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Harrison’s Manual of Medicine



GRAM-Negative Enteric Bacilli

Escherichia coli

Klebsiella, Enterobacter, Serratia

Proteus, Morganella, Providencia
Pseudomonas and Related Organisms
Legionella Infections

The gram-negative enteric bacilli are a diverse group of bacteria that reside in the human colon. Nearly every organ and body cavity can be infected with these organisms. The mortality rate is significant in many gram-negative bacillary infections and correlates with the severity of illness.
Escherichia coli
PATHOGENESIS AND CLINICAL SYNDROMES   E. coli is a major cause of enteric infections and UTIs, a common component of polymicrobial intraabdominal infections, and an occasional cause (either alone or in combination with other pathogens) of a variety of other infections, including pneumonia, osteomyelitis, cellulitis, myositis, septic arthritis, and sinusitis. Hosts compromised by neutropenia, vascular disease, diabetes mellitus, or traumatic injury are at added risk for invasive infections. Bacteremia and sepsis syndrome are serious potential consequences of E. coli infections. Strains bearing the K1 capsular serotype are important agents of neonatal meningitis.
Strains producing enteric infections are classified as enterotoxigenic (ETEC), enteropathogenic (EPEC), enteroinvasive (EIEC), or Shiga toxin–producing (STEC)/enterohemorrhagic (EHEC). Enteroaggregative E. coli (EAEC) and diffusely adherent E. coli (DAEC) cause persistent diarrhea, mainly affecting young children in developing countries. ETEC strains are common agents of traveler’s diarrhea, producing watery, noninflammatory diarrheal syndromes. EPEC strains are causes of childhood diarrhea, especially in developing countries. EIEC strains cause dysentery syndromes similar to that caused by Shigella species and are rare in the United States. EHEC strains, typically of serotype O157:H7, cause colitis in which stools lack inflammatory cells but may be grossly bloody. A minority of pts subsequently develop the hemolytic-uremic syndrome (HUS), in which Shiga-like cytotoxins are involved.
Acute UTIs usually occur in sexually active females; bacteria colonize the periurethral region and ascend the urethra. Sequelae may include asymptomatic bacteriuria, urethritis, cystitis, pyelitis, and pyelonephritis. Polymicrobial intraabdominal infections typically follow fecal spillage into the peritoneum; E. coli and other facultative enteric gram-negative organisms are responsible for the early peritonitis and sepsis syndrome that often follows such catastrophes. E. coli bacteremia usually originates from the bowel, biliary tree, or urinary tract.
DIAGNOSIS   The diagnosis of E. coli infection rests on the combination of suspicious clinical findings and laboratory isolation of the organism. Specific identification is generally made biochemically. Growth of E. coli from a normally sterile site (e.g., blood, CSF, pleural fluid) should be considered diagnostic of infection at that site. In contrast, isolation from a normally nonsterile site (e.g., the GI tract) must be interpreted thoughtfully. Gram’s staining is not specific for E. coli. Diagnosis of ETEC, EPEC, EIEC, EAEC, and DAEC infection requires special assays and is rarely indicated since disease due to these organisms is self-limited. Screening for E. coli O157:H7 infection is conducted on sorbitol-MacConkey agar, and the pathogen is identified by serotyping. Tests for Shiga-like toxins or their corresponding genes, which would detect both O157 and non-O157 strains, are being developed.

The frequency of ampicillin resistance precludes its empirical use, and rates of resistance to first-generation cephalosporins, trimethoprim-sulfamethoxazole (TMP-SMZ), amoxicillin/clavulanic acid, and piperacillin are also high in some populations. Rates of resistance are low to second-, third-, and fourth- generation cephalosporins; quinolones; monobactams; carbapenems; and aminoglycosides. Traveler’s diarrhea is often self-limited but may be treated with a fluoroquinolone. Antibiotic treatment of STEC/EHEC infections may increase the incidence of HUS. Thus these infections are managed supportively; signs of HUS should be sought for 1 week after onset of diarrhea. In many circumstances, therapy for E. coli infections must be individualized; several weeks of treatment may be required for serious or deep-seated infections.

Klebsiella, Enterobacter, Serratia
ETIOLOGY   These genera, lactose-fermenting members of the tribe Klebsielleae, are opportunistic and nosocomial pathogens.
CLINICAL MANIFESTATIONS   K. pneumoniae causes a small proportion of cases of community-acquired lobar pneumonia, typically in alcoholic men >40 years of age who have comorbid conditions (e.g., diabetes, chronic obstructive pulmonary disease). The disease mimics pneumococcal pneumonia. Pulmonary necrosis and empyema occur with progression. A bulging fissure is a late radiographic finding. The Klebsielleae cause complicated UTIs, intraabdominal infections, cellulitis, surgical wound infections, and neonatal meningitis or meningitis associated with neurosurgery. Klebsiella infection at any site can result in bacteremia. E. cloacae and E. aerogenes are responsible for most Enterobacter infections and cause clinical syndromes similar to those caused by Klebsiella except for community-acquired pneumonia. These species are important causes of hospital-acquired infections and bacteremia in the setting of neutropenia. S. marcescens causes the majority of Serratia infections. Hospital-acquired lung, genitourinary tract, catheter, and wound infections are common.
DIAGNOSIS   Most Klebsiella, Enterobacter, and Serratia organisms are readily isolated and identified by standard culture techniques.

