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Infection and Sepsis Frank M.P. van Haren, Norbert Foudraine, and Michael Gillham

Infection may be acquired in a hospital (nosocomial) or in the community. Most infections encountered in a cardiothoracic intensive care unit (ICU) are nosocomial; important exceptions are infective endocarditis and postpneumonic empyema. Community-acquired pneumonia is rarely managed in the cardiothoracic ICU and is not discussed here. Nosocomial infections are reasonably common following cardiac surgery; incidences of 5.0% and 21.7% have been reported.1,2 They are associated with the development of multiple organ failure, prolonged hospital stay, and increased mortality rates.1,2 In cardiac surgery patients, the three common locations of nosocomial infection are the lungs, the central venous catheters, and the surgical site.1 This chapter is divided into three sections: (1) the prevention of infection; (2) the diagnosis and management of common infections in cardiac and thoracic surgery patients; and (3) antimicrobial therapy.

PREVENTION OF NOSOCOMIAL INFECTION The normal floras of the skin, gut, and oropharynx are responsible for most nosocomial infections.3 Risk factors for nosocomial infection include the presence of indwelling invasive devices, immunosuppression due to drugs or critical illness, hyperglycemia, inappropriate use of antimicrobials, and inadequate infection-control policies. Infection may also pass among patients and staff by direct contact (usually by the hands of healthcare workers) or, occasionally, by droplet or airborne spread. The incidence of cross-transmission of nosocomial pathogens has been reported to be 10.7 and 39.3 per 1000 patient days.4,5 General strategies for preventing nosocomial infection are discussed first; strategies for preventing specific infections are discussed in the subsequent material. 510

Standard Precautions Strict adherence to a hand hygiene policy is the most effective way of preventing nosocomial infection. Hands that are dirty or are contaminated with blood or other bodily fluids should be washed with an antimicrobial soap and water. Hand decontamination may be carried out with either an alcohol-based hand rub or with an antimicrobial soap and water; this should be carried out prior to and following all patient contact. Nonsterile gloves should be worn for any intervention in which contact with bodily fluids is possible. A gown, a mask, and eye protection should be worn during any activity that is likely to generate splash or spray of bodily fluids (e.g., suctioning the trachea). When the gloves are removed, hand decontamination should be repeated.6

Patient Isolation In addition to standard precautions, which apply to all patients at all times, there are two types of patient isolation: protective and source. Protective isolation is for patients who are highly susceptible to infection. Source isolation is for patients who are colonized by or infected by a microorganism that presents a risk to other patients or to staff. In protective isolation, patients should be nursed in a positive-pressure single room; in source isolation, if airborne transmission is possible, patients should be nursed in a negative-pressure single room in which the air is vented to the outdoors. A single room with standard ventilation is sufficient for patients with infections that are spread by droplet or contact. For protection against contact-transmitted pathogens— such as methicillin-resistant Staphylococcus aureus (MRSA)—gloves and gown should be worn. For protection against transmission of pathogens by droplet (e.g., influenza,

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Neisseria meningitidis) or air (e.g., tuberculosis), eye protection and a mask should be worn. In the case of airborne transmission, it should be an N-95 mask or a respirator. A sign on the door should indicate which type of isolation is in force and should specify whether contact, droplet, or airborne precautions are required. Gloves, masks, and gowns should be discarded before leaving the room, and hands should be washed. The door to the room should be kept closed when not in use. Patient isolation is not commonly required in a cardiothoracic ICU. Protective isolation using contact and droplet precautions may be used for transplant recipients who are heavily immunosuppressed, but it is not indicated following routine heart or lung transplantation. Source isolation using contact precautions may be used in patients colonized by multiresistant microorganisms such as extended-spectrum β-lactamase (ESBL)-producing, gram-negative bacilli or MRSA. Source isolation with airborne precautions should be used with patients who have active pulmonary tuberculosis.

Antimicrobial Prophylaxis Antimicrobial prophylaxis reduces the incidence of surgical site infections and should be administered to all patients prior to cardiac or thoracic surgery 30 to 120 minutes prior to skin incision.7 In most circumstances a firstgeneration cephalosporin such as cephazolin is appropriate. Cephazolin is active against many staphylococci, streptococci, and some Enterobacteriaceae species (defined in Table 35-1). When infection with Haemophilus influenzae is likely (e.g., in patients with chronic obstructive pulmonary disease undergoing lung resection) Table 35-1

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a second-generation cephalosporin such as cefuroxime may be justified. With the increasing prevalence of MRSA, some units favor a glycopeptide (vancomycin or teicoplanin) for prophylaxis. However, in a recent metaanalysis of randomized trials, glycopeptide use was not associated with a reduction in surgical site infections.8 Because of this, and because of concerns regarding the development of glycopeptide-resistant organisms, routine prophylaxis should remain a β-lactam.9 A glycopeptide may be used in patients who are allergic to β-lactams or when colonization with MRSA has been confirmed. The appropriate duration of treatment is controversial. The Society of Thoracic Surgeons recommends that 48 hours is effective and is unlikely to promote antimicrobial resistance.10 Single-dose regimes may also be effective but there are inconclusive data; regimes longer than 48 hours may increase the incidence of antimicrobial resistance.10 In addition, intranasal mupirocin, commenced preoperatively and continued twice daily for 5 days postoperatively, may reduce the incidence of Staphylococcus aureus infections among patients who are nasal carriers of this organism.11 Selective decontamination of the digestive tract includes the application of topical, nonabsorbable antibiotics in the oropharynx, stomach, and intestines in combination with systemic antibiotics during the first days of mechanical ventilation. It reduces the incidence of ventilator-associated pneumonia (VAP) and lowers mortality rates in selected high-risk patients (e.g., those with severe burns)12; however, it potentially increases antimicrobial resistance—especially in institutions with endemic multiresistant microorganisms—and is not widely used in cardiac surgery units.

Commonly Isolated Bacteria in Patients With Nosocomial Infections

Microorganism

Notes

Gram-Positive Cocci Staphylococcus aureus (2)

Commonly present on skin and in upper respiratory tract of healthy individuals Is responsible for all types of nosocomial infections, but particularly surgical site infections

Coagulase-negative staphylococci (1)

Commensal of the skin Weakly pathogenic but can cause CRBI and surgical site infections Common contaminant of blood cultures

Enterococci (4) (e.g., E. faecalis and E. faecium)

Commensal of the gastrointestinal tract Previously classified as Streptococci (group D) Responsible for CRBI and UTIs

Streptococci

Commensal of the skin and upper respiratory tract Cause many community-acquired infections (e.g., infective endocarditis, pneumonia, meningitis), but are relatively uncommon causes of nosocomial infection S. pneumoniae can cause nosocomial pneumonia. Continued

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Table 35-1

Commonly Isolated Bacteria in Patients With Nosocomial Infections—cont’d

Microorganism

Notes

Gram-Negative Bacilli Enterobacteriaceae The following genera cause nosocomial infection: Enterobacter (5) (e.g., E. cloacae) Escherichia (6) (e.g., E. coli) Klebsiella (8) (e.g., K. pneumoniae) Proteus (e.g., P. mirabilis) Serratia (e.g., S. marcescens) Morganella (e.g., M. morganii)

Constitute part of the normal gut flora (i.e., enteric-gram negative bacilli) Responsible for most types of nosocomial infections, but particularly pneumonia and UTIs

Nonfermenting Gram-Negative Bacilli Pseudomonas aeruginosa (3) Stenotrophomonas maltophilia Burkholderia spp.

Ubiquitous in nature Commonly colonize hospitalized patients Opportunistic pathogens Rarely cause infection in healthy people Responsible for most types of nosocomial infection but particularly pneumonia, wound infections, and catheter-related infection Burkholderia spp. cause infections in patients with cystic fibrosis (see Chapter 13).

Gram-Negative Coccobacilli Haemophilus influenzae

Common commensal of the upper respiratory tract Cause of nosocomial pneumonia

Acinetobacter spp. (sometimes classified as a nonfermenting gram-negative bacillus)

Commensal on skin and in both the respiratory and gastrointestinal tracts Cause of nosocomial pneumonia

Moraxella catarrhalis

Commensal of the upper respiratory tract Cause of nosocomial pneumonia

Anaerobes (e.g., Bacteroides spp., Prevotella spp., Fusobacterium spp., Peptostreptococcus spp.)

Commensals of the upper respiratory tract and gut Rarely cause pure-growth infections but may complicate polymicrobial infections, particularly those due to intraabdominal sepsis. Rarely cause pneumonia

Fungi Candida spp. (e.g., C. albicans (7))

Commensals of gastrointestinal, genitourinary, and respiratory tracts Associated with CRBI Rarely cause pneumonia

From Fridkin SK, Gaynes RP: Antimicrobial resistance in intensive care units. Clin Chest Med 20:303-316, 1999. CRBI, catheter-related bloodstream infection; UTI, urinary tract infection. Note: The numbers in parentheses indicate the relative incidence of the pathogen as a cause of nosocomial infection. Collectively, microorganisms (1) through (8) account for 70% of all nosocomial infections.7

Adjuvant Therapies Nosocomial infection is reduced by tight glucose control (see Chapter 36), by adopting a restrictive blood transfusion policy, and by using leukoreduced blood components (see Chapter 30).

Infection Surveillance Infection surveillance is an important method of reducing the incidence of nosocomial infection and is an 512

essential component of quality assurance.13 It has a number of components. At its most simple, infection surveillance involves the daily assessment of each patient in the ICU for signs of infection—in particular, careful inspection of vascular access sites and surgical site wounds, daily measurement of the leukocytes, and regular measurement of body temperature. In addition, procalcitonin and C-reactive protein levels may be useful in diagnosing and prognosticating sepsis.14,15 If infection is suspected, appropriate specimens should be sent for microbiologic analysis. Specific investigations,

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such as transesophageal echocardiography, computed tomography (CT), or bronchoscopy, may also be indicated. Indwelling catheters should be removed as soon as they are no longer required. Ideally, the infection control service or microbiology laboratory should electronically track all nosocomial infections, along with the relevant microbiologic isolates and sensitivities. Outbreaks of infection and emerging antimicrobial resistance can then be identified early and dealt with effectively. These data should be used to guide local empiric antimicrobial therapy. The term active surveillance refers to the practice of obtaining samples for microbiologic analysis in patients without clinical evidence of infection. It is not indicated routinely but may be performed in certain patients, such as those on mechanical cardiac support and those transferred from hospitals that have a high incidence of drug-resistant microorganisms (e.g., MRSA, ESBL-producing gramnegative bacilli). Positive cultures do not automatically imply the need for antimicrobial therapy, but they may be an indication for source isolation and can be used to guide antimicrobial therapy should the patient become ill.

Table 35-2

Infection and Sepsis

Risk Factors for Major Infections (Mediastinitis, Vein-Harvest Site, Sepsis) Following Cardiac Surgery

SPECIFIC INFECTIONS The microorganisms responsible for most nosocomial infections encountered in the ICU are listed in Table 35-1.

Surgical Site Infections Sternal wound infections may be classified as superficial (down to the sternum) or deep (sternal osteomyelitis or mediastinitis). Surgical site infections may also occur in saphenous vein or radial artery wounds. Mediastinitis occurs in 0.5% to 2% of patients following sternotomy16 and is associated with a substantial increase in mortality rates.17 Risk factors for major infection (defined as mediastinitis, vein harvest site infection, or septicemia) following cardiac surgery are listed in Table 35-2. Mediastinitis can also be caused by perforation of the esophagus or trachea (deep mediastinitis) or by thoracic extension of neck infections.

