Multidrug-Resistant Bacteria: Common Organisms, Risk Factors, and Management
The most clinically significant multidrug-resistant organisms (MDROs) are carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Acinetobacter baumannii (CRAB), and methicillin-resistant Staphylococcus aureus (MRSA), with management requiring immediate infectious disease consultation, targeted infection control measures, and empiric broad-spectrum antibiotics tailored to local resistance patterns before narrowing based on culture results. 1, 2
Common Multidrug-Resistant Organisms
Definition and Classification
Multidrug resistance (MDR) is formally defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories. 1, 3 This standardized definition, established through joint ECDC/CDC expert consensus, applies to the most epidemiologically important healthcare-associated pathogens. 3
Key MDRO Pathogens by Prevalence
Carbapenem-resistant Enterobacterales (CRE) represent the most concerning gram-negative threat, with Klebsiella pneumoniae showing carbapenem resistance rates exceeding 7.9% in surveillance data, though actual clinical prevalence is higher in many healthcare settings. 4 Among CRE isolates from clinical infections, Klebsiella species account for approximately 29% of MDR gram-negative infections, while E. coli represents 24%. 5
Carbapenem-resistant Pseudomonas aeruginosa (CRPA) demonstrates resistance rates of 16.5% or higher, with P. aeruginosa being the most common non-MDR organism (47%) but also representing 20% of MDR infections when resistance develops. 4, 5
Carbapenem-resistant Acinetobacter baumannii (CRAB) shows the highest resistance rates, with greater than 30% of isolates demonstrating carbapenem resistance, and A. baumannii accounting for 38% of MDR gram-negative infections in hospitalized patients. 4, 5
Methicillin-resistant Staphylococcus aureus (MRSA) remains an important gram-positive MDRO, though percentages have declined in several European countries in recent years. 4
Vancomycin-resistant Enterococcus (VRE), defined as ampicillin and vancomycin-resistant enterococci with high-level aminoglycoside resistance, represents another critical gram-positive threat. 4
Risk Factors for MDRO Infection
Healthcare-Associated Risk Factors
Prior antibiotic use is the single most significant modifiable risk factor for MDR infection (p=0.001-0.002), particularly when broad-spectrum antibiotics have been used for more than 5 days. 6, 2 This applies across all MDRO types and represents the primary driver of resistance selection pressure.
ICU admission is independently associated with MDR infection (p=0.001), with critically ill patients facing substantially elevated risk. 6 The combination of severe illness, invasive procedures, and concentrated antibiotic use in ICU settings creates ideal conditions for MDRO acquisition.
Indwelling medical devices—including urethral/suprapubic catheters, central venous catheters, and endotracheal tubes—significantly increase MDR risk (p=0.003-0.03). 6, 5 For spinal cord injury patients specifically, indwelling urethral or suprapubic catheters confer an odds ratio of 2.76 (95% CI 2.04-3.74) for MDR urinary infections. 5
Prolonged hospitalization exceeding 5 days increases risk for both MDR and non-MDR healthcare-associated infections (p=0.001). 6
Patient-Specific Risk Factors
Age over 60 years is associated with increased susceptibility to healthcare-associated infections, though this applies more broadly to non-MDR infections (p=0.02). 6
Immunosuppressive therapy significantly elevates infection risk (p=0.02), though this factor affects both MDR and non-MDR infections. 6
Male sex is an independent predictor of multidrug resistance in certain populations (OR 1.55,95% CI 1.16-2.06, p=0.003). 5
Severity of underlying illness—such as high cervical spinal cord injury with complete lesions (C1-C4/AIS A-C)—correlates with higher MDR infection rates (p=0.01). 5
Empiric Treatment Approach
Initial Management Algorithm
Obtain infectious disease consultation immediately upon suspecting or confirming MDRO infection, as this is a strong recommendation across all guidelines due to limited treatment options, need for pharmacokinetic/pharmacodynamic optimization, and complex disease evaluation. 2, 4, 1
Collect cultures from appropriate specimens (blood, wound/tissue, respiratory, urine) before initiating antibiotics to guide definitive therapy. 2, 1
Perform antimicrobial susceptibility testing or genotypic characterization (e.g., carbapenemase detection) to guide antibiotic selection. 2, 1
Empiric Antibiotic Selection for Healthcare-Associated MDRO Infections
For critically ill patients with suspected healthcare-associated MDRO infection, initiate meropenem 1g IV every 8 hours, which provides coverage for CRE, CRPA, and most gram-negative pathogens. 2 Alternative carbapenems include doripenem 500mg IV every 8 hours or imipenem/cilastatin 1g IV every 8 hours. 2
Add vancomycin 25-30 mg/kg loading dose, then 15-20 mg/kg every 8 hours to cover MRSA and ampicillin-susceptible enterococci. 2 Target vancomycin trough levels of 15-20 mcg/mL for serious infections. 2
Consider adding linezolid 600mg IV every 12 hours or daptomycin 6 mg/kg IV every 24 hours if VRE risk is present based on local epidemiology or patient risk factors. 2
Targeted Therapy Based on Culture Results
For CRE infections, ceftazidime-avibactam 2.5g IV every 8 hours infused over 3 hours is recommended as first-line therapy. 2, 1 Alternative regimens include meropenem-vaborbactam 4g IV every 8 hours or imipenem-cilastatin-relebactam 1.25g IV every 6 hours. 2, 1
For CRAB infections, colistin-carbapenem combination therapy is recommended despite the high nephrotoxicity risk of colistin. 2, 1
For CRPA infections, ceftolozane/tazobactam or ceftazidime/avibactam are recommended based on susceptibility testing. 2, 1, 7
For MRSA infections, continue vancomycin with target trough 15-20 mcg/mL for serious infections, or switch to daptomycin 6-8 mg/kg IV every 24 hours for soft tissue/bone infections. 2
For VRE infections, linezolid 600mg IV every 12 hours or daptomycin 6 mg/kg IV every 24 hours are recommended. 2
Critical Pharmacokinetic Optimization
Administer prolonged infusions of beta-lactams—infusing over 3-4 hours rather than standard 30-minute boluses—to optimize time above MIC for pathogens with high MICs. 2, 7 This is particularly critical in critically ill patients with altered pharmacokinetics and for treating organisms with elevated MICs near susceptibility breakpoints. 2
Treatment Duration and De-escalation
Narrow antibiotics within 48-72 hours based on culture results and clinical response. 2 Treatment duration depends on infection source control, clinical response, and specific pathogen, typically ranging 7-14 days for soft tissue infections with adequate source control. 2
Ensure adequate source control through debridement, drainage, or device removal, as antibiotics alone are insufficient for MDRO infections with undrained collections or retained foreign bodies. 2
Infection Control Measures
Universal Interventions
All guidelines advocate a targeted (vertical) approach to MDRO control rather than universal (horizontal) interventions, distinguishing MDRO management from strategies used for MRSA or VRE. 1
Hand hygiene reinforcement is universally considered the single most important intervention to control MDRO outbreaks, with alcohol-based products recommended. 1 Education programs and compliance monitoring should be implemented across all healthcare settings. 1
Targeted Control Measures
Contact precautions with gown and gloves are required for all MDRO-colonized or infected patients in acute care facilities. 1
Single-room isolation is recommended for MDRO patients when available, with cohorting of patients with the same organism as an acceptable alternative when single rooms are limited. 1
Note flagging in electronic medical records ensures that MDRO status is communicated across care transitions and readmissions. 1
Environmental disinfection protocols must be enhanced for MDRO-affected areas, though specific disinfectant choice and frequency remain areas of controversy between guidelines. 1
Controversial Interventions
Active surveillance screening, healthcare worker screening, patient decolonization, and staff cohorting remain controversial, with guidelines differing substantially on recommendations for these interventions. 1 The evidence base for these measures is extremely limited, and further research is urgently required. 1
Common Pitfalls to Avoid
Never use tigecycline monotherapy for serious MDRO infections due to poor tissue penetration and increased mortality risk. 2
Avoid aminoglycosides as monotherapy for anything beyond simple cystitis due to poor tissue penetration, though they remain valuable as combination therapy partners. 2
Do not assume all carbapenems have antipseudomonal activity—ertapenem explicitly lacks coverage for Pseudomonas and should never be used when CRPA is suspected. 7
Avoid underdosing antibiotics for MDRO infections; use maximum recommended doses to prevent treatment failure and resistance emergence. 7, 2
Do not delay infectious disease consultation for MDRO infections, as specialized expertise significantly impacts outcomes through optimized antimicrobial selection, dosing, and duration. 2, 4
Clinical Significance and Prognosis
MDRO infections represent a leading cause of healthcare-associated morbidity and mortality worldwide, with substantially worse outcomes than susceptible organism infections. 4, 1 Prolonged hospital stays, higher healthcare costs, and limited treatment options characterize MDRO infections. 4 The availability of only a small number of effective antimicrobial agents—often last-resort antibiotics with high toxicity or poor efficacy—makes prevention and early appropriate therapy critical. 4, 8