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General Considerations !!navigator!!

Gram-negative bacilli (GNB) are normal components of the human colonic microbiota and/or a number of environmental habitats and can colonize mucosal and skin surfaces, especially in pts in long-term-care facilities and hospital settings. GNB cause a wide variety of infections involving diverse anatomic sites in both healthy and compromised hosts; extraintestinal infections due to Escherichia coli and, to a lesser degree, Klebsiella species are most common. Isolation of GNB from any sterile site almost always implies infection, whereas isolation from nonsterile sites requires clinical correlation. Early appropriate antimicrobial therapy improves outcomes. Given worldwide increases in multidrug-resistant GNB (e.g., due to extended-spectrum β-lactamases [ESBLs] and AmpC β-lactamases), combination empirical antimicrobial therapy pending susceptibility results may be appropriate for critically ill pts.

Extraintestinal Pathogenic E. Coli (Expec) !!navigator!!

In contrast to intestinal pathogenic E. coli (see below), ExPEC strains are often found in the intestinal microbiota of healthy individuals but cause disease only when they enter a normally sterile extraintestinal site (e.g., the urinary tract, peritoneal cavity, or lungs). Most ExPEC strains have virulence factor profiles distinct from those of other commensal strains and from those of pathogenic strains that cause intestinal infections.

Clinical Manifestations

The clinical presentation depends in large part on the site of the body infected by ExPEC.

  • UTI: The urinary tract is the site most frequently infected by ExPEC; see Chap. 147 Dysuria, Urinary Tract Infections, Bladder Pain, and Interstitial Cystitis for more details. E. coli causes 80-90% of 6-8 million episodes of acute uncomplicated UTI in ambulatory premenopausal women.
  • Abdominal and pelvic infection: The abdomen and pelvis represent the second most common site of infection by ExPEC, which may be isolated in the setting of a polymicrobial infection; see Chap. 84 Intraabdominal Infections for more details. Syndromes include peritonitis, intraabdominal abscesses, and cholangitis.
  • Pneumonia: ExPEC is generally the third or fourth most commonly isolated GNB in hospital-acquired pneumonia and can be a common cause of pneumonia in pts residing in long-term-care facilities; see Chap. 134 Pneumonia, Bronchiectasis, and Lung Abscess for more details.
  • Meningitis: E. coli is one of the two leading causes of neonatal meningitis (the other being group B Streptococcus). Strains with the K1 capsular serotype are generally involved.
  • Cellulitis/musculoskeletal infection: E. coli often contributes to infection of decubitus ulcers and diabetic lower-extremity ulcers, cellulitis, and burn-site or surgical-site infections. Hematogenously acquired osteomyelitis, particularly vertebral, is more commonly caused by E. coli than is generally appreciated. See Chap. 87 Infections of the Skin, Soft Tissues, Joints, and Bones for more details.
  • Bacteremia: E. coli bacteremia can arise from primary infection at any site, but originates most commonly from the urinary tract (50-67% of episodes) and next most commonly from the abdomen (25% of episodes). E. coli bacteremia is almost always clinically significant and may be associated with sepsis. Endovascular infections are rare but have been described.

Diagnosis

ExPEC grows readily on standard media under either aerobic or anaerobic conditions. More than 90% of strains ferment lactose and are indole positive.

TREATMENT

Extraintestinal Infections Caused by E. coli

  • Rates of resistance to ampicillin, first-generation cephalosporins, trimethoprim-sulfamethoxazole (TMP-SMX), and fluoroquinolones are >20%. This resistance precludes empirical use of these agents for serious infections. ESBLs are increasingly common (8-60%) in E. coli.
  • Carbapenems, amikacin, piperacillin-tazobactam, ceftazidime-avibactam, and ceftolozane-tazobactam are the most predictably active agents overall, but carbapenemase-producing strains are on the rise.
  • It is important to use the most appropriate narrower-spectrum agent whenever possible and to avoid treating colonized but uninfected pts, thus combating the increase in antibiotic resistance.

Intestinal Pathogenic E. Coli !!navigator!!

Microbiology and Clinical Manifestations

At least five distinct pathotypes of intestinal pathogenic E. coli exist; see Chap. 85 Infectious Diarrheas and Bacterial Food Poisoning for more details. As mentioned above, these strains are rarely encountered as part of the commensal microbiota in healthy individuals.