Prevention Prevention of surgical site infections involves meticulous aseptic technique, appropriate timing of prophylactic antimicrobials, tight perioperative glucose control, and strict adherence to a hand hygiene policy. Diagnosis Surgical site infections typically present with localized cellulitis (erythema, warmth, and tenderness) and purulent discharge. With deep infections there may be sternal instability, chest pain, and systemic upset. Wound swabs and blood cultures (two sets) should be obtained before antimicrobials are given. If mediastinitis is suspected, a

From Fowler VG Jr, O’Brien SM, Muhlbaier LH, et al: Clinical predictors of major infections after cardiac surgery. Circulation 112:I358-I365, 2005.

contrast computed tomography (CT) scan of the chest may be performed to confirm the diagnosis.18 However, most surgeons elect to proceed directly to reexploration, as it is diagnostic, provides tissue or pus for culture, and is therapeutic.

Microbiology Staphylococci, either S. aureus or a coagulase-negative staphylococcus (mainly S. epidermidis), are responsible for the majority of postoperative sternal wound infections, with gram-negative bacilli accounting for most of the remainder.19-21 More than 50% of leg wound infections are polymicrobial; multiple enteric gram-negative organisms are commonly identified.19 Polymicrobial mediastinal infection implies a serious breach of aseptic technique, such as that which may occur during lifesaving chest reopening in the ICU. Mediastinitis due to perforation of the esophagus or trachea is also likely to be polymicrobial, commonly involving enteric gram-negative bacilli and oropharyngeal streptococci, gram-negative coccobacilli, and anaerobes. Treatment For superficial cellulitis, oral antimicrobial therapy for 5 to 7 days is usually sufficient. If pus is draining from the wound, the skin sutures may be removed to 513

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facilitate drainage. If there is copious pus, sternal instability, severe pain, or systemic upset, intravenous antimicrobials should be given and reexploration considered. At the completion of reexploration, the sternum is usually rewired over multiple mediastinal drains. The drains may be continuously irrigated with antimicrobial or antiseptic solution for several days.22 If there is extensive necrosis of the sternum and mediastinal tissues, closure of the sternum may be delayed. Once infection has settled and granulation tissue has formed, the wound may be closed directly or, more commonly, via a muscle flap reconstruction.23 Right ventricular laceration is a rare but usually fatal complication of open sternal wounds.24 A vacuum-assisted closure device may be used to promote the healing of open sternal (and leg) wounds and is an effective bridge between débridement and delayed definitive closure.25 Intravenous antimicrobials should be continued for at least 2 weeks; a longer course may be indicated if there are ongoing signs of infection or osteomyelitis or if a prosthetic valve is in situ. Infected leg wounds occasionally require surgical débridement and either delayed closure or closure by secondary intention (i.e., by the formation of granulation tissue).

Empiric Antimicrobial Therapy. Empiric antimicrobial therapy should be guided by local patterns of prevalence and resistance, in particular the frequency of occurrence of MRSA. Superficial sternal infections may be treated with an antistaphylococcal penicillin (e.g., nafcillin) or a first-generation cephalosporin (e.g., cephazolin). This treatment should be reviewed after 48 to 72 hours on the basis of the patient’s clinical response and the culture results. For deep sternal wound infections, it is prudent Table 35-3

to provide empiric cover against MRSA and coagulasenegative staphylococci (e.g., with vancomycin) and against gram-negative bacilli (e.g., with an aminoglycoside). For infected leg wounds, empiric treatment with amoxicillin/clavulanic acid or cefuroxime is appropriate. For mediastinitis due to esophageal perforation, an aminoglycoside plus either amoxicillin/clavulanic acid or cefuroxime and metronidazole is appropriate.

Pleural Space Infections Definitions and Causes Pleural space infections include complicated exudative pleural effusions and empyema. Pleural effusions may be classified as transudative or exudative on the basis of their biochemistry (Table 35-3).26 Transudative effusions are due to disturbances in the capillary Starling forces (see Equation 1-12) caused by conditions such as heart failure and liver cirrhosis. Transudative fluid is typically clear, low in protein, and acellular. Exudative effusions are due to inflammation or infection and are associated with conditions such as bacterial pneumonia (parapneumonic effusions), tuberculosis, connective tissue disorders, lung or pleural malignancy, pulmonary embolism, and postpericardectomy syndrome (see Chapter 20). Exudative effusions may be further classified as simple or complicated (see Table 35-3). Simple exudative effusions result from increased permeability of the pleura to protein and fluid, and they do not necessarily imply infection. Complicated exudative effusions result from invasion of the pleural space by microorganisms. They are characterized by a high neutrophil count, high lactate dehydrogenase concentration (due to neutrophil lysis),

Chemistries of Transudative Pleural Effusions, Exudative Pleural Effusions (Simple and Complicated), and Empyema

From Maskell NA, Butland RJ: BTS guidelines for the investigation of a unilateral pleural effusion in adults. Thorax 58(suppl 2): ii8-ii17, 2003; Chapman S, Davies RJ: Recent advances in parapneumonic effusion and empyema. Curr Opin Pulmon Med 10:299-304, 2004; Light RW, MacGregor MI, Luchsinger PC, et al: Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med 77: 507-513, 1972. LDH, lactate dehydrogenase. *If effusion protein is 25 to 35 g/l, the Light criteria should be used. Light’s criteria: if any one of the following is true, the fluid is an exudate: Fluid/plasma protein ratio >0.5. Fluid/plasma LDH ratio >0.6. Fluid LDH >2⁄3 the upper limit for normal plasma LDH.

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and a low glucose concentration and pH (due to anaerobic glucose utilization by bacteria and neutrophils).27 The fluid is cloudy because of the presence of cellular debris. Activation of the coagulation cascade leads to fibrin deposition and the formation of loculations within the effusion. Undrained, complicated effusions can lead to empyema, which is defined as pus within the pleural space. There is marked fibroblast activity, which leads to thickening and fibrosis of the pleura. Even when there is active infection, bacteria are not commonly seen on gram stain or grown from fluid sampled from a complicated effusion or empyema. Neutrophils and other inflammatory cells rapidly clear bacteria from the pleural space, which may reduce the number of bacteria to below the threshold visible on microscopy. Treatment with antimicrobials prior to fluid sampling may affect staining of bacteria for microscopy and may also inhibit microorganism growth in vitro. Some pathogenic microorganisms, notably anaerobes, are fastidious (i.e., have complicated nutritional requirements), which makes it difficult to grow them in vitro. Community-acquired bacterial pneumonia is the most common cause of empyema. Sometimes empyema arises spontaneously, commonly in patients with lung disease but occasionally in young, healthy people. In the latter case, the causative organism is often one of the Streptococcus milleri group. Other causes of empyema include subdiaphragmatic infection (e.g., cholecystitis); postoperative infection (e.g., mediastinitis or bronchopleural fistula); esophageal perforation (e.g., following surgery or perforation by a foreign body); and infections related to chest trauma or intercostal drain sites.

Diagnosis Patients with complicated effusions and empyema are typically systemically unwell and show signs of sepsis. They may have productive cough, chest pain, and respiratory distress. The appearances of chest radiographs are variable. Free-flowing effusions produce characteristic changes on erect and supine films (see Chapter 6). Loculated effusions or pleural thickening may produce nondependent pleural-based opacities (Fig. 35-1). There may be signs of the underlying cause of empyema, such as consolidation of the lung (pneumonia) or an air fluid level (bronchopleural fistula). Ultrasound scanning is useful to confirm the presence and volume of fluid in the pleural space, to identify septations, and to guide diagnostic thoracocentesis.28 Thickening and enhancement of the parietal pleura in conjunction with pleural collection as seen on contrast-enhanced CT scan are strongly suggestive of empyema (Fig. 35-2).29 CT scanning may also identify the cause. Septations are not easily seen on CT scans. Microbiology Causative microorganisms include Streptococci species (S. pneumoniae, S. milleri group, viridans group); S. aureus;

Infection and Sepsis

Figure 35.1: Erect chest radiograph of a left-sided nondependent pleural collection consistent with empyema.

enteric gram-negative bacilli (particularly Klebsiella pneumoniae and Escherichia coli); Pseudomonas aeruginosa; Haemophilus influenzae; and anaerobes.30 With hospitalacquired empyema, similar microorganisms are identified, but it is more common to find Enterococcus species, MRSA, S. milleri, and multi-drug-resistant gram-negative bacilli (particularly P. aeruginosa).30 Occasionally, Candida species are responsible for empyema.

Treatment of Exudative Effusions Simple parapneumonic effusions usually resolve spontaneously with treatment of the underlying pneumonia. In general, thoracocentesis should be performed in all

Figure 35.2: Transverse CT scan of a right-sided, loculated empyema. The parietal pleura (arrows) is thickened. Both an anterior and a posterior pleural collection are seen, along with a thinner collection laterally.

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parapneumonic effusions because clinical differentiation between simple and complicated effusions is unreliable.31 Effusions in patients with hypoalbuminemia, heart failure, or atelectasis are at low risk for infection and do not require sampling (but may need draining if they are large). Effusions in patients with either pneumonia or sepsis and effusions that are associated with thickening of the parietal pleura on CT scan or loculations on ultrasound scanning should be sampled.31 If thoracocentesis reveals a complicated effusion, it should be drained to prevent progression to empyema.32 If the effusion is relatively free-flowing, tube thoracostomy using a large-bore tube (e.g., 36F) is appropriate. If there are numerous septations or there has not been substantial radiographic resolution of the effusion within 24 hours of tube thoracostomy, intrapleural fibrinolytic therapy may be considered. With this technique, 100,000 IU of urokinase or 250,000 IU of streptokinase in 100 ml of 0.9% saline is instilled into the chest cavity and the tube clamped for 1 to 4 hours. This can be repeated once or twice a day for 2 to 4 days. Systemic fibrinolysis does not occur. The value of intrapleural fibrinolytic therapy, in terms of radiographic and clinical improvement, has been demonstrated in a number of small studies. However, in a recent large, randomized trial, intrapleural streptokinase was not associated with a reduced need for surgery or with improved survival rates.33 Thus, if the technique is not rapidly effective, patients should undergo surgery. Antimicrobial therapy for complicated effusions is the same as for empyema, described subsequently.

Treatment of Empyema Once a fluid sample has been obtained by needle thoracocentesis, intravenous antimicrobials should be commenced empirically. For community-acquired empyema, amoxicillin/clavulanic acid or a secondgeneration cephalosporin (e.g., cefuroxime) combined with metronidazole may be used.34 An alternative for patients allergic to penicillins is clindamycin plus a fluoroquinolone (e.g., ciprofloxacin). For hospitalacquired empyema, a carbapenem plus vancomycin is appropriate.34 Antimicrobial therapy should be adjusted on the basis of culture and sensitivity results, but empiric cover against anaerobes should continue because these organisms are commonly present but frequently are not isolated on culture. Aminoglycosides have poor penetration into empyemas and are best avoided. Following drainage of an empyema, antimicrobial therapy should continue for a minimum of 3 weeks.34 Effective drainage of an organized empyema in which there are extensive loculations and pleural thickening requires surgery. There are two main approaches: (1) open thoracotomy and decortication; (2) videoassisted thoracoscopic débridement. The latter is a relatively new technique that appears to be safe and effective in experienced hands.35,36 During surgery, loculations must be broken down, pus drained, and any thickened visceral 516

pleura excised (decortication) to allow the collapsed lung to reexpand. Specimens for culture should be obtained at the time of surgery and their results used to guide antimicrobial therapy. Decortication of a chronically organized empyema can result in substantial perioperative blood loss. Postoperatively there may be marked systemic inflammatory response, including fever, tachycardia, third-space fluid losses, and vasodilatation. Positive-pressure ventilation may be difficult because of air leaks, acute lung injury, and poor reexpansion of the affected lung.

