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Citrobacter Species
Citrobacter Species
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141 Citrobacter Species
Stella Antonara and Monica I. Ardura
MICROBIOLOGY AND EPIDEMIOLOGY The genus Citrobacter has undergone significant taxonomic revision through the use of newer techniques based on DNA relatedness. The genus contains 11 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, and C. rodentium.1–5 All species except C. rodentium (pathogenic for mice) have been recovered from human clinical specimens. However, C. freundii and C. koseri and C. braakii are the most important human pathogens. C. freundii, C. koseri, and C. amalonaticus appear to be distinct organisms, but 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. Citrobacter spp. are gram-negative bacilli in the family Enterobacteriaceae. They ferment glucose and other carbohydrates, are catalase and oxidase positive, and reduce nitrate. Most isolates are motile and use citrate as a sole carbon source, but they lack urease and lysine decarboxylase activity. Production of hydrogen sulfide varies, occurring in C. freundii and a few other species. On Salmonella-Shigella agar, lactose-negative and hydrogen sulfide–positive isolates of Citrobacter spp. produce black colonies resembling those of Salmonella spp. The lysine decarboxylase reaction allows separation of the hydrogen sulfide–producing isolates of Citrobacter spp. from Salmonella spp.1–5 Selected isolates of C. freundii have O (somatic) cell wall antigens closely related to the O antigens of Salmonella spp. and therefore crossreact with Salmonella typing antisera.1 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 biochemical and serologic methods. Identification of Citrobacter species also can be successfully achieved by the use of proteomic methods such as matrixassisted laser desorption/ionization–time of flight (MALDI-TOF) mass spectrometry.6,7 Any limitation in the identification of rarely encountered species depends on the inclusion of those species in the system’s database. Citrobacter spp. primarily are inhabitants of the intestinal 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 not common agents of human disease, and most often are 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, and wounds. The most common Citrobacter spp. isolated from human sources are C. freundii (all sites previously listed), C. koseri (all sites but most commonly the CSF and brain), C. amalonaticus (all sites except CSF), C. braakii (primarily stool), and C. youngae (primarily stool).2 The pathogenesis of infection has not been fully characterized. Most C. koseri isolates produce hemolysins, are piliated, and are resistant to
killing by pooled human sera. The proclivity to cause central nervous system (CNS) infection and particularly brain abscesses is not well understood. Tropism for the CNS may be associated with 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.8 C. freundii invades and replicates within brain microvascular endothelial cells in vitro.9 C. koseri can enter macrophages, survive phagolysosomal fusion, and replicate intracellularly in the neonatal rat model; infected macrophages can then infiltrate blood vessels in the brain, starting the process leading to brain abscess formation.1,10 Myeloid differentiation primary response gene 88 (MYD88)–dependent pathways in primary astrocytes are crucial for the induction of an inflammatory response and containment of C. koseri in CNS infection.11 In the pediatric population, infections occur most commonly in neonates.12,13 Organisms can be transmitted by vertical transmission from mothers or by nosocomial spread, although most are considered sporadic cases from an unknown source. Direct mother-to-infant transmission has been confirmed by ribotyping and DNA fingerprinting.14,15 It is likely that individual strains circulating in the community periodically gain access to a hospital nursery from the hands of nursery personnel and visitors.14,16,17 One nursery outbreak of C. freundii was traced to contaminated infant formula.18
CLINICAL MANIFESTATIONS Citrobacter spp. are opportunistic pathogens in humans that can lead to invasive disease, including infections of the urinary tract, respiratory tract, CNS, skin, and soft tissue. The bacteria can cause 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.12,13 Bacterial sepsis is associated with meningitis in about one half of cases. From 1969 to 1989 in Dallas, TX, Citrobacter spp. accounted for 9% of 91 cases of gram-negative enteric meningitis in infants 1 day to 2 years of age.19 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 (<1 week of life) or late-onset (>1 week of life) disease and can be fulminant or insidious. In 2002 and 2003, Citrobacter spp. caused 2.9% of early-onset sepsis in very low birth weight infants.20 No early features distinguish meningitis due to Citrobacter spp. from meningitis due to other gram-negative rods. Approximately 80% of infants with meningitis due to Citrobacter spp. develop one or more intracerebral abscesses (Fig. 141.1). In contrast, less than 10% of cases of infants with meningitis due to other gram-negative organisms have associated abscesses.12,13 Neonatal brain abscesses also can 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
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PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria
Citrobacter spp. were more frequent compared with historical cohorts and occurred solely in neonates.21 Brain abscesses can evolve any time during the acute course, including several weeks after commencement of treatment. The prognosis for meningitis due to Citrobacter spp. in neonates is poor. Approximately 30% to 35% of infected infants die, and only 15% to 20% survive with a structurally normal brain at completion of therapy; however, data on long-term prognosis are limited.12 Although at least 40% of survivors show some form of developmental delay or physical impairment, or both, there are reports of infants with brain abscesses due to Citrobacter spp. who develop normally.22 Other Citrobacter spp. infections in infants occur rarely. Gastroenteritis, osteomyelitis, pyogenic arthritis, pulmonary infections, and pneumatosis intestinalis have been described.13 In older children, adults, and immunocompromised hosts, Citrobacter spp. is associated most commonly with urinary tract, bloodstream, intra-abdominal, skin, soft tissue, and respiratory tract infections.23 Citrobacter spp. are the cause of urinary tract infection (UTI) in less than 3% of adults and children.24,25 In a review of 37 pediatric cases, the mean age was 6.9 years, with a range of 1 month to 18 years.24 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, including dysuria, fever, incontinence, frequency, flank pain, and hematuria. C. freundii accounted for 71% of cases, and C. koseri for the remainder. UTIs involving Citrobacter spp. and 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 after lung transplantation in 190 pediatric patients.26 Infections in immunocompromised patients more frequently are caused by multidrug-resistant strains.23,27–29 Eye infections, including keratitis and endogenous and traumatic endopthalmitis caused by Citrobacter spp., have been reported.30–32 An outbreak of severe gastroenteritis associated with several cases of hemolytic uremic syndrome occurred in a nursery school.33 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.
