DÄ internationalArchive35-36/2021Multiresistant Gram-Negative Pathogens

Review article

Multiresistant Gram-Negative Pathogens

A Zoonotic Problem

Dtsch Arztebl Int 2021; 118: 579-86. DOI: 10.3238/arztebl.m2021.0184

Köck, R; Herr, C; Kreienbrock, L; Schwarz, S; Tenhagen, B; Walther, B

Background: Extended-spectrum-β-lactamase-producing, carbapenemase-producing, and colistin-resistant Enterobacterales (ESBL-E, CPE, and Col-E) are multiresistant pathogens that are increasingly being encountered in both human and veterinary medicine. In this review, we discuss the frequency, sources, and significance of the zoonotic transmission of these pathogens between animals and human beings.

Methods: This review is based on pertinent publications retrieved by a selective literature search. Findings for Germany are presented in the global context.

Results: ESBL-E are common in Germany in both animals and human beings, with a 6–10% colonization rate in the general human population. A major source of ESBL-E is human-to-human transmission, partly through travel. Some colonizations are of zoonotic origin (i.e., brought about by contact with animals or animal-derived food products); in the Netherlands, more than 20% of cases are thought to be of this type. CPE infections, on the other hand, are rare in Germany in both animals and human beings. Their main source in human beings is nosocomial transmission. Col-E, which bear mcr resistance genes, have been described in Germany mainly in food-producing animals and their meat. No representative data are available on Col-E in human beings in Germany; in Europe, the prevalence of colonization is less than 2%, with long-distance travel as a risk factor. The relevance of animals as a source of Col-E for human beings is not yet entirely clear.

Conclusion: Livestock farming and animal contact affect human colonization with the multiresistant Gram-negative pathogens CPE, ESBL-E and Col-E to differing extents. Improved prevention will require the joint efforts of human and veterinary medicine.

LNSLNS

Among all multiresistant pathogens, those currently at the focus of medical research include extended-spectrum-β-lactamase-producing Enterobacterales (ESBL-E with resistance to third-generation cephalosporins) and carbapenemase-producing and colistin-resistant Enterobacterales (CPE and Col-E, respectively). The treatment options for ESBL-E and CPE are limited, and many calculated treatment strategies are ineffective against severe infections (1); thus, there is often a delay before effective treatment can be initiated. Meta-analyses have shown excess mortality of patients with ESBL-E (85% higher) and CPE infections (180% higher) compared to patients infected with non-multiresistant variants of the same pathogen (2, 3).

For other multiresistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), non-nosocomial transmission routes such as zoonotic exchange between animals and man can play an important role in colonization and infection in particular geographical regions (4, 5). It should thus be asked whether this is also true for the Gram-negative multiresistant pathogens mentioned above. This matter is of particular interest because antibiotics from the three substance classes that define ESBL-E, CPE und Col-E are used very differently in human and veterinary medicine, with a resulting unequal distribution of selection pressure: in human patients, third-generation cephalosporins are most commonly used, followed by carbapenem and colistin (6), while in animals colistin is given more commonly than third-generation cephalosporins, and carbapenems are not approved for use (7). The study of the (zoonotic) modes of transmission of multiresistant pathogens is further complicated by the fact that transmission does not necessarily require the entire pathogen as such; resistance genes can also be transmitted by way of the mobile genetic elements (Box) on which they are located. Thus, even when modern genetic fingerprinting methods show that multiresistant pathogens isolated from human beings and animals differ from each other, this still does not rule out the possibility of a zoonotic transmission chain. Conversely, the demonstration of the same resistance gene in two pathogens does not imply that they must be derived from a single reservoir, as such genes can, for example, be located on more than one type of plasmid. In this review, we first summarize current epidemiological knowledge of the presence of ESBL-E, CPE, and Col-E in human beings and animals, and then discuss the extent to which these multiresistant pathogens are spread by zoonotic transmission.

Mobile genetic elements
Box
Mobile genetic elements

Methods

This selective review is based on publications retrieved by a search in PubMed with the following searching strategy: ((ESBL OR colistin OR carbapenemase OR carbapenem) AND (zoonosis OR zoonotic OR farmers OR children OR livestock OR meat OR food OR pig OR poultry OR chicken OR cattle OR fish OR animals OR pets OR dogs OR cats OR horses) AND (prevalence OR carriage OR coloniz* OR colonis*) AND Germany). Data from other countries and authorities are included for comparison.