  • Shiga toxin-producing E. coli (STEC)/enterohemorrhagic E. coli (EHEC)/Shiga toxin-producing enteroaggregative E. coli (ST-EAEC): In addition to diarrhea, STEC/EHEC infection results in the hemolytic-uremic syndrome (HUS) in 2-8% of pts, particularly those who are very young or elderly. ST-EAEC results in a higher rate of HUS (20%), with a higher incidence among adults, especially young women.
    • STEC/EHEC/ST-EAEC is associated with ingestion of contaminated food (e.g., undercooked ground beef, fresh produce) and water; person-to-person transmission (e.g., at day-care centers) is an important route for secondary spread.
    • Disease can be caused by <102 colony-forming units (CFU) of STEC/EHEC/ST-EAEC.
    • In contrast to the other pathotypes, STEC/EHEC/ST-EAEC (including E. coli O157:H7) causes infection more frequently in industrialized countries than in developing countries.
  • Enterotoxigenic E. coli (ETEC): These strains are a major cause of endemic diarrhea among children residing in tropical and low-income countries and are the most common agent of traveler's diarrhea; 106 -108 CFU are needed to cause disease.
  • Enteropathogenic E. coli (EPEC): EPEC is an important cause of diarrhea among infants in developing countries.
  • Enteroinvasive E. coli (EIEC): EIEC, an uncommon cause of diarrhea, produces inflammatory colitis (stools containing mucus, blood, and inflammatory cells) similar to that caused by Shigella and primarily affects children and travelers in developing countries; 108 -1010 CFU are needed to cause disease.
  • Enteroaggregative and diffusely adherent E. coli (EAEC): EAEC was initially described in young children in developing countries. More recent studies indicate that EAEC infection requires a large inoculum and may be a common cause of prolonged, watery diarrhea in all age groups in industrialized countries.

Diagnosis

Specific diagnosis is usually unnecessary for management, but detection of STEC/EHEC/ST-EAEC has public health importance. To detect the latter, simultaneous culture (screening for E. coli strains that do not ferment sorbitol followed by serotyping for O157) and testing for Shiga toxins or toxin genes is recommended.

TREATMENT

Intestinal Infections Caused by E. coli

Klebsiella !!navigator!!

Epidemiology !!navigator!!

K. pneumoniae colonizes the colon in 5-35% of healthy individuals and, from a medical standpoint, is the most important Klebsiella species. K. oxytoca primarily causes infections in long-term care and hospital settings. K. pneumoniae subspecies rhinoscleromatis, which causes rhinoscleroma, and K. pneumoniae subspecies ozaenae, which causes chronic atrophic rhinitis, infect pts in tropical climates.

Clinical Manifestations !!navigator!!

As in other GNB infections, the clinical presentation depends on the infected anatomic site.

  • Pneumonia: Klebsiella is a common cause of pneumonia among residents of long-term care facilities and hospitalized pts. In Asia and South Africa, community-acquired pneumonia due to hypervirulent strains of K. pneumoniae is increasingly common, particularly among younger, healthy pts.
    • The presentation is similar to that of pneumonia caused by other enteric GNB, with purulent sputum production and pulmonary infiltrates on CXR.
    • Infection can progress to pulmonary necrosis, pleural effusion, and empyema.
  • UTI: K. pneumoniae causes 1-2% of cases of uncomplicated cystitis and 5-17% of cases of complicated UTI.
  • Abdominal infections: Klebsiella causes a spectrum of disease similar to that of E. coli, but with less frequent occurrence. Hypervirulent strains have become a common cause of monomicrobial community-acquired liver abscess, spontaneous bacterial peritonitis, and splenic abscess.
  • Bacteremia: Bacteremia can arise from a primary infection at any site; infections of the urinary tract, respiratory tract, and abdomen (especially hepatic abscess) each account for 15-30% of episodes.
  • Other infections: Klebsiella cellulitis or soft-tissue infection most frequently affects devitalized tissue and immunocompromised hosts. Klebsiella can also cause endophthalmitis, nosocomial sinusitis, and osteomyelitis.

Diagnosis !!navigator!!

Klebsiellae usually ferment lactose, although the K. pneumoniae subspecies rhinoscleromatis and ozaenae are nonfermenters and are indole negative.

TREATMENT

Klebsiella Infections

  • Klebsiellae are intrinsically resistant to ampicillin and ticarcillin and are inconsistently susceptible to nitrofurantoin.
    • The increase in plasmid-encoded ESBLs has led to increasing resistance to third- and fourth-generation cephalosporins, aminoglycosides, tetracyclines, and TMP-SMX.
    • Fluoroquinolone resistance is increasing, especially among ESBL-containing strains.
  • Empirical treatment of serious or health care-associated Klebsiella infections with amikacin or carbapenems is prudent; however, carbapenemase-producing strains are increasing in frequency. Optimal therapy for carbapenemase strains is unclear, but tigecycline, the polymyxins (e.g., colistin), and ceftazidime-avibactam (ineffective against metallo-carbapenemases) are used most frequently on the basis of in vitro susceptibility profiles. When resistance to these agents is documented, combination therapy is often used.

