Citrobacter species

Authors: Shan-Chwen Chang, M.D., Ph.D.

MICROBILOGY Guided Medline Search

Citrobacter species are straight, facultative anaerobic, Gram-negative bacilli and are typically motile by means of peritrichous flagellae. This genus was proposed in 1932 by Werkman and Gillen (48). Before 1993, only three species, Citrobacter freundii, Citrobacter koseri (Citrobacter diversus), and Citrobacter amalonaticus, were recognized. C. freundii is the type species in this genus, and the later two species have been called other names. C. koseri was accepted to replace the name C. diversus by the Judicial Commission of the International Committee on Systematic Bacteriology in 1993 (26). In the same year, Brenner et al. classified Citrobacter into 11 genomospecies by DNA hybridization: C. freundii, C. koseri, C. amalonaticus, C. farmeri, C. youngae, C. braakii, C. werkmanii, C. sedlakii, and unnamed genomospecies 9, 10 and 11 (8). Later, genomospecies 9, 10 and 11 were named as C. rodentium, C. gillenii, and C. murliniae (9, 44).

EPIDEMIOLOGY Guided Medline Search

Citrobacter species are commonly found in water, soil, food, and the intestinal tracts of animals and humans. Many Citrobacter infections are nosocomially acquired; however, they can also be community acquired. According to data from the National Nosocomial Infection Surveillance (NNIS) Study, during 1986-1989, Citrobacter accounted for 2% of total nosocomial infections (43). In patient with Citrobacter infections, the bacteria can be transmitted vertically from mother or horizontally from carriers or other hospital sources (13). The infection may occur as sporadic cases or nosocomial outbreaks. Vertical or nosocomial transmission may account for the origin of bacteria in some sporadic cases, and transmission from carriers such as family members or other contacts accounts for others.

CLINICAL MANIFESTATIONS Guided Medline Search

Two groups of patients are at risk of acquiring Citrobacter infections. The first one is neonates, who may develop sepsis and meningitis and have a propensity for development of brain abscesses. C. koseri can cause an unusually severe form of neonatal meningitis, associated with necrotizing encephalitis and brain abscesses (13, 18, 27). The second group is debilitated or immunocompromised patients. Like other Enterobacteriaceae, Citrobacter can cause a wide spectrum of infections in humans, such as infections in the urinary tract, respiratory tract, wounds, bone, peritoneum, endocardium, meninges, and bloodstream (32). Among the various sites of infection, the urinary tract is the most common, followed by the respiratory tract, and skin/soft tissues. Among 1441 nosocomial Citrobacter infection patients, 812 had urinary tract infection, 321 had surgical wound infection, 226 had pneumonia, and 82 had bloodstream infection. Citrobacter infection is not uncommon, and some authors have reported an increase in the incidence of Citrobacter infections (42).

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LABORATORY DIAGNOSIS Guided Medline Search

Patients with Citrobacter infection can be identified and confirmed only by culture. Citrobacter species can grow in various culture medium. All species identified as Citrobacter ferment glucose with production of gas. With few exceptions the organisms are motile and utilize citrate. Different species can be differentiated by biochemical tests. The interpretation of antimicrobial susceptibility testing follows the criteria used for Enterobacteriaceae.

PATHOGENESIS Guided Medline Search

The organisms probably colonize the oral cavity, lower gastrointestinal tract, or respiratory tract first. Later it may result into infection of various sites, including bacteremia and central nervous system (CNS) infection. Nosocomial outbreaks are largely due to gastrointestinal and hand carriage by hospital personnel (17, 31, 38).

The particular propensity of C. koseri for CNS is not well understood. A specific outer-membrane protein of 32-kilodalton was proposed to be related to the tropism of this organism for nervous tissues and causing meningitis and abscesses (28, 30).

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SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro,Guided Medline Search In Vivo

Single Drug

Different species of Citrobacter demonstrate different antimicrobial susceptibility profiles. C. freundii is generally much more resistant to antimicrobial agents than C. koseri (C. diversus), with C. amalonaticus having a susceptibility profile intermediate between those two species. In the 1970s, isolates of C. koseri (C. diversus) were usually resistant to ampicillin and carbenicillin but susceptible to cephalothin; in contrast, isolates of C. freundii were usually susceptible to ampicillin and carbenicillin but resistant to cephalothin (22, 25, 33). This characteristic was even proposed for use in species identification (46). However, C. freundii had become more resistant to many antimicrobial agents, including ampicillin and carbenicillin, so classification of species by antibiotic susceptibility pattern is no longer valid.

