A. Major Pathogenic Species

1. Staph. aureus
2. Staph. epidermidis
3. Staph. saprophyticus

B. Properties of Staphylococci

1. G+ cocci arranged in clumps
2. Pathogenic factors include
   1. Cell wall - highly inflammatory lipoteichoic acids
   2. Proteases, lipases, and hyaloronidase
   3. Coagulase - prothrombin activator (uncertain pathogenic significance)
   4. Toxins - including some that cause toxic shock syndrome
   5. Hemolysins
   6. Over 95% of all staph isolates are penicillin resistant (ß-lactamase producing)
3. Highly pyogenic (pus-forming) organisms
4. Normal flora in skin and respiratory tract: facultative pathogen
5. Staph aureus
   1. About 2,800 kilobase genome
   2. Common plasmids, prophages, transposons
   3. Cell wall is ~50% peptidoglycan - N-acetylglucosamine, N-acetylmuramic acid
   4. Riboitol teichoic acids covalently bound to peptidoglycan
   5. Lipoteichoic acid linked to glycolipid terminus, anchored to cytopasmic membrane
   6. About 50% of healthy persons are colonized (~20% persistently)
   7. 1-5% of colonized persons may carry methicillin resistant Staph aureus (MRSA)
6. Antitiobic Resistant Staph aureus [2]
   1. Nearly all Staph aureus carry ß-lactamase, making them penicillin resistant
   2. MRSA originates from introduction of the large (~20-55kb) genetic element SCCmec
   3. SCCmec (staphylococcal cassette chromosome mec) transfer into sensitive staph renders them resistant to methicillin and related antibiotics through mec gene
   4. Mec codes for altered penicillin binding protein (PBP) 2A
   5. SCCmec is integrated into Staph aureus chromosome at specific location
   6. Five types of SCCmec identified; type 4 usually community acquired
   7. MRSA is now the most common cause of skin and soft-tissue infections in some emergency rooms in USA [3,5]
   8. Both community acquired and (more commonly) hospital acquired MRSA are significant proportions
   9. Majority of MRSA infections are skin and soft tissue infections
   10. Vancomycin intermediate-resistant (VISA) isolates reported very uncommon
   11. Highly vancomycin resistant Staph aureus (VRSA) reported but usually sensitive to newer antibiotics (see below)
7. MRSA Epidemiology [6]
   1. Increasing incidence and expansion outside of hospital populations
   2. Most were health-care associated: Community-onset (58%), hostpial-onset (27%)
   3. Community associated infections (no health-care risk factor) in 13%
   4. Increased risk in men (risk 3:2), blacks (2:1), age >65 years

C. Etiology of Infection

1. Many Staph species are normal inhabitants of skin and mucous membranes
   1. Skin carriage is probably most important
   2. Nasal carriage may be the major contributor to Staph bacteremia [4]
2. Infections occur with breakdown of these barriers
   1. Interruption of normal skin barrier
   2. Modification of respiratory barrier surfaces (for example, by viral infection)
   3. Mucous membrane breaks
   4. Nosocomial - intravenous lines and invasive treatments (barrier interruption)
3. Acquired Immunodeficiency
   1. Diabetes mellitus (types 1 and 2), particularly during diabetic ketoacidosis
   2. Therapy leading to leukocyte defects - immunosuppressive therapy, neutropenia
   3. Possible increased risk in patients with uremia
4. Genetic Leukocyte Defects
   1. Chediak-Higashi syndrome
   2. Chronic granulomatous disease
   3. Job's syndrome
5. Pathology
   1. Early, marked inflammation with neutrophils
   2. Leukocytic infiltrate with neutrophils and macrophages
   3. Rapid development of pus, especially with protease and coagulases, collagenases
   4. Tissue necrosis with loss of normal structure is very common
   5. Fibrosis replaces normal tissue
   6. Vascular invasion is common, followed by endothelial cell activation

