Although staphylococci have a marked tendency to form clusters (from the Greek staphyle, bunch of grapes), some single cells, pairs, and short chains are also seen. Staphylococci have a typical Gram-positive cell wall structure. Like all medically important cocci, they are nonflagellate, nonmotile, and non–spore-forming. Staphylococci grow best aerobically but are facultatively anaerobic. In contrast to streptococci, staphylococci produce catalase. More than one dozen species of staphylococci colonize humans; of these, S aureus is by far the most virulent. The ability of S aureus to form coagulase separates it from other, less virulent species (Table 24–1). It is common to lump the other species together as coagulase-negative staphylococci (CoNS).
TABLE 24–1Features of Human Staphylococci ||Download (.pdf) TABLE 24–1 Features of Human Staphylococci
|SPECIES ||COAGULASE ||α-TOXIN ||SAgs ||HABITAT ||BIOFILM ||BOILS ||UTIa ||DEEP INFECTIONS |
|Staphylococcus aureus ||+ ||+ ||+ ||Anterior nares, perineum ||+ ||+ ||– ||Pneumonia, osteomyelitis, abscesses, TSS |
|S epidermidis ||– ||– ||– ||Anterior nares, skin ||+ ||– ||– ||Device colonization |
|S saprophyticus ||– ||– ||– ||Gastrointestinal tract ||– ||– ||+ ||None |
|Others ||– ||– ||– ||Variable ||Variable ||– ||– ||Device colonization |
Staphylococci form clusters and are catalase-positive
Coagulase distinguishes S aureus from other species
In growing cultures, the cells of S aureus are uniformly Gram-positive and regular in size, fitting together in clusters with the precision of pool balls. In older cultures, in resolving lesions, and in the presence of some antibiotics, the cells often become more variable in size, and many lose their Gram positivity.
The cell wall of S aureus consists of a typical Gram-positive peptidoglycan interspersed with considerable amounts of teichoic acid. The peptidoglycan of the cell wall is commonly overlaid with polysaccharide and surface proteins. Although thin polysaccharide capsules are frequently present, their significance in human infections is unknown, and they will not be discussed further. Surface proteins such as clumping factor (Clf ), which binds to fibrinogen, and fibronectin-binding proteins (FnBPs) likely play a role in the early stages of infection. Another protein, protein A, is unique in that it binds the Fc portion of IgG molecules, leaving the antigen-reacting Fab portion directed externally (turned around). It is present in most clinical isolates of S aureus. Protein A is also able to stimulate cytokines (TNF-α), platelets, and B cells.
Surface proteins bind fibrinogen and fibronectin
Protein A binds IgG and stimulates cytokines and B cells
After overnight incubation on blood agar, S aureus produces white colonies that tend to turn a buff-golden color with time, which is the basis of the species epithet aureus (golden). Most, but not all, strains show a rim of clear β-hemolysis surrounding the colony. The most important test used to distinguish S aureus from other staphylococci is the production of coagulase, an enzyme which binds prothrombin in a manner that provides for the cleavage of fibrinogen to fibrin. It is demonstrated by incubating staphylococci in plasma; this produces a fibrin clot in a few hours.
Colonies are white or golden and hemolytic
Coagulase produces a fibrin clot
TOXINS AND BIOLOGICALLY ACTIVE EXTRACELLULAR ENZYMES
Staphylococcus aureus produces a number of named cytolytic toxins (α, β, δ, γ), of which α-toxin is the most important. α-Toxin, sometimes called α-hemolysin, is a protein secreted by almost all strains of S aureus, but not by coagulase-negative staphylococci. It is a pore-forming cytotoxin that lyses the cytoplasmic membranes by direct insertion into the lipid bilayer to form transmembrane pores (Figure 24–2). The resultant egress of vital molecules leads to cell death. This action is similar to other biologically active cytolysins such as streptolysin O, complement, and the effector proteins of cytotoxic T lymphocytes. α-Toxin is not active against neutrophils but does lyse a wide variety of other cells including keratinocytes. Another pore-forming toxin is active against neutrophils and known as a leukocidin (Panton-Valentine leukocidin or PVL), causes tissue necrosis but is found in only a small portion of clinical isolates (<10%).
