gms | German Medical Science

GMS Hygiene and Infection Control

Deutsche Gesellschaft für Krankenhaushygiene (DGKH)

ISSN 2196-5226

Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria?

Antibiotikaresistenz: Was ist so besonders an den Gram-negativen multiresistenten Bakterien?

Consensus Paper

  • corresponding author Martin Exner - Institute of Hygiene and Public Health, Bonn University, Bonn, Germany
  • Sanjay Bhattacharya - Tata Medical Center, Kolkata, India
  • Bärbel Christiansen - Department of Internal Hygiene, Schleswig-Holstein University Hospital, Kiel, Germany
  • Jürgen Gebel - Institute of Hygiene and Public Health, Bonn University, Bonn, Germany
  • Peter Goroncy-Bermes - Schülke & Mayr GmbH, Norderstedt, Germany
  • Philippe Hartemann - Departement Environnement et Santé Publique S.E.R.E.S., Faculté de Médecine, Nancy, France
  • Peter Heeg - Institute of Medical Microbiology and Hygiene, University of Tübingen, Germany
  • Carola Ilschner - Institute of Hygiene and Public Health, Bonn University, Bonn, Germany
  • Axel Kramer - Institute of Hygiene and Environmental Medicine, University Medicine Greifswald, Germany
  • Elaine Larson - School of Nursing, Columbia University, New York, USA; Mailman School of Public Health, Columbia University, New York, USA
  • Wolfgang Merkens - Schülke & Mayr GmbH, Norderstedt, Germany
  • Martin Mielke - Robert Koch Institute (RKI), Berlin, Germany
  • Peter Oltmanns - Schülke & Mayr GmbH, Norderstedt, Germany
  • Birgit Ross - Hospital Hygiene, Essen University Hospital, Essen, Germany
  • Manfred Rotter - Hygiene Institute, Medical University Vienna, Austria
  • Ricarda Maria Schmithausen - Institute of Hygiene and Public Health, Bonn University, Bonn, Germany
  • Hans-Günther Sonntag - Institute of Hygiene and Medical Microbiology, University of Heidelberg, Germany
  • Matthias Trautmann - Department of Hospital Hygiene, Stuttgart Hospital, Stuttgart, Germany

GMS Hyg Infect Control 2017;12:Doc05

doi: 10.3205/dgkh000290, urn:nbn:de:0183-dgkh0002900

Published: April 10, 2017

© 2017 Exner et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at


In the past years infections caused by multidrug-resistant Gram-negative bacteria have dramatically increased in all parts of the world. This consensus paper is based on presentations, subsequent discussions and an appraisal of current literature by a panel of international experts invited by the Rudolf Schülke Stiftung, Hamburg. It deals with the epidemiology and the inherent properties of Gram-negative bacteria, elucidating the patterns of the spread of antibiotic resistance, highlighting reservoirs as well as transmission pathways and risk factors for infection, mortality, treatment and prevention options as well as the consequences of their prevalence in livestock. Following a global, One Health approach and based on the evaluation of the existing knowledge about these pathogens, this paper gives recommendations for prevention and infection control measures as well as proposals for various target groups to tackle the threats posed by Gram-negative bacteria and prevent the spread and emergence of new antibiotic resistances.

Keywords: multidrug-resistant Gram-negative bacteria, epidemiology, surveillance, reservoirs, resistance patterns, therapy, infection control measures, biocides, disinfection, agriculture


In den letzten Jahren haben die durch multiresistente Gram-negative Bakterien (MRGN) verursachten Infektionen in allen Teilen der Welt dramatisch zugenommen. Der vorliegende Konsensus basiert auf Vorträgen mit sich anschließenden Diskussionen und späterer Auswertung der einschlägigen Literatur durch ein internationales Expertengremium, das von der Rudolf Schülke Stiftung, Hamburg, zu dem Meeting nach Hamburg eingeladen worden war. Im Fokus standen die Epidemiologie und die besonderen Eigenschaften Gram-negativer Bakterien, die Ausbreitung der Antibiotikaresistenz, die Reservoire, Übertragungswege und Risikofaktoren für Infektionen, die Mortalität, die Therapie und die Möglichkeiten der Prävention einschließlich der Konsequenzen des Vorkommens in der industriellen Tierhaltung. Dem One Health Ansatz folgend und basierend auf der Bewertung des Wissensstandes zu diesen Erregern werden Empfehlungen zur Prävention und Bekämpfung sowie Vorschläge für verschiedene Zielgruppen unterbreitet, um der Bedrohung durch MRGN zu begegnen, ihre Ausbreitung zu verhindern und die Entstehung neuer Antibiotikaresistenzen zu unterbinden.

Schlüsselwörter: multiresistente Gram-negative Bakterien, Epidemiologie, Surveillance, Reservoire, Resistenzmuster, Therapie, Prävention, Infektionsbekämpfung, Biozide, Desinfektion, Landwirtschaft

1 Introduction

Antibiotic resistance has been referred to as “the silent tsunami facing modern medicine” [1]. It has been the topic of numerous international health summits and political summits. An abundance of comprehensive reports, guidelines and recommendations both on an international and on a national level have been published to tackle the threats posed by antibiotic resistance. Despite this awareness in science and politics and the more recent attention by mass media, antibiotic resistance continues to increase throughout the world.

In this context, the rise of multidrug resistance in Gram-negative bacteria (MDR-GNB) has become a particularly serious challenge for healthcare professionals. During a two-day symposium held by Rudolf-Schülke-Stiftung, Hamburg, an expert panel of renowned infection preventionists from Germany, Austria, India and the U.S. discussed current perspectives with regard to prevention of emergence and spread of multidrug-resistant Gram-negative bacteria (MDR-GNB). The consensus report below outlines key elements of a One Health approach, taking into considerations various aspects such as special features of Gram-negative bacteria and their antibiotic resistance, the epidemiological situation worldwide, reservoirs, transmission paths, risk groups, treatment options, and effectiveness of existing prevention strategies.

2 Main properties of Gram-negative bacteria and multidrug resistance in Gram-negative bacteria

Gram-negative bacteria (GNB) differ from Gram-positive bacteria with respect to the structure of the cell wall. This results in differences in the penetration and retention of chemical agents. Gram-negative bacteria have what is referred to as envelope, consisting of three principal layers:

the outer membrane, containing the (possibly fatal) lipopolysaccharide/endotoxin,
the peptidoglycan cell wall with peptide chains, partially cross-linked, and
the cytoplasmic or inner membrane.

Gram-positive bacteria generally lack the outer membrane. The main function of the outer membrane is to serve as a permeability barrier, excluding certain drugs and antibiotics from penetrating the cell [2]. This feature is one of the main factors contributing to the intrinsic antibiotic resistances observed in Gram-negative bacteria.

Medically important Gram-negative bacteria include the following pathogens:

  • Acinetobacter spp.
  • Bordetella pertussis
  • Campylobacter spp.
  • Enterobacteriaceae: Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Salmonella spp., Serratia marcescens, Shigella spp., Yersinia spp.
  • Haemophilus influenzae
  • Helicobacter pylori
  • Legionella pneumophila
  • Neisseria spp.
  • Pseudomonas aeruginosa
  • Vibrio cholerae

Gram-negative bacteria can acquire resistance to one or more important classes of antibiotics, which usually prove effective against them such as:

Ureidopenicillins (piperacillin)
Third- or fourth-generation cephalosporins (cefotaxime, ceftazidime)
Carbapenems (imipenem, meropenem)
Fluorquinolones (ciprofloxacin)
Polymyxins (colistin and polymyxin B)
Aminoglycosides (gentamicin, amikacin)
Glycylcycline (tigecycline)
Tetracyclines (doxycycline, minocycline)
Sulphonamides (co-trimoxazole)

Definition of multidrug resistance varies between countries. In Germany, in the context of hospital hygiene, the term multidrug-resistant organism (MDRO) is used for Gram-negative bacteria which are resistant to three or four out of the first four antibiotic groups listed above. More specifically, 3MDRO (German: 3MRGN) means multidrug-resistant Gram-negative organisms exhibiting resistance to three out of the first four antibiotic groups stated above, 4MDRO means resistance to all four groups. It is important to note that the antibiotic groups are not considered to be equally clinically relevant. Hence, beta-lactamase resistant Enterobacteriaceae, which are sensitive to fluorchinolones and carbapenems, are not included herein [3].

An international panel of experts developed the following definitions: Multidrug-resistant (MDR) means acquired non-susceptibility to at least one agent in three or more antimicrobial categories, extensively drug-resistant (XDR) is defined as non-susceptibility to at least one agent in all, but two or fewer antimicrobial categories, and pandrug-resistant as non-susceptibility to all agents in all available antimicrobial categories [4]. When comparing and evaluating studies or guidelines and recommendations existing differences in definitions should be kept in mind.

Among these acquired resistances, “The Big Five Carbapenemases” are of particular relevance. The “Big Five” are:

KPC (Klebsiella pneumoniae carbapenemase)
IMP (Imipenemase metallo-beta-lactamase)
NDM (New Delhi metallo-beta-lactamase)
VIM (Verona integron-encoded metallo-beta-lactamase)
OXA (Oxacillin carbapenemases)

Enterobacteriaceae, primarily Escherichia coli and Klebsiella pneumoniae, are among the most frequently affected bacteria. Carbapenems are often the last line of effective treatment available for infections with MDRO Enterobacteriaceae.

Until recently, the polypeptide colistin has been used as a reserve antibiotic for the treatment of critically ill patients in the event of multidrug resistance of GNB, especially in the event of resistance to carbapenem. However, the emergence of the transferrable gene mcr-1, which causes resistance to colistin, is now being reported from several countries, including China, the U.K., Denmark, the U.S. and Germany where it has been detected in intestinal bacteria in farm animals. Resistance to colistin is particularly common in isolates of Escherichia coli and in salmonella from poultry populations [5], [6]. In China, the gene was found in humans, including residents of long-term-care facilities, as well as in animals and foodstuffs [7], [8], [9], [10].

Colistin belongs to the polymyxin group of antibiotics. It binds to lipolysaccharides and phosopholipids in the outer membrane of GNB. All resistance mechanisms studied so far in this context eventually result in a reduced affinity of polymyxin to the bacterial surface [11].

3 Acquisition and spread of antibiotic resistance in Gram-negative bacteria

Antibiotic resistance is essentially a result of natural selection. Genetic variations in bacterial populations may carry mutations, which prove to be advantageous for their survival in the presence of antimicrobial agents.

Antibiotic resistance can be intrinsic to specific microorganisms, which can be explained by their inherent structural or functional characteristics. Gram-negative bacteria are usually naturally insensitive to vancomycin because this antibiotic agent is not able to penetrate the outer membrane. Klebsiella exhibit an innate insensitivity towards ampicillin as a result of beta-lactamase production. Pseudomonas aeruginosa is naturally insensitive, e.g., to sulphonamides, tetracycline, chloramphenicol and trimethoprim.

Apart from innate resistance, bacteria can acquire resistance. Mutations in bacterial DNA can render antibiotics ineffective, conveying a survival advantage to the mutated bacterial strain. This basically means, bacteria without these advantages die or cannot reproduce in the presence of antibiotic agents, while resistant bacteria are able to proliferate with less competition. Consequently, the more antibiotics are used and disseminated, the greater the likelihood that resistance strains will emerge.

Mutations in chromosomal genes can induce an increase in the expression of intrinsic resistance mechanisms (antibiotic-inactivating enzymes or efflux pumps) [12].

Resistance genes may also be acquired from other bacteria. They can be transferred between bacteria of the same species but also of another species or genus. Mechanisms of horizontal gene transfer include transduction, transformation and conjugation. Vectors carrying one or more resistance genes may be plasmids (resistance plasmid 1 is a common example in GNB), transposons (e.g. Tn5053) or integrons (e.g., Verona integron-encoded metallo-beta-lactamase producing GNB). As for GNB, in particular for Enterobacteriacea, there is evidence suggesting that resistance genes and associated insertion elements carried on plasmids are often found concentrated in large multiresistance regions (MRR) [13]. For instance, ESBL- and carbapenemase-encoding plasmids may carry resistance determinants for other antimicrobial groups, including aminoglycosides and fluorquinolones [12].

The possibility of a plasmid-mediated horizontal transmission of resistance genes between livestock and humans (e.g. via the food chain) has been observed for ESBL-genes and the colistin resistance gene mcr-1 in GNB [7], [8], [14]. The inter-species transmission of multidrug-resistant strains from humans to animals and vice versa was also suggested following findings by a veterinary diagnostic laboratory that the clonally related human B2-O25:H4-ST131 CTX-M-15-type ESBL-producing E. coli isolates is present in dogs and horses [15].

Yet another mechanism of emergence of antibiotic resistance has been investigated for E. coli. Induction of a mutagenic SOS-response by ciprofloxacin in E. coli caused changes of their rod-like shape into multichromosome-containing filaments. Bos et al. showed that initial resistance emerged from successful segregation of mutant chromosomes at the tips of filaments followed by budding of resistant progeny. They proposed that the first stages of emergence of resistance occur via the generation of multiple chromosomes within the filament and are achieved by mutation and possibly recombination between the chromosomes [16].

An in-vitro experiment with chemostat cultures of Pseudomonas aeruginosa by Feng et al. suggests that the development of resistance during patient treatment may be explained by a new acquisition of resistance rather than by gene transfer. They conclude from their studies that the risk of developing resistance may possibly be reduced by treating with antibiotics in the highest concentration the patient can tolerate for the shortest time needed to eliminate the infection [17].

One major factor believed to accelerate the spread of antibiotic resistance is excessive use of antibiotic agents, including also the use without treatment indication. The emergence of resistance has occurred following the introduction of each new class of antibiotics. A survey of van Boeckel et al. on the total antibiotic sales in selected countries from 2000 to 2010 reveals India to be the country with the highest consumption (2010: nearly 13 billion standard units, standard unit means a single dose unit, i.e. pill/capsule/or ampoule), followed by China (approx. 10 billion standard units) and the U.S. (more than 6 billion standard units, with a moderate decrease from 2000 to 2010). Substantial increases in per capita consumption of antibiotics were also reported from Australia and New Zealand. Consumption of polymyxin increased in each country apart from China [18].

Many studies have assumed that the broad spectrum of antibiotics used in livestock do not only cause resistance problems in pig populations, but also in public health [19], [20], [21]. Multidrug-resistant bacteria with zoonotic potential have developed in response to antibiotic use in food animals [22]. In addition, a correlation between the frequency of treatment and the occurrence of multidrug-resistant bacteria in animals has been demonstrated. The higher the treatment frequency (the average number of days each animal in the herd is treated with antibiotics), the higher the rate of resistance identified in isolates from animal products [23]. Thus, the use of antibiotics in both the health care system and in livestock production may promote dissemination of resistance genes as a direct consequence of selective pressure [24], [25], [26].

4 Surveillance and epidemiology

4.1 USA

In the U.S., the National Healthcare Safety Network (NHSN) collects data on hospital-associated infections (HAI). In their 2009–2010 report period (2,039 hospitals), a slight decline in MRSA was observed, while an increasing occurrence of multidrug-resistant Gram-negative bacteria (E. coli, K. pneumonia, P. aeruginosa, A. baumanni, Enterobacter spp.) was reported. Although generally less common as a causative organism of HAIs, both multidrug resistance and carbapenem resistance were reported in more than 60% of Acinetobacter spp. among most HAI types. 70%–80% of facilities reporting HAI with Acinetobacter spp. reported at least one multidrug-resistant strain [27]. A 2010–2012 survey (Study for Monitoring Antimicrobial Resistance Trends) on the resistance rates of intra-abdominal isolates from U.S. intensive care units and non-intensive care units revealed A. baumannii isolates from ICU patients to be most likely to exhibit resistance to more than four antibiotic classes [28]. The most significant overall increase in carbapenem resistance was observed for Klebsiella species (from 1.6% to 10.4%) in the NNIS/NHSN reporting [29].

