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89 STAPHYLOCOCCAL INFECTIONS

89 STAPHYLOCOCCAL INFECTIONS
Harrison’s Manual of Medicine

89

STAPHYLOCOCCAL INFECTIONS

Staphylococcus Aureus

Epidemiology and Pathogenesis

Diagnosis

Prevention and Control
Coagulase-Negative Staphylococci
Bibliography

The staphylococci are hardy and ubiquitous colonizers of human skin and mucous membranes. They cause a variety of syndromes, including superficial and deep pyogenic infections, systemic intoxications, and UTIs. Staphylococci are nonmotile, nonsporulating gram-positive cocci, 0.5–1.5 µm in diameter, that occur singly and in pairs, short chains, and irregular three-dimensional clusters. The more virulent staphylococci clot plasma (“coagulase-positive”), while the less virulent ones do not (“coagulase-negative”). Of coagulase-positive staphylococci, S. aureus is the only important human pathogen. Coagulase-negative staphylococci, especially S. epidermidis, adhere avidly to prosthetic materials and are increasingly important nosocomial pathogens. S. saprophyticus, another coagulase-negative species, is a common cause of UTIs.
STAPHYLOCOCCUS AUREUS
Epidemiology and Pathogenesis
Humans constitute the major reservoir of S. aureus in nature. The mucous membranes of the anterior nasopharynx are the principal site of carriage, with ~30% of healthy adults being colonized at any point in time.
S. aureus causes two types of syndromes: intoxications and infections. In intoxications, the manifestations of illness are attributable solely to the action of one or a few toxins. Infections involve bacterial colonization, invasion across epithelial or mucosal barriers, adherence, evasion of host defenses, and destruction of host tissues. Hosts at particular risk for staphylococcal infection include those with frequent or chronic disruptions in epithelial integrity, disordered leukocyte chemotaxis, phagocytes defective in oxidative killing, or indwelling foreign bodies. Pts with disorders of immunoglobulin or complement are also at increased risk of infection.
STAPHYLOCOCCAL INTOXICATIONS   Toxic Shock Syndrome   TSS is an acute, life-threatening intoxication characterized by fever, hypotension, rash, multiorgan dysfunction, and desquamation during the early convalescent period. Overt infection with S. aureus is not required; mere colonization with a toxigenic strain may suffice. TSS toxin 1 and staphylococcal enterotoxin B are responsible for virtually all cases. The reported incidence of TSS among menstruating women is 1 case per 100,000. About half of all cases are nonmenstrual and occur in individuals of both sexes. TSS is primarily a disease of the young but can affect all ages. Nonmenstrual TSS can ensue after superinfection of skin lesions of many types, including chemical or thermal burns, insect bites, varicella infections, and surgical wounds. Mortality is ~2.5% for menstrual TSS and ~6.4% for nonmenstrual TSS.
TSS is a clinically defined syndrome whose differential diagnosis is that of a severe febrile exanthem with hypotension. Other diagnoses to consider include streptococcal TSS, staphylococcal scalded skin syndrome, Kawasaki syndrome, Rocky Mountain spotted fever, leptospirosis, meningococcemia, gram-negative sepsis, exanthematous viral syndromes, and severe drug reactions. Staphylococcal and streptococcal TSS can be clinically indistinguishable. Recovery of S. aureus supports the diagnosis, as does demonstration of toxin production by the isolate and serologic susceptibility to the toxin.

TREATMENT
Treatment of TSS involves drainage of the toxin production site, aggressive fluid resuscitation, and administration of antibiotics. Recent surgical wounds should be explored and irrigated. Pressors should be used for hypotension unresponsive to fluids. Electrolyte abnormalities must be corrected. Clindamycin (900 mg IV q8h) should be given either alone or with a b-lactam antibiotic [or vancomycin for pts perceived to be at risk for infection with methicillin-resistant S. aureus (MRSA)]. A 14-d course of therapy is reasonable, some of which may be oral. For severe illness or an undrainable focus of infection, immunoglobulin (a single dose of 400 mg/kg IV) should be given. The risk of recurrent menstrual illness can be assessed by testing for seroconversion to TSST-1: women who do not seroconvert after acute illness should refrain indefinitely from using tampons or barrier contraceptives.

