InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 170) Evidence indicates that initiation of appropriate empirical antimicrobial therapy early in the course of GNB infections (particularly serious infections) leads to improved outcomes. The ever-increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) GNB; the lag between published (historical) and current resistance rates; and variations by species, geographic location, regional antimicrobial use, and hospital site (e.g., intensive care units [ICUs] versus wards) necessitate familiarity with evolving patterns of antimicrobial resistance for the selection of appropriate empirical therapy. Factors predictive of isolate resistance include recent antimicrobial use, a health care association (e.g., recent or ongoing hospitalization, dialysis, residence in an LTCF), or international travel (e.g., to Asia, Latin America, Africa, southern Europe). For appropriately selected patients, it may be prudent initially, while susceptibility results are


InternalMed_Harrison

InternalMed_Harrison. in an LTCF), or international travel (e.g., to Asia, Latin America, Africa, southern Europe). For appropriately selected patients, it may be prudent initially, while susceptibility results are awaited, to use two potentially active agents with the rationale that at least one agent will be active. If broad-spectrum treatment has been initiated, it is critical to switch to the most appropriate narrower-spectrum agent when information on antimicrobial susceptibility becomes available. Such responsible antimicrobial stewardship will slow down the ever-escalating cycle of selection for increasingly resistant bacteria, decrease the likelihood of Clostridium difficile infection, decrease costs, and maximize the useful longevity of available antimicrobial agents. Likewise, it is important to avoid treatment of patients who are colonized but not infected (e.g., who have a positive sputum culture without evidence of pneumonia). At present, the most reliably active agents against enteric GNB are


InternalMed_Harrison

InternalMed_Harrison. treatment of patients who are colonized but not infected (e.g., who have a positive sputum culture without evidence of pneumonia). At present, the most reliably active agents against enteric GNB are the carbapenems (e.g., imipenem), the aminoglycoside amikacin, the fourth-generation cephalosporin cefepime, the β-lactam/β-lactamase inhibitor combination piperacillin-tazobactam, and the polymyxins (e.g., colistin or polymyxin B). The number of antimicrobials effective against certain Enterobacteriaceae is shrinking. Truly pan-resistant GNB exist, and it is unlikely that new agents will come to market in the short term. Accordingly, the presently available antimicrobials must be used judiciously.


InternalMed_Harrison

InternalMed_Harrison. β-Lactamases, which inactivate β-lactam agents, are the most important mediators of resistance to these drugs in GNB. Decreased permeability and/or active efflux of β-lactam agents, although less common, may occur alone or in combination with β-lactamasemediated resistance. Broad-spectrum β-lactamases (e.g., TEM, SHV), which mediate resistance to many penicillins and first-generation cephalosporins, are frequently expressed in enteric GNB. These enzymes are inhibited by β-lactamase inhibitors (e.g., clavulanate, sulbactam, tazobactam). They usually do not hydrolyze thirdand fourth-generation cephalosporins or cephamycins (e.g., cefoxitin).


InternalMed_Harrison

InternalMed_Harrison. Extended-spectrum β-lactamases (ESBLs; e.g., CTX-M, SHV, TEM) are modified broad-spectrum enzymes that confer resistance to the same drugs as well as to third-generation cephalosporins, aztreonam, and (in some instances) fourth-generation cephalosporins. GNB that express ESBLs may also possess porin mutations that result in decreased uptake of cephalosporins and β-lactam/ β-lactamase inhibitor combinations. The prevalence of acquired ESBL production, particularly of CTX-M-type enzymes, is increasing in GNB worldwide, in large part due to the presence of the responsible genes on large transferable plasmids with linked or associated resistance to fluoroquinolones, trimethoprim-sulfamethoxazole (TMP-SMX), aminoglycosides, and tetracyclines. To date, ESBLs are most prevalent in


InternalMed_Harrison

InternalMed_Harrison. K. pneumoniae, K. oxytoca, and E. coli but also occur (and are probably underrecognized) in Enterobacter, Citrobacter, Proteus, Serratia, and other enteric GNB. At present, the rough regional prevalence of ESBL-producing GNB is India > China > rest of Asia, Latin America, Africa, southern Europe > northern Europe > United States, Canada, and Australia. International travel to high-prevalence regions increases the likelihood of colonization with these strains. ESBL-producing GNB were initially described in hospitals (ICUs > wards) and LTCFs, where outbreaks occurred in association with extensive use of third-generation cephalosporins. However, over the last decade, the incidence of uncomplicated cystitis due to CTX-M ESBL-containing E. coli has increased worldwide (including in the United States) among healthy ambulatory women without health care or antimicrobial exposure. Antimicrobial use in food animals has also been implicated in the rise of ESBLs.


InternalMed_Harrison

InternalMed_Harrison. The carbapenems are the most reliably active β-lactam agents against ESBL-expressing strains. Clinical experience with alternatives is more limited, but, for organisms susceptible to piperacillintazobactam (minimal inhibitory concentration [MIC], ≤4 μg/mL), this agent—at a dosage of 4.5 g q6h—may offer a carbapenemsparing alternative, at least for E. coli. The role of tigecycline is unclear despite its excellent in vitro activity; Proteus, Morganella, and Providencia are inherently resistant, and attainable serum and urine levels are low. Therefore, caution appears to be prudent, especially with serious infections, until more clinical data become available. Oral options for the treatment of strains expressing CTX-M ESBLs are limited, with fosfomycin being the most reliably active agent (see section below on the treatment of extraintestinal E. coli infections).


InternalMed_Harrison

InternalMed_Harrison. AmpC β-lactamases, when induced or stably derepressed to high levels of expression, confer resistance to the same substrates as ESBLs plus the cephamycins (e.g., cefoxitin and cefotetan). The genes encoding these enzymes are primarily chromosomally located and therefore may not exhibit the linked or associated resistance to fluoroquinolones, TMP-SMX, aminoglycosides, and tetracyclines that is common with ESBLs. These enzymes are problematic for the clinician: resistance may develop during therapy with third-generation cephalosporins, resulting in clinical failure, particularly in the setting of bacteremia. Although chromosomal AmpC β-lactamases are present in nearly all members of the Enterobacteriaceae family, the risk of clinically significant induction of high expression levels or selection of stably derepressed mutants with cephalosporin treatment is greatest with Enterobacter cloacae and Enterobacter aerogenes, lower with Serratia marcescens and Citrobacter freundii, and lowest


InternalMed_Harrison

InternalMed_Harrison. of stably derepressed mutants with cephalosporin treatment is greatest with Enterobacter cloacae and Enterobacter aerogenes, lower with Serratia marcescens and Citrobacter freundii, and lowest with Providencia and Morganella morganii. In addition, rare strains of E. coli, K. pneumoniae, and other Enterobacteriaceae have acquired plasmids containing inducible AmpC β-lactamase genes. Carbapenems are a viable treatment option. The fourth-generation cephalosporin cefepime may be an appropriate option if the concomitant presence of an ESBL can be excluded and source control is achieved. Other carbapenem-sparing alternatives to consider if isolates are susceptible in vitro are fluoroquinolones, piperacillintazobactam, TMP-SMX, tigecycline, and aminoglycosides, although clinical data are limited.


InternalMed_Harrison

InternalMed_Harrison. Carbapenemases (e.g., KPC [class A]; NDM-1, VIM, and IMP [class B]; and OXA-48 [class D]) confer resistance to the same drugs as ESBLs and also to cephamycins and carbapenems. Similar to ESBLs, carbapenemases are usually encoded on large transferable plasmids, which often encode linked resistance to fluoroquinolones, TMP-SMX, tetracyclines, and aminoglycosides. Unfortunately, carbapenemase-producing Enterobacteriaceae are becoming increasingly common, particularly in Asia, and infection with these strains is associated with elevated mortality rates. This reality has prompted the Centers for Disease Control and Prevention (CDC) to categorize carbapenem-resistant Enterobacteriaceae as an “urgent threat” to health care. Carbapenemase production by Enterobacteriaceae is most prevalent in K. pneumoniae and E. coli but has been described in nearly all members of the family. Automated susceptibility systems may be unreliable for detection of carbapenemases. An elevated MIC or a diminished


InternalMed_Harrison

InternalMed_Harrison. pneumoniae and E. coli but has been described in nearly all members of the family. Automated susceptibility systems may be unreliable for detection of carbapenemases. An elevated MIC or a diminished zone diameter for meropenem or imipenem should prompt genotypic confirmation, if available. Alternatively, the phenotype can be confirmed with a modified Hodge test (which detects classes A, B, and D, although results can be false positive) and/or inhibition tests with boronic acid (class A), EDTA (class B), or dipicolinic acid (class B). Carbapenem resistance may also occur in the absence of carbapenemase production and can be mediated by AmpC β-lactamase and ESBL production coupled with modifications in permeability/efflux.


InternalMed_Harrison

InternalMed_Harrison. For treatment of carbapenem-resistant Enterobacteriaceae, tigecycline and colistin are the parenteral agents with the most reliable in vitro activity. However, because tigecycline reaches only low serum and urine concentrations, caution is warranted in using it to treat bacteremia and perhaps urinary tract infection (UTI), although a few case reports describe some success with tigecycline therapy for UTI. Colistin has nephrotoxic and neurotoxic potential. Furthermore, increasing resistance has been described to both of these agents. Thus the clinician is left with few or no therapeutic options. Aminoglycosides may have some utility if active. Fosfomycin is often active in vitro, but clinical data are limited, concerns exist about the development of resistance with monotherapy, and no parenteral formulation is available in the United States. Although control data are lacking, combination therapy is being used in this setting with the goals of increasing efficacy and decreasing the


InternalMed_Harrison

InternalMed_Harrison. parenteral formulation is available in the United States. Although control data are lacking, combination therapy is being used in this setting with the goals of increasing efficacy and decreasing the emergence of resistance.


InternalMed_Harrison

InternalMed_Harrison. Resistance to fluoroquinolones usually is due to alterations of the target site (DNA gyrase and/or topoisomerase IV), with or without decreased permeability, active efflux, or protection of the target site. Resistance to this drug class is increasingly prevalent among GNB and is associated with resistance to other antimicrobial classes; for example, 20–80% of ESBL-producing enteric GNB are also resistant to fluoroquinolones. At present, quinolones should be considered unreliable as empirical therapy for infections due to GNB in critically ill patients.


InternalMed_Harrison

InternalMed_Harrison. In this era of increasing antimicrobial resistance, it is critical to culture the local site of infection before the initiation of antimicrobial therapy and, for systemically ill patients, to obtain blood samples for culture. Antimicrobial resistance may not always be identified by in vitro testing; therefore, it is important to assess the clinical response to treatment. Moreover, as discussed above, resistance may emerge during therapy through the induction or stable derepression of AmpC β-lactamases. In addition, drainage of abscesses, resection of necrotic tissue, and removal of infected foreign bodies are often required for cure. GNB are commonly involved in polymicrobial infections, in which the role of each individual pathogen is uncertain (Chap. 201). Although some GNB are more pathogenic than others, 1027 it is usually prudent, if possible, to design an antimicrobial regimen active against all of the GNB identified, because each is capable of pathogenicity in its own right.