Postpneumonectomy Empyema Empyema that occurs within the first few weeks after pneumonectomy is usually caused by a bronchopleural fistula. Patients present with fever, cough, purulent or hemorrhagic sputum, respiratory distress and, occasionally, sepsis and acute respiratory failure. Chest radiographs typically demonstrate increased air content and reduced fluid levels within the pleural space. There may be soiling of the nonoperative lung demonstrated by pulmonary infiltrates on the chest radiograph (see Fig. 12-6). Empyema that occurs more than 3 months after pneumonectomy is usually due to hematogenous spread of infection into the pleural space. Patients typically present subacutely with malaise, flulike symptoms, low-grade fever, and weight loss. The diagnosis of a bronchopleural fistula is usually confirmed by bronchoscopy or a contrast-enhanced CT scan of the chest. Alternatively, methylene blue can be instilled into the pleural space and recovered from the sputum. Needle aspiration of the thoracic space is rarely helpful in the acute setting, but if it is undertaken, it should be guided by ultrasound. Two sets of blood cultures should be obtained before starting antimicrobial therapy. Causative organisms and empiric antimicrobial therapy are as described for hospital-acquired empyema. In particular, antimicrobials against MRSA and P. aeruginosa must be administered until culture results are available. Surgical treatment of a bronchopleural fistula is described in Chapter 12.

Infective Endocarditis Infective endocarditis37 is infection of the cardiac endothelium or of prosthetic material implanted in the heart (e.g., heart valves or pacemaker leads). It typically develops following bacteremia, for instance, after a medical procedure or injection drug use, in patients with underlying cardiac disease. Rapid diagnosis and treatment are essential because the mortality rate resulting from untreated infective endocarditis is high.

Pathophysiology and Risk Factors The initiating event of infective endocarditis is the formation of fibrin-platelet thrombus on damaged endothelium or prosthetic material.38 With bacteremia, microorganisms seed on the thrombus. Bacterial replication

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and further thrombosis lead to the formation of infected vegetations (see Fig. 7-11). Clinical disease may take several weeks to develop following a bacteremic episode. Infection may result in localized tissue destruction, which can cause valve regurgitation, abscesses, or fistulae. Abscesses (see Fig. 7-14) and fistulae typically involve the aortic root. Very occasionally, large vegetations cause valve stenosis. There may be systemic emboli, including cerebral and pulmonary emboli. Pulmonary emboli arise from right-sided vegetations, whereas cerebral emboli arise from left-sided vegetations. Systemic embolization resulting from right heart lesions can occur in a patient with an intracardiac shunt or a patent foramen ovale. Right-sided lesions are associated with injection drug use. The risk for infective endocarditis with various cardiac lesions is summarized in Table 10-7; congenital cardiac lesions and rheumatic heart disease underlie most cases.

Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. As much as one third of cases of infective endocarditis are culture-negative.

Microbiology Gram-positive microorganisms are responsible for the majority of cases of infective endocarditis. They include (1) streptococci, particularly viridans streptococci (e.g., Streptococcus sanguis, S. mutans, S. mitis); β-hemolytic streptococci (e.g., S. pyogenes, S. agalactiae); and nonhemolytic streptococci (e.g., S. bovis); (2) staphylococci, particularly Staphylococcus aureus and coagulase-negative staphylococci (primarily S. epidermidis); (3) enterococci (e.g., Enterococcus faecium, E. faecalis). Viridans streptococci and S. aureus cause most cases of native valve endocarditis, whereas S. aureus and coagulase-negative staphylococci are important causes of prosthetic valve endocarditis occurring early after implantation (Table 35-4). Less common (<10%) causes of infective endocarditis include gramnegative bacilli, fungi, and the HACEK group of microorganisms. The HACEK group are fastidious, slow-growing, gram-negative coccobacilli from the oropharynx which, although constituting only 3% to 4% of infective endocarditis, are increasing in prevalence. They are composed of Haemophilus species,

Clinical Features Infective endocarditis may have an acute or a subacute course. The acute form is commonly caused by S. aureus. Signs of sepsis are common, and valvular destruction and abscess formation (with aortic valve involvement) occur early. More commonly, infective endocarditis has a subacute course with symptoms of fever, malaise, and musculoskeletal pain extending over several weeks. Acute valvular regurgitation is less common with subacute endocarditis. Signs of cardiac involvement include a new or changing murmur, abnormalities of cardiac conduction, or clinical features of heart failure and valvular regurgitation. First-degree heart block with a progressively lengthening PR interval strongly suggests an aortic root abscess. Neurologic complications occur in about one third of patients. They may take the form of a generalized encephalopathy—thought to be due to multiple microemboli—or of a focal neurologic deficit due to a macroembolus with or without cerebral abscess formation.

Table 35-4

Diagnosis The diagnosis of infective endocarditis rests on clinical, microbiologic, and echocardiographic criteria, as outlined in Table 35-5.37,39 Infective endocarditis should be suspected in any at-risk patient who develops a febrile illness. Three sets of blood cultures should be obtained between 30 and 60 minutes apart, and an echocardiogram should be performed (see material under Investigations). Blood samples should be incubated for at least 1 week because fastidious bacteria and fungi can occasionally be grown after the standard incubation period of 5 days.

Common Causative Microorganisms in Native and Prosthetic Valve Infective Endocarditis

Prosthetic Valve Microorganism

Native Valve (%)

Early (<60 days) (%)

Late (>12 months) (%)

Streptococci spp.

30 to 65

1

30 to 33

Staphylococcus aureus

25 to 40

20 to 24

15 to 20

Coagulase-negative staphylococci

3 to 8

30 to 35

10 to 12

Enterococcus spp.

5 to 17

5 to 10

8 to 12

Gram-negative bacilli

4 to 10

10 to 15

4 to 7

From Mylonakis E, Calderwood SB: Infective endocarditis in adults. N Engl J Med 345:1318-1330, 2001.

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Table 35-5

Modified Duke Criteria for Diagnosing Infective Endocarditis

Major Criteria Microbiologic Typical microorganisms isolated from two separate blood cultures: viridans streptococci, Streptococcus bovis, HACEK group,* Staphylococcus aureus, or community-acquired enterococcal bacteremia, without a primary focus Microorganisms consistent with infective endocarditis isolated from persistently positive blood cultures** A single positive blood culture for Coxiella burnetii or phase I IgG antibody titer to C. burnetii that is greater than 1:800 Evidence of endocardial involvement Positive echocardiogram† (TEE recommended in patients with prosthetic valves, those rated as at least “possible endocarditis” by clinical criteria, and those with complicated endocarditis [paravalvular abscess]) New valvular regurgitation

Minor Criteria Predisposition to endocarditis by certain cardiac conditions or injection drug use Fever (>38°C) Vascular phenomena (conjunctival hemorrhage, Janeway lesions) Immunologic phenomena (Roth spots, Osler nodes, polyarthritis, glomerulonephritis) Positive microbiology not meeting major criteria From Mylonakis E, Calderwood SB: Infective endocarditis in adults. N Engl J Med 345:1318-1330, 2001; Li JS, Sexton DJ, Mick N, et al: Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 30:633-638, 2000. TEE, transesophageal echocardiography. Note: A definite diagnosis requires: (1) two major criteria; (2) one major criterion plus three minor criteria; or (3) five minor criteria. A possible diagnosis requires: (1) one major criterion and one minor criterion; (2) three minor criteria. *See text for details. **The term persistently positive blood cultures is defined as at least two blood cultures drawn more than 12 hours apart, or three of three or a majority of four or more blood cultures drawn over the span of at least 1 hour. † An echocardiogram is positive when any of the following are seen: (1) a discrete, echogenic, oscillating intracardiac mass located at the site of endocardial injury; (2) a periannular abscess; (3) a new dehiscence of a prosthetic valve.

Brain CT scanning may reveal asymptomatic cerebral abscesses. Mycotic aneurysms may involve the large arteries. A variety of peripheral embolic, vascular, and immunologic phenomena may be identified. Petechiae are small purplish spots that may be present in the conjunctiva, the mucous membranes of the mouth, and on the skin—commonly on the fingertips. Splinter hemorrhages are red or brown linear marks under the fingernails or toenails. Osler nodes are small painful pink nodules on the pads of the fingers and toes. Janeway lesions are nontender red-blue macular lesions on the palmar surface of the hands and feet. Roth spots are superficial retinal hemorrhages that may be seen on fundoscopy. Circulating immune complexes can cause polyarthritis or glomerulonephritis. However, renal dysfunction is more likely to be due to heart failure or sepsis than to glomerulonephritis. Splenomegaly is common. 518

Pain localized to a specific region (e.g., liver, bone, soft tissue) may represent an embolic abscess.

Investigations Normochromic normocytic anemia, leukocytosis, and elevated acute-phase reactants (fibrinogen, C-reactive protein, and the erythrocyte sedimentation rate) are common findings. In addition to blood cultures and an echocardiogram (see earlier discussion under Diagnosis), a chest radiograph, and an electrocardiogram should be obtained in all patients. Transesophageal echocardiography may be required to diagnose small vegetations and to fully delineate aortic root abscesses or fistulae. A contrast CT scan of the brain, abdomen, or chest should be performed if there are clinical signs of systemic embolization. Suspected bony emboli may be confirmed by a radionuclide bone scan.

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Treatment If infective endocarditis is suspected clinically and the presentation is acute, empiric antimicrobial treatment (see subsequent material) should be started as soon as blood cultures have been obtained. If the presentation is subacute, it may be reasonable to await the results of blood cultures before starting antimicrobials. Continued pyrexia despite appropriate antimicrobial therapy suggests an undrained abscess. This should be investigated by a repeat echocardiogram, chest, abdominal and pelvic CT scan and, if indicated, a radionuclide bone scan. Surgery is indicated in the following circumstances: ● ●

●

● ●

Severe valvular regurgitation Local extravalvular involvement, such as paravalvular abscess, pericarditis, fistula formation, or aneurysm formation Prosthetic valve infective endocarditis that occurs within 3 months of valve implantation Systemic emboli Persisting sepsis or worsening valvular function despite appropriate antimicrobial therapy.

