Patrick A. Murphy
John G. Bartlett, MD, wrote this chapter in previous editions.
Usually, the three types of infections reviewed in detail in this chapter are managed initially with intravenous antibiotics administered in the hospital. Patients with these infections are often seen first in an office setting, and the long courses of antimicrobials used to treat them are then completed after discharge from the hospital. These infections involve diverse bacteria and different anatomic sites but share a propensity for relapse caused by the persistence of bacteria at the infected site. This explains the requirement for prolonged courses of antimicrobial treatment. Antimicrobials may be administered by two different routes out of hospital: the oral route, to complete a course initiated parenterally during hospitalization, and the intravenous route, using the same regimen provided for inpatients and administered by home health agencies (see Gilbert et al., at http://www.hopkinsbayview.org./PAMreferences.).
Expanding Role of Oral Antibiotics
In the past, there was reluctance to prescribe oral antimicrobials to be taken at home for most serious infections; however, this approach is gaining acceptance because of a number of studies indicating their efficacy (1, 2, 3, 4, 5). The advantages of home use of oral agents are patient convenience, the notable reduction in cost, and a reduction in nosocomial infections. Table 40.1 summarizes these and other considerations. Current estimates of the cost of hospital care that includes intravenous antimicrobials are about $1,000 per day, whereas for intravenous antimicrobials given at home the average charge is 300 to $400 per day and for oral agents the cost is 1 to $6 per day. The benefit of patient convenience is obvious. With regard to nosocomial infections, the cost in terms of morbidity, mortality, hospital lengths of stay, and charges is substantial (6). Of particular concern in recent years has been nosocomial acquisition of tuberculosis (especially the multiply resistant strains); Clostridium difficile, associated colitis, which is now recognized largely as a nosocomial complication; and Legionnaires disease. Hospitals also remain the major source of problem pathogens such as Pseudomonas aeruginosa, multiply resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus.
Some types of infectious diseases have traditionally been treated with parenteral antimicrobials but may sometimes be treated with oral agents: P. aeruginosa urinary
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tract infections (including bacterial prostatitis), pulmonary infections in patients with cystic fibrosis, some forms of osteomyelitis, tricuspid valve endocarditis caused by S. aureus in intravenous drug abusers, fever in the patient with neutropenia (see Chapter 10), some cases of pyelonephritis, most cases of pneumonia (see Chapter 33), and selected fungal infections that traditionally have required amphotericin B.
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TABLE 40.1 Advantages and Disadvantages of Home Treatment with Oral Antimicrobial Agents |
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Newer Antimicrobial Agents
Much of the progress in this area has resulted from the development of oral antimicrobial agents in four classes that have an expanded spectrum of activity: cephalosporins, fluoroquinolones, β-lactam–β-lactamase inhibitor combinations, and the triazole antifungal agents. Among the cephalosporins and carbacephams, the agents with an expanded spectrum of activity for oral administration include cefaclor, cefuroxime axetil, cefprozil, cefpodoxime, loracarbef, and cefixime. All of these agents are active against most strains of Enterobacteriaceae; activity against major gram-positive cocci is variable, and none of these agents is active against P. aeruginosa, enterococci, or MRSA. In general, these drugs are advocated for respiratory tract infections, skin and soft tissue infections, and urinary tract infections. The fluoroquinolones include norfloxacin, ciprofloxacin, ofloxacin, gatifloxacin, moxifloxacin, and levofloxacin. There are slight differences among these agents in bioavailability, spectrum of activity, pharmacology, and side effects. In general, ciprofloxacin is favored for infections involving P. aeruginosa; levofloxacin, gatifloxacin, and moxifloxacin are preferred for infections in which Streptococcus pneumoniae is an established or suspected pathogen. S. aureus strains are developing resistance to the fluoroquinolones, and resistance to one implies resistance to the entire group. The only available oral β-lactam–β-lactamase inhibitor is amoxicillin plus clavulanate (Augmentin), which has effect against the spectrum of amoxicillin plus organisms that are penicillin-resistant because of β-lactamase production: S. aureus, many gram-negative bacilli, Haemophilus influenzae, and many anaerobes.
For oral treatment of serious anaerobic infections, either of two older drugs, metronidazole and clindamycin, is usually an option.
Newer Antifungal Agents
The triazoles—fluconazole, itraconazole and voricnazole—have supplanted amphotericin B for many fungal infections. All three are effective against most strains of Candida albicans and may be used for mucocutaneous candidiasis, but their use for parenchymal and systemicCandida infections is limited. Fluconazole has established efficacy for cryptococcosis. Itraconazole now appears to be the preferred agent for most cases of histoplasmosis, blastomycosis, and paracoccidioidomycosis and for many cases of coccidioidomycosis and aspergillosis.
