PART III  Etiologic Agents of Infectious Diseases

SECTION A  Bacteria

115 Staphylococcus aureus

Robert S. Daum

Staphylococcus aureus is the most virulent species of the genus Staphylo-

coccus and the most common pathogen isolated among pediatric patients
in North America. The pathogenicity of S. aureus reflects its ability to
acquire and integrate accessory genetic elements that confer virulence. S.
aureus is responsible for community- and healthcare-associated infec-
tions and toxin-mediated diseases, and it is a major cause of mortality.
The species also is adept at evolving strategies to elude antimicrobial
therapy, leading to limited therapeutic options.
MICROBIOLOGY AND PATHOGENESIS
Staphylococci are aerobic or facultatively anaerobic gram-positive cocci
that can persist in distressed environments, such as acidic conditions,
high sodium concentrations, and wide temperature variations. Staphylo-
cocci can survive on fomites, in dust, or on clothing for at least several
days. The defining characteristics of S. aureus are the production of the
extracellular enzyme coagulase and protein A (Fig. 115.1). Clinical

Fatty acid
modifying Panton–Valentine
IgG enzyme leukocidin
(FAME) (PVL)
Protein A
Lipase Leukocidin R Enterotoxins A, B, C1-3, D, E, H
V8
Microcapsule Toxic shock syndrome toxin-1
protease
Exfoliative toxins A, B
Cell wall
(peptidoglycan)
INVASINS
α-Toxin
β-Hemolysin Capsular
γ-Hemolysin polysaccharide + Clumping factor
δ-Hemolysin types 1, 2, 5, + Fibrinogen-binding protein
Phospholipase C and 8 + Fibronectin-binding protein A
Metalloprotease (elastase) + Fibronectin-binding protein B
Hyaluronidase, hyaluronate lyase + ADHESINS + Collagen-binding protein A
+ Coagulase
+ Polysaccharide/adhesin
Lipoteichoic acid + Polysaccharide intracellular adhesin
Penicillin- + 220kd adhesin
binding
proteins Damaged tissue
β-Lactamase Extracellular matrix (ECM)
Ribitol
teichoic Foreign material
acid
FIGURE 115.1  Virulence factors and relevant surface adhesins of Staphylococcus aureus. (Redrawn from Daum RS. Staphylococcus aureus vaccine. In: Plotkin SA,
Orenstein WA (eds). Vaccines. 7th ed. Philadelphia, Saunders/Elsevier, 2016.)

692
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manifestations of S. aureus infection can result from tissue invasion,
hematogenous dissemination, or toxin release, which incite inflamma-
tory cascades and tissue necrosis. Isolation of S. aureus from skin and
mucosal sites also may represent asymptomatic colonization because the
organism can be a commensal flora.
Capsule and Cell Wall
Many clinical S. aureus isolates have a polysaccharide capsule; 11 capsular
serotypes have been described, but most experts believe that probably
only 4 exist.1 The high prevalence of two of the capsular polysaccha-
ride types (5 and 8) in almost all collections of clinically important
human and veterinary isolates suggests an important but uncertain role
in pathogenesis. Bloodstream infection (BSI) has also been caused by
unencapsulated organisms; for example, the so-called type 336 isolates
and USA300.2,3 Immunization with the type 5 and 8 polysaccharide
conjugated to Pseudomonas exotoxoid A was the basis for two recent
immunization trials, neither of which met primary end points.4–6
The cell wall of S. aureus is composed of peptidoglycan, capsular
polysaccharide when present, ribitol teichoic acid, lipoteichoic acid, and
many surface proteins, including protein A, which binds to the Fc region
of the immunoglobulin G (IgG) molecule.7 Binding of IgG antibody to
the staphylococcal cell surface in this nonphysiologic manner is ineffec-
tual and decreases the efficiency with which S. aureus is opsonized and
phagocytosed.8–10
Surface Proteins
Many proteins found on the surface of S. aureus isolates have been
implicated in pathogenesis. Adherence of S. aureus to mammalian
extracellular matrix components is mediated by a family of adhesins, the
microbial surface components that recognize adhesive matrix molecules
(MSCRAMMs).11 Coagulase is found on the bacterial cell surface and in
its environment. Coagulase binds to host prothrombin and forms staphy-
lothrombin, an enzyme that catalyzes the formation of fibrin from
fibrinogen.12 The A and B clumping factors are cell surface proteins that
bind to fibrinogen, producing the typical clusters of staphylococci when
mixed with plasma.13 Coagulase and the clumping factors breach host
defenses by causing localized clotting; the clumping factors also may aid
adherence to traumatized skin, endothelial structures, and foreign sur-
faces. Recognition of the role of S. aureus clumping factors has prompted
investigation into their potential use as vaccine antigens.14
Iron is an essential component of cytochromes and other redox pro-
teins. A cell wall–bound system of iron acquisition and importation has
been identified in S. aureus and is under investigation to define an appar-
ently essential role in pathogenesis.15 However, a trial of an iron-
scavenging protein, ISDB, was terminated prematurely for lack of
demonstrable benefit.16
Toxins
The virulence of S. aureus is due to a combination of variously elaborated
proteins, including extracellular products (e.g., the α, β, γ, and δ hemo-
lysins [also called toxins]), leukocidins, proteases, lipase, deoxyribonucle-
ase, a fatty acid–modifying enzyme, and hyaluronidase.17–23 The most
extensively studied of the exotoxins is α-hemolysin, which causes hemo-
lysis of erythrocytes, necrosis of the skin, and the release of cytokines and
eicosanoids that can produce shock. S. aureus is lethal when injected into
animals. S. aureus mutants lacking α-hemolysin generally are less viru-
lent,24 although pathogenic S. aureus isolates that do not produce
α-hemolysin have been identified. S. aureus β-hemolysin is a sphingo-
myelinase that can injure lipid-rich membranes; however, most human
isolates do not express β-hemolysin. The high prevalence of γ-leukocidin
genes in isolates that cause necrotizing skin infections suggests the
importance of this toxin in causing dermonecrosis. S. aureus has several
leukocidins, which are synergohymenotropic toxins that damage mem-
branes of certain cells as a result of the concerted action of two elaborated,
secreted proteins. The Panton-Valentine leukocidin (PVL) is a pore-
forming cytotoxin,25 and its toxic effect is said to result from the syner-
gistic action of the proteins lukS-PV and lukF-PV.26 PVL has been
associated with severe inflammatory lesions, presumably through the
activation of granulocytes.27 PVL-producing strains have been associated
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Staphylococcus aureus 115
FIGURE 115.2  Staphylococcal scalded skin syndrome (Ritter disease) in an infant
1 week old. (Courtesy of J.H. Brien©.)
with severe skin infections and lung infections,28 specifically necrotizing
pneumonia.29 The importance of PVL in the pathogenesis of S. aureus
infections, a controversial topic because of variation in the susceptibility
of host species, has been clarified in human infections.30–32
S. aureus causes a variety of so-called toxin-mediated diseases, includ-
ing staphylococcal scalded skin syndrome (SSSS), toxic shock syndrome
(TSS), and staphylococcal food poisoning; all of these are caused by the
action of exotoxins and enterotoxins. Exfoliative toxins A (ETA) and B
(ETB) cleave the glycoprotein desmoglein 1, promoting the spread of
S. aureus under the stratum corneum33,34 and resulting in blistering of the
superficial epidermis, which is characteristic of SSSS and bullous impe-
tigo (Fig. 115.2). Toxic shock syndrome toxin-1 (TSST-1) and staphylo-
coccal enterotoxins B (SEB) and C (SEC) have been implicated in most
cases of TSS. These toxins have superantigen activity; that is, they stimu-
late T lymphocytes nonspecifically, resulting in cytokine release and
clinical toxic shock. At a skin or mucosal port of entry TSST-1 can
interfere with the release of inflammatory mediators locally, which may
account for a surprisingly benign appearance at the local infective site.
An expanding family of enterotoxins has been implicated in staphylococ-
cal food poisoning, but the most frequently implicated molecule is
enterotoxin A (SEA).
Genetic Basis and Regulation of Pathogenicity
Factors and Antimicrobial Resistance
The whole genome of S. aureus has been sequenced many times. It has a
circular chromosome of about 2.8 million base pairs.35 Genes for many
housekeeping functions are highly conserved. The genome also carries
mobile genetic elements, such as plasmids, transposons, prophages, and
pathogenicity islands, many of which encode virulence factors or deter-
minants of antibiotic resistance. These factors represent a subset of a large
class of accessory gene products (including surface proteins, exotoxins,
and other enzymes) that provide one or more advantages in particular
environments, although these accessory products are not required for
growth and cell division.
S. aureus has evolved a remarkable network of regulatory mechanisms
that control subsets of genes that are upregulated or downregulated
under certain growth and environmental conditions. The most exten-
sively studied is the agr locus with its two-component signal transduction
system and its effector RNAIII molecule. The agr locus upregulates genes
that encode capsular polysaccharides; α-δ toxins; two-component syn-
ergohymenotropic toxins; enterotoxins; exfoliatins; and proteases; it
downregulates other genes, such as those that encode MSCRAMMs,
other adhesins, and protein A. Other two-component signal transduction
systems implicated in pathogenesis are saeRS, srrAB, arlSR, and lytRS.
Protein systems that bind deoxyribonucleic acid (DNA), such as sarA
and its regulatory homologues, also regulate virulence factors. Addition-
ally, the σ-factor, σB, can combine with the ribonucleic acid (RNA)
polymerase core enzyme to form a holoenzyme that can recognize
693
 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
promoter elements for at least 36 S. aureus genes involved in bacterial
stress responses. Taken together, membrane sensing systems (e.g., agr)
and DNA-binding regulatory systems afford S. aureus a versatile environ-
mental response system and confer the capacity to respond to a myriad
of environmental stimuli, such as high or low sodium chloride concen-
trations, subinhibitory concentrations of protein synthesis inhibitors, a
low pH, or a condition in which essential nutrients (e.g., amino acids)
are limited.
S. aureus can overcome environmental antibiotic pressure through the
acquisition and transmission of resistance genes from other, usually less
pathogenic, species and isolates of the same species. Resistance to
β-lactam antibiotics (e.g., penicillins, cephalosporins, and carbapenems)
is one example. The β-lactam antibiotics bind to S. aureus penicillin-
binding proteins (PBPs), thereby inhibiting cell wall synthesis.
Resistance to penicillin was documented almost immediately after the
medication’s introduction into clinical practice in the 1940s. It is medi-
ated by the elaboration of a β-lactamase, which is encoded by a transpo-
son borne on a plasmid. Almost all clinical isolates of S. aureus can
elaborate this enzyme, rendering antibiotics susceptible to β-lactamase
hydrolysis clinically ineffective.
The development of β-lactamase–resistant semisynthetic penicillins
temporarily overcame this widely prevalent clinical problem. However,
some strains became resistant to semisynthetic compounds by acquiring
mecA, a gene that elaborates PBP2a, a peptidoglycan-synthesizing enzyme
that has decreased affinity for β-lactam antibiotics.36,37 These resistant
strains are called methicillin-resistant Staphylococcus aureus (MRSA) and
are responsible for nosocomial outbreaks and for the current community-
based MRSA epidemic. MRSA strains are resistant to all β-lactams except
ceftaroline.
The mecA resistance gene is located on a mobile genetic element
called the staphylococcal chromosome cassette mec (SCCmec),38 which
is present in all MRSA isolates, with occasional exceptions. SCCmec
contains a mec complex, comprised of mecA and its variably present
mec1 and mecR1 regulatory genes, and a ccr complex, comprised of
genes that mediate insertion and excision of SCCmec from the genome.
Insertion of SCCmec into the S. aureus genome is the genetic event
that converts a methicillin-susceptible strain into a methicillin-resistant
one. Currently 11 SCCmec elements have been sequenced or partially
characterized. In the United States, mobile elements SCCmec types I
to III generally are found in healthcare-associated MRSA (HA-MRSA)
isolates, and SCCmec types IV and V generally are found in community-
associated MRSA (CA-MRSA) isolates, although these distinctions are
blurring.39
Although the mechanism of the movement of SCCmec elements from
strain to strain is unknown, the large size of types I to III is believed to
limit easy transfer of the elements. Types IV and V, however, are small
and mobile. Types IV and V have been found in multiple S. aureus genetic
backgrounds, which supports the hypothesis that they are readily trans-
ferred from strain to strain.40–42 To date, types VI through XI have been
identified in only a limited number of strains.
EPIDEMIOLOGY
Colonization
Humans and other mammals are the natural reservoirs for S. aureus.
Asymptomatic colonization is frequent in humans, and traditionally the
anterior nares were thought to be a predominant site. However, the skin,
nails, pharynx, axillae, perineum, throat, rectum, and vagina are common
sites of colonization. Colonization rates range from 25% to 50%; higher
rates are found in children, in people with dermatologic conditions (e.g.,
eczema), in those who perform needle injections frequently (e.g., intra-
venous drug abusers), in those with indwelling intravascular devices (e.g.,
patients receiving dialysis), and in healthcare personnel (HCP). Even
higher rates have been documented with the use of highly sensitive detec-
tion methods, leading some to speculate that colonization may be uni-
versal.43 Although it has been held that most people are colonized
intermittently (and fewer are persistently or rarely colonized44), scant
explicit data are available. Traditionally, nasal S. aureus carriage has been
a risk factor for developing an infection,45–47 although most colonized
individuals do not do so. CA-MRSA colonization affects more body sites,
which correlates with an increased risk of infection.
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Healthcare-Associated Infections
S. aureus can develop resistance to all classes of antimicrobial agents. The
first MRSA strain was reported less than a year after the introduction of
semisynthetic penicillins in the early 1960s, even though these penicil-
lins were active against β-lactamase–producing, so-called methicillin-
susceptible S. aureus (MSSA). Multidrug-resistant HA-MRSA strains
spread worldwide in hospital settings. The National Healthcare Safety
Network (NHSN) (formerly the National Nosocomial Infections Sur-
veillance System), an agency of the Centers for Disease Control and
Prevention (CDC), has reported S. aureus as a major pathogen of HAIs.
In 2003 MRSA accounted for 64% of nosocomial S. aureus isolates in
intensive care units (ICUs) in U.S. hospitals, an increase from 36% in
1992.48 From January, 2006, to October, 2007, S. aureus was the second
most common cause of HAIs, exceeded only by coagulase-negative
staphylococci (CoNS).49
In pediatric ICUs in the U.S., S. aureus is the major nosocomial
pathogen in a variety of clinical situations; it accounts for 9% of HA
bloodstream infections (HA-BSIs), 17% of cases of HA pneumonia, and
20% of surgical site infections.50 Current patterns of HA-MRSA isolates
reveal decreasing rates of isolation51 and decreasing resistance to non–β-
lactam antibiotics; this suggests a shift in nosocomial MRSA epidemiol-
ogy, probably reflecting the movement of “biologically fit” CA-MRSA
isolates into the hospital.40,52
In recent years MSSA has become a healthcare-associated pathogen,
predominantly over MRSA in some settings, but more frequently associ-
ated with BSI and the requirement for intensive care.
Community-Associated MRSA Infections
Prevalent MRSA infection outside the healthcare setting was first reported
in 1982 in Detroit, Michigan, among intravenous (IV) drug users.53 This
and subsequent reports of CA-MRSA were associated with risk factors for
infection similar to those for HA-MRSA, including IV drug administra-
tion, recent hospitalization or surgery, presence of indwelling catheters
or devices, dialysis, or residence in a longterm care facility.54–57 In the late
1990s CA-MRSA infections emerged; these infections occurred mostly
in children with no identifiable predisposing MRSA risk factors,58–62 and
they commonly resulted in skin and soft tissue infections (SSTIs). Some
serious infections required hospitalization or were fatal.63 The number
and geographic distribution of CA-MRSA infections grew substantially.
Strong evidence supports the de novo rise of MRSA in the community,
rather than movement of HA-MRSA into the community.64,65
A CA-MRSA infection can be defined as one that occurs in an outpa-
tient or that develops within 72 hours of admission to the hospital in a
patient without any of the factors used to define risk for HA-MRSA:
recent hospitalization or surgery, prolonged antibiotic therapy, underly-
ing chronic disease, indwelling catheter or other device, healthcare
contact, or residence in a longterm facility.66 Molecular definitions also
have been used to distinguish HA-MRSA from CA-MRSA strains.67
Outbreaks of CA-MRSA infections have been reported in group childcare
settings,57,68 sports teams,69,70 correctional facilities,71,72 and military
units,73,74 which suggests that close contact and suboptimal hygiene
practices play a role in the spread of infection.
CA-MRSA isolates also can be distinguished from HA-MRSA by their
lack of multidrug resistance. Most CA-MRSA isolates are susceptible to
clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), and doxy-
cycline, whereas HA-MRSA isolates usually are resistant to these agents.
Multilocus sequence typing, SCCmec typing, and pulsed-field gel electro-
phoresis have elucidated important differences between HA-MRSA and
CA-MRSA isolates. In the U.S., HA-MRSA usually contain SCCmec type
II and genes that mediate resistance to several non–β-lactam antibiot-
ics. In contrast, CA-MRSA isolates usually contain SCCmec type IV or
type V and lack non–β-lactam antibiotic resistance genes.59 Even among
CA-MRSA isolates, however, determinants of non–β-lactam agent
resistance can be found elsewhere in the cell, such as on plasmids or
in the chromosome. For example, erythromycin resistance is common
among both HA-MRSA and CA-MRSA strains and can be mediated
by a variety of phenotypic and genetic mechanisms. When the erm
gene that commonly mediates erythromycin resistance is present, the
constitutive or inducible MLSB phenotype (discussed later in the chapter)
is conferred.75,76
 Staphylococcus aureus 115
Another difference between CA-MRSA and HA-MRSA isolates is their
repertoire of toxin genes.77 The most striking examples are the lukS-PV
and lukF-PV genes that encode for PVL and are transferred from strain
to strain by an as yet unknown mechanism.78 These toxin genes have been
associated with MSSA and MRSA strains that cause SSTIs, necrotizing
pneumonia, and empyema.79–81 More severe infections, such as severe
sepsis, thrombosis, and thromboembolism, also are caused by isolates
containing the PVL genes.30 Interestingly, although SCCmec IV or
SCCmec V and PVL together seem to confer a selective advantage for
spread (i.e., transmission and colonization) and pathogenicity (i.e.,
excess rate of infection per colonized individual), the genes encoding PVL
are transferred separately from the SCCmec element. Most circulating
CA-MRSA organisms in the U.S. belong to a genetic lineage called USA
300 (from a nomenclature scheme based on pulsed-field gel electropho-
retic pattern). These organisms contain an island of foreign DNA called
the arginine catabolic mobile element (ACME)–encoded arc cluster. The
role of ACME is the subject of controversy, but it is believed to confer an
improved survival advantage on skin and spermidine susceptibility.82–84

