Lecture 26– Staphyloccal Infections

Reading Assignments: (1) Text Chapters 11, 62 (pp. 582-584) (2) HANDOUT: Cunha, B. 1999. Patient 75, pp. 176-178. In: Infectious Disease Pearls, Hanley and Belfus, Inc., Philadelphia, PA, (3) HANDOUT: Murray, P.R., D.S. Rosenthal, G.S. Kobayasi, and M.A. Pfaller. 1998. pp. 175-188. In: Medical Microbiology. Mosby-Year Book, St. Louis, MO. (4) Gilligan, P.H., M.L. Smiley, and D.S. Shapiro. 1997. Cases in Medical Microbiology and Infectious Diseases (2nd ed.), pp. 152-155. American Society for Microbiology, Washington, D.C.

I. Introduction

A. Staphylococci (Gr. staphyle, bunch of grapes)- round, Gram-positive cocci that can divide in any plane; usually are arranged in grapelike clusters.

B. Readily readily grown on laboratory media; many species members of the normal flora of the skin and mucous membranes.

C. Three of the 16 species found on man are pathogenic:

1. S. aureus - very common and virulent bacterial pathogen; colonizer of the anterior nares. Forms coagulase - separates it from the other, less virulent species.

2. S. epidermidis - common members of the skin flora, less virulent; cause infections in compromised hosts

3. S. saprophyticus

II. Staphylococcus aureus

A. Virulence Factors

1. Cell Surface Structures

a. Capsule– polysaccharide capsule or slime layer - present on some strains. Inhibits phagocytosis in the absence of specific antibody. (Slime layer is important in the adherence of S. epidermidis to intravenous catheters and prosthetic implants. See See Reading Assignment (3)- Fig. 22-3)

b. Peptidoglycan – the major structural component of the cell wall.

(1) During septicemia, peptidoglycan can act like endotoxin in Gram - cells, contributing to septic shock.

(2) Chemoattractant for leukocytes

c. Teichoic acids – polymers of ribitol phosphate

(1) Mediate adherence to mucosal cells.

(2) Antigenic. Antibodies to teichoic acid develop in certain stapylococcal infections – endocarditis.

(3) Activates complement

(4) Surface receptors for specific staphylococcal bacteriophages; allows “phagetyping” of strains for epidemiologic purposes.

d. Protein A – protein that is covalently linked to peptidoglycan; coats the surface of most S. aureus strains.

(1) Binds to the Fc terminus of IgG molecules (IgG1, IgG2, IgG4) binding antibodies “upside down” and preventing them from functioning.

(2) Released into the environment – binds free antibodies and consumes complement.

e. Clumping factor – bound coagulase – binds nonenzymatically to fibrinogen, causing the cells to clump or aggregate.

2. Extracellular Toxins and Enzymes (use Worksheet to categorize these)

a. Pore forming cytotoxins – (alpha, beta, delta, gamma, leukocidin)

(1) Lyse neutrophils and cause necrosis of tissues in vivo.

(2) Damage other cells including vascular endothelium, renal endothelium, neurons, myocardial cells.

(3) Controlled by a two component regulatory system, called Agr (accessory gene regulator).

b. Exfoliative Toxin (exfoliatin, epidermolytic toxin) – serine protease that splits the intercellular bridges in the stratum granulosum causing generalized desquamation.

(1) Sufficient toxin may be produced at a local site to cause epithelial desqamation at remote sites of the body – SSSS.

(2) Toxin is antigenic and circulating antibody will confer immunity to its effects.

c. Toxic Shock Syndrome Toxin (TSST-1) – associated with STSS

(1) Produced in vivo during the course of an infection; systemic disease caused by absorption of the toxin from the local site.

(2) Superantigen which causes shock

d. Enterotoxins (A to E) – associated with food poisoning

(1) Produced by 50% of S. aureus strains

(2) Heat stable – resist boiling for 30 min.

(3) Superantigens

(4) CNS action - produce vomiting and watery (non bloody) diarrhea: act first on the neural receptors in the gut and then the vomiting control center of the brain. Symptoms can be reproduced in experimental animals by injecting the toxin alone.

e. Enzymes:

(1) Coagulase – converts fibrinogen to fibrin. Deposits of fibrin on the surface protect organisms from phagocytosis.

(2) Fibrinolysin

(3) Catalase

(4) Hyaluronidase

(5) Proteases

(6) Nucleases

(7) Lipases


SEE TEXT p. 139 – Paradigm – The Multifactorial Nature of Pathogenesis)

1. What experimental approach has been tried to determine the relative importance of any single S. aureus virulence factor????

2. What experimental evidence confirms the central importance of toxins in the pathogenesis of STSS or SSSS???

B. Epidemiology

1. Ubiquitous and hardy- part of the normal flora of the skin and mucous membranes.

a. S. epidermidis- found on the skin and anterior nares

b. S. aureus – found in the nose (30-90% carriage rate), especially hospital staff and patients.


