082098 Staphylococcus aureus Infections - Goodsamim.com

The New England Journal of Medicine
Review Articles
Medical Progress
STAPHYLOCOCCUS AUREUS INFECTIONS
FRANKLIN D. LOWY, M.D.
Micrococcus, which, when limited in its extent and activity,
causes acute suppurative inflammation (phlegmon), produces,
when more extensive and intense in its action on
the human system, the most virulent forms of septicæmia
and pyæmia. 1
IN an elegant series of clinical observations and
laboratory studies published in 1880 and 1882,
Ogston described staphylococcal disease and its
role in sepsis and abscess formation. 1,2 More than 100
years later, Staphylococcus aureus remains a versatile
and dangerous pathogen in humans. The frequencies
of both community-acquired and hospital-acquired
staphylococcal infections have increased steadily, with
little change in overall mortality. Treatment of these
infections has become more difficult because of the
emergence of multidrug-resistant strains. This review
focuses on developments in our understanding of the
pathogenesis, epidemiology, and management of lifethreatening
staphylococcal disease since this topic was
last examined in the Journal. 3,4
STAPHYLOCOCCAL COMPONENTS
AND PRODUCTS
S. aureus is a member of the Micrococcaceae family
(Fig. 1). On microscopical examination, the organisms
appear as gram-positive cocci in clusters (Fig.
2). S. aureus is distinguished from other staphylococcal
species on the basis of the gold pigmentation of
colonies and positive results of coagulase, mannitolfermentation,
and deoxyribonuclease tests. 5
Genome
The staphylococcal genome consists of a circular
chromosome (of approximately 2800 bp), with prophages,
plasmids, and transposons. Genes governing
virulence and resistance to antibiotics are found on
From the Division of Infectious Diseases, Department of Medicine,
Montefiore Medical Center, and the Departments of Medicine, Microbiology,
and Immunology, Albert Einstein College of Medicine — both in
Bronx, N.Y. Address reprint requests to Dr. Lowy at the Department of
Medicine, Montefiore Medical Center, 111 E. 210th St., Bronx, NY 10467.
©1998, Massachusetts Medical Society.
the chromosome, as well as the extrachromosomal elements.
6 These genes are transferred between staphylococcal
strains, species, or other gram-positive bacterial
species through the extrachromosomal elements. 7
Cell Wall
The staphylococcal cell wall is 50 percent peptidoglycan
by weight. Peptidoglycan consists of alternating
polysaccharide subunits of N-acetylglucosamine
and N-acetylmuramic acid with 1,4-b linkages.
The peptidoglycan chains are cross-linked by tetrapeptide
chains bound to N-acetylmuramic acid and
by a pentaglycine bridge specific for S. aureus. Peptidoglycan
may have endotoxin-like activity, stimulating
the release of cytokines by macrophages, activation
of complement, and aggregation of platelets.
Differences in the peptidoglycan structure of staphylococcal
strains may contribute to variations in their
capacity to cause disseminated intravascular coagulation.
8 Ribitol teichoic acids, covalently bound to peptidoglycan,
are major constituents of the cell wall.
Lipoteichoic acid is a glycerol phosphate polymer
linked to a glycolipid terminus anchored in the cytoplasmic
membrane.
Capsule
Most staphylococci produce microcapsules. Of
the 11 types of microcapsular polysaccharide serotypes
that have been identified, types 5 and 8 account
for 75 percent of human infections. Most
methicillin-resistant S. aureus isolates are type 5. The
chemical composition of four of these antiphagocytic
polysaccharides, including types 5 and 8, has been
determined, and all four have been shown to be
chemically related. 9
Surface Proteins
Many staphylococcal surface proteins have certain
structural features in common. These features include
a secretory signal sequence at the N terminal, positively
charged amino acids that extend into the cytoplasm,
a hydrophobic membrane-spanning domain,
and a cell-wall–anchoring region, all at the carboxyl
terminal. A ligand-binding domain at the N terminal
that is exposed on the surface of the bacterial cell enables
some of these proteins to function as adhesins. 10
Protein A, the prototype of these proteins, has antiphagocytic
properties that are based on its ability to
bind the Fc portion of immunoglobulin (Fig. 1).
Several of these related proteins bind extracellularmatrix
molecules and have been designated microbialsurface
components recognizing adhesive matrix
molecules (MSCRAMM). Recent studies suggest
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Figure 1. Structure of S. aureus.
Panel A shows the surface and secreted proteins. The synthesis of many of these proteins is dependent on the growth phase, as
shown by the graph, and is controlled by regulatory genes such as agr. Panels B and C show cross sections of the cell envelope.
Many of the surface proteins have a structural organization similar to that of clumping factor, including repeated segments of amino
acids (Panel C). TSST-1 denotes toxic shock syndrome toxin 1.
that these proteins play an important part in the ability
of staphylococci to colonize host tissue. 11
Toxins
Staphylococci produce numerous toxins that are
grouped on the basis of their mechanisms of action.
Cytotoxins, such as the 33-kd protein-alpha toxin,
cause pore formation and induce proinflammatory
changes in mammalian cells. The consequent cellular
damage may contribute to manifestations of the
sepsis syndrome. 12,13 The pyrogenic-toxin superantigens
are structurally related, sharing various degrees
of amino acid sequence homology. They function as
superantigens by binding to major histocompatibility
complex (MHC) class II proteins, causing extensive
T-cell proliferation and cytokine release. 14 Different
domains of the enterotoxin molecule are responsible
for the two diseases caused by these proteins, the
toxic shock syndrome and food poisoning. 15 Despite
little amino acid sequence homology, toxic shock
syndrome toxin 1 is structurally similar to enterotoxins
B and C. The gene for toxic shock syndrome toxin
1 is found in 20 percent of S. aureus isolates. 14
The exfoliative toxins, including epidermolytic toxins
A and B, cause skin erythema and separation, as
seen in the staphylococcal scalded skin syndrome.