Current isolates of C. koseri (C. diversus) remain more susceptible than C. freundii to various anti-Gram-negative agents, except ampicillin. However, isolates of C. freundii in recent years have demonstrated resistance not only to traditional agents such as ampicillin, carbenicillin, and cephalothin, but also to newer agents such as piperacillin, third-generation cephalosporins, and monobactams. Table 1 shows the antimicrobial susceptibilities of Citrobacter isolates obtained from blood cultures from M.D. Anderson, Houston, Texas. C. freundii is more resistant than C. koseri to most antimicrobial agents (41). The minimum inhibitory concentrations (MICs) of various antimicrobial agents for C. freundii were higher than those C. koseri. Aminoglycosides (gentamicin, netilmicin, amikacin), fluoroquinolones (enoxacin, ciprofloxacin), and carbapenems (imipenem) were the most active agents against both C. freundii and C. koseri (41).

Other fluoroquinolones and carbapenems, such as fleroxacin, levofloxacin, lomefloxacin, sparfloxacin, moxifloxacin, gatifloxacin, gemifloxacin, meropenem, and biapenem, also displayed good in vitro activity against Citrobacter (3, 4, 6, 12, 21, 39, 40, 51). These new fluoroquinolones usually have MIC90s of 1 mg/mL or less against Citrobacter and the new carbapenems have MIC90s of 0.125 m>g/mL or less in most studies. Some newer parenteral cephems, such as cefepime and cefpirome, also have good in vitro activity against Citrobacter (MIC50s ≤ 0.125 mg/mL; MIC90s ≤ 8 mg/mL) (5, 24, 36).  

Table 2 shows comparative antimicrobial susceptibility of C. freundii isolates collected at a university hospital in Taiwan during 1987-1988 and 1997-1998. Compared to earlier isolates, the susceptibility to many agents of C. freundii isolates in recent years decreased. However, the in vitro activity of newer cephems (cefepime and cefpirome) and carbapenems (imipenem and meropenem) remained very good against recent isolates of C. freundii (47).

As for oral b-lactam agents, penicillins and first- and second-generation cephalosporins do not have activity against most C. freundii isolates but may have activity against some C. koseri isolates. Some newer or third-generation oral cephalosporins, such as cefixime, cefpodoxime proxetil, cefprozil, cefetamet pivoxil, and ceftibuten, have good activity against C. koseri but only moderate or poor activity against C. freundii (10, 15, 49, 50). The MIC90s for C. koseri are usually 4 mg/mL or less, but for C. freundii they usually exceed 16 mg/mL.

β-lactamase production is a common phenomenon in both C. freundii and C. koseri isolates. The b-lactamase produced by C. freundii is a type I b-lactamase that is not inhibited by clavulanic acid, sulbactam, and tazobactam. Therefore, for C. freundii, the MICs of b-lactam antibiotics in combination with a b-lactamase inhibitor, such as ampicillin plus sulbactam, amoxicillin plus clavulanic acid, ticarcillin plus clavulanic acid, and piperacillin plus tazobactam, are similar or identical to those of the b-lactam antibiotics alone (11, 35).

Other agents, such as tetracycline, chloramphenicol, and trimethoprim/sulfamethoxazole showed good antimicrobial activities in previous studies or case reports, although few data exist about their antimicrobial activities against isolates after 1990. Disk susceptibility tests in the National Taiwan University Hospital generally showed in vitro resistance to tetracycline, chloramphenicol, and trimethoprim/sulfamethoxazole in C. freundii isolates (Table 3). These agents appear to have good in vitro activity against C. koseri; however, the susceptibility of C. koseri to trimethoprim/sulfamethoxazole seems decreasing in recent years. One study from Belgium demonstrated 100% susceptibility of 23 strains of C. koseri to trimethoprim/sulfamethoxazole (2).

