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    Topic review

    Multi-Drug Resistance

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    Submitted by: Emanuele Palomba

    Definition

    Multidrug-resistance is a long debated term. Since 1980 it was used to imply the resistance of a microorganism to multiple pharmaceutical agents, without the number or types of antimicrobials being specified.
    Currently, the most widely accepted definition of multidrug-resistant (MDR) bacteria include a lack of susceptibility in three or more antimicrobial categories active against the isolated microorganism.

    1. Current definition

          Multidrug-resistance is a long debated term. Since 1980 it was used to imply the resistance of a microorganism to multiple pharmaceutical agents, without the number or types of antimicrobials being specified.

           In 2011 a group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureusEnterococcus spp., Enterobacterales (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp. [1] In order to assess antimicrobial susceptibility within different groups of pathogens, lists of antimicrobial categories (Table 1-5) were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). 

           The ECDC-CDC consensus proposed the following definitions for the characterization of bacterial isolates:

    • MDR: multidrug-resistant, non-susceptibility to at least 1 agent in ≥ 3 antimicrobial categories 
    • XDR: extensively drug-resistant, non-susceptibility to at least 1 agent in all but 2 or fewer antimicrobial categories
    • PDR: pandrug-resistant, non-susceptibility to all agents in all categories

           When a species had intrinsic resistance to an antimicrobial category, that category was removed from the list prior to applying the criteria for the definitions and wasn’t counted when calculating the number of categories to which the bacterial isolate was non-susceptible.

           Within the definition of MDR, a unique rule was applied defining antibiotic resistance for methicillin resistant S. aureus (MRSA): finding an isolate resistant to oxacillin or cefoxitin predicts non-susceptibility to all categories of β-lactamase inhibitors and carbapenems, hence a MRSA will always be characterized as MDR.

      Table 1. Antimicrobial categories tested for S. aureus.

    Antimicrobial category

    Antimicrobial agent

    Aminoglycosides

     

    Gentamicin

     

    Ansamycins

    Rifampin/rifampicin

    Anti-MRSA cephalosporins

    Ceftaroline

    Anti-staphylococcal β-lactams (or cephamycins)

    Oxacillin (or cefoxitin)a

    Fluoroquinolones

    Ciprofloxacin

    Moxifloxacin

    Folate pathway inhibitors

    Trimethoprim-sulphamethoxazole

    Fucidanes

    Fusidic acid

    Glycopeptides

    Vancomycin

    Teicoplanin

    Telavancin

     

    Glycylcyclines

    Tigecycline

    Lincosamides

    Clindamycin

    Lipopeptides

    Daptomycin

    Macrolides

    Erythromycin

    Oxazolidinones

    Linezolid

    Phenicols

    Chloramphenicol

    Phosphonic acids

    Fosfomycin

    Streptogramins

    Quinupristin-dalfopristin

    Tetracyclines

    Tetracycline

    Doxycycline

    Minocycline

    Table 2. Antimicrobial categories tested for Enterococcus spp.

    Antimicrobial category

    Antimicrobial agent

    Species with intrinsic resistance to antimicrobial categories

    Aminoglycosides (except streptomycin)

    Gentamicin (high level)

     

    Streptomycin

    Streptomycin (high level)

     

    Carbapenems

    Imipenem

    Meropenem

    Doripenem

    Enterococcus faecium

    Fluoroquinolones

    Ciprofloxacin

    Levofloxacin

    Moxifloxacin

     

    Glycopeptides

    Vancomycin

    Teicoplanin

     

    Glycylcyclines

    Tigecycline

     

    Lipopeptides

    Daptomycin

     

    Oxazolidinones

    Linezolid

     

    Penicillins

    Ampicillin

     

    Streptogramins

    Quinupristin-dalfopristin

    Enterococcus faecalis

    Tetracycline

    Doxycycline

    Minocycline

     

       Table 3. Antimicrobial categories tested for Enterobacterales.

    Antimicrobial category

    Antimicrobial agent

    Species with intrinsic resistance to antimicrobial agents or categories 

    Aminoglycosides

    Gentamicin

    Providencia rettgeri (P. rettgeri), Providencia stuartii (P. stuartii)

    Tobramycin

    P. rettgeri, P. stuartii

    Amikacin

     

    Netilmicin

    P. rettgeri, P. stuartii

    Anti-MRSA cephalosporins

    Ceftaroline (approved only for Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca)

     

    Antipseudomonal penicillins + β-lactamase inhibitors

    Ticarcillin-clavulanic acid

    Escherichia hermannii (E. hermanii)

    Piperacillin-tazobactam

    E. hermanii

    Carbapenems

    Ertapenem

     

    Imipenem

     

