Professor of Medicine
MedStar Health Washington, DC

Activity Goal

The goal of this activity is to advance knowledge in the treatment of metallo-β-lactamase (MBL)-producing, carbapenem-resistant (CR) gram-negative bacterial infections (GNBIs), with specific reference to their epidemiology, resistance challenges, and approved treatment options, with comparative data to support clinical decision making.

Intended Audience

The primary intended audience for the activity includes infectious disease physicians, critical care specialists, pulmonologists, and PharmDs in these specialties. Secondary audiences include other health care professionals who may treat and monitor seriously ill patients with resistant infections, such as nurse practitioners, physician assistants, and microbiologists.

Learning Objectives

After completing this activity, participants should be better able to:

1. Describe current knowledge as to the epidemiology of MBL-producing, CR-GNBIs.
2. Review approved treatment options for CR-GNBIs.
3. Cite comparative in vitro and clinical data to support decision making for patients with CR-GNBIs.

Physician Accreditation Statement

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation

Global designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Accreditation Statement

Global is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education with Commendation.

Pharmacist Credit Designation

Global designates this continuing education activity for 1.0 contact hour (0.1 CEU) of the ACPE. (Universal Activity Number 0530-9999-24-027-H01-P)

This is an knowledge-based activity.

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Instructions for Obtaining Credit

To receive credit, participants must participate in the activity, complete and pass the post-test with a minimum score of 70%, and complete the evaluation. CME certificates will be sent via email to those successfully completing the activity.

System Requirements

PC

• 1.4 GHz Intel Pentium 4 or faster processor (or equivalent)
• Windows 10, 8.1 (32-bit/64-bit); Windows 7 (32-bit/64-bit) 512 MB of RAM (1 GB recommended)
• Google Chrome (v70.0 and above), Mozilla Firefox (v65.0 and above), and Edge (v42.0 and above)

Mac

• 1.83 GHz Intel Core Duo or faster processor 512 MB of RAM (1 GB recommended)
• MAC OS X 10.12 or higher
• Google Chrome (v70.0 and above), Apple Safari (v12.0 and above), and Mozilla Firefox (v65.0 and above)

Fee Information and Refund/Cancellation Policy

There is no fee for this educational activity.

Disclosures of Relevant Financial Relationships

Global adheres to the policies and guidelines, including the Standards for Integrity and Independence in Accredited CE, set forth to providers by the Accreditation Council for Continuing Medical Education (ACCME) and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scientifically rigorous. All persons in a position to control the content of an accredited continuing education program provided by Global are required to disclose all financial relationships with any ineligible company within the past 24 months to Global. All financial relationships reported are identified as relevant and mitigated by Global in accordance with the Standards for Integrity and Independence in Accredited CE in advance of delivery of the activity to learners. The content of this activity was vetted by Global to assure objectivity and that the activity is free of commercial bias. All relevant financial relationships have been mitigated.

The faculty have the following relevant financial relationships with ineligible companies:

• Consulting fees (eg, advisory boards): Cepheid, Ferring, Melinta, Pfizer, Shionogi
• Speakers’ bureaus: Cepheid, Ferring, Melinta

• Consulting fees (eg, advisory boards): BugWorks Research, Genentech, Micurx Pharmaceuticals, Omnix Medical Ltd, Pulmatrix, Qpex Biopharma, Shionogi, Spero Therapeutics, Venatorx Pharmaceuticals
• Speakers’ bureau: Shionogi
• Other (Independent Data Monitoring Committee): Janssen Pharmaceutica

• Consulting fees (eg, advisory boards): Merck, Pfizer
• Honoraria: Merck, Pfizer

The planners and managers have the following relevant financial relationships with ineligible companies:

The planners and managers at Global Education Group have no relevant financial relationships to disclose.

The planners and managers at ACE have no relevant financial relationships to disclose.

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global and ACE do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

This activity is jointly provided by Global Education Group and Applied Clinical Education.

This activity is supported by an educational grant from Shionogi Inc.

This activity is distributed by Pharmacy Practice News,
Infectious Disease Special Edition, and CMEZone.com.

Infections caused by metallo-β-lactamase (MBL)-producing, carbapenem-resistant (CR) gram-negative (GN) bacteria (GNB) pose a significant health threat due to the increasing prevalence of these pathogens and the limited treatment options available.^1-9 These pathogens are primarily found among Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.^9-16 Conventionally, carbapenems represent the gold standard treatment for multidrug-resistant (MDR) GNB infections (GNBIs); however, these agents are rendered ineffective by MBLs given their mechanism of resistance. More specifically, MBLs confer resistance to nearly all β-lactam antibiotics, including carbapenems. This occurs primarily via hydrolysis through zinc-dependent mechanisms.¹⁷ The spread of MBLs is facilitated by their presence on mobile genetic elements, which enables rapid dissemination among various bacterial pathogens and across different species of bacteria.^17,18 The increase in MBL GNB resistance has generally been driven by the escalating prevalence and complexity of a variety of β-lactamases and carbapenemases, such as those seen in Klebsiella pneumoniae.^9-16

