Methicillin-Resistant

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CRITICAL CARE
SPECIAL EDITION
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THE SCIENCE BEHIND
PATIENT OUTCOMES
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Methicillin-Resistant
Staphylococcus aureus
Authors
Donald E. Fry,
MD, FACS
Professor Emeritus
Department of Surgery
University of New Mexico
School of Medicine
Albuquerque, New Mexico
Marin H. Kollef, MD
Professor of Medicine
Washington University School
of Medicine
Director, Medical Critical Care
Director, Respiratory Care
Services
Barnes-Jewish Hospital
St. Louis, Missouri
Section I:
The Pathophysiology of Skin Infections
By Donald E. Fry, MD, FACS
Section II:
Pharmacoeconomic Considerations in the
Treatment of Hospital-Associated
Methicillin-Resistant Staphylococcus aureus
By Alan D. Tice, MD
te
Section III:
Toxin Inhibition and Gram-Positive Infection:
Focus on Methicillin-Resistant Staphylococcus
aureus Expressing the Panton-Valentine
Leukocidin Gene
Associate Professor
John A. Burns School of
Medicine
University of Hawaii
Honolulu, Hawaii
By Marin H. Kollef, MD
d.
Alan D. Tice, MD
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Section I:
The Pathophysiology of
Skin Infections
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Donald E. Fry, MD, FACS
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Professor Emeritus
Department of Surgery
University of New Mexico School of Medicine
Albuquerque, New Mexico
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Introduction
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Infections of the skin and adjacent subcutaneous tissues
are among the most common bacterial infections at major
medical centers.1 The spectrum of these infections may vary
from a simple, self-contained cellulitis to a severe, lifethreatening, and rapidly evolving necrotizing fasciitis. Many
types of infections are seen between these 2 extremes.
Erysipelas, furuncle, carbuncle, impetigo, and hidradenitis
suppurativa are a few of the names that are used for the
variable expressions of skin and soft tissue infections.
Clinical infection is the activation of the local inflammatory response secondary to the proliferation of microbial
pathogens within human tissue. An understanding of the
pathophysiology of this complex process in the skin and
soft tissues requires an understanding of the anatomy of
the skin, knowledge of the potential pathogens that cause
the infections, and insight into the human inflammatory
response that attempts to contain and eradicate the
microbes.
Pathophysiology
The Pathogen
Infection arising from the skin is caused either by bacterial colonists that normally reside on the skin or by
exogenous microbes that are carried into the skin and
soft tissues as colonization that pre-existed on the
wounding device. For example, gas gangrene from
Clostridium perfringens is colonization that existed on the
device causing the puncture, rather than being a normal
colonist of the skin by the mechanism of wounding.
Human skin normally has a diverse and rather large population of bacterial colonists (Table 1).2,3 They colonize
the skin surface and transiently colonize the follicles and
glandular openings before being expelled by normal
secretions. Infection of the skin is most commonly the
result of normal skin colonization that breaches the barrier with the wounding process. Of the many different
bacterial strains that colonize skin, only a limited number
are actually pathogenic. Staphylococcus aureus and
Streptococcus pyogenes are the specific bacteria that are
most likely to cause infection from skin colonization.
The gram-positive cocci of normal skin colonization
have particular virulence factors that make them aggressive pathogens in the injury site or within the obstructed
glandular drainage systems of the skin. S. aureus is most
noted for the production of coagulase, a potent enzyme
that activates the coagulation cascade of the host.4 The
precipitation of fibrin from the coagulation cascade creates an environment that protects the staphylococci from
the phagocytic mechanisms of the host. Coagulase also
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The anatomic structure of the skin provides a barrier to
infection but also opportunities for infection to occur. The
squamous epithelium of the epidermis provides a waterimpervious and resilient barrier against bacteria. This barrier function is the most basic and effective of the nonspecific host defenses. The surface of the skin is always
colonized, but infection only occurs when a breach of the
barrier occurs.
Infection occurs in the skin by 2 mechanisms. The most
common mechanism of infection occurs when there is a
violation of the barrier from mechanical injury in the form
of cuts, abrasions, punctures, or thermal injury. The
microbe is introduced into the soft tissues with injury, and
begins to multiply and invade the soft tissues. This multiplication and invasion results in activation of the human
2
inflammatory cascade, which then results in the erythema,
induration, and pus that characterizes infection.
However, the skin also has openings that are potential
microbial havens. These openings in the skin communicate
with hair follicles, sweat glands, and sebaceous glands.
Normal surface bacteria are constantly gaining access to
these openings, but the normal flow of sweat and sebaceous products keeps colonists from proliferating and
invading the adjacent soft tissues. Any obstruction to the
flow of sweat, oils, and sebaceous secretions can lead to
infection.