K. pneumoniae and K. oxytoca are intrinsically resistant to ampicillin and ticarcillin. There is an increasing degree of resistance to third-generation cephalosporins due to extended-spectrum b-lactamases (ESBLs). Strains with ESBLs often have linked resistance to aminoglycosides, tetracyclines, and TMP-SMZ and may have fluoroquinolone resistance as well. At this time, rates of resistance to quinolones, cephamycins (cefoxitin), fourth-generation cephalosporins, and amikacin are generally low. Enterobacter strains are often resistant to first-, second-, and third-generation cephalosporins but have largely retained their sensitivity to imipenem, fourth-generation cephalosporins, aminoglycosides, TMP-SMZ, and quinolones. Imipenem, amikacin, cefepime, and quinolones are the most active agents against Serratia.

Proteus, Morganella, Providencia
ETIOLOGY   Proteus, Morganella, and Providencia, of the tribe Proteeae, are actively motile bacteria that do not ferment lactose.
CLINICAL MANIFESTATIONS   P. mirabilis causes 90% of Proteus infections and is a frequent cause of complicated UTI and of UTI in the setting of an indwelling urinary catheter. Its urease activity alkalinizes the urine and promotes formation of struvite stones. Proteus occasionally causes pneumonia, sinusitis, abdominal abscesses, biliary infection, wound and soft tissue infection, and osteomyelitis. The urinary tract serves as the portal of entry in most cases of Proteus bacteremia.
M. morganii, P. stuartii, and P. rettgeri are the strains of Morganella and Providencia responsible for human infections, mainly of the urinary tract and less commonly of wounds, soft tissue, lungs, catheter sites, and abdomen.
DIAGNOSIS   Microbiologic isolation from a normally sterile site is necessary for diagnosis. P. mirabilis swarms on moist agar and is nearly always indole negative; virtually all other strains in the tribe Proteeae are indole positive.

P. mirabilis is sensitive to most antibiotics except tetracycline, although 10–20% of strains are resistant to ampicillin and first-generation cephalosporins. Infected struvite stones must often be removed. The indole-positive Proteeae tend to be more resistant to antibiotics than are most P. mirabilis strains. Morganella and Providencia may be highly resistant to antibiotics. Imipenem, amikacin, and the fourth-generation cephalosporins are most active.

ETIOLOGY   Pseudomonas spp. and phylogenetically related organisms are ubiquitous, free-living, opportunistic gram-negative pathogens. Of this group, P. aeruginosa is the most common agent of human disease. A small aerobic rod, it is widespread in nature and has a predilection for moist environments. Burkholderia cepacia and Stenotrophomonas maltophilia are occasional nosocomial pathogens. B. pseudomallei causes melioidosis; B. mallei causes glanders.
PATHOGENESIS   P. aeruginosa infections occur after normal cutaneous or mucosal barriers are breached, immunologic defenses are compromised, or the normal flora is eradicated by broad-spectrum antibiotics.
EPIDEMIOLOGY   P. aeruginosa causes hospital-acquired infections. Individuals with cystic fibrosis, diabetes mellitus, IV drug use, neutropenia, wounds, burns, and urinary catheterization are predisposed to infection. Rates of Pseudomonas infection, particularly pneumonia, are increasing among pts with advanced AIDS, although the secondary effects of highly active antiretroviral therapy may reverse this trend. B. cepacia causes infection in circumstances similar to those predisposing to Pseudomonas infection. Melioidosis is endemic to Southeast Asia. Glanders is associated with close contact with horses and other equines.
CLINICAL MANIFESTATIONS   P. aeruginosa causes pneumonia, UTI, bacteremia with ecthyma gangrenosum, endocarditis, sinusitis, “swimmer’s ear,” malignant otitis externa (in diabetics), contact lens–associated keratitis, vertebral osteomyelitis associated with complicated UTI, sternoclavicular pyarthrosis associated with IV drug use, pyoderma, burn wound infection, and hot-tub folliculitis. Melioidosis and glanders present as acute or chronic pulmonary or nonpulmonary suppurative diseases or as acute septicemia.
DIAGNOSIS   P. aeruginosa can be identified by Gram’s staining and culture. Its blue-green pigment and fruity odor are distinctive. B. pseudomallei has a characteristic bipolar “safety-pin” appearance on staining with methylene blue. In addition to culture, serologic methods are available for diagnosis of B. pseudomallei and B. mallei infections.

