What is the best treatment options for Citrobacter braakii infections. What resistance patterns are out there. How is this bacteria alike and different from other Citrobacter species.

Comment by InpharmD Researcher

Citrobacter braakii is an infrequently encountered pathogen that primarily affects immunocompromised patients and poses therapeutic challenges because of its resistance mechanisms. Similar to other Citrobacter species, C. braakii exhibits substantial genetic diversity and a propensity for multidrug resistance mediated by both chromosomal and plasmid-encoded mechanisms. Its antimicrobial susceptibility profile resembles that of the C. freundii complex, with high resistance to β-lactams such as ampicillin, amoxicillin–clavulanate, and cefazolin, and variable susceptibility to ceftriaxone. Based on limited published data—largely case reports and in vitro analyses of clinical isolates—cefepime and carbapenems appear to provide the most reliable coverage. The available literature also suggests relatively low resistance to fluoroquinolones, with several case reports documenting successful clinical use (Tables 2–3). Overall, further research is needed to better define the epidemiology, clinical significance, and resistance patterns of C. braakii, and to inform optimized antimicrobial stewardship and clinical management strategies.

PubMed

Background

A 2023 review provides a detailed examination of the Citrobacter species, focusing on the growing threat they pose to public health due to their increasing antimicrobial resistance. Among the species discussed, Citrobacter braakii is highlighted for its involvement in various infections, including urinary tract infections and meningitis. This species has been isolated from different clinical samples across the globe, including wound infections and cases presenting with severe underlying medical conditions such as diabetes and cardiovascular disease. The review emphasizes that Citrobacter braakii exhibits resistance to multiple antibiotics, including beta-lactams and fluoroquinolones, posing a significant challenge for treatment. The resistance is often mediated by chromosomal and plasmid mechanisms, complicating empirical treatment options and necessitating the use of combination therapies that are often costly and potentially hazardous. The 2023 review also explores the epidemiology and virulence factors associated with Citrobacter braakii, which contribute to its pathogenicity in causing opportunistic infections in immunocompromised patients. The study notes the species' capability to form biofilms and produce toxins, factors which enhance its ability to colonize and invade host tissues. These characteristics, coupled with its multidrug-resistant nature, underscore the critical need for improved infection control measures and comprehensive surveillance to mitigate the spread of Citrobacter braakii infections in healthcare settings. [1]

A 2020 publication detailed the genetic diversity, antimicrobial resistance, and virulence characteristics of Citrobacter spp., with a focus on Citrobacter braakii. This study involved the analysis of 128 Citrobacter isolates collected from human diarrheal patients, foods, and the environment in Shijiazhuang, Hebei Province, China. Among these, 45 isolates were identified as C. braakii, which were classified into 42 distinct sequence types (STs), indicating a high genetic diversity. Notably, Lineage III contained all C. braakii isolates and displayed the highest prevalence of quinolone resistance among the lineages, with 52.6% of the isolates showing resistance. The antimicrobial resistance profile revealed that C. braakii isolates exhibited multidrug resistance (MDR) with 46.7% being resistant to at least one antibiotic from three or more distinct classes. Additionally, the study identified significant quinolone resistance in C. braakii with several isolates harboring mutations in the quinolone resistance-determining regions (QRDR) of the gyrA gene. The isolates also carried various plasmid-mediated quinolone resistance (PMQR) genes, including qnr and aac(6')-Ib-cr. Furthermore, C. braakii isolates were also assessed for their virulence potential, with some isolates showing high cytotoxicity and adhesion properties, indicating a potential pathogenic role in causing diarrheal disease. [2]

According to a 2022 study, Citrobacter braakii was isolated from solid-organ transplant patients during a surveillance for multidrug-resistant Enterobacteriaceae. Among the 57 strains of cefpodoxime-resistant Citrobacter spp. identified, 10 were Citrobacter braakii. These strains displayed resistance to multiple antibiotics, including cephalosporins, aminoglycosides, and trimethoprim-sulfamethoxazole. Notably, one clinical isolate obtained from a urine specimen in the study was Citrobacter braakii, indicating its presence in both colonizing and potential infection scenarios. Pulsed-field gel electrophoresis (PFGE) revealed 36 unique strains of Citrobacter among 32 patients, highlighting the genetic diversity of these isolates. Moreover, Citrobacter braakii was recognized for its novel association with class I integrons in this study, marking the first report of integrons encoding resistance mechanisms in this species. Despite the prevalence of multidrug-resistant strains, the study noted that these low-virulence species only led to a single recorded infection with a colonizing strain over 18 months, suggesting limited pathogenic potential in the hospitalized, immunocompromised population. [3]