The mechanism of action of these toxins remains
controversial. Panton–Valentine leukocidin is a leukocytolytic
toxin that has been epidemiologically associated
with severe cutaneous infections. 16
Enzymes and Other Bacterial Components
Staphylococci produce various enzymes, such as
protease, lipase, and hyaluronidase, that destroy tissue.
These bacterial products may facilitate the spread
of infection to adjoining tissues, although their role
in the pathogenesis of disease is not well defined.
b-Lactamase is an enzyme that inactivates penicillin.
Penicillin-binding proteins are enzymes located
in the cytoplasmic membrane that are involved in
cell-wall assembly. 5 A novel penicillin-binding protein
is responsible for staphylococcal resistance to the
penicillinase-resistant penicillins and cephalosporins.
Coagulase, a prothrombin activator, converts fibrinogen
to fibrin. Its contribution to bacterial virulence
is uncertain.
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The New England Journal of Medicine
EPIDEMIOLOGY OF STAPHYLOCOCCAL
DISEASE
Colonization and Infection
Humans are a natural reservoir of S. aureus. Thirty
to 50 percent of healthy adults are colonized, with
10 to 20 percent persistently colonized. 21,22 Both
methicillin-sensitive and methicillin-resistant isolates
are persistent colonizers. 22,23 Persons colonized with
S. aureus are at increased risk for subsequent infections.
24 Rates of staphylococcal colonization are high
among patients with type 1 diabetes, 25 intravenous
drug users, 26 patients undergoing hemodialysis, 27
surgical patients, 28,29 and patients with the acquired
immunodeficiency syndrome. 30 Patients with qualitative
or quantitative defects in leukocyte function
are also at increased risk for staphylococcal disease. 31
Transmission
Persons colonized with S. aureus strains are at increased
risk of becoming infected with these strains.
Most cases of nosocomial infection are acquired
through exposure to the hands of health care workers
after they have been transiently colonized with
staphylococci from their own reservoir or from contact
with an infected patient. Outbreaks may also result
from exposure to a single long-term carrier or
environmental sources, but these modes of transmission
are less common. 22,32
Figure 2. Staphylococci with Polymorphonuclear Leukocytes in
a Sputum Sample (Gram’s Stain, ¬1000).
Genetic Regulation of Virulence-Determinant Expression
Global regulatory genes that coordinate the expression
of various groups of staphylococcal genes
have been identified. 17,18 The most extensively studied
gene, agr, induces the expression of exoprotein
(extracellular protein) while suppressing the expression
of surface protein through a bacterial-density–
sensing octapeptide. 19 Surface proteins are predominantly
synthesized during the exponential growth
phase, and the secreted proteins are synthesized during
the stationary phase (Fig. 1A). This sequential
expression of genes may have clinical importance.
Different stages of staphylococcal infection appear
to require different panels of virulence determinants.
During the initial stages of infection, the expression
of surface proteins that bind extracellular-matrix molecules
favors successful colonization of host tissues,
whereas the synthesis of exoproteins favors the spread
to adjacent tissues. This hypothesis is supported by
studies in animals showing that the inactivation of
regulatory genes reduces bacterial virulence. 20
Temporal Trends in S. aureus Disease
The numbers of both community-acquired and
hospital-acquired staphylococcal infections have increased
in the past 20 years. This trend parallels the
increased use of intravascular devices. 33,34 During
the period from 1990 through 1992, S. aureus was
the most common cause of nosocomial cases of pneumonia
and surgical-wound infections and the second
most common cause (after coagulase-negative staphylococci)
of nosocomial bloodstream infections, according
to data from the National Nosocomial Infections
Surveillance system of the Centers for Disease
Control and Prevention (CDC). 35
A second trend, resulting in part from selective
antibiotic pressure, has been the dramatic worldwide
increase in the proportion of infections caused by
methicillin-resistant S. aureus. 36,37 Initially noted in
tertiary care hospitals, methicillin-resistant strains
are increasingly found in the community. 38 Data
from the National Nosocomial Infections Surveillance
system for the period from 1987 to 1997 show
that the number of methicillin-resistant S. aureus infections
in intensive care units has continued to increase
(Fig. 3). Methicillin-resistant strains have also
become resistant to other antimicrobial agents. 37
The same 10-year CDC survey showed that the proportion
of methicillin-resistant isolates with sensitivity
only to vancomycin increased from 22.8 percent
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No. of Infections
3000
2000
1000
0
1987
No. of infections
Percent of infections resistant to methicillin
Percent of methicillin-resistant infections
sensitive only to vancomycin
1988
1989
1990
1991
1992
Year
1993
1994
1995
1996
1997
Figure 3. S. aureus Infections in Intensive Care Units in the
National Nosocomial Infections Surveillance System, 1987
through 1997.
Data include total infections, infections with methicillin-resistant
strains, and infections with methicillin-resistant strains sensitive
only to vancomycin. Isolates were tested for sensitivity to
the following antimicrobial agents: gentamicin, tobramycin,
amikacin, ciprofloxacin, clindamycin, erythromycin, chloramphenicol,
trimethoprim–sulfamethoxazole, and vancomycin.
Some hospitals did not test for susceptibility to all these antibiotics.
Data were kindly provided by Dr. Robert Gaynes, Hospital
Infection Program, National Center for Infectious Diseases.
in 1987 to 56.2 percent in 1997 (Fig. 3). These isolates
constitute the subgroup of strains from which
the S. aureus strains with intermediate sensitivity to
vancomycin (glycopeptide-intermediate S. aureus)
have recently emerged. 39 New molecular typing techniques
have clearly documented the ability of epidemic,
disease-producing clones of methicillin-resistant
S. aureus to populate hospitals and spread to
diverse geographic regions rapidly. 40,41 The rapid
spread and pathogenicity of these clones suggest
that they possess unique, as yet undefined, determinants
of virulence.
PATHOGENESIS OF STAPHYLOCOCCAL
DISEASE
S. aureus has a diverse arsenal of components and
products that contribute to the pathogenesis of infection.
