Antimicrobial Stewardship in the Era of Pan-Resistance: Navigating the Post-Antibiotic Landscape in Critical Care

Dr Neeraj Manikath , claude.ai

Abstract

Background: The emergence of pan-drug resistant organisms has fundamentally altered the antimicrobial landscape in critical care medicine. This review examines contemporary strategies for antimicrobial stewardship, with particular focus on novel therapeutic approaches and optimization of existing agents.

Methods: A comprehensive literature review of antimicrobial resistance patterns, novel therapeutic agents, and stewardship strategies in critical care settings from 2018-2024.

Key Topics: This review addresses three critical areas: comparative effectiveness of cefiderocol versus ceftazidime-avibactam for NDM-producing Klebsiella pneumoniae, the emerging role of phage therapy in clinical practice, and optimized colistin dosing strategies to minimize nephrotoxicity.

Conclusions: Successful management of pan-resistant infections requires a multifaceted approach combining novel antimicrobials, innovative therapies, and refined dosing strategies. Critical care physicians must adapt their prescribing practices to navigate this challenging landscape while maintaining therapeutic efficacy.

Keywords: Antimicrobial stewardship, pan-resistance, cefiderocol, phage therapy, colistin, critical care

Introduction

The World Health Organization has declared antimicrobial resistance one of the top ten global public health threats facing humanity¹. In the intensive care unit (ICU), where the sickest patients receive the most aggressive interventions, this crisis manifests as a perfect storm of risk factors: prolonged antibiotic exposure, invasive devices, compromised immune systems, and high bacterial load environments².

The emergence of carbapenem-resistant Enterobacteriaceae (CRE), particularly those harboring New Delhi metallo-β-lactamase (NDM), has created therapeutic dilemmas that challenge traditional antimicrobial paradigms³. Pan-drug resistant (PDR) organisms—defined as resistance to all agents in all antimicrobial categories—now represent the ultimate therapeutic challenge, forcing clinicians to consider previously abandoned agents and novel therapeutic approaches⁴.

This review examines three critical frontiers in antimicrobial stewardship for critical care practitioners: the comparative utility of next-generation β-lactams, the clinical integration of phage therapy, and the renaissance of colistin with improved dosing strategies.

The Landscape of Pan-Resistance in Critical Care

Epidemiology and Risk Factors

The prevalence of extensively drug-resistant (XDR) and PDR organisms in ICUs has increased dramatically over the past decade. A recent multicenter study demonstrated that 23% of Klebsiella pneumoniae isolates in ICUs were carbapenem-resistant, with 15% classified as XDR⁵. Risk factors for acquisition include:

Patient factors: Prolonged ICU stay (>7 days), mechanical ventilation, central venous catheterization, previous antibiotic exposure
Environmental factors: ICU design, staffing ratios, compliance with infection control measures
Institutional factors: Antimicrobial stewardship program maturity, surveillance capabilities

Mechanisms of Resistance

Understanding resistance mechanisms is crucial for therapeutic decision-making:

Carbapenemases:

Class A: KPC (Klebsiella pneumoniae carbapenemase)
Class B: NDM, VIM, IMP (metallo-β-lactamases)
Class D: OXA-48-like enzymes

Non-β-lactamase mechanisms:

Porin loss (OmpK35, OmpK36 in Klebsiella)
Efflux pump overexpression
Target site modifications

Cefiderocol vs. Ceftazidime-Avibactam for NDM-Producing Klebsiella

Cefiderocol: The Trojan Horse Strategy

Cefiderocol represents a paradigm shift in β-lactam design, utilizing a siderophore-conjugated approach to overcome multiple resistance mechanisms⁶. Its iron-chelating moiety facilitates active transport across bacterial cell walls via iron uptake systems, earning it the moniker "Trojan horse antibiotic."