As a consequence of this development, the Multi-Site Gram-Negative Bacilli Surveillance Initiative (MuGSI) was established as part of the Emerging Infections Program of CDC in 2012. It conducts active population- and laboratory-based surveillance in a defined surveillance catchment for six carbapenem-resistant organisms which include Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, and Acinetobacter baumannii.

A report on “Antibiotic Resistance Threats in the United States, 2013” was published by the Centers for Disease Control and Prevention (CDC) [30]. The data show that most antibiotic-resistant infections happen in the general community, but most deaths related to antibiotic resistance occur in healthcare settings. In this report, current antibiotic resistance threats for each microorganism are divided in three threat levels (urgent, serious, concerning). For GNB (non-HAI included), the following categories apply:

  • Carbapenem-resistant Enterobacteriaceae (CRE): Out of 140,000 healthcare-associated Enterobacteriaceae infections per year, more than 9,000 are caused by CRE (urgent threat level)
  • Neisseria gonorrhoea: Of 820,000 cases per year, 30% now demonstrate resistance to at least one antibiotic (urgent threat level)
  • Multidrug-resistant Acinetobacter: Of 12,000 healthcare-associated Acinetobacter infections, 7,000 are multidrug-resistant causing approx. 500 deaths per year (serious threat level)
  • ESBL-producing Enterobacteriaceae (ESBL-E): Of 140,000 Enterobacteriaceae infections per year, 26,000 are drug-resistant causing 1,700 deaths (serious threat level)
  • Multidrug-resistant Pseudomonas aeruginosa: Of 51,000 Pseuodomonas infections per year, 6,700 are multidrug-resistant causing 440 deaths (serious threat level)

However, it should be noted that the most urgent threat level pathogen in the U.S. is the Gram-positive bacterium Clostridium difficile, causing 250,000 infections with 14,000 deaths per year. C. difficile associated deaths are said to have increased by 400 % between 2000 and 2007 in the U.S. [30], [31]. C. difficile is also known to have an inherent resistance to several antibiotics. Moreover, a “hypervirulent” strain (NAP-1) has emerged potentially producing more toxins than other strains and exhibiting resistances to antibiotics such as vancomycin, fidaxomicin, and metronizdazole [31], [32].

4.2 India

India with a population of 1.25 billion and a GNI/capita of 5,350 USD compared to 44,540 and 53,960 respectively for Germany and the U.S. has a completely different healthcare structure and faces public health problems like limited access to improved water and/or sanitation and higher death rates from communicable diseases. Administration of antibiotics is often a more feasible option than access to safe potable water and medical advice. The total expenditure on health in India per capita is $109 compared to $6,471 in the U.S. Isolation facilities are scarce, inadequate disposal of biomedical and general waste and poor sanitation are examples for additional problems, and screening for multidrug-resistant organisms (MDRO) is not standard practice in most Indian hospitals.

Reports from various studies from hospitals in India suggest that the prevalence of ESBL-producing GNB range between 19% and 60%, and that of carbapenem-resistant GNB between 5.3% and 59% [33]. An alarming finding from a molecular characterization study of carbapenem-resistant Enterobacteriacea in Mumbai, West India, revealed that 18.5% (21/113) of the clinical isolates investigated possessed dual carbapenemase genes [34]. Moreover, recently a series of 24 cases of colistin-resistant Klebsiella pneumoniae has been reported from a new oncology center at Kolkata. The prevalence of ESBL- and carbapenemase-producers in this area was estimated to be 70% and 39%, respectively, resulting in a high first line use of meropenem and colistin in this hospital [35]. In a study from South India, ESBL-production was detected in 53% of isolates from patients with community-acquired bacteremia caused by E. coli and Klebsiella spp. Among those isolates, the authors also found resistance to multiple groups of antibiotics [36].

Antibiotic resistance has become a major public health concern in India. However, as of today, a mandatory national surveillance system, uninform strategies and quality control systems for sample selection and methods of susceptibility testing or mandatory antibiotic stewardship are lacking. A catalogue of strategies has been proposed, including educational and awareness programmes for community health services and the founding of an “Alliance Against Antimicrobial Resistance” [37]. Two new initiatives have been started in India in 2017. The first one is the Indian Council of Medical Research (ICMR) sponsored Antimicrobial Resistance Surveillance Network where several new Regional Centers have been established in addition to the previously existing nodal centers. Secondly, a CDC-ICMR and AIIMS (All India Institute of Medical Sciences, New Delhi) supported Capacity Building project on AMR and Health Care Associated Infection (HCAI) surveillance across the country were set up. Hopefully these two new initiatives will enable better infection control, better HCAI and antimicrobial resistance surveillance along with strengthening infrastructure for such activities across many regions of India (personal communication).

4.3 Europe

Despite great variations within the 30 states reporting to the EARS-Net (European Antimicrobial Resistance Surveillance Network) in 2016, important resistance trends for Gram-negative bacteria are recognizable [38]:

  • Lower resistance levels reported in the northern and western compared to the southern and eastern European countries
  • Significant increase (from 2012 to 2015) of resistances to third-generation cephalosporins in K. pneumoniae and E. coli, also in combination with ESBL
  • Significant increase (from 2012 to 2015) of combined resistance of third-generation cephalosporins with fluoroquinolones and aminoglycosides for E. coli and K. pneumoniae
  • EU/EEA population-weighted mean for carbapenem resistance 8.1% for K. pneumoniae, 0.1% for E. coli (data referring to 2015)
  • Wide inter-country variations for carbapenem resistance in K. pneumoniae between 0 and 61.9%
  • High percentages of combined resistance to fluorquinolones, third-generation cephalosporins and aminoglycosides often associated with reported high percentage of carbapenem resistance (for K. pneumoniae)
  • Significant increases for carbapenem resistance and resistance to multiple antimicrobial groups also in P. aeruginosa and Acinetobacter spp.
  • Carbapenem resistance for E. coli remained stable
  • Highest levels of resistance reported for Acinetobacter spp. (with carbapenem resistance reaching over 80% in some countries in the south and southeastern parts of Europe and in the Baltic States)
  • Isolates (e.g. of K. pneumoniae) with polymyxin resistance were reported by some of the countries included in EARS, showing that resistance to polymyxin is significantly higher in carbapenem-resistant than in carbapenem-susceptible isolates.

The editors of the report point out that data on polymyxin susceptibility from EARS-Net are to be interpreted with caution due to variations in methodology and potential selective testing. The joint CLSI-EUCAST Polymixin Breakpoints Working Group has published a method to determine colistin minimial inhibitory concentration distribution in 2016 [39].

As for C. difficile, a surveillance protocol was updated in November 2015 to improve standardization of testing and the quality of data reports [40]. It is estimated that approximately 9% of all hospital-associated infections are caused by C. difficile [40].

4.4 Germany

In Germany, the national surveillance system KISS (abbreviation for the German word for hospital infection surveillance system) collects data of nosocomial infections from certain hospital risk areas (e.g., intensive care) and high-risk patient groups (e.g., neonates). A KISS-module for the surveillance of colonized or infected ICU patients with selected MDRO, and of all hospitalized patients with MRSA and C. difficile associated diarrhea (CDAD) in intensive care wards also exists. The German Antimicrobial Resistance Surveillance System (ARS) is cooperating partner of the European Antimicrobial Resistance Surveillance Network (EARS-Net). In addition, a surveillance database for antibiotic consumption for hospitals has been established (AVS).

Evaluation of KISS data show that while MRSA remains stable or is slightly decreasing, other MDROs among ICU patients are becoming more common, and hospitalized patients are twice as likely to acquire CDAD as they are to acquire MRSA [41]. According to the point prevalence study in 2011, which was carried out according to the ECDC protocol, the most common pathogens found to cause nosocomial infections in Germany were E. coli (18%), Enterococci (E. faecalis and E. faecium, 13.2%), S. aureus (13.1 %), and C. difficile (8.1%). The five most commonly used classes of antibiotics were second-generation cephalosporins, followed by fluorquinolones, penicillins with beta-lactamase inhibitors, third-generation cephalosporins, and carbapenems. A substantial amount of C. difficile infections was noted, thus confirming the KISS data [42]. Maechler et al. report that the acquisition rate of carbapenem-resistant organisms (CRO) in intensive care units was more than double the rate of other MDRO under surveillance by MDRO-KISS. CRO prevalence was 0.29 per 100 patients [43]. As a result of the increase in carbapenem resistance, the German Health Ministry has released an ordinance for mandatory notification of laboratory-confirmed colonization with carbapenem-resistant organisms as of May 2016 [44].

Apart from data extracted from hospital surveillance systems, the prevalence of antibiotic resistance in the community is an important aspect for screening, infection control and treatment regimens. In a study with 3,344 participants from southern Germany, 6.3% faecal samples collected between October 2002 to November 2012 were found to be positive for ESBL-producing E. coli [45], suggesting that, in Germany, too, the community has to be taken into consideration as a reservoir for antibiotic-resistant organisms and travelling abroad also contributes to colonization with these bacteria.

4.5 Common trends

Although there are shortcomings in the report and surveillance systems throughout the world and the reliability and comparability of data is limited, there are many patterns which are evident and which call for immediate action. For example, carbapenem resistance is likely to rise as a result of antibiotic resistance to other antibiotic groups (such as 3rd generation cephalosporins) and an increased use of reserve antibiotics. Similarly, colistin resistance is thought to be associated with the rise in CRO (carbapenem resistant organisms) and increased usage of colistin as a reserve antibiotic.

Besides GNB, C. difficile infections, including those with drug-resistant highly virulent strains, are on the rise and need continuous monitoring. The acquisition and spread of antibiotic resistance is a rapid, dynamic, global process which is neither restricted to a specific bacterium, to specific geographical areas or environments nor to humans or animals, nor to the healthcare system. On the other hand, the fact that methicillin-resistant S. aureus is actually receding or being contained in some places shows that it is possible to reverse the trend by adequate policies such as systematic risk-adapted screening, standard and contact infection control precautions and antibiotic stewardship.

5 Methods for MDRO detection

Multidrug-resistant organisms (MDRO) may be detected directly from clinical samples (e.g. stool, rectal, swab, throat swab, wound swab, skin swab, etc.) by either culture-based phenotypic methods or PCR-based genotypic methods. Culture-based methods are generally time consuming (results taking 2–5 days), labour-intensive and may suffer from problems of relatively low analytical sensitivity. However, culture-based methods are relatively inexpensive, may be performed in laboratories without automation or advanced technology. Examples are the modified Hodge test (MHT) and the Carba NP Test [46], [47]. Genotypic methods such as multiplex and singleplex PCR amplification and pulsed-field gel electrophoresis (PFGE) are not widely available in hospital laboratories around the world and are more expensive. PCR-based methods provide more rapid results (within 1–2 days) and have a high degree of analytical sensitivity because of their ability to detect low numbers. However, unlike culture-based methods, they are not able to give detailed antibiotic susceptibility test results (except for the gene of interest) and may suffer from the problem of specificity [48], [49], [50].

Examples for recent developments are the RAPIDEC® CARBA NP assay for rapid detection of carbapenemases in Enterobacteriacea, P. aeruginosa and Acinetobacter spp., an immunochromatographic assay (the OXA-48 K-SeT assay) to detect OXA-48-like carbapenemase-producing Enterobacteriaceae from culture colonies, as well as a highly discriminatory universal blaSHV, blaTEM and blaCTX-M subtyping assay of clinically important ESBL genes, based on PCR and Sanger sequencing [51], [52], [53], [54].

In addition, underestimation of the presence of multidrug-resistant pathogens may occur as GNB have the capacity to survive in the viable-but-not-culturable state (VBNC-state) as well as in biofilms, making detection by conventional methods difficult [55]. For example, multidrug-resistant A. baumannii has been shown to form biofilms on the surfaces of respiratory epithelial surfaces and also in the environment [56], [57].

As each bacterium and the respective resistance mechanism is associated with different epidemiological risks and new mechanisms are being detected with new diagnostic methods, it becomes apparent that a holistic and proactive approach to tackle antibiotic resistance is imperative.

6 Habitats and reservoirs of (antibiotic-resistant) Gram-negative bacteria

6.1 Natural habitats and reservoirs

Natural habitats and reservoirs of GNB are, depending on the species, soil, water, sewage, plants (fruit, vegetables, herbs), dairy products, raw meat as well as the gastrointestinal tract of humans and animals, the skin and the upper respiratory system (cf. Table 1 [Tab. 1]).

6.2 Reservoirs of Gram-negative bacteria in healthcare facilities

Investigations of outbreaks with MDR Gram-negative bacteria have revealed a number of reservoirs in hospitals. These are, for example:

  • Colonized/infected patients
  • Biofilms, in humidifiers of incubators in neonatal wards and other devices which are likely to form biofilms (cf. [55] (Table 1 [Tab. 1]); [58])
  • Sinks/hand washing basins, faucets, drains, sink traps [59]
  • Standard toilets with a rim [60]
  • Sewage/drainage system [61], [62], [63]
  • All surfaces in hospitals such as beds/bedside surfaces, fabrics (linen, pillows, privacy curtains) [55], [64]
  • Computer keyboards and faucet handles [65]
  • Duodenoscopes/endoscopes [66]
  • Hospital foodstuff [67]

Most GNB thrive in a moist, humid environment. Consequently, typical reservoirs include shower heads, bars of soap, liquid soap, artificial fingernails, pools/hot tubs/water fountains, dialysis tubing, infusion pumps, respiratory equipment and cleaning mops. However, according to a systematic review of the persistence of nosocomial pathogens on inanimate surfaces, certain Gram-negative species are also able to survive on inanimate, dry surfaces, even for months. Prominent examples are Acinetobacter spp., and Klebsiella spp. [68], [69]. On the other hand, according to a recent study by Weber et al. [70], carbapenemase-resistant Enterobacteriaceae on various actively inoculated surfaces in CRE-patient rooms showed less than 15% survival within 24 hours and only infrequent (8.4%) and low levels of contamination (5.1 cfu/120 cm2). Further studies are necessary before concluding from these findings that the risk of CRE-transmission from environmental surfaces is relatively low (cf. comment by A. Voss [71] on [68], [70]).

Outbreak investigations can contribute to the identification of transmission paths within medical facilities. Apart from direct person-to-person transmission involving (the hands of) colonised or infected patients, visitors and staff, transmission via all kinds of surfaces as well as aerosols, both dust and droplets, must be taken into consideration. The sewage system and horizontal drainage systems as reservoirs have proven to be associated with various possibilities of transmission paths. One recently discovered path were clogged pipes, which caused backwater, which can, in turn, contaminate sinks. When spirales (drain snakes) were used to unclog drains and are thereafter used in different areas of a hospital, the pathogens can be transferred via the spirales [72]. Cleaning processes with aerosolization such as high pressure cleaning with high-pressure water/steam bear the risk of contaminating food or surfaces. All ecological niches for Gram-negative bacteria such as sink drains, traps and toilet brims can become a risk when surrounding surfaces (e.g. of counters used for preparing infusions) or hands become contaminated by aerosol/droplet formation. It is important to note that plasmids carrying resistance genes can be transmitted across species barriers as was the case in the multi-species outbreak described above [72].