Proteus !!navigator!!

Epidemiology !!navigator!!

P. mirabilis is part of the normal microbiota in 50% of healthy people and causes 90% of Proteus infections. P. vulgaris and P. penneri are isolated primarily from pts in hospitals and long-term care facilities.

Clinical Manifestations !!navigator!!

Most Proteus infections arise from the urinary tract. Proteus species account for 1-2% of uncomplicated UTIs, 5% of hospital-acquired UTIs, and 10-15% of complicated UTIs (especially those associated with urinary catheters).

  • Proteus produces high levels of urease that result in alkalinization of urine and ultimately in formation of struvite and carbonate-apatite calculi.
  • Infections at other sites are uncommon but include pneumonia, abdominal infections, soft-tissue infections, and bacteremia.

Diagnosis !!navigator!!

Proteus strains are typically lactose negative, produce H2S, and exhibit swarming motility on agar plates. P. mirabilis and P. penneri are indole negative, whereas P. vulgaris is indole positive.

TREATMENT

Proteus Infections

  • P. mirabilis is susceptible to most agents except tetracycline, cefazolin, nitrofurantoin, polymyxins, and tigecycline. Resistance to ampicillin, first-generation cephalosporins, and fluoroquinolones is increasing.
  • P. vulgaris and P. penneri are more resistant; induction of variants with stable derepression of chromosomal AmpC β-lactamase may occur with P. vulgaris isolates. Carbapenems, fourth-generation cephalosporins, amikacin, TMP-SMX, and fosfomycin exhibit excellent activity: 90-100% of Proteus isolates are susceptible.

Other Gram-Negative Enteric Pathogens !!navigator!!

  • Enterobacter (e.g., E. cloacae, E. aerogenes), Acinetobacter (e.g., A. baumannii), Serratia (e.g., S. marcescens), and Citrobacter (e.g., C. freundii, C. koseri) usually cause nosocomial infections. Risk factors include immunosuppression, comorbid disease, prior antibiotic use, and ICU stays.
  • Infections caused by Morganella (e.g., M. morganii) and Providencia (e.g., P. stuartii, P. rettgeri) resemble Proteus infections in terms of epidemiology, pathogenicity, and clinical manifestations but occur almost exclusively among persons in long-term care facilities and, to a lesser degree, among hospitalized pts.

Clinical Manifestations !!navigator!!

These organisms generally cause a spectrum of disease similar to that caused by other GNB, including pneumonia (particularly ventilator-associated), UTI (especially catheter-related), intravascular device-related infection, surgical-site infection, and abdominal infection.

  • Citrobacter, Morganella, and Providencia infections are generally associated with UTIs.
  • Acinetobacter has caused skin and soft-tissue infections in victims of trauma (e.g., soldiers in war zones, victims of natural disasters). A. baumannii infections occur frequently among pts admitted to ICUs.
TREATMENT

Infections Caused by Other Gram-Negative Enteric Pathogens

  • Significant antibiotic resistance among these organisms makes therapy challenging.
    • Many of these organisms (e.g., Serratia, Providencia, Acinetobacter, Citrobacter, Enterobacter, Morganella) have a derepressible AmpC β-lactamase that results in resistance to third-generation cephalosporins, monobactams, and-in many cases-β-lactam/β-lactamase inhibitor combinations.
    • Morganella and Providencia are inherently resistant to the polymyxins and tigecycline.
  • Carbapenems and amikacin are most reliably active, and fourth-generation cephalosporins are active provided the organism does not express an ESBL. Susceptibility testing is essential. Some isolates may retain susceptibility only to colistin and polymyxin B.

Aeromonas !!navigator!!

Aeromonas organisms (e.g., A. hydrophila, A. caviae, A. veronii, A. dhakensis) proliferate in potable water, freshwater, and soil and are a putative cause of gastroenteritis. Aeromonas causes bacteremia and sepsis in infants and compromised hosts, especially those with cancer, hepatobiliary disease, trauma, or burns. The organisms can produce skin lesions similar to the ecthyma gangrenosum caused by Pseudomonas aeruginosa. Aeromonas causes nosocomial infections related to catheters, surgical incisions, and use of leeches.

TREATMENT

Aeromonas Infections

  • Aeromonas is usually susceptible to fluoroquinolones (e.g., ciprofloxacin, 500 mg PO q12h or 400 mg IV q12h), third- and fourth-generation cephalosporins, carbapenems, and aminoglycosides.
  • Susceptibility testing is critical to guide therapy since Aeromonas can produce various β-lactamases, including carbapenemases.

Outline

Section 7. Infectious Diseases