Staphylococcus aureus α-toxin. A fragment of a rabbit erythrocyte lysed with α-toxin is shown. Note the ring-shaped pores in the membrane created by insertion of the toxin. (Bhakdi S, Tranum-Jensen J: Mechanism of complement cytolysis and the concept of channel-forming proteins, Philos Trans R Soc Lond B Biol Sci 1984 Sep 6;306(1129):311-324.)
α-Toxin inserts in lipid bilayer to form transmembrane pores
PV leukocidin attacks neutrophils
Exfoliatin is produced by a small proportion of S aureus strains. It binds to a specific cell membrane ganglioside found only in the stratum granulosum of the keratinized epidermis of the skin. There it causes intercellular splitting of the epidermis between the stratum spinosum and stratum granulosum, presumably by disruption of intercellular junctions. The toxin itself is a protease which acts on desmosomes important to interkeratinocyte adhesion. Two variants of exfoliatin are antigenic in humans, and the circulating antibody confers immunity to their effects.
Exfoliatin splits intraepidermal junctions
Staphylococcal Superantigen Toxins
The superantigens (SAgs) are a family of secreted proteins that are able to stimulate systemic effects as a result of absorption from the gastrointestinal tract after ingestion or at a site where they are produced in vivo by multiplying bacteria. There are now more than 15 described staphylococcal superantigen toxins (StaphSAgs), the most important of which in human disease are antigenic variants of the long-known staphylococcal enterotoxins (SEA, SEB, etc) and the more recently discovered toxic shock syndrome toxin (TSST-1). An individual strain may produce one or more toxins, but less than 20% of S aureus strains produce any StaphSAg. As superantigens they are strongly mitogenic for T cells and do not require proteolytic processing before binding with class II major histocompatibility complex (MHC) molecules on antigen-presenting cells. This process not only bypasses the specificity of antigen processing but results in massive cytokine release. The StaphSAg toxins share physiochemical and biologic activity similarities with each other and StrepSAgs produced by group A streptococci.
StaphSAgs bind MHC II without processing
Superantigens cause massive cytokine release
The ability of S aureus enterotoxins to stimulate gastrointestinal symptoms (primarily vomiting) in humans and animals has long been known. Once formed, these toxins are quite stable, retaining activity even after boiling or exposure to gastric and jejunal enzymes. In addition to their superantigen actions, they appear to act by stimulating reflexes in the abdominal viscera, which are transmitted to medullary emetic centers in the brain stem via the vagus nerve.
Once formed, enterotoxins are stable to boiling and digestive enzymes
Vomiting is stimulated by brain stem mechanism
Infections produced by S aureus are typified by acute, aggressive, locally destructive purulent lesions. The most familiar of these is the common boil, a painful lump in the skin that has a necrotic center and fibrous reactive shell. Infections in organs other than the skin such as the lung, kidney, or bone are also focal and destructive, but have greater potential for extension within the organ and beyond to the blood and other organs. Such infections typically produce high fever and systemic toxicity and may be fatal in only a few days. A subgroup (<10%) of S aureus infections has manifestations produced by secreted toxins in addition to those caused by the primary infection. Symptoms include diarrhea, rash, skin desquamation, and multiorgan effects as in staphylococcal toxic shock syndrome (TSS). Ingestion of preformed staphylococcal enterotoxin causes a form of food poisoning in which vomiting begins in only a few hours.
In many ways, S aureus is the “all-time champion” of microbial pathogens. Although tuberculosis and malaria have greater global prevalence and the spread of AIDS is more ominous, the ferocity of staphylococcal infections has remained constant for as long as we can tell. In Shakespeare's Lear (1606) quoted above, the king is not himself infected. He has just chosen two prototype staphylococcal lesions (boil, carbuncle) as the vilest of symbols to characterize his ungrateful daughters and his treatment at their hands. Today, in any hospital in the world S aureus still heads the list of pathogens isolated from the bloodstream of seriously ill patients.