D. Diseases produced by S. aureus

1. Cellulits
   1. Nearly always involves staphylococci
   2. May have mixed organisms, particularly in diabetics
   3. Increasing incidence of cellulitis caused by community acquired MRSA (CA-MRSA) [9]
2. Impetigo [8]
   1. Superficial, keratinized skin infection
   2. Corneal layer sloughs off
   3. Epidermis splits open
   4. Organism spreads below epidermal barrier but remains contagious
   5. Bullous impetigo is a toxin mediated, localized form of staph scalded skin syndrome (SSSS)
3. Bacteremia
   1. High rates of bacteremia with any deep Staph aureus infections
   2. Catheter related infections are common
   3. Catheter related bacteremia can be diagnosed rapidly with special staining [10]
   4. High risk of subclinical as well as serious endocarditis in bacteremic patients
4. Endocarditis
   1. Increasing rates of Staph aureus endocarditis
   2. Accounts for ~30% of endocarditis cases in normal persons
   3. Accounts for >80% of endocarditis in intravenous drug abusers (usually right sided)
   4. Most common pathogen in prosthetic valve endocarditis
   5. High risk of progression to cardiac abscess
   6. Vegetations are present in 10-30% of patients with staph bacteremia
   7. High mortality rates if undertreated
5. Pneumonia
   1. Very serious infection
   2. Alveolar wall destruction with permanent scarring
   3. Frequent bacteremia associated with staphylococcal pneumonia
6. Osteomyelitis - most common organism isolated (~50%)
7. Glomerulonephritis [19]
   1. Two main clinical presentations of Staph with glomerulonephritis:
   2. Immune complex glomerulonephritis and superantigen-associated glomerulonephritis
   3. Immune complex form associated with S. epidermidis infection of CNS shunts and with

S. aureus systemic infections

1. Superantigen form associated with nephrotic range proteinuria, purpura, elevated serum IgA and IgG, and normal complement levels
2. Superantigen form associated with massive IgA deposition in glomeruli, leading to pathological diagnosis of Henoch-Schonlein purpura (HSP)

• Implants
  1. Orthopedic implants: hip and knee replacement devices
  2. Vascular prostheses
  3. Heart valves
• Adrenal Hemorrhage [12]
  1. Waterhouse-Friderichsen-like Syndrome reported in children with Staph aureus bacteremia
  2. Rapidly progressive illness with necrotizing pneumonia and multisystem failure
  3. Specific strain of Staph aureus associated with disease
• Staph aureus Toxin Associated Diseases
  1. Staphylococcal food poisoning
  2. Scalded skin syndrome (SSSS)
  3. Toxic Shock Syndrome
  4. Necrotizing fasciitis - MRSA increasingly reported [7]
  5. Superantigen associated glomulonephritis (see above)
• Staph Food Poisoning
  1. Disease is due to Staphylococcal toxin, not to live, infectious organisms
  2. Usually found in meats, potato and egg salads, cream pastries
  3. Acute vomiting and diarrhea within 1-6 hours of toxin ingestion
  4. Duration 1-2 days usually with marked nausea
  5. Dehydration is common, without fever
  6. Generally limited disease
  7. Supportive care may be required for high-risk groups (very elderly, chronic disease)
• SSSS [8]
  1. Generalized form of bullous impetigo
  2. Exfoliative toxins A and B are produced locally (impetigo) or systemically (SSSS)
  3. These toxins act as specific proteases against cell adhesion protein desmoglien 1
  4. Cleavage of desmoglein 1 causes blister formation
  5. Risk of death from SSSS <5% in children
  6. Risk of death from SSSS up to 60% in adults with renal failure or immunosuppression
  7. Blisters resemble pemphigus vulgaris (which involve desmogliens 1 and 3)
• Toxic Shock Syndrome (TSS)
  1. Women <30 years using tampons were highest risk group
  2. Originally reported in children with staphylococcal infections
  3. Majority of cases of TSS had vaginal cultures positive for staphylococcus
  4. May occur with staphylococcal infections at other sites, often occult
  5. Overall, ~30% of cases of TSS are associated with tampon use
  6. Caused by toxic shock syndrome toxin 1 (TSST-1)
  7. TSST-1 is coded for by a bacteriophage
  8. TSST-1 is a superantigen which binds to class II MHC, and activates T lymphocytes
  9. Lymphocyte activation leads to cytokine release
  10. Symptoms of sepsis syndrome are common
  
  

  E. Staph epidermidis

  1. Usually nosocomial infections through central venous catheters
  2. Peripheral intravenous catheter associated cellulitis and bacteremia
  3. Catheter related infections reduced by using antibiotic coated catheters
  4. Usually resistant to oxacillin, erythromycin (clarithromycin), and some cephalosporins
  5. Occasional cellulitis (not related to catheters)
  
  

  F. Staph saprophyticus

  1. Most commonly a urinary tract pathogen
  2. Most commonly seen in elderly persons
  
  