Risks and Burdens of Home Treatment
The use of oral agents in the home setting for infections traditionally treated with intravenous antibiotics in the hospital is not without some risks and burdens. Supportive care requiring some hospital resources for very sick patients is an example. Although monitoring of drug levels is rarely an issue with oral agents, compliance is always a concern, and physicians have been notoriously unable to predict which patients will take their medications (see Chapter 4). In many communities, this issue is now addressed for tuberculosis by direct observation of pill taking, although here the circumstances are somewhat different because antituberculosis drugs can be given twice weekly and the need is justified on the basis of public health concerns. Certain pathogens are difficult or impossible to treat with currently available oral agents. These include the fluoroquinolone-resistant strains of P. aeruginosa, many infections involving methicillin-resistant S. aureus, and cytomegalovirus (CMV). An additional concern about outpatient management is the fact that patients are not under direct observation, so emergency care is not immediately available for serious side effects. The major example is immunoglobulin E–mediated hypersensitivity caused by β-lactam agents, which occurs with a frequency of about 1:2,500 to 1:25,000 courses of penicillin G. Finally, there may be concern about legal liability when the use of oral antibiotics is not considered the standard of care, even if efficacy and safety seem well established. Because many third-party payers now mandate home care for stable patients who require long-term antibiotics, the latter concern is unlikely to deter expanded home treatment.
Osteomyelitis
Definition
Osteomyelitis is an infection of bone. There are four major categories: osteomyelitis due to hematogenous spread of infection, osteomyelitis secondary to a contiguous focus of infection, infection of prosthetic joints, and osteomyelitis associated with vascular insufficiency. These four categories differ in terms of patient age, bones involved, predisposing conditions, usual bacterial pathogens, and presentation (Table 40.2). Osteomyelitis is also classified as acute or chronic: acute osteomyelitis indicates newly recognized bone infection, whereas chronic osteomyelitis indicates prior infection or clinical symptoms exceeding 10 days (3).
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TABLE 40.2 Type of Osteomyelitis |
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Clinical Presentation and Bacteriology
Hematogenous
Hematogenous osteomyelitis is classically described as a disease of children, usually younger than 16 years of age, which is usually caused by S. aureus (3). The tendency for this infection to occur during active growth reflects the enhanced susceptibility of the vascular network of the metaphysis, especially of the femur or tibia. About one third of the patients have a history of preceding nonpenetrating trauma in the area that is subsequently involved. The infection begins in the metaphyseal sinusoidal veins; it is contained by the epiphyseal growth plate and tends to spread laterally, with perforation of the cortex and lifting of the loose periosteum.
Hematogenous osteomyelitis of the long bones in adults is rare, different in presentation, and bacteriologically distinct. In these patients, the growth cartilage has been resorbed so that the subarticular space is more vulnerable, and the periosteum is firmly attached so that subperiosteal abscess formation is uncommon. The most common form of hematogenous osteomyelitis in adults involves the vertebrae (Fig. 40.1), and the most common pathogens are gram-negative bacilli and S. aureus. The initial site of infection is the richly vascularized bone adjacent to cartilage; there is subsequent involvement of adjacent bone plates and of the intervertebral disc. The infection may extend longitudinally to involve adjacent vertebrae, anteriorly to produce a paraspinal abscess, or posteriorly to form an epidural abscess.
Patients with acute hematogenous osteomyelitis usually present with precipitous onset of pain, swelling, chills, and fever. With vertebral osteomyelitis, there is fever with back pain, stiffness, and often point tenderness over the infected vertebra. Many patients have a more subacute presentation, with vague symptoms of 1 to 2 months’ duration before presentation and few constitutional complaints. One well-described variant is the Brodie abscess (also called a cold abscess): subacute staphylococcal osteomyelitis located in the metaphysis of a long bone, which manifests with local pain and fever. Patients with recurrent or chronic osteomyelitis often simply note increased or persistent drainage and pain after an episode involving the same anatomic location.
Contiguous Infection
Osteomyelitis secondary to a contiguous focus of infection accounts for at least half of all cases. The most common precipitating factor is previous surgery, usually involving the lower extremities, such as open reduction of fractures of the femur or tibia. Next in frequency is a soft tissue infection involving the digits of the hands or feet. These infections usually become apparent within 1 month after the precipitating event, although many patients have chronic or recurrent infections that occur intermittently for years or decades.
Prosthetic Joint Infections
Infections that complicate prosthetic joints are classified as acute (within 12 weeks after surgery) or chronic (within 3 to 24 months after surgery) (3). Later infections may result from transient bacteremia in a fashion analogous to the pathogenesis of endocarditis, with the joint serving as a susceptible nidus. The presentation of an infected prosthesis is a painful, unstable joint, often with little or no fever and nonspecific radiographic findings. The diagnosis is best established with semiquantitative culture of an aspirate from the joint space or bone–cement interface.
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Staphylococcus epidermidis accounts for 75% of cases; next in frequency are S. aureus, streptococci, Peptococcus magnus, enteric gram-negative bacilli, and Candida species.
