Chapter 6: Surgical Infections

1. Sepsis is both the presence of infection and the host response to infection (systemic inflammatory response syndrome, SIRS). Sepsis is a clinical spectrum, ranging from sepsis (SIRS plus infection) to severe sepsis (organ dysfunction), to septic shock (hypotension requiring vasopressors). Outcomes in patients with sepsis are improved with an organized approach to therapy that includes rapid resuscitation, antibiotics, and source control.

2. Source control is a key concept in the treatment of most surgically relevant infections. Infected or necrotic material must be drained or removed as part of the treatment plan in this setting. Delays in adequate source control are associated with worsened outcomes.

3. Principles relevant to appropriate antibiotic prophylaxis for surgery: (a) select an agent with activity against organisms commonly found at the site of surgery, (b) the initial dose of the antibiotic should be given within 30 minutes prior to the creation of the incision, (c) the antibiotic should be redosed during long operations based upon the half-life of the agent to ensure adequate tissue levels, and (d) the antibiotic regimen should not be continued for more than 24 hours after surgery for routine prophylaxis.

4. When using antimicrobial agents for therapy of serious infection, several principles should be followed: (a) identify likely sources of infection, (b) select an agent (or agents) that will have efficacy against likely organisms for these sources, (c) inadequate or delayed antibiotic therapy results in increased mortality, so it is important to begin therapy rapidly with broader coverage, (d) when possible, obtain cultures early and use results to refine therapy, (e) if no infection is identified after 3 days, strongly consider discontinuation of antibiotics, based upon the patient’s clinical course, (f) discontinue antibiotics after an appropriate course of therapy.

5. The incidence of surgical site infections can be reduced by appropriate patient preparation, timely perioperative antibiotic administration, maintenance of perioperative normothermia and normoglycemia, and appropriate wound management.

6. The keys to good outcomes in patients with necrotizing soft tissue infection are early recognition and appropriate debridement of infected tissue with repeated debridement until no further signs of infection are present.

7. Transmission of HIV and other infections spread by blood and body fluid from patient to health care worker can be minimized by observation of universal precautions, which include routine use of barriers when anticipating contact with blood or body fluids, washing of hands and other skin surfaces immediately after contact with blood or body fluids, and careful handling and disposal of sharp instruments during and after use.

Although treatment of infection has been an integral part of the surgeon’s 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 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, the 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 that women who delivered prior to 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 room to the wards. The low mortality noted in the midwives’ ward, Semmelweis realized, was because 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 prior to 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.¹ Increasingly frustrated by the indifference of the medical profession, he began writing open letters to well-known obstetricians in Europe, and was committed to an asylum due to concerns that he was losing his mind. He died shortly thereafter. His achievements were only recognized after Pasteur’s description of the germ theory of disease.

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 and Streptococcus pneumoniae (pneumococcus).

Joseph Lister, the son of a wine merchant, was appointed professor of surgery at the Glasgow Royal Infirmary in 1859. In his early practice, he noted that over 50% of his patients undergoing amputation died because of postoperative infection. After hearing of Pasteur’s theory, Lister experimented with the use of a 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 survived with amputation, and one died of causes unrelated to the wound. In spite of initial resistance, his methods were quickly adopted throughout Europe.

From 1878 until 1880, Robert Koch was the District Medical Officer for Wollstein, 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, Koch’s postulates, as they came to be called, became critical to our understanding of surgical infections and remain so today.²

The first intra-abdominal operation to treat infection via “source control” (i.e., surgical intervention 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.³ McBurney’s 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 a coronation on hand.” However, Treves was adamant, stating, “It will be a funeral, if you don’t 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 I, continued work on the natural antibacterial action of the blood and antiseptics. In 1928, while studying influenza virus, he 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. 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 Altemeier, and others provided the key, when they observed that aerobes and anaerobes could synergize to cause serious soft tissue and severe intra-abdominal infection.^4,5 Thus, the concepts that resident microbes were nonpathogenic 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-scientists over the last several decades.^6,7 These tenets became firmly established after microbiology laboratories demonstrated the invariable presence of aerobes and anaerobes in peritoneal cultures obtained at the time of surgery for intra-abdominal infection due to a perforated viscus or gangrenous appendicitis. Clinical trials provided ample 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 body’s response to infection rather than from it.”⁸ The discovery of the first cytokines began to allow insight into the human organism’s 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 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.

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 defenses 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 components of these defenses (e.g., via immunosuppressants, foreign body, 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. Barrier function, however, 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).⁹

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 also held in check by chemicals that sebaceous glands secrete and by the constant shedding of epithelial cells. The endogenous 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 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. 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 tracts 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 gastrointestinal tract, with vast numbers being found within the oropharynx and distal colon or rectum, although the specific organisms differ.

One would suppose that the entire gastrointestinal tract would be populated via those microbes found in the oropharynx, but this is not the case.⁹ This is because after ingestion these organisms routinely are 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 ~10² to 10³ 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 10⁵ to 10⁸ 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 colon, and approximately 10¹¹ to 10¹² CFU/g are present in feces. Large numbers of facultative and strict anaerobes (Bacteroides fragilis,distasonis, and thetaiotaomicron, Bifidobacterium, Clostridium, Eubacterium, Fusobacterium, Lactobacillus, and Peptostreptococcus species) as well as several orders of magnitude fewer aerobic microbes (Escherichia coli and other Enterobacteriaceae, Enterococcus faecalis and faecium, Candida 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 infection should perforation of the gastrointestinal tract occur. It is of great interest that only some of these microbial species predominate in established intra-abdominal infections.

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, fibrinogen within the inflammatory fluid has the ability to trap large numbers of microbes during the process in which it polymerizes into fibrin. Within the peritoneal cavity, unique host defenses exist, including a diaphragmatic pumping mechanism whereby particles, including microbes within peritoneal fluid are expunged from the abdominal cavity via specialized structures (stomata) on the undersurface of the diaphragm that lead to thoracic lymphatic channels. Concurrently, containment by the omentum, the so-called “gatekeeper” of the abdomen and intestinal ileus, serves to wall off infections. However, the latter processes and fibrin trapping have a high likelihood of contributing to the formation of an intra-abdominal 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 (e.g., antibodies).¹⁰ The response in macrophages is initiated by genome-encoded pattern recognition receptors which respond to invading microbes. With exposure to a foreign organism, these receptors recognize microbial pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are one well-defined example of a PAMP that plays an important role in pathogen signaling.¹¹ 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. This results in recruitment and proliferation of inflammatory cells. Macrophage cytokine synthesis is upregulated. Secretion of tumor necrosis factor-alpha (TNF-α), of interleukins (IL)-1β, 6, and 8; and of gamma interferon (IFN-γ) occurs within the tissue milieu, and, depending on the magnitude of the host defense response, the systemic circulation.¹² Concurrently, a counterregulatory response is initiated consisting of binding protein (TNF-BP), cytokine receptor antagonists (e.g., IL-1ra), and anti-inflammatory 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 both extracellular (C5b6-9 membrane attack complex) and intracellular microbial destruction (via cellular ingestion into phagocytic vacuoles). Concurrently, the classical and alternate complement pathways are activated both via direct contact with and via IgM>IgG binding 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 substances 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 the 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 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: (a) eradication, (b) containment, often leading to the presence of purulence—the hallmark of chronic infections (e.g., a furuncle in the skin and soft tissue or abscess within the parenchyma of an organ or potential space), (c) locoregional infection (cellulitis, lymphangitis, and aggressive soft tissue infection) with or without distant spread of infection (metastatic abscess), or (d) systemic infection (bacteremia or fungemia). Obviously, 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. In addition, 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 the presence of microorganisms in host tissue or the bloodstream. 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 previously comprise the systemic inflammatory response syndrome (SIRS). A documented or suspected infection with some of the findings of SIRS define sepsis.¹³

SIRS can be caused by a variety of disease processes, including pancreatitis, polytrauma, malignancy, transfusion reaction, as well as infection (Fig. 6-1). There are a variety of systemic manifestations of infection, with the classic factors of fever, tachycardia, and tachypnea, broadened to include a variety of other variables (Table 6-1).¹³ Sepsis (SIRS caused by infection) 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; peptidoglycans and teichoic acids from gram-positive organisms; many different microbial cell wall components, such as mannan from yeast and fungi; and many others.

