Staphylococcal infections; MRSA

I. What every physician needs to know.

Staphylococcus aureus (S. aureus), a commensal organism that asymptomatically colonizes the nares, and to a lesser degree, the vagina, pharynx, axillae, and skin in about 30 percent of healthy people. The ability of S. aureus to gain entry to, and then cause illness in almost any part of the body, including those areas that have healthy tissue, is an important characteristic of this organism. S. aureus commonly causes infections in the skin and soft tissue, bones, joints, and the respiratory system. It also is a frequent cause of surgical site and to a lesser degree, endovascular infections.

Methicillin-resistant S. aureus (MRSA) was first reported in 1961, that is, within a year after Methicillin was introduced to combat the resistance of the organism to penicillin, which had been observed within 1-2 years after the introduction of the latter antibiotic. MRSA now comprises more than fifty percent of all S. aureus strains that cause disease. In comparison with patients who have methicillin-sensitive S. aureus (MSSA) bacteremia, those with MRSA bacteremia tend to have higher in-hospital and 30-day mortality rates, a higher rate of acute renal failure, and longer intensive care unit (ICU) stays. Endocarditis and bacteremia more commonly occur in patients with an MRSA infection, in comparison with those who have an MSSA infection.

The two widely recognized categories of MRSA infection are hospital-acquired (i.e. HA-MRSA) and community-acquired (i.e. CA-MRSA). HA-MRSA has been recognized since the 1960s; however, it was not until the 1990s that CA-MRSA was identified. The mecAgene, which is found in staphylococcal cassette chromosome SCCmec, codes for penicillin-binding protein (PBP) 2A, and this confers resistance to beta-lactam and non-beta-lactam antibiotics. Differences in SCCmec distinguish HA-MRSA from CA-MRSA, that is, Type I, II or III SCCmec is the genetic element that is typically found in HA-MRSA, while CA-MRSA usually contains types IV and V SCCmec, and the Panton-Valentine leukocidin (PVL) gene.

The PVL gene is responsible for producing the PVL toxin, which is an important virulence factor for CA-MRSA, since it destroys leukocytes. HA-MRSA is usually produced by the USA100 or USA200 clones, while CA-MRSA is usually caused by the USA300 or USA400 clones. In terms of susceptibility to antibiotics, HA-MRSA demonstrates resistance to clindamycin, tetracyclines, gentamicin, trimethoprim-sulfamethoxazole, and fluoroquinolones, while CA-MRSA can often be treated with these non-beta-lactam antibiotics.

HA-MRSA develops more than 48 hours after a patient is hospitalized, or within 1 year of being exposed to a healthcare facility. HA-MRSA causes severe illness, and most often occurs in older patients. This pathogen is an important cause of skin and skin and soft tissue infection (SSTI), pneumonia, and bloodstream infections.

Infections caused by CA-MRSA frequently occur in children and young adults who were previously healthy, and have had no contact with healthcare settings. It is now the most common identifiable cause of SSTIs in patients who present to emergency rooms in the USA. Less frequently, it also causes severe sepsis, necrotizing pneumonia, necrotizing fasciitis, or Waterhouse-Friderichsen syndrome, often in patients who do not have any underlying illnesses.

It is important to be aware that despite the differences described above for HA-MRSA and CA-MRSA, over time, it has become increasingly difficult to distinguish between them, since patients can become colonized with MRSA in one setting, but then demonstrate evidence of infection in another location. This would apply to a patients who become colonized with HA-MRSA during a hospital stay, but do not develop symptoms of infection until several months after their hospital discharge. Some authors have concluded that CA-MRSA is replacing HA-MRSA in healthcare facilities.

II. Diagnostic Confirmation: Are you sure your patient has methicillin-resistant staphylococcus aureus?

MRSA infection can result in many illnesses (including skin and soft-tissue infections [SSTIs], pneumonia, osteomyelitis, and endocarditis) and the clinical manifestations will vary depending on the patient’s diagnosis.

Please see below.