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FIGURE 40.1. A: L3–4 staphylococcal osteomyelitis of 3 months’ duration, with disc narrowing and sclerosis seen on plain film. B:Computed tomographic scan in same patient showing small soft tissue abscess and minimal bone destruction. Note hazy bone outline (From Post MJD, ed. Computed tomography of the spine. Baltimore: Williams & Wilkins, 1984:740.) |
Vascular Insufficiency
Osteomyelitis associated with vascular insufficiency is most common in patients with diabetes mellitus or severe atherosclerosis (7,8). The most common sites of infection are the toes and small bones of the feet, usually with overlying soft tissue infections (Fig. 40.2). These infections are often detected on routine radiographs performed to evaluate the chronic draining sinuses or skin ulcers that are so common in the patients at risk. Probing that demonstrates extension of ulcers to bone is essentially diagnostic of osteomyelitis, and this finding supersedes all scanning techniques in terms of specificity (7,8). Both the adjacent soft tissue infection and the osteomyelitis usually involvepolymicrobial flora that may include anaerobic bacteria, coliforms, pseudomonads, streptococci, and S. aureus.
Laboratory Evaluation
Diagnostic studies include radiographs, radionuclide studies, computed tomography (CT), or magnetic resonance imaging (MRI) to demonstrate typical bone changes and cultures to identify the etiologic organism.
The earliest changes on plain radiographs are lytic lesions; other findings may include soft tissue swelling, periosteal reaction, cortical irregularity, demineralization, and sequestrum formation. However, typical changes are not visible on plain films until 30% to 50% of the bone has been resorbed, and this usually requires 10 to 14 days. In a patient with a normal plain film but clinical findings suggesting osteomyelitis, a technetium bone scan or an 111Indium leukocyte scan can be helpful. Both of these
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tests are sensitive in early osteomyelitis (70% to 90%), but they lack specificity (50% to 75%) (3,9,10). The bone scan uses technetium99Tc as a marker bound to diphosphonate, which concentrates in bone because of incorporation at sites of osteoblastic activity. Abnormal studies may occur when there is increased blood flow associated with soft tissue infections or with osteoblastic activity caused by other processes, such as degenerative joint disease. If a three-phase technetium scan (immediate, showing flow; 15-minute, showing blood pooling; and 4-hour showing bone imaging) is used, soft tissue infections give positive images in the first two phases but only bony infection gives positive images in all three phases. Most authorities regard 99Tc scanning as the preferred scintigraphic method (9,11). CT and MRI are also useful in showing osteomyelitis. CT scans are especially helpful for guiding needle biopsy or percutaneous aspirations. MRI is quite sensitive and may show osteomyelitis before changes are evident by scintigraphy (3). Prosthetic material that is ferromagnetic is a contraindication to MRI, but most materials now used in orthopedic surgery do not interfere.
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FIGURE 40.2. Arrows indicate, from left to right, infected soft corn, sinus tract, and osteomyelitis in the distal interphalangeal joint. As destruction increases, the joint becomes dislocated. (From Gamble FO, Yale I. Clinical foot roentgenology. Baltimore: Williams & Wilkins, 1966. ) |
Because antimicrobial treatment, often prolonged, is the mainstay of management, accurate bacteriologic data are helpful for making the diagnosis and planning treatment. The list of possible organisms is long, and sensitivity patterns for these organisms show considerable variation, making empiric selection of antimicrobials hazardous. These considerations may justify an aggressive attempt to identify the responsible organism. Conclusive bacteriologic studies require isolation of the pathogen from bone or blood cultures.
Under ideal circumstances, an orthopedist should perform a needle aspiration over the involved bone, either blindly or, preferably, under CT guidance (12). If subperiosteal pus is obtained, surgical drainage is mandatory. If no pus is obtained, the needle is inserted into bone to obtain a specimen. The diagnostic yield with a needle aspirate of bone is approximately 60%, and for a surgical biopsy it is approximately 90% (3). Cultures from draining sinus tracts tend to show poor correlation with cultures obtained directly from bone (12). Needle aspirate specimens should be submitted for Gram stain and for culture of aerobic and anaerobic bacteria. Care must be exercised in the interpretation of culture results, even of bone aspirates, because these are often contaminated, especially if the specimen is obtained by traversing soft-tissue infections (13). Organisms recovered in low concentrations, especially those growing only in the broth culture, must be viewed with skepticism. Common skin contaminants include S. epidermidis, diphtheroids, and Propionibacterium. These organisms tend to cause osteomyelitis only in the presence of prosthetic devices. Gram staining of exudate or tissue aspirate should verify the culture results and represents an important correlate in determining the etiologic organism. The semiquantitative results of cultures are an important and often overlooked component of interpreting culture results, especially when the organisms detected are common contaminants.
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Treatment
General Principles
Immobilization was commonly advocated for the treatment of osteomyelitis in the pre–antimicrobial era. However, it appears to be less important at present, and most authorities conclude that strict immobilization is unnecessary.