Vancomycin-Intermediate S. aureus and

Vancomycin-Resistant S. aureus Infections
S. aureus isolates with decreased susceptibility to vancomycin also FIGURE 115.3  Bullous impetigo in a neonate. (Courtesy of J.H. Brien©.)
emerged in the late 1990s. These vancomycin-intermediate S. aureus
(VISA) strains, defined as having a minimal inhibitory concentration
(MIC) of vancomycin greater than 2 µg/mL, typically have been isolated
from patients with underlying medical conditions in whom vancomycin hidradenitis. When the lesion is associated with a hair shaft, the term
therapy has failed85,86; these strains usually also are resistant to teicoplanin furuncle is often used (see Fig. 68.6). Rupture yields a purulent discharge.
(a glycopeptide not licensed in the U.S.). Therefore, the term glycopeptide- A carbuncle is a larger lesion formed by the coalescence of furuncles.
intermediately susceptible S. aureus (GISA) may be more appropriate. In With most small skin abscesses the symptoms pain and erythema are
2002 the first high-level vancomycin-resistant S. aureus (VRSA) strain local, although fever can be present. Systemic signs can accompany larger
was reported (MIC of vancomycin >16 µg/mL); this isolate apparently lesions. In the neonate a skin abscess or boil can progress rapidly to BSI
acquired the vanA vancomycin resistance genes from Enterococcus organ- and clinical sepsis.
isms. To date, 13 VRSA isolates have been reported in the U.S., and all S. aureus is the leading cause of breast abscess in infants, which com-
strains evaluated have carried the vanA gene.87–89 monly occurs within the first 3 weeks of life, when the breasts are enlarged
physiologically (Fig. 115.4) The abscess usually is unilateral and accom-
CLINICAL MANIFESTATIONS panied by erythema and induration. Occasionally fever, leukocytosis, or
BSI can occur. Isolation of the pathogen from the abscess’s discharge aids
Skin and Soft Tissue Infections management.94
Local cleansing and incision and drainage are essential components of
Impetigo the management of abscesses.95,96 Sometimes small abscesses (<5 cm) can
be treated without systemic antimicrobial therapy95; however, in a ran-
S. aureus is a major cause of several infections of the skin and its append- domized, placebo-controlled trial, TMP-SMX had a higher clinical cure
ages. The most superficial is impetigo, which begins as a small, tender, rate.97 Neonates with skin abscesses and infants with a breast abscess
erythematous papule. Often the integument has been interrupted, such should be treated. Systemic antibiotic treatment also is required for any
as by an insect bite, a varicella vesicle, eczema, or a minor abrasion from patient with severe or extensive disease, rapid progression of associated
trauma. Bullous impetigo is a specific S. aureus infection in which cellulitis, systemic illness, associated comorbidity or immunosuppres-
transparent bullae rupture easily, exposing a moist base surrounded by a sion, abscess in an area difficult to drain (e.g., face, genitalia, hand), or
thin rim of scale (Fig. 115.3). Bullous impetigo is mediated by the pro- associated phlebitis.98
duction of ETA and ETB.90,91
Several studies have demonstrated the superiority of topical or sys-
temic antibiotics over simple cleansing for the treatment of impetigo. For
uncomplicated singular sites of impetigo in children outside the neonatal
period, topical mupirocin can be appropriate. Mupirocin ointment
should be applied 3 times daily for 7 to 10 days. Retapamulin recently
was licensed for topical therapy for children 9 months of age or older
who have impetigo caused by Streptococcus pyogenes or MSSA (but not
MRSA).92 This drug’s place in the therapeutic armamentarium has yet to
be determined. Many experts prefer systemic antimicrobial therapy for
the treatment of bullous impetigo.93
Oral or parenteral antimicrobial therapy should be considered if the
impetigo is widespread. Because of the high prevalence of MRSA, a culture
should be performed before the initiation of systemic therapy in most
patients. Neonates with minor bullous impetigo (frequently near the
umbilicus) who are afebrile and well sometimes can be managed with oral
empiric systemic antimicrobial therapy with an agent active against MRSA.