Mechanism of Action:

Iron-dependent active uptake via bacterial iron transporters
Stability against all major β-lactamase classes (A, B, C, D)
Maintains activity despite porin deficiency
Less susceptible to efflux pumps

Clinical Evidence: Head-to-Head Comparison

The CREDIBLE-CR study provided pivotal evidence for cefiderocol's efficacy against carbapenem-resistant pathogens⁷. However, direct comparison with ceftazidime-avibactam for NDM producers reveals nuanced considerations:

Cefiderocol Advantages:

Stable against metallo-β-lactamases (NDM, VIM, IMP)
Active against OXA-48-like producers
Retains activity against porin-deficient strains
Lower risk of resistance development

Ceftazidime-Avibactam Advantages:

More clinical experience and established dosing
Better penetration in certain tissue compartments
Lower acquisition cost
Established combination therapy protocols

Clinical Decision Algorithm

🔶 CLINICAL PEARL: For NDM-producing Klebsiella, cefiderocol should be considered first-line when:

Confirmed NDM production (molecular or phenotypic testing)
Previous ceftazidime-avibactam failure
Concurrent OXA-48 co-production
Severe infections (pneumonia, bacteremia) where resistance development risk is high

⚠️ OYSTER ALERT: Ceftazidime-avibactam may appear active in vitro against some NDM producers due to testing methodology limitations. Always correlate with molecular resistance mechanisms when available.

Dosing and Optimization

Cefiderocol:

Standard dose: 2g IV q8h (3-hour infusion)
Renal adjustment required (CrCl <120 mL/min)
Consider TDM in critical illness (target: free drug concentration >4× MIC for 75% of dosing interval)

Ceftazidime-Avibactam:

Standard dose: 2.5g IV q8h (2-hour infusion)
Extended infusion may improve PK/PD target attainment
Renal dose adjustment critical

Resistance Development and Combination Therapy

🔧 STEWARDSHIP HACK: Monitor for cefiderocol resistance development by following:

Serial MIC testing (watch for >4-fold increases)
Clinical response patterns (early treatment failure)
Consider combination with aztreonam for synergistic coverage

Recent studies suggest combination therapy may prevent resistance emergence:

Cefiderocol + aztreonam: Synergistic against NDM producers⁸
Ceftazidime-avibactam + aztreonam: Standard for NDM-OXA co-producers⁹

Phage Therapy: From Laboratory Curiosity to Clinical Reality

Historical Context and Modern Renaissance

Bacteriophage therapy, pioneered in the early 20th century, has experienced a remarkable renaissance driven by the antimicrobial resistance crisis¹⁰. The FDA's compassionate use programs have facilitated access to phage therapy for critically ill patients with limited alternatives.

Mechanism and Advantages

How Phages Work:

Specific binding to bacterial surface receptors
Injection of genetic material
Hijacking of bacterial cellular machinery
Lysis and progeny release

Unique Advantages:

Species-specific targeting (minimal microbiome disruption)
Self-amplifying at infection site
Can penetrate biofilms
Synergistic with antibiotics
Rapid resistance testing possible

Current Clinical Applications

When to Consider Phage Therapy:

Last-Resort Scenarios:
- PDR infections with no effective antibiotics
- Chronic infections (osteomyelitis, prosthetic joint infections)
- Biofilm-associated infections resistant to conventional therapy
Specific Clinical Contexts:
- Acinetobacter baumannii ventilator-associated pneumonia
- Pseudomonas aeruginosa respiratory infections in cystic fibrosis
- Klebsiella pneumoniae bacteremia in immunocompromised hosts

🔶 CLINICAL PEARL: Phage therapy is NOT limited to terminal cases. Early consideration in XDR infections may improve outcomes and reduce the need for toxic antimicrobial combinations.

Clinical Implementation Framework

Pre-Treatment Assessment:

Confirm PDR/XDR phenotype
Isolate pathogen and send for phage susceptibility testing
Assess infection source control feasibility
Evaluate patient's immune status
Obtain appropriate approvals (compassionate use/clinical trial)

Treatment Monitoring:

Serial bacterial cultures and phage sensitivity testing
Monitor for phage resistance (typically emerges within 7-14 days)
Assess for immune responses (neutralizing antibodies)
Combine with source control and supportive care

Practical Considerations

Access Pathways:

Compassionate use programs (FDA, European Medicines Agency)
Clinical trials (check ClinicalTrials.gov)
Institutional phage banks (limited availability)
Commercial producers (expanding availability)

⚠️ OYSTER ALERT: Phage resistance can develop rapidly. Always plan for combination approaches or sequential phage therapy. Banking multiple phages active against the target organism is crucial.

Combination with Antibiotics

Emerging evidence suggests phage-antibiotic combinations may be synergistic:

Phages can resensitize bacteria to antibiotics¹¹
Antibiotics may prevent phage resistance development
Sequential therapy (phage followed by antibiotic) shows promise

The Return of Colistin: Optimized Dosing for the Resistant Era

Why Colistin Matters Again

Despite its nephrotoxic reputation, colistin remains one of the few agents active against many PDR Gram-negative organisms. Recent pharmacokinetic insights have revolutionized dosing strategies, potentially improving both efficacy and safety¹².