Antimicrobial therapy alone is usually successful in infective endocarditis due to Streptococcus species. However, when due to S. aureus, fungi, or gram-negative microorganisms such as Serratia species and P. aeruginosa, surgery is commonly required. Risk factors for systemic embolization include vegetations greater than 10 mm diameter or highly mobile lesions attached to the anterior leaflet of the mitral valve.38 Given that more than 50% of systemic emboli involve the central nervous system, early surgery should be considered in patients with large or mobile vegetations, particularly if they are caused by S. aureus or a fungus. If medical therapy is planned for high-risk patients (i.e., those with large vegetations or valve dysfunction or if there is an aggressive causative microorganism), frequent echocardiographic assessment (e.g., every 48 to 72 hours) should be performed, and if vegetations are growing or valve function is deteriorating, surgery is indicated. The timing of surgery for patients with central nervous system emboli is problematic. If surgery is performed shortly after an embolic stroke, there is the potential for an intracerebral bleed during the perioperative period, but if surgery is delayed, there is the potential for further emboli or other complications to develop. In one study, surgery performed within 1 week of a cerebral event was associated with neurologic deterioration in 44% of patients.40 This risk fell progressively to 2.3% at 4 weeks. The risk of death fell from 31% to 7% during the same period. Thus, ideally, surgery should be delayed for 4 weeks following a neurologic event. However, in the face of recurrent emboli, persistent sepsis, or acute heart failure, surgery may have to occur earlier. Repair, rather than replacement, of an incompetent valve is preferred because it reduces the risk of recurrence

Infection and Sepsis

of endocarditis. Otherwise, when replacement is required, the usual criteria for selection of valve type should be applied (see Chapter 10). An exception to this is prosthetic aortic valve endocarditis, when the use of an aortic homograft, rather than a mechanical or a stentmounted xenograft, is associated with a reduced incidence of recurrence.41 The incidence of prostheticvalve endocarditis is highest in the first 2 months following implantation; it decreases progressively over the first year.42

Antimicrobial Therapy. For native-valve endocarditis, empiric treatment should include penicillin G (for streptococci or enterococci) plus an antistaphylococcal penicillin such as nafcillin and an aminoglycoside (e.g., gentamicin). For prosthetic-valve endocarditis, empiric treatment with vancomycin (or linezolid) plus gentamicin and rifampicin is appropriate. Antimicrobial therapy should then be rationalized on the basis of culture results. Suggested antimicrobial regimens for various microorganisms are provided in Table 35-6.37 Recommended antimicrobial prophylaxis prior to medical procedures is listed in Table 10-8.

Nosocomial Pneumonia Nosocomial pneumonia includes hospital-acquired pneumonia and VAP. The focus in this chapter is on the latter, although many of the recommendations apply equally to both. VAP is a common complication of mechanical ventilation, occurring in up to 17% of patients ventilated for longer than 48 hours. It usually develops 5 to 10 days after ICU admission.43 It is the most common nosocomial infection in cardiothoracic ICUs.1,16

Prevention In addition to the general strategies outlined earlier, the incidence of VAP is reduced by early extubation; maintaining an endotracheal cuff pressure above 20 cm H2O; nursing patients in a semirecumbent, 45-degree, head-up position; kinetic therapy (lateral rotation); and the use of noninvasive ventilation.44 Postpyloric feeding, compared with gastric feeding, has not been shown to reduce the risk of aspiration or pneumonia and should be introduced only if there is intolerance of gastric feeding.45 Continuous subglottic suctioning using custom-designed endotracheal tubes is also effective but is not widely practiced. Pharmacologic strategies to reduce bacterial colonization of the lower respiratory tract also decrease the incidence of VAP. They include application to the oropharynx of topical antimicrobials or disinfectants (chlorhexidine), selective decontamination of the digestive tract (see earlier discussion), avoidance of unnecessary antimicrobial therapy, and avoidance of antacids.44 The indications and drug choices for prophylaxis of stress ulcers are listed in Chapter 34. Sucralfate, compared with ranitidine, is associated with a reduced 519

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Table 35-6

Antimicrobial Therapy for Common Causes of Infective Endocarditis

Pathogen

Native Valve

Prosthetic Valve

Penicillin-susceptible viridans streptococci, Streptococcus bovis, and other streptococci with MIC of penicillin ≤ 0.1 μg/ml

Penicillin G or ceftriaxone for 4 weeks*

Penicillin G for 6 weeks and gentamicin for 2 weeks*

Relatively penicillin-resistant streptococci (MIC >0.1 to 0.5 μg/ml)

Penicillin G for 4 weeks and gentamicin for 2 weeks*

Penicillin G for 6 weeks and gentamicin for 4 weeks*

Streptococcal species with MIC of penicillin >0.5 μg/ml, Enterococcus spp., or nutritionally deficient cocci, e.g., Abiotrophia or Graniculata spp.

Penicillin G (or ampicillin) and gentamicin for 4-6 weeks*

Penicillin G (or ampicillin) and gentamicin for 6 weeks*

Methicillin-susceptible staphylococci (MSSA)

Nafcillin or oxacillin for 4-6 weeks, with or without addition of gentamicin for first 3-5 days of therapy**

Nafcillin or oxacillin with rifampicin for 6 weeks and gentamicin for 2 weeks**

Methicillin-resistant staphylococci

Vancomycin, with or without addition of gentamicin for first 3-5 days of therapy

Vancomycin with rifampicin for 6 weeks and gentamicin for 2 weeks

Right-sided staphylococcal native-valve infective endocarditis in selected patients

Nafcillin or oxacillin with gentamicin for 2 weeks

HACEK organisms

Ceftriaxone for 4 weeks

Ceftriaxone for 6 weeks

Adapted from Mylonakis E, Calderwood SB: Infective endocarditis in adults. N Engl J Med 345:1318-1330, 2001. Copyright © 2001 Massachusetts Medical Society. HACEK organisms, see text for details; MIC, minimum inhibitory concentration; MSSA, methicillin-sensitive Staphylococcus aureus. *Vancomycin therapy is indicated for patients with confirmed immediate hypersensitivity to β-lactam antimicrobials. **For patients with infective endocarditis due to MSSA who are allergic to penicillins, a first-generation cephalosporin or vancomycin can be substituted for nafcillin or oxacillin. Cephalosporins are contraindicated with immediate hypersensitivity reactions to β-lactam antimicrobials.

incidence of VAP; however, this advantage is offset by a slightly increased incidence of stress ulcer bleeding.44

Diagnosis VAP is usually diagnosed clinically and radiographically. Clinical signs include deteriorating gas exchange, purulent secretions, pyrexia, an abnormal leukocyte count including immature forms, and increased levels of C-reactive protein. The cardinal radiographic feature is the presence of a new pulmonary infiltrate. Commonly, only a few features of VAP are present, and it is difficult to make the diagnosis with confidence. This uncertainty has led to the development of clinical scoring systems for VAP, one of which is shown in Table 35-7; a Clinical Pulmonary Infection Score46 greater than 6 is considered diagnostic of VAP.47 If VAP is suspected, a sputum specimen should be obtained prior to starting antimicrobial therapy. It may be an aspirate obtained by blind tracheobronchial suctioning or a washing obtained during bronchoscopy. For the diagnosis of hospital-acquired pneumonia in nonventilated patients, a sputum specimen should be obtained from deep coughing. The presence of squamous cells indicates that the sample contains oropharyngeal rather 520

than tracheobronchial secretions, and any positive culture results should be interpreted with caution. Microorganisms that are commonly isolated in tracheal secretions but rarely cause pneumonia in immunocompetent patients include the viridans group of streptococci, commensal Neisseria species, Corynebacterium species, Candida species, and coagulase-negative staphylococci. Potentially pathogenic microorganisms include S. aureus, S. pneumoniae, enteric gram-negative bacilli, P. aeruginosa, H. influenzae, and Moraxella catarrhalis. Bacterial colonization of the lower respiratory tract is common in hospitalized patients, so the presence of microorganisms on gram stain or culture of tracheobronchial secretions is in itself not indicative of nosocomial pneumonia and is not an indication for antimicrobial therapy. An exception is quantitative culture of bronchial washings or protected brush specimens obtained during bronchoscopy. Pneumonia may be diagnosed on the basis of the presence of potentially pathogenic microorganisms: more than 104 or 105 colony-forming units/ml in broncoalveolar lavage and more than 103 colonyforming units/ml in protected brush specimens.44 Detection of 5% or more neutrophils or macrophages with intracellular organisms on a Wright-Giemsa stain of

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Table 35-7

Clinical Pulmonary Infection Score for Ventilator-Associated Pneumonia

Table 35-8

Infection and Sepsis

Risk Factors for Colonization With Multidrug-Resistant (MDR) Microorganisms

From American Thoracic Society, Infectious Diseases Society of America: Guidelines for the Management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388-416, 2005.

From Pugin J, Auckenthaler R, Mili N, et al: Diagnosis of ventilatorassociated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid. Am Rev Respir Dis 143:1121-1129, 1991; Singh N, Falestiny MN, Rogers P, et al: Pulmonary infiltrates in the surgical ICU: prospective assessment of predictors of etiology and mortality. Chest 114:1129-1136, 1998; Singh N, Rogers P, Atwood CW, et al: Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 162:505-511, 2000. ARDS, acute respiratory distress syndrome. Note: A score of more than 6 at baseline or 72 hours is diagnostic of pneumonia.

factors, duration of hospital stay is the most important: beyond 5 days, the causative microorganism is more likely to be multidrug-resistant. In this situation, MRSA and multiresistant Pseudomonas aeruginosa are commonly responsible, especially in the setting of a high prevalence of these microorganisms. The likely causative microorganisms and the empiric antimicrobial therapy recommended by the American Thoracic Society44 are listed in Table 35-9. Note that in contrast to empyema, VAP is rarely caused by anaerobes. These recommendations advocate an aggressive antimicrobial strategy, which ensures coverage of all likely pathogens. Within institutions, empiric treatment should take into account local patterns of prevalence and resistance. Therapy should be adjusted when culture results become available. The duration of antimicrobial treatment should be 7 to 8 days, assuming the following criteria are met44: (1) the patient has received appropriate therapy from the start; (2) there is a good clinical response to treatment; (3) there is no evidence of infection by Pseudomonas species, Acinetobacter species, or Stenotrophomonas species. If these criteria are not met, a 10- to -14 day course is appropriate.44

Intravascular Catheter-Related Infection a smear of cytocentrifuged bronchoalveolar lavage fluid is also diagnostic of VAP. Culture of blood and, if appropriate, pleural fluid should also be performed.44

Microbiology and Antimicrobial Therapy The most likely causative microorganism is determined by whether a patient has risk factors for colonization by multidrug-resistant organisms (Table 35-8). Of these risk

Intravascular catheter-related infections include exit site infections and catheter-related blood stream infections. The two conditions commonly coexist.

Exit Site Infections Signs of an exit site infection include localized redness, swelling, tenderness, and purulent discharge. As soon as 521

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Table 35-9

Pathogens Responsible for Nosocomial Pneumonia in Patients With and Without Risk Factors for Colonization by Multidrug-Resistant Microorganisms

From American Thoracic Society, Infectious Diseases Society of America: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388-416, 2005. ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus. Note: If an extended-spectrum β-lactamase-producing bacteria is suspected, a carbapenem is a reliable choice.

infection is identified, the catheter should be removed, samples obtained for cultures (pus swab of the exit site, catheter tip, and peripheral blood cultures), and empiric antimicrobial therapy considered. In the absence of systemic symptoms or particular risk factors, removal of the catheter may be sufficient. Alternatively, oral treatment with an antistaphylococcal penicillin for 7 days is appropriate. This may be modified by the clinical response to treatment and the results of microbiologic cultures. For patients in whom the consequences of bacteremia are dire, such as those who are immunocompromised or are receiving mechanical cardiac support, empiric treatment should be as for a catheter-related blood stream infection. Similarly, if blood cultures are subsequently positive, treatment as for a catheter-related blood stream infection is indicated.