In summary, aminoglycosides, fluoroquinolones, carbapenems, and some newer cephems (including cefepime and cefpirome) have the highest in vitro antimicrobial activities against C. freundii. There are high proportions of resistance to other agents. For C. koseri (C. diversus), in addition to aminoglycosides, fluoroquinolones, carbapenems, and newer cephems (cefepime and cefpirome), many other agents, such as the third-generation cephalosporins, aztreonam, piperacillin, piperacillin plus tazobactam, and some new oral cephems (including cefixime, cefpodoxime proxetil, cefprozil, cefetamet pivoxil, and ceftibuten) also have good in vitro activities.

In vitro susceptibility data from the National Taiwan University Hospital show that isolates of C. freundii have a tendency to be more resistant (Table 2) and similar to the M.D. Anderson Hospital experience (41). C. freundii can be easily induced to become resistant to b-lactams in vitro (16). Similarly, patients who received previous antibiotic treatment acquired cephalosporin-resistant or multiply-resistant Citrobacter infection more easily (23, 37, 45). In addition, fluoroquinolone-resistant Citrobacter isolates were often detected in some geographic areas (Table 2) (1). Therefore continuous monitoring of the vitro susceptibilities of Citrobacter to various antimicrobial agents is mandatory to provide information on choosing drugs for the treatment of Citrobacter infections.

Combination Drugs

To our knowledge, there have been few, if any, systemic in vitro studies of antimicrobial combinations against Citrobacter.

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Antimicrobial Therapy Guided Medline Search Smart search

Drug of Choice

There are no comparative studies of antibiotic therapy for Citrobacter infections. Thus, treatment of Citrobacter infections follows the principles for treatment of other Enterobacteriaceae infections. Based on the in vitro antimicrobial susceptibilities described above, aminoglycosides, fluoroquinolones, carbapenems, and the new cephems, such as cefepime and cefpirome, would appear to be preferred therapeutic agents for C. freundii infections.

For treatment of C. koseri infections, more active agents are available than for treatment of C. freundii infections. In addition to the agents mentioned above for C. freundii infections, the third-generation cephalosporins, aztreonam, piperacillin, piperacillin plus tazobactam, and many new oral cephems (including cefixime, cefpodoxime proxetil, cefprozil, cefetamet pivoxil, and ceftibuten) can also be used for treatment of C. koseri infections. Of these agents, the third-generation cephalosporins, aztreonam, and piperacillin could be considered first-line drugs for empirical treatment of C. koseri infections.

Once a specific strain is isolated from a patient, therapeutic agents should be selected according to the in vitro susceptibility results of that strain. For strains susceptible to several different agents, there are no comparative studies that suggest superiority of one agent over another. We assume that there is probably little difference among various agents that are active in vitro. However, treatment with agents that are active in vitro give better results than treatment with agents that are resistant in vitro (42, 45). Of course, the site of infection influences choice of agents. For example, agents with blood-brain barrier penetration are more suitable for Citrobacter CNS infection.

Special Situations

Bacteremia:

Shih et al. found that the combination of a b-lactam and an aminoglycoside had better therapeutic results than a single agent alone for Citrobacter bacteremia (45). Of the 18 patients who received combination therapy with a b-lactam and an aminoglycoside, only one (5.6%) died, whereas five (45.5%) of 11 patients who received monotherapy with a third-generation cephalosporin died. Combination therapy was also more protective than single-agent regimens. Seven (25.9%) of 27 patients who received single-agent treatment died (45). Thus, for treating patients with Citrobacter bacteremia, the combination of a b-lactam agent and an aminoglycoside is preferred. This probably could be applied to other patients with severe or complicated Citrobacter infections. Combination therapy should also be considered for patients with major underlying diseases or immunocompromised patients with Citrobacter infections.

Meningitis:

Recommendations for treatment of Citrobacter meningitis are based largely on the authors’ personal experience, published case reports, and general experience with Gram-negative bacillary meningitis.

