Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

46. Staphylococci

Karen Bloch MD, MPH

STAPHYLOCOCCUS AUREUS

Essentials of Diagnosis

  • Large gram-positive cocci (0.7–1.5 µm in size).
  • Colonies surrounded by zone of hemolysis on blood agar.
  • Colonies pigmented pale yellow to deep orange macroscopically.
  • Cluster in grapelike bunches microscopically.
  • Biochemically differentiated from streptococci by presence of the enzyme catalase.
  • Biochemically differentiated from other staphylococci by presence of the enzyme coagulase.
  • Analysis of chromosomal DNA can identify clonal isolates (useful in epidemiologic studies).

General Considerations

  1. Epidemiology.Staphylococcus aureuscolonizes the human skin, vagina, nasopharynx, and gastrointestinal tract. Colonization occurs shortly after birth and may be either transient or persistent. Published studies differ widely in estimates of the prevalence of S aureus carriage. Between 10% and 35% of healthy adults have transient or persistent nasopharyngeal colonization. This percentage is increased among health care workers and individuals with repetitive needle exposure such as diabetics, patients on hemodialysis, and injection drug users. Vaginal carriage in premenopausal women approaches 10%, with the highest prevalence rates found at the start of the menstrual cycle.

Phage typing and molecular techniques have demonstrated that invasive disease is usually caused by the colonizing strain; therefore it is not surprising that groups with the highest prevalence of colonization are at the highest risk for S aureus infection. Fortunately, progression to infection is relatively unusual, occurring in only 2.5% of colonized nursing home patients and 37% of postoperative patients (compared with 11% of noncolonized postsurgical patients).

Acute infections in noncolonized patients are usually attributed to physical contact with a colonized individual. Studies have proven that health care workers can serve as vectors for transmission of staphylococci. The importance of person-to-person transmission underscores the need for strict hand washing in hospital settings. Other, less common, methods of acquisition include airborne transmission and spread from clothing and bed linens.

  1. Microbiology.Staphylococci are aerobic, nonmotile, gram-positive cocci frequently cultured from environmental and clinical specimens. Although these organisms are generally considered commensal (ie, nonpathogenic normal flora) when cultured from the skin, nasopharynx, intestinal tract, and vagina, they may at times cause life-threatening disease. The clinical interpretation of a culture growing staphylococci depends on the bacterial species, host characteristics, and culture source.

Staphylococci share common characteristics that allow differentiation from other gram-positive cocci (Table 46-1). All species produce the enzyme catalase. Staphylococci are distinguished microscopically from other gram-positive cocci by a propensity to form clusters, as suggested by the genus name, which comes from the Greek staphule, meaning “bunch of grapes.” Despite these common properties, individual staphylococcal species differ with respect to microbiologic properties, epidemiologic patterns, and clinical manifestations. Many of these differences relate to the production of the enzyme coagulase, and the genus has traditionally been subdivided into S aureus (which is coagulase-positive) and the relatively homogeneous coagulase-negative staphylococci (CoNS).

On blood agar media, S aureus can be distinguished macroscopically from CoNS by a ring of hemolysis surrounding the colonies. Colonies often have a golden-yellow hue (aureus meaning golden in Latin) as a result of the presence of carotenoids. While these morphologic characteristics may serve as general guides for differentiation of S aureus from the CoNS, definitive diagnosis is made by demonstrating the presence of coagulase through agglutination of rabbit plasma.

S aureus possesses a number of properties that contribute to organism virulence and host disease (Table 46-1): the presence of an extracellular capsule (sometimes called a slime layer), the enzymes catalase and coagulase, and membrane exotoxins that inhibit host immune defenses. More than 70% of strains harbor transmissible plasmids that produce beta-lactamase under certain conditions. These inducible beta-lactamases inactivate penicillin and some first-generation cephalosporins. In addition, an increasing proportion of isolates have intrinsic (as opposed to inducible) resistance to all beta-lactam-containing antibiotics. These strains, known collectively as methicillin-resistant S aureus (MRSA), produce penicillin-binding proteins with low affinity for penicillin, nafcillin, and other beta-lactam drugs. Because antibiotics cannot attach to their target site, the bacteria are not inhibited or killed in the presence of these drugs. Finally, some bacteria produce toxins that damage specific host organ systems such as the gastrointestinal tract (enterotoxins) and dermis (epidermolytic toxins).

Table 46-1. Properties of staphylococci associated with virulence and disease.

Factor

Action or Associated Syndrome

S aureus (%)1

CoNS (%)1

Cell Capsule

o   Impairs opsonization and phagocytosis

++–+++

+

Catalase

o   Degrades H2O2 to H2O + O2

o   Prevents PMN3 respiratory burst

++++

++++

Coagulase

o   Catalyzes conversion of fibrinogen to fibrin

o   Fibrin matrix inhibits phagocyte migration

o   Promotes abscess formation

++++

0

Inducible Beta-Lactamase

o   Cleaves beta-lactam ring

o   Transmissible by plasmid

o   Confers resistance to penicillin

+++

+++

Intrinsic Beta-Lactam Resistance

o   Production of low-affinity penicillin-binding proteins

o   Confers resistance to all beta-lactams (including methicillin)

++

+++

Exotoxins

o   Hemolysis

o   Skin necrosis

o   Phagocyte inhibition

+

0

Epidermolytic Toxins

o   Exfoliation

+

0

TSST-1

o   Toxic shock syndrome

+

0

Enterotoxins

o   Nausea/vomiting

+

0

Biofilm Production

o   Adhesion to prosthetic material

+2

+++

1Symbols: 0, none; +, variable; ++, some (<50%); +++, common (>50%); ++++, uniform (>95%)
2Mucoid strains
3PMN: Polymorphonuclear cell

  1. Pathogenesis.Much is now known about the process of S aureusinfection, which proceeds in a series of steps. Adherence, a necessary condition for colonization, occurs when a bacterium attaches to the teichoic acid component of the host cell wall. Adherence and colonization do not activate the host immune system. Invasion occurs when the epidermis is disrupted through an injury or an iatrogenic procedure, and bacteria gain access to the tissues or bloodstream, activating immune defenses. The interplay between bacterial virulence factors (Table 46-1) and host susceptibility factors (Table 46-2) determines whether bacterial proliferation occurs. The final step in the pathogenesis of clinically apparent infection is tissue injury, either localized, as with an abscess, or systemic, as in toxic shock syndrome.

