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Trish M. Perl, MD, MSc Professor of Medicine, Pathology and Epidemiology Johns Hopkins University Senior Epidemiologist Johns Hopkins Health System

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Presentation on theme: "Trish M. Perl, MD, MSc Professor of Medicine, Pathology and Epidemiology Johns Hopkins University Senior Epidemiologist Johns Hopkins Health System"— Presentation transcript:

1 Trish M. Perl, MD, MSc Professor of Medicine, Pathology and Epidemiology Johns Hopkins University Senior Epidemiologist Johns Hopkins Health System Beyond ESBL’s and KPC’s: The Silent Pandemic in Gram Negative Organisms

2 Thanks and Disclosures Disclosures: Pfizer (advisory board), Merck (grant), Medimmune (grant)Disclosures: Pfizer (advisory board), Merck (grant), Medimmune (grant) I will be talking about off label uses of some antibiotics in these highly resistant organismsI will be talking about off label uses of some antibiotics in these highly resistant organisms

3 Objectives Describe emerging patterns of resistance in GNRsDescribe emerging patterns of resistance in GNRs Review risk factors associated with resistant GNRsReview risk factors associated with resistant GNRs Discuss some therapeutic considerations while treating resistant GNRsDiscuss some therapeutic considerations while treating resistant GNRs

4 How Big is the Problem? Luna et al. Crit Care Res Pract 2014:

5 What about the specifics Luna et al. Crit Care Res Pract 2014:

6 Why Do I Care

7 Mechanisms of Gram (-) Resistance Production of a β-lactamaseProduction of a β-lactamase –Acquired on a plasmid or transposon  ESBL  KPC –Encoded within a chromosome  Amp C

8 Extended-spectrum β-lactamases (ESBL) Production of a β-lactamase acquired on a plasmid or transposonProduction of a β-lactamase acquired on a plasmid or transposon –Non-inducible (produced all of the time) –Transferable First described: TEM-1, TEM-2, and SHV-1First described: TEM-1, TEM-2, and SHV-1 –Mutations increase the size of the active site pocket or alter its binding characteristics to allow larger cephalosporins to enter –Resistance to PCN, 1 st and 2 nd generation cephalosporins –Easily inhibited by β-lactamase inhibitors Over 200 types documentedOver 200 types documented

9 Extended-spectrum β-lactamases (ESBL) Most common in Klebsiella spp. and E. coliMost common in Klebsiella spp. and E. coli Modifications of TEM and SHV enzymesModifications of TEM and SHV enzymes –Cause decreased susceptibility to 3 rd generation cephalosporins and aztreonam Rarely found in other organisms (Proteus, Serratia, Salmonella, Citrobacter, PSA, etc)Rarely found in other organisms (Proteus, Serratia, Salmonella, Citrobacter, PSA, etc) Over 200 types documentedOver 200 types documented

10 Gales et al Clinical Infectious Diseases 2001;32:S146-S155 Global distribution of ESBL’s

11 Gales et al Clinical Infectious Diseases 2001;32:S146-S155 Global Distribution of ESBL’s

12 Management of Infections with ESBLs Cephamycins (cefotetan, cefoxitin), β- lactam/βLIs, fluoroquinolones, and carbapenems have in vitro activityCephamycins (cefotetan, cefoxitin), β- lactam/βLIs, fluoroquinolones, and carbapenems have in vitro activity Drug of choice: carbapenem (s)Drug of choice: carbapenem (s) –Resistant to ESBL-mediated hydrolysis –Includes: ertapenem (1 gm IV/IM daily) AlternativesAlternatives –FQ: cross-resistance common –β-lactam/βLIs: inoculum issues –Tigecycline No evidence to support “double coverage”No evidence to support “double coverage”

13 What Happens to Patients Treated with Cephalosporins? 60-70% failure when 3rd generation cephalosporins are used to treat bacteremia60-70% failure when 3rd generation cephalosporins are used to treat bacteremia Inoculum effectInoculum effect –Liberated enzyme from dead bacterial cells reduces the concentration of the antibiotic –MIC of cephalosporins increases when the inoculum of organisms is increased fold ( cfu/mL) UTI may be exception because of high urinary β- lactam concentration in urine.UTI may be exception because of high urinary β- lactam concentration in urine. Paterson et al. J Clin Micro. 2001;39:2206.