6.3 Reservoirs of Gram-negative bacteria in livestock

Livestock, especially pigs, cattle and poultry, as well as pets and sheeps are a well-known reservoir for MDR-GNB (e.g. [7], [15], [73], [74], [75], [76]). The primary focus here is on ESBL-producing Enterobacteriaceae (ESBL-E). Hot spots for transmission in the pig production chain are the stable air as well as stressful crowding situations, e.g. in humid, warm waiting areas before the abattoirs, whereas carcasses in cold store do not constitute a major problem. While it has been clearly established that farmers are at a higher risk of acquiring MRSA than the general population – primarily as a result of transmission by air/contaminated dust – the risk of colonization with ESBL-E has not been fully elucidated [77]. However, studies do exist suggesting that a direct transfer from livestock to humans is possible [78].

Transmission of MDRO via food products and water is also possible. Numerous publications have demonstrated that drinking water, meat products or milk can be contaminated with MDR-GNB and constitute a potential vehicle for pathogen transmission [7], [21], [79], [80], [81], [82], [83].

Moreover, with the projected change in farming systems in middle-income countries towards large-scale intensive farming, routine use of antibiotics in subtherapeutic doses, which are likely to accelerate resistance, is bound to increase. According to van Boeckel et al., global consumption of antimicrobials in livestock is estimated to rise by 67% from 2010 to 2030 [84].

7 Mortality from antibiotic-resistant Gram-negative bacteria

Infections caused by MDR-GNB include urinary tract infections, blood stream infections (sepsis), pneumonia, meningitis, diarrhea, gonorrhea, otitis, ocular infections including endophthalmitis, device-related infections (e.g. related to central vascular catheter placement) and wound or intraabdominal infections.

Between October 2014 to May 2015, 40 carbapenem resistant blood stream infections were observed in patients admitted to Tata Medical Center, Kolkata, India. These were due to E. coli, K. pneumoniae, P. aeruginosa and A. baumannii in 12, 15, 8 and 10 patients respectively. The median age of the patients in this group was 48 years (range: 9.5 to 84.3 years). Twenty-one patients had haematologic malignancy and 19 had solid organ cancers. The 30-day all-cause mortality noted because of these four multi-drug resistant bacteria (E. coli, K. pneumoniae, P. aeruginosa and A. baumannii) was 0%, 40%, 50% and 60%, respectively. The median time to mortality was 3 days after a positive blood culture with carbapenem resistant Gram-negative bacteria (range 1–30 days). Stool surveillance cultures done in patients admitted to the hospital during the same period showed that 85% of the patients were colonised with one or more MDROs (n=156). Almost all E. coli and Klebsiella isolates in stool were ESBL-producers. 20% of the E. coli and 45% of Klebsiella isolates in stool were carbapenem-resistant. Similarly, 36% of throat swab surveillance cultures showed one or more MDROs (n=55). 40% of the Klebsiella isolates from throat swabs were carbapenem-resistant [85].

Data from WHO [86] confirm that the risk for bacterium-attributable death from antibiotic resistant microorganisms is significantly greater – twice that of patients with non-resistant bacteria (e.g. this applies to E. coli which are resistant to 3rd gen. cephalosporins, K. pneumoniae with resistance to carbapenems). In their metaanalysis of nine studies published up to April 2012 on mortality following carbapenem-resistant Enterobacteriaceae infections, the authors calculated that 26–44% of deaths in 7 studies were attributable to carbapenem resistance [87]. They compared all-cause deaths of patients with carbapenem-resistant infections with those with carbapenem-susceptible infections. On the other hand, an analysis of 24 studies for acquiring infections caused by MDR-GNB in ICU published in 2016 cannot confirm a direct association between infections due to Gram-negative MDR bacteria and mortality in ICU patients, which supports the need for further studies [88].

One of the main reasons for high mortality due to MDR-GNB infection is a late onset of appropriate initial antibiotic therapy. Later administration of a suitable antibiotic was found to be associated with an adverse outcome, particularly in patients with a high-risk source such as lungs, peritoneum or unknown origin of bacteraemia caused by E. coli, K. pneumoniae, Enterobacter spp., and P. aeruginosa. The adequately treated patient group had a 27.4% mortality rate compared to 38.4% for the inadequately treated group. These findings are underlined by observations that the median time from detection of the positive blood culture to the time of death can be very short (1–5 day for P. aeruginosa and 1–30 days for Acinetobacter in the surveillance report from Tata Medical Center, India, see paragraph above [85]). Thus, for the calculated antibiotic therapy, the immediate initiation of treatment (within the first hour after diagnosis) is crucial for the survival of the patient. In the first 6 hours, the mortality risk of the antibiotic untreated septic shock was reported to increase hourly by 7.6% [89].

In everyday practice, appropriate antibiotic therapy is not always readily available on site, even if effective antibiotics exist such as colistin for CR Klebsiella-induced pneumonia. In a study from Greece the vital role of combination therapy in the management of MDRO bacteraemia was explored. It was found that out of the 205 patients with blood stream infections caused by carbapenemase-producing K. pneumoniae, the all-cause 28-day mortality was 40%. A significantly higher mortality rate was observed in patients treated with monotherapy than in those treated with combination therapy (44.4% versus 27.2%; P=0.018). The lowest mortality rate (19.3%) was observed in patients treated with carbapenem-containing combinations. Combination therapy was strongly associated with survival (HR of death for monotherapy versus combination, 2.08; 95% CI, 1.23 to 3.51; P=0.006), mostly due to the effectiveness of the carbapenem-containing regimens [90].

8 Risk factors for acquiring infections caused by MDR-GNB

8.1 Hospital patients

The following risk factors associated with healthcare-associated infections caused by antimicrobial resistant versus susceptible A. baumannii were identified for U.S. hospitals [91]:

  • Antibiotic use prior to infection
  • Length of stay prior to infection
  • Hospital A vs. B
  • Respiratory infection
  • Active duty in Iraq (“Iraqibacter of soldiers”) [92], [93]

Similarly, in a systematic review of observational and experimental studies (published up to October 2015) with regard to the prevalence of antibiotic resistance in urinary tract infections caused by E. coli in children and young people aged 0–17, the authors infer that children who had previously received antibiotics in primary care were more likely to exhibit resistance to antibiotics persisting for up to six months after treatment [94].

Previous carriage of resistant organisms appears to be another risk factor. In a case-control study including 276 CRE carriers in whom CRE carriage presumably ended, following at least 2 negative screening samples on separate days, Bart et al. found 36 (13%) to show recurrence within one year after presumed eradication [95]. The recurrence rate was 25% when the carrier status was presumed to have been eradicated 6 months after the last known CRE-positive sample, compared with 7.5% if presumed to be eradicated after 1 year. The authors conclude that the CRE carrier status should be maintained for at least 1 year following the last positive sample and they advise screening of all prior CRE carriers independent of their current carriage status. Duration of carriage is also extended in case of multiple hospitalization within one year [96].

With regard to specific hospital wards, neonates and immunocompromised patients from intensive care units, oncology and transplantation wards are at special risk. A large number of studies confirm risk factors such as recent organ or stem-cell transplantion, receipt of mechanical ventilation, extended hospital stay, previous treatment with cephalosporins and carbapenems [97], [98], [99]. Qureshi et al. recently reported 20 patients at Pittsburgh Med Center known to be infected or colonized with colistin-resistant A. baumannii. It was found mainly among patients who had received colistin methansulfonate (i.v. or inhaled) for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection (predominantly ventilator-associated pneumonia) prior to identification of colistin resistance. A 30-day all-cause mortality rate of 30% was recorded. Lipid A modification by the addition of phosphoethanolamine was responsible for colistin resistance [100].

In January of 2016, the German Robert Koch Institute published a statement on the question of screening of refugees and asylum seekers for MDRO which is kept updated [101]. Few existing studies do suggest that the proportion of asylum seeking people, including unaccompanied minors, which are colonised with multidrug-resistant ESBL-forming Gram-negative bacteria is significantly higher than that of the general German population [101], [102], [103]. The available national screening guidelines have not been changed. They recommend to screen patients upon admission to hospital for MRSA and carbapenem-resistant organisms in case they are from regions with a high prevalence of MDRO or in case they had contact to the healthcare system outside of Germany or if their clinical history is unclear. In the most recent study published in Germany, 9.8% of the refugees were colonized with MRSA, and 23.3% with resistant Gram-negative bacteria [104]. Therefore, the authors recommend screening and special infection control measures in hospitals when refugees are admitted to hospitals, in order to ensure best medical practice and safety for all hospital patients regardless of their country of origin.

8.2 Nursing homes and long-term care residents

Age >60 years is independently associated with MDR-GNB [105]. New acquisition of MDR-GNB in nursing homes and long-term care facilities within a relatively short period of time is common in the United States and may reach up to 50%, depending on the species [106], [107]. Prevalence of MDR-GNB is now being reported to exceed that of vancomycin-resistant Enterococci and MRSA in the U.S. [108]. Molecular typing suggests that person-to-person transmission within common areas in LTCF (long-term-care facilities) is one important path of transmission.

The following risk factors have been identified for various MDR-GNB among residents in nursing homes and/or long-term care facilities (cf. [107], [108], [109], [110], [111], [112]): indwelling devices (urinary catheters and/or feeding tubes), faecal incontinence, functional disability, diabetes mellitus, previous antibiotic exposure, travelling to high prevalence countries and antimicrobial use during travels, advanced dementia. In a prospective cohort study including 22 nursing homes in the greater Boston area (U.S.A.), advanced dementia was associated with a spread of MDR-GNB within a nursing home but also between nursing homes. Genetically related MDR-GNB strains were detected in 18 of the 22 nursing homes. Residents with advanced dementia should therefore be regarded as a high-risk group.

8.3 Neurological rehabilitation clinics and intensive in-home care

Neurological rehabilitation clinics also show high prevalence rates of MDRO, including GNB. Risk factors include direct transfer from acute care hospitals, previous antimicrobial treatment during the past 3 months and wounds [113].

Other non-acute settings outside the hospital which are often neglected as risk factors include ambulatory care-givers [113], intensive in-home care or structured residential services (group care settings) [114], [115].

8.4 Leisure and business travel, medical tourism

According to a systematic assessment of 11 studies (published up to August 2015) conducted by Hassing et al., international travel is considered to be an important risk factor for the carriage of multidrug-resistant Enterobacteriaceae, with prevalences of >20% [116]. In particular, the risk is increased for persons travelling to (southern) Asia and for persons with travel-related diarrhea and antibiotic use. In the southeastern Asian countries Thailand, Singapore, Malaysia, Vietnam, Indonesia, Philippines, Laos, Cambodia, Myanmar, Brunei 39.4% of 436 isolates (E. coli, K. pneumoniae, K. oxytoca and P. mirabilis) were positive for ESBL production. The prevalence of carbapenem-resistant (CR) A. baumannii varied between 76 and 90%, of CR P. aeruginosa between 23 and 47% [117]. Similarly, Kuenzli et al. found high colonization rates of ESBL-producing E. coli (ESBL-E) in Swiss travellers to South Asia [118]. In a prospective cohort study with 275 German volunteers travelling to 53 different countries stool samples and travel-associated risk factors such as type of travel, nutritional habits, occurrence of gastroenteritis were investigated before and after the journey [119]. Pre-travel analysis demonstrated a ESBL-E colonization rate of 6.8%. Thirty point four percent of the previously uncolonized subjects were colonized with ESBL-producing E. coli, and 8.6% were carriers of ESBL-producing Klebsiella pneumoniae upon returning to Germany, especially from those travelling to India and to South East Asia. The authors recommend active surveillance and contact isolation upon admission to healthcare facilities for patients having travelled to India and South East Asia in the previous 6 months [119]. Colonization of travellers with MDR-GNB appears to be transient and disappears after 3–6 months [120].

Apart from holiday and business travel, medical tourism and wellness tourism may be potential risk factors. According to the Medical Tourism Facts and Figures 2015 Report (International Medical Tourism) 6 million people travel for medical treatment from one country to another [121]. A comprehensive survey issued by OECD criticizes the “grave lack of systematic data concerning health services trade, both overall and at a disaggregated level in terms of individual modes of delivery, and of specific countries. This is both in terms of the trade itself, as well as its implications”. The report explicitly mentions infection and cross-border spread of antimicrobial resistance and dangerous pathogens as a risk associated with the treatment processes [122].

Based on the important findings concerning risk assessment of MDR-GNB described above, the subsequent chapters will pinpoint important treatment and prevention principles.

9 Principal treatment options

The current paradox is that while antibiotic resistance and associated morbidity and mortality are increasing, research for new antibiotics and novel mechanisms of action has been decreasing. High costs for the development and a poor return of investments are considered to be the main reasons for this situation. Only a few new agents are presently under clinical trial, among them the non-β-lactam β-lactamase inhibitor avibactam and plazomicin, a novel aminoglycoside [123], [124], [125].

9.1 Antibiotic stewardship

With respect to treatment options of infections caused by MDR-GNB suitable and regionally adopted antibiotic treatment regimens are to be laid down for each medical facility and expert decisions have to be made for each individual patient. For example, tigecycline and doripenem have been successfully tried for treating infections caused by multidrug-resistant Acinetobacter spp. As a rule, using the highest concentration of an antibiotic the patient can tolerate for the shortest time needed to eliminate the infection is recommended [126], [127], and combination treatment may offer an advantage over monotherapy in critically ill patients with severe infections caused by carbapenemase-producing Klebsiella spp. [128]. On the other hand, combination regimens are often associated with more severe side effects [129].

9.2 Decolonization

Topical (skin) decolonization of MDR-GNB has proven difficult or ineffective. A recent review of various decolonization agents indicated that chlorhexidine gluconate and sodium hypochlorite show the strongest evidence for activity against Gram-negative organisms [130]. Use of triclosan, hexachlorophene and povidone-iodine is not recommended at this time.

Selective digestive and oropharyngeal decontamination as a measure to prevent surgical site infection may have a positive effect [131], but more studies are needed to verify the benefits and to investigate a possible selection for resistance among Gram-negative bacteria.

9.3 Antisepsis

Other novel treatment approaches such as the use of antiseptics, probiotics, and bacteriophages are presently being studied. The topical application of systemic antibiotics for skin, mucous membrane and wound infections is obsolete with only one exception: The same antibiotic is given orally or parenterally in case of metastatic infection [132], [133]. Antiseptics are more effective than antibiotics in vitro [134], [135], equally effective in vivo [136], [137] and, administered topically, as compatible as antibiotic eye drops [138]. In contrast to antiseptics with a microbiostatic specific mode of action (chlorhexidine, triclosane, QAC, silver ions [cf. [138], [139], [140]]), microbicidal antiseptics are without risk of development of microbial resistance [141], [142], [143], [144].

10 Prevention strategies

10.1 Control of resistance emergence and dissemination

In the 2014 draft of the Review on Antimicrobial Resistance issued by the U.K. government [145] the authors begin with the optimistic statement on the chances to bring the growing threat of antibiotic resistance under control: “We believe that this crisis can be avoided. The cost of taking action can be small if we take the right steps soon. And the benefits will be large and long-lasting especially for emerging economies […].” However, if antimicrobial resistance is left untackled, they continue, an estimated 10 million deaths per year attributable to AMR every year by 2050 will be the consequence. In the final document published in 2016, O’Neill, chair of the review, reflects “Indeed, even at the current rates, it is fair to assume that over one million people will have died from AMR since I started this Review in the summer of 2014. This is truly shocking.” [146].

