Bacteria, Pathogen of the Month

Multidrug-Resistant Citrobacter Freundii Now on the Rise. Why We Can’t Have Nice Things.

Author Chandana Balasubramanian , 30-Nov-2021

Pathogen of the Month

Citrobacter freundii is now a pathogen of concern. Once considered non-virulent, the bacteria have increasingly become multi-drug resistant (MDR) or antimicrobial-resistant (AMR). According to the World Health Organization (WHO), AMR is one of the top ten global public health threats that face humanity [1]. The Centers for Disease Control and Prevention (CDC) estimates that from 2012-2017, AMR pathogens caused more than 2.8 million infections and over 35,000 deaths annually in the United States [2].

 

The discovery of penicillin – the first antibiotic – was groundbreaking. The drug was discovered by Alexander Fleming in 1928 and made commercially available around 1945 due to research by Howard Florey and Ernest Chain at Oxford. Penicillin changed the course of modern medicine. When it had once been common for people to die of urinary tract infections, tonsillitis, and pneumonia, the evolution of antibiotics continues to save millions of lives around the world [3].

 

However, as the saying goes, “with great power comes great responsibility” (Stan Lee, Creator of the Marvel Universe).

Unfortunately, the main reasons for today’s AMR crisis are:

 

  •       the overuse of antibiotics,
  •       inappropriate use of antibiotics in animals, and
  •       incorrect use of antibiotics which do not eliminate the pathogen.

 

To help clinicians deal with AMR, the Infectious Diseases Society of America (IDSA) released new guidelines in November 2021 to treat three of the most drug-resistant pathogens. These include the family to which Citrobacter spp. belongs [4].

 

What is Citrobacter freundii?

Citrobacter freundii is a facultative, gram-negative, anaerobic bacteria. It is rod-shaped and about 1-5 µm long. Most Citrobacter freundii cells have flagella and are motile, but some do not.

It is a member of the family Enterobacteriaceae, which has 15 genomospecies. Some of the most commonly discussed are Citrobacter amalonaticus and Citrobacter koseri.

Because they are facultative, they can prefer aerobic respiration in the presence of oxygen. However, they can switch to anaerobic respiration without oxygen and ferment carbon using citrate. Additionally, Citrobacter koseri can also ferment lactose [5].

 

Where is it Found?

Citrobacter freundii is normally found in water, soil, food, and the intestines of humans and animals. The bacteria was first discovered in 1932 by isolating a pure culture from soil [6].

It is a common component of our gut flora, and many strains are considered “good gut bacteria” and are beneficial. However, some strains have transformed over time to develop resistance to common antibiotics (MDR). As a result, infections can be hard or even impossible to treat.

 

What Diseases are Caused by the Bacteria Citrobacter freundii?

Citrobacter freundii can cause urinary tract infections, meningitis, brain abscesses, sepsis, pneumonia, diarrhea, and respiratory and wound-related infections [7].

 

How is it Transmitted? Is This Type of Citrobacter Dangerous?

Citrobacter freundii is, most often, a healthcare-associated infection (HAI) and is nosocomially transmitted. Patients acquire them after hospitalization.

Infections caused by Citrobacter freundii are called ‘Opportunistic Illnesses’ (OIs). The bacteria is considered an opportunistic microbe. This is because the bacteria prefer to infect immunocompromised patients, the elderly, people with multiple comorbidities, and those exposed to an intensive care unit (ICU) or hospital setting for a long time [8].

Symptoms often include a burning sensation during urination, a more frequent urge to urinate, foul-smelling urine, blood in the urine. Other symptoms include high-grade fever, vomiting, seizures, and more.

Left untreated, Citrobacter spp. infections can be dangerous and even fatal. Invasive infections have a high mortality rate of 33 – 48% [7].

 

How to Diagnose a Citrobacter freundii Infection?

The only way to diagnose a Citrobacter freundii infection is through a culture test. Citrobacter freundii ferment glucose, produce gas, and consume citrate. Most of them are motile. In their anaerobic mode, they ferment carbon.

 

What are the Drugs it is Resistant to?