14 How About Cephamycins? Role of cefamycins: more stable than other cephalosporins to ESBL-mediated hydrolysis, but limited clinical infoRole of cefamycins: more stable than other cephalosporins to ESBL-mediated hydrolysis, but limited clinical info Role of cefepime:Role of cefepime: –Also inoculum effect problem –If must use: high doses (2 g q 8) +/- AG

15 Fluoroquinolones and ESBLs Conflicting dataConflicting data –85 ESBL-producing K pneumoniae bacteremias (many centers, ) had lower mortality with carbapenems (3.7%) than FQ (36.4%) –133 ESBL-producing K. pneumo and E. coli bacteremias (one center, ) had no mortality difference between carbapenems (13%) and FQ (10%) Rx Evidence for inoculum effect with cipro in one studyEvidence for inoculum effect with cipro in one study Paterson DL, et al. Clin Infect Dis. 2004;39: Kang et al. Antimicrob Agent Chemo. 2004;48:4574. Endimiani A et al. Clin Infect Dis. 2004;38:243.

16 De-repressed Amp C β-lactamases  β-lactamases that hydrolyses penicillins, 1 st – 2 nd and 3 rd G cephalosporins and monobactams  Enzyme is NOT inhibited by clavulanic acid  Most of the time, chromosomely mediated  INDUCIBLE resistance in Enterobacter spp., Serratia spp., Morganella spp. and Citrobacter spp. and in other Enterobacteriaceae

17 Derepressed Amp C β-lactamases Currently no micro testing for Amp CCurrently no micro testing for Amp C 20-30% risk of clinical failure when 3 rd generation cephalosporin is used to treat Enterobacter spp.20-30% risk of clinical failure when 3 rd generation cephalosporin is used to treat Enterobacter spp. Once de-repressed mutants are selected, they are stable (and can spread to other patients)Once de-repressed mutants are selected, they are stable (and can spread to other patients) FQ and carbapenems can be used, cefepime more controversialFQ and carbapenems can be used, cefepime more controversial

18 What About Cefepime? 96 patients with confirmed infections with Amp C β- lactamase–producing organisms.96 patients with confirmed infections with Amp C β- lactamase–producing organisms. Propensity score matching of patients infected with Amp C β-lactamase–positive organisms treated with cefepime or meropenem yielded 32 well-balanced patient pairs.Propensity score matching of patients infected with Amp C β-lactamase–positive organisms treated with cefepime or meropenem yielded 32 well-balanced patient pairs. No difference in 30-day mortality (odds ratio, 0.63; 95% confidence interval [CI](,0.23–2.11; P =.36) or length of hospital stay after infection (relative risk, 0.96; 95% CI,.79–1.26; P =.56) between the 2 groups.No difference in 30-day mortality (odds ratio, 0.63; 95% confidence interval [CI](,0.23–2.11; P =.36) or length of hospital stay after infection (relative risk, 0.96; 95% CI,.79–1.26; P =.56) between the 2 groups. Caution is the small numbers of patients studied.Caution is the small numbers of patients studied. Tamma et al. CID 2013:57;781

19 Unexpected Epidemiology Outbreak of ESBL K. pneumoniae in 2008 (clonal) 156 patients colonized –22% infected 35% of the hospital kitchen– screened surfaces or foodstuff were colonized 6 (14%) of 44 food handlers found to be fecal carriers HCWs negative Calbo et al. (2011) Clin Infect Dis 52:

20 ESBL-producing Enterobacteriaceae in Retail Meat 262 fresh meat samples (Netherlands)262 fresh meat samples (Netherlands) 30% of all food samples positive for ESBL- producing Enterobacteriaceae30% of all food samples positive for ESBL- producing Enterobacteriaceae –80% of chicken samples Similarity between strains and ESBL enzymes in food and human samplesSimilarity between strains and ESBL enzymes in food and human samples Overdevest et al. (2011) Emerg Infect Dis 17(7):

21 MLST Patterns of E. coli from Chicken / Other Meat and Human Rectal Swabs and Blood Cultures Overdevest et al. (2011) Emerg Infect Dis 17(7):

22 Patients, Retail Meat and Poultry Share same ESBL Genes, Plasmids & Strains Of 98 retail meat samples:Of 98 retail meat samples: –94% contained ESBL-producing isolates –39% of these belonged to E. coli genotypes also present in human samples “These findings are suggestive for transmission of ESBL genes, plasmids and E. coli isolates from poultry to humans, most likely through the food chain.” Leverstein-van Hall et al. (2011) Clin Microbiol Infect (Epub 6 April)

23 Carbapenemases The emergence of ESBL-producing Enterobacteriaceae has lead to an increase in carbapenem use.The emergence of ESBL-producing Enterobacteriaceae has lead to an increase in carbapenem use. Carbapenemases confer resistance to all  -lactams (penicillins / cephalosporins and carbapenems) and the bla gene is commonly associated with resistance genesCarbapenemases confer resistance to all  -lactams (penicillins / cephalosporins and carbapenems) and the bla gene is commonly associated with resistance genes The carbapenemases are classified into 3 categoriesThe carbapenemases are classified into 3 categories New York City--carbapenem-resistant K pneumoniae rose from 9% in 2002 to 18% in 2004, to 38% in 2008.New York City--carbapenem-resistant K pneumoniae rose from 9% in 2002 to 18% in 2004, to 38% in KPC, the most important carbapenemase in Enterobacteriaceae, is endemic in USA [8% of Klebsiella in 2007 – 37 States]KPC, the most important carbapenemase in Enterobacteriaceae, is endemic in USA [8% of Klebsiella in 2007 – 37 States] 30 day mortality 41.7%30 day mortality 41.7% Southern Medical Journal 2011(104), Tumbarello et al. CID 2012;55(7);

24 The resistance in Enterobacteriaceae:  -lactamases Southern Medical Journal Volume 104, Number 1, January 2011 Nordmann P., Cuzon G., Naas T., Lancet Infect Dis 2009; 9:

25 Slide Spread of KPC-containing Klebsiella pneumoniae from Greece - Travelling Wernli D et al. PLoS Medicine 2011

26 The resistance in Enterobacteriaceae:  -lactamases

27 KPC outbreak in Chicago, 2008 Of 40 KPC patients, only 4 definitively acquired KPC in acute care hospitalOf 40 KPC patients, only 4 definitively acquired KPC in acute care hospital Most (60%) linked to 1 LTACHMost (60%) linked to 1 LTACH Won et al. Clin Infect Dis 2011; 53:

28 NDM-1 NDM-1 (New Dehli metallo-  -lactamase) first described in Dec 2009 in Swedish patient returning from India with MDR- K. pneumoniae infectionNDM-1 (New Dehli metallo-  -lactamase) first described in Dec 2009 in Swedish patient returning from India with MDR- K. pneumoniae infection According to most recent data, first strains appeared in India as early as 2006According to most recent data, first strains appeared in India as early as 2006 Epidemiology first associated with India, Pakistan and the UK and then cases reported in many countriesEpidemiology first associated with India, Pakistan and the UK and then cases reported in many countries Y Yong et al. Antimicrob Ag Chemother 2009;53:

29 NDM-1 Microbiology Kumarasamy K. et al Lancet Infect Dis 2010; 10 August 11

30 NDM-1 Around the World Rolain, J.M., et al. Soc Clin Microbiol Infect Dis 2010;16:

31 Sources: More Unexpected Epidemiology Measure the prevalence of NDM-1 gene in drinking water and in pooled water from streets and small streams (“seepage”) in New DelhiMeasure the prevalence of NDM-1 gene in drinking water and in pooled water from streets and small streams (“seepage”) in New Delhi Sep 26-Oct 10, 2010Sep 26-Oct 10, 2010 Swabs of seepage water (n=171) and public tap water (n=50) collected from sites within 12 km radius of New DelhiSwabs of seepage water (n=171) and public tap water (n=50) collected from sites within 12 km radius of New Delhi Samples sent to UK and assessed for bla NDM-1 by PCR and DNA probingSamples sent to UK and assessed for bla NDM-1 by PCR and DNA probing Compared to sewage effluent samples (n=70) from Cardiff, Wales (UK) as controlsCompared to sewage effluent samples (n=70) from Cardiff, Wales (UK) as controls Performed susceptibility testing and typingPerformed susceptibility testing and typing Assessed plasmid transfer vs temperatureAssessed plasmid transfer vs temperature TR Walsh et al. Lancet Infect Dis 2011;11: 355–62

32 Results NDM-1 positive samples, New Delhi  Water 2/50 (4%)  Seepage 51/171 (30%) ALL seepage and water samples grew bacteria on cefotaxime containing media 94% seepage and 28% water samples grew bacteria on meropenem containing media Main commercial and financial center

33 Mean Temperatures in New Delhi (Bar) vs Ideal Plasmid Transfer Temperatures (Line)

34 Bacterial Strains Carrying NDM-1* Previously described Citrobacter fruendiiCitrobacter fruendii Escherichia coliEscherichia coli Klebsiella pneumoniaeKlebsiella pneumoniae Shigea boydiiShigea boydii Vibrio choleraVibrio cholera Aeromonas caviaeAeromonas caviae Salmonella spp.Salmonella spp. Not previously described P. aeruginosa P. putida P. pseudoalcaligines P. oryzihabitans Sutonella indologenes Stenotrophomonas maltophilia Achromobacter spp. Kingella denitrificans All NDM-1 Enterobacteriaceae had multiresistant phenotypes *All NDM-1 Enterobacteriaceae had multiresistant phenotypes

35 The Newest Twist 60 yo male transferred to a US hospital60 yo male transferred to a US hospital TA grew NDM-1 producing K. pneumoniaeTA grew NDM-1 producing K. pneumoniae Surveillance cultures grew NDM-1 producing Salmonella Surveillance cultures grew NDM-1 producing Salmonella Argues for prompt identification of patients at riskArgues for prompt identification of patients at risk Savard et al AAC 2011

36 Can Carbapenems Be Used? Not recommended if resistantNot recommended if resistant If MIC in susceptible range, consider extended infusion meropenemIf MIC in susceptible range, consider extended infusion meropenem –Meropenem 2 g IV Q 8H –Dose infused over 3 hours as opposed to 30 minutes

37 Colistin (Polymixin E) Colistin has no activity against Proteus, Serratia, Providentia, Burkholderia, GN or GP cocciColistin has no activity against Proteus, Serratia, Providentia, Burkholderia, GN or GP cocci Broth dilution titers ≤ 2 µg/mL accepted as susceptibleBroth dilution titers ≤ 2 µg/mL accepted as susceptible Antibacterial action: cell membrane disrupted by binding of drug to phospholipidsAntibacterial action: cell membrane disrupted by binding of drug to phospholipids Concentration dependentConcentration dependent Dose: 5 mg/kg/day divided into 2 dosesDose: 5 mg/kg/day divided into 2 doses Major toxicitiesMajor toxicities –Renal impairment –Neuromuscular blockade –Neurotoxicity (many different manifestations)

38 Tigecycline for Resistant GNR 18 pts who got ≥ 7 days of tigecycline18 pts who got ≥ 7 days of tigecycline Acinetobacter—10 casesAcinetobacter—10 cases –4 negative outcomes/5 positive outcomes –5/9 cases had intermediate resistance at start  4/5 died due to infection  1 case of emergence of resistance on therapy (MIC went from 2 to 12 mcg/mL)  1 case of persistent bacteremia Enterobacteriaceae—8 casesEnterobacteriaceae—8 cases –2 KPCs, 5 ESBLs, 2 AMP-Cs –3 negative outcomes/2 positive/3 unknown –1 case of persistent bacteremia