For C. koseri meningitis in neonates, early appropriate antibiotic treatment is important since the mortality rate is high (>30%), and a high proportion of patients develop neurologic sequelae (>50%) (13, 18, 27). Currently, a third-generation cephalosporin in combination with an aminoglycoside is the treatment of choice for treating C. koseri meningitis (13, 27). The dosage should be high enough to treat CNS infections, for example: using cefotaxime 300 mg/kg/day (6). In addition, patients should receive a minimum of 21 days of antibiotic therapy after sterilization of the cerebrospinal fluid to minimize the possibility of recurrent infection. If a brain abscess develops, the duration of treatment needs to be prolonged to more than 6 week after sterilization of cerebrospinal fluid.

Alternative Therapy

Many agents that are active in vitro as mentioned above could be used as alternative therapy. Shih et al. suggested that fluoroquinolones could be good alternative agents in treating Citrobacter bacteremia in patients allergic to b-lactams (45).

In C. koseri meningitis, trimethoprim/sulfamethoxazole was effective for a patient with C. koseri meningitis and ventriculitis (19). Due to its good CNS penetration and better intracellular penetration into phagocytes, trimethoprim/sulfamethoxazole has been suggested as an alternative agent for treating C. koseri meningitis/brain abscesses, even in patients who failed to respond to other antimicrobial treatments (13, 27). Chloramphenicol also has good CNS penetration and good activity against C. koseri, and has been used extensively to treat C. koseri meningitis/brain abscesses (27). Imipenem has also been used successfully to treat an infant with C. koseri meningitis (20).

It is not known (a) whether a fluoroquinolone, a carbapenem, or a so-called fourth-generation new cephalosporin could be as effective as or even better than a third-generation cephalosporin; (b) whether the combination of an aminoglycoside with a fluoroquinolone, a carbapenem, or a fourth-generation cephalosporin could be as effective as, or better than, a third-generation cephalosporin in combination with an aminoglycoside in the treatment of Citrobacter infection. It is also not really known whether there is any difference between treatment of Citrobacter infections and treatment of other Enterobacteriaceae infections.

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ADJUNCTIVE THERAPY Guided Medline Search

For patients with C. koseri brain abscesses, surgical drainage or aspiration of the abscesses should be strongly considered, but it is not always feasible because the abscesses are often multiple or inaccessible. Brain abscesses caused by C. koseri have been reported to be cured by medical therapy alone (7, 29, 34). However, combination of antimicrobial therapy and surgical drainage/aspiration, if feasible, would be the preferred therapy. Sometimes aspiration will confirm the etiology when CSF and blood cultures do not find any pathogen. After antibiotic treatment, some infants will require ventriculoperitoneal shunting for hydrocephalus.

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ENDPOINTS OF MONITORING THERAPY Guided Medline Search

For most Citrobacter infections, the endpoints for monitoring therapy are similar to those for other Enterobacteriaceae infections. The antimicrobial agents should be given until symptoms and signs of infection disappear, such as resolution of dysuria, pyuria, and/or flank pain in patients with urinary tract infection; resolution of fever, cough, and sputum production in patients with pneumonia; resolution of purulent discharge and evidence of wound healing in patients with wound infections; and resolution of fever and negative blood culture in patients with bacteremia.

For C. koseri meningitis, almost daily lumbar punctures are suggested for monitoring the effect of antimicrobial treatment until the spinal fluid is sterile. Because of the high prevalence of brain abscesses in infants with Citrobacter meningitis, computed tomography (CT) is mandatory in every case. If the initial scan does not detect any brain abscesses, CT scanning should be repeated at least weekly to monitor if brain abscesses appear during the course of therapy (27).

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VACCINES Guided Medline Search

There is no commercially available vaccine for prevention of Citrobacter infection.

PREVENTION AND INFECTION CONTROL MEASURES Guided Medline Search

Since several nosocomial outbreaks of Citrobacter infections have been reported and the sources of the organisms have been found to be the gastrointestinal tracts or hands of hospital staff members, infection control measures to prevent person-to-person transmission, such as hand washing, are the most important measures to prevent Citrobacter infection. As to the sporadic reports of vertical transmission from mother to child, there is no good recommendation to prevent the transmission. Good habits of hygiene probably may prevent transmission from environmental sources or carrier of family members.