InternalMed_Harrison

InternalMed_Harrison. than others, 1027 it is usually prudent, if possible, to design an antimicrobial regimen active against all of the GNB identified, because each is capable of pathogenicity in its own right. Lastly, for patients treated initially with a broad-spectrum empirical regimen, the regimen should be de-escalated as expeditiously as possible once susceptibility results are known and the patient has responded to therapy.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 168) Avoidance of inappropriate antimicrobial use is a key measure in preventing infections due to antimicrobial-resistant strains and the further development of antimicrobial resistance. Antimicrobial stewardship programs should be adopted to facilitate achievement of this goal. Diligent adherence to hand-hygiene protocols by health care personnel, cleaning/disinfection of objects that come into contact with patients (e.g., stethoscopes and blood pressure cuffs), and contact precautions should be implemented for patients colonized or infected with carbapenem-resistant (and perhaps other XDR) GNB. Avoidance of the use of indwelling devices (e.g., urinary and intravascular catheters, endotracheal tubes) and, when such devices are necessary, placement according to an appropriate protocol decrease infection risk. Likewise, protocols for daily use evaluation and removal as soon as possible should be implemented. Patient positioning (e.g., head of bed at ≥30°) and good oral


InternalMed_Harrison

InternalMed_Harrison. protocol decrease infection risk. Likewise, protocols for daily use evaluation and removal as soon as possible should be implemented. Patient positioning (e.g., head of bed at ≥30°) and good oral hygiene decrease the incidence of pneumonia among ventilated patients. Increasing data support the implementation of universal decolonization to prevent infection in ICU patients.


InternalMed_Harrison

InternalMed_Harrison. Strains of E. coli are united by a core genome of ~2000 genes. A strain’s ability to cause infections and the nature of such infections are defined by ancillary genes that encode various virulence factors. This experiment of nature is fluid and ongoing, as demonstrated by the recent evolution of Shiga toxin–producing enteroaggregative E. coli.


InternalMed_Harrison

InternalMed_Harrison. For the most part, commensal E. coli variants, which constitute the bulk of the normal facultative intestinal flora in most humans, confer benefits to the host (e.g., resistance to colonization with pathogenic organisms). These strains generally lack the specialized virulence traits that enable extraintestinal and intestinal pathogenic E. coli strains to cause disease outside and within the gastrointestinal tract, respectively. However, even commensal E. coli strains can be involved in extraintestinal infections in the presence of an aggravating factor, such as a foreign body (e.g., a urinary catheter), host compromise (e.g., local anatomic or functional abnormalities, such as urinary or biliary tract obstruction or systemic immunocompromise), or an inoculum that is large or contains a mixture of bacterial species (e.g., fecal contamination of the peritoneal cavity).


InternalMed_Harrison

InternalMed_Harrison. ExPEC strains are the most common enteric GNB to cause infections. The emerging propensity of these strains to acquire new antimicrobial resistance mechanisms (e.g., ESBL and carbapenemase production) has posed challenges in managing ExPEC infection. One clonal group—ST131, the members of which are usually resistant to fluoroquinolones and increasingly express an ESBL (CTX-M)—has undergone global dissemination. Like commensal E. coli (but in contrast to intestinal pathogenic


InternalMed_Harrison

InternalMed_Harrison. E. coli), ExPEC strains are often found in the intestinal flora of healthy individuals and do not cause gastroenteritis in humans. Entry from their site of colonization (e.g., the colon, vagina, or oropharynx) into a normally sterile extraintestinal site (e.g., the urinary tract, peritoneal cavity, or lungs) is the rate-limiting step for infection. ExPEC strains have acquired genes encoding diverse extraintestinal virulence factors that enable the bacteria to cause infections outside the gastrointestinal 1028 tract in both normal and compromised hosts (Table 186-1). These virulence genes define ExPEC and, for the most part, are distinct from those that enable intestinal pathogenic strains to cause diarrheal disease (Table 186-2). All age groups, all types of hosts, and nearly all organs and anatomic sites are susceptible to infection by ExPEC. Even previously healthy hosts can become severely ill or die when infected with ExPEC; however, adverse outcomes are more common among hosts


InternalMed_Harrison

InternalMed_Harrison. and anatomic sites are susceptible to infection by ExPEC. Even previously healthy hosts can become severely ill or die when infected with ExPEC; however, adverse outcomes are more common among hosts with comorbid illnesses and host defense abnormalities. The diversity and the medical and economic impact of ExPEC infections are evident from consideration of the following specific syndromes.


InternalMed_Harrison

InternalMed_Harrison. Extraintestinal Infectious Syndromes • Urinary tract infection The urinary tract is the site most frequently infected by ExPEC. An exceedingly common infection among ambulatory patients, UTI accounts for 1% of ambulatory care visits in the United States and is second only to lower respiratory tract infection among infections responsible for hospitalization. UTIs are best considered by clinical syndrome (e.g., uncomplicated cystitis, pyelonephritis, and catheter-associated UTIs) and within the context of specific hosts (e.g., premenopausal women, compromised hosts; Chap. 162). E. coli is the single most common pathogen for all UTI syndrome/host group combinations. Each year in the United States, E. coli causes 80–90% of an estimated 6–8 million episodes of uncomplicated cystitis in premenopausal women. Furthermore, 20% of women with an initial cystitis episode develop frequent recurrences.


InternalMed_Harrison

InternalMed_Harrison. Uncomplicated cystitis, the most common acute UTI syndrome, is characterized by dysuria, urinary frequency, and suprapubic pain. Fever and/or back pain suggests progression to pyelonephritis. Even with appropriate treatment of pyelonephritis, fever may take 5–7 days to resolve completely. Persistently elevated or increasing fever and neutrophil counts should prompt evaluation for intrarenal or perinephric abscess and/or obstruction. Renal parenchymal damage and loss of renal function during pyelonephritis occur primarily with urinary obstruction, which can be preexisting or, rarely, occurs de novo in diabetic patients who develop renal papillary necrosis as a result of kidney infection. Pregnant women are at unusually high risk for developing pyelonephritis, which can adversely affect the outcome of pregnancy. As a result, prenatal screening for and treatment of asymptomatic bacteriuria are standard. Prostatic infection is a potential complication of UTI in men. The diagnosis and


InternalMed_Harrison

InternalMed_Harrison. the outcome of pregnancy. As a result, prenatal screening for and treatment of asymptomatic bacteriuria are standard. Prostatic infection is a potential complication of UTI in men. The diagnosis and treatment of UTI, as detailed in Chap. 162, should be tailored to the individual host, the nature and site of infection, and local patterns of antimicrobial susceptibility.


InternalMed_Harrison

InternalMed_Harrison. abdominal and pelvic infection The abdomen/pelvis is the second most common site of extraintestinal infection due to E. coli. A wide variety of clinical syndromes occur in this location, including acute peritonitis secondary to fecal contamination, spontaneous bacterial peritonitis, dialysis-associated peritonitis, diverticulitis, appendicitis, intraperitoneal or visceral abscesses (hepatic, pancreatic, splenic), infected pancreatic pseudocysts, and septic cholangitis and/or cholecystitis. In intraabdominal infections, E. coli can be isolated either alone or (as often occurs) in combination with other facultative and/ or anaerobic members of the intestinal flora (Chap. 159).


InternalMed_Harrison

InternalMed_Harrison. pneUmonia E. coli is not usually considered a cause of pneumonia (Chap. 153). Indeed, enteric GNB account for only 1–3% of cases of community-acquired pneumonia, in part because these organisms only transiently colonize the oropharynx in a minority of healthy individuals. However, rates of oral colonization with E. coli and other GNB increase with severity of illness and antibiotic use. Consequently, GNB are a more common cause of pneumonia among residents of LTCFs and are the most common cause (60–70% of cases) of hospital-acquired pneumonia (Chap. 168), particularly among postoperative and ICU patients (e.g., ventilator-associated pneumonia). Pulmonary infection is usually acquired by small-volume aspiration but occasionally occurs via hematogenous spread, in which case multifocal nodular infiltrates can be seen. Tissue necrosis, probably due to bacterial cytotoxins, is common. Despite significant institutional variation, E. coli is generally the third or fourth most commonly


InternalMed_Harrison

InternalMed_Harrison. nodular infiltrates can be seen. Tissue necrosis, probably due to bacterial cytotoxins, is common. Despite significant institutional variation, E. coli is generally the third or fourth most commonly isolated GNB in hospital-acquired pneumonia, accounting for 5–8% of episodes in both U.S.-based and Europe-based studies. Regardless of the host, pneumonia due to ExPEC is a serious disease, with high crude and attributable mortality rates (20–60% and 10–20%, respectively).


InternalMed_Harrison

InternalMed_Harrison. meningitis (See also Chap. 164) E. coli is one of the two leading causes of neonatal meningitis, the other being group B Streptococcus. Most E. coli strains that cause neonatal meningitis possess the K1 capsular antigen and derive from a limited number of meningitis-associated clonal groups. Ventriculomegaly commonly occurs. After the first month of life, E. coli meningitis is uncommon, occurring predominantly in the setting of surgical or traumatic disruption of the meninges or in the presence of cirrhosis. In patients with cirrhosis who develop meningitis, the meninges are presumably seeded as a result of poor hepatic clearance of portal vein bacteremia.


InternalMed_Harrison

InternalMed_Harrison. cellUlitis/mUscUloskeletal infection E. coli contributes frequently to infections of decubitus ulcers and occasionally to infections of ulcers and wounds of the lower extremity in diabetic patients and other hosts with neurovascular compromise. Osteomyelitis secondary to contiguous spread can occur in these settings. E. coli also causes cellulitis or infections of burn sites and surgical wounds (accounting for ~10% of surgical site infections), particularly when the infection originates TABLE 186-2 InTEsTInAL PATHOgEnIC E. COLI STEC/EHEC/STEAEC Food, water, person-toperson; all ages, industrialized countries ETEC Food, water; young children in and travelers to developing countries EIEC Food, water; children in and travelers to developing countries EAEC ?Food, water; children in and travelers to developing countries; all ages, industrialized countries Hemorrhagic colitis, hemolytic-uremic syndrome Watery diarrhea, persistent diarrhea


InternalMed_Harrison

InternalMed_Harrison. EAEC ?Food, water; children in and travelers to developing countries; all ages, industrialized countries Hemorrhagic colitis, hemolytic-uremic syndrome Watery diarrhea, persistent diarrhea Traveler’s diarrhea, acute diarrhea, persistent diarrhea Shiga toxin Heat-stable and labile enterotoxins, colonization factors Localized adherence, attaching and effacing lesion on intestinal epithelium Invasion of colonic epithelial cells, intracellular multiplication, cell-to-cell spread Aggregative/diffuse adherence, virulence factors regulated by AggR Lambda-like Stx1or Stx2-encoding bacteriophage


InternalMed_Harrison

InternalMed_Harrison. Aggregative/diffuse adherence, virulence factors regulated by AggR Lambda-like Stx1or Stx2-encoding bacteriophage Abbreviations: EAEC, enteroaggregative E. coli; EHEC, enterohemorrhagic E. coli; EIEC, enteroinvasive E. coli; EPEC, enteropathogenic E. coli; ETEC, enterotoxigenic E. coli; STEAEC, Shiga toxin–producing enteroaggregative E. coli; STEC, Shiga toxin–producing E. coli. a Classic syndromes; see text for details on disease spectrum. b Pathogenesis involves multiple genes, including genes in addition to those listed.