Antimicrobial Treatment: Acute Osteomyelitis
For newly diagnosed or acute osteomyelitis, the standard recommendation has been a 3- to 6-week course of parenteral antimicrobials (3). This recommendation is based on several studies noting that patients often developed recurrent or chronic disease when treatment lasted less than 21 days. The standard regimen for acute staphylococcal osteomyelitis in adults is a penicillinase-resistant penicillin such as nafcillin, given intravenously at a dosage of 1.5 to 2 g every 6 hours. Alternative parenteral regimens are cefazolin (1.0 to 1.5 g every 8 hours), vancomycin (1 g every 12 hours), or clindamycin (600 mg every 8 hours) (3). In stable patients, these regimens can be initiated in the hospital and completed at home.
To decrease cost, length of hospitalization, and patient discomfort, a modified regimen, consisting of a short course of parenteral antimicrobials followed by a prolonged course of oral agents, has been developed (3). The intravenous antimicrobial is given for at least 3 days, or until the patient is afebrile, or for an arbitrarily defined period such as 1 to 2 weeks. An alternative oral agent selected by in vitrosensitivity tests is then taken by mouth, usually at home, to complete a total 3- to 6-week course, usually 4 weeks. The drugs recommended for oral administration are clindamycin (300 mg every 6 hours), an oral antistaphylococcal penicillin such as dicloxacillin or cephalexin (500 mg every 6 hours), or a fluoroquinolone. It should be noted that the importance of bactericidal activity and the relative merits of drugs for bone penetration as factors in drug selection are debated issues that remain unresolved.
Antimicrobial Treatment: Chronic Osteomyelitis
Therapeutic guidelines are less precise for chronic osteomyelitis. Because necrotic bone may serve as a nidus for sequestered bacteria, surgical excision of dead tissue and adequate debridement are often essential components of treatment. Antimicrobial selection should be based on bacteriologic diagnosis using deep aspirates or, preferably, cultures obtained from bone. The daily dosage, route of administration, and duration of treatment are somewhat arbitrary, but most authorities recommend prolonged courses. The initial treatment may consist of parenteral antimicrobials for 1 to 3 months in the hospital or in the home, followed by oral agents for several months. An alternative approach is the use, from the outset of treatment, of oral agents to which the patient's infecting organism is sensitive, for extended periods, such as 6 months or longer (3). Fluoroquinolones such as ofloxacin or ciprofloxacin, alone or in combination with clindamycin or metronidazole, have established efficacy for osteomyelitis with a mixed anaerobic–coliform flora (3). Oral cephalosporins may also be used for infections involving gram negative bacilli; metronidazole by mouth is preferred for oral treatment of deep infections involving anaerobes, although clindamycin and amoxicillin–clavulanate (Augmentin) are probably effective as well. A variety of dosages of these drugs have been proposed; guidelines should be sought in published reports or the most current editions of manuals on the use of antibiotics for specific infections.
Unconfirmed Infections
Many patients who appear to have osteomyelitis or infections of orthopedic devices need a considerable amount of improvised treatment. It is not uncommon to have a patient present with subacute backache, fever, and leukocytosis, and to be unable to establish a bacteriological diagnosis by blood cultures, needle punctures, or cultures of operative specimens, even though the patient may have evidence of bony destruction with local abscess formation. If the patient is an intravenous drug user, it may be assumed that the cause is MRSA, and appropriate treatment should be initiated. In a patient who does not self-inject, S. aureus is still the most common cause of spinal osteomyelitis, although most such strains are not MRSA. The effect of therapy may be monitored indirectly by following changes in the evidence of inflammation. Fever, leukocytosis and local pain should improve. Neurologic signs should not develop, nor should they progress if already present. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) should steadily fall; the hematocrit value and the serum albumin should steadily rise. If these changes occur, the diagnosis can be presumed to be correct. If not, other diagnoses should be considered.
Empiric treatment is also commonly required for osteomyelitis of the foot bones in diabetics, chronic osteomyelitis of limb bones (usually old compound fracture sites), and infections of orthopedic hardware such as metal plates and artificial joints. In all of these cases, a bacteriologic diagnosis may not be forthcoming despite the usual investigations including operative exploration. If the patient had an earlier infectious episode in which an organism was isolated, it is usually safe to assume that the same organism has recurred. If there is no information at all, then one must guess at an etiology, and monitor treatment empirically, as above.
Late Complications
The major complication of osteomyelitis is recurrence that may happen months, years, or decades after the initial
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event. The patient should be warned of this potential complication. The clinical features of recurrences are fever, draining sinuses, local pain, increased ESR, and the typical changes noted on radiographs or scans, as summarized previously. The usual response is to treat again with the same regimen, perhaps with a more prolonged period of intravenous therapy, a higher antimicrobial dose, or the addition of a second agent. After intravenous (IV) therapy is completed, the patient is usually switched to an oral regimen, which is taken for another few months. If the infection recurs again, there may be surgical options such as amputation or removal of a prosthesis. Chronic osteomyelitis may be complicated by secondary amyloidosis, although it has become extremely rare since the advent of antimicrobials. Another complication is epidermoid carcinoma arising in a draining sinus of osteomyelitis, which occurs in 0.2% to 1.5% of cases, with a mean delay of 34 years (14).
