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Methicillin-resistant Staphylococcus aureus (MRSA)

Staphylococcus aureus strain resistant to methicillin and other β-lactam antibiotics and one of the leading causes of hospital-acquired infections.

This digitally-colorized scanning electron microscopic (SEM) image depicts a number of mustard-colored, spheroid-shaped Staphylococcus aureus bacteria that were in the process of escaping their destruction by blue-colored human white blood cells. Magnification – 20,000x. | Image credit: National Institute of Allergy and Infectious Diseases.

Staphylococcus aureus strain resistant to methicillin and other β-lactam antibiotics and one of the leading causes of hospital-acquired infections.

  • Methicillin resistance in S. aureus is defined as an oxacillin minimum inhibitory concentration (MIC) of greater ≥ 4 micrograms/mL

MRSA infection subclassification:

Staphylococcus aureus strain resistant to methicillin and other β-lactam antibiotics and one of the leading causes of hospital-acquired infections.
  • Hospital-associated (HA-MRSA) infections
  • Community-associated (CA-MRSA) infections X

Microbiology

Clinical suspicion in patients with risk factors related to MRSA infection is crucial in diagnostic and therapeutic intervention. Confirmation of MRSA infection should not delay treatment with empiric antibiotics against MRSA. Clinicians should send samples from suspected sources of infection for analysis including blood, sputum, urine, or wound scraping.

Bacterial culture:

Sputum cultures are not very specific or sensitive to diagnose MRSA pneumonia, therefore bronchoalveolar lavage or a deep tracheal aspirate for intubated or tracked patients can be performed to identify the organism in patients with HAP or VAP.
  • Positive Gram stain with cocci in clusters: Suggestive of S. aureus

DNA polymerase chain reaction (PCR):

M/sensitive test and gold standard test if cultures are inconclusive
  • DNA PCR of MRSA from nares is a frequently employed diagnostic test to rule out MRSA colonization.
Methicillin-resistant Staphylococcus aureus (MRSA) from phenotype to genotype. a) Microscopic appearance of S. aureus. The inset shows growth of S. aureus on a selective plate (Mannitol salt agar). Scale bar = 10 μm. b) Pulsed-field gel electrophoresis to detect relatedness among different MRSA isolates. Isolates 2 and 3 appear very similar and are considered clonally related [22]. c) Multiple PCR for Staphylococcal Chromosome Cassette mec (SCCmec) typing, showing results for SCCmec type I, II, III and IV [25]. d) The Ridom Seq-Net website, in collaboration with Seq-Net (www.spaserver.ridom.de), for spa typing. | M: molecular size marker. | Pantosti, A., & Venditti, M. (2009). What is MRSA? European Respiratory Journal, 34(5), 1190–1196. https://doi.org/10.1183/09031936.00007709

Etiology

MecA gene:

The key reason for MRSA resistance to beta-lactam antibiotics is due to the presence of the mecA gene sequence, which is known to generate transpeptidase PB2a that lowers the affinity of the organism to bind to beta-lactam antibiotics.

Methicillin resistance has occurred in S. aureus by mutation of a penicillin-binding protein, a chromosome-encoded protein. This type of resistance is transferred between S. aureus organisms by bacteriophages. This is one of the only medically relevant examples of chromosome-mediated drug resistance by phage transduction.

Risk factors:

Commonly associated risk factors for MRSA infection are:
  • Prolonged hospitalization, intensive care admission, recent hospitalization, admission to nursing homes
  • Recent antibiotic use, invasive procedures, hemodialysis, and discharge with long-term central venous access or long-term indwelling urinary catheter
  • MRSA colonization
  • HIV infection, open wounds

Pathology

MRSA can cause a range of organ-specific infections, the most common being the skin and subcutaneous tissues, followed by invasive infections like osteomyelitis, meningitis, pneumonia, lung abscess, and empyema. Infective endocarditis caused by MRSA is associated with an increased morbidity and mortality compared to any other organism and is linked to intravenous drug abuse.

Methicillin-resistant Staphylococcus aureus colonization.
Methicillin-resistant Staphylococcus aureus colonization: a | Impact of methicillin-resistant Staphylococcus aureus (MRSA) colonization on hospital-acquired infection and community transmission. b | MRSA screening by anatomic site. Swab culture of nares is the most standard and widely used method for detecting MRSA carriers; however, recent data have shown that extranasal colonization is frequent. Extranasal MRSA screening increased MRSA detection by one-third over that detected by MRSA nares screening alone, indicating that sole assessments of MRSA nasal carriage are not sufficient. ICU, intensive care unit; SSTI, skin and soft tissue infection. | Turner, N.A., Sharma-Kuinkel, B.K., Maskarinec, S.A. et al. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research. Nat Rev Microbiol 17, 203–218 (2019). https://doi.org/10.1038/s41579-018-0147-4

Skin and soft tissue infections (SSTI): These infections are multidrug-resistant leading to frequent recurrence, increased hospitalization, and mortality

  • Cellulitis
  • Necrotizing fasciitis
  • Diabetic foot ulcers
Cutaneous MRSA abscess located on the hip of a prison inmate, which had begun to spontaneously drain, releasing its purulent contents
Cutaneous MRSA abscess located on the hip of a prison inmate, which had begun to spontaneously drain, releasing its purulent contents. | CDC: http://www.cdc.gov/mrsa/mrsa_initiative/skin_infection/mrsa_photo_7826.html.)