InternalMed_Harrison

InternalMed_Harrison. close to the perineum. Hematogenously acquired osteomyelitis, especially of vertebral bodies, is more commonly caused by E. coli than is generally appreciated; this organism accounts for up to 10% of cases in some series (Chap. 158). E. coli occasionally causes orthopedic device– associated infection or septic arthritis and rarely causes hematogenous myositis. Upper-leg myositis or fasciitis due to E. coli should prompt an evaluation for an abdominal source with contiguous spread. endovascUlar infection Despite being one of the most common causes of bacteremia, E. coli rarely seeds native heart valves. When the organism does seed native valves, it usually does so in the setting of prior valvular disease. E. coli infections of aneurysms, the portal vein (pylephlebitis), and vascular grafts are quite uncommon.


InternalMed_Harrison

InternalMed_Harrison. miscellaneoUs infections E. coli can cause infection in nearly every organ and anatomic site. It occasionally causes postoperative mediastinitis or complicated sinusitis and uncommonly causes endophthalmitis, ecthyma gangrenosum, or brain abscess.


InternalMed_Harrison

InternalMed_Harrison. bacteremia E. coli bacteremia can arise from primary infection at any extraintestinal site. In addition, primary E. coli bacteremia can arise from percutaneous intravascular devices or transrectal prostate biopsy or from the increased intestinal mucosal permeability seen in neonates and in the settings of neutropenia and chemotherapy-induced mucositis, trauma, and burns. Roughly equal proportions of E. coli bacteremia cases originate in the community and in health care settings. In most studies, E. coli and Staphylococcus aureus are the two most common blood isolates of clinical significance. Isolation of E. coli from the blood is almost always clinically significant and is typically accompanied by the sepsis syndrome, severe sepsis (sepsis-induced dysfunction of at least one organ or system), or septic shock (Chap. 325).


InternalMed_Harrison

InternalMed_Harrison. The urinary tract is the most common source of E. coli bacteremia, accounting for one-half to two-thirds of episodes. Bacteremia from a urinary tract source is particularly common among patients with pyelonephritis, urinary tract obstruction, or urinary instrumentation in the presence of infected urine. The abdomen is the second most common source, accounting for 25% of episodes. Although biliary obstruction (stones, tumor) and overt bowel disruption, which typically are readily apparent, are responsible for many of these cases, some abdominal sources (e.g., abscesses) are remarkably silent clinically and require identification via imaging studies (e.g., CT). Therefore, the physician should be cautious in designating the urinary tract as the source of E. coli bacteremia in the absence of characteristic signs and symptoms of UTI. Soft tissue, bone, pulmonary, and intravascular catheter infections are other sources of E. coli bacteremia.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis Strains of E. coli that cause extraintestinal infections usually grow both aerobically and anaerobically within 24 h on standard diagnostic media and are easily identified by the clinical microbiology laboratory according to routine biochemical criteria. More than 90% of ExPEC strains are rapid lactose fermenters and are indole positive. TREATMEnT extraintestinal e. coli infections


InternalMed_Harrison

InternalMed_Harrison. In the past, most E. coli isolates were highly susceptible to a broad range of antimicrobial agents. Unfortunately, this situation has changed. In general, the high prevalence of resistance precludes empirical use of ampicillin and amoxicillin-clavulanate, even for community-acquired infections. The prevalence of resistance to first-generation cephalosporins and TMP-SMX is increasing among community-acquired strains in the United States (with current rates of 10–40%) and is even higher outside North America. Until recently, TMP-SMX was the drug of choice for the treatment of uncomplicated cystitis in many locales. Although continued empirical use of TMP-SMX will predictably result in ever-diminishing cure rates, a wholesale switch to alternative agents (e.g., fluoroquinolones) will just as predictably accelerate the widespread emergence of resistance to these antimicrobial classes, as has already occurred in some areas. More than 90% of isolates that cause uncomplicated cystitis


InternalMed_Harrison

InternalMed_Harrison. as predictably accelerate the widespread emergence of resistance to these antimicrobial classes, as has already occurred in some areas. More than 90% of isolates that cause uncomplicated cystitis remain susceptible to nitrofurantoin and fosfomycin.


InternalMed_Harrison

InternalMed_Harrison. The prevalence of resistance to fluoroquinolones among E. coli 1029 isolates from U.S. outpatients has increased steadily over the last decade (i.e., from 3% in 2000 to 17.1% in 2010, according to one survey). Resistance rates are generally higher in the ambulatory setting outside the United States and are even higher in populations for which fluoroquinolone prophylaxis is used extensively (e.g., patients with leukemia, transplant recipients, and patients with cirrhosis) and among isolates from LTCFs and hospitals. For example, the National Healthcare Safety Network (NHSN) reported fluoroquinolone resistance in 41.8% of central line–associated bloodstream infection (CLABSI) E. coli isolates in 2009–2010, and the International Nosocomial Infection Control Consortium (INICC) reported that 53.4% of ICU E. coli isolates were resistant to quinolones in 2004–2009. Furthermore, the NHSN reported 19% resistance to thirdand fourth-generation cephalosporins in CLABSI E. coli isolates, and the


InternalMed_Harrison

InternalMed_Harrison. 53.4% of ICU E. coli isolates were resistant to quinolones in 2004–2009. Furthermore, the NHSN reported 19% resistance to thirdand fourth-generation cephalosporins in CLABSI E. coli isolates, and the INICC found that 66.6% of ICU E. coli isolates were resistant to third-generation cephalosporins.


InternalMed_Harrison

InternalMed_Harrison. ESBL-producing strains are increasingly prevalent among both health care–associated (5–10%) and ambulatory isolates (regiondependent figures). An increasing number of reports describe com-munity-acquired UTIs caused by E. coli strains that produce CTX-M ESBLs. Data suggest that acquisition of CTX-M-producing, fluoroquinolone-resistant strains may result from consumption of meat products from food animals treated with thirdand fourth-generation cephalosporins and fluoroquinolones. Oral treatment options for such strains are limited; however, in vitro and limited clinical data indicate that, for cystitis, fosfomycin and nitrofurantoin appear to be useful options. Carbapenems and amikacin are the most predictably active agents overall, but carbapenemase-producing strains are on the rise (1–5% among health care–associated isolates in the United States and higher rates in many other countries). Tigecycline and the polymyxins, with or without a second agent, have been used most frequently


InternalMed_Harrison

InternalMed_Harrison. among health care–associated isolates in the United States and higher rates in many other countries). Tigecycline and the polymyxins, with or without a second agent, have been used most frequently against these extremely resistant isolates.


InternalMed_Harrison

InternalMed_Harrison. This evolving antimicrobial resistance—a source of serious concern—necessitates not only the increasing use of broad-spectrum agents but also the use of the most appropriate narrower-spectrum agent whenever possible and the avoidance of treatment of colonized but uninfected patients.


InternalMed_Harrison

InternalMed_Harrison. INTESTINAL PATHOGENIC STRAINS Pathotypes Certain strains of E. coli are capable of causing diarrheal disease. Other important intestinal pathogens are discussed in Chaps. 160, 161, and 190–193. At least in the industrialized world, intestinal pathogenic strains of E. coli are rarely encountered in the fecal flora of healthy persons and instead appear to be essentially obligate pathogens. These strains have evolved a special ability to cause enteritis, enterocolitis, and colitis when ingested in sufficient quantities by a naive host. At least five distinct pathotypes of intestinal pathogenic E. coli exist: (1) Shiga toxin–producing E. coli (STEC), which includes the subsets of enterohemorrhagic E. coli (EHEC) and the recently evolved Shiga toxin–producing enteroaggregative E. coli (STEAEC); (2) enterotoxigenic E. coli (ETEC); (3) enteropathogenic


InternalMed_Harrison

InternalMed_Harrison. E. coli (EPEC); (4) enteroinvasive E. coli (EIEC); and (5) enteroaggregative E. coli (EAEC). Diffusely adherent E. coli (DAEC) and cytodetaching E. coli are additional putative pathotypes. Lastly, a variant termed adherent invasive E. coli (AIEC) has been associated with Crohn’s disease (although a causal role remains unproven) but does not cause acute diarrheal disease. Transmission occurs predominantly via contaminated food and water for ETEC, STEC/EHEC/STEAEC, EIEC, and EAEC and by person-to-person spread for EPEC (and occasionally STEC/EHEC/STEAEC). Gastric acidity confers some protection against infection; therefore, persons with decreased stomach acid levels are especially susceptible. Humans are the major reservoir (except for STEC/EHEC, with regard to which bovines are the main concern); host range appears to be dictated by species-specific attachment factors. Although there is some overlap, each pathotype possesses a largely unique combination of virulence traits that results


InternalMed_Harrison

InternalMed_Harrison. host range appears to be dictated by species-specific attachment factors. Although there is some overlap, each pathotype possesses a largely unique combination of virulence traits that results in a distinctive intestinal pathogenic mechanism (Table 186-2). These strains are largely incapable of causing disease outside the 1030 intestinal tract. Except in the cases of STEC/EHEC/STEAEC and EAEC, disease due to this group of pathogens occurs primarily in developing countries.


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InternalMed_Harrison. enteroHemorrHagic e. coli/sHiga toXin–prodUcing enteroaggregative e. coli STEC/EHEC/STEAEC strains constitute an emerging group of pathogens that can cause hemorrhagic colitis and the hemolytic-uremic syndrome (HUS). Several large outbreaks resulting from the consumption of fresh produce (e.g., lettuce, spinach, sprouts) and of undercooked ground beef have received significant attention in the media. An outbreak in central Europe in 2011 due to STEAEC (O104:H4) that was probably transmitted by sprouts, with some subsequent human-to-human transmission, resulted in more than 800 cases of HUS and 54 deaths. Within this group of organisms, O157:H7 is the most prominent serotype, but many other serotypes have also been associated with these syndromes, including O6, O26, O45, O55, O91, O103, O111, O113, O121, O145, and OX3.