Abscess
S. aureus commonly causes superficial abscesses of the skin. Moist and FIGURE 115.4  Abscess and cellulitis due to community-acquired methicillin-
hairy skin is particularly susceptible to furuncles, boils, folliculitis, and resistant Staphylococcus aureus (CA-MRSA). (Courtesy of J. H. Brien©.)

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 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
Any abscess can heal with scarring. Some patients may suffer from
recurrent furunculosis, which can be difficult to manage. Systemic and
topical antimicrobial agents, along with careful hand and nail hygiene,
may help reduce recurrences.
Recurring MRSA SSTIs are common and pose a management chal-
lenge. Underlying skin conditions (e.g., eczema, diaper dermatitis)
should be managed aggressively. Attempts to decolonize a patient with
nasal mupirocin or applications of an antiseptic (e.g., chlorhexidine)
often are unsuccessful; in addition, the right time to attempt such decolo-
nization is unclear. Consideration of congenital or acquired immunode-
ficiency may be warranted in patients with recurrent disease, especially
if the response to therapy is slow or healing occurs with remarkable
scarring.99
Cellulitis
Cellulitis is an infection of the subcutaneous tissues and the dermis
that manifests as an area of erythema, warmth, edema, and tenderness.
S. aureus is a major cause of the infection in all age groups and at all clinical
sites. If systemic signs are present, a blood culture should be performed
before antimicrobial therapy is started. When present, purulent material
should be cultured. Culturing an aspirate or biopsy specimen from a
patient with nonpurulent cellulitis can yield the infecting bacterium.100
Treatment involves oral or parenteral antimicrobial therapy, depend-
ing on the extent of disease and whether systemic signs or toxicity is
present.
Wound Infection
The likelihood of a postoperative or posttraumatic wound infection
increases with the use of sutures, especially in poorly vascularized tissues.
Measures that often can prevent infections include frequent dressing
changes, meticulous daily wound care, and strict handwashing. S. aureus
wound infections generally are recognized within a few days after trauma
or surgery; inflammation is a local sign, and constitutional signs of illness
may be present. The exudate often is cloudy, hemorrhagic, and notably
odorless. Extension of a wound infection into deeper tissues can occur,
resulting in cellulitis, lymphadenitis, lymphangitis, or necrotizing fasciitis.
Bursitis usually is the complication of a contiguous skin infection, fre-
quently with trauma, and must be differentiated from pyogenic arthritis.
Treatment of a wound infection includes exploration of the wound,
drainage, removal of any foreign material, and optimization of skin
hygiene. Topical or systemic antimicrobial therapy may be a useful
adjunct for mild infections. Parenteral antimicrobial therapy should be
considered for clinically serious or extensive infections and for wound
infections on the head and neck.
Ocular Infections
S. aureus is an important cause of purulent conjunctivitis. The causative
organism can be visualized by Gram stain or isolated from purulent
discharge. Conjunctivitis usually resolves without treatment, although
topical ophthalmic antimicrobial agents frequently are used. S. aureus is
the most frequently recognized cause of a stye or a hordeolum, an infec-
tion of the sebaceous gland or the eyelash follicle, respectively. Use of a
topical antimicrobial agent may prevent the spread of infection to adja-
cent hair follicles, but frequent application of warm compresses usually
suffices for treatment.101
Preseptal (periorbital) cellulitis can result from extension of sinusitis
or from autoinoculation of skin flora after a break in the skin due to local
trauma, an insect bite, an abscess, or impetigo.102 (Fig. 115.5). S. aureus
is the leading cause of skin lesion–related preseptal cellulitis. Because
of the elasticity and thinness of the skin in and around the eyelid, the
clinical presentation can be dramatic, with a rapid onset of lid swelling,
erythema, and tenderness.103 Low-grade fever and leukocytosis can be
present, although typically the child does not appear systemically ill.
Visual acuity is not affected, and movement of the globe is not painful
or limited. Treatment of preseptal cellulitis usually is initiated parenter-
ally; oral therapy can be substituted after a clinical response has been
demonstrated.
S. aureus is presumed to be the leading cause of orbital (postseptal)
cellulitis after surgical or accidental trauma to the orbit, and it can be
696
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FIGURE 115.5  Preseptal cellulitis due to MRSA infection after minor trauma.
(Courtesy of J.H. Brien©.)
responsible for orbital cellulitis that complicates sinusitis.104 Patients or
parents note a red, swollen “eye”; the physical examination reveals one
or more of the following: decreased or painful movement of the globe,
impaired visual acuity, chemosis, or proptosis.103 Complicating cavernous
sinus thrombosis should be suspected if the patient has abnormal neu-
rologic findings.105 Treatment requires confirmation of the pathogen and
antimicrobial susceptibility. CT helps distinguish between orbital phleg-
mon, subperiosteal abscess, and orbital abscess; staphylococci are more
often associated with abscesses. These diagnoses mandate assessment for
surgical drainage in addition to IV antibiotics.106 An extended course of
antimicrobial therapy is given parenterally.
S. aureus endophthalmitis is an uncommon infection in children and
usually follows ocular surgery or penetrating trauma to the globe.107
Symptoms include blurred vision, redness, pain, lid swelling, and the
presence of a hypopyon. Systemic signs or fever and lethargy often are
present. Treatment includes antibiotics, both given parenterally and
instilled directly into the vitreal cavity, and vitrectomy. Visual outcomes
are poor.108
Invasive Infections
Osteomyelitis
S. aureus is the major cause of hematogenous osteomyelitis, accounting
for up to 90% of cases. The metaphyses of long, tubular bones are affected
most frequently, although infection can occur in any bone.109–112 Previous
minor trauma may predispose a person to infection, probably as the
result of subclinical minor vascular injury or because a small area of bony
necrosis acts as a nidus for seeding during what otherwise would have
been asymptomatic bacteremia.113 The classic clinical picture includes
fever and point tenderness over the affected area of bone (usually at the
metaphysis), decreased range of motion, and minor local signs of inflam-
mation. Infants and toddlers can manifest only irritability, limp, or
refusal to bear weight. Diagnosis requires a high degree of suspicion.
Symptoms usually are present 1 week or less before they come to medical
attention, but occasionally they are present for several weeks before
recognition.114
Evaluation should include a blood culture because BSI is detectable in
about 50% of patients.115 At the time of clinical presentation the eryth-
rocyte sedimentation rate (ESR) and C-reactive protein (CRP) level
usually are elevated, although normal values can be seen, particularly
among neonates or patients with sickle cell disease, distal digital infec-
tion, or subacute cases (e.g., Brodie abscess). Other acute phase reactants
(e.g., leukocyte count) may be normal.116 A radiograph of the affected
bone is likely to have a normal appearance in the first days after the onset
of symptoms, or it may show only deep soft tissue swelling adjacent to
the bony metaphysis; periosteal elevation or lucencies within the bone
typically are not apparent until 10 to 21 days after the onset of infection.
A technetium-99 methylene phosphonate scan, performed in three
phases, identifies increases in regional perfusion and tracer uptake by
inflamed bone. Scintigraphy is especially useful for detecting multifocal