    Meropenem

     

    Doripenem

     

    Non-extended spectrum cephalosporins; 1st and 2nd generation cephalosporins

    Cefazolin

    Citrobacter freundii (C. freundii), Enterobacter aerogenes (E. aerogenes), Enterobacter cloacae (E. cloacae), Hafnia alvei (H. alvei), Morganella morganii (M. morganii), Proteus penneri (P. penneri), Proteus vulgaris (P. vulgaris), P. rettgeri, P. stuartii, Serratia marcescens (S. marcescens)

    Cefuroxime

    M. morganii, P. penneri, P. vulgaris, S. marcescens

    Extended-spectrum cephalosporins; 3rd and 4th generation cephalosporins

    Cefotaxime or ceftriaxone

     

    Ceftazidime

     

    Cefepime

     

    Cephamycins

    Cefoxitin

    C. freundii, E. aerogenes, E. cloacae, H. alvei

    Cefotetan

    C. freundii, E. aerogenes, E. cloacae, H. alvei

    Fluoroquinolones

    Ciprofloxacin

     

    Folate pathway inhibitors

    Trimethoprim-sulphamethoxazole

     

    Glycylcyclines

    Tigecycline

    M. morganii, Proteus mirabilis (P. mirabilis), P. penneri, P. vulgaris, P. rettgeri, P. stuartii

    Monobactams

    Aztreonam

     

    Penicillins

    Ampicillin

    Citrobacter koseri (C. koseri), C. freundii, E. aerogenes, E. cloacae, E. hermanii, H. alvei, Klebsiellae spp., M. morganii, P. penneri, P. vulgaris, P. rettgeri, P. stuartii, S. marcescens

    Penicillins + β-lactamase inhibitors

    Amoxicillin-clavulanic acid

    C. freundii, E. aerogenes, E. cloacae, H. alvei, M. morganii, P. rettgeri, P. stuartii, S. marcescens

    Ampicillin-sulbactam

    C. freundii, C. koseri, E. aerogenes, E. cloacae, H. alvei, P. rettgeri, S. marcescens

    Phenicols

    Chloramphenicol

     

    Phosphonic acids

    Fosfomycin

     

    Polymyxins

    Colistin

    M. morganii, P. mirabilis, P. penneri, P. vulgaris, P. rettgeri, P. stuartii, S. marcescens

    Tetracyclines

    Tetracycline

    M. morganii, P. mirabilis, P. penneri, P. vulgaris, P. rettgeri, P. stuartii

    Doxycycline

    M. morganii, P. penneri, P. vulgaris, P. rettgeri, P. stuartii

    Minocycline

    M. morganii, P. penneri, P. vulgaris, P. rettgeri, P. stuartii

    Table 4. Antimicrobial categories tested for P. aeruginosa.

    Antimicrobial category

    Antimicrobial agent

    Aminoglycosides

    Gentamicin

    Tobramycin

    Amikacin

    Netilmicin

    Antipseudomonal carbapenems

    Imipenem

    Meropenem

    Doripenem

    Antipseudomonal cephalosporins

    Ceftazidime

    Cefepime

    Antipseudomonal fluoroquinolones

    Ciprofloxacin

    Levofloxacin

    Antipseudomonal penicillins + β-lactamase inhibitors

    Ticarcillin-clavulanic acid

    Piperacillin-tazobactam

    Monobactams

    Aztreonam

    Phosphonic acids

    Fosfomycin

    Polymyxins

    Colistin

    Polymyxin B

       Table 5. Antimicrobial categories tested for Acinetobacter spp.

    Antimicrobial category

    Antimicrobial agent

    Aminoglycosides

    Gentamicin

    Tobramycin

    Amikacin

    Netilmicin

    Antipseudomonal carbapenems

    Imipenem

    Meropenem

    Doripenem

    Antipseudomonal fluoroquinolones

    Ciprofloxacin

    Levofloxacin

    Antipseudomonal penicillins + β-lactamase inhibitors

    Piperacillin-tazobactam

    Ticarcillin-clavulanic acid

    Extended-spectrum cephalosporins

    Cefotaxime

    Ceftriaxone

    Ceftazidime

    Cefepime

    Folate pathway inhibitors

    Trimethoprim-sulphamethoxazole

    Penicillins + β-lactamase inhibitors

    Ampicillin-sulbactam

    Polymyxins

    Colistin

    Polymyxin B

    Tetracyclines

    Tetracycline

    Doxycycline

    Minocycline

    2. Epidemiology of MDR bacteria 

    2.1 European data

           European Antimicrobial Resistance Surveillance Network (EARS-Net) collects data on invasive isolates (blood and cerebrospinal fluid) from 30 countries (all EU member and two EEA countries).