Understanding Colistin Pharmacokinetics

🔧 STEWARDSHIP HACK: Colistin is administered as colistimethate sodium (CMS), an inactive prodrug that converts to active colistin in vivo. Understanding this conversion is key to optimal dosing.

Key Pharmacokinetic Principles:

CMS → colistin conversion is slow and incomplete
Colistin has a large volume of distribution
Renal clearance is highly variable
Traditional dosing was based on flawed assumptions

Modern Dosing Strategies

Loading Dose Imperative:

Why needed: Slow CMS→colistin conversion creates delayed therapeutic levels
Standard loading dose: 300 mg CBA (colistin base activity) regardless of renal function
Timing: Administer immediately, don't delay for renal function assessment

Maintenance Dosing:

For Normal Renal Function (CrCl >80 mL/min):

150 mg CBA q12h
Consider 100 mg CBA q8h for difficult-to-treat organisms (MIC ≥1 mg/L)

Renal Adjustment:

CrCl 50-79 mL/min: 130 mg CBA q12h
CrCl 30-49 mL/min: 100 mg CBA q12h
CrCl <30 mL/min: 100 mg CBA q24h

🔶 CLINICAL PEARL: In critically ill patients with augmented renal clearance (CrCl >130 mL/min), standard dosing may be insufficient. Consider therapeutic drug monitoring or empiric dose increase to 200 mg CBA q12h.

Nephrotoxicity Mitigation Strategies

Risk Factors for Nephrotoxicity:

Age >65 years
Baseline renal impairment
Concurrent nephrotoxins (vancomycin, aminoglycosides, contrast)
Hemodynamic instability
Duration >7 days

Protective Strategies:

Hydration Protocol:
- Ensure adequate volume status before initiation
- Target urine output >0.5 mL/kg/h
- Avoid hypovolemia during treatment
Nephrotoxin Avoidance:
- Minimize concurrent nephrotoxins where possible
- Use alternative agents when equivalent efficacy exists
- Time contrast exposure carefully
Monitoring Protocol:
- Daily creatinine and electrolytes
- Magnesium and phosphorus (colistin causes tubular wasting)
- Urinalysis for proteinuria and casts
- Consider novel biomarkers (NGAL, KIM-1) for early detection

⚠️ OYSTER ALERT: Colistin nephrotoxicity is typically reversible but may take weeks to months to resolve completely. Factor this into discharge planning and outpatient monitoring.

Combination Therapy and Synergy

Rationale for Combinations:

Prevent resistance development
Achieve synergistic killing
Potentially reduce colistin dosing requirements

Evidence-Based Combinations:

Colistin + Carbapenem:

Synergistic against many CRE isolates
Consider meropenem 2g q8h (extended infusion) + colistin
Monitor for carbapenem-induced seizures

Colistin + Rifampin:

Excellent biofilm penetration
Useful for catheter-related infections
Rifampin 600 mg q24h (adjust for drug interactions)

Colistin + Tigecycline:

Broad spectrum coverage
Good tissue penetration
Loading dose tigecycline: 200 mg, then 100 mg q12h

Therapeutic Drug Monitoring

When to Consider TDM:

Critical infections (meningitis, endocarditis)
Organisms with elevated MICs (≥1 mg/L)
Patients with altered pharmacokinetics
Treatment failures

Target Levels:

Steady-state colistin concentration: 2-3 mg/L
For MIC 0.5 mg/L organisms: target 1-2 mg/L
For MIC ≥1 mg/L organisms: target 2-4 mg/L

Stewardship Strategies in the Pan-Resistant Era

Diagnostic Stewardship

Rapid Diagnostics:

Implement rapid molecular testing (PCR, MALDI-TOF MS)
Point-of-care testing for resistance markers
Continuous surveillance for emerging resistance

🔧 STEWARDSHIP HACK: Use rapid carbapenemase detection tests (Xpert Carba-R, NG-Test CARBA 5) to guide early therapy decisions within 1-2 hours of positive blood cultures.