infection. Although scintigraphy is sensitive, the results can be normal in
neonates and patients with sickle cell disease with osteomyelitis. MRI is
the most accurate diagnostic test, and it also can identify critical fascial
and deep muscle phlegmon and abscess.117
Establishing the causative organism by needle aspiration or biopsy of
the bone is important, especially if blood cultures are negative. Surgical
intervention beyond a diagnostic needle aspiration usually is not required
for simple acute osteomyelitis, but it can be indicated urgently if extensive
subperiosteal or soft tissue infection or ischemic compartment syndrome
is present, and it must be repeated frequently. Surgery often is required
for chronic infection to remove sequestra and to debride affected bone.
IV antibiotics should be initiated and subsequently modified accord-
ing to microbiology test results. Most experts recommend a course of
antimicrobial therapy extending up to 4 weeks or longer for S. aureus
osteomyelitis, with parenteral therapy used initially. Deep vein thrombo-
sis adjacent to the bony site of infection and septic thromboembolism
increasingly have become recognized as complications of S. aureus
osteomyelitis, especially when they are caused by CA-MRSA or PVL-
positive MSSA. These conditions usually develop in the proximal long
bones and vertebrae.118 The total duration of the therapy and the transi-
tion to oral therapy is individualized, depending on the extent of infec-
tion, susceptibility test results, the clinical setting and course.114,119,120 One
study has shown that a total course of therapy of 3 weeks to be noninfe-
rior,120 and another study has shown that early transition to oral therapy
also is effective, even when CA-MRSA is the cause.121
Techniques for monitoring the therapeutic response vary, and few
explicit data are available. Most experts use a rapid fall in the CRP level
as evidence of an appropriate antibiotic choice, and an eventual fall in
the ESR as a guide to an adequate duration of therapy. In general, serial
imaging of the infected bone does not provide useful information about
the duration of therapy.
S. aureus can cause osteomyelitis secondary to an adjacent deep soft
tissue focus; by concurrent direct inoculation; or by contiguous spread,
such as through an accidental puncture wound of the foot or the patella,
a bite, trauma, an infected paronychia, or a surgical procedure.122 Osteo-
myelitis that develops after a puncture wound frequently is called
osteochondritis, partly to remind clinicians of the clinical and patho-
physiologic features that distinguish it from hematogenous osteomyelitis.
Symptoms and signs of acute hematogenous osteomyelitis usually are
absent, although many patients have localized pain, fever, and erythema.
The blood typically is sterile, and the CRP level can be minimally
increased or normal. Surgical debridement is an important component
of the therapeutic strategy in nonhematogenous osteomyelitis/
osteochondritis syndromes; antimicrobial therapy is adjunctive. The
optimal duration of antimicrobial therapy for osteochondritis is unclear,
but it frequently can be short (e.g., 7 to 14 days) after adequate surgical
debridement in selected cases.114
Diskitis
Diskitis, or inflammation of an intervertebral disk, is uncommon and
occurs primarily in children younger than 5 years of age. Diskitis may be
difficult to distinguish from vertebral osteomyelitis, and the two entities
probably have a similar pathogenesis (see chapters 76 and 78). Children
with diskitis usually are not febrile or ill, but they refuse to walk, limp or,
in older children, have back pain. MRI helps distinguish diskitis from
vertebral osteomyelitis. S. aureus is the most frequently identified organ-
ism in both entities, although specimens are collected more frequently
and are positive more frequently in patients with vertebral osteomyelitis.
Diskitis may resolve spontaneously without antimicrobial therapy; ver-
tebral osteomyelitis does not.
Diskitis without adjacent vertebral involvement sometimes can be
managed with observation alone. If the adjacent vertebrae are involved,
vertebral osteomyelitis cannot be excluded, and these patients should
receive a course of antimicrobial therapy appropriate for osteomyelitis.
Follow-up imaging studies are appropriate in this circumstance.123
Pyogenic Arthritis
Hematogenous seeding of the synovium during S. aureus BSI is the most
common pathogenesis of infectious arthritis in children. Pyogenic
arthritis usually is heralded by warmth, tenderness, erythema, and limited
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Staphylococcus aureus 115
range of motion of the involved joint. Manifestations of a hip infection
can be more subtle because of the depth of tissue surrounding the joint.
In infants a subtle increase in resistance to movement or pain with
movement may be the only clue. An imaging study (e.g., ultrasonogra-
phy) is valuable.124 Infants with osteomyelitis of the femur or humerus
especially are prone to pyogenic arthritis of the contiguous joint due to
the vascular and capsular anatomy in this region at this age125 (see
Fig. 76.4).
If pyogenic arthritis is suspected, blood culture and aspiration of joint
fluid are performed urgently; the hip usually is drained surgically. The
fluid is evaluated by Gram stain and culture, total and differential cell
counts, and glucose and protein levels. In occasional cases of S. aureus
arthritis, bacteria visualized on Gram stain are not isolated in culture
because of the bacteriostatic nature of synovial fluid or previous antimi-
crobial therapy.
Treatment consists of surgical drainage and antimicrobial therapy.
Antimicrobial therapy should be initiated when clinical suspicion is high
and is continued for at least 3 weeks. Multiple aspiration procedures may
be necessary. Open surgical drainage is used when serial aspiration does
not produce a rapid response; as initial management when the hip or
shoulder joint is affected; or when establishing effective drainage by
simple aspiration is technically difficult and the risk of longterm compli-
cations is high.114 A poor outcome is associated with delay of appropriate
management and concomitant osteomyelitis.126
Abscesses of Muscle and Viscera
S. aureus is the most common cause of pyomyositis (including iliopsoas
and obturator internus abscess) and liver abscess, and it is an important
cause of renal, perinephric, splenic, and pancreatic abscesses. These are
all complications of BSI, which may have been asymptomatic; the patient
may come to medical attention because of symptoms related to the focal
infection or for fever of unknown origin (FUO) or associated with severe
sepsis. Necrotizing fasciitis, especially due to CA-MRSA, usually occurs
as a complication of skin infection but also can occur after seeding of a
deep site during BSI (see Fig. 75.2). Pyomyositis usually manifests with
fever and an insidious or acute onset of cramping muscle pain, tender-
ness and, especially, induration of a large muscle group, such as those
near the buttock, thigh, or hip. An obturator internus abscess can cause
a painful limp, pelvic girdle pain, or refusal to walk. An iliopsoas abscess
can cause predominantly flank pain and tenderness. A visceral abscess
and nephric abscesses are most likely to manifest as FUO, possibly
accompanied by nonspecific abdominal or flank symptoms. A blood
culture is positive in fewer than one half of cases that present because of
FUO or localized complaints.
CT or MRI is highly likely to identify abnormalities. Management
usually entails surgical decompression, debridement and drainage, and
prolonged parenteral antibiotic therapy. Multiple, small visceral abscesses
frequently can be treated with antibiotic therapy alone if the pathogen is
identified and susceptibility test results are available. Necrotizing fasciitis
is a surgical emergency and requires decompression and debridement of
the involved tissue and antimicrobial therapy.
Upper Respiratory Tract Infections
Head and Neck Infections
S. aureus is an infrequent cause of acute otitis media or sinusitis, but it
should be considered in a child who fails multiple courses of empiric,
oral antimicrobial therapy and in chronic or complicated disease. Both
MSSA and MRSA increasingly have been isolated in cases of otorrhea
that develops after tympanostomy tube insertion, and as complications
of paranasal sinusitis.104,127,128
S. aureus is the leading cause of nasolacrimal duct abscess, suppurative
parotitis, abscess of a lymph node below the angle of the jaw in very
young infants (Fig. 115.6), and retropharyngeal abscess in children
younger than 3 years of age (see Fig. 28.1). Infection occurs presumably
after nasopharyngeal or oropharyngeal colonization, sometimes in
association with a viral infection. In older children and adolescents
S. aureus is the leading cause of peritonsillar and parapharyngeal abscess
associated with recurrent pharyngeal infections and suppurative cervical
lymphadenitis.
697
 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
A cheobronchial epithelium to the congested and hemorrhagic parenchyma
B appearance on radiographs, lung abscesses uncomplicated by pleural
FIGURE 115.6  Two-month-old infant with necrotizing lymphadenitis due to
MSSA. The infant had no intraoral, skin, or middle-ear abnormality. Note the
location of the mass (A and B) and elevation of the earlobe (A). (Courtesy of J.H.
Brien©.)
Tracheitis
Bacterial tracheitis caused by S. aureus can occur in an airway inflamed
by a viral process or injured by medical manipulation. Affected patients
manifest hoarseness and stridor (if the larynx is involved concomitantly)
and can deteriorate suddenly, showing respiratory distress and s high
temperature. The diagnosis can be suspected by the results of imaging
studies and is confirmed by direct visualization of thick, purulent secre-
tions in the trachea and subglottic edema, along with a positive Gram
stain of secretions and recovery of S. aureus upon culture. Management
includes establishment of an artificial airway and IV antibiotic therapy129
(see Chapter 28).
Lower Respiratory Tract Infections
Pneumonia
S. aureus can cause rapidly progressive pneumonia after inhalation of the
organism or seeding of the lungs during BSI. Clinical features include
fever, cough, grunting, and tachypnea, which can evolve into rapidly pro-
gressive and severe respiratory distress. A chest radiograph demonstrates
multiple, patchy alveolar infiltrates that tend to coalesce to form large
consolidations (Fig. 115.7). Pleural effusion and empyema accompany
698
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about 90% of pulmonary infections; spontaneous pneumothorax
occurs in 25% to 50%. A pneumatocele (an air- or fluid-filled cavitation
resulting from dissolution of intra-alveolar septa) occurs in more than
50% of cases. Most cases occur in previously healthy children, although
predisposing factors (e.g., young age [younger than 1 year], chronic lung
disease, immunosuppression, and presence of a foreign body or skin
infection) may increase the likelihood of S. aureus pneumonia. A seasonal
peak in S. aureus pneumonia is associated with viral respiratory tract
infections such as influenza, presumably because viral illness transiently
alters pulmonary defense mechanisms.130
S. aureus necrotizing community-acquired pneumonia (CAP) has
increased dramatically in immunocompetent children. It can be caused
by both MSSA and MRSA strains, which usually contain the PVL
genes.28,131–134 Leukopenia, and rapidly progressive unilateral or bilateral
diffuse parenchymal pulmonary infiltrates are typical.29 Severe sepsis
syndrome can be present and has a high fatality rate. Histologic findings
at autopsy reveal dense S. aureus with necrosis extending from the tra-
of the lung29,80 (Fig. 115.8).
A high index of suspicion for S. aureus is critical in evaluating possible
cases and aggressively treating them with empiric therapy active against
MRSA and MSSA. The diagnosis is confirmed by recovery of the organ-
ism from pleural fluid, blood, or tracheobronchial aspirate. The duration
of parenteral antimicrobial therapy depends on the clinical course. When
compared with nonoperative treatment, early intervention for empyema
with video-assisted thoracoscopic surgery (VATS) or open surgical
debridement reduces mortality and the duration of antimicrobial
therapy.135
Lung Abscess
Lung abscess can result as a complication of aspiration of infected mate-
rial or a foreign body, can develop during pneumonia, or can result from
hematogenous seeding during S. aureus BSI or septic thrombophlebitis.
When bacteriology is proved as the mechanism of infection in children
with aspiration, S. aureus can be recovered with or without facultative
and anaerobic oral bacteria.136,137
Clinical features of S. aureus lung abscess include fever, cough, chest
pain, dyspnea, anorexia, and weight loss.136 CT helps determine the extent
of disease and aids in following abscess resolution. Despite a dramatic
empyema usually can be treated adequately with IV antimicrobial therapy
alone, as evidenced by resolution seen on follow-up chest radiographs.138
Surgical drainage occasionally is required.139 In these situations percuta-
neous drainage is a well-established technique.140–142
Cardiovascular Infections
Endocarditis
S. aureus is the most common cause of infective endocarditis (IE).143 IE
occurs more frequently in patients with congenital heart disease, whether
surgically repaired or not, but can follow S. aureus BSI in any patient; or,
it can be associated with device-associated persistent BSI.144 Children
whose cardiac lesions cause high-velocity blood flow and those with
prosthetic valves or patches have an increased risk of developing S. aureus
IE.145,146
Fever, a new or changed heart murmur, and continuous BSI are the
hallmarks of IE. The presentation can be indolent or acute; common
complaints include myalgia, arthralgia, general malaise, weight loss, and
anorexia. Clinical progression can be rapid, with associated lethargy and
cardiac failure, particularly when the aortic valve is involved. Right-sided
endocarditis can be the source of emboli to the lungs, causing lung
abscesses. Small vessel embolic phenomena, such as petechiae, splinter
and conjunctival hemorrhages, and Janeway lesions, rarely manifest in
children.145
The diagnosis is straightforward when echocardiography demonstrates
a vegetation or abscess. However, this evidence may be lacking in children.
A negative finding on a transthoracic or transesophageal echocardiogram
does not exclude IE.147,148 The modified Duke criteria have been used to
identify children with IE based on major and minor clinical criteria (see
Chapter 37).
 Staphylococcus aureus 115

FIGURE 115.7  Progressive MRSA pneumonia with pneumatoceles in a previously

healthy 9-month-old boy. Chest radiographic findings spanning 4 days showed a
perihilar right lower lobe infiltrate (A) progressing to a worsening infiltrate and large
hydropneumothorax with mediastinal shift (B and C) despite appropriate therapy. Axial
CT of the chest without contrast (lung windows) showed partial loculation of hydro-
pneumothorax, multilobar consolidation, pneumatoceles, and atelectasis (D and E).
Video-assisted thoracoscopic surgery (VATS) was performed, and a chest tube was
E placed for 3 days. MRSA was isolated from pleural fluid. After 2 weeks of clindamycin
therapy the chest radiograph had only minor abnormalities. (Courtesy of S.S. Long.)