A. History Part I: Pattern Recognition:

A patient with a SSTI due to MRSA may present with a skin lesion that looks like a spider bite or furuncle. The skin lesion may be painful, erythematous, swollen, and filled with purulent material.
A patient with pneumonia due to MRSA may present with dyspnea, fever, chills, cough (with or without hemoptysis), generalized weakness, tachycardia.
A patient with osteomyelitis due to MRSA may present with joint pain, fever, chills, pain and swelling over the affected site.
A patient with endocarditis due to MRSA may present with fever, chills, heart murmur, dyspnea, tachycardia, hemoptysis, arthralgias, myalgias, anorexia, pallor, Janeway lesions, Osler nodes, Roth spots, generalized weakness.

B. History Part 2: Prevalence:

Risk factors for the development of CA-MRSA are:

Antibiotic therapy within the past 3 months.
Hospitalization within the past year.
Long-term care facility residence.
Chronic illness.
Military service.
HIV infection.
Diabetes mellitus.
Injection drug abuse.
Homosexual men.
Prison inmates.
Sharing razors or needles.
Long period of hospitalization.

C. History Part 3: Competing diagnoses that can mimic methicillin-resistant Staphylococcus aureus.

Differential diagnosis for:

Skin and soft-tissue infection:

Lyme disease.
Spider bite.
Venous thrombosis.
Ruptured Baker’s cyst.
Erythema nodosum.
Gout.
Septic arthritis.
Post-radiation dermatitis.
Osteomyelitis.

Pneumonia:

Lung cancer.
Pulmonary embolus.
Chronic obstructive pulmonary disease (COPD).
Foreign body aspiration.
Lung abscess.
Bronchiectasis.
Pulmonary edema.
Asthma.
Bronchitis.
Sepsis.
Tuberculosis.
Acute Respiratory Distress Syndrome (ARDS).

Osteomyelitis:

Cellulitis.
Gout.
Fracture (stress or traumatic).
Septic arthritis.
Inflammatory arthritis (e.g. Reiter’s syndrome, psoriatic arthritis, rheumatoid arthritis).
Bone cancer (e.g. osteosarcoma, Ewing’s sarcoma).
Bone infarction.
Pseudogout.
Gas gangrene.

Endocarditis:

Polymyalgia rheumatica.
Atrial myxoma.
Tuberculosis.
Microscopic polyangiitis.
Henoch-Schonlein purpura.
Acute rheumatic fever.
Polyarteritis nodosa.
Drug reaction.
Systemic lupus erythematosus.
Gout.
Poststreptococcal glomerulonephritis.

D. Physical Examination Findings.

SSTI: Erythematous, painful, swollen skin lesion often containing purulent material.
Osteomyelitis: Swelling, pain, and warmth over the affected area.
Pneumonia: Rhonchi or other adventitious breath sounds, tachypnea.
Endocarditis: Heart murmur, Janeway lesions, Osler nodes, Roth spots.

E. What diagnostic tests should be performed?

N/A

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Blood cultures: If S. aureus is isolated from any blood culture, then appropriate antibiotic therapy for MRSA must be started promptly. Repeat blood cultures should be collected in 48-72 hours, to determine whether or not the bacteremia has resolved.
Wound culture (i.e. collected during an incision and drainage procedure): Important to determine the bacterial etiology of the SSTI.
Bone biopsy: Important for patients with osteomyelitis, to determine the causative organism.
Sputum culture: May be helpful for patients with pneumonia, to help determine the causative organism.
Complete blood count (CBC): For all patients, to assess for leukocytosis.
Basic metabolic panel (BMP): For all patients, to assess baseline renal function.
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP): Markers of inflammation, and may be helpful to aid in the diagnosis of osteomyelitis.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

In order to confirm a diagnosis of:

SSTI, imaging studies are not routinely needed.
Endocarditis in patients with S. aureus bacteremia, a transesophageal echocardiogram (which is more sensitive than a transthoracic echocardiogram) should be considered.
Pneumonia, a chest X-ray should be obtained.
Osteomyelitis, the following imaging studies should be considered:

Plain X-rays.

Computed tomography (CT) scan.

Magnetic resonance imaging (MRI).