The incidence of CR Enterobacterales (CRE) infections has risen in parallel and more than doubled between 2013 and 2020, with MBL-producing strains being major contributors.¹⁹ Infections caused by MBL-producing P. aeruginosa are also increasing and are particularly challenging due to their resistance to most β-lactams, including β-lactam–β-lactamase inhibitor (BLBI) combinations.²⁰ Co-production of other β-lactamases that hydrolyze aztreonam further limits treatment options.^{9,11,12,15,21,22} MBL GNBIs are also associated with high mortality rates, ranging from 30% to 50%, highlighting the urgent need for effective therapies.²³

The clinical presentation and severity of infections caused by MBL-producing CR-GNB varies widely, depending on the site of infection and the patient’s underlying health condition. Common examples of these infections include bloodstream infections (BSIs), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), complicated urinary tract infections (cUTIs), and complicated intraabdominal infections (cIAIs).²⁴ These infections are often associated with prolonged hospital stays, increased health care costs, and high mortality rates, particularly in critically ill patients.²⁴ The most clinically relevant MBLs include the New Delhi metallo-β-lactamase (NDM), Verona integron-encoded metallo-β-lactamase (VIM), and imipenemase (IMP) types.^24,25 Among these, NDM-producing Enterobacterales pose particular difficulties due to their global dissemination and poor clinical outcomes.²⁴

The diagnosis of infections with MBL-producing organisms represents a major challenge to their effective control and treatment. This is a particularly acute issue for clinical microbiology laboratories. Rapid detection of MBL-producing GNB is crucial for guiding early and appropriate treatment, as the mechanism of carbapenem resistance dictates the preferred therapeutic approach.²³ Various FDA-approved molecular platforms can identify clinically relevant MBLs and other important β-lactamases. Phenotypic testing methods are widely used, but they lack sensitivity and specificity; molecular methods, including polymerase chain reaction (PCR) and whole-genome sequencing, offer more accurate detection, but they are not universally available in all clinical settings.^23,24 Clinical guidelines recommend a combination approach, particularly for severe infections, until antibiotic-susceptibility testing results are available.²³

Treatment for MBL-producing GNBIs is as challenging as the identification of these pathogens. Cefiderocol, a siderophore cephalosporin, is the only recently approved antibiotic in the United States with demonstrated in vitro activity against these pathogens.⁸ Other antibiotics, such as polymyxins, fosfomycin, and tetracyclines, exhibit in vitro activity against MBL-producing GNB but may have suboptimal clinical efficacy. The combination of ceftazidime-avibactam with aztreonam is considered a “bridge” treatment strategy.^14,15,21,22 In this combination, ceftazidime-avibactam inhibits extended-spectrum β-lactamases (ESBLs) and K. pneumoniae carbapenemases (KPCs) often co-produced by MBL-producing GNB, allowing aztreonam to bind effectively to bacterial penicillin-binding proteins. Limited data suggest that the ceftazidime-avibactam-aztreonam combination is a potential treatment for patients with MBL-producing GNBIs.^{14,15,21,26-28} Several other therapeutics are also in clinical development.^8,23 In addition to antibiotic treatment, infection prevention and control measures, including active surveillance and antimicrobial stewardship programs, play vital roles in limiting the spread of highly resistant MBL-producing GNBIs.

This activity provides an overview of β-lactamases, focusing on the MBL variants, rapid diagnostic methods for detecting MBL-producing GNBIs, available treatment options for MBL-producing Enterobacterales and P. aeruginosa, and clinical treatment guideline recommendations. It also reviews supporting data for new agents in development with activity against MBL-producing Enterobacterales and P. aeruginosa.

β-lactam antibiotics are widely used to treat bacterial infections and account for 65% of all US prescriptions for injectable antibiotics.²⁹ Although these agents are well tolerated and efficacious, antimicrobial resistance has become a major public health concern. Resistance to penicillin was first detected in 1940, and resistance has emerged with each new generation of antibiotics, exacerbated by the advent of MDR pathogens.²³ Various mechanisms may cause β-lactam resistance, including efflux pump expression, mutations in penicillin-binding proteins, alterations to membrane permeability, and the production of β-lactamase enzymes.²³ Understanding β-lactamases is essential for clinicians to make informed decisions about antibiotic therapy and infection control.

Bacterial β-lactamases hydrolyze the β-lactam ring of antibiotics, rendering these agents ineffective. These enzymes are now widespread in many GNBs, particularly enteric and nonlactose fermenters, where they collectively confer resistance to β-lactam–containing antibiotics.² The presence of β-lactamases in GNB includes chromosomally encoded and transferable enzymes that migrate on mobile elements across different species.²⁹ Furthermore, their prevalence and complexity are continually increasing.