In order to prevent further spread, it is crucial to eliminate sources for resistance development and reservoirs for multidrug-resistant bacteria in the environment. Human, agricultural, aqua farming, hospital and industrial waste and waste water are a path for antimicrobials as well as resistance genes and gene pools originating from a vast bacterial spectrum via waste water treatment plants, waste water and sludge/manure, thus contaminating drinking water, surface water/groundwater and agricultural soil. Standardized, reliable testing of environmental samples must be employed to detect the contents of resistant bacterial strains and antimicrobial residue/agents in surface water, agricultural soil and drinking water in order to adopt necessary control measures.

The extent to which certain sub-lethal concentrations of antimicrobial agents may induce resistance and facilitate horizontal gene transfer of resistance genes has not yet been fully eludicated [147], [148].

One major prevention strategy is to curtail production, prescription and consumption of antibiotics both in human and in veterinary medicine. Education of the general population, of healthcare personnel, veterinarians and pharmacists about means of prevention and proper treatment of infections is also indispensable for this process. Obligatory antibiotic stewardship programs in human and in veterinary medicine, in dentistry as well as in animal breeding should be enforced throughout the world.

An equally important critical control point is the approach to eliminate the need to employ antibiotics by offering access to clean, affordable water and sanitation to all people, by implementing infection control precautions in medical facilities and everyday life, by promoting vaccination, and by introducing animal breeding and food-production processes which render the use of antibiotics unnecessary. Standardized surveillance and mandatory notification of infections caused by multidrug-resistant organisms supply crucial data for continual risk assessment and risk management decisions.

A plethora of guidelines, recommendations and strategic action plans, frameworks for action, including manuals for developing national action plans with support tools already exist on a national and international level, on the prudent use of antibiotics, on combating emergence and dissemination of antimicrobial resistance, on One Health approaches to tackle antibiotic resistance, on antibiotic use and resistance in food animals (cf. e.g. websites of WHO, ECDC, CDC, CDDEP (Center for Disease Dynamics, Economics & Policy), national public health services and health ministries). Policy makers must be called upon to ensure that these strategies are implemented and their implementation is strictly adhered to.

10.2 Reservoir- and transmission-based prevention strategies in healthcare and long-term care facilities

Prevention strategies in healthcare include reservoir-based and transmission-based measures. They may be classified in different levels of evidence (e.g. strong and conditional or classes I through IV, as in the U.K. and German national recommendations, respectively [3], [149]. Even though Gram-negative bacteria require special attention, they are always part of a bundle of measures directed to all potential pathogens in a particular environment.

The following strategies are generally recommended:

  • Implementing a mandatory antibiotic stewardship regimen
  • Surveillance: Recording, reporting and evaluating multidrug resistance
  • Patient history and risk-based screening: Assessing travel history (business, leisure, refugees), screening of risk patients, contact precautions
  • Assessing medical history/hospital stay within the last 12 months and screening of risk patients, contact precautions
  • Training and education of personnel responsible for screening and contact precautions
  • Principle of rapid diagnosis, quick transmission of information, quick treatment: Alert or flagging system (flagging and electronic recording of MDRO carriers in patient charts/patient database), appropriate information of caregivers, patients, visitors and all hospital personnel
  • Monitoring and reinforcing infection control standard precautions
  • Additional contact precautions for patients known to be or to have been colonized or infected with MDR-GNB
  • Safe decontamination practices and cleaning protocols: e.g., avoiding aerosol formation (foam, sprays), avoiding bacterial dissemination by inadequate disinfection techniques and materials, avoiding incorrect dosage
  • Antiseptic prevention and therapy of localized infections
  • Discarding secretions/body fluids in designated areas and cleaning sinks (not in hand wash sinks)
  • Patient education: toilet use, emptying of urinary bags, etc.
  • Safe disposal of (hospital) waste including safe standard procedures for removing blockage/clogging.

Compliance is a major issue often discussed in this context, including one special aspect: training and education of patients and their families along with the staff may increase compliance with and effectiveness of existing guidelines. As a consequence, patients may be able to participate in social and family-centred care programs which would otherwise not be an option [150].

The following measures are subject to debate and/or vary according to availability of resources:

  • Active screening: who, which microorganisms, how, with which consequences?
  • Antiseptic skin wash?
  • Single room and/or cohort isolation [151], [152], [153]?
  • Environmental sampling: when, where and how?
  • Monitoring disinfectant effectiveness: how often and how?
10.2.1 Reservoir-based prevention

As mentioned earlier (Chapter 6), potential reservoirs for MDR-GNB such as the plumbing system, sanitary facilities as well as medical instruments, e.g. complex endoscopes, are often difficult to decontaminate. Therefore, it is an interesting topic to consider modifications in technical or/and architectural design:

  • Hygienically intelligent/optimized sanitary facilities like rimless toilets, appropriate sink and faucet design (sloped angles to minimize splashing, offset drain, sealed overflow, faucet spout for easy maintenance). New self-disinfecting sink drains where shown to reduce the P. aeruginosa bioburden in a neonatal intensive care unit [154].
  • Optimized workflows and space for 2 beds per room as a standard, sinks with appropriate design (see above), sufficient space for personal belongings.
  • No cabinets or storage areas beneath sinks.
  • Point-of-use water filters in facilities for immunocompromised patients.
  • Measures to prevent biofilm formation (adjustment of water flow rate and water pressure).
  • Materials/medical devices/surfaces which are easy to clean and disinfect and which prevent biofilm formation (e.g. specific (coated) materials for urinary catheters).
  • Maintaining a good quality of water supply in hospital and community settings (for example through adequate and appropriate levels of chlorination) and checking the water quality microbiologically by sensitive techniques [155].
10.2.2 Example for transmission-based prevention strategies: Disinfection of surfaces

Effective disinfection is one of the most important parts of the multi-barrier approach to prevent dissemination of MDR-GNB [156], [157]. This is not only applicable to areas of medical care of humans, but also to veterinary medicine and, for example, to livestock breeding. Schmidthausen et al. demonstrated that a comprehensive cleaning and disinfection regimen as part of an intervention bundle in the stables of a pig farm was able to effectively eradicate MRSA and β-lactamase producing Enterobacteriaceae [158].

Frequently used biocides contain quaternary ammonium compounds, alcohols, aldehydes, peroxides, chlorine compounds, amphoteric substances. In a comparative evaluation of the efficacy of surface disinfectant cleaners composed of different active agents against multidrug-resistant clinical isolates of GNB, Reichel et al. confirmed that the tested surface disinfectants exhibited sufficient efficacy when tested according to the method described in the standard EN 13727:2012 under dirty conditions. However, in their conclusion the authors do state that individual clinical isolates (e.g. one 4MRGN P. aeruginosa isolate) might exhibit reduced susceptibility to selected biocidal agents (e.g. aldehyde-containing surface-active substances) [159].

Also, quaternary ammonium compounds have been found to be less effective against S. marcescens than other active agents: Investigations to clarify an outbreak with S. marcescens in a German hospital showed that disinfection with a product containing 3 quaternary ammonium compounds was ineffective against S. marcescens clinical isolates which were detected on the lid and the bottom of a disinfectant wipe container. The removal of the first wipe with the lid open was thought to have caused contamination. When products containing peroxides were used, disinfection was successful (paper presented by Goroncy-Bermes at the RSS Symposium November 2015 [160]). Recent research has indicated that bacterial genes (qac genes) may encode efflux pumps capable of expelling quaternary ammonium compound structures from bacterial cells (MRSA), rendering these compounds less effective [161]. A high prevalence of qacE resistance genes was found among clinical isolates of MDR Acinetobacter baumannii in a Malaysian tertiary care hospital [162]. Silveira et al. report a hospital sewage ST17 Enterococcus faecium with a transferable Inc18-like plasmid carrying genes for resistance to antibiotics and to quaternary ammonium compounds [163].

Still, as regards the correlation between non-susceptibility to surface disinfectants and to antibiotics, research so far suggests that in general there is no risk of selection for antibiotic resistance provided disinfectants are used in the correct dosage [164], [165], except for Triclosan and quaternary ammonium compounds (QAC) which are among the active agents suspected to trigger resistance, especially when used in sublethal doses (cf. [166], [167], [168]).

These findings show that continuous research and development in disinfection is essential. Legal challenges such as the Biocidal Products Regulations, which will lead to a reduction in the active agents available for disinfection in the medical field, complex approval processes for marketing biocides and incurring costs impede investments in innovative research by industry. Rather than taking risk/benefit assessment as the basis for classification of substances, the hazard of a substance is evaluated independent from its route of exposure and its health benefits. User acceptance of effective substances with a long list of hazard labels will be low and substances for targeted, niche application for professional use will become scarce. Thus, there is growing concern that the availability of effective biocides in future cannot be ensured (paper presented by Oltmanns at the RSS symposium November 2015 [169]).

Apart from the availability of suitable active agents, training and education of cleaning staff, disinfection protocols which are easy to implement and disinfection techniques which are easy to perform are an essential contribution to safe and effective disinfection.

10.2.3 Prevention strategies in agriculture: Example of pig stables in Germany

Experimental studies on the decontamination of pig stables [170] were based on knowledge that hygiene and sanitation measures are a compelling necessity to combat endemic hospitalism (autochthonous risk) in modern livestock production [171], [172], [173]. This means preventing and inhibiting the spread of facultative pathogenic bacteria that occur in animal husbandry and in hospitals and healthcare systems (hospitalism germs) [173]. In this context there is an increasing demand for the further development of new concepts and procedures to control or even eradicate drug-resistant bacteria and, thus, interrupt infection chains. Single treatment of animals for purposes of decolonization or therapy, similar to practices in human medicine, requires too much effort and fails entirely if high numbers of animals are affected within a large herd [173], [174], [175]. Moreover, not only do animals present potential reservoirs or vectors for transferring resistance genes and resistant bacteria, but farmers and farm workers, the stable environment including surfaces, installations, and many more factors should also be considered for their transmission potential [176], [177], [178]. Generally, farm management systems should include specific hygiene and sanitation measures to interrupt infection chains [173], [179], [180]. The twelve measures of prophylaxis and therapy of Mayr [181] coincide, to a large extent.

Sanitation of the stable environment

Although all of the recommendations given below are based on the infrastructure and regulations in Germany, they may give some ideas and trigger developments for sanitation measures in agriculture in other countries.

  • Construct a closed-off quarantine stable and sick stable in which potentially introduced diseases can be controlled or treated in order to prevent an outbreak [173], [182], [183].
  • Uninstall all technical installations and supply lines, including water/feed and ventilation systems [179], [180].
  • Remove damaged floors, separations, and all materials (wood, etc.) that could provide potential reservoirs for pathogens and replace with easily cleanable and smooth materials [174].
  • Exchange technical equipment (driving boards, etc.) within individual stables and compartments [184].
  • Disinfest manure according to stipulations of the waste removal law [173], [185].
Elimination and reduction of pathogenic bacteria
  • Clean using a high-pressure cleaner and water.
  • Foam and repeat cleansing with water.
  • Dry all objects and surfaces to be disinfected [173].
  • Apply disinfecting agents with bactericidal, virucidal, fungicidal, and antiparasitic properties to all surfaces, in wet form, in sufficient concentration [186] and nebulize hot steam onto all hard-to-reach spots (for example, main ventilation shafts, etc.). This final disinfection serves to eliminate MRSA and ESBL E. coli, as well as other bacterial groups [187].
  • Allow sufficient drying time and “stable rest” before resuming stabling of any animal [173].
Enhancement of the individual defense mechanisms and control of the resistance status
  • Limit the purchase of new pigs to those that are accompanied with health certificates from the supply farms [181].
  • Specifically vaccinate with a focus on the viral respiratory diseases that have a high prevalence in the applicable region [181].
  • Certification of a negative MRSA and ESBL E. coli status by appropriate monitoring [188].

It has to be emphasized that combating antibiotic resistance has to based on a multi-faceted approach comprising the developed and the developing world. Prevention of the spread of antibiotic resistance “from farm to fork” is one essential constituent in the One Health approach [189].

11 A look into the future

It is undisputed that collaborative efforts such as the “World Alliance Against Antibiotic Resistance”, and the “Joint Programming Initiative on Antimicrobial Resistance”, among others, are needed to tackle the hazards posed by antibiotic resistance [190].

For example, novel approaches in pharmaceutical research such as overcoming the intrinsic resistance of GNB by designing glycopeptide analogues which can permeate the outer membrane of GNB can lead to interesting therapeutic options, which may help counteract the impact antibiotic resistance has on the therapy options of immunosuppressed patients [191].

In addition, there is need for alternative approaches focussing on infection prevention, which make the use of antimicrobial agents unnecessary. Novel designs for equipment and fittings which serve as a reservoir for GNB, are of special interest. These include plumbing systems, sinks and sink drains, water outlets, medical devices as well as washing machines (cf. [55]).

“At the present time, our best defense against (MDRO) … remains old-fashioned, stringent infection control measures combined with the application of effective antimicrobial stewardship” [192]. Although this sentence sounds like an easy “take home message” it does implicate that infection control measures are only as good as they are implemented stringently and concomitantly with antimicrobial stewardship, which is difficult but not impossible to achieve. Thus, for example, endemic MDR A. baumannii in ICUs of Chungnam National University Hospital in Daejeon, South Korea, was brought under control by introducing an enforcing antimicrobial stewardship along with comprehensive, intensified infection control measures, including cohorting of patients in designated areas and promotion and monitoring of hand hygiene and environmental cleaning and disinfection protocols [193].

It has also been shown that Organizational Culture (staff engagement) is positively correlated with prevention attitudes and compliance with contact precaution protocols and negatively correlated with carbapenem-resistant Enterobacteriaceae acquisition rates [194]. The principle of “Patient Safety First” should be laid down in quality assurance regulations and include preventing antibiotic resistance and handling of MDRO, respectively, but it must also be part of a culture of patient safety. It cannot be overemphasized that awareness, rules and regulations will not automatically result in a change in routines nor in skilled and effective performance of the necessary chores.

Again, theses measures do not specifically target GNB. However, as we search for strategies, it becomes apparent that detailed investigations on Gram-negative bacteria, their intrinsic resistance, the spread of acquired resistance, the difficulties in reliable and rapid diagnosis, their ubiquitous reservoirs have forced all those involved with the prevention of infection to develop a “global perspective” and a “One Health perspective” which will eventually benefit all efforts to curtail antibiotic resistance.

Meanwhile – shortly before publication of this paper – WHO has published a Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics [195]. It addresses the urgent need for research efforts for GNB-MDR as they pose a particular threat to hospitals, nursing homes and patients requiring ventilation and catheterization. They are to be considered the most critical group of multidrug-resistant bacteria.