These components and products have overlapping
roles and can act either in concert or alone.
A great deal is known about the contribution of
these bacterial factors to the development of infection.
14,31,42,43 Considerably less is known about their
80
70
60
50
40
30
20
10
0
Percent of Infections
interaction with each other and with host factors
and their relative importance in infection.
The virulence of S. aureus infection is remarkable,
given that the organism is a commensal that colonizes
the nares, axillae, vagina, pharynx, or damaged skin
surfaces. 21,22 Infections are initiated when a breach of
the skin or mucosal barrier allows staphylococci access
to adjoining tissues or the bloodstream. Whether an
infection is contained or spreads depends on a complex
interplay between S. aureus virulence determinants
and host defense mechanisms.
The biology of colonization of the nares, the primary
reservoir for staphylococci, is incompletely
understood. Mucin appears to be the critical host
surface that is colonized in a process involving interactions
between staphylococcal protein and mucin
carbohydrate. 44,45 The role of other commensals,
secretory IgA, or specific staphylococcal adhesins is
unknown.
The risk of infection is increased by the presence
of foreign material. Elek and Conen 46 first demonstrated
the ability of sutures to reduce the threshold
for infection. Several factors contribute to the increased
susceptibility to infection. Phagocytic function
in the presence of foreign material is seriously
impaired. 47 Devices such as intravenous catheters are
rapidly coated with serum constituents, such as
fibrinogen or fibronectin, which enable staphylococci
to adhere through MSCRAMM-mediated mechanisms
and to elaborate glycocalices that further facilitate
colonization. 48,49 Intravenous catheters are
frequently implicated in the pathogenesis of nosocomial
endocarditis. The introduction of long-term
indwelling catheters has led to cases of nosocomial
endocarditis that resemble the animal model of endocarditis.
The catheter traumatizes the valvular surface,
creating a nonbacterial thrombus on the cardiac
valve that facilitates subsequent bacterial adherence. 50
Invasive Infections
Staphylococcal bacteremia may be complicated by
endocarditis, metastatic infection, or the sepsis syndrome.
The endothelial cell is central to these pathogenic
processes. Not only is it a potential target for
injury, but also its activation contributes to the progression
of endovascular disease. Staphylococci avidly
adhere to endothelial cells and bind through adhesin–receptor
interactions. 51-53 In vitro studies demonstrate
that after adherence, staphylococci are phagocytized
by endothelial cells (Fig. 4). 52,55
The intracellular environment protects staphylococci
from host defense mechanisms as well as the
bactericidal effects of antibiotics. Vesga et al. 56 demonstrated
that the intraendothelial-cell milieu fosters
the formation of small-colony variants. These factors
may enhance bacterial survival and contribute to the
development of persistent or recurrent infections. 57
Staphylococcal strains that cause endocarditis are
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The New England Journal of Medicine
Figure 4. Endothelial-Cell Phagocytosis of S. aureus in Vitro.
The left-hand panel shows staphylococci after incubation with human umbilical-vein endothelial cells in tissue culture for 30
minutes. The bacteria have been phagocytized, enclosed within membrane-bound vacuoles, and transported into the cell. The bar
represents 0.5 µm. The right-hand panel shows an endothelial cell from a section of rabbit aorta incubated with staphylococci. The
bacteria were incubated with tissue for 30 minutes and then incubated with medium for 5 1 /2 hours. The endothelial cell contains a
large number of bacteria enclosed within vacuoles. The cell has ruptured, releasing bacteria into the medium. The bar represents
1.0 µm. Reprinted from Lowy et al. 54 with the permission of the publisher.
resistant to serum, adhere to both damaged and undamaged
native valvular surfaces, are resistant to
platelet microbicidal proteins, 58 and elaborate proteolytic
enzymes that facilitate spread to adjacent tissues.
5 The adherence of staphylococci to the platelet–fibrin
thrombus that forms on damaged valvular
surfaces may involve the adherence of MSCRAMM
proteins to exposed matrix molecules. Staphylococcal
endocarditis also occurs on undamaged valves.
The invasion of endothelial cells by S. aureus may
initiate the cellular alterations, including the expression
of tissue factor, that promote the formation of
vegetations (Fig. 5). 52,53,55,60,61
The capacity to invade endovascular tissue also favors
spread to other tissues. The tissue tropism of
S. aureus cannot be explained solely on the basis of
patterns of blood flow. MSCRAMM may mediate
the adherence of staphylococci to exposed matrix
molecules in the presence of endovascular injury, as
a means of tissue invasion. Alternatively, staphylococci
may bind endothelium directly. The potential
role of MSCRAMM is best illustrated by collagenbinding
protein. Its presence facilitates infection of
bones and joints in animals. 62
The cellular events leading to septic shock are similar
in staphylococcal infection and infection with
gram-negative bacteria. In both cases, monocytes
and macrophages have a central role, although polymorphonuclear
leukocytes, endothelial cells, and
platelets also play a part. The monocytes release tumor
necrosis factor a and interleukin-1, interleukin-6,
and interleukin-8 after contact with intact staphylococci,
peptidoglycan, or lipoteichoic acid. 63,64 In
contrast, the expression of interleukin-1 and interleukin-6
by endothelial cells requires bacterial phagocytosis.
65 As a result of cytokine and cellular activation,
the complement and coagulation pathways are activated,
arachidonic acid is metabolized, and plateletactivating
factor is released. These events, in turn,
cause fever, hypotension, capillary leak, disseminated
intravascular coagulopathy, depression of myocardial
function, and multiorgan dysfunction. Several staphylococcal
components appear to be capable of initiating
the sepsis syndrome. 66 Peptidoglycan, especially
when combined with lipoteichoic acid, reproduces
many of the physiologic responses of endotoxin in
animal models of sepsis. 67,68 Alpha toxin alone reproduces
many of the findings of sepsis, including
hypotension, thrombocytopenia, and reduced oxygenation,
in animal models. 12
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Figure 5. Pathogenesis of Staphylococcal Invasion of Tissue.
