CARBAPENEM RESISTANCE IN
CLINICAL CARE
DR.T.V.RAO MD
Dr.T.V.Rao MD 1
IMPORTANCE OF CARBAPENEMS IN CLINICAL CARE
• CARBAPENEMS ARE A POWERFUL GROUP OF BROAD SPECTRUM BETA-
LACTAM (PENICILLIN-R...
TODAYS CONCERN IN DRUG RESISTANCE IS GRAM
NEGATIVE BACTRIA MAINLY ENTEROBACTERIACEAE
• SCIENTISTS FROM THE PUBLIC HEALTH E...
WHAT ARE ENTEROBACTERIACEAE?
• ENTEROBACTERIACEAE ARE A FAMILY OF BACTERIA THAT INCLUDE KLEBSIELLA SPECIES AND
ESCHERICHIA...
WHAT ARE CARBAPENEMS
• CARBAPENEMS ARE A CLASS OF Β-
LACTAM ANTIBIOTICS WITH A BROAD
SPECTRUM OF ANTIBACTERIAL ACTIVITY.
T...
CARBAPENEMS ARE VERY SIMILAR TO THE
PENICILLIN'S
• IN TERMS OF STRUCTURE, THE
CARBAPENEMS ARE VERY SIMILAR TO
THE PENICILL...
CARBAPENEM
• CARBAPENEMS ARE ONE OF THE ANTIBIOTICS OF LAST RESORT FOR MANY
BACTERIAL INFECTIONS, SUCH AS ESCHERICHIA COLI...
SPECTRUM OF ACTIVITY
Drug
Strep spp. &
MSSA
Entero-bacteriaeae
Non-
fermentors
Anaerobes
Imipenem + + + +
Meropenem + + + ...
CARBAPENEMASES
Classification Enzyme Most Common Bacteria
Class A KPC, SME, IMI,
NMC, GES
Enterobacteriaceae
(rare reports...
APPROVED FOR CLINICAL USE
• HE FOLLOWING DRUGS BELONG TO THE CARBAPENEM CLASS AND ARE APPROVED FOR USE BY
HEALTH AUTHORITI...
SPECTRUM OF USE
• THESE AGENTS HAVE THE BROADEST ANTIBACTERIAL SPECTRUM COMPARED TO
OTHER Β-LACTAM CLASSES SUCH AS PENICIL...
BASIS OF MECHANISMS OF DRUG
RESISTANCE
• CHANGE IN DRUG TARGET
• PRODUCTION OF AN ENZYME
THAT MODIFIES OR INACTIVATES
THE ...
Resistant Strains
Rare
Resistant Strains
Dominant
Antimicrobial
Exposure
SELECTION FOR ANTIMICROBIAL-
RESISTANT STRAINS
Dr...
CARBAPENEMASES
• BETA-LACTAMASES WITH VERSATILE HYDROLYTIC CAPACITIES.
• ABILITY TO HYDROLYZE PENICILLINS, CEPHALOSPORINS,...
WHAT ARE
CARBAPENEM-RESISTANT ENTEROBACTERIACEAE
• CRE, WHICH STANDS FOR CARBAPENEM-
RESISTANT ENTEROBACTERIACEAE, ARE A
F...
KLEBSIELLA PNEUMONIAE
CARBAPENEMASE
• KPC IS A CLASS A B-LACTAMASE
• CONFERS RESISTANCE TO ALL B-LACTAMS INCLUDING EXTENDE...
Carbapenems: Resistance Issues
Outer
membrane
Periplasm
Cytoplasmic
membrane
D2 Porin (OprD)
Carbapenem nucleus
Ertapenem ...
MECHANISMS OF CARBAPENEM
RESISTANCE: IMPERMEABILITY
• OPRD FORMS NARROW TRANSMEMBRANE CHANNELS
THAT ARE NORMALLY ACCESSIBL...
KPC ENZYMES
• LOCATED ON PLASMIDS;
CONJUGATIVE AND
NONCONJUGATIVE
• BLAKPC IS USUALLY FLANKED BY
TRANSPOSON SEQUENCES
• BL...