Table 46-2. Host susceptibility factors for infection with staphylococci.

Factor

Example

Impairment

Repetitive needle exposure

o   Insulin–dependent diabetics

o   Injection drug users

o   Hemodialysis patients

o   Increased colonization

o   Breaks in skin integrity

Qualitative PMN1impairment

o   Chronic granulo – matous disease

o   Leukocyte adhesion disorder

o   Decreased phagocytosis

Quantitative PMN impairment

o   Post-chemotherapy neutropenia

o   Congenital neutropenia

o   Decreased phagocytosis

Impaired PMN chemotaxis

o   Job's syndrome

o   Decreased migration to site of infection

Exfoliative skin condition

o   Thermal burns

o   Bullous skin diseases

o   Break in skin integrity

Foreign body

o   Prosthetic joints

o   Vascular access devices

o   Ventriculoperitoneal shunts

o   Break in skin integrity (at time of insertion)

o   Local alteration in immunity

1PMN, polymorphonuclear cell.

CLINICAL SYNDROMES

S aureus causes a wide spectrum of clinical disease, ranking among the most common bacterial causes of skin and soft tissue infection, gastroenteritis, wound infection, septic arthritis, bacteremia, endocarditis, and osteomyelitis. This section focuses on syndromes unique to S aureus and on syndromes for which S aureus is the most common bacterial agent.

PYOGENIC CUTANEOUS INFECTIONS

Clinical Findings

  • Signs and Symptoms.S aureus is the leading bacterial cause of pyogenic skin lesions (Box 46-1). Folliculitis, infection of the hair follicles, is a local suppurative process causing indurated papules or pustules, often with a hair exiting from the center of the lesion. There is local erythema and tenderness, but the patient is not systemically ill.

A furuncle (“boil”) begins as a hair follicle infection and extends locally to form an abscess, characterized by liquefaction of necrotic tissue. Clinically, this presents as a well-circumscribed, fluctuant, tender, erythematous collection. Infection on occasion spreads to the surrounding epidermis, causing cellulitis. Common sites for furuncles include the face, neck, axilla, back and groin.

Carbuncles differ from furuncles in that they extend to the deeper subcutaneous tissues. They are most commonly found on the posterior neck and upper back. These infections are less circumscribed than furuncles and may be associated with draining fistulae. Patients with carbuncles are often systemically ill, exhibiting fevers, chills, and malaise.

  • Laboratory Findings.Folliculitis and furunculosis are usually localized processes, and the peripheral WBC count is normal. Carbunculosis is associated with a systemic immune response, manifested by leukocytosis and a predominance of immature WBC. Blood cultures are frequently positive in patients with carbuncles.
  • Differential Diagnosis.The differential diagnosis of folliculitis includes pseudofolliculitis barbae, insect bites, acne vulgaris, foreign body reactions, and milia. Alternative diagnoses for furunculosis include pilonidal cysts, cystic acne, and hidradenitis suppurativa. A carbuncle may be confused with a furuncle, a deep-seated skin infection such as necrotizing fasciitis, or a kerion.
  • Complications.These infections are generally self-limited and do not disseminate beyond the skin. Local complications include cellulitis and osteomyelitis of adjacent bone. There have been anecdotal reports of facial lesions ascending intracranially to cause septic cavernous vein thrombosis. Bacteremia, a relatively common complication of carbunculosis, may result in secondary infections including endocarditis, hematogenous osteomyelitis, and pneumonia.

BOX 46-1 Cutaneous Syndromes Caused by S aureus

 

Pyogenic

Impetigo

SSSS1

More Common

· Folliculitis
   Papules
   Pustules

· Furuncles
   Abscesses

· Scarlatiniform eruption

· Blisters eroding to honey–colored crust

· Local tenderness

· Regional lymphadenopathy

· Bullous impetigo
   Local erythroderma
   Flaccid bullae rupturing to brown crust
   Involvement of face, trunk, perineum

Less Common

· Carbuncles
   Coalescent abscesses with draining fistulae

· Fever

· Systemically ill

· Elevated WBC count

· Fever

· Bacteremia

· Generalized SSS
   Diffuse dermal desquamatino
   Nikolsky's sign
   Fever
   Leukocytosis
   Bacteremia

1Staphylococcal scalded skin syndrome

 

Diagnosis

Pyogenic skin infections are diagnosed by clinical exam, with culture of purulent material obtained by incision and drainage to confirm staphylococcal infection and determine antibiotic susceptibility patterns. Blood cultures may also guide antibiotic therapy in patients with signs of systemic illness.

Treatment

Treatment for folliculitis and furunculosis is primarily supportive (Box 46-2). Stringent attention to hygiene is key; the affected areas should be washed at least twice daily with a mild antibacterial soap, and overlying clothing should be loose fitting. Furuncles either spontaneously drain or require incision and drainage once they have matured (come to a head). Antibiotic therapy is rarely necessary for these conditions. Carbuncles require both local surgical débridement and parenteral antibiotic therapy.

Recurrent pyogenic skin infections are common in patients with nasopharyngeal colonization. Eradication of staphylococcal carriage with mupiricin may be indicated after repeated episodes of furunculosis. This regimen has good short-term efficacy; however, recolonization frequently occurs, and emergence of mupiricin resistance has been reported.

BOX 46-2 Empiric Treatment of S aureus Skin Infections

 

Pyogenic

Impetigo

SSSS1

First Choice

· Folliculitis and furuncles Local hygiene I & D of mature furuncles

· Carbuncles
Surgical débridement PRSP2
1–2 g IV every 4 h for 10–14 days

· Pediatric:
   Dicloxacillin, 12.5–50 mg/kg/d orally, divided into 4 daily doses OR mupiricin 2% ointment topically 3 times daily3

· Adult:
   Dicloxacillin 500 mg orally every 6 h for 7 days

· Aggressive hydration

· Close monitoring of fluid status

· Pediatric:
   PRSP,2 150 mg/kg/d IV, every 6 h for 10–14 days

· Adult:
   PRSP,2 1–2 gm IV every 4 h for 10–14 days

Second Choice

· Carbuncles Surgical débridement Cefazolin, 1–2 g IV every 8 h for 10–14 days

· Pediatric:
   Cephalexin, 25–50 mg/kg/d orally, divided into 4 daily doses for 7 days