The sequence of events progresses from left to right. Circulating staphylococci bind to sites of endovascular damage where platelet–fibrin
thrombi (PFT) have formed. The bacteria may attach through MSCRAMM-mediated mechanisms. Alternatively, they may
adhere to endothelial cells directly through adhesin–receptor interactions or by means of bridging ligands that include serum constituents
such as fibrinogen. Modifications of the endothelium resulting from microenvironmental changes (such as alterations in
the extracellular matrix [ECM]) can signal changes in cellular susceptibility to infection. 59 After phagocytosis by endothelial cells,
the bacteria elaborate proteolytic enzymes that facilitate the spread to adjoining tissues and the release of staphylococci into the
bloodstream. Tissue factor is expressed by infected endothelial cells, facilitating the deposition of fibrin and the formation of vegetations.
60 Once in the adjoining subepithelial tissues, the bacteria elicit an inflammatory response that results in abscess formation.
This sequence of events contributes to the establishment of metastatic foci of infection, as well as the pathogenesis of endocarditis
when cardiac endothelium is involved.
After phagocytosis, endothelial cells express Fc receptors and adhesion molecules (vascular-cell adhesion molecules [VCAM] and
intercellular adhesion molecules [ICAM]) and release interleukin-1, interleukin-6, and interleukin-8. As a result, leukocytes adhere
to endothelial cells, with diapedesis to the site of infection. Changes in the conformation of endothelial cells result in increased
vascular permeability, with transudation of plasma proteins. Both tissue-based macrophages and circulating monocytes release
interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor a (TNF-a) after exposure to staphylococci. Macrophage activation
occurs after the release of interferon-g by T cells. Cytokines released into the bloodstream from monocytes or macrophages,
as well as endothelial cells, contribute to the manifestations of the sepsis syndrome and vasculitis associated with systemic staphylococcal
disease. Expression of Fc receptors may contribute to the vasculitis occasionally encountered during bacteremia by acting
as a binding site for immunoglobulin (Ig) or immune complexes. PMN denotes polymorphonuclear leukocyte.
Toxin-Mediated Disease
Pyrogenic-toxin superantigens cause life-threatening
disease that is characterized by the rapid onset
of high fever, shock, capillary leak, and multiorgan
dysfunction. Superantigens are T-cell mitogens that
bind directly to invariant regions of MHC class II
molecules, bypassing intracellular protein ingestion
and digestion and subsequent peptide presentation
by antigen-presenting cells. The MHC-bound superantigens
then attach to T cells according to the composition
of the variable region of the T-cell–receptor
b chain. Toxic shock syndrome toxin 1 binds all variable-region
b2–positive T cells, causing an expansion
of clonal T cells (5 to 20 percent of resting T cells
as compared with 0.01 percent of T cells for processed
antigens), resulting in the massive release of
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The New England Journal of Medicine
cytokines by both macrophages and T cells. These
cytokines mediate the toxic shock syndrome, whose
pathophysiology mimics that of endotoxin shock. In
both syndromes, bacterial products induce the release
of excessive quantities of cytokines, which then
cause tissue damage. 14,66,69
Host Response to Infection
The typical pathological finding of staphylococcal
disease is abscess formation. Leukocytes are the primary
host defense against S. aureus infection. 70 The
migration of leukocytes to the site of infection results
from the orchestrated expression of adhesion
molecules on endothelial cells. This cytokine-mediated
process is triggered by bacteria and tissue-based
macrophages. After infection, cytokines are first demonstrable
within vessels, extending into tissues as
inflammatory cells migrate to the sites of infection. 71
S. aureus–infected endothelial cells also express intercellular
adhesion molecule 1 (CD54), vascularcell
adhesion molecule 1 (CD106), and MHC class
I molecules and probably contribute to this process
(Fig. 5). 72 Genetically manipulated mice lacking intercellular
adhesion molecule 1 have a defect in leukocyte
migration that results in increased mortality,
but they also have less severe staphylococcal infections
than normal mice, perhaps as a result of decreased
leukocyte-mediated damage. 73
The presence of opsonizing antibody directed
against capsule, peptidoglycan, or complement facilitates
phagocytosis in vitro. 9,74,75 The role of antibody
in vivo is less certain, since the titer of antistaphylococcal
antibodies is not correlated with protection
from infection, except in the case of toxic shock syndrome,
in which the presence of anti–toxic shock
syndrome toxin 1 is protective. 76,77 At present, it is
not known which staphylococcal components are
capable of inducing protection from subsequent infection.
DISEASES CAUSED BY S. AUREUS
S. aureus infection is a major cause of skin, softtissue,
respiratory, bone, joint, and endovascular disorders.
The discussion below is limited to life-threatening
staphylococcal infections. The majority of
these infections occur in persons with multiple risk
factors for infection. 78 More detailed discussions of
the clinical manifestations of staphylococcal diseases
can be found in several recent reports. 31,43,78
Bacteremia
The overall rate of mortality from staphylococcal
bacteremia, which has not changed in the past 15
years, ranges from 11 to 43 percent. 79 Factors associated
with increased mortality include an age of
more than 50 years, nonremovable foci of infection,
and serious underlying cardiac, neurologic, or respiratory
disease. Bacteremia caused by methicillinresistant
strains is not associated with increased mortality.
The change in the Acute Physiology and
Chronic Health Evaluation (APACHE II) score from
the day before to the day of S. aureus bacteremia was
recently found to predict the clinical course and outcome.