Prescription Optimization

De-escalation Protocols:

48-72 hour reassessment mandatory
Culture-directed therapy when possible
Avoid prolonged broad-spectrum coverage

Duration Optimization:

Biomarker-guided therapy (procalcitonin, CRP)
Source control assessment
Minimum effective duration principles

Infection Prevention Integration

Environmental Measures:

Enhanced contact precautions for XDR/PDR organisms
Cohorting strategies in high-prevalence units
Environmental cleaning protocols

Active Surveillance:

Weekly screening in high-risk units
Targeted screening based on risk factors
Rapid identification and isolation

Future Directions and Emerging Therapies

Novel Antimicrobials in Development

Next-Generation β-Lactams:

Zidebactam (WCK 5222): β-lactam/β-lactamase inhibitor/PBP2 inhibitor
Nacubactam combinations: Novel β-lactamase inhibitor
Xeruborbactam combinations: Broad-spectrum β-lactamase inhibitor

Alternative Mechanisms:

Teixobactin analogues: Novel cell wall synthesis inhibitors
Antimicrobial peptides: Host defense peptide mimics
Efflux pump inhibitors: Resistance mechanism reversers

Precision Medicine Approaches

Pharmacogenomics:

CYP450 polymorphisms affecting drug metabolism
Transporter gene variations
Immune response predictors

Personalized Dosing:

Machine learning-based dose optimization
Real-time pharmacokinetic monitoring
Integrated clinical decision support

Practical Implementation: A 10-Step Approach

Step-by-Step Management Protocol

Rapid Identification: Implement rapid diagnostic testing for resistance mechanisms
Source Control: Assess and address infection source immediately
Empiric Therapy: Start appropriate broad-spectrum coverage based on local epidemiology
Resistance Testing: Send isolates for comprehensive resistance testing including molecular methods
Targeted Therapy: Switch to pathogen-directed therapy within 48-72 hours
Combination Consideration: Evaluate need for combination therapy based on severity and resistance profile
Monitoring Protocol: Implement intensive monitoring for efficacy and toxicity
Duration Assessment: Reassess treatment duration daily using clinical and biomarker criteria
De-escalation: Remove unnecessary agents as clinical condition improves
Prevention: Implement contact precautions and surveillance measures

Key Clinical Pearls and Oysters

🔶 PEARLS (Things You Should Remember)

Cefiderocol Timing: Start within 6 hours for best outcomes in severe NDM infections
Phage Therapy Access: Establish relationships with phage therapy centers BEFORE you need them
Colistin Loading: Always give a loading dose, regardless of renal function
Combination Synergy: Test for synergy in vitro when planning combination therapy
TDM Integration: Use therapeutic drug monitoring for critical infections with novel agents

⚠️ OYSTERS (Common Pitfalls to Avoid)

False Susceptibility: Don't trust ceftazidime-avibactam susceptibility reports for confirmed NDM producers
Phage Resistance: Don't expect phage therapy to work indefinitely—plan for resistance
Colistin Nephrotoxicity: Don't use traditional colistin dosing—follow modern pharmacokinetic principles
Monotherapy Mistakes: Don't use monotherapy for PDR infections in critically ill patients
Duration Errors: Don't continue combination therapy longer than necessary

🔧 STEWARDSHIP HACKS

Rapid Rounds: Implement daily antimicrobial stewardship rounds in ICUs
Decision Trees: Use algorithmic approaches for complex resistance patterns
Pharmacy Integration: Leverage clinical pharmacists for dosing optimization and monitoring
Surveillance Systems: Implement automated alerts for resistance patterns and drug interactions
Education Programs: Regular case-based education for ICU staff on emerging resistance trends

Conclusions

The era of pan-resistance demands a fundamental shift in how critical care physicians approach antimicrobial therapy. Success requires integration of novel therapeutic approaches, optimization of existing agents, and implementation of robust stewardship principles. The combination of advanced diagnostics, precision dosing, and innovative therapies like phage therapy offers hope in seemingly hopeless situations.

Critical care practitioners must embrace these new paradigms while maintaining vigilance for emerging resistance patterns. The battle against antimicrobial resistance is far from over, but with thoughtful stewardship and judicious use of our expanding therapeutic armamentarium, we can continue to provide effective care for our most vulnerable patients.

The future of antimicrobial therapy in critical care will likely involve personalized medicine approaches, artificial intelligence-driven dosing optimization, and novel therapeutic modalities we are only beginning to understand. Staying current with these developments and implementing evidence-based practices will be crucial for maintaining our effectiveness against evolving bacterial threats.

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Conflicts of Interest: The authors declare no conflicts of interest.

Funding: This work received no specific funding.

Author Contributions: All authors contributed to the conception, writing, and revision of this manuscript.

Thursday, August 14, 2025