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InternalMed_Harrison. The ability of STEC/EHEC/STEAEC to produce Shiga toxin (Stx2 and/or Stx1) or related toxins is a critical factor in the occurrence of clinical disease. Shigella dysenteriae strains that produce the closely related Shiga toxin Stx can cause the same syndrome. Stx2 and its Stx2C variant (which may be variably present in combination with Stx2 and/or Stx1) appear to be more important than Stx1 in the development of HUS. All Shiga toxins studied to date are multimers comprising one enzymatically active A subunit and five identical B subunits that mediate binding to globosyl ceramides, which are membrane-associated glycolipids expressed on certain host cells. As in ricin, the A subunit cleaves an adenine from the host cell’s 28S rRNA, thereby irreversibly inhibiting ribosomal function and potentially leading to apoptosis. Stx2-mediated activation of complement may also play a role in the development of HUS.


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InternalMed_Harrison. Additional properties, such as acid tolerance and epithelial cell adherence, are necessary for full pathogenicity among STEC strains. Most disease-causing isolates possess the chromosomal locus for enterocyte effacement (LEE). This pathogenicity island was first described in EPEC strains and contains genes that mediate adherence to intestinal epithelial cells and a system that subverts host cells by the translocation of bacterial proteins (type III secretion system). EHEC strains make up the subgroup of STEC strains that possess stx1 and/ or stx2 as well as LEE. STEAEC (LEE-negative) evolved from EAEC via the acquisition of a number of genes, including those that encode Stx2, the Iha adhesin, tellurite resistance, a type VI secretion system, and the CTX-M-15 ESBL.


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InternalMed_Harrison. Domesticated ruminant animals, particularly cattle and young calves, serve as the major reservoir for STEC/EHEC. Ground beef—the most common food source of STEC/EHEC strains—is often contaminated during processing. Furthermore, manure from cattle or other animals (including that in the form of fertilizer) can contaminate produce (potatoes, lettuce, spinach, sprouts, fallen fruits, nuts, strawberries), and fecal runoff from this source can contaminate water systems. Dairy products and petting zoos are additional sources of infection. By contrast, humans appear to be the reservoir for STEAEC. It is estimated that <102 colony-forming units (CFU) of STEC/EHEC/STEAEC can cause disease. Therefore, not only can low levels of food or environmental contamination (e.g., in water swallowed while swimming) result in disease, but person-to-person transmission (e.g., at day-care centers and in institutions) is an important route for secondary spread. Laboratory-associated infections also occur.


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InternalMed_Harrison. swimming) result in disease, but person-to-person transmission (e.g., at day-care centers and in institutions) is an important route for secondary spread. Laboratory-associated infections also occur. Illness due to this group of pathogens occurs both as outbreaks and as sporadic cases, with a peak incidence in the summer months.


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InternalMed_Harrison. In contrast to other intestinal pathotypes, STEC/EHEC/ STEAEC causes infections more frequently in industrialized countries than in developing regions. O157:H7 strains are the fourth most commonly reported cause of bacterial diarrhea in the United States (after Campylobacter, Salmonella, and Shigella). Colonization of the colon and perhaps the ileum results in symptoms after an incubation period of 3 or 4 days. Colonic edema and an initial nonbloody secretory diarrhea may develop into the STEC/EHEC/ STEAEC hallmark syndrome of grossly bloody diarrhea (identified by history or examination) in >90% of cases. Significant abdominal pain and fecal leukocytes are common (70% of cases), whereas fever is not; absence of fever can incorrectly lead to consideration of noninfectious conditions (e.g., intussusception and inflammatory or ischemic bowel disease). Occasionally, infections caused by C. difficile, K. oxytoca (see “Klebsiella Infections,” below), Campylobacter, and Salmonella present


InternalMed_Harrison

InternalMed_Harrison. intussusception and inflammatory or ischemic bowel disease). Occasionally, infections caused by C. difficile, K. oxytoca (see “Klebsiella Infections,” below), Campylobacter, and Salmonella present in a similar fashion. STEC/EHEC disease is usually self-limited, lasting 5–10 days. An uncommon but feared complication of this infection is HUS, which occurs 2–14 days after diarrhea in 2–8% of cases, most often affecting very young or elderly patients. Distinctive features of STEAEC infection, as compared with classical STEC/EHEC disease, include a higher incidence among adults, especially young women, and a higher rate of HUS (~20%). It is estimated that >50% of all cases of HUS in the United States and 90% of HUS cases in children are caused by STEC/EHEC. This complication is mediated by the systemic translocation of Shiga toxins. Erythrocytes may serve as carriers of Stx to endothelial cells located in the small vessels of the kidney and brain. The subsequent development of thrombotic


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InternalMed_Harrison. systemic translocation of Shiga toxins. Erythrocytes may serve as carriers of Stx to endothelial cells located in the small vessels of the kidney and brain. The subsequent development of thrombotic microangiopathy (perhaps with direct toxin-mediated effects on various nonendothelial cells) commonly produces some combination of fever, thrombocytopenia, renal failure, and encephalopathy. Although the mortality rate with dialysis support is <10%, residual renal and neurologic dysfunction may persist.


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InternalMed_Harrison. enterotoXigenic e. coli In tropical or developing countries,


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InternalMed_Harrison. ETEC is a major cause of endemic diarrhea. After weaning, children in these locales commonly experience several episodes of ETEC infection during the first 3 years of life. The incidence of disease diminishes with age, a pattern that correlates with the development of mucosal immunity to colonization factors (i.e., adhesins). In industrialized countries, infection usually follows travel to endemic areas, although occasional food-borne outbreaks occur. ETEC is the most common agent of traveler’s diarrhea, causing 25–75% of cases. The incidence of infection may be decreased by prudent avoidance of potentially contaminated fluids and foods, particularly items that are poorly cooked, unpeeled, or unrefrigerated (Chap. 149). ETEC infection is uncommon in the United States, but outbreaks secondary to consumption of food products imported from endemic areas have occurred. A large inoculum (106–1010 CFU) is needed to produce disease, which usually develops after an incubation period of 12–72


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InternalMed_Harrison. to consumption of food products imported from endemic areas have occurred. A large inoculum (106–1010 CFU) is needed to produce disease, which usually develops after an incubation period of 12–72 h.


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InternalMed_Harrison. After adherence of ETEC via colonization factors (e.g., CFA/I, CS1-6), disease is mediated primarily by a heat-labile toxin (LT-1) and/ or a heat-stable toxin (STa) that causes net fluid secretion via activation of adenylate cyclase (LT-1) and/or guanylate cyclase (STa) in the jejunum and ileum. The result is watery diarrhea accompanied by cramps. LT-1 consists of an A and a B subunit and is structurally and functionally similar to cholera toxin. Strong binding of the B subunit to the GM1 ganglioside on intestinal epithelial cells leads to the intracellular translocation of the A subunit, which functions as an ADPribosyltransferase. Mature STa is an 18or 19-amino-acid secreted peptide whose biologic activity is mediated by binding to the guanylate cyclase C found in the brush-border membrane of enterocytes and results in increased intracellular concentrations of cyclic GMP. Characteristically absent in ETEC-mediated disease are histopathologic changes within the small bowel; mucus,


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InternalMed_Harrison. of enterocytes and results in increased intracellular concentrations of cyclic GMP. Characteristically absent in ETEC-mediated disease are histopathologic changes within the small bowel; mucus, blood, and inflammatory cells in stool; and fever. The disease spectrum ranges from a mild illness to a life-threatening cholera-like syndrome. Although symptoms are usually self-limited (typically lasting for 3 days), infection may result in significant morbidity and mortality (mostly from profound volume depletion) when access to health care or suitable rehydration fluids is limited and when small and/or undernourished children are affected.


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InternalMed_Harrison. enteropatHogenic e. coli EPEC causes disease primarily in young children, including neonates. The first E. coli pathotype recognized as an agent of diarrheal disease, EPEC was responsible for outbreaks of infantile diarrhea (including some outbreaks in hospital nurseries) in industrialized countries in the 1940s and 1950s. At present, EPEC infection is an uncommon cause of diarrhea in developed countries but is an important cause of diarrhea (both sporadic and epidemic) among infants in developing countries. Breast-feeding diminishes the incidence of EPEC infection. Rapid person-to-person spread may occur. Upon colonization of the small bowel, symptoms develop after a brief incubation period (1 or 2 days). Initial localized adherence via bundle-forming pili leads to a characteristic effacement of microvilli, with the formation of cuplike, actin-rich pedestals mediated by factors in the LEE. Diarrhea production is a complex and regulated process in which host cell modulation by a type


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InternalMed_Harrison. of microvilli, with the formation of cuplike, actin-rich pedestals mediated by factors in the LEE. Diarrhea production is a complex and regulated process in which host cell modulation by a type III secretion system plays an important role. Strains lacking bundle-forming pili have been categorized as atypical EPEC (aEPEC); increasing data support a role for these strains as intestinal pathogens. Diarrheal stool often contains mucus but not blood. Although EPEC diarrhea is usually self-limited (lasting 5–15 days), it may persist for weeks.


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InternalMed_Harrison. enteroinvasive e. coli EIEC, a relatively uncommon cause of diarrhea, is rarely identified in the United States, although a few food-related outbreaks have been described. In developing countries, sporadic disease is infrequently recognized in children and travelers. EIEC shares many genetic and clinical features with Shigella, both of which evolved from a common ancestor. However, unlike Shigella, EIEC produces disease only with a large inoculum (108–1010 CFU), with onset generally following an incubation period of 1–3 days. Initially, enterotoxins are believed to induce secretory small-bowel diarrhea. Subsequently, colonization and invasion of the colonic mucosa, followed by replication therein and cell-to-cell spread, result in the development of inflammatory colitis characterized by fever, abdominal pain, tenesmus, and scant stool containing mucus, blood, and inflammatory cells. Symptoms are usually self-limited (7–10 days).


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InternalMed_Harrison. enteroaggregative and diffUsely adHerent e. coli EAEC has young children. However, recent studies indicate that it may be a relatively common cause of diarrhea in all age groups in industrialized countries. EAEC has also been recognized increasingly as an important cause of traveler’s diarrhea. It is highly adapted to humans, the probable reservoir. A large inoculum is required for infection, which usually manifests as watery and sometimes persistent diarrhea in healthy, malnourished, and HIV-infected hosts. In vitro, the organisms exhibit a diffuse or “stacked-brick” pattern of adherence to small-intestine epithelial cells. Virulence factors that probably are necessary for disease are regulated in part by the transcriptional activator AggR and include the aggregative adherence fimbriae (AAF/I-III); the Hda adhesin; the mucinase Pic; the enterotoxins Pet, EAST-1, ShET1, and HlyE; and dispersin, an antiaggregation protein that promotes mucosal spread. Some strains of DAEC are capable


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InternalMed_Harrison. (AAF/I-III); the Hda adhesin; the mucinase Pic; the enterotoxins Pet, EAST-1, ShET1, and HlyE; and dispersin, an antiaggregation protein that promotes mucosal spread. Some strains of DAEC are capable of causing diarrheal disease, primarily in children 2–6 years of age in some developing countries, and may perhaps cause traveler’s diarrhea. The Afa/Dr adhesins may contribute to the pathogenesis of such infections.


