Escherichia coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, Morganella, Providencia, Cronobacter, and Edwardsiella are gram-negative enteric bacilli that are members of the family Enterobacteriaceae. Salmonella, Shigella, and Yersinia, also in the family Enterobacteriaceae, are discussed in Chaps. 62, 63, and 68, respectively. These pathogens cause a wide variety of infections involving diverse anatomic sites in both healthy and compromised hosts. Increasing antimicrobial resistance in this group has put them at the forefront of an evolving public health crisis. In addition, new infectious syndromes have emerged. Therefore, a thorough knowledge of clinical presentations and appropriate therapeutic choices is necessary for optimal outcomes.
E. coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, Morganella, Providencia, Cronobacter, and Edwardsiella are components of the normal animal and human colonic microbiota and/or the microbiota of a variety of environmental habitats, including long-term-care facilities (LTCFs) and hospitals. As a result, except for certain pathotypes of intestinal pathogenic E. coli, these genera are global pathogens. The incidence of infection due to these agents is increasing because of the combination of an aging population and increasing antimicrobial resistance. In healthy humans, E. coli is the predominant species of gram-negative bacilli (GNB) in the colonic flora; Klebsiella and Proteus are less prevalent. GNB (primarily E. coli, Klebsiella, and Proteus) only transiently colonize the oropharynx and skin of healthy individuals. In contrast, in LTCFs and hospital settings, a variety of GNB emerge as the dominant microbiota of both mucosal and skin surfaces, particularly in association with antimicrobial use, severe illness, and extended length of stay. LTCFs are emerging as an important reservoir for resistant GNB. This colonization may lead to subsequent infection; for example, oropharyngeal colonization may lead to pneumonia. Interestingly, the use of ampicillin or amoxicillin was associated with an increased risk of subsequent infection due to the hypervirulent variant of Klebsiella pneumoniae in Taiwan; this association suggests that changes in the quantity or prevalence of colonizing bacteria may be important. Serratia and Enterobacter infection may be acquired through a variety of infusates (e.g., medications, blood products). Edwardsiella infections are acquired through freshwater and marine environment exposures and are most common in Southeast Asia.
TREATMENT Infections Caused by Gram-Negative Enteric Bacilli
(See also Chap. 41) 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 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 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.
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-lactamase-mediated 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 third- and fourth-generation cephalosporins or cephamycins (e.g., cefoxitin).
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 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.
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 piperacillin-tazobactam (minimal inhibitory concentration [MIC], ≤4 μg/mL), this agent—at a dosage of 4.5 g q6h—may offer a carbapenem-sparing 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).
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 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, piperacillin-tazobactam, TMP-SMX, tigecycline, and aminoglycosides, although clinical data are limited.
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 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.
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 emergence of resistance.
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.
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. 73). Although some GNB are more pathogenic than others, 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.