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References

1. Aoyama H, Fujimaki K, Sato K, Fujii T, Inoue M, Hirai K, Mitsuhashi S. Clinical isolate of Citrobacter freundii highly resistant to new quinolones. Antimicrob Agents Chemother 1988;38:922-924. [PubMed]

2. Arens S, Verhaegen J, Verbist L. Differentiation and susceptibility of Citrobacter isolates from patients in a university hospital. Clin Microbiol Infect 1997;3:53-57. [PubMed]

3. Balfour JAB, Todd PA, Peters DH. Fleroxacin: a review of its pharmacology and therapeutic efficacy in various infections. Drugs 1995;49:794-850. [PubMed]

4. Balfour JAB, Wiseman LR. Moxifloxacin. Drugs 1999;57:363-373. [PubMed]

5. Barradell LB, Bryson HM. Cefepime: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1994;47:471-505. [PubMed]

6. Bauernfeind A. Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin. J Antimicrob Chemother 1997;40:639-651. [PubMed]

7. Baumeister FA, Hofer M, Kuster H, Belohradsky BH. CSF interleukin-6 in neonatal Citrobacter ventriculitis after meningitis. Infection 2000;28:243-245. [PubMed]

8. Brenner DJ, Grimont PA, Steigerwalt AG, Fanning GR, Ageron E, Riddle CF. Classification of Citrobacter farmeri sp. nov., Citrobacter youngae sp. nov., Citrobacter sedlakii sp. nov., and three unnamed Citrobacter genospecies. Int J Syst Bacteriol 1993;43:645-658. [PubMed]

9. Brenner DJ, O’hara CM, Grimont PA, Janda JM, Falsen E, Aldova E, Ageron E, Schindler J, Abbott SL, Steigerwalt AG. 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. [PubMed]

10. Bryson HM, Brogden RN. Cefetamet pivoxil: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1993;45-589-621. [PubMed]

11. Bryson HM, Brogden RN. Piperacillin/tazobactam: a review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs 1994;47:506-535. [PubMed]

12. Davis R, Bryson HM. Levofloxacin: a review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs 1994;47:677-700. [PubMed]

13. Doran TI. The role of Citrobacter in clinical disease of children: review. Clin Infect Dis 1999;28:384-394. [PubMed]

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References

1. Aoyama H, Fujimaki K, Sato K, Fujii T, Inoue M, Hirai K, Mitsuhashi S. Clinical isolate of Citrobacter freundii highly resistant to new quinolones. Antimicrob Agents Chemother 1988;38:922-924. [PubMed]

2. Arens S, Verhaegen J, Verbist L. Differentiation and susceptibility of Citrobacter isolates from patients in a university hospital. Clin Microbiol Infect 1997;3:53-57. [PubMed]

3. Balfour JAB, Todd PA, Peters DH. Fleroxacin: a review of its pharmacology and therapeutic efficacy in various infections. Drugs 1995;49:794-850. [PubMed]

4. Balfour JAB, Wiseman LR. Moxifloxacin. Drugs 1999;57:363-373. [PubMed]

5. Barradell LB, Bryson HM. Cefepime: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1994;47:471-505. [PubMed]

6. Bauernfeind A. Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin. J Antimicrob Chemother 1997;40:639-651. [PubMed]

7. Baumeister FA, Hofer M, Kuster H, Belohradsky BH. CSF interleukin-6 in neonatal Citrobacter ventriculitis after meningitis. Infection 2000;28:243-245. [PubMed]

8. Brenner DJ, Grimont PA, Steigerwalt AG, Fanning GR, Ageron E, Riddle CF. Classification of Citrobacter farmeri sp. nov., Citrobacter youngae sp. nov., Citrobacter sedlakii sp. nov., and three unnamed Citrobacter genospecies. Int J Syst Bacteriol 1993;43:645-658. [PubMed]

9. Brenner DJ, O’hara CM, Grimont PA, Janda JM, Falsen E, Aldova E, Ageron E, Schindler J, Abbott SL, Steigerwalt AG. 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. [PubMed]

10. Bryson HM, Brogden RN. Cefetamet pivoxil: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1993;45-589-621. [PubMed]

11. Bryson HM, Brogden RN. Piperacillin/tazobactam: a review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs 1994;47:506-535. [PubMed]

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