Infectious Diseases

Staphylococcus aureus (S. aureus)

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Staphylococcus aureus -- a gram-positive coccus found singly, in pairs, tetrads, and irregular grapelike clusters. It is non-motile, non-spore forming, catalase positive, coagulase positive, and facultative anaerobe. It is both a colonizer (e.g., nares (primary reservoir), pharynx, axilla, groin, and/or damaged skin surfaces) and a disease-producing pathogen.

What is the best treatment?

Methicillin susceptible Staphylococcus aureus (MSSA)

B-lactam antibiotics are the drugs of choice—rapidly bactericidal, several studies indicate worse outcomes in patients with MSSA bacteremia treated with vancomycin versus cefazolin or nafcillin. Nafcillin is preferred over cefazolin for serious infections, such as bacteremia/endocarditis, although the latter is an alternative in the presence of a penicillin allergy. There are case reports describing failures with cefazolin due to the presence of a B-lactamase that hydrolyzes the drug in the setting of a high organism inoculum. Whether there is a clinically significant difference in treatment outcomes between the two drugs remains controversial. For patients with history of IgE-mediated reaction to penicillin or severe, life-threatening allergies, such as angioedema or anaphylaxis, consider penicillin desensitization or vancomycin. See Table I.

Table I.

Treatment of MSSA

Methicillin resistant Staphylococcus aureus (MRSA)

  • The preferred agent depends on the clinical syndrome being treated. See Table II.

Table II.

Treatment of MRSA

What alternative therapies are available?

  • For patients with persistent MRSA bacteremia with concern for vancomycin treatment failure, recommend a change in therapy (rather than addition of other therapies) to vancomycin. There are very limited clinical data, but consider the combination of high dose daptomycin (10 mg/kg/day) with a second susceptible agent (e.g., gentamicin 1 mg/kg/ IV Q8; rifampin 600 mg PO/IV daily or 300-450 mg PO/IVD BID; linezolid 600 mg PO/IV BID, TMP-SMX 5 mg/kg IV BID).

  • If reduced susceptibility to vancomycin and daptomycin (MIC > 1), options are limited. Consider any of the following agents as monotherapy or in combination with another agent: quinupristin-dalfopristin 7.5 mg/kg/dose IV Q8, TMP-SMX 5 mg/kg/dose IV BID, linezolid 600 mg PO/IV BID, telavancin 10 mg/kg/dose IV QD.

What are mechanisms of resistance and what laboratory methods are used for detection of resistance?

  • Methicillin resistance: Encoded by mecA gene. Recommended tests for detection of MRSA include cefoxitin disk screen test, the latex agglutination test for PBP2a, or a plate containing 6 ug/mL of oxacillin in Hueller-Hinton agar supplemented with NaCl.

  • Heteroresistant vancomycin intermediate resistant S. aureus (hVISA): Strains with a small, resistant subpopulation of cells. It is not detected by standard susceptibility testing methods. Current "gold standard" is population analysis, but it is too labor intensive and impractical for a clinical laboratory. Several other tests (e.g., macrodilution Etest, Etest glycopeptide resistance) are more sensitive and specific, but optimal assay predictive of outcomes is unknown.

  • Vancomycin intermediate S. aureus (VISA), MICs 4-8 ug/mL: Mechanism of resistance not entirely understood but involves thickening of the peptidoglycan cell wall. Not all susceptibility testing methods detect VISA and VRSA. VISA isolates are not detected by disk diffusion and may not be picked up by all automated MIC methods. VISA are usually detected by non-automated MIC methods, such as reference broth microdilution, agar dilution, and Etest using a 0.5 McFarland standard to prepare inoculum. Automated methods and vancomycin screen agar plates usually detect VISA strains with a vancomycin MIC of 8ug/mL, but the sensitivity of these methods for detection of VISA strains with MICs of 4 ug/mL requires further study.

  • Vancomycin resistant S. aureus (VRSA), MIC greater than or equal to 16 ug/mL: Transfer of vanA gene from vancomycin-resistant enterococcus to S. aureus. VRSA are detected by reference broth microdilution, agar dilution, Etest, MicroScan overnight and Synergies plus, BD Phoenix system, Vitek 2 system, disk diffusion, and the vancomycin screen agar plate (brain heart infusion (BHI) agar containing 6 ug/mL of vancomycin). Labs that use automated MIC methods that have not been validated for VRSA detection and labs using disk diffusion should add a commercial vancomycin screen agar plate to enhance detection of VRSA.