The 2 primary classes of bacterial β-lactamases differ structurally and mechanistically but serve the same purpose^1,2:

• MBLs use a zinc ion to activate the β-lactam toward nucleophilic attack by a hydroxide anion held between 2 zinc ions.
• Active-site serine β-lactamases (SBLs) use an active serine group as a nucleophile to attack the β-lactamase ring, forming a covalent intermediate that is subsequently hydrolyzed.

Two main classification systems are used for β-lactamases: molecular (Ambler) and functional (Bush-Jacoby-Medeiros; Figure 1).³⁰ In the more commonly used Ambler system, classification is based on the enzymes’ genetic amino acid sequences and mechanisms. β-lactamases in classes A, C, and D contain serine as the enzyme active site, and those in class B contain zinc. In the Bush-Jacoby-Medeiros classification, β-lactamases are categorized into 3 classes according to the β-lactam substrate degradation pattern and inhibitor effects.³⁰ Most MBLs identified in clinical isolates belong to subclass B1 and are named based primarily on where they were first described, with the 3 most common being NDM, VIM, and IMP.¹ The B1 subclass is the most clinically relevant, as the β-lactamase genes encoding subclass B1 MBLs are primarily plasmid-borne.¹

Figure 1. Ambler and Bush-Jacoby-Medeiros classifications.³⁰

Genes/enzymes: AmpC, CARB, CAU-1, FEZ-1, GOB-1, ImiS, IND-1, SFC-1, Sfh-I, SHV-38

AIM, Adelaide imipenemase; CHDL, carbapenem-hydrolyzing class D β-lactamase; CphA, carbapenem-hydrolyzing Aeromonas; CTX-M, cefotaximase; DIM, Dutch imipenemase; ESAC, extended-spectrum AmpC; ESBL, extended-spectrum β-lactamase; GES, Guiana extended-spectrum; GIM, German imipenemase; IMI, imipenem-hydrolyzing β-lactamase; IMP, imipenemase; KPC, Klebsiella pneumoniae carbapenemase; MBL, metallo-β-lactamase; NDM, New Delhi metallo-β-lactamase; NMC-A, non-metallo-carbapenemase-A; OXA, oxacillinase; PSE, penicillan-sensitive enzyme; Ser, serine; SIM, Seoul imipenemase; SME, Serratia marcescens enzyme; SPM, São Paulo metallo-β-lactamase; TEM, Temoniera; VIM, Verona integron-encoded metallo-β-lactamase.

Reproduced with permission. Open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0/

Carbapenemases are categorized as MBL Ambler class B or SBL functional A or D subgroups. They confer resistance to nearly all β-lactams, including penicillins, cephalosporins, and carbapenems; and are not inhibited by clavulanic acid, sulbactam, tazobactam, avibactam, penicillanic acid sulfones, or diazabicyclooctanes.^1,23 Enterobacterales and P. aeruginosa MBLs are associated with extremely drug-resistant (XDR) phenotypes, often including resistance to multiple aminoglycosides, fluoroquinolones, other agents, and β-lactams.¹

MBLs can also be broadly viewed as those that are chromosomal in nature and those that are due to plasmid-associated enzymes. Chromosomally encoded MBL genes are typically derived from environmental organisms, whereas acquired MBLs are carried on mobile genetic elements that facilitate their dissemination (Table 1).^2,9,32-39 Acquired MBLs in GNB include cfiA, IMP, VIM, São Paulo MBL (SPM), and German IMP. The IMP group includes more than 85 variants, and the VIM-type MBLs include more than 69.¹ Co-expression of MBL and ESBL genes, such as bla_TEM, bla_SHV, and bla_OXA, has been reported, complicating the resistance profiles of these bacteria.⁴⁰

MBL enzymes are encountered worldwide, with considerable regional variance. Initially confined to health care settings, these pathogens have increasingly been identified in community-acquired infections, raising concerns about their potential for widespread dissemination.

The greatest burden lies in South and Southeast Asia, where NDM types are most prevalent (Figure 2).¹ Bacteria with IMP, VIM, and NDM enzymes have been identified in various community, health care, and environmental settings in these regions. Indeed, retrospective analyses by the SENTRY Antimicrobial Surveillance Program suggest that bla_NDM-1 was circulating in India as early as 2006 and that this enzyme has since become endemic and co-expressed with other carbapenemases.^1,41-43 Transmission of β-lactamase-producing bacterial pathogens depends on multiple factors, including geographic location, population density, hygiene, and antibiotic use.²

Figure 2. Global distribution of acquired MBLs.¹

Full-tone color is used when the indicated MBL is the most prevalent in the country; lighter tone is used to indicate the most prevalent MBL in countries where serine carbapenemases (KPC or OXA-48-like) are more prevalent.

IMP, imipenemase; KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; MBL, metallo-β-lactamase; OXA, oxacillinase; SPM, São Paulo metallo-β-lactamase; VIM, Verona imipenemase.

