1182 PART 5 Infectious Diseases

and radicular pain in addition to the symptoms associated with their

osteomyelitis. Surgical intervention in this setting often constitutes a

medical emergency.

MRI is the most reliable imaging modality to help establish the diagnosis of osteomyelitis (Fig. 147-3). Routine x-rays are an appropriate

first step, but findings may be normal for up to 14 days after the onset

of symptoms. If an MRI is not possible, CT is an acceptable alternative.

Bone infections that result from contiguous spread tend to develop

from soft tissue infections, such as those associated with diabetic or

vascular ulcers, surgery, or trauma. Exposure of bone, a draining fistulous tract, failure to heal, or continued drainage suggests involvement

of underlying bone. Bone involvement is established by bone culture

and histopathologic examination (revealing evidence of PMN infiltration). Contamination of culture material from adjacent tissue can make

the diagnosis of osteomyelitis difficult in the absence of pathologic

confirmation. Samples obtained during surgery are the most reliable.

An MRI is the most reliable radiologic test to distinguish between osteomyelitis and overlying soft tissue infection with underlying osteitis.

In both children and adults, S. aureus is the most common cause of

septic arthritis in native joints. If left untreated, this infection is rapidly

progressive and may be associated with extensive joint destruction. It

presents with intense pain on motion of the affected joint, swelling,

and fever. Aspiration of the joint reveals turbid fluid, with >50,000

PMNs/μL and gram-positive cocci in clusters seen on Gram’s stain

(Fig. 147-1). In adults, septic arthritis may result from trauma, surgery,

or hematogenous dissemination. The most commonly involved joints

include the knees, shoulders, hips, and phalanges. Infection frequently

develops in joints previously damaged by osteoarthritis or rheumatoid

arthritis. Iatrogenic infections resulting from aspiration or injection of

agents into the joint also occur. In these settings, the patient experiences increased pain and swelling in the involved joint in association

with fever.

Pyomyositis is an unusual infection of skeletal muscles that is seen

primarily in tropical climates but also occurs in immunocompromised (e.g., HIV-infected) patients. It is believed to arise from occult

bacteremia. Pyomyositis presents as fever, swelling, and pain overlying

the involved muscle. Aspiration of fluid from the involved tissue yields

pus. Although a history of trauma may be associated with the infection,

its pathogenesis is poorly understood.

Respiratory Tract Infections Respiratory tract infections

caused by S. aureus occur in selected clinical settings. S. aureus

is a cause of serious respiratory tract infections in newborns and

infants; these infections present with shortness of breath, fever, and

respiratory failure. Chest x-ray may reveal pneumatoceles (shaggy,

thin-walled cavities). Pneumothorax and empyema are recognized

complications.

In adults, nosocomial S. aureus pulmonary infections are common

among intubated patients in intensive care units. Nasally colonized

patients are at increased risk of these infections. The clinical presentation is no different from pulmonary infections caused by other

bacterial pathogens. Patients produce increased volumes of purulent

sputum and develop respiratory distress, fever, and new pulmonary

infiltrates. Distinguishing bacterial pneumonia from respiratory failure

or other causes of new pulmonary infiltrates in critically ill patients is

difficult and relies on a constellation of clinical, radiologic, and laboratory findings.

Community-acquired respiratory tract infections due to S. aureus

often follow viral infections—most commonly influenza. Patients

may present with fever, bloody sputum production, and midlung-field

pneumatoceles or multiple, patchy pulmonary infiltrates. Diagnosis is

made by sputum Gram’s stain and culture. Blood cultures, although

useful, are usually negative.

Bacteremia, Sepsis, and Infective Endocarditis S. aureus

bacteremia may be complicated by sepsis, endocarditis, vasculitis, or

metastatic seeding (establishment of suppurative collections at other

tissue sites). Among the more commonly seeded tissue sites are bones,

joints, kidneys, and lungs. The frequency of metastatic seeding during

bacteremia has been estimated to be as high as 31%. The incidence of

these complications increases with the duration of the bacteremia.

Recognition of these complications by clinical criteria alone is challenging. Comorbid conditions that are frequently seen in association

with S. aureus bacteremia and that increase the risk of complications

include diabetes, HIV infection, and renal insufficiency. Other host

factors that increase the risk of complications include presentation

with community-acquired S. aureus bacteremia, lack of an identifiable

primary focus of infection, and the presence of prosthetic devices or

material.

Clinically, S. aureus sepsis presents in a manner similar to that documented for sepsis due to other bacteria. The well-described progression

of hemodynamic changes—beginning with respiratory alkalosis and

clinical findings of hypotension and fever—is commonly seen. The

microbiologic diagnosis is established by positive blood cultures.