The basic human habitat of S aureus is the anterior nares. Ten to thirty percent of the population carry the organism at this site at any given time, and rates among hospital personnel and patients may be much higher. From the nasal site, the bacteria are shed to the exposed skin and clothing of the carrier and others with whom they are in direct contact. Spread is augmented by touching the face and, of course, nose picking. It is blocked by handwashing. Once present on the skin, even transiently, S aureus can gain deeper access either through skin appendages or trauma (Figure 24–3). Although outbreak investigations show that some strains have enhanced virulence, still no laboratory tests can be used to separate them from the large pool of colonized individuals.
Staphylococcal disease. The source of infection is most commonly endogenous from colonized anterior nares or by direct contact with someone carrying S aureus. An abscess (boil) is the typical lesion. In a small proportion of cases, the strain may produce a circulating exotoxin similar to the staphylococcal superantigens (StaphSAgs), which can produce toxic shock syndrome in association with a local infection (lower right) or with menses (lower left). For details of menstrual-associated toxic shock syndrome, see Figure 24–8.
Anterior nares colonization is common
Strains with increased virulence cannot be distinguished
Most S aureus infections acquired in the community are autoinfections with strains that the subject has been carrying in the anterior nares, on the skin, or both. Community outbreaks are usually associated with poor hygiene and fomite transmission from individual to individual. Unlike many pathogenic bacteria, S aureus can survive periods of drying; for example, recurrent skin infections can result from use of clothing contaminated with pus from a previous infection.
Community infections are endogenous
S aureus survives drying
Hospital outbreaks caused by a single strain of S aureus most commonly involve patients who have undergone surgical or other invasive procedures. The source of the outbreak may be a patient with an overt or unapparent staphylococcal infection (eg, decubitus ulcer), which is then spread directly to other patients on the hands of hospital personnel. A nasal or perineal carrier among medical, nursing, or other hospital personnel may also be the source of an outbreak, especially when carriage is heavy and numerous organisms are disseminated. The most hazardous source is a medical attendant who works despite having a staphylococcal lesion such as a boil. Hospital outbreaks of S aureus infection can be self-perpetuating: infected patients and those who attend them frequently become carriers, and the total environmental load of the causative staphylococcus is increased.
Hospital spread is on the hands of medical personnel
Outbreaks involve nasal carrier or worker with lesion
Staphylococcal food poisoning is one of the most common foodborne illnesses in the world. It has been an unhappy and embarrassing sequel to innumerable group picnics and wedding receptions in which gastronomic delicacies have been exposed to temperatures that allow bacterial multiplication. Characteristically, the food is moist and rich (eg, red meat, poultry, creamy dishes). The food becomes contaminated by a preparer who is a nasal carrier or has a staphylococcal lesion. If the food is left unrefrigerated for hours between preparation and serving, the staphylococci are able to multiply and produce enterotoxin in the food. Because of the heat resistance of the toxin, toxicity persists even if the food is subsequently cooked before eating.
Enterotoxin is produced in rich foods before they are ingested
A boil (or furuncle) is an abscess and a prototype for the purulent lesions produced by many other bacteria. The initial stages of attachment by S aureus are mediated by a number of surface proteins, which bind to host cells or elements on their surface. Proteins that bind to the glycoprotein fibronectin that is ubiquitous on mucosal surfaces are of particular importance in the early stages of infection. These FnBPs mediate adhesion to and perhaps invasion of mammalian cells. This allows S aureus to persist and to produce α-toxin and other cytolysins, which injure the cell (Figure 24–4). As the lesions become destructive and spread below the surface, other proteins that bind to collagen and other elements of the extracellular matrix may play a role. At this stage, actions of coagulase and Clf on fibrinogen-binding, and the antiphagocytic effect of protein A binding to IgG, all combine to limit the effectiveness of host phagocytes. If the strain produces the PV leukocidin the compromise of innate defenses would be enhanced. The continued production of α-toxin destroys keratinocytes and other cells allowing the lesion to expand. The inflammatory cells, fibrin, and other tissue components form a wall, which becomes the painfully familiar boil (Figure 24–5). A carbuncle (Figure 24–6) is an extension of this process in which, rather than discharging at the surface, the process forms multiple compartments. There is evidence that S aureus can regulate this multifactored process deploying adhesions and extracellular products at the stages they are needed.
