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InternalMed_Harrison. BIOMARKERS A number of substances can serve as markers of severe inflammation. The two currently in use are C-reactive protein (CRP) and procalcitonin (PCT). Levels of these acute-phase reactants increase in the presence of an inflammatory response, particularly to bacterial pathogens. CRP may be of use in the identification of worsening disease or treatment failure, and PCT may play a role in determining the need for antibacterial therapy. These tests should not be used on their own but, when interpreted in conjunction with other findings from the history, physical examination, radiology, and laboratory tests, may help with antibiotic stewardship and appropriate management of seriously ill patients with CAP.


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InternalMed_Harrison. The cost of inpatient management exceeds that of outpatient treatment by a factor of 20, and hospitalization accounts for most CAP-related expenditures. Thus the decision to admit a patient with CAP to the hospital has considerable implications. Certain patients clearly can be managed at home, and others clearly require treatment in the hospital, but the choice is sometimes difficult. Tools that objectively assess the risk of adverse outcomes, including severe illness and death, can minimize unnecessary hospital admissions. There are currently two sets of criteria: the Pneumonia Severity Index (PSI), a prognostic model used to identify patients at low risk of dying; and the CURB-65 criteria, a severity-of-illness score.


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InternalMed_Harrison. To determine the PSI, points are given for 20 variables, including age, coexisting illness, and abnormal physical and laboratory findings. On the basis of the resulting score, patients are assigned to one of five classes with the following mortality rates: class 1, 0.1%; class 2, 0.6%; class 3, 2.8%; class 4, 8.2%; and class 5, 29.2%. Determination of the PSI is often impractical in a busy emergency-department setting because of the number of variables that must be assessed. However, clinical trials demonstrate that routine use of the PSI results in lower admission rates for class 1 and class 2 patients. Patients in class 3 could ideally be admitted to an observation unit until a further decision can be made.


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InternalMed_Harrison. The CURB-65 criteria include five variables: confusion (C); urea >7 mmol/L (U); respiratory rate ≥30/min (R); blood pressure, systolic ≤90 mmHg or diastolic ≤60 mmHg (B); and age ≥65 years. Patients with a score of 0, among whom the 30-day mortality rate is 1.5%, can be treated outside the hospital. With a score of 2, the 30-day mortality rate is 9.2%, and patients should be admitted to the hospital. Thrombocytopenia Severe acidosis (pH <7.30) Among patients with scores of ≥3, mortality rates are 22% overall; these patients may require ICU admission. It is not clear which assessment tool is superior. Whichever system is used, these objective criteria must always be tempered by careful consideration of factors relevant to individual patients, including the ability to comply reliably with an oral antibiotic regimen and the resources available to the patient outside the hospital.


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InternalMed_Harrison. Neither PSI nor CURB-65 is accurate in determining the need for ICU admission. Septic shock or respiratory failure in the emergency department is an obvious indication for ICU care. However, mortality rates are higher among less ill patients who are admitted to the floor and then deteriorate than among equally ill patients monitored in the ICU. A variety of scores have been proposed to identify patients most likely to have early deterioration (Table 153-4). Most factors in these scores are similar to the minor severity criteria proposed by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) in their guidelines for the management of CAP.


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InternalMed_Harrison. Antimicrobial resistance is a significant problem that threatens to diminish our therapeutic armamentarium. Misuse of antibiotics results in increased antibiotic selection pressure that can affect resistance locally or even globally by clonal dissemination. For CAP, the main resistance issues currently involve S. pneumoniae and CA-MRSA. S. pneumoniae In general, pneumococcal resistance is acquired (1) by direct DNA incorporation and remodeling resulting from contact with closely related oral commensal bacteria, (2) by the process of natural transformation, or (3) by mutation of certain genes.


InternalMed_Harrison

InternalMed_Harrison. The minimal inhibitory concentration (MIC) cutoffs for penicillin in pneumonia are ≤2 μg/mL for susceptibility, >2–4 μg/mL for intermediate, and ≥8 μg/mL for resistant. A change in susceptibility thresholds resulted in a dramatic decrease in the proportion of pneumococcal isolates considered nonsusceptible. For meningitis, MIC thresholds remain at the former higher levels. Fortunately, resistance to penicillin appeared to plateau even before the change in MIC thresholds. Pneumococcal resistance to β-lactam drugs is due solely to low-affinity penicillin-binding proteins. Risk factors for penicillin-resistant pneumococcal infection include recent antimicrobial therapy, an age of <2 years or >65 years, attendance at day-care centers, recent hospitalization, and HIV infection.


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InternalMed_Harrison. In contrast to penicillin resistance, resistance to macrolides is increasing through several mechanisms. Target-site modifica tion caused by ribosomal methylation in 23S rRNA encoded by the ermB gene results in high-level resistance (MICs, ≥64 μg/mL) to macrolides, lincosamides, and streptogramin B–type antibiotics. The efflux mechanism encoded by the mef gene (M phenotype) is usually associated with low-level resistance (MICs, 1–32 μg/mL). These two mechanisms account for ∼45% and ∼65%, respectively, of resistant pneumococcal isolates in the United States. High-level resistance to macrolides is more common in Europe, whereas lower-level resistance predominates in North America.


InternalMed_Harrison

InternalMed_Harrison. Pneumococcal resistance to fluoroquinolones (e.g., ciprofloxacin and levofloxacin) has been reported. Changes can occur in one or both target sites (topoisomerases II and IV) from mutations in the gyrA and parC genes, respectively. In addition, an efflux pump may play a role in pneumococcal resistance to fluoroquinolones. Isolates resistant to drugs from three or more antimicrobial 807 classes with different mechanisms of action are considered MDR strains. The propensity for an association of pneumococcal resistance to penicillin with reduced susceptibility to other drugs, such as macrolides, tetracyclines, and trimethoprim-sulfamethoxazole, also is of concern. In the United States, 58.9% of penicillin-resistant pneumococcal isolates from blood are also resistant to macrolides.


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InternalMed_Harrison. The most important risk factor for antibiotic-resistant pneumococcal infection is use of a specific antibiotic within the previous 3 months. Therefore, a patient’s history of prior antibiotic treatment is a critical factor in avoiding the use of an inappropriate antibiotic. CA-MRSA CAP due to MRSA may be caused by the classic hospital-acquired strains or by the more recently identified, genotypically and phenotypically distinct community-acquired strains. Most infections with the former strains have been acquired either directly or indirectly by contact with the health care environment and would now be classified as HCAP. However, in some hospitals, the CA-MRSA strains are displacing the classic hospital-acquired strains—a trend suggesting that the newer strains may be more robust and blurring this distinction.


InternalMed_Harrison

InternalMed_Harrison. Methicillin resistance in S. aureus is determined by the mecA gene, which encodes for resistance to all β-lactam drugs. At least five staphylococcal chromosomal cassette mec (SCCmec) types have been described. The typical hospital-acquired strain usually has type II or III, whereas CA-MRSA has a type IV SCCmec element. CA-MRSA isolates tend to be less resistant than the older hospital-acquired strains and are often susceptible to trimethoprimsulfamethoxazole, clindamycin, and tetracycline in addition to vancomycin and linezolid. However, the most important distinction is that CA-MRSA strains also carry genes for superantigens, such as enterotoxins B and C and Panton-Valentine leukocidin, a membrane-tropic toxin that can create cytolytic pores in polymorphonuclear neutrophils, monocytes, and macrophages.


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InternalMed_Harrison. Gram-Negative Bacilli A detailed discussion of resistance among gram-negative bacilli is beyond the scope of this chapter (Chap. 186). Fluoroquinolone resistance among isolates of Escherichia coli from the community appears to be increasing. Enterobacter species are typically resistant to cephalosporins; the drugs of choice for use against these bacteria are usually fluoroquinolones or carbapenems. Similarly, when infections due to bacteria producing extended-spectrum β-lactamases are documented or suspected, a fluoroquinolone or a carbapenem should be used; these MDR strains are more likely to be involved in HCAP.


InternalMed_Harrison

InternalMed_Harrison. Since the etiology of CAP is rarely known at the outset of treatment, initial therapy is usually empirical, designed to cover the most likely pathogens (Table 153-5). In all cases, antibiotic treatment should be initiated as expeditiously as possible. The CAP treatment guidelines in the United States (summarized in Table 153-5) represent joint statements from the IDSA and the ATS; the Canadian guidelines come from the Canadian Infectious Disease Society and the Canadian Thoracic Society. In all these guidelines, coverage is always provided for the pneumococcus and the atypical pathogens. In contrast, guidelines from some European countries do not always include atypical coverage based on local epidemiologic data. The U.S./Canadian approach is supported by retrospective data derived from administrative databases including thousands of patients. Atypical pathogen coverage provided by the addition of a macrolide to a cephalosporin or by the use of a fluoroquinolone alone has been


InternalMed_Harrison

InternalMed_Harrison. from administrative databases including thousands of patients. Atypical pathogen coverage provided by the addition of a macrolide to a cephalosporin or by the use of a fluoroquinolone alone has been consistently associated with a significant reduction in mortality rates compared with those for β-lactam coverage alone.


InternalMed_Harrison

InternalMed_Harrison. Therapy with a macrolide or a fluoroquinolone within the previous 3 months is associated with an increased likelihood of infection with a resistant strain of S. pneumoniae. For this reason, a fluoroquinolone-based regimen should be used for patients recently given a macrolide, and vice versa (Table 153-5). 1. Previously healthy and no antibiotics in past 3 months PO once, then 250 mg qd]) or 2. Comorbidities or antibiotics in past 3 months: select an alternative from a different class • A respiratory fluoroquinolone (moxifloxacin [400 mg PO qd], gemifloxacin [320 mg PO qd], levofloxacin [750 mg PO qd]) or • A β-lactam (preferred: high-dose amoxicillin [1 g tid] or amoxicillin/ clavulanate [2 g bid]; alternatives: ceftriaxone [1–2 g IV qd], cefpodoxime [200 mg PO bid], cefuroxime [500 mg PO bid]) plus a macrolidea 3. In regions with a high rate of “high-level” pneumococcal macrolide resistance,b consider alternatives listed above for patients with comorbidities.