The overall incidence of S. aureus endocarditis has increased

over the past 20 years. S. aureus is now the leading cause of endocarditis worldwide, accounting for 25–35% of cases. This increase

is due, at least in part, to the increased use of intravascular devices

and, more recently, the upsurge in injection drug use. Studies using

transesophageal echocardiography found an endocarditis incidence

of ~25% among patients with intravascular catheter–associated S.

aureus bacteremia. Other factors associated with an increased risk of

endocarditis are hemodialysis, the presence of intravascular prosthetic

devices at the time of bacteremia, and immunosuppression. Patients

with implantable cardiac devices (e.g., permanent pacemakers) are at

increased risk of endocarditis or device-related infections. Despite the

availability of effective antibiotics, mortality rates from these infections

continue to range from 20 to 40%, depending on both the host and

the nature of the infection. Complications of S. aureus endocarditis

include cardiac valvular insufficiency, peripheral emboli, metastatic

seeding, vasculitis, and central nervous system (CNS) involvement

(e.g., mycotic aneurysms, embolic strokes).

S. aureus endocarditis is encountered in four clinical settings: (1)

right-sided endocarditis in association with injection drug use; (2) leftsided native-valve endocarditis; (3) prosthetic-valve endocarditis; and

FIGURE 147-3 S. aureus vertebral osteomyelitis and epidural abscess involving the

thoracic disk between T9 and T10. Sagittal postcontrast MRI of the spine illustrates

destruction of the T9–T10 intervertebral space with enhancement (long arrow).

There is impingement on the thoracic cord and an epidural collection extending

from T9 through T11 (short arrows).

1183CHAPTER 147 Staphylococcal Infections

FIGURE 147-4 CT scan illustrating septic pulmonary emboli in a patient with

methicillin-resistant Staphylococcus aureus bacteremia.

(4) nosocomial endocarditis. In each of these settings, the diagnosis

is suspected from the patient’s history and the recognition of physical

signs suggestive of endocarditis. These findings include cardiac manifestations, such as new or changing cardiac valvular murmurs; cutaneous evidence, such as vasculitic lesions, Osler’s nodes, or Janeway

lesions; evidence of right- or left-sided embolic disease; and a history

suggesting a risk for S. aureus bacteremia. In the absence of antecedent

antibiotic therapy, blood cultures are almost uniformly positive. Transthoracic echocardiography, while less sensitive than transesophageal

echocardiography, is less invasive and often identifies valvular vegetations. The Duke criteria (Chap. 128) are commonly used to help

establish this diagnosis.

Acute right-sided tricuspid valvular S. aureus endocarditis is most

often seen in patients who inject drugs. The classic presentation

includes a high fever, a toxic clinical appearance, pleuritic chest pain,

and the production of purulent, sometimes bloody, sputum. Chest

x-rays or CT scans reveal evidence of septic pulmonary emboli (small,

peripheral, circular lesions that may cavitate with time) (Fig. 147-4). A

high percentage of affected patients have no history of antecedent valvular damage. At the outset of their illness, patients may present with

fever alone, without cardiac or other localizing findings. As a result, a

high index of clinical suspicion is essential for diagnosis.

Individuals with antecedent cardiac valvular damage more commonly present with left-sided native-valve endocarditis involving the

damaged valve. These patients tend to be older than those with rightsided endocarditis, their prognosis is worse, and their incidence of

complications (including peripheral emboli, cardiac decompensation,

cerebrovascular events and metastatic seeding) is increased.

S. aureus is one of the more common causes of prosthetic-valve

endocarditis. This infection is especially fulminant in the early postoperative period and is associated with increased morbidity and mortality. In most instances, medical therapy alone is not sufficient and

urgent valve replacement is necessary. Patients are prone to develop

valvular insufficiency or myocardial abscesses originating from the

region of valve implantation.

The increased frequency of nosocomial endocarditis (15–30% of

cases, depending on the series) reflects in part the increased use of

intravascular devices. This form of endocarditis is most commonly

caused by S. aureus. These patients are often critically ill, are receiving

antibiotics for various other indications, and have comorbid conditions. As a result, blood cultures may be negative and the diagnosis

missed.

Prosthetic Device–Related Infections S. aureus accounts for

a large proportion of prosthetic device–related infections. These

infections include intravascular and peritoneal catheters, prosthetic

valves, orthopedic devices, pacemakers, left-ventricular-assist devices,

or vascular grafts. In contrast with the more indolent presentation of

NSaS infections, S. aureus device-related infections are often acute,

have both local and systemic manifestations, and tend to progress

more rapidly. It is relatively common for a pyogenic collection to be

present at the device site. Aspiration of these collections and performance of blood cultures are important components in establishing a

diagnosis. S. aureus infections tend to occur more commonly soon

after implantation unless the device is used for access (e.g., intravascular or hemodialysis catheters). In the latter instance, infections can

occur at any time. As in most prosthetic-device infections, successful

therapy usually involves removal of the device. Left in place, the device

serves as a potential nidus for either persistent or recurrent infections.

Urinary Tract Infections Urinary tract infections (UTIs) are

infrequently caused by S. aureus. The presence of S. aureus in the urine

often suggests hematogenous dissemination. Ascending S. aureus

infections occasionally result from instrumentation of the genitourinary tract.

Infections Associated with Community-Acquired MRSA

Although skin and soft tissues are by far the most common sites of

infection associated with CA-MRSA, 5–10% of these infections are

invasive and can be life-threatening. The latter unique infections,

including necrotizing fasciitis, necrotizing pneumonia, and sepsis with

Waterhouse-Friderichsen syndrome or purpura fulminans, were rarely

associated with S. aureus prior to the emergence of CA-MRSA. These

life-threatening infections reflect the increased virulence of CA-MRSA

strains.