Staphylococcal Scalded Skin Syndrome   SSSS encompasses a range of cutaneous diseases of varying severity caused by exfoliative toxin–producing strains of S. aureus. The most severe form is termed Ritter’s disease in newborns and toxic epidermal necrolysis (TEN) in older subjects. TEN or Ritter’s disease often begins with a nonspecific prodrome. The acute phase starts with an erythematous rash beginning in the periorbital and perioral areas and spreading to the trunk and limbs. The skin has a sandpaper texture and is often tender. Periorbital edema is common. In infants and children, fever and irritability or lethargy are common, but systemic toxicity is not. Within hours or days, wrinkling and sloughing of the epidermis begin; Nikolsky’s sign is present. The denuded areas are red and glistening but not purulent. Exfoliation may continue in large sheets or in ragged snippets of tissue. Large flaccid bullae may develop. Significant fluid and electrolyte loss and secondary infection can occur at this stage. Within ~48 h, exfoliated areas dry and secondary desquamation begins. The entire illness resolves within ~10 d. Mortality (from hypovolemia or sepsis) is ~3% in children but up to 50% in adults.

TREATMENT
Treatment includes antistaphylococcal antibiotics, fluid and electrolyte management, and local care of denuded skin.

Staphylococcal Food Poisoning   Staphylococcal food poisoning, caused by the ingestion of any of the enterotoxins produced by S. aureus in contaminated food before it is eaten, has a high attack rate and is most common during summer. This brief illness begins abruptly 2–6 h after ingestion of contaminated food, with nausea, vomiting, crampy abdominal pain, and diarrhea. The diarrhea is usually noninflammatory and is of lower volume than that in cholera or toxigenic Escherichia coli infection. Fever and rash are absent, and the pt is neurologically normal.

TREATMENT
The majority of cases are self-limited and require no specific treatment.