Catheter-Related Blood Stream Infections Bacteremia can occur with any intravascular catheter— arterial, peripheral venous, central venous—but it occurs most commonly with central venous catheters. Risk Factors and Risk Reduction. The risk for infection48 is related to the length of time the catheter has been in place; it is close to zero for the first 3 days and increases 522

markedly after 5 to 7 days. Scheduled replacement of central venous catheters after a set time period increases the risk of mechanical complications during insertion and is not recommended.49 Risk of infection is increased by the use of large-bore, multilumen catheters and is reduced by the use of catheters impregnated with antiseptics (e.g., chlorhexidine or silver sulfadiazine) or antimicrobials (e.g., minocycline or rifampicin). Central venous catheters inserted via the subclavian route are less likely to cause infection than catheters inserted via the internal jugular or femoral route, and the subclavian site should be used if the need for central venous access is likely to be longer than 5 days (except for dialysis; see Chapter 33). Peripherally inserted central venous catheters are, in high-risk hospitalized patients, associated with a rate of catheter-related blood stream infections similar to that observed with conventional central venous catheters.50 In addition, peripherally inserted catheters are more vulnerable to thrombosis and dislodgment and are less useful for drawing blood specimens. Sterile gauze dressings have a lower rate of infection than polyurethane dressings. Infection risk is increased when the catheter is used for parenteral nutrition compared with other uses. Catheter-related infections are

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more likely in patients who are mechanically ventilated, shocked, or immunocompromised or have malignancy. Poor aseptic technique at the time of insertion is an important predictor of future infection. Thus, lines inserted in an emergency should be removed after 48 hours. The risk of infection is lower when the skin is prepared with 2% chlorhexidine rather than alcohol or iodine. The need for each vascular catheter should be reviewed daily; it is prudent to remove peripheral intravenous cannulas after 48 to 72 hours.51,52 All exit sites should be inspected for signs of infection, and the diagnosis of catheter-related blood stream infection considered in any patient with an unexplained fever or leukocytosis.

Antimicrobial Therapy. In the absence of a high local incidence of drug-resistant pathogens, intravenous treatment with an antistaphylococcal penicillin and an aminoglycoside is appropriate. If there is a high local incidence of MRSA, vancomycin should be used instead of the antistaphylococcal pencillin. In patients who are immunocompromised or have severe sepsis, a third- or fourth-generation cephalosporin should be added to provide additional cover against enteric gram-negative organisms and Pseudomonas aeruginosa.53 The recommended treatment duration is 5 to 7 days for coagulasenegative staphylococci; 10 to 14 days for S. aureus, gram-negative bacilli, and fungi; 4 to 6 weeks if there is associated infective endocarditis, infected thrombus, or osteomyelitis.56

Microbiology. The majority of catheter-related blood stream infections are caused by gram-positive cocci (coagulase-negative staphylococci, S. aureus, and Enterococcus faecalis); aerobic gram-negative bacilli (e.g., P. aeruginosa and Klebsiella pneumoniae); and rarely Candida species. Of these, coagulase-negative staphylococci, particularly S. epidermidis, are the most common causative agents but they tend to cause less severe disease than other microorganisms, such as S. aureus and Candida species.

Urinary Tract Infections

Diagnosis and Treatment. Catheter-related blood stream infections are defined as bacteremia in association with (1) clinical evidence of infection (fever, rigors, leukocytosis, tachycardia, hypotension); (2) no other cause for bacteremia; (3) the same microorganism identified in a peripheral blood culture and on the catheter tip.48,53 If the diagnosis is suspected, peripheral blood cultures should be obtained. If the index of suspicion of a catheter-related infection is low (i.e., no local signs of infection, catheter in situ for fewer than 3 days, probable other site of infection), the catheter may be left in place and the results of cultures awaited. If the index of suspicion is high, then in addition to blood cultures, the catheter should be removed, the tip cultured, and empiric antimicrobial therapy started. Prior to removing the catheter, the skin should be swabbed with disinfectant to reduce contamination of the tip during removal. Once removed, the catheter tip should be cut with sterile scissors so that it falls into a sterile specimen container. Removal and reinsertion of a new catheter over a guide wire is controversial. Guide wire exchanges avoid the risk of a second central venous puncture and, with antimicrobial cover in the controlled environments of clinical trials, they do not increase the infection rate.54,55 However, guide wire exchanges require temporary loss of central venous access and in day-to-day practice are difficult to perform in a completely sterile manner. Thus, in most situations, we recommend the insertion of a second catheter in a new site.

Nosocomial urinary tract infection (UTI) is related primarily to the presence of a urinary catheter. Members of the Enterobacteriaceae family (see Table 35-1) of enteric gram-negative bacilli, particularly E. coli, cause most UTIs. These microorganisms colonize the perineum and urethra and gain access to the bladder via the urinary catheter, either at the time of its insertion or subsequently. A blocked urinary catheter with a residual bladder urine volume further predisposes to UTI. Bacteriuria is defined as the presence of 100 or more colony-forming units of bacteria per ml of urine and occurs in about 25% of patients who have a urinary catheter in situ for 2 to 10 days.57 In itself, it is not an indication for antimicrobial treatment. The distinction between clinical infection and asymptomatic colonization is not straightforward. Symptoms such as urinary frequency and dysuria are not experienced in catheterized, sedated patients, but suprapubic pain or discomfort may be. The presence of red or white blood cells in the urine is also not necessarily indicative of infection. Most catheter-related UTIs involve the lower urinary tract, but occasionally pyelonephritis occurs. The presence of flank pain, nausea, vomiting, and signs of systemic sepsis are consistent with a diagnosis of upper UTI. If an upper UTI is suspected, blood cultures should be taken and ultrasound imaging of the renal tract and kidneys should be performed to rule out ureteric obstruction. Occasionally, sepsis (or even septic shock) develops within a few hours of urinary catheterization due to bacteremia. Unlike outcomes in other forms of septic shock, outcomes of urinary tract sepsis are very good if appropriate antimicrobial therapy is commenced early. Empiric treatment with gentamicin or, if there is renal dysfunction, intravenous aztreonam or ciprofloxacin is appropriate. Antimicrobial therapy should continue for 5 days. Removal of the urinary catheter increases the likelihood that treatment will be successful, but if the catheter is still required, changing it is not indicated. 523

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Intraabdominal Infections The main causes of abdominal sepsis in postoperative cardiac surgery patients are mesenteric infarction, perforated peptic ulcer, cholecystitis, and diverticulitis. These conditions, with the exception of diverticulitis, are discussed in Chapter 34. Pseudomembranous colitis is due to bacterial overgrowth by toxin-producing Clostridium difficile; it too is discussed in Chapter 34. Infections are commonly polymicrobial, and empiric antimicrobial therapy should be directed against enteric gram-negative bacilli (i.e., Enterobacteriaceae), Enterococcus species, and enteric anaerobes (e.g., Bacteroides fragilis). This may be achieved by means of “triple” therapy: gentamicin (for gram-negative bacilli), metronidazole (for anaerobes), and amoxicillin (for Enterococcus species). Aztreonam may be substituted for gentamicin in patients with renal failure. Depending on local resistance patterns, alternative strategies include the use of meropenem or piperacillin/tazobactam. In high-risk patients, treatment with theconazole may decrease mortality as infection with Candida may occur.58

Sepsis and Septic Shock Infection can cause systemic inflammation (see Chapter 2) which, depending on the severity, is defined as sepsis, severe sepsis, or septic shock (Table 35-10).59 Note that although there must be clinical evidence of infection, positive blood cultures are not mandatory for diagnosing sepsis. The likelihood that a blood culture will be positive is determined by the severity of the illness. In one large series, blood cultures were positive in 17% of patients with sepsis and 69% with septic shock.60

Table 35-10

Definitions of Sepsis Syndromes

Sepsis SIRS (see Table 2-1) plus evidence of infection Severe Sepsis Sepsis associated with organ dysfunction, hypoperfusion, or hypotension Septic Shock Sepsis with hypotension despite adequate fluid resuscitation (From American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864-874, 1992. Hypotension, a systolic blood pressure less than 90 mmHg or a reduction of more than 40 mmHg from baseline; SIRS, systemic inflammatory response syndrome. Note: Signs of hypoperfusion include oliguria, lactic acidosis, and altered mentation. See also Table 20-3.

524

Conversely, signs of sepsis are absent in 30% of patients with positive blood cultures.61 Sepsis and, to a lesser extent, severe sepsis are common accompaniments of nosocomial infections, particularly those due to surgical site infections and VAP. However, septic shock is relatively uncommon in the cardiothoracic ICU. When septic shock does occur, mortality rates are very high. Also, septic shock must be distinguished from noninfective causes of severe systemic inflammation, notably those that sometimes occur following cardiopulmonary bypass. The pathophysiology and causes of postoperative systemic inflammation and vasodilatory shock are outlined in Chapter 2.

Clinical Presentation Patients with sepsis typically have systemic upset with fever, sweating, chills, rigors, and tachycardia. Fever may be absent in patients receiving extracorporeal membrane oxygenation or renal replacement therapy and in patients who are severely immunocompromised. The complete blood count may demonstrate an increased or decreased leukocyte count with immature forms (band neutrophils, metamyelocytes). Inflammatory markers (C-reactive protein and procalcitonin) are typically elevated. In severe sepsis, there are signs of organ dysfunction, such as oliguria, confusion, hypoxemia, hypotension, and lactic acidosis. A persistently elevated lactate level despite appropriate resuscitation measures is an important marker of death in patients with septic shock.62,63 There may be thrombocytopenia and coagulopathy. A primary focus of sepsis may be identified; for instance, purulent discharge from the sternal wound, abdominal distension and tenderness, or a new pulmonary infiltrate on the chest radiograph. However, localizing signs are commonly absent in critically ill or immunocompromised patients. Early signs of sepsis are easily missed in sedated patients and when there is another cause for hemodynamic instability such as ventricular dysfunction. Hypotension, in association with hyperdynamic circulation (warm peripheries, bounding pulses), is characteristic of septic shock. However, patients who have not been adequately fluid resuscitated or have severely impaired cardiac function may have cool peripheries and weak pulses. Also, myocardial depression occurs in approximately 50% of patients with severe sepsis or septic shock and is independent of preexisting myocardial dysfunction. Elevated troponin levels in patients with sepsis indicate left ventricular dysfunction and are associated with worse prognoses.64 By contrast, there is no consistent relationship between elevated B-type natriuretic peptide and adverse outcome due to sepsis.64 Treatment Evidence-based guidelines for the management of severe sepsis and septic shock have been developed,65 and they form the basis of the recommendations that follow.

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With severe sepsis and septic shock, early institution of antimicrobial therapy, hemodynamic resuscitation, and source control are critical to survival.