Severe sepsis is characterized as sepsis (defined previously) combined with the presence of new-onset organ failure. Severe sepsis is the most common cause of death in noncoronary critical care units and the 11^th most common cause of death overall in the United States, with a mortality rate of 10.3 cases/100,000 population in 2010.¹⁴ A number of organ dysfunction scoring systems have been described.^15,16,17 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 mm Hg) despite adequate fluid resuscitation, without other identifiable causes. Septic shock is the most severe manifestation of infection, occurring in approximately 40% of patients with severe sepsis; it has an attendant mortality rate of 30% to 66%.^18,19

While classification of severity of shock has been successful in driving efforts to improve patient outcomes, staging of sepsis by other patient characteristics remains in its infancy. The impetus for development of such a scheme is related to the heterogeneity of the patient population developing sepsis, an example of which would include two patients, both in the intensive care unit (ICU), who develop criteria consistent with septic shock. While both have infection and sepsis-associated hypotension, one might expect a different outcome in a young, healthy patient who develops urosepsis than in an elderly, immunosuppressed lung transplant recipient who develops invasive fungal infection. One schema for providing such a classification is the predisposition, infection, response and organ failure (PIRO) classification.²⁰ This scheme has borrowed from the tumor-node-metastasis staging scheme developed for oncology. The PIRO staging system stratifies patients based on their predisposing conditions (P), the nature and extent of the infection (I), the nature and magnitude of the host response (R), and the degree of concomitant organ dysfunction (O). Clinical trials using this classification system have confirmed the validity of this concept.^21,22

A partial list of common pathogens that cause infections in surgical patients is provided in Table 6-2.

Bacteria

Bacteria are responsible for the majority of surgical infections. Specific species are identified using Gram’s stain and growth characteristics on specific media. The Gram’s stain is an important evaluation that allows rapid classification of bacteria by color. This color is related to the staining characteristics of the bacterial cell wall: gram-positive bacteria stain blue and Gram-negative bacteria stain red. Bacteria are classified based upon a number of additional characteristics, including morphology (cocci and bacilli), the pattern of division (e.g., single organisms, groups of organisms in pairs [diplococci], clusters [staphylococci], and chains [streptococci]), and the presence and location of spores.

Gram-positive bacteria that frequently cause infections in surgical patients include aerobic skin commensals (Staphylococcus aureus and epidermidis and Streptococcus pyogenes) and enteric organisms such as Enterococcus faecalis and faecium. Aerobic skin commensals cause a large percentage of surgical site infections (SSIs), either alone or in conjunction with other pathogens; enterococci can cause nosocomial infections (urinary tract infections [UTIs] and bacteremia) in immunocompromised or chronically ill patients, but are of relatively low virulence in healthy individuals.

There are many pathogenic Gram-negative bacterial species that are capable of causing infection in surgical patients. Most Gram-negative organisms of interest to the surgeon are bacilli belonging to the family Enterobacteriaceae, including Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Enterobacter, Citrobacter, and Acinetobacter spp. Other Gram-negative bacilli of note include Pseudomonas spp., including Pseudomonas aeruginosa and fluorescens and Xanthomonas spp.

Anaerobic organisms are unable to grow or divide poorly in air, as most do not possess the enzyme catalase, which allows for metabolism of reactive oxygen species. Anaerobes are the predominant indigenous flora in many areas of the human body, with the particular species being dependent on the site. For example, Propionibacterium acnes and other species are a major component of the skin microflora and cause the infectious manifestation of acne. As noted previously, large numbers of anaerobes contribute to the microflora of the oropharynx and colon.

Infection due to Mycobacterium tuberculosis was once one of the most common causes of death in Europe, causing one in four deaths in the seventeenth and eighteenth centuries. In the nineteenth and twentieth centuries, thoracic surgical intervention was often required for severe pulmonary disease, now an increasingly uncommon occurrence in developed countries. This organism and other related organisms (M avium-intracellulare and M leprae) are known as acid-fast bacilli. Other acid-fast bacilli include Nocardia spp. These organisms typically are slow-growing, sometimes necessitating observation in culture for weeks to months prior to final identification, although deoxyribonucleic acid (DNA)-based analysis is increasingly available to provide a means for preliminary, rapid detection.

Fungi

Fungi typically are identified by use of special stains (e.g., potassium hydroxide (KOH), India ink, methenamine silver, or Giemsa). Initial identification is assisted by observation of the form of branching and septation in stained specimens or in culture. Final identification is based on growth characteristics in special media, similar to bacteria, as well as on the capacity for growth at a different temperature (25°C vs. 37°C). Fungi of relevance to surgeons include those that cause nosocomial infections in surgical patients as part of polymicrobial infections or fungemia (e.g., Candida albicans and related species), rare causes of aggressive soft tissue infections (e.g., Mucor, Rhizopus, and Absidia spp.), and so-called opportunistic pathogens that cause infection in the immunocompromised host (e.g., Aspergillus fumigatus, niger, terreus, and other spp., Blastomyces dermatitidis, Coccidioides immitis, and Cryptococcus neoformans). Agents currently available for antifungal therapy are described in Table 6-3.

Viruses

Due to their small size and necessity for growth within cells, viruses are difficult to culture, requiring a longer time than is typically optimal for clinical decision making. Previously, viral infection was identified by indirect means (i.e., the host antibody response). Recent advances in technology have allowed for the identification of the presence of viral DNA or ribonucleic acid (RNA) using methods such as polymerase chain reaction. Similarly to many fungal infections, most clinically relevant viral infections in surgical patients occur in the immunocompromised host, particularly those receiving immunosuppression to prevent rejection of a solid organ allograft. Relevant viruses include adenoviruses, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and varicella-zoster virus. Surgeons must be aware of the manifestations of hepatitis B and C virus, as well as human immunodeficiency virus infections, including their capacity to be transmitted to health care workers (see General Principles section). Prophylactic and therapeutic use of antiviral agents is discussed in Chap. 11.

General Principles

Maneuvers to diminish the presence of exogenous (surgeon and operating room environment) and endogenous (patient) microbes are termed prophylaxis, and consist of the use of mechanical, chemical, and antimicrobial modalities, or a combination of these methods.

As described previously, the host resident microflora of the skin (patient and surgeon) and other barrier surfaces represent a potential source of microbes that can invade the body during trauma, thermal injury, or elective or emergent surgical intervention. For this reason, operating room personnel are versed in mild mechanical exfoliation of the skin of the hands and forearms using antibacterial preparations, and the intraoperative aseptic technique is employed. Similarly, application of an antibacterial agent to the skin of the patient at the proposed operative site takes place prior to creating an incision. Also, if necessary, hair removal should take place using a clipper rather than a razor; the latter promotes overgrowth of skin microbes in small nicks and cuts. Dedicated use of these modalities clearly has been shown to diminish the quantity of skin microflora, and although a direct correlation between praxis and reduced infection rates has not been demonstrated, comparison to infection rates prior to the use of antisepsis and sterile technique makes clear their utility and importance.

The aforementioned modalities are not capable of sterilizing the hands of the surgeon or the skin or epithelial surfaces of the patient, although the inoculum can be reduced considerably. Thus, entry through the skin, into the soft tissue, and into a body cavity or hollow viscus invariably is associated with the introduction of some degree of microbial contamination. For that reason, patients who undergo procedures that may be associated with the ingress of significant numbers of microbes (e.g., colonic resection) or in whom the consequences of any type of infection due to said process would be dire (e.g., prosthetic vascular graft infection) should receive an antimicrobial agent.

Source Control

The primary precept of surgical infectious disease therapy consists of drainage of all purulent material, débridement of all infected, devitalized tissue, and debris, and/or removal of foreign bodies at the site of infection, plus remediation of the underlying cause of infection.²³ A discrete, walled-off purulent fluid collection (i.e., an abscess) requires drainage via percutaneous drain insertion or an operative approach in which incision and drainage take place. An ongoing source of contamination (e.g., bowel perforation) or the presence of an aggressive, rapidly spreading infection (e.g., necrotizing soft tissue infection) invariably requires expedient, aggressive operative intervention, both to remove contaminated material and infected tissue (e.g., radical débridement or amputation) and to remove the initial cause of infection (e.g., bowel resection). Other treatment modalities such as antimicrobial agents, albeit critical, are of secondary importance to effective surgery with regard to treatment of surgical infections and overall outcome. Rarely, if ever, can an aggressive surgical infection be cured only by the administration of antibiotics, and never in the face of an ongoing source of contamination. Also, it has been repeatedly demonstrated that delay in operative intervention, whether due to misdiagnosis or the need for additional diagnostic studies, is associated with increased morbidity and occasional mortality.²⁴

Appropriate Use of Antimicrobial Agents

A classification of antimicrobial agents, mechanisms of action, and spectrum of activity is shown in Table 6-4. Prophylaxis consists of the administration of an antimicrobial agent or agents prior to initiation of certain specific types of surgical procedures in order to reduce the number of microbes that enter the tissue or body cavity. Agents are selected according to their activity against microbes likely to be present at the surgical site, based on knowledge of host microflora. For example, patients undergoing elective colorectal surgery should receive antimicrobial prophylaxis directed against skin flora, gram negative aerobes, and anaerobic bacteria. There are a wide variety of agents that meet these criteria with recently published guidelines.²⁵

By definition, prophylaxis is limited to the time prior to and during the operative procedure; in the vast majority of cases only a single dose of antibiotic is required, and only for certain types of procedures (see Surgical Site Infections). However, patients who undergo complex, prolonged procedures in which the duration of the operation exceeds the serum drug half-life should receive an additional dose or doses of the antimicrobial agent.²⁵ There is no evidence that administration of postoperative doses of an antimicrobial agent provides additional benefit, and this practice should be discouraged, as it is costly and is associated with increased rates of microbial drug resistance. Guidelines for prophylaxis are provided in Table 6-5.

