SURGICAL INFECTION

Although treatment of infection has been an integral part of the surgeons

practice since the dawn of time, the body of knowledge that led to the present
field of surgical infectious disease was derived from the evolution of germ
theory and antisepsis. Application of the latter to clinical practice, concurrent
with the development of anesthesia, was pivotal in allowing surgeons to perform
complex procedures that were previously associated with high rates of
morbidity and mortality because of postoperative infections. Until recently the
occurrence of infection related to the surgical wound was the rule rather than
the exception. The development of modalities to effectively prevent and treat
infection has occurred only within the last several decades.
The first intraabdominal operation to treat infection via source control
(i.e., surgical intervention to eliminate the source of infection) was
appendectomy. McBurneys classic report on early operative intervention for
appendicitis was presented before the New York Surgical Society in 1889. Sir
Alexander
Fleming in 1928 noted a zone of inhibition around a mold colony (Penicillium
notatum) that serendipitously grew on a plate of Staphylococcus, and he named
the active substance penicillin. This first effective antibacterial agent
subsequently led to the development of hundreds of potent antimicrobials, set
the
stage for their use as prophylaxis against postoperative infection, and became
a critical component of the armamentarium to treat aggressive, lethal surgical
infections.
Concurrent with the development of numerous antimicrobial agents were
advances in the field of clinical microbiology. Many new microbes were identified,
including numerous anaerobes; the autochthonous microflora of the skin,
gastrointestinal tract, and other parts of the body that the surgeon encountered
in the process of an operation were characterized in great detail. Subsequently,

the initial clinical observations of surgeons such as Frank Meleney, William

Altemeier, and others provided the observation that aerobes and anaerobes
could
synergize to cause serious soft tissue and severe intraabdominal infection.
The discovery of the first cytokines began to allow insight into the organisms
response to infection, and led to an explosion in our understanding of the
host inflammatory response. Expanding knowledge of the multiple pathways
activated during the response to invasion by infectious organisms has permitted
the design of new therapies targeted at modifying the inflammatory response
to infection. Preventing and treating this process of multiple-organ failure
during infection is one of the major challenges of modern critical care and
surgical infectious disease.
PATHOGENESIS OF INFECTION
Host Defenses
The mammalian host possesses several layers of endogenous defense
mechanisms that serve to prevent microbial invasion, limit proliferation of
microbes
within the host, and contain or eradicate invading microbes. They include
sitespecific defenses that function at the tissue level, and components that freely
circulate throughout the body in both blood and lymph. Systemic host defenses
are recruited to a site of infection, a process that begins immediately on
introduction of microbes into a sterile area of the body. Perturbation of one or
more components of these defenses (e.g., via immunosuppressants, chronic
illness, and burns) may have substantial negative impact on resistance to
infection.
Entry of microbes into the mammalian host is precluded by the presence
of a number of barriers that possess either an epithelial (integument) or mucosal
(respiratory, gut, and urogenital) surface. However, barrier function is not
solely limited to physical characteristics: host barrier cells may secrete
substances that limit microbial proliferation or prevent invasion. Also, resident or
commensal microbes (endogenous or autochthonous host microflora) adherent
to the physical surface and to each other may preclude invasion, particularly

of virulent organisms (colonization resistance).

The most extensive physical barrier is the integument or skin. In addition
to the physical barrier posed by the epithelial surface, the skin harbors its own
resident microflora that may block the attachment and invasion of
noncommensal microbes. Microbes also are held in check by chemicals that
sebaceous
glands secrete and by the constant shedding of epithelial cells. Diseases of the
skin (e.g., eczema and dermatitis) are associated with overgrowth of skin
commensal organisms, and barrier breaches invariably lead to the introduction of
these microbes.
The respiratory tract possesses several host defense mechanisms that facilitate
the maintenance of sterility in the distal bronchi and alveoli under normal
circumstances. In the upper respiratory tract, respiratory mucus traps larger
particles including microbes. Smaller particles arriving in the lower respiratory
tract are cleared via phagocytosis by pulmonary alveolar macrophages.
Any process that diminishes these host defenses can lead to development of
bronchitis or pneumonia.
The urogenital, biliary, pancreatic ductal, and distal respiratory tracts do not
possess resident microflora in healthy individuals, although microbes may be
present if these barriers are affected by disease or if microorganisms are
introduced from an external source. In contrast, significant numbers of microbes
are
encountered in many portions of the gastrointestinal tract, with vast numbers
being found within the oropharynx and distal colorectum, although the specific
organisms differ. Organisms ingested into the stomach from the oropharynx are
routinely killed in the highly acidic, low-motility environment of the
stomach during the initial phases of digestion. Thus, small numbers of microbes
populate the gastric mucosa (approximately 102103 colony-forming
units [CFU]/mL); this population expands in the presence of drugs or disease
states that diminish gastric acidity. Microbes that are not destroyed within the
stomach enter the small intestine, in which a certain amount of microbial
proliferation takes place, such that approximately 105108 CFU/mL are present
in the terminal ileum.