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology

  • There are no seasonal differences that have been described.

  • HA-MRSA: Hemodialysis, the presence of an indwelling catheter or a percutaneous device, surgery within the last 12 months, residence in a long-term care facility, and hospitalization within the last 12 months are environmental risks.

  • CA-MRSA: Household contacts of a patient with CA-MRSA infection, incarcerated persons, military personnel, men who have sex with men, athletes (particularly those involved in contact sports), and intravenous drug users are environmental risks. The Centers for Disease Control and Prevention (CDC) has proposed the five Cs of CA-MRSA transmission (Crowding, frequent skin-to-skin Contact, Compromised skin integrity, Contaminated items and surfaces, and lack of Cleanliness).

  • Since MRSA was first described in 1961, it was initially, almost exclusively health care-associated, but, by the mid-1990s, MRSA strains emerged among previously healthy individuals in the community who lacked healthcare-associated risk factors.

    1. CA-MRSA: Using data from The Surveillance Network (TSN) between 1999 and 2006, the frequency of CA-MRSA isolates increased seven-fold, suggesting outpatients are a major reservoir of CA-MRSA. In two studies performed in 2004 and 2008, among patients presenting to 11 emergency rooms throughout the United States, MRSA accounted for 59% of all SSTI. Between 1997 and 2005, the overall rate of outpatient/Emergency Department (ED) visits for SSTI increased from 32.1 to 48.1 visits per 1000 population and accounted for an estimated 14 million outpatient visits in 2005.

    2. HA-MRSA: Using data from the National Nosocomial Infections Surveillance (NNIS) between 1992 and 2003, the proportion of MRSA among S. aureus isolates in Intensive Care Units (ICU) increased from 35.9% in 1992 to 64.4% in 2003. However, this trend has stabilized somewhat. In 2006-07, 56% of S. aureus device associated infections were due to MRSA. Most recent data suggests an overall decrease in MRSA health-care associated infections in the United States.

    3. Invasive MRSA infections: In 2005, 94,000 people in the United States had invasive MRSA infection with approximately 19,000 deaths. Approximately 86% are health-care associated, and 14% are community-associated. Between 2005 and 2008, a 28% decrease in hospital-onset invasive MRSA infections and 17% decrease in invasive health-care associated community-onset infections was observed

  • Infection control issues

  • There is variability between institutions with respect to the use of contact precautions for patients with MRSA. Some use contact precautions for patients who are either colonized or infected; others use contact precautions only for those patients with active infection. Some hospitals recommend standard precautions with hand hygiene for patients with MRSA without any additional barrier precautions, unless personal protective equipment is called for anticipated contact with body substances or contaminated equipment.

  • The use of contact precautions (i.e., gowns and gloves) is recommended by several published guidelines: 2008 SHEA/IDSA Strategies to Prevent MRSA transmission in Hospitals (AII) and 2006 CDC Healthcare Infection Control Practices Advisory Committee Management of multi-drug resistant organisms in healthcare settings (BI).

  • Some have noted potential unintended adverse consequences associated with use of contact isolation and argue that, if efforts to prioritize hand hygiene as a more universally applicable approach to HAI prevention are successful, the role for contact isolation may be more limited. Contact precautions are recommended for VISA/VRSA strains.

  • Currently, there is no vaccine available.

  • Vancomycin is not routinely recommended for perioperative prophylaxis against MRSA (BII) 2008 SHEA/ IDSA Strategies to Prevent Surgical Site Infections (SSI) in Acute Care Hospitals. There is no published data to indicate benefit, but may consider use in specific circumstances: documented outbreak of MRSA SSI, high endemic rates of MRSA SSI, target high-risk patients who are at increased risk of MRSA SSI (CT surgery and high-risk surgical procedures in which implant is placed).

  • The role of decolonization of S. aureus nasal carriers with agents, such as mupirocin and chlorhexidine, remains controversial. A recently published study suggests that the combination of mupirocin and chlorhexidine is effective in reducing surgical site infections among patients who are S. aureus nasal carriers. There does not appear to be any clear benefit of this combination or mupirocin alone preventing infections among hospitalized non-surgical patients.

What host factors protect against this infection?

  • Innate immunity, in particular, activity by neutrophils, is the primary host defense. However, as it is part of normal human flora, S. aureus can circumvent human host defense to cause infection.