first-generation cephalosporins. C. freundii and some other Citrobacter spp. harbor chromosomal AmpC-type β-lactamases that can inactivate third-generation cephalosporins (see Chapter 140).34 This enzyme is not inhibited by β-lactamase inhibitors such as tazobactam or clavulanate. A US national surveillance study of hospital-associated bloodstream infections reported resistance patterns for 23 C. freundii isolates.35 Resistance to piperacillin, piperacillin/tazobactam, ceftriaxone, and ceftazidime occurred commonly (39%–48%); 96% of the ceftazidime-resistant isolates were susceptible to cefepime. Some strains of C. freundii also harbor extended-spectrum β-lactamases and Klebsiella pneumoniae–type carbapenemases (KPCs) that are found more commonly in Klebsiella spp. (see Chapter 138). These plasmidmediated enzymes are problematic because they are readily transferred from one strain to another in a healthcare environment.36,37 Citrobacter spp. usually are susceptible to fourth-generation cephalosporins such as cefepime (compared with third-generation cephalosporins such as ceftriaxone or ceftazidime) due to relative stability to inactivation by AmpC enzymes. Emergence of cefepime resistance in a clinical C. freundii strain due to a novel plasmid-mediated AmpCtype β-lactamase has been reported.38 The carbapenems typically are active. C. koseri susceptibility to trimethoprim-sulfamethoxazole and the aminoglycosides varies. Among 117 Citrobacter spp. from US hospitals in 2007, the rates of susceptibility to the agents listed were 100% for meropenem and imipenem, 98% for cefepime, 95% for ceftriaxone, 86% for ceftazidime, 94% for piperacillin/tazobactam, 96% for gentamicin, 95% for tobramycin, and 97% for ciprofloxacin and levofloxacin.39 In an antimicrobial surveillance study examining 776 Citrobacter species collected between 2008 and 2012 using the revised Clinical and Laboratory Standards Institute (CLSI) breakpoints for carbapenems, there was no significant change in the sensitivity of imipenem (97.1%), ertapenem (97.7%), meropenem (98.8%), and doripenem (98.9%).40 Multidrugresistant isolates may be susceptible to colistin, polymyxin B, and tigecycline.41 Optimal antimicrobial therapy for C. koseri meningitis has not been established, but a combination of a third- or fourth-generation cephalosporin plus an aminoglycoside to which the organism is susceptible is reasonable.13 Monotherapy with high-dose cefotaxime or ceftriaxone or with imipenem-cilastatin has been successful.42,43 Meropenem seems a logical carbapenem choice due to less potential for neurotoxicity. With recognition of the possible role of intracellular C. koseri in the pathogenesis of cerebral abscesses and possible poor CNS penetration of aminoglycosides, treatment with a third-generation cephalosporin in combination with ciprofloxacin has been used successfully.44 In infants with meningitis, a repeat lumbar puncture after 24 to 48 hours of antibiotic therapy should be performed to ensure CSF sterility. Neuroimaging should be obtained for all neonates with invasive Citrobacter infections. Neurosurgical drainage of abscesses has been used with various degrees of success. For patients with an accessible brain abscess, neurosurgical drainage is recommended if clinically feasible. For children who have progressive hydrocephalus and fibrous compartmentalization of the ventricular space, instillation of intraventricular urokinase also has been performed.45 In the presence of CNS abscesses, cultures of CSF should be performed regularly until sterility is documented. Meningitis without abscess formation usually is treated for a minimum of 21 days after the first sterile CSF culture. For intracranial abscesses, a 4- to 6-week course from initial sterile CSF cultures is the minimal duration usually recommended, depending on clinical and radiologic improvement.12,13 Testing for hearing loss and neurologic and developmental delays should be performed in all infants with Citrobacter spp. CNS infection. Prevention of infections due to Citrobacter spp. is related predominantly to preventing healthcare-associated infections. Strict cohorting of infected or colonized neonates is prudent but may not effectively control nursery outbreaks. Meticulous handwashing is mandatory.
TREATMENT
ACKNOWLEDGMENT
Most data on in vitro antimicrobial susceptibility and therapeutic management are for infections due to C. freundii and C. koseri. These organisms can harbor a wide variety of β-lactamases. Both species are resistant uniformly to ampicillin, and C. freundii is also resistant to
We acknowledge the substantial contributions of D.W. Powell and M.J. Marcon to this chapter in previous editions.
FIGURE 141.1 Computed tomography of a neonate with multiple brain abscesses caused by Citrobacter koseri.
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All references are available online at www.expertconsult.com.
Key Points: Diagnosis and Management of Infections With Citrobacter Species MICROBIOLOGY • Catalase-positive, oxidase-negative, gram-negative rod • Lactose fermenting on MacConkey media • Chromosomal AmpC-producing; resistant to ampicillin and first-generation cephalosporins EPIDEMIOLOGY • Normal enteric flora; also found in the environment • In infants <2 months, proclivity for CNS disease, including meningitis and brain abscesses • Most cases are sporadic; vertical and horizontal transmission are described. • Outbreaks support person-to-person transmission. DIAGNOSIS • C. koseri is recovered easily in cultures from CSF samples, without use of specialized media. • Use of PYR disk can differentiate atypical Citrobacter species (positive) from Salmonella species (negative).
