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Citrobacter Species
Microbiology And Epidemiology
The genus Citrobacter has undergone significant taxonomic revision through the use of newer techniques based on DNA relatedness. The genus contains 13 named species: Citrobacter freundii, C. koseri (formerly C. diversus ) , C. amalonaticus, C. youngae, C. farmeri, C. braakii, C. werkmanii, C. sedlakii, C. gillenii, C. murliniae, C. rodentium, C. pasteurii , and C. europaeus. All species except C. rodentium (pathogenic for mice) have been recovered from human clinical specimens; however, C. freundii , C. koseri, and C. braakii are the most important human pathogens. C. freundii , C. koseri , and C. amalonaticus appear to be distinct organisms; however, only C. koseri appears to be genetically homogeneous. Several other named species form a closely related group and are difficult to differentiate biochemically; they are sometimes referred to as C. freundii -complex organisms.
Members of the genus Citrobacter share all the general properties and biochemical characteristics of the family Enterobacteriaceae, including gram-negative rod, catalase-positive and oxidase-negative, growth on MacConkey agar, reduction of nitrate to nitrite, growth both aerobically and anaerobically, and fermentation of glucose and other carbohydrates. Most isolates are motile and utilize citrate as a sole carbon source but lack urease and lysine decarboxylase activity; production of hydrogen sulfide is variable, occurring with C. freundii and a few other species. On salmonella-shigella agar, lactose-negative/hydrogen-sulfide positive isolates of Citrobacter spp. produce black colonies resembling Salmonella spp. The lysine decarboxylase reaction allows for the separation of the hydrogen sulfide-producing isolates of Citrobacter spp. from Salmonella spp . while pyrrolidinyl peptidase activity (PYR disk) can be used to differentiate biochemically atypical Citrobacter strains (positive) from Salmonella (negative). Select isolates of C. freundii have “O” (somatic) cell wall antigens closely related to the O antigens of Salmonella spp. and thus cross-react with Salmonella typing antisera. In addition, rare isolates of C. freundii and C. braakii cross-react with some commercial Escherichia coli O157 typing antisera. For this reason, it is always prudent to confirm the identification of suspected Salmonella spp. and E. coli O157 by the use of both biochemical and serologic methods. Identification of Citrobacter species also can be determined by the use of proteomic methods such as matrix-assisted laser desorption/ionization time-of-flight. , Any limitation in the identification of rarely encountered species depends on the inclusion of those species in the systems database.
Citrobacter spp. are primarily inhabitants of the intestinal and genitourinary tract of mammals and other vertebrates. Their isolation from environmental sources such as water and soil likely is the result of fecal excretion. Citrobacter spp. are most often recovered from stool as colonizing flora of the gastrointestinal tract. When associated with significant human infection, Citrobacter can be recovered from blood, cerebrospinal fluid (CSF), urine, respiratory tract secretions, wounds, and less commonly from intra-abdominal and pulmonary sites. The most common Citrobacter spp. isolated from human sources are C. freundii (all sites listed above) , C. koseri (all sites, but CSF and brain most commonly), C. amalonaticus (all sites except CSF), C. braakii (primarily stool), and C. youngae (primarily stool).
The pathogenesis of Citrobacter infections has not been fully characterized. Most C. koseri isolates produce hemolysins, are piliated, and are resistant to killing by pooled human sera. The proclivity for Citrobacter spp. to cause central nervous system (CNS) infection and particularly brain abscesses is not well understood. Tropism for the CNS may be due to specific outer membrane proteins. In one study, 79% of strains of C. koseri isolated from CSF had a unique 32-kd outer-membrane protein, which was found in only 9% of isolates from other kinds of specimens. C. freundii has been shown to invade and replicate within brain microvascular endothelial cells in vitro. C. koseri has the ability to enter macrophages, survive phagolysosomal fusion, and replicate intracellularly in the neonatal rat model; infected macrophages can then infiltrate blood vessels in the brain, thus starting the process leading to brain abscess formation. , MyD88 dependent pathways in primary astrocytes have been shown to be crucial for the induction of an inflammatory response and containment of C. koseri in CNS infection.
In the pediatric population, infections due to Citrobacter spp. occur most frequently in neonates. , Organisms can be transmitted by vertical transmission from mothers or by nosocomial spread, though most are considered sporadic cases from an unknown source. Direct mother-to-infant transmission has been confirmed by ribotyping and DNA fingerprinting. , It is likely that individual strains of Citrobacter spp. circulating in the community periodically gain access to a hospital nursery from the hands of nursery personnel and visitors. , One nursery outbreak of C. freundii was traced to contaminated infant formula.