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InternalMed_Harrison. Inpatients, Non-ICU • A respiratory fluoroquinolone (e.g., moxifloxacin [400 mg PO or IV qd] or • A β-lactamc (e.g., ceftriaxone [1–2 g IV qd], ampicillin [1–2 g IV q4–6h], cefotaxime [1–2 g IV q8h], ertapenem [1 g IV qd]) plus a macrolided (e.g., oral clarithromycin or azithromycin [as listed above] or IV azithromycin [1 g once, then 500 mg qd]) Inpatients, ICU • A β-lactame (e.g., ceftriaxone [2 g IV qd], ampicillin-sulbactam [2 g IV q8h], or cefotaxime [1–2 g IV q8h]) plus either azithromycin or a fluoroquinolone (as listed above for inpatients, non-ICU) If Pseudomonas is a consideration: • An antipseudomonal β-lactam (e.g., piperacillin/tazobactam [4. 5 g IV q6h], cefepime [1–2 g IV q12h], imipenem [500 mg IV q6h], meropenem [1 g IV q8h]) plus either ciprofloxacin (400 mg IV q12h) or levofloxacin (750 mg IV qd) • The above β-lactams plus an aminoglycoside (amikacin [15 mg/kg qd] or tobramycin [1. 7 mg/kg qd]) plus azithromycin • The


InternalMed_Harrison

InternalMed_Harrison. If CA-MRSA is a consideration: • Add linezolid (600 mg IV q12h) or vancomycin (15 mg/kg q12h initially, aDoxycycline (100 mg PO bid) is an alternative to the macrolide. bMICs of >16 μg/mL in 25% of isolates. cA respiratory fluoroquinolone should be used for penicillin-allergic patients. dDoxycycline (100 mg IV q12h) is an alternative to the macrolide. eFor penicillin-allergic patients, use a respiratory fluoroquinolone and aztreonam (2 g IV q8h). fFor penicillin-allergic patients, substitute aztreonam. Abbreviations: CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; ICU, intensive care unit. Once the etiologic agent(s) and susceptibilities are known, therapy may be altered to target the specific pathogen(s). However, this decision is not always straightforward. If blood cultures yield


InternalMed_Harrison

InternalMed_Harrison. Once the etiologic agent(s) and susceptibilities are known, therapy may be altered to target the specific pathogen(s). However, this decision is not always straightforward. If blood cultures yield S. pneumoniae sensitive to penicillin after 2 days of treatment with a macrolide plus a β-lactam or with a fluoroquinolone alone, should therapy be switched to penicillin alone? The concern here is that a β-lactam alone would not be effective in the potential 15% of cases with atypical co-infection. No standard approach exists. In all cases, the individual patient and the various risk factors must be considered.


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InternalMed_Harrison. Management of bacteremic pneumococcal pneumonia also is controversial. Data from nonrandomized studies suggest that combination therapy (especially macrolide/β-lactam) is associated with a lower mortality rate than monotherapy, particularly in severely ill patients. The exact reason is unknown, but possible explanations include an additive or synergistic antibacterial effect, antimicrobial tolerance, atypical co-infection, or the immunomodulatory effects of the macrolides. For CAP patients admitted to the ICU, the risk of infection with


InternalMed_Harrison

InternalMed_Harrison. For CAP patients admitted to the ICU, the risk of infection with P. aeruginosa or CA-MRSA is increased. Empirical coverage should be considered when a patient has risk factors or a Gram’s stain suggestive of these pathogens (Table 153–5). If CA-MRSA is suspected, either linezolid or vancomycin can be added to the initial empirical regimen; however, there is increasing concern about vancomycin’s loss of potency against MRSA, poor penetration into epithelial lining fluid, and lack of effect on toxin production relative to linezolid. Although hospitalized patients have traditionally received initial therapy by the IV route, some drugs—particularly the fluoroquinolones—are very well absorbed and can be given orally from the outset to select patients. For patients initially treated IV, a switch to oral treatment is appropriate as long as the patient can ingest and absorb the drugs, is hemodynamically stable, and is showing clinical improvement.


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InternalMed_Harrison. The duration of treatment for CAP has generated considerable interest. Patients were previously treated for 10–14 days, but studies with fluoroquinolones and telithromycin suggest that a 5-day course is sufficient for otherwise uncomplicated CAP. Even a single dose of ceftriaxone has been associated with a significant cure rate. A longer course may be required for patients with bacteremia, metastatic infection, or infection with a virulent pathogen such as P. aeruginosa or CA-MRSA.


InternalMed_Harrison

InternalMed_Harrison. In addition to appropriate antimicrobial therapy, certain general considerations apply in dealing with CAP, HCAP, or HAP/VAP. Adequate hydration, oxygen therapy for hypoxemia, and assisted ventilation when necessary are critical to successful treatment. Patients with severe CAP who remain hypotensive despite fluid resuscitation may have adrenal insufficiency and may respond to glucocorticoid treatment. The value of adjunctive therapy, such as glucocorticoids, statins, and angiotensin-converting enzyme inhibitors, remains unproven in the management of CAP.


InternalMed_Harrison

InternalMed_Harrison. Failure to Improve Patients slow to respond to therapy should be reevaluated at about day 3 (sooner if their condition is worsening rather than simply not improving), and several possible scenarios should be considered. A number of noninfectious conditions mimic pneumonia, including pulmonary edema, pulmonary embolism, lung carcinoma, radiation and hypersensitivity pneumonitis, and connective tissue disease involving the lungs. If the patient truly has CAP and empirical treatment is aimed at the correct pathogen, lack of response may be explained in a number of ways. The pathogen may be resistant to the drug selected, or a sequestered focus (e.g., lung abscess or empyema) may be blocking access of the antibiotic(s) to the pathogen. The patient may be getting either the wrong drug or the correct drug at the wrong dose or frequency of administration. Another possibility is that CAP is the correct diagnosis but an unsuspected pathogen (e.g., CA-MRSA, M. tuberculosis, or a fungus) is the


InternalMed_Harrison

InternalMed_Harrison. drug at the wrong dose or frequency of administration. Another possibility is that CAP is the correct diagnosis but an unsuspected pathogen (e.g., CA-MRSA, M. tuberculosis, or a fungus) is the cause. Nosocomial superinfections—both pulmonary and extrapulmonary—are other possible explanations for a patient’s failure to improve or deterioration. In all cases of delayed response or deteriorating condition, the patient must be carefully reassessed and appropriate studies initiated, possibly including such diverse procedures as CT or bronchoscopy.


InternalMed_Harrison

InternalMed_Harrison. Complications As in other severe infections, common complications of severe CAP include respiratory failure, shock and multiorgan failure, coagulopathy, and exacerbation of comorbid illnesses. Three particularly noteworthy conditions are metastatic infection, lung abscess, and complicated pleural effusion. Metastatic infection (e.g., brain abscess or endocarditis) is very unusual and will require a high degree of suspicion and a detailed workup for proper treatment. Lung abscess may occur in association with aspiration or with infection caused by a single CAP pathogen, such as CA-MRSA,


InternalMed_Harrison

InternalMed_Harrison. P. aeruginosa, or (rarely) S. pneumoniae. Aspiration pneumonia is typically a polymicrobial infection involving both aerobes and anaerobes. A significant pleural effusion should be tapped for both diagnostic and therapeutic purposes. If the fluid has a pH of <7, a glucose level of <2. 2 mmol/L, and a lactate dehydrogenase concentration of >1000 U/L or if bacteria are seen or cultured, then it should be completely drained; a chest tube is often required and video-assisted thoracoscopy may be needed for late treatment or difficult cases.


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InternalMed_Harrison. Follow-Up Fever and leukocytosis usually resolve within 2–4 days in otherwise healthy patients with CAP, but physical findings may persist longer. Chest radiographic abnormalities are slowest to resolve (4–12 weeks), with the speed of clearance depending on the patient’s age and underlying lung disease. Patients may be discharged from the hospital once their clinical conditions, including comorbidities, are stable. The site of residence after discharge (nursing home, home with family, home alone) is an important discharge timing consideration, particularly for elderly patients. For a hospitalized patient, a follow-up radiograph ∼4–6 weeks later is recommended. If relapse or recurrence is documented, particularly in the same lung segment, the possibility of an underlying neoplasm must be considered.


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InternalMed_Harrison. The prognosis of CAP depends on the patient’s age, comorbidities, and site of treatment (inpatient or outpatient). Young patients without comorbidity do well and usually recover fully after ~2 weeks. Older patients and those with comorbid conditions can take several weeks longer to recover fully. The overall mortality rate for the outpatient group is <1%. For patients requiring hospitalization, the overall mortality rate is estimated at 10%, with ~50% of deaths directly attributable to pneumonia. The main preventive measure is vaccination (Chap. 148). Recommendations of the Advisory Committee on Immunization Practices should be followed for influenza and pneumococcal vaccines.


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InternalMed_Harrison. A pneumococcal polysaccharide vaccine (PPV23) and a protein conjugate pneumococcal vaccine (PCV13) are available in the United States. The former product contains capsular material from 23 pneumococcal serotypes; in the latter, capsular polysaccharide from 13 of the most frequent pneumococcal pathogens affecting children is linked to an immunogenic protein. PCV13 produces T cell–dependent antigens that result in long-term immunologic memory. Administration of this vaccine to children has led to an overall decrease in the prevalence of antimicrobial-resistant pneumococci and in the incidence of invasive pneumococcal disease among both children and adults. However, vaccination can be followed by the replacement of vaccine serotypes with nonvaccine serotypes, as was seen with serotypes 19A and 35B after introduction of the original 7-valent conjugate vaccine. PCV13 now is also recommended for the elderly and for younger immunocompromised patients. Because of an increased risk of


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InternalMed_Harrison. 19A and 35B after introduction of the original 7-valent conjugate vaccine. PCV13 now is also recommended for the elderly and for younger immunocompromised patients. Because of an increased risk of pneumococcal infection, even among patients without obstructive lung disease, smokers should be strongly encouraged to stop smoking.


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InternalMed_Harrison. Two forms of influenza vaccine are available: intramuscular inactivated vaccine and intranasal live-attenuated cold-adapted vaccine. The latter is contraindicated in immunocompromised patients. In the event of an influenza outbreak, unprotected patients at risk from complications should be vaccinated immediately and given chemoprophylaxis with either oseltamivir or zanamivir for 2 weeks—i.e., until vaccine-induced antibody levels are sufficiently high. HCAP represents a transition between classic CAP and typical HAP. The definition of HCAP is still in some flux because of a lack of consistent large-scale studies. Several early studies were limited to patients with culture-positive pneumonia. In these studies, the incidence of MDR pathogens in HCAP was as high as or higher than in HAP/VAP. MRSA in particular was more common in HCAP than in traditional 809 HAP/VAP. Conversely, prospective studies in nontertiary-care centers have found a low incidence of MDR pathogens in HCAP.