Prophylaxis
Patients with orthopedic devices such as prosthetic joints are at risk for infection after transient bacteremia. However, unlike the situation with endocarditis, there are no guidelines from authoritative sources to direct preventive treatment. It is reasonable to administer prophylactic antibiotics for those procedures that are considered a risk by the American Heart Association (AHA) for patients susceptible to endocarditis (see Table 93.13 in Chapter 93). However, the major pathogens for infected orthopedic devices are S. aureus, S. epidermidis, and to a lesser extent, Streptococcus species, whereas endocarditis prophylaxis is directed primarily against Streptococcus. For the former organisms, some recommend prophylaxis with an oral cephalosporin or clindamycin: one dose taken 1 hour before dental work in patients with periodontal disease or potential dental infection and two subsequent doses. However, the American Academy of Oral Medicine has deferred issuing a formal standard for antibiotic prophylaxis in patients with orthopedic prostheses.
Lung Abscess
Definition
The term lung abscess refers to pulmonary suppuration with parenchymal necrosis caused by bacterial infection. The lesions are traditionally classified on the basis of clinical and bacteriologic observations. Lung abscesses are considered acute or chronic depending on the duration of symptoms at the time of initial presentation, with the usual dividing line being 4 to 6 weeks. Clinically, lung abscesses are often grouped as putrid lung abscess, in reference to the foul odor of sputum that is regarded as diagnostic of anaerobic infection, or nonspecific lung abscess, indicating that aerobic sputum cultures have not grown out a pathogen. Anaerobic bacteria are the presumed pathogens in these latter cases also. Lung abscesses may also be classified clinically as primary or secondary, depending on predisposing conditions. Primarylung abscesses are those that occur in patients who are prone to aspiration or in previously healthy patients. Secondary abscesses are complications of a local lesion such as a pulmonary malignancy or of a systemic disease that compromises immunologic defenses. Approximately 80% of lung abscesses are primary; 60% are putrid, and 40% are nonspecific (probably mostly anaerobic) (15). Patients with lung abscess often present in the ambulatory care setting because of the chronicity of these infections. Most patients are hospitalized for diagnostic studies and initial treatment with intravenous antibiotics. The hospital course is usually followed by prolonged courses of antibiotics and followup chest radiographs.
Clinical Presentation and Bacteriology
Many bacteria are potential pulmonary pathogens, but few organisms are likely to cause parenchymal necrosis. The most common pathogens are anaerobic bacteria that make up the normal flora of the gingival crevice and are aspirated during periods of altered consciousness. The usual pathogens in such cases are Prevotella species, Bacteroides species, anaerobic streptococci, and Fusobacterium nucleatum (16). The most common aerobic bacteria that cause suppurative pulmonary infections are S. aureus and Klebsiella pneumoniae; less common causal pathogens are Streptococcus pyogenes, S. pneumoniae, H. influenzae, P. aeruginosa, Legionella, Nocardia, and enteric gram-negative bacilli other than K. pneumoniae. It is important to exclude other etiologic agents, such as mycobacteria and fungi that may cause chronic abscesses requiring an entirely different antimicrobial regimen. Tuberculosis should be suspected in any patient with a lung abscess, especially in patients with a cough that has lasted for 1 month to 1 year, nonputrid sputum, and typical clinical features of night sweats and weight loss.
Patients with anaerobic lung abscesses usually have indolent complaints that last for weeks or even months. Common symptoms include fever, malaise, cough, and sputum production. Pleuritic pain and hemoptysis are common and may persuade a chronically ill patient to seek medical attention. Chills are occasionally noted, but true rigors are rare. The common observation of anemia and weight loss reflects the chronicity of many of these infections. The sputum is usually purulent, and putrid odor is noted in approximately 60% of bacteriologically confirmed anaerobic lung abscesses. The usual sites of involvement are the anatomic segments of the lung where aspiration is most likely to occur by gravitational flow in the recumbent
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position. These are the superior segments of the lower lobes and the posterior segments of the upper lobes. Less common abscess sites are the basilar segments of the lower lobes, which are dependent in the upright or semi-upright position.
Lung abscesses caused by aerobic bacteria are usually found in specific clinical settings. Staphylococcal pulmonary infections with abscess formation are particularly common in young children and in adults with influenza or hospital-acquired pneumonia.
Klebsiella is often suspected as a cause of lung abscess in alcoholic patients, but even in these patients anaerobic organisms are far more common. The immunologically compromised patient may have pulmonary suppuration caused by a variety of bacterial and nonbacterial organisms, but anaerobes appear to be distinctly unusual in this population.