· Adult:
   Cephalexin, 500 mg orally every 6 h for 7 days

· Pediatric:
   Cefazolin, 20 mg/kg/d IV every 8 h for 10–14 days

· Adult:
   Cefazolin, 1–2 g IV every 8 h for 10–14 days

Penicillin Allergic

· Carbuncles Surgical débridement Vancomycin, 15 mg/ kg/ twice daily for 10–14 days

· Pediatric:
   Erythromycin, 40 mg/kg/d orally, divided into 4 doses for 7 days

· Adult:
   Erythromycin, 500 mg orally every 6 h for 7 days

· Pediatric:
   Vancomycin, 40 mg/kg/d IV di – vided into 6–h doses

· Adult:
   Vancomycin, 15 mg/kg/d IV every 12 h for 10–14 days

1Staphylococcal scalded skin syndrome
2Penicillinase–resistant, semisynthetic penicillin–nafcillin or oxacillin
3Topical therapy only indicated for mild, self–limited disease

NONPYOGENIC SKIN INFECTIONS

Clinical Findings

  • Signs and Symptoms.Impetigo and staphylococcal scalded skin syndrome (SSSS) are primarily childhood diseases. More than 70% of cases of impetigo are caused by S aureus, with the remainder attributed to pyogenic streptococci or mixed infection. Impetigo begins as a scarlatiniform eruption in a previously traumatized area that blisters then ruptures to form a wet, honey-colored crust (Figure 46-1). Common sites for infection are the face and trunk. The primary symptom in impetigo is localized pain; fever and constitutional symptoms are rarely seen (Box 46-1). Physical exam often reveals regional lymphadenopathy.

Staphylococcal scalded skin syndrome encompasses three distinct clinical scenarios: bullous impetigo, staphylococcal scarlet fever, and generalized scalded skin syndrome. The histologic finding common to all these conditions is cleavage of the epidermis at the level of the stratum granulosum caused by an exfoliative toxin. Bullous impetigo, the most common of the three types of SSSS, is almost exclusively seen in children < 5 years old. The disease begins as localized erythroderma progressing rapidly to form multiple vesicles, which coalesce into flaccid bullae. Constitutional symptoms are minimal during the early phases, and the bullae spontaneously rupture after 1–2 days to form nontender, brown, varnishlike crusts (Figure 46-2). Commonly involved areas include the face, trunk, and perineum. A variant of this condition, staphylococcal scarlet fever, causes a scarlatiniform rash with late, limited desquamation, without an intermediate bullae stage.

Generalized scalded skin syndrome (known as Ritter's syndrome in neonates) differs from the more benign bullous impetigo in that there is diffuse dermal involvement, causing extensive desquamation. Nikolsky's sign, the sloughing of intact skin on light touch, is frequently seen. Following spontaneous bullae rupture, the skin is denuded and painful (Figure 46-3), and fever is common.

  • Laboratory Findings.Patients with generalized SSSS may have leukocytosis with a predominance of immature white cells. Blood cultures, particularly in adults, may be positive.
  • Differential Diagnosis.The differential diagnosis of impetigo includes herpes simplex and varicella zoster infections, contact dermatitis, scabies, and tinea corporis. SSSS may be confused with other bullous skin diseases (pemphigus vulgaris and bullous pemphigoid), Stevens-Johnson syndrome, thermal burn, and dermatitis herpetiformis.
 

Figure 46-1. Perioral impetigo with honey-colored crusting of denuded cutaneous lesions. (Reprinted with permission from Pediatr Ann 1993;22:236.)

 

Figure 46-2. Discrete, superficial, crusted lesions seen after bullae rupture in bullous impetigo. (Reprinted with permission from Pediatr Ann 1993;22:236.)

  • Complications.Suppurative lymphadenitis, cellulitis, and staphylococcal sepsis are uncommon complications of impetigo. Complications of generalized SSSS include dehydration, bacteremia, and secondary infections. Mortality in children with generalized SSSS is 1–10%, whereas the mortality rate among adults is > 50%.
 

Figure 46-3. Diffuse epidermal desquamation characteristic of the generalized staphylococcal scaled skin syndrome (SSSS). (Reproduced by permission of Pediatr Rev 1996;17:18.)

 

Diagnosis

Impetigo is diagnosed by the presence of the classic golden crusts on physical examination; a microbiologic diagnosis is rarely necessary. SSSS can be diagnosed by rupturing an intact bulla and culturing the extravasated fluid for S aureus. Latex agglutination or ELISA confirms the presence of the staphylococcal exfoliative toxin.

Treatment

Mild cases of (nonbullous) impetigo may be treated with topical mupiricin; however, more serious infections need oral antibiotics (Box 46-2). Bullous impetigo requires treatment with an oral antistaphylococcal agent. The high rates of morbidity and mortality in generalized SSSS mandate hospitalization for aggressive hydration and parenteral antibiotics. Extensive desquamation predisposes patients to secondary infections, and they should receive aggressive topical care such as that given to burn victims.

TOXIC SHOCK SYNDROME

The toxic shock syndrome (TSS) is a heterogeneous complex of symptoms attributed to TSST-1 toxin-producing S aureus. Two variants have been described: menstruation-associated and nonmenstrual disease. Cases of menstruation-associated disease are correlated with the use of superabsorbent tampons. Diaphragm contraception, parturition, indwelling foreign bodies, and recent surgery predispose to nonmenstrual disease.

Clinical Findings

  • Signs and Symptoms.Myalgias, headache, malaise, watery diarrhea, and confusion (in the face of a normal neurologic exam) are early symptoms of TSS, typically preceding the rash by 2–3 days. Erythroderma is initially seen on the palms and soles, progressing to a confluent generalized rash. Hypotension and fever are invariably present at this stage. Multisystem organ failure may be present early or late in the disease course. Dermal desquamation, particularly of the palms and soles is a late sequela of TSS, occurring 7–14 days after the onset of symptoms.
  • Laboratory Findings.The laboratory abnormalities in TSS reflect the diverse organ systems involved. Laboratory abnormalities included as criteria for case definition (see Table 46-3) include an elevation in creatine phosphokinase, acute renal insufficiency, sterile pyuria, elevated liver function tests, and thrombocytopenia. Disordered electrolytes (particularly hypocalcemia and hypophosphatemia), neutrophil predominance on white blood cell differential, and anemia, while not explicitly mentioned in the case definition, may also be found in patients with TSS.