Empiric therapy comprises the use of an antimicrobial agent or agents when the risk of a surgical infection is high, based on the underlying disease process (e.g., ruptured appendicitis), or when significant contamination during surgery has occurred (e.g., inadequate bowel preparation or considerable spillage of colon contents). Obviously, prophylaxis merges into empirical therapy in situations in which the risk of infection increases markedly because of intraoperative findings. Empirical therapy also often is employed in critically ill patients in whom a potential site of infection has been identified and severe sepsis or septic shock occurs. Invariably, empirical therapy should be limited to a short course of drug (3 to 5 days), and should be curtailed as soon as possible based on microbiologic data (i.e., absence of positive cultures) coupled with improvements in the clinical course of the patient.

Similarly, empirical therapy merges into therapy of established infection in some patients as well. However, among surgical patients, the manner in which therapy is employed, particularly in relation to the use of microbiologic data (culture and antibiotic sensitivity patterns), differs depending on whether the infection is monomicrobial or polymicrobial. Monomicrobial infections frequently are nosocomial infections occurring in postoperative patients, such as UTIs, pneumonia, or bacteremia. Evidence of systemic inflammatory response syndrome (fever, tachycardia, tachypnea, or elevated leukocyte count) in such individuals, coupled with evidence of local infection (e.g., an infiltrate on chest roentgenogram plus a positive Gram’s stain in bronchoalveolar lavage samples) should lead the surgeon to initiate empirical antibiotic therapy. An appropriate approach to antimicrobial treatment involves de-escalation therapy, where initial antimicrobial selection is broad, with a later narrowing of agents based on patient response and culture results. Initial drug selection must be based on initial evidence (Gram-positive vs. Gram-negative microbes, yeast), coupled with institutional and unit-specific drug sensitivity patterns. It is important to ensure that antimicrobial coverage chosen is adequate, since delay in appropriate antibiotic treatment has been shown to be associated with significant increases in mortality. A critical component of this approach is appropriate collection of culture specimens to allow for thorough analysis, since within 48 to 72 hours, culture and sensitivity reports will allow refinement of the antibiotic regimen to select the most efficacious agent.The clinical course of the patient is monitored closely, and in some cases (e.g., UTI) follow-up studies (urine culture) should be obtained after completion of therapy.

Although the primary therapeutic modality to treat polymicrobial surgical infections is source control as delineated previously, antimicrobial agents play an important role as well. Culture results are of lesser importance in managing these types of infections, as it has been repeatedly demonstrated that only a limited cadre of microbes predominate in the established infection, selected from a large number present at the time of initial contamination. Invariably it is difficult to identify all microbes that comprise the initial polymicrobial inoculum. For this reason, the antibiotic regimen should not be modified solely on the basis of culture information, as it is less important than the clinical course of the patient. For example, patients who undergo appendectomy for gangrenous, perforated appendicitis, or bowel resection for intestinal perforation, should receive an antimicrobial agent or agents directed against aerobes and anaerobes for 3 to 5 days, occasionally longer. If the patient regains bowel function during this time, conversion from an intravenous to an oral regimen (e.g., ciprofloxacin plus metronidazole) can occur. This is safe, and may facilitate earlier discharge.

A survey of several decades of clinical trials examining the effect of antimicrobial agent selection on the treatment of intra-abdominal infection revealed striking similarities in outcome among regimens that possessed aerobic and anaerobic activity (~10% to 30% failure rates): most failures could not be attributed to antibiotic selection, but rather were due to the inability to achieve effective source control.²⁶

Duration of antibiotic administration should be decided at the time the drug regimen is prescribed. As mentioned previously, prophylaxis is limited to a single dose administered immediately prior to creating the incision. Empiric therapy should be limited to 3 to 5 days or less, and should be curtailed if the presence of a local site or systemic infection is not revealed.²⁷ In fact, prolonged use of empirical antibiotic therapy in culture-negative critically ill patients is associated with increased mortality, highlighting the need to discontinue therapy when there is no proven evidence of infection.²⁸

Therapy for monomicrobial infections follows standard guidelines: 3 to 5 days for UTIs, 7 to 10 days for pneumonia, and 7 to14 days for bacteremia. Longer courses of therapy in this setting do not result in improved care and are associated with increased risk of superinfection by resistant organisms.^29,30 There is some evidence that measuring and monitoring serum procalcitonin trends in the setting of infection allows earlier cessation of antibiotics without decrement in the rate of clinical cure.³¹ Antibiotic therapy for osteomyelitis, endocarditis, or prosthetic infections in which it is hazardous to remove the device consists of prolonged courses of an antibiotic or several agents in combination for 6 to 12 weeks. The specific agents are selected based on analysis of the degree to which the organism is killed in vitro using the minimum inhibitory concentration (MIC) of a standard pure inoculum of 10⁵ CFU/mL of the organism isolated from the site of infection or bloodstream. Sensitivities are reported in relation to the achievable blood level of each antibiotic in a panel of agents. The least toxic, least expensive agent to which the organism is most sensitive should be selected, although the latter parameter is of paramount importance. Serious or recrudescent infection may require therapy with two or more agents, particularly if a multidrug-resistant pathogen is causative, limiting therapeutic options to drugs to which the organism is only moderately sensitive. Commonly an agent may be administered intravenously for 1 to 2 weeks, following which the treatment course is completed with an oral drug. However, this should only be undertaken in patients who demonstrate progressive clinical improvement, and the oral agent should be capable of achieving high serum levels as well (e.g., fluoroquinolones).

The majority of studies examining the optimal duration of antibiotic therapy for the treatment of polymicrobial infection have focused on patients who develop peritonitis. CoGeNT data exist to support the contention that satisfactory outcomes are achieved with 12 to 24 hours of therapy for penetrating gastrointestinal trauma in the absence of extensive contamination, 3 to 5 days of therapy for perforated or gangrenous appendicitis, 5 to 7 days of therapy for treatment of peritoneal soilage due to a perforated viscus with moderate degrees of contamination, and 7 to 14 days of therapy to adjunctively treat extensive peritoneal soilage (e.g., feculent peritonitis) or that occurring in the immunosuppressed host.³² It bears repeating that the eventual outcome is more closely linked to the ability of the surgeon to achieve effective source control than to the duration of antibiotic administration. One small randomized trial has reported similar outcomes of 3 day vs. standard duration therapy in secondary microbial peritonitis.³³

In the later phases of postoperative antibiotic treatment of serious intra-abdominal infection, the absence of an elevated white blood cell (WBC) count, lack of band forms of PMNs on peripheral smear, and lack of fever (<100.5°F) provide close to complete assurance that infection has been eradicated.³⁴ Under these circumstances, antibiotics can be discontinued with impunity. However, the presence of one or more of these indicators does not mandate continuing antibiotics or altering the antibiotic(s) administered. Rather, a search for an extra-abdominal source of infection or a residual or ongoing source of intra-abdominal infection (e.g., abscess or leaking anastomosis) should be sought, the latter mandating maneuvers to effect source control.

Allergy to antimicrobial agents must be considered prior to prescribing them. First, it is important to ascertain whether a patient has had any type of allergic reaction in association with administration of a particular antibiotic. However, one should take care to ensure that the purported reaction consists of true allergic symptoms and signs, such as urticaria, bronchospasm, or other similar manifestations, rather than indigestion or nausea. Penicillin allergy is quite common, the reported incidence ranging from 0.7% to 10%. Although avoiding the use of any beta-lactam drug is appropriate in patients who manifest significant allergic reactions to penicillins, the incidence of cross-reactivity appears low for all related agents, with 1% cross-reactivity for carbapenems,³⁵ 5% to 7% cross-reactivity for cephalosporins, and extremely small or nonexistent cross-reactivity for monobactams.