Exfoliated cells and hyperviscous secretions may
occlude the flow of the normal secretions. Skin edema
from contusions, abrasions, congestive heart failure, hypoalbuminemia, and radiation can all increase the hydrostatic pressure within the skin and obstruct the flow of normal
secretions. With retention of bacteria in the ductal systems of the skin, proliferation of the pathogen occurs, the
invasive and digestive enzymes of the pathogen degrade
the epithelial barrier, and invasive infection occurs.
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Table 1. Bacteria That Normally
Colonize the Skin of Humans
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Brevibacter species
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Corynebacterium species
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Micrococcus species
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Propionibacter species
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Staphylococcus albus
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Staphylococcus aureus
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Streptococcus pyogenes
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Staphylococcus hominis
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Staphylococcus epidermidis
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Note: Some authors have noted that the human skin has more bacterial
colonists than the human body has cells.
Adapted from references 2 through 4.
heparinase, which allow the extracellular matrix of the host
tissues to be digested, with enhanced invasiveness of the
pathogen being the consequence.5
Staphylococcal infections that occur from skin injuries
(eg, an infected cut) or spontaneous events from the glandular elements of the skin (eg, folliculitis or impetigo) have
traditionally been viewed as methicillin-sensitive organisms.
In recent years, new strains of community-associated
methicillin-resistant S. aureus (CA-MRSA) have developed.
Infections with CA-MRSA are predominantly skin and soft
tissue infections.6 The resistance of CA-MRSA to β-lactam
antibiotics is carried by a gene cassette (mec-type IV) that
does not mediate resistance to certain non–β-lactam drugs
but does carry the gene for the Panton-Valentine leukocidin.7 This particular virulence factor is toxic to human
leukocytes but also results in a tissue toxicity that gives an
exaggerated local inflammatory response characterized by
necrosis and eschar formation.
S. pyogenes has virulence factors that relate both to cell
structure and to exotoxin production.8 M-proteins on the
cell wall surface of streptococci retard phagocytosis and
are fundamental to the virulence of these bacteria.
Streptococci without M-protein are without virulence.9 A
variety of very potent exotoxins are produced, including
gives the particularly pyogenic character to staphylococcal infections.
S. aureus may also produce hemolysins and leukocidins.
They in turn produce collagenase, hyaluronidase, and
Activation Event
Cut, scrape, burn
Folliculitis
Initiatior Events
Coagulation activation
Platelet degranulation
Mast cell degranulation
Bradykinin synthesis
Complement activation
Phagocytic Phase
Vasodilation
Increased permeability
Edema formation
Neutrophil infiltration
Monocyte infiltration
Phagocytosis
Cytokine regulation
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Vasoactive Phase
d.
Figure 1. the sequential events in the activation of human inflammation. An
activator event occurs with skin injury or the development of infection within a
glandular element of the skin. Tissue injury activates the Initiator events, which in
turn lead to the vasoactive phase of inflammation. The phagocytic phase follows.
3
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Inoculum
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Virulence
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Adjuvant
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Intrinsic
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Acquired
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Probability/
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Figure 2. A hypothetical equation of the interaction of the complex entities that are
involved in determining whether infection will occur after skin injury or will be
controlled or aggressively advance.
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cytic response. The efficiency and robustness of the
response dictate whether contamination is eradicated
before infection occurs, or whether the evolving infection
can be contained and minimized.
The vasoactive response of inflammation has numerous
components. Relaxation of the vascular smooth muscle and
modification of the vascular endothelial cell results in
vasodilatation of the microcirculation, increased bulk flow,
increased vascular permeability, and tissue edema in the
local area of inflammatory activation.11 The increase in bulk
flow increases the delivery of phagocytic cells (and also
oxygen, opsonins, antibodies, etc) to the area, but reduces
flow velocity and shear on the endothelial surface to facilitate subsequent leukocyte margination. Increased permeability provides routes for phagocytic cells to exit the microcirculation, and edema formation creates aqueous conduits
to permit phagocytic migration through the extracellular
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hemolysins and enzymes that digest the extracellular
matrix. The array of exotoxins produced by the group A
streptococcus can be so toxic that the infection has a
potent necrotizing character. Multitoxin-producing S. pyogenes is the pathogen associated with the “flesh-eating”
bacterial infections of soft tissues. These are better known
as necrotizing soft tissue infections.