12 Conclusions

In view of these developments, the authors have agreed on the following principle key points to be addressed to various target groups where applicable:

Policy makers

  • Issue guidelines
  • Support efforts in research and development (see below)
  • Establish legal framework for mandatory implementation of guidelines
  • Take care of water and sanitation and waste management
  • Support education and training for the general public
  • Support adequate education and training for medical students and personnel

General public

  • Increase knowledge about infection prevention and prudent use of antibiotics

Resident physicians/dentists

  • Comply with antibiotic stewardship
  • Substitute antibiotics by analogous or even higher effective measures, i.e. antiseptics, probiotics, and bacteriophages

Hospital and medical facilities

  • Create a patient safety culture
  • Implement prevention and infection control precautions
  • Implement novel strategies for building sink/sink drainage and sewage systems
  • Implement adequate design of patient rooms and wards

Healthcare professionals and caregivers

  • Comply with rules and regulations
  • Promote patient empowerment
  • Take advantage of training and education

Infection control preventionists

  • Devise guidelines and recommendations
  • Identify research gaps
  • Monitor implementation of guidelines


  • Research & development (pharmaceuticals, medical devices, architectural, disinfectants, fittings and furnishings)


  • Reduce antibiotic use in farming/animal breeding
  • Implement sanitation of stable environment
  • Eliminate and reduce pathogenic bacteria by cleaning and disinfection
  • Enhance individual defense mechanisms and monitoring of resistance status

Research & development

  • Develop new antibiotics against MDRO-GNB
  • Develop safer and more effective biocides against MDRO-GNB
  • Provide means for rapid diagnosis of sepsis and MDRO-GNB-associated sepsis
  • Explore role of specific dietary and nutritional interventions in reducing/ suppressing gut colonization by MDR-GNBs
    • Role of bael fruit/yoghurt (curd)
    • Micronutrients: Vitamins/minerals
  • Explore role of interventions to reduce or eliminate gut colonization with MDR-GNBs:
    • Role of probiotics
    • Rifaximin
    • Oral colistin
    • Oral neomycin
    • Bowel wash
  • Explore feasibility of vaccines against certain MDR-GNB (e.g. against Klebsiella)
  • Explore role of pre-operative or pre-intervention (e.g. transplantation) screening for MDR-GNB in reducing post-intervention infective morbidity and mortality
  • Develop new strategies in the design and infrastructure of water sanitation and hygiene programs for various settings.



This paper is based on the proceedings of the Rudolf Schülke Symposium ”Worldwide Significance of Gram-Negative Antibiotic Resistant Rods: Epidemiology, Prevention and Control Strategies“ held in Hamburg, 26 and 27 November 2015. All presentations are available for download from

Symposium participants: S. Bhattacharya, B. Christiansen, M. Exner, J. Gebel, P. Goroncy-Bermes, P. Hartemann, P. Heeg, C. Ilschner, A. Kramer, E. Larson, W. Merkens, M. Mielke, P. Oltmanns, B. Ross, M. Rotter, R. Schmithausen, H. G. Sonntag, M. Trautmann.

Competing interests

The authors declare that they have no competing interests.