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InternalMed_Harrison. Diagnosis A practical approach to the evaluation of diarrhea is to distinguish noninflammatory from inflammatory cases; the latter is suggested by grossly bloody or mucoid stool or a positive test for fecal leukocytes (Chap. 160). ETEC, EPEC, and DAEC cause noninflammatory diarrhea and are uncommon in the United States; in this country, the incidence of EAEC infection, which also causes noninflammatory diarrhea, may be underrecognized. The diagnosis of these infections requires specialized assays (e.g., polymerase chain reaction–based tests for pathotype-specific genes) that are not routinely available and are rarely needed because the diseases are self-limited. ETEC causes the majority and EAEC a minority of cases of noninflammatory traveler’s diarrhea. Definitive diagnosis generally is not necessary. Empirical antimicrobial (or symptom-based) treatment, along with rehydration therapy, is a reasonable approach. If diarrhea persists for >10 days despite treatment, Giardia or


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InternalMed_Harrison. is not necessary. Empirical antimicrobial (or symptom-based) treatment, along with rehydration therapy, is a reasonable approach. If diarrhea persists for >10 days despite treatment, Giardia or Cryptosporidium (or, in immunocompromised hosts, certain other microbial agents) should be sought. The diagnosis of infection with EIEC, a rare cause of inflammatory diarrhea in the United States, also requires specialized assays. The CDC now recommends that all patients with community-acquired diarrhea, whether inflammatory or not, be evaluated for STEC/EHEC/STEAEC infection by simultaneous culture (which is important for outbreak detection and control) and assay for the detection of Shiga toxin or its associated genes. The reasons for this recommendation are that bloody stool is not always present and detection of fecal white blood cells is 1031 not optimally sensitive for the diagnosis of STEC/EHEC/STEAEC infection. The use of both tests increases the rate of identification of infection over


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InternalMed_Harrison. and detection of fecal white blood cells is 1031 not optimally sensitive for the diagnosis of STEC/EHEC/STEAEC infection. The use of both tests increases the rate of identification of infection over rates obtained with either test alone. O157 STEC/EHEC may be identified via culture by screening for E. coli strains that do not ferment sorbitol, with subsequent serotyping and testing for Shiga toxin. Selective or screening media are not available for the culture of non-O157 strains. Detection of Shiga toxins or toxin genes via DNA-based, enzyme-linked immunosorbent, and cytotoxicity assays offers the advantages of rapidity plus detection of non-O157 STEC/EHEC/ STEAEC strains. Specimens positive for toxin but culture-negative for O157 should be forwarded to the local or state public health laboratory.


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InternalMed_Harrison. TREATMEnT intestinal e. coli infections (See also Chap. 128) The mainstay of treatment for all diarrheal syndromes is replacement of water and electrolytes. This measure is especially important for STEC/EHEC/STEAEC infection because appropriate volume expansion may decrease renal damage and improve outcome. The use of prophylactic antibiotics to prevent traveler’s diarrhea generally should be discouraged, especially in light of high rates of antimicrobial resistance. However, in selected patients (e.g., those who cannot afford a brief illness or are predisposed to infection), the use of rifaximin, which is nonabsorbable and is well tolerated, is reasonable. When stools are free of mucus and blood, early patient-initiated treatment of traveler’s diarrhea with a fluoroquinolone or azithromycin decreases the duration of illness, and the use of loperamide may halt symptoms within a few hours. Although dysentery caused by EIEC is self-limited, treatment hastens the resolution of symptoms,


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InternalMed_Harrison. decreases the duration of illness, and the use of loperamide may halt symptoms within a few hours. Although dysentery caused by EIEC is self-limited, treatment hastens the resolution of symptoms, particularly in severe cases. In contrast, antimicrobial therapy for STEC/ EHEC/STEAEC infection (the presence of which is suggested by grossly bloody diarrhea without fever) should be avoided because antibiotics may increase the incidence of HUS (possibly via increased production/ release of Stx). The role of plasmapheresis and inhibition of C5 (eculizumab) in the treatment of HUS is unresolved.


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InternalMed_Harrison. K. pneumoniae is the most important Klebsiella species from a medical standpoint, causing community-acquired, LTCF-acquired, and nosocomial infections. K. oxytoca is primarily a pathogen in LTCF and hospital settings. Klebsiella species are broadly prevalent in the environment and colonize mucosal surfaces of mammals. In healthy humans, the prevalence of K. pneumoniae colonization is 5–35% in the colon and 1–5% in the oropharynx; the skin is usually colonized only transiently. Person-to-person spread is the predominant mode of acquisition. Most Klebsiella infections in Western countries are caused by “classic” K. pneumoniae (cKP) and occur in hospitals and LTCFs. The most common clinical syndromes due to cKP are pneumonia, UTI, abdominal infection, intravascular device infection, surgical site infection, soft tissue infection, and subsequent bacteremia. cKP strains have gained notoriety because their propensity for acquiring antimicrobial resistance determinants makes treatment


InternalMed_Harrison

InternalMed_Harrison. site infection, soft tissue infection, and subsequent bacteremia. cKP strains have gained notoriety because their propensity for acquiring antimicrobial resistance determinants makes treatment challenging. Clonal group ST258, many members of which produce the KPC carbapenemase, is undergoing international dissemination. The spread of NDM-1 carbapenemase-producing strains from India in association with medical tourism has captured the attention of physicians and the lay press.


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InternalMed_Harrison. cKP strains appear to be phenotypically and clinically distinct from hypervirulent K. pneumoniae (hvKP), an emerging variant that was first recognized in Taiwan in 1986. Although hvKP infections have occurred globally in all ethnic groups, the majority have been reported in the Asian Pacific Rim. This concentration of cases raises the question of whether a geo-specific distribution of the organism or increased susceptibility of Asian hosts is responsible. In contrast to the usual health care–associated venue for cKP infections in the West, hvKP causes serious lifeand organ-threatening infections in younger, healthy individuals from the community and can spread metastatically 1032 from primary sites of infection. hvKP infection initially was characterized and distinguished from traditional infections due to cKP by presentation as community-acquired pyogenic liver abscess (Fig. 186-1, top), (2) occurrence in patients lacking a history of hepatobiliary disease, and (3) a propensity for


InternalMed_Harrison

InternalMed_Harrison. infections due to cKP by presentation as community-acquired pyogenic liver abscess (Fig. 186-1, top), (2) occurrence in patients lacking a history of hepatobiliary disease, and (3) a propensity for metastatic spread to distant sites (e.g., eyes, central nervous system, lungs), which occurred in 11–80% of cases. More recently, this variant has been recognized as the cause of a variety of serious community-acquired extrahepatic abscesses/ infections in the absence of liver involvement, including pneumonia, meningitis, endophthalmitis (Fig. 186-1, middle), splenic abscess, and necrotizing fasciitis. The affected individuals often have diabetes mellitus and are of Asian ethnicity; however, nondiabetics and all ethnic groups can be affected. Survivors often suffer catastrophic morbidity, such as loss of vision and neurologic sequelae.


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InternalMed_Harrison. K. pneumoniae subspecies rhinoscleromatis is the causative agent of rhinoscleroma, a granulomatous mucosal upper respiratory infection that progresses slowly (over months or years) and causes necrosis and occasionally obstruction of the nasal passages. K. pneumoniae subspecies ozaenae has been implicated as a cause of chronic atrophic rhinitis and rarely of invasive disease in compromised hosts. These two K. pneumoniae subspecies are usually isolated from patients in tropical climates and are genomically distinct from both cKP and hvKP.


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InternalMed_Harrison. INFECTIOuS SYNDROMES Pneumonia Although cKP accounts for only a small proportion of cases of community-acquired pneumonia in Western countries (Chap. 153), cKP and K. oxytoca are common causes of pneumonia among LTCF residents and hospitalized patients because of increased rates of oropharyngeal colonization. Mechanical ventilation is an important risk factor. In Asia and South Africa, community-acquired pneumonia due to hvKP is becoming increasingly common and often occurs in younger patients with no underlying disease. Klebsiella is also a common cause of pneumonia in severely malnourished children in developing countries.


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InternalMed_Harrison. As in all pneumonias due to enteric GNB, production of purulent sputum and evidence of airspace disease are typical. Presentation with earlier, less extensive infection is now more common than that with the classically described lobar infiltrate and bulging fissure. Pulmonary infection due to hvKP that has spread metastatically (e.g., from a hepatic abscess) usually includes nodular bilateral densities, more commonly in the lower lobes. Pulmonary necrosis, pleural effusion, and empyema can occur with disease progression. uTI cKP accounts for only 1–2% of UTI episodes among otherwise healthy adults but for 5–17% of episodes of complicated UTI, including infections associated with indwelling urinary catheters. UTI due to hvKP presents more commonly as renal or prostatic abscess due to bacteremic spread than as ascending infection.


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InternalMed_Harrison. Abdominal Infection cKP causes a spectrum of abdominal infections similar to that caused by E. coli but is less frequently isolated from these infections. hvKP is a common cause of monomicrobial community-acquired pyogenic liver abscess and in the Asian Pacific Rim has been recovered with steadily increasing frequency over the past two decades, replacing E. coli as the most common pathogen causing this syndrome. hvKP is increasingly described as a cause of spontaneous bacterial peritonitis and splenic abscess.


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InternalMed_Harrison. Other Infections cKPand K. oxytoca–mediated cellulitis or soft tissue infection most frequently affects devitalized tissue (e.g., decubitus and diabetic ulcers, burn sites) and immunocompromised hosts. cKP and K. oxytoca cause some cases of surgical site infection and nosocomial sinusitis in addition to occasional cases of osteomyelitis contiguous to soft tissue infection, nontropical myositis, and meningitis (both during the neonatal period and after neurosurgery). By contrast, hvKP has become an important cause of community-acquired


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InternalMed_Harrison. FIGuRE 186-1 New hypervirulent variant of K. pneumoniae (hvKP). Top: Abdominal CT scan of a previously healthy 24-year-old Vietnamese man shows a primary liver abscess (red arrow) with metastatic spread to the spleen (black arrow). (Courtesy of Drs. Chiu-Bin Hsaio and Diana Pomakova.) Middle: A previously healthy 33-year-old Chinese man presented with endophthalmitis. (From Virulence 4:2, 1-12 Feb. 15, 2013.) Bottom: A hypermucoviscous phenotype (which does not necessarily equate with a mucoid phenotype) has been associated with hvKP strains. This phenotype has been semiquantitatively defined by a positive “string test” (formation of a viscous string >5 mm long when bacterial colonies on an agar plate are stretched by an inoculation loop). (Courtesy of Dr. Russo.) monomicrobial necrotizing fasciitis; meningitis; brain, subdural, and epidural abscess; and endophthalmitis (Fig. 186-1, middle), particularly in the Asian Pacific Rim but also globally. Cytotoxin-producing strains of K.