KEY REFERENCES 12. Graham DR, Band JD. Citrobacter diversus brain abscess and meningitis in neonates. JAMA 1981;245:1923–1925. 13. Doran TI. The role of Citrobacter in clinical disease of children: review. Clin Infect Dis 1999;28:384–394. 19. Unhanand M, Mustafa MM, McCracken GH Jr, Nelson JD. Gram-negative enteric bacillary meningitis: a twenty-one-year experience. J Pediatr 1993;122:15–21. 20. Stoll BJ, Hansen NI, Higgins RD, et al. Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections contin-
• MALDI-TOF can differentiate Citrobacter spp. from other Enterobacteriaceae. TREATMENT • A combination of surgical and antimicrobial therapy typically is used. • Empiric therapy with a third- or fourth-generation cephalosporin plus an aminoglycoside is common but depends on local antimicrobial susceptibility data. • Targeted therapy should be guided by antimicrobial susceptibilities of the clinical isolate. DURATION OF THERAPY • Duration of therapy for meningitis is similar to that for other enteric gram-negative neonatal pathogens. • Prolonged therapy (4–6 weeks after documented CSF sterilization) is required for brain abscesses and is guided by clinical and imaging improvement.
ues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002-2003. Pediatr Infect Dis J 2005;24:635–639. 35. Pfaller MA, Sader HS, Fritsche TR, Jones RN. Antimicrobial activity of cefepime tested against ceftazidime-resistant gram-negative clinical strains from North American hospitals: report from the SENTRY Antimicrobial Surveillance Program (1998-2004). Diagn Microbiol Infect Dis 2006;56:63–68. 40. Rennie RP, Jones RN. Effects of breakpoint changes on carbapenem susceptibility rates of Enterobacteriaceae: results from the SENTRY Antimicrobial Surveillance Program, United States, 2008 to 2012. Can J Infect Dis Med Microbiol 2014;25:285–287.
Citrobacter Species
REFERENCES 1. Janda JM, Albott SL. The enterobacteria, Chapter 9. In: Janda JM, Albott SL (eds) The Enterobacteria, 2nd ed. Washington, DC, American Society for Microbiology, 2006, pp 115–135. 2. Brenner DJ, O’Hara CM, Grimont PA, et al. Biochemical identification of Citrobacter species defined by DNA hybridization and description of Citrobacter gillenii sp. nov. (formerly Citrobacter genomospecies 10) and Citrobacter murliniae sp. nov. (formerly Citrobacter genomospecies 11). J Clin Microbiol 1999;37:2619–2624. 3. Forsythe SJ, Abbott SL, Pitout J. Klebsiella, Enterobacter, Citrobacter, Cronobacter, Serratia, Plesiomonas, and Enterobacteriaceae. In: Jorgensen JH, Pfaller MA, Carroll KC, et al. (eds) Manual of Clinical Microbiology, 11th ed. Washington, DC, ASM Press, 2015, pp 714–737. 4. Winn WC, Allen SD, Janda WM. The enterobacteriaceae. In: Koneman EW (ed) Color Atlas and Textbook of Diagnostic Microbiology, 6th ed. Philadelphia, Lippincott-Williams & Wilkins, 2006, pp 211–302. 5. Forbes BA, Sahm DF, Weissfeld AS. Enterobacteriaceae. In: Forbes BA, Sahm DF, Weissfeld AS (eds) Bailey & Scott’s Diagnostic Microbiology, 12th ed. St Louis, Mosby, 2007, pp 323–333. 6. Kwak HL, Han SK, Park S, et al. Development of a rapid and accurate identification method for Citrobacter species isolated from pork products using a matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). J Microbiol Biotechnol 2015;25:1537–1541. 7. Richter SS, Sercia L, Branda JA, et al. Identification of Enterobacteriaceae by matrixassisted laser desorption/ionization time-of-flight mass spectrometry using the VITEK MS system. Eur J Clin Microbiol Infect Dis 2013;32:1571–1578. 8. Li J, Musser JM, Beltran P, et al. Genotypic heterogeneity of strains of Citrobacter diversus expressing a 32-kilodalton outer membrane protein associated with neonatal meningitis. J Clin Microbiol 1990;28:1760–1765. 9. Badger JL, Stins MF, Kim KS. Citrobacter freundii invades and replicates in human brain microvascular endothelial cells. Infect Immun 1999;67:4208–4215. 10. Townsend SM, Gonzalez-Gomez I, Badger JL. fliP influences Citrobacter koseri macrophage uptake, cytokine expression and brain abscess formation in the neonatal rat. J Med Microbiol 2006;55:1631–1640. 11. Liu S, Kielian T. MyD88 is pivotal for immune recognition of Citrobacter koseri and astrocyte activation during CNS infection. J Neuroinflamm 2011;8:35. 12. Graham DR, Band JD. Citrobacter diversus brain abscess and meningitis in neonates. JAMA 1981;245:1923–1925. 13. Doran TI. The role of Citrobacter in clinical disease of children: review. Clin Infect Dis 1999;28:384–394. 14. Harvey BS, Koeuth T, Versalovic J, et al. Vertical transmission of Citrobacter diversus documented by DNA fingerprinting. Infect Control Hosp Epidemiol 1995;16:564–569. 15. Papasian CJ, Kinney J, Coffman S, et al. Transmission of Citrobacter koseri from mother to infant documented by ribotyping and pulsed-field gel electrophoresis. Diagn Microbiol Infect Dis 1996;26:63–67. 16. Parry MF, Hutchinson JH, Brown NA, Wu CH. Estreller L. Gram-negative sepsis in neonates: a nursery outbreak due to hand carriage of Citrobacter diversus. Pediatrics 1980;65:1105–1109. 17. Goering RV, Ehrenkranz NJ, Sanders CC, Sanders WE Jr. Long term epidemiological analysis of Citrobacter diversus in a neonatal intensive care unit. Pediatr Infect Dis J 1992;11:99–104. 18. Thurm V, Gericke B. Identification of infant food as a vehicle in a nosocomial outbreak of Citrobacter freundii: epidemiological subtyping by allozyme, whole-cell protein and antibiotic resistance. J Appl Bacteriol 1994;76:553–558. 19. Unhanand M, Mustafa MM, McCracken GH Jr, Nelson JD. Gram-negative enteric bacillary meningitis: a twenty-one-year experience. J Pediatr 1993;122:15–21. 20. Stoll BJ, Hansen NI, Higgins RD, et al. Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002-2003. Pediatr Infect Dis J 2005;24:635–639. 21. Goodkin HP, Harper MB, Pomeroy SL. Intracerebral abscess in children: historical trends at Children’s Hospital Boston. Pediatrics 2004;113:1765–1770. 22. Leggiadro RJ. Favorable outcome possible in Citrobacter brain abscess. Pediatr Infect Dis J 1996;15:557.