Cox D. Antibiotic resistance: the race to stop the silent tsunami facing modern medicine. The Guardian. 2015 Aug 21. Available from: External link
Silhavy TJ, Kahne D, Walker S. The bacterial cell envelope. Cold Spring Harb Perspect Biol. 2010 May;2(5):a000414. DOI: 10.1101/cshperspect.a000414 External link
Hygienemaßnahmen bei Infektionen oder Besiedlung mit multiresistenten gramnegativen Stäbchen. Empfehlung der Kommission für Krankenhaushygiene und Infektionsprävention (KRINKO) beim Robert Koch-Institut (RKI) [Hygiene measures for infection or colonization with multidrug-resistant gram-negative bacilli. Commission recommendation for hospital hygiene and infection prevention (KRINKO) at the Robert Koch Institute (RKI)]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2012 Oct;55(10):1311-54. DOI: 10.1007/s00103-012-1549-5 External link
Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012 Mar;18(3):268-81. DOI: 10.1111/j.1469-0691.2011.03570.x External link
Irrgang A, Roschanski N, Tenhagen BA, Grobbel M, Skladnikiewicz-Ziemer T, Thomas K, Roesler U, Käsbohrer A. Prevalence of mcr-1 in E. coli from Livestock and Food in Germany, 2010-2015. PLoS ONE. 2016;11(7):e0159863. DOI: 10.1371/journal.pone.0159863 External link
Federal Institute for Risk Assessment (Bundesinstitut für Risikoforschung). Transferrable colistin resistance found in bacteria from German farm animals. Press release 01/2016. BfR; 2016. Availabe from: External link
Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016 Feb;16(2):161-8. DOI: 10.1016/S1473-3099(15)00424-7 External link
Falgenhauer L, Waezsada SE, Yao Y, Imirzalioglu C, Käsbohrer A, Roesler U, Michael GB, Schwarz S, Werner G, Kreienbrock L, Chakraborty T; RESET consortium. Colistin resistance gene mcr-1 in extended-spectrum β-lactamase-producing and carbapenemase-producing Gram-negative bacteria in Germany. Lancet Infect Dis. 2016 Mar;16(3):282-3. DOI: 10.1016/S1473-3099(16)00009-8 External link
Du H, Chen L, Tang YW, Kreiswirth BN. Emergence of the mcr-1 colistin resistance gene in carbapenem-resistant Enterobacteriaceae. Lancet Infect Dis. 2016 Mar;16(3):287-8. DOI: 10.1016/S1473-3099(16)00056-6 External link
Giufrè M, Monaco M, Accogli M, Pantosti A, Cerquetti M; PAMURSA Study Group. Emergence of the colistin resistance mcr-1 determinant in commensal Escherichia coli from residents of long-term-care facilities in Italy. J Antimicrob Chemother. 2016 Aug;71(8):2329-31. DOI: 10.1093/jac/dkw195 External link
Pogue JM, Cohen DA, Marchaim D. Editorial commentary: Polymyxin-resistant Acinetobacter baumannii: urgent action needed. Clin Infect Dis. 2015 May;60(9):1304-7. DOI: 10.1093/cid/civ044 External link
Ruppé É, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensive Care. 2015 Dec;5(1):21. DOI: 10.1186/s13613-015-0061-0 External link
Partridge SR. Analysis of antibiotic resistance regions in Gram-negative bacteria. FEMS Microbiol Rev. 2011 Sep;35(5):820-55. DOI: 10.1111/j.1574-6976.2011.00277.x External link
Leverstein-van Hall MA, Dierikx CM, Cohen Stuart J, Voets GM, van den Munckhof MP, van Essen-Zandbergen A, Platteel T, Fluit AC, van de Sande-Bruinsma N, Scharinga J, Bonten MJ, Mevius DJ; National ESBL surveillance group. Dutch patients, retail chicken meat and poultry share the same ESBL genes, plasmids and strains. Clin Microbiol Infect. 2011 Jun;17(6):873-80. DOI: 10.1111/j.1469-0691.2011.03497.x External link
Ewers C, Grobbel M, Stamm I, Kopp PA, Diehl I, Semmler T, Fruth A, Beutlich J, Guerra B, Wieler LH, Guenther S. Emergence of human pandemic O25:H4-ST131 CTX-M-15 extended-spectrum-beta-lactamase-producing Escherichia coli among companion animals. J Antimicrob Chemother. 2010 Apr;65(4):651-60. DOI: 10.1093/jac/dkq004 External link
Bos J, Zhang Q, Vyawahare S, Rogers E, Rosenberg SM, Austin RH. Emergence of antibiotic resistance from multinucleated bacterial filaments. Proc Natl Acad Sci USA. 2015 Jan;112(1):178-83. DOI: 10.1073/pnas.1420702111 External link
Feng Y, Hodiamont CJ, van Hest RM, Brul S, Schultsz C, Ter Kuile BH. Development of Antibiotic Resistance during Simulated Treatment of Pseudomonas aeruginosa in Chemostats. PLoS One. 2016 Feb 12;11(2):e0149310. DOI: 10.1371/journal.pone.0149310 External link
Van Boeckel TP, Gandra S, Ashok A, Caudron Q, Grenfell BT, Levin SA, Laxminarayan R. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis. 2014 Aug;14(8):742-50. DOI: 10.1016/S1473-3099(14)70780-7 External link
Plagemann O. Vergleichende Untersuchungen zur Antibiotikaresistenz bei Escherichia-coli-Staemmen vom Schwein aus den Jahren 1971–1974 und 1978–1979. Teil 2. Tierarztl Umsch. 1981:22-9.
Schmithausen J. Der Einsatz von Arzneimitteln in der Ferkelerzeugung. Eine Situationsanalyse in 11 Betrieben [Dissertation]. Bonn: Faculty of Agriculture, Bonn University; 1981.
Dahms C, Hübner NO, Wilke F, Kramer A. Mini-review: Epidemiology and zoonotic potential of multiresistant bacteria and Clostridium difficile in livestock and food. GMS Hyg Infect Control. 2014 Sep 30;9(3):Doc21. DOI: 10.3205/dgkh000241 External link
Wegener HC, Aarestrup FM, Gerner-Smidt P, Bager F. Transfer of antibiotic resistant bacteria from animals to man. Acta Vet Scand Suppl. 1999;92:51-7.
Hering J, Hille K, Frömke C, von Münchhausen C, Hartmann M, Schneider B, Friese A, Roesler U, Merle R, Kreienbrock L. Prevalence and potential risk factors for the occurrence of cefotaxime resistant Escherichia coli in German fattening pig farms--a cross-sectional study. Prev Vet Med. 2014 Sep;116(1-2):129-37. DOI: 10.1016/j.prevetmed.2014.06.014 External link
Hawkey PM, Jones AM. The changing epidemiology of resistance. J Antimicrob Chemother. 2009 Sep;64 Suppl 1:i3-10. DOI: 10.1093/jac/dkp256 External link
Mathew AG, Cissell R, Liamthong S. Antibiotic resistance in bacteria associated with food animals: a United States perspective of livestock production. Foodborne Pathog Dis. 2007;4(2):115-33. DOI: 10.1089/fpd.2006.0066 External link
Phillips I, Casewell M, Cox T, De Groot B, Friis C, Jones R, Nightingale C, Preston R, Waddell J. Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data. J Antimicrob Chemother. 2004 Jan;53(1):28-52. DOI: 10.1093/jac/dkg483 External link
Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A, Kallen A, Limbago B, Fridkin S; National Healthcare Safety Network (NHSN) Team and Participating NHSN Facilities. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol. 2013 Jan;34(1):1-14. DOI: 10.1086/668770 External link
Hackel MA, Badal RE, Bouchillon SK, Biedenbach DJ, Hoban DJ. Resistance Rates of Intra-Abdominal Isolates from Intensive Care Units and Non-Intensive Care Units in the United States: The Study for Monitoring Antimicrobial Resistance Trends 2010-2012. Surg Infect (Larchmt). 2015 Jun;16(3):298-304. DOI: 10.1089/sur.2014.060 External link
Centers for Disease Control and Prevention (CDC). Vital signs: carbapenem-resistant Enterobacteriaceae. MMWR Morb Mortal Wkly Rep. 2013 Mar;62(9):165-70.
Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. Atlanta, GA; 2013. Available from: External link
White House. National Action Plan for Combating Antibiotitic-Resistant Bacteria. March 2015. Available from: docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf External link
Ghose C. Clostridium difficile infection in the twenty-first century. Emerg Microbes Infect. 2013 Sep;2(9):e62. DOI: 10.1038/emi.2013.62 External link
Bhattacharya S. Is screening patients for antibiotic-resistant bacteria justified in the Indian context? Indian J Med Microbiol. 2011 Jul-Sep;29(3):213-7. DOI: 10.4103/0255-0857.83902 External link
Kazi M, Drego L, Nikam C, Ajbani K, Soman R, Shetty A, Rodrigues C. Molecular characterization of carbapenem-resistant Enterobacteriaceae at a tertiary care laboratory in Mumbai. Eur J Clin Microbiol Infect Dis. 2015 Mar;34(3):467-72. DOI: 10.1007/s10096-014-2249-x External link
Goel G, Hmar L, Sarkar De M, Bhattacharya S, Chandy M. Colistin-resistant Klebsiella pneumoniae: report of a cluster of 24 cases from a new oncology center in eastern India. Infect Control Hosp Epidemiol. 2014 Aug;35(8):1076-7. DOI: 10.1086/677170 External link
Abhilash KP, Veeraraghavan B, Abraham OC. Epidemiology and outcome of bacteremia caused by extended spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella spp. in a tertiary care teaching hospital in south India. J Assoc Physicians India. 2010 Dec;58 Suppl:13-7.
Kumar SG, Adithan C, Harish BN, Sujatha S, Roy G, Malini A. Antimicrobial resistance in India: A review. J Nat Sci Biol Med. 2013 Jul;4(2):286-91. DOI: 10.4103/0976-9668.116970 External link
European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2015. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2017. Available from: External link
CLSI Subcommittee on Antimicrobial Susceptibility Testing. Continuing Conversation About Colistin. CLSI AST News Update. 2016 Dec;1(2):7-8. Available from: External link
Barbut F, Oliver Cornely O, Fitzpatrick F, Kuijper EJ, Nagy E, Rupnik M, Tvede M, Wilcox M. Clostridium difficile infection in Europe. A CDI Europe Report. 2013. Available from External link
Geffers C, Gastmeier P. Nosocomial infections and multidrug-resistant organisms in Germany: epidemiological data from KISS (the Hospital Infection Surveillance System). Dtsch Arztebl Int. 2011 Feb;108(6):87-93. DOI: 10.3238/arztebl.2011.0087 External link
Behnke M, Hansen S, Leistner R, Diaz LA, Gropmann A, Sohr D, Gastmeier P, Piening B. Nosocomial infection and antibiotic use: a second national prevalence study in Germany. Dtsch Arztebl Int. 2013 Sep;110(38):627-33. DOI: 10.3238/arztebl.2013.0627 External link
Maechler F, Peña Diaz LA, Schröder C, Geffers C, Behnke M, Gastmeier P. Prevalence of carbapenem-resistant organisms and other Gram-negative MDRO in German ICUs: first results from the national nosocomial infection surveillance system (KISS). Infection. 2015 Apr;43(2):163-8. DOI: 10.1007/s15010-014-0701-6 External link
Bundesministerium für Gesundheit. Verordnung zur Anpassung der Meldepflichten nach dem Infektionsschutzgesetz an die epidemische Lage (IfSG-Meldepflicht-Anpassungsverordnung – IfSGMeldAnpV). Drucksache 75/16. 2016. Available from: External link
Valenza G, Nickel S, Pfeifer Y, Eller C, Krupa E, Lehner-Reindl V, Höller C. Extended-spectrum-β-lactamase-producing Escherichia coli as intestinal colonizers in the German community. Antimicrob Agents Chemother. 2014;58(2):1228-30. DOI: 10.1128/AAC.01993-13 External link
Diekema DJ, Pfaller MA. Rapid detection of antibiotic-resistant organism carriage for infection prevention. Clin Infect Dis. 2013 Jun;56(11):1614-20. DOI: 10.1093/cid/cit038 External link
Ahmed-Bentley J, Chandran AU, Joffe AM, French D, Peirano G, Pitout JD. Gram-negative bacteria that produce carbapenemases causing death attributed to recent foreign hospitalization. Antimicrob Agents Chemother. 2013 Jul;57(7):3085-91. DOI: 10.1128/AAC.00297-13 External link
Bhattacharya S. Early diagnosis of resistant pathogens: how can it improve antimicrobial treatment? Virulence. 2013 Feb;4(2):172-84. DOI: 10.4161/viru.23326 External link
Landman D, Salvani JK, Bratu S, Quale J. Evaluation of techniques for detection of carbapenem-resistant Klebsiella pneumoniae in stool surveillance cultures. J Clin Microbiol. 2005 Nov;43(11):5639-41. DOI: 10.1128/JCM.43.11.5639-5641.2005 External link
Anandan S, Damodaran S, Gopi R, Bakthavatchalam YD, Veeraraghavan B. Rapid Screening for Carbapenem Resistant Organisms: Current Results and Future Approaches. J Clin Diagn Res. 2015 Sep;9(9):DM01-3. DOI: 10.7860/JCDR/2015/14246.6530 External link
Dortet L, Jousset A, Sainte-Rose V, Cuzon G, Naas T. Prospective evaluation of the OXA-48 K-SeT assay, an immunochromatographic test for the rapid detection of OXA-48-type carbapenemases. J Antimicrob Chemother. 2016 Jul;71(7):1834-40. DOI: 10.1093/jac/dkw058 External link
Kabir MH, Meunier D, Hopkins KL, Giske CG, Woodford N. A two-centre evaluation of RAPIDEC® CARBA NP for carbapenemase detection in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. J Antimicrob Chemother. 2016 May;71(5):1213-6. DOI: 10.1093/jac/dkv468 External link
Strauß LM, Dahms C, Becker K, Kramer A, Kaase M, Mellmann A. Development and evaluation of a novel universal β-lactamase gene subtyping assay for blaSHV, blaTEM and blaCTX-M using clinical and livestock-associated Escherichia coli. J Antimicrob Chemother. 2015 Mar;70(3):710-5. DOI: 10.1093/jac/dku450 External link
Osei Sekyere J, Govinden U, Essack SY. Review of established and innovative detection methods for carbapenemase-producing Gram-negative bacteria. J Appl Microbiol. 2015 Nov;119(5):1219-33. DOI: 10.1111/jam.12918 External link
Bloomfield S, Exner M, Flemming HC, Goroncy-Bermes P, Hartemann P, Heeg P, Ilschner C, Krämer I, Merkens W, Oltmanns P, Rotter M, Rutala WA, Sonntag HG, Trautmann M. Lesser-known or hidden reservoirs of infection and implications for adequate prevention strategies: Where to look and what to look for. GMS Hyg Infect Control. 2015;10:Doc04. DOI: 10.3205/dgkh000247 External link
Lee HW, Koh YM, Kim J, Lee JC, Lee YC, Seol SY, Cho DT, Kim J. Capacity of multidrug-resistant clinical isolates of Acinetobacter baumannii to form biofilm and adhere to epithelial cell surfaces. Clin Microbiol Infect. 2008 Jan;14(1):49-54. DOI: 10.1111/j.1469-0691.2007.01842.x External link
Rodríguez-Baño J, Martí S, Soto S, Fernández-Cuenca F, Cisneros JM, Pachón J, Pascual A, Martínez-Martínez L, McQueary C, Actis LA, Vila J; Spanish Group for the Study of Nosocomial Infections (GEIH). Biofilm formation in Acinetobacter baumannii: associated features and clinical implications. Clin Microbiol Infect. 2008 Mar;14(3):276-8. DOI: 10.1111/j.1469-0691.2007.01916.x External link
Zheng R, Zhang Q, Guo Y, Feng Y, Liu L, Zhang A, Zhao Y, Yang X, Xia X. Outbreak of plasmid-mediated NDM-1-producing Klebsiella pneumoniae ST105 among neonatal patients in Yunnan, China. Ann Clin Microbiol Antimicrob. 2016 Feb;15:10. DOI: 10.1186/s12941-016-0124-6 External link
Snyder LA, Loman NJ, Faraj LA, Levi K, Weinstock G, Boswell TC, Pallen MJ, Ala’Aldeen DA. Epidemiological investigation of Pseudomonas aeruginosa isolates from a six-year-long hospital outbreak using high-throughput whole genome sequencing. Euro Surveill. 2013 Oct;18(42). pii=20611. DOI: 10.2807/1560-7917.ES2013.18.42.20611 External link
Engelhart S, Wolf D, Abels S, Exner M. Toiletten als Reservoir für 4-fach resistente Pseudomonas aeruginosa [Abstract, 12. Kongress für Krankenhaushygiene 2014]. HygMed. 2014;39(Suppl DGKH):13. Available from: External link
Vergara-López S, Domínguez MC, Conejo MC, Pascual Á, Rodríguez-Baño J. Wastewater drainage system as an occult reservoir in a protracted clonal outbreak due to metallo-β-lactamase-producing Klebsiella oxytoca. Clin Microbiol Infect. 2013 Nov;19(11):E490-8. DOI: 10.1111/1469-0691.12288 External link
La Forgia C, Franke J, Hacek DM, Thomson RB Jr, Robicsek A, Peterson LR. Management of a multidrug-resistant Acinetobacter baumannii outbreak in an intensive care unit using novel environmental disinfection: a 38-month report. Am J Infect Control. 2010 May;38(4):259-63. DOI: 10.1016/j.ajic.2009.07.012 External link
Scotta C, Juan C, Cabot G, Oliver A, Lalucat J, Bennasar A, Albertí S. Environmental microbiota represents a natural reservoir for dissemination of clinically relevant metallo-beta-lactamases. Antimicrob Agents Chemother. 2011 Nov;55(11):5376-9. DOI: 10.1128/AAC.00716-11 External link
Oikonomou O, Sarrou S, Papagiannitsis CC, Georgiadou S, Mantzarlis K, Zakynthinos E, Dalekos GN, Petinaki E. Rapid dissemination of colistin and carbapenem resistant Acinetobacter baumannii in Central Greece: mechanisms of resistance, molecular identification and epidemiological data. BMC Infect Dis. 2015 Dec 9;15:559. DOI: 10.1186/s12879-015-1297-x External link
Bures S, Fishbain JT, Uyehara CF, Parker JM, Berg BW. Computer keyboards and faucet handles as reservoirs of nosocomial pathogens in the intensive care unit. Am J Infect Control. 2000 Dec;28(6):465-71. DOI: 10.1067/mic.2000.107267 External link
Kola A, Piening B, Pape UF, Veltzke-Schlieker W, Kaase M, Geffers C, Wiedenmann B, Gastmeier P. An outbreak of carbapenem-resistant OXA-48 - producing Klebsiella pneumonia associated to duodenoscopy. Antimicrob Resist Infect Control. 2015 Mar 25;4:8. DOI: 10.1186/s13756-015-0049-4 External link
Carstens A. Ausbruch von KPC-2 produzierenden multiresistenten Bakterien in einer Klinik in Südhessen. Ausbruchsmanagement und Rolle des Öffentlichen Gesundheitsdienstes. Hess Arztebl. 2015;(4):196-8.
Kramer A, Schwebke I, Kampf G. How long do nosocomial pathogens persist on inanimate surfaces? A systematic review. BMC Infect Dis. 2006 Aug;6:130. DOI: 10.1186/1471-2334-6-130 External link