Table 46-3. Major criteria for diagnosis of toxic shock syndrome.

1. Temperature >38.9°C

2. Systolic blood pressure < 90 mm Hg

3. Diffuse erythroderma followed in 1–2 weeks by desquamation

4. Involvement of at least three of the following organ systems:

§  Gastrointestinal: vomiting or diarrhea

§  Musculoskeletal: myalgia or creatinine phosphokinase >5 times normal level

§  Mucous membrane: conjunctival injection, vaginal or oropharyngeal hyperemia

§  Renal: BUN or creatinine >2 times normal level or pyuria without evidence of UTI

§  Hepatic: bilirubin or transaminases >2 times normal level

§  Blood: platelet count of <100,000/mm3

§  Central nervous system: confusion without focal neurologic deficits

5. Serologic exclusion of Rocky Mountain spotted fever, measles, and leptospirosis


Probable diagnosis:
   Desquamation plus 3 other major criteria
   All five major criteria in the absence of desquamation

  • Differential Diagnosis.Other entities causing rash, hypotension, or fever that may be confused with staphylococcal TSS include streptococcal TSS, Rocky Mountain spotted fever, viral infection with exanthem (such as measles or EBV), meningococcemia, leptospirosis, the septic shock syndrome, Kawasaki's disease, and drug-induced reactions (such as erythema multiforme or toxic epidermal necrolysis). A thorough history with particular attention to tick exposures, ill contacts, travel, pets, and medication use is essential in excluding the mimicking conditions.
  • Complications.Case fatality rates for TSS range from 3% to 6% and are higher for nonmenstrual disease. Digital gangrene may occur as a result of sustained hypotension and impaired extremity perfusion. Neuropsychiatric symptoms such as emotional lability, impaired memory, and decreased concentration are common sequelae in survivors.

Diagnosis

Formal criteria for the diagnosis of TSS have been developed to facilitate surveillance and standardize case definition (Table 46-3). Increased awareness of the association between menstruation, tampon use, and TSS has led to improved diagnosis of menstruation-associated disease. Nonmenstrual disease lacks unifying epidemiologic characteristics, which makes diagnosis more difficult. Postoperative TSS is particularly difficult to diagnose, as surgical wound inflammation may be minimal, and early signs are nonspecific.

The diagnosis of TSS is supported by a culture of TSST-1-producing S aureus from an infected focus, although this is not a criterion for case definition. TSST-1-producing staphylococci are isolated from the vagina in 85% of menstruation-associated disease but are isolated from infected foci in only 40–60% of cases of nonmenstrual disease. S aureus bacteremia rarely occurs with TSS.

Treatment

Treatment requires identification and removal of foreign bodies (such as tampons) and irrigation and débridement of infected wounds. Aggressive hydration and close hemodynamic monitoring are essential in the early stages of TSS. All patients should be treated with parenteral agents active against staphylococci (Box 46-3). In vitro, clindamycin inhibits TSST-1 protein synthesis, providing at least a theoretical basis for combination therapy with this agent and a penicillinase-resistant penicillin.

PRIMARY BACTEREMIA & ENDOCARDITIS

Staphylococci (both S aureus and CoNS) have emerged as the two most common organisms cultured from patients with primary bloodstream infections. The term “primary bacteremia” refers to positive blood cultures without an identifiable anatomic focus of infection. Differentiation of primary bacteremia from infective endocarditis (IE), in which infection of the cardiac valves leads to continuous bacterial seeding of the bloodstream, may challenge even the most experienced clinician. Primary S aureus bacteremia is associated with insulin-dependent diabetes, the presence of a vascular graft, and, most significantly, the presence of an indwelling intravascular catheter. Risk factors for IE include structurally abnormal valves, recent injection drug use, and the presence of a prosthetic cardiac valve.

BOX 46-3 Treatment of Staphylococcal Toxic Shock Syndrome

 

Agent/Dose/Route/Duration

Supportive Measures

· Removal of foreign bodies/tampons

· Irrigation of the vaginal vault

· Irrigation and débridement of infected wounds

· Close hemodynamic monitoring

· Vigorous fluid or vasopressor support

· Consider IV gamma–globulin, 400 mg/kg as a single dose1

First Choice

· PRSP,2 2 g IV every 4 h for 10–14 days PLUS

· Clindamycin, 900 mg IV every 8 h

Second Choice

· Cefazolin, 1–2 g IV every 8 h for 10–14 days PLUS

· Clindamycin, 900 mg IV every 8 h

Penicillin Allergic PLUS

· Vancomycin, 15 mg/kg IV every 12 h for 10–14 days

· Clindamycin, 900 mg IV every 8 h

1No controlled studies; reserve for life–threatening situations
2Penicillinase–resistant, semisynthetic penicillin–nafcillin or oxacillin

Clinical Findings

  • Signs and Symptoms.Patients with primary S aureus bacteremia are systemically ill, with fever, chills, malaise, and hypotension. S aureus endocarditis is usually an acute disease, with a presentation indistinguishable from S aureus bacteremia. For the most part, patients lack the classic cutaneous stigmata associated with subacute bacterial endocarditis (Box 46-4). A new or changed cardiac murmur, or evidence of embolic disease, in the setting of S aureus bacteremia strongly supports the diagnosis of IE. Endocarditis in injection drug users involves the tricuspid valve in 75% of cases, and respiratory complaints, attributable to septic pulmonary embolization with infarction, predominate.
  • Laboratory Findings.Laboratory findings in primary bacteremia and IE are nonspecific; an elevated WBC count is the most common abnormality. The erythrocyte sedimentation rate, which is elevated in subacute IE, may be normal. Because endocarditis causes continuous seeding of the bloodstream, it is common to see “high-grade” bacteremia, with multiple positive blood cultures from different venous sites drawn at disparate time intervals.
  • Imaging.The classic radiographic finding in patients with right-sided endocarditis is the presence of multiple pleural-based densities (so-called “cannon-ball lesions”) caused by septic pulmonary emboli. Radiologic signs with left-sided disease are manifestations of congestive heart failure, ranging from increased interstitial markings to parenchymal opacification from pulmonary edema.
  • Differential Diagnosis.Culture of S aureus from the blood should prompt a thorough search for an infected primary focus. Common local infections predisposing to secondary bacteremia include infections of indwelling intravenous catheters or other prosthetic material, postoperative wound infections, septic arthritis, osteomyelitis, and cellulitis. In the absence of an identifiable anatomic focus of infection, the clinician must differentiate primary bacteremia from infective endocarditis.
  • Complications.Complications of S aureus bacteremia are primarily from bacterial seeding of the viscera, with subsequent end-organ infections such as endocarditis (a sequela of uncomplicated bacteremia in 5–10% of cases), osteomyelitis, septic arthritis, cerebral abscess, and perinephric abscess. Mortality with primary bacteremia ranges from 25% to 40%. Factors associated with a fatal outcome include the absence of a removable source of infection (such as an intravenous line), age > 60 years, and underlying pulmonary disease.