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23. Samonis G, Anaissie E, Elting L, Bodey GP. Review of Citrobacter bacteremia in cancer patients over a sixteen-year period. Eur J Clin Microbiol Infect Dis 1991;10:479–485. 24. Gill MA, Schutze GE. Citrobacter urinary tract infections in children. Pediatr Infect Dis J 1999;18:889–892. 25. Zhanel GG, Hisanaga TL, Laing NM, et al. Antibiotic resistance in outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents 2005;26:380–388. 26. Danziger-Isakov LA, Sweet S, Delamorena M, et al. Epidemiology of bloodstream infections in the first year after pediatric lung transplantation. Pediatr Infect Dis J 2005;24:324–330. 27. Bui KT, Mehta S, Khuu TH, et al. Extended spectrum beta-lactamase-producing Enterobacteriaceae infection in heart and lung transplant recipients and in mechanical circulatory support recipients. Transplantation 2014;97:590–594. 28. Collin BA, Leather HL, Wingard JR, Ramphal R. Evolution, incidence, and susceptibility of bacterial bloodstream isolates from 519 bone marrow transplant patients. Clin Infect Dis 2001;33:947–953. 29. Linares L, Cervera C, Cofan F, et al. Epidemiology and outcomes of multiple antibiotic-resistant bacterial infection in renal transplantation. Transplant Proc 2007;39:2222–2224. 30. Roy R, Pradeep Kumar P, Malathi J, et al. Endophthalmitis caused by Citrobacter species: a case series. Can J Ophthalmol 2013;48:216–217. 31. Chiu CH, Peng MY, Wang YC, Chang FY. Endogenous endophthalmitis caused by Citrobacter koseri. Am J Med Sci 2009;338:509–510. 32. Goold LA, Warrier SK, Wittles NK, Nathan F. Microbial keratitis secondary to infection with Citrobacter koseri. Cornea 2010;29:479. 33. Tschape H, Prager R, Streckel W, et al. Verotoxinogenic Citrobacter freundii associated with severe gastroenteritis and cases of haemolytic uraemic syndrome in a nursery school: green butter as the infection source. Epidemiol Infect 1995;114:441–450. 34. Hanson ND, Sanders CC. Regulation of inducible AmpC beta-lactamase expression among Enterobacteriaceae. Curr Pharmaceut Design 1999;5:881–894. 35. Pfaller MA, Sader HS, Fritsche TR, Jones RN. Antimicrobial activity of cefepime tested against ceftazidime-resistant gram-negative clinical strains from North American hospitals: report from the SENTRY Antimicrobial Surveillance Program (1998-2004). Diagn Microbiol Infect Dis 2006;56:63–68. 36. Rasheed JK, Biddle JW, Anderson KF, et al. Detection of the Klebsiella pneumoniae carbapenemase type 2 carbapenem-hydrolyzing enzyme in clinical isolates of Citrobacter freundii and K. oxytoca carrying a common plasmid. J Clin Microbiol 2008;46:2066–2069. 37. Shahid M. Citrobacter spp. simultaneously harboring blaCTX-M, blaTEM, blaSHV, blaampC, and insertion sequences IS26 and orf513: an evolutionary phenomenon of recent concern for antibiotic resistance. J Clin Microbiol 2010;48:1833–1838. 38. Ahmed AM, Shimamoto T. Emergence of a cefepime- and cefpirome-resistant Citrobacter freundii clinical isolate harbouring a novel chromosomally encoded AmpC beta-lactamase, CMY-37. Int J Antimicrob Agents 2008;32:256–261. 39. Jones RN, Kirby JT, Rhomberg PR. Comparative activity of meropenem in US medical centers (2007): initiating the 2nd decade of MYSTIC program surveillance. Diagn Microbiol Infect Dis 2008;61:203–213. 40. Rennie RP, Jones RN. Effects of breakpoint changes on carbapenem susceptibility rates of Enterobacteriaceae: results from the SENTRY Antimicrobial Surveillance Program, United States, 2008 to 2012. Can J Infect Dis Med Microbiol 2014;25:285–287. 41. Zhang R, Cai JC, Zhou HW, et al. Genotypic characterization and in vitro activities of tigecycline and polymyxin B for members of the Enterobacteriaceae with decreased susceptibility to carbapenems. J Med Microbiol 2011;60:1813–1819. 42. Haimi-Cohen Y, Amir J, Weinstock A, Varsano I. The use of imipenem-cilastatin in neonatal meningitis caused by Citrobacter diversus. Acta Paediatr 1993;82:530–532. 43. Rae CE, Fazio A, Rosales JP. Successful treatment of neonatal Citrobacter freundii meningitis with ceftriaxone. DICP 1991;25:27–29. 44. McPherson C, Gal P, Ransom JL. Treatment of Citrobacter koseri infection with ciprofloxacin and cefotaxime in a preterm infant. Ann Pharmacother 2008;42: 1134–1138. 45. Martinez-Lage JF, Martinez-Lage Azorin L, Almagro MJ, et al. Citrobacter koseri meningitis: a neurosurgical condition? Eur J Paediatr Neurol 2010;14:360–363.