  G. Treatment

  1. S. epidermidis
     1. Nearly always oxacillin and macrolide resistant
     2. Vancomycin is usually the drug of choice
  2. Methicillin Sensitive S. aureus [1]
     1. These are usually "methicillin sensitive organisms" although MRSA is increasing [2,17]
     2. Methicillin-sensitive respond to oxacillin (dicloxacillin) and macrolides (clarithromycin)
     3. First generation cephalosporins are also effective, including cephalexin, cefazolin
     4. Penicillin alone is not effective as nearly all strains of S. aureus contain ß-lactamase
     5. Penicillins with ß-lactamase inhibitors (clavulanate, sulbactam) are usually active
     6. Clindamycin is active and usually better tolerated than erythromycin
     7. Ofloxacin and newer fluoroquinolones are also active
     8. Increasing community incidence of MRSA in the community and hospital acquired
     9. Combinations with rifampin (Rifadin®) may be effective in serious infections (see below)
  3. MRSA [1,2,5,9,17,18]
     1. Essentially all methicillin (oxacillin) resistant Staph also resistant to cephalosporins
     2. Vancomycin remains agent of choice for most infections
     3. Community associated MRSA usually more sensitive to other antibiotics, particularly clindamycin, compared with hospital acquired MRSA [5,9,15]
     4. Parenteral agents: vancomycin, daptomycin, tigecycline, linezolid, Synercid®
     5. Oral: clindamycin, doxycycline, linezolid, minocycline, trimethoprim/sulfamethoxazole (sulfa)
     6. MRSA organisms are typically sensitive to sulfa agents, but these are second line
     7. Vancomycin intermediate and resistant staphylococci have been reported, are very uncommon, and usually with coexistant vancomycin resistant enterococci [2]
     8. All infections should undergo full sensitivity testing
     9. Increasing use of MRSA screening / eradication programs in healthcare workers
  4. Quinupristin/Dalfopristin (Synercid®) [4]
     1. Bactericidal against streptococci and staphylococci
     2. Bacteriostatic against enterococci
     3. Nearly 70% of vancomycin resistant Enterococcus faecium (VREF) had clinical responses
     4. Active against methicillin and vancomycin resistant Staph aureus (MRSA, VRSA)
     5. Dose is typically 5mg/kg iv q12 hours
  5. Daptomycin (Cubicin®) [16]
     1. Cyclic lipopeptide permeates gram positive bacterial membrane
     2. Rapidly bactericidal in vitro with activity across all gram positives
     3. Kills VRSA, VISA, MRSA and sensitive staphylococci
     4. IV once daily (reduce in renal insufficiency)
     5. Injection site reactions and gastrointestinal disorders most common adverse effects
     6. Dose: 4-6mg/kg q24 hours IV (adults and children)
     7. Daptomycin 6mg IV qd is as effective with fewer adverse effects compared with low- dose gentamicin+antistaphylococcal penicillin or vancomycin for endocarditis [20]
  6. Tigecycline (Tygacil®) [18]
     1. Parenteral derivative of minocycline
     2. Active against most MRSA
     3. FDA approved for complicated skin and soft tissue infection
     4. Nausea and vomiting common
     5. Dose: 100mg x 1 IV loading, then 50mg q12 hours
  7. Linezolid (Zyvox®) [11]
     1. Oxazolidinone which inhibits protein synthesis by bacterial ribosome
     2. Activity against all gram positive organisms
     3. Cytostatic activity against methicillin resistant and vancomycin intermediate Staph
     4. Resistance has been reported in critically ill patients []
     5. Oral and IV available, usual dose is 600mg twice daily adults, 10mg/kg q8 hours children
  8. Osteomyelitis
     1. May require surgical drainage in severe cases (particularly in diabetics)
     2. Ofloxacin or ciprofloxacin with rifampin (450mg po q12 hour) is effective
     3. In patients with hip or knee implants, intravenous (IV) therapy is first given
     4. After 2 weeks of IV therapy, ciprofloxacin 750mg and rifampin 450mg both bid given
     5. Combination therapy had ~100% cure rate after 3-6 months without implant removal
  9. Use of antibacterial or antiseptic indwelling catheters can reduce infection risk
  10. Topical mupirocin (Bactroban®) reduces nasal carriage and wound infection risk [1]
  
  

  H. Staphylococcus Vaccine [14]

  1. Staph is a major problem in patients on hemodialysis
  2. Capsular polysaccharide (types 5 and 8) vaccine in development
  3. This vaccine showed 57% reduction in Staphylococcal bacteremia over 40 weeks

References

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4. Von Eiff C, Becker K, Machka K, et al. 2001. NEJM. 344(1):11
5. Daum RS. 2007. NEJM. 357(4):380 (Case Discussion)
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16. Daptomycin. 2004. Med Let. 46(1175):11
17. Fridkin SK, Hageman JC, Morrison M, et al. 2005. NEJM. 352(14):1436
18. Community Acquired MRSA. 2006. Med Let. 48(1228):13
19. Denton MD, Sigumarthy SR, Chua S, Colvin RB. 2006. NEJM. 354(26):2803 (Case Record)
20. Fowler VG Jr, Boucher HW, Corey GR, et al. 2006. NEJM. 355(7):653