699
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 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
A to other sites, or both. The treatment of suppurative phlebitis includes
B
FIGURE 115.8  Pathologic findings from a patient with fatal necrotizing pneumonia
due to S. aureus show a gross specimen of lung with microabscesses (A), and
the histologic appearance of a section of lung with S. aureus colonies and hemor-
rhage (B). (Hematoxylin-eosin stain.) (From Adem PV, et al. Staphylococcus aureus
sepsis and the Waterhouse-Friderichsen syndrome in children. N Engl J Med
2005;353:1245–1251.)
Treatment requires 4 to 6 weeks of high-dose bactericidal antimi-
crobial therapy, administered intravenously, because of the relatively
avascular nature of valves, the high organism load, and the decreased
ability of polymorphonuclear leukocytes to function in endocarditis
lesions. Guidelines for the treatment of S. aureus endocarditis, includ-
ing consideration of combination therapy with aminoglycosides, can
be found in Baltimore and colleagues149 and Chapter 37. Fever may
persist for about 1 week after the start of antimicrobial therapy.150
Sustained bacteremia that spans several days in usual. Serial blood
cultures should be obtained until sterility is demonstrated. Occasionally,
surgical intervention is necessary, particularly when embolic phenomena
to major organs, intractable cardiac failure, or aortic insufficiency is
documented, or when BSI persists despite appropriate antimicrobial
therapy, particularly when a prosthetic valve or other foreign material is
involved. Prosthetic valve endocarditis caused by S. aureus poses a risk of
mortality.151,152
Close follow-up should be maintained after therapy has been con-
cluded because some patients can relapse and require definitive surgical
intervention or removal of foreign material.
Pericarditis
Bacterial pericarditis in children is a rare complication of S. aureus BSI
or other focal (usually pleural) infection. Pericarditis should be suspected
in any patient with BSI and cardiomegaly. Signs and symptoms include
fever, dyspnea, cough, and precordial chest pain. The chest radiograph
shows an enlarged heart, and echocardiography demonstrates the pres-
ence of pericardial fluid. The diagnosis is made by examination of the
pericardial fluid for inflammatory cells and bacteria. Management
includes urgent pericardial decompression, closed or open pericardial
700
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drainage, and parenteral antimicrobial therapy.153–155 Mortality is due to
cardiac tamponade or the systemic inflammatory response syndrome; the
likelihood of both these complications is decreased by early medical and
surgical treatment. Patients who develop constrictive pericarditis require
pericardiectomy.
Suppurative Phlebitis and Septic Thrombophlebitis
Suppurative phlebitis and septic thrombophlebitis are serious endovas-
cular infections that occur along a continuum of clinical severity; they are
most commonly caused by S. aureus. Suppurative phlebitis usually occurs
in a catheterized vessel wall and is characterized by a fluctuant, palpable
vein that is warm, tender, and erythematous; pus sometimes can be
found at the catheter insertion site or by needle aspiration. Infection can
progress to obstruction of the vessel or dissemination of infected thrombi
removal of a device, drainage or resection of the infected segment of the
vessel, and IV antimicrobial therapy.
Septic thrombophlebitis also occurs in association with invasive S.
aureus infection without catheterization of the infected vessel. The veins
involved usually are major deep veins, especially pelvic or lower extremity
vessels, and they commonly are contiguous with an area of osteomyelitis,
pyogenic arthritis, pyomyositis, or other soft tissue infection.118 Longterm
IV antibiotic therapy is warranted for this serious endovascular infection,
with its attendant severe complications and mortality. Anticoagulant
therapy and placement of an inferior vena cava filter are considered when
infected clots disperse septic emboli to the lungs.156
Central Nervous System Infections
Meningitis
S. aureus meningitis can occur as a complication of BSI or endocarditis,
or from extension of a parameningeal focus, including sinusitis, osteomy-
elitis of the skull bone, subdural empyema, epidural abscess, or rupture
of a brain abscess into the lateral cerebral ventricles or the subarachnoid
space. Congenital anomalies, such as a dermal sinus or meningomyelo-
cele, can provide a portal of entry. Any neurosurgical procedure increases
the risk of staphylococcal meningitis; insertion of a cerebrospinal fluid
(CSF) shunt is the most common predisposing procedure.157
Treatment consists of parenteral antimicrobial therapy for 3 to 6
weeks, depending on the pathophysiology of the meningitis and removal
of a device when present. (Treatment of device-related infection is dis-
cussed later in the chapter.)
Brain Abscess
A brain abscess caused by S. aureus can result from direct extension of
an adjacent infectious focus (e.g., sinusitis,104 mastoiditis, otitis media);
from inoculation of bacteria during a surgical procedure or as a conse-
quence of trauma; or from seeding of the brain during bacteremia. A
brain abscess more frequently complicates S. aureus BSI than BSI due to
other pathogens158,159 (see Chapter 46). An S. aureus etiology should be
considered, especially when brain abscess complicates severe S. aureus
BSI or the patient has had a neurosurgical procedure or penetrating
trauma. Cyanotic congenital heart disease also is a predisposing risk
factor.160
Clinical features of brain abscess in children include headache, vomit-
ing, irritability, focal neurologic defect, seizures, or other manifestations
of increased intracranial pressure. The onset of symptoms can be insidi-
ous, depending on the pathophysiology; fever can be absent or low grade.
The physical examination findings depend on the location of the abscess.
Signs of meningitis are expected only if the abscess ruptures into a
ventricle.
Imaging techniques are most often definitive in diagnosing a brain
abscess. Enhanced MRI is superior to CT, although both modalities are
useful.161 The principal advantages of MRI are the abilities to distinguish
the central core of an abscess from a surrounding area of ring enhance-
ment, identify adjacent areas of cerebral edema, and detect abscesses in
the posterior fossa.
Treatment consists of parenteral antimicrobial therapy and surgical
drainage of the abscess, frequently by aspiration. In rare cases enucleation