MECHANISMS OF CARBAPENEM RESISTANCE:
EFFLUX SYSTEMS IN P.AERUGINOSA
• UPREGULATION OF MEXAB-OPRM EFFLUX SYSTEM
• ASSOCIATE...
EMERGENCE OF BACTERIAL RESISTANCE
• IN THE UNITED STATES AND UNITED
KINGDOM, STRAINS OF CARBAPENEM-
RESISTANT ENTERIC BACT...
KPC’S IN ENTEROBACTERIACEAE
Species Comments
Klebsiella spp. K. pneumoniae-cause of outbreaks
K. oxytoca-sporadic occurren...
MECHANISMS OF RESISTANCE
• A CLINICAL ISOLATE OF E. COLI FROM THE SPUTUM SAMPLE OF A PATIENT ADMITTED
TO A BEIJING HOSPITA...
MECHANISMS OF RESISTANCE
• FOUND TO SHOW UNUSUAL RESISTANCE TO CARBAPENEM THAT DOES NOT RELY ON THE
PRESENCE OF CARBAPENEM...
MAJOR TYPES OF CARBAPENEM-RESISTANT
ENTEROBACTERIACEAE (CRE)
• TYPES OF CRE ARE SOMETIMES
KNOWN AS KPC (KLEBSIELLA
PNEUMON...
WHO ARE LIABLE TO GET
CARBAPENEM-RESISTANT ENTEROBACTERIACEAE
(CRE)
• PATIENTS WHOSE CARE REQUIRES
DEVICES LIKE VENTILATOR...
WHEN TO SUSPECT A KPC-PRODUCER
• ENTEROBACTERIACEAE – ESPECIALLY KLEBSIELLA PNEUMONIAE
THAT ARE RESISTANT TO EXTENDED-SPEC...
PATIENTS CARBAPENEM-RESISTANT
ENTEROBACTERIACEAE (CRE) INFECTION
• CRE INFECTIONS ARE MOST COMMONLY
SEEN IN PEOPLE WITH EX...
PATIENTS AT RISK WITH CARBAPENEM-RESISTANT
ENTEROBACTERIACEAE (CRE) INFECTION
• PATIENTS WHOSE CARE REQUIRES
DEVICES LIKE ...
SPREAD OF CRE INFECTION
• TO GET A CRE INFECTION, A PERSON
MUST BE EXPOSED TO CRE BACTERIA.
CRE BACTERIA ARE MOST OFTEN
SP...
CRE CAN BE A IATROGENIC INFECTION
• CRE CAN CAUSE INFECTIONS
WHEN THEY ENTER THE BODY,
OFTEN THROUGH MEDICAL
DEVICES LIKE ...
MECHANISM OF RESISTANCE IN CRE
• RESISTANCE TO CARBAPENEM CAN BE DUE
TO A FEW DIFFERENT MECHANISMS. ONE OF
THE MORE COMMON...
KPC BREAKS DOWN CARBAPENEM
• KPC BREAKS DOWN
CARBAPENEM MAKING THEM
INEFFECTIVE. IN ADDITION TO
KPC, OTHER ENZYMES, SUCH A...
CDC INFORMS
• SOME CRE BACTERIA HAVE
BECOME RESISTANT TO
ALMOST ALL AVAILABLE
ANTIBIOTICS AND CAN BE
DEADLY—ONE REPORT CIT...
KPC – QUESTIONS
• IF I HAVE DETECT KPC-PRODUCTION,
SHOULD I CHANGE SUSCEPTIBLE
CARBAPENEM RESULTS TO
RESISTANT?
• NOT ENOU...
TESTING OTHER DRUGS
•TIGECYCLINE:
• TEST BY ETEST IF POSSIBLE – DISK
DIFFUSION TENDS TO OVERCALL
RESISTANCE
• NO CLSI BREA...
TESTING OTHER DRUGS
• POLYMIXIN B OR COLISTIN
• COULD TEST EITHER, BUT COLISTIN USED
CLINICALLY
• DISK DIFFUSION TEST DOES...