STAPHYLOCOCCAL INFECTIONS   Skin and Soft Tissue Infections   S. aureus is the most common etiologic agent of skin and soft tissue infections. Staphylococcal infections originating in hair follicles range in severity from trivial to life-threatening. Folliculitis, denoting infection of follicular ostia, presents as domed, yellow pustules with a narrow red margin. Infection is often self-limited, although healing may be hastened by topical antiseptics and more severe cases may benefit from topical or systemic antibiotics. A furuncle (“boil”) reflects deep-seated necrotic infection of a hair follicle, most often located on the buttocks, face, or neck. Furuncles are painful and tender and are often accompanied by fever and constitutional symptoms. Surgical drainage and systemic antibiotics are frequently required. Carbuncles denote deep infection of a group of contiguous follicles. These painful necrotic lesions, commonly accompanied by high fever and malaise, occur most often on the back of the neck, shoulders, hips, and thighs, typically in middle-aged or elderly men. Surrounding and underlying connective tissue is intensely inflamed; bacteremia may be present. Surgical drainage and systemic antibiotics are indicated.
Cellulitis, a spreading infection of subcutaneous tissue, is occasionally caused by S. aureus. Although b-hemolytic streptococci are much more commonly responsible, secondary infection of surgical and traumatic wounds is more likely to be staphylococcal, and empirical treatment directed against both S. aureus and streptococci is reasonable.
Respiratory Tract Infections   Staphylococcal pneumonia is a relatively uncommon but severe infection characterized clinically by chest pain, systemic toxicity, and dyspnea and pathologically by intense neutrophilic infiltration, necrosis, and abscess formation. It is typical in tracheally intubated hospitalized pts and after viral respiratory infection. The diagnosis is often readily established by Gram’s staining of expectorated sputum. Empyema is a common sequela of staphylococcal pneumonia and increases the already considerable morbidity of this infection.
Hematogenous seeding of the lungs with S. aureus follows embolization from an intravascular nidus of infection. Common settings for septic pulmonary embolization are right-sided endocarditis, which is especially common among injection drug users, and septic thrombophlebitis, which is usually a complication of indwelling venous catheterization. CXR typically shows multiple nodular infiltrates.
Infections of the CNS   S. aureus is a major cause of brain abscess, especially as a result of embolization during left-sided endocarditis. Brain abscess can also develop by direct extension from frontoethmoid or sphenoid sinuses or from soft tissue.
S. aureus is the most common cause of spinal epidural abscess, most often in association with vertebral osteomyelitis or diskitis. While the diagnosis is suggested by fever, back pain, radicular pain, lower extremity weakness, bowel or bladder dysfunction, and leukocytosis, the presentation is often subtle (e.g., difficulty walking in the absence of objective findings). The principal danger is spinal cord necrosis, which must be recognized early if sequelae are to be averted. Spinal MRI detects an epidural collection, and needle aspiration or open drainage confirms the infectious etiology. Prompt surgical decompression is often required, although a trial of antibiotics alone may be considered if focal neurologic deficits are absent.
Endovascular Infections   S. aureus is the most common cause of acute bacterial endocarditis of both native and prosthetic valves. Staphylococcal endocarditis presents as an acute febrile illness, rarely of more than a few weeks’ duration; complications include meningitis, brain or visceral abscess, peripheral embolization, valvular incompetence with heart failure, myocardial abscess, and purulent pericarditis. The diagnosis is suggested by a heart murmur and conjunctival hemorrhages, subungual petechiae, or purpuric lesions on the distal extremities. It is confirmed by multiple positive blood cultures and valvular vegetations on echocardiography. Evaluation for metastatic infection is often warranted. Staphylococcal endocarditis carries a mortality rate of ~40% and mandates prompt antimicrobial therapy. Indications for valve replacement are the same as for endocarditis caused by other organisms. Early consultation with a cardiothoracic surgeon is advisable; about half of pts require valve replacement—many urgently. Once removal of an infected valve is indicated, nothing is gained and much may be lost by delaying surgery. S. aureus infection of a prosthetic valve almost always requires surgery.
Right-sided endocarditis, most often a complication of injection drug use or venous catheterization, is frequently complicated in turn by septic pulmonary emboli but otherwise has a lower rate of serious complications than left-sided disease. Short-course parenteral therapy (2 weeks) may be curative, and the prognosis is relatively good. Surgery is rarely required.
S. aureus is the major cause of endovascular infections other than endocarditis. Vascular infection may follow hematogenous seeding of damaged vessels, resulting in development of a “mycotic aneurysm”; spread from a contiguous focus of infection, often resulting in an infected pseudoaneurysm; or contamination of an intravascular device, resulting in “septic phlebitis.” Staphylococcal infection of an atherosclerotic artery, which may be aneurysmal to begin with, is potentially catastrophic. Such infections are associated with high-grade bacteremia, may result in rupture and massive hemorrhage, and are almost never curable without surgical resection and bypass of the infected vessel. Septic phlebitis is also associated with high-grade bacteremia and systemic toxicity but is less likely than arteritis to result in rupture. Persistent bacteremia suggests the need for surgical removal of infected thrombus or vein, but the technical difficulty of surgery may warrant an attempt at cure with antibiotics and anticoagulants alone.
Several criteria increase the probability that a pt has endocarditis as opposed to simple bacteremia: community-acquired (vs. nosocomial) infection, absence of an identifiable primary site of infection, and evidence of metastatic infection. Transesophageal echocardiography has demonstrated valvular abnormalities in up to one-fourth of bacteremic pts; this test should be performed in pts with persistent fever or bacteremia.
Musculoskeletal Infections   S. aureus is the most common cause of acute osteomyelitis in adults and one of the leading causes in children. Acute osteomyelitis results from either hematogenous seeding of bone, especially damaged bone, or direct extension from a contiguous focus of infection. The most common site of hematogenous staphylococcal osteomyelitis in adults is the vertebral bodies; in children, it is the highly vascular metaphyses of long bones. Acute osteomyelitis in adults usually presents with constitutional symptoms and pain over the affected area, often developing over weeks or months. The diagnosis may be subtle; leukocytosis and an elevated ESR or C-reactive protein level are laboratory clues. Bacteremia may or may not be demonstrable. Cure usually follows 4 weeks of parenteral antibiotics.
S. aureus is also a major cause of chronic osteomyelitis, which develops at sites of previous surgery, trauma, or devascularization.
A special form of osteomyelitis is that associated with prosthetic joints or orthopedic fixation devices. Pain, fever, swelling, and decreased range of motion are cardinal features of an infected prosthesis. A plain film may suggest loosening of the prosthesis, often as radiolucency at the interface between bone and cement. Cure with antibiotics alone is rare.
S. aureus is a prominent cause of septic arthritis in adults. Predisposing factors include injection drug use, rheumatoid arthritis, use of systemic or intraarticular steroids, penetrating trauma, and previous damage to joints. In addition to parenteral antibiotics, cure requires either repeated joint aspirations or open or arthroscopic debridement and drainage. Failure to drain joints adequately risks permanent loss of function.
S. aureus infections of muscle (pyomyositis) are relatively uncommon in the U.S. Psoas abscess, the major exception, is easily diagnosed by abdominal CT or MRI.
Diagnosis
S. aureus infection generally is readily diagnosed by isolation of the organism from purulent material or normally sterile body fluid. Gram’s staining of purulent material from a staphylococcal abscess invariably reveals abundant neutrophils and intra- and extracellular gram-positive cocci—singly or in pairs, short chains, tetrads, or clusters. S. aureus grows readily on standard laboratory media. Rarely, if ever, should S. aureus growing from even a single blood culture be considered a contaminant. The diagnosis of staphylococcal intoxications (e.g., TSS) may be more difficult and may rely entirely on clinical data.