Used with permission of American Society for Microbiology – Journals, from Boyd SE, Livermore DM, Hooper DC, Hope WW. Metallo-β-lactamases: structure, function, epidemiology, treatment options, and the development pipeline. Antimicrob Agents Chemother. 2020;64(10):e00397-20. Permission conveyed through Copyright Clearance Center, Inc.

In North America, MBLs have remained uncommon, although cases involving VIM, IMP, and NDM have been reported with increasing prevalence since 2010.¹ The Antibiotic Resistance Laboratory Ne2rk, initiated by the Centers for Disease Control and Prevention characterizes clinical isolates of CR Enterobacterales, CR P. aeruginosa and CR A. baumannii and conducts colonization screens to detect the presence of mobile carbapenemase genes in North America.⁴⁴ What the future holds for region regarding the spread of MBLs is unclear. Hence vigilance is required.

In Europe, KPC predominates in Mediterranean countries, whereas NDM producers are most common in Romania, Poland, and Denmark; this is assumed to be caused by inter-regional spread (epidemiologic stage 4).⁴³ VIM is the predominant MBL in Spain, Italy, and Hungary, also associated with inter-regional spread. Data published by the European Centre for Disease Prevention and Control’s European Survey of Carbapenemase-Producing Enterobacteriaceae project in 2017 showed that SBLs were more prevalent than MBLs in most countries.¹

MBLs in Meropenem-Resistant Enterobacterales Isolates

The global ATLAS (Antimicrobial Testing Leadership and Surveillance) program estimated the frequency of resistance determinants in Enterobacterales isolates (N=39,368) collected in 2018 and 2019.⁴⁵ Its report showed that 5.7% of all isolates were meropenem-nonsusceptible (MEM-NS) Enterobacterales, 36.7% of the 2228 identified carbapenem resistance mechanisms were MBLs, and the proportions of KPC or oxacillinase (OXA)-48–like β-lactamases were both approximately 25% (Figure 3).⁴⁵ Most of the identified MBL genes encoded NDM variants (88.4%), whereas 11.1% and 0.5% encoded VIM and IMP variants, respectively. However, considerable variation among regions was observed, with the proportion of MEM-NS isolates ranging from 1.9% (North America) to 8.4% (Asia/Pacific), and the majority were KPC (71.5%).⁴⁵

Figure 3. Proportion of carbapenem-resistant mechanisms identified.⁴⁵

GES, Guiania extended-spectrum β-lactamase; IMP, imipenemase; KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; OXA, oxacillinase; VIM, Verona imipenemase.

Reproduced with permission. Open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0/

Rapid Diagnostics and Antimicrobial Stewardship

Optimal treatment for CRE infections generally and for MBLs varies considerably, depending on the precise resistance mechanism. Importantly, conventional phenotypic susceptibility testing cannot determine underlying resistance mechanisms, underscoring the need to rapidly detect MBL production in the causative pathogen.²³ Several molecular platforms are commercially available to identify MBLs and other important SBLs (Table 2).²³ Put simply, one cannot look at a general susceptibility report from the microbiology lab and determine what mechanisms of resistance may be presented in a CR organism.

Early detection of MBL-producing bacteria allows for the timely initiation of appropriate antimicrobial therapy, avoiding the use of ineffective β-lactam antibiotics.²³ This targeted approach can significantly improve outcomes, particularly in critically ill patients. Indeed, rapid diagnostics involving organism identification and genotypic resistance mechanism detection have been shown to decrease mortality in GN BSIs, as have the coordinated efforts of antimicrobial stewardship teams.^23,46 A systematic review and meta-analysis demonstrated that mortality rates fell with molecular rapid diagnostic testing vs conventional BSI testing (odds ratio [OR], 0.66).⁴⁶ Stratified analysis revealed a significantly lower mortality risk when rapid testing was used with antimicrobial stewardship programs (OR, 0.64) but not without such support (OR, 0.72). In addition, time to effective therapy decreased by a weighted mean difference of 5.03 hours with molecular rapid diagnostic testing, and hospital length of stay decreased by 2.48 days.

Timely identification of MBL-producing pathogens enables health care facilities to implement timely infection control, antimicrobial stewardship, and epidemiological surveillance measures to prevent the spread of these highly resistant bacteria within the hospital environment.^23,47,48 Awareness of the presence of MBL enzymes helps clinicians make informed decisions about antibiotic use, support antimicrobial stewardship efforts by reducing unnecessary broad-spectrum antibiotic use, and preserve the effectiveness of last-line antibiotics.^46-48 Timely MBL detection also aids in tracking the prevalence and spread of MBL-producing organisms, which is essential for public health interventions and policymaking.⁴⁸