Cardiorespiratory Resuscitation. Fluid resuscitation should be commenced as soon as tissue hypoperfusion is recognized, and it should be goal directed, aiming for the following: (1) a central venous pressure of 8 to 12 mmHg (12 to 15 mmHg in mechanically ventilated patients); (2) a mean arterial pressure of at least 65 mmHg; (3) a urine output of at least 0.5 ml/kg/min; (4) a superior vena cava (SSVCO2) or mixed venous (SVO2) oxygen saturation of at least 70%. Either a balanced salt or a colloid solution may be used (see Chapter 32). If SSVCO2 or SVO2 remains less than 70% despite an adequate central venous pressure, packed red cells should be transfused to achieve a hemoglobin concentration of 9 to 10 g/dl or dobutamine should be administered (to a maximum of 20 μg/kg/min) to achieve this goal. (Once tissue hypoperfusion has resolved, red cell transfusion should occur only if the hemoglobin concentration falls below about 7 g/dl (see Chapter 30) If mean arterial pressure remains less than 65 mmHg despite adequate fluid resuscitation, vasopressor therapy should be commenced. Either dopamine or norepinephrine is recommended, but norepinephrine is probably the superior agent in this circumstance (see Chapter 3). Low-dose vasopressin (0.01 to 0.04 units/min) may be added if patients are refractory to high-dose norepinephrine (e.g., >0.4 μg/kg/min). In postoperative cardiac surgery patients, epicardial pacing at a high rate (100 to 120/min) may optimize cardiac performance. Monitoring should include pulse oximetry, urine output, intraarterial pressure, central venous pressure, and SSVCO2. In mechanically ventilated patients, monitoring arterial pulse pressure variation provides a reliable indicator of fluid responsiveness.66 Patients with significant ventricular or valvular dysfunction may benefit from pulmonary artery catheterization and an echocardiogram. Intubation and ventilation should be instituted early in patients with respiratory insufficiency (see Chapter 27). If there is acute lung injury, a lung-protective ventilation strategy should be employed (see Chapter 29). Antimicrobial Therapy and Source Control. Appropriate antimicrobial therapy within the first hour of the onset of hypotension is associated with increased survival rates in patients with septic shock.67 Thus, if sepsis is considered a likely cause of hypotension, empiric antimicrobial therapy should be commenced as soon as two sets of blood cultures and other relevant specimens have been obtained. Empiric therapy should be as for nosocomial pneumonia, or based on the most likely site of infection. Identification and control of the source of the infection is also important. This includes débridement of the

Infection and Sepsis

sternal wound if mediastinitis is suspected and laparotomy if intraabdominal sepsis is suspected.

Adjuvant and Experimental Therapies. A number of other therapies, with varying degrees of evidential support, may be used to treat severe sepsis and septic shock. Recommended strategies are65: (1) tight glycemic control, aiming for a blood glucose level of less than 110 mg/dl (< 6.1 mmol/l; see Chapter 36); (2) stress ulcer prophylaxis (see Chapter 34); (3) intravenous hydrocortisone 200 to 300 mg/day in divided doses in patients who require vasopressor therapy despite adequate fluid resuscitation; (4) recombinant activated protein C in patients with severe disease. Recombinant activated protein C has been the subject of two large randomized, controlled trials.68,69 In the first trial, improved survival rates were demonstrated in patients with severe sepsis, particularly in those with severe disease (an Acute Physiology and Chronic Health Evaluation [APACHE] II score >25, multiorgan involvement). By contrast, in the subsequent trial, no survival benefit was seen in patients with severe sepsis but a low risk of death was observed (APACHE II score <25, single-organ involvement, or perceived low risk death on clinical grounds). Currently, recombinant activated protein C is approved by the U.S. Federal Drug Administration for use in patients with severe sepsis or septic shock who have an APACHE score greater than 25. It is important to note that activated protein C can cause clinically significant bleeding—including intracerebral hemorrhage—and is therefore contraindicated in coagulopathic patients. Patients who develop renal failure should be treated with renal replacement therapy (see Chapter 33), but some data show that hemofiltration may also have a role in cytokine removal and improvement in hemodynamics in patients with sepsis.70,71 However, these data are very limited and conflicting,72 and currently hemofiltration is not recommended for disease modulation in sepsis. Similarly, polyclonal immunoglobulin may improve outcomes of sepsis.73 As with hemofiltration, the data are limited, and this treatment is not routine. In patients with septic shock even though cardiac output is high, microcirculatory flow is greatly impaired (see Chapter 2). This has led some researchers to explore the use of vasodilators in volume resuscitated patients with sepsis in an attempt to improve end-organ perfusion.74,75

Approach to the Febrile Postoperative Patient Body temperature varies according to the site of measurement and the time of day. Pyrexia may be defined as an oral temperature above 38.0°C. Rectal temperature is normally 0.3°C to 0.4°C higher than oral temperature. Pyrexia has infectious and noninfectious causes; noninfectious causes are listed in Table 35-11. 525

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Table 35-11

Noninfectious Causes of Pyrexia

Blood products

Thromboembolism

SIRS

Dissecting aortic aneurysm

Hemorrhage

Myocardial infarction

Retroperitoneal

Postpericardectomy syndrome

Central nervous system

Malignant hyperthermia

Lung

Pancreatitis

Adrenal

Hyperthyroidism

Pulmonary atelectasis

Addisonian crisis

Drug reaction

Collagen vascular disease

Intramuscular injections

Malignancy

Alcohol withdrawal

Seizures

Cerebral disease (e.g., subarachnoid hemorrhage)

Transplant rejection

SIRS, systemic inflammatory response syndrome.

Nosocomial infection is very uncommon within the first 72 hours after surgery, but it should always be considered in patients who were hospitalized prior to surgery. An exception to this is UTI, which can develop within a few hours of urethral catheterization. In the early postoperative period noninfectious causes, such as blood products, the inflammatory response to surgery and cardiopulmonary bypass, myocardial infarction, acute brain injury, and retroperitoneal hematoma, should be considered. Patients who develop pyrexia beyond the first 2 to 3 days of hospital admission should be thoroughly investigated for possible nosocomial infection, in particular for surgical site infection, intravascular catheter-related infection, VAP, and UTI. All wounds should be inspected and the sternum palpated for signs of instability. Pressure points (buttocks, heels, back) should be inspected for pressure sores. Thorough chest and cardiovascular examinations should be performed. Auscultation of the lungs may reveal signs of consolidation or pleural fluid. A new murmur may indicate endocarditis. Nosocomial infective endocarditis is extremely unlikely within a week of surgery, but beyond this time it should be considered in patients who have undergone valve surgery or have intracardiac prosthetic material. The abdomen should be examined for signs of tenderness or distension that may indicate mesenteric ischemia, diverticulitis, or cholecystitis. 526

A complete blood count (with differential white cell count), C-reactive protein and procalcitonin levels, and a chest radiograph should be obtained. Sputum, urine, wound swabs (if there is clinical evidence of infection), peripheral blood cultures (two sets), and pleural fluid (if present) should be sent for microbiologic analysis. Ideally, blood cultures should be taken during spikes in temperature (>38.3°C). Consideration should be given to removing and culturing the tip of any vascular catheters that have been in situ for more than 3 days. If there is clinical suspicion of intraabdominal pathology, liver function tests, amylase levels, and an ultrasound scan of the liver and biliary tract or an abdominal CT scan should be obtained. If nosocomial infective endocarditis or infected pacemaker leads are a possibility, an echocardiogram should be obtained. Ultrasonography of the atrial veins to rule out thrombus (which may be infected) should be performed if a central venous catheter has been in situ for a prolonged period. Noninfectious causes of pyrexia that should be considered later than the first few days after surgery include deep venous thrombosis, atelectasis, drug or alcohol withdrawal, pancreatitis, acute brain injury, and drugs. Physical signs of deep venous thrombosis should be sought and if indicated (see Chapter 23), ultrasonography of the leg and pelvic veins should be performed. Uncommon causes of infection, such as sinusitis and meningitis, can occasionally occur in postoperative cardiac surgery patients. Sinusitis should be considered in patients who have had a nasogastric or nasotracheal tube in situ for several days. The diagnosis may be supported by a contrast-enhanced CT scan of the head showing opacification or fluid-air levels within one of the cranial sinuses. The radiologic diagnosis of sinusitis should be confirmed by needle aspiration for microscopy and culture because only 50% of patients with radiologic abnormalities have microbiologically proven sinusitis. Meningitis should be considered in patients in whom a cerebrospinal fluid catheter has been in situ. In the absence of instrumentation of the subarachnoid space, nosocomial meningitis is highly unlikely. The diagnosis may be confirmed by sampling the cerebrospinal fluid (assuming there is no evidence of raised intracranial pressure) or supported by performing a magnetic resonance or contrast-enhanced CT scan of the brain. If there are signs of sepsis, empiric antimicrobial therapy should be commenced as described earlier for nosocomial pneumonia. If the patient’s condition is stable, antimicrobial therapy should be deferred until the results of cultures are known. Isolated pyrexia is not an indication for empiric antimicrobial therapy except in exceptional circumstances (e.g., patients with neutropenia). Daily blood cultures should be obtained while pyrexia persists. When obtaining blood cultures, a strict aseptic technique should be used, including preparation of the

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skin with 2% chlorhexidine and the use of a sterile field and sterile surgical gloves. Contamination of two separate sets of blood cultures taken through two different venipuncture sites is extremely uncommon. Coagulase-negative staphylococci are a common contaminant of blood cultures. Although these microorganisms can cause catheter-related infection, surgical site infections, and prosthetic valve infective endocarditis, they rarely cause nosocomial pneumonia. The decision to administer an antimicrobial (usually vancomycin) for a sustained period on the basis of a single positive blood test is difficult. If the risk for clinical infection is low (i.e., no prosthetic heart valve, no indwelling vascular catheters for longer than 3 days, growth from only one blood sample), it is reasonable to give a single dose of vancomycin and await the results of further cultures. If the criteria of vascular catheter-related infection have been met (see previous material), a full course of vancomycin is appropriate.

Infection and Sepsis

The benefits of symptomatic antipyretic treatment (e.g., regular acetaminophen) have not been conclusively shown to outweigh its risks, so they should not be given routinely.76,77 An exception is in patients with suspected brain injury; they should be actively cooled to normothermia or, if certain criteria are met (see Chapter 37), to hypothermia.