Toxin-Mediated Diseases • FOOD POISONING S. aureus is

among the most common causes of foodborne outbreaks in the United

States. Staphylococcal food poisoning results from the inoculation of

toxin-producing S. aureus into food by colonized food handlers. Toxin

is then elaborated in such growth-promoting food as custards, potato

salad, or processed meats. Even if the bacteria are killed by warming,

the heat-stable toxin is not destroyed. The onset of illness is rapid,

occurring within 1–6 h of ingestion; it is characterized by nausea

and vomiting, although diarrhea, hypotension, and dehydration may

occur. The differential diagnosis includes diarrhea of other etiologies,

especially that caused by similar toxins (e.g., the toxins elaborated

by Bacillus cereus). The rapidity of onset, the absence of fever, and

the epidemic nature of the presentation (without secondary spread)

should arouse suspicion of staphylococcal food poisoning. Symptoms

generally resolve within 8–10 h. The diagnosis can be established by the

demonstration of bacteria or the documentation of enterotoxin in the

implicated food. Treatment is entirely supportive.

TOXIC SHOCK SYNDROME TSS gained attention in the early 1980s,

when a nationwide outbreak occurred among young, otherwise healthy,

menstruating women. Epidemiologic investigation demonstrated that

these cases were associated with the use of a highly absorbent tampon

recently introduced to the market. Subsequent studies established the

role of TSST-1 in these illnesses. Withdrawal of the tampon from the

market resulted in a rapid decline in the incidence of this disease.

However, menstrual and nonmenstrual cases continue to be reported.

Nonmenstrual cases are seen in patients with surgical or postpartum

wound infections, especially when packing of the wound occurs.

The clinical presentation is similar in menstrual and nonmenstrual

TSS. Evidence of clinical S. aureus infection is not a prerequisite.

TSS results from the elaboration of an enterotoxin or the structurally

related enterotoxin-like TSST-1. More than 90% of menstrual cases

are caused by TSST-1, whereas a high percentage of nonmenstrual

cases are caused by enterotoxins (e.g., enterotoxin B). TSS begins with

relatively nonspecific flulike symptoms. In menstrual cases, the onset

usually comes 2 or 3 days after the start of menstruation. Patients

present with fever, hypotension, and erythroderma of variable intensity. Mucosal involvement is common (e.g., conjunctival hyperemia).

The illness can rapidly progress to symptoms that include vomiting,

diarrhea, confusion, myalgias, and abdominal pain. These symptoms

reflect the multisystemic nature of the disease, with involvement of the

liver, kidneys, gastrointestinal tract, and/or CNS. Desquamation of the

skin occurs during convalescence, usually 1–2 weeks after the onset of

illness. Laboratory findings may include azotemia, leukocytosis, hypoalbuminemia, thrombocytopenia, and liver function abnormalities.

Diagnosis of TSS still depends on a constellation of findings rather

than one specific finding and on a lack of evidence of other possible

infections (Table 147-2). These other diagnoses include drug toxicities,

1184 PART 5 Infectious Diseases

viral exanthems, Rocky Mountain spotted fever, sepsis, and Kawasaki

disease. Illness occurs only in persons who lack antibody to TSST-1.

Recurrences are possible if antibody fails to develop after the illness.

STAPHYLOCOCCAL SCALDED-SKIN SYNDROME SSSS primarily affects

newborns and children. The illness may vary from a localized blister to

exfoliation of much of the skin surface. The skin is usually fragile and

often tender, with thin-walled, fluid-filled bullae (Fig. 147-5). Gentle

pressure results in rupture of the lesions, leaving denuded underlying

skin. The mucous membranes are usually spared. In more generalized

infection, there are often constitutional symptoms, including fever,

lethargy, and irritability with poor feeding. Significant amounts of

fluid can be lost in more extensive cases. Illness usually follows localized infection at one of a number of possible sites. SSSS is much less

common among adults but can follow infections caused by exfoliative

toxin–producing strains.

NON–S. AUREUS STAPHYLOCOCCAL

INFECTIONS

Although less virulent than S. aureus, NSaS are among the most common causes of prosthetic-device infections, including endocarditis.

They also are increasingly a cause of native-valve endocarditis and

life-threatening bloodstream infections in neonates and in neutropenic

patients. Approximately half of the identified NSaS species have been

associated with human infections. Of these species, Staphylococcus

epidermidis is the most common human pathogen. It is part of the

normal human flora and is found on the skin (where it is the most

abundant bacterial species) as well as in the oropharynx and vagina.

Staphylococcus saprophyticus, a novobiocin-resistant species, is a common pathogen in UTIs.

■ PATHOGENESIS

S. epidermidis is the NSaS species most often associated with prostheticdevice infections. Infection is a two-step process, with initial adhesion

to the device followed by colonization. S. epidermidis is uniquely

adapted to colonize these devices because of its capacity to elaborate

the extracellular polysaccharide (glycocalyx or slime) that facilitates

formation of a protective biofilm on the device surface.

