As multidrug resistance ( Latin compound ) is called in medicine a form of antibiotic or antiviral drug - resistance , when germs ( bacteria or viruses ) as so-called superbugs to several different antibiotics or antivirals are insensitive. They are also called MRE germs ( M ulti R esistente E referred rreger). The same applies to the unicellular parasites of the genus Plasmodium , to which the pathogen causing malaria belong.
After in the last decades multiresistant gram-positive bacteria (keywords MRSA , glycopeptide-resistant enterococci or vancomycin-resistant enterococci ) were the main cause of nosocomial infections ("hospital infections ") in the focus of the medical professionals, this has been the case since the end of the 20th century towards some gram negative bacteria. Their resistance is mostly based on the production of β-lactamases (beta-lactamases), these are enzymes that break down or change certain active substances within the group of β-lactam antibiotics and thus render them ineffective. Particular attention is paid to the extended spectrum β-lactamases (ESBL), as this subgroup of lactamases makes other antibiotic groups such as certain penicillins (e.g. piperacillin ) and cephalosporins ineffective. The genes that code the genetic information for these enzymes can be exchanged between different gram-negative bacterial species via a plasmid ; this form of antibiotic resistance spreads among them through this horizontal gene transfer .
In a publication from 2003, scientists from the Robert Koch Institute (RKI) pointed to the findings of basic research on ESBL and to conclusions for prevention , for example with regard to hospital hygiene. In 2007 the RKI published a summary in its Epidemiological Bulletin series on the molecular-biological basis of cephalosporin resistance in enterobacteria . Already in this document attention is drawn to the coupling of β-lactam and fluoroquinolone resistance. The antibiotic group of the fluoroquinolones has a different chemical structure and a different mechanism of action than the β-lactam antibiotics, they are so-called gyrase inhibitors . At the beginning of the 21st century, people in some European countries became aware of the widespread resistance to another clinically important group of antibiotics, the carbapenems . They are inactivated by bacterial enzymes called carbapenemases , which are found again in some gram-negative bacteria. Important subgroups of these enzymes are called VIM (Verona-Integron-Metallo-β-Lactamases) and NDM (New Delhi-Metallo-β-Lactamases). But enzymes named after a bacterium also fall into this group, e.g. B. the Klebsiella pneumoniae Carbapenemase ( KPC ), whose occurrence was not limited to Klebsiella pneumoniae .
Since the multi-resistance in Gram-negative bacteria is caused by so many different resistance genes or enzymes, a new definition was required, in which the focus was not on the resistance mechanisms, but to which clinically important groups of antibiotics the bacteria are resistant. This led to the definition of m ulti r esistenten g ram s egativen rod bacteria ( MRGN ) through the set up at the RKI Commission for Hospital Hygiene and Infection Prevention (KRINKO), which was published 2012th Four groups of antibiotics were defined which are used clinically in the event of a severe infection with gram-negative bacteria (both members of the enterobacteria and so-called nonfermenters ).
In addition to these multi-resistant pathogens mentioned, the multi-resistance of pathogens that cause serious infectious diseases is also a major problem - viewed worldwide . Since such diseases are rare in Germany or Europe, they are not so in the focus of reporting. Examples are multi-drug resistant Mycobacterium tuberculosis strains (causative agent of tuberculosis , or protozoan pathogen of the genus) Plasmodium (formerly the protozoa counted), the malaria cause and the active substances or active substance combination used against several commonly are resistant (see section chemoprophylaxis and therapy of malaria ) .
Multi-resistance of bacteria to antibiotics is a growing problem in medicine. There are various causes that lead to an increase in multi-resistance:
- Unreliable drug intake ( compliance ) by the patient:
In the event of underdosing or premature termination of treatment, the pathogens are only partially killed. The bacteria or viruses that survive are often those with an increased natural resistance . Their genetic makeup is passed on to future generations, so that the next use of the same drug will no longer be successful. It is not the person but the pathogen that becomes resistant to the antibiotic. If the intake of an antibiotic is terminated prematurely, the surviving more resistant pathogens no longer have any competition . Incomplete ingestion thus causes a selection , whereby more resistant germs, which would not have survived the prescribed dosage, can now multiply unhindered and form a new resistant strain. With this type of medical malpractice , expect a relapse . In addition, the resistant pathogens can be transmitted to other people. Multi-resistant pathogens arise when processes that lead to the formation of resistance are repeated in the presence of other antibiotics.