The relatively low-oxygen, static environment of the colon is accompanied

by the exponential growth of microbes that comprise the most extensive host
endogenous microflora. Anaerobic microbes outnumber aerobic species
approximately 100:1 in the distal colorectum, and approximately 10111012
CFU/g are present in feces. Large numbers of facultative and strict anaerobes
(Bacteroides fragilisand other species) and several orders of magnitude fewer
aerobic microbes (Escherichia coliand other Enterobacteriaceae
species,Enterococcus faecalis and E. faecium, Candida albicansand other
Candida
species) are present Once microbes enter a sterile body compartment (e.g.,
pleural or peritoneal cavity) or tissue, host defenses act to limit and/or eliminate
pathogens.
Initially, several primitive and relatively nonspecific host defenses act to contain
the nidus of infection. Within the peritoneal cavity, unique host defenses
exist, including a diaphragmatic pumping mechanism whereby small particles
within peritoneal fluid are expunged from the abdominal cavity via specialized
structures on the undersurface of the diaphragm. Concurrently, containment by
the omentum, the so-called gatekeeper of the abdomen and intestinal ileus,
serves to wall off infection, albeit with the likely result of abscess formation.
Microbes also immediately encounter host defense mechanisms that reside
within the tissues of the body. These include resident macrophages and
complement (C) proteins and immunoglobulins (Ig, antibodies). Resident
macrophages secrete a wide array of substances in response to the
abovementioned processes, which appear to regulate the cellular components of
the
host defense response. Macrophage cytokine synthesis is upregulated and
includes secretion of tumor necrosis factor-alpha (TNF-), interleukins (IL)-1,
6, and 8; and interferon-(INF-) within the tissue milieu, and, depending on
the magnitude of the host defense response, the systemic circulation.
Concurrently, a counterregulatory response is initiated consisting of binding
proteins
(TNF-BP), cytokine receptor antagonists (IL-1ra), and antiinflammatory cytokines
(IL-4 and IL-10).
The interaction of microbes with these first-line host defenses leads to

microbial opsonization (C1q, C3bi, and IgFc), phagocytosis, and extracellular

(C5b6-9 membrane attack complex) and intracellular microbial destruction
(phagocytic vacuoles). The classical and alternate complement pathways
are activated both via direct contact with and via IgM and IgG binding to
microbes (IgM>IgG), leading to the release of a number of different complement
protein fragments (C3a, C4a, C5a) that are biologically active, acting to
markedly enhance vascular permeability. Bacterial cell wall components and
a variety of enzymes that are expelled from leukocyte phagocytic vacuoles
during microbial phagocytosis and killing act in this capacity as well.
Simultaneously, the release of substances chemotactic to polymorphonuclear
leukocytes (PMNs) in the bloodstream takes place. These consist of C5a,
microbial cell wall peptides containing N-formyl-methionine, and macrophage
cytokines such as IL-8. This process of host defense recruitment leads to further
influx of inflammatory fluid and PMNs into the area of incipient infection,
a process that begins within several minutes and may peak within hours or
days. The magnitude of the response is related to several factors: (1) the initial
number of microbes, (2) the rate of microbial proliferation in relation to
containment and killing by host defenses, (3) microbial virulence, and (4) the
potency of host defenses. In regard to the latter, drugs or disease states that
diminish any or multiple components of host defenses are associated with higher
rates and potentially more grave infections.
Definitions
Several possible outcomes can occur subsequent to microbial invasion and the
interaction of microbes with resident and recruited host defenses: (1)
eradication; (2) containment, often leading to the presence of purulencethe
hallmark of chronic infection (e.g., a furuncle in the skin and soft tissue or
abscess
within the parenchyma of an organ or potential space); (3) locoregional infection
(cellulitis, lymphangitis, and aggressive soft tissue infection) with or without
distant spread of infection (metastatic abscess); or (4) systemic infection
(bacteremia or fungemia). The latter represents the failure of resident
and recruited host defenses at the local level, and is associated with significant
morbidity and mortality in the clinical setting. Additionally, it is not uncommon
that disease progression occurs such that serious locoregional infection

is associated with concurrent systemic infection. A chronic abscess also may

intermittently drain and/or be associated with bacteremia.
Infection is defined by identification of microorganisms in host tissue or the
blood stream, plus an inflammatory response to their presence. At the site of
infection the classic findings of rubor, calor, and dolor in areas such as the skin
or subcutaneous tissue are common. Most infections in normal individuals
with intact host defenses are associated with these local manifestations, plus
systemic manifestations such as elevated temperature, elevated white blood
cell (WBC) count, tachycardia, or tachypnea. The systemic manifestations
noted above comprise the systemic inflammatory response syndrome (SIRS).
SIRS can be caused by a variety of disease processes, including pancreatitis,
polytrauma, malignancy, and transfusion reaction, and infection. SIRS caused
by infection is termed sepsis, and is mediated by the production of a cascade
of proinflammatory mediators produced in response to exposure to microbial
products. These products include lipopolysaccharide (endotoxin, LPS) derived
from gram-negative organisms and many others. Patients have developed sepsis
if they have met clinical criteria for SIRS and have evidence of a local or
systemic source of infection. Severe sepsis is characterized as sepsis (defined
above) combined with the presence of new-onset organ failure. Severe sepsis is
the most common cause of death in noncoronary critical care units, with more
than 200,000 deaths occurring annually in the United States. With respect to
clinical criteria, a patient with sepsis and the need for ventilatory support, with
oliguria unresponsive to aggressive fluid resuscitation, or with hypotension
requiring vasopressors should be considered to have developed severe sepsis.
Septic shock is a state of acute circulatory failure identified by the presence of
persistent arterial hypotension (systolic blood pressure<90 mmHg) despite
adequate fluid resuscitation, without other identifiable causes. Septic shock
is the most severe manifestation of infection, occurring in approximately 40

percent of patients with severe sepsis; it has an attendant mortality rate of

6080 percent.