Staphylococcal disease cellular view. Initial attachment to fibronectin is mediated by fibronectin-binding proteins (FnBP), and the major injury is caused by the pore-forming α-toxin. Cells are destroyed by leaking their cytosol. The α-toxin also inserts in the polymorphonuclear neutrophils. Resistance to phagocytosis and the formation of a wall are aided by fibrinogen-binding Clf.
Furuncle (boil). Note the focal nature of the lesion. This one appears about to “point” and drain its walled-off pus externally. (Reproduced with permission from Nester EW: Microbiology: A Human Perspective, 6th edition. 2009.)
Staphylococcal carbuncle. Multiple abscesses have coalesced to form this angry cellulitis with draining sinuses. (Reproduced with permission from Connor DH, Chandler FW, Schwartz DQ, et al: Pathology of Infectious Diseases. Stamford CT: Appleton & Lange, 1997.)
FnBPs bind to fibronectin on cell surface
Coagulase, protein A, and PV leukocidin compromise defenses
α-Toxin production destroys cells
The fate of the lesion depends on the ability of the host to localize the process, which differs depending on the tissue involved. In the skin, spontaneous resolution of the boil by granulation and fibrosis is the rule. In the lung, kidney, bone, and other organs, the process may continue to spread with satellite foci and involvement of broad areas. In all instances, the action of the cytotoxins is highly destructive, creating cavities and massive necrosis with little respect to anatomic boundaries. In the worst cases, the staphylococci are not contained, spreading to the bloodstream and distant organs. Circulating staphylococci may also shed cell wall peptidoglycans, producing massive complement activation, leukopenia, thrombocytopenia, and a clinical syndrome of septic shock.
Destruction and spread are prominent
Peptidoglycan fragments may trigger shock
If the strain of S aureus causing any of the effects described above also produces one or more of the exotoxins, those actions are added to those of the primary infection. The primary infection serves as a site for absorption of the toxin and need not be extensive or even clinically apparent for the toxic action to occur. In staphylococcal food poisoning, there is no infection at all. The contaminating bacteria produce StaphSAg in the food, which can initiate its enterotoxic action on the intestine within hours of its ingestion.
Preformed enterotoxin acts within hours
The in vivo production of exfoliative toxin takes at least a few days and may exert its effect locally or systemically. Toxin absorbed at the infection site reaches its infant stratum granulosum binding site through the circulation causing widespread desquamation by its action on the keratinized epidermis as in the staphylococcal scalded skin syndrome (Figure 24–7A and B). In older children, exfoliative toxin-producing strains may also cause a localized blister-like lesion called bullous impetigo.
Staphylococcal scalded skin syndrome in a neonate. A. This infant has a small focal staphylococcal breast abscess and looks as if he has been sunburned or dipped in boiling water. B. Note the peeling of the superficial layers of the skin as a result of the action of circulating exfolatin.
Exfoliative toxin causes blisters or scalded skin syndrome
In staphylococcal TSS, TSST-1 is produced during the course of a staphylococcal infection with systemic disease as a result of absorption of toxin from the local site. In comparison with other StaphSAgs, TSST-1 is more readily adsorbed across mucosal membranes. Menstruation-associated TSS requires a combination of improbable events. At any one time, less than 15% of women carry S aureus in their vaginal flora, and less than 20% of these have the potential to produce TSST-1. During menstruation, the relatively high protein level and pH in the vagina favor accelerated growth of these staphylococci. In the presence of such a strain, the combination of menstruation and the composition of high-absorbency tampons provide pH and ionic conditions that enhance both the growth of the staphylococci and the production of TSST-1. Toxin absorbed from the vagina can then circulate to produce the multiple effects of massive superantigen-mediated cytokine release (Figure 24–8A and B).
Pathogenesis of staphylococcal toxic shock syndrome. A. The vagina is colonized with normal flora and a strain of S aureus containing the StaphSAg gene. B. The conditions with tampon usage facilitate growth of the S aureus and toxic shock syndrome toxin (TSST-1) StaphSAg production. C. The toxin is absorbed from the vagina and circulates. The systemic effects may be due to the direct effect of the toxin or via cytokines released by the superantigen mechanism. The toxin is shown binding directly with the Vβ portion of the T-cell receptor and the class II major histocompatibility complex (MHC) receptor. This Vβ stimulation signals the production of cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF).