- Frequent, often unnecessary use of antibiotics: Antibiotics
are prescribed for viral infections , although they do not help at all. This leads to more frequent contact of possible pathogens with the antibiotic ingested. Due to natural mutations, bacteria that are randomly resistant to the antibiotic used can now assert themselves better against the non-resistant bacterial strains and multiply more quickly. Such resistant strains can mutate into virulent pathogens that get into the environment or are transmitted to other people.
- Use of antibiotics in the food industry :
In intensive animal husbandry, antibiotics are often added to animal feed in order to increase the yield . Many of these antibiotics are related or identical to those used in human medicine. Because they are ingested by humans in small amounts when they eat the meat and thus promote selection , resistant bacterial strains can in turn develop, which can also cause problems in human medicine.
- Use of antibiotics that is not appropriate to the test or appropriate to the indication:
Highly effective, so-called broad-spectrum antibiotics are often used for bacterial infections. B. penicillin would still be sufficiently effective. This broad use of highly effective antibiotics, in turn, promotes the selection of multi-resistant bacteria. In an emergency, this highly effective drug may no longer be effective.
- Special case of HIV therapy:
Since a cure for an HIV infection is not yet possible, lifelong therapy with antivirals has been necessary up to now . It was discovered early on that so-called monotherapy with just one drug is not effective for long. The HIV virus is able to become resistant to the drug very quickly. Therefore, a multiple combination is given from the beginning to reduce the likelihood of developing resistance. Nevertheless, multiple resistance often develops during therapy. New drugs are therefore constantly being developed.
Multi-resistant problem strains
The epidemiological surveillance in the so-called surveillance systems to deliver reliable data on scientists heaped antibiotic resistance. The specifications as to which pathogens with which antibiotic resistance are monitored at all change over time, since bacteria may be isolated in nosocomial infections that were previously assumed to be opportunistic pathogens . Or the laboratory examination of medical samples with the help of an antibiogram shows that a certain pathogen shows new resistance.
In SARI program (see below) samples are tested for 13 common pathogens and their antibiotic resistance is Staphylococcus aureus , pneumoniae Streptococcus , coagulase-negative staphylococci , Enterococcus faecium , Enterococcus faecalis , Escherichia coli , Klebsiella pneumoniae , Enterobacter cloacae , Serratia marcescens , Citrobacter spp., Pseudomonas aeruginosa , Acinetobacter baumannii and Stenotrophomonas maltophilia (as of 2015). The KISS system ( Hospital Infection Surveillance System ), coordinated by the National Reference Center for the Surveillance of Nosocomial Infections at the Institute for Hygiene and Environmental Medicine, Charité Berlin, provided data on MRSA, VRE and ESBL-producing Gram-negative bacteria in 2008. The selection of the pathogen groups has been adapted to the new findings on multi-resistant gram-negative bacteria and now includes vancomycin-resistant enterococci ( Enterococcus faecalis and Enterococcus faecium ), 3MRGN and 4MRGN; MRSA is recorded in a separate MRSA-KISS module (as of 2015).
