Clostridioides difficile

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Clostridioides difficile
Electron microscopic picture of Clostridioides difficile

Electron microscopic picture of Clostridioides difficile

Systematics
Department : Firmicutes
Class : Clostridia
Order : Clostridiales
Family : Clostridiaceae
Genre : Clostridioides
Type : Clostridioides difficile
Scientific name
Clostridioides difficile
( Hall & O'Toole 1935) Prévot 1938
Classification according to ICD-10-GM
A04.79 Clostridium difficile enterocolitis, unspecified
A04.70 Enterocolitis due to Clostridium difficile without megacolon, without other organ complications
A04.71 Enterocolitis due to Clostridium difficile without megacolon, with other organ complications
A04.72 Enterocolitis due to Clostridium difficile with megacolon, without other organ complications
A04.73 Enterocolitis due to Clostridium difficile with megacolon, with other organ complications
U69.4! Recurrent infection with Clostridium difficile
ICD-10 online (GM version 2020)

Clostridioides difficile (until August 2016 Clostridium difficile ) is an anaerobic , gram-positive , endospore-forming rod- shaped bacterium belonging to the genus Clostridioides sensu lato . C. difficile is one of the most common hospital germs (nosocomial pathogens) . In healthy people, C. difficile is a harmless intestinal bacterium. If competing species of the normal intestinal flora aresuppressedby antibiotics , C. difficile can multiply andproduce poisons , whichtriggeran infectious diarrheal disease ( Clostridioides difficile infection , abbr.CDI ) and possibly lead to life-threatening pseudomembranous colitis , in particular if an antibiotic-associated diarrhea has occurredbefore. In British hospitals is C. difficile much more frequently than in other countries.

features

As an anaerobes , Clostridioides difficile can be assigned to the early bacteria that are adapted to the earth's atmosphere at the beginning of life. This contained practically no oxygen . Even later on, anaerobes did not develop any way of protecting themselves from the aggressive oxygen in today's atmosphere. A life in the air is therefore not possible for C. difficile , since the oxygen found in the air or in running water is also poisonous for clostridia. In order to survive in air, C. difficile encapsulates itself into spores that are resistant to oxygen and drought.

Clostridial spores are found all over the world in soil, dirt, or dust. In the absence of oxygen, the clostridial spores decapsulate and are therefore able to multiply. 1 to 4% of the healthy population carries C. difficile unnoticed in the intestine and can transmit the spores if there is insufficient hygiene . C. difficile is a potentially dangerous pathogen for humans, especially if, for example, antibiotics are used in hospital treatment . Related anaerobic bacteria are: Clostridium perfringens , the causative agent of gas fire , Clostridium tetani , the causative agent of tetanus , and Clostridium botulinum , the causative agent of botulism .

Contagion, outbreak of disease

Clostridioides difficile enriched from a stool sample by filtration

About 20 to 40% of hospital patients are colonized with C. difficile . The spores are excreted in the stool. The spores, which are insensitive to heat and many disinfectants, are particularly common in hospitals, old people's homes and baths. The infection occurs faecal-oral (i.e. from the stool to the mouth) and is favored by poor hygiene. However, spores have now also been found in the air in intensive care units.

Clostridioides difficile infection (CDI) breaks out when certain antibiotics are administered, especially antibiotics that attack bacteria (intestinal flora) that naturally live in the intestine , such as clindamycin , cephalosporins and quinolone antibiotics . When these antibiotics are used, many types of bacteria in the intestinal flora that are important for digestive functions die. The clostridia can multiply quickly in the "gaps" that have arisen. Other risk factors include: age over 65 years, regular intake of immunosuppressants , non-steroidal anti-inflammatory drugs or proton pump inhibitors, chemotherapy or radiotherapy that damage the bowel , inflammatory bowel disease , diabetes mellitus , chronic kidney disease, and a severely weakened immune system , such as in the later course of AIDS .

Infants are colonized up to 100% with C. difficile . Colonization begins at birth or occurs in the first half of life. Possible causes for their tolerance would be their lack of C. difficile toxin A receptors on the immature enterocytes and an immunological response with immunoglobulin G antitoxin. 45% of healthy two-year-olds are still colonized, and 3% or less of healthy adults.