PROTECT YOUR PATIENTS FROM CRE.
• FOLLOW CONTACT PRECAUTIONS AND
HAND HYGIENE RECOMMENDATIONS WHEN
TREATING PATIENTS WITH ...
PATIENT ARE TOLD TO FOLLOW
CLEAN YOUR OWN HANDS OFTEN,
ESPECIALLY:
BEFORE PREPARING OR EATING FOOD
BEFORE TOUCHING YOUR EY...
DOCTORS AND NURSES SHOULD CARE TO
PREVENT CRE INFECTIONS
• EXPECT ALL DOCTORS, NURSES
AND OTHER HEALTHCARE
PROVIDERS WASH ...
HEALTH CARE PROVIDERS CAN
• KNOW IF PATIENTS IN YOUR
FACILITY HAVE CRE.
REQUEST IMMEDIATE ALERTS
WHEN THE LAB IDENTIFIES C...
IF WE DO NOT STOP MISUSE OF ANTIBIOTICS AND PRACTICE
ANTIBIOTIC POLICY – WE ARE WALKING INTO DARKNESS
Dr.T.V.Rao MD 42
VISIT ME FOR MORE ARTICLES OF INTEREST ON
INFECTIOUS DISEASES ON …..
Dr.T.V.Rao MD 43
• PROGRAMME CREATED AND DESIGNED BY DR.T.V.RAO MD
FOR MEDICAL AND PARAMEDICAL PROFESSIONAL FOR
GLOBAL EDUCATION ON ANTIBIO...
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Carbapenem resistance in clinical care

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Carbapenem resistance in Clinical care

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Carbapenem resistance in clinical care

  1. 1. CARBAPENEM RESISTANCE IN CLINICAL CARE DR.T.V.RAO MD Dr.T.V.Rao MD 1
  2. 2. IMPORTANCE OF CARBAPENEMS IN CLINICAL CARE • CARBAPENEMS ARE A POWERFUL GROUP OF BROAD SPECTRUM BETA- LACTAM (PENICILLIN-RELATED) ANTIBIOTICS WHICH, IN MANY CASES, ARE OUR LAST EFFECTIVE DEFENCE AGAINST MULTI-RESISTANT BACTERIAL INFECTIONS. WHAT IS OF CONCERN, HOWEVER, IS THAT RESISTANCE IS BEGINNING TO EMERGE TO CARBAPENEMS. NEW ANTIBIOTICS NEED TO BE DEVELOPED TO COUNTER BACTERIA WITH THIS TYPE OF RESISTANCE; WHAT IS MORE, HOSPITALS NEED GOOD INFECTION CONTROL AND ANTIBIOTIC POLICY TO PREVENT THEIR SPREAD.Dr.T.V.Rao MD 2
  3. 3. TODAYS CONCERN IN DRUG RESISTANCE IS GRAM NEGATIVE BACTRIA MAINLY ENTEROBACTERIACEAE • SCIENTISTS FROM THE PUBLIC HEALTH ENGLAND RECENTLY CO-AUTHORED A PAPER PUBLISHED IN THE LANCET INFECTIOUS DISEASES ON THE EMERGENCE OF A NEW ANTIBIOTIC RESISTANCE MECHANISM - NEW DELHI METALLO BETA LACTAMASE (NDM-1). THIS IS AN ENZYME THAT INACTIVATES CARBAPENEM ANTIBIOTICS. IT IS CODED BY LOOPS OF DNA -PLASMIDS- THAT CAN MOVE BETWEEN BACTERIA. BACTERIA WITH NDM ARE MOST WIDESPREAD IN THE INDIAN SUBCONTINENT BUT HAVE SPREAD TO VARIOUS COUNTRIES AROUND THE WORLD, INCLUDING THE UK, OFTEN VIA PATIENTS PREVIOUSLY HOSPITALISED IN DEVELOPING COUNTRIES INDIA OR PAKISTAN.( REF – PUBLIC HEALTH ENGLAND) Dr.T.V.Rao MD 3