Morbidity in left-sided IE is due to progressive valve destruction or embolic phenomena. Valve failure results in congestive heart failure, which may be insidious or may present as acute pulmonary edema following rupture of the chordae tendineae. New-onset heart block is the earliest sign of a myocardial ring abscess. Recurrent systemic emboli on appropriate therapy or persistent bacteremia are indications for surgical valve replacement. The mortality rate for left-sided IE ranges from 20% to 44%, as compared with < 5% for right-sided disease.

  • Differential Diagnosis.Differentiating primary bacteremia from IE causing continuous intravascular seeding is often difficult: the probability that blood cultures growing S aureus represent IE varies from 10% to 40%, depending on the population studied. The distinction between these two syndromes is important as IE requires prolonged therapy and carries a worse prognosis.

Several sets of diagnostic criteria for IE have been proposed. The most sensitive is the Duke Criteria, which incorporates echocardiogram findings with clinical factors to stratify the risk of IE. Patients with community-acquired S aureus bacteremia or nosocomially acquired cases with known cardiac valvular disease or prosthetic valves have the highest probability of having IE and should be evaluated for cardiac involvement with a transthoracic echocardiogram.

BOX 46-4 S aureus Native Valve Endocarditis

 

Right-sided

Left-sided

Common

· Fever

· Leukocytosis

· Heart murmur (~50%)

· Pleuritic chest pain

· Cough

· Hemoptysis

· Dyspnea

· Fever

· Leukocytosis

· Heart murmur (~85%)

· Systemic emboli

· Hemodynamic compromise

· Congestive heart failure

Uncommon

· Hemodynamic compromise

· Congestive heart failure

· Systemic emboli

· Osler's nodes

· Janeway lesions

· Splinter hemorrhages

· Roth spots

Treatment

Optimal empiric treatment for primary bloodstream infection is based on the likelihood that an organism is resistant to methicillin (defined as an MIC ≥ 8 µg/ml). Penicillinase-resistant semisynthetic penicillins (PRSP) such as oxacillin or nafcillin are the recommended agents for community-acquired infections, or nosocomial infections in institutions with documented low prevalence rates for MRSA. In facilities with significant isolation rates for MRSA, empiric treatment with vancomycin is indicated. A PRSP should be substituted as soon as the bacteria is proven susceptible, as vancomycin is less active against S aureus, and patients treated with this agent have longer duration of fever and bacteremia. Regardless of which agent is used, treatment for uncomplicated bacteremia should be continued 10–14 days.

Bacteremia attributed to an infected indwelling central venous catheter is difficult to eradicate without removal of the foreign body. Subcutaneous infection along the catheter tunnel, hemodynamic instability, fever or rigors more than 48 hours after initiating antibiotic treatment, persistently positive blood cultures, or septic venous thrombophlebitis mandate prompt catheter removal.

Therapy for IE is guided by the clinical scenario (Box 46-5). Patients with uncomplicated, right-sided, methicillin-sensitive S aureus endocarditis respond to 2 weeks of treatment. Extrapulmonary embolic disease, persistent symptoms or bacteremia after more than 96 hours of therapy, high-level aminoglycoside resistance, or concurrent left-sided valvular involvement require a full course of therapy, lasting 4–6 weeks.

BOX 46-5 Treatment of S aureus Endocarditis

Scenario

Agent/Dose/Route/Duration1

Left–sided Native Valve Endocarditis

· PRSP, 2 g IV every 4 h for 4–6 weeks PLUS

· Gentamicin, 1 mg/kg IV every 8 h for 3–5 days

Right–sided Native Valve Endocarditis2

· PRSP, 2 g IV every 4 h for 2 weeks PLUS

· Gentamicin, 1 mg/kg IV every 8 h for 2 weeks

Penicillin Allergy

· Cefazolin,3 2 g IV every 4 h for 4–6 weeks PLUS

· Gentamicin, 1 mg/kg IV every 8 h for 3–5 days OR

· Vancomycin, 15 mg/kg every 12 h for 4–6 weeks

MRSA (Native Valve)

· Vancomycin, 15 mg/kg every 12 h for 4 – 6 weeks

Prosthetic Valve (PVE)

· PRSP, 2 g IV every 4 h for ≥6 weeks PLUS

· Rifampin, 300 mg every 8 h for ≥6 weeks PLUS

· Gentamicin, 1 mg/kg IV every 8 h for 2 weeks

MRSA (Prosthetic Valve)

· Vancomycin, 15 mg/kg every 12 h for ≥6 weeks PLUS

· Rifampin, 300 mg every 8 h for ≥6 weeks PLUS

· Gentamicin, 1 mg/kg IV every 8 h for 2 weeks

1Penicillinase–resistant, semisynthetic penicillin–nafcillin or oxacillin
22–week course not indicated if patient unable to tolerate PRSP or if evidence of metastatic disease beside septic pulmonary emboli
3Cephalosporins contraindicated if penicillin allergy is immediate hyper – sensitivity reaction

Aminoglycosides act synergistically with beta-lactams against staphylococci; their use reduces the time to clearing of the bacteria from the bloodstream, although they do not affect mortality rates in IE. Synergy occurs at relatively low doses of aminoglycosides, with optimal peak and trough levels for gentamicin 3.0 and 0.5 µm/mL, respectively.

The penicillin allergic patient with IE presents a treatment challenge. For patients without a history of immediate-type hypersensitivity, a first-generation cephalosporin is the preferred agent. Patients with a history of anaphylaxis or other severe penicillin allergy should receive vancomycin. The potential for antagonism between vancomycin and rifampin exists, and adjuvant therapy with rifampin should be reserved for patients failing monotherapy.