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InternalMed_Harrison. fasciitis; meningitis; brain, subdural, and epidural abscess; and endophthalmitis (Fig. 186-1, middle), particularly in the Asian Pacific Rim but also globally. Cytotoxin-producing strains of K. oxytoca have been implicated as a cause of hemorrhagic antibiotic-associated non–C. difficile colitis.


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InternalMed_Harrison. Bacteremia Klebsiella infection at any site can produce bacteremia. Infections of the urinary tract, respiratory tract, and abdomen (especially hepatic abscess) each account for 15–30% of episodes of Klebsiella bacteremia. Intravascular device–related infections account for another 5–15% of episodes, and surgical site and miscellaneous infections account for the rest. Klebsiella is a cause of sepsis in neonates and of bacteremia in neutropenic patients. Like enteric GNB in general, Klebsiella rarely causes endocarditis or endovascular infection. Klebsiellae are readily isolated and identified in the laboratory. These organisms usually ferment lactose, although the subspecies rhinoscleromatis and ozaenae are nonfermenters and are indole negative. hvKP usually possesses a hypermucoviscous phenotype (Fig. 186-1, bottom), although the sensitivity and specificity of this test are undefined and probably less than optimal. A better diagnostic test for hvKP is desirable.


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InternalMed_Harrison. cKP and K. oxytoca have similar antibiotic resistance profiles. These species are intrinsically resistant to ampicillin and ticarcillin, and nitrofurantoin is inconsistently active against them. NHSN data for 2009–2010 documented resistance to thirdand fourth-generation cephalosporins in 28.9% of CLABSI isolates of cKP and K. oxytoca, and INICC data for 2004–2009 identified resistance to third-generation cephalosporins in 76.3% of ICU isolates of K. pneumoniae. This increasing resistance is mediated primarily by plasmid-encoded ESBLs. In addition, such plasmids usually encode resistance to aminoglycosides, tetracyclines, and TMP-SMX. Furthermore, isolates of cKP that produce CTX-M ESBLs have been obtained from ambulatory patients with no recent health care contact (see the section on the treatment of extraintestinal E. coli infections for treatment considerations). Resistance to β-lactam/β-lactamase inhibitor combinations and cephamycins independent of ESBL-encoding plasmids has also


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InternalMed_Harrison. treatment of extraintestinal E. coli infections for treatment considerations). Resistance to β-lactam/β-lactamase inhibitor combinations and cephamycins independent of ESBL-encoding plasmids has also been described with increasing frequency, particularly in Latin America. The prevalence of fluoroquinolone resistance is 15–20% overall and is 50% among ESBL-containing strains. Given both the undesirability of treating the latter strains with penicillins or cephalosporins and the fluoroquinolone resistance often associated with ESBLs, empirical treatment of serious or health care–associated cKP and K. oxytoca infections with amikacin or carbapenems is prudent, as dictated by local susceptibilities. Predictably, however, the ESBL-driven use of carbapenems has selected for strains of cKP and


InternalMed_Harrison

InternalMed_Harrison. K. oxytoca that express carbapenemases. NHSN data for 2009–2010 documented resistance to carbapenems in 12.8% of CLABSI isolates of cKP and K. oxytoca. Treatment of infections due to strains that produce carbapenemases is highly challenging; increasingly, these strains are nearly pan-resistant. The optimal choice for therapy is unclear. Tigecycline and the polymyxins (e.g., colistin) are the most active agents in vitro and are used most frequently. However, resistance to these agents is already emerging, and strains of cKP resistant to all known antimicrobial agents have been described in the United States and globally. Combination therapy is often used in this setting.


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InternalMed_Harrison. Proteus mirabilis causes 90% of Proteus infections, which occur in the community, LTCFs, and hospitals. Proteus vulgaris and Proteus penneri are associated primarily with infections acquired in LTCFs or hospitals. Proteus species are part of the colonic flora of a wide variety of mammals, birds, fish, and reptiles. The ability of these GNB to generate histamine from contaminated fish has implicated them in the pathogenesis of 1033 scombroid (fish) poisoning (Chap. 474). P. mirabilis colonizes healthy humans (prevalence, 50%), whereas P. vulgaris and P. penneri are isolated primarily from individuals with underlying disease. The urinary tract is by far the most common site of Proteus infection, with adhesins, flagella, IgA-IgG protease, iron acquisition systems, and urease representing the principal known urovirulence factors. Proteus less commonly causes infection at a variety of other extraintestinal sites.


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InternalMed_Harrison. INFECTIOuS SYNDROMES uTI Most Proteus infections arise from the urinary tract. P. mirabilis causes only 1–2% of UTIs in healthy women, and Proteus species collectively cause only 5% of hospital-acquired UTIs. However, Proteus is responsible for 10–15% of cases of complicated UTI, primarily those associated with catheterization; indeed, among UTI isolates from chronically catheterized patients, the prevalence of Proteus is 20–45%. This high prevalence is due in part to bacterial production of urease, which hydrolyzes urea to ammonia and results in alkalization of the urine. Alkalization of urine, in turn, leads to precipitation of organic and inorganic compounds, which contributes to formation of struvite and carbonate-apatite crystals, formation of biofilms on catheters, and/or development of frank calculi. Proteus becomes associated with the stones and biofilms; thereafter, it usually can be eradicated only by removal of the stones or the catheter. Over time, staghorn calculi may


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InternalMed_Harrison. of frank calculi. Proteus becomes associated with the stones and biofilms; thereafter, it usually can be eradicated only by removal of the stones or the catheter. Over time, staghorn calculi may form within the renal pelvis and lead to obstruction and renal failure. Thus, urine samples with unexplained alkalinity should be cultured for Proteus, and identification of a Proteus species in urine should prompt consideration of an evaluation for urolithiasis.


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InternalMed_Harrison. Other Infections Proteus occasionally causes pneumonia (primarily in LTCF residents or hospitalized patients), nosocomial sinusitis, intraabdominal abscesses, biliary tract infection, surgical site infection, soft tissue infection (especially decubitus and diabetic ulcers), and osteomyelitis (primarily contiguous); in rare cases, it causes nontropical myositis. In addition, Proteus uncommonly causes neonatal meningitis, with the umbilicus frequently implicated as the source; this disease is often complicated by development of a cerebral abscess. Otogenic brain abscess also occurs. Bacteremia The majority of Proteus bacteremia episodes originate from the urinary tract; however, any of the less common sites of infection as well as intravascular devices are also potential sources. Endovascular infection is rare. Proteus species are occasional agents of sepsis in neonates and of bacteremia in neutropenic patients.


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InternalMed_Harrison. Proteus is readily isolated and identified in the laboratory. Most strains are lactose negative, produce H2S, and demonstrate characteristic swarming motility on agar plates. P. mirabilis and P. penneri are indole negative, whereas P. vulgaris is indole positive. The inability to produce ornithine decarboxylase differentiates P. penneri from P. mirabilis.


InternalMed_Harrison

InternalMed_Harrison. P. mirabilis is usually susceptible to most antimicrobial agents except tetracycline, nitrofurantoin, the polymyxins, and tigecycline. Resistance to ampicillin and first-generation cephalosporins has been acquired by 10–50% of strains. Overall, 10–15% of P. mirabilis isolates are resistant to fluoroquinolones; 5% of isolates in the United States now produce ESBLs. Furthermore, isolates of P. mirabilis that produce CTX-M ESBLs have been recovered from ambulatory patients with no recent health care contact (see the section on the treatment of extraintestinal E. coli infections for treatment considerations). P. vulgaris and P. penneri exhibit more extensive drug resistance than does P. mirabilis. Resistance to ampicillin and first-generation cephalosporins is the rule, and 30–40% of isolates are resistant to fluoroquinolones. Induction or selection of variants with stable derepression of chromosomal AmpC β-lactamase may 1034 occur with P. vulgaris isolates. Carbapenems, fourth-generation


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InternalMed_Harrison. are resistant to fluoroquinolones. Induction or selection of variants with stable derepression of chromosomal AmpC β-lactamase may 1034 occur with P. vulgaris isolates. Carbapenems, fourth-generation cephalosporins (e.g., cefepime), amikacin, TMP-SMX, and fosfomycin display excellent activity against Proteus species (90–100% of isolates susceptible).


InternalMed_Harrison

InternalMed_Harrison. E. cloacae and E. aerogenes are responsible for most Enterobacter infections (65–75% and 15–25%, respectively); Cronobacter sakazakii (formerly Enterobacter sakazakii) and Enterobacter gergoviae are less commonly isolated (1% for each). Enterobacter species cause primarily health care–related infections. The organisms are widely prevalent in foods, environmental sources (including equipment at health care facilities), and a variety of animals. Few healthy humans are colonized, but the percentage increases significantly with LTCF residence or hospitalization. Although colonization is an important prelude to infection, direct introduction via IV lines (e.g., contaminated IV fluids or pressure monitors) also occurs. Extensive antibiotic resistance has developed in Enterobacter species and probably has contributed to the emergence of the organisms as prominent nosocomial pathogens. Individuals who have previously received antibiotic treatment, have comorbid disease, and are ICU residents


InternalMed_Harrison

InternalMed_Harrison. has contributed to the emergence of the organisms as prominent nosocomial pathogens. Individuals who have previously received antibiotic treatment, have comorbid disease, and are ICU residents are at greatest risk for infection. Enterobacter causes a spectrum of extraintestinal infections similar to that described for other GNB.


InternalMed_Harrison

InternalMed_Harrison. Pneumonia, UTI (particularly catheter-related), intravascular device– related infection, surgical site infection, and abdominal infection (primarily postoperative or related to devices such as biliary stents) are the most common syndromes encountered. Nosocomial sinusitis, meningitis related to neurosurgical procedures (including use of intra-cranial pressure monitors), osteomyelitis, and endophthalmitis after eye surgery are less frequent. C. sakazakii is associated with neonatal bacteremia, necrotizing enterocolitis, and meningitis (which is often complicated by brain abscess or ventriculitis); contaminated formula has been implicated as a source for such infections. Enterobacter bacteremia can result from infection at any anatomic site. In bacteremia of unclear origin, the contamination of IV fluids or medications, blood components or plasma derivatives, catheter-flushing fluids, pressure monitors, and dialysis equipment should be considered, particularly in an outbreak setting.