Methicillin-resistant Staphylococcus aureus (MRSA) strains
Since 1963, Staphylococcus aureus strains have been described that have a mutation in their penicillin binding protein II (PBP IIa) and thus against all beta-lactam antibiotics (including against so-called beta-lactamase- resistant AB: methicillin , oxacillin , flucloxacillin including so-called staphylococcal antibiotics) are resistant. If they are also resistant to other drug classes, only a few preparations can be used for treatment (e.g. glycopeptides such as vancomycin or teicoplanin or newer and more expensive drugs such as linezolid from the class of oxazolidinones or tigecycline from the class of glycylcyclines) . MRSA are now found all over the world and are becoming an increasing problem , especially in intensive care medicine . The incidence of the disease in intensive care units is already> 50% in the USA, and> 30% in southern Europe and France. In Germany, the incidence in hospitals is around 15 to 20%, but is subject to large regional fluctuations. MRSA can also be isolated from around 2.5% of all residents of old people's and nursing homes. MRSA is the most common cause of skin and soft tissue infections, and of medical intervention. Like other S. aureus strains, MRSA can also occur as a colonization germ on the nasal and pharyngeal mucosa without the patient becoming ill. This creates germ reservoirs that can infect other immunocompromised patients. Germ colonization among hospital staff is particularly dangerous, as there is a continuous risk of infection for patients with immunodeficiency (e.g. with open wounds, intravascular catheters, dialysis or ventilation). Further developments of antibiotics against MRSA strains are conceivable.
Vancomycin Intermediate Sensitive Staphylococcus aureus (VISA) strains
For some years now, MRSA strains have appeared in Japan that are also intermediately insensitive to glycopeptides. Individual cases have also occurred in the United States, France, Hong Kong, and Thailand. It is likely that these strains will continue to spread as well.
Vancomycin-resistant Staphylococcus aureus (VRSA) strains
Only very few cases of S. aureus strains (VRSA) that are actually resistant to vancomycin have been described in the USA. In contrast to the VISA strains, they are characterized in that they have the vanA gene , which codes for glycopeptide resistance and which is derived from vancomycin / glycopeptide-resistant enterococci (VRE / GRE) .
Vancomycin Resistant Enterococci (VRE) strains
This resistant group of bacteria is also known as glycopeptide-resistant enterococci (GRE), vancomycin is a well-known representative from the group of glycopeptide antibiotics . The bacterial species are representatives of the gram-positive genus Enterococcus, Enterococcus faecalis and Enterococcus faecium . In 2011, they were the second most common pathogen causing bloodstream infections in intensive care patients. It often affects immunosuppressed and seriously ill patients. There are so-called hospital-associated tribes that are endemic to a hospital. Compared to colonization strains, which can be part of the intestinal flora or skin flora of humans, they have a higher rate of antibiotic resistance. In addition to glycopeptide antibiotics, they are resistant to aminoglycosides and beta-lactam antibiotics. According to surveillance studies in Germany, 11–13% of the E. faecium strains isolated from nosocomial infections are resistant to vancomycin (as of 2008).
Extended spectrum β-lactamase (ESBL) producing pathogens
Extended spectrum β-lactamase- producing pathogens are bacteria which, through a point mutation within the genes expressing the β-lactamase enzyme , are now able to produce the extended spectrum β-lactamase . This altered enzyme can break down a wider range of β-lactam-containing antibiotics. Bacteria carrying ESBL are therefore resistant to penicillins , cephalosporins (generation 1–4) and monobactams . Mainly E. coli and Klebsiella (gram-negative bacteria) have ESBL genes.
Carbapenem-resistant Klebsiella pneumoniae (KPC) strains
The formation of a carbapenemase ( carbapenem-hydrolyzing beta-lactamase ), the so-called KPC, was observed for the first time in 2001 in a certain Klebsiella pneumoniae strain . The CCP makes the Klebsiella (gram-negative bacteria) resistant to certain antibiotics, the carbapenems . These include the drugs imipenem and meropenem . However, the activity of carbapenemase is suppressed in the presence of clavulanic acid . The investigated carbapenem -resistant Klebsiella pneumoniae strain ( carbapenem-resistant Klebsiella pneumoniae , CRKP) "1534" continued to show resistance to all cephalosporins and aztreonam and is therefore largely insensitive to many modern antibiotics. Different variants of the Klebsiella carbapenemases are known, such as KPC-1, KPC-2 and KPC-3.