OSTEOMYELITIS

Clinical Findings

  • Signs and Symptoms.Osteomyelitis is divided into two subcategories based on the acuity of onset. Acute osteomyelitis, more commonly seen in children, is associated with sudden onset of bony pain, fever, and malaise. Acute disease is often the result of seeding of the bone during S aureusbacteremia, with the most common anatomic locations corresponding to highly vascularized osseous areas such as the metaphyses of long bones. Chronic osteomyelitis is a more indolent process, characterized by low-grade fevers and chronic nonhealing ulcers or draining sinus tracts in the skin overlying the infected bone. Bony necrosis is pathognomonic for chronic osteomyelitis. Chronic osteomyelitis commonly affects the feet and lower extremities and is often preceded by minor injury or surgery of tissues adjacent to the affected bone. Individuals with impaired vascular perfusion, such as diabetics, are at a particularly high risk for chronic bone infections.
  • Laboratory Findings.The laboratory findings are nonspecific and include an elevated WBC count and erythrocyte sedimentation rate. Blood cultures may be positive in acute osteomyelitis.
  • Imaging

Advances in imaging technology have improved the ability to diagnose osteomyelitis. Plain films are of limited use for acute osteomyelitis, as bony abnormalities are not detectable until at least 10 days after the onset of symptoms. Both the MRI scan and the technetium bone scan have increased sensitivity for detecting early osteomyelitis. The technetium scan uses a radiolabeled isotope, which localizes to areas of osseous regeneration. This technique is limited by the difficulty in differentiating bony regeneration due to injury from that due to infection. Another imaging modality, the indium scan, involves the venous injection of radiolabeled autologous WBC, which localize to sites of granulocyte aggregation in infected bone. The clinical utility of the indium scan is limited by poor discrimination of osteomyelitis from simple cellulitis and low sensitivity for diagnosing the chronic form of osteomyelitis.

  • Complications.Bacteremia caused by osteomyelitis may lead to secondary end-organ infections. More commonly osteomyelitis causes extensive local bony destruction. Patients with peripheral vascular disease, particularly diabetics, may require surgical revascularization to cure osteomyelitis of the lower extremities. In situations where surgical revascularization is not an option or has failed, localized amputation may be necessary.

Diagnosis

Because of the need for prolonged antibiotic therapy with osteomyelitis, a concerted effort to obtain a microbiologic diagnosis before initiating therapy should be made. Culture of cutaneous sinus tracts has an unacceptably low sensitivity and specificity and is not recommended for diagnostic purposes. All patients should have a surgical bone biopsy, as this is the only reliable way of obtaining adequate culture results to guide therapy.

BOX 46-6 Treatment of Osteomyelitis

 

Children

Adults

General Care

· Débridement of devitalized bone

Methicillin Sensitive

· PRSP,1 150 mg/kg/day IV divided every 6 h FOLLOWED BY 2

· Dicloxacillin, 500–100 mg/kg/d orally divided into 4 daily doses

· Treat for 4–6 weeks

· PRSP,1 2.0 gm IV every 4 h

· Treat for 4–6 weeks

MRSA

· Vancomycin, 40 mg/kg/d IV divided every 6 h

· Treat for 4–6 weeks

· Vancomycin, 15 mg/kg every 12 h

· Treat for 4–6 weeks

Penicillin Allergic

· Cefazolin, 20 mg/kg IV every 8 h FOLLOWED BY 2,3

· Clindamycin, 30 mg/kg/d orally divided into 4 daily doses OR

· Vancomycin, 40 mg/kg/d IVdivided every 6 h

· Treat for 4–6 weeks

· Cefazolin,3 2.0 g IV every 8 h OR

· Vancomycin, 15 mg/kg every 12 h

· Treat for 4–6 weeks

1Penicillinase–resistant, semisynthetic penicillin–nafcillin or oxacillin
2Consider change to oral regimen when WBC count has normalized and ESR is reduced by at least 20%
3Cephalosporins contraindicated if penicillin allergy is immediate hypersensitivity reaction

Treatment

The treatment of osteomyelitis presents a particular challenge as antibiotics penetrate bone poorly; antibiotic concentrations in bone are only 5% that of serum. All successful treatment regimens require high dosing for prolonged durations (Box 46-6). Standard regimens require intravenous therapy for 4–6 weeks. The requirement of multiple daily doses is impractical for outpatient administration and has led to increasing interest in less complicated regimens. Treatment with parenteral antibiotics followed by oral therapy in children achieves cure rates equivalent to those of standard parenteral regimens but has not been studied sufficiently in adults to make recommendations regarding oral antibiotics for this age group.

Surgical débridement is required for chronic osteomyelitis, particularly in the presence of necrotic bone or sequestrum. Patients with chronic osteomyelitis should receive at least 6 weeks of parenteral therapy after surgical débridement. Infections in patients who are unable to tolerate surgery or who have refractory disease can be suppressed with ciprofloxacin (750 mg orally twice daily) and rifampin (600 mg orally each day), given indefinitely.

COAGULASE-NEGATIVE STAPHYLOCOCCI

Essentials of Diagnosis

  • Gram-positive cocci.
  • No zone of hemolysis surrounding colonies on blood agar.
  • Colonies gray or white macroscopically.
  • Cluster in grapelike bunches microscopically.
  • Biochemically differentiated from streptococci by production of the enzyme catalase.
  • Biochemically differentiated from S aureusby absence of the enzyme coagulase.
  • Analysis of chromosomal DNA can identify clonal isolates (useful in epidemiologic studies).

General Considerations

  • Epidemiology.Like S aureus, coagulase-negative staphylococci (CoNS) are normal human flora. S epidermidis is the most common bacteria cultured from intact skin, while S saprophyticus is commonly cultured from the vagina of asymptomatic women. With the exception of S saprophyticus, which causes cystitis in young, sexually active women, infections with CoNS occur almost exclusively in the presence of foreign bodies.
  • Microbiology.As with all Staphylococcus species, CoNS are aerobic, nonmotile, gram-positive cocci. This group is comprised of > 30 species, of which about half are known human pathogens. The most clinically important are S epidermidis, S saprophyticus, and S haemolyticus. Although species can be differentiated by biochemical tests, this is rarely clinically indicated, as the high prevalence of methicillin-resistance among CoNS mandates treatment with vancomycin. Molecular analysis can determine if organisms from the same species are clonally related, which may be useful for epidemiologic investigations.
  • Pathogenesis.Less is known about the mechanisms through which CoNS cause disease. As noted above, adherence, colonization, and invasion occur almost exclusively in the setting of indwelling foreign bodies, such as intravenous catheters or implanted prosthetic devices. CoNS attach to foreign material by the production of an exopolysaccharide slime layer and are able to alter the local immune response through a poorly understood mechanism, hindering host eradication. These organisms are much less virulent than S aureus and generally produce indolent infections with inflammation restricted to local tissues.