TSST-1-producing strain must colonize vagina
Menstruation and tampons enhance local toxin production
Some cases of full-blown staphylococcal TSS are associated with strains that do not produce TSST-1. This is particularly true of nonmenstrual cases. Other StaphSAgs have been detected in these strains and have been shown to produce experimental toxic shock. TSS may be the result of in vivo production of any of the StaphSAgs, with TSST-1 simply the most common offender. The mechanisms by which the pyrogenic exotoxins produce the multiple renal, cutaneous, intestinal, and cardiovascular manifestations of TSS are not known.
Nonmenstrual TSS cases may have any StaphSAg-producing strain
The natural history of staphylococcal infections indicates that immunity is of short duration and is incomplete. Chronic furunculosis, for example, can recur over many years. The relative roles of humoral and cellular immune mechanisms are uncertain, and attempts to induce immunity artificially with various staphylococcal products have been disappointing at best. Women suffering menstruation-associated TSS, often have low or absent antibody levels to TSST-1 and often fail to mount a significant antibody response during the disease. This may be due to SAgs stimulation of TH1 responses with minimal TH2 component.
Relapsing infections show little evidence of immunity
TSS patients have poor antibody responses
STAPHYLOCOCCAL INFECTIONS: CLINICAL ASPECTS
MANIFESTATIONS: PRIMARY INFECTION
The furuncle or boil (Figure 24–5) is a superficial skin infection that typically develops in a hair follicle, sebaceous gland, or sweat gland. Blockage of the gland duct with inspissation of its contents causes predisposition to infection. Furunculosis is often a complication of acne vulgaris. Infection at the base of the eyelash gives rise to the common stye. The infected patient is often a carrier of the offending Staphylococcus, usually in the anterior nares. The course of the infection is usually benign, and the infection resolves upon spontaneous drainage of pus. No surgical or antimicrobial treatment is needed. Infection can spread from a furuncle with the development of one or more abscesses in adjacent subcutaneous tissues. This lesion, known as a carbuncle, occurs most often on the back of the neck (Figure 24–6), but it may involve other skin sites. Carbuncles are serious lesions that may result in bloodstream invasion (bacteremia).
Focal lesions drain spontaneously
Boils develop in hair follicles
Multiple boils become a carbuncle
Some individuals are subject to chronic furunculosis, in which repeated attacks of boils are caused by the same strain of S aureus. There is little, if any, evidence of acquired immunity to the disease; indeed, delayed-type hypersensitivity to staphylococcal products appears responsible for much of the inflammation and necrosis that develops. Chronic staphylococcal disease may be associated with factors that depress host immunity, especially in patients with diabetes or congenital defects of polymorphonuclear leukocyte function. However, in most instances, predisposing disease other than acne is not present.
Links to immune dysfunction are limited
Staphylococcus aureus has been long known as a secondary invader in group A streptococcal pustular impetigo (see Chapter 25), but is increasingly seen producing the skin pustules of impetigo on its own. Strains of S aureus that produce exfoliatin cause a characteristic form called bullous impetigo, characterized by blisters containing many staphylococci in the superficial layers of the skin. Bullous impetigo is a localized form of staphylococcal scalded skin syndrome.
Produces pustular or bullous impetigo
Staphylococcus aureus can cause a wide variety of infections of deep tissues by bacteremic spread from a skin lesion that may be unnoticed. These include infections of bones, joints, deep organs, and soft tissues, including surgical wounds. More than 90% of the cases of acute osteomyelitis in children are caused by S aureus. Staphylococcal pneumonia is typically secondary to some other insult to the lung, such as influenza, aspiration, or pulmonary edema. At deep sites, the organism has the same tendency to produce localized, destructive abscesses as it does in the skin. All too often the containment is less effective, and spread with multiple metastatic lesions occurs. Bacteremia and endocarditis can develop. All are serious infections that constitute acute medical emergencies. In all these situations, diabetes, leukocyte defects, or general reduction of host defenses by alcoholism, malignancy, old age, or steroid or cytotoxic therapy can be predisposing factors. Severe S aureus infections, including endocarditis, are particularly common in drug abusers using injection methods.