Extended-spectrum-β-lactamase-producing Enterobacterales

In any comparative analysis of data on multiresistant pathogens, a distinction must be drawn between studies of the frequency of resistant isolates in a bacterial population (Figure 1A) and studies employing selective techniques (Figure 1B) to determine the percentage of probes that contain multiresistant pathogens (in the present review, “prevalence”) in selected materials or groups. Studies of the first kind can be used to answer clinical questions such as the suitability of an antibiotic for calculated therapy. Studies of the second kind demonstrate the spread of a multiresistant pathogen and reveal what percentage of the collective is positive. In Germany, in 2019, 11.3% of Escherichia (E.) coli and 11.9% of Klebsiella pneumoniae from clinical testing samples were resistant to cefotaxime (an indicator of ESBL-E) (8). These percentages have barely changed in the past ten years. In consequence, clinical guidelines for the in-hospital calculated antibiotic therapy of severe infections such as urosepsis, abdominal infections, and nosocomial pneumonia have had to be revised.

Investigative methods to assess the frequency of pathogens and resistance
Figure 1
Investigative methods to assess the frequency of pathogens and resistance

In Germany, asymptomatic colonization of the bowel with ESBL–E.-coli is present in 6.3–10.3% of adults and 2.3% of children (9, 10, 11, 12, 13, 14) and serves as a reservoir for infections that can arise later (15). Nonetheless, in the absence of any demonstration of preventive efficacy, decolonization treatments are not recommended (16). There have been a few studies suggesting the use of ertapenem for perioperative anti-infectious prophylaxis when colonic surgery is performed on known ESBL-E carriers (17), but further independent investigations are lacking. Clonal transmission in hospitals plays a lesser role in the spread of ESBL–E.-coli (18, 19, 20), which is why there is no recommendation in Germany for patients with ESBL–E.-coli to be placed in single rooms as long as they have no additional types of antibiotic resistance, e.g., against carbapenems (4MRGN) or fluoroquinolones (3MRGN) (21, 22). The main risk factors for colonization with ESBL–E.-coli are antibiotic use and foreign travel (11, 13, 23, 24). 64–85% colonization has been reported among travelers returning from Southeast Asia and India, and 13–44 % in those returning from Africa and the Middle East (23, 25, 26, 27, 28, 29); these percentages are much higher than in the general population in Germany. Little is known about the sources of acquisition of ESBL-E during foreign travel; diarrhea and antibiotic use are independent risk factors for colonization, which is usually acquired within a few days after the beginning of the trip (23, 25, 29, 30). A vegetarian diet was found to have a protective effect in one study (23). The colonization rates observed in returning travelers resemble those in the local populations of the countries visited (31). After the return from a trip, ESBL-E colonization may spontaneously disappear, but it persists for at least six months in 6–28% of cases (23, 27). As the mechanisms of acquisition of ESBL–E.-coli during travel are incompletely understood, no preventive recommendations can be given to travelers, aside from the principle of rational antibiotic use and caution in the consumption of food and drinking water (“cook it, peel it, or leave it”). Check-ups upon return are not recommended. ESBL-E are clinically relevant in enteritis as well: the frequency of third-generation cephalosporin resistance in Salmonella (S.) enterica is less than 2% in Europe overall, but markedly higher (over 50%) in Italy (especially in S. Infantis and S. Kentucky) (32). Moreover, ESBL have been reported in enteropathogenic or enterotoxic E. coli (33); this must be borne in mind in the antibiotic treatment of travel-associated diarrheal diseases. Meat, and particularly poultry meat, is often contaminated with E. coli during the slaughtering process. Some authors have reported finding the same ESBL resistance genes in E. coli isolates from chicken meat and from human urinary tract infections (34). This suggests a pathway of transmission. Epidemiological studies of ESBL–E.-coli in farm animals followed, with the following conclusions:

  • ESBL–E.-coli was present in most of the animal facilities and in many slaughtered animals. In Germany, it was demonstrated in 61–85% of facilities with pigs (35, 36), 87% of those with cattle (37), and up to 100% of those with poultry (38, 39).
  • Food sold in retail outlets in Germany very commonly contains ESBL–E.-coli: 66–75% of samples of chicken meat, 40% of turkey meat, 6–13% of pork, 4% of beef, and 18% of unpasteurized milk samples, 3–23% of shrimp, 20% of mussels, and 2% of cut lettuce and fresh herbs (reviews in [40] and [e1, e2]).
  • The ESBL–E.-coli colonization rates of farmers (6–33%) and slaughterhouse workers (10–33%) were somewhat higher than in the general population (36, e3, e4, e5). Contact with farm animals may thus be a risk factor for ESBL–E.-coli colonization (here, too, there are no specific recommendations of ways to avoid colonization).