Laboratory Examination
The initial evaluations in patients with symptoms of lung abscess are those recommended for patients with suspected pulmonary infections in general. These include a chest radiograph, a complete blood count (CBC), blood cultures, and an examination of expectorated sputum. Gram staining of respiratory secretions typically shows a mixed or polymicrobial flora. The lung abscess usually is readily apparent with the chest radiograph (Fig. 40.3), although other causes of a pulmonary cavity must be considered in the differential diagnosis. Alternative considerations include a cavitating neoplasm, cavitating pulmonary infarction, tuberculosis, fungal infection, an infected pulmonary cyst or bulla, and a loculated empyema (i.e., pleural space infection) with an air–fluid level caused by a bronchopleural fistula, gas-producing organisms, or Wegener granulomatosis.
When a cavitary lesion appears to be caused by bacterial infection, there is controversy about the approach to identifying the likely pathogen. Sputum should be examined using Gram stain and Ziehl–Nielson stain to determine from the outset whether an anaerobic pathogen or Mycobacterium tuberculosis is the likely cause of the abscess.
Expectorated sputum is easily obtained from most patients, and standard cultures usually show a predominance of an aerobic organism when it is the etiologic pathogen. The problem with these specimens is that they are inappropriate for anaerobic culture, and the results with aerobic cultures are often misleading because of contamination by bacteria that reside in the upper airway.
Bronchoscopy is generally not useful for microbiologic studies except for mycobacterial and nonbacterial pathogens; an exception is specimens that are obtained with a specialized double catheter and are cultured quantitatively for aerobes and anaerobes.
Antimicrobial Treatment
Antimicrobials are the mainstay of treatment for lung abscess (Table 40.3). The best-studied regimens are those for anaerobic lung abscesses, because these account for most cases. Nevertheless, there is considerable controversy regarding the selection of agents and the duration of treatment.
Anaerobic Infections
With regard to drug selection, the initial antimicrobial agent recommended by most authorities is clindamycin, which is active against most anaerobic bacteria. In approximately 25% of patients, anaerobic organisms resistant to penicillin are present, and almost all of these organisms are highly sensitive to clindamycin. Not surprisingly, comparative trials showed that clindamycin was superior to penicillin in terms of primary response rate and duration of fever after the institution of treatment (17), two factors that may allow earlier hospital discharge. The initial treatment is usually given parenterally (600 mg intravenously every 8 hours) until the patient is afebrile and there is subjective improvement. This usually requires 3 to 7 days but may require considerably longer in patients with very large lung abscesses, those with prolonged symptoms before treatment, and those with pleural complications (primary empyema). The major alternative antimicrobials are amoxicillin–clavulanate (875 mg orally twice daily) or penicillin (10 million units intravenously daily) plus metronidazole (500 to 750 mg twice daily).
Aerobic Infections
Guidelines for antimicrobial selection are less precise for lung abscesses involving other organisms. In these cases, the antimicrobial is selected on the basis of in vitro sensitivity tests. Abscesses involving S. aureus or gram-negative bacilli are regarded as more serious infections, and intravenous antimicrobials should be given for a more prolonged period; in selected stable patients, the intravenous regimen can be completed at home.
Duration of Treatment
Rigorous studies to determine the optimal duration of antimicrobial treatment for lung abscesses have not been done. The duration of treatment is arbitrary, but most authorities recommend at least 6 weeks or longer depending on results of serial radiographs. Antimicrobials are given until the chest radiograph either is clear or shows only a small stable residual lesion (Fig. 40.3). These recommendations are based on experiences in which patients have had relapses despite treatment for at least 1 month; in these patients, the infiltrate was still resolving when drugs were
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discontinued, and the patients were subsequently readmitted for recurrent abscesses in the same pulmonary segment. The usual oral regimen with clindamycin is 300 mg four times daily.
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FIGURE 40.3. A: July 6, 1976. The patient developed fever and coughed up foul sputum after an epileptic attack. The huge cavity with an air–fluid level in the left lower lobe suggests a pyopneumothorax. However, the irregularity of the cavity wall indicates that it lies within the lung rather than in the pleura. B: August 3, 1976. On antibiotic therapy, the cavity has become much smaller and there is no longer an air–fluid level. C: September 20, 1976. Although the patient is clinically well, the cavity has increased in size. Its wall is thin and smooth, and there are infiltrations in the lung around the cavity. The ballooning of the cavity was noted after an attack of asthma. The increase in size was caused entirely by air trapping because of the bronchospasm and does not indicate reactivation of the infection. (From Rabin CB, Baron MG. Radiology of the chest. 2nd ed. Baltimore: Williams & Wilkins, 1980:340.) |
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TABLE 40.3 Antimicrobial Regimens for Primary Lung Abscess |
Regardless of the total duration of treatment, adequate followup is necessary to ensure resolution with serial radiographs. These should be obtained at 2- to 3-week intervals, or earlier if there is clinical deterioration. Most patients with lung abscess treated with antimicrobials improve clinically before there is demonstrable improvement in the chest radiograph; cavities gradually close, but 20% to 30% persist beyond 6 weeks, and the roentgenographic criteria for cure as defined previously may require several months (18).
