PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria
Enterobacter, Cronobacter, and Pantoea Species Dennis J. Cunningham and Amy Leber
MICROBIOLOGY AND EPIDEMIOLOGY The genera Enterobacter, Cronobacter, and Pantoea are all members of the Enterobacteriaceae family. The genus Enterobacter has undergone significant taxonomic revision. Although there are more than 15 named species, molecular techniques likely will identify additional species.1–9 Many former members of this genus have been transferred to other genera in the family Enterobacteriaceae, including to Klebsiella, Serratia, Hafnia, and Pantoea genera. Some have been transferred to new genera, including to Lelliottia, Pluralibacter, and Kosakonia.2 The genus Pantoea has been proposed to accommodate several isolates with significant biochemical and nucleic acid diversity that formerly were included in the heterogeneous taxon called the Enterobacter agglomerans group.10 There are more than 20 species, with P. agglomerans and P. ananatis most associated with human infections. Some commercial biochemical identification systems include P. agglomerans or P. agglomerans group in their databases, but they may not differentiate correctly among Pantoea species. The Enterobacter spp. most commonly recovered from human sources include E. cloacae, E. aerogenes, and to a lesser extent, Pantoea (formerly Enterobacter) agglomerans group, Cronobacter spp., E. gergoviae, and E. asburiae. E. cloacae is by far the most common clinical isolate. A number of newly named species (formerly included in the E. cloacae group) are difficult to differentiate by biochemical test methods.1–5 Organisms formerly classified as E. sakazakii comprised a diverse group and are renamed as Cronobacter spp., which comprise at least seven named species, of which C. sakazakii and C. malonaticus are most frequently isolated from human infections. Some commercial biochemical identification systems use the
terms E. cloacae group and C. sakazakii group to describe these closely related and difficult to distinguish organisms. Improved identification methods are needed. Matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF) mass spectrometry demonstrates overall good performance in the identification of gramnegative bacilli.11 It shows promise for differentiating among Enterobacter, Cronobacter, and Pantoea species.12–14 Enterobacter, Cronobacter, and Pantoea spp. are nonfastidious in nature and grow on blood and chocolate agar and selective media for enteric bacteria. On MacConkey agar, E. cloacae and E. aerogenes commonly appear as pink, lactose-fermenting, mucoid colonies similar in appearance to Klebsiella pneumoniae and K. oxytoca. Most isolates of Cronobacter spp. and P. agglomerans group organisms produce a nondiffusible, yellow pigment, which often is more intense when grown on enriched media at 25°C versus 35°C. Colonies of Cronobacter can appear dry, wrinkled, and leathery on some media. Most isolates of Enterobacter spp. are motile, use citrate as a sole carbon source, and give a positive Voges-Proskauer test result but do not produce indole or hydrogen sulfide. With the exception of the P. agglomerans group organisms, most isolates have ornithine decarboxylase activity. Motility and ornithine reactions help to differentiate Enterobacter spp. from the common human isolates of Klebsiella spp. Commercial or conventional biochemical identification systems usually perform well for identifying and differentiating E. cloacae, E. aerogenes, P. agglomerans, and Cronobacter spp., but the other species present a greater challenge and are not all represented in the databases of commercial systems. A report of Enterobacter spp. or Cronobacter spp. may be sufficient for most clinical purposes, although knowledge of the
Enterobacter, Cronobacter, and Pantoea Species