BACTEREMIA & ENDOCARDITIS

The rising incidence of CoNS bacteremia in the last decade may be attributed to the increasingly common use of prosthetic devices, especially intravascular catheters, among hospitalized patients. Positive peripheral blood cultures are indicative of infection rather than skin contamination in only 10% of cases, and the challenge lies in differentiating these two entities.

Clinical Findings

  • Signs and Symptoms.Clinical signs of CoNS bacteremia are often minimal; the finding of fever and leukocytosis support infection rather than colonization, particularly in a host with an indwelling vascular catheter or implanted prosthetic material. While erythema or purulence at a catheter site is compelling evidence supporting catheter-associated bacteremia, only 50% of patients with bacteremia from vascular lines develop local signs of infection.

Although CoNS rarely infect native cardiac valves, they are the most common cause of early (defined as occurring < 12 months postoperatively) prosthetic valve endocarditis (PVE). The majority of cases of early PVE are caused by intraoperative seeding. Infections are indolent, with fever the most common sign. Diagnosis may be delayed by the lack of physical findings specific for endocarditis; most patients do not develop audible murmurs until valve destruction is advanced.

  • Laboratory Findings.Laboratory abnormalities in CoNS bacteremia and endocarditis are variable. Prosthetic valve endocarditis due to CoNS is usually an indolent process, with nonspecific laboratory findings, including anemia and hematuria. Patients who have CoNS native valve endocarditis present with typical laboratory findings for subacute endocarditis, including elevated erythrocyte sedimentation rate (~90%), anemia (~75%), positive rheumatoid factor (~33%), and hematuria (~33%). Leukocytosis is present in only 40–45% of patients with either bacteremia or endocarditis.
  • Imaging.Transthoracic echocardiography may be useful in native valve endocarditis or in the later stages of PVE when there is significant valve dehiscence. Diagnosis of PVE may be difficult in the early stages when bacteremia may be intermittent. A diagnosis of PVE is supported by new conduction abnormalities on the electrocardiogram, suggestive of valve ring abscess. The most sensitive technique for diagnosing valvular infection is the transesophageal echocardiogram, which allows excellent visualization of the valve ring and prosthesis.
  • Differential Diagnosis.A positive blood culture for CoNS represents one of two entities: contamination with skin flora (~90% of cases) or a true infection. The presence of prosthetic biomaterial, either in the form of a temporary indwelling venous catheter or an implanted device, increases the probability of infection as the majority of bloodstream infections are caused by seeding from infected foci. Patients with CoNS bacteremia should have all temporary indwelling catheters removed or replaced, and the tip sent for a semiquantitative culture.
  • Complications.Hemodynamic instability consistent with septic shock occurs in 10–20% of patients with CoNS bacteremia. Complications of CoNS native valve endocarditis are comparable to those seen with subacute bacterial endocarditis: systemic embolization, valve ring abscess with conduction system disturbance, or congestive heart failure occur in two-thirds of patients, and ~25–50% of patients require valve replacement. Of early PVE cases caused by CoNS, > 85% are complicated by congestive heart failure or prolonged fever despite appropriate antibiotic therapy.

Diagnosis

The diagnosis of CoNS bacteremia or endocarditis is supported by multiple positive cultures from separate venipunctures. Molecular techniques proving clonality of two or more species may argue for true infection (rather than contamination), but access to these tests is generally restricted to research laboratories. In health care settings where molecular testing is not available, the finding of multiple isolates with identical antibiotic susceptibility patterns supports infection rather than contamination. However, the finding of even a single positive culture may be clinically significant and should be interpreted in the context of the patient's clinical condition.

Treatment

The recommended regimens for CoNS bacteremia are given in Box 46-7. Although > 70% of CoNS are resistant to PRSPs, beta-lactam resistance is heterotypically expressed, and antibiograms may falsely suggest methicillin sensitivity.

BOX 46-7 Treatment of CoNS Bacteremia and Prosthetic Valve Endocarditis

 

Bacteremia

PV endocarditis

General Care

· Remove indwelling catheters if persistent fever or bacteremia, hypotension, or tunnel infection

· Surgical consult for congestive failure or valve ring abscess

Antibiotic Regimens

· Vancomycin, 15 mg/kg every 12 h

· Treat for 10–14 days

· Vancomycin, 15 mg/kg every 12 h for ≥6 weeks PLUS

· Rifampin, 300 mg every 8 h for ≥6 weeks PLUS

· Gentamicin, 1 mg/kg IV every 8 h for 2 weeks

Bacteremia from infected indwelling vascular lines may be cured in > 75% of cases with the catheter remaining intact. Indications for catheter removal include hemodynamic instability, cutaneous tunnel infections, and persistent fever or bacteremia after > 48 h of antibiotic treatment.

A diagnosis of PVE is usually an indication for surgical replacement of the infected valve. A trial of conservative therapy with antibiotics alone may be attempted in hemodynamically stable patients without evidence of congestive heart failure or ring abscess. Treatment requires at least 6 weeks of therapy, with synergistic dosing of gentamicin for the initial 2-week period (Box 46-7). The clinician should have a low threshold for surgical intervention in patients with persistent fever or bacteremia, or in patients who develop new signs of congestive heart failure. Patients who complete medical therapy should be followed closely after discontinuation of antibiotics, as relapse is also an indication for surgery.

URINARY TRACT INFECTIONS

S saprophyticus is a common cause of uncomplicated urinary tract infection (UTI) in young women, accounting for as many as 15% of all cases of cystitis in this group. There is a seasonal variation in incidence, with the majority of cases occurring in late summer and fall. Risk factors for S saprophyticus UTI include recent sexual intercourse, delayed postcoital urination, and contraception with diaphragm/spermicide combinations.