Implanted prosthetic material is rapidly coated with host matrix

molecules such as fibrinogen or fibronectin. These molecules serve

as potential bridging ligands, facilitating initial bacterial attachment

to the device surface. A number of staphylococcal surface-associated proteins, such as autolysin (AtlE), fibrinogen-binding protein,

and accumulation-associated protein (AAP), appear to play a role

in attachment to either modified or unmodified prosthetic surfaces.

The polysaccharide intercellular adhesin facilitates subsequent staphylococcal colonization, aggregation, and accumulation on the device

surface. Intercellular adhesin (ica) genes are more commonly found in

strains of S. epidermidis that are associated with device infections than

in strains associated with colonization of mucosal surfaces. Biofilm acts

as a barrier, protecting bacteria from host defense mechanisms as well

as from antibiotics while providing a suitable environment for bacterial

maturation, survival, and potential spread to other tissue sites.

Two additional NSaS species, Staphylococcus lugdunensis and Staphylococcus schleiferi, produce more serious infections (native-valve

endocarditis and osteomyelitis) than do other NSaS. The basis for this

enhanced virulence is not known, although both species appear to

share more virulence determinants with S. aureus (e.g., clumping factor

and lipase) than do other NSaS.

The capacity of S. saprophyticus to cause UTIs in young women

appears related to the presence of adhesins that facilitate adherence to

uroepithelial cells. A 160-kDa hemagglutinin/adhesin may contribute

to this affinity.

■ DIAGNOSIS

Although the detection of NSaS at sites of infection or in the bloodstream by standard microbiologic culture methods is not difficult,

interpretation of these results is frequently problematic. Because these

organisms are present in large numbers on the skin, they often contaminate cultures. It has been estimated that only 10–20% of blood cultures

positive for NSaS reflect true bacteremia. Similar problems arise with

cultures obtained from other sites. Among the clinical findings suggestive of true bacteremia are fever, evidence of local infection (e.g., erythema or purulent drainage at the IV catheter site), leukocytosis, and

systemic signs of sepsis. Laboratory findings suggestive of true bacteremia include repeated isolation of the same strain (i.e., the same species

with the same antibiogram or with a closely related DNA fingerprint)

TABLE 147-2 Case Definition of Staphylococcus aureus Toxic Shock

Syndrome

Clinical Criteria

An illness with the following clinical manifestations:

• Fever: temperature ≥102.0°F (≥38.9°C)

• Rash: diffuse macular erythroderma

• Desquamation: 1–2 weeks after rash onset

• Hypotension: systolic blood pressure ≤90 mmHg for adults or less than the fifth

percentile, by age, for children <16 years old

• Multisystem involvement (≥3 of the following organ systems)

• Gastrointestinal: vomiting or diarrhea at illness onset

• Muscular: severe myalgia or creatine phosphokinase level at least twice

ULN

• Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia

• Renal: blood urea nitrogen or creatinine level at least twice ULN for

laboratory or urinary sediment with pyuria (≥5 leukocytes per high-power

field) in the absence of urinary tract infection

• Hepatic: total bilirubin or aminotransferase level at least twice ULN for

laboratory

• Hematologic: platelet count <105

/μL

• Central nervous system: disorientation or alterations in consciousness

without focal neurologic signs in the absence of fever and hypotension

Laboratory Criteria

Negative results in the following tests, if obtained:

• Blood or cerebrospinal fluid cultures for another pathogena

• Serologic tests for Rocky Mountain spotted fever, leptospirosis, or measles

Case Classification

Probable: a case that meets the laboratory criteria and in which four of the five

clinical criteria are fulfilled

Confirmed: a case that meets the laboratory criteria and in which all five of the

clinical criteria are fulfilled, including desquamation (unless the patient dies

before desquamation occurs)

a

Blood cultures may be positive for S. aureus.

Abbreviation: ULN, upper limit of normal.

Source: Centers for Disease Control and Prevention (www.cdc.gov/nndss/

conditions/toxic-shock-syndrome-other-than-streptococcal/case-definition/2011/).

FIGURE 147-5 Staphylococcal scalded skin syndrome in a 6-year-old boy.

Nikolsky’s sign, with separation of the superficial layer of the outer epidermal layer,

is visible. (Adapted from LA Schenfeld: Staphylococcal scalded skin syndrome:

N Engl J Med 342:1178, 2000.)

1185CHAPTER 147 Staphylococcal Infections

from separate cultures, growth of the strain within 48 h, and bacterial

growth in both aerobic and anaerobic bottles.

■ CLINICAL SYNDROMES

NSaS cause a variety of prosthetic device–related infections, including

those that involve prosthetic cardiac valves and joints, vascular grafts,

intravascular devices, and CNS shunts. In all of these settings, the clinical presentation is similar. The signs of localized infection are often

subtle, the rate of disease progression is slow, and the systemic findings

are often limited. Signs of infection, such as purulent drainage, pain

at the site, or loosening of prosthetic implants, are sometimes evident.