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InternalMed_Harrison. The patients at greatest risk for HCAP are not well defined. Patients from nursing homes are not always at elevated risk for infection with MDR pathogens. Careful evaluation of nursing home residents with pneumonia suggests that their risk of MDR infection is low if they have not recently received antibiotics and are independent in most activities of daily living. Recent hospitalization (i.e., in the preceding 90 days) is also a major risk factor for infection with MDR pathogens. Conversely, nursing home patients are at increased risk of infection with influenza virus and other atypical pneumonia pathogens. Undue concern about MDR pathogens occasionally results in failure to cover atypical pathogens when treating nursing home patients. In addition, patients receiving home infusion therapy or undergoing chronic dialysis are probably at particular risk for MRSA pneumonia but may not be at greater risk for infection with Pseudomonas or Acinetobacter than are other patients who develop


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InternalMed_Harrison. or undergoing chronic dialysis are probably at particular risk for MRSA pneumonia but may not be at greater risk for infection with Pseudomonas or Acinetobacter than are other patients who develop CAP.


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InternalMed_Harrison. In general, the management of HCAP due to MDR pathogens is similar to that of MDR HAP/VAP. This topic will therefore be covered in subsequent sections on HAP and VAP. The prognosis of HCAP is intermediate between that of CAP and VAP and is closer to that of HAP. Most hospital-acquired pneumonia research has focused on VAP. However, the information and principles based on this research can be applied to non-ICU HAP and HCAP as well. The greatest difference between VAP and HCAP/HAP studies is the dependence on expectorated sputum for a microbiologic diagnosis of VAP (as for that of CAP), which is further complicated by frequent colonization by pathogens in patients with HAP or HCAP. Therefore, most of the literature has focused on HCAP or HAP resulting in intubation, where, once again, access to the lower respiratory tract facilitates an etiologic diagnosis.


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InternalMed_Harrison. Etiology Potential etiologic agents of VAP include both MDR and non-MDR bacterial pathogens (Table 153-6). The non-MDR group is nearly identical to the pathogens found in severe CAP (Table 153-2); it is not surprising that such pathogens predominate if VAP develops in the first 5–7 days of the hospital stay. However, if patients have other risk factors for HCAP, MDR pathogens are a consideration, even early in the hospital course. The relative frequency of individual MDR pathogens can vary significantly from hospital to hospital and even between different critical care units within the same institution. Most hospitals have problems with P. aeruginosa and MRSA, but other MDR pathogens are often institution-specific. Less commonly, fungal and viral pathogens cause VAP, usually affecting severely immunocompromised patients. Rarely, community-associated viruses cause mini-epidemics, usually when introduced by ill health care workers.


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InternalMed_Harrison. Streptococcus pneumoniae Pseudomonas aeruginosa Other Streptococcus spp. MRSA Haemophilus influenzae Acinetobacter spp. MSSA Antibiotic-resistant Antibiotic-sensitive Enterobacteriaceae Enterobacteriaceae Enterobacter spp. Escherichia coli ESBL-positive strains Klebsiella pneumoniae Klebsiella spp. Proteus spp. Legionella pneumophila Enterobacter spp. Burkholderia cepacia Serratia marcescens Aspergillus spp. Abbreviations: ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive S. aureus.


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InternalMed_Harrison. 810 Epidemiology Pneumonia is a common complication among patients requiring mechanical ventilation. Prevalence estimates vary between 6 and 52 cases per 100 patients, depending on the population studied. On any given day in the ICU, an average of 10% of patients will have pneumonia—VAP in the overwhelming majority of cases. The frequency of diagnosis is not static but changes with the duration of mechanical ventilation, with the highest hazard ratio in the first 5 days and a plateau in additional cases (1% per day) after ~2 weeks. However, the cumulative rate among patients who remain ventilated for as long as 30 days is as high as 70%. These rates often do not reflect the recurrence of VAP in the same patient. Once a ventilated patient is transferred to a chronic-care facility or to home, the incidence of pneumonia drops significantly, especially in the absence of other risk factors for pneumonia. However, in chronic ventilator units, purulent tracheobronchitis becomes a significant


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InternalMed_Harrison. the incidence of pneumonia drops significantly, especially in the absence of other risk factors for pneumonia. However, in chronic ventilator units, purulent tracheobronchitis becomes a significant issue, often interfering with efforts to wean patients off mechanical ventilation (Chap. 323). Three factors are critical in the pathogenesis of VAP: colonization of the oropharynx with pathogenic microorganisms, aspiration of these organisms from the oropharynx into the lower respiratory tract, and compromise of the normal host defense mechanisms. Most risk factors and their corresponding prevention strategies pertain to one of these three factors (Table 153-7). The most obvious risk factor is the endotracheal tube, which bypasses the normal mechanical factors preventing aspiration. While the presence of an endotracheal tube may prevent large-volume aspiration, microaspiration is actually exacerbated by secretions pooling above the cuff. The endotracheal tube and the concomitant need


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InternalMed_Harrison. Oropharyngeal colonization with pathogenic bacteria Elimination of normal flora Avoidance of prolonged antibiotic courses Large-volume oropharyngeal Short course of prophylactic aspiration around time of antibiotics for comatose patientsa intubation Gastroesophageal reflux Postpyloric enteral feedingb; avoidance of high gastric residuals, prokinetic agents Bacterial overgrowth of stomach Avoidance of prophylactic agents that raise gastric pHb; selective decontamination of digestive tract with nonabsorbable antibioticsb Cross-infection from other colonized Hand washing, especially with patients alcohol-based hand rub; intensive infection control educationa; isolation; proper cleaning of reusable equipment Large-volume aspiration Endotracheal intubation; rapid-sequence intubation technique; avoidance of sedation; decompression of small-bowel obstruction Prolonged duration of ventilation Daily awakening from sedation,a weaning protocolsa


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InternalMed_Harrison. Prolonged duration of ventilation Daily awakening from sedation,a weaning protocolsa Secretions pooled above Head of bed elevateda; continuous endotracheal tube aspiration of subglottic secretions with specialized endotracheal tubea; avoidance of reintubation; minimization of sedation and patient transport Altered lower respiratory host Tight glycemic controlb; lowering of defenses hemoglobin transfusion threshold aStrategies demonstrated to be effective in at least one randomized controlled trial. bStrategies with negative randomized trials or conflicting results. for suctioning can damage the tracheal mucosa, thereby facilitating tracheal colonization. In addition, pathogenic bacteria can form a glycocalyx biofilm on the tube’s surface that protects them from both antibiotics and host defenses. The bacteria can also be dislodged during suctioning and can reinoculate the trachea, or tiny fragments of glycocalyx can embolize to distal airways, carrying bacteria with them.


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InternalMed_Harrison. In a high percentage of critically ill patients, the normal oropharyngeal flora is replaced by pathogenic microorganisms. The most important risk factors are antibiotic selection pressure, cross-infection from other infected/colonized patients or contaminated equipment, and malnutrition. Of these factors, antibiotic exposure poses the greatest risk by far. Pathogens such as P. aeruginosa almost never cause infection in patients without prior exposure to antibiotics. The recent emphasis on hand hygiene has lowered the cross-infection rate.


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InternalMed_Harrison. How the lower respiratory tract defenses become overwhelmed remains poorly understood. Almost all intubated patients experience microaspiration and are at least transiently colonized with pathogenic bacteria. However, only around one-third of colonized patients develop VAP. Colony counts increase to high levels, sometimes days before the development of clinical pneumonia; these increases suggest that the final step in VAP development, independent of aspiration and oropharyngeal colonization, is the overwhelming of host defenses. Severely ill patients with sepsis and trauma appear to enter a state of immunoparalysis several days after admission to the ICU—a time that corresponds to the greatest risk of developing VAP. The mechanism of this immunosuppression is not clear, although several factors have been suggested. Hyperglycemia affects neutrophil function, and trials suggest that keeping the blood sugar level close to normal with exogenous insulin may have beneficial effects,


InternalMed_Harrison

InternalMed_Harrison. factors have been suggested. Hyperglycemia affects neutrophil function, and trials suggest that keeping the blood sugar level close to normal with exogenous insulin may have beneficial effects, including a decreased risk of infection. More frequent transfusions also adversely affect the immune response.


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InternalMed_Harrison. Clinical Manifestations The clinical manifestations are generally the same in VAP as in all other forms of pneumonia: fever, leukocytosis, increase in respiratory secretions, and pulmonary consolidation on physical examination, along with a new or changing radiographic infiltrate. The frequency of abnormal chest radiographs before the onset of pneumonia in intubated patients and the limitations of portable radiographic technique make interpretation of radiographs more difficult than in patients who are not intubated. Other clinical features may include tachypnea, tachycardia, worsening oxygenation, and increased minute ventilation. Diagnosis No single set of criteria is reliably diagnostic of pneumonia in a ventilated patient. The inability to identify such patients compromises efforts to prevent and treat VAP and even calls into question estimates of the impact of VAP on mortality rates.


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InternalMed_Harrison. Application of clinical criteria consistently results in overdiagnosis of VAP, largely because of three common findings in at-risk patients: (1) tracheal colonization with pathogenic bacteria in patients with endotracheal tubes, (2) multiple alternative causes of radiographic infiltrates in mechanically ventilated patients, and (3) the high frequency of other sources of fever in critically ill patients. The differential diagnosis of VAP includes a number of entities such as atypical pulmonary edema, pulmonary contusion, alveolar hemorrhage, hypersensitivity pneumonitis, acute respiratory distress syndrome, and pulmonary embolism. Clinical findings in ventilated patients with fever and/or leukocytosis may have alternative causes, including antibiotic-associated diarrhea, sinusitis, urinary tract infection, pancreatitis, and drug fever. Conditions mimicking pneumonia are often documented in patients in whom VAP has been ruled out by accurate diagnostic techniques. Most of these


InternalMed_Harrison

InternalMed_Harrison. urinary tract infection, pancreatitis, and drug fever. Conditions mimicking pneumonia are often documented in patients in whom VAP has been ruled out by accurate diagnostic techniques. Most of these alternative diagnoses do not require antibiotic treatment; require antibiotics different from those used to treat VAP; or require some additional intervention, such as surgical drainage or catheter removal, for optimal management.


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InternalMed_Harrison. This diagnostic dilemma has led to debate and controversy. The major question is whether a quantitative-culture approach as a means of eliminating false-positive clinical diagnoses is superior to the clinical approach enhanced by principles learned from quantitative-culture studies. The most recent IDSA/ATS guidelines for HAP/VAP suggest that either approach is clinically valid.


