Multi-drug resistant microorganisms

Transcription

1 Multi-drug resistant microorganisms Arzu TOPELI Director of MICU Hacettepe University Faculty of Medicine, Ankara-Turkey Council Member of WFSICCM

2 Deaths in the US declined by 220 per 100,000 with the introduction of sulfonamides and penicillin. This far outweighs any other medical advance in the past century. Armstrong, et al. JAMA 1999 From 1983 to 2010, FDA approval of new antibiotics has continuously declined, from 4 per year in the early 1980s to less than 1 antibiotic per year now In USA, antibiotic resistance is responsible for nearly 100,000 deaths caused by hospital-acquired infections per year at an estimated annual cost of $23 billion. Roberts, et al. CID 2009;49:1175

3 E coli We are losing our first-line antimicrobials. Dr. Margaret Chan, director general of WHO (March 2012)

4 ESKAPE Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Acinetobacter baumannii Pseudomonas aeruginosa Enterobacter spp.

5 Antibiotic resistance Global problem! Poor hygiene Common use of OTC antibiotics in developing countries Veterinary practices International travel Very important in ICUs! Antibiotic overuse Comorbidities Larger immunocompromised population Sicker patients Invasive procedures Prolonged stay Ineffective infection control and compliance Inappropriate physical environment Decreased nurse/patient ratio

6 Kumar, et al. Crit Care Med 2006;34:

7 Mortality according to antibiotic appropriateness Appropriate Therapy Inappropriate Therapy Clec'h et al Luna et al Rello et al It is a lot more difficult to get it right if the bacteria are MDR.

8 Definitions

9 MDR: Acquired non-susceptibility to 1 agent in 3 anti-microbial categories XDR: non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) PDR: non-susceptibility to all agents in all antimicrobial categories. ECDC & CDC

10 Pseudomonas

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12 Standardized definitions Comparison of data Leading to better ways to cope with the problem Standardization of laboratories

13 Epidemiology

14 EPIC II 75 countries, 1300 ICUs, 14,000 pts, point prevalence study 51% infected 64% respiratory infection 70% culture (+): 62% gr (-); 47% gr (+), 19% fungi 71% receiving AB Pts who had longer ICU stay prior to study had infections with resistant Staph, Acinetobacter, Pseudomonas or Candida spp. Hospital mortality in infected pts is 1.5x greater than non-infected pts (p<0.001).

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17 International Nosocomial Infection Control Consortium (INICC) Study

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21 95,000 pt, 650,000 days

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24 4% of patients were infected. 9% in ICU 3% in ward Risk factors Older age Longer hospitalization Large hospital ICU admission Central line catheterization Mechanical ventilation

25 Mortality in MRSA vs MSSA bacteremia 58.7 vs 30.9% (p<0.01) Independent factors related with mortality MRSA (OR 5.6; p=0.03) Presence of fatal chronic underlying disease Presence of infective endocarditis Presence of septic shock Central line catheterization

26 51% infection rate 3.6% with MRSA ICU mortality in MRSA vs MSSA 29.1% vs 20.5% (p<0.01) Hospital mortality in MRSA vs MSSA 36.4% vs 27% (p<0.01)

27 7 days 10 days

28 p<0.001

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30 Predictors of 28 d mortality OR (CI) MDR isolate 1.49 ( ) Uncontrolled infection source 5.86 ( ) Timing to adequate treatment Before 6th day since blood culture Since 6th day 0.38 ( ) 0.20 ( )

31 Pathogenesis

32 Selection for antimicrobial-resistant strains Resistant Strains Rare S Antimicrobial Exposure R S Resistant Strains Dominant

33 Introduction of resistant strains: Transferred patients Community-reservoir Colonized health-care workers Selection of resistant strains: Pre-existing resistant flora Changes in the prevalence of AB resistant microorganisms Dissemination of resistant strains: Failures in infection control practices Induction of resistant strains: Mutation Genetic transfer Bonten & Mascini. Intensive Care Med (2003) 29:1 2