specific species is important in the setting of a potential nosocomial outbreak or when the clinical significance of the isolate is questioned. Enterobacter spp. and Pantoea spp. are common inhabitants of the gastrointestinal tract of humans and other mammals, and they can be found in water, sewage, soil, plant material, and foods. Even the more common human isolates, E. cloacae and E. aerogenes, have been described as having a ubiquitous animal and environmental distribution. Pantoea spp. are commonly associated with plants or are well-known agents of disease in plants. In humans, Enterobacter spp. and Pantoea spp. are opportunistic pathogens and are among the most common causes of nosocomial pneumonia, urinary tract infection, surgical wound infection, and catheter-related bloodstream infection (BSI). These organisms frequently colonize the skin and respiratory, urinary, and gastrointestinal tracts of hospitalized patients. These sites act as portals of entry for localized or invasive disease.1–5 Enterobacter spp. and Pantoea spp. also cause community-acquired urinary tract, skin, soft tissue, and other infections, although at much lower rates than other gram-negative bacilli such as E. coli, Proteus spp., and Klebsiella spp. Community-acquired infections due to P. agglomerans have been associated with foreign bodies and with plant thorn and wood splinter injuries. Enterobacter spp. accounted for 5% of all bacterial pathogens and 9% of gram-negative bacilli in more than 4000 episodes of nosocomial or community-acquired BSIs in North America and Latin America in 1997.15 Of almost 75,000 gram-negative bacilli recovered from BSIs in patients in intensive care units (ICUs) in the United States between 1993 and 2004, Enterobacter spp. accounted for 14% of isolates.16 Two US studies indicate that Enterobacter spp. represent the fourth and seventh most common pathogens causing BSI in pediatric ICUs (PICUs) and neonatal ICUs (NICUs), respectively.17,18 A 2003 US study of ICU nosocomial bacterial infections reported that Enterobacter spp. accounted for 10%, 4%, 9%, and 7% of pneumonia, BSI, surgical site, and urinary tract infections, respectively, due to gram-negative bacilli.19 Enterobacter spp. also accounted for 15% of all gram-negative BSIs in children in Israel.20 An outbreak of E. gergoviae among adult kidney transplant recipients was associated with a common source of contamination, which was presumed to be urinary catheters or stents.21 An endogenous source of Enterobacter spp. is most common in nosocomial infections. Approximately 40% of infants are fecal carriers of Klebsiella or Enterobacter spp. on discharge from NICUs. Colonization in nursery settings has been associated with overcrowding, inadequate handwashing, low birth weight, prematurity, endotracheal intubation, prolonged hospitalization, contaminated infant formula or parenteral nutrition fluid, and the use of antibiotics or central venous catheters (CVCs). Risk factors for infection include immunosuppression from any cause, prematurity, use of devices (e.g., CVC, endotracheal tube, urinary catheter), and prior use of antibiotics. The role of microbial virulence factors in the pathogenicity of these organisms has been reviewed.5
CLINICAL MANIFESTATIONS BSI is the most common form of invasive infection due to Enterobacter spp.6–9,22,23 Signs and symptoms in children are similar to those due to other gram-negative enteric bacteria. Fever occurs in 83% to 87% and hypotension or shock in 8% to 28% of patients. Leukocytosis or leukopenia can develop, and mortality rates for children range from 6% to 24%. Lower respiratory tract infection, including pneumonia with BSI, is the second most common pediatric infection due to Enterobacter spp. In pediatric national nosocomial surveillance studies, Enterobacter spp. were the third and fourth leading causes of nosocomial pneumonia in PICUs and NICUs, respectively, rising from 7.4% in 1992 to 13% in 1997.17,18 Pneumonia due to Enterobacter spp. occurs more often in infants younger than 2 months of age than in older infants and children. Other Enterobacter spp. infections in infants and children include meningitis, brain abscess, endocarditis, pyogenic arthritis, and peritonitis. Klebsiella or Enterobacter spp. accounted for 16% of meningitis cases due to gram-negative enteric bacteria during a 21-year period in Dallas.24 Enterobacter spp. also are associated with nosocomial gastrointestinal,
TABLE 140.1 Pediatric Enterobacter spp. Infections Reported by the National Nosocomial Infections Surveillance System Percentage of Cases Infection
Pneumonia Lower respiratory tract other than pneumonia
Eye, ear, nose, throat
ICU, intensive care unit; ND, no data. Data from Andresen J, Asmar BI, Dajani AS. Increasing Enterobacter bacteremia in pediatric patients. Pediatr Infect Dis J 1994;13:787–792; Delétoile A, Decré D, Courant S, et al. Phylogeny and identification of Pantoea species and typing of Pantoea agglomerans strains by multilocus gene sequencing. J Clin Microbiol 2009;47:300–310.
