Staphylococcus aureus

Staphylococcus (page 6)

© 2008 Kenneth Todar, PhD

Host Defense against Staphylococcal Infections

Phagocytosis is the major mechanism for combating staphylococcal infection. Antibodies are produced which neutralize toxins and promote opsonization. However, the bacterial capsule and protein A may interfere with phagocytosis. Biofilm growth on implants is also impervious to phagocytes. Staphylococci may be difficult to kill after phagocytic engulfment because they produce carotenoids and catalase which neutralize singlet oxygen and superoxide, which are primary phagocytic killing mechanisms within the phagolysosome.

Treatment

Hospital acquired infection is often caused by antibiotic resistant strains (e.g. MRSA) and can only be treated with vancomycin or an alternative. Until recently, infections acquired outside hospitals have been treated with penicillinase-resistant ß-lactams. However, many of the community associated (CA) staphylococcal infections are now methicillin resistant. Particularly in Georgia, Texas, and California, the prevalence of CA-MRSA is widespread. Over 60% of abscess isolates from the emergency department of an Austin, Texas hospital yielded MRSA. These organisms are uniformly resistant to penicillins and cephalosporins. The infections have been treated with combination therapy using sulfa drugs and minocycline or rifampin.

Vaccines

No vaccine is generally available that stimulates active immunity against staphylococcal infections in humans. A vaccine based on fibronectin binding protein induces protective immunity against mastitis in cattle and might also be used as a vaccine in humans. However, vaccine therapies represent a new and innovative approach in broadening the available clinical tools against the global health problem of community and healthcare-associated S. aureus bacterial infections.

Hyperimmune serum or monoclonal antibodies directed towards surface components (e.g., capsular polysaccharide or surface protein adhesions) could theoretically prevent bacterial adherence and promote phagocytosis by opsonization of bacterial cells. Also, human hyperimmune serum could be given to hospital patients before surgery as a form of passive immunization.

When the precise molecular basis of the interactions between staphylococcal adhesins and host tissue receptors is known, it might be possible to design compounds that block the interactions and thus prevent bacterial colonization. These could be administered systemically or topically.

An experimental bivalent vaccine against Staphylococcus aureus is reported to be safe and immunogenic for approximately 40 weeks in patients with end-stage renal disease undergoing hemodialysis. The vaccine called StaphVAX is composed of S. aureus type 5 and 8 capsular polysaccharides conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A. In randomized trials, one injection of the vaccine was administered to 892 hemodialysis patients. Between weeks 3 and 40, 11 cases of S. aureus bacteremia were diagnosed in the vaccinated group compared with 26 cases in a control group. Nearly 90% of patients receiving the vaccine generated antibodies to the two capsular polysaccharides. A decrease in vaccine efficacy after week 40 correlated with a decrease in S. aureus antibodies. The investigators did not believe that use of StaphVAX would be limited to hemodialysis patients. For example, the vaccine might be used in cases where healthy individuals come into the hospital for elective surgery, such as a joint replacement. Such patients do not require protection for the rest of their lives; what they need is protection for a short period while they are in the hospital.

The pharmaceutical company Nabi has developed a trivalent staphylococcal polysaccharide conjugate vaccine called TriStaph™. It contains the two main capsular types, 5 and 8, found in the outer coating of more than 80% of S. aureus strains, conjugated to nontoxic recombinant Pseudomonas exotoxin A. To enhance the efficacy of this vaccine, a surface polysaccharide, 336, is added. S. aureus Type 336 accounts for the approximately 20% of S. aureus infections that do not form a polysaccharide capsule in the human bloodstream. The 336 conjugate vaccine, evaluated in a phase I/II human trial, was shown to be safe and to generate antibodies in humans that are specific and mediate protection against 336-positive strains of S. aureus. Together, these three polysaccharide conjugates cover all clinically-significant serological types of S. aureus.

Since toxins are major contributors to the virulence of S. aureus causing infections in the hospital as well as the community, Nabi identified two vaccine candidates that cover relevant toxins. One of the toxins in animal models is produced by almost all clinical isolates and the other is a toxin associated with severe skin and soft tissue infections caused by the newly emerging multi-drug resistant community-acquired MRSA strains. Genetic engineering technology was used to render the toxins nontoxic so they can be used safely. Adding these two components to Tristaph produces a multi-targeted S. aureus polysaccharide conjugate vaccine and toxoid vaccine called PentaStaph™.

Table 2. Possible virulence determinants expressed in the pathogenesis of Staphylococcus aureus infections

boils and pimples (folliculitis)
Colonization: cell-bound (protein) adhesins
Invasion: Invasins: staphylokinase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, leukocidin
Resistance to immune responses: coagulase
Toxigenesis: cytotoxic toxins (hemolysins and leukocidin)

pneumonia
Colonization: cell-bound (protein) adhesins
Invasion:
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, leukocidin, hemolysins, carotenoids, superoxide dismutase, catalase, growth at low pH
Resistance to immune responses: coagulase, antigenic variation
Toxigenesis: Cytotoxic toxins (hemolysins and leukocidin)

food poisoning (emesis or vomiting)
Toxigenesis: Enterotoxins A-G

septicemia (invasion of the bloodstream)
Invasion:
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, protein A, leukocidin, hemolysins, carotenoids, superoxide dismutase, catalase, growth at low pH
Resistance to immune responses: coagulase, protein A, antigenic variation
Toxigenesis: cytotoxic toxins (hemolysins and leukocidin)

osteomyelitis (invasion of bone)
Colonization: cell-bound (protein) adhesins
Invasion:
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, protein A, leukocidin, hemolysins, carotenoids, superoxide dismutase, catalase, growth at low pH
Resistance to immune responses: coagulase, protein A, antigenic variation
Toxigenesis: cytotoxic toxins (hemolysins and leukocidin)

toxic shock syndrome
Colonization: cell-bound (protein) adhesins
Resistance to immune responses: coagulase, antigenic variation
Toxigenesis: TSST toxin, Enterotoxins A-G

surgical wound infections
Colonization: cell-bound (protein) adhesins
Invasion:
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, protein A, leukocidin, hemolysins, carotenoids, superoxide dismutase, catalase, growth at low pH
Resistance to immune responses: coagulase, protein A, antigenic variation
Toxigenesis: cytotoxic toxins (hemolysins and leukocidin)

scalded skin syndrome (analogous to scarlet fever)
Colonization: cell-bound (protein) adhesins
Invasion:
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, leukocidin, hemolysins
Resistance to immune responses: coagulase, antigenic variation
Toxigenesis: Exfoliatin toxin