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141 Citrobacter Species
Stella Antonara and Monica I. Ardura
MICROBIOLOGY AND EPIDEMIOLOGY The genus Citrobacter has undergone significant taxonomic revision through the use of newer techniques based on DNA relatedness. The genus contains 11 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, and C. rodentium.1–5 All species except C. rodentium (pathogenic for mice) have been recovered from human clinical specimens. However, C. freundii and C. koseri and C. braakii are the most important human pathogens. C. freundii, C. koseri, and C. amalonaticus appear to be distinct organisms, but 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. Citrobacter spp. are gram-negative bacilli in the family Enterobacteriaceae. They ferment glucose and other carbohydrates, are catalase and oxidase positive, and reduce nitrate. Most isolates are motile and use citrate as a sole carbon source, but they lack urease and lysine decarboxylase activity. Production of hydrogen sulfide varies, occurring in C. freundii and a few other species. On Salmonella-Shigella agar, lactose-negative and hydrogen sulfide–positive isolates of Citrobacter spp. produce black colonies resembling those of Salmonella spp. The lysine decarboxylase reaction allows separation of the hydrogen sulfide–producing isolates of Citrobacter spp. from Salmonella spp.1–5 Selected isolates of C. freundii have O (somatic) cell wall antigens closely related to the O antigens of Salmonella spp. and therefore crossreact with Salmonella typing antisera.1 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 biochemical and serologic methods. Identification of Citrobacter species also can be successfully achieved by the use of proteomic methods such as matrixassisted laser desorption/ionization–time of flight (MALDI-TOF) mass spectrometry.6,7 Any limitation in the identification of rarely encountered species depends on the inclusion of those species in the system’s database. Citrobacter spp. primarily are inhabitants of the intestinal 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 not common agents of human disease, and most often are 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, and wounds. The most common Citrobacter spp. isolated from human sources are C. freundii (all sites previously listed), C. koseri (all sites but most commonly the CSF and brain), C. amalonaticus (all sites except CSF), C. braakii (primarily stool), and C. youngae (primarily stool).2 The pathogenesis of infection has not been fully characterized. Most C. koseri isolates produce hemolysins, are piliated, and are resistant to
killing by pooled human sera. The proclivity to cause central nervous system (CNS) infection and particularly brain abscesses is not well understood. Tropism for the CNS may be associated with 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.8 C. freundii invades and replicates within brain microvascular endothelial cells in vitro.9 C. koseri can enter macrophages, survive phagolysosomal fusion, and replicate intracellularly in the neonatal rat model; infected macrophages can then infiltrate blood vessels in the brain, starting the process leading to brain abscess formation.1,10 Myeloid differentiation primary response gene 88 (MYD88)–dependent pathways in primary astrocytes are crucial for the induction of an inflammatory response and containment of C. koseri in CNS infection.11 In the pediatric population, infections occur most commonly in neonates.12,13 Organisms can be transmitted by vertical transmission from mothers or by nosocomial spread, although most are considered sporadic cases from an unknown source. Direct mother-to-infant transmission has been confirmed by ribotyping and DNA fingerprinting.14,15 It is likely that individual strains circulating in the community periodically gain access to a hospital nursery from the hands of nursery personnel and visitors.14,16,17 One nursery outbreak of C. freundii was traced to contaminated infant formula.18
CLINICAL MANIFESTATIONS Citrobacter spp. are opportunistic pathogens in humans that can lead to invasive disease, including infections of the urinary tract, respiratory tract, CNS, skin, and soft tissue. The bacteria can cause 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.12,13 Bacterial sepsis is associated with meningitis in about one half of cases. From 1969 to 1989 in Dallas, TX, Citrobacter spp. accounted for 9% of 91 cases of gram-negative enteric meningitis in infants 1 day to 2 years of age.19 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 (<1 week of life) or late-onset (>1 week of life) disease and can be fulminant or insidious. In 2002 and 2003, Citrobacter spp. caused 2.9% of early-onset sepsis in very low birth weight infants.20 No early features distinguish meningitis due to Citrobacter spp. from meningitis due to other gram-negative rods. Approximately 80% of infants with meningitis due to Citrobacter spp. develop one or more intracerebral abscesses (Fig. 141.1). In contrast, less than 10% of cases of infants with meningitis due to other gram-negative organisms have associated abscesses.12,13 Neonatal brain abscesses also can 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
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PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria
Citrobacter spp. were more frequent compared with historical cohorts and occurred solely in neonates.21 Brain abscesses can evolve any time during the acute course, including several weeks after commencement of treatment. The prognosis for meningitis due to Citrobacter spp. in neonates is poor. Approximately 30% to 35% of infected infants die, and only 15% to 20% survive with a structurally normal brain at completion of therapy; however, data on long-term prognosis are limited.12 Although at least 40% of survivors show some form of developmental delay or physical impairment, or both, there are reports of infants with brain abscesses due to Citrobacter spp. who develop normally.22 Other Citrobacter spp. infections in infants occur rarely. Gastroenteritis, osteomyelitis, pyogenic arthritis, pulmonary infections, and pneumatosis intestinalis have been described.13 In older children, adults, and immunocompromised hosts, Citrobacter spp. is associated most commonly with urinary tract, bloodstream, intra-abdominal, skin, soft tissue, and respiratory tract infections.23 Citrobacter spp. are the cause of urinary tract infection (UTI) in less than 3% of adults and children.24,25 In a review of 37 pediatric cases, the mean age was 6.9 years, with a range of 1 month to 18 years.24 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, including dysuria, fever, incontinence, frequency, flank pain, and hematuria. C. freundii accounted for 71% of cases, and C. koseri for the remainder. UTIs involving Citrobacter spp. and 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 after lung transplantation in 190 pediatric patients.26 Infections in immunocompromised patients more frequently are caused by multidrug-resistant strains.23,27–29 Eye infections, including keratitis and endogenous and traumatic endopthalmitis caused by Citrobacter spp., have been reported.30–32 An outbreak of severe gastroenteritis associated with several cases of hemolytic uremic syndrome occurred in a nursery school.33 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.