InternalMed_Harrison

InternalMed_Harrison. of IV fluids or medications, blood components or plasma derivatives, catheter-flushing fluids, pressure monitors, and dialysis equipment should be considered, particularly in an outbreak setting. Enterobacter can also cause bacteremia in neutropenic patients. Enterobacter endocarditis is rare, occurring primarily in association with illicit IV drug use or prosthetic valves.


InternalMed_Harrison

InternalMed_Harrison. Enterobacter is readily isolated and identified in the laboratory. Most strains are lactose positive and indole negative.


InternalMed_Harrison

InternalMed_Harrison. Enterobacter strains. Ampicillin and firstand second-gener ation cephalosporins have little or no activity. Extensive use of third-generation cephalosporins can induce or select for variants with stable derepression of AmpC β-lactamase, which confers resistance to these agents as well as monobactams (e.g., aztreonam) and—in many cases—β-lactam/β-lactamase inhibitor combinations. Resistance may emerge during therapy; in one study, this phenomenon was documented in 20% of clinical isolates. De novo resistance should be considered when clinical deterioration follows initial improvement, and third-generation cephalosporins should be avoided in the treatment of serious Enterobacter infections. Cefepime is stable in the presence of AmpC β-lactamases; thus, it is a suitable option for treatment of Enterobacter infections so long as no coexistent ESBL is present. Detection of ESBLs in Enterobacter is difficult because of the presence of AmpC β-lactamase; nonetheless, their prevalence


InternalMed_Harrison

InternalMed_Harrison. of Enterobacter infections so long as no coexistent ESBL is present. Detection of ESBLs in Enterobacter is difficult because of the presence of AmpC β-lactamase; nonetheless, their prevalence (particularly in E. cloacae) is known to be variable worldwide but is generally increasing and is now 5–50% overall. This increase is evidenced by NHSN data, which documented resistance to thirdand fourth-generation cephalosporins in 37.4% of CLABSI Enterobacter isolates in the United States; fortunately, carbapenems, amikacin, and tigecycline have generally retained excellent activity (90–99% susceptibility) and fluoroquinolones have good activity (85–95% susceptibility). Once susceptibility data become available, it is critical to de-escalate the antimicrobial regimen whenever possible.


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InternalMed_Harrison. S. marcescens causes the majority (>90%) of Serratia infections; Serratia liquefaciens, Serratia rubidaea, Serratia fonticola, Serratia grimesii, Serratia plymuthica, and Serratia odorifera are isolated occasionally. Serratiae are found primarily in the environment (including in health care institutions), particularly in moist settings. Serratiae have been isolated from a variety of animals, insects, and plants, but healthy humans are rarely colonized. In LTCFs or hospitals, reservoirs for the organisms include the hands and fingernails of health care personnel, food, milk (on neonatal units), sinks, respiratory and other medical equipment or devices, pressure monitors, IV solutions or parenteral medications (particularly those generated by compounding pharmacies), prefilled syringes and multiple-access medication vials (e.g., heparin, saline), blood products (e.g., platelets), hand soaps and lotions, irrigation solutions, and even disinfectants. Infection results from either direct


InternalMed_Harrison

InternalMed_Harrison. multiple-access medication vials (e.g., heparin, saline), blood products (e.g., platelets), hand soaps and lotions, irrigation solutions, and even disinfectants. Infection results from either direct inoculation (e.g., via IV fluid) or colonization (primarily of the respiratory tract). Sporadic infection is most common, but epidemics (often involving MDR strains in adult and neonatal ICUs) and common-source outbreaks also occur. The spectrum of extraintestinal infections caused by Serratia is similar to that for other GNB. Serratia species are usually considered causative agents of health care– associated infection and account for 1–3% of hospital-acquired infections. However, population-based laboratory surveillance studies in Canada and Australia demonstrated that community-acquired infections occur more commonly than was previously appreciated.


InternalMed_Harrison

InternalMed_Harrison. The respiratory tract, the genitourinary tract, intravascular devices, the eye (contact lens–associated keratitis and other ocular infections), surgical wounds, and the bloodstream (from contaminated infusions) are the most common sites of Serratia infection; the former five sites are the most common sources of Serratia bacteremia. Soft tissue infections (including myositis, fasciitis, mastitis), osteomyelitis, abdominal and biliary tract infection (postprocedural), and septic arthritis (primarily from intraarticular injections) occur less commonly. Serratiae are uncommon causes of neonatal or postsurgical meningitis and of bacteremia in neutropenic patients. Endocarditis is rare. Serratiae are readily cultured and identified by the laboratory and are usually lactose and indole negative. Some S. marcescens strains and S. rubidaea are red pigmented.


InternalMed_Harrison

InternalMed_Harrison. Serratiae are readily cultured and identified by the laboratory and are usually lactose and indole negative. Some S. marcescens strains and S. rubidaea are red pigmented. Most Serratia strains (>80%) are resistant to ampicillin, amoxi cillin-clavulanate, ampicillin-sulbactam, first-generation cepha losporins, cephamycins, nitrofurantoin, and colistin. In general, >90% of Serratia isolates are susceptible to other antibiotics appropriate for use against GNB. Induction or selection of variants with stable derepression of chromosomal AmpC β-lactamases may develop during therapy. Both in the United States and globally, the prevalence of ESBL-producing isolates is generally low (<5%), but rates of 20–30% have been reported in Asia and Latin America. Acquisition of carbapenemase-encoding genes is uncommon but increasing.


InternalMed_Harrison

InternalMed_Harrison. C. freundii and Citrobacter koseri cause most human Citrobacter infections, which are epidemiologically and clinically similar to Enterobacter infections. Citrobacter species are commonly present in water, food, soil, and certain animals. Citrobacter is part of the normal fecal flora in a minority of healthy humans, but colonization rates are higher in LTCFs and hospitals—the settings in which nearly all Citrobacter infections occur. Citrobacter species account for 1–2% of nosocomial infections. The affected hosts are usually immunocompromised or have comorbid disease. Citrobacter causes extraintestinal infections similar to those described for other GNB.


InternalMed_Harrison

InternalMed_Harrison. The urinary tract accounts for 40–50% of Citrobacter infections. Less commonly involved sites include the biliary tree (particularly with stones or obstruction), the respiratory tract, surgical sites, soft tissue (e.g., decubitus ulcers), the peritoneum, and intravascular devices. Osteomyelitis (usually from a contiguous focus), adult central nervous system infection (from neurosurgical or other types of meningeal disruption), and myositis occur rarely. Citrobacter (primarily C. koseri) also causes 1–2% of neonatal meningitis cases, of which 50–80% are complicated by brain abscess. Further, case reports in adults suggest that C. koseri infection has a predilection for abscess formation. Bacteremia is most often due to UTI, biliary/abdominal infection, or intravascular device infection. Citrobacter occasionally causes bacteremia in neutropenic patients. Endocarditis and endovascular infections are rare.


InternalMed_Harrison

InternalMed_Harrison. Citrobacter species are readily isolated and identified; 35–50% of isolates are lactose positive, and 100% are oxidase negative. C. freundii is indole negative, whereas C. koseri is indole positive.


InternalMed_Harrison

InternalMed_Harrison. C. freundii is more extensively resistant to antibiotics than is C. koseri. More than 90% of isolates are resistant to ampicillin and firstand sec-ond-generation cephalosporins. Citrobacter species (except C. koseri) possess AmpC β-lactamases; induction or selection of variants with stable derepression may develop during therapy. Resistance to antipseudomonal penicillins, aztreonam, fluoroquinolones, gentamicin, and third-generation cephalosporins is variable but increasing. The prevalence of ESBL-producing isolates is <5%. Carbapenems, amikacin, cefepime, tigecycline (with which clinical experience is limited), fosfomycin (which is available in the United States only as an oral formulation), and colistin (which is an agent of last resort because of potential toxicities) are most active, with >90% of strains susceptible.


InternalMed_Harrison

InternalMed_Harrison. M. morganii, Providencia stuartii, and (less frequently) Providencia rettgeri are the members of their respective genera that cause human infections. The epidemiologic associations, pathogenic properties, and clinical manifestations of these organisms resemble those of Proteus species. However, Morganella and Providencia occur more commonly among LTCF residents; to a lesser degree, they affect hospitalized patients. In settings with extensive use of polymyxins and tigecycline, these organisms may become increasingly common because of their intrinsic resistance to these agents.


InternalMed_Harrison

InternalMed_Harrison. These species are primarily urinary tract pathogens, causing UTIs that are most often associated with long-term (>30-day) catheterization. Such infections commonly lead to biofilm formation and catheter encrustation (sometimes causing catheter obstruction) or to the development of struvite bladder or renal stones (sometimes causing renal obstruction and serving as foci for relapse). Morganella is also commonly isolated from snakebite infection. Other, less common infectious syndromes include surgical site infection, soft tissue infection (primarily involving decubitus and diabetic ulcers), burn site infection, pneumonia (particularly ventilator-associated), intravascular device infection, and intraabdominal infection. Rarely, the other extraintestinal infections described for GNB also occur. Bacteremia is uncommon; any infected site can serve as the source, but the urinary tract accounts for most cases, with the next most common sources 1035 being surgical site, soft tissue, and


InternalMed_Harrison

InternalMed_Harrison. occur. Bacteremia is uncommon; any infected site can serve as the source, but the urinary tract accounts for most cases, with the next most common sources 1035 being surgical site, soft tissue, and hepatobiliary infections.


InternalMed_Harrison

InternalMed_Harrison. M. morganii and Providencia are readily isolated and identified. Nearly all isolates are lactose negative and indole positive.


InternalMed_Harrison

InternalMed_Harrison. Morganella and Providencia may be extensively resistant to antibiotics. Most isolates are resistant to ampicillin, first- generation cephalosporins, nitrofurantoin, fosfomycin, tigecycline, and the polymyxins; 40% are resistant to fluoroquinolones. Morganella and Providencia possess inducible AmpC β-lactamases; clinically significant induction or selection of stably derepressed mutants may develop during therapy. Resistance to antipseudomonal penicillins, aztreonam, gentamicin, TMP-SMX, and secondand third-generation cephalosporins is emerging but is still variably prevalent. The β-lactamase inhibitor tazobactam increases susceptibility to β-lactam agents, but sulbactam and clavulanic acid do not. Carbapenems, amikacin, and cefepime are the most active agents (>90% of isolates susceptible); however, resistance to the carbapenems, when present, is a concern because of the inherent resistance of Morganella and Providencia to the polymyxins and tigecycline. Removal of a colonized


InternalMed_Harrison

InternalMed_Harrison. however, resistance to the carbapenems, when present, is a concern because of the inherent resistance of Morganella and Providencia to the polymyxins and tigecycline. Removal of a colonized catheter or stone is critical for eradication of UTI.