Molecular and Biochemical Assays

Available methods for detecting MBLs can be categorized into molecular and biochemical assays. Several molecular platforms can identify multiple bacterial species and corresponding resistance mechanisms.²³ These assays allow for direct testing of blood cultures or respiratory samples and can detect polymicrobial infections and resistance markers. Biochemical assays can detect the presence of carbapenemases, but these are intended for infection control purposes, not treatment guidance.²³

Phenotypic Carbapenemase Detection Assays

Rapid confirmation and differentiation of carbapenemase production are crucial for initiating early effective therapy for CR-GNBIs. Recently, an algorithm was developed to guide laboratory-based screening of CR P. aeruginosa, which can guide antimicrobial stewardship efforts and improve the selection of appropriate therapy (Figure 4).⁴⁷

Figure 4. Testing algorithm for CR Pseudomonas aerginosa.⁴⁷

CR, carbapenem-resistant; eCIM, EDTA-modified carbapenem inactivation method; EDTA, ethylenediaminetetraacetic acid; IMP, imipenemase; KPC, Klebsiella pneumoniae carbapenemase; mCIM, modified carbapenem-inactivated method; NDM, New Delhi metallo-β-lactamase; PCR, polymerase chain reaction; VIM, Verona imipenemase.

Reproduced with permission. Open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0/

A recent study evaluated the accuracy of 11 phenotypic assays for detecting carbapenemase-producing glucose-nonfermenting GN bacilli.⁴⁹ Among 96 CR isolates, 29% produced carbapenemases, with 86% of carbapenemase-producing P. aeruginosa isolates producing class B MBLs, primarily VIM and IMP carbapenemases. Several assays, including all rapid chromogenic assays and the modified carbapenem-inactivation method, had 90% sensitivity for detecting carbapenemase-producing P. aeruginosa, and most tests had 90% specificity (except the Manual Blue Carba assay, Modified Carba NP assay, boronic acid synergy test, and metallo-β-lactamase Etest). Conversely, most tests performed poorly for A. baumannii isolates; although several achieved 90% specificity, none achieved a sensitivity of greater than 90%. Furthermore, some assays were inefficient at identifying MBLs (eg, the Manual Carba NP CLSI; MBL Etest; modified Hodge test; and carbapenem-inactivation method).⁴⁹

A multicenter study evaluated a qualitative PCR assay (Cepheid Xpert Carba-R) designed to rapidly detect carbapenem resistance genes, including bla_KPC, bla_VIM, bla_NDM, and bla_IMP.⁵⁰ Compared with reference methods, the overall sensitivity was 100% for isolates grown on both blood and MacConkey agars, and overall specificity was 97.1% to 98.1%.⁵⁰

Immunochromatographic assays can detect MBL enzymes rapidly, and they are simple to perform and interpret, making them suitable for point-of-care use. A study evaluating recombinase-aided amplification directly on clinical samples demonstrated rapid detection of the NDM gene in a single one-step reaction that was comparable to standard PCR.⁴⁸

Clinical Guideline Recommendations for MBL Detection

Clinical guideline recommendations for the diagnosis and management of infections caused by MDR GN bacilli have been issued by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID; endorsed by the European Society of Intensive Care Medicine) and the Infectious Diseases Society of America (IDSA).^51,52 The IDSA guidelines on antimicrobial-resistant infections do not explicitly outline methods for MBL detection; however, they emphasize the importance of accurate and timely identification of resistance mechanisms, including MBLs, to guide appropriate antibiotic therapy.⁵² The ESCMID guidelines provide more detailed recommendations on the laboratory detection of carbapenemases, including MBLs.⁵¹ ESCMID recommends using phenotypic methods, such as combination disk tests, for initial screening of MBL production and molecular methods, such as PCR-based techniques or whole-genome sequencing, to confirm MBL genes. The guidelines also recommend using rapid molecular or immunochromatographic tests to detect carbapenemases, including MBLs, in clinical settings where quick results are needed.⁵¹

Conventional treatment options for CR-GNB are limited to antibiotics, such as colistin and tigecycline, often used in combination with other agents. However, these agents have many limitations ranging from tolerability and toxicity issues to the promotion of future resistance. Historically, colistin, a polymyxin antibiotic, was the gold standard for CR-GNB treatment, but this agent is associated with significant nephrotoxicity and neurotoxicity. Tigecycline, conventionally used for various MDR infections, has limitations in treating BSIs due to its low serum concentration and poor lung penetration.⁵³

The following section reviews current treatment options for MBL-producing CR-GNBIs, focusing on newer monotherapies and key clinical trial data. Table 3 summarizes key antimicrobial susceptibility data of different CR Enterobacterales for current CR-GNBI treatment options.⁵⁴

Cefiderocol

Cefiderocol is the first siderophore-conjugated cephalosporin approved for adults with cUTIs (including pyelonephritis), HAP, and VAP caused by susceptible GNB.⁵⁵ It exhibits activity against various GNB, including CR isolates, and is stable against certain carbapenemases, including MBLs such as IMP, VIM, and NDM.^56-58 Cefiderocol binds to extracellular free iron and uses bacterial active iron transport channels to penetrate outer cell membranes, allowing it to overcome many GNB resistance mechanisms (Figure 5).^59,60 Furthermore, its side-chain properties confer stability against hydrolysis by various β-lactamases, including SBLs and MBLs.