urinary tract, surgical site, eye, ear, nose, and throat infections (Table 140.1).17,18 Cronobacter spp. have particular importance in young infants because of an association with powdered infant formula feeding25 and because of a propensity for causing necrotizing enterocolitis and meningitis in a fashion similar to Citrobacter koseri (see Chapter 141). C. sakazakii is the only member of the genus that can use sialic acid, and this may contribute to its association with neonatal infections because sialic acid is found in breast milk, infant formula, the gastrointestinal tract, and the brain.26 Neonatal meningitis due to Cronobacter is associated with a high prevalence of brain abscess or cyst formation, high mortality rate (40% to 80%), and long-term neurologic sequelae in survivors. There is controversy about whether the intracerebral cystic lesions visualized on computed tomography (CT) in neonates with Cronobacter meningitis result from infarction leading to sterile liquefaction cysts or from abscess formation. Cronobacter has been isolated from brain cysts, suggesting a need to obtain cyst aspirates for Gram stain and culture if possible. When Cronobacter is recovered from neonatal blood or cerebrospinal fluid (CSF) culture, serial CT or magnetic resonance imaging studies should be performed to evaluate brain cyst or abscess formation to guide optimal management.27 The World Health Organization has recommended preparation guidelines and continued improvement of powdered infant formula manufacturing processes to reduce this mode of acquisition of Cronobacter spp.25 Pantoea agglomerans is an uncommon human pathogen. It has been reported to cause BSIs, including neonatal BSI related to administration of contaminated intravenous solutions, and has been associated with contamination of indwelling catheters. Septic shock, respiratory failure, and death occurred in 7 of 8 patients in one outbreak related to contaminated parenteral fluid.28 Another study reported 5 sporadic cases of Pantoea agglomerans BSI in preterm neonates over a 2-year period at one hospital; no source was identified.29 Inflections can be polymicrobial, making the role of Pantoea difficult to determine.30 Other reported infections include peritonitis during chronic ambulatory peritoneal dialysis, suppurative arthritis, skin and soft tissue infections presumably resulting from medical devices, a foreign body, and a plant thorn injury during rose gardening31,32 Pantoea spp. endophthalmitis developed in a patient after ocular trauma while using a lawn mower; a metal fragment was found lodged in the lens of the eye.33
TREATMENT Antibiotic susceptibility patterns for Enterobacter spp. vary between centers and among species, making monitoring of antimicrobial susceptibility patterns critical. Cronobacter spp. and E. gergoviae may be susceptible to ampicillin, cefazolin, and other narrow-spectrum cephalosporins, but E. cloacae, E. aerogenes, and several other Enterobacter spp. are uniformly resistant to these agents.34
PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria
E. cloacae, E. aerogenes, and other selected Enterobacteriaceae, including Citrobacter freundii, Proteus vulgaris, Morganella morganii, Serratia spp., and Providencia spp., harbor a chromosomal gene (ampC) coding for AmpC-type β-lactamase production.35 Frequently produced at low levels on initial laboratory isolation, high-level production is induced after in vitro or in vivo exposure to selected β-lactam antibiotics, particularly compounds such as ampicillin, first- or second-generation cephalosporins, and clavulanic acid. Initial isolates can appear susceptible to extended spectrum β-lactam agents by in vitro test methods, particularly rapid susceptibility test methods. AmpC β-lactamase production can be stably de-repressed in these organisms due to a chromosomal mutation of the ampD gene that normally plays a role in repressing ampC gene transcription. These strains, referred to as stably de-repressed mutants, can emerge during selective antimicrobial pressure within days of starting a course of β-lactam therapy and produce high levels of AmpC β-lactamase constitutively.34–36 Emergence of resistance appears to occur more often in Enterobacter spp. than in other enteric bacteria known to harbor ampC genes.36 Highlevel AmpC production renders the organism resistant to many β-lactam antibiotics, including third-generation cephalosporins and extendedspectrum β-lactam/β-lactamase inhibitor combination drugs. Susceptibility to fourth-generation cephalosporins and carbapenems is retained. No routine procedures are recommended by the Clinical Laboratory and Standards Institute (CLSI) for laboratory detection of inducible AmpC-mediated resistance in Enterobacter spp. and related organisms. A double-disk approximation test can be used, in which a known AmpC inducer antibiotic disk and an indicator antibiotic disk are placed in adjacent positions on a lawn of a test organism. A measurable reduction (i.e., flattening) in the zone of inhibition on the side of the indicator antibiotic disk adjacent to the inducer antibiotic disk suggests AmpC production.37 An alternative approach is a disk diffusion test format similar to the CLSI confirmation disk test for the presence of extendedspectrum β-lactamases (ESBLs). (see Chapter 138).38 In areas where inducible AmpC resistance is common, it seems prudent to report E. cloacae and other known AmpC producers as resistant to third-generation cephalosporins and extended-spectrum β-lactam/βlactamase inhibitor combination drugs or at least to caution against their