Clinical Findings

  • Signs and Symptoms.S saprophyticus causes typical symptoms of cystitis: fever, dysuria, and suprapubic pain. Approximately 20% of women show signs of upper tract disease. It is likely that the number of cases of S saprophyticuspyelonephritis is significantly higher, as localization studies suggest that renal infections may occur in the absence of flank pain.
  • Laboratory Findings.In uncomplicated pyelonephritis and cystitis, the laboratory findings are restricted to hematuria and pyuria. A Gram stain of centrifuged urine sediment typically reveals gram-positive cocci.
  • Complications.Complications secondary to S saprophyticus are rare. There have been anecdotal case reports of bacteremia and endocarditis complicating S saprophyticus urinary tract infections. Infection in males, though unusual, is associated with anatomic abnormalities of the urinary tract or urethral catheterization, and ~40% require hospitalization.

Diagnosis

Definitive diagnosis of S saprophyticus UTI is by culture of organisms from a sterile midstream urine collection. A colony count of > 102 bacteria in an appropriate clinical setting (a young woman with symptoms of cystitis) is considered to be diagnostic. However, because cystitis in young women is usually uncomplicated and easily treated empirically, many authorities do not recommend urine cultures and proceed with therapy if microscopy reveals red or white cells in the sediment of a spun urine.

Treatment

S saprophyticus is sensitive to the antibiotics empirically used to treat community-acquired, uncomplicated UTIs (see Chapter 16). Treatment failures of S saprophyticus UTIs have been reported with single-day therapy (particularly with the fluoroquinolones), leading to the current recommendation of 3 days of antibiotics, regardless of which agent is used. Of note, S saprophyticus is variably sensitive to vancomycin, and this agent should not be used for empiric therapy.

BOX 46-8 Nosocomial Control of MRSA1

Nasopharyngeal Colonization

· Single room or cohorting of colonized patients

· Use of gloves for patient contact

· Strict hand washing

Wound/Tracheostomy/Urinary Tract Colonization or Infection

· Single room or cohorting of colonized patients

· Use of gloves for patient contact

· Strict hand washing

· Gown for direct contact

· Dress wounds for hospital transport

· Mask (if aerosolization or splashing likely)

Burns or Extensive Skin Involvement/Lower Respiratory Tract Involvement

· Single room or cohorting of colonized patients

· Use of gloves for patient contact

· Strict hand washing

· Gown

· Dress wounds for hospital transport

· Mask (if aerosolization or splashing likely)

1Modified from Mulligan et al., Methicillin–resistant S. aureus: a consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and management. Am J Med 1993;94:313.

Prevention & Control

Prevention efforts for the ubiquitous methicillin-sensitive S aureus and CoNS have centered around strict aseptic technique for procedures and compulsive attention to hand washing. Intranasal mupiricin may be effective in eradicating S aureus carriage during a hospital outbreak or if epidemiologic investigation implicates a health care worker as a vector for nosocomial infections.

Staphylococcal infection control efforts have concentrated on limiting the nosocomial spread of MRSA (Box 46-8). Patients colonized or infected with MRSA should be isolated or cohorted, and health care workers should don protective gowns and gloves before patient contact. Hand washing after contact with colonized patients is particularly important as MRSA can survive > 3 h on cutaneous surfaces but is rapidly eradicated by washing with an antibacterial soap. Airborne transmission rarely occurs but is of concern if a patient with respiratory colonization produces copious secretions or requires frequent tracheal suctioning. Both patient isolation and use of masks by contacts is advisable in this setting.

 

REFERENCES

Archer GL, Climo MW: Antimicrobial susceptibility of coagulase-negative staphylococci. Antimicrob Agents Chemother 1994;38:2231.

Chesney PJ: Toxic shock syndrome. In Crossley KB, Archer GL: The Staphylococci in Human Disease, 1st ed. Churchill Livingstone, 1997.

Dagan R: Impetigo in childhood: changing epidemiology and new treatment. Pediatr Ann 1993;22:235. (A thorough discussion of pediatric bullous and nonbullous impetigo.)DiNubile MJ: Short-course antibiotic therapy for right-sided endocarditis caused by Staphylococcus aureus in injection drug users. Ann Intern Med 1994;121:873.

Gemmell CG: Staphylococcal scalded skin syndrome. J Med Microbiol 1995;43:318. (Emphasizes the role of toxins in the pathogenesis of SSSS and reviews the disease in adults.)Gentry LO: Antibiotic therapy for osteomyelitis. Infect Dis Clin N Am 1990:4;485.

Jarvis WR: The epidemiology of colonization. Infect Control Hosp Epidemiol 1996;17:47. (A summary of the impact of colonization on nosocomial infection.)Kloos WE, Bannerman TL: Update on clinical significance of coagulase-negative staphylococci. Clin Microbiol Rev 1994;7:117. (Thorough discussion of specimen collection, strain identification, and antibiotic susceptibilities.)Kunin CM: Urinary tract infections in women. Clin Infect Dis 1994;18:1.

Lew DP, Waldvogel FA: Osteomyelitis. N Engl J Med 1997:336;999.

Low DE: Clinical microbiology: issues in identification and susceptibility testing. In Crossley KB, Archer GL: The Staphylococci in Human Disease, 1st ed. Churchill Livingstone, 1997.

Mortara LA, Bayer AS: Staphylococcus aureus bacteremia and endocarditis. Infect Dis Clin North Am 1993;7:53.

Mulligan ME, Murray-Leisure KA, et al: Methicillin-resistant Staphylococcus aureus: a consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and management. Am J Med 1993;94:313.

Raad II, Bodey GP: Infectious complications of indwelling vascular catheters. Clin Infect Dis 1992;15:197.

Rupp ME, Archer GL: Coagulase-negative staphylococci: pathogens associated with medical progress. Clin Infect Dis 1994;19:231.

Stamm WE, Hooton TM: Management of UTI infections in adults. N Engl J Med 1993;329:1328.

Stevens DL: The toxic shock syndromes. Inf Dis Clin North Am 1996;10:727.

Wenzel RP et al: The significance of nasal carriage of Staphylococcus aureus and the incidence of postoperative wound infection. J Hosp Infect 1995;31:13. (Discusses the prevalence and significance of nasal carriage, and reviews methods of eradication.)Whitener C, Capulo G, Weilekamp MR, Karchmer AW: Endocarditis due to coagulase-negative staphylococci. Infect Dis Clin North Am 1993;7:81.

Wilson WR, Karchmer AW, et al: Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA 1995;274:1706. (A consensus statement by authorities in the field for treatment of IE.)