  • HA-MRSA: Hospitalization during the previous year, recent surgery, exposure to broad-spectrum antibiotics, residence in long-term care facility, hemodialysis, and indwelling percutaneous medical devices and catheters increase risk.

  • CA-MRSA: Healthy adults and children without the above risk factors are at higher risk, and it appears to be more easily transmitted in settings where people are in close contact (e.g., households, daycare centers, military installations, prisons, athletes). Other groups at increased risk include Native Americans, Pacific Islanders, and men who have sex with men.

  • Certain strains (but not all strains) of MRSA (in particular, the USA300 strain of CA-MRSA) and MSSA have been observed to cause necrotizing infections, including necrotizing pneumonia with necrotic lesions of the tracheal mucosa and alveolar septa as well as necrotizing fasciitis. Such strains carry the Panton-Valentine leukocidin (PVL), a two component toxin that lyses polymorphonuclear neutrophils (PMNs), monocytes, and macrophages. PVL induces release of histamine from basophils and stimulates PMNs to release enzymes (e.g., B-glucuronidase and lysozyme), chemotactic factors (e.g., leukotriene-B4 and IL-8), and oxygen metabolites.

What are the clinical manifestations of infection with this organism?

  • Staphylococcus aureus can invade and cause disease in previously normal tissue at virtually all sites. The most commonly encountered diseases associated with S. aureus include:

  • Skin and soft tissue infections (SSTI): A wide range of manifestations, including furuncles, abscesses, cellulitis [purulent > non-purulent cellulitis], surgical wound infections, and necrotizing fasciitis. CA-MRSA skin infections have been incorrectly mistaken (by patient and doctor) for "spider bites." Although S. aureus has historically been an unusual cause of necrotizing fasciitis, in recent years, CA-MRSA has emerged as a cause of monomicrobial necrotizing fasciitis.

  • Bacteremia: Higher rates of mortality are seen with MRSA compared with MSSA. Potential reasons include difference in patient population/severity of illness although a meta-analysis found that association between MRSA bacteremia and mortality persists even after adjusting for comorbidities or severity of illness, as well as decreased efficacy of MRSA therapy relative to MSSA therapy, potential delays in initiation of appropriate therapy).

    • Careful history and physical exam is recommended to assess for sites of primary or metastatic sites of infection, including intravenous catheter sites, any areas containing prosthetic material, bones and joints, epidural space and intervertebral disks, heart valves, the liver, kidney, and spleen.

    • Look for evidence of focal pain, point tenderness, joint effusions, murmurs, or peripheral stigmata of endocarditis. Perform radiographic studies as indicated by exam (e.g., spinal MRI in patient with worsening back pain to r/o vertebral osteomyelitis and/or epidural abscess).

    • Echocardiogram should be performed in patients with S. aureus bacteremia to evaluate for endocarditis.

    • Surveillance blood cultures 2-4 days after initial positive cultures recommended to document clearance of bacteremia.

  • Endocarditis: S. aureus is the most common cause of bacterial endocarditis worldwide with MRSA IE being more common in the United States compared to Europe and Australia. S. aureus is also the leading cause of prosthetic valve endocarditis. Transesophageal echocardiography (TEE) is superior to transthoracic echocardiography (TTE) for detection of vegetations and identification of complications, such as intracardiac abscess and valve perforation.

  • Pneumonia: This is an uncommon cause of community-acquired pneumonia (CAP) but, with the emergence of CA-MRSA, has been described as a cause of severe CAP. Severe MRSA CAP has been associated with a preceding/concurrent influenza-like illness, necrotizing/cavitary infiltrates and empyemas. MRSA is an important cause of health-care associated pneumonia, including ventilator-associated pneumonia (VAP).

  • Bone and joint infections: This includes osteomyelitis, septic arthritis, and prosthetic joint infections. It can arise from direct inoculation due to trauma, a medical procedure, or a contiguous focus of infection, vascular insufficiency (e.g., diabetes), or hematogenous seeding.

  • Central nervous system infections: This includes meningitis, brain abscess/subdural empyema, and septic cavernous thrombosis. It typically occurs as a complication of a neurosurgical procedure, in association with a contiguous focus of infection, or hematogenously as a complication of bacteremia or endocarditis.