           Results on antimicrobial resistance are elaborated determining a population-weighted EU/EEA mean percentage and the temporal trends in resistance percentages by country is calculated based on data from the last four years. Several factors may influence the estimates and may results in over as well as underestimation of resistance percentages, nevertheless more than half countries reported a population coverage of 80% or higher.

            Data from EARS-Net 2018 report[2], stated that more than half (58.3%) of the Escherichia coli isolates responsible for invasive diseases were resistant to at least one of the antimicrobial groups unde regular surveillance. The highest population-weighted mean resistance percentage was reported for aminopenicillins (57.4%), followed by fluoroquinolones (25.3%), third-generation cephalosporins (15.1%), and aminoglycosides (11.1%), with a significant increasing trend. On the contrary, E. coli resistance to carbapenems remains rare in Europe, ranging from 0 to 2%. Italy is one of the European countries with the highest percentage of antimicrobial resistance: in 2017, 41.7% of E. coli isolated from blood and cerebrospinal fluid were resistant to fluoroquinolones, and 28.7% were resistant to third-generation cephalosporins.  

           Likewise E. coli, Klebsiella pneumoniae can also be resistant to multiple antimicrobial agent. In the EARS-Net 2018 report, more than a third (37.2%) of all K. pneumoniae isolates that were resistant to at least one of the tested antimicrobial groups. The highest population-weighted mean resistance percentage was reported for third-generation cephalosporins (31.7%), followed by fluoroquinolones (31.6%), aminoglycosides (22.7%), and carbapenems (7.5%). Percentages of invasive isolates of carbapenem-resistant K. pneumoniae (CR-Kp) in Europe show a large variability, ranging from 0 to 64.7%. The population-weighted mean percentage varied between 2014 and 2017, and was 7.3% in 2014 and 7.2% in 2017. In Italy, 53.6% of K. pneumoniae invasive isolates were resistant to third-generation cephalosporins and 26.8% to carbapenems.

           Regarding P. aeruginosa, data from 2018 stated that 32.1% of the isolates were resistant to at least one of the antimicrobial groups under regular surveillance (see  Table 4). The highest population-weighted mean resistance percentage in 2018 was reported for fluoroquinolones (19.7%), followed by piperacillin ± tazobactam (18.3%), carbapenems (17.2%), ceftazidime (14.1%) and aminoglycosides (11.8%). There were significantly decreasing trends in the population-weighted mean percentages of piperacillin ± tazobactam resistance, ceftazidime resistance, aminoglycoside resistance and carbapenem resistance between 2015 and 2018. By excluding all laboratories apart from those that consistently reported data for all four years, only the decreasing trends for aminoglycoside resistance and carbapenem resistance remained statistically significant. Resistance to two or more antimicrobial groups was common and seen in 19.2% of all tested isolates. The population-weighted mean percentage of combined resistance, defined as resistance to at least three of the antimicrobial groups under surveillance, significantly decreased between 2015 and 2018. Large inter-country variations were seen for all antimicrobial groups, with generally higher resistance percentages reported from southern and eastern Europe than northern Europe

           More than half of the Acinetobacter species isolates reported by European countries (56.4%) were resistant to at least one of the antimicrobial groups under regular surveillance (i.e. fluoroquinolones, aminoglycosides and carbapenems). The highest population-weighted mean resistance percentage in 2018 was reported for fluoroquinolones (36.2%), followed by aminoglycosides (31.9%) and carbapenems (31.9%). Resistance to one or two antimicrobial groups was considerably less common than combined resistance to all three groups under surveillance. In 2018, the population-weighted mean percentage for combined resistance to fluoroquinolones, aminoglycosides and carbapenems was 28.8%. Large inter-country variations were noted for all antimicrobial groups under regular surveillance, with generally higher resistance percentages reported from southern and eastern Europe than from northern Europe. Single resistance to one antimicrobial group was less common in countries reporting comparatively low proportions of fully susceptible isolates.

           The population-weighted mean percentage of MRSA was 16.4% in 2018. This is a result of a significantly decreasing trend between 2015 and 2018. In 2018, large differences in national MRSA percentages were noted, ranging from 0% to 43.0% . Close to a third of the countries reported significantly decreasing trends during the period 2015–2018, including countries with both low and high percentages of MRSA. Among MRSA, combined resistance to other antimicrobial groups was common. The most common resistance combination was MRSA and resistance to fluoroquinolones. Rifampicin resistance was less common.

           In 2018, the population-weighted mean percentage of high-level gentamicin resistance in E. faecalis was 27.1%, with national percentages ranging from 6.7% to 41.6%. The European trend decreased significantly between 2015 and 2018, with similar significantly decreasing national trends reported from almost one quarter of the countries. Vancomycin resistance in E. faecalis remained low in most countries.