Acute osteomyelitis is primarily caused by S aureus
Pneumonia and deep tissue lesions are highly destructive
Bacteremic spread and endocarditis are most common in drug abusers
MANIFESTATIONS CAUSED BY STAPHYLOCOCCAL TOXINS
Staphylococcal scalded skin syndrome results from the production of exfoliatin in a staphylococcal lesion, which can be minor (eg, conjunctivitis). Erythema and intraepidermal desquamation takes place at remote sites from which S aureus cannot be isolated (Figure 24–7). The disease is most common in neonates and children less than 5 years of age. The face, axilla, and groin tend to be affected first, but the erythema, bullous formation, and subsequent desquamation of epithelial sheets, can spread to all parts of the body. The disease occasionally occurs in adults, particularly those who are immunocompromised. Milder versions of what is probably the same disease are staphylococcal scarlet fever, in which erythema occurs without desquamation, and bullous impetigo, in which local desquamation occurs.
Widespread desquamation in neonates is caused by exfoliatin-producing strains
Toxic shock syndrome (TSS) was first described in children, but came to public attention during the early 1980s when hundreds of cases were reported in young women using intravaginal tampons. The disease is characterized by high fever, vomiting, diarrhea, sore throat, and muscle pain. Within 48 hours, it may progress to severe shock with evidence of renal and hepatic damage. A skin rash may develop, followed by desquamation at a deeper level than in scalded skin syndrome. Blood cultures are usually negative. The outbreak receded with the withdrawal of certain brands of highly absorbent tampons.
Fever, vomiting, diarrhea, and muscle pain are early findings
Shock, renal, and hepatic injury may follow
Staphylococcal Food Poisoning
Ingestion of staphylococcal enterotoxin-contaminated food results in acute vomiting and diarrhea within 1 to 5 hours. There is prostration, but usually no fever. Recovery is rapid, except sometimes in the elderly and in those with another disease.
Vomiting is prominent without fever
Laboratory procedures to assist in the diagnosis of staphylococcal infections are quite simple. Most acute, untreated lesions contain numerous polymorphonuclear leukocytes and large numbers of Gram-positive cocci in clusters. Staphylococci grow overnight on blood agar incubated aerobically. Catalase and coagulase tests performed directly from the colonies are sufficient for identification. In clinical laboratories the coagulase test (tube coagulase) is used only to confirm more convenient rapid slide tests which have a high correlation with the classic test. The rapid tests are based on the detection of Clf, protein A, and other structures unique to S aureus. Staphylococcus aureus isolates can be subdivided by a variety of typing systems and by their pattern of lysis by bacteriophages (phage typing). In epidemiologic investigations, molecular methods such as pulsed field gel electrophoresis are now used to “fingerprint” the spread of virulent clones. Antibiotic susceptibility tests are indicated because of the emerging resistance to multiple antimicrobials, particularly methicillin-resistant S aureus (MRSA). Deep staphylococcal infections such as osteomyelitis and deep abscesses present special diagnostic problems when the lesion cannot be directly aspirated or surgically sampled. Blood cultures are usually positive in conditions such as acute staphylococcal arthritis, osteomyelitis, and endocarditis, but less often in localized infection such as deep abscesses.
Gram stain and culture are primary diagnostic methods
Aspirates and blood cultures are necessary for deep infections
Most boils and superficial staphylococcal abscesses resolve spontaneously without antimicrobial therapy. Those that are more extensive, deeper, or in vital organs require a combination of surgical drainage and antimicrobials for optimal outcome. Penicillins and cephalosporins are active against S aureus cell wall peptidoglycan and vary in their susceptibility to inactivation by staphylococcal β-lactamases. Although penicillin G is the treatment of choice for susceptible strains, the penicillinase-resistant penicillins (methicillin, nafcillin, oxacillin) and first-generation cephalosporins are now used because of the high frequency of penicillin resistance (>80%). For MRSA strains resistant to these agents or in patients with β-lactam hypersensitivity, the alternatives are vancomycin, clindamycin, or erythromycin. Synergy between cell wall-active antibiotics and the aminoglycosides is present when the staphylococcus is sensitive to both types of agents. Such combinations are often used in severe systemic infections when effective and rapid bactericidal action is needed, particularly in compromised hosts.