Symptoms

The typical picture of C. difficile is bowel inflammation with diarrhea . In addition, the intestinal inflammation can lead to fever and abdominal cramps. The diarrhea leads to desiccosis . Usually it is a mild to moderate course of the disease. However, what is feared is the severe course that leads to so-called pseudomembranous colitis . This leads to an exudation of fibrin from the inflamed intestinal wall, which combines with granulocytes and destroyed intestinal cells to form a white layer on the intestinal wall. This can lead to a slackening and grotesque expansion of the intestine, the toxic megacolon . In this section of the large intestine, C. difficile multiplies rapidly , causing the intestinal walls to dissolve. The subsequent spread of bacteria throughout the body, known as sepsis , is an acute risk to life.

Disease mechanism

The intestinal inflammation and the diarrhea are not caused by C. difficile itself, but by the toxins produced by it (enterotoxin TcdA ; cytotoxin TcdB ). These lead to the destruction of the intestinal cells as well as a disruption of the salt absorption in the intestine, which leads to a large loss of fluid and salts. The patient notices this loss of fluid as diarrhea. Since 2005, there has been an increase in strains that only produce enterotoxin B compared to previous years. Since 2001 a new type has been spreading, starting from the USA. This so-called NAP1 strain (North American Pulsed field type 1, also known as R027 in Europe) is characterized by a binary toxin and, due to a small mutation in the repressor gene tcdC, is able to produce 16 × more toxin A and 23 × more toxin B to produce. Accordingly, its virulence is much higher than that of the old strains.

In 2011 it was discovered that intestinal cells have enzymes that inhibit the clostridium toxin through nitrosylation. Only a massive spread of the clostridia overwhelms the capacity of the enzymes and thus causes inflammation of the intestine.

Detection of Clostridioides difficile

Endoscopic picture of pseudomembranous colitis in the rectum with typical volcanic exudation of fibrin

Evidence of the toxins produced in the stool is evidence of disease. The detection can be done by a cell culture , whereby the exotoxin B inhibits cell growth. The test can also detect the smallest amounts of exotoxin, but it is time-consuming. The result is only available after 48 hours. This is why an ELISA test is often carried out, which is quicker and easier, even if it is sometimes false negative. The complex cultivation of the anaerobic bacteria does not make sense in sick people, since the bacteria themselves do not cause diarrhea. It is only used for diagnostics in healthy carriers or for epidemiological investigations. Pseudomembranous colitis can only be detected by a colonoscopy .

Prevention and treatment

The use of antibiotics must be targeted and controlled. He is z. B. pointless in viral diseases .

To combat a Clostridioides difficile infection, in addition to replacing liquid and salts by means of infusion to treat the diarrhea, the pathogen itself must be killed. Since some antibiotics (especially ampicillin , clindamycin , cephalosporins ) can promote an infection with C. difficile , the infection can alternatively be treated with the antibiotic metronidazole . If the patient cannot tolerate metronidazole or if the woman is pregnant or breastfeeding, the antibiotic vancomycin must be used. It is not uncommon for a renewed infection with C. difficile several weeks after therapy . This must be treated again with metronidazole.

Antibiotic resistance is known to vancomycin. There have been some reports of relapses after therapy with metronidazole and reports of resistance to the drug. Several relapses have been reported in some patients who were initially cured. Parallel treatment with metronidazole and vancomycin in the acute stage and treatment with vancomycin over a longer period (5–6 weeks) has proven to be sustainable. Accompanying colonoscopies to monitor the healing success and to confirm the findings are recommended. The toxic megacolon can be tried with the same antibiotics. However, often the enlarged part of the intestine needs to be removed quickly.

The administration of bacteria from a healthy intestinal flora as capsules can also have a healing effect or help prevent repopulation with C. difficile . The natural intestinal flora of a healthy donor can also be introduced into the patient's intestine as a fecal transplant ( syn .: Stool transplant ). This treatment, also known as fecal microbiota transfer , is primarily used for recurrent (recurrent) Clostridoides difficile infections (rCDI) with verified evidence. This allows natural intestinal bacteria to colonize again, which, according to a study published in the New England Journal of Medicine , can reduce the overgrowth of C. difficile . Fecal microbiota transfer is (as of 2020) the treatment of choice for recurrent CDI.

In March 2012, a double-blind study was published in The Lancet Infectious Diseases . A research group at the University of Cologne headed by study director Oliver A. Cornely has shown that the antibiotic fidaxomicin goes beyond the standard of treatment that has been customary up to now in terms of lasting treatment success. The tolerance is just as good as that of the conventionally used antibiotic vancomycin . Dificlir (fidaxomicin) was approved based on two similarly structured Phase III non-inferiority studies. In these, 200 mg fidaxomicin every 12 hours orally was compared with vancomycin 125 mg every 6 hours orally for 10 days each.