80 The frequency of complications from staphylococcal
bacteremia is high, ranging from 11 to 53
percent. As many as 31 percent of patients with bacteremia
who do not have evidence of endocarditis
do have evidence of metastatic infection. 61,79,81-83
An increasing percentage of bacteremic infections
are related to catheterization. 34 The rate of complications
is lower for catheter-related infections than
for all cases of bacteremia (24 percent), as is the
overall mortality rate (15 percent). 83 Patients with
bacteremia or fever that persists for more than 72
hours after the catheter has been removed may have
an increased risk of complications. 84 The incidence
of endocarditis in patients with catheters, estimated
on the basis of clinical indicators, is also low, ranging
from 0 to 18 percent. 83 Some studies, however, suggest
that the incidence of endocarditis may be higher.
Espersen and Frimodt-Møller 85 reported that the
diagnosis of S. aureus endocarditis was made at autopsy
and not suspected clinically in 55 percent of
the patients in their series (65 of 119). Using transesophageal
echocardiography, Fowler et al. 86 recently
found that 25 percent of selected patients with
staphylococcal bacteremia (26 of 103) and 23 percent
of those with catheters as the primary focus (16
of 69) had transesophageal echocardiographic evidence
of endocarditis in the absence of clinical or
transthoracic echocardiographic findings.
Endocarditis
The incidence of S. aureus endocarditis has increased
and now accounts for 25 to 35 percent of
cases. 81,87 It occurs in intravenous drug users, elderly
patients, patients with prosthetic valves, and hospitalized
patients. In all four groups, the initial presentation
may be limited to fever and malaise, making
diagnosis difficult. Unlike endocarditis caused by
less virulent pathogens, S. aureus endocarditis is characterized
by a rapid onset, high fever, frequent involvement
of normal cardiac valves, and the absence
of physical stigmata of the disease on initial presentation.
88 In one study, 13 percent of febrile intravenous
drug users evaluated in an emergency room had
endocarditis, and the diagnosis could not have been
predicted on the basis of available clinical or laboratory
data. 89
In cases of endocarditis related to intravenous
drug use, the disease is frequently right-sided, the
patients are young, the mortality rate is low, and the
majority of patients do not have antecedent valvular
disease. The prognosis is worse for intravenous drug
users who have advanced disease associated with human
immunodeficiency virus (HIV) infection than it
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is for those without HIV infection. 90 In cases of endocarditis
that are not related to drug use, the disease
is often left-sided, the patients are older, the
mortality rate is high (20 to 44 percent), and the
disease usually involves previously damaged cardiac
valves. 61,81,88 In one review, the incidence of both
embolic and neurologic complications of left-sided
S. aureus endocarditis was 50 percent. 88
S. aureus is one of the most common pathogens
in nosocomial and prosthetic-valve endocarditis, and
intravascular catheters are the most frequent source
of bacterial inoculation. The mortality rate for nosocomial
endocarditis, regardless of the pathogen, is
40 to 56 percent, and the rate is even higher when
the pathogen is S. aureus. 91 In many of these cases,
the diagnosis is obscured by other conditions or the
administration of antibiotics. Prosthetic-valve endocarditis,
especially in the early postoperative period,
is often fulminant and is characterized by the formation
of myocardial abscesses and the development of
valvular insufficiency. Fang et al. 92 noted a 43 percent
incidence of endocarditis in patients with prosthetic
valves who had nosocomial bacteremia. The
most common pathogen was S. aureus.
Metastatic Infections
S. aureus has a tendency to spread to particular
sites, including the bones, joints, kidneys, and
lungs. 78,82,88 Suppurative collections at these sites
serve as potential foci for recurrent infections. 78 Patients
with persistent fever despite appropriate therapy
should be evaluated for the presence of suppurative
collections.
Sepsis
A minority of bacteremic or local infections
progress to sepsis. Risk factors for sepsis include advanced
age, immunosuppression, chemotherapy, and
invasive procedures. The presentation of staphylococcal
sepsis is similar to that of gram-negative sepsis,
with fever, hypotension, tachycardia, and tachypnea.
S. aureus is one of the most common gram-positive
pathogens in cases of sepsis. 66 Severe cases progress
to multiorgan dysfunction, disseminated intravascular
coagulation, lactic acidosis, and death. 66 In both
gram-positive and gram-negative sepsis, the levels of
circulating tumor necrosis factor a, interleukin-1,
and interleukin-6 are predictive of the outcome. 93
Toxic Shock Syndrome
Staphylococcal toxic shock syndrome came to
prominence in 1980–1981, when numerous cases
were associated with the introduction of superabsorbent
tampons for use during menstruation. The disease
is characterized by a fulminant onset, often in
previously healthy persons. The diagnosis is based
on clinical findings that include high fever, erythematous
rash with subsequent desquamation, hypotension,
and multiorgan damage. Alternative diagnoses,
including Rocky Mountain spotted fever, streptococcal
scarlet fever, and leptospirosis, must be ruled
out. The toxic shock syndrome often develops from
a site of colonization rather than infection. 94
Although toxic shock syndrome toxin 1 accounts
for more than 90 percent of cases of the syndrome
that are associated with menstruation, other enterotoxins
account for 50 percent of cases unrelated to
menstruation. Nonmenstrual cases have increased
and now account for approximately one third of all
cases. These nonmenstrual cases have been associated
with localized infections, surgery, or insect bites.
Patients with nonmenstrual toxic shock syndrome
have a higher mortality rate than those with menstrual
toxic shock syndrome. 76
MECHANISMS OF RESISTANCE
TO ANTIMICROBIAL AGENTS
Penicillin is inactivated by b-lactamase, a serine
protease that hydrolyzes the b-lactam ring. Less than
5 percent of isolates remain sensitive to penicillin.
Resistance to methicillin confers resistance to all
penicillinase-resistant penicillins and cephalosporins.