New Delhi metallo-β-lactamase 1 (NDM-1) strains
According to an article in the journal " The Lancet , according to" bacterial strains were world with as NDM-1 designated gene discovered, against all known antibiotics, except tigecycline and colistin should be resistant. The gene has so far appeared in the gram-negative enterobacteria Escherichia coli and Klebsiella pneumoniae and is particularly widespread in India and Pakistan . However, cases have already been discovered in Great Britain , the Netherlands , Australia and Sweden , often after operations (especially cosmetic surgery) in the first-mentioned Asian countries.
Multi-resistant gram-negative bacteria (MRGN)
The increasing number of different resistance genes in gram-negative bacteria led to a new definition by the Commission for Hospital Hygiene and Infection Prevention (KRINKO) set up at the RKI, which was published in 2012; MRGN is used as the abbreviation for this group of bacteria . The terms MDR (“Multidrug-resistant”) or MDRGN (“Multidrug-resistant Gram-negative bacteria”) are also used in English-language publications.
The KRINKO definition defines four medically relevant antibiotic groups that are used in the event of a severe infection with gram-negative bacteria (both members of enterobacteria and so-called nonfermenters) and the criteria 3MRGN (resistance to 3 of the 4 antibiotic groups) and 4MRGN (resistance to all 4 antibiotic groups) are listed. In the KRINKO recommendation on hygiene measures in the case of infections or colonization with MRGN published in the Federal Health Gazette , Table 3 shows several examples under which conditions a bacterium is classified as multi-resistant in the sense of 3MRGN or 4MRG, which happens depending on the antibiotics, to which it is resistant. Bacteria types listed there are for example:
- Acinetobacter baumannii (nonfermenter) as 3MRGN A. baumannii with resistance (R) to piperacillin, cefotaxime and ciprofloxacin , but sensitive (S) to imipenem and meropenem; as 4MRGN A. baumannii with resistance (R) to piperacillin, cefotaxime, imipenem, meropenem and ciprofloxacin, but sensitive (S) to sulbactam (sulbactam is not included in the definition ofmulti-resistance). A. baumannii can cause pneumonia , wound infections and sepsis . Until a few years ago there was littledata on the incidence of the bacterium. However, since 2000, outbreaks of nosocomial infections causedby A. baumannii have been reportedmore frequently, mostly from carbapenem-resistant isolates. An analysis of A. baumannii isolates in German university hospitals showed that in 2006 9% of them were multi-resistant. The genetic investigation of A. baumannii isolatescollected worldwideshowed that there are only a few clonal lines. The resistance genes that u. a. responsible for carbapenem resistance were added after or during the global spread of these genetically identical strains. The results of genetic examinations of A. baumannii isolates found in hospitalized patients indicate that the colonization or infection did not occur until the period of medical treatment.
- Pseudomonas aeruginosa (nonfermenter) as 3MRGN P. aeruginosa with resistance (R) to piperacillin, imipenem, meropenem and ciprofloxacin, but sensitive (S) to ceftazidime and cefepime ; as 4MRGN P. aeruginosa with resistance (R) to piperacillin, cefepime, imipenem and ciprofloxacin, but sensitive (S) to colistin and intermediate (I) to ceftazidime and meropenem (intermediate results are evaluated as resistant results). In Europe in 2009, 16% of the investigated isolates of P. aeruginosa were multiresistant in terms of 3MRGN or 4MRGN. P. aeruginosa is a hospital germ that shows multiple resistance to antibiotics due to its metabolism and cell membrane structure. With around 10% of all hospitalinfections, P. aeruginosa is one of the most common hospital germs in Germany (as of 2008).
- Klebsiella pneumoniae (enterobacteria) as 3MRGN K. pneumoniae with ciprofloxacin (R) and ESBL; as 4MRGN K. pneumoniae with piperacillin (R), cefotaxime (R), imipenem (R), meropenem (R) and ciprofloxacin (R), but sensitive (S) to ceftazidime (according to the definition, cefotaxime or ceftazidime R or I be). This combination could also be referred to as the KPC strain (see above).