TREATMENT
The essential elements of therapy for staphylococcal infections are drainage of purulent collections of pus, debridement of necrotic tissue, removal of foreign bodies, and administration of antibiotics. The importance of adequate drainage cannot be overemphasized. In skin and soft tissue infections, surgical drainage alone is occasionally curative. It is almost impossible to eradicate S. aureus infection in the presence of a foreign body.
Antimicrobial Resistance Today, >90% of S. aureus strains are resistant to penicillin. In tertiary care institutions, MRSA isolates are increasingly prevalent and are resistant to the action of all b-lactam antibiotics and often to chloramphenicol, tetracyclines, and macrolides. In the last decade, community-acquired MRSA has been found in pts without apparent risk factors.
In 1996, the first vancomycin-intermediate S. aureus (VISA) strain, with decreased susceptibility to vancomycin, appeared. Vancomycin resistance is expressed in a heterogeneous manner, and VISA should be suspected in any pt for whom seemingly appropriate therapy with vancomycin is ineffective. Risk factors for VISA infection include a history of dialysis, multiple prior courses of antibiotic therapy, admission to the ICU, and prior infection with MRSA.
Selection of Antibiotics Nafcillin or oxacillin, b-lactamase-resistant penicillins, are the drugs of choice for parenteral treatment of serious staphylococcal infections. Penicillin remains the drug of choice for infections caused by susceptible organisms. Combinations of a penicillin plus a b-lactamase inhibitor are also effective but are best reserved for polymicrobial infections. Penicillin-allergic pts can usually be treated with a cephalosporin, although caution is essential if the adverse reaction to penicillin was anaphylaxis; first-generation agents (e.g., cefazolin) are preferred. For pts who are intolerant of all b-lactam agents, the best alternatives for parenteral administration are vancomycin and clindamycin. Dicloxacillin and cephalexin are recommended for oral administration for minor infections or for continuation therapy; clindamycin is an alternative for most strains. Routine use of quinolones is not recommended.
Vancomycin remains the drug of choice for treatment of infections caused by MRSA. Two new agents offer promise for treatment of MRSA infections, but further studies are needed before their routine use can be recommended: quinupristin/dalfopristin, a streptogramin combination, is bactericidal for S. aureus, and linezolid, an oxazolidone, is bacteriostatic but with only rare resistance. To date, all isolates of VISA have been susceptible to alternative agents.
There is usually no significant benefit to treating S. aureus infections with more than a single drug to which the organism is susceptible. An aminoglycoside/b-lactam combination hastens the sterilization of blood in endocarditis and is often used for the first 5–7 days of therapy for S. aureus bacteremia. Thereafter, the added toxicity of an aminoglycoside outweighs its benefit. Use of rifampin with a b-lactam antibiotic (or vancomycin) occasionally results in sterilization in otherwise refractory infections, particularly those involving foreign bodies or avascular tissue. Rifampin should never be administered as monotherapy because resistance emerges rapidly.
Route and Duration of Therapy To minimize seeding of secondary sites, bacteremic infections should be treated with high doses of antibiotics (e.g., 2 g of nafcillin IV q4h). For infections requiring high serum antibiotic levels for adequate tissue levels (e.g., endocarditis, osteomyelitis, infections of the CNS), parenteral therapy should be used for the duration. Oral agents may suffice for treatment of nonbacteremic infections in which high antibiotic levels are not requisite, such as skin, soft tissue, or upper respiratory tract infections.
Except for bacteremia and osteomyelitis, duration of therapy for S. aureus infections can be tailored to the severity of illness, the immunologic status of the host, and the response to therapy. Acute osteomyelitis in adults requires at least 4 weeks of parenteral therapy, with the actual duration depending on vascular supply at the site of infection and response to treatment. Chronic osteomyelitis is occasionally treated parenterally for 6–8 weeks and then orally for several months. Acute endocarditis and other endovascular infections should be treated with parenteral antibiotics for 4 weeks (6 weeks for prosthetic valves). Simple bacteremia requires shorter therapy, but a 2-week course of parenteral therapy is recommended for all patients with S. aureus bacteremia. A challenge in treating staphylococcal bacteremia is deciding whether to administer parenteral therapy for 2 or 4 weeks. A conservative approach supported by numerous studies dictates that 4 weeks should be standard unless specific criteria are met (Fig. 89-1). For more information on antimicrobial therapy for S. aureus infections, please refer to Table 89-1.