This high level of resistance requires the presence of
the mec gene that encodes penicillin-binding protein
2a. 95 The mec genes probably originated from a different
species of staphylococci. 96 Although many
methicillin-resistant strains appear to be descendants
of a limited number of clones, some appear to be
multiclonal in origin, suggesting the horizontal transfer
of mec DNA. 96-98 Other staphylococcal genes, including
bla (for b-lactamase) and fem (for factors
essential for methicillin resistance), affect the expression
of resistance. The expression of resistance to
methicillin is often heterogeneous, and the percentage
of a bacterial population that expresses the
resistance phenotype varies according to the environmental
conditions. Antimicrobial-sensitivity testing
has been modified to enhance the detection of
the resistance phenotype. 95
There has been increasing concern about the possible
emergence of vancomycin-resistant S. aureus
strains. Resistance to vancomycin has been reported
in clinical isolates of S. haemolyticus, 99 a coagulase-negative
species. The enterococcal plasmid-bearing gene
for resistance to vancomycin has been transferred by
conjugation to S. aureus in vitro. 100 Four recent case
reports (one from Japan and three from the United
States) have documented the isolation of clinical
strains with intermediate sensitivity to vancomycin
(minimal inhibitory concentration, 8 mg per milliliter).
39,101 The mechanism of resistance in these isolates
is not known but is not due to the van genes
present in enterococci. Both increased cell-wall synthesis
and alterations in the cell wall that prevent vancomycin
from reaching sites of cell-wall synthesis have
been suggested as mechanisms. 39,102 Screening for
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The New England Journal of Medicine
TABLE 1. ANTIMICROBIAL THERAPY FOR SERIOUS S. AUREUS INFECTIONS.*
SENSITIVITY OR RESISTANCE
OF ISOLATE DRUG OF CHOICE ALTERNATIVE COMMENTS
Sensitive to penicillin
Sensitive to methicillin
Resistant to methicillin
Resistant to methicillin
with intermediate sensitivity
to vancomycin§
Not yet known
Penicillin G (4 million
units every 4 hr)
Nafcillin or oxacillin
(2 g every 4 hr)
Vancomycin (1 g every
12 hr)†
Uncertain
Vancomycin (1 g every
12 hr)
Nafcillin (2 g every 4 hr), oxacillin
(2 g every 4 hr), cefazolin (2 g
every 8 hr), vancomycin (1 g every
12 hr)
Cefazolin (2 g every 8 hr)†, vancomycin
(1 g every 12 hr)†
TMP–SMZ (TMP, 5 mg/kg of body
weight every 12 hr),† minocycline
(100 mg every 12 hr orally),† ciprofloxacin
(400 mg every 12 hr),†
trovafloxacin (300 mg every 24 hr),
levofloxacin (500 mg every 24
hr),† as well as investigational
drugs (quinupristin–dalfopristin,
oxzolidinones, new carbapenem
[L-695,256])
Same as for methicillin-resistant
strains
Less than 5 percent of isolates are sensitive to penicillin
Patients with penicillin allergy can be treated with a cephalosporin
if the allergy does not involve an anaphylactic
or accelerated reaction; vancomycin is the alternative;
desensitization to b-lactams may be necessary in some
cases‡
Sensitivity testing is necessary before an alternative drug
is used; adjunctive drugs (those that should be used
only in combination with other antimicrobial agents)
include gentamicin, rifampin, and fusidic acid (not
readily available in the United States); quinupristin–dalfopristin
is bactericidal against methicillin-resistant isolates
unless the strain is erythromycin-resistant; the
newer quinolones may retain in vitro activity against
ciprofloxacin-resistant isolates; resistance may develop
during therapy; the efficacy of adjunctive therapy is unknown‡
Same as for methicillin-resistant strains
— Empirical therapy is given when the susceptibility of the
isolate is not known. Vancomycin with or without an
aminoglycoside is recommended for suspected community-
or hospital-acquired S. aureus infections because
of the increased frequency of methicillin-resistant
strains in the community
*The route of administration is intravenous unless otherwise indicated. TMP–SMZ denotes trimethoprim–sulfamethoxazole.
†The dosage must be adjusted in patients with reduced creatinine clearance.
‡For the treatment of prosthetic-valve endocarditis, the addition of gentamicin (1 mg per kilogram every 8 hours) and rifampin (300 mg orally every
8 hours) is recommended, with adjustment of the dosage of gentamicin if the creatinine clearance is reduced.
§Vancomycin-resistant S. aureus isolates have not been reported to date.
strains of S. aureus with intermediate sensitivities to
glycopeptides including vancomycin (glycopeptideintermediate
strains) can be performed with the use
of brain–heart infusion agar plates supplemented with
6 mg of vancomycin per milliliter. Confirmation of
sensitivity by the broth-dilution method is recommended.
103 Vancomycin-resistant S. aureus strains are
likely to pose a major therapeutic challenge in the
future.
TREATMENT OF S. AUREUS INFECTION
Penicillin remains the drug of choice if the isolate
is sensitive to it (Table 1). A semisynthetic penicillin
(nafcillin or oxacillin) is indicated for b-lactamase–
producing strains. In patients with histories of delayed-type
penicillin allergy, a cephalosporin such as
cefazolin or cephalothin is an acceptable alternative.
In vitro data from experimental and clinical studies
suggest that vancomycin is a less effective antistaphylococcal
drug than the b-lactams. 104,105 Therefore,
the selection of vancomycin as an alternative to a
b-lactam in a patient with a history of allergy should
be carefully considered.
Vancomycin is the drug of choice for methicillin-resistant
isolates. Patients unable to tolerate vancomycin
have been treated with fluoroquinolones,
trimethoprim–sulfamethoxazole, clindamycin, or minocycline.
Each of these drugs has been effective in
cases that require bactericidal therapy. 95,106 They are
not as effective as vancomycin, however, either because
they have less antistaphylococcal activity or because
resistance develops during therapy. 95,107 Quinolones
with enhanced antistaphylococcal activity have
recently become available, but their use may also be
limited by the development of resistance during
therapy. A number of potentially active drugs are
under investigation, including quinupristin–dalfopristin,
a new carbapenem, and a new family of antimicrobial
drugs, oxzolidinones. 106 The glycopeptide-intermediate
strains reported to date have been
variably sensitive to chloramphenicol, gentamicin,
rifampin, trimethoprim–sulfamethoxazole, and tetracycline.