of the abscess is performed. Evolving abscesses in the non-necrotizing
cerebritis stage and some small intracerebral abscesses can be treated with
antimicrobial agents alone.158 Corticosteroid therapy is limited to cases
in which increased intracranial pressure is an important component.
Patients typically are treated with antimicrobial agents parenterally
for 6 weeks. Mortality associated with brain abscess is relatively low,
but up to 60% of patients have neurologic sequelae, most commonly
seizures.162
Spinal Epidural Abscess
S. aureus is the most common cause of a spinal epidural abscess, which
is a collection of purulent material external to the dura in the spinal canal,
usually in the posterior aspect of the thoracic or lumbar vertebrae.
Abscesses arise as a result of seeding of the epidural space during BSI or
through direct extension of an adjacent focus of infection, such as pyo-
myositis or osteomyelitis. Complaints in children can be nonspecific and
include fever, vomiting, lethargy, and irritability. Localized tenderness
and refusal to lie prone also can be noted. In older children, localized or
radicular pain can be present. Paresis of limb muscles and loss of bowel
or bladder control are specific and ominous signs because paralysis and
loss of sensory modalities at levels below the affected area can ensue
rapidly. A history of a clinical illness compatible with bacteremia some-
times is elicited.163
Spinal epidural abscess must be distinguished from diskitis, extradural
neoplasm, hematoma, disk herniation, and vertebral osteomyelitis. MRI
is the diagnostic procedure of choice.164 Lumbar puncture is deferred
when this diagnosis is suspected; if it is performed, CSF findings are
similar to those in other parameningeal infections (i.e., a variable,
modest pleocytosis, normal glucose, and modestly increased protein
concentration).
Therapy includes immediate surgical decompression, debridement of
the epidural space, and parenteral antimicrobial therapy, which generally
is administered for 6 weeks.165 Medical management alone is rarely
considered in immunocompetent patients with a normal or stable neu-
rologic examination and no signs of septicemia. Continuous reassess-
ment is necessary to identify progressive pain or the onset of any
neurologic abnormality that necessitates urgent surgery.166
Device-Related Infections
Indwelling Vascular Catheters
Staphylococci are the most common causes of catheter-associated infec-
tions. For peripheral venous catheters, S. aureus is the most common
infecting species; for central venous catheters (CVCs), coagulase-negative
staphylococci are recovered more commonly. Cutaneous colonization at
the insertion site is the most important predictor of catheter-associated
infections related to short-term, percutaneously inserted catheters. For
surgically implanted CVCs, organisms introduced through the hub and
lumen are the most important source of infection.
Local redness, pain, and warmth at the site of a simple peripheral
catheter suggest local phlebitis, which is managed by removal of the
device. Diagnosing a central line–associated BSI (CLABSI) can be more
difficult. Fever and the presence of pain, fluctuance, erythema, purulence
or soft tissue infection at the site suggest CLABSI. Most often, however,
the catheter entrance site appears normal.
Blood for culture is taken via the catheter; a positive culture can rep-
resent CLABSI or BSI from another source. Isolation of S. aureus should
not be regarded as the result of a procedural contaminant; repeated
samplings or, occasionally, blood drawn simultaneously by venipuncture
help to clarify the issue. Semiquantitative culture of the catheter tip after
removal can implicate the catheter as the infectious nidus when the
colony count exceeds 15 colonies; a negative culture of the catheter tip
does not exclude CLABSI.
S. aureus exit-site infections, whether in the presence of a tunnel track
infection or BSI, are managed by removing the catheter and administer-
ing antimicrobial therapy. Because of the propensity of S. aureus BSI to
persist and to cause clinical sepsis or to seed the endocardium, abdominal
viscera, brain, lung, or bone, many experts recommend removal of an
intravascular catheter when S. aureus infection is documented, even in
the absence of an exit-site infection.
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Staphylococcus aureus 115
Vancomycin is the preferred empiric therapy for suspected S. aureus
catheter-associated infection. Combination bactericidal therapy and an
extended course of antimicrobial therapy (e.g., 4 to 6 weeks) frequently
are recommended because of the known tendency of S. aureus BSI to
seed and form abscesses at multiple sites. This point is controversial
because of the lack of specific data (see Chapter 100). Consistent
use of a “bundle” of techniques for placing and handling catheters is
among the measures that have been shown to reduce the infection
rate; these measures include skin disinfection with chlorhexidine, an
aseptic placement technique, use of a BioPatch dressing, dedicated
teams for ongoing catheter care, and the earliest possible removal of the
catheter.
Cerebrospinal Fluid Shunt Devices
A contaminated CSF shunt or subcutaneous reservoir device is the most
common predisposing cause of staphylococcal meningitis.157 Presumably
S. aureus gains access to the catheter during surgical insertion, although
the device and CSF can be seeded by a subsequent adjacent primary SSTI
or tract infection or during BSI – the presence of the catheter increases
the likelihood that the organism will survive and multiply.
Most CSF shunt infections occur within 2 months of shunt placement
or revision. Low-grade fever and dysfunction of the shunt are variably
present. For ventriculoperitoneal (VP) shunts, symptoms and signs
attributable to peritonitis commonly can be present.167,168 If the patient
had recently undergone surgery, a wound infection may be evident. A
first episode of an S. aureus shunt infection is predictive of a subsequent
S. aureus shunt infection.169
Examination of the CSF (typically obtained by percutaneous puncture
of the shunt reservoir/tubing) may reveal only mild abnormalities, such
as modest pleocytosis, a normal glucose level, and a normal or minimally
elevated protein concentration. Microorganisms infrequently are visual-
ized on Gram stain. Culture of CSF is the most sensitive test; however,
culture of CSF obtained by lumbar puncture frequently is not diagnostic
of a VP shunt infection.
Most experts recommend combined medical and surgical treatment
for CSF shunt infections. Typically a temporary external ventricular drain
is used, while IV antimicrobial therapy is administered, until the CSF is
sterile and inflammation subsides, at which time a new shunt can be
placed.170,171 The timing of this procedure is important – insertion of the
new catheter into an infected field must be avoided. However, maintain-
ing an externalized catheter as a drainage device carries its own risk of
infection, which accelerates after 5 to 7 days of use.
Toxin-Mediated Syndromes
Staphylococcal Food Poisoning
Staphylococcal food poisoning is caused by ingestion of S. aureus entero-
toxins. It accounts for up to one third of foodborne gastrointestinal ill-
nesses (see Chapter 59). Protein-rich foods (e.g., ham and chicken) often
are implicated as the outbreak source, as are dairy products and egg and
potato salads. The individual who inadvertently inoculates the food with
S. aureus may have a clinical infection but usually is colonized
asymptomatically.172,173
Illness begins shortly after consumption (4 hours on average) because
ingestion of preformed toxin causes the clinical manifestation. Classic
symptoms are nausea, vomiting, abdominal pain, and diarrhea; headache
and prostration are less common. Fever occurs in about 25% of patients.
Hospitalization is required infrequently, and death occurs rarely.
S. aureus can be isolated from the vomitus or feces of ill people.
Culture of the contaminated food may yield the offending organism.
Therapy is supportive; antibiotics are not useful. The syndrome can be
prevented by proper handling of food and careful hygiene practices by
food handlers. When cases are recognized, the Department of Public
Health must be notified.
Staphylococcal Scalded Skin Syndrome
SSSS is an illness mediated by exfoliative toxins ETA and ETB.90,91 Hema-
togenous spread of the toxins produces fever and widespread erythema
of the skin, which can be tender and quickly forms thin-walled,
701
 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
fluid-containing bullae that rupture, leaving a moist base of skin. Gentle
friction applied to the skin produces Nikolsky sign, a sloughing of
superficial sheets of skin (see Fig. 13.2). Desquamation follows rapidly
and can be widespread, especially in the neonate.174,175
SSSS is diagnosed clinically or by isolation of S. aureus from a local
site (not necessarily the exfoliating site), ideally with demonstration by
the isolate of toxin production or the toxin gene. Histologic evaluation
of the skin reveals the separation of skin layers at the granular layer
within the epidermis, rather than the separation of the dermis and epi-
dermis seen in drug-induced toxic epidermal necrolysis.176
Management of SSSS is primarily supportive, and careful attention is
paid to electrolyte levels because fluid shifts can occur across the denuded
skin. Antiseptic measures should be taken to prevent infection of the
unprotected, affected areas. Parenteral antimicrobial therapy is adminis-
tered to reduce the staphylococcal burden. Topical antimicrobial agents
are not helpful.176
Toxic Shock Syndrome
TSS is caused by S. aureus strains that produce TSST-1 or certain entero-
toxins (specifically SEB and SEC).177 It is characterized by fever, rash,
hypotension, and multisystem organ dysfunction178 (Box 115.1). The
incidence of TSS peaked in the early 1980s; the condition was attributed
to the use of superabsorbent tampons by menstruating adolescents and
women.179 Subsequent public education and manufacturing regulations
helped reduce the number of TSS cases, and now nonmenstrual TSS
accounts for approximately one half of all TSS cases.180
BOX 115.1  Staphylococcal Toxic Shock Syndrome: Clinical Case
Definition
An illness with the following clinical manifestations:
Fever: Temperature >38.9°C (102°F)
Rash: Diffuse macular erythroderma
Desquamation: 1–2 weeks after onset of illness, particularly on
palms and soles
Hypotension: Systolic blood pressure ≥90 mm Hg for adults or
less than 5th percentile by age for children <16 years;
orthostatic drop in diastolic blood pressure ≥15 mm Hg from
lying to sitting, orthostatic syncope, or orthostatic dizziness
Multisystem involvement: 3 or more of the following:
1. Gastrointestinal: Vomiting or diarrhea at onset of illness
2. Muscular: Severe myalgia or creatine phosphokinase level
≥2 times the upper limit of normal for laboratory
3. Mucous membrane: Vaginal, oropharyngeal, or conjunctival
hyperemia
4. Renal: Blood urea nitrogen or creatinine ≥2 times the upper
limit of normal for laboratory or urinary sediment with pyuria
(≥5 leukocytes per high-power field) in the absence of
urinary tract infection
5. Hepatic: Total bilirubin, serum glutamic-oxaloacetic
transaminase (SGOT), or serum alanine aminotransferase
(ALT) or aspartate aminotransferase (AST) ≥2× the upper
limit of normal for laboratory
6. Hematologic: Platelets <100,000/mm3
7. CNS: Disorientation or alteration in consciousness without
focal neurologic signs when fever and hypotension are
absent
Negative results on the following tests, if obtained:
1. Blood, throat, or cerebrospinal fluid cultures (for all
microorganisms except Staphylococcus aureus)
2. Rise in antibody titer to Rickettsia or Leptospira species or
rubeola
Modified from Wharton M, Chorba TL, Vogt RL, et al. Case definitions for public health surveil-
lance. MMWR Recomm Rep 1990;39:1–43.
702
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Risk factors for TSS include colonization and disruption of the skin,
colonization of mucous membranes, or any infection caused by a toxin-
producing strain of S. aureus. TSS often is associated with surgery or
trauma, manifesting several days after the event. The sudden onset of
fever, chills, headache, vomiting, sore throat, myalgia, and diarrhea is
followed by hypotension, respiratory distress, edema, and rash within 24
to 48 hours. Dizziness, listlessness, and disorientation are clues to hypo-
tension and cerebral dysfunction; coma can ensue.
The initial S. aureus focus can show no signs of inflammation or
purulence. Initially the rash can appear like that seen in scarlet fever, but
it classically is described as diffuse erythroderma, or “sunburn.” The rash
typically desquamates 1 to 2 weeks after the onset of illness, most notably
on the palms and soles.
Mucous membrane involvement includes conjunctival hyperemia,
strawberry tongue, beefy red oropharyngeal membranes (sometimes
with ulcerations), and lesions representing reactivation of the herpes
simplex virus.
A vaginal culture yields the organism in 85% of menstrual TSS cases.
In nonmenstrual TSS cases a nasopharyngeal or a wound culture may
yield S. aureus; a blood culture should be obtained (to diagnose concur-
rent BSI) but is seldom positive.
Management consists of treating intravascular volume depletion,
shock, and respiratory failure, in addition to the S. aureus infection. Any
relevant focus of infection should be drained and any foreign body
removed if possible. IV antimicrobial therapy, including an antibiotic
that inhibits protein synthesis (e.g., clindamycin or linezolid), may be
preferable. The response to effective therapy can be rapid. For a patient
who does not respond to these interventions, most experts recommend
immune globulin intravenous (IGIV), based on the presence of antibody
to staphylococcal enterotoxins and TSST-1.181,182 End-organ failure, par-
ticularly renal failure and acute respiratory distress syndrome, can occur
within the first few days of illness and are responsible for the attendant
3% mortality rate.
Severe Sepsis Syndrome
Severe sepsis syndrome is defined as isolation of S. aureus from a clini-
cally important site, hypotension (i.e., systolic blood pressure less than
the 5th percentile for age for children or less than 90 mm Hg for adults),
and respiratory distress syndrome or respiratory failure, in addition to
involvement of the central nervous system (CNS), liver, kidneys, muscles,
or skin; or abnormal hemostasis; or the presence of leukopenia or
thrombocytopenia. Severe sepsis syndrome is similar to TSS but does not
meet all the clinical criteria for TSS, and the S. aureus isolates do not
produce TSST-1.81
Increasingly, severe sepsis occurs in children and adolescents with no
underlying medical conditions or other identifiable risk factors.81,183–185
Both MSSA and MRSA are implicated; genes encoding PVL frequently
are identified in the infecting strain.
A primary infectious process (e.g., pyogenic arthritis or pneumonia)
often is identified before clinical deterioration begins. However, patients
can have an overwhelming infection and experience subsequent rapid
decline without a primary tissue site of infection.81,183,184 Skin lesions are
common and manifest as erythroderma, pustules, petechiae, and/or
purpura. Waterhouse-Friderichsen syndrome,186 staphylococcal purpura
fulminans,187 and necrotizing fasciitis have been reported.188
The diagnosis is made by isolation of S. aureus from a clinically
important site, such as the blood, a joint space, or respiratory secretions
(with concomitant systemic illness). A high index of suspicion is critical
to instituting appropriate parenteral antimicrobial therapy and aggressive
cardiopulmonary support. Mortality rates based on reviews of case
reports approach 64%.183
MANAGEMENT
Treatment of invasive S. aureus infections should be rapid and aggressive.
IV antimicrobial therapy should be started promptly, and the source of
BSI and sites of possible metastatic infection should be sought aggres-
sively. Abscesses should be drained, and CVCs or other foreign bodies
should be removed when possible. Associated endocarditis or other
endovascular infections always should be considered in patients with
S. aureus BSI because this species has a tropism for endothelial cells, and