2. Transmission (See Reading Assignment (3) - Box 22.1)

a. Shedding from human lesions and fomites from these lesions.

b. Contaminated food

c. Pneumonia – aspiration of secretions- in compromised patients (commonly follows influenza infection)

d. Who is at risk? (see Box 22.1) Contact spread in hospitals very important where staff and patients carry antibiotic resistant strains in the nose or on the skin. In hospitals, the highest risk is in the newborn nursery, intensive care units, operating rooms and cancer chemotherapy wards.

C. Pathogenesis and Clinical Spectrum of Staphylococcal Infections

S. aureus causes a spectrum of diseases ranging from invasive to toxigenic presentations. (See Text p. 137- 141). Outside of a hospital setting, most stapylococcal infections occur sporadically and are endogenous in origin; inside the hospital, staphylococcal infections are exogenous and can be the cause of epidemics.


1. Acute Inflammation and Focal Abscess –

Infections are characterized by intense suppuration, necrosis of local tissues, and a tendency for the infected area to become walled off in a pus-filled local abscess. The abscess usually forms at or near the site of entry of the organisms in the tissue. In most instances, the infection remains localized but it may spread by extension through tissue planes or along the lymphatics to regional lymph nodes. The most serious disease - when the infection spreads via the bloodstream to form multiple metastatic abscesses in any body organ. (metastatic – the transfer of disease from one organ or part to another not directly connected with it.)

What is the pathogenesis of abscess formation by S. aureus?

How does S. aureus spread from the initial site of infection ?

Why do patients with the hereditary defect chronic granulomatous disease suffer from repeated S. aureus infections?

2. Toxigenic Disease

Results from the absorption of toxins formed by S. aureus multiplying at the site of carriage, infection, or outside the body (e.g. food poisoning).

What is the pathogenesis of stapylococcal food poisoning?

What is the pathogenesis of SSSS and bullous impetigo?

What is the pathogenesis of TSS?

D. Clinical Presentations of S. aureus Infections:

(1) Skin and Soft Tissue Infections (causes 70% of all these infections)

a. Folliculitis

b. Furuncle

c. Carbuncle

d. Impetigo (found together with Group A strep 30% of the time)

e. Eyelid infections (blepharitis – inflammation of the eyelids).

f. Postpartum breast infections (mastitis)

g. Cellulitis

(2) Deeper Infections (usually associated with some predisposing factor in the host such as diabetes, leukocyte defects, intravenous drug usage, or general reduction in host defenses –alcoholism, malignancy, old age, steroid therapy, chemotherapy, antecedent infections)

a. Wound infections (from trauma, burns, or surgery (causes 1/3 to 1/2 of surgical wound infections)) can progress to infection of deep organs or soft tissue.

b. Pneumonia –primary pneumonia seen in postoperative patients (defenses compromised) or following viral respiratory infections, especially influenza. Pneumonia can be followed by empyema. (Lung abscesses can follow hematogenous spread.)

c. Infections of Joints - arthritis (hematogenous or traumatic)

d. Infections of Bones - osteomyelitis (hematogenous or traumatic)

(c. and d. very common in children)

e. Endocarditis on normal or prosthetic valves (common in intravenous drug users)

f. Septicemia which can occur from any localized lesion, (especially associated with wound infections and intraveous drug abuse) can lead to metastatic abscesses in any organ.

Related Case Studies: Text pp. 135-136 and pp. 582-584. Reading Assignment (3) pp. 187-188.

(3) Toxigenic Diseases

a. Food poisoning (characterized by a short incubation period (1-8 h) with vomiting more prominent than diarrhea) due to ingestion of enterotoxin, which is preformed in foods. Related Case Study: Text pp. 135-136.

b. Stapylococcal Scalded Skin Syndrome (SSSS) and Bullous Impetigo (a mild, localized version of SSSS)

1. Most common in neonates and children less than 5 yrs. old.

2. There is a preceding superficial infection (such as impetigo or infection of the umbilical stump.)

3. Onset is abrupt with erythema closely resembling scarlet fever. Face, axilla and groin affected first, but erythema and large bullae form on all parts of the body. This is followed by desquamation of the skin. Within 1-2 days the skin becomes wrinkled and peels off on light stroking. S. aureus is not found in the unopenend bullae but may be secondary invaders of the damaged skin. Other bacteria may also cause secondary infections. Worst case scenario- there may be acute toxemia followed by death. Pathogenesis???

c. Toxic Shock Syndrome (TSS)

1. Life threatening disease which first came to public attention in the early 1980's when hundreds of cases were associated with a highly absorbent intravaginal tampons. The outbreak receded with the withdrawal from the market of certain brands of tampons.

2. Within 5 days of the beginning of menses in a woman using tampons, there is an abrupt onset of high fever, vomiting, diarrhea, sore throat, and muscle pain. Within 48h, symptoms may progress to shock, with cardiac and renal failure (multiorgan failure). A skin rash may develop, followed by desquamation at a deeper level than in scalded skin syndrome.

3. Blood cultures are negative. Organisms can be found in the vagina, and on the tampons.

4. Today, it is still associated with menstruation and tampon use, but it is also seen in men and women with wounds and other localized infections.