Inadequate Response to Treatment
Failure to show progressive improvement, especially if accompanied by clinical symptoms, necessitates a change in medical therapy, bronchoscopy (to rule out obstruction), or, on rare occasions, surgery. The major indications for surgery are an abscess that is totally refractory to antimicrobial treatment, life-threatening or persistent hemorrhage, and abscesses occurring in association with an obstructed bronchus (15).
Endocarditis
Definition and Epidemiology
Endocarditis, an infection involving the heart valves, usually is caused by bacteria but occasionally by other microbes such as Rickettsia or fungi. There is a spectrum of clinical findings, but patients with the subacute form of the disease may have symptoms that are notably vague and nonspecific. The principal criteria for making the diagnosis are documented fever, heart murmur, and positive blood cultures. A unique feature of the disease is that most patients have continuous bacteremia, so that blood cultures are positive in 95% of patients, regardless of the temporal relationship between blood samplings and temperature profile.
The annual incidence of acquired native valve endocarditis in the United States is 2 to 6 per 100,000 population, with variation from one site to another. The incidence is much higher among injection drug users: 150 to 2,000 per 100,000. Mitral valve prolapse (MVP) is the most common structural abnormality predisposing to endocarditis: the annual incidence in patients with MVP is approximately 100 per 100,000.Prosthetic valve endocarditis may account for up to 25% of cases in developed countries. The incidence of endocarditis after prosthetic valve insertion is approximately 1% in the first 12 months and 2% to 3% at 60 months (19).
All patients with endocarditis should be hospitalized for a complete diagnostic evaluation, supportive care, and initiation of treatment with antibiotics, given intravenously. This discussion addresses the management of these patients in the ambulatory care setting after hospital discharge.
Treatment
Antimicrobial Treatment Out of Hospital
Antimicrobials are selected for patients with endocarditis according to in vitro sensitivity tests, with the emphasis on bactericidal activity. Most patients are treated with
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specific regimens according to guidelines from authoritative sources. The standard of treatment has traditionally been 4 to 6 weeks of intravenous antibiotic therapy. Many authorities now endorse a 2-week regimen of penicillin and either gentamicin or streptomycin for infections caused by penicillin-sensitive strains of Streptococcus viridans and Streptococcus bovis, and most recommend prolonged courses for patients with prosthetic valve endocarditis. If intravenous antibiotics are planned for several weeks, part of the parenteral course can be administered at home to expedite hospital discharge.
Abbreviated courses of intravenous or oral antibiotics have been suggested for staphylococcal tricuspid valve endocarditis occurring as a complication of intravenous drug abuse. The advantages of this plan are that it is substantially less expensive, it reduces the problem of venous access, and it appears to be highly effective. The oral regimen studied most extensively is ciprofloxacin (750 mg twice daily) plus rifampin (300 mg twice daily), but S. aureus is showing escalating rates of resistance to all fluoroquinolones, so use should be restricted to cases showing good bactericidal activity in vitro. Alternatively, treatment may begin with intravenous agents such as nafcillin (2 g every 4 hours) with or without gentamicin (1 mg/kg every 8 hours) for 2 weeks, followed by oral administration of ciprofloxacin or cephalexin (500 mg every 6 hours) (20,21). The duration of treatment should be 4 weeks.
Patients with prosthetic valve endocarditis have infections that have proved particularly difficult to cure without intervening surgery. Nevertheless, intravenous antimicrobials are given with the aim of avoiding reoperation; this is a realistic goal with antimicrobial-sensitive organisms. The most common pathogen in these cases is S. epidermidis, which is treated for at least 6 weeks with intravenous drugs selected on the basis of in vitro sensitivity tests. The usual regimen is a penicillinase-resistant penicillin (nafcillin or oxacillin, 2 g every 4 hours) or vancomycin (30 µg/kg daily) for at least 6 weeks combined with gentamicin (1 µg/kg every 8 hours) for the first 2 weeks. For methicillin-resistant strains, the regimen is vancomycin and rifampin (300 mg orally every 12 hours) for at least 6 weeks and gentamicin for 2 weeks. Many authorities recommend prolonged courses of oral antimicrobials after the initial intravenous regimen, such as dicloxacillin or cephalexin in a divided dose of 2 g per day. Because these patients are often stable, it is reasonable to complete a course of dicloxacillin or cephalexin combined with rifampin, 600 to 900 mg/day, out of hospital. This oral regimen is continued for arbitrarily defined periods that range from several weeks to 6 months or longer. Because rifampin reduces the effect of warfarin, which is part of the medical regimen of patients with prosthetic valves, patients taking rifampin typically need an increase in their warfarin dosage.