Fever is frequently but not always present, and there may be mild leukocytosis. Acute-phase reactant levels, erythrocyte sedimentation rate,

and C-reactive protein concentration may be elevated.

Infections that are not associated with prosthetic devices include,

as noted, native-valve endocarditis due to NSaS, which accounts for

~5% of cases. Infections in preterm infants and neutropenic patients

are often associated with the need for intravascular devices. S. lugdunensis appears to be a more aggressive pathogen in this setting, causing

greater mortality and rapid valvular destruction with abscess formation

than other NSaS.

TREATMENT

Staphylococcal Infections

GENERAL PRINCIPLES OF THERAPY

Source control (e.g., incision and drainage of suppurative collections or removal of infected prosthetic devices), coupled with rapid

institution of appropriate antimicrobial therapy, is essential for the

management of all staphylococcal infections. The emergence of

MRSA as a community-based pathogen has increased the importance of culturing all sites of infection in order to determine antimicrobial susceptibility.

DURATION OF ANTIMICROBIAL THERAPY

Therapy for S. aureus bacteremia is generally prolonged (4–6 weeks)

because of the high risk of complications (e.g., endocarditis, metastatic foci of infection). Among the findings associated with

complicated bacteremias are (1) persistently positive blood cultures

96 h after institution of therapy, (2) acquisition of the infection in

the community, (3) failure to promptly remove or drain an identified focus of infection (i.e., an intravascular catheter), and (4) the

presence of deep-seated infections. Patients with uncomplicated

bacteremias are defined by a removable focus of infection, prompt

response to antimicrobial therapy (i.e., no fever or positive blood

cultures after 3–4 days), no evidence of metastatic foci of infection,

and no implanted prostheses. In these latter infections, short-course

therapy (2 weeks) can be given; however, these findings are not

always predictive of uncomplicated bacteremias. Transesophageal

echocardiography to rule out endocarditis is generally necessary

because neither clinical nor laboratory findings can reliably detect

cardiac involvement. A thorough radiologic investigation to identify potential metastatic collections is also indicated. All symptomatic body sites must be carefully evaluated.

Recent studies have demonstrated that parenteral therapy is not

always necessary to complete a course of treatment for invasive

staphylococcal infections such as endocarditis or osteomyelitis.

NSaS treatment is complicated by the possibility that a single isolate may be a contaminant. Therapy for 7–14 days is recommended

for documented infections (i.e., blood cultures of the same strain

≥24 hours apart) in the absence of endocarditis or additional sites

of infection.

CHOICE OF ANTIMICROBIAL AGENTS

The choice of antimicrobial agents to treat both coagulase-positive

and coagulase-negative staphylococcal infections is often difficult

because of the prevalence of multidrug-resistant strains and the

limited number of clinical trials that have compared the available agents. Staphylococcal resistance to most antibiotic families,

including β-lactams, aminoglycosides, fluoroquinolones, and (to

a lesser extent) glycopeptides, has increased. This trend is even

more apparent with NSaS; >80% of nosocomial isolates are resistant to methicillin, and these methicillin-resistant strains are often

resistant to many other antibiotics. Because the selection of antimicrobial agents for S. aureus infections is similar to that for NSaS

infections, treatment options for these pathogens are discussed

together and are summarized in Table 147-3.

Few strains of staphylococci (≤5%) remain susceptible to penicillin. This is a result of the widespread dissemination of plasmids

containing the enzyme penicillinase. Penicillin-resistant isolates

are treated with semisynthetic penicillinase-resistant penicillins

(SPRPs), such as oxacillin or nafcillin. Methicillin, the first of the

SPRPs, is no longer used. Cephalosporins are alternative therapeutic

agents for these infections. Second- and third-generation cephalosporins offer no therapeutic advantage over first-generation cephalosporins for the treatment of staphylococcal infections, and some

third-generation cephalosporins (e.g., ceftazidime) have considerably less activity. The carbapenems have excellent activity against

methicillin-sensitive S. aureus but not against MRSA.

The isolation of MRSA was reported within 1 year of the introduction of methicillin. Since then, the prevalence of MRSA has

steadily increased. In many U.S. hospitals, 40–50% of S. aureus isolates are resistant to methicillin. Resistance to methicillin indicates

resistance to all SPRPs as well as to all cephalosporins (except ceftaroline). Production of a novel penicillin-binding protein (PBP2a)

is responsible for methicillin resistance. This protein is synthesized by the mecA gene, which (as stated above) is part of a large

mobile genetic element—a pathogenicity or genomic island—called

SCCmec. It is hypothesized that mecA was acquired via horizontal

transfer from related staphylococcal species. Phenotypic expression

of methicillin resistance may be constitutive (i.e., expressed in all

cells in a population) or heterogeneous (i.e., displayed by only a

proportion of the total cell population). Detection of methicillin

resistance is enhanced by growth of cultures at reduced temperatures (≤35°C for 24 h) and with increased concentrations of salt in

the medium. Culture techniques are increasingly being replaced by

PCR-based or other methods (e.g., latex agglutination) that allow

for the rapid detection of methicillin resistance.