39,101,103 The initial case involving a glycopeptide-intermediate
strain was treated with surgical
débridement and ampicillin–sulbactam plus an aminoglycoside.
39
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MEDICAL PROGRESS
Antimicrobial combinations have been used to increase
bactericidal activity or to prevent the development
of antimicrobial resistance. The combination
of b-lactams and aminoglycosides increases bacterial
killing in vitro and in animal models of endocarditis.
108 In a clinical trial comparing a single drug with
combination therapy for the treatment of endocarditis,
combination therapy resulted in more rapid
clearance of bacteria from the bloodstream, but the
clinical outcome was the same with the two approaches.
109 Many clinicians use an aminoglycoside,
when possible, for the first few days of therapy.
Rifampin is another potent antistaphylococcal drug,
but resistance invariably develops if it is used alone.
Although the efficacy of rifampin as an adjunctive
drug in patients with life-threatening infections remains
controversial, it is recommended in combination
with gentamicin and vancomycin or nafcillin for
the treatment of prosthetic-valve endocarditis. 110 Rifampin
has also been combined with quinolones in
an effort to prevent the development of resistance. 111
The duration of therapy for invasive, life-threatening
infections, including those that cause endocarditis,
osteomyelitis, or arthritis, is four weeks or longer.
The appropriate duration of treatment for bacteremias
originating from a removable focus of infection,
such as an intravascular catheter, is controversial. A
two-week period of therapy has been recommended
for infections considered to pose a low risk of complications
(those caused by catheterization in nonimmunocompromised
patients without valvular abnormalities,
with prompt removal of the catheter, rapid
clearance of bacteremia, and no evidence of metastatic
infection). 61,83 However, a meta-analysis concluded
that, despite the reportedly low complication rates,
the available data do not justify short-course therapy
in such patients. 83 There is also concern that endocarditis
has been underdiagnosed because of a reliance
on clinical criteria. 85,86 Despite some promising
studies, tests for serum anti–teichoic acid antibodies
to help identify patients at risk for complications have
not proved useful. 31,112
When short-course therapy is being considered,
performance of transesophageal echocardiography
clearly reduces the likelihood of missing a diagnosis of
endocarditis, but it does not eliminate the possibility
of recurrent infections resulting from metastatic suppurative
collections. Risk factors that would reliably
identify patients at risk for the development of metastatic
suppurative collections have not been identified.
In a few studies, parenteral therapy given for two
weeks or oral therapy given for four weeks was effective
in intravenous drug users with tricuspid-valve
endocarditis. Most of the patients were nonimmunocompromised
and had uncomplicated, tricuspid-valve
endocarditis caused by methicillin-sensitive
S. aureus. Defervescence occurred promptly after the
institution of therapy with either regimen. The parenteral
regimen consisted of a semisynthetic penicillin
plus an aminoglycoside (1 mg per kilogram of body
weight every 8 hours), whereas the oral regimen
combined ciprofloxacin (750 mg every 12 hours)
with rifampin (300 mg every 12 hours). 110,111,113-115
The oral regimen may also be used for long-term
suppressive therapy. The possible development of
antimicrobial-resistant strains during therapy remains
a concern with this regimen.
In addition to antimicrobial therapy, drainage of
suppurative collections is necessary. The likelihood
of sterilizing an infected site in the presence of a foreign
device is low. In one study, the success rate for
treating Hickman catheter–associated infections without
removal of the catheters was 18 percent. 116 On
the basis of this and similar studies, the recommendation
is to remove the device when possible. Recent
studies suggest that in patients with prosthetic-valve
endocarditis, valve replacement results in a better outcome
than medical management alone. 117
The treatment of toxic shock syndrome is directed
against the consequences of the toxin. Management
includes fluid replacement for shock, careful monitoring
and antibiotic therapy to eliminate staphylococcal
colonization or infection, and removal of infected
material. Glucocorticoids are of uncertain value.
In vitro studies have shown that the use of intravenous
immune globulin with high titers of antienterotoxin
antibodies prevents T-cell stimulation by enterotoxins,
suggesting that immune globulin may have a
role in the treatment of the toxic shock syndrome. 118
PREVENTION OF STAPHYLOCOCCAL
DISEASE
The use of topical agents to eliminate staphylococcal
colonization in high-risk groups, such as patients
undergoing hemodialysis or surgery, has been
shown to reduce the incidence of subsequent infections.
27 Mupirocin, a topical antistaphylococcal agent
that inhibits RNA and protein synthesis, eliminates
nasal colonization in carriers and can reduce the incidence
of wound infections. 24,119 Although the development
of resistance to mupirocin to date has
been limited, prolonged use of the drug has been associated
with resistance. 120
A capsular polysaccharide–protein conjugate antistaphylococcal
vaccine has produced improved phagocytosis
in vitro and improved survival in experimental
models of staphylococcal infection, including
endocarditis. 121,122 Balaban et al. 123 demonstrated
that immunization with RNAIII-activating protein,
an agr-encoded protein involved in regulating the
expression of staphylococcal exoproteins, is protective
in an experimental model of cutaneous infection.
Other potential approaches involve the development
of multicomponent vaccines incorporating
proteins identified as having a role in the pathogenesis
of staphylococcal disease.
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The New England Journal of Medicine
At present, prevention of the spread of infection
relies on the application of appropriate principles of
infection control. These approaches have been effective
in reducing the nosocomial spread of staphylococcal
infection. Guidelines for the isolation of subjects
colonized with glycopeptide-intermediate or
vancomycin-resistant S. aureus strains have recently
been published. 124,125
Supported in part by grants from the American Heart Association and
the National Institute on Drug Abuse (DA09656 and DA11868).
I am indebted to Drs. Abigail Zuger, Timothy J. Foster, and David
Hammerman for their critical review of the manuscript; to Dr. Robert
Gaynes for providing unpublished data from the National Nosocomial
Infections Surveillance system; and to Dr. Christine Lawrence
for providing the photograph of staphyloccoci with Gram’s stain.