A 1997 clinical paper presents findings on Citrobacter braakii within a study conducted at the University Hospital St Rafael in Leuven, Belgium. This research involved the collection of 126 samples from 116 patients over a six-month period, during which the identification, differentiation, and susceptibility of various Citrobacter species were analyzed. Citrobacter braakii was identified as the second most common species, following Citrobacter freundii, with a prevalence of 21.6% among the isolates. This species demonstrated a significant presence in the urinary and respiratory tracts, and it was often associated with predisposing factors such as intubation, tracheostomy, or serious debilitating conditions. In terms of antimicrobial susceptibility, Citrobacter braakii exhibited resistance patterns that were comparable to those seen in the C. freundii complex. Specifically, the strains were generally resistant to ampicillin, amoxicillin-clavulanate, and cefazolin, with percentages of resistance being 96%, 96%, and 98%, respectively. However, these strains were found to be sensitive to newer antibiotics like ceftazidime, cefepime, and imipenem. The findings underscore the opportunistic nature of Citrobacter braakii as a pathogen in hospital settings, where it contributes to infections frequently encountered in patient populations with underlying health issues. [4]

A 2007 observational study examined the antibiotic sensitivity pattern of Citrobacter species isolated from various clinical specimens at Kasturba Medical College, Mangalore. Using the Kirby-Bauer disk diffusion method, the study evaluated 709 isolates to determine their antimicrobial susceptibility. Results revealed that all isolates were susceptible to Imipenem, demonstrating a 100% susceptibility rate, while there was a complete resistance to Ampicillin. The variability in susceptibility to third-generation cephalosporins was notable, with rates ranging from 29% to 43%, indicating a significant level of resistance. Further detailed investigation using agar dilution methods determined the minimum inhibitory concentration (MIC) of Cephotaxime, considering MIC values equal to or less than 8 µg/ml as susceptible. Among the assessed strains, 253 were fully susceptible, 71 exhibited intermediate susceptibility, and 385 were fully resistant to Cephotaxime. The study emphasized that the use of beta-lactamase inhibitor combinations with beta-lactam antibiotics increased sensitivity, suggesting a potential strategy to mitigate resistance. These findings underscore the complex nature of antibiotic resistance in Citrobacter species, highlighting the critical need for tailored antibiotic stewardship in clinical settings to effectively manage infections. [5]

A 2018 case report described a 67-year-old man with acute myeloid leukemia who developed septic shock due to Citrobacter braakii during chemotherapy with high-dose cytosine arabinoside. Treatment with cefepime led to rapid clinical improvement, highlighting the antibiotic’s effectiveness against this rare pathogen. The authors emphasized that reported cases of C. braakii sepsis are limited and that further case accumulation is needed to clarify risk factors. Additional details are unavailable as the full article is published in Japanese. [6]

References: [1] Jabeen I, Islam S, Hassan AKMI, Tasnim Z, Shuvo SR. A brief insight into Citrobacter species - a growing threat to public health. Front Antibiot. 2023;2:1276982. Published 2023 Dec 5. doi:10.3389/frabi.2023.1276982
[2] Liu L, Qin L, Hao S, et al. Lineage, Antimicrobial Resistance and Virulence of Citrobacter spp. Pathogens. 2020;9(3):195. Published 2020 Mar 6. doi:10.3390/pathogens9030195
[3] Pepperell C, Kus JV, Gardam MA, Humar A, Burrows LL. Low-virulence Citrobacter species encode resistance to multiple antimicrobials. Antimicrob Agents Chemother. 2002;46(11):3555-3560. doi:10.1128/AAC.46.11.3555-3560.2002
[4] Arens S, Verbist L. Differentiation and susceptibility of Citrobacter isolates from patients in a university hospital. Clin Microbiol Infect. 1997;3(1):53-57. doi:10.1111/j.1469-0691.1997.tb00251.x
[5] Shetty J, Kotigadde S. Antibiotic sensitivity pattern of Citrobacter isolated from various clinical specimens in a tertiary care hospital. Indian J Pathol Microbiol. 2007;50(3):666-668.
[6] Seo H, Manabe M, Ogata Y, et al. Rinsho Ketsueki. 2018;59(5):492-494. doi:10.11406/rinketsu.59.492
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the best treatment options for Citrobacter braakii infections. What resistance patterns are out there. How is this bacteria alike and different from other Citrobacter species.