Severe allergic manifestations to a specific class of agents, such as anaphylaxis, generally preclude the use of any agents in that class, except under circumstances in which use of a certain drug represents a lifesaving measure. In some centers, patients undergo intradermal testing using a dilute solution of a particular antibiotic to determine whether a severe allergic reaction would be elicited by parenteral administration. A pathway, including such intradermal testing, has been effective in reduction of vancomycin use to 16% in surgical patients with reported allergy to penicillin.³⁶ This type of testing is rarely employed because it is simpler to select an alternative class of agent. Should administration of a specific agent to which the patient is allergic become necessary, desensitization using progressively higher doses of antibiotic can be undertaken, providing the initial testing does not cause severe allergic manifestations.

Misuse of antimicrobial agents is rampant in both the inpatient and outpatient setting, and is associated with an enormous financial impact on health care costs, adverse reactions due to drug toxicity and allergy, the occurrence of new infections such as Clostridium difficile colitis, and the development of multiagent drug resistance among nosocomial pathogens. Each of these factors has been directly correlated with overall drug administration. It has been estimated that in the United States, in excess of $20 billion is spent on antibiotics each year, and the appearance of so-called “super bugs”—microbes sensitive to few if any agents—has been sobering.³⁷ The responsible practitioner limits prophylaxis to the period during the operative procedure, does not convert prophylaxis into empirical therapy except under well-defined conditions, sets the duration of antibiotic therapy from the outset, curtails antibiotic administration when clinical and microbiologic evidence does not support the presence of an infection, and limits therapy to a short course in every possible instance. Prolonged treatment associated with drains and tubes has not been shown to be beneficial.

Surgical Site Infections

Surgical site infections (SSIs) are infections of the tissues, organs, or spaces exposed by surgeons during performance of an invasive procedure. SSIs are classified into incisional and organ/space infections, and the former are further subclassified into superficial (limited to skin and subcutaneous tissue) and deep incisional categories.^38,39 The development of SSIs is related to three factors: (a) the degree of microbial contamination of the wound during surgery, (b) the duration of the procedure, and (c) host factors such as diabetes, malnutrition, obesity, immune suppression, and a number of other underlying disease states. Table 6-6 lists risk factors for development of SSIs. By definition, an incisional SSI has occurred if a surgical wound drains purulent material or if the surgeon judges it to be infected and opens it.

Surgical wounds are classified based on the presumed magnitude of the bacterial load at the time of surgery (Table 6-7).⁴⁰ Clean wounds (class I) include those in which no infection is present; only skin microflora potentially contaminate the wound, and no hollow viscus that contains microbes is entered. Class I D wounds are similar except that a prosthetic device (e.g., mesh or valve) is inserted. Clean/contaminated wounds (class II) include those in which a hollow viscus such as the respiratory, alimentary, or genitourinary tracts with indigenous bacterial flora is opened under controlled circumstances without significant spillage of contents.

While elective colorectal cases have classically been included as class II cases, a number of studies in the last decade have documented higher SSI rates (9% to 25%).^41,42,43 One study identified two-thirds of infections presenting after discharge from hospital, highlighting the need for careful follow-up of these patients.⁴¹ Infection is also more common in cases involving entry into the rectal space.⁴² In a recent single center quality improvement study using a multidisciplinary approach, one group of clinicians has demonstrated the ability to decrease SSI from 9.8% to 4.0%.⁴³

Contaminated wounds (class III) include open accidental wounds encountered early after injury, those with extensive introduction of bacteria into a normally sterile area of the body due to major breaks in sterile technique (e.g., open cardiac massage), gross spillage of viscus contents such as from the intestine, or incision through inflamed, albeit nonpurulent tissue. Dirty wounds (class IV) include traumatic wounds in which a significant delay in treatment has occurred and in which necrotic tissue is present, those created in the presence of overt infection as evidenced by the presence of purulent material, and those created to access a perforated viscus accompanied by a high degree of contamination. The microbiology of SSIs is reflective of the initial host microflora such that SSIs following creation of a class I wound are invariable, due solely to skin microbes found on that portion of the body, while SSIs subsequent to a class II wound created for the purpose of elective colon resection may be caused by either skin microbes or colonic microflora, or both.

In the United States, hospitals are required to conduct surveillance for the development of SSIs for a period of 30 days after the operative procedure.⁴⁴ Such surveillance has been associated with greater awareness and a reduction in SSI rates, probably in large part based upon the impact of observation and promotion of adherence to appropriate care standards. Beginning in 2012, all hospitals receiving reimbursement from the Center for Medicare and Medicaid Services are required to report SSIs.

A recent refinement of risk indexes has been implemented through the National Healthcare Safety Network, a secure, web-based system of surveillance utilized by the Centers for Disease Control and Prevention for surveillance of health care associated infections. This refinement utilized data reported from 847 hospitals in nearly one million patients over a two- year period to develop procedure-specific risk indices for SSIs.⁴⁵

SSIs are associated with considerable morbidity and occasional lethality, as well as substantial health care costs and patient inconvenience and dissatisfaction.⁴⁶ For that reason, surgeons strive to avoid SSIs by using the maneuvers described in the previous section. Also, the use of prophylactic antibiotics may serve to reduce the incidence of SSI rates during certain types of procedures. For example, it is well accepted that a single dose of an antimicrobial agent should be administered immediately prior to commencing surgery for class I D, II, III, and IV types of wounds. It seems reasonable that this practice should be extended to patients in any category with high National Nosocomial Infection Surveillance (NNIS) scores, although this remains to be proven. Thus, the utility of prophylactic antibiotics in reducing the rate of wound infection subsequent to clean surgery remains controversial, and these agents should not be employed under routine circumstances (e.g., in healthy young patients). However, because of the potential dire consequences of a wound infection after clean surgery in which prosthetic material is implanted into tissue, patients who undergo such procedures should receive a single preoperative dose of an antibiotic.

A number of health care organizations within the United States have become interested in evaluating performance of hospitals and physicians with respect to implementing processes that support delivery of standard of care. One major process of interest is reduction in SSIs, since the morbidity (and subsequent cost) of this complication is high. Several of these organizations are noted in Table 6-8. Appropriate guidelines in this area incorporating the principles discussed previously have been developed and disseminated.⁴⁷ However, observers have noted that adherence to these guidelines has been poor.⁴⁸ Most experts believe that better adherence to evidence-based practice recommendations and implementing systems of care with redundant safeguards will result in reduction of surgical complications and better patient outcomes. More important, the Center for Medicare and Medicaid Services, the largest third party insurance payer in the United States, has required reporting by hospitals of many processes related to reduction of surgical infections, including appropriate use of perioperative antibiotics. This information, which is currently reported publicly by hospitals, has led to significant improvement in reported rates of these process measures. However, the effect of this approach on the incidence of SSIs is not known at this time.

Surgical management of the wound also is a critical determinant of the propensity to develop a SSI. In healthy individuals, class I and II wounds may be closed primarily, while skin closure of class III and IV wounds is associated with high rates of incisional SSIs (~25% to 50%). The superficial aspects of these latter types of wounds should be packed open and allowed to heal by secondary intention, although selective use of delayed primary closure has been associated with a reduction in incisional SSI rates.⁴⁹ It remains to be determined whether NNIS-type stratification schemes can be employed prospectively in order to target specific subgroups of patients which will benefit from the use of prophylactic antibiotic and/or specific wound management techniques. One clear example based on CoGeNT data from clinical trials is that class III wounds in healthy patients undergoing appendectomy for perforated or gangrenous appendicitis can be primarily closed as long as antibiotic therapy directed against aerobes and anaerobes is administered. This practice leads to SSI rates of approximately 3% to 4%.⁵⁰

Recent investigations have studied the effect of additional maneuvers in an attempt to further reduce the rate of SSIs. The adverse effects of hyperglycemia on WBC function have been well described.⁵¹ A number of recent studies in patients undergoing several different types of surgery describe increased risk of SSI in patients with hyperglycemia.^52,53 Although randomized trials have not been performed, it is recommended that clinicians maintain appropriate blood sugar control in patients in the perioperative period to minimize the occurrence of SSI.