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InternalMed_Harrison. Quantitative-culture approacH The essence of the quantitative-culture approach is to discriminate between colonization and true infection by determining the bacterial burden. The more distal in the respiratory tree the diagnostic sampling, the more specific the results and therefore the lower the threshold of growth necessary to diagnose pneumonia and exclude colonization. For example, a quantitative endotracheal aspirate yields proximate samples, and the diagnostic threshold is 106 cfu/mL. The protected specimen brush method, in contrast, obtains distal samples and has a threshold of 103 cfu/mL. Conversely, sensitivity declines as more distal secretions are obtained, especially when they are collected blindly (i.e., by a technique other than bronchoscopy). Additional tests that may increase the diagnostic yield include Gram’s staining, differential cell counts, staining for intracellular organisms, and detection of local protein levels elevated in response to infection.


InternalMed_Harrison

InternalMed_Harrison. The Achilles heel of the quantitative approach is the effect of antibiotic therapy. With sensitive microorganisms, a single antibiotic dose can reduce colony counts below the diagnostic threshold. Recent changes in antibiotic therapy are the most significant. After 3 days, the operating characteristics of the tests are almost the same as if no antibiotic therapy has been given. Conversely, colony counts above the diagnostic threshold during antibiotic therapy suggest that the current antibiotics are ineffective. Even the normal host response may be sufficient to reduce quantitative-culture counts below the diagnostic threshold if sampling is delayed. In short, expertise in quantitative-culture techniques is critical, with a specimen obtained as soon as pneumonia is suspected and before antibiotic therapy is initiated or changed.


InternalMed_Harrison

InternalMed_Harrison. In a study comparing the quantitative with the clinical approach, use of bronchoscopic quantitative cultures resulted in significantly less antibiotic use at 14 days after study entry and in lower rates of mortality and severity-adjusted mortality at 28 days. In addition, more alternative sites of infection were found in patients randomized to the quantitative-culture strategy. A critical aspect of this study was that antibiotic treatment was initiated only in patients whose gram-stained respiratory sample was positive or who displayed signs of hemodynamic instability. Fewer than one-half as many patients were treated for pneumonia in the bronchoscopy group, and only one-third as many microorganisms were cultured.


InternalMed_Harrison

InternalMed_Harrison. clinical approacH The lack of specificity of a clinical diagnosis of VAP has led to efforts to improve the diagnostic criteria. The Clinical Pulmonary Infection Score (CPIS) was developed by weighting of the various clinical criteria usually used for the diagnosis of VAP (Table 153-8). Use of the CPIS allows the selection of low-risk patients who may need only short-course antibiotic therapy or no treatment at all. Moreover, studies have demonstrated that the absence of bacteria in gram-stained endotracheal aspirates makes pneumonia an unlikely cause of fever or pulmonary infiltrates. These findings, coupled with a heightened awareness of the alternative diagnoses possible in patients with suspected VAP, can prevent inappropriate overtreatment for pneumonia. Furthermore, data show that the absence of an MDR pathogen in tracheal aspirate cultures eliminates the need for MDR coverage when empirical antibiotic therapy is narrowed. Since the most likely explanations for the mortality


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InternalMed_Harrison. the absence of an MDR pathogen in tracheal aspirate cultures eliminates the need for MDR coverage when empirical antibiotic therapy is narrowed. Since the most likely explanations for the mortality benefit of bronchoscopic quantitative cultures are decreased antibiotic selection pressure (which reduces the risk of subsequent infection with MDR pathogens) and identification of alternative sources of infection, a clinical diagnostic approach that incorporates such principles may result in similar outcomes.


InternalMed_Harrison

InternalMed_Harrison. Other large randomized studies that did not demonstrate a similar beneficial impact of quantitative culture on outcomes did not tightly link antibiotic treatment to the results of quantitative culture and other tests. Given the conflicting results only partially explained by methodologic issues, the IDSA/ATS guidelines therefore suggest that the choice depends on availability and local expertise. aAt the time of the original diagnosis, the progression of the infiltrate is not known and results of tracheal aspirate culture are often unavailable; thus, the maximal score is initially 8–10. Abbreviations: ARDS, acute respiratory distress syndrome; CHF, congestive heart failure. Many studies have demonstrated higher mortality rates with initially inappropriate empirical antibiotic therapy. The key to appropriate antibiotic management of VAP is an appreciation of the resistance patterns of the most likely pathogens in a given patient.


InternalMed_Harrison

InternalMed_Harrison. If not for the higher risk of infection with MDR pathogens (Table 153-1), VAP could be treated with the same antibiotics used for severe CAP. However, antibiotic selection pressure leads to the frequent involvement of MDR pathogens by selecting either for drug-resistant isolates of common pathogens (MRSA and Enterobacteriaceae producing extended-spectrum β-lactamases or carbapenemases) or for intrinsically resistant pathogens (P. aeruginosa and Acinetobacter species). Frequent use of β-lactam drugs, especially cephalosporins, appears to be the major risk factor for infection with MRSA and extended-spectrum β-lactamase–positive strains.


InternalMed_Harrison

InternalMed_Harrison. P. aeruginosa has demonstrated the ability to develop resistance to all routinely used antibiotics. Unfortunately, even if initially sensitive, P. aeruginosa isolates also have a propensity to develop resistance during treatment. Either de-repression of resistance genes or selection of resistant clones within the large bacterial inoculum associated with most pneumonias may be the cause. Acinetobacter species, Stenotrophomonas maltophilia, and Burkholderia cepacia are intrinsically resistant to many of the empirical antibiotic regimens employed (see later in this chapter). VAP caused by these pathogens emerges during treatment of other infections, and resistance is always evident at initial diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Recommended options for empirical therapy are listed in Table 153-9. Treatment should be started once diagnostic specimens have been obtained. The major factor in the selection of agents is the presence of risk factors for MDR pathogens. Choices among the various options listed depend on local patterns of resistance and—a very important factor—the patient’s prior antibiotic exposure. The majority of patients without risk factors for MDR infection can be treated with a single agent. The major difference from CAP is the markedly lower incidence of atypical pathogens in VAP; the exception is Legionella, which can be a nosocomial pathogen, especially with breakdowns in the treatment of potable water in the hospital. Moxifloxacin (400 mg IV q24h), ciprofloxacin (400 mg IV q8h), or levofloxacin (750 mg IV q24h) or Ampicillin/sulbactam (3 g IV q6h) or Ertapenem (1 g IV q24h) Patients with Risk Factors for MDR Pathogens 1. A β-lactam: Piperacillin/tazobactam (4. 5 g IV q6h) or


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InternalMed_Harrison. Patients with Risk Factors for MDR Pathogens 1. A β-lactam: Piperacillin/tazobactam (4. 5 g IV q6h) or Imipenem (500 mg IV q6h or 1 g IV q8h), or meropenem (1 g IV q8h) 2. A second agent active against gram-negative bacterial pathogens: 3. An agent active against gram-positive bacterial pathogens: Vancomycin (15 mg/kg q12h initially with adjusted doses) Abbreviation: MDR, multidrug-resistant. The standard recommendation for patients with risk factors for MDR infection is for three antibiotics: two directed at P. aeruginosa and one at MRSA. The choice of a β-lactam agent provides the greatest variability in coverage, yet the use of the broadest-spectrum agent—a carbapenem, even in an antibiotic combination—still represents inappropriate initial therapy in 10–15% of cases.


InternalMed_Harrison

InternalMed_Harrison. Once an etiologic diagnosis is made, broad-spectrum empirical therapy can be modified to specifically address the known pathogen. For patients with MDR risk factors, antibiotic regimens can be reduced to a single agent in more than one-half of cases and to a two-drug combination in more than one-quarter of cases. Only a minority of cases require a complete course with three drugs. A negative tracheal-aspirate culture or growth below the threshold for quantitative cultures, especially if the sample was obtained before any antibiotic change, strongly suggests that antibiotics should be discontinued. Identification of other confirmed or suspected sites of infection may require ongoing antibiotic therapy, but the spectrum of pathogens (and the corresponding antibiotic choices) may be different from those for VAP. If the CPIS decreases over the first 3 days, antibiotics should be stopped after 8 days. An 8-day course of therapy is just as effective as a 2-week course and is associated with


InternalMed_Harrison

InternalMed_Harrison. from those for VAP. If the CPIS decreases over the first 3 days, antibiotics should be stopped after 8 days. An 8-day course of therapy is just as effective as a 2-week course and is associated with less frequent emergence of antibiotic-resistant strains.


InternalMed_Harrison

InternalMed_Harrison. The major controversy regarding specific therapy for VAP concerns the need for ongoing combination treatment of Pseudomonas infection. No randomized controlled trials have demonstrated a benefit of combination therapy with a β-lactam and an aminoglycoside, nor have subgroup analyses in other trials found a survival benefit with such a regimen. The unacceptably high rates of clinical failure and death for VAP caused by P. aeruginosa despite combination therapy (see “Failure to Improve,” later) indicate that better regimens are needed—including, perhaps, aerosolized antibiotics. VAP caused by MRSA is associated with a 40% clinical failure rate when treated with standard-dose vancomycin. One proposed solution is the use of high-dose individualized treatment, although the risk of renal toxicity increases with this strategy. In addition, the MIC of vancomycin has been increasing, and a high percentage of clinical failures occur when the MIC is in the upper range of sensitivity (i.e., 1.


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InternalMed_Harrison. increases with this strategy. In addition, the MIC of vancomycin has been increasing, and a high percentage of clinical failures occur when the MIC is in the upper range of sensitivity (i.e., 1. 5–2 μg/mL). Linezolid appears to be 15% more efficacious than even adjusted-dose vancomycin and is clearly preferred in patients with renal insufficiency and those infected with high-MIC isolates of MRSA.


InternalMed_Harrison

InternalMed_Harrison. Treatment failure is not uncommon in VAP, especially that caused by MDR pathogens. In addition to the 40% failure rate for MRSA infection treated with vancomycin, VAP due to Pseudomonas has a 50% failure rate, no matter what the regimen. Causes of clinical failure vary with the pathogen(s) and the antibiotic(s). Inappropriate therapy can usually be minimized by use of the recommended triple-drug regimen (Table 153-9). However, the emergence of β-lactam resistance during therapy is an important problem, especially in infection with Pseudomonas and Enterobacter species. Recurrent VAP caused by the same pathogen is possible because the biofilm on endotracheal tubes allows reintroduction of the microorganism. However, studies of VAP caused by Pseudomonas show that approximately half of recurrent cases are caused by a new strain. Inadequate local levels of vancomycin are the likely cause of treatment failure in VAP due to MRSA.