Level of evidence

D - Case reports or unreliable data  Read more→



Please see Tables 1-3 for your response.


Antimicrobial Resistance and Molecular Characterization of Citrobacter spp. Causing Extraintestinal Infections
Design

Prospective study

N= 46

Objective To investigate molecular characteristics and antimicrobial susceptibility patterns of Citrobacter spp. from extraintestinal infections
Study Groups All patients (n= 46)
Inclusion Criteria Citrobacter spp. isolates obtained from urine, sputum, bile, secretion, and blood samples from 2014 to 2018 in Maanshan people's hospital, Anhui Province, China
Exclusion Criteria Not specified
Methods Forty-six clinical Citrobacter spp. isolates were analyzed by multilocus sequence typing (MLST) using seven housekeeping genes. Antimicrobial susceptibility testing was performed by disk diffusion method according to CLSI recommendations. Adhesion and cytotoxicity to HEp-2 cells were assessed. 
Duration September 2014 through August 2018
Outcome Measures

Primary: Molecular characteristics and antimicrobial susceptibility patterns

Secondary: Adhesion and cytotoxicity to HEp-2 cells

Baseline Characteristics   All patients (n= 46)
Age, year, median (IQR) 65.1 (0.1–91.0)
Male 33 (71.7%)
Urinary system disease 16 (34.8%)
Respiratory system disease 4 (8.7%)
Cardiovascular disease 3 (6.5%)
Hepatobiliary tract disease 5 (10.9%)
Brain diseases 3 (6.5%)
Diabetes mellitus 2 (4.3%)
Pelvis fracture 1 (2.2%)
Myelitis 1 (2.2%)
Non-Hodgkin lymphoma 1 (2.2%)
Unknown 10 (21.7%)
Results Prevalence of resistance to different antibiotics by species C. freundii (n = 26) C. koseri (n = 14) C. braakii (n = 6)
Ampicillin 20 (76.9%) 14 (100.0%) 5 (83.3%)
Cefotaxime 9 (34.6%) 2 (14.3%) 3 (50.0%)
Ceftazidime 6 (23.1%) 1 (7.1%) 3 (50.0%)
Cefepime 1 (3.8%) 2 (14.3%) 0 (0%)
Cefoxitin 23 (88.5%) 0 (0%) 5 (83.3%)
Aztreonam 5 (19.2%) 2 (14.3%) 2 (33.3%)
Imipenem 3 (11.5%) 0 (0%) 0 (0%)
Meropenem 1 (3.8%) 0 (0%) 0 (0%)
Nalidixicacid 8 (30.8%) 0 (0%) 0 (0%)
Ciprofloxacin 3 (11.5%) 0 (0%) 0 (0%)
Levofloxacin 3 (11.5%) 0 (0%) 0 (0%)
Gentamicin 4 (15.4%) 1 (7.1%) 0 (0%)
Amikacin 0 (0%) 0 (0%) 0 (0%)
Streptomycin 7 (26.9%) 2 (14.3%) 2 (33.3%)
Kanamycin 4 (15.4%) 0 (0%) 0 (0%)
Tetracycline 5 (19.2%) 1 (7.1%) 0 (0%)
Doxycycline 4 (15.4%) 1 (7.1%) 0 (0%)
SXT 8 (30.8%) 1 (7.1%) 0 (0%)
Azithromycin 17 (65.4%) 7 (50.0%) 6 (100.0%)
MDR 17 (65.4%) 3 (21.4%) 5 (83.3%)
Adverse Events Not specified
Study Author Conclusions We analyzed 46 extraintestinal clinical Citrobacter isolates (26 C. freundii, 6 C. braakii, and 14 C. koseri isolates) from 2014 to 2018 in Maanshan people’s hospital of Anhui Province, China. The isolates showed high diversity with 38 STs, all of which were novel STs. Nine of the 38 STs belonged to four CCs, but no isolates or STs from this study shared the same CCs with isolates from other countries or other Chinese isolates reported. MDR was prevalent among the isolates causing extraintestinal infections at 54.3%, and four isolates (8.7%) were carbapenem resistant (IMP or MEM). All eight quinolone resistant C. freundii isolates carried the Thr59Ile mutation in the gyrA gene. Only a small proportion of the isolates were found to be highly cytotoxic and adhesive with no correlation to sample sources. This study has shed more light on the genetic diversity and antibiotic resistance of extraintestinal infection causing Citrobacter in China.
Critique The study provides valuable insights into the genetic diversity and antimicrobial resistance of Citrobacter spp. causing extraintestinal infections. However, the small sample size and lack of detailed patient outcome data may limit the generalizability of the findings. Additionally, the study did not explore the molecular mechanisms of carbapenem resistance in detail, which could be an area for future research. 
References:
[1] Liu L, Zhang L, Zhou H, et al. Antimicrobial Resistance and Molecular Characterization of Citrobacter spp. Causing Extraintestinal Infections. Front Cell Infect Microbiol. 2021;11:737636. Published 2021 Aug 27. doi:10.3389/fcimb.2021.737636