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35 Resistance mechanisms Plasmids Rings of extra chromosomal DNA Can be transferred between different species of bacteria Carry resistance genes Most common and effective mechanism of spreading resistance from bacteria to bacteria (Bacterial Conjugation)

36 Resistance mechanisms of some microorganisms S aureus Producing PBP with reduced affinity for -lactam AB through mec A gene Klebsiella Plasmid mediated production of ESBL or carbapenemase Pseudomonas and Acinetobacter Upregulation of efflux pumps Decreasing expression of outer membrane porin channels Plasmid mediated metallo- -lactamase or carbapenemase

37 Resistance mechanisms in gr (-) Disruption of -lactam ring of AB by enzymatic hydrolysis is the most important mechanism. >900 -lactamases Classification of -lactamases Functional group Category name Molecular class Target Examples 1 C Cephalosporins E coli AmpC 2 Serine -lactamases A Penicillins, cephalosporins, aztreonam D Extended spectrum cephalosporins, some carbapenems TEM-1, TEM-2, SHV-1, most ESBLs, some carbapenemases (KPC) OXA family, several carbapenemases 3 Metallo- -lactamases B Carbapenems IMP family, VIM family, NDM-1 Mehrad B, et al. Chest 2015;147:1413

38 β-lactamases Enzymes produced by certain bacteria that provide resistance to certain antibiotics Produced by both gram positive and gram negative bacteria Found on both chromosomes and plasmids Hydrolysis of beta-lactam ring of basic penicillin structure This opens up the ring, thus making the drug ineffective! β-lactam antibiotics Penicillins Cephalosporins Carbapenems

39 Extended spectrum β-lactamases Extended spectrum cephalosporins, such as the third generation cephalosporins, were originally thought to be resistant to hydrolysis by beta-lactamases! Mid 1980's it became evident that a new type of beta-lactamase was being produced by Klebsiella & E coli that could hydrolyze the extended spectrum cephalosporins. These are collectively termed the ESBL's

40 If an ESBL is detected, all penicillins, cephalosporins, and aztreonam should be reported as resistant, regardless of in vitro susceptibility test results. Genes encoding for ESBLs are frequently located on plasmids that also carry resistance genes for Aminoglycosides Tetracycline TMP-SULFA Chloramphenicol Carbapenems are the therapeutic option of choice. Fluoroquinolones

41 Management

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43 7 April

44 40-50% of prescribed AB are unnecessary Campaigns Decrease in AB prescription in the community by 25-34% 83% of admitted patients are already receiving AB without appropriate diagnosis!

45 Prevent infection Prevent transmission Early and effective diagnosis and treatment Optimal use of AB

46 Conventional methods Gram stain Clinical scores Biomarkers Cultures without taking the central line Differential time to positivity Relatively new and promising methods Molecular techniques Nucleic acid techniques Septi-fest Genes: mec A, Van MALDI-TOF E-test for AB susceptibility Paired central/peripheral cultures

47 INICC multidimensional approach for CLAB reduction 1. Infection control bundle 2. Education 3. Outcome surveillance 4. Process surveillance CLABSI rate From 22.7/1000 to 12/1000 CL days RR 0.61 ( ; p=0.007) 39% reduction 5. Feedback of CLAB rates 6. Performance feedback on infection control practices

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49 Low rate of resistance Moenomycin (poor PK properties) Carbohdrate scaffold chemistry Improved drug like property and less toxicity

50 Current strategies Developing new AB Interrupting MDR microorganism cross-transmission Increse antimicrobial stewardship efforts Protective role of the microbiome Developing and using more microbiomesparing antimicrobial therapy Developing techniques to maintain and restore indigenous microbiota Discovering and exploiting host protective mechanisms normally afforded by an intact microbiome

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53 In conclusion Infections are becoming more and more important because of increased AB resistance. First, we have to be aware of the problem and take it very seriously. In current practice we should: Use AB wisely, relying on more objective diagnostic tests. Do surveillance of not only microorganisms but also our AB use practices (DDD). Implement very strict infection control practices including isolation.

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