In one study, CamSA , a bile salt analog, was able to completely rid mice of their C. difficile infections.

In 2019, a potentially effective antibiotic against Clostridium difficile was found with the molecule halicin .

Hygiene measures

In order to prevent the spread of infection, certain hygiene measures must be strictly observed when dealing with the sick. This includes basic hygiene , whereby hand washing is of particular importance: In the event of contact with the spore-forming Clostridioides difficile, adhering spores can only be reduced by hand washing, as they are not inactivated by the usual alcohol-based skin disinfectants.

In addition, the Commission for Hospital Hygiene and Infection Prevention (KRINKO) recommends, in addition to barrier measures, in case of suspected or diagnosed Clostridioides difficile infection (CDI), to accommodate the symptomatic patient in a single room of their own wet cell and to maintain this isolation for at least 48 hours after the symptoms of diarrhea have ceased.

history

It was first described in 1935 by Hall and O'Toole, who examined the normal intestinal flora in infants. They discovered a common organism in over 50% of healthy infants, but not in adults. Since the infants examined showed no signs of illness, C. difficile (initially called "Bacillus difficilus") was considered harmless. C. difficile can only reproduce in the absence of air. Cultivation in laboratories is accordingly difficult. The epithet difficile , which comes from Latin means difficult , points to this fact .

In 1974, Tedesco et al. Reported that of 200 patients who received the antibiotic clindamycin , 41 developed diarrhea and 20 developed pseudomembranous colitis . In 1978, Bartlett et al. Discovered that the antibiotic-associated pseudomembranous colitis was caused by C. difficile . In the following years, the two poisons exotoxins A and B were recognized as the actual cause of the disease. Clinical studies showed that almost any antibiotic could cause pseudomembranous colitis; Vancomycin became the standard of care. In the past 20 years, C. difficile has become the most common pathogen causing hospital-acquired diarrhea. In the 1970s the most common trigger was the antibiotic clindamycin, in the 1980s it was the cephalosporins , and currently the fluoroquinolones seem to play an important role.

Situation in the mid-2000s

In 2006, the US disease agency CDC (Centers for Disease Control and Prevention) in Atlanta came to the conclusion that C. difficile was underestimated for a long time and has become more aggressive, especially recently. A research group led by Michael Warny from the University of Sherbrooke in Canada suspected a genetic change in the bacterium as the cause. In the course of an epidemic in the province of Québec, the scientists isolated a variant in 72 of 124 infected patients that lacked a gene called tcdC . This gene contains the building instructions for a protein , which normally limits bacterial poison production. The genetically modified bacterium produced the toxins enterotoxin A and B in 16 and 23 times as large quantities as the non-mutated variants. The researchers blame this increased poison production of the mutated bacterial strains for the increasingly severe infections and secondary diseases. In addition, they also found resistance to the fluoroquinolones class of antibiotics often prescribed in North America in these bacteria . In addition, a group of researchers led by Clifford McDonald from the CDC has found another poison called Cdt in the aggressive variant of C. difficile . Seven percent of the patients they observed died of the Clostridium infection.

According to M. Warny, the infection rate in C. difficile doubled within three years before 2005 in Great Britain as well. Two epidemics with Clostridioides difficile of subtype 027 were observed in the Netherlands between 2003 and 2005 . The head of the German consulting laboratory for C. difficile in Mainz, Christoph von Eichel-Streiber, was of the opinion that the mutated pathogen variant had already arrived in Belgium and that it was only a matter of time before it arrived in Germany. Up to 2006 this new type NAP1 was detected in Europe in England, France, Belgium, the Netherlands, Poland, Croatia and (1 case) in Austria.

In April 2007, the first detection of Clostridioides difficile of the subtype 027 was made in Trier (Germany). The infection with this particularly aggressive strain leads to a 5 times higher risk of death than with the known strains. When the disease broke out in the Trier / Bitburg area in October 2007, 23 cases were counted. This increased occurrence was examined by experts from the Robert Koch Institute Berlin. Nine people died in Trier between April 2007 and December 2007 from this dangerous variant of Clostridioides difficile ; The bacterium could be detected in a total of 19 patients in Trier.

In the spring of 2008, a study became known that more than half of the clinics in Great Britain had a C. difficile infection rate that was at least ten times higher than in other countries. In the group of people over 65, the death rate was ten times higher than in other countries.

The bacterium is increasingly spreading outside of hospitals (as of the end of 2009).