Figure 5. Mechanism action for cefiderocol.⁶⁰

Fe, ferrum.

Reproduced with permission. Open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. http://creativecommons.org/licenses/by/4.0/

Cefiderocol antibacterial activity was recently evaluated in vitro in 452 MBL-producing strains, including Enterobacterales, P. aeruginosa, and A. baumannii.⁵⁷ Among MBL-producing Enterobacterales, 91.5% had cefiderocol MIC values ≤4 mg/L according to the Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoint, and 67.5% had MIC values ≤2 mg/L according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility breakpoint. Among MBL-producing P. aeruginosa, 100% had cefiderocol MIC values ≤4 mg/L (CLSI susceptibility breakpoint), and 97.4% had cefiderocol MIC values ≤2 mg/L (EUCAST susceptibility breakpoint). For A. baumannii complex, MIC values were ≤4 mg/L for 60% of MBL-producing strains and ≤2 mg/L for 44%. For all MBL-producing strains, MIC distribution curves for cefiderocol were in the lowest numerical values vs other β-lactams, BLBLI combinations, and ciprofloxacin.⁵⁷

Another study evaluated cefiderocol activity and synergy of BLBI-based combinations against Enterobacterales and MEM-NS P. aeruginosa, including MBL-producers.⁶¹ It showed that among MBL-producers, cefiderocol in combination with ceftazidime-avibactam showed a synergy rate of 20%, and VIM-producing isolates were almost all susceptible to cefiderocol. Other preclinical data have demonstrated the in vitro activity of cefiderocol against A. baumannii complex and Stenotrophomonas maltophilia, with 96% to 99% susceptibility against clinical isolates in vitro.⁶²

Clinical Data for Cefiderocol

Approval of cefiderocol for cUTIs was based on a study demonstrating superior efficacy in clinical response (73%) compared with imipenem-cilastatin (55%) and microbiological eradication in hospitalized adults.^55,63 Approval in HAP/VAP was based on the APEKS-NP trial, which showed noninferiority in all-cause mortality at day 14 vs meropenem in hospitalized adults (12.4% vs 11.6% for meropenem).^55,64 Other recent data emerged from the CREDIBLE-CR study, in which cefiderocol performed similarly to BAT in a heterogeneous patient cohort with infections caused by CR-GNB—most frequently A. baumannii, K. pneumoniae, and Pseudomonas spp.⁶⁵

Together, APEKS-NP and CREDIBLE-CR included 34 patients with infections caused by MBLs (11 and 23, respectively).²⁵ Overall, in this subpopulation vs the comparators, cefiderocol was associated with higher rates of clinical cure and microbiological eradication at the end of therapy, as well as lower day-28 mortality (Figure 6; 70.8% [n=17/24] vs 40% [n=4/10] for a clinical cure; 58.3% [n=14/24] vs 30% [n=3/10] for eradication; and 12.5% [n=3/24] vs 50% [n=5/10] for mortality).^19,25 Clinical cure rates were higher for non-NDM vs NDM infections (100% [n=8/8] vs 56.2% [n=9/16]).¹⁹ Furthermore, cefiderocol demonstrated superiority in clinical cure and microbiological eradication for isolates containing OXA-48 carbapenemases (n=10).⁶⁶ Despite the small number of patients, the authors concluded that “the clinical and microbiological outcomes were consistent with the studies’ overall findings of efficacy against Enterobacterales.”⁶⁶

Figure 6. Clinical cure, microbiological eradication, and all-cause mortality at day 28 in infections caused by MBL-producing bacteria in the CREDIBLE-CR and APEKS-NP phase 3 studies.²⁵

ACM, all-cause mortality; EOT, end of treatment; MBL, metallo-β-lactamase; TOC, test of cure.

Real-World Data for Cefiderocol

Several real-world studies corroborate the efficacy of cefiderocol in a range of organisms. PROVE, an ongoing retrospective study reported clinical cure rates in several of the most difficult-to-treat populations treated with cefiderocol.⁶⁷ Interim results showed cefiderocol achieved clinical cure in 65% of critically ill patients with P. aeruginosa infections, with 81% survival at 30 days. In patients with A. baumannii infections, cefiderocol treatment achieved clinical cure in 60% of cases, with 76% survival at 30 days.⁶⁷

A cohort analysis in intensive care unit (ICU) patients with P. aeruginosa (55.7%) and A. baumannii (25.7%) respiratory tract infections reported similar outcomes for cefiderocol monotherapy and combination regimens, with 30-day mortality rates of 20% and 28.6%, respectively.⁶⁸ A prospective study of cefiderocol treatment in 10 patients, mostly with VAP and bacteremia caused by MDR or XDR P. aeruginosa, demonstrated clinical and microbiological cures in 90% and 80% of patients, respectively, with a 90-day mortality rate of 50%.⁶⁹