Kramer A, Assadian O. Survival of Microorganisms on Inanimate Surfaces. In: Borkow G, editor. Use of Biocidal Surfaces for Reduction of Healthcare Acquired Infections. Cham: Springer; 2014. p. 7-26. DOI: 10.1007/978-3-319-08057-4_2 External link
Weber DJ, Rutala WA, Kanamori H, Gergen MF, Sickbert-Bennett EE. Carbapenem-resistant Enterobacteriaceae: frequency of hospital room contamination and survival on various inoculated surfaces. Infect Control Hosp Epidemiol. 2015 May;36(5):590-3. DOI: 10.1017/ice.2015.17 External link
Voss A. CRE – too weak to spread!? In: Reflections on Infection Prevention and Control [Blog]. 2015 Jun 9. Available from: External link
Carstens A, Kepper U, Exner M, Hauri A, Kaase M, Wendt C. Plasmid-vermittelter Multispezies-Ausbruch mit Carbapenem-resistenten Enterobacteriaceae. Epid Bull. 2014;(47):455-9. Available from: External link
Ewers C, Bethe A, Semmler T, Guenther S, Wieler LH. Extended-spectrum β-lactamase-producing and AmpC-producing Escherichia coli from livestock and companion animals, and their putative impact on public health: a global perspective. Clin Microbiol Infect. 2012 Jul;18(7):646-55. DOI: 10.1111/j.1469-0691.2012.03850.x External link
Kilonzo-Nthenge A, Rotich E, Nahashon SN. Evaluation of drug-resistant Enterobacteriaceae in retail poultry and beef. Poult Sci. 2013 Apr;92(4):1098-107. DOI: 10.3382/ps.2012-02581 External link
Valentin L, Sharp H, Hille K, Seibt U, Fischer J, Pfeifer Y, Michael GB, Nickel S, Schmiedel J, Falgenhauer L, Friese A, Bauerfeind R, Roesler U, Imirzalioglu C, Chakraborty T, Helmuth R, Valenza G, Werner G, Schwarz S, Guerra B, Appel B, Kreienbrock L, Käsbohrer A. Subgrouping of ESBL-producing Escherichia coli from animal and human sources: an approach to quantify the distribution of ESBL types between different reservoirs. Int J Med Microbiol. 2014 Oct;304(7):805-16. DOI: 10.1016/j.ijmm.2014.07.015 External link
Nüesch-Inderbinen M, Stephan R. Epidemiology of extended-spectrum β-lactamase-producing Escherichia coli in the human-livestock environment. Curr Clin Micro Rpt. 2016;3(1):1-9. DOI: 10.1007/s40588-016-0027-5 External link
Schmithausen RM, Schulze-Geisthoevel SV, Stemmer F, El-Jade M, Reif M, Hack S, Meilaender A, Montabauer G, Fimmers R, Parcina M, Hoerauf A, Exner M, Petersen B, Bierbaum G, Bekeredjian-Ding I. Analysis of Transmission of MRSA and ESBL-E among Pigs and Farm Personnel. PLoS One. 2015 Sep 30;10(9):e0138173. DOI: 10.1371/journal.pone.0138173 External link
Dahms C, Hübner NO, Kossow A, Mellmann A, Dittmann K, Kramer A. Occurrence of ESBL-Producing Escherichia coli in Livestock and Farm Workers in Mecklenburg-Western Pomerania, Germany. PLoS ONE. 2015;10(11):e0143326. DOI: 10.1371/journal.pone.0143326 External link
Kola A, Kohler C, Pfeifer Y, Schwab F, Kühn K, Schulz K, Balau V, Breitbach K, Bast A, Witte W, Gastmeier P, Steinmetz I. High prevalence of extended-spectrum-β-lactamase-producing Enterobacteriaceae in organic and conventional retail chicken meat, Germany. J Antimicrob Chemother. 2012 Nov;67(11):2631-4. DOI: 10.1093/jac/dks295 External link
Gwida M, Hotzel H, Geue L, Tomaso H. Occurrence of Enterobacteriaceae in Raw Meat and in Human Samples from Egyptian Retail Sellers. Int Sch Res Notices. 2014 Nov 11;2014:565671. DOI: 10.1155/2014/565671 External link
Coleman BL, Salvadori MI, McGeer AJ, Sibley KA, Neumann NF, Bondy SJ, Gutmanis IA, McEwen SA, Lavoie M, Strong D, Johnson I, Jamieson FB, Louie M; ARO Water Study Group. The role of drinking water in the transmission of antimicrobial-resistant E. coli. Epidemiol Infect. 2012 Apr;140(4):633-42. DOI: 10.1017/S0950268811001038 External link
Coleman BL, Louie M, Salvadori MI, McEwen SA, Neumann N, Sibley K, Irwin RJ, Jamieson FB, Daignault D, Majury A, Braithwaite S, Crago B, McGeer AJ. Contamination of Canadian private drinking water sources with antimicrobial resistant Escherichia coli. Water Res. 2013 Jun 1;47(9):3026-36. DOI: 10.1016/j.watres.2013.03.008 External link
Davis GS, Waits K, Nordstrom L, Weaver B, Aziz M, Gauld L, Grande H, Bigler R, Horwinski J, Porter S, Stegger M, Johnson JR, Liu CM, Price LB. Intermingled Klebsiella pneumoniae Populations Between Retail Meats and Human Urinary Tract Infections. Clin Infect Dis. 2015 Sep;61(6):892-9. DOI: 10.1093/cid/civ428 External link
Van Boeckel TP, Brower C, Gilbert M, Grenfell BT, Levin SA, Robinson TP, Teillant A, Laxminarayan R. Global trends in antimicrobial use in food animals. Proc Natl Acad Sci U S A. 2015 May 5;112(18):5649-54. DOI: 10.1073/pnas.1503141112 External link
Chandy M, Bhattacharya S. The problem of multi-drug resistant Gram-negative Infections among Cancer patients in Eastern India [Abstract]. In: 11th Indo-Australian Biotechnology conference on innovation in the immunology of infection, cancer and autoimmune diseases and vaccines; 2015 Sep 7-8; Westmead, Sydney, Australia. p. 39.
World Health Organization (WHO). Antimicrobial Resistance: Global Report on Surveillance. Geneva; 2014. Available from: External link
Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerging Infect Dis. 2014 Jul;20(7):1170-5. DOI: 10.3201/eid2007.121004 External link
Paramythiotou E, Routsi C. Association between infections caused by multidrug-resistant gram-negative bacteria and mortality in critically ill patients. World J Crit Care Med. 2016 May 4;5(2):111-20. DOI: 10.5492/wjccm.v5.i2.111 External link
Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE, Dodek P, Wood G, Kumar A, Simon D, Peters C, Ahsan M, Chateau D; Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009 Nov;136(5):1237-48. DOI: 10.1378/chest.09-0087 External link
Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, Stefanou I, Sypsa V, Miriagou V, Nepka M, Georgiadou S, Markogiannakis A, Goukos D, Skoutelis A. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014;58(4):2322-8. DOI: 10.1128/AAC.02166-13 External link
Ellis D, Cohen B, Liu J, Larson E. Risk factors for hospital-acquired antimicrobial-resistant infection caused by Acinetobacter baumannii. Antimicrob Resist Infect Control. 2015;4:40. DOI: 10.1186/s13756-015-0083-2 External link
Davis KA, Moran KA, McAllister CK, Gray PJ. Multidrug-resistant Acinetobacter extremity infections in soldiers. Emerg Infect Dis. 2005 Aug;11(8):1218-24. Available from: External link
Howard A, O’Donoghue M, Feeney A, Sleator RD. Acinetobacter baumannii: an emerging opportunistic pathogen. Virulence. 2012 May;3(3):243-50. DOI: 10.4161/viru.19700 External link
Bryce A, Hay AD, Lane IF, Thornton HV, Wootton M, Costelloe C. Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary care: systematic review and meta-analysis. BMJ. 2016 Mar;352:i939. DOI: 10.1136/bmj.i939 External link
Bart Y, Paul M, Eluk O, Geffen Y, Rabino G, Hussein K. Risk Factors for Recurrence of Carbapenem-Resistant Enterobacteriaceae Carriage: Case-Control Study. Infect Control Hosp Epidemiol. 2015 Aug;36(8):936-41. DOI: 10.1017/ice.2015.82 External link
Zimmerman FS, Assous MV, Bdolah-Abram T, Lachish T, Yinnon AM, Wiener-Well Y. Duration of carriage of carbapenem-resistant Enterobacteriaceae following hospital discharge. Am J Infect Control. 2013 Mar;41(3):190-4. DOI: 10.1016/j.ajic.2012.09.020 External link
Bhattacharya S, Goel G, Mukherjee S, Bhaumik J, Chandy M. Epidemiology of antimicrobial resistance in an oncology center in eastern India. Infect Control Hosp Epidemiol. 2015 Jul;36(7):864-6. DOI: 10.1017/ice.2015.96 External link
Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol. 2008 Dec;29(12):1099-106. DOI: 10.1086/592412 External link
Steinmann J, Kaase M, Gatermann S, Popp W, Steinmann E, Damman M, Paul A, Saner F, Buer J, Rath P. Outbreak due to a Klebsiella pneumoniae strain harbouring KPC-2 and VIM-1 in a German university hospital, July 2010 to January 2011. Euro Surveill. 2011 Aug;16(33). pii=1994. Available from: External link
Qureshi ZA, Hittle LE, O’Hara JA, Rivera JI, Syed A, Shields RK, Pasculle AW, Ernst RK, Doi Y. Colistin-resistant Acinetobacter baumannii: beyond carbapenem resistance. Clin Infect Dis. 2015 May 1;60(9):1295-303. DOI: 10.1093/cid/civ048 External link
Robert Koch Institut. Stellungnahme des Robert Koch-Instituts zur Frage des Screenings von Asylsuchenden auf multiresistente Erreger (MRE). Berlin: RKI; 2016. Available from: External link
Heudorf U, Krackhardt B, Karathana M, Kleinkauf N, Zinn C. Multidrug-resistant bacteria in unaccompanied refugee minors arriving in Frankfurt am Main, Germany, October to November 2015. Euro Surveill. 2016;21(2). pii=30109. DOI: 10.2807/1560-7917.ES.2016.21.2.30109 External link
Reinheimer C, Kempf VA, Göttig S, Hogardt M, Wichelhaus TA, O’Rourke F, Brandt C. Multidrug-resistant organisms detected in refugee patients admitted to a University Hospital, Germany June?December 2015. Euro Surveill. 2016;21(2). pii=30110. DOI: 10.2807/1560-7917.ES.2016.21.2.30110 External link
Heudorf U, Albert-Braun S, Hunfeld KP, Birne FU, Schulze J, Strobel K, Petscheleit K, Kempf VA, Brandt C. Multidrug-resistant organisms in refugees: prevalences and impact on infection control in hospitals. GMS Hyg Infect Control. 2016;11:Doc16. DOI: 10.3205/dgkh000276 External link
Cardoso T, Ribeiro O, Aragão IC, Costa-Pereira A, Sarmento AE. Additional risk factors for infection by multidrug-resistant pathogens in healthcare-associated infection: a large cohort study. BMC Infect Dis. 2012 Dec;12:375. DOI: 10.1186/1471-2334-12-375 External link
Fisch J, Lansing B, Wang L, Symons K, Cherian K, McNamara S, Mody L. New acquisition of antibiotic-resistant organisms in skilled nursing facilities. J Clin Microbiol. 2012 May;50(5):1698-703. DOI: 10.1128/JCM.06469-11 External link
O’Fallon E, Kandel R, Kandell R, Schreiber R, D’Agata EM. Acquisition of multidrug-resistant gram-negative bacteria: incidence and risk factors within a long-term care population. Infect Control Hosp Epidemiol. 2010 Nov;31(11):1148-53. DOI: 10.1086/656590 External link
O’Fallon E, Schreiber R, Kandel R, D’Agata EM. Multidrug-resistant gram-negative bacteria at a long-term care facility: assessment of residents, healthcare workers, and inanimate surfaces. Infect Control Hosp Epidemiol. 2009 Dec;30(12):1172-9. doi: 10.1086/648453 External link
Hogardt M, Proba P, Mischler D, Cuny C, Kempf VA, Heudorf U. Current prevalence of multidrug-resistant organisms in long-term care facilities in the Rhine-Main district, Germany, 2013. Euro Surveill. 2015 Jul;20(26). pii=21171. DOI: 10.2807/1560-7917.ES2015.20.26.21171 External link
D’Agata EM, Habtemariam D, Mitchell S. Multidrug-Resistant Gram-Negative Bacteria: Inter- and Intradissemination Among Nursing Homes of Residents With Advanced Dementia. Infect Control Hosp Epidemiol. 2015 Aug;36(8):930-5. DOI: 10.1017/ice.2015.97 External link
Mody L, Gibson KE, Horcher A, Prenovost K, McNamara SE, Foxman B, Kaye KS, Bradley S. Prevalence of and risk factors for multidrug-resistant Acinetobacter baumannii colonization among high-risk nursing home residents. Infect Control Hosp Epidemiol. 2015 Oct;36(10):1155-62. DOI: 10.1017/ice.2015.143 External link
Rogers B. Antimicrobial resistant Escherichia coli. Clinical, epidemiological and molecular characteristics in the Australian region [PhD Thesis]. University of Queensland, School of Medicine; 2014. DOI: 10.14264/uql.2015.767 External link
Neumann N, Mischler D, Cuny C, Hogardt M, Kempf VA, Heudorf U. Multiresistente Erreger bei Patienten ambulanter Pflegedienste im Rhein-Main-Gebiet 2014 : Prävalenz und Risikofaktoren [Multidrug-resistant organisms (MDRO) in patients in outpatient care in the Rhine-Main region, Germany, in 2014: Prevalence and risk factors]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2016 Feb;59(2):292-300. DOI: 10.1007/s00103-015-2290-7 External link
Gleich S, Böhm D, Horvath L. Außerklinische Intensivpflege: Aktuelle Herausforderungen im Hygienemanagement. Epid Bull. 2015;(39):419-24. DOI: 10.17886/EpiBull-2015-009.2 External link
Heudorf U, Cuny C, Herrmann M, Kempf V, Mischler D, Schulze J, Zinn C. MRE (MRSA, ESBL, MRGN) im außerakutklinischen Bereich – Aktuelle Daten aus dem MRE-Netz Rhein-Main 2012-2014. Umweltmed Hyg Arbeitsmed. 2015;20(6):307-16. Available from: External link
Hassing RJ, Alsma J, Arcilla MS, van Genderen PJ, Stricker BH, Verbon A. International travel and acquisition of multidrug-resistant Enterobacteriaceae: a systematic review. Euro Surveill. 2015;20(47). p=30074. DOI: 10.2807/1560-7917.ES.2015.20.47.30074 External link
Suwantarat N, Carroll KC. Epidemiology and molecular characterization of multidrug-resistant Gram-negative bacteria in Southeast Asia. Antimicrob Resist Infect Control. 2016;5:15. DOI: 10.1186/s13756-016-0115-6 External link
Kuenzli E, Jaeger VK, Frei R, Neumayr A, DeCrom S, Haller S, Blum J, Widmer AF, Furrer H, Battegay M, Endimiani A, Hatz C. High colonization rates of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli in Swiss travellers to South Asia – a prospective observational multicentre cohort study looking at epidemiology, microbiology and risk factors. BMC Infect Dis. 2014 Oct;14:528. DOI: 10.1186/1471-2334-14-528 External link
Lübbert C, Straube L, Stein C, Makarewicz O, Schubert S, Mössner J, Pletz MW, Rodloff AC. Colonization with extended-spectrum beta-lactamase-producing and carbapenemase-producing Enterobacteriaceae in international travelers returning to Germany. Int J Med Microbiol. 2015 Jan;305(1):148-56. DOI: 10.1016/j.ijmm.2014.12.001 External link
Pires J, Kuenzli E, Kasraian S, Tinguely R, Furrer H, Hilty M, Hatz C, Endimiani A. Polyclonal Intestinal Colonization with Extended-Spectrum Cephalosporin-Resistant Enterobacteriaceae upon Traveling to India. Front Microbiol. 2016;7:1069. DOI: 10.3389/fmicb.2016.01069 External link
Youngman I. Medical Tourism Facts and Figures 2015. Available from: External link
Lunt N, Smith R, Exworthy M, Green ST, Horsfall D, Mannion R. Medical Tourism: Treatments, Markets and Health System Implications: A scoping review. Paris: OECD; 2011. Available from: External link
Lee CS, Doi Y. Therapy of Infections due to Carbapenem-Resistant Gram-Negative Pathogens. Infect Chemother. 2014 Sep;46(3):149-64. DOI: 10.3947/ic.2014.46.3.149 External link
Stock I. Erkrankungen durch Carbapenemase-bildende Enterobacteriaceae. Eine besondere Herausforderung für die antibakterielle Therapie [Infectious diseases caused by carbapenemase-producing Enterobacteriaceae--a particular challenge for antibacterial therapy]. Med Monatsschr Pharm. 2014 May;37(5):162-72; quiz 173-4.
The PEW Charitable Trusts. Antibiotics Currently in Clinical Development. 2014. Available from: External link
Feng Y, Hodiamont CJ, van Hest RM, Brul S, Schultsz C, Ter Kuile BH. Development of Antibiotic Resistance during Simulated Treatment of Pseudomonas aeruginosa in Chemostats. PLoS ONE. 2016;11(2):e0149310. DOI: 10.1371/journal.pone.0149310 External link
Gibson GA, Bauer SR, Neuner EA, Bass SN, Lam SW. Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli. Antimicrob Agents Chemother. 2015 Nov;60(1):431-6. DOI: 10.1128/AAC.01414-15 External link
Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of the available evidence. Antimicrob Agents Chemother. 2014;58(2):654-63. DOI: 10.1128/AAC.01222-13 External link
Manchanda V, Sanchaita S, Singh N. Multidrug resistant acinetobacter. J Glob Infect Dis. 2010 Sep;2(3):291-304. DOI: 10.4103/0974-777X.68538 External link
Septimus EJ, Schweizer ML. Decolonization in Prevention of Health Care-Associated Infections. Clin Microbiol Rev. 2016 Apr;29(2):201-22. DOI: 10.1128/CMR.00049-15 External link
Price R, MacLennan G, Glen J; SuDDICU Collaboration. Selective digestive or oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of death in general intensive care: systematic review and network meta-analysis. BMJ. 2014 Mar 31;348:g2197. DOI: 10.1136/bmj.g2197 External link
Kramer A, Daeschlein G, Kammerlander G, Andriessen A, Aspöck C, Bergemann R, Eberlein T, Gerngross H, Görtz G, Heeg P, Jünger M, Koch S, König B, Laun R, Peter RU, Roth B, Ruef C, Sellmer W, Wewalka G, Eisenbeiß W. Konsensusempfehlung zur Auswahl von Wirkstoffen für die Wundantiseptik. Z Wundheilung. 2004;(3):110-20.
World Union of Wound Healing Societies (WUWHS). Wound infection in clinical practice. An international consensus. 2nd ed. 2011.
Neu HC, Fu KP. Cefuroxime, a beta-lactamase-resistant cephalosporin with a broad spectrum of gram-positive and -negative activity. Antimicrob Agents Chemother. 1978 Apr;13(4):657-64. DOI: 10.1128/AAC.13.4.657 External link
Koburger T, Hübner NO, Braun M, Siebert J, Kramer A. Standardized comparison of antiseptic efficacy of triclosan, PVP-iodine, octenidine dihydrochloride, polyhexanide and chlorhexidine digluconate. J Antimicrob Chemother. 2010 Aug;65(8):1712-9. DOI: 10.1093/jac/dkq212 External link