Superficial lesions resolve spontaneously
Penicillinase-resistant β-lactams are used in pending susceptibility tests
When penicillin was introduced to the general public after World War II, virtually all strains of S aureus were highly susceptible. Since then, the selection of preexisting strains able to produce a penicillinase has shifted these proportions to the point at which 80% to 90% of isolates are now penicillin-resistant. The penicillinase is encoded by plasmid genes and acts by opening the β-lactam ring, making the drug unable to bind with its target.
Most strains of S aureus are now penicillin-resistant
Penicillinase production is plasmid mediated
Alterations in the β-lactam target, the peptidoglycan transpeptidases (often called penicillin- binding proteins, or PBPs), are the basis for resistance to methicillin. These MRSA strains are also resistant to the other penicillinase-resistant penicillins such as oxacillin. The most common mechanism is the acquisition of a gene (mecA) coding for a new transpeptidase, which has reduced affinity for β-lactam antibiotics, but is still able to carry out its enzymatic function of cross-linking peptidoglycan.
Methicillin-resistant strains produce new PBP
The incidence of MRSA has great geographic variation. Most American hospitals report MRSA rates of 5% to 25%, but outbreaks are increasing and resistance rates over 50% have been reported in other countries. Tests are generally performed with methicillin or oxacillin under technical conditions that facilitate detection of what may be a small resistant subpopulation, and the results extrapolated to other relevant agents. For example, oxacillin resistance is considered proof of resistance to methicillin, nafcillin, dicloxacillin, and all cephalosporins. Methods for direct detection of the mecA gene have been developed but are not yet practical for widespread use. Vancomycin is often used to treat serious infections with MRSA. The recent emergence of S aureus with decreased susceptibility to vancomycin is still uncommon but of great concern. For strains resistant to both methicillin and vancomycin, daptomycin, linezolid, and ceftaroline are new alternatives.
MRSA rates are variable but increasing
MRSA detection requires special conditions
Vancomycin use for MRSA is threatened
MRSA originally associated primarily with strains acquired in hospitals have increasingly emerged in the community (CA-MRSA). At least one clone of CA-MRSA emerging in the United States (USA 300) has distinctive features beyond methicillin resistance. These strains produce particularly aggressive skin and soft tissue infections. This may be due to the almost universal presence of the PV leukocidin in these isolates.
CA-MRSAs produce PV leukocidin
In patients subject to recurrent infection such as chronic furunculosis, preventive measures are aimed at controlling reinfection and, if possible, eliminating the carrier state. Clothes and bedding that may cause reinfection should be dry-cleaned or washed at a sufficiently high temperature (70°C or higher) to destroy staphylococci. In adults, the use of chlorhexidine or hexachlorophene soaps in showering and washing increases the bactericidal activity of the skin. In such individuals, or persons found to be a source of an outbreak, anterior nasal carriage can be reduced and often eliminated by the combination of nasal creams containing topical antimicrobials (eg, mupirocin, neomycin, and bacitracin) and oral therapy with antimicrobials that are concentrated within phagocytes and nasal secretions (eg, rifampin or ciprofloxacin). Attempts to reduce nasal carriage more generally among medical personnel in an institution are usually fruitless and encourage replacement of susceptible strains with multiresistant ones.
Antistaphylococcal soaps block infection
Elimination of nasal carriage is difficult
Chemoprophylaxis is effective in surgical procedures such as hip and cardiac valve replacements, in which infection with staphylococci can have devastating consequences. Methicillin, a cephalosporin, or vancomycin given during and shortly after surgery may reduce the chance for intraoperative infection while minimizing the risk for superinfection associated with longer periods of antibiotic administration.