InternalMed_Harrison

InternalMed_Harrison. E. tarda is the only member of the genus Edwardsiella that is associated with human disease. This organism is found predominantly in freshwater and marine environments and in the associated aquatic animal species. Human acquisition occurs primarily during interaction with these reservoirs and ingestion of inadequately cooked aquatic animals. E. tarda infection is rare in the United States; recently reported cases are mostly from Southeast Asia. This pathogen shares clinical features with Salmonella species (as an intestinal pathogen; Chap. 190), Vibrio vulnificus (as an extraintestinal pathogen; Chap. 193) and Aeromonas hydrophila (as both an intestinal and extraintestinal pathogen; Chap. 183e).


InternalMed_Harrison

InternalMed_Harrison. Gastroenteritis is the predominant infectious syndrome (50–80% of infections). Self-limiting watery diarrhea is most common, but severe colitis also occurs. The most common extraintestinal infection is wound infection due to direct inoculation, which is often associated with freshwater, marine, or snake-related injuries. Other infectious syndromes result from invasion of the gastrointestinal tract and subsequent bacteremia. Most afflicted hosts have comorbidities (e.g., hepatobiliary disease, iron overload, cancer, or diabetes mellitus). A primary bacteremic syndrome, sometimes complicated by meningitis, has a 40% case-fatality rate. Visceral (primarily hepatic) and intra-peritoneal abscesses also occur. Endocarditis and empyema have been described. Although E. tarda can readily be isolated and identified, most laboratories do not routinely seek to identify it in stool samples. Production of hydrogen sulfide is a characteristic biochemical property.


InternalMed_Harrison

InternalMed_Harrison. E. tarda is susceptible to most antimicrobial agents appropriate for use against GNB. Gastroenteritis is generally self-limiting, but treatment with a fluoroquinolone may hasten resolution. In the setting 1036 of severe sepsis, fluoroquinolones, thirdand fourth-generation cephalosporins, carbapenems, and amikacin—either alone or in combination—are the safest choices pending susceptibility data. Species of Hafnia, Kluyvera, Cedecea, Pantoea, Ewingella, Leclercia, and Photorhabdus are occasionally isolated from diverse clinical specimens, including blood, sputum, urine, cerebrospinal fluid, joint fluid, bile, and wounds. These organisms are rare and usually cause infection in a compromised host or in the setting of an invasive procedure or a foreign body. Cephalosporinases from Kluyvera have been implicated as the progenitors of CTX-M ESBLs.


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InternalMed_Harrison. Acinetobacter Infections David L. Paterson, Anton Y. Peleg Infections with bacteria of the genus Acinetobacter are established as a significant problem worldwide. Acinetobacter baumannii is par-ticularly formidable because of its propensity to acquire antibiotic resistance determinants. Endemic infections caused by strains of 187 A. baumannii resistant to multiple antibiotic classes, including carbapenems, are a serious concern in many specialized hospital units, especially intensive care units (ICUs). The foremost implication of infection with carbapenem-resistant A. baumannii is the need to use “last-line” antibiotics such as colistin, polymyxin B, or tigecycline; these options have the potential to render these bacteria resistant to all available antibiotics.


InternalMed_Harrison

InternalMed_Harrison. Acinetobacter species are oxidase-negative, nonfermenting, short, gram-negative bacilli. They were traditionally thought of as nonmotile—a characteristic from which the genus name was derived (from the Greek akineto, meaning “nonmotile”). However, recent work has shown that Acinetobacter organisms demonstrate motility under certain growth conditions. The bacteria grow well at 37°C in aerobic conditions on a range of laboratory media (e.g., blood agar). Some species may not grow on MacConkey agar. Differentiation of Acinetobacter species is difficult with the means typically available to most clinical microbiology laboratories, including commercial semiautomated identification systems. The commonly used matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) systems are undergoing evaluation for species-level identification of Acinetobacter. DNA–DNA hybridization is a method used for speciation in reference laboratories. Naturally occurring


InternalMed_Harrison

InternalMed_Harrison. MS) systems are undergoing evaluation for species-level identification of Acinetobacter. DNA–DNA hybridization is a method used for speciation in reference laboratories. Naturally occurring oxacillinase genes (blaOXA) have been identified in several Acinetobacter species, and their detection by polymerase chain reaction can aid in species identification.


InternalMed_Harrison

InternalMed_Harrison. Widely distributed in nature, Acinetobacter species can be found in water, in soil, and on vegetables. Acinetobacter is a component of the human skin flora and is sometimes identified as a contaminant in blood samples collected for culture. Fecal carriage can be detected in both healthy and hospitalized individuals. However, despite the ubiquity of some Acinetobacter species, the natural habitat of the most clinically important species, A. baumannii, remains to be fully defined. A. baumannii infections have been diagnosed in patients on all inhabited continents. The vast majority of infections occur in hospitalized patients and other patients with significant health-care contact. Outbreaks of carbapenem-resistant A. baumannii are particularly problematic. A significant issue is the introduction of carbapenem-resistant A. baumannii into hospitals as a result of medical transfers, especially from hospitals where the organism is highly endemic.


InternalMed_Harrison

InternalMed_Harrison. The Americas In 1991 and 1992, outbreaks of carbapenem-resistant A. baumannii infection occurred in a hospital in New York City. Subsequently, numerous other hospitals in the United States and South America have had outbreaks of carbapenem-resistant A. baumannii. Infections with A. baumannii among military personnel from the United States and Canada injured in Iraq or Afghanistan were widely observed beginning in 2002. Acinetobacter was one of the most common causes of bloodstream infections and bone and soft tissue infections after war-related injury. An epidemiologic investigation revealed that A. baumannii could be grown from environmental sites in field hospitals and that the environmental strains were closely related genotypically to clinical isolates. Europe A. baumannii infections have posed a substantial clinical challenge in many parts of Europe since the early 1980s. Three clones (European clones I, II, and III) have been the predominant causes of


InternalMed_Harrison

InternalMed_Harrison. A. baumannii infection in hospitals in Europe. Carbapenem resistance in A. baumannii is a significant issue in many European countries, most notably the United Kingdom, Greece, Italy, Spain, and Turkey. Asia, Australia, the Middle East, and Africa Although surveillance data are sparse from many countries in these regions, problems with carbapenem-resistant A. baumannii abound. Community-acquired infections are well described in northern Australia and some parts of Asia. These infections may be more likely in men >45 years of age who have histories of cigarette smoking, alcoholism, diabetes mellitus, or chronic obstructive airway disease. Community-acquired strains are more susceptible to antimicrobial agents than are hospital-acquired strains, but the clinical presentation of community-acquired disease is quite distinct and is characterized by overwhelming infection with severe pneumonia, septic shock, and multiorgan failure.


InternalMed_Harrison

InternalMed_Harrison. A. baumannii colonizes patients exposed to heavily contaminated hospital environments or to the hands of health care workers in these locations. Emerging data suggest that the organism can be found in the air in rooms of patients infected with Acinetobacter. Colonization of the upper airways in mechanically ventilated patients may lead to nosocomial pneumonia. Colonization of the skin may lead to central line–associated bloodstream infection, catheter-associated urinary tract infection (UTI), wound infection, or postneurosurgical meningitis. Throat carriage and microaspiration may be involved in the pathogenesis of community-acquired pneumonia due to A. baumannii.


InternalMed_Harrison

InternalMed_Harrison. Much less is known about the virulence mechanisms of and host responses to A. baumannii than about these aspects of other pathogenic gram-negative bacteria. Because of the emergence of multidrugresistant strains, including those resistant to all available antibiotics, the impetus to study A. baumannii pathogenesis has grown. Novel targets for antibacterial drug development are desperately required, and drugs that have antivirulence mechanisms may provide new therapeutic options. Specific virulence mechanisms in A. baumannii include iron acquisition and transport systems; outer-membrane protein A (OmpA), which mediates mammalian cell adhesion, invasion, and cytotoxicity through mitochondrial damage and initiation of caspase-dependent apoptosis; lipopolysaccharide (LPS); and proteins important in the formation of biofilm on abiotic and biotic surfaces. Biofilm formation on abiotic surfaces is dependent on a pilus assembly system, which in turn is controlled by a traditional


InternalMed_Harrison

InternalMed_Harrison. important in the formation of biofilm on abiotic and biotic surfaces. Biofilm formation on abiotic surfaces is dependent on a pilus assembly system, which in turn is controlled by a traditional two-component regulatory system mediated by bfmR. Also important in biofilm formation are a gene that encodes a biofilm-associated protein (Bap); OmpA; the quorum-sensing gene abaI, which controls the secretion of 3-hydroxy-C12-homoserine lactone; and the pga locus, which is essential for the production of the polysaccharide poly-β-1,6-Nacetylglucosamine. Most recently, a global virulence regulator known as GacSA was described as important in regulating A. baumannii de-stain. Given their small size, they may be misidentified as either 1037 biofilms, motility, growth in human serum, and virulence in a mam-gram-negative or gram-positive cocci. malian infection model. New model systems for the study of A. baumannii infection, including both nonmammalian (invertebrate) and mammalian models, have


InternalMed_Harrison

InternalMed_Harrison. in a mam-gram-negative or gram-positive cocci. malian infection model. New model systems for the study of A. baumannii infection, including both nonmammalian (invertebrate) and mammalian models, have been described. Furthermore, the use of A. baumannii transposongenerated mutant libraries to screen for mutants with attenuated growth in human biologic fluids (serum and ascites fluid) has allowed the identification of new virulence mechanisms. These include phospholipase D; capsule production mediated by ptk and epsA; penicillin-binding protein 7/8 encoded by the pbpG gene; and a glycosyltransferase important for LPS biosynthesis encoded by the lpsB gene.


InternalMed_Harrison

InternalMed_Harrison. The LPS of A. baumannii appears to play a significant role in eliciting host responses. In studies with knockout mice, Toll-like receptor 4 and CD14 were shown to be important in host recognition, signaling, and cytokine production in response to A. baumannii. Humoral responses targeting iron-regulated outer-membrane proteins and the O-polysaccharide component of LPS also have been described. APPROACH TO THE PATIENT: Acinetobacter must be considered in the differential diagnosis of hospital-acquired pneumonia, central line–associated bloodstream infection, posttraumatic wound infection in military personnel, and postneurosurgical meningitis.


InternalMed_Harrison

InternalMed_Harrison. CLINICAL MANIFESTATIONS Pneumonia It may be difficult to distinguish between upper-airway colonization with A. baumannii and hospital-acquired pneumonia. An estimated 5–10% of cases of ventilator-associated pneumonia are due to A. baumannii, although much regional variation exists. Typically, patients with A. baumannii ventilator-associated pneumonia have had a prolonged stay in an ICU; in outbreak situations, however, patients may acquire the infection within days of arrival in an ICU. Community-acquired pneumonia due to A. baumannii has been described in tropical regions of Australia and Asia. The disease typically occurs during the “wet” season among people with a history of alcohol abuse. Infection may result in fulminant pneumonia requiring admission to an ICU, with a mortality rate of ~50%.