FIGURE 89-1. Factors to be considered in determining the duration of therapy for S. aureus bacteremia. (Modified by Parsonnet and Deresiewicz from Fowler VG Jr et al: Outcome of Staphylococcus aureus bacteremia according to compliance with recommendations of infectious disease specialists: Experience with 244 patients. Clin Infect Dis 27:478, 1998.)

Table 89-1 Antimicrobial Therapy for Infections Caused by Staphylococcus aureus

Prevention and Control
Pts with exposed wounds and those with nasal colonization are important reservoirs of S. aureus, whose transmission can be reduced most effectively by meticulous hand washing before and after pt contact. More stringent infection control measures must be taken to prevent the nosocomial spread of resistant strains.
COAGULASE-NEGATIVE STAPHYLOCOCCI
Coagulase-negative staphylococci are a major cause of nosocomial infection and are the organisms most frequently isolated from the blood of hospitalized patients. Most such infections are indolent, are caused by strains resistant to multiple antibiotics, and are associated with a medical device of some kind, removal of which is usually required to effect cure.
CLINICAL SYNDROMES   Coagulase-negative staphylococci are the most common pathogens complicating the use of IV catheters, hemodialysis shunts and grafts, CSF shunts, peritoneal dialysis catheters, pacemaker wires and electrodes, prosthetic joints, vascular grafts, and prosthetic valves. Coagulase-negative staphylococcal infection of IV catheters may be accompanied by signs of inflammation at the site of insertion, and the degree of systemic toxicity (including fever) ranges from minimal to considerable. The diagnosis is established by culture of blood drawn from the catheter and by venipuncture. Infection of CSF shunts usually becomes evident within several weeks of implantation; malfunction of the shunt may be the only manifestation of infection. Infection of a prosthetic joint often becomes evident long after implantation.
Coagulase-negative staphylococci are a prominent cause of bacteremia in immunosuppressed pts. Those with neutropenia may have high-grade bacteremia resulting in significant systemic toxicity. A serious consequence of bacteremia is seeding of a secondary foreign body.
Coagulase-negative staphylococci are the foremost cause of prosthetic valve endocarditis, accounting for the majority of infections occurring within several months of implantation and for many late infections. They also cause <5% of cases of native valve endocarditis, usually affecting abnormal valves.
S. saprophyticus is a major cause of UTI, especially among sexually active young women. The syndrome, which is indistinguishable from that caused by other etiologic agents, is amenable to therapy with most drugs commonly used to treat UTIs.
DIAGNOSIS   Although coagulase-negative staphylococci are the most common cause of nosocomial bacteremia, they are also the most common contaminant of blood cultures. “True positives” are more likely when a clinical illness suggests infection, when an indwelling catheter or some other risk factor is involved, and when multiple cultures of blood drawn from separate sites yield organisms similar in phenotype and antimicrobial susceptibility pattern.

TREATMENT
When coagulase-negative staphylococcal infection is related to a foreign body, removing the foreign body often constitutes adequate therapy. Most such infections require this measure, but cures of such infections with antibiotics alone have been reported. Infections of peritoneal dialysis catheters can be cured with antibiotics alone often enough that an attempt should be made to do so. Coagulase-negative staphylococcal infections of central venous catheters are also amenable to medical therapy, although relapses are common. Persistent bacteremia during therapy is an absolute indication for removing a catheter, and bacteremia after a catheter’s removal suggests seeding of a secondary site.
Most strains of coagulase-negative staphylococci isolated from pts in U.S. hospitals are resistant not only to penicillin but also to penicillinase-resistant penicillins and cephalosporins. Nosocomial isolates are usually resistant to other classes of antibiotics as well. Vancomycin, to which the vast majority of coagulase-negative staphylococci remain susceptible, is by necessity the drug of choice for empirical treatment of serious infections caused by these organisms. Strains proven to be susceptible to nafcillin (oxacillin) or penicillin should be treated with one of these agents or with a first-generation cephalosporin.
Synergistic antibiotic combinations are often useful. Rifampin plays a unique and important role by virtue of its potency against most staphylococci, its excellent penetration into tissues (including those that are poorly vascularized), and its high levels within human cells and biofilm. Unfortunately, rifampin must be used with other antibiotics because of frequent and rapid emergence of microbial resistance during monotherapy. The concomitant use of a b-lactam antibiotic to which the organism is susceptible plus rifampin (300 mg PO bid) plus an aminoglycoside (usually gentamicin) affords the best chance for eradication of infection of a medical device without its removal. Vancomycin is substituted for the b-lactam if so dictated by an organism’s susceptibility pattern or a pt’s drug allergy.

Bibliography

For a more detailed discussion, see Parsonnet J, Deresiewicz RL: Staphylococcal Infections, Chap. 139, p. 889, in HPIM-15.

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