Either vancomycin or daptomycin are recommended as the

drugs of choice for the treatment of invasive MRSA infections.

MRSA susceptibility to vancomycin has decreased in many areas of

the world. It is important to note that vancomycin is less effective

than SPRPs for the treatment of infections due to methicillinsusceptible strains. In patients with a history of serious β-lactam

allergies, alternatives to SPRPs for the treatment of invasive infections should be used only after careful consideration. Desensitization to β-lactams remains an option for life-threatening infections.

Three types of staphylococcal resistance to vancomycin have

emerged. (1) Minimal inhibitory concentration (MIC; an in vitro

measure of susceptibility) “creep” refers to the incremental increase

in vancomycin MICs that has been detected in various geographic

areas. Studies suggest that morbidity and mortality may be increased

in infections due to S. aureus strains with vancomycin MICs of

≥1.5 μg/mL. (2) In 1997, an S. aureus strain with reduced susceptibility to vancomycin (vancomycin-intermediate S. aureus [VISA])

was reported from Japan. Subsequently, additional VISA clinical

isolates were reported. These strains were resistant to methicillin

and many other antimicrobial agents. The VISA strains appear

to evolve (under vancomycin selective pressure) from strains that

are susceptible to vancomycin but are heterogeneous, with a small

proportion of the bacterial population expressing the resistance

phenotype. The mechanism of VISA resistance is in part due to an

abnormally thick cell wall. Vancomycin is trapped by the abnormal

peptidoglycan cross-linking and is unable to gain access to its target

site. Regulatory genes involved in cell wall metabolism appear to

play an important role in this type of resistance. (3) In 2002, the first

clinical isolate of fully vancomycin-resistant S. aureus (VRSA) was

reported. Resistance in this and several additional clinical isolates

1186 PART 5 Infectious Diseases

TABLE 147-3 Antimicrobial Therapy for Staphylococcal Infectionsa

SENSITIVITY/RESISTANCE

OF ISOLATE DRUG OF CHOICE ALTERNATIVE(S) COMMENTS

Parenteral Therapy for Serious Infections

Sensitive to penicillin Penicillin G (4 mU q4h) Nafcillin or oxacillin (2 g q4h), cefazolin

(2 g q8h), vancomycin (15–20 mg/kg q8hb

)

Fewer than 5% of isolates are sensitive to

penicillin. The clinical microbiology laboratory

must verify that the strain is not a β-lactamase

producer.

Sensitive to methicillin;

Resistant to penicillin

Nafcillin or oxacillin (2 g q4h) Cefazolin (2 g q8h), daptomycin (6–10 mg/

kg IV q24hb,d), vancomycin (15–20 mg/

kg q8hb

)

Patients with a penicillin allergy can be treated

with a cephalosporin if the allergy does

not involve an anaphylactic or accelerated

reaction; desensitization to β-lactams may

be indicated in selected cases of serious

infection when maximal bactericidal activity is

needed (e.g., prosthetic-valve endocarditisc

).

Vancomycin is a less effective option than a

β-lactam.

Resistant to methicillin Vancomycin (15–20 mg/kg q8–12hb

),

daptomycin (6–10 mg/kg IV q24hb,d) for

bacteremia, endocarditis, osteomyelitis,

and complicated skin infections

Linezolid (600 mg q12h PO or IV),

ceftaroline (600 mg IV q8–12h), telavancin

(7.5–10 mg/kg IV q24h)b

,

TMP-SMX (5 mg [based on TMP]/kg IV

q8–12h)f

Additional agents include tedizolid

(200 mg once daily IV), oritavancin (single

dose of 1200 mg), dalbavancin (single

dose of 1500 mg), delafloxacin (300 mg

q 12 h IV), omadacycline 100 mg OD).

These drugs are primarily approved for

the treatment of skin and soft tissue

infections.g

Sensitivity testing is necessary before an

alternative drug is selected. The efficacy of

adjunctive therapy is not well established

in many settings. Linezolid, ceftaroline, and

telavancin have in vitro activity against most

VISA and VRSA strains. See footnote for

treatment of prosthetic-valve endocarditis.c

Resistant to methicillin with

intermediate or complete

resistance to vancomycine

Daptomycin (6–10 mg/kg q24hb,d) for

bacteremia, endocarditis, osteomyelitis,

and complicated skin infections

Same as for methicillin-resistant strains

(check antibiotic susceptibilities)

or

Same as for methicillin-resistant strains; check

antibiotic susceptibilities. Ceftaroline is used

either alone or in combination with daptomycin.

Ceftaroline (600 mg IV q8–12h)

Newer agents include tedizolid (200 mg

once daily IV or PO), oritavancin (single

dose of 1200 mg), and dalbavancin

(single dose of 1500 mg). These drugs are

approved only for the treatment of skin

and soft tissue infections.

Not yet known (i.e., empirical

therapy)

Vancomycin (15–20 mg/kg q8–12hb

),

daptomycin (6–10 mg/kg q24hb,d) for

bacteremia, endocarditis, osteomyelitis,

and complicated skin infections

— Empirical therapy is given when the

susceptibility of the isolate is not known.