  4. 4. WHAT ARE ENTEROBACTERIACEAE? • ENTEROBACTERIACEAE ARE A FAMILY OF BACTERIA THAT INCLUDE KLEBSIELLA SPECIES AND ESCHERICHIA COLI (E. COLI), WHICH ARE FOUND IN NORMAL HUMAN INTESTINES (GUT). SOMETIMES THESE BACTERIA CAN SPREAD OUTSIDE THE GUT AND CAUSE SERIOUS INFECTIONS, SUCH AS PNEUMONIA, BLOODSTREAM INFECTIONS, URINARY TRACT INFECTIONS, WOUND INFECTIONS, AND MENINGITIS. ENTEROBACTERIACEAE ARE ONE OF THE MOST COMMON CAUSES OF BACTERIAL INFECTIONS IN BOTH HEALTHCARE AND COMMUNITY SETTINGS. CARBAPENEM ARE A TYPE OF ANTIBIOTIC FREQUENTLY USED TO TREAT SEVERE INFECTIONS.Dr.T.V.Rao MD 4
  5. 5. WHAT ARE CARBAPENEMS • CARBAPENEMS ARE A CLASS OF Β- LACTAM ANTIBIOTICS WITH A BROAD SPECTRUM OF ANTIBACTERIAL ACTIVITY. THEY HAVE A STRUCTURE THAT RENDERS THEM HIGHLY RESISTANT TO MOST Β- LACTAMASES.[1] CARBAPENEM ANTIBIOTICS WERE ORIGINALLY DEVELOPED FROM THE CARBAPENEM THIENAMYCIN, A NATURALLY DERIVED PRODUCT OF STREPTOMYCES CATTLEYA. Dr.T.V.Rao MD 5
  6. 6. CARBAPENEMS ARE VERY SIMILAR TO THE PENICILLIN'S • IN TERMS OF STRUCTURE, THE CARBAPENEMS ARE VERY SIMILAR TO THE PENICILLIN'S (PENAMS), BUT THE SULFUR ATOM IN POSITION 1 OF THE STRUCTURE HAS BEEN REPLACED WITH A CARBON ATOM, AND AN UNSATURATION HAS BEEN INTRODUCED—HENCE THE NAME OF THE GROUP, THE CARBAPENEMS.Dr.T.V.Rao MD 6
  7. 7. CARBAPENEM • CARBAPENEMS ARE ONE OF THE ANTIBIOTICS OF LAST RESORT FOR MANY BACTERIAL INFECTIONS, SUCH AS ESCHERICHIA COLI (E. COLI) AND KLEBSIELLA PNEUMONIAE.[3] RECENTLY, ALARM HAS BEEN RAISED OVER THE SPREAD OF DRUG RESISTANCE TO CARBAPENEM ANTIBIOTICS AMONG THESE COLIFORMS, DUE TO PRODUCTION OF THE NEW DELHI METALLO-Β-LACTAMASE, NDM-1. THERE ARE CURRENTLY NO NEW ANTIBIOTICS IN DEVELOPMENT TO COMBAT BACTERIA RESISTANT TO CARBAPENEMS, AND WORLDWIDE SPREAD OF THE RESISTANCE GENE IS CONSIDERED A POTENTIAL NIGHTMARE SCENARIO Dr.T.V.Rao MD 7
  8. 8. SPECTRUM OF ACTIVITY Drug Strep spp. & MSSA Entero-bacteriaeae Non- fermentors Anaerobes Imipenem + + + + Meropenem + + + + Ertapenem + + Limited activity + Doripenem + + + +
  9. 9. CARBAPENEMASES Classification Enzyme Most Common Bacteria Class A KPC, SME, IMI, NMC, GES Enterobacteriaceae (rare reports in P. aeruginosa) Class B (metallo-b-lactamse) IMP, VIM, GIM, SPM P. aeruginosa Enterobacteriacea Acinetobacter spp. Class D OXA Acinetobacter spp.