Other types of enterobacteria are rarely classified as 3MRGN or 4MRGN. In Proteus spp. (e.g. Proteus mirabilis ), Morganella morganii and Providencia spp. Decreased susceptibility to imipenem can occur naturally, preventing classification as 3MRGN or 4MRGN. Enterobacter cloacae , Enterobacter aerogenes (the current name is Klebsiella aerogenes ), Citrobacter freundii , Serratia marcescens or other species with chromosomal AmpC also have a natural resistance to cephalosporins due to this gene. Only if they are also resistant to ciprofloxacin are they called 3MRGN.
Other problem germs
- Multi-resistant gram-positive bacteria (MRGP / MDRGP)
- Multi-resistant gram-negative bacteria
- Bacteria of the genus Campylobacter as a cause of campylobacteriosis
- Bacteria of the genus Salmonella , commonly referred to as Salmonella , as the cause of diarrheal diseases (in addition to previously multi-resistant strains of Salmonella choleraesuis and Salmonella Typhimurium, now also of Salmonella saintpaul and Salmonella anatum ) Salmonella ssp. are not included in the KRINKO definition of MRGN, as they are usually not involved in nosocomial infections. However, there are species with ESBL and carbapenem resistance.
- Some serogroups of the enterohaemorrhagic Escherichia coli bacterium (EHEC), in particular the pathogen strain HUSEC 41 of the sequence type ST678, also called serotype O104.
At the beginning of 2016, multi-resistant Escherichia coli bacteria that were themselves resistant to colistin were found in a patient in Pennsylvania in the USA . In this bacterial strain, in addition to 14 other resistance genes, the MCR-1 gene was found on two ring-shaped pieces of genetic material (plasmids) , which now makes these bacteria resistant even to the last reserve antibiotic. According to the researchers, MCR-1 heralds the emergence of truly pan-resistant bacteria. After a targeted search was started for the first time, this gene has now been found worldwide and thus also in Germany in samples of multi-resistant pathogens. EHEC and other E. coli with special virulence properties are not included in the KRINKO definition of MRGN, because if they occur, special protective measures are required due to their virulence.
- Other multi-resistant pathogens
Possible starting points result from the causes described.
For targeted preventive measures, reliable data on antibiotic resistance (occurrence and spread of multi-resistant pathogens as well as the recording of their resistance) and antibiotic consumption are required. For this purpose, there have been several so-called surveillance systems in Germany since the beginning of the 21st century , for example the surveillance of antibiotic use and bacterial resistance in intensive care units (SARI), which are provided by the National Reference Center for Surveillance of Nosocomial Infections at the Institute for Hygiene and Environmental Medicine, Charité Berlin and organized by the Institute for Environmental Medicine and Hospital Hygiene at the University of Freiburg since 2000. The Robert Koch Institute (RKI) published an overview of such systems in 2015.
Development of new antibiotics
The World Health Organization (WHO) published a list of antibiotic-resistant bacteria for the first time in 2017, which represent the "greatest threat to human health" (English: "[...] that pose the greatest threat to human health."). This is intended to advance the research and development of new antibiotic active ingredients, since many of the known antibiotics used in medicine fail with these multi-resistant pathogens and doctors run out of treatment options. Various approaches are pursued in research.
The bacteria listed are divided into three categories according to the urgency with which new active ingredients are needed:
- Category 1: critical ("Priority 1: Critical") includes Acinetobacter baumannii , carbapenem-resistant; Pseudomonas aeruginosa , carbapenem resistant; Enterobacteriaceae, carbapenem-resistant, ESBL-producing.
- Category 2: high ("Priority 2: High") includes Enterococcus faecium , vancomycin-resistant; Staphylococcus aureus , methicillin resistant, vancomycin intermediate and resistant; Helicobacter pylori , clarithromycin-resistant; Campylobacter spp., Fluoroquinolone resistant; Salmonellae , fluoroquinolone resistant; Neisseria gonorrhoeae , cephalosporin-resistant, fluoroquinolone-resistant.
- Category 3: medium ("Priority 3: Medium") includes Streptococcus pneumoniae , not sensitive to penicillin; Haemophilus influenzae , ampicillin resistant; Shigella spp., Fluoroquinolone resistant.
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