Vancomycin with or without a β-lactam is

recommended for suspected community- or

hospital-acquired Staphylococcus aureus

infections because of the increased frequency

of methicillin-resistant strains in the community.

If isolates with an elevated MIC to vancomycin

(≥1.5 μg/mL) are common in the community,

daptomycin may be preferable.

Oral Therapy for Skin and Soft Tissue Infections

Sensitive to methicillin Dicloxacillin (500 mg qid), cephalexin

(500 mg qid), or cefadroxil (1 g q12h)

Minocycline or doxycycline (100 mg

q12hb

), TMP-SMX (1 or 2 DS tablets bid),

clindamycin (300–450 mg tid), linezolid

(600 mg PO q12h), tedizolid (200 mg PO

q24h)

It is important to know the antibiotic

susceptibility of isolates in the specific

geographic region. All collections should be

drained, and drainage should be cultured.

Resistant to methicillin Clindamycin (300–450 mg tid), TMP-SMX

(1 or 2 DS tablets bid), minocycline or

doxycycline (100 mg q12hb

), linezolid

(600 mg bid), or tedizolid (200 mg once

daily)

Delafloxacin 450 mg q 12 h, omadacycline

300 mg OD

It is important to know the antibiotic

susceptibility of isolates in the specific

geographic region. All collections should be

drained, and drainage should be cultured.

a

Recommended dosages are for adults with normal renal and hepatic function. b

The dosage must be adjusted for patients with reduced creatinine clearance. c

For the

treatment of prosthetic-valve endocarditis, the addition of gentamicin (1 mg/kg q8h) and rifampin (300 mg PO q8h) is recommended, with adjustment of the gentamicin

dosage if the creatinine clearance rate is reduced. d

Daptomycin cannot be used for the treatment of pneumonia. e

Vancomycin-resistant S. aureus isolates from clinical

infections have been reported. f

TMP-SMX may be less effective than vancomycin. g

Limited data are available on the efficacy of these drugs for the treatment of invasive

infections.

Abbreviations: DS, double-strength; TMP-SMX, trimethoprim-sulfamethoxazole; VISA, vancomycin-intermediate S. aureus; VRSA, vancomycin-resistant S. aureus.

Source: Modified from C Liu et al: Clin Infect Dis 52:285, 2011; DL Stevens et al: Clin Infect Dis 59:148, 2014; DL Stevens et al: Med Lett Drugs Ther 56:39, 2014; and LM

Baddour et al: Circulation 132:1435, 2015.

1187CHAPTER 147 Staphylococcal Infections

was due to the presence of vanA, the gene responsible for expression of vancomycin resistance in enterococci. This observation

suggested that resistance was acquired as a result of horizontal conjugal transfer from a vancomycin-resistant strain of Enterococcus

faecalis. Several of the patients infected with the VRSA strain had

both MRSA and vancomycin-resistant enterococci cultured from

infection sites. The vanA gene is responsible for the synthesis of the

dipeptide d-Ala-d-Lac in place of d-Ala-d-Ala. Vancomycin cannot

bind to the altered peptide. While isolates with MICs of ≥1.5 μg/mL

have been relatively common in some areas, VISA and VRSA isolates are uncommon.

Daptomycin, a parenteral bactericidal agent with antistaphylococcal activity, is approved for the treatment of bacteremia (including right-sided endocarditis) and complicated skin infections. It

is not effective in respiratory infections. This drug has a unique

mechanism of action: it disrupts the cytoplasmic membrane. Staphylococcal resistance to daptomycin has been reported. Resistance

can emerge during therapy; patients previously treated with vancomycin may have elevated daptomycin MICs. Patients need to be

monitored for rhabdomyolysis with creatine phosphokinase measurement and for eosinophilic pneumonia.

Linezolid—the first oxazolidinone—is bacteriostatic against

staphylococci; it offers the advantage of comparable bioavailability

after oral or parenteral administration. Cross-resistance with other

inhibitors of protein synthesis has not been detected. Resistance to

linezolid has been increasingly reported. Serious adverse reactions

to linezolid include thrombocytopenia, occasional cases of neutropenia, and rare instances of lactic acidosis or peripheral and optic

neuropathy. These reactions tend to occur after relatively prolonged

courses of therapy.

Tedizolid, a second oxazolidinone, is available as both oral

and parenteral preparations. It exhibits enhanced in vitro activity

against antibiotic-resistant gram-positive bacteria, including staphylococci. Tedizolid is administered once a day. Data on its efficacy

for the treatment of deep-seated infections are limited.

Ceftaroline is a fifth-generation cephalosporin with bactericidal

activity against MRSA (including strains with reduced susceptibility

to vancomycin and daptomycin). It is generally well tolerated. Ceftaroline is approved for use in nosocomial pneumonias and for SSTIs. It

has increasingly been used to treat invasive MRSA infections.

Telavancin is a parenteral lipoglycopeptide derivative of vancomycin that is approved for the treatment of complicated SSTIs

and for nosocomial pneumonias. The drug has two targets: the

cell wall and the cell membrane. It remains active against VISA

strains. Because of its potential nephrotoxicity, telavancin should be

avoided in patients with renal disease.