InternalMed_Harrison

InternalMed_Harrison. Treatment failure is very difficult to diagnose. Pneumonia due to a new superinfection, the presence of extrapulmonary infection, and drug toxicity must be considered in the differential diagnosis of treatment failure. Serial CPIS calculations appear to track the clinical response accurately, while repeat quantitative cultures may clarify the microbiologic response. A persistently elevated or rising CPIS by day 3 of therapy is likely to indicate treatment failure. The most sensitive component of the CPIS is improvement in oxygenation. Apart from death, the major complication of VAP is prolongation of mechanical ventilation, with corresponding increases in length of stay in the ICU and in the hospital. In most studies, an additional week of mechanical ventilation resulting from VAP is common. The additional expense of this complication often warrants costly and aggressive efforts at prevention.


InternalMed_Harrison

InternalMed_Harrison. In rare cases, some types of necrotizing pneumonia (e.g., that due to P. aeruginosa) result in significant pulmonary hemorrhage. More commonly, necrotizing infections result in the long-term complications of bronchiectasis and parenchymal scarring leading to recurrent pneumonias. The long-term complications of pneumonia are underappreciated. Pneumonia results in a catabolic state in a patient already nutritionally at risk. The muscle loss and general debilitation from an episode of VAP often require prolonged rehabilitation and, in the elderly, commonly result in an inability to return to independent function and the need for nursing home placement.


InternalMed_Harrison

InternalMed_Harrison. Clinical improvement, if it occurs, is usually evident within 48–72 h of the initiation of antimicrobial treatment. Because findings on chest radiography often worsen initially during treatment, they are less helpful than clinical criteria as an indicator of clinical response in severe pneumonia. Seriously ill patients with pneumonia often undergo follow-up chest radiography daily, at least until they are being weaned off mechanical ventilation.


InternalMed_Harrison

InternalMed_Harrison. Prognosis VAP is associated with significant mortality. Crude mortality rates of 50–70% have been reported, but the real issue is attributable mortality. Many patients with VAP have underlying diseases that would result in death even if VAP did not occur. Attributable mortality exceeded 25% in one matched-cohort study, while more recent studies have suggested much lower rates. Patients who develop VAP are at least twice as likely to die as those who do not. Some of the variability in VAP mortality rates is clearly related to the type of patient and ICU studied. VAP in trauma patients is not associated with attributable mortality, possibly because many of the patients were otherwise healthy before being injured. However, the causative pathogen also plays a major role. Generally, MDR pathogens are associated with significantly greater attributable mortality than non-MDR pathogens. Pneumonia caused by some pathogens (e.g., S. maltophilia) is simply a marker for a patient whose immune


InternalMed_Harrison

InternalMed_Harrison. are associated with significantly greater attributable mortality than non-MDR pathogens. Pneumonia caused by some pathogens (e.g., S. maltophilia) is simply a marker for a patient whose immune system is so compromised that death is almost inevitable.


InternalMed_Harrison

InternalMed_Harrison. Prevention (Table 153-7) Because of the significance of the endotracheal tube as a risk factor for VAP, the most important preventive intervention is to avoid endotracheal intubation or minimize its duration. Successful use of noninvasive ventilation via a nasal or full-face mask avoids many of the problems associated with endotracheal tubes. Strategies that minimize the duration of ventilation through daily holding of sedation and formal weaning protocols also have been highly effective in preventing VAP.


InternalMed_Harrison

InternalMed_Harrison. Unfortunately, a tradeoff in risks is sometimes required. Aggressive attempts to extubate early may result in reintubation(s) and increase aspiration, posing a risk of VAP. Heavy continuous sedation increases the risk, but self-extubation because of insufficient sedation also is a risk. The tradeoffs also apply to antibiotic therapy. Short-course antibiotic prophylaxis can decrease the risk of VAP in comatose patients requiring intubation, and data suggest that antibiotics decrease VAP rates in general. However, the major benefit appears to be a decrease in the incidence of early-onset VAP, which is usually caused by the less pathogenic non-MDR microorganisms. Conversely, prolonged courses of antibiotics consistently increase the risk of VAP caused by the more lethal MDR pathogens. Despite its virulence and associated mortality, VAP caused by Pseudomonas is rare among patients who have not recently received antibiotics.


InternalMed_Harrison

InternalMed_Harrison. Minimizing the amount of microaspiration around the endotracheal tube cuff also is a strategy for avoidance of VAP. Simply elevating the head of the bed (at least 30° above horizontal but preferably 45°) decreases VAP rates. Specially modified endotracheal tubes that allow removal of the secretions pooled above the cuff also may prevent VAP. The risk-to-benefit ratio of transporting the patient outside the ICU for diagnostic tests or procedures should be carefully considered, since VAP rates are increased among transported patients.


InternalMed_Harrison

InternalMed_Harrison. Emphasis on the avoidance of agents that raise gastric pH and on oropharyngeal decontamination has been diminished by the equivocal and conflicting results of recent clinical trials. The role in the pathogenesis of VAP that is played by the overgrowth of bacterial components of the bowel flora in the stomach also has been downplayed. MRSA and the nonfermenters P. aeruginosa and Acinetobacter species are not normally part of the bowel flora but reside primarily in the nose and on the skin, respectively. Therefore, emphasis on controlling overgrowth of the bowel flora may be relevant only in certain populations, such as liver transplant recipients and patients who have undergone other major intraabdominal procedures or who have bowel obstruction.


InternalMed_Harrison

InternalMed_Harrison. In outbreaks of VAP due to specific pathogens, the possibility of a breakdown in infection control measures (particularly contamination of reusable equipment) should be investigated. Even high rates of pathogens that are already common in a particular ICU may be a result of cross-infection. Education and reminders of the need for consistent hand washing and other infection-control practices can minimize this risk. While significantly less well studied than VAP, HAP in nonintubated patients—both inside and outside the ICU—is similar to VAP. The main differences are the higher frequency of non-MDR pathogens and the better underlying host immunity in nonintubated patients. The lower frequency of MDR pathogens allows monotherapy in a larger proportion of cases of HAP than of VAP.


InternalMed_Harrison

InternalMed_Harrison. The only pathogens that may be more common in the non-VAP population are anaerobes. The greater risk of macroaspiration by nonintubated patients and the lower oxygen tensions in the lower respiratory tract of these patients increase the likelihood of a role for anaerobes. While more common in patients with HAP, anaerobes are usually only contributors to polymicrobial pneumonias except in patients with large-volume aspiration or in the setting of bowel obstruction/ileus. As in the management of CAP, specific therapy targeting anaerobes probably is not indicated (unless gross aspiration 813 is a concern) since many of the recommended antibiotics are active against anaerobes.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis is even more difficult for HAP in the nonintubated patient than for VAP. Lower respiratory tract samples appropriate for culture are considerably more difficult to obtain from nonintubated patients. Many of the underlying diseases that predispose a patient to HAP are also associated with an inability to cough adequately. Since blood cultures are infrequently positive (<15% of cases), the majority of patients with HAP do not have culture data on which antibiotic modifications can be based. Therefore, de-escalation of therapy is less likely in patients with risk factors for MDR pathogens. Despite these difficulties, the better host defenses in non-ICU patients result in lower mortality rates than are documented for VAP. In addition, the risk of antibiotic failure is lower in HAP. Rebecca M. Baron, Miriam Baron Barshak


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InternalMed_Harrison. Rebecca M. Baron, Miriam Baron Barshak Lung abscess represents necrosis and cavitation of the lung following microbial infection. Lung abscesses can be single or multiple but usually are marked by a single dominant cavity >2 cm in diameter. The low prevalence of lung abscesses makes them difficult to study in randomized controlled trials. Although the incidence of lung abscesses has decreased in the postantibiotic era, they are still a source of significant morbidity and mortality.


InternalMed_Harrison

InternalMed_Harrison. Lung abscesses are usually characterized as either primary (~80% of cases) or secondary. Primary lung abscesses usually arise from aspiration, are often caused principally by anaerobic bacteria, and occur in the absence of an underlying pulmonary or systemic condition. Secondary lung abscesses arise in the setting of an underlying condition, such as a postobstructive process (e.g., a bronchial foreign body or tumor) or a systemic process (e.g., HIV infection or another immunocompromising condition). Lung abscesses can also be characterized as acute (<4–6 weeks in duration) or chronic (~40% of cases).


InternalMed_Harrison

InternalMed_Harrison. The majority of the existing epidemiologic information involves primary lung abscesses. In general, middle-aged men are more commonly affected than middle-aged women. The major risk factor for primary lung abscesses is aspiration. Patients at particular risk for aspiration, such as those with altered mental status, alcoholism, drug overdose, seizures, bulbar dysfunction, prior cerebrovascular or cardiovascular events, or neuromuscular disease, are most commonly affected. In addition, patients with esophageal dysmotility or esophageal lesions (strictures or tumors) and those with gastric distention and/or gastroesophageal reflux, especially those who spend substantial time in the recumbent position, are at risk for aspiration.


InternalMed_Harrison

InternalMed_Harrison. It is widely thought that colonization of the gingival crevices by anaerobic bacteria or microaerophilic streptococci (especially in patients with gingivitis and periodontal disease), combined with a risk of aspiration, is important in the development of lung abscesses. In fact, many physicians consider it extremely rare for lung abscesses to develop in the absence of teeth as a nidus for bacterial colonization. The importance of these risk factors in the development of lung abscesses is highlighted by a significant reduction in abscess incidence in the late 1940s that coincided with a change in oral surgical technique: beginning at that time, these operations were no longer performed with the patient in the seated position without a cuffed endotracheal tube, and the frequency of perioperative aspiration events was thus decreased. In addition, the introduction of penicillin around the same time significantly reduced the incidence of and mortality rate from lung abscess.


InternalMed_Harrison

InternalMed_Harrison. PATHOGENESIS Primary Lung Abscesses The development of primary lung abscesses is thought to originate when chiefly anaerobic bacteria (as well as microaerophilic streptococci) in the gingival crevices are aspirated into the lung parenchyma in a susceptible host (Table 154-1). Thus, patients who develop primary lung abscesses usually carry an overwhelming burden of aspirated material or are unable to clear the bacterial load. Pneumonitis develops initially (exacerbated in part by tissue damage caused by gastric acid); then, over a period of 7–14 days, the anaerobic bacteria produce parenchymal necrosis and cavitation whose extent depends on the host–pathogen interaction (Fig. 154-1). Anaerobes are thought to produce more extensive tissue necrosis in polymicrobial infections in which virulence factors of the various bacteria can act synergistically to cause more significant tissue destruction.