first-generation cephalosporins. C. freundii and some other Citrobacter spp. harbor chromosomal AmpC-type β-lactamases that can inactivate third-generation cephalosporins (see Chapter 140).34 This enzyme is not inhibited by β-lactamase inhibitors such as tazobactam or clavulanate. A US national surveillance study of hospital-associated bloodstream infections reported resistance patterns for 23 C. freundii isolates.35 Resistance to piperacillin, piperacillin/tazobactam, ceftriaxone, and ceftazidime occurred commonly (39%–48%); 96% of the ceftazidime-resistant isolates were susceptible to cefepime. Some strains of C. freundii also harbor extended-spectrum β-lactamases and Klebsiella pneumoniae–type carbapenemases (KPCs) that are found more commonly in Klebsiella spp. (see Chapter 138). These plasmidmediated enzymes are problematic because they are readily transferred from one strain to another in a healthcare environment.36,37 Citrobacter spp. usually are susceptible to fourth-generation cephalosporins such as cefepime (compared with third-generation cephalosporins such as ceftriaxone or ceftazidime) due to relative stability to inactivation by AmpC enzymes. Emergence of cefepime resistance in a clinical C. freundii strain due to a novel plasmid-mediated AmpCtype β-lactamase has been reported.38 The carbapenems typically are active. C. koseri susceptibility to trimethoprim-sulfamethoxazole and the aminoglycosides varies. Among 117 Citrobacter spp. from US hospitals in 2007, the rates of susceptibility to the agents listed were 100% for meropenem and imipenem, 98% for cefepime, 95% for ceftriaxone, 86% for ceftazidime, 94% for piperacillin/tazobactam, 96% for gentamicin, 95% for tobramycin, and 97% for ciprofloxacin and levofloxacin.39 In an antimicrobial surveillance study examining 776 Citrobacter species collected between 2008 and 2012 using the revised Clinical and Laboratory Standards Institute (CLSI) breakpoints for carbapenems, there was no significant change in the sensitivity of imipenem (97.1%), ertapenem (97.7%), meropenem (98.8%), and doripenem (98.9%).40 Multidrugresistant isolates may be susceptible to colistin, polymyxin B, and tigecycline.41 Optimal antimicrobial therapy for C. koseri meningitis has not been established, but a combination of a third- or fourth-generation cephalosporin plus an aminoglycoside to which the organism is susceptible is reasonable.13 Monotherapy with high-dose cefotaxime or ceftriaxone or with imipenem-cilastatin has been successful.42,43 Meropenem seems a logical carbapenem choice due to less potential for neurotoxicity. With recognition of the possible role of intracellular C. koseri in the pathogenesis of cerebral abscesses and possible poor CNS penetration of aminoglycosides, treatment with a third-generation cephalosporin in combination with ciprofloxacin has been used successfully.44 In infants with meningitis, a repeat lumbar puncture after 24 to 48 hours of antibiotic therapy should be performed to ensure CSF sterility. Neuroimaging should be obtained for all neonates with invasive Citrobacter infections. Neurosurgical drainage of abscesses has been used with various degrees of success. For patients with an accessible brain abscess, neurosurgical drainage is recommended if clinically feasible. For children who have progressive hydrocephalus and fibrous compartmentalization of the ventricular space, instillation of intraventricular urokinase also has been performed.45 In the presence of CNS abscesses, cultures of CSF should be performed regularly until sterility is documented. Meningitis without abscess formation usually is treated for a minimum of 21 days after the first sterile CSF culture. For intracranial abscesses, a 4- to 6-week course from initial sterile CSF cultures is the minimal duration usually recommended, depending on clinical and radiologic improvement.12,13 Testing for hearing loss and neurologic and developmental delays should be performed in all infants with Citrobacter spp. CNS infection. Prevention of infections due to Citrobacter spp. is related predominantly to preventing healthcare-associated infections. Strict cohorting of infected or colonized neonates is prudent but may not effectively control nursery outbreaks. Meticulous handwashing is mandatory.
TREATMENT
ACKNOWLEDGMENT
Most data on in vitro antimicrobial susceptibility and therapeutic management are for infections due to C. freundii and C. koseri. These organisms can harbor a wide variety of β-lactamases. Both species are resistant uniformly to ampicillin, and C. freundii is also resistant to
We acknowledge the substantial contributions of D.W. Powell and M.J. Marcon to this chapter in previous editions.
FIGURE 141.1 Computed tomography of a neonate with multiple brain abscesses caused by Citrobacter koseri.
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All references are available online at www.expertconsult.com.
Key Points: Diagnosis and Management of Infections With Citrobacter Species MICROBIOLOGY • Catalase-positive, oxidase-negative, gram-negative rod • Lactose fermenting on MacConkey media • Chromosomal AmpC-producing; resistant to ampicillin and first-generation cephalosporins EPIDEMIOLOGY • Normal enteric flora; also found in the environment • In infants <2 months, proclivity for CNS disease, including meningitis and brain abscesses • Most cases are sporadic; vertical and horizontal transmission are described. • Outbreaks support person-to-person transmission. DIAGNOSIS • C. koseri is recovered easily in cultures from CSF samples, without use of specialized media. • Use of PYR disk can differentiate atypical Citrobacter species (positive) from Salmonella species (negative).