Bone and joint infection:

Staphylococci are the most common cause of bone and joint infections. Oxacillin resistance has become increasingly common among these patients.
  • Osteomyelitis of spine, long bones of upper and lower extremities by extension of local infection from a wound or as a part of hematogenous infection
  • Septic arthritis of both native and prosthetic joints

Necrotizing pneumonia:

Life threatening pneumonia characterized by multilobar cavitating alveolar infiltrates with severe respiratory symptoms, high fevers, hemoptysis, and hypotension. It rapidly progresses to sepsis and septic shock with leukopenia and elevated C-reactive protein (> 350 mg/dL).
Necrotising pneumonia
Necrotising pneumonia on a) a chest radiograph and b) a computed tomography (CT) scan obtained on day 3. The CT scan shows multiple bilateral nodular and cavity lesions. | Micek ST, Dunne M, Kollef MH. Pleuropulmonary complications of Panton-Valentine leukociclin-positive community-acquired methicilin-resistant Staphylococcus aureus: importance of treatment with antimicrobials inhibiting exotoxin production. Chest 2005;128:2732–2738.

Bacteremia:

Commonly seen in intensive care unit patients with central line insertions and is associated with mortality rates of 15-60%.

Endocarditis:

Mortality in about a third of the infected patients (30-37%)
  • Right-sided MRSA endocarditis: Associated with IV drug use and IV catheters. Patients with tricuspid valve vegetations may have septic pulmonary emboli causing nodular infiltrates and cavitating lesions in the lungs.
  • Left-sided MRSA endocarditis (mitral & aortic valves): Secondary infections in distant foci such as bones and joints, kidneys, brain, and other organs

Management

The selection of empiric antibiotic therapy for the treatment of MRSA infection depends on the type of disease, local S. aureus resistance patterns, availability of the drug, side effect profile, and individual patient profile.

SSTIs:

For most uncomplicated SSTIs suspected of MRSA infection, empirical treatment with oral antibiotics is preferred. Parenteral antibiotics are indicated for invasive SSTIs or with signs of systemic involvement, inadequate response to oral therapy, or if an SSTI occurs adjacent to an indwelling device. Regardless of the initial empiric antibiotic choice, subsequent therapy should be tailored based on the careful review of culture and susceptibility data. The duration of therapy for treatment of MRSA SSTIs may range from 5 to 14 days depending on the extent of infection and response to treatment.
  • Empirical treatment:
    • Trimethoprim/sulfamethoxazole
    • Tetracyclines: Doxycycline or minocycline, and clindamycin
    • Alternative regimens: Linezolid and tedizolid, and delafloxacin
  • Parenteral antibiotics:
    • IV vancomycin: DOC in hospitalized patients (empiric and definitive therapy)
    • Alternatives:
      • Daptomycin (preferred)
      • Other short-acting options: Ceftaroline and telavancin
      • Long-acting options: Dalbavancin and oritavancin

Bacteremia:

Source control is a significant part of the treatment for MRSA bacteremia along with empiric MRSA coverage until the susceptibility results are available.
  • Empiric therapy: Vancomycin and daptomycin
  • Alternatives: Telavancin and ceftaroline
  • Combination regimens (for difficult to treat cases):
    • Daptomycin + ceftaroline
    • Vancomycin + ceftaroline
    • Daptomycin + trimethoprim-sulfamethoxazole
    • Ceftaroline + trimethoprim-sulfamethoxazole.
  • No role for: Linezolid, quinupristin-dalfopristin, tigecycline, or fluoroquinolones

Follow-up cultures should be repeated to document clearance of the infection from the bloodstream. Persistent, positive cultures after 48 hours of treatment should prompt further evaluation related to drug susceptibility and source control.

Endocarditis:

  • Native valve endocarditis: 6 week duration
    • IV vancomycin (first line) or IV daptomycin (alternative)
  • Prosthetic valve endocarditis: 6 week duration
    • IV vancomycin (first line) or IV daptomycin (alternative) + gentamicin (first 2 weeks)
  • Salvage therapy: Telavancin, ceftaroline and quinupristin-dalfopritin
  • Not indicated: Clindamycin or linezolid

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