Long-Term Followup and Prognosis
Patients with endocarditis treated medically or surgically should be monitored carefully after discontinuation of antimicrobials. Majorcomplications during this recovery phase include congestive heart failure, relapse, mycotic aneurysms, and recurrences involving new organisms.
Blood cultures are commonly recommended after discontinuation of antibiotic treatment, usually 2 to 3 days later. Patients who have had an inadequate course of therapy usually relapse within this time frame. Relapse after the recommended course of therapy is least common with viridans streptococci (about 2%); it is more common with most other pathogens (19). Patients most likely to relapse are those with prosthetic valve endocarditis and/or endocarditis involving organisms resistant to antibiotics. The presence of positive blood cultures without a clearly identifiable portal of entry in the recovery phase is presumptive evidence of relapse. The usual recommendation is another course of antibiotics or surgery for a refractory infection. The choice between these two approaches is made on the basis of the extent of the initial treatment course, underlying valve disease, and the in vitro sensitivity of the organism, with particular attention to bactericidal activity. The patient should also be warned of the possibility of relapse and should be instructed to monitor temperature, especially in the evening, when elevations are most likely to be noted.
Some patients with endocarditis that involves prosthetic valves respond initially to treatment, but relapse within a month or two when treatment is discontinued. Many such patients are too old or sick to have any realistic prospect of surviving an operation to replace the prosthesis or have multiple prostheses so that it is not clear where the infection is. Under these circumstances, it is generally possible to find an antimicrobial regimen that can be taken by mouth indefinitely, and that will suppress the clinical manifestations of infection without eliminating it.
Many of the infections that are impossible to eliminate with antimicrobial treatment are because of S. aureus. When discussions about lifelong antimicrobial treatment are initiated, one needs to find drugs that can be taken by mouth and that have few side effects. For S. aureus strains that are not methicillin-resistant, dicloxacillin or cephalexin is very satisfactory, though each must be taken several times per day. For MRSA strains, the situation is difficult. Most MRSA are now resistant to both quinolones and clindamycin, though these drugs are useful if the organism is sensitive. Linezolid is effective against almost all MRSA strains, but its hematologic toxicity makes it unsuitable for prolonged use. That leaves three oral drugs, rifampin, minocycline, and trimethoprim. Most of the toxic reactions to trimethoprim-sulfamethoxazole are caused by the sulfonamide component, whereas almost all the anti-MRSA activity resides in the trimethoprim. Hence,
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it is better to use trimethoprim alone, rather than in combination with sulfamethoxazole.
A lifetime oral anti-MRSA regimen can be achieved by using either rifampin 300 mg every 12 hours plus minocycline 100 mg every 12 hours; or rifampin 300 mg every 12 hours plus trimethoprim 300 mg every 12 hours. Rifampin should never be used as a single drug, because S. aureus will undergo a single step mutation to high level resistance. When used in combination, as suggested, resistance seems to be rare. Patients have been successfully maintained on these regimens for as long as 10 years. The doses of agents may need to be adjusted for body weight and renal function. In the event of allergy to one component, the patient can be shifted to a combination of the other two agents.
Cardiac function should be monitored carefully during and after antibiotic treatment for endocarditis. Valve replacement is a rather common practice during active infection, especially in the 6% to 20% of patients who satisfy certain, often somewhat arbitrary criteria. It should be noted, however, that the mortality rate of surgery performed during active infection is substantially higher than that of surgery performed on an elective basis. When possible, valve replacement should be conducted 6 weeks or longer after antibiotics have been discontinued. The major indication is congestive heart failure that proves difficult to control with medical management.
Mycotic aneurysms may become apparent at any time during the course of endocarditis, but most become clinically apparent several months or even years after treatment. These lesions usually occur at arterial bifurcations and have been reported in up to 15% of cases. The vessels most often involved are intracranial; next in frequency are chest and abdominal arteries. The diagnostic evaluation usually consists of CT imaging, when the central nervous system (CNS) is involved, or arteriography for lesions suspected there or in other locations. Surgical correction is almost always indicated.
Anticoagulation is usually avoided during active endocarditis because of the danger of bleeding from unrecognized aneurysms or from embolic infarctions. However, in patients who are receiving anticoagulants for prosthetic valves, anticoagulation should be continued in the absence of a bleeding complication.
It must be remembered that any patient who has recovered from endocarditis is at risk for a second episode of endocarditis with a different infecting organism. It is presumed that valve scarring caused by the first infection provides a surface to which other organisms that happen to get into the blood can bind. These patients should be warned about this potential complication with any endoscopic, surgical, or dental procedures. It is good practice to supply all patients who are at risk for endocarditis with the wallet-sized card provided by the AHA that contains recommendations for antibiotic prophylaxis to be used with various procedures (see Chapter 93). This serves the dual role of emphasizing the importance of prophylaxis to the patient and ensuring that specific guidelines will be available to health professionals who may be performing procedures on the patient that can cause bacteremia.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.