Agents with antipseudomonal activity include aminoglycosides, selected third-generation cephalosporins (e.g., ceftazidime, cefoperazone), cefepime, selected extended-spectrum penicillins (e.g., ticarcillin, ticarcillin/clavulanate, mezlocillin, piperacillin, piperacillin/tazobactam), carbapenems (e.g., imipenem, meropenem), monobactams (e.g., aztreonam), and fluoroquinolones (e.g., ciprofloxacin, levofloxacin). Local patterns of antimicrobial susceptibility should influence the choice of initial empirical therapy, while the susceptibility profile of the isolate from a particular case should dictate definitive therapy. For most severe infections, two agents are used in combination for synergy—e.g., a b-lactam antibiotic such as ceftazidime (1–2 g) plus an aminoglycoside such as gentamicin (1–1.5 mg/kg) IV q8h. The appropriate duration of antibiotic therapy depends on the type, location, and severity of infection. Uncomplicated lower UTIs due to P. aeruginosa may be amenable to short-course treatment with a single agent. Surgical intervention is necessary for drainage and debridement of pus and necrotic material and for removal of infected foreign bodies. For left-sided P. aeruginosa endocarditis, valve replacement should be performed early. Chronic lung infection in cystic fibrosis requires frequent pulmonary toileting; antibiotics should be given for acute exacerbations. Delivery by the aerosolized route has been used successfully in some instances. Nonmalignant external otitis and Pseudomonas dermatitis associated with exposure to contaminated water are self-limited and usually require no specific therapy.
TMP-SMZ is the drug of choice for S. maltophilia infections. Ceftazidime or imipenem is the agent of choice for melioidosis and is given in conjunction with appropriate surgical drainage of abscesses. Treatment of B. cepacia infection is complicated by this organism’s intrinsic resistance to many antibiotics.

ETIOLOGY   Legionellae are aerobic, gram-negative bacilli whose natural habitats are fresh-water aquatic environments. They may multiply in man-made aquatic reservoirs. L. pneumophila causes 80–90% of human Legionella infections.
PATHOGENESIS   The modes of transmission of Legionella to humans include aerosolization, aspiration, and direct instillation into the lung during respiratory tract manipulations. Direct human-to-human transmission is thought not to occur.
EPIDEMIOLOGY   Legionella infections account for 3–15% of community-acquired pneumonias and for 10–50% of nosocomial pneumonias when a hospital’s water supply is colonized with the organisms. Most sporadic cases probably go undiagnosed. Host-specific risk factors include cigarette smoking, chronic lung disease, advanced age, and immunosuppression. Pontiac fever occurs in epidemics, with high attack rates reflecting airborne transmission.
CLINICAL MANIFESTATIONS   Legionella pneumonia (Legionnaires’ disease) features high fever, nonproductive cough, and GI symptoms. Shortness of breath and confusion are not uncommon. Clues to the diagnosis of Legionnaires’ disease are presented in Table 93-1. Chest examination reveals rales early in the course and evidence of consolidation as the disease progresses. Abnormalities on CXR are virtually uniformly evident on presentation but are nonspecific. Pleural effusion is evident in one-third of cases. Pontiac fever, another disease syndrome linked to legionellae, is an acute, self-limited, flulike illness characterized by malaise, fatigue, myalgias, fever, and headache. Pneumonia does not develop. Extrapulmonary legionellosis may occur; the heart is the site most commonly involved.

Table 93-1 Clinical Clues Suggestive of Legionnaires’ Disease

DIAGNOSIS   The utilities of special tests for the diagnosis of Legionnaires’ disease are presented in Table 93-2.

Table 93-2 Utility of Special Laboratory Tests for the Diagnosis of Legionnaires’ Disease

Newer macrolides and quinolones are now the agents of choice (Table 93-3). For severely ill pts, rifampin (600 mg PO or IV q12h) is combined with a newer macrolide or a quinolone for initial therapy. A clinical response usually occurs within 3–5 d, after which the pt may be switched to oral therapy to complete a 10- to 14-d course. Immunosuppressed pts with advanced disease should be given a 3-week course. Tetracyclines and TMP-SMZ are alternative agents. Pontiac fever is treated supportively, without antibiotics.

Table 93-3 Antibiotic Therapy for Legionella Infectiona


For a more detailed discussion, see Russo TA: Diseases Caused by Gram- Negative Enteric Bacilli, Chap. 153, p. 953; Ohl CA, Pollack M: Infections Due to Pseudomonas Species and Related Organisms, Chap. 155, p. 963; and Chang FY, Yu VL: Legionella Infection, Chap. 151, p. 945, in HPIM- 15.



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