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532 · August 20, 1998
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New England Journal of Medicine
CORRECTION
Staphylococcus aureus Infections
To the Editor: In his review of Staphylococcus aureus infections, Dr.
Lowy (Aug.
20 issue) 1 states that bacteremia involving methicillinresistant
Staphylococcus aureus (MRSA) is not associated with
higher mortality than bacteremia involving methicillin-susceptible S.
aureus (MSSA). However, Romero-Vivas et al., 2 who conducted the
largest study, noted a significantly higher fatality rate among patients
with MRSA bacteremia. In their comparison of 100 cases of MSSA
bacteremia and 84 cases of MRSA bacteremia, the mortality rates
were 32 percent and 58.3 percent, respectively (P

New England Journal of Medicine
4. Wood MJ. The comparative efficacy and safety of teicoplanin
and vancomycin. J Antimicrob Chemother 1996;37:209-222.
[Erratum, J Antimicrob Chemother 1996;38:919; J Antimicrob
Chemother 1997;40:147.]
To the Editor: In his splendid review of S. aureus infections, Lowy
discusses life-threatening infections. Although he states that patients
with human immunodeficiency virus (HIV) infection are at increased
risk for staphylococcal colonization, he does not detail the peculiar
characteristics of this infection in such patients. S. aureus pneumonia
has been reported to occur in HIV-infected patients at a frequency
exceeding that in the general population. 1
We conducted a retrospective case–control study in the department of
infectious diseases of a 1700-bed university hospital in Rome. For the
period from 1986 through 1997, we identified 350 episodes of bacterial
pneumonia (as defined elsewhere 2 ) and 28 episodes of S. aureus
pneumonia. The attack rate for S. aureus pneumonia was 8.31 cases
per 1000 HIV-related hospital admissions. S. aureus pneumonia was
a community-acquired infection in two thirds of the HIV-positive patients,
a finding at variance with the frequently reported finding that in
immunocompetent patients, a nosocomial origin of S. aureus pneumonia
is more common.
In conclusion, we emphasize the importance of S. aureus as an etiologic
agent of life-threatening pulmonary infections in HIV-positive
persons. Although other microorganisms can cause pneumonia, HIVpositive
patients who have an acute onset with lobar involvement and
pleural effusion on chest radiography should be carefully evaluated
for the possibility of S. aureus pneumonia.
Evelina Tacconelli, M.D.
Mario Tumbarello, M.D.
Roberto Cauda, M.D.
Università Cattolica Sacro Cuore
00168 Rome, Italy
References
1. Tumbarello M, Tacconelli E, Lucia MB, Cauda R, Ortona L. Predictors
of Staphylococcus aureus pneumonia associated with human
immunodeficiency virus infection. Respir Med 1996;90:531-537.
2. Tumbarello M, Tacconelli E, de Gaetano K, et al. Bacterial pneumonia
in HIV-infected patients: analysis of risk factors and prognostic
indicators. J Acquir Immune Defic Syndr Hum Retrovirol
1998;18:39-45.
Dr. Lowy replies:
To the Editor: Blot et al. cite several studies suggesting that the outcome
of infections caused by MRSA is worse than that of infections
caused by MSSA. Other reports argue against the greater virulence
of MRSA strains. 1,2 As Blot et al.
note, these studies must be interpreted
cautiously, because of the frequent association of MRSA
infections with a greater severity of illness, an underlying disease of
a different nature, prolonged hospitalization, and increased antibiotic
use. These variables make comparative analyses difficult, especially
for retrospective studies.
The virulence of staphylococcal infection
may be more closely tied to particular strains than to the presence or
absence of methicillin resistance.
As Dr. Conde suggests, teicoplanin was not mentioned because it
is not available in the United States. Although it has some pharmacologic
advantages, teicoplanin has been reported to have less antistaphylococcal
activity than vancomycin, or at best, similar activity. 3
Tacconelli et al. describe an important presentation of staphylococcal
disease in HIV-positive patients. The incidence of staphylococcal
disease in general appears to be increased in this population.
There have also been reports of an increased incidence of bloodstream,
skin, and soft-tissue infections, as well as respiratory tract
infections. 4,5 The basis of these infections is uncertain, but it may
be related to the immunocompromised status of the patients, an increased
colonization rate, and the use of more frequent invasive procedures
that breach skin or mucosal barriers.
There is an error on page 520 of my article (first column, last paragraph,
second line). The size of the chromosome should be 2.8
megabase pairs, not 2800 base pairs.
Franklin D. Lowy, M.D.
Montefiore Medical Center
Bronx, NY 10467
References
1. French GL, Cheng AF, Ling JM, Mo P, Donnan S. Hong Kong
strains of methicillin-resistant and methicillin-sensitive Staphylococcus
aureus have similar virulence. J Hosp Infect 1990;15:117-
125.
2. Harbath S, Rutschmann O, Sudre P, Pittet D. Impact of methicillin
resistance on the outcome of patients with bacteremia caused by
Staphylococcus aureus. Arch Intern Med 1998;158:182-189.
3. Chambers HF. Parenteral antibiotics for the treatment of bacteremia
and other serious staphylococcal infections. In: Crossley
KB, Archer GL, eds. The staphylococci in human disease. New
York: Churchill Livingstone, 1997:583-601.
4. Weinke T, Schiller R, Fehrenbach FJ, Pohle HD. Association between
Staphylococcus aureus nasopharyngeal colonization and
septicemia in patients infected with human immunodeficiency
virus. Eur J Clin Microbiol Infect Dis 1992;11:985-989.
5. Krumholz HM, Sande MA, Lo B. Community-acquired bacteremia
in patients with acquired immunodeficiency syndrome:
clinical
N Engl J Med 1998;339:2025
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presentation, bacteriology, and outcome. Am J Med 1989;86:776-
779.
N Engl J Med 1998;339:2025
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