           The European population-weighted mean percentage of vancomycin resistance in E. faecium was 17.3%, which represents a significant increase from 2015 when the percentage was 10.5%. National percentages ranged from 0.0% to 59.1%. Only 12 of the 30 reporting countries reported resistance percentages below 5%. Several of the countries reporting comparatively high percentages of resistance to vancomycin also reported significantly increasing trends for the last four years. For several countries, the increase during the four-year period was considerable. With few exceptions, national percentages of high-level aminoglycoside resistance in E. faecium were higher than for E. faecalis.

    2.2. United States Data

           The 2019 CDC’s Antibiotic Resistance Threats in the United States, reporting data regarding the year 2017, states that more than 2.8 million antibiotic-resistant infections occur in the U.S. each year, and more than 35000 people die as a result.[3]

           According to the report, in 2017 there were 13100 cases of infections caused by carbapenem-resistant Enterobacterales were reported, showing a slow but steady increasing trend since 2012. Moreover, extended-spectrum beta-lactamase (ESBL) producing Enterobacterales were isolated in 197400 cases in hospitalized patients. Within the same year MDR P. aeruginosa infections caused 2700 estimated deaths and 32600 cases in hospitalized patients.
    Regarding carbapenem-resistant Acinetobacter spp, there were 8500 estimated cases of infection in hospitalized patients, with 89% of the isolates non-susceptible to any fluoroquinolones, 75% to any extended-spectrum β-lactam, 61% to ampicillin-sulbactam and 66% of the isolates non-susceptible to trimethoprim-sulfamethoxazole (TMP-SMX).

           Vancomycin-resistant enterococci accounted for 54500 cases, with 30% of all healthcare-associated enterococcals infections showing non-susceptibility to vancomycin.
    Estimated cases of MRSA infections showed a constant reduction between 2005 and 2017, with 323700 cases and 10600 estimated deaths, with approximately 5% of patients in U.S. hospitals carrying MRSA in their nose or on their skin.

    3. Future perspectives

           The ECDC/ CDC definition of multidrug-resistance, based on the criteria used for tuberculosis, can prove to be impractical[4]. Firstly, finding a universal consensus is difficult to achieve, since not all antimicrobials are available and tested by laboratories in all countries, and there is no common testing policy for laboratories. Furthermore, differences between European (EUCAST) and US (CLSI or FDA) breakpoints can affect fundamentally whether isolates are regarded as MDR or XDR. Secondly, some antibiotic resistances are now very common and stable, so they are seldom tested for, but if they are present the organism needs only one further resistance to count as MDR according to the “three classes of resistance” rule. Lastly, assigning antibiotics to separate classes without considering resistance mechanisms can lead to further discussion, making it difficult to reach a shared consensus.

           More viable definitions for MDR bacteria are needed. Lack of universal agreement influences recruitment and classification of patients in clinical trials and hampers effective surveillance of MDR strains. A useful pragmatic approach to defining MDR can be to consider oral and parenteral drugs separately. For oral drugs, multi-resistance can be defined as a microorganism susceptible to only one or no readily available oral agent active against infections systemically or in the upper urinary tract. For parenteral antibiotics a similar approach can be considered. Specific agents to which impaired susceptibility might be significant include carbapenems, relevant cephalosporins (cefotaxime for Enterobacterales, ceftazidime for P. aeruginosa), aztreonam, ceftolozane/tazobactam, ceftazidime/avibactam, temocillin, piperacillin/tazobactam, colistin, quinolones, fosfomycin, tigecycline and aminoglycosides (including amikacin).

     

    The entry is from 10.3390/ijms21165619

    References

    1. A-P Magiorakos , A Srinivasan, R B Carey, Y Carmeli, M E Falagas, C G Giske, S Harbarth, J F Hindler, G Kahlmeter, B Olsson-Liljequist, D L Paterson, L B Rice, J Stelling, M J Struelens, A Vatopoulos, J T Weber, D L Monnet; Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect . 2011, 18(3), 268-81, .
    2. Surveillance of Antimicrobial Resistance in Europe . ECDC. Retrieved 2020-8-13
    3. 2019 CDC’s Antibiotic Resistance Threats in the United States . CDC. Retrieved 2020-8-13
    4. Hawkey, Peter; Warren, Roderic E; Livermore, David M; McNulty, Cliodna A M; Enoch, David A; Otter, Jonathan A; Wilson, Peter R; Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrob Chemother 2018, Mar 1;73(suppl_3), iii2-iii78, 10.1093/jac/dky027.
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