There has been a small series of investigations comparing meat from conventional and organic farming. Hardly any difference was found with respect to the frequency of ESBL-E contamination in chicken meat (e6, e7, e8, e9). Some of the organically farmed samples displayed lower quantities of ESBL-E (e6) and a lesser frequency of multiresistance (e9), but the demonstrated resistance genes were similar (e6, e7, e8, e9). This observation may indicate transmission between conventionally and organically farmed animals in hatcheries or during the slaughtering process (e7). Domestic animals are also zoonotic reservoirs for ESBL-E: ESBL–E.-coli colonization is present in 3.6–14% of dogs, 1.4% of cats, and 4.1%–10.7% of horses, and is significantly associated with the consumption of raw meat by dogs (e10, e11, e12, e13, e14). ESBL-E are also an increasingly common clinical problem in domestic animals, including pets: the frequency of ESBL-producing isolates of E. coli and K. pneumoniae in samples from dogs, cats, and horses has been found to be over  20% (e11, e15, e16).

But what percentage of contaminations with ESBL-E, particularly E. coli, in human beings is derived from zoonotic sources? A model created in the Netherlands (Figure 2) (e17) reflects an attempt to estimate this percentage through a comparison of resistance genes. Most ESBL–E.-coli colonizations in the general human population (67%) are attributable to person-to-person transmission. For colonizations derived from food of animal origin, the model estimated a frequency of 19%, while 12% arose from direct contact with domestic and farm animals. This model is not fully applicable to the German situation, but it underscores the importance of controlling zoonotic sources even if this does not, in itself, suffice to solve the overall problem of the spread of ESBL in the human population.

Estimated percentages of various sources of intestinal colonization with ESBL and pAmpCforming Escherichia coli in the Netherlands, 2005–2017
Figure 2
Estimated percentages of various sources of intestinal colonization with ESBL and pAmpCforming Escherichia coli in the Netherlands, 2005–2017

Carbapenemase-producing Enterobacterales

The overall CPE burden in Europe is significant. There are an estimated 15,947 human infections with K. pneumoniae per year, causing 2,118 attributable deaths (e18). Most of these infections occur in Italy, Greece, Romania, and Cyprus (e18). In these countries, too, the frequency of carbapenem-resistant isolates among all K. pneumoniae from blood cultures is markedly higher than Germany, where it was only 0.5% in 2019 (8) (Figure 3, Table 1). One cause of the uneven geographic distribution of CPE is the more common use of carbapenems (partly in response to the spread of ESBL-E): in Germany in 2019, carbapenems accounted for 2.03 of the approximately 49 defined daily doses (DDD) given per 100 in-hospital patient-days (6), while the comparable figure in Italy (83 regional hospitals, 2017) was 4.4 of 92 DDD per 100 patient-days (e19). There has also been demonstrated clonal transmission of “successful” CPE bacterial lineages that underwent epidemic spread via hospital facilities (e20, e21).

Percentage of Klebsiella pneumoniae isolates from blood cultures in Europe that are resistant to carbapenems
Figure 3
Percentage of Klebsiella pneumoniae isolates from blood cultures in Europe that are resistant to carbapenems
Species distribution of reported cases of carbapenemresistant Enterobacterales in Germany, 2020
Table 1
Species distribution of reported cases of carbapenemresistant Enterobacterales in Germany, 2020