Situation in the 2010s

A study from 2013 points to the increasing spread of C. difficile in the intestines of infants. Just a few weeks after birth, the intestines appear to be colonized with the bacterium in almost 50% of infants. However, due to the lack of comparative data, it cannot be said whether the infection is increasing in infants.

The ORF reported on the situation in Austria on January 23, 2015.

Reporting requirement

In Germany, a Clostridioides difficile infection with a clinically severe course is a reportable disease according to Section 6 of the Infection Protection Act (IfSG). What an infection with a clinically severe course is is defined in the double letters to § 6 paragraph 1 sentence 1 number 1a letter a IfSG. In addition to the illness, death from such an infection must also be reported.

In Austria, diseases associated with severe Clostridium difficile are notifiable diseases according to Section 1, Paragraph 1, No. 2 of the Epidemic Act 1950 . Cases of illness and death must be reported. Doctors and laboratories, among others, are obliged to report this ( Section 3 Epidemics Act).

See also

literature

  • JG Bartlett, TW Chang, M. Gurwith, SL Gorbach, AB Onderdonk: Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. In: N Engl J Med . 298, 1978, pp. 531-534.
  • John G. Bartlett, Trish M. Perl: The New Clostridium difficile - What Does It Mean? In: N Engl J Med. 353, 2005, pp. 2503-2505.
  • R. Fekety, AB Shah: Diagnosis and treatment of Clostridium difficile colitis. In: JAMA , 269, 1993, pp. 71-75.
  • RH George, JM Symonds, F. Dimock, JD Brown, Y. Arabi, N. Shinagawa, MR Keighley, J. Alexander-Williams, DW Burdon: Identification of Clostridium difficile as a cause of pseudomembranous colitis. In: Br Med J . 1 (6114), 1978, p. 695.
  • DN Gerding, S. Johnson, LR Peterson, ME Mulligan, J. Silva Jr .: Clostridium difficile-associated diarrhea and colitis. In: Infection Control and Hospital Epidemiology . 16, 1995, pp. 459-477.
  • IC Hall, E. O'Toole: Intestinal flora in newborn infants with a description of a new pathogenic anaerobic Bacillus difficilis. In: Am J Dis Child. 49, 1935, p. 390.
  • S. Hafiz, CL Oakley: Clostridium difficile: isolation and characteristics. In: J Med Microbiol. 9 (2), 1976, pp. 129-136.
  • Vivian G. Loo, Louise Poirier, Mark A. Miller, Matthew Oughton, Michael D. Libman, Sophie Michaud, Anne-Marie Bourgault, Tuyen Nguyen, Charles Frenette, Mirabelle Kelly, Anne Vibien, Paul Brassard, Susan Fenn, Ken Dewar, Thomas J. Hudson, Ruth Horn, Pierre Rene, Yury Monczak, Andre Dascal: A Predominantly Clonal Multi-Institutional Outbreak of Clostridium difficile-Associated Diarrhea with High Morbidity and Mortality. In: N Engl J Med. 353, 2005, pp. 2442-2449.
  • L. Clifford McDonald, George E. Killgore, Angela Thompson, Robert C. Owens, Jr., Sophia V. Kazakova, Susan P. Sambol, Stuart Johnson, Dale N. Gerding: An Epidemic, Toxin Gene-Variant Strain of Clostridium difficile . In: N Engl J Med. 353, 2005, pp. 2433-2441.
  • Thomas Schneider, Tim Eckmanns, Ralf Ignatius, Klaus Weist, Oliver Liesenfeld: Clostridium difficile-associated diarrhea : an increasing clinical problem caused by new highly virulent pathogens. In: Deutsches Ärzteblatt . 104, issue 22, June 1, 2007, p. A-1588, MEDIZIN: Review article
  • LD Smith, EO King: Occurrence of Clostridium difficile in infections of man. In: J Bacteriol. 84, 1962, pp. 65-67.
  • FJ Tedesco, RW Barton, DH Alpers: Clindamycin-associated colitis: a prospective study. In: Ann Intern Med . 81, 1974, pp. 429-433.
  • C. Wenisch, B. Parschalk, M. Hasenhundle u. a .: Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. In: Clin Infect Dis. 22, 1996, pp. 813-818.
  • TD Wilkins, DM Lyerly: Clostridium difficile testing: after 20 years, still challenging. In: J Clin Microbiol. 41, 2003, pp. 531-534.
  • E. Mylonakis, ET Ryan, SB Calderwood: Clostridium difficile-associated diarrhea: a review. In: Arch Intern Med . 161, 2000, pp. 525-533.
  • Deutsches Ärzteblatt: Medicine May 26, 2010: Intensive Care Medicine C difficile also in the air.htm Clostridium difficile also in the air.