  10. 10. APPROVED FOR CLINICAL USE • HE FOLLOWING DRUGS BELONG TO THE CARBAPENEM CLASS AND ARE APPROVED FOR USE BY HEALTH AUTHORITIES:[CITATION NEEDED] IMIPENEM, IN GENERAL GIVEN AS PART OF IMIPENEM/CILASTATIN (FDA APPROVAL 1985[6]) IMIPENEM CAN BE HYDROLYSED IN THE MAMMALIAN KIDNEY BY A DEHYDROPEPTIDASE ENZYME TO A NEPHROTOXIC METABOLITE, AND SO IS GIVEN WITH A DEHYDROPEPTIDASE INHIBITOR, CILASTATIN MEROPENEM (FDA APPROVAL 1996) ERTAPENEM (FDA APPROVAL 2001, SINCE APPROVED FOR MULTIPLE INDICATIONS) DORIPENEM (FDA APPROVAL 2007) PANIPENEM/BETAMIPRON (JAPANESE APPROVAL 1993) BIAPENEM (JAPANESE APPROVAL 2001) Dr.T.V.Rao MD 10
  11. 11. SPECTRUM OF USE • THESE AGENTS HAVE THE BROADEST ANTIBACTERIAL SPECTRUM COMPARED TO OTHER Β-LACTAM CLASSES SUCH AS PENICILLINS AND CEPHALOSPORINS. IN ADDITION, THEY ARE GENERALLY RESISTANT TO THE TYPICAL BACTERIAL ENZYME, Β-LACTAMASE, WHICH IS ONE OF THE PRINCIPAL Β-LACTAM RESISTANCE MECHANISMS OF BACTERIA. CARBAPENEMS CIRCUMVENT Β-LACTAMASE BY BINDING IT WITH HIGH AFFINITY AND ACYLATING THE ENZYME, RENDERING IT INACTIVE.[8] CARBAPENEMS ARE ACTIVE AGAINST BOTH GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA, AND ANAEROBES, WITH THE EXCEPTION OF INTRACELLULAR BACTERIA (ATYPICALS), SUCH AS THE CHLAMYDIAE. CARBAPENEMS ALSO ARE THUS FAR THE ONLY Β-LACTAMS CAPABLE OF INHIBITING L,D-TRANSPEPTIDASES Dr.T.V.Rao MD 11
  12. 12. BASIS OF MECHANISMS OF DRUG RESISTANCE • CHANGE IN DRUG TARGET • PRODUCTION OF AN ENZYME THAT MODIFIES OR INACTIVATES THE AGENT • REDUCED ACCUMULATION OF THE AGENT • LIMITED UPTAKE • ACTIVE EFFLUX • LOSS OF A PATHWAY INVOLVED IN DRUG ACTIVATION Dr.T.V.Rao MD 12
  13. 13. Resistant Strains Rare Resistant Strains Dominant Antimicrobial Exposure SELECTION FOR ANTIMICROBIAL- RESISTANT STRAINS Dr.T.V.Rao MD 13
  14. 14. CARBAPENEMASES • BETA-LACTAMASES WITH VERSATILE HYDROLYTIC CAPACITIES. • ABILITY TO HYDROLYZE PENICILLINS, CEPHALOSPORINS, MONOBACTAMS, AND CARBAPENEMS. • 2 MAJOR GROUPS • METALLO-B-LACTAMASES (MBLS) • MAJOR R IN PSEUDOMONAS, ACINETOBACTER, AND ENTEROBACTER • CONFER HIGH LEVEL OF R • SERINE B-LACTAMASES • OXACILLINASES OR D B-LACTAMASES (OXAA) • NOT AS DIVERSE • FOUND MOSTLY IN ACINETOBACTER • CONFER ONLY LOW LEVEL OF HYDROLYTIC ACTIVITY THERFORE ANOTHER R IS NECESSARY TO RAISE MIC • CLASS A CARBAPENEMASES • FOUND IN PSEUDOMONAS AND ENTEROBACTER, BUT PREDOMINANT TYPE IS FOUND ON A PLASMID IN KLEBSIELLA Dr.T.V.Rao MD 14