Citrobacter freundii isolates have demonstrated resistance to traditional agents of antimicrobial chemotherapy. These include ampicillin, carbenicillin, and cephalothin. They also exhibit resistance to agents like third-generation cephalosporins and monobactams [9] [10].

A 2019 in-vitro, multi-center study out of China by Zhou et al. found that among 20 Citrobacter strains isolated from animals, resistance was mostly to ampicillin, tetracycline, streptomycin, florfenicol, chloramphenicol, and aztreonam, while all the strains found in environmental samples were resistant to few antibiotics [11].

In 2018, Yang et al. isolated a highly multi-drug resistant, carbapenemase-producing Citrobacter freundii strain (CWH001) resistant to all tested antimicrobials except tetracycline [12].

This situation is disturbing because carbapenem is a class of antibiotics used to treat severe infections. Carbapenem-resistant Enterobacteriaceae become resistant to almost all available antibiotics. These bacteria produce carbapenemases, enzymes that can render most antibiotics ineffective. There are three classes of enzymes that drive carbapenem resistance. They are:

  •       class A carbapenemases,
  •       class B metallo-β-lactamases (MBL), and
  •       class D β-lactamases (OXA).

 

A carbapenemase enzyme called OXA-48 (class D) is being produced by a growing number of carbapenem-resistant bacteria and rapidly spreading in the Mediterranean region and the Middle East. Recently, even European countries like the Netherlands, Belgium, Italy, the United Kingdom, and Switzerland have found the presence of OXA-48. More drug-resistant OXA enzymes are being discovered, including OXA-181 and OXA-163.

These OXA enzymes can evade common diagnostic tests, which is problematic. More research is required to help improve the accuracy and effectiveness of diagnostic tests and therapies for carbapenemase-producing Enterobacteriaceae [13].

 

How is it Treated?

Until recently, Carbapenems were the most effective antibiotics to treat serious Citrobacter freundii infections. However, due to rising carbapenem resistance, it became challenging to treat these infections using carbapenems.

MDR or AMR bacteria are very difficult to manage. Clinicians may need to use higher-strength antibiotics as therapy for these infections. In these cases, the strong drugs can also be toxic for immunocompromised patients.

Clinicians may refer to the recently released IDSA November 2021 guidance on treating AMR gram-negative infections.

 

The Evolving Battle Against MDR and AMR Bacteria

Bacterial resistance to drugs can happen in two ways:

  •       One bacterium can have several genes, each resistant to a specific antibiotic, or
  •       A bacterium can use one mechanism to identify multiple antibiotics at a time.

 

Antibiotic-resistant genes in bacteria are often located on plasmids. Plasmids are small, circular DNA strands that can transfer and spread antibiotic resistance between bacteria. They can even transfer resistance to multiple antibiotics in one shot. In healthcare facilities, MDR varieties of bacteria may become dominant strains and create more worrisome superbugs [14].

Plasmids that contain MDR genes are often conjugative – which means they can transfer themselves and other plasmids. Scientists and researchers are now using genetically-engineering plasmids as a new CRISPR-based therapy to fight against AMR. This advancement offers hope in the fight against AMR. However, while this may help attack drug-resistant genes present on plasmids, it does not address bacteria where drug resistance is coded into their chromosomal DNA [15].

The main issue in the fight against AMR pathogens is that they mutate faster than our research and technology can keep up. While scientists continue to study these mutations and develop new therapies, clinicians must limit antibiotic use to appropriate and essential use only. If not, we will continue to produce stronger superbugs that can cause widespread infection and even death.

Additionally, more countries and public health agencies must support data-driven research into the sciences of emerging infectious diseases and pathogens. For example, 200+ scientific publications have used the comprehensive GIDEON infectious disease database to research infectious diseases and pathogens. Raising awareness among the scientific community about access to credible online resources like GIDEON’s vast library of online e-books can be extremely beneficial.