Web links

Commons : Clostridium difficile  - collection of images, videos and audio files

Individual evidence

  1. ↑ Robert Koch Institute, Berlin: RKI-Ratgeber Clostridioides , queried July 25, 2020
  2. ↑ KRINKO recommendation: hygiene measures for Clostridioides difficile infection (CDI). 2019, p. 907. Retrieved September 26, 2019.
  3. ^ Intensive care medicine: C. difficile also in the air. on: aerzteblatt.de , May 26, 2010.
  4. ↑ KRINKO recommendation: hygiene measures for Clostridioides difficile infection (CDI). 2019, p. 909. Retrieved September 26, 2019.
  5. ↑ Franz Allerberger a. a .: Clostridium difficile infection . In: Österreichische Ärztezeitung . No. 5 , March 10, 2014 ( aerztezeitung.at [PDF]).
  6. ↑ Tor C Savidge, Petri Urvil, Numan Oezguen, Kausar Ali, Aproteem Choudhury: Host S-nitrosylation inhibits clostridial small molecule – activated glucosylating toxins. In: Nature Medicine . 2011. doi: 10.1038 / nm.2405 .
  7. ↑ dradio.de
  8. ↑ Fecal transplant cures C. difficile infection. on: aerzteblatt.de , January 17, 2013.
  9. ↑ Don't poo-poo technique: Fecal transplant can cure superbug, doctors say. In: CBC . November 13, 2007.
  10. ↑ Andreas Stallmach u. a .: Fecal microbiota transfer. Faced indications, donor screening and application forms. In: Deutsches Ärzteblatt. Volume 117, Issue 3, January 17, 2020, pp. 31–38.
  11. ↑ E. van Nood, A. Vrieze, M. Nieuwdorp, S. Fuentes, EG Zoetendal, WM de Vos, CE Visser, EJ Kuijper, JFWM Bartelsman, JPG Tijssen, P. Speelman, MGW Dijkgraaf, JJ Keller: Duodenal. Infusion of Donor Feces for Recurrent Clostridium difficile. In: NEJM. doi: 10.1056 / NEJMoa1205037 .
  12. ↑ Andreas Stallmach u. a .: Fecal microbiota transfer. Faced indications, donor screening and application forms. 2020.
  13. ↑ Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomized controlled trial . thelancet.com, abstract
  14. ↑ Success in the treatment of the potentially fatal Clostridium difficile infection. "Fidaxomicin has been approved for the treatment of adults with CDI in the US since May 2011 and in Europe since December 2011."
  15. ↑ New Medicines (PDF; 198 kB) Information from the Medicines Commission of the German Medical Association (AkdÄ) , as of March 15, 2013.
  16. ↑ A. Howerton, M. Patra, E. Abel-Santos: A new strategy for the prevention of Clostridium difficile infection. In: The Journal of Infectious Diseases. Volume 207, Number 10, May 2013, pp. 1498-1504, ISSN  1537-6613 . doi: 10.1093 / infdis / jit068 . PMID 23420906 .
  17. ↑ Julia Merlot, DER SPIEGEL: Fighting Resistance: Artificial Intelligence Discovers Promising Antibiotic - DER SPIEGEL - Science. Retrieved February 22, 2020 .
  18. ↑ KRINKO recommendation: hygiene measures for Clostridioides difficile infection (CDI). 2019, p. 912. Retrieved September 26, 2019.
  19. ↑ KRINKO recommendation: hygiene measures for Clostridioides difficile infection (CDI). 2019, pp. 912 and 916. Retrieved September 26, 2019.
  20. ↑ The Lancet - press release - study offers insight ... In: www.wissenschaft-online.de. Retrieved November 25, 2016 .
  21. ↑ UK c.diff deaths 'rising sharply'. BBC April 26, 2008.
  22. ↑ Resistant pathogens leave the clinic . Deutschlandfunk , November 2, 2009
  23. ^ I. Adlerberth, H. Huang, E. Lindberg, N. Aberg, B. Hesselmar, R. Saalman, CE Nord, AE Wold, A. Weintraub: Toxin-producing Clostridium difficile strains as long-term gut colonizers of healthy infants . In: Journal of Clinical Microbiology. doi: 10.1128 / JCM.01701-13 .
  24. ↑ Underestimated : Hospital germ in Austria . science.ORF.at, .23. January 2015.