KEY REFERENCES 12. Graham DR, Band JD. Citrobacter diversus brain abscess and meningitis in neonates. JAMA 1981;245:1923–1925. 13. Doran TI. The role of Citrobacter in clinical disease of children: review. Clin Infect Dis 1999;28:384–394. 19. Unhanand M, Mustafa MM, McCracken GH Jr, Nelson JD. Gram-negative enteric bacillary meningitis: a twenty-one-year experience. J Pediatr 1993;122:15–21. 20. Stoll BJ, Hansen NI, Higgins RD, et al. Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections contin-
• MALDI-TOF can differentiate Citrobacter spp. from other Enterobacteriaceae. TREATMENT • A combination of surgical and antimicrobial therapy typically is used. • Empiric therapy with a third- or fourth-generation cephalosporin plus an aminoglycoside is common but depends on local antimicrobial susceptibility data. • Targeted therapy should be guided by antimicrobial susceptibilities of the clinical isolate. DURATION OF THERAPY • Duration of therapy for meningitis is similar to that for other enteric gram-negative neonatal pathogens. • Prolonged therapy (4–6 weeks after documented CSF sterilization) is required for brain abscesses and is guided by clinical and imaging improvement.
ues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002-2003. Pediatr Infect Dis J 2005;24:635–639. 35. Pfaller MA, Sader HS, Fritsche TR, Jones RN. Antimicrobial activity of cefepime tested against ceftazidime-resistant gram-negative clinical strains from North American hospitals: report from the SENTRY Antimicrobial Surveillance Program (1998-2004). Diagn Microbiol Infect Dis 2006;56:63–68. 40. Rennie RP, Jones RN. Effects of breakpoint changes on carbapenem susceptibility rates of Enterobacteriaceae: results from the SENTRY Antimicrobial Surveillance Program, United States, 2008 to 2012. Can J Infect Dis Med Microbiol 2014;25:285–287.
Citrobacter Species
REFERENCES 1. Janda JM, Albott SL. The enterobacteria, Chapter 9. In: Janda JM, Albott SL (eds) The Enterobacteria, 2nd ed. Washington, DC, American Society for Microbiology, 2006, pp 115–135. 2. Brenner DJ, O’Hara CM, Grimont PA, et al. Biochemical identification of Citrobacter species defined by DNA hybridization and description of Citrobacter gillenii sp. nov. (formerly Citrobacter genomospecies 10) and Citrobacter murliniae sp. nov. (formerly Citrobacter genomospecies 11). J Clin Microbiol 1999;37:2619–2624. 3. Forsythe SJ, Abbott SL, Pitout J. Klebsiella, Enterobacter, Citrobacter, Cronobacter, Serratia, Plesiomonas, and Enterobacteriaceae. In: Jorgensen JH, Pfaller MA, Carroll KC, et al. (eds) Manual of Clinical Microbiology, 11th ed. Washington, DC, ASM Press, 2015, pp 714–737. 4. Winn WC, Allen SD, Janda WM. The enterobacteriaceae. In: Koneman EW (ed) Color Atlas and Textbook of Diagnostic Microbiology, 6th ed. Philadelphia, Lippincott-Williams & Wilkins, 2006, pp 211–302. 5. Forbes BA, Sahm DF, Weissfeld AS. Enterobacteriaceae. In: Forbes BA, Sahm DF, Weissfeld AS (eds) Bailey & Scott’s Diagnostic Microbiology, 12th ed. St Louis, Mosby, 2007, pp 323–333. 6. Kwak HL, Han SK, Park S, et al. Development of a rapid and accurate identification method for Citrobacter species isolated from pork products using a matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). J Microbiol Biotechnol 2015;25:1537–1541. 7. Richter SS, Sercia L, Branda JA, et al. Identification of Enterobacteriaceae by matrixassisted laser desorption/ionization time-of-flight mass spectrometry using the VITEK MS system. Eur J Clin Microbiol Infect Dis 2013;32:1571–1578. 8. Li J, Musser JM, Beltran P, et al. Genotypic heterogeneity of strains of Citrobacter diversus expressing a 32-kilodalton outer membrane protein associated with neonatal meningitis. J Clin Microbiol 1990;28:1760–1765. 9. Badger JL, Stins MF, Kim KS. Citrobacter freundii invades and replicates in human brain microvascular endothelial cells. Infect Immun 1999;67:4208–4215. 10. Townsend SM, Gonzalez-Gomez I, Badger JL. fliP influences Citrobacter koseri macrophage uptake, cytokine expression and brain abscess formation in the neonatal rat. J Med Microbiol 2006;55:1631–1640. 11. Liu S, Kielian T. MyD88 is pivotal for immune recognition of Citrobacter koseri and astrocyte activation during CNS infection. J Neuroinflamm 2011;8:35. 12. Graham DR, Band JD. Citrobacter diversus brain abscess and meningitis in neonates. JAMA 1981;245:1923–1925. 13. Doran TI. The role of Citrobacter in clinical disease of children: review. Clin Infect Dis 1999;28:384–394. 14. Harvey BS, Koeuth T, Versalovic J, et al. Vertical transmission of Citrobacter diversus documented by DNA fingerprinting. Infect Control Hosp Epidemiol 1995;16:564–569. 15. Papasian CJ, Kinney J, Coffman S, et al. Transmission of Citrobacter koseri from mother to infant documented by ribotyping and pulsed-field gel electrophoresis. Diagn Microbiol Infect Dis 1996;26:63–67. 16. Parry MF, Hutchinson JH, Brown NA, Wu CH. Estreller L. Gram-negative sepsis in neonates: a nursery outbreak due to hand carriage of Citrobacter diversus. Pediatrics 1980;65:1105–1109. 17. Goering RV, Ehrenkranz NJ, Sanders CC, Sanders WE Jr. Long term epidemiological analysis of Citrobacter diversus in a neonatal intensive care unit. Pediatr Infect Dis J 1992;11:99–104. 18. Thurm V, Gericke B. Identification of infant food as a vehicle in a nosocomial outbreak of Citrobacter freundii: epidemiological subtyping by allozyme, whole-cell protein and antibiotic resistance. J Appl Bacteriol 1994;76:553–558. 19. Unhanand M, Mustafa MM, McCracken GH Jr, Nelson JD. Gram-negative enteric bacillary meningitis: a twenty-one-year experience. J Pediatr 1993;122:15–21. 20. Stoll BJ, Hansen NI, Higgins RD, et al. Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002-2003. Pediatr Infect Dis J 2005;24:635–639. 21. Goodkin HP, Harper MB, Pomeroy SL. Intracerebral abscess in children: historical trends at Children’s Hospital Boston. Pediatrics 2004;113:1765–1770. 22. Leggiadro RJ. Favorable outcome possible in Citrobacter brain abscess. Pediatr Infect Dis J 1996;15:557.