Case Report: Citrobacter braakii CLABSI in a hematopoietic stem cell transplant patient

Design

Case report

Case presentation

A 41-year-old female on day 126 post-transplant, presented with symptoms including chills, fever, shortness of breath, and diarrhea. The patient had a medical history of BCR-ABL mutated B cell acute lymphoblastic leukemia (B-ALL) and was on immunosuppressive therapy, including tacrolimus and dasatinib. The initial treatment approach involved using intravenous cefepime following the identification of C. braakii in blood cultures and a catheter tip culture, with the central venous catheter subsequently removed to control the source of the infection. The blood cultures cleared 24 hours after the initiation of cefepime, and after the susceptibility results were obtained, therapy was transitioned to oral levofloxacin. The patient completed a 14-day antimicrobial therapy course, starting from the confirmation of negative blood cultures, resulting in symptomatic improvement. 

Study Author Conclusions

The case highlights the relationship between Citrobacter braakii and immunocompromised patients, emphasizing the need for careful selection of empiric antimicrobial therapy due to potential AmpC resistance. 
References:
[1] Tollkuci E, Myers R. Citrobacter braakii CLABSI in a hematopoietic stem cell transplant patient. J Oncol Pharm Pract. 2021;27(7):1792-1794. doi:10.1177/10781552211001423

Bacteremia due to Citrobacter braakii: A case report and literature review

Design

Case report

Case presentation

A 38-year-old Japanese woman diagnosed with bacteremia due to Citrobacter braakii, a pathogen infrequently isolated from human specimens. The patient, who was affected by cervical cancer with invasion into the rectum and bladder, exhibited symptoms of fever, chills, and nausea upon admission. Initial empirical treatment with cefmetazole was initiated based on a presumed diagnosis of a urinary tract infection. However, blood cultures soon revealed the presence of gram-negative bacilli, which were swiftly identified as Citrobacter braakii through matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, despite earlier biochemical testing suggesting Citrobacter freundii. Further genetic analysis confirmed the identification of C. braakii by 16S ribosomal RNA sequencing, overcoming prior limitations in phenotypic identification. The patient's bacteremia was attributed to a likely gastrointestinal source, exacerbated by a rectal fistula, while the patient’s recovery was successfully managed with a 14-day course of ciprofloxacin tailored to the antibiotic susceptibility profile.

Study Author Conclusions

The case highlights the challenges in accurately identifying C. braakii using conventional biochemical methods and underscores the importance of genetic testing for precise identification. Further studies are needed to clarify the clinical characteristics of C. braakii infections.  
References:
[1] Hirai J, Uechi K, Hagihara M, et al. Bacteremia due to Citrobacter braakii: A case report and literature review. J Infect Chemother. 2016;22(12):819-821. doi:10.1016/j.jiac.2016.07.003