Mayr-Kanhäuser S, Kränke B, Aberer W. Efficacy of octenidine dihydrochloride and 2-phenoxyethanol in the topical treatment of inflammatory acne. Acta Dermatovenerol Alp Pannonica Adriat. 2008 Sep;17(3):139-43.
Novakov Mikic A, Budakov D. Comparison of local metronidazole and a local antiseptic in the treatment of bacterial vaginosis. Arch Gynecol Obstet. 2010 Jul;282(1):43-7. DOI: 10.1007/s00404-009-1241-7 External link
Kramer A, Behrens-Baumann W. Prophylactic use of topical anti-infectives in ophthalmology. Ophthalmologica. 1997;211 Suppl 1:68-76. DOI: 10.1159/000310889 External link
Yazdankhah SP, Scheie AA, Høiby EA, Lunestad BT, Heir E, Fotland TØ, Naterstad K, Kruse H. Triclosan and antimicrobial resistance in bacteria: an overview. Microb Drug Resist. 2006;12(2):83-90. DOI: 10.1089/mdr.2006.12.83 External link
Silver S. Bacterial silver resistance: molecular biology and uses and misuses of silver compounds. FEMS Microbiol Rev. 2003 Jun;27(2-3):341-53. DOI: 10.1016/S0168-6445(03)00047-0 External link
McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev. 1999 Jan;12(1):147-79.
Hübner NO, Siebert J, Kramer A. Octenidine dihydrochloride, a modern antiseptic for skin, mucous membranes and wounds. Skin Pharmacol Physiol. 2010;23(5):244-58. DOI: 10.1159/000314699 External link
Hübner NO, Kramer A. Review on the efficacy, safety and clinical applications of polihexanide, a modern wound antiseptic. Skin Pharmacol Physiol. 2010;23 Suppl:17-27. DOI: 10.1159/000318264 External link
Kim SA, Rhee MS. Marked synergistic bactericidal effects and mode of action of medium-chain fatty acids in combination with organic acids against Escherichia coli O157:H7. Appl Environ Microbiol. 2013 Nov;79(21):6552-60. DOI: 10.1128/AEM.02164-13 External link
Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. Review on Antimicrobial Resistance. December 2014. Available from: AMR%20Review%20Paper%20-%20Tackling%20a%20crisis %20for%20the%20health%20and%20wealth%20of%20nations_1.pdf External link
Tackling drug-resistant infections globally: Final Report and Recommendations. Review on Antimicrobial Resistance. May 2016. Available from: External link
Berendonk TU, Manaia CM, Merlin C, Fatta-Kassinos D, Cytryn E, Walsh F, Bürgmann H, Sørum H, Norström M, Pons MN, Kreuzinger N, Huovinen P, Stefani S, Schwartz T, Kisand V, Baquero F, Martinez JL. Tackling antibiotic resistance: the environmental framework. Nat Rev Microbiol. 2015 05;13(5):310-7. DOI: 10.1038/nrmicro3439 External link
Berglund B. Environmental dissemination of antibiotic resistance genes and correlation to anthropogenic contamination with antibiotics. Infect Ecol Epidemiol. 2015 Sep 8;5:28564. DOI: 10.3402/iee.v5.28564 External link
Wilson AP, Livermore DM, Otter JA, Warren RE, Jenks P, Enoch DA, Newsholme W, Oppenheim B, Leanord A, McNulty C, Tanner G, Bennett S, Cann M, Bostock J, Collins E, Peckitt S, Ritchie L, Fry C, Hawkey P. Prevention and control of multi-drug-resistant Gram-negative bacteria: recommendations from a Joint Working Party. J Hosp Infect. 2016 Jan;92 Suppl 1:S1-44. DOI: 10.1016/j.jhin.2015.08.007 External link
Haverkate MR, Bootsma MC, Weiner S, Blom D, Lin MY, Lolans K, Moore NM, Lyles RD, Weinstein RA, Bonten MJ, Hayden MK. Modeling spread of KPC-producing bacteria in long-term acute care hospitals in the Chicago region, USA. Infect Control Hosp Epidemiol. 2015 Oct;36(10):1148-54. DOI: 10.1017/ice.2015.163 External link
Landelle C, Legrand P, Lesprit P, Cizeau F, Ducellier D, Gouot C, Bréhaut P, Soing-Altrach S, Girou E, Brun-Buisson C. Protracted outbreak of multidrug-resistant Acinetobacter baumannii after intercontinental transfer of colonized patients. Infect Control Hosp Epidemiol. 2013 Feb;34(2):119-24. DOI: 10.1086/669093 External link
Hayden MK, Lin MY, Lolans K, Weiner S, Blom D, Moore NM, Fogg L, Henry D, Lyles R, Thurlow C, Sikka M, Hines D, Weinstein RA; Centers for Disease Control and Prevention Epicenters Program. Prevention of colonization and infection by Klebsiella pneumoniae carbapenemase-producing enterobacteriaceae in long-term acute-care hospitals. Clin Infect Dis. 2015 Apr;60(8):1153-61. DOI: 10.1093/cid/ciu1173 External link
Schmidt P, Garske D, Geffers C, Simon A, Zernikow B, Hasan C. Hygienerichtlinien auf der Kinderpalliativstation der Vestischen Kinder- und Jugendklinik Datteln. Hyg Med. 2015;40(7/8):297-305.
Fusch C, Pogorzelski D, Main C, Meyer CL, El Helou S, Mertz D. Self-disinfecting sink drains reduce the Pseudomonas aeruginosa bioburden in a neonatal intensive care unit. Acta Paediatr. 2015 Aug;104(8):e344-9. DOI: 10.1111/apa.13005 External link
Bhalchandra R, Chandy M, Ramanan VR, Mahajan A, Soundaranayagam JR, Garai S, Bhattacharya S. Role of water quality assessments in hospital infection control: experience from a new oncology center in eastern India. Indian J Pathol Microbiol. 2014 Jul-Sep;57(3):435-8. DOI: 10.4103/0377-4929.138745 External link
Dancer SJ. Controlling hospital-acquired infection: focus on the role of the environment and new technologies for decontamination. Clin Microbiol Rev. 2014 Oct;27(4):665-90. DOI: 10.1128/CMR.00020-14 External link
Alfa MJ, Lo E, Olson N, MacRae M, Buelow-Smith L. Use of a daily disinfectant cleaner instead of a daily cleaner reduced hospital-acquired infection rates. Am J Infect Control. 2015 Feb;43(2):141-6. DOI: 10.1016/j.ajic.2014.10.016 External link
Schmithausen RM, Kellner SR, Schulze-Geisthoevel SV, Hack S, Engelhart S, Bodenstein I, Al-Sabti N, Reif M, Fimmers R, Körber-Irrgang B, Harlizius J, Hoerauf A, Exner M, Bierbaum G, Petersen B, Bekeredjian-Ding I. Eradication of methicillin-resistant Staphylococcus aureus and of Enterobacteriaceae expressing extended-spectrum beta-lactamases on a model pig farm. Appl Environ Microbiol. 2015 Nov;81(21):7633-43. DOI: 10.1128/AEM.01713-15 External link
Reichel M, Schlicht A, Ostermeyer C, Kampf G. Efficacy of surface disinfectant cleaners against emerging highly resistant gram-negative bacteria. BMC Infect Dis. 2014 May;14:292. DOI: 10.1186/1471-2334-14-292 External link
Goroncy Bermes P. Efficacy of Biocides against Gram-negativ Bacteria [Conference presentation]. In: RSS Symposium “Worldwide Significance of Gram-Negative Antibiotic Resistant Rods: Epidemiology, Prevention and Control Strategies”; 2015 Nov 26-27; Hamburg, Germany. Available from: External link
Jennings MC, Minbiole KP, Wuest WM. Quaternary Ammonium Compounds: An Antimicrobial Mainstay and Platform for Innovation to Address Bacterial Resistance. ACS Infect Dis. 2015 Jul;1(7):288-303. DOI: 10.1021/acsinfecdis.5b00047 External link
Babaei M, Sulong A, Hamat R, Nordin S, Neela V. Extremely high prevalence of antiseptic resistant Quaternary Ammonium Compound E gene among clinical isolates of multiple drug resistant Acinetobacter baumannii in Malaysia. Ann Clin Microbiol Antimicrob. 2015 Mar;14:11. DOI: 10.1186/s12941-015-0071-7 External link
Silveira E, Marques P, Freitas AR, Mourão J, Coque TM, Antunes P, Peixe L, Novais C. A hospital sewage ST17 Enterococcus faecium with a transferable Inc18-like plasmid carrying genes coding for resistance to antibiotics and quaternary ammonium compounds (qacZ). J Glob Antimicrob Resist. 2015 Mar;3(1):49-51. DOI: 10.1016/j.jgar.2014.11.005 External link
Schwaiger K, Harms KS, Bischoff M, Preikschat P, Mölle G, Bauer-Unkauf I, Lindorfer S, Thalhammer S, Bauer J, Hölzel CS. Insusceptibility to disinfectants in bacteria from animals, food and humans-is there a link to antimicrobial resistance? Front Microbiol. 2014 Mar 18;5:88. DOI: 10.3389/fmicb.2014.00088 External link
Oggioni MR, Coelho JR, Furi L, Knight DR, Viti C, Orefici G, Martinez JL, Freitas AT, Coque TM, Morrissey I; BIOHYPO consortium. Significant Differences Characterise the Correlation Coefficients between Biocide and Antibiotic Susceptibility Profiles in Staphylococcus aureus. Curr Pharm Des. 2015;21(16):2054-7.
Gebel J, Exner M, French G, Chartier Y, Christiansen B, Gemein S, Goroncy-Bermes P, Hartemann P, Heudorf U, Kramer A, Maillard JY, Oltmanns P, Rotter M, Sonntag HG. The role of surface disinfection in infection prevention. GMS Hyg Infect Control. 2013;8(1):Doc10. DOI: 10.3205/dgkh000210 External link
Gebel J, Sonntag HG, Werner HP, Vacata V, Exner M, Kistemann T. The higher disinfectant resistance of nosocomial isolates of Klebsiella oxytoca: how reliable are indicator organisms in disinfectant testing? J Hosp Infect. 2002 Apr;50(4):309-11. DOI: 10.1053/jhin.2002.1201 External link
Reiss I, Borkhardt A, Füssle R, Sziegoleit A, Gortner L. Disinfectant contaminated with Klebsiella oxytoca as a source of sepsis in babies. Lancet. 2000 Jul 22;356(9226):310. DOI: 10.1016/S0140-6736(00)02509-5 External link
Oltmanns P, Hendrich S. Restrictions in the use of biocides for disinfection procedures [Conference presentation]. In: RSS Symposium “Worldwide Significance of Gram-Negative Antibiotic Resistant Rods: Epidemiology, Prevention and Control Strategies”; 2015 Nov 26-27; Hamburg, Germany. Available from: External link
Schmithausen RM, Kellner SR, Schulze-Geisthoevel SV, Hack S, Engelhart S, Bodenstein I, Al-Sabti N, Reif M, Fimmers R, Körber-Irrgang B, Harlizius J, Hoerauf A, Exner M, Bierbaum G, Petersen B, Bekeredjian-Ding I. Eradication of methicillin-resistant Staphylococcus aureus and of Enterobacteriaceae expressing extended-spectrum beta-lactamases on a model pig farm. Appl Environ Microbiol. 2015 Nov;81(21):7633-43. DOI: 10.1128/AEM.01713-15 External link
Böhm R, Schamper B, Beck A. Ökotoxikologische Untersuchungen zur Desinfektionsmittelanwendung im Tierseuchenfall [Conference presentation]. In: 21. Kongress der Deutschen Veterinärmedizinischen Gesellschaft DVG; 1995 Mar 21-24; Bad Nauheim, Germany.
Petersen B, Knura-Deszczka S, Pönsgen-Schmidt E, Gymnich S. Computerised food safety monitoring in animal production. Livest Prod Sci. 2002;76(3):207-13. DOI: 10.1016/S0301-6226(02)00120-3 External link
Sommer H, Greuel E, Müller W. Tierhygiene, Gesunderhaltung von Rindern und Schweinen. Stuttgart: Ulmer; 1976.
Weese JS, Rousseau J. Attempted eradication of methicillin-resistant staphylococcus aureus colonisation in horses on two farms. Equine Vet J. 2005 Nov;37(6):510-4. DOI: 10.2746/042516405775314835 External link
Weese JS, Rousseau J, Traub-Dargatz JL, Willey BM, McGeer AJ, Low DE. Community-associated methicillin-resistant Staphylococcus aureus in horses and humans who work with horses. J Am Vet Med Assoc. 2005 Feb;226(4):580-3. DOI: 10.2460/javma.2005.226.580 External link
Blanc F, Bocquier F, Agabrielc J, D’hourd P, Chilliard Y. Adaptive abilities of the females and sustainability of ruminant livestock systems. A review. Anim Res. 2006;55(6):489-510. DOI: 10.1051/animres:2006040 External link
Mesa RJ, Blanc V, Blanch AR, Cortés P, González JJ, Lavilla S, Miró E, Muniesa M, Saco M, Tórtola MT, Mirelis B, Coll P, Llagostera M, Prats G, Navarro F. Extended-spectrum beta-lactamase-producing Enterobacteriaceae in different environments (humans, food, animal farms and sewage). J Antimicrob Chemother. 2006 Jul;58(1):211-5. DOI: 10.1093/jac/dkl211 External link
Smet A, Martel A, Persoons D, Dewulf J, Heyndrickx M, Catry B, Herman L, Haesebrouck F, Butaye P. Diversity of extended-spectrum beta-lactamases and class C beta-lactamases among cloacal Escherichia coli Isolates in Belgian broiler farms. Antimicrob Agents Chemother. 2008 Apr;52(4):1238-43. DOI: 10.1128/AAC.01285-07 External link
Strauch D, Böhm R. Reinigung und Desinfektion in der Nutztierhaltung und Veredelungswirtschaft. Stutgart: Enke; 2002.
Selbitz HJ, Truyen U, Valentin-Weigand P, editors. Tiermedizinische Mikrobiologie, Infektions- und Seuchenlehre. 9., vollständig überarbeitete Auflage. Stuttgart: Enke; 2010.
Mayr A. Wesen, Bedeutung und Bekämpfung des infektiösen Hospitalismus in der Tierproduktion. Zentralbl Vet Med. 1983;30(9):637-59. DOI: 10.1111/j.1439-0450.1983.tb01890.x External link
Link M. Atemwegs- und parasitäre Erkrankungen bei Schweinen: Vorbeugende Maßnahmen und Therapie [Respiratory and parasitic deseases of pigs: preventive and therapeutic measures]. In: Konferenz Markt und Produktion in der ökologischen Schweinehaltung; 2003 Mar 05-06; Fulda, Germany. p. 96-105. Available from: External link
Sommer MA. Epidemiologische Untersuchungen zur Tiergesundheit in Schweinezuchtbeständen unter besonderer Berücksichtigung von Managementfaktoren und des Einsatzes von Antibiotika und Homöopathika [Dissertation]. Hannover: Tierärztliche Hochschule; 2009. URN: urn:nbn:de:gbv:95-97842 External link
Catry B, Van Duijkeren E, Pomba MC, Greko C, Moreno MA, Pyörälä S, Ruzauskas M, Sanders P, Threlfall EJ, Ungemach F, Törneke K, Munoz-Madero C, Torren-Edo J; Scientific Advisory Group on Antimicrobials (SAGAM). Reflection paper on MRSA in food-producing and companion animals: epidemiology and control options for human and animal health. Epidemiol Infect. 2010 May;138(5):626-44. DOI: 10.1017/S0950268810000014 External link
Sommer H, Greuel E, Müller W. Hygiene der Rinder- und Schweineproduktion. Stuttgart: Ulmer; 1991.
Exner M. Divergent opinions on surface disinfection: myths or prevention? A review of the literature. GMS Krankenhhyg Interdiszip. 2007 Sep;2(1):Doc19. Available from: External link
Exner M, Tuschewitzki GJ, Scharnagel J. Influence of biofilms by chemical disinfectants and mechanical cleaning. Zentralbl Bakteriol Mikrobiol Hyg B. 1987 Apr;183(5-6):549-63.
Schmithausen RM, Stemmer F, Schulze-Geisthoevel SV, Tappe EV, El-Jade MR, Bekeredjian-Ding I, Petersen B. ESBL-E and MRSA monitoring integrated into a chain-oriented herd health management system [unpublished data].
Founou LL, Founou RC, Essack SY. Antibiotic Resistance in the Food Chain: A Developing Country-Perspective. Front Microbiol. 2016;7:1881. DOI: 10.3389/fmicb.2016.01881 External link
Roca I, Akova M, Baquero F, Carlet J, Cavaleri M, Coenen S, Cohen J, Findlay D, Gyssens I, Heuer OE, Kahlmeter G, Kruse H, Laxminarayan R, Liébana E, López-Cerero L, MacGowan A, Martins M, Rodríguez-Baño J, Rolain JM, Segovia C, Sigauque B, Tacconelli E, Wellington E, Vila J. The global threat of antimicrobial resistance: science for intervention. New Microbes New Infect. 2015 Apr 16;6:22-9. DOI: 10.1016/j.nmni.2015.02.007 External link
Yarlagadda V, Manjunath GB, Sarkar P, Akkapeddi P, Paramanandham K, Shome BR, Ravikumar R, Haldar J. Glycopeptide Antibiotic To Overcome the Intrinsic Resistance of Gram-Negative Bacteria. ACS Infect Dis. 2016 Feb;2(2):132-9. DOI: 10.1021/acsinfecdis.5b00114 External link
Paterson DL, Harris PN. Editorial commentary: the new Acinetobacter equation: hypervirulence plus antibiotic resistance equals big trouble. Clin Infect Dis. 2015 Jul;61(2):155-6. DOI: 10.1093/cid/civ227 External link
Cheon S, Kim MJ, Yun SJ, Moon JY, Kim YS. Controlling endemic multidrug-resistant Acinetobacter baumannii in Intensive Care Units using antimicrobial stewardship and infection control. Korean J Intern Med. 2016 Mar;31(2):367-74. DOI: 10.3904/kjim.2015.178 External link
Fedorowsky R, Peles-Bortz A, Masarwa S, Liberman D, Rubinovitch B, Lipkin V. Carbapenem-resistant Enterobacteriaceae carriers in acute care hospitals and postacute-care facilities: The effect of organizational culture on staff attitudes, knowledge, practices, and infection acquisition rates. Am J Infect Control. 2015 Sep 1;43(9):935-9. DOI: 10.1016/j.ajic.2015.05.014 External link
World Health Organization (WHO). Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. 2017 Feb 27. Available from: External link
Tacconelli E, Cataldo MA, Dancer SJ, De Angelis G, Falcone M, Frank U, Kahlmeter G, Pan A, Petrosillo N, Rodríguez-Baño J, Singh N, Venditti M, Yokoe DS, Cookson B; European Society of Clinical Microbiology. ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients. Clin Microbiol Infect. 2014 Jan;20 Suppl 1:1-55. DOI: 10.1111/1469-0691.12427 External link
Kilonzo-Nthenge A, Rotich E, Nahashon SN. Evaluation of drug-resistant Enterobacteriaceae in retail poultry and beef. Poult Sci. 2013 Apr;92(4):1098-107. DOI: 10.3382/ps.2012-02581 External link
Al Atrouni A, Joly-Guillou ML, Hamze M, Kempf M. Reservoirs of Non-baumannii Acinetobacter Species. Front Microbiol. 2016 Feb 1;7:49. DOI: 10.3389/fmicb.2016.00049 External link
Eveillard M, Kempf M, Belmonte O, Pailhoriès H, Joly-Guillou ML. Reservoirs of Acinetobacter baumannii outside the hospital and potential involvement in emerging human community-acquired infections. Int J Infect Dis. 2013 Oct;17(10):e802-5. DOI: 10.1016/j.ijid.2013.03.021 External link
Manchanda V, Sanchaita S, Singh N. Multidrug resistant acinetobacter. J Glob Infect Dis. 2010 Sep;2(3):291-304. DOI: 10.4103/0974-777X.68538 External link
Quigley L, O’Sullivan O, Stanton C, Beresford TP, Ross RP, Fitzgerald GF, Cotter PD. The complex microbiota of raw milk. FEMS Microbiol Rev. 2013 Sep;37(5):664-98. DOI: 10.1111/1574-6976.12030 External link