The respective effects of body temperature and the level of inhaled oxygen during surgery on SSI rates also have been studied, and both hypothermia and hypoxia during surgery are associated with a higher rater of SSIs. Although an initial study provided evidence that patients who received high levels of inhaled oxygen during colorectal surgery developed fewer SSIs,⁵⁴ a recent meta-analysis suggest that the overall benefit is small and may not warrant use.⁵⁵ Further evaluation via multicenter studies is needed prior to implementation of hyperoxia as standard therapy, but it is clear that intraoperative hypothermia and hypoxia should be prevented.

Effective therapy for incisional SSIs consists solely of incision and drainage without the additional use of antibiotics. Antibiotic therapy is reserved for patients in whom evidence of significant cellulitis is present, or who concurrently manifest a systemic inflammatory response syndrome. The open wound often is allowed to heal by secondary intention, with dressings being changed twice a day. The use of topical antibiotics and antiseptics to further wound healing remains unproven, although anecdotal studies indicate their potential utility in complex wounds that do not heal with routine measures.⁵⁶ Despite a paucity of prospective studies,⁵⁷ vacuum-assisted closure is increasingly used in management of large, complex open wounds and can be applied to wounds in locations that are difficult to manage with dressings (Fig. 6-2). One also should consider obtaining wound cultures in patients who develop SSIs and whom have been hospitalized or reside in long-term care facilities due to the increasing incidence of infection caused by multidrug resistant organisms. The treatment of organ/space infections is discussed in the following section.

Intra-Abdominal Infections

Microbial contamination of the peritoneal cavity is termed peritonitis or intra-abdominal infection, and is classified according to etiology. Primary microbial peritonitis occurs when microbes invade the normally sterile confines of the peritoneal cavity via hematogenous dissemination from a distant source of infection or direct inoculation. This process is more common among patients who retain large amounts of peritoneal fluid due to ascites, and among those individuals who are being treated for renal failure via peritoneal dialysis. These infections invariably are monomicrobial and rarely require surgical intervention. The diagnosis is established based on identification of risk factors as noted previously, physical examination that reveals diffuse tenderness and guarding without localized findings, absence of pneumoperitoneum on an imaging study, the presence of more than 100 WBCs/mL, and microbes with a single morphology on Gram’s stain performed on fluid obtained via paracentesis. Subsequent cultures typically will demonstrate the presence of gram positive organisms in patients undergoing peritoneal dialysis. In patients without this risk factor organisms can include E. coli, K. pneumoniae, pneumococci, and others, although many different pathogens can be causative. Treatment consists of administration of an antibiotic to which the organism is sensitive; often 14 to 21 days of therapy are required. Removal of indwelling devices (e.g., a peritoneal dialysis catheter or a peritoneovenous shunt) may be required for effective therapy of recurrent infections.

Secondary microbial peritonitis occurs subsequent to contamination of the peritoneal cavity due to perforation or severe inflammation and infection of an intra-abdominal organ. Examples include appendicitis, perforation of any portion of the gastrointestinal tract, or diverticulitis. As noted previously, effective therapy requires source control to resect or repair the diseased organ; débridement of necrotic, infected tissue and debris; and administration of antimicrobial agents directed against aerobes and anaerobes.⁵⁸ This type of antibiotic regimen should be chosen because in most patients the precise diagnosis cannot be established until exploratory laparotomy is performed, and the most morbid form of this disease process is colonic perforation, due to the large number of microbes present. A combination of agents or single agents with a broad spectrum of activity can be used for this purpose; conversion of a parenteral to an oral regimen when the patient’s ileus resolves provides results similar to those achieved with intravenous antibiotics. Effective source control and antibiotic therapy is associated with low failure rates and a mortality rate of approximately 5% to 6%; inability to control the source of infection is associated with mortality greater than 40%.⁵⁹

The response rate to effective source control and use of appropriate antibiotics has remained approximately 70% to 90% over the past several decades.⁶⁰ Patients in whom standard therapy fails typically develop one or more of the following: an intra-abdominal abscess, leakage from a gastrointestinal anastomosis leading to postoperative peritonitis, or tertiary (persistent) peritonitis. The latter is a poorly understood entity that is more common in immunosuppressed patients in whom peritoneal host defenses do not effectively clear or sequester the initial secondary microbial peritoneal infection. Microbes such as Enterococcus faecalis and faecium, Staphylococcus epidermidis, Candida albicans, and Pseudomonas aeruginosa commonly are identified, typically in combination, and their presence may be due to their lack of responsiveness to the initial antibiotic regimen, coupled with diminished activity of host defenses. Unfortunately, even with effective antimicrobial agent therapy, this disease process is associated with mortality rates in excess of 50%.⁶¹

Formerly, the presence of an intra-abdominal abscess mandated surgical reexploration and drainage. Today, the vast majority of such abscesses can be effectively diagnosed via abdominal computed tomographic (CT) imaging techniques and drained percutaneously. Surgical intervention is reserved for those individuals who harbor multiple abscesses, those with abscesses in proximity to vital structures such that percutaneous drainage would be hazardous, and those in whom an ongoing source of contamination (e.g., enteric leak) is identified. The necessity of antimicrobial agent therapy and precise guidelines that dictate duration of catheter drainage have not been established. A short course (3 to 7 days) of antibiotics that possess aerobic and anaerobic activity seems reasonable, and most practitioners leave the drainage catheter in situ until it is clear that cavity collapse has occurred, output is less than 10 to 20 mL/d, no evidence of an ongoing source of contamination is present, and the patient’s clinical condition has improved.

Organ-Specific Infections

Hepatic abscesses are rare, currently accounting for approximately 15 per 100,000 hospital admissions in the United States. Pyogenic abscesses account for approximately 80% of cases, the remaining 20% being equally divided among parasitic and fungal forms.⁶² Formerly, pyogenic liver abscesses mainly were caused by pylephlebitis due to neglected appendicitis or diverticulitis. Today, manipulation of the biliary tract to treat a variety of diseases has become a more common cause, although in nearly 50% of patients no cause is identified. The most common aerobic bacteria identified in recent series include E coli, K pneumoniae, and other enteric bacilli, enterococci, and Pseudomonas spp., while the most common anaerobic bacteria are Bacteroides spp., anaerobic streptococci, and Fusobacterium spp. Candida albicans and other related yeast cause the majority of fungal hepatic abscesses. Small (<1 cm), multiple abscesses should be sampled and treated with a 4 to 6 week course of antibiotics. Larger abscesses invariably are amenable to percutaneous drainage, with parameters for antibiotic therapy and drain removal similar to those mentioned previously. Splenic abscesses are extremely rare and are treated in a similar fashion. Recurrent hepatic or splenic abscesses may require operative intervention—unroofing and marsupialization or splenectomy, respectively.

Secondary pancreatic infections (e.g., infected pancreatic necrosis or pancreatic abscess) occur in approximately 10% to 15% of patients who develop severe pancreatitis with necrosis. The surgical treatment of this disorder was pioneered by Bradley and Allen, who noted significant improvements in outcome for patients undergoing repeated pancreatic débridement of infected pancreatic necrosis.⁶³ Current care of patients with severe acute pancreatitis includes staging with dynamic, contrast material-enhanced helical CT scan to evaluate the extent of pancreatitis (unless significant renal dysfunction exists in which case one should forego the use of contrast material) coupled with the use of one of several prognostic scoring systems. Patients who exhibit clinical signs of instability (e.g., oliguria, hypoxemia, large-volume fluid resuscitation) should be carefully monitored in the ICU and undergo follow-up contrast enhanced CT examination when renal function has stabilized to evaluate for development of local pancreatic complications (Fig. 6-3). A recent change in practice has been the elimination of the routine use of prophylactic antibiotics for prevention of infected pancreatic necrosis. Enteral feedings initiated early, using nasojejunal feeding tubes placed past the ligament of Treitz, have been associated with decreased development of infected pancreatic necrosis, possibly due to a decrease in gut translocation of bacteria. These topics have been recently reviewed.^64,65

The presence of secondary pancreatic infection should be suspected in patients whose systemic inflammatory response (fever, elevated WBC count, or organ dysfunction) fails to resolve, or in those individuals who initially recuperate, only to develop sepsis syndrome 2 to 3 weeks later. CT-guided aspiration of fluid from the pancreatic bed for performance of Gram’s stain and culture analysis can be useful. A positive Gram’s stain or culture from CT-guided aspiration, or identification of gas within the pancreas on CT scan, mandate surgical intervention.