The SENTRY program monitors predominant bacterial pathogens and antimicrobial resistance patterns at more than 200 medical centers in 45 countries. A recent report highlights a continuous rise in MDR-GNBIs, including CR isolates, emphasizing the need for effective treatments.⁷⁰ Importantly, a study analyzing cefiderocol efficacy against GN clinical isolates as part of the SENTRY program indicated cefiderocol potential against serious infections by GN organisms, demonstrating high susceptibility rates among Enterobacterales, P. aeruginosa, Acinetobacter spp, and S. Maltophilia, including CRE, XDR, and BLBI-resistant isolates.⁷¹

Plazomicin

Plazomicin, an aminoglycoside, was approved in 2018 for adults with cUTIs, including pyelonephritis, caused by Escherichia coli, K. pneumoniae, E. cloacae, and Proteus mirabilis.^72,73 It is recommended for patients with limited or no alternative treatment options due to its activity against aminoglycoside-modifying enzymes and significant in vitro activity against MDR Enterobacteriaceae, including aminoglycoside-resistant isolates.⁷³

A phase 3 open-label study (CARE) evaluated the efficacy and safety of plazomicin vs colistin in combination therapy regimens for serious CR-GNBIs.⁷⁴ The primary end point, a composite of death from any cause at 28 days or clinically significant disease-related complications, occurred in 24% and 50% of patients treated with plazomicin and colistin, respectively. In a phase 3 study (EPIC) comparing plazomicin vs meropenem in patients with CR cUTIs, plazomicin demonstrated a composite cure rate of 81.7% vs 70.1% with meropenem at 15 to 19 days.⁷⁵ However, none of the patients in this study had an MBL infection.

That said, plazomicin effectiveness against MBL-producing Enterobacterales is compromised due to 16S rRNA methylation by methylating enzymes. These enzymes, frequently located on transferable plasmids, have been increasingly reported among aminoglycoside-resistant clinical isolates, particularly Enterobacterales-producing NDM and A. baumannii. Isolates with 16S-RMTases show high minimal inhibitory concentration (MIC) values to all legacy aminoglycosides and plazomicin.⁷⁶

The CR-GNBI treatment landscape continuously evolves with emerging therapies and combinations. Several of these are described below and in Table 4.^5,26,77-94

Ceftazidime-Avibactam

Ceftazidime-avibactam combines an extended-spectrum anti-pseudomonal cephalosporin with a BLBI. It is effective against a broad range of MBL-producing Enterobacteriaceae, including KPC-producing isolates. A phase 3 study (REPRISE) compared ceftazidime-avibactam to BAT in patients with ceftazidime-resistant Enterobacteriaceae and P. aeruginosa infections.⁷⁷ It showed similar overall clinical cure rates for ceftazidime-avibactam and BAT (90.9% and 91.2%, respectively). In a prospective observational study (CRACKLE) involving patients with CRE infections, ceftazidime-avibactam treatment was associated with improved survival vs colistin, with 30-day mortality rates of 9% and 32%, respectively.⁷⁸ Of note, however, this combination has no intrinsic activity against MBLs.

Ceftazidime-Avibactam-Aztreonam

Because many MBL-producing GNs co-express ESBLs, ceftazidime is also given in combination with avibactam and aztreonam. In a prospective study in patients with BSIs mostly due to MBL-producing Enterobacterales, combination treatment with ceftazidime-avibactam-aztreonam was associated with lower 30-day mortality (19.2% vs 44%), lower rates of clinical failure at day 14, and shorter length of stay than other active antibiotics.²⁶ A retrospective study of this combination in 24 patients with P. aeruginosa and MBL VIM-type-producing Enterobacterales infections reported a 30-day mortality of 17% and a 14-day clinical failure rate of 8% (18% and 9% in patients with bacteremia).⁷⁹ A meta-analysis evaluating ceftazidime-avibactam-aztreonam vs polymyxins in patients with BSIs caused by MBL-CRE found a pooled risk ratio for 30-day mortality of 0.51 (P<0.001).⁹⁵

A real-world cohort study in 27 hospitalized patients with severe infections caused by GNB with difficult-to-treat resistance (DTR), ceftazidime-avibactam-aztreonam was primarily used for NDM-producing Enterobacterales, with a 33% probability of infection-free survival.⁷⁸ In comparison, cefiderocol and imipenem-cilastatin-relebactam regimens were primarily used for DTR–nonfermenting infections and were associated with 48% and 67% probabilities of infection-free survival, respectively. In another real-world study, the triple combination achieved clinical success in 6 of 10 patients with K. pneumoniae HUB-ST147 infections caused by an XDR strain producing NDM-1/OXA-48/CTX-M-15, although 2 patients had recurrence within 90days.⁷⁹ Case reports have also described successful treatment of MBL-producing infections with this combination.^15,27