  • Ocular disease: This includes orbital cellulitis, endogenous endophthalmitis, panophthalmitis, lid abscesses, and septic venous thrombosis

  • Staphylococcal toxic shock syndrome (TSS): This is an illness characterized the following constellation of signs and symptoms with the isolation of S. aureus from a mucosal or normally sterile site: fever, hypotension, diffuse macular rash with subsequent desquamation 1-2 weeks after onset of illness particularly palms and soles, multi-organ involvement with three or more systems involved (e.g., liver, hematologic, renal, mucus membranes, gastrointestinal, muscular, central nervous system), negative serologies for measles, leptospirosis, Rocky Mountain spotted fever and negative blood, throat, or CSF cultures for organisms other than S. aureus.

    • It is associated with toxic shock syndrome toxin-1 (TSST-1) and was associated with use of high-absorbency tampons during menses in the early 1980s.

    • Non-menstrual TSS has been observed in patients with staphylococcal colonization of other mucosal or skin surfaces.

  • Staphylococcal scalded skin syndrome: This is a superficial skin disorder that can manifest as local blistering to generalized scalding. It is typically due to mucosal or skin colonization with a toxin-producing strain of S. aureus.

  • Staphylococcal food poisoning: This occurs because of ingestion of preformed enterotoxin that has been released into contaminated food. Disease occurs 2-6 hours after ingestion with nausea, vomiting, abdominal pain, and diarrhea. It is typically self-limited with resolution of symptoms within 6-12 hours.

  • CA-MRSA has also been associated with several severe clinical syndromes not previously observed with S. aureus,including necrotizing fasciitis, necrotizing pneumonia, and Waterhouse-Friderichson syndrome.

What common complications are associated with infection with this pathogen?

  • Complicated skin and soft tissue infections include deep soft-tissue infections, surgical and/or traumatic wounds, major abscesses, infected ulcers and burns, and necrotizing fasciitis.

  • Complicated bacteremia includes those patients who do NOT meet the following criteria for uncomplicated bacteremia: exclusion of endocarditis; no implanted prosthesis; follow-up blood cultures drawn 2-4 days after initial set do not grow MRSA; defervescence within 72 hours of therapy; and no evidence of metastatic sites of infection. These patients may present with persistently positive blood cultures and metastatic foci of infection (e.g., infection at distant site from the primary focus including hepatic, splenic, and perinephric abscesses).

  • Endocarditis may also be complicated by metastatic foci of infection as described, depending on location of vegetation. With right-sided endocarditis, one may see septic pulmonary emboli. With left-sided endocarditis, one may see septic CNS emboli and hepatic, splenic, perinephric abscesses. Other complications of endocarditis include perivalvular or myocardial abscess, new heart block, valvular insufficiency, valve perforation or dehiscence, decompensated heart failure, and persistent bacteremia.

  • Complications of pneumonia may include parapneumonic effusion, empyema, and pulmonary abscess.

  • As mentioned previously, Staphylococcus aureus can invade and cause disease in previously normal tissue at virtually all sites, and patients can present with multiple sites of infection/disseminated infection and sepsis due to S. aureus with multi-organ involvement.

How should I identify the organism?

  • As clinically indicated, obtain cultures of abscess, blood, sputum, and bone.

  • Gram stain reveals gram-positive cocci that can occur singly, in pairs, tetrads, and irregular grapelike clusters

  • Blood agar and thioglycolate broth is the preferred media or tissue culture

  • Large, round, golden-yellow colonies often with hemolysis (in contrast to Staphylococcus epidermidis where the colonies are relatively small and white without hemolysis.) are the expected colony morphology or cytopathic effect.

  • Catalase positive and oxidase negative, coagulase positive are used for specific identification. Staphaurex is a rapid latex agglutination test for identification of S. aureus through detection of clumping factor and protein A. The coagulase test distinguishes S. aureus from S. epidermidis,which is coagulase negative. MIC testing is performed to distinguish between MRSA and MSSA. Other methods recommended by the Clinical and Laboratory Standards Institute (CLSI) to test for MRSA include the cefoxitin disk screen test, the latex agglutination test for PBP2a, or a plate containing 6 ug/mL of oxacillin in Mueller-Hinton agar supplemented with NaCl).

  • Growth usually occurs within 18-24 hours.