Pathogenesis ?

Related Case Study: Reading Assignment (2) – stapled to back of Reading Assignment (3)

E. Laboratory Diagnosis

1. Specimens – See Previous Handout: Laboratory Diagnosis (Lecture 14) – Wound and Abscess Cultures - a variety of specimens - surface swab, pus, blood, tracheal aspirate, or spinal fluid for culture depending on the site of infection.

2. Direct Smears – Gram stained smears of pus and sputum will show typical staphlococci, however it is not possible to distinquish different species - such as S. saprophyticus and S. aureus.

3. Culture – Plated on blood agar. S. aureus - golden yellow colonies with B hemolysis. Mannitol salts agar – commonly used screening media for nasal carriage of S. aureus.

4. Coagulase Test – S. aureus is coagulase positive, S. epidermidis and S. saprophyticus are negative.

5. Antibiotic Sensitivity Testing

a. If resistance to Penicillin G, + B lactamase test

b. Oxycillin resistance correlates with the presence of the chromosomal gene mecA, a gene that codes for the altered penicillin binding protein, PBP2a, that makes S. aureus “methicillin resistant” (MRSA).

6. Subtyping of epidemic strains

a. Antibiograms

b. Phage typing

c. Plasmid profiling

d. Pulse Field Gel Electrophoresis (PFGE)– see Reading Assignment (4) for a good discussion of this technique.

F. Treatment

1. Superficial suppurative lesions like abscesses are treated with drainage and antibiotic therapy.

2. Prolonged intravenous antibiotic treatment may be necessary for severe staphylococcal septic conditions such as osteomyelitis, endocarditis, pneumonia and toxic shock syndrome. It is difficult to eradicate S. aureus in vivo because the organisms rapidly develop resistance to many antibiotics and the drugs cannot reach the central necrotic part of suppurative lesions. It is also difficult to eradicate the carrier state.

3. Chemopropylaxis is used for surgical patients (such as hip replacement and cardiac valve replacements).

4. Antibiotic Resistance- A HUGE PROBLEM!

a. 90% Resistant to Penicillin G – produce B lactamase under control of tranmissible plasmids.

b. “Methicillin resistance” - MRSA strains- increasingly prevalent since the 1980's; endemic in many hospitals and epidemic in some (30% MRSA).

(1) Resistant to penicillinase-stable penicillins, including nafcillin, oxycillin, methicillin, cephalosporins, monobactams, and carbapenems.

(2) Chromosomally mediated by the mecA gene-codes for a modified penicillin binding protein (PBP2a) with greatly reduced affinity for all beta-lactam antibiotic agents.

(3) Since the 1980's, vancomycin has been the drug of last choice for treating MRSA infections.

c. VISA (Vancomycin Intermediate Resistant S.aureus)/GISA (Glycopeptide Intermediate Resistant S. aureus)

(1) Believed to arise from transfer of genes from vancomycin resistant enterococci (VRE).

(2) 1st reported in Japan in 1996, followed by 2 unrelated cases in the United States in 1997. In these cases, the patients were treated with multiple courses of vancomycin for repeated MRSA infections over the six months before the infection with VISA. In one of these two patients, the patient had documented VRE.

(3) Third case in the U.S. (Jan-Feb. 1999 Emerging Infectious Diseases)

(4) S. aureus strains fully resistant to vancomycin are expected to emerge.

G. Immunity/Control and Prevention

1. There is no effective immunization with toxoids or bacterial vaccines. The nature of the immune response to S. aureus is incompletely understood because of its multiple virulence factors. (A humoral immune response is made to toxigenic disease.)

2. Cleanliness, hygiene, and aseptic management of lesions can control the spread of stapylococci from lesions. It is very difficult to control spread from carriers. Carriers are treated with nasal creams (mupirocin) in conjunction with oral antibiotic therapy.


3. Coagulase Negative Staphylococci

a. S. epidermidis

1. Normal commensals of the skin, anterior nares, and ear canals.

2. Frequently contaminate specimens collected from or through the skin.

3. Important causes of nosocomial infections in patients implanted with catheters and prosthetic devices. Devices may be contaminated during implantation, seeded during bacteremia, or S. aureus may get in when shunts and catheters are temporarily disconnected and manipulated.

4. Associated with endocarditis of prosthetic heart valves and infections of artificial joints such as hip joints.

4. Pathogenesis – determined by the ability to attach to the surface of the artificial device and mutiply. Initial adherence – hydrophobic interactions between synthetic polymers and surface of S. epidermidis. After the initial adherence, the bacteria produce a viscous extracellular slime which provides additional adhesion, and covers the bacteria - protecting them from host defense mechanisms and from antibiotics. Persistent bacteremia can result.

5. Multiple resistance to many antibiotics further allows S. epidermidis to persist in the body.

6. Treatment – remove the device; antibiotic therapy to prevent reoccurrence.

b. S. saprophyticus

1. Causes urinary tract infections in young, sexually active women (10-20% )