MICROORGANISMS AND ANTIMICROBIAL THERAPY Antimicrobial Activity and Resistance Antimicrobial classes and their spectrums of activity, important side effects, and usual adult doses are listed in Table 35-12 and Table 35-13. Microorganisms that are commonly associated with problematic antimicrobial resistance are listed in Table 35-14. Text continued on Page 531

Table 35-12

Antimicrobials

Class

Activity

Side Effects1 (Incomplete list; please check your formulary)

β-Lactams Penicillin G (IV) and penicillin V (oral)

Streptococci, susceptible staphylococci, and Clostridium perfringens

Anaphylaxis (0.2%) Rash (4% to 8%)

Narrow-spectrum β-lactamase-resistant penicillins (e.g., nafcillin, oxacillin, and flucloxacillin) Also called antistaphylococcal penicillins

MSSA, not MRSA Most streptococci, but not primarily indicated for them

As for penicillin G Abnormal LFTs (cholestatic), predominantly only with flucloxacillin

Amoxicillin and ampicillin

As for penicillin G but with additional cover (e.g., activity against many Enterococci, Haemophilus influenzae, and some Enterobacteriaceae2) Inhibited by β-lactamase-producing pathogens, so may be combined with a β-lactamase inhibitor

As for antistaphylococcal penicillins

Extended-spectrum penicillins (e.g., ticarcillin, piperacillin, carbenicillin); also called antipseudomonal penicillins

All penicillin- and amoxicillin-susceptible organisms and many strains of Pseudomonas aeruginosa Inhibited by β-lactamase-producing pathogens, so may be combined with a β-lactamase inhibitor

As for penicillin G Ticarcillin may cause coagulopathy

β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) Used with amoxicillin, ampicillin, ticarcillin, and piperacillin

Extend the spectrum of penicillins to include β-lactamase-producing strains of S. aureus, H. influenzae, Moraxella catarrhalis, and Enterobacteriaceae2 and anaerobes Continued

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Table 35-12

Antimicrobials—cont’d

Class

Side Effects1 (Incomplete list; please check your formulary)

Activity β-Lactams

First-generation cephalosporin (e.g., cephazolin, cephradine)

Staphylococci and streptococci (not MRSA)

Rate of allergy approximately half that of penicillin

Second-generation cephalosporins (e.g., cefuroxime, cephamandole)

As for first-generation agents, plus increased activity against gram-negatives (e.g., Enterobacteriaceae,2 H influenzae, M catarrhalis)

Rate is higher in those sensitive to penicillins Transaminitis, eosinophilia, and positive Coombs test seen in 1% to 7% Seizures and neutropenia are rare complications

Third-generation cephalosporins (e.g., ceftazidime, cefotaxime, ceftriaxone)

As above, with greater activity against Enterobacteriaceae2 Ceftazidime has increased activity against P. aeruginosa but is less active against staphylococci and streptococci Unreliable against anaerobes

Ceftriaxone associated with biliary sludging Use of third-generation cephalosporins has the potential to induce resistance during prolonged therapy, in particular when used for Enterobacter spp. infection.

Fourth-generation cephalosporins (e.g., cefepime, cefpirome)

Exceptional activity against many gram-negative bacilli,3 staphylococci, and streptococci Resistant to β-lactamases produced by some Enterobacteriaceae2 that inhibit other cephalosporins

This does not happen with fourth-generation agents, which are resistant to the β-lactamase produced by the Enterobacter spp.

Cephamycins (e.g., cefoxitin, cefotetan)

Staphylococci (not MRSA), some streptococci and good activity against anaerobes (e.g., Bacteroides fragilis)

Monobactams (e.g., aztreonam)

Most gram-negative bacilli3 but not Acinetobacter spp. Good alternative to aminoglycoside in patients with renal failure

Transaminitis

Carbapenems (e.g., imipenem, ertapenem, meropenem)

Staphylococci (not MRSA), streptococci, many gram-negative bacilli,3 anaerobes (e.g., B. fragilis and C. perfringens)4 Ertapenem not effective against P. aeruginosa Usually effective against ESBLs

Half of patients allergic to penicillin are allergic to carbapenems Dose-related seizures with imipenem

Non-β-Lactams

528

Glycopeptides (e.g., vancomycin, teicoplanin)

Most gram-positives Staphylococci (including MRSA and Staphylococcus epidermidis), streptococci (including penicillinresistant S. pneumoniae), enterococci, and Clostridium difficile

Rapid IV vancomycin causes hypotension (“red man syndrome”) due to histamine release Possible nephrotoxicity (vancomycin)

Aminoglycosides (e.g., gentamicin, tobramycin, amikacin)

Many gram-negative bacilli3 May be used for synergy with other agents to treat staphylococci (including some MRSA), streptococci, and enterococci

Nephrotoxicity, ototoxicity

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Table 35-12

Infection and Sepsis

Antimicrobials—cont’d

Class

Side Effects1 (Incomplete list; please check your formulary)

Activity Non-β-Lactams

Fluoroquinolones (e.g., ciprofloxacin and moxifloxacin)

Many gram-negative bacilli3, M catarrhalis Moxifloxacin covers atypical respiratory pathogens Some antistaphylococcal activity but in-treatment resistances can develop

Diarrhea, nausea, arthralgia, tendinitis, photosensitivity

Macrolides (e.g., erythromycin, roxithromycin)

S. pneumoniae, M. catarrhalis, H. influenzae, S. aureus (not MRSA), and atypical respiratory pathogens5

Diarrhea, nausea, and cholestatic jaundice QT prolongation with IV erythromycin

Clindamycin, lincomycin

Staphylococci (including some community MRSA), streptococci, and B. fragilis

High association with C. difficile pseudomembranous colitis

Streptogramins (e.g., quinupristin/dalfopristin)

Staphylococci (including MRSA and S. epidermidis), streptococci, and Enterococcus faecium (not E. faecalis)

Hypersensitivity reactions

Tetracyclines (e.g., doxycycline)

Broad-spectrum Rarely used in ICU

Hypersensitivity reactions, anorexia, flushing, and tinnitus

Sulphamethoxazole/trimethoprim

Broad-spectrum Indicated for Stenotrophomonas maltophilia and Pneumocystis jiroveci pneumonia

Allergic reactions, including Stevens-Johnson syndrome, reversible renal and hepatic toxicity, bone marrow depression, neurotoxicity

Nitroimidazoles (e.g., metronidazole)

Anaerobes (including C. perfringens and B. fragilis6)

Oxazolidinediones (e.g., linezolid)

Staphylococci (including MRSA, vancomycin-resistant S. aureus, S. epidermidis), streptococci, and enterococci (including vancomycin-resistant spp.)

Thrombocytopenia (reversible) in 2.4%

All antimicrobials have gastrointestinal disturbance as a side effect to a greater or lesser extent, and all may cause Clostridium difficile-associated pseudomembranous colitis. 2 Enterobacteriaceae include Escherichia, Proteus, Providencia, Morganella, Klebsiella, Enterobacter, and Serratia spp. 3 H. influenzae, Enterobacteriaceae (see above), Pseudomonas, and Acinetobacter spp. 4 Clinically important bacteria resistant to the carbapenems are Enterococcus faecium, methicillin-resistant S. aureus, S. epidermidis, C. difficile, and Stenotrophomonas maltophilia. 5 Mycoplasma, Chlamydia and Legionella spp. Not Actinomyces and Propionibacterium 6 ESBLs, extended-spectrum β-lactamases; IV, intravenous; LFTs, liver function tests; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus. 1

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Table 35-13

Usual Adult Dose of Some Common Antimicrobial Agents

β-Lactams

Non-β-Lactams

Penicillin G

1 to 4 MU every 4 hr

Vancomycin

1 g every 12 hr

Dicloxacillin

0.25 to 0.50 g every 6 hr

Gentamicin

5 mg/kg every 24 hr

Nafcillin

0.5 to 2 g every 4 to 6 hr

Ciprofloxacin (IV)

200 to 400 mg every 12 hr

Flucloxacillin

0.5 to 2 g every 6 hr

Erythromycin

0.5 to 1 g every 6 hr

Amoxycillin and ampicillin

0.5 to 2 g every 6 hr

Clindamycin

150 to 450 mg every 6 hr

Ticarcillin

3 g every 4 hr

Quinupristin/dalfopristin

7.5 mg/kg every 8 hr*

Cephazolin

1 to 2 g every 6 to 8 hr

Metronidazole

500 mg every 8 hr

Cefuroxime

0.75 to 1.5 g every 8 hr

Trimethoprim/ sulphamethoxazole

160 to 320 mg (trimethoprim) or 2 to 4 tablets every 12 hr**

Ceftazidime

1 to 2 g every 8 hr

Linezolid

400 to 600 mg every 12 hr

Ceftriaxone

1 to 2 g every 12 to 24 hr

Cefepime

1 to 2 g every 8 to 12 hr

Cefoxitin

1 to 2 g every 8 hr

Aztreonam

2 g every 8 hr

Meropenem

1 g every 8 hr

Ertapenem

1 g every 24 hr

IV, intravenous; MU, megaunit. *These two agents are premixed at a 3:7 ratio, with the dose quoted being the total dose of both agents. **This includes 5 times as much sulphamethoxazole because the two antimicrobial agents are formulated at a ratio of 1:5.

Table 35-14

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Microorganisms that Commonly Cause Nosocomial Infection and Are Associated With Problematic Antimicrobial Resistance

Pathogen

Notes

Treatment Options

Methicillin-resistant Staphylococcus aureus (MRSA)

MRSA denotes resistance to all β-lactams (see Table 35-12); 60% of all S. aureus isolates in ICU patients in the US are methicillin resistant.

Glycopeptides and linezolid Aminoglycosides, minocycline, and trimethoprim/sulphamethoxazole may have activity.

Glycopeptide intermediate S. aureus

Currently rare in the US

Linezolid or quinupristin/dalfopristin Most strains are still susceptible to teicoplanin.

Vancomycin-resistant S. aureus

First clinical isolate in 2002; likely resistance acquired from an enterococcus

Linezolid or quinupristin/dalfopristin. Minocycline and trimethoprim/ sulphamethoxazole may have activity.

Coagulase-negative staphylococci (e.g., S. epidermidis, S. saprophyticus, and S. hemolyticus)

Account for 36% of bacteremias in ICU patients in the US; 89% are methicillin resistant. Rarely causes severe sepsis.

Glycopeptides

Continued

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Table 35-14

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Microorganisms that Commonly Cause Nosocomial Infection and are Associated With Problematic Antimicrobial Resistance—cont’d

Pathogen

Notes

Treatment Options

Enterococcus faecium

Intrinsic resistance to cephalosporins, penicillins (except amoxicillin), clindamycin, fluoroquinolones, and low-dose aminoglycosides. Now 28.5% enterococci isolates in ICU patients in the US are vancomycin resistant.

Quinupristin/dalfopristin, and linezolid

Enterobacter spp.

Third-generation cephalosporin use is a risk factor for developing resistance; tends to be resistant to first- and second-generation, but if not resistant can develop during treatment.

Carbapenem or fourth-generation cephalosporin

Pseudomonas aeruginosa

Intrinsically resistant to most antimicrobials; many advocate dual treatment (see text).

Most active agent is meropenem, then imepenem, ceftazidime, cefepime, ciprofloxacin, piperacillin, and the aminoglycosides.

ESBL-producing organisms (e.g., Klebsiella pneumoniae, Escherichia coli )

Resistance to third-generation cephalosporins, aztreonam, extendedspectrum penicillins, and β-lactamase inhibitors; commonly have resistance to aminoglycosides and fluoroquinolones.

Carbapenem or fourth-generation cephalosporin

Acinetobacter spp.

Usually have resistance to penicillins, aztreonam, cephalosporins, and aminoglycosides.

The carbapenems are the antimicrobials of choice, but resistance to them may emerge during treatment. Alternatively trimethoprim/sulphamethoxazole may be used.

Stenotrophomonas maltophilia

Intrinsic resistance to most β-lactam antimicrobials, including carbapenems; aminoglycosides and fluoroquinolones have poor activity.

Trimethoprim/sulphamethoxazole, in high dosages (15 mg/kg/day of the trimethoprim component) is the preferred agent.

Enterococcus faecalis

Linezolid

(From National Nosocomial Infections Surveillance System: National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 32:470-485, 2004; Richards MJ, Edwards JR, Culver DH, et al: Nosocomial infections in medical intensive care units in the United States: National Nosocomial Infections Surveillance System. Crit Care Med 27:887-892, 1999.) ESBL, extended-spectrum β-lactamases.