organisms with the PVL gene have the propensity to cause thrombosis
and thromboembolism.118,189,190
If rapid improvement does not occur or BSI continues after more than
24 hours of therapy, the therapeutic approach should be carefully
reevaluated because irreversible organ damage can progress rapidly. Once
the antimicrobial susceptibility of the organism is known, therapy should
be tailored to use the appropriate antimicrobial agent or agents with the
narrowest appropriate spectrum of activity.
The CA-MRSA epidemic has refocused attention on the importance
of adjunctive local treatments, such as incision and drainage. For many
purulent SSTIs, incision and drainage may suffice. Guidelines have been
published for management involving antibiotics and drainage.98,191
Because susceptibility to β-lactam antibiotics cannot be assumed, obtain-
ing a specimen for culture is essential for patients who require antibiotic
treatment, to further guide therapy.192
Antistaphylococcal Agents
The compounds presented in the following sections are discussed further
in Chapter 292.
β-Lactam Antibiotics
Previously, semisynthetic β-lactam penicillins (nafcillin, oxacillin,
cloxacillin, and dicloxacillin), were the gold standard for treatment of
staphylococcal infections. These agents inhibit cell wall synthesis and thus
are bactericidal, well tolerated, and have a long record of therapeutic
effectiveness. When an MSSA strain is isolated, β-lactams are the drugs
of choice for serious staphylococcal infections. Parenteral compounds in
wide use in the U.S. include oxacillin and nafcillin; dicloxacillin is available
for oral use, although some children find the taste of the suspension
unpleasant.
The combination drugs made up of a β-lactam plus a β-lactamase
inhibitor (i.e., (ampicillin-sulbactam, amoxicillin-clavulanate, ticarcillin-
clavulanate, and piperacillin-tazobactam) are active against MSSA but
offer no advantage over the semisynthetic penicillins. The antistaphylo-
coccal activity of the so-called first-generation cephalosporins is superior
to that of later generations of cephalosporins. Cefazolin (for parenteral
administration) and cephalexin (for oral administration) are useful class
compound examples; their efficacy is similar to that of the semisynthetic
penicillins for the treatment of MSSA infections that are not life threaten-
ing, and cefazolin is associated with fewer episodes of premature drug
discontinuation and drug-emergent events.193
Until 2010 none of the β-lactam antibiotics, β-lactamase inhibitors,
or cephalosporins had proved useful for therapy of MRSA infections.
However, in 2010 the drug ceftaroline was licensed for treatment of
CAP and complicated SSTIs. Designated a fifth-generation cephalospo-
rin, ceftaroline is active against MRSA strains and has broad-spectrum
activity against many gram-positive and gram-negative bacteria. Cef-
taroline has been used as salvage therapy in adults with invasive MRSA
infections who have responded slowly to vancomycin. No data have
been reported on the drug’s use in children,194 although evaluation is
underway.
Clindamycin
Clindamycin is a lincosamide antibiotic that inhibits protein synthesis at
the chain elongation step by interfering with transpeptidation of the 50S
ribosomal subunit. Most HA-MRSA isolates are resistant to clindamycin,
but most CA-MRSA isolates are susceptible,191 particularly in chil-
dren.60,77,98,195,196 Despite its increasingly frequent use in the treatment of
CA-MRSA infections, clindamycin is not licensed by the U.S. Food and
Drug Administration (FDA) for this purpose.
Erythromycin resistance of S. aureus is prevalent and can impair the
effectiveness of clindamycin. The erythromycin ribosomal methylase
(erm) gene codes for the enzyme that modifies the binding site not only
for macrolides, but also for lincosamides and streptogramin B antibiotics.
Consequently, cross-resistance to these three classes of antibiotics, the
so-called macrolide–lincosamide–streptogramin B (MLSB) phenotype, is
common among S. aureus isolates.197 Phenotypic expression of the MLSB
phenotype can be constitutive or inducible with exposure to a macrolide.
When it is constitutive, the isolate tests as resistant to all MLSB antibiotics.
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Staphylococcus aureus 115
When it is inducible, however, the isolate tests as resistant to erythromy-
cin and susceptible to clindamycin.
Clinical laboratories test for inducible clindamycin resistance with the
disk diffusion D-test or with automated simultaneous broth dilution
testing in the presence of erythromycin (see Chapter 290 and Fig.
290.4).198,198 To date, although the incidence of erythromycin resistance
among CA-MRSA isolates is high, the incidence of clindamycin resistance
is not. Clinicians should be aware that treatment failure with clindamycin
is possible if the target organisms have demonstrable inducible resistance
in vitro.198,199
Clindamycin also is a potent suppressor of bacterial toxin synthesis.
Clindamycin therapy may be clinically superior in toxin-mediated
staphylococcal syndromes, although explicit data are lacking. When
clindamycin is used in this setting, combination therapy with oxacillin
or nafcillin, or with vancomycin, frequently is used.
Clindamycin is bacteriostatic and does not cross the blood-brain
barrier; it is not used alone in the treatment of endocarditis or other
intravascular or CNS infections that can occur during S. aureus invasive
infection. The poor taste of clindamycin suspensions can hamper adher-
ence to oral therapy in outpatients.
Clindamycin resistance rates among S. aureus isolates, both MRSA and
MSSA, should be monitored locally. In areas where the resistance rates
exceed 10% to 15%, empiric therapy with this agent probably should be
avoided.200–202
Vancomycin
Vancomycin is a glycopeptide that inhibits synthesis and assembly of the
second stage of cell wall peptidoglycan in gram-positive bacteria. It is
the therapeutic agent of choice for HA-MRSA infections. However, the
emergence of VISA and VRSA isolates, in addition to the so-called MIC
creep to 1 to 2 µg/mL, has the potential to limit the effectiveness of
vancomycin.203–205 Some experts recommend the use of higher doses in
serious infections to elicit higher serum trough levels of vancomycin;
however, the effectiveness, necessity, and safety of these strategies in
children is controversial.98
Vancomycin should be considered for children suspected of having
serious CA-MRSA infections, such as SSTIs with systemic manifestations
that require hospitalization, severe sepsis, TSS, CNS infection, necrotizing
pneumonia, and necrotizing fasciitis. Considerations for empiric use for
osteoarticular infections include the local prevalence of CA-MRSA,
degree of illness, site of infection, and adequacy of culture specimens
obtained to guide therapy.
Because vancomycin is less bactericidal than oxacillin or nafcillin for
MSSA and can result in treatment failure or relapse, it should not be used
for therapy of MSSA infections unless it is necessary (e.g., the patient has
a type 1 allergic reaction to β-lactam agents). In severely ill patients,
semisynthetic penicillin frequently is given in addition to vancomycin
until culture and susceptibility test results are available. Vancomycin is
available only in IV form for use in the therapy of S. aureus infections,
and the concentration obtained in the alveolar space is poor. Oral van-
comycin is not absorbed.
Oritavancin
Oritavancin is a semisynthetic lipoglycopeptide that was approved by the
FDA in 2014 for the treatment of SSTIs caused by gram-positive organ-
isms. Oritavancin is active against MRSA, VISA, VRSA, daptomycin-
nonsusceptible isolates and vancomycin-resistant Enterococcus. Due to a
long serum half-life (393 hours), concentration-dependent bactericidal
activity, and a three-pronged mechanism of action, a single dose of ori-
tivancin has been shown to be noninferior to repeated vancomycin
dosing for treatment of SSTI in adults.206,207 Due to slow tissue elimina-
tion, no oritivancin dosing adjustments are needed in patients with renal
or hepatic insufficiency.
In addition to achieving steric inhibition of transglycosylation,
oritavancin can bind pentaglycyl cross-bridges, which inhibits pep-
tidoglycan transpeptidation and cross-linking. It interacts with the
bacterial cell membrane, leading to depolarization, increased membrane
permeability, and cell death of both stationary and exponential growth
phase bacteria. These mechanisms distinguish oritavancin from vanco-
mycin.208 Membrane depolarization also provides effectiveness against
703
 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
daptomycin-nonsusceptible bacteria. To date, no oritavancin resistance
has been detected in clinical isolates of S. aureus. Lack of evaluation in
children and expense currently limit its use.
Dalbavancin
Dalbavancin is a semisynthetic lipoglycopeptide derivative of teicoplanin.
It contains a long lipophilic side chain that extends its potency and
half-life. Dalbavancin has been approved by the FDA for the treatment
of SSTI caused by gram-positive organisms, and it is dosed once per
week. Dalbavancin binds to the D-ala-D-ala residue, destabilizing the cell
membrane and resulting in bacterial cell death. Active against both MSSA
and MRSA, dalbavancin is more potent than vancomycin against strains
with a vancomycin MIC of 2 µg/mL or less. The kinetics in children 12 to
17 years of age appear to be similar to those in adults209; no data are avail-
able for younger children. Dalbavancin is noninferior to vancomycin and
linezolid. Because of its extended half-life, one or two doses of dalbavancin
can be used after incision and drainage to treat SSTIs in ambulatory
patients. The drug is very expensive and must be given parenterally.
Linezolid and Tedizolid
Linezolid and tedizolid are oxazolidinones that inhibit protein synthesis
by binding to the 50S ribosomal subunit during the formation of the
initiation complex.210 They have broad in vitro activity against MRSA,
GISA, VISA, and VRSA isolates. They are well tolerated, and linezolid is as
effective as vancomycin in children with SSTIs and pneumonia caused by
MRSA.211–213 The oral bioavailability of both compounds is almost 100%,
which facilitates transition from IV to oral therapy.
Linezolid and tedizolid are bacteriostatic against S. aureus and therefore
are not preferred for the treatment of endocarditis or other intravascular
infections. If possible, linezolid should be avoided in patients taking
adrenergic or serotonergic agents.214 Drug interactions may occur less
frequently with tedizolid than with linezolid. Both compounds can be
associated (possibly to a lesser degree for tedizolid) with the development
of thrombocytopenia, which can be idiosyncratic and severe; anemia;
and neutropenia.215 The complete blood count should be monitored in
patients receiving therapy for longer than 2 weeks, those with underlying
myelosuppression, or those taking other drugs that cause bone marrow
suppression. A small number of cases of optic and peripheral neuropathy
and lactic acidosis have been reported in adults during prolonged courses
of therapy with linezolid.
Resistance to linezolid has emerged in patients receiving longterm
therapy. Resistant isolates have mutations in the 23S rRNA gene in the
domain V region, of which S. aureus has five copies.216,217 A mutation in
two or more of the rRNA genes is required for the resistant phenotype.
This kind of resistance probably also occurs with tedizolid. Additional
resistance mechanisms have been identified in ribosomal proteins L4
and L3. Plasmid-borne cfr genes have been identified that encode a
methyltransferase that mediates linezolid resistance by methylation of
carbon-8 on the 23S rRNA base. cfr genes confer cross-resistance to
phenicols, lincosamides, pleuromutilins, and streptogramin A antibiot-
ics.218 Available data suggest that isolates with cfr genes are nonetheless
responsive to tedizolid therapy.219
Both linezolid and tedizolid are available in IV and oral forms. Line-
zolid is available in a convenient pediatric suspension. The compounds
are extremely expensive, and negotiation with some third-party payers
may be required for each use. Patients also can experience delays in pro-
curing linezolid from private pharmacies that do not stock it routinely. A
generic form of linezolid was recently released that costs about 20% less.
Trimethoprim-Sulfamethoxazole
TMP-SMX interferes with the biosynthesis of tetrahydrofolic acid, which
is essential for microbial synthesis of proteins and nucleotides. Although
most S. aureus isolates are susceptible in vitro, TMP-SMX was seldom
used to treat S. aureus infections until the recent epidemic of CA-MRSA.
Reports now are available on clinical experience using TMP-SMX to treat
CA-MRSA SSTIs220 or more severe S. aureus infections. One study sug-
gested that the efficacy of TMP-SMX was similar to that of clindamycin
for skin infections of unspecified cause, including cellulitis.220 For the
treatment of invasive S. aureus infection, data show IV TMP-SMX to be
704
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inferior to vancomycin for MSSA and only equivalent to vancomycin
for MRSA (these data were obtained before the CA-MRSA era221).
The observation that thymidine can be released from injured tissue or
bacteria has suggested a possible explanation for discordant in vitro and
clinical outcomes.222 Additional information is needed to establish the
appropriate role for TMP-SMX in the anti–S. aureus armamentarium.
Tetracyclines (Including Tigecycline)
Tetracyclines inhibit bacterial protein synthesis by binding to the 30S
ribosomal subunit, thereby blocking the attachment of the transfer
RNA amino acid to the ribosome. Tetracyclines such as doxycycline and
minocycline have emerged as alternative oral antimicrobial agents for
mildly to moderately ill patients with MRSA SSTIs. Most isolates are
susceptible in vitro.191,223
Tigecycline, a novel glycylcycline that was recently licensed for par-
enteral use, has potent activity against S. aureus in vitro, regardless of
methicillin or vancomycin susceptibility.224,225 However, in 2010 the FDA
issued a warning linking tigecycline to an increased mortality risk in
patients being treated for hospital-acquired pneumonia, CAP, compli-
cated intra-abdominal infections, and complicated SSTIs; this suggests
that tigecycline should not be used in the treatment of S. aureus infections.
All tetracyclines are bacteriostatic and should not be used for the
treatment of endocarditis or other intravascular or CNS infections.
Tetracyclines also should not be used to treat pregnant women.
Quinupristin-Dalfopristin
The drug Synercid is a combination of two streptogramin antibiotics, one
from group B (quinupristin) and one from group A (dalfopristin), in a
30/70 ratio. Quinupristin-dalfopristin has good in vitro activity against
S. aureus, including MRSA. The two streptogramins bind to sequential
sites on the 50S ribosomal subunit and have a synergistic bactericidal
effect that results from inhibition of protein synthesis.226 Recent trials
have shown a lower bacteriologic success rate compared with standard
therapy.227 Quinupristin-dalfopristin is not cross-resistant to S. aureus
isolates with MLSB resistance because the streptogramin A component
remains active; however, few data are available to ensure the clinical
validity of this issue. Quinupristin-dalfopristin is available only in IV
form, and evaluation in children has been minimal. Infusion site inflam-
mation, thrombophlebitis, arthralgias, drug-drug interactions, myalgias,
gastrointestinal toxic effects, and increased serum unconjugated bilirubin
concentrations have limited widespread use.
Daptomycin
Daptomycin is a novel cyclic lipopeptide with a mechanism of action that
is not completely understood. It appears to bind to the gram-positive
bacterial cell membrane, which is followed by calcium-dependent inser-
tion228 that results in a decrease in membrane potential, causing cell
death by rapidly stopping DNA, RNA, and protein synthesis. It has potent
bactericidal activity against MRSA.229 Daptomycin was comparable to
vancomycin in the treatment of complicated SSTIs230; however, it showed
decreased effectiveness for the treatment of CAP compared with standard
treatment, probably because of its propensity for binding surfactant.231
Daptomycin has been licensed by the FDA for the treatment of compli-
cated SSTIs, BSI, and right-sided endocarditis; however, it is not approved
for the treatment of left-sided endocarditis.232 Daptomycin is available
in IV form only. Studies evaluating its use in children suggest good
efficacy.233 When the cell wall is thickened (e.g., in a VISA isolate or after
exposure of an S. aureus isolate to vancomycin), resistance to daptomycin
becomes evident, presumably because the compound cannot reach its
cell membrane target.234,235 Resistance to daptomycin can occur during
therapy and was documented in 6 of 120 patients receiving daptomycin
for endocarditis, or BSI.236 In addition, daptomycin-resistant isolates can
be cross-resistant to vancomycin.235
Telavancin
Telavancin is a lipoglycopeptide that was licensed by the FDA in 2009 for
the treatment of complicated SSTIs. The compound depolarizes bacterial
membranes and inhibits cell wall formation. No formal evaluation has
 Staphylococcus aureus 115
Empiric therapy for S. aureus infection

