Increase in Infections Involving Gram-Negative Multidrug-Resistant Bacteria

  • Infections involving multi-resistant Gram-negative bacteria cause increased morbidity and mortality.

  • Multi-resistant pathogens are classified based on their resistance to different groups of antibiotics.

  • Carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, and enterobacteria with resistance to carbapenems and third-generation cephalosporins have been classified as particularly dangerous by the World Health Organization (WHO) [11].

In recent years, infections involving multi-resistant Gram-negative bacteria (MRGN) have increased dramatically worldwide. A worrying increase in these pathogens has been observed in outpatient and inpatient healthcare facilities in particular. As pointed out by several studies, duodenoscopes have also become conspicuous in the context of transmissions of MRGN [2][6][8][9].

Multidrug-resistance defined differently

Multidrug-resistance is defined differently from country to country. However, the different definitions have in common that pathogens are grouped together based on their resistance to different groups of antibiotics. In German-speaking regions, the multidrug-resistance of Gram-negative pathogens is assessed based on the four antibiotic groups of penicillins, cephalosporins, carbapenems, and fluoroquinolones, which are prescribed as primary therapeutic agents in the case of severe infections. Pathogens are classified as 3MRGN or 4MRGN. 3MRGN means that the Gram-negative pathogens are resistant to three of the four groups of antibiotics named above. 4MRGN signifies resistance to all four groups of antibiotics.

An additional well-known definition has been developed by an international committee of experts. Scientists use the terms “multidrug-resistant“ (MDR), “extensively drug-resistant” (XDR), and “pandrug-resistant” (PDR) to describe resistance. These terms are also often defined differently, which sometimes makes it difficult to achieve a shared understanding. The group of experts therefore created separate antibiotic categories for each organism or group of organisms. These categories are used to classify anti-microbial agents into more therapeutically relevant groups. According to this expert definition, the term MDR now signifies that a pathogen is resistant to at least one agent out of three or more categories of antibiotic. In the case of XDR, bacteria isolates only remain sensitive to one or two categories of antibiotic. Under this definition, the term PDR signifies that a pathogen is resistant to all agents in all categories of antibiotic.

Carbapenem-resistant pathogens classified as threatening

Antibiotic resistance is triggered by various bacterial resistance mechanisms, which enable pathogens to survive. The formation of antibiotic-inactivating enzymes (beta-lactamases) is one of the best-known defense strategies used by bacteria. MRGN such as Escherichia coli and Klebsiella pneumoniae (enterobacteria) as well as Pseudomonas aeruginosa and Acinetobacter baumannii (non-fermenters) are particularly prevalent and can also play a role in endoscopic examinations. These pathogens can trigger severe and fatal infections in healthcare facilities.

According to estimates by the Centers for Disease Control and Prevention (CDC), 610 people die of infections involving carbapenem-resistant enterobacteria every year in the USA [1]. Together with carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Pseudomonas aeruginosa, the WHO classifies enterobacteria exhibiting resistance to carbapenems and third-generation cephalosporins as particularly threatening pathogens that urgently require the development of new antibiotics [11].

Resistance mechanism mediated via plasmids

Beta-lactamases also include the carbapenemases, which are able to cleave to penicillins, cephalosporins, and carbapenems. These enzymes are divided into different groups (classes A to D) based on their sequences of amino acids. Extended-spectrum beta-lactamases and Klebsiella pneumoniae carbapenemases (KPCs) belong to class A; Verona integron-encoded metallo-beta-lactamase (VIM) and New Delhi metallo-beta lactamase (NDM) are examples of class B; and OXA-48 (oxacillinase) belongs to class D.

Most of the genetic information for the synthesis of carbapenemases is found on plasmids; it can therefore be transferred not only within the same species of bacteria, but also between different species and genera of the Enterobacteriaceae family. Although KPCs are primarily found in Klebsiella pneumoniae, they are also increasingly being detected in Enterobacter spp., Citrobacter spp., Providenica spp., Morganella morganii, Serratia marcescens, and Escherichia coli. The resistance mechanism coded on the plasmids is therefore also contributing to the rapid spread of KPCs.

Sources and further readings

  1. Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control and Prevention, Accessed on 06.23.2021.

  2. Epstein L et al. New Delhi metallo-β-lactamase-producing carbapenem-resistant Escherichia coli associated with exposure to duodenoscopes. JAMA. 2014 Oct 8;312(14):1447–55.

  3. Exner M et al. Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria? GMS Hygiene and Infection Control 2017, Vol. 12.

  4. Galdys AL et al. Bronchoscope-associated clusters of multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Klebsiella pneumoniae. Infect Control Hosp Epidemiol. 2019 Jan;40(1):40–46.

  5. 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 gramnegative 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.

  6. Kola A et al. An outbreak of carbapenem-resistant OXA-48 - producing Klebsiella pneumonia associated to duodenoscopy. Antimicrob Resist Infect Control. 2015 Mar 25;4:8.

  7. Magiorakos AP et al. 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.

  8. Shenoy ES et al. Transmission of Mobile Colistin Resistance (mcr-1) by Duodenoscope. Clin Infect Dis. 2019 Apr 8;68(8):1327–1334.

  9. Verfaillie CJ et al. Withdrawal of a novel-design duodenoscope ends outbreak of a VIM-2-producing Pseudomonas aeruginosa. Endoscopy. 2015 Jun;47(6):493–502.

  10. Wendorf KA et al. Endoscopic retrograde cholangiopancreatography-associated AmpC Escherichia coli outbreak. Infect Control Hosp Epidemiol. 2015 Jun;36(6):634–42.

  11. WHO publishes list of bacteria for which new antibiotics are urgently needed, World Health Organization, Accessed on 06.22.2021.