Indium-labeled white cell scan.

Positron emission tomography (PET) scan done in association with CT scan.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

None.

III. Default Management.

Obtain CBC and BMP for all patients, and blood cultures from febrile patients (before giving the first dose of antibiotic therapy).
Additional steps will depend on the suspected diagnosis. For patients with possible:

a) SSTI –

An incision and drainage procedure for the abscess is necessary. In some instances, incision, and drainage is all that is necessary without any antibiotic therapy.

Send fluid from the wound for culture and sensitivity, before giving the first dose of antibiotic therapy.

b) Osteomyelitis –

Obtain ESR and CRP.

Obtain plain X-rays of the affected site.

If plain X-rays do not confirm that osteomyelitis is present, then consider obtaining an MRI.

Start antibacterial therapy in the emergency room.

Bone biopsy by an orthopedist should be considered, once the diagnosis of osteomyelitis has been established.

c) Pneumonia –

Obtain a chest X-ray.

Consider obtaining a sputum culture, before administering the first dose of antibiotic therapy.

d) Endocarditis –

For patients with clinical stigmata of endocarditis, the prompt initiation of antibiotic therapy is necessary.

An echocardiogram should be ordered, but for stable patients, it does not need to be done emergently.

Consider early valve replacement for patients with left-sided endocarditis due to MRSA (consult cardiology and infectious diseases).
If the patient has a central venous catheter or other likely source of infection in place, then its removal will be necessary to allow for adequate treatment.

A. Immediate management.

Antibiotic therapy should be initiated in the emergency room, after collection of the cultures (i.e. blood/sputum/wound) that are appropriate for the suspected diagnosis.

B. Physical Examination Tips to Guide Management.

Monitoring of the site affected by a SSTI for resolution of erythema and tenderness is important to confirm a good response to antibiotic therapy (and the incision and drainage procedure, if one was carried out).
For patients with osteomyelitis, who presented with erythema, pain, and/or swelling at the affected site, this area should be monitored for evidence of clinical improvement.
Monitoring of lung sounds is important for patients with pneumonia, since adventitious lung sounds should resolve with appropriate therapy.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

For patients who present with leukocytosis, a daily CBC should be collected, until it has resolved.
For bacteremic patients, blood cultures should be collected once daily, until they become sterile.
For patients who are receiving potentially nephrotoxic antibiotics, their renal function should be monitored once daily by obtaining a BMP.
For patients with osteomyelitis, the ESR and CRP should be checked once daily, until these values are near normal (or the patient is ready for discharge from the hospital).

D. Long-term management.

Not applicable for this diagnosis since the MRSA infection is expected to resolve with appropriate antibiotic therapy.

E. Common Pitfalls and Side-Effects of Management

The prompt initiation of bactericidal antibiotic therapy is very important for patients who have an MRSA infection.
The performance of an incision and drainage procedure for patients who have an abscess due to a SSTI is necessary, to allow for resolution of the infection.

Antibiotics available for the treatment of MRSA infections:

Vancomycin 15-22.5mg/kg IV q 12 hours (recommended for the treatment of MRSA bacteremia, as well as all other types of MRSA infections).
Daptomycin 6mg/kg IV q 24 hours (recommended for the treatment of MRSA bacteremia, but should not be used to treat pneumonia).
Trimethoprim-sulfamethoxazole 10-15mg/kg/day in 2 or 3 divided doses.
Linezolid 600mg IV or PO q 12 hours (may not be adequate for the treatment of MRSA bacteremia).
Clindamycin 600-900mg IV q 6-8 hours (should not be used as monotherapy for bacteremia or endocarditis, due to the possibility of treatment failure).
Quinupristin-dalfopristin 7.5mg/kg IV q 12 hours.
Tigecycline 100mg IV once, followed by 50mg IV q 12 hours (may not achieve high enough serum levels to adequately treat bacteremia).
Teicoplanin 400mg IV q 12 hours (recommended as an alternative for the treatment of osteomyelitis, if vancomycin cannot be used).

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

The doses of the selected antibiotic(s) may need to be adjusted for patients who have abnormal renal function.