  15. 15. WHAT ARE CARBAPENEM-RESISTANT ENTEROBACTERIACEAE • CRE, WHICH STANDS FOR CARBAPENEM- RESISTANT ENTEROBACTERIACEAE, ARE A FAMILY OF BACTERIA THAT ARE DIFFICULT TO TREAT BECAUSE THEY HAVE HIGH LEVELS OF RESISTANCE TO ANTIBIOTICS. KLEBSIELLA SPECIES AND ESCHERICHIA COLI (E. COLI) ARE EXAMPLES OF ENTEROBACTERIACEAE, A NORMAL PART OF THE HUMAN GUT BACTERIA, THAT CAN BECOME CARBAPENEM-RESISTANT. Dr.T.V.Rao MD 15
  16. 16. KLEBSIELLA PNEUMONIAE CARBAPENEMASE • KPC IS A CLASS A B-LACTAMASE • CONFERS RESISTANCE TO ALL B-LACTAMS INCLUDING EXTENDED-SPECTRUM CEPHALOSPORINS AND CARBAPENEMS • OCCURS IN ENTEROBACTERIACEAE • MOST COMMONLY IN KLEBSIELLA PNEUMONIAE • ALSO REPORTED IN: K. OXYTOCA, CITROBACTER FREUNDII, ENTEROBACTER SPP., ESCHERICHIA COLI, SALMONELLA SPP., SERRATIA SPP., • ALSO REPORTED IN PSEUDOMONAS AERUGINOSA (COLUMBIA) Dr.T.V.Rao MD 16
  17. 17. Carbapenems: Resistance Issues Outer membrane Periplasm Cytoplasmic membrane D2 Porin (OprD) Carbapenem nucleus Ertapenem Imipenem PBP 1 PBP 2 PBP 3 PBP 4 PBP 5 Penicillin-binding proteins (PBPs) Mutated or missing D2 porin Courtesy of John Quinn, MD. Dr.T.V.Rao MD 17
  18. 18. MECHANISMS OF CARBAPENEM RESISTANCE: IMPERMEABILITY • OPRD FORMS NARROW TRANSMEMBRANE CHANNELS THAT ARE NORMALLY ACCESSIBLE ONLY TO CARBAPENEMS, NOT TO OTHER ß-LACTAMS • LOSS OF OPRD PORIN IS ASSOCIATED WITH DECREASED PERMEABILITY OF CARBAPENEMS AND INCREASED CARBAPENEM MICS, WHEREAS OTHER ß-LACTAMS REMAIN ACTIVEDr.T.V.Rao MD 18
  19. 19. KPC ENZYMES • LOCATED ON PLASMIDS; CONJUGATIVE AND NONCONJUGATIVE • BLAKPC IS USUALLY FLANKED BY TRANSPOSON SEQUENCES • BLAKPC REPORTED ON PLASMIDS WITH: • NORMAL SPECTRUM B-LACTAMASES • EXTENDED SPECTRUM B-LACTAMASES • AMINOGLYCOSIDE RESISTANCEDr.T.V.Rao MD 19
  20. 20. MECHANISMS OF CARBAPENEM RESISTANCE: EFFLUX SYSTEMS IN P.AERUGINOSA • UPREGULATION OF MEXAB-OPRM EFFLUX SYSTEM • ASSOCIATED WITH INCREASED MICS OF MEROPENEM, NOT IMIPENEM • COREGULATION OF MEXE-MEXF-OPRN EFFLUX SYSTEM WITH OPRD PORIN IN P AERUGINOSA • UPREGULATION OF EFFLUX ASSOCIATED WITH OPRD • ASSOCIATED WITH INCREASED MICS OF FLUOROQUINOLONES AS WELL AS CARBAPENEMS • MECHANISM SOMETIMES SELECTED BY FLUOROQUINOLONES, RARELY BY CARBAPENEMS Dr.T.V.Rao MD 20
  21. 21. EMERGENCE OF BACTERIAL RESISