What are examples of concerns regarding Multi-Drug Resistant (MDR) and Extensively Drug-Resistant (XDR) Enterobacterales?

From the Guidelines

Major concerns regarding multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacterales include their limited treatment options, high mortality rates, and rapid spread in healthcare settings, as highlighted by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines 1. These concerns are multifaceted, involving:

• Limited treatment options due to resistance to multiple antibiotic classes, leaving only toxic or newer agents as potential treatments
• High mortality rates, with attributable deaths ranging from 1.5 for MDR Pseudomonas aeruginosa to 6.2 for carbapenem-resistant (CR) Klebsiella pneumoniae, as reported by the European Center of Disease and Control (ECDC) 1
• Rapid spread in healthcare settings through contaminated equipment, healthcare worker hands, and patient-to-patient transmission
• Economic burden due to prolonged hospitalizations, expensive antibiotics, isolation requirements, and increased mortality
• Ability to silently colonize patients without symptoms, creating reservoirs for transmission, and transfer resistance genes horizontally to other bacteria, further complicating control efforts The ESCMID guidelines emphasize the need for antimicrobial stewardship, strict infection control practices, surveillance, and development of new antimicrobial agents to address these concerns 1. Key considerations in managing MDR and XDR Enterobacterales infections include:
• Parsimonious use of available antibiotics to prevent further development of resistance
• Use of newly developed antibiotics with activity against MDR-GNB, such as those approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) since 2017 1
• Implementation of evidence-based guidelines for treatment of infections caused by MDR-GNB in hospitalized patients, as recommended by the ESCMID guidelines 1

From the FDA Drug Label

As with other antibacterial drugs, prolonged use of FORTAZ may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Resistance to ceftazidime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability. Prescribing Imipenem and Cilastatin for Injection (I.V.) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Concerns regarding MDR XDR Enterobacterales:

• Development of resistance through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability 2
• Overgrowth of nonsusceptible organisms with prolonged use of antibacterial drugs 2
• Increased risk of development of drug-resistant bacteria with unnecessary use of antibacterial drugs 2, 3
• Potential for superinfection with prolonged therapy 2, 3

From the Research

Concerns Regarding MDR and XDR Enterobacterales

• The increasing global threat of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae, including carbapenem-resistant Enterobacterales (CRE), poses significant challenges to public health due to limited antibiotic choices and high case-fatality rates 4, 5.
• The production of extended-spectrum β-lactamases (ESBLs) and carbapenemases by MDR Enterobacteriaceae contributes to the development of resistance, making treatment difficult 4, 6.
• The emergence of polymyxin-resistant strains, including Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii, is a serious concern, as these pathogens are resistant to almost all available antibacterial drugs 7.

Treatment Challenges and Options

• Carbapenem-sparing strategies should be considered to avoid the selection of carbapenemase-producing Enterobacteriaceae, and combination therapy may be preferred over monotherapy for CRE 4, 5.
• Meropenem-vaborbactam (MV) presents a promising therapeutic option for treating CRE infections, demonstrating similar clinical and microbiological responses as other comparators, with potential advantages in mortality outcomes and renal-related adverse events 8.
• Other treatment options, such as ceftazidime-avibactam, ceftolozane-tazobactam, and tigecycline, have shown efficacy against certain MDR and XDR Gram-negative bacteria, including CRE 5, 6.

Infection Control and Prevention

• Strict infection control measures, including antibiotic stewardship and isolation cohorts, are necessary to limit the spread of MDR and XDR Enterobacterales and alleviate the worsening trends of resistance 4, 5, 6.
• The development of new antibiotics and alternative treatment strategies is crucial to combat the increasing threat of MDR and XDR Enterobacteriaceae 5, 7.