 

References
[1]  World Health Organization (WHO), “Antimicrobial resistance,” WHO, 17 11 2021. [Online][Accessed 30 11 2021].
[2]Centers for Disease Control and Prevention (CDC), “Antibiotic/Antimicrobial Resistance (AR/AMR),” CDC, 20 07 2020. [Online] [Accessed 30 11 2021].
[3]R. I. Aminov, “A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future,” Frontiers in Microbiology, vol. Published online, p. 1:134, 2010.
[4]T. D. Pranita, S. L. Aitken, R. A. Bonomo, A. J. Mathers, D. van Duin and C. J. Clancy, “IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections: Version 2.0,” Infectious Diseases Society of America (IDSA), 22 11 2021. [Online] [Accessed 30 11 2021].
[5]K. P. Ranjan and N. Ranjan, “Citrobacter: An emerging health care-associated urinary pathogen,” Urology Annals, vol. 5, no. 4, p. 313–314, 2013.
[6]J. T. Wang, S. C. Chang, Y. C. Chen and K. T. Luh, “Comparison of antimicrobial susceptibility of Citrobacter freundii isolate in two different time periods,” J Microbiol Immunol Infect., vol. 33, no. 4, pp. 258-62, 2000.
[7]C. Pepperell, J. V. Kus, M. A. Gardam, A. Humar and L. L. Burrows, “Low-Virulence Citrobacter Species Encode Resistance to Multiple Antimicrobials,” Antimicrobial Agents and Chemotherapy, vol. 46, no. 11, p. 3555–3560, 2002.
[8]A. F. Monegro, V. Muppidi and H. Regunath, “Hospital Acquired Infections,” StatPearls Publishing [Internet], 30 08 2021. [Online][Accessed 30 11 2021].
[9]T. D. Gootz, D. B. Jackson and J. C. Sherris, “Development of resistance to cephalosporins in clinical strains of Citrobacter spp,” Antimicrob Agents Chemother, vol. 25, no. 5, pp. 591-5, 1984.
[10]P. Gaibani, S. Ambretti, P. Farruggia, G. Bua, A. Berlingeri, M. V. Tamburini, M. Cordovana, L. Guerra, M. Mazzetti, G. Roncarati, C. Tenace, M. L. Moro, C. Gagliotti, M. P. Landini and S. Vittorio, “Outbreak of Citrobacter freundii carrying VIM-1 in an Italian Hospital, identified during the carbapenemases screening actions, June 2012,” Int J Infect Dis, vol. 17, no. 9, pp. 714-7, 2013.
[11]W. Zhou, Q. Chen, C. Qian, K. Shen, X. Zhu, D. Zhou, W. Lu, Z. Sun, H. Liu, K. Li, T. Xu, Q. Bao and J. Lu, “In Vitro Susceptibility and Florfenicol Resistance in Citrobacter Isolates and Whole-Genome Analysis of Multidrug-Resistant Citrobacter freundii,” International Journal of Genomics, 2019.
[12]L. Yang, P. Li, B. Liang, X. Hu, J. Li, J. Xie, C. Yang, R. Hao, L. Wang, L. Jia, P. Li, S. Qiu and H. Song, “Multidrug-resistant Citrobacter freundii ST139 co-producing NDM-1 and CMY-152 from China,” Scientific Reports, vol. 10653, 2018.
[13]A. Stewart, P. Harris, A. Henderson, and D. Paterson, “Treatment of Infections by OXA-48-Producing Enterobacteriaceae,” Antimicrobial Agents and Chemotherapy, vol. 62, no. 11, 2018.
[14]M. Rozwandowicz, M. S. M. Brouwer, J. Fischer, J. A. Wagenaar, B. Gonzalez-Zorn, B. Guerra, D. J. Mevius, and J. Hordijk, “Plasmids carrying antimicrobial resistance genes in Enterobacteriaceae,” Journal of Antimicrobial Chemotherapy, vol. 73, no. 5, p. 1121–1137, 2018.
[15]M. Rodrigues, S. W. McBride, K. Hullahalli, K. L. Palmer, and B. A. Duerkop, “Conjugative Delivery of CRISPR-Cas9 for the Selective Depletion of Antibiotic-Resistant Enterococci,” Antimicrobial Agents and Chemotherapy, vol. 63, no. 11, 2019.
Author
Chandana Balasubramanian

Chandana Balasubramanian is an experienced healthcare executive who writes on the intersection of healthcare and technology. She is the President of Global Insight Advisory Network, and has a Masters degree in Biomedical Engineering from the University of Wisconsin-Madison, USA.

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