InternalMed_Harrison

InternalMed_Harrison. Secondary Lung Abscesses The pathogenesis of secondary abscesses depends on the predisposing factor. For example, in cases of bronchial


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InternalMed_Harrison. FIGURE 154-1 Representative chest CT scans demonstrating development of lung abscesses. This patient was immunocompromised due to underlying lymphoma and developed severe Pseudomonas aeruginosa pneumonia, as represented by a left lung infiltrate with concern for central regions of necrosis ( panel A, black arrow). Two weeks later, areas of cavitation with air fluid levels were visible in this region and were consistent with the development of lung abscesses ( panel B, white arrow). (Images provided by Dr. Ritu Gill, Division of Chest Radiology, Brigham and Women’s Hospital, Boston.) obstruction from malignancy or a foreign body, the obstructing lesion prevents clearance of oropharyngeal secretions, leading to abscess development. With underlying systemic conditions (e.g., immunosuppression after bone marrow or solid organ transplantation), impaired host defense mechanisms lead to increased susceptibility to development of lung abscesses caused by a broad range of pathogens, including


InternalMed_Harrison

InternalMed_Harrison. after bone marrow or solid organ transplantation), impaired host defense mechanisms lead to increased susceptibility to development of lung abscesses caused by a broad range of pathogens, including opportunistic organisms (Table 154-1).


InternalMed_Harrison

InternalMed_Harrison. Lung abscesses also arise from septic emboli, either in tricuspid valve endocarditis (often involving Staphylococcus aureus) or in Lemierre’s syndrome, in which an infection begins in the pharynx (classically involving Fusobacterium necrophorum) and then spreads to the neck and the carotid sheath (which contains the jugular vein) to cause septic thrombophlebitis. PATHOLOGY AND MICROBIOLOGY Primary Lung Abscesses In primary lung abscesses, the dependent segments (posterior upper lobes and superior lower lobes) are the most common locations, given the predisposition of aspirated materials to be deposited in these areas. Generally, the right lung is affected more commonly than the left because the right mainstem bronchus is less angulated. In secondary abscesses, the location of the abscess may vary with the underlying cause.


InternalMed_Harrison

InternalMed_Harrison. The microbiology of primary lung abscesses is often polymicrobial, primarily including anaerobic organisms as well as microaerophilic streptococci (Table 154-1). The retrieval and culture of anaerobes can be complicated by the contamination of samples with microbes from the oral cavity, the need for expeditious transport of the cultures to the laboratory, the need for early plating with special culture techniques, the prolonged time required for culture growth, and the need for collection of specimens prior to administration of antibiotics. When attention is paid to these factors, rates of recovery of specific isolates have been reported to be as high as 78%.


InternalMed_Harrison

InternalMed_Harrison. Because it is not clear that knowing the identity of the causative anaerobic isolate alters the response to treatment of a primary lung abscess, practice has shifted away from the use of specialized techniques to obtain material for culture, such as transtracheal aspiration and bronchoalveolar lavage with protected brush specimens that allow recovery of culture material while avoiding contamination from the oral cavity. When no pathogen is isolated from a primary lung abscess (which is the case as often as 40% of the time), the abscess is termed a nonspecific lung abscess, and the presence of anaerobes is often presumed. A putrid lung abscess refers to foul-smelling breath, sputum, or empyema and is essentially diagnostic of an anaerobic lung abscess.


InternalMed_Harrison

InternalMed_Harrison. Secondary Lung Abscesses In contrast, the microbiology of secondary lung abscesses can encompass quite a broad bacterial spectrum, with infection by Pseudomonas aeruginosa and other gram-negative rods most common. In addition, a broad array of pathogens can be identified in patients from certain endemic areas and in specific clinical scenarios (e.g., a significant incidence of fungal infections among immunosuppressed patients following bone marrow or solid organ transplantation). Because immunocompromised hosts and patients without the classic presentation of a primary lung abscess can be infected with a wide array of unusual organisms (Table 154-1), it is of special importance to obtain culture material in order to target therapy.


InternalMed_Harrison

InternalMed_Harrison. Clinical manifestations may initially be similar to those of pneumonia, with fevers, cough, sputum production, and chest pain; a more chronic and indolent presentation that includes night sweats, fatigue, and anemia is often observed with anaerobic lung abscesses. A subset of patients with putrid lung abscesses may report discolored phlegm and foul-tasting or foul-smelling sputum. Patients with lung abscesses due to non-anaerobic organisms, such as S. aureus, may present with a more fulminant course characterized by high fevers and rapid progression. Findings on physical examination may include fevers, poor dentition, and/or gingival disease as well as amphoric and/or cavernous breath sounds on lung auscultation. Additional findings may include digital clubbing and the absence of a gag reflex.


InternalMed_Harrison

InternalMed_Harrison. The differential diagnosis of lung abscesses includes other noninfectious processes that result in cavitary lung lesions, including lung infarction, malignancy, sequestration, vasculitides (e.g., granulomatosis with polyangiitis), lung cysts or bullae containing fluid, and septic emboli (e.g., from tricuspid valve endocarditis). The presence of a lung abscess is determined by chest imaging. Although a chest radiograph usually detects a thick-walled cavity with an air-fluid level, computed tomography (CT) permits better definition and may provide earlier evidence of cavitation. CT may also yield additional information regarding a possible underlying cause of lung abscess, such as malignancy, and may help distinguish a peripheral lung abscess from a pleural infection. This distinction has important implications for treatment, because a pleural space infection, such as an empyema, may require urgent drainage.


InternalMed_Harrison

InternalMed_Harrison. As described earlier (see “Pathology and Microbiology,” above), more invasive diagnostics (such as transtracheal aspiration) were traditionally undertaken for primary lung abscesses, whereas empirical therapy that includes drugs targeting anaerobic organisms currently is used more often. While sputum can be collected noninvasively for Gram’s stain and culture, which may yield a pathogen, it is likely that the infection will be polymicrobial, and culture results may not reflect the presence of anaerobic organisms. Many physicians consider putrid-smelling sputum to be virtually diagnostic of an anaerobic infection.


InternalMed_Harrison

InternalMed_Harrison. When a secondary lung abscess is present or empirical therapy fails to elicit a response, sputum and blood cultures are advised in addition to serologic studies for opportunistic pathogens (e.g., viruses and fungi causing infections in immunocompromised hosts). Additional diagnostics, such as bronchoscopy with bronchoalveolar lavage or protected brush specimen collection and CT-guided percutaneous needle aspiration, can be undertaken. Risks posed by these more invasive diagnostics include spillage of abscess contents into the other lung (with bronchoscopy) and pneumothorax and bronchopleural fistula development (with CT-guided needle aspiration). However, early diagnostics in secondary abscesses, especially in immunocompromised hosts, are particularly important, because the patients involved may be especially fragile and at risk for infection with a broad array of pathogens and, therefore, less likely than other patients to respond to empirical therapy.


InternalMed_Harrison

InternalMed_Harrison. The availability of antibiotics in the 1940s and 1950s established therapy with this drug class as the primary approach to the treatment of lung abscess. Previously, surgery had been relied upon much more frequently. For many decades, penicillin was the antibiotic of choice for primary lung abscesses in light of its anaerobic coverage; however, because oral anaerobes can produce β-lactamases, clindamycin has proved superior to penicillin in clinical trials. For primary lung abscesses, the recommended regimens are (1) clindamycin (600 mg IV three times daily; then, with the disappearance of fever and clinical improvement, 300 mg PO four times daily) or (2) an IV-administered β-lactam/β-lactamase combination, followed—once the patient’s condition is stable—by orally administered amoxicillin-clavulanate. This therapy should be continued until imaging demonstrates that the lung abscess has cleared or regressed to a small scar. Treatment duration may range from 3–4 weeks to as long as 14


InternalMed_Harrison

InternalMed_Harrison. This therapy should be continued until imaging demonstrates that the lung abscess has cleared or regressed to a small scar. Treatment duration may range from 3–4 weeks to as long as 14 weeks. One small study suggested that moxifloxacin (400 mg/d PO) is as effective and well tolerated as ampicillin-sulbactam. Notably, metronidazole is not effective as a single agent: it covers anaerobic organisms but not the microaerophilic streptococci that are often components of the mixed flora of primary lung abscesses.


InternalMed_Harrison

InternalMed_Harrison. In secondary lung abscesses, antibiotic coverage should be 815 directed at the identified pathogen, and a prolonged course (until resolution of the abscess is documented) is often required. Treatment regimens and courses vary widely, depending on the immune state of the host and the identified pathogen. Other interventions may be necessary as well, such as relief of an obstructing lesion or treatment directed at the underlying condition predisposing the patient to lung abscess. Similarly, if the condition of patients with presumed primary lung abscess fails to improve, additional studies to rule out an underlying predisposing cause for a secondary lung abscess are indicated.


InternalMed_Harrison

InternalMed_Harrison. Although it can take as long as 7 days for patients receiving appropriate therapy to defervesce, as many as 10–20% of patients may not respond at all, with continued fevers and progression of the abscess cavity on imaging. An abscess >6–8 cm in diameter is less likely to respond to antibiotic therapy without additional interventions. Options for patients who do not respond to antibiotics and whose additional diagnostic studies fail to identify an additional pathogen that can be treated include surgical resection and percutaneous drainage of the abscess, especially in poor surgical candidates. Possible complications of percutaneous drainage include bacterial contamination of the pleural space as well as pneumothorax and hemothorax.


InternalMed_Harrison

InternalMed_Harrison. Larger cavity size on presentation may correlate with the development of persistent cystic changes (pneumatoceles) or bronchiectasis. Additional possible complications include recurrence of abscesses despite appropriate therapy, extension to the pleural space with development of empyema, life-threatening hemoptysis, and massive aspiration of lung abscess contents. Reported mortality rates for primary abscesses have been as low as 2%, while rates for secondary abscesses are generally higher—as high as 75% in some case series. Other poor prognostic factors include an age >60, the presence of aerobic bacteria, sepsis at presentation, symptom duration of >8 weeks, and abscess size >6 cm.