Aztreonam-Avibactam

A single-product formulation of aztreonam-avibactam is in clinical development to streamline the ceftazidime-avibactam-aztreonam combination.²³ The European Medicines Agency recently approved aztreonam-avibactam treatment for various indications, including cIAIs, cUTIs, HAP, and infections caused by aerobic GN bacteria, for which treatment options are limited.⁹⁶

Two phase 3 clinical trials (REVISIT and ASSEMBLE) evaluated aztreonam-avibactam combination treatment for treating serious bacterial infections caused by GNB, including MBLs.^97,82,83 In REVISIT, aztreonam-avibactam ± metronidazole demonstrated cure rates of 76.4% for cIAIs and 45.9% for HAP and VAP, which were noninferior to meropenem-colistin (74% and 41.7% for cIAIs and HAP/VAP, respectively).⁸² In ASSEMBLE, which compared the aztreonam-avibactam combination with BAT in hospitalized adults with infections due to MBLs, reported cure rates were 42% and 0%, respectively.⁸³ However, this trial was terminated due to recruitment challenges.

Cefepime-Taniborbactam

Cefepime-taniborbactam is an investigational combination inhibiting β-lactamase with activity against Enterobacterales spp and P. aeruginosa expressing SBLs and MBLs. In vitro studies demonstrate potent activity against a wide range of resistant phenotypes, including MBL-positive isolates.⁸⁴ A phase 3 trial in patients with cUTIs, including acute pyelonephritis, demonstrated the superiority of cefepime-taniborbactam to meropenem, with similar safety profiles.⁸⁵ However, the FDA issued a Complete Response Letter regarding the New Drug Application for cefepime-taniborbactam in February 2024, requesting additional data on chemistry, manufacturing, controls, testing methods, and manufacturing process.⁸⁶

Cefepime-Zidebactam (WCK 5222)

Zidebactam is a novel β-lactamase inhibitor currently under clinical investigation in combination with cefepime for treating CR and MDR GN infections. Pharmacokinetic/pharmacodynamic studies have shown potent activity against CR Enterobacterales and MDR-producing P. aeruginosa, including MBL-positive isolates.⁵ Cefepime-zidebactam is currently in phase 3 clinical investigation for treating cUTIs or acute pyelonephritis.

Clinical guideline recommendations for the treatment of infections caused by MDR GN bacilli, as issued by ESCMID and IDSA, are summarized in Table 5.^51,52 Both guidelines recommend cefiderocol as the preferred treatment for MBL infections or ceftazidime-avibactam-aztreonam for some MBL-producing organisms.^51,52 The main difference between the recommendations is that IDSA offers guidance on P. aeruginosa isolates that are MBL-producing and includes when treatment for MBLs should be considered before confirmation testing.

MBL-producing Enterobacterales represent an urgent public health threat that remains a challenge worldwide due to high rates of morbidity and mortality. Rapid diagnostic tests are important to detect MBLs and guide timely and optimal treatment initiation, and numerous FDA-approved platforms are now available. Cefiderocol, a siderophore cephalosporin, is currently the only FDA-approved agent for treating infections caused by MBL-producing CR pathogens. Cefiderocol is stable against hydrolysis by IMP, VIM, and NDM MBLs. Guideline recommendations and clinical data support cefiderocol as a preferred treatment for MBL infections or ceftazidime-avibactam in combination with aztreonam for some MBL-producing organisms. In addition, emerging therapeutics are in clinical development to expand treatment options for MBL-producing Enterobacterales to improve patient outcomes. Antimicrobial stewardship remains essential in preserving the effectiveness of current and emerging therapies and mitigating further resistance development.

Case 1

Roger is a critically ill 62-year-old man in the ICU with VAP and sepsis. He was initially treated with broad-spectrum agents, including ceftolozane-tazobactam. He failed to respond, and subsequent cultures from a lower airway sample revealed XDR/DTR P. aeruginosa. Because of the resistance pattern seen from cultures, cefiderocol was administered in a 3-hour IV infusion at a standard dose of 2 g every 8 hours diluted in 100 mL of normal saline solution. The patient clinically improved and was eventually liberated from the ventilator.

Case 2

Felicia is a 50-year-old woman who developed a catheter-related infection while in the ICU. Despite removal of the catheter, the infection was difficult to eradicate, as it was caused by K. pneumoniae. The isolate was found to produce Oxa48 and NDM-1 carbapenemases. It was susceptible only to amikacin and colistin. Previous treatment regimens included meropenem and amikacin. After the bacteremia failed to clear, and considering the microbiology findings, the patient was switched to a combination of ceftazidime-avibactam (2–0.5 g 3 times daily) and aztreonam (2 g 3 times daily) for 10 days, administered in that order. Blood cultures eventually cleared.