use as monotherapy for serious infections.39 It is equally important to repeat testing of secondary isolates of Enterobacter spp. and other gramnegative bacilli recovered from normally sterile body sites when recovered 24 to 48 hours after commencing appropriate antibiotic therapy. Enterobacter spp. can contain plasmids encoding for ESBLs and other genes coding resistance to other classes of antibiotics.3 In a North American and Latin American survey of gram-negative BSIs in which 399 Enterobacter spp. isolates were tested, meropenem, imipenem, and cefepime were the most active agents; more than 99% of isolates were susceptible. The fluoroquinolones and aminoglycosides also had good activity; 90% to 96% of isolates were susceptible. No other antibiotic demonstrated activity for more than 78% of isolates.15 Optimal antibiotic therapy for infections due to Enterobacter spp. is unclear. For serious infections, it may be prudent to avoid the use of a single-agent, extended-spectrum cephalosporin or a β- lactam/βlactamase inhibitor combination other than a fourth-generation cephalosporin because of possible rapid selection of resistance. Addition of an aminoglycoside is reasonable for a serious infection outside the central nervous system (CNS). For treatment of meningitis, meropenem is the optimal choice, and many experts add an aminoglycoside in this setting.40–42 For patients with type I hypersensitivity reactions to β-lactams, use of a fluoroquinolone plus an aminoglycoside may be effective. Careful monitoring of the patient’s clinical course, particularly for occurrence of CNS complications, is essential, especially with Cronobacter infection. Appropriate specimens must be obtained sequentially to demonstrate a sustained bacteriologic response. Prompt removal of contaminated prosthetic devices is essential to eradicate the organism and effect a cure. Failure to remove these devices compromises a rapid bacteriologic response and increases the likelihood that resistant organisms will emerge. Good handwashing technique and assiduous application of other infection control practices are essential to prevent nosocomial transfer of organisms. The use of broad-spectrum antimicrobial agents should be strictly limited; unnecessary antimicrobial therapy should be avoided. All references are available online at www.expertconsult.com.
Key Points: Diagnosis and Management of Enterobacter Species Infections MICROBIOLOGY
• Members of Enterobacteriaceae: facultative, gram-negative bacilli that are catalase positive and oxidase negative, reduce nitrate to nitrite, and ferment glucose and other carbohydrates • Indole negative; most species are motile and usually are encapsulated. • Good growth on blood, chocolate, and MacConkey agar (usually); often produce large, mucoid colonies that are pink, indicating lactose fermentation
• Many species have intrinsic low-level resistance to thirdgeneration cephalosporins and β-lactam–β-lactamase inhibitor combination drugs. • An infectious diseases consultation is prudent when treating patients with Enterobacter, Cronobacter, or Pantoea infection. When selecting antimicrobial agents for empiric therapy, local antibiograms can help to guide the decision. • Therapy with third-generation cephalosporins or β-lactam/βlactamase inhibitor combinations should be avoided because these agents can induce ampC resistance. • Meropenem is the drug of choice for meningitis. Some experts add an aminoglycoside. • Cefepime plus an aminoglycoside is an effective combination therapy for serious infections outside the central nervous system. • In patients allergic to cefepime, a fluoroquinolone plus gentamicin may be reasonable therapy.
EPIDEMIOLOGY • Common inhabitants of the gastrointestinal tract of humans and other mammals; found in water, sewage, soil, plant material, and foods • Enterobacter aerogenes and E. cloacae are the most common clinically encountered species. • Important pathogen in a wide variety of infections, including the bloodstream, central nervous system, and respiratory and urinary tracts; substantial cause of nosocomial infections • Risk factors include foreign bodies and medical devices, neutropenia, and immunosuppression. DIAGNOSIS • Recovery in culture using standard laboratory procedures • Identification by biochemical methods or MALDI-TOF; susceptibility testing by automated or manual methods
DURATION OF THERAPY • For patients with meningitis, treatment is 4 to 6 weeks after cerebral spinal fluid sterilization is documented. • For patients with bacteremia and no foreign body, treatment is 2 to 3 weeks after sterilization of the blood is documented. • For patients with persistent bacteremia or when a foreign body is not removed, the duration of therapy is 4 to 6 weeks after sterilization of the blood is documented, but it may not be curative.
KEY REFERENCES 11. Richter SS, Sercia L, Branda JA, et al. Identification of Enterobacteriaceae by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using the VITEK MS system. Eur J Clin Microbiol Infect Dis 2013;32: 1571–1578.
12. Krasny L, Rohlova E, Ruzickova H, et al. Differentiation of Cronobacter spp. by tryptic digestion of the cell suspension followed by MALDI-TOF MS analysis. J Microbiol Methods 2014;98:105–113. 40. Lee CC, Lee NY, Yan JJ, et al. Bacteremia due to extended-spectrum beta-lactamase producing Enterobacter cloacae: role of carbapenems therapy. Antimicrob Agents Chemother 2010;54:3551–3556.
Enterobacter, Cronobacter, and Pantoea Species
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