InternalMed_Harrison

InternalMed_Harrison. Mitigation of underlying risk factors may be the best approach to prevention of lung abscesses, with attention directed toward airway protection, oral hygiene, and minimized sedation with elevation of the head of the bed for patients at risk for aspiration. Prophylaxis against certain pathogens in at-risk patients (e.g., recipients of bone marrow or solid organ transplants or patients whose immune systems are significantly compromised by HIV infection) may be undertaken. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. For patients with a lung abscess and a low likelihood of malignancy (e.g., smokers <45 years old) and with risk factors for aspiration, it is reasonable to administer empirical treatment and then to pursue further evaluation if therapy does not elicit a response. However, some clinicians may opt for up-front cultures, even in primary lung abscesses. In patients with risk factors for malignancy or other underlying conditions (especially immunocompromised hosts) or with an atypical presentation, earlier diagnostics should be considered, such as bronchoscopy with biopsy or CT-guided needle aspiration. Bronchoscopy should be performed early in patients whose history, symptoms, or imaging findings are consistent with possible bronchial obstruction. In patients from areas endemic for tuberculosis or patients with other risk factors for tuberculosis (e.g., underlying HIV infection), induced sputum samples should be examined early in the workup to rule out this disease. Adolf W. Karchmer


InternalMed_Harrison

InternalMed_Harrison. Adolf W. Karchmer The prototypic lesion of infective endocarditis, the vegetation (Fig. 155-1), is a mass of platelets, fibrin, microcolonies of microorganisms, and scant inflammatory cells. Infection most commonly involves heart valves but may also occur on the low-pressure side of a ventricular septal defect, on mural endocardium damaged by aberrant jets of blood or foreign bodies, or on intracardiac devices themselves. The analogous process involving arteriovenous shunts, arterio-arterial shunts (patent ductus arteriosus), or a coarctation of the aorta is called infective endarteritis.


InternalMed_Harrison

InternalMed_Harrison. Endocarditis can be classified according to the temporal evolution of disease, the site of infection, the cause of infection, or the predisposing risk factor (e.g., injection drug use). While each classification criterion provides therapeutic and prognostic insight, none is sufficient alone. Acute endocarditis is a hectically febrile illness that rapidly damages cardiac structures, seeds extracardiac sites, and, if untreated, progresses to death within weeks. Subacute endocarditis follows an indolent course; causes structural cardiac damage only slowly, if at all; rarely metastasizes; and is gradually progressive unless complicated by a major embolic event or a ruptured mycotic aneurysm.


InternalMed_Harrison

InternalMed_Harrison. In developed countries, the incidence of endocarditis ranges from 4 to 7 cases per 100,000 population per year and has remained relatively stable during recent decades. While congenital heart diseases remain a constant predisposition, predisposing conditions in developed countries have shifted from chronic rheumatic heart disease (still a common predisposition in developing countries) to illicit IV drug use, degenerative valve disease, and intracardiac devices. The incidence of endocarditis is notably increased among the elderly. In developed countries, 25–35% of cases of native valve endocarditis (NVE) are associated with health care, and 16–30% of all cases of endocarditis involve prosthetic valves. The risk of prosthesis infection is greatest during the first 6–12 months after valve replacement; gradually declines to a low, stable rate thereafter; and is similar for mechanical and bioprosthetic devices. The incidence of endocarditis involving cardiovascular implantable electronic


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InternalMed_Harrison. gradually declines to a low, stable rate thereafter; and is similar for mechanical and bioprosthetic devices. The incidence of endocarditis involving cardiovascular implantable electronic devices (CIED), primarily permanent pacemakers and implantable cardioverter-defibrillators, ranges from 0.5 to 1.14 cases per 1000 device recipients and is higher among patients with an implantable cardioverter-defibrillator than among those with a permanent pacemaker.


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InternalMed_Harrison. Although many species of bacteria and fungi cause sporadic episodes of endocarditis, a few bacterial species cause the majority of cases (Table 155-1). The oral cavity, skin, and upper respiratory tract are the respective primary portals for viridans streptococci, staphylococci, and HACEK organisms (Haemophilus species, Aggregatibacter aphrophilus, A. actinomycetemcomitans, Cardiobacterium species, Eikenella species, and Kingella species). Streptococcus gallolyticus subspecies gallolyticus (formerly S. bovis biotype 1) originates from the gastrointestinal tract, where it is associated with polyps and colonic tumors, and enterococci enter the bloodstream from the genitourinary tract. Health care–associated NVE, most commonly caused by Staphylococcus aureus, coagulase-negative staphylococci (CoNS), and enterococci, may have either a nosocomial onset (55%) or a community onset (45%); community-onset cases develop in patients who have had extensive contact with the health care system over


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InternalMed_Harrison. (CoNS), and enterococci, may have either a nosocomial onset (55%) or a community onset (45%); community-onset cases develop in patients who have had extensive contact with the health care system over the preceding 90 days. Endocarditis complicates 6–25% of episodes of catheter-associated S. aureus bacteremia; the higher rates are detected in high-risk patients studied by transesophageal echocardiography (TEE) (see “Echocardiography,” later).


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InternalMed_Harrison. FIGURE 155-1 Vegetations (arrows) due to viridans streptococcal endocarditis involving the mitral valve. Prosthetic valve endocarditis (PVE) arising within 2 months of valve surgery is generally nosocomial, the result of intraoperative contamination of the prosthesis or a bacteremic postoperative complication. This nosocomial origin is reflected in the primary microbial causes: S. aureus, CoNS, facultative gram-negative bacilli, diphtheroids, and fungi. The portals of entry and organisms causing cases beginning >12 months after surgery are similar to those in community-acquired NVE. PVE due to CoNS that presents 2–12 months after surgery often represents delayed-onset nosocomial infection. Regardless of the time of onset after surgery, at least 68–85% of CoNS strains that cause PVE are resistant to methicillin.


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InternalMed_Harrison. Endocarditis related to a permanent pacemaker or an implantable cardioverter-defibrillator involves the device or the endothelium at points of device contact. Occasionally, there is concurrent aortic or mitral valve infection. One-third of cases of CIED endocarditis present within 3 months after device implantation or manipulation, one-third present at 4–12 months, and one-third present at >1 year. S. aureus and CoNS, both of which are commonly resistant to methicillin, cause the majority of cases.


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InternalMed_Harrison. Injection drug use–associated endocarditis, especially that involving the tricuspid valve, is commonly caused by S. aureus, which in many cases is resistant to methicillin. Left-sided valve infections in addicts have a more varied etiology. In addition to the usual causes of endocarditis, these cases can be due to Pseudomonas aeruginosa and Candida species, and sporadic cases can be caused by unusual organisms such as Bacillus, Lactobacillus, and Corynebacterium species. Polymicrobial endocarditis occurs among injection drug users. HIV infection in drug users does not significantly influence the causes of endocarditis.


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InternalMed_Harrison. From 5% to 15% of patients with endocarditis have negative blood cultures; in one-third to one-half of these cases, cultures are negative because of prior antibiotic exposure. The remainder of these patients are infected by fastidious organisms, such as nutritionally variant bacteria (now designated Granulicatella and Abiotrophia species), HACEK organisms, Coxiella burnetii, and Bartonella species. Some fastidious organisms occur in characteristic geographic settings (e.g., C. burnetii and Bartonella species in Europe, Brucella species in the Middle East). Tropheryma whipplei causes an indolent, culture-negative, afebrile form of endocarditis.


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InternalMed_Harrison. The undamaged endothelium is resistant to infection by most bacteria and to thrombus formation. Endothelial injury (e.g., at the site of impact of high-velocity blood jets or on the low-pressure side of a cardiac structural lesion) allows either direct infection by virulent organisms or the development of a platelet-fibrin thrombus—a condition called nonbacterial thrombotic endocarditis (NBTE). This thrombus serves as a site of bacterial attachment during transient bacteremia. The cardiac conditions most commonly resulting in NBTE are mitral regurgitation, aortic stenosis, aortic regurgitation, ventricular septal defects, and complex congenital heart disease. NBTE also arises as a result of a hypercoagulable state; this gives rise to marantic endocarditis (uninfected vegetations seen in patients with malignancy and chronic diseases) and to bland vegetations


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InternalMed_Harrison. Percentage of Cases aThe total number of cases is larger than the sum of rightand left-sided cases because the location of infection was not specified in some cases. bIncludes viridans streptococci; Streptococcus gallolyticus; other non–group A, groupable streptococci; and Abiotrophia and Granulicatella spp. (nutritionally variant, pyridoxal-requiring streptococci). cPrimarily E. faecalis or nonspeciated isolates; occasionally E. faecium or other, less likely species. dMethicillin resistance is common among these S. aureus strains. eIncludes Haemophilus spp., Aggregatibacter aphrophilus, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella spp., and Kingella spp. Note: Data are compiled from multiple studies. complicating systemic lupus erythematosus and the antiphospholipid antibody syndrome.


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InternalMed_Harrison. Organisms that cause endocarditis enter the bloodstream from mucosal surfaces, the skin, or sites of focal infection. Except for more virulent bacteria (e.g., S. aureus) that can adhere directly to intact endothelium or exposed subendothelial tissue, microorganisms in the blood adhere at sites of NBTE. The organisms that commonly cause endocarditis have surface adhesin molecules, collectively called microbial surface components recognizing adhesin matrix molecules (MSCRAMMs), that mediate adherence to NBTE sites or injured endothelium. Adherence is facilitated by fibronectin-binding proteins present on many gram-positive bacteria; by clumping factor (a fibrinogenand fibrin-binding surface protein) on S. aureus; by fibrinogen-binding surface proteins (Fss2), collagen-binding surface protein (Ace), and Ebp pili (the latter mediating platelet adherence) in Enterococcus faecalis; and by glucans or FimA (a member of the family of oral mucosal adhesins) on streptococci. Fibronectin-binding


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InternalMed_Harrison. (Ace), and Ebp pili (the latter mediating platelet adherence) in Enterococcus faecalis; and by glucans or FimA (a member of the family of oral mucosal adhesins) on streptococci. Fibronectin-binding proteins are required for S. aureus invasion of intact endothelium; thus these surface proteins may facilitate infection of previously normal valves. If resistant to the bactericidal activity of serum and the microbicidal peptides released locally by platelets, adherent organisms proliferate to form dense microcolonies. Microorganisms also induce platelet deposition and a localized procoagulant state by eliciting tissue factor from the endothelium or, in the case of S. aureus, from monocytes as well. Fibrin deposition combines with platelet aggregation and microorganism proliferation to generate an infected vegetation. Organisms deep in vegetations are metabolically inactive (nongrowing) and relatively resistant to killing by antimicrobial agents. Proliferating surface organisms are shed


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InternalMed_Harrison. an infected vegetation. Organisms deep in vegetations are metabolically inactive (nongrowing) and relatively resistant to killing by antimicrobial agents. Proliferating surface organisms are shed into the bloodstream continuously.


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InternalMed_Harrison. The clinical manifestations of endocarditis—other than constitutional symptoms, which probably result from cytokine production— arise from damage to intracardiac structures; embolization of vegetation fragments, leading to infection or infarction of remote tissues; hematogenous infection of sites during bacteremia; and tissue injury due to the deposition of circulating immune complexes or immune responses to deposited bacterial antigens.