In Germany, approximately 3500–4500 cases of CPE are reported per year by microbiological laboratories, with the carbapenemases OXA-48 (mainly K. pneumoniae) and VIM-1 (mainly Enterobacter and Citrobacter) predominating (e22). Most CPE in Germany is attributable to spread in health-care facilities (e23, e24, e25, e26). The main risk factors for CPE are hospitalization outside Germany (e.g., in Greece or Italy) and in facilities in which outbreaks occur. It follows that patients with a relevant history of this type who are admitted to a hospital in Germany should be prophylactically isolated and screened to determine whether they are colonized (21, e26). The marked rise in the number of reported cases is of concern. According to an expert assessment of the epidemiologic situation, CPE now arise in Germany not just in rare, imported cases, as previously, but also by regional spread between health-care facilities (e27). This development must be combatted with hygienic measures and the rational use of carbapenems. CPE have rarely been found in domestic and farm animals and in wild animals (e28). Unlike ESBL-E, the presence of CPE in farm animal and in food in Germany is limited to a very small number of facilities (e29, e30, e31, e32, e33, e34). In the period 2016–2019, CPE were found in 0.05% (4/7900) of samples from farm animals and from food that were selectively studied for carbapenem-resistant E. coli (e35). CPE have also been sporadically found in domestic animals, including pets. The main problem here seems to be nosocomial transmission in veterinary hospitals (e36, e37). In countries that have a higher prevalence of CPE in farm animals or domestic animals than Germany, bidirectional transmission between animals and their owners has been described (e38, e39, e40). Overall, however, there is no evidence to suggest that zoonotic sources account for a relevant percentage of CPE in the German population, or among patients with CPE infections in Germany. Travel-associated acquisition has been observed but is rarer than with ESBL-E (23, 28, 29, e41, e42, e43).

Colistin-resistant Enterobacterales

In German hospitals in 2019, a mean of 49 DDD of antibiotics per 100 patient-days were ordered, with colistin accounting for 0.01 DDD (6). Colistin is used in veterinary medicine to treat E. coli diarrhea, mainly in pigs and poultry (e44, e45). In 2019, 66 tons of colistin were given to farm animals in Germany, with high variability among species and with a marked drop in use in recent years (to as little as 30% of previous amounts, depending on the species) (e46). The low selection pressure for colistin resistance in human medicine is reflected in low resistance rates. In 18 European countries, the rate of colistin resistance was found to be 0.3% in clinical E. coli isolates and 5.4% in K. pneumoniae isolates (e47), with an upward trend in southern Europe (e48). In some countries, the large number of cases of CPE (Figure 3) led to increased colistin use to treat severe infections. For a long time, colistin resistance was mainly transmitted chromosomally (e49), but many subtypes of a colistin resistance gene that is transmissible by plasmid (mcr-1 to mcr-10) have been identified since 2015 in both human beings and animals (Tables 2 and 3 [e50, e51]). In Germany, Col-E with mcr genes have been spread since 2010 at the latest, mainly in the food chains of turkey and chicken meat (e52), but also in pigs (e52) and wild boars (e35). In Portugal, Col-E have been found in food of vegetable origin as well (e53); this underscores the complexity of transmission of multiresistant pathogens through the manifold interactions of man, animal, and environment. A critical observation was the finding of E. coli from a pig that contained mcr- and carbapenemase-coding genes simultaneously, implying that the use of colistin can lead to selection of CPE (e54).

The presence of m cr-positive and colistin-resistant (MIC >2 mg/L) Enterobacterales in food-producing animals and in food
Table 2
The presence of m cr-positive and colistin-resistant (MIC >2 mg/L) Enterobacterales in food-producing animals and in food
The prevalence of colonization with colistin-resistant, mcr-positive Enterobacterales in human beings
Table 3
The prevalence of colonization with colistin-resistant, mcr-positive Enterobacterales in human beings

There are hardly any studies investigating the mcr gene in human beings in Germany. One study revealed 19 mcr-positive isolates (0.1%) among 21,006 clinical E. coli isolates in the years 2014/15, derived from 183 hospitals across many countries and continents, reflecting the degree to which this type of resistance is present worldwide (e55). A study from Germany revealed a single mcr-positive isolate among 162 E. coli urinary tract infections (e56). Few data are available on the prevalence of asymptomatic colonization with Col-E (Table 3), but this seems to be rare in Europe up to the present. As with ESBL–E.-coli, foreign travel is a risk factor for the acquisition of Col-E, with colonization rates varying from 3% to 11% (Table 3; mainly Peru, Asia, and Saudi Arabia). The sources of mcr-E. coli in the destination countries are unclear (risk factors: diarrhea and antibiotic intake during the trip [e43]). There is evidence of a role for occupational animal exposure in Vietnam, where a 33% colonization rate was found in farmers exposed to mcr-1-positive poultry, compared to 9% in the urban population (e57). mcr-positive Salmonellae have also been described as pathogens causing diarrhea (e58, e59, e60). In Europe, the use of colistin in human medicine for selective bowel decontamination may contribute to the appearance of Col-E (e61). In one study, 1.2% (5/428) of patients who had been given colistin for this purpose were colonized with colistin-resistant pathogens, including one patient with mcr-E. coli and one person who had such a pathogen even before treatment (e62). In another study, colistin was given in order to eliminate intestinal colonization with ESBL-E (e63); this failed, leading instead to reduced intestinal microbiome diversity and to the presence of mcr-1 genes after treatment. There is no comprehensive model yet for assessing the importance of different sources of human colonization with Col-E.