Gram-Positive Organisms Virtually all streptococci are sensitive to penicillin G and first-generation cephalosporins. A significant proportion (>30%) of S. pneumoniae have reduced susceptibility to penicillin. With the exception of meningitis, infections due to S. pneumoniae with penicillin minimum inhibitory concentration (the concentration of antimicrobial required to inhibit bacterial growth in vitro; MIC) less than 4 μg/ml may be treated with high-dose penicillin G or amoxicillin. Otherwise, a third-generation cephalosporin or vancomycin is required.

More than 95% of strains of S. aureus produce β-lactamase (penicillinase)78 and are therefore resistant to penicillin G, amoxicillin, and extended-spectrum penicillins. Agents with intrinsic activity against penicillinase-producing strains of S. aureus include the antistaphylococcal penicillins (e.g., methicillin, nafcillin, and flucloxacillin), many cephalosporins (including cefazolin), carbapenems, aminoglycosides, and clindamycin. Also, activity against methicillin-sensitive S. aureus is conferred by the addition of a β-lactamase inhibitor (e.g., clavulanic acid, sulbactam, and tazobactam) to a penicillinase sensitive penicillin. 531

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Increasingly, S. aureus is resistant to all β-lactam antimicrobials. In 2003, the incidence of MRSA among S. aureus isolates from U.S. hospitals was 60%.16 Many of these isolates are also resistant to aminoglycosides and clindamycin. Effective treatment can still be provided by a glycopeptide or by linezolid. Strains of S. aureus that are resistant to vancomycin have been reported, but they are rare. Coagulase-negative staphylococci are variably sensitive to β-lactams and aminoglycosides. If infection with a coagulase-negative staphylococcus is suspected, the treatment is with vancomycin until sensitivities are known. Enterococci are intrinsically resistant to many antimicrobials, including cephalosporins, penicillinaseresistant penicillins (e.g., nafcillin), clindamycin, sulphamethoxazole/trimethoprim, and low-dose aminoglycosides. Enterococci are usually sensitive to amoxicillin and glycopeptides. However, in some ICUs, acquired resistance to these agents is very high. Some enterococci have an altered penicillin-binding protein or produce a β-lactamase, rendering them resistant to amoxicillin. Vancomycin-resistant enterococci are also becoming more prevalent; more than 30% of isolates from ICUs in the United States show this characteristic.16

Gram-Negative Organisms Antimicrobials with important gram-negative activity include the aminoglycosides, extended-spectrum penicillins, aztreonam, third- and forth-generation cephalosporins, fluoroquinolones, and carbapenems. Among some Enterobacteriaceae (see Table 35-1), particularly K. pneumoniae and E. coli, antimicrobial resistance occurs due to the production of ESBL enzymes that inactivate penicillins and cephalosporins. These strains are commonly multiresistant because of many other resistance genes carried on the same plasmid as the gene-encoding the ESBL. In 2001, ESBL-producing strains of K. pneumoniae constituted less than 10% of isolates in the United States, but in Latin America they were as high as 45%.79 ESBL-producing microorganisms usually remain sensitive to carbapenems. High levels of resistance due to chromosomally encoded cephalosporinases are also seen with isolates of Enterobacter species; carbapenems and cefepime are usually effective. Nonfermenting gram-negative microorganisms, such as Pseudomonas aeruginosa, Acinetobacter species, and Stenotrophomonas maltophilia, have high rates of intrinsic and acquired antimicrobial resistance. This is particularly important for P. aeruginosa, which is an important nosocomial pathogen. Useful antimicrobial agents for infection with P. aeruginosa include antipseudomonal (extended-spectrum) penicillins (e.g., piperacillin/ tazobactam); aminoglycosides; antipseudomonal cephalosporins (i.e., ceftazidime and cefepime); carbapenems (particularly meropenem); and antipseudomonal fluoroquinolones (e.g., ciprofloxacin, levofloxacin). Because of the potential for in-treatment resistance, many clinicians recommend combination antimicrobial treatment for 532

infections due to P. aeruginosa. However, a recent metaanalysis found no difference in outcome when an aminoglycoside was added to β-lactam therapy for gramnegative infections, including those due to P. aeruginosa.80

Other Microorganisms The first-line treatment for anaerobes is metronidazole. Other effective antimicrobials include amoxicillin/clavulanic acid, the cefamycins (e.g., cefoxitin), clindamycin, and the carbapenems. Third- and fourth-generation cephalosporins are only variably effective. Treatment for fungal infections involves fluconazole, amphotericin, or caspofungin. The role of newer antifungal agents in ICU patients, such as the new azoles and echinocandins, remains to be determined.81 Strategies to Reduce the Development of Antimicrobial Resistance Inappropriate use of antimicrobial drugs (either in the absence of infection or in inadequate dosages or durations) promotes microorganism resistance and increases morbidity and mortality rates. In one study, it was found that inadequate antimicrobial treatment was given to more than 30% of ICU patients who had nosocomial infections; such treatment was associated with increased mortality rates when compared with patients receiving appropriate treatment.82 Strategies to minimize antimicrobial resistance include limiting the use of and the choice of antimicrobials and using combination therapy, cycling drugs, and physician education programs. In particular, reduced use of thirdand fourth-generation cephalosporins, carbapenems, and vancomycin and increased use of extended-spectrum penicillins and combination therapy with aminoglycosides are beneficial.83 Wherever possible, antimicrobial therapy should be based on microbiologically proven infection and should be administered for an appropriate period of time. For infections that are hard to diagnose (e.g., nosocomial pneumonia, infective endocarditis) and infections in which the consequences of delayed treatment are severe (e.g., infective endocarditis, severe sepsis, and septic shock), empiric treatment is justified, but it should be commenced only when an appropriate threshold of clinical suspicion has been reached. Once the results of cultures become available, empiric agents should be replaced by one or more appropriate, specific agents, depending on the infection site and the specific pathogenic microorganism.

Pharmacodynamic and Pharmacokinetic Considerations Bacteriostatic Versus Bactericidal Activity Antimicrobials may be bacteriostatic (i.e., they inhibit microorganism growth) or bactericidal (i.e., they kill microorganisms). This distinction is blurred because it is partly dependent on the antimicrobial effect-site concentration, the organism involved, and whether the

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drug is used in combination with other antimicrobials. For instance, vancomycin is bacteriostatic against many enterococci but bactericidal against other gram-positive microorganisms. For most infections, bacteriostatic activity is satisfactory because it permits normal host defenses to destroy pathogens. However, bactericidal agents offer an advantage when host defenses are impaired (e.g., in immunocompromised patients) or when access to the infection site by host defenses is reduced (e.g., in infective endocarditis). Antimicrobials that are bacteriostatic include the tetracyclines and erythromycin; other agents commonly used in the ICU are, if given in appropriate doses, bactericidal.

Concentration-Dependent Versus Time-Dependent Inhibition Antimicrobials exhibit either concentration-dependent or time-dependent inhibition of pathogens.84 With concentration-dependent inhibition, the higher the plasma concentration of drug, the greater the inhibition of pathogens. Concentration-dependent inhibition is characteristic of the aminoglycosides. Maximum drug concentrations greater than 10 times the MIC are needed for effective therapy. The optimal dosing regimen for antimicrobials that display concentration-dependent inhibition is a large, once-daily dose. Once-daily dosing of aminoglycosides is associated with increased efficacy and reduced toxicity compared with the same total dose given as multiple, divided doses.85 With time-dependent inhibition, the goal is to maximize the time during which Table 35-15

Infection and Sepsis

the plasma concentration is above the MIC. Timedependent killing is a characteristic of β-lactams and vancomycin. Theoretically, the ideal dosing regime of drugs that display time-dependent killing is a continuous infusion or frequent intermittent boluses; the latter is the usual strategy for β-lactam dosing. Some agents, notably the fluoroquinolones, display both time- and concentration-dependent inhibition.

Combination Treatment Combination antimicrobial therapy is useful in three situations: (1) empiric therapy against severe infection; (2) treatment of mixed infections; (3) provision of synergistic antimicrobial therapy. An important example of the last circumstance is the treatment of infective endocarditis due to penicillin-sensitive enterococci. The addition of an aminoglycoside provides an enhanced antibacterial effect. The issue of combination therapy for Pseudomonas aeruginosa was discussed previously. Different antimicrobial classes act by means of different mechanisms. For instance, β-lactams and glycopeptides inhibit bacterial cell wall synthesis; aminoglycosides, erythromycin, and clindamycin (and others) bind to ribosomes and inhibit protein synthesis; and fluoroquinolones affect nucleic acid synthesis. Combination therapy works best when antimicrobials with different mechanisms of action are used. Effective combinations include β-lactams and an aminoglycoside or vancomycin and an aminoglycoside, although renal toxicity is a very real risk with the latter combination.

Antimicrobials Requiring Dose Adjustment in the Presence of Renal Dysfunction

No Adjustment Required Ceftriaxone Moxifloxacin Erythromycin Roxithromycin Clindamycin Quinupristin/dalfopristin Doxycycline* Metronidazole Linezolid Rifampicin

Dose Adjustment With Mild Dysfunction (GFR 50 to 80 ml/min)

Dose Adjustment With Moderate Dysfunction (GFR 10 to 50 ml/min)

Dose Adjustment With Severe Dysfunction (GFR < 10 ml/min)

Vancomycin Cephamandole Cefoxitin Aminoglycosides

Penicillin G Amoxycillin ± clavulanate Flucloxacillin Ticarcillin Cephazolin Cefuroxime Cefataxime Ceftazidime Cefepime Cefotetan Aztreonam Imipenem Meropenem Ertapenem Teicoplanin Ciprofloxacin Norfloxacin Lincomycin Sulphamethoxazole Trimethoprim

Nafcillin Dicloxacillin Piperacillin ± tazobactam Clarithromycin

*All tetracyclines except doxycycline should be avoided with renal impairment.

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Pharmacokinetic Considerations To avoid toxicity, many antimicrobials require dose adjustments in the presence of renal or hepatic dysfunction. Antimicrobials that require dose adjustment in renal dysfunction are listed in Table 35-15. Aminoglycosides and vancomycin are nephrotoxic, but they can be used safely in patients with renal dysfunction as long as trough blood levels are carefully monitored. In patients with renal impairment requiring aminoglycosides, (which display concentration-dependent inhibition) a standard or a slightly reduced dose (e.g., gentamicin 3 to 5 mg/kg) may be given less frequently (e.g., every 36 to 48 hr), based on the trough drug level. If a trough level is high it should be measured every 12 hours until a satisfactory concentration is reached. At which time a further lower dose may be given. With vancomycin, which displays timedependent inhibition, a smaller dose (e.g., 500 mg instead of the usual 1000 mg) may be given with the same dosing interval (i.e., every 12 to 24 hr), depending on trough blood levels. When renal function is severely impaired, alternatives to these agents (e.g., aztreonam for aminoglycosides, teicoplanin for vancomycin) should be used. Renally eliminated drugs may also have nonrenal toxicity; for instance, some β-lactams and fluoroquinolones cause central nervous system toxicity, and their dosages must be reduced in patients with severe renal dysfunction. Dose adjustment is less well defined for hepatic dysfunction. This is because most drug-induced hepatotoxicity is idiosyncratic (see Table 34-6). Antimicrobials that should be administered at reduced dosages or avoided entirely in patients with hepatic dysfunction are listed in Table 34-7. Certain antimicrobials (notably the macrolides, azole antifungals, and rifampicin) function as substrates, inhibitors, and inducers of the CYP3A hepatic enzyme system (see Table 4-3) and therefore can cause important drug interactions.

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