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InternalMed_Harrison. The clinical endocarditis syndrome is highly variable and spans a continuum between acute and subacute presentations. NVE, PVE, and endocarditis due to injection drug use share clinical and laboratory manifestations (Table 155-2). The causative microorganism is primarily responsible for the temporal course of endocarditis. β-Hemolytic streptococci, S. aureus, and pneumococci typically result in an acute course, although S. aureus occasionally causes subacute disease. Endocarditis caused by Staphylococcus lugdunensis (a coagulasenegative species) or by enterococci may present acutely. Subacute endocarditis is typically caused by viridans streptococci, enterococci, CoNS, and the HACEK group. Endocarditis caused by Bartonella species, T. whipplei, or C. burnetii is exceptionally indolent. Feature Frequency, %


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InternalMed_Harrison. Feature Frequency, % Fever 80–90 Chills and sweats 40–75 Anorexia, weight loss, malaise 25–50 Myalgias, arthralgias 15–30 Back pain 7–15 Heart murmur 80–85 New/worsened regurgitant murmur 20–50 Arterial emboli 20–50 Splenomegaly 15–50 Clubbing 10–20 Neurologic manifestations 20–40 Peripheral manifestations (Osler’s nodes, subungual 2–15 hemorrhages, Janeway lesions, Roth’s spots) Petechiae 10–40 Laboratory manifestations 818 In patients with subacute presentations, fever is typically low-grade and rarely exceeds 39.4°C (103°F); in contrast, temperatures of 39.4°–40°C (103°–104°F) are often noted in acute endocarditis. Fever may be blunted in patients who are elderly, are severely debilitated, or have renal failure.


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InternalMed_Harrison. Cardiac Manifestations Although heart murmurs are usually indicative of the predisposing cardiac pathology rather than of endocarditis, valvular damage and ruptured chordae may result in new regurgitant murmurs. In acute endocarditis involving a normal valve, murmurs may be absent initially but ultimately are detected in 85% of cases. Congestive heart failure (CHF) develops in 30–40% of patients as a consequence of valvular dysfunction. Occasionally, CHF is due to endocarditis-associated myocarditis or an intracardiac fistula. Heart failure due to aortic valve dysfunction progresses more rapidly than does that due to mitral valve dysfunction. Extension of infection beyond valve leaflets into adjacent annular or myocardial tissue results in perivalvular abscesses, which in turn may cause intracardiac fistulae with new murmurs. Abscesses may burrow from the aortic valve annulus through the epicardium, causing pericarditis, or into the upper ventricular septum, where they may interrupt


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InternalMed_Harrison. intracardiac fistulae with new murmurs. Abscesses may burrow from the aortic valve annulus through the epicardium, causing pericarditis, or into the upper ventricular septum, where they may interrupt the conduction system, leading to varying degrees of heart block. Mitral perivalvular abscesses, which are usually more distant from the conduction system, only rarely cause conduction abnormalities; if such abnormalities occur in this setting, the conduction pathway is most likely disrupted near the atrioventricular node or in the proximal bundle of His. Emboli to a coronary artery occur in 2% of patients and may result in myocardial infarction.


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InternalMed_Harrison. Noncardiac Manifestations The classic nonsuppurative peripheral manifestations of subacute endocarditis (e.g., Janeway lesions; Fig. 155-2A) are related to prolonged infection; with early diagnosis and treatment, these have become infrequent. In contrast, septic embolization mimicking some of these lesions (subungual hemorrhage, Osler’s nodes) is common in patients with acute S. aureus endocarditis (Fig. 155-2B). Musculoskeletal pain usually remits promptly with treatment but must be distinguished from focal metastatic infections (e.g., spondylodiscitis), which may complicate 10–15% of cases. Hematogenously seeded focal infection occurs most often in the skin, spleen, kidneys, skeletal system, and meninges. Arterial emboli, one-half of which precede the diagnosis, are clinically apparent in up to 50% of patients. Endocarditis caused by S. aureus, vegetations >10 mm in diameter (as measured by echocardiography), and infection involving the mitral valve, especially the anterior leaflet,


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InternalMed_Harrison. up to 50% of patients. Endocarditis caused by S. aureus, vegetations >10 mm in diameter (as measured by echocardiography), and infection involving the mitral valve, especially the anterior leaflet, are independently associated with an increased risk of embolization. Symptoms, pain, or ischemia-induced dysfunction relate to the organ or area suffering embolic arterial occlusion (e.g., kidney, spleen, bowel, extremity). Cerebrovascular emboli presenting as strokes or occasionally as encephalopathy complicate 15–35% of cases of endocarditis. Again, one-half of these events precede the diagnosis of endocarditis. The frequency of stroke is 8 per 1000 patient-days during the week prior to diagnosis; the figure falls to 4.8 and 1.7 per 1000 patient-days during the first and second weeks of effective antimicrobial therapy, respectively. This decline exceeds that which can be attributed to change in vegetation size. Only 3% of strokes occur after 1 week of effective therapy. Emboli occurring


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InternalMed_Harrison. antimicrobial therapy, respectively. This decline exceeds that which can be attributed to change in vegetation size. Only 3% of strokes occur after 1 week of effective therapy. Emboli occurring late during or after effective therapy do not in themselves constitute evidence of failed antimicrobial treatment.


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InternalMed_Harrison. FIGURE 155-2 A. Janeway lesions on toe (left) and plantar surface (right) of the foot in subacute Neisseria mucosa endocarditis. (Image courtesy of Rachel Baden, MD.) B. Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis. gitis, intracranial hemorrhage due to hemorrhagic infarcts or ruptured mycotic aneurysms, and seizures. (Mycotic aneurysms are focal dilations of arteries occurring at points in the artery wall that have been weakened by infection in the vasa vasorum or where septic emboli have lodged.) Microabscesses in brain and meninges occur commonly in S. aureus endocarditis; surgically drainable intracerebral abscesses are infrequent. Immune complex deposition on the glomerular basement membrane causes diffuse hypocomplementemic glomerulonephritis and renal dysfunction, which typically improve with effective antimicrobial therapy. Embolic renal infarcts cause flank pain and hematuria but rarely cause renal dysfunction.


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InternalMed_Harrison. Manifestations of Specific Predisposing Conditions Almost 50% of endocarditis associated with injection drug use is limited to the tricuspid valve and presents with fever but with faint or no murmur and no peripheral manifestations. Septic pulmonary emboli, which are common with tricuspid endocarditis, cause cough, pleuritic chest pain, nodular pulmonary infiltrates, or occasionally pyopneumothorax. Infection of the aortic or mitral valves presents with the typical clinical features of endocarditis, including peripheral manifestations.


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InternalMed_Harrison. If not associated with a retained intracardiac device or masked by the symptoms of concurrent comorbid illness, health care–associated endocarditis has typical manifestations. CIED endocarditis may be associated with obvious or cryptic generator pocket infection and results in fever, minimal murmur, and pulmonary symptoms due to septic emboli. Late-onset PVE presents with typical clinical features. In cases arising within 60 days of valve surgery (early onset), typical symptoms may be obscured by comorbidity associated with recent surgery. In both early-onset and more delayed presentations, paravalvular infection is common and often results in partial valve dehiscence, regurgitant murmurs, CHF, or disruption of the conduction system.


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InternalMed_Harrison. In order to avoid delayed or missed diagnosis, careful clinical, micro-biologic, and echocardiographic evaluation should be pursued when febrile patients have endocarditis predispositions, cardiac or noncardiac features of endocarditis, or microbiologic findings consistent with endocarditis (e.g., a stroke or splenic infarct, multiple positive blood cultures for an endocarditis-associated organism).


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InternalMed_Harrison. The Duke Criteria The diagnosis of infective endocarditis is established with certainty only when vegetations are examined histologically and microbiologically. Nevertheless, a highly sensitive and specific diagnostic schema—known as the modified Duke criteria—is based on clinical, laboratory, and echocardiographic findings commonly encountered in patients with endocarditis (Table 155-3). While developed as a research tool rather than for patient management, the criteria can be a helpful diagnostic tool. If the criteria are to be maximally helpful in evaluating patients, appropriate data must be collected. Furthermore, clinical judgment must be exercised in order to use the criteria effectively. Documentation of two major criteria, of one major criterion and three minor criteria, or of five minor criteria allows a clinical diagnosis of definite endocarditis. The diagnosis of endocarditis is rejected if an alternative diagnosis is established, if symptoms resolve and do not recur with


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InternalMed_Harrison. minor criteria allows a clinical diagnosis of definite endocarditis. The diagnosis of endocarditis is rejected if an alternative diagnosis is established, if symptoms resolve and do not recur with ≤4 days of antibiotic therapy, or if surgery or autopsy after ≤4 days of antimicrobial therapy yields no histologic evidence of endocarditis. Illnesses not classified as definite endocarditis or rejected as such are considered cases of possible infective endocarditis when either one major and one minor criterion or three minor criteria are fulfilled. Requiring some clinical features of endocarditis for classification as possible infective endocarditis increases the specificity of the schema without significantly reducing its sensitivity. Unless there are extenuating circumstances, patients with definite or possible endocarditis are treated as such.


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InternalMed_Harrison. The criteria emphasize bacteremia and echocardiographic findings typical of endocarditis. The requirement for multiple positive blood cultures over time is consistent with the continuous low-density 1. Positive blood culture Typical microorganism for infective endocarditis from two separate blood cultures Viridans streptococci, Streptococcus gallolyticus, HACEK group organisms, Staphylococcus aureus, or Community-acquired enterococci in the absence of a primary focus, Persistently positive blood culture, defined as recovery of a microorganism consistent with infective endocarditis from: All of 3 or a majority of ≥4 separate blood cultures, with first and last


InternalMed_Harrison

InternalMed_Harrison. Persistently positive blood culture, defined as recovery of a microorganism consistent with infective endocarditis from: All of 3 or a majority of ≥4 separate blood cultures, with first and last Single positive blood culture for Coxiella burnetii or phase I IgG antibody titer of >1:800 2. Evidence of endocardial involvement Positive echocardiogramb Oscillating intracardiac mass on valve or supporting structures or in the path of regurgitant jets or in implanted material, in the absence of an alternative anatomic explanation, or Abscess, or New partial dehiscence of prosthetic valve, 1. Predisposition: predisposing heart conditionsc or injection drug use 2. Fever ≥38.0°C (≥100.4°F) 3. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions 4. Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, rheumatoid factor 5.