Dalbavancin and oritavancin are long-acting, parenterally

administered lipoglycopeptides that have been used to treat complicated SSTIs. Because of their long half-lives, they can be administered on a weekly basis. Both have been used as single-dose

regimens for the treatment of SSTIs. Anecdotal data support their

use for the treatment of invasive staphylococcal infections.

Although the quinolones are active against staphylococci in

vitro, the frequency of staphylococcal resistance to these agents

has increased, especially among methicillin-resistant isolates. Of

particular concern in MRSA is the possibility of quinolone resistance emerging during therapy. Therefore, quinolones are not

recommended for the treatment of MRSA infections. Resistance to

the quinolones is most commonly chromosomal and results from

mutations of the topoisomerase IV or DNA gyrase genes, although

multidrug efflux pumps also may contribute. Although the newer

quinolones exhibit increased in vitro activity against staphylococci,

it is uncertain whether this increase translates into enhanced in

vivo activity. Delafloxacin, a fluoroquinolone with broad-spectrum

activity, has excellent activity against MRSA, retaining activity

against some isolates resistant to other fluoroquinolones.

Tigecycline, a broad-spectrum minocycline analogue, has bacteriostatic activity against MRSA and is approved for use in SSTIs

as well as intraabdominal infections caused by S. aureus. It is not

recommended for the treatment of invasive infections.

Other older antibiotics, such as minocycline, doxycycline, clindamycin, and trimethoprim-sulfamethoxazole, continue to be successfully used to treat MRSA infections.

The benefit of antistaphylococcal combinations to enhance bactericidal activity in the treatment of deep-seated infections remains controversial. Clinical studies have not documented a therapeutic benefit

from the addition of gentamicin or rifampin to single-drug regimens;

recent reports have raised concern about the potential nephrotoxicity of gentamicin and adverse reactions from, or drug interactions

with, rifampin. As a result, the use of gentamicin in combination

with β-lactams or other antimicrobial agents is no longer routinely

recommended for the treatment of invasive infections such as nativevalve endocarditis. Rifampin continues to be used for the treatment of

prosthetic device–related infections and for osteomyelitis.

Omadacycline and eravacycline are broad-spectrum semisynthetic tetracycline derivatives with activity against MRSA. They are

currently approved for the treatment of SSTIs.

The use of bacteriophages with activity against staphylococci is

now being investigated as adjunctive therapy in invasive infections.

ANTIMICROBIAL THERAPY FOR SELECTED SETTINGS

Empirical Therapy Empirical coverage for MRSA is indicated when

antibiotic susceptibility is not known. Vancomycin or daptomycin are

generally recommended. It remains uncertain whether daptomycin is

preferable when elevated vancomycin MICs (>1.5 μg/mL) are common in a specific locale.

Salvage Therapy Salvage therapy for complicated S. aureus infections is sometimes needed when the bacteremia persists (i.e., for

more than 3 or 4 days) despite appropriate treatment. The risk of

a poor outcome (i.e., increased mortality, metastatic infections)

is increased with the duration of bacteremia. There is little highquality evidence to serve as a guide to salvage therapy. The combination of daptomycin or vancomycin with a β-lactam antibiotic

(e.g., ceftaroline) has been successfully used to treat patients with

persistent MRSA bacteremia, even those patients with isolates

displaying reduced susceptibility to these antimicrobial agents.

This combination appears to enhance the bactericidal activity of

daptomycin by reducing the bacterial cell-surface charge and thus

allowing enhanced daptomycin binding. For vancomycin, the combination may allow more strategic binding to the target site with

reduced cell-wall thickness. Other combinations have included

trimethoprim-sulfamethoxazole or rifampin combined with daptomycin. Linezolid or ceftaroline have also been used as single

alternative agents.

Endocarditis S. aureus endocarditis is usually an acute, lifethreatening infection. Thus, prompt collection of blood for cultures should be followed by immediate institution of empirical

antimicrobial therapy. For native-valve endocarditis, therapy with a

β-lactam is recommended. If a MRSA strain is isolated, vancomycin

(15–20 mg/kg every 8–12 h, given in equal doses up to a total of 2 g,

with the dose adjusted in the case of renal disease) or daptomycin

(6–10 mg/kg every 24 h) is recommended. The vancomycin dose

should be adjusted on the basis of trough drug levels. Patients are

generally treated for 6 weeks. For prosthetic-valve endocarditis, surgery in addition to antibiotic therapy is often necessary. The combination of a β-lactam agent—or, if the isolate is β-lactam-resistant,

vancomycin or daptomycin—with an aminoglycoside (gentamicin,

1 mg/kg IV every 8 h) for 2 weeks and rifampin (300 mg orally or

IV every 8 h) for ≥6 weeks is recommended.

Bone and Joint Infections For hematogenous osteomyelitis or

septic arthritis in children, a 4-week course of therapy is usually

adequate. In adults, treatment is often more prolonged. For chronic

forms of osteomyelitis, surgical debridement is necessary in combination with antimicrobial therapy. For joint infections, a critical

component of therapy is the repeated aspiration or arthroscopy of