Acknowledgement

All of the authors have received research support from the German Ministry of Education and Research in the framework of the research network on zoonotic infectious diseases: Robin Köck, Birgit Walther, Stefan Schwar, and und Bernd-Alois Tenhagen received research support as part of the #1Health-PREVENT research alliance (01KI1727 and 01KI2009A/C/D/F, respectively), Caroline Herr and Lothar Kreienbrock in the framework of the Public Health Service projects “ZooM – the Zoonotic Significance of Multiresistant Pathogens: FAQs at the Intersection of Veterinary and Human Medicine” (01KI1806) and Development of Aids for the Design of Sampling Tests for Foods Potentially Contaminated by Zoonotic Pathogens” (01KI1813).“

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 25 November 2020, revised version accepted on 7 March 2021.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
PD Dr. med. Robin Köck
DRK Kliniken Berlin, Institut für Hygiene,
Spandauer Damm 130, 14050 Berlin, Germany
kockr@uni-muenster.de

Cite this as:
Köck R, Herr C, Kreienbrock L, Schwarz S, Tenhagen BA, Walther B: Multiresistant Gram-negative pathogens—a zoonotic problem. Dtsch Arztebl Int 2021; 118: 579–86. DOI: 10.3238/arztebl.m2021.0184

Supplementary material

eReferences:
www.aerzteblatt-international.de/m2021.0184

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Institute for Hygiene, DRK Kliniken Berlin: PD Dr. med. Robin Köck
Institute for Hygiene, University Hospital Münster: PD Dr. med. Robin Köck
Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Munich: Prof. Dr. med. Caroline Herr
Global Environmental Health and Climate Change, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Clinical Centre of the Ludwig Maximilian University Munich: Prof. Dr. med. Caroline Herr
Institute for Biometry, Epidemiology and Information Processing, University of Veterinary Medicine Hannover: Prof. Dr. rer. nat. Lothar Kreienbrock
Institute of Microbiology and Epizootics, Department of Veterinary Medicine at the Freie Universtität Berlin: Prof. Dr. med. vet. Stefan Schwarz
Department Biological Safety, German Federal Institute for risk assessment, Berlin: PD Dr. med. vet. Bernd-Alois Tenhagen
Advanced Light and Electron Microscopy, Robert Koch Institute, Berlin: Dr. med. vet. Birgit Walther
Mobile genetic elements
Box
Mobile genetic elements
Investigative methods to assess the frequency of pathogens and resistance
Figure 1
Investigative methods to assess the frequency of pathogens and resistance
Estimated percentages of various sources of intestinal colonization with ESBL and pAmpCforming Escherichia coli in the Netherlands, 2005–2017
Figure 2
Estimated percentages of various sources of intestinal colonization with ESBL and pAmpCforming Escherichia coli in the Netherlands, 2005–2017
Percentage of Klebsiella pneumoniae isolates from blood cultures in Europe that are resistant to carbapenems
Figure 3
Percentage of Klebsiella pneumoniae isolates from blood cultures in Europe that are resistant to carbapenems
Species distribution of reported cases of carbapenemresistant Enterobacterales in Germany, 2020
Table 1
Species distribution of reported cases of carbapenemresistant Enterobacterales in Germany, 2020
The presence of m cr-positive and colistin-resistant (MIC >2 mg/L) Enterobacterales in food-producing animals and in food
Table 2
The presence of m cr-positive and colistin-resistant (MIC >2 mg/L) Enterobacterales in food-producing animals and in food
The prevalence of colonization with colistin-resistant, mcr-positive Enterobacterales in human beings
Table 3
The prevalence of colonization with colistin-resistant, mcr-positive Enterobacterales in human beings
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