External bacteria can be introduced into the host and be
the pathogen(s) of skin and soft tissue infection. Most commonly, bacteria introduced from farming accidents or soft
tissue infections after operations or traumatic injury of the
human intestinal tract will be polymicrobial, with gramnegative rods and potentially enteric anaerobic bacteria.10
Much less frequently, one may see Clostridium perfringens
associated with the introduction of spores into the tissues
from puncture wounds, Pasteurella species with cat bites,
or Vibrio species with cutaneous injuries sustained in salt
water. Depending on the mechanism of injury, the immune
status of the patient (or if there is underlying illness), and
the external microbial environment, any bacterial species
introduced into the wounded area that results in a critical
inoculation of contaminants can cause skin and soft tissue
infection.
Table 2. Adjuvant Factors That
Enhance the Virulence of Bacterial
Contamination Within a Soft
Tissue Wound
Variable
The Inflammatory Response
Debris from injury or suture material
placed into the wound can enhance
infection; neutrophils ingest bacteria
on nonbiologic surfaces very poorly.
Necrotic
tissue
Dead tissue does not swell with edema;
neutrophils cannot penetrate tissue
without the benefit of edema.
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4
Foreign
bodies
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Whether infection originates within a cutaneous wound
or from within a glandular structure, activation of the
inflammatory response within the skin and soft tissues is
the first line of the innate host response. Disrupted tissue,
the release of tissue factor, exposed collagen, and released
ADP activate the initiator events of human inflammation.
The initiator events include the activation of the coagulation cascade, aggregation and degranulation of platelets,
activation of the mast cells, activation of the bradykinin
pathway, and activation of the complement cascade (Figure
1).10 These redundant and interactive responses result in an
immediate vasoactive response and a secondary phago-
Pathophysiologic Effect
Hemoglobin Iron is a critical trace metal for the
growth of bacteria; hemoglobin in a
wound is a rich source of iron and
protein.
Dead space Dead space in a large wound or after
surgical repair accumulates serum;
neutrophils cannot phagocytose bacteria
in suspended media.
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A
matrix. The vigor of this tissue level response is regulated
by the intensity of the inflammatory signaling (ie, chemoattractant molecules, tumor necrosis factor, interleukin-1, and
other soluble messengers that enhance inflammation) that
arises from the 5 initiators identified above. In addition to
the vasoactive consequences of activation of the initiator
events, cleavage products and secreted proteins serve as
chemoattractants. Chemoattractants are molecules that
bind to specific receptor sites on the surface of leukocytes
and provide a chemical gradient and direction for
phagocytic migration into the area of injury or infection.
The phagocytic response occurs with the actual infiltration of the injured or infected tissue with neutrophils followed by monocytes. The activation of endothelial selectin
and integrin receptors allows them to serve as adhesion
molecules that initially cause slowing on the surface tissue,
and then result in adherence of the phagocytic cell to the
endothelial cell.12 Diapedesis is then directed by the
chemoattractant gradient from the epicenter of injury or
infection. Phagocytosis of bacteria is initiated and then
amplified by the release of tumor necrosis factor–α, interleukin-1, and other pro-inflammatory cytokines.13 Successful mobilization of the innate response to a skin injury
results in eradication of the would-be pathogens. An effective response is one in which the infection is limited to a
localized cellulitis or soft tissue abscess. Invasion of tissue
with spreading cellulitis, lymphangitis, and lymphadenitis
represents the summed virulence of the pathogen in excess
of the efficiency of the mobilized host response. Aggressive
tissue destruction, progressive tissue necrosis, vertical
extension of the infection to the fascial level, and bacteremia reflect either virulence beyond the control of the
host or host defenses that are inadequate to meet the challenge of the pathogen. In the latter scenario, systemic dissemination of the microbe, dissemination of its toxins, or
dissemination of pathophysiologic quantities of the proinflammatory signals results in the systemic inflammatory
response syndrome (SIRS).14
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References
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1.
Centers for Disease Control and Prevention.
Soft tissue infections among injection drug users—San Francisco,
California, 1996-2000. MMWR Morb Mortal Wkly Rep. 2001;50:
381-384.
2.
De Pauw BE, Donnelly JP. Infections in the immunocompromised
host: general principles. In: Mandell GL, Bennett JE, Dolin R, eds.
Principles and Practice of Infectious Disease., 5th ed. New York,
NY: Churchill Livingstone; 2000:3079-3090.
3.
Kok M, Pechere J-C. Nature and pathogenicity of micro-organisms.
In: Armstrong D, Cohen J, eds. Infectious Diseases. London,
England: Mosby; 1999:1.1.1-1.1.26.
4.
Harrington DJ. Bacterial collagenases and collagen-degrading
enzymes and their potential role in human disease. Infect Immun.
1996;64:1885-1891.
5.
Printzen G. Relevance, pathogenicity and virulence of microorganisms in implant related infections. Injury. 1996;27(suppl 3):SC9-SC15.
