What is the recommended approach for treating Gram-negative (GN) multi-drug resistant (MDR) infections?

Challenges in Treating Gram-Negative Multidrug-Resistant Infections

The primary challenges in treating Gram-negative MDR infections include limited therapeutic options with very low-certainty evidence, the critical need to balance appropriate empirical coverage against antibiotic stewardship to preserve last-resort agents, and the requirement for optimal source control as the single most important intervention. 1, 2

Core Clinical Challenges

Limited Evidence Base and Treatment Uncertainty

• Most treatment recommendations for MDR-GNB are based on very-low-certainty evidence or no evidence at all, with only randomized controlled trials providing high-certainty data 1
• The paucity of evidence on new beta-lactam/beta-lactamase inhibitors (BLBLIs) against carbapenem-resistant organisms creates significant uncertainty in treatment selection 1
• Antibiotic approval trials were syndrome-based and included only a few patients with the MDR bacteria for which these antibiotics were developed, limiting real-world applicability 1
• The quality of evidence for determining effective interventions is generally low, with outbreak studies being unreliable and endemic setting studies usually of low quality 1

The Empirical Treatment Dilemma

• A difficult antibiotic stewardship balance exists between achieving appropriate empirical therapy for CR-GNB infections and conserving last-resort therapies 1
• Delayed appropriate therapy increases length of stay, total costs, and carries approximately 20% increased risk of in-hospital mortality 3
• Time to appropriate antibiotic therapy is an independent predictor of 30-day mortality in patients with resistant organisms 3
• The empirical treatment phase is relevant to a much larger population than targeted treatment, yet local guidelines guided by local epidemiology are needed to address this phase 1

Pathogen-Specific Treatment Complexity

For Carbapenem-Resistant Enterobacterales (CRE)

• Testing against new BLBLIs and polymyxins is recommended for CR-GNB resistant to all β-lactams 1
• Treatment options include ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam, but availability varies globally 4, 2
• In low-resource settings, costs of new antibiotics may prohibit their use entirely 1

For Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

• There is very low-certainty evidence for combination therapy with polymyxins, aminoglycosides, or fosfomycin over monotherapy 1
• No recommendation for or against specific combinations can be provided due to lacking evidence 1
• Ceftolozane-tazobactam and ceftazidime-avibactam show activity, but optimal use requires careful stewardship 1, 2

For Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• Polymyxin-meropenem combination therapy is NOT recommended based on high-certainty RCT evidence showing no mortality benefit 1, 2
• Polymyxin-rifampin combination therapy is NOT recommended based on moderate-certainty evidence 1
• For sulbactam-susceptible CRAB with HAP/VAP, ampicillin-sulbactam is suggested, but for sulbactam-resistant strains, polymyxins or high-dose tigecycline must be used despite limited evidence 1
• Cefiderocol is conditionally recommended AGAINST for CRAB treatment based on low-certainty evidence showing higher mortality (49% vs 18% with best available therapy) 1

Source Control as Priority Intervention

• Optimal source control is the single most critical intervention for pan-resistant organisms, followed by selection of the least resistant antibiotic based on MICs relative to breakpoints 1, 2
• Source control should always be a priority to optimize outcomes and shorten antibiotic treatment durations 1
• Surgical debridement, drainage of abscesses, and removal of infected devices must be performed whenever feasible 2

Diagnostic and Monitoring Challenges

• Follow-up cultures are recommended in case of treatment failure, especially for CR-GNB, to detect resistance development 1
• Antimicrobial susceptibility testing or genotypic characterization of resistance is essential to guide appropriate antibiotic selection 4
• Susceptibility testing of MDR-GNB needs critical enhancements, particularly for carbapenem MIC testing and carbapenemase class identification 5
• Broth microdilution methods should be adopted for colistin susceptibility testing rather than standard methods 5

Pharmacokinetic/Pharmacodynamic Optimization Difficulties

• Prolonged infusion of β-lactams is recommended for pathogens with high MICs, but optimal dosing in critically ill patients has areas of uncertainty 4, 6
• Extended or continuous infusion (3-4 hours) of cefepime, piperacillin-tazobactam, meropenem, and doripenem is required for severe infections 4, 2
• Therapeutic drug monitoring is recommended for aminoglycosides, vancomycin, and β-lactams, but implementation varies 2

Antibiotic Stewardship Conflicts

• Carbapenem use for 3rd-generation cephalosporin-resistant Enterobacterales varies by epidemiological setting and sepsis severity 1
• Carbapenem-sparing therapy is possible for non-severe infections and low-risk sources, with piperacillin-tazobactam or amoxicillin-clavulanate as alternatives 1
• Colistin should be reserved as a last-resort antibiotic for CRAB and MBL-producing Enterobacterales 1
• New BLBLIs should be spared when alternatives exist, stratifying patients by sepsis severity and urgency of sepsis control 1

Global Equity and Access Issues

• Antibiotics, both old and new, are not equally available worldwide 1
• Differential costs of new antibiotics for different socio-economic settings are needed to allow better equity of patient management 1
• Antibiotics critical to management of priority pathogens should be defined and universal availability ensured 1

Infection Control Controversies

• Important areas of controversy exist between guidelines regarding contact precautions, single-room isolation, and active surveillance cultures 1
• Differences in approach to environmental cleaning and disinfection, staff and patient cohorting, healthcare worker screening, and patient decolonization remain unresolved 1
• All MDR-GNB guidelines advocate a targeted approach rather than universal interventions 1
• Single interventions are more likely to fail than bundled interventions (failure rate 45% vs 28%), but determining the relative impact of each bundle element remains difficult 1

Pan-Resistant Organism Management

• For pan-resistant CR-GNB (resistant also to polymyxins), treatment with the least resistant antibiotic based on MICs relative to breakpoints is recommended, but mainly optimal source control 1
• No high-quality evidence exists to guide specific antibiotic choices for pan-resistant organisms 1, 2

Research and Evidence Gaps

• Investigator-initiated RCTs are needed addressing infections due to 3GcephRE and CR-GNB specifically 1
• Infection source-specific guidance is mostly lacking except for 3GcephRE 1
• Further research is urgently required to inform evidence-based approaches to MDR-GNB prevention and control 1
• Pharmacokinetic/pharmacodynamic optimization requires further study, taking into account resistance selection as a major endpoint 6