39 Should We Consider Several Agents? 3 Italian Centers, 125 patients with bloodstream infections with KPC;3 Italian Centers, 125 patients with bloodstream infections with KPC; Tumbarello et al. CID 2012;55(7);943-50

40 Tigecycline-Issues Susceptibility breakpointsSusceptibility breakpoints –S. aureus ≤.5 µg/mL –Streptococcus and enterococcus ≤.25 µg/mL –Enterobacteriaceae ≤ 2 µg/mL –Anaerobes ≤ 4 µg/mL Peak serum concentrations do not exceed 1 µg/mL; may be a problem in treatment of bacteremiaPeak serum concentrations do not exceed 1 µg/mL; may be a problem in treatment of bacteremia Side effectsSide effects –N/V in 25-30% of pts –No photosensitivity, rash rare –If TCN allergic then assume Tigecycline allergic Paterson DL. Curr Opinion in Pharmaco. 2006;6:486.Stein GE and Craig WA. CID. 2006;43:

41 Desperation Rahal JJ. Clin Infect Dis. 2006;43:S95.

42 New Agents Ceftibiprole and ceftarolineCeftibiprole and ceftaroline –MRSA activity! (high affinity for PBP-2a) –But Gram (-) spectrum not different from ceftriaxone DoripenemDoripenem –In vitro, some activity against carbapenem resistant PAE

43 Does Contamination of a Prior Room Increase the Risk of Acquisition? StudyPathogen Likelihood of acquiring HCAI if prior room occupancy Martinez VRE – cultured w/in room 2.6x Huang VRE – prior room occupant 1.6x MRSA – prior room occupant 1.3x Drees VRE – cultured w/in room 1.9x VRE – prior room occupant 2.2x VRE – prior room occupant w/in previous 2 weeks 2.0x Shaughnessy C. difficile – prior room occupant 2.4x Rosa A. baumannii resistant to carbapenems 2.8X Nseir A. baumannii – prior room occupant 3.8x P. aeruginosa – prior room occupant 2.1x Martinez et al. Arch Intern Med 2003; 163: ; Huang et al. Arch Intern Med 2006; 166: ; Drees et al. CID 2008; 46: ; Shaughnessy. ICHE2011;32: ; Rosa et al. ICHE 2014:35;430-3; Nseir et al. Clin Microbiol Infect 2010 (in press).

44 Do KPC’s Contaminate Rooms? 31% of interactions with patients with Klebsiella resulted in HCW or gown/glove contamination31% of interactions with patients with Klebsiella resulted in HCW or gown/glove contamination Activities associated with contamination included manipulation of catheter or drain, more than 2 contacts with the patient or the environment, being a PT, RT> RN> MDActivities associated with contamination included manipulation of catheter or drain, more than 2 contacts with the patient or the environment, being a PT, RT> RN> MD Rock et al. ICHE 2014; 35:426-8

45 NDM-1 Infection Prevention Approaches Themes –Pro-active planning –Preemptive screening/isolation of high risk patients –Contact precautions –Screening of patients in surrounding area –Peri-rectal/rectal swab + –Enhanced IC/AM –Monitoring in laboratory with appropriate protocols—eg modified Hodge test

46 Summary Resistant Gram-Negative organisms are emerging as significant pathogens that disseminate quickly and widely.Resistant Gram-Negative organisms are emerging as significant pathogens that disseminate quickly and widely. ESBLs and CREs are of increasing importance and require a thoughtful approach to antibiotic choiceESBLs and CREs are of increasing importance and require a thoughtful approach to antibiotic choice Transmission and sources may be novel and associated with food and waterTransmission and sources may be novel and associated with food and water You still need to wash your hands and isolate patientsYou still need to wash your hands and isolate patients


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