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23. Samonis G, Anaissie E, Elting L, Bodey GP. Review of Citrobacter bacteremia in cancer patients over a sixteen-year period. Eur J Clin Microbiol Infect Dis 1991;10:479–485. 24. Gill MA, Schutze GE. Citrobacter urinary tract infections in children. Pediatr Infect Dis J 1999;18:889–892. 25. Zhanel GG, Hisanaga TL, Laing NM, et al. Antibiotic resistance in outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents 2005;26:380–388. 26. Danziger-Isakov LA, Sweet S, Delamorena M, et al. Epidemiology of bloodstream infections in the first year after pediatric lung transplantation. Pediatr Infect Dis J 2005;24:324–330. 27. Bui KT, Mehta S, Khuu TH, et al. Extended spectrum beta-lactamase-producing Enterobacteriaceae infection in heart and lung transplant recipients and in mechanical circulatory support recipients. Transplantation 2014;97:590–594. 28. Collin BA, Leather HL, Wingard JR, Ramphal R. Evolution, incidence, and susceptibility of bacterial bloodstream isolates from 519 bone marrow transplant patients. Clin Infect Dis 2001;33:947–953. 29. Linares L, Cervera C, Cofan F, et al. Epidemiology and outcomes of multiple antibiotic-resistant bacterial infection in renal transplantation. Transplant Proc 2007;39:2222–2224. 30. Roy R, Pradeep Kumar P, Malathi J, et al. Endophthalmitis caused by Citrobacter species: a case series. Can J Ophthalmol 2013;48:216–217. 31. Chiu CH, Peng MY, Wang YC, Chang FY. Endogenous endophthalmitis caused by Citrobacter koseri. Am J Med Sci 2009;338:509–510. 32. Goold LA, Warrier SK, Wittles NK, Nathan F. Microbial keratitis secondary to infection with Citrobacter koseri. Cornea 2010;29:479. 33. Tschape H, Prager R, Streckel W, et al. Verotoxinogenic Citrobacter freundii associated with severe gastroenteritis and cases of haemolytic uraemic syndrome in a nursery school: green butter as the infection source. Epidemiol Infect 1995;114:441–450. 34. Hanson ND, Sanders CC. Regulation of inducible AmpC beta-lactamase expression among Enterobacteriaceae. Curr Pharmaceut Design 1999;5:881–894. 35. Pfaller MA, Sader HS, Fritsche TR, Jones RN. Antimicrobial activity of cefepime tested against ceftazidime-resistant gram-negative clinical strains from North American hospitals: report from the SENTRY Antimicrobial Surveillance Program (1998-2004). Diagn Microbiol Infect Dis 2006;56:63–68. 36. Rasheed JK, Biddle JW, Anderson KF, et al. Detection of the Klebsiella pneumoniae carbapenemase type 2 carbapenem-hydrolyzing enzyme in clinical isolates of Citrobacter freundii and K. oxytoca carrying a common plasmid. J Clin Microbiol 2008;46:2066–2069. 37. Shahid M. Citrobacter spp. simultaneously harboring blaCTX-M, blaTEM, blaSHV, blaampC, and insertion sequences IS26 and orf513: an evolutionary phenomenon of recent concern for antibiotic resistance. J Clin Microbiol 2010;48:1833–1838. 38. Ahmed AM, Shimamoto T. Emergence of a cefepime- and cefpirome-resistant Citrobacter freundii clinical isolate harbouring a novel chromosomally encoded AmpC beta-lactamase, CMY-37. Int J Antimicrob Agents 2008;32:256–261. 39. Jones RN, Kirby JT, Rhomberg PR. Comparative activity of meropenem in US medical centers (2007): initiating the 2nd decade of MYSTIC program surveillance. Diagn Microbiol Infect Dis 2008;61:203–213. 40. Rennie RP, Jones RN. Effects of breakpoint changes on carbapenem susceptibility rates of Enterobacteriaceae: results from the SENTRY Antimicrobial Surveillance Program, United States, 2008 to 2012. Can J Infect Dis Med Microbiol 2014;25:285–287. 41. Zhang R, Cai JC, Zhou HW, et al. Genotypic characterization and in vitro activities of tigecycline and polymyxin B for members of the Enterobacteriaceae with decreased susceptibility to carbapenems. J Med Microbiol 2011;60:1813–1819. 42. Haimi-Cohen Y, Amir J, Weinstock A, Varsano I. The use of imipenem-cilastatin in neonatal meningitis caused by Citrobacter diversus. Acta Paediatr 1993;82:530–532. 43. Rae CE, Fazio A, Rosales JP. Successful treatment of neonatal Citrobacter freundii meningitis with ceftriaxone. DICP 1991;25:27–29. 44. McPherson C, Gal P, Ransom JL. Treatment of Citrobacter koseri infection with ciprofloxacin and cefotaxime in a preterm infant. Ann Pharmacother 2008;42: 1134–1138. 45. Martinez-Lage JF, Martinez-Lage Azorin L, Almagro MJ, et al. Citrobacter koseri meningitis: a neurosurgical condition? Eur J Paediatr Neurol 2010;14:360–363.
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