Chemoprophylaxis during high-risk surgery is effective
Other than S aureus, there are more than 40 species of staphylococci. In medical practice, the less than 20 species that have been isolated from human infections are typically lumped together by a negative characteristic—failure to produce coagulase. These coagulase-negative staphylococci (CoNS) also do not produce α-toxin, exfoliatin, or any of the StaphSAg toxins. They have been shown to have surface adhesins and the ability to produce extracellular polysaccharide biofilms. By far the most common CoNS species isolated from human infections is S epidermidis, and S saprophyticus is a significant cause of urinary tract infections. Clinical laboratories rarely speciate CoNS isolates, although a simple test (novobiocin resistance) is often used to separate S saprophyticus from other urinary isolates.
Staphylococcus epidermidis and many other species of CoNS are normal commensals of the skin, anterior nares, and ear canals of humans. Their large numbers and ubiquitous distribution result in frequent contamination of specimens collected from or through the skin. In the past, they were rarely the cause of significant infections, but with the increasing use of implanted catheters and prosthetic devices, they have emerged as important agents of hospital-acquired infections. Immunosuppressed or neutropenic patients and premature infants have been particularly affected.
Common colonizers of the skin
Commonly colonize implanted medical devices
Organisms may contaminate prosthetic devices during implantation, seed the device during a subsequent bacteremia, or gain access to the lumina of shunts and catheters when they are temporarily disconnected or manipulated. The outcome of the bacterial contamination is determined by the ability of the microbe to attach to the surface of the foreign body and to multiply there. Central to this process is the ability of these species to form a viscous extracellular polysaccharide biofilm. Initial adherence is facilitated by the hydrophobic nature of the synthetic polymers used in medical devices and the ability of polysaccharides produced by the organism to mediate attachment to the plastic and between CoNS cells. As it expands, this biofilm provides additional adhesion, encases the entire bacterial population (Figure 24–9), and serves as a barrier to antimicrobial agents and host defense mechanisms.
Coagulase negative staphylococcal slime. A. S epidermidis cocci are shown attached to the surface of a plastic catheter and are starting to produce extracellular polysaccharide slime. B. After 48 hours, the bacteria are fully embedded in the slime glycocalyx. (Reproduced with permission from Connor DH, Chandler FW, Schwartz DQ, et al: Pathology of Infectious Diseases. Stamford CT: Appleton & Lange, 1997.)
Polysaccharide production mediates attachment to plastics and between cells
The abovementioned circumstances are found almost exclusively in hospitals and other medical facilities. The most common device colonized is the intravenous catheter, but the same mechanisms apply to any implanted device such as cerebrospinal fluid shunts and artificial heart valves. The ensuing disease is typically low grade with little more than a slowly advancing fever to arouse suspicion. Staphylococcus aureus can also produce biofilms, and although a less frequent colonizer of medical devices, it is likely to produce a more aggressive course and metastatic infections. Removal of the contaminated device is the only sure way to avoid these complications.
Catheters, shunts, and artificial valves become colonized
The biology of S saphrophyticus infection is entirely different. Its usual habitat is the gastrointestinal tract, and from that location the organism gains access to the urinary tract. Among sexually active women, S saphrophyticus is second only to Escherichia coli as a cause of acute urinary tract infection. This process is aided by surface adhesins to uroepithelial cells and the production of a urease. Thus, although other CoNS are causes of infection among compromised patients in hospitals, S saphrophyticus produces community-acquired infection in women who are otherwise healthy.
S saphrophyticus causes urinary infections
The interpretation of cultures that grow CoNS is difficult. In most cases, the finding is attributable to skin contamination during collection of the specimen. The presence of at least moderate numbers of organisms or repeated isolations from the same site argue for infection over skin contamination. Specimens collected directly from catheters and shunts typically show large numbers of staphylococci. Most CoNS now encountered are resistant to penicillin, and many are also methicillin-resistant. Resistance to multiple antimicrobials usually active against Gram-positive cocci, including vancomycin, is more common than with S aureus. Eradication of CoNS from prosthetic devices and associated tissues with chemotherapy alone is very difficult unless the device is also removed.
Repeated positives suggest infection
Multiple antimicrobic resistance is common