  • Most studies describing the sensitivity of culture techniques have been for detection of MRSA. The sensitivity of routine culture based methods (read at 48 hours) for MRSA detection is 86.9% (74.7-93.7%) with specificity of 89.7% (77.7-95.6%). If chromogenic agar media is used, the sensitivity is 78.3% (71.0-84.1%) and specificity 98.6% (97.7-99.1%) if read at 18-24 hours; if incubation time is extended to 48 hours, then the sensitivity is 87.6% (82.1-91.6%) and specificity 94.7% (91.6-96.8%)

  • Several S. aureus polymerase chain reaction (PCR) assays are available; currently, the majority of PCR assays focus on detection of MRSA from nasal swab specimens and the sensitivity is 92.5% (87.4-95.9%) and specificity is 97.0% (94.5-98.4%). The major advantage of PCR-based assays is its rapid turnaround time, which can be as fast as 2 hours, depending on lab workflow and whether samples are batched.

  • Although most currently available assays focus on MRSA screening PCR from nasal swabs, there is a PCR assay that allows one to distinguish between S. aureus and MRSA from nasal swab (Cepheid Xpert SA Nasal Complete sensitivity 92-93%, specificity 91%-98%), as well as a commercially available PCR that allows for rapid distinction between S. aureus and MRSA from positive blood cultures (BD GeneOhm sensitivity 98-100%, specificity 97-98%).

  • The above methods are the primary methods available commercially for identification of the pathogen.

How does this organism cause disease?

  • Panton-Valentine leukocidin (PVL): A cytotoxin that lyses neutrophils found in USA300, the predominant CA-MRSA clone, as well as some strains of CA-MSSA. Although some of the increased virulence of CA-MRSA has been attributed to PVL, its precise role in CA-MRSA pathogenesis remains controversial.

  • Alpha toxin (alpha hemolysin): A pore-forming toxin that lyses macrophages, erythrocytes, lymphocytes, and has pro-inflammatory effects. It is a well-established major virulence determinant of S. aureus.

  • Phenol-soluble modulins: A class of surfactant-like, amphipathic, alpha-helical peptides, some of which are capable of lysing neutrophils, erythrocytes, and monocytes. It has proinflammatory effects.

  • Arginine catabolic mobile element (ACME): Contains genes that potentially help survival on human skin, found in USA300 strains, perhaps contributing to success of transmission.

  • Superantigens are responsible for food poisoning (enterotoxin A-D), toxic shock syndrome (toxic shock toxin-1 TSST-1), and staphylococcal scalded skin syndrome (exfoliation A and B)

  • The proinflammatory and cytolytic toxins alpha toxin, phenol-soluble modulins, and PVL appear to impact the severity of disease caused by CA-MRSA strain USA300, although the exact contribution of each toxin is unknown.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Anderson, D, Kaye, K, Classen, D.. "Strategies to prevent surgical site infections in acute care hospitals". Infect Control Hosp Epidemiol. vol. 29. 2008. pp. S51-61.

(This is the joint SHEA/IDSA practice guidelines on surgical site infection prevention, including the role of vancomycin for antimicrobial prophylaxis.)

Calfee, D, Salgado, C, Classen, D. "Strategies to prevent transmission of MRSA in acute care hospitals". ICHE. vol. 29. 2008. pp. S62-80.

(This is the joint SHEA/IDSA guidelines on prevention of MRSA transmission in hospitals.)

"Centers for Disease Control and Prevention (CDC). Laboratory Detection of Vancomycin-Intermediate/Resistant Staphylococcus aureus (VISA/VRSA)".

(CDC website - guidance for clinical laboratories on detection of VISA, VRSA.)

Daum, RS. "Skin and soft tissue infections caused by MRSA". NEJM. vol. 357. 2007. pp. 380-90.

(This is a review of the epidemiology of CA-MRSA and the approach to management of its most common clinical manifestation, SSTI.)

Liu, C, Bayer, A, Cosgrove, S. "Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of MRSA infections in adults and children". Clin Infect Dis. vol. 52. 2011. pp. 285-322.

(This source provides evidence-based guidance on the management of MRSA infections with references.)

Luteijn, JM, Hubben, GA, Pechlivanoqlou, P, Bonten, MJ, Postma, MJ. "Diagnostic accuracy of culture-based and PCR-based detection tests for MRSA: a meta-analysis". Clin Microbiol Infect. vol. 17. 2011. pp. 146-54.

(This is meta-analysis describing sensitivity and specificity of culture-based and PCR based methods for detection of MRSA.)

Tenover, Moellering, RC. "The rationale for revising the clinical and laboratory standards institute vancomycin minimal inhibitory concentration interpretive criteria for S. aureus". Clin Infect Dis. vol. 44. 2007. pp. 1208-15.

(This source reviews mechanisms of vancomycin resistance and rationale behind current susceptibility breakpoints.)
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