SURGICAL INFECTION

Although treatment of infection has been an integral part of the surgeons practice since the dawn of time, the body and 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 the clinical practice, concurrent with the development of anesthesia, was pivotal in allowing surgeons to expand their repertoire to encompass complex procedures that previously were associated with extremely high rates of morbidity and mortality due to postoperative infections. However, until recently, the occurrence of infection related to the surgical wound was the rule rather than the exception. In fact, development of modalities to effectively prevent and treat infection has occurred only within the last several decades. A number of observations by nineteenth-century physicians and investigators were critical to our current understanding of the pathogenesis, prevention, and treatment of surgical infections. In 1846, Ignaz Semmelweis, a Magyar physician, took a post at the Allgemein Krankenhaus in Vienna. He noticed that the mortality from puerperal (childbed) fever was much higher in the teaching ward (1:11) than in the ward where patients were delivered by midwives (1:29). He also made the interesting observation those women who delivered before arrival on the teaching ward had a negligible mortality rate. The tragic death of a colleague due to overwhelming infection after a knife scratch received during an autopsy of a woman who had died of puerperal fever led Semmelweis to observe that pathologic changes in his friend were identical to those of women dying from this postpartum disease. He then hypothesized that puerperal fever was caused by putrid material transmitted from patients dying of this disease by carriage on the examining fingers of the medical students and physicians who frequently went from the autopsy rooms to wards. The low mortality noted in the midwives ward, Semmelweis realized, was due to the fact that midwives did not participate in autopsies. Fired with the zeal of his revelation, he posted a notice on the door to the ward requiring all caregivers to rinse their hands thoroughly in chlorine water before entering the area. This simple intervention reduced mortality from puerperal fever to 1.5%, surpassing the record of the midwives. In 1861, he published his classic work on childbed fever based on records from his practice. Unfortunately, Semmelweis ideas were not well accepted by the authorities of the time. Despondent, he committed suicide in 1865 by intentionally cutting his fingers during the autopsy of a woman who died of puerperal fever, presumably as the ultimate proof of his tenets. Louis Pasteur performed a body of work during the latter part of the nineteenth century that provided the underpinnings of modern microbiology, at the time known as germ theory. His work in humans followed experiments identifying infectious agents in silkworms. He was able to elucidate the principle that contagious diseases are caused by specific microbes and that these microbes are foreign to the infected organism. Using this principle, he developed techniques of sterilization critical to oenology and identified several bacteria responsible for human illnesses, including Staphylococcus, Streptococcus, and pneumococcus. Joseph Lister, the son of a wine merchant, was appointed professor of surgery at the Glasgow Royal Infirmary in 1850. In his early practice, he noted that more than 50% of his patients undergoing amputation died due to postoperative infection. After hearing Pasteurs theory, Lister experimented with the use of solution of carbolic acid, which he knew was being used to treat sewage. He first reported his findings to the British Medical Association in 1867 using dressings saturated with carbolic acid on 12 patients with compound fractures; 10 recovered without amputation, one

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survived with amputation, and one died of causes unrelated to the wound. In spite of the initial resistance, his methods were quickly adopted throughout Europe. From 1878 until 1880, Robert Koch was the District Medical Officer for Wollstein (then Prussia, now a part of Poland), which was an area in which anthrax was endemic. Performing experiments in his home, without the benefit of scientific equipment and academic contact, Koch developed techniques for culture of Bacillus anthracis and proved the ability of this organism to cause anthrax in healthy animals. He developed the following four postulates to identify the association of organisms with specific diseases: (a) the suspected pathogenic organism should be present in all cases of the disease and absent from healthy animals, (b) the suspected pathogen should be isolated from a diseased host and grown in a pure culture in vitro, (c) cells from a pure culture of the suspected organism should cause disease in a healthy animal, and (d) the organism should be reisolated from the newly diseased animal and shown to be the same as the original. He used these same techniques to identify the organisms responsible for cholera and tuberculosis. During the next century, Kochs postulates, as they came to be called, became critical to our understanding of surgical infections and remain so today. The first intra-abdominal operation to treat infection via source control (i.e., surgical interventions to eliminate the source of infection) was appendectomy. This operation was pioneered by Charles McBurney at the New York College of Physicians and Surgeons, among others. McBurneys classic report on early operative intervention for appendicitis was presented before the New York Surgical Society in 1889. Appendectomy for the treatment of appendicitis, previously an often fatal disease, was popularized after the 1902 coronation of King Edward VII of England was delayed due to his need for an appendectomy, which was performed by Sir Frederick Treves. The king desperately needed an appendectomy but strongly opposed going into the hospital, protesting, I have coronation on hand. However, Treves was adamant, stating, I will be a funeral, if you dont have the operation. Treves carried the debate, and the king lived. During the twentieth century, the discovery of effective antimicrobials added another tool to the armamentarium of modern surgeons. Sir Alexander Fleming, after serving in the British Army Medical Corps during World War 1, continued to work on the natural antibacterial action of the blood and antiseptics. In 1928, while studying the influenza virus, he noted a zone of inhibition around a mold colony (Penicillium notatum) that serendipitously grew 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, GI tract, and other parts of the body that the surgeon encountered in the process of an operation were characterized in great detail. However, it remained unclear whether these organisms, anaerobes in particular, were commensals or pathogens. Subsequently, the initial clinical observations of surgeons such as Frank Meleney, William Altemeler, and others provided the key, when they observed that aerobes and anaerobes could synergize to cause serious soft tissue and severe intra-abdominal infection. Thus, the concepts those resident Access www.medicalvillage.blogspot.com for more specialty notes.

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microbes were non-pathogenic until they entered a sterile body cavity at the time of surgery, and that many, if not most, surgical infections were polymicrobial in nature, became critical ideas and were promulgated by a number of clinician-scientist over the last several decades. These tenets became firmly established after microbiology laboratories demonstrated the invariable presence of aerobes and anaerobes in peritoneal culture obtained at the time of surgery for intra-abdominal infection due to a perforated viscous or gangrenous appendicitis. Clinical trials provided evidence that optimal therapy for these infections required effective source control, plus the administration of antimicrobial agents directed against both types of pathogens. William Osler, a prolific writer and one of the fathers of American medicine, made an observation in 1904 in his treatise The Evolution of Modern Medicine that was to have profound implications for the future of treatment of infection: Except on few occasions, the patient appears to die from the bodys response to infection rather from it. 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, which seems to cause much of the end-organ dysfunction and failure. 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. These defenses are integrated and redundant so that the various components function as a complex, highly regulated system that is extremely effective in coping with microbial invaders. They include site-specific defense that function at the tissue level, as well as components that freely circulate throughout the body in both blood and lymph. Systemic host defenses invariably are recruited to a site of infection, a process that begins immediately upon introduction of microbes into a sterile area of the body. Perturbation of one or more component 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 are held in check by chemicals that sebaceous glands secrete and by the constant shedding of epithelial cells. The endogenous Access www.medicalvillage.blogspot.com for more specialty notes.

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microflora of the integument primarily comprises gram-positive aerobic microbes belonging to the genera Staphylococcus and Streptococcus, as well as Corynebacterium and Propionibacterium species. These organisms, plus Enterococcus faecalis and faecium, Escherichia coli, and other Enterobacteriaceae, and yeast such as Candida albicans, can be isolated from the infraumbilical regions of the body. Diseases of the skin (e.g., eczema and dermatitis) are associated with overgrowth of skin commensal organisms, and barriers 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, the respiratory mucus traps larger particles, including microbes. This mucus is then passed into the upper airways and oropharynx by ciliated epithelial cells, where the mucus is cleared via coughing. 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 tract do not possess resident microflora in healthy individuals. Although microbes may be present if these barriers are affected by disease (e.g., malignancy, inflammation, calculi, or foreign body), or if microorganisms are introduced from an external source (e.g., urinary catheter or pulmonary aspiration). In contrast, significant numbers of microbes are encountered in many portions of the GI tract, with vast numbers being found within the oropharynx and distal colorectum, although the specific organisms differ. One would suppose that the entire GI tract would be populated via those microbes found in the oropharynx, but this is not the case. This is because after ingestion, these organisms routinely are killed in the highly acidic, low motility environment of the stomach during the initial phase of digestion. Thus, small numbers of microbes populate the gastric mucosa [approximately 10 to 10 colony-forming units (CFU)/mL]; this population expands in the presence of drugs and disease states that diminish gastric activity. 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 10 to 10 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 10 to 10 CFU/g are present in feces. Large numbers of facultative and strict anaerobes (Bacteroides fragilis, diastasonis, and thetalotaomicron, Bifidobacterium, Clostridium, Eubacterium, Fusobacterium, Lactobacillus, and Peptostreptococcus species) as well as several orders of magnitude fewer aerobic microbes (E. coli and other Enterobacteriaceae, E. faecalis and faecium, C. albicans and other Candida spp.) are present. Intriguingly, although colonization resistance on the part of this extensive, well-characterized host microflora effectively prevents invasion of enteric pathogens such as Salmonella, Shigella, Vibrio, and other enteropathogenic bacterial species, these same organisms provide the initial inoculum for the infection should perforation of the GI tract occur. It is great interest that only some of these microbial species predominate in established intra-abdominal infection.

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SURGICAL INFECTION

Once microbes enter a sterile body compartment (e.g., pleural or peritoneal cavity) or tissue, additional host defenses act to limit and/or eliminate these pathogens. Initially, several primitive and relatively nonspecific host defenses act to contain the nidus of infection, which may include microbes as well as debris, devitalized tissue, and foreign bodies, depending on the nature of the injury. These defenses include the physical barrier of the tissue itself, as well as the capacity of proteins such as lactoferrin and transferrin to sequester the critical microbial growth factor iron, thereby limiting microbial growth. In addition, fibrogen within the peritoneal cavity, unique host defenses exist, including a diaphragmatic pumping mechanism whereby particles such as microbes 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. However, the latter processes and fibrin trapping have a high likelihood of contributing to the formation of an intraabdominal abscess. Microbes also immediately encounter a series of host defense mechanisms that reside within the vast majority of tissues of the body. These include resident macrophages and low levels of complement (C) proteins and immunoglobulins (Ig, antibodies). Resident macrophages secrete a wide array of substances in response to the above-mentioned processes, some of which appear to regulate the cellular components of the host defense response. Macrophages cytokine synthesis is upregulated. Secretion of tumor necrosis factor alpha (TNF-), of interleukins (IL)-1, 6, and 8; and interferon-gamma (INF-) occurs 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 defense leads to microbial opsonisation (C1q, C3bI, and IgFc), phagocytosis, and both extracellular (CSb6-9 membrane attack complex) and intracellular microbial destruction (phagocytic vacuoles). Concurrently, the classic and alternate complex pathways are activated both via direct contact with and via IgM > IgG blinding to microbes, 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 substance to which polymorphonuclear leukocytes (PMNs) in the bloodstream are attracted takes place. These consist of C5a, microbial cell wall peptides containing N-formyl-methionine, and macrophage secretion of cytokines such as IL-8. This process of host defense recruitment leads to further influx of inflammatory fluid into the area of incipient infection, and is accompanied by diapedesis of large numbers of PMNs, a process that begins within several minutes and may peak within hours or days. The magnitude of response and eventual outcome generally are related to several factors: (a) the initial number of microbes, (b) the rate of microbial proliferation in relation to containment and killing by host defenses, (c) microbial virulence, and (d) the potency of host defenses. In regard to the latter, drugs or diseases states that diminish any multiple components of host defenses are associated with higher rates and potentially more grave infections.

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