6.
Said-Salim B, Mathema B, Kreiswirth BN. Community-acquired
methicillin-resistant Staphylococcus aureus: an emerging pathogen.
Infect Control Hosp Epidemiol. 2003;24:392-396.
7.
Lina G, Piemont Y, Godail-Gamot F, et al. Involvement of PantonValentine leukocidin-producing Staphylococcus aureus in primary
skin infections and pneumonia. Clin Infect Dis. 1999;29:1128-1132.
8.
Stevens DL. The toxins of group A streptococcus, the flesh-eating
bacteria. Immunol Invest. 1997;26:129-150.
9.
Fischetti VA, Gotschlich EC, Siviglia G, Zabriskie JB. Streptococcal
M protein: an antiphagocytic molecule assembled on the cell wall.
J Infect Dis. 1977;136(suppl):S222-S233.
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efficiency of responsiveness. Clinical variables that are
thought to impair the host include blood transfusion,
hypoalbuminemia, corticosteroid therapy, hypoxemia, tissue
ischemia, hypothermia, hyperglycemia, malnutrition, and
coexistent diseases associated with immunosuppression
(eg, renal failure). Whether the contaminant is eliminated
before infection occurs, whether mild cellulitis or a small
tissue abscess remains as a localized and relatively innocent
event, or whether an aggressive and life-threatening infection is the consequence is determined by this complex
interaction. Understanding this relationship between the
pathogen and the host sets the stage for a pathophysiologic approach to treating the patient with infections such as a
soft tissue infection.
Determinants of Infection
11. Fry DE. Microcirculatory arrest theory of SIRS and MODS. In: Baue
AE, Faist E, Fry DE, eds. Multiple Organ Failure: Pathophysiology,
Prevention, and Therapy. New York, NY: Springer; 2000:92-100.
12. Brown EJ, Lindberg FP. Leukocyte adhesion molecules in host
defense against infection. Ann Med. 1996;28:210-218.
13. Klebanoff SJ, Vedes MA, Harlan JM, et al. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986;136:4220-4225.
te
14. Fry DE. Multiple organ dysfunction syndrome: past, present and
future. Surg Infect. 2000;1:155-163.
d.
Thus, either the development of infection after skin injury
or enhanced severity of the infection, once it occurs, is the
consequence of multiple complex events illustrated in the
hypothetical equation form in Figure 2.15 The forces favoring
infection are the inoculum of bacteria in the tissue, the virulence characteristics of the bacterial contaminant, and the
local environment that enhances microbial aggressiveness
(Table 2).15 The forces of pro-infection are then pitted
against the intrinsic capacity of the host, which is then
modulated by acquired clinical conditions that impair the
10. Solomkin JS, Mazuski JE, Baron EJ, et al. Guidelines for the selection of anti-infective agents for complicated intra-abdominal
infections. Clin Infect Dis. 2003;37:997-1005.
15. Fry DE. Surgical site infection: pathogenesis and prevention.
Medscape Surgery, February 2003. Available at:
www.medscape.com/clinicalupdate/ssi. Accessed: June 16, 2006.
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Section II:
Pharmacoeconomic
Considerations
In the Treatment of
Hospital-Associated
Methicillin-Resistant
Staphylococcus aureus
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Associate Professor
John A. Burns School of Medicine
University of Hawaii
Honolulu, Hawaii
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Alan D. Tice, MD
Economic analyses of the evaluation and therapy of
methicillin-resistant Staphylococcus aureus (MRSA) infections are difficult but increasingly important, as issues
regarding resistance to antibacterial agents continue to
emerge and outbreaks with new and more virulent strains
continue. An understanding of the factors involved in the
significant financial costs of MRSA must consider a variety
of perspectives as well as the value of a careful clinical
assessment of every person infected.
There are a number of economic perspectives that
should be considered and reconsidered when therapeutic
decisions are made.
When Is Antibiotic Therapy Warranted?
The Cost of Treatment
If antibiotic treatment is necessary, choosing a drug
based on its cost is one way to reduce the overall financial burden of treatment. However, there are other
important considerations involved in antimicrobial selection, including:
• the underlying disease(s)
• clinical efficacy of the drug
• adverse effects of treatment (including likelihood of
allergic reaction)
• the likelihood of patient compliance with treatment
• the status of available healthcare resources
• patients’ health insurance coverage
• patients’ ability to care for themselves
• costs associated with I.V. administation (including
home infusion costs)
• availability of oral formulations
• the cost of therapeutic failure.
Indeed, the price of an effective oral therapy for MRSA
may well be worthwhile when other potential costs are factored into the equation.6 In a study of patients with community-acquired pneumonia, Davis et al demonstrated that
conversion from I.V. to oral therapy can reduce associated
treatment costs, without compromising efficacy.7 Table 1
summarizes the potential costs associated with antibiotic
therapy and offers potential cost-saving strategies. Certain
options may initially be more expensive, but they may save
money in the long run through reductions in hospital
stays, for which costs start at $1,000 per day.8 Table 2
illustrates the additional mortality, hospital costs, etc,
associated with MRSA in the surgical setting.
Perspectives on “cost effectiveness” vary greatly with
the observer. Some hospitals, for instance, may see
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The recovery of S. aureus on a culture is not, in and of
itself, an indication for antibiotic therapy. Reports of
MRSA strike fear into many healthcare workers and nursing home managers. In fact, roughly one third of otherwise healthy individuals carry S. aureus (usually in and
around their nasal area), with no apparent symptoms.1
Some of these bacteria are MRSA.
On the other hand, many infections are not treated
aggressively, causing severe disease and other complications that could have been avoided. The challenge facing
clinicians is distinguishing those patients who are truly
infected from those who are not (ie, those who need
aggressive treatment from those who do not). Indeed, clinical acumen is becoming increasingly important, and it has
significant financial implications when it comes to MRSA.
While a quick and inexpensive assessment for MRSA
6
can be done with on-site Gram stain testing, this procedure is typically done in an outside laboratory; results may
not be available in a timely manner. Waiting for results can
lead to costly delays in treatment decisions.2 For example,
delays in initiating adequate antibiotic therapy have been
associated with greater mortality in ventilator-associated
pneumonia.3 They can also increase patient anxiety.
A rapid means of detecting S. aureus and determining
whether or not it is MRSA would be extremely useful. New
and more expensive techniques for rapid identification of
S. aureus and even MRSA markers are in development,
but they are not yet available for bedside use.4 These
newer tests, while costly in and of themselves, may prove
cost-effective in the long run, especially given the
increasing number of hospitalizations for MRSA and the
need for prolonged courses of therapy.5
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Table 1. Antibiotic Cost Factors in Hospitalized Patients, With Potential
Strategies for Cost-Efficiency
Cost-saving Strategies
Price of acquisition (cost per dose or per day)
Purchase bulk through groups or
consortia.
A
Obvious Cost
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Hidden Costs
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Cost of I.V. administration
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Selectively use antibiotics with long half-lives that may be
given q12h or q24h.
Use I.V.-to-PO switch programs.
Consider treating more infections with oral antibiotics in
both outpatient and hospital settings.
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Consider avoiding drugs that require serum drug level
monitoring.
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Cost of monitoring
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Cost of adverse reactions
Cost of therapeutic failure (ie, prolonged treatment or
need for retreatment with different antibiotic)
Adapted from references 4 through 7.
Minimize or avoid use of antibiotics
associated with emergence of resistant organisms.
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Cost of increased antibiotic resistance and outbreaks due
to resistant organisms (includes cost of infection control
of isolating patients)
MRSA infections as a great expense involving prolonged,
complex, and expensive stays when nosocomial infections occur. For these institutions, the objective is to get
patients out of the hospital as soon as possible. This can
Consider avoiding poorly tolerated
antibiotics.
Consider avoiding antibiotics likely to fail because of
improper spectrum.
Consider avoiding antibiotics with poor tissue penetration.
be accomplished with some oral antibiotics or outpatient
parenteral antibiotic therapy (OPAT), if resources and
local expertise are available.
From a pharmacy perspective, however, the acquisition
Table 2. Adjusted Clinical Outcomes and Hospital Charges For Patients With MRSA
in the Surgical Setting
Outcome
Uninfected Control Subjects
(n=193)
MRSA SSI (n=121)
Death, n (%)
4 (2.1)
25 (20.7)
After surgery
5 (3-8)
23 (12-38)
After infection
NA
15 (7-30)
Total duration of hospitalization,
median days (IQR)
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29,455 (15,637-41,764)
92,363 (40,198-136,479)
d.
Hospital charges, median $ (IQR)
IQR, interquartile range; MRSA, methicillin-resistant Staphylococcus aureus; SSI, skin and soft tissue infection
Adapted from reference 4.
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References
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cost of an antibiotic may be a critical factor in antibiotic
selection. Many hospital pharmacies operate on a fixed
budget, and staff performance may be measured based
on the ability to control expenses.
Despite the common and frequent use of antibiotic
therapy for S. aureus infections, there may be a lack of
information about the agents’ adverse effects. Older oral
agents have not been approved by the US Food and Drug
Administration for the treatment of infections due to
MRSA, and there have been few comparative studies.9
Nevertheless, the older antimicrobials are often used as
first-line therapy for suspected or documented MRSA.
Clinicians must not only consider drug costs but overall
treatment costs and, of course, patient outcomes when
selecting therapy.
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Mainous AG 3rd, Hueston WJ, Everett CJ, Diaz VA. Nasal carriage
of Staphylococcus aureus and methicillin-resistant S. aureus in the
United States, 2001-2002. Ann Fam Med. 2006;4:132-137.
2.
Lode H. Management of serious nosocomial bacterial infections:
do current therapeutic options meet the need? Clin Microbiol
Infect. 2005;11:778-787.
3.
Kollef MH, Ward S. The influence of mini-BAL cultures on patient
outcomes: implications for the antibiotic management of ventilator-associated pneumonia. Chest. 1998;113:412-420.
4.
Paule SM, Pasquariello AC, Thomson RB Jr, Kaul KL, Peterson LR.
Real-time PCR can rapidly detect methicillin-susceptible and
methicillin-resistant Staphylococcus aureus directly from positive
blood culture bottles. Am J Clin Pathol. 2005;124:404-407.
5.
Lodise TP, McKinnon PS. Clinical and economic impact of methicillin resistance in patients with Staphylococcus aureus bacteremia.
Diagn Microbiol Infect Dis. 2005;52:113-122.
6.
Tice AD, Hoaglund PA, Nolet B, McKinnon PS, Mozaffari E. Cost
perspectives for outpatient intravenous antimicrobial therapy.
Pharmacotherapy. 2002;22:63S-70S.
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Cost-Effective Treatment Approaches
Cost-effective antimicrobial therapy starts with an initial, thorough evaluation and the initiation of therapy with
an antibiotic. Possible treatment approaches might also
include wound debridement, incision and drainage, a culture, parenteral therapy, and hospitalization. A daily clinical evaluation as well as a review of the culture results
can quickly provide useful answers about whether more
expensive care is needed or a switch to an oral or less
expensive antibiotic is possible.10 Daily outpatient
assessments for clinical response, adverse effects, and
related medical problems also may be quite cost-effective compared with hospitalization.
Conclusion
7.
Davis SL, Delgado G Jr, McKinnon PS. Pharmacoeconomic considerations associated with the use of intravenous-to-oral moxifloxacin for community-acquired pneumonia. Clin Infect Dis.
2005;41(suppl2):S136-S143.
8.
Engemann JJ, Carmeli Y, Cosgrove SE, et al. Adverse clinical and
economic outcomes attributable to methicillin resistance among
patients with Staphylococcus aureus surgical site infection.
Clin Infect Dis. 2003;36:592-598.
9.
Khawcharoenporn T, Tice A. HMJ. In press.
10. Parodi S, Rhew DC, Goetz MB. Early switch and early discharge
opportunities in intravenous vancomycin treatment of suspected
methicillin-resistant staphylococcal species infections. J Manag
Care Pharm. 2003;9:317-326.
te
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The bottom line in the evaluation of antimicrobial
agents should be the patient. However, economic issues
are a major consideration in antibiotic selection and use.
The factors involved are multiple, complex, interrelated,
and changing. The best approach is to conduct a comprehensive evaluation when a patient presents with a possible infection; if warranted, initiate aggressive intervention at the start and moderate it as clinical and
laboratory information accumulates. Given the increasing
incidence of MRSA, more clinical input, laboratory cultures, economic studies, clinical research, and clinician
teamwork are urgently needed.
8
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Section III:Toxin Inhibition
And Gram-Positive Infection:
A
Focus on Methicillin-Resistant
Staphylococcus aureus Expressing the
Panton-Valentine Leukocidin Gene
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Marin H. Kollef, MD
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Professor of Medicine
Washington University School of Medicine
Director, Medical Critical Care
Director, Respiratory Care Services
Barnes-Jewish Hospital
St. Louis, Missouri
Introduction
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Over the past 20 years, methicillin-resistant
Staphylococcus aureus (MRSA) has been isolated with
increased frequency in hospitalized patients as well as in the
community. MRSA infections have been associated with
greater morbidity, mortality, and hospital costs than their
methicillin-sensitive S. aureus (MSSA) counterparts.
Until recently, treatment options for serious infections
caused by MRSA have been limited to a few agents, most
notably vancomycin. However, with the introduction of
new antimicrobial agents, it has become possible to develop new treatment strategies for MRSA, including toxinproducing strains of MRSA that have been identified.
Cell Wall
Chromosome
SCCmec
Cell
Membrane
PVL
Wall teichoic acid
Surface protein adhesins
Octameric pore
IL- 8
LTB4
Ca2+ channel opening
Mitochondrial injury
Necrosis
Apoptosis
Neutrophil
te
Figure. CA-MRSA interacts with a neutrophil.
d.
Illustration of CA-MRSA interaction with a neutrophil resulting in cell death by either necrosis or apoptosis. Surface proteins and wall teichoic acid
expression facilitate bacterial adherence to cell surfaces. Release of PVL facilitates octameric pore formation within the membranes of neutrophils. Low
concentrations of PVL result in fewer octameric pores forming which allow further entry of PVL into the cytoplasm resulting in mitcochondial injury and
apoptosis. Greater concentrations of PVL lead to more octameric pores forming with Ca2+ channel opening and necrosis. Additionally, formation of the
octameric pores by PVL induces release of neutrophil chemotactic factors including IL-8 and leukotriene B4.
Ca2+, calcium; CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus; IL-8, Interleukin-8; LTB4, leukotriene B4;
PVL, Panton-Valentine leukocidin; SCC, staphylococcal chromosomal cassette
9
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THE SCIENCE BEHIND PATIENT OUTCOMES
Table. Comparison of HA-MRSA and CA-MRSA
CA-MRSA
Setting
Hospital, nursing home,
dialysis clinic
Community, entering
hospitals
Ethnic predominance
White
Non-white (African-American, Asian,
Hispanic)
Yes
(hospital, nursing home)
Yes (family, day care,
military barracks,
locker room, prison)
Diabetes, head trauma,
renal failure
None
None
Skin and soft tissue
Uncommon
Common in skin and lung
Uncommon
Common with pneumonia
Absent
Can occur
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HA-MRSA
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A
Characteristic
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Horizontal transmission
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Predisposing underlying illnesses
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Preceding influenza illness
Panton-Valentine leukocidin
Susceptible to non–
β-lactam antibiotics
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mecA gene
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Waterhouse-Friderichsen
syndrome
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Tissue necrosis
20
Predominant site of infection
Present
Present
Historically not found
Usually present
Usually not
Often yes
CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus; HA-MRSA, healthcare-associated methicillin-resistant
Staphylococcus aureus
Adapted from reference 5.
Epidemiology
S. aureus strains can express many potential virulence
factors, including surface proteins that promote colonization of host tissues, exotoxins and superantigens that cause
tissue damage and the symptoms of septic shock, and
invasins that promote bacterial spread in tissues
(eg, leukocidin, kinases, hyaluronidase).6
Panton-Valentine leukocidin (PVL) is a cytotoxin produced by fewer than 5% of S. aureus strains, and it has
been associated with primary skin infections and severe
necrotizing pneumonia. In a study in which investigators
screened 172 strains of S. aureus, PVL genes were detected in 93% of strains associated with furunculosis and in 85%
d.
10
Virulence
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Gram-positive cocci, in particular S. aureus, account for
20% to 30% of all cases of hospital-acquired pneumonia
(HAP).1 Nosocomial strains of MRSA are found worldwide,2
and data from the US National Nosocomial Infections
Surveillance System show that MRSA now accounts for
more than 55% of S. aureus–related infections in the intensive care setting.3
Traditionally, MRSA has been considered a healthcareassociated organism if it is isolated from a patient at least
72 hours after admission in a healthcare facility (acutecare hospital or long-term care facility) and communityacquired if isolated from a patient at the time of admission
or within 48 to 72 hours of hospital admission. However,
without the use of sophisticated laboratory techniques, it
is often difficult to know if the MRSA was actually acquired
in the community or from previous contact with the
healthcare system; therefore, some prefer to categorize
different types of MRSA as “healthcare-associated” (HAMRSA), “community-associated (CA-MRSA) with risk factors for healthcare acquisition,” or “community-associated without risk factors for healthcare acquisition.”4
In comparing CA-MRSA with HA-MRSA, Naimi et al
found that among MRSA infections, 12% were classified as
CA-MRSA; CA-MRSA patients were younger than HAMRSA patients (average age, 23 years vs 68 years;
P<0.001); more CA-MRSA patients than HA-MRSA patients
were non-white (32% vs 11%; P<0.001); and CA-MRSA
patients generally had a lower median income level than
HA-MRSA patients ($25,395 vs $28,290; P=0.02) (Table).5
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A
of strains associated with severe necrotic hemorrhagic
pneumonia, both of which were community-acquired. PVL
genes were not detected in strains associated with other
types of infections, such as HAP, toxic shock syndrome,
infective endocarditis, or mediastinitis.7,8
Conclusion
ll
The optimal management strategy for toxin-producing
strains of S. aureus is still unknown. Pending further clinical
investigations, clinicians should consider the use of antibiotics that can inhibit specific toxin production in patients
with serious infection.
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Toxin Production
py
PVL is a synergohymenotropic toxin assembled from 2
component proteins.9 PVL creates lytic pores in the cell
membranes of neutrophils and induces release of neutrophil chemotactic factors including interleukin-8 and
leukotriene B4 (Figure).10
In a study of 422 patients with acute, purulent skin and
soft tissue infections in 11 university-affiliated emergency
departments, S. aureus was isolated in 320 patients
(76%).11 Overall, the prevalence of MRSA was 59% on
average, with a high of 74% at one participating institution.
Staphylococcal chromosomal cassette mec (SCCmec) type
IV and the PVL toxin gene were detected in 98% of all
MRSA isolates.
Antibiotic susceptibility among all strains isolated varied
significantly. However, the study found that antibiotic therapy was not concordant with the results of susceptibility
testing in 57% patients with MRSA infection who received
antibiotics. As a result, the authors recommended that
when antimicrobial therapy is indicated for the treatment
of complicated skin and soft tissue infections, clinicians
should consider obtaining cultures and modifying empiric
therapy to provide MRSA coverage.
In addition, Katayama et al noted that MRSA strains produce a cell wall penicillin-binding protein with a low affinity for β-lactam antibiotics.12 The authors added that a
notable difference between MRSA and MSSA is that a higher percentage of MRSA strains possess toxins such as PVL.
Indeed, when selecting antimicrobial therapy, minimum
inhibitory concentrations (MICs) and coverage of the infection and the host are typically considered.11 Based on findings such as these, however, clinicians may also want to
consider the issue of toxin penetration during the selection
process.
In addition to antibiotic therapy, alternative treatments
may become available for toxin-producing strains of
S. aureus. Polyclonal immunoglobulin has been proposed
as a therapy for patients with serious CA-MRSA infections.13,14 Potential mechanisms of action include neutralization of circulating cytokines and downregulation of
their expression.
References
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Lynch JP. Hospital-acquired pneumonia: risk factors, microbiology,
and treatment. Chest. 2001;119:373S-384S.
2.
Diekema DJ, Pfaller MA, Schmitz FJ, et al. Survey of infections due
to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States,
Canada, Latin America, Europe, and the Western Pacific region for
the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin
Infect Dis. 2001;32:S114-S132.
3.
National Nosocomial Infections Surveillance (NNIS) System Report,
data summary from January 1992 through June 2003, issued
August 2003. Am J Infect Control. 2003;31:481-498.
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1.
4.
Salgado CD, Farr BM, Calfee DP. Community-acquired methicillinresistant Staphylococcus aureus: a meta-analysis of prevalence
and risk factors. Clin Infect Dis. 2003;36:131-139.
5.
Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and healthcare-associated methicillin-resistant
Staphylococcus aureus infection. JAMA. 2003;290:2976-2984.
6.
Baba T, Takeuchi F, Kuroda M, et al. Genome and virulence determinants of high virulence community-acquired MRSA. Lancet.
2002;359:1819-1827.
7.
Foster TJ. The Staphylococcus aureus “superbug.” J Clin Invest.
2004;114:1693-1696.
8.
Lina G, Piemont Y, Godail-Gamot F, et al. Involvement of PantonValentine leukocidin-producing Staphylococcus aureus in primary
skin infections and pneumonia. Clin Infect Dis. 1999;29:1128-1132.
9.
Boussaud V, Parrot A, Mayaud C, et al. Life-threatening hemoptysis
in adults with community-acquired pneumonia due to PantonValentine leukocidin-secreting Staphylococcus aureus. Intensive
Care Med. 2003;29:1840-1843.
10. Konig B, Prevost G, Piemon Y, Konig W. Effects of Staphylococcus
aureus leukocidins on inflammatory mediator release from human
granulocytes. J Infect Dis. 1995;171:607-613.
11. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant
S. aureus infections among patients in the emergency department.
N Engl J Med. 2006;355:666-674.
12. Katayama Y, Zhang HZ, Chambers HF. PBP 2a mutations producing
very-high-level resistance to beta-lactams. Antimicrob Agents
Chemother. 2004;48:453-459.
te
13. Genestier A-L, Michallet M-C, Prevost G, et al. Staphylococcus
aureus Panton-Valentine leukocidin directly targets mitochondria
and induces Bax-independent apoptosis of human neutrophils.
J Clin Invest. 2005;115:3117-3127.
d.
14. Hampson FG, Hancock SW, Primhak RA. Disseminated sepsis due
to a Panton-Valentine leukocidin producing strain of community
acquired methicillin resistant Staphylococcus aureus and use of
intravenous immunoglobulin therapy. Arch Dis Child. 2006;91:201.
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Methicillin-Resistant
Staphylococcus aureus
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