MILDLY ILL MODERATELY ILL SEVERELY ILL

Afebrile, previously healthy Febrile, previously healthy Febrile, previously healthy,
ill-appearing or
SSTI SSTI immunocompromised
Bone and joint infection
Pulmonary infection SSTI or SSTI complicated
by necrotizing fasciitis
Bone and joint infection
Pulmonary infection including
Incision and drainage necrotizing pneumonia
Hospitalize
+/– Endovascular infection
I&D as appropriate
Oral antimicrobial therapy Severe sepsis
+
Clindamycin Toxic shock syndrome
Parenteral antimicrobial therapy
or Clindamycin (in areas where
TMP-SMX resistance/D-test positivity rate low)
or or Hospitalize
Doxycycline or Vancomycin (in areas where clindamycin I&D as appropriate
Minocycline resistance/D-test positivity rate high) Surgical evaluation and
(>8 years)
intervention if needed
+
Parenteral antimicrobial therapy
Vancomycin
±
Clindamycin
±
Gentamicin
±
IGIV

FIGURE 115.9  Schema for the empiric treatment of community-associated S. aureus infections, determined by the severity of the illness. SSTI, Skin and soft tissue
infection; I&D, incision and drainage; TMP-SMX, trimethoprim-sulfamethoxazole; IGIV, immune globulin for intravenous use.

been done in children. The drug is administered once daily. Telavancin
carries a “black box” warning that it worsens renal dysfunction. As can
vancomycin, telavancin can cause red man syndrome. A few resistant
isolates have been, obtained although the mechanism is not known.
Rifampin
Rifampin is a bactericidal agent that blocks protein synthesis by inhibiting
RNA polymerase. It is highly active against almost all S. aureus isolates,
but resistance emerges rapidly when rifampin is used as monotherapy.
Combination regimens using rifampin with clindamycin, TMP-SMX, or
doxycycline sometimes are recommended for the treatment of CA-MRSA
infections or for treating device- or prosthesis-associated S. aureus infec-
tions. Whether such regimens are more effective is unclear. Rifampin is
available in both oral and IV forms, although a suspension suitable for
use in young children is not available.
Aminoglycosides
Aminoglycosides (e.g., gentamicin) are potent bactericidal inhibitors
of protein synthesis. Aminoglycosides alone are believed to be poorly
efficacious against S. aureus infections, although they are synergistic with
β-lactam antibiotics and vancomycin in vitro. They are commonly used
in combination therapy for severe infections, such as endocarditis, but
whether this offers a clinical advantage is the subject of controversy.
in vitro test results. A study sponsored by the National Institutes of
Health is underway to determine the optimal oral therapy of S. aureus
large-lesion SSTI in outpatients.220 A similar study comparing clindamy-
cin, TMP-SMX and placebo therapies for small abscess will be published
(Daum R, et al. In press).
Empiric Therapy for MRSA Infections Requiring
Hospitalization
Vancomycin is indicated for empiric therapy of putative S. aureus infec-
tions when the patient is severely ill.98,237 VISA isolates have been identified
that are associated with vancomycin treatment failure.238,239 The Clinical
and Laboratory Standards Institute defines VISA as an MIC of vancomycin
greater than 2 µg/mL. In 2002 the CDC reported the first documented
infection caused by S. aureus with high-level resistance (MIC >16 µg/mL)
to vancomycin, or VRSA; 12 additional VRSA strains have been isolated
since.87–89,240,241 VISA and VRSA isolates probably occur more frequently
than is documented because optimal tests to detect decreased vancomycin
susceptibility often are not performed in clinical laboratories.242
Information about parenteral therapy with clindamycin, daptomycin,
tigecycline, linezolid, telavancin, and other agents useful in the therapy
of MRSA infections in hospitalized children can be found in Chapter 292
and in the guidelines established by the Infectious Diseases Society of
America.98,243

Empiric Therapy for Community- PREVENTION

Associated Infections
CA-MSSA and CA-MRSA skin infections cannot be differentiated on
clinical grounds.192 In areas where CA-MRSA is prevalent, empiric
β-lactam therapy is not appropriate. Fig. 115.9 suggests an approach to
the management of these cases. Therapy should be adjusted according to
Efforts to prevent S. aureus HAIs have included general measures such as
improved hand hygiene and attention to careful implementation of
measures aimed at diminishing infections associated with intravascular
catheters. Other efforts aimed specifically at reducing infections caused by
MRSA have included identification of MRSA carriers upon hospitaliza-
tion, and isolation and cohorting of patients who are colonized. Contact

705
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Precautions are used in the care of patients with a MRSA infection. Some
states have legislated mandatory screening for MRSA upon admission to
the hospital or, in some cases, to an intensive care unit. However, such a
screening approach has several problems: high cost, focusing finite
resources on a single pathogen, lack of agreement on best practices to
determine MRSA carriage, lack of evidence-based management when
colonization is found, and the insignificant impact of an effective
institution-based strategy on MRSA infections in the community.243
In the community setting, some sports teams have increased efforts to
schedule equipment washing, discourage towel sharing, restrict infected
members from play until lesions have healed, and encourage good
hygiene among team members.244,245 Several correctional facilities have
introduced practices to reduce the spread of CA-MRSA, as recommended
by the Federal Bureau of Prisons.72 Chlorhexidine-impregnated cloths
were used successfully in prisons to reduce the density of skin coloniza-
tion,246 and they are frequently are used preoperatively; however, this
approach was unsuccessful in preventing SSTIs among military recruits.247
MRSA decolonization has been attempted in outbreak situations and
to prevent recurrent SSTI, with little success. Few randomized, controlled
trials have evaluated the efficacy of topical antibiotics and skin antisepsis
in the eradication of S. aureus carriage.99,248–251 Intranasal mupirocin
ointment appears to have the most success in reducing previous
HA-MRSA nasal colonization, and it has shown a subsequent decrease
in carriage at other body sites. A 5-day application of intranasal mupi-
rocin resulted in decreased short-term rates of colonization, but recolo-
nization occurred in at least one half of the treated subjects, usually
within a few months.99 Unacceptably high recolonization rates, concern
about mupirocin resistance,252,253 and limited data about the drug’s
effectiveness against CA-MRSA prevent intranasal mupirocin from being
recommended for routine use. Focusing on reducing the density of colo-
nization and environmental contamination, as well as improving
underlying skin conditions, may be more prudent.
Vaccine Development
A vaccine to prevent S. aureus infection remains a formidable challenge.
Experts disagree on whether S. aureus infections can be prevented by
vaccination and, if so, whether such a vaccine should be deployed uni-
versally or targeted to high-risk groups.
The traditional idea that production of an opsonophagocytic antibody
(or antibodies) correlates with protection has been challenged by available
data. In two vaccine trials of types 5 and 8 polysaccharide conjugate
vaccine, immunization failed to provide protection against BSI.254 Recently
a protein vaccine containing an iron-scavenging, cell wall–anchored
protein (ISDB) was developed. Enrollees in the study of this vaccine were
adults undergoing elective cardiac surgery that required a sternotomy. The
clinical end point was the occurrence of S. aureus mediastinitis or bactere-
mia. However, the study was halted for lack of efficacy and because of
concern that vaccine recipients who developed S. aureus invasive infection
had a worse outcome than placebo recipients.16 A clinical trial of a
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uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados.
4-component vaccine, including the capsular antigens manufactured by
Pfizer, currently is enrolling adults undergoing elective spinal surgery.
In an initial trial, attempts to protect neonates passively with a high-
titer, anti–clumping factor A polyclonal antibody product (Veronate)
appeared to have promising results; however, a confirmatory trial did not
confirm efficacy (Hetherington S. Personal communication, 2006.). A
clinical trial using a monoclonal antibody (pagibaximab) directed against
lipoteichoic acid was conducted among small premature infants in an
attempt to prevent infections caused by S. aureus and coagulase-negative
staphylococci; however, efficacy was lacking.
Recent attention has focused on the role of the Th17/IL-17 lymphocyte
pathway.255 One candidate vaccine (rAls3p-N) derived from a Candida
adhesin protected mice against bacteremic challenge. Efficacy was
retained in mice that were B-lymphocyte deficient but not in those that
were T-lymphocyte deficient. Adoptive transfer of CD4+ lymphocytes,
but not B220+ lymphocytes, transferred immunity. The vaccine appar-
ently stimulates proinflammatory Th1, Th17, and Th1/Th17 lympho-
cytes, and these cytokines enhance neutrophil recruitment and activation.
As of February, 2015, the manufacturer had yet to decide whether to
evaluate this vaccine against S. aureus in an efficacy trial.
All references are available online at www.expertconsult.com.
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