MDR, XDR, and PDR Antibiotic Resistance: Definitions and Treatment Strategies
MDR (multidrug-resistant) bacteria are non-susceptible to at least one agent in three or more antimicrobial categories; XDR (extensively drug-resistant) bacteria remain susceptible to only one or two antimicrobial categories; and PDR (pan-drug-resistant) bacteria are non-susceptible to all agents in all antimicrobial categories 1.
Standardized Definitions
These internationally standardized definitions were established through a joint ECDC-CDC expert consensus to create uniform terminology for acquired resistance patterns 1:
- MDR: Non-susceptibility to ≥1 agent in ≥3 antimicrobial categories
- XDR: Non-susceptibility to ≥1 agent in all but ≤2 antimicrobial categories (i.e., susceptible to only 1-2 categories)
- PDR: Non-susceptibility to all agents in all antimicrobial categories
For proper classification, bacterial isolates must be tested against all or nearly all antimicrobial agents within the relevant categories, avoiding selective reporting 1.
Organism-Specific Applications
For Acinetobacter baumannii specifically 2:
- XDR-AB: Non-susceptibility to carbapenem AND at least one agent in all but 2 antimicrobial categories
- PDR-AB: Non-susceptibility to all agents in all antimicrobial categories
General Management Principles
Infectious disease consultation is strongly recommended for all MDRO infections 2. This is a strong recommendation despite low-quality evidence, reflecting the complexity and high stakes of these infections.
Critical Treatment Optimization Strategies
- Prolonged infusion of β-lactams is recommended for pathogens with high MICs (strong recommendation) 2
- Antimicrobial susceptibility testing or genotypic resistance characterization must guide antibiotic selection 2
- Combination therapy based on susceptibility results should be employed for severe infections 2
Treatment Strategies by Organism and Infection Site
Carbapenem-Resistant Acinetobacter baumannii (CRAB)
For CRAB pneumonia, use colistin with or without carbapenems, plus adjunctive inhaled colistin 2. Importantly, tigecycline monotherapy should NOT be used for CRAB pneumonia (strong recommendation) 2.
For CRAB bloodstream infections, use colistin-carbapenem combination therapy 2.
The European guidelines provide additional nuance 3:
- Do NOT use polymyxin-meropenem or polymyxin-rifampin combinations (strong recommendation)
- For severe/high-risk CRAB infections, consider combination therapy with two in vitro active antibiotics from: polymyxin, aminoglycoside, tigecycline, or sulbactam combinations
- For CRAB with meropenem MIC ≤8 mg/L, carbapenem combination therapy using high-dose extended-infusion dosing is considered good practice
Recent evidence suggests sulbactam-durlobactam demonstrates at least comparable activity to colistin for carbapenem-resistant A. baumannii, though availability is limited 4.
Carbapenem-Resistant Enterobacterales (CRE)
New β-lactam/β-lactamase inhibitor combinations are now the cornerstone of CRE treatment, having largely replaced older approaches like colistin due to superior efficacy and tolerability 5, 4.
For CRE Bloodstream Infections:
- Ceftazidime-avibactam 2.5 g IV q8h infused over 3 hours 2
- Polymyxin-based combination therapy (alternative option) 2
For CRE Complicated Urinary Tract Infections:
- Ceftazidime-avibactam 2.5 g IV q8h 2
- Meropenem-vaborbactam 4 g IV q8h OR imipenem-cilastatin-relebactam 1.25 g IV q6h 2
- Plazomicin 15 mg/kg IV q12h 2
- Single-dose aminoglycoside for simple cystitis 2
For CRE Intra-abdominal Infections:
- Ceftazidime-avibactam 2.5 g IV q8h in combination with metronidazole 2
Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)
Ceftolozane-tazobactam, ceftazidime-avibactam, or imipenem-cilastatin-relebactam are most effective against PDR P. aeruginosa 6, 7. Ceftazidime-avibactam has better activity against MDR/XDR strains, especially those with specific resistance mechanisms 7.
Emerging options include imipenem-relebactam, cefepime-zidebactam, and cefiderocol 7.
Pan-Drug-Resistant (PDR) Infections
For pan-resistant carbapenem-resistant Gram-negative bacteria (including those resistant to polymyxins), treat with the least resistant antibiotic(s) based on MICs relative to breakpoints 3. This is considered good clinical practice based on expert opinion.
Cefiderocol and the combination of ceftazidime-avibactam plus aztreonam represent current last-resort options for metallo-β-lactamase producers 4.
For PDR organisms by species 6:
- A. baumannii: Tigecycline combined with colistimethate, imipenem, amikacin, or ampicillin-sulbactam
- K. pneumoniae: Historically tigecycline and colistin; newer agents as above
- E. coli: Nitrofurantoin, fosfomycin, or pivmecillinam
Critical Pitfalls to Avoid
- Never use tigecycline monotherapy for CRAB pneumonia - this is strongly contraindicated 2
- Avoid polymyxin-meropenem or polymyxin-rifampin combinations for CRAB - strong evidence against these regimens 3
- Do not rely on selective susceptibility reporting - comprehensive testing is essential for proper MDR/XDR/PDR classification 1
- Resistance phenotype alone does not predict mortality - physiological deterioration (APACHE II score, GCS, vasopressor requirements, albumin, CRP) are stronger independent predictors than resistance pattern 8
Clinical Context and Prognosis
While XDR and PDR infections are associated with longer ICU stays, higher disease severity scores, and increased mortality rates, multivariate analysis shows that mortality is more strongly associated with physiological deterioration than resistance phenotype itself 8. This emphasizes the importance of aggressive supportive care and early appropriate therapy guided by susceptibility testing.
The prevalence of these resistant organisms varies significantly by setting, with some ICUs reporting XDR rates of 12.5% and PDR rates of 6% among Gram-negative isolates 8, while others report even higher rates with 55% MDR, 15% XDR, and 2% PDR among Gram-negatives 9.