Clinical Manifestations
Citrobacter spp. are opportunistic pathogens in humans that can lead to invasive disease, including infections of the CNS, urinary tract, respiratory tract, skin/soft tissue as well as osteomyelitis, suppurative arthritis, bacteremia, endocarditis, endophthalmitis, and intra-abdominal infections, particularly in neonates and immunocompromised hosts.
In infants, sepsis and meningitis are the most common clinical manifestations of infection with Citrobacter spp. , Bacterial sepsis is associated with meningitis in about one-half of cases; in one series of 30 infants with Citrobacter meningitis, 80% had concurrent positive blood cultures. From 1969 to 1989 in Dallas, TX, Citrobacter spp. accounted for 9% of 91 cases of gram-negative enteric meningitis in infants aged 1 day to 2 years. C. koseri was responsible for 90% of cases, and C. freundii caused most of the remaining cases. Neonatal sepsis and meningitis can manifest as early-onset or late-onset disease and can be fulminant or insidious. In 2002 to 2003, Citrobacter spp. caused 2.9% of early-onset sepsis in very low birth weight infants. No early features distinguish meningitis due to Citrobacter spp. from meningitis due to other gram-negative rods. Importantly, >75% of infants with meningitis due to Citrobacter spp. develop ≥1 intracerebral abscesses ( Fig. 141.1 ). , In contrast, <10% of cases of infants with meningitis due to other gram-negative organisms have associated abscess(es). , Neonatal brain abscesses can also occur with infections caused by Cronobacter (formerly Enterobacter ) sakazakii, Proteus mirabilis, and Serratia marcescens . In a contemporary review of brain abscesses in children, intracranial abscesses caused by Citrobacter spp. were more frequent compared with historical cohorts, occurring solely in neonates. Brain abscesses can occur at any time during the acute course, including several weeks after the start of treatment and relapse/recurrence has been described.
The prognosis for meningitis due to Citrobacter spp. in neonates generally is poor. Approximately 30%–35% of infected infants die, and only 15%–20% survive with a structurally normal brain at the completion of therapy; however, data on long-term prognosis are limited. Although at least 40% of survivors show some form of developmental delay, physical impairment, or both, there are reports of infants with brain abscesses due to Citrobacter spp. who develop normally.
Other illnesses in infants due to Citrobacter spp. occur less frequently including gastroenteritis, osteomyelitis, pyogenic arthritis, pulmonary infections, and pneumatosis intestinalis. In older children and adults and immunocompromised hosts, Citrobacter spp. can cause urinary tract, bloodstream, intra-abdominal, skin and soft-tissue, and respiratory tract infections. Citrobacter spp. are the cause of urinary tract infection (UTI) in <3% of adults and children. , In a review of 37 pediatric cases, the mean age was 6.9 years, with a range of 1 month to 18 years. Females predominated, and 56% of patients had underlying urinary tract or renal anomalies or neurologic impairment. Presenting symptoms were similar to those of UTI from other causes, with dysuria, fever, incontinence, frequency, flank pain, or hematuria. C. freundii accounted for 71% of cases, and C. koseri for the remainder. Mixed UTI involving other enteric bacilli occurred in about 25% of patients. In immunocompromised patients, Citrobacter spp. causes bacteremia but rarely leads to CNS disease. C. freundii caused 2.3% of bloodstream infections in the first year following lung transplantation in 190 pediatric patients. Infections in immunocompromised patients are also more frequently caused by multi-drug resistant strains. ,
Eye infections, including keratitis and endogenous and traumatic endophthalmitis caused by Citrobacter spp., have been reported. An outbreak of severe gastroenteritis associated with several cases of hemolytic-uremic syndrome occurred in a nursery school. The source of this outbreak was sandwiches prepared with green butter containing a toxigenic strain of C. freundii . The butter had been made with contaminated parsley grown in an organically fertilized garden. Nosocomial outbreaks are frequently caused by multi-drug resistant strains, including carbapenemase-expressing Citrobacter spp. , Transfusion-transmitted infections with C. koseri leading to bacteremia have also been reported. ,
Key Points
Diagnosis and Management of Infections With Citrobacter Species
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