The approach of open necrosectomy with repeated debridements, although life saving, is associated with significant morbidity and prolonged hospitalization. Efforts to reduce the amount of surgical injury, while still preserving the improved outcomes associated with debridement of the infected sequestrum have led to a variety of less invasive approaches.⁶⁶ These include endoscopic approaches, laparoscopic approaches and other minimally invasive approaches. There are a limited number of randomized trials reporting the use of these new techniques currently. An important concept common to all of these approaches, however, is the attempt to delay surgical intervention, since a number of trials have identified increased mortality when intervention occurs during the first two weeks of illness.

Data supporting the use of endoscopic approaches to this problem include nearly a dozen case series and a randomized trial.^67,68 The reported mortality rate was 5%, with a 30% complication rate. Most authors noted the common requirement for multiple endoscopic debridements (similar to the open approach), with a median of 4 endoscopic sessions required. Fewer series report experience with the laparoscopic approach, either transgastric or transperitoneal, entering the necrosis through the transverse mesocolon or gastrocolic ligament. The laparoscopic technique is carefully described in a recent publication.⁶⁹ Laparoscopic intervention is limited by the difficulty in achieving multiple debridements and the technical expertise required to achieve an adequate debridement. Mortality in 65 patients in 9 case series reported was 6% overall.

Debridement of necrosis through a lumbar approach has been advocated by a number of authors. This approach, developed with experience in a large number of patients,⁷⁰ has been recently subjected to a single center randomized prospective trial.⁷¹ This approach includes delay of intervention when possible until 4 weeks after the onset of disease. Patients receive transgastric or preferably retroperitoneal drainage of the sequestrum. If patients do not improve over 72 hours, they are treated with video-assisted retroperitoneal drainage (VARD), consisting of dilation of the retroperitoneal drain tract, placement of and irrigation, and debridement of the pancreatic bed (Fig. 6-4). Repeat debridements are performed as clinically indicated, with most patients requiring multiple debridements. In the trial reported, patients randomized to VARD (n=43) compared to those randomized to the standard open necrosectomy (n=45) had a decreased incidence of the composite endpoint of complications and death (40% vs. 69%), with comparable mortality rate, hospital, and ICU lengths of stay. Patients randomized to VARD had fewer incisional hernias, new-onset diabetes, and need for pancreatic enzyme supplementation.

It is apparent that patients with infected pancreatic necrosis can safely undergo procedures that are more minimal than the gold-standard open necrosectomy with good outcomes. However, to obtain good outcomes these approaches require an experienced multidisciplinary team consisting of interventional radiologists, gastroenterologists, surgeons, and others. Important concepts for successful management include careful preoperative planning, delay (if possible) to allow maturation of the fluid collection, and the willingness to repeat procedures as necessary till the majority if not all nonviable tissue has been removed.

Infections of the Skin and Soft Tissue

These infections can be classified according to whether or not surgical intervention is required. For example, superficial skin and skin structure infections such as cellulitis, erysipelas, and lymphangitis invariably are effectively treated with antibiotics alone, although a search for a local underlying source of infection should be undertaken. Generally, drugs that possess activity against the causative gram-positive skin microflora are selected. Furuncles or boils may drain spontaneously or require surgical incision and drainage. Antibiotics are prescribed if significant cellulitis is present or if cellulitis does not rapidly resolve after surgical drainage. Community-acquired methicillin resistant Staphylococcus aureus (MRSA) infection should be suspected if infection persists after treatment with adequate drainage and administration of first line antibiotics. These infections may require more aggressive drainage and altered antimicrobial therapy.⁷²

Aggressive soft tissue infections are rare, difficult to diagnose, and require immediate surgical intervention plus administration of antimicrobial agents. Failure to do so results in an extremely high mortality rate (~80%–100%), and even with rapid recognition and intervention, current mortality rates are high (16%–24%).⁷³ Eponyms and classification in the past have been a hodgepodge of terminology, such as Meleney’s synergist gangrene, rapidly spreading cellulitis, gas gangrene, and necrotizing fasciitis, among others. Today it seems best to delineate these serious infections based on the soft tissue layer(s) of involvement (e.g., skin and superficial soft tissue, deep soft tissue, and muscle) and the pathogen(s) that cause them.

Patients at risk for these types of infections include those who are elderly, immunosuppressed, or diabetic; those who suffer from peripheral vascular disease; or those with a combination of these factors. The common thread among these host factors appears to be compromise of the fascial blood supply to some degree, and if this is coupled with the introduction of exogenous microbes, the result can be devastating. However, it is of note that over the last decade, extremely aggressive necrotizing soft tissue infections among healthy individuals due to streptococci have been described as well.

Initially, the diagnosis is established solely upon a constellation of clinical findings, not all of which are present in every patient. Not surprisingly, patients often develop sepsis syndrome or septic shock without an obvious cause. The extremities, perineum, trunk, and torso are most commonly affected, in that order. Careful examination should be undertaken for an entry site such as a small break or sinus in the skin from which grayish, turbid semipurulent material (“dishwater pus”) can be expressed, as well as for the presence of skin changes (bronze hue or brawny induration), blebs, or crepitus. The patient often develops pain at the site of infection that appears to be out of proportion to any of the physical manifestations. Any of these findings mandates immediate surgical intervention, which should consist of exposure and direct visualization of potentially infected tissue (including deep soft tissue, fascia, and underlying muscle) and radical resection of affected areas. Radiologic studies should not be undertaken in patients in whom the diagnosis seriously is considered, as they delay surgical intervention and frequently provide confusing information. Unfortunately, surgical extirpation of infected tissue frequently entails amputation and/or disfiguring procedures; however, incomplete procedures are associated with higher rates of morbidity and mortality (Fig. 6-5).

During the procedure a Gram’s stain should be performed on tissue fluid. Antimicrobial agents directed against Gram-positive and Gram-negative aerobes and anaerobes (e.g., vancomycin plus a carbapenem), as well as high-dose aqueous penicillin G (16,000,000 to 20,000,000 U/d), the latter to treat clostridial pathogens, should be administered. Approximately 50% of such infections are polymicrobial, the remainder being caused by a single organism such as Streptococcus pyogenes, Pseudomonas aeruginosa, or Clostridium perfringens. The microbiology of these polymicrobial infections is similar to that of secondary microbial peritonitis, with the exception that Gram-positive cocci are more commonly encountered. Most patients should be returned to the operating room on a scheduled basis to determine if disease progression has occurred. If so, additional resection of infected tissue and debridement should take place. Antibiotic therapy can be refined based on culture and sensitivity results, particularly in the case of monomicrobial soft tissue infections. Hyperbaric oxygen therapy may be of use in patients with infection caused by gas-forming organisms (e.g., Clostridium perfringens), although the evidence to support efficacy is limited to underpowered studies and case reports.In the absence of such infection, hyperbaric oxygen therapy has not shown to be effective.⁷⁴

Postoperative Nosocomial Infections

Surgical patients are prone to develop a wide variety of nosocomial infections during the postoperative period, which include SSIs, UTIs, pneumonia, and bacteremia. SSIs are discussed earlier, and the latter types of nosocomial infections are related to prolonged use of indwelling tubes and catheters for the purpose of urinary drainage, ventilation, and venous and arterial access, respectively.

The presence of a postoperative UTI should be considered based on urinalysis demonstrating WBCs or bacteria, a positive test for leukocyte esterase, or a combination of these elements. The diagnosis is established after >10⁴ CFU/mL of microbes are identified by culture techniques in symptomatic patients, or >10⁵ CFU/mL in asymptomatic individuals. Treatment for 3 to 5 days with a single antibiotic directed against the most common organisms (e.g., E. Coli, K. pneumonia) that achieves high levels in the urine is appropriate. Initial therapy is directed by Gram’s stain results and is refined as culture results become available. Postoperative surgical patients should have indwelling urinary catheters removed as quickly as possible, typically within 1 to 2 days, as long as they are mobile, to avoid the development of a UTI.

Prolonged mechanical ventilation is associated with nosocomial pneumonia. These patients present with more severe disease, are more likely to be infected with drug-resistant pathogens, and suffer increased mortality compared to patients who develop community-acquired pneumonia. The diagnosis of pneumonia is established by presence of a purulent sputum, elevated leukocyte count, fever, and new chest X-ray abnormalities, such as consolidation. The presence of two of the clinical findings, plus chest X-ray findings, significantly increases the likelihood of pneumonia.⁷⁵ Consideration should be given to performing bronchoalveolar lavage to obtain samples for Gram’s stain and culture. Some authors advocate quantitative cultures as a means to identify a threshold for diagnosis.⁷⁶ Surgical patients should be weaned from mechanical ventilation as soon as feasible, based on oxygenation and inspiratory effort, as prolonged mechanical ventilation increases the risk of nosocomial pneumonia.

Infection associated with indwelling intravascular catheters has become a common problem among hospitalized patients. Because of the complexity of many surgical procedures, these devices are increasingly used for physiologic monitoring, vascular access, drug delivery, and hyperalimentation. Among the several million catheters inserted each year in the United States, approximately 25% will become colonized, and approximately 5% will be associated with bacteremia. Duration of catheterization, insertion or manipulation under emergency or nonsterile conditions, use for hyperalimentation, and the use of multilumen catheters increase the risk of infection. Use of a central line insertion protocol that includes full barrier precautions and chlorhexidine skin prep has been shown to decrease the incidence of infection.⁷⁷ Although no randomized trials have been performed, peripherally inserted central venous catheters have a catheter-related infection rate similar to those inserted in the subclavian or jugular veins.⁷⁸

Many patients who develop intravascular catheter infections are asymptomatic, often exhibiting solely an elevation in the blood WBC count. Blood cultures obtained from a peripheral site and drawn through the catheter that reveal the presence of the same organism increase the index of suspicion for the presence of a catheter infection. Obvious purulence at the exit site of the skin tunnel, severe sepsis syndrome due to any type of organism when other potential causes have been excluded, or bacteremia due to Gram-negative aerobes or fungi should lead to catheter removal. Selected catheter infections due to low-virulence microbes such as Staphylococcus epidermidis can be effectively treated in approximately 50% to 60% of patients with a 14- to 21-day course of an antibiotic, which should be considered when no other vascular access site exists.⁷⁹ The use of antibiotic-bonded catheters and chlorhexidine sponges at the insertion site have been associated with lower rates of colonization.⁷⁷ Use of ethanol or antimicrobial catheter “locks” have shown promise in reducing incidence of infection in dialysis catheters.⁸⁰ The surgeon should carefully consider the need for any type of vascular access device, rigorously attend to their maintenance to prevent infection, and remove them as quickly as possible. Use of systemic antibacterial or antifungal agents to prevent catheter infection is of no utility and is contraindicated.

Sepsis

Severe sepsis is increasing in incidence, with over 1.1 million cases estimated per year in the United States with an annual cost of 24 billion dollars. This rate is expected to increase as the population of aged in the United States increases. One third of sepsis cases occur in surgical populations and sepsis is a major cause of morbidity and mortality.⁸¹ The treatment of sepsis has improved dramatically over the last decade, with mortality rates dropping to under 30%. Factors contributing to this improvement in mortality relate both to recent randomized prospective trials demonstrating improved outcomes with new therapies, and to improvements in the process of care delivery to the sepsis patient. The “Surviving Sepsis Campaign,” a multidisciplinary group that worked to develop treatment recommendations has published guidelines incorporating evidence-based treatment strategies most recently in 2013.¹³ These guidelines are summarized in Table 6-9.

Patients presenting with severe sepsis should receive resuscitation fluids to achieve a central venous pressure target of 8-12 mm Hg, with a goal of mean arterial pressure of ≥ 65 mHg and urine output of ≥ 0.5 mL/kg/h. Delaying this resuscitative step for as little as 3 hours until arrival in the ICU has been shown to result in poor outcome.⁸² Typically this goal necessitates early placement of central venous catheter.

A number of studies have demonstrated the importance of early empirical antibiotic therapy in patients who develop sepsis or nosocomial infection. This therapy should be initiated as soon as possible with broad spectrum antibiotics directed against most likely organisms, since early appropriate antibiotic therapy has been associated with significant reductions in mortality, and delays in appropriate antibiotic administration are associated with increased mortality. Use of institutional and unit specific sensitivity patterns are critical in selecting an appropriate agent for patients with nosocomial infection. It is key, however, to obtain cultures of appropriate areas without delaying initiating antibiotics so that appropriate adjustment of antibiotic therapy can take place when culture results return.

Additionally, early identification and treatment of septic sources is key for improved outcomes in patients with sepsis. Although there are no randomized trials demonstrating this concept, repeated evidence in studies of patients who develop intraabdominal infection, necrotizing soft tissue infection, and other types of infections demonstrate increased mortality with delayed treatment. As discussed earlier, one exception is that of infected pancreatic necrosis.

Multiple recent trials have evaluated the use of vasopressors and inotropes for treatment of septic shock. The current first-line agent for treatment of hypotension is norepinephrine. It is important to titrate therapy based on other parameters such as mixed venous oxygen saturation and plasma lactate levels as well as mean arterial pressure to reduce the risk of vasopressor-induced perfusion deficits. Several recent randomized trials have failed to demonstrate benefit with use of pulmonary arterial catheterization, leading to a significant decrease in its use.

A number of other adjunctive therapies are useful in treatment of the patient with severe sepsis and septic shock. Low-dose corticosteroids (hydrocortisone at ≤300 mg/day) can be used in patients with septic shock who are not responsive to fluids and vasopressors. However, a recent randomized trial failed to show survival benefit. Patients with acute lung injury associated with sepsis should receive mechanical ventilation with tidal volumes of 6 mL/kg and pulmonary airway plateau pressures of ≤30 cm H₂O. Finally, red blood cell transfusion should be reserved for patients with hemoglobin of <7 grams/dL, with a more liberal transfusion strategy reserved for those patients with severe coronary artery disease, ongoing blood loss, or severe hypoxemia.

Resistant Organisms:

In the 1940s, penicillin was first produced for widespread clinical use. Within a year of its introduction, the first resistant strains of Staphylococcus aureus were identified. There are two major components that are responsible for antibiotic resistance. First, there may be a genetic component innate to the organism that prevents an effect of a particular antibiotic. For instance, if an organism does not have a target receptor specific to the mechanism of action of a particular antibiotic, the antibiotic will not be effective against this organism. A good example is penicillin and Gram-negative organisms, as thesemicrobes lack penicillin-binding proteins. The second component driving resistance is that related to antibiotic selection. Over generations of exposure to a particular antibiotic, selection pressure will drive proliferation of more organisms resistant to that antibiotic. It is this mechanism that leads to antibiotic resistance in the world today, given that there are millions of kilograms of antibiotics used annually in people, in agriculture, and for animal use. This has led to antibiotic resistance described in all classes of antibiotics in common use today. Antibiotic resistance comes at a high cost, with a significant increase in mortality associated with infection from resistant organisms, and an economic cost of billions of dollars per year.

Resistance mechanisms are varied, and include one of three routes. Resistance can be intrinsic to the organism (natural resistance), can be mutational and mediated by changes in the chromosomal makeup of the organism, and finally can be mediated by extrachromosomal transfer of genetic material via transposons or plasmids. Resistance due to mutation includes mechanisms mediated by target site modification, reduced permeability/uptake, metabolic bypass, or derepression of multidrug efflux systems. Genes transferred via plasmid or transposon include those that cause drug inactivation, increases in antibiotic efflux systems, target site modification, and metabolic bypass.

There are several drug resistant organisms of interest to the surgeon. MRSA occurs as a hospital-associated infection more common in chronically ill patients receiving multiple courses of antibiotics. However, recent strains of MRSA have emerged in the community among patients without preexisting risk factors for disease.⁷² These strains, which produce a toxin known as Panton-Valentin leukocidin, make up an increasingly high percentage of surgical site infections since they are resistant to commonly employed prophylactic antimicrobial agents.⁸³ Extended spectrum β-lactamase (ESBL)-producing strains of Enterobacteraceae, originally geographically localized and infrequent, have become much more widespread and common in the last decade.⁸⁴ These strains, typically Klebsiella or E coli species, produce a plasmid-mediated inducible β-lactamase. Commonly encountered plasmids also confer resistance to many other antibiotic classes (multidrug resistance). A common laboratory finding with ESBL is sensitivity to first-, second-, or third- generation cephalosporins with resistance to others. Unfortunately, use of this seemingly active agent leads to rapid induction of resistance and failure of antibiotic therapy. The appropriate antibiotic choice in this setting is a carbepenem. While Enterococcus used to be considered a low virulence organism in the past, infections caused by E faecium and faecalis have been found to be increasingly virulent, especially in the immunocompromised host. The last decade has seen increased isolation of a vancomycin-resistant strain of Enterococcus.⁸⁵ This resistance is transposon-mediated via the vanA gene and is typically seen in E faecium strains. A real concern in this setting is transfer of genetic material to S aureus in a host coinfected with both organisms. This is thought to be the mechanism behind the half dozen recently described cases of vancomycin resistance in S aureus.

Blood-Borne Pathogens

While alarming to contemplate, the risk of human immunodeficiency virus (HIV) transmission from patient to surgeon is low. As of May 2011, there had been six cases of surgeons with HIV seroconversion from a possible occupational exposure, with no new cases reported since 1999. Of the numbers of health care workers with likely occupationally acquired HIV infection (n = 200), surgeons were one of the lower risk groups (compared to nurses at 60 cases and nonsurgeon physicians at 19 cases).⁸⁶ The estimated risk of transmission from a needlestick from a source with HIV-infected blood is estimated at 0.3%. Transmission of HIV (and other infections spread by blood and body fluid) from patient to health care worker can be minimized by observation of universal precautions, which include the following: (a) routine use of barriers (such as gloves and/or goggles) when anticipating contact with blood or body fluids, (b) washing of hands and other skin surfaces immediately after contact with blood or body fluids, and (c) careful handling and disposal of sharp instruments during and after use.

Postexposure prophylaxis for HIV has significantly decreased the risk of seroconversion for health care workers with occupational exposure to HIV. Steps to initiate postexposure prophylaxis should be initiated within hours rather than days for the most effective preventive therapy. Postexposure prophylaxis with a two- or three-drug regimen should be initiated for health care workers with significant exposure to patients with an HIV-positive status. If a patient’s HIV status is unknown, it may be advisable to begin postexposure prophylaxis while testing is carried out, particularly if the patient is at high risk for infection due to HIV (e.g., intravenous narcotic use). Generally, postexposure prophylaxis is not warranted for exposure to sources with unknown status, such as deceased persons or needles from a sharps container.

The risks for surgeons of acquiring HIV infection have recently been evaluated by Goldberg and coauthors.⁸⁷ They noted that the risks are related to the prevalence of HIV infection in the population being cared for, the probability of transmission from a percutaneous injury suffered while caring for an infected patient, the number of such injuries sustained, and the use of postexposure prophylaxis. Annual calculated risks in Glasgow, Scotland, ranged from one in 200,000 for general surgeons not utilizing postexposure prophylaxis to as low as one in 10,000,000 with use of routine postexposure prophylaxis after significant exposures.

Hepatitis B virus (HBV) is a DNA virus that affects only humans. Primary infection with HBV generally is self-limited, but can cause fulminant hepatitis or progress to a chronic carrier state. Death from chronic liver disease or hepatocellular cancer occurs in roughly 30% of chronically infected persons. Surgeons and other health care workers are at high risk for this blood-borne infection and should receive the HBV vaccine; children are routinely vaccinated in the United States.⁸⁸ This vaccine has contributed to a significant decline in the number of new cases of HBV per year in the United States, from approximately 250,000 annually in the 1980s to 3,350 in 2010.^89,90 This is truly one of the unsung victories in vaccination strategy in the last 20 years.

Hepatitis C virus (HCV), previously known as non-A, non-B hepatitis, is a RNA flavivirus first identified specifically in the late 1980s. This virus is confined to humans and chimpanzees. A chronic carrier state develops in 75% to 80% of patients with the infection, with chronic liver disease occurring in three-fourths of patients who develop chronic infection. The number of new infections per year has declined since the 1980s due to routine testing of blood donors for this virus. Fortunately, HCV is not transmitted efficiently through occupational exposures to blood, with the seroconversion rate after accidental needlestick approximately 1.8%.⁹¹ To date, a vaccine to prevent HCV infection has not been developed. Experimental studies in chimpanzees with HCV immunoglobulin using a model of needlestick injury have failed to demonstrate a protective effect, and no effective antiviral agents for postexposure prophylaxis are available. Treatment of patients who develop HCV infection includes ribavirin and pegylated gamma interferon.⁹²

Several infectious organisms have been studied by the United States and the former Soviet Union and presumably other entities for potential use as biologic weapons. Programs involving biologic agents in the United States were halted by presidential decree in 1971. However, concern remains that these agents could be used by rogue states or terrorist organizations as weapons of mass destruction, as they are relatively inexpensive to make in terms of infrastructure development. A related issue is the recent controversy regarding publication of genetic sequences and synthesis of virulent viruses, such as the 1918 influenza strain, responsible for death of an estimated 3% of the world population. Given these concerns, physicians, including surgeons should familiarize themselves with the manifestations of infection due to these pathogens. The typical agent is selected for the ability to be spread via the inhalational route, as this is the most efficient mode of mass exposure. Several potential agents are discussed in the following sections.

Bacillus anthracis (Anthrax)

Anthrax is a zoonotic disease occurring in domesticated and wild herbivores. The first identification of inhalational anthrax as a disease occurred among woolsorters in England in the late 1800s. The largest recent epidemic of inhalational anthrax occurred in Sverdlovsk, Russia, in 1979 after accidental release of anthrax spores from a military facility. Inhalational anthrax develops after a 1- to 6-day incubation period, with nonspecific symptoms, including malaise, myalgia, and fever. Over a short period of time, these symptoms worsen, with development of respiratory distress, chest pain, and diaphoresis. Characteristic chest roentgenographic findings include a widened mediastinum and pleural effusions. A key aspect in establishing the diagnosis is eliciting an exposure history. Rapid antigen tests are currently under development for identification of this gram-positive rod. Postexposure prophylaxis consists of administration of either ciprofloxacin or doxycycline.⁹³ If an isolate is demonstrated to be penicillin-sensitive, the patient should be switched to amoxicillin. Inhalational exposure followed by the development of symptoms is associated with a high mortality rate. Treatment options include combination therapy with ciprofloxacin, clindamycin, andrifampin; clindamycin added to block production of toxin, while rifampin penetrates into the central nervous system and intracellular locations.

Yersinia pestis (Plague)

Plague is caused by the Gram-negative organism Yersinia pestis. The naturally occurring disease in humans is transmitted via flea bites from rodents. It was the first biologic warfare agent, and was used in the Crimean city of Caffa by the Tartar army, whose soldiers catapulted bodies of plague victims at the Genoese. When plague is used as a biologic warfare agent, clinical manifestations include epidemic pneumonia with blood-tinged sputum if aerosolized bacteria are used, or bubonic plague if fleas are used as carriers. Individuals who develop a painful enlarged lymph node lesion termed a “bubo” associated with fever, severe malaise, and exposure to fleas should be suspected to have plague. Diagnosis is confirmed via aspirate of the bubo and a direct antibody stain to detect plague bacillus. Typical morphology for this organism is that of a bipolar safety-pin–shaped Gram-negative organism. Postexposure prophylaxis for patients exposed to plague consists of doxycycline. Treatment of the pneumonic or bubonic/septicemic form includes administration of either streptomycin, an aminoglycoside, doxycycline, ciprofloxacin, levofloxacin, or chloramphenicol.⁹⁴

Smallpox

Variola, the causative agent of smallpox, was a major cause of infectious morbidity and mortality until its eradication in the late 1970s. During the European colonization of North America, British commanders may have used it against native inhabitants and the colonists by distribution of blankets from smallpox victims. Even in the absence of laboratory-preserved virus, the prolonged viability of variola virus has been demonstrated in scabs up to 13 years after collection; the potential for reverse genetic engineering using the known sequence of smallpox also makes it a potential biologic weapon. This has resulted in the United States undertaking a vaccination program for key health care workers.⁹⁵ Variola virus is highly infectious in the aerosolized form; after an incubation period of 10 to 12 days, clinical manifestations of malaise, fever, vomiting, and headache appear, followed by development of a characteristic centripetal rash (which is found to predominate on the face and extremities). The fatality rate may reach 30%. Postexposure prophylaxis with smallpox vaccine has been noted to be effective for up to 4 days postexposure. Cidofovir, an acyclic nucleoside phosphonate analogue, has demonstrated activity in animal models of poxvirus infections and may offer promise for the treatment of smallpox.⁹⁶

Francisella tularensis (Tularemia)

The principal reservoir of this Gram-negative aerobic organism is the tick. After inoculation, this organism proliferates within macrophages. This organism has been considered a potential bioterrorist threat due to a very high infectivity rate after aerosolization. Patients with tularemia pneumonia develop a cough and demonstrate pneumonia on chest roentgenogram. Enlarged lymph nodes occur in approximately 85% of patients. The organism can be cultured from tissue samples, but this is difficult, and the diagnosis is based on acute-phase agglutination tests. Treatment of inhalational tularemia consists of administration of an aminoglycoside or second-line agents such as doxycycline and ciprofloxacin.