Multidrug-resistant organism infections

Multidrug-resistant organisms (MDROs) are pathogens, usually bacteria, that are resistant to one or more agent in three or more antimicrobial categories. MDRO infections result in increased hospital stay and mortality. The most common MDROs include methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and certain multidrug-resistant gram-negative microorganisms. The numerous risk factors for developing MDRO infections include health care exposure and prior use of antimicrobials. The treatment of MDRO infections is often complicated due to the limited antimicrobial options and is guided by antibiotic susceptibilities and the site and severity of infection. Measures for infection prevention and control are an essential part of MDRO management.

• Antimicrobial resistance: the ability of microorganisms (e.g., bacteria, fungi) to withstand the effects of antimicrobial agents (e.g., antibiotics, antifungals) as a result of genetic changes ^[1][2]
• Multidrug resistance: resistance of an isolate of microorganisms to ≥ 1 agent in ≥ 3 antimicrobial categories ^[3][4]

• MDRO infections cause:
  • ∼ 35,000 deaths annually in the US ^[5]
  • 1.3 million deaths globally ^[6]

Epidemiological data refers to the US, unless otherwise specified.

General principles

• MDRO infections can be community-acquired or nosocomial.
• The most significant MDROs are bacteria.
• Other relevant MDROs include Candida auris. ^[7][8]
• See also “Drug-resistant Mycobacterium tuberculosis.”

Risk factors for MDRO infection ^[9][10]

• Health care exposure
  • Hospitalization: prolonged stay, ICU or long-term care facility admission (e.g., assisted living facility)
  • Prior antibiotic use
  • Exposure to individuals with MDROs
  • Indwelling medical devices (e.g., urinary or IV catheters, endotracheal tubes)
  • Invasive medical procedures (e.g., surgery, transplantation)
• Patient factors
  • Age > 60 years ^[10]
  • Chronic conditions (e.g., diabetes mellitus, cancer, CKD)
  • Prior history of MDRO colonization or infection
  • Immunocompromised state
  • Malnutrition ^[11]

To remember the most common MDROs, think “ESKAPE”: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales. ^[8]

Methicillin-resistant Staphylococcus aureus (MRSA) ^[8][12]

MRSA infection can be nosocomial or community-acquired.

• Resistance
  • All β-lactam antibiotics (i.e., penicillins, cephalosporins, monobactams, and carbapenems)
  • S. aureus may also be resistant to the following (unrelated to methicillin resistance):
    • Aminoglycosides
    • Macrolides
    • Lincosamides
    • Quinolones
    • Glycopeptides (e.g., vancomycin-resistant S. aureus)
• Mechanism of resistance: The staphylococcal mecA gene encodes a modified penicillin-binding protein (PBP) that inhibits the binding of β-lactam antibiotics. ^[13]

MRSA infections should always be treated; decolonization may be considered in certain individuals (e.g., those admitted to the ICU or with recurrent MRSA infections). ^[14]

The resistance mechanism of MRSA relies on modified PBPs, not on the production of β-lactamase.

Vancomycin-resistant enterococci (VRE) ^[8][15][16]

• Pathogens: bacterial strains of the genus Enterococcus (e.g., E. faecalis, E. faecium)
• Resistance
  • Vancomycin (possibly also teicoplanin)
  • Enterococci may also be resistant to the following (unrelated to vancomycin resistance):
    • Macrolides
    • Most penicillins (intrinsic resistance to penicillinase-resistant penicillins, such as oxacillin, and cephalosporins)
    • Quinolones (acquired or intrinsic resistance)
    • Aminoglycosides (intrinsic resistance)
    • Tetracyclines
• Mechanism of resistance
  • Bacterial strains of the genus Enterococcus acquire van genes (e.g., through transposition of plasmid-encoded genes such as the vanA gene).
  • Van genes (e.g., vanA gene) alter peptidoglycan synthesis (e.g., changing the D-alanine-D-alanine sequence to D-alanine-D-lactate), inhibiting vancomycin from binding to peptidoglycans.

Enterobacterales

ESBL-producing bacteria ^[5]

Bacteria that produce extended-spectrum β-lactamase (ESBL) cause multiple diseases, including nosocomial UTIs and health care-associated pneumonia.

• Pathogens: gram-negative bacteria that carry the ESBL gene (e.g., Enterobacteriaceae such as Klebsiella spp., Escherichia coli)
• Resistance
  • Penicillins
  • Cephalosporins
  • Aztreonam
• Mechanism of resistance
  • Production of ESBL that cleaves penicillins, cephalosporins, and monobactam
  • Other mechanisms (e.g., changes in outer membrane proteins) can lead to ertapenem resistance. Resistance to carbapenems is rare. ^[17]

AmpC β-lactamase-producing bacteria ^[5][18]

• Pathogens: most commonly Enterobacter cloacae complex, Citrobacter freundii, Klebsiella aerogenes
• Resistance
  • Penicillins (e.g., amoxicillin)
  • Cephalosporins (except for cefepime)
  • Monobactam (e.g., aztreonam)
• Mechanism of resistance
  • Production of AmpC that hydrolyzes β-lactam antibiotics
  • AmpC β-lactamase production can be induced by exposure to certain β-lactam antibiotics (e.g., amoxicillin, ceftriaxone).

Carbapenem-resistant Enterobacterales (CRE) ^[5][8]

• Pathogens: bacteria in the order Enterobacterales (e.g., E. coli, K. pneumoniae)
• Resistance
  • ≥ 1 carbapenem
  • CRE may additionally be resistant to penicillins, cephalosporins, and/or aztreonam.
• Mechanism of resistance, e.g.: ^[5][19]
  • Noncarbapenemase β-lactamase (e.g., ESBL): causes outer membrane porin disruption
  • Carbapenemases (e.g., K. pneumoniae carbapenemases, New Delhi metallo-β-lactamase): hydrolyzes almost all β-lactam antibiotics

Multidrug-resistant Pseudomonas aeruginosa ^[5][8]

P. aeruginosa causes multiple diseases, e.g., pneumonia, severe soft tissue infections (in infected wounds), UTIs, otitis external, and keratitis.

• Resistance
  • MDR P. aeruginosa: resistance to ≥ 1 antibiotic in ≥ 3 generally susceptible antibiotic classes (i.e., fluoroquinolones, penicillins, cephalosporins, aminoglycosides, and carbapenems) ^[5]
  • P. aeruginosa: intrinsic resistance to several antibiotics (e.g., most penicillins, most cephalosporins, and macrolides) ^[20][21]
• Mechanism of resistance: multiple mechanisms (e.g., decreased expression of porins in outer membrane, increased efflux pumps, ESBL)

P. aeruginosa has a high level of intrinsic resistance to antibiotics.

Acinetobacter baumannii ^[5]

• Resistance
  • MDR A. baumannii: ≥ 1 agent in ≥ 3 antibiotic categories used to treat Acinetobacter infections (i.e., cephalosporins, fluoroquinolones, aminoglycosides, carbapenems, piperacillin/tazobactam, ampicillin/sulbactam) ^[4]
  • Carbapenem-resistant A. baumannii: ≥ 1 carbapenems used to treat Acinetobacter infections (i.e., imipenem, meropenem, doripenem) ^[4]
• Mechanisms of resistance, e.g.: ^[5][8][22]
  • Enzymes (e.g., OXA carbapenemases, serine β-lactamases, aminoglycoside-modifying enzymes)
  • Alterations in outer membrane proteins and PBPs, efflux pumps
  • Genetic mutations

Candida auris is an invasive fungal pathogen that can colonize the skin and cause fungemia.

• Resistance ^[23]
  • Fluconazole: 90% of isolates
  • Amphotericin B: 30% of isolates
  • Echinocandins: 5% of isolates
• Mechanism of resistance: genetic mutations (often acquired after antifungal exposure) ^[23]

General principles ^[5][9]

• Engage antibiotic stewardship programs during antibiotic therapy selection and initiation.
• Consider infectious diseases consult in infections due to MDROs, especially in cases of carbapenem-resistant organisms.
• Select antibiotic therapy based on the pathogen, antibiotic susceptibilities, and site and severity of the infection.
  • Antibiotics to which the MDRO has resistance may still be effective at higher doses, increased frequency, and/or extended infusions. ^[24]
  • A combination of multiple antibiotics may be needed.
• Implement measures for infection prevention and control.

Antibiotic regimens for the same pathogen may differ based on the infection site and severity.

Antimicrobial therapy

Dosages depend on the specific disease and severity.

Infection prevention ^[9]

• Standard precautions
• Isolation precautions (e.g., in acute care settings) ^[30]
• Report notifiable diseases to the local health department.
• See also “Prevention of common health care-associated infections.”

Certain MDROs (e.g., carbapenem-resistant microorganisms, vancomycin-resistant S. aureus, C. auris) are reportable in the US. ^[9]

Decolonization ^[9][14]

• Not routinely recommended
• May be used in selected settings (e.g., patients in the ICU, preoperative) for MRSA eradication with either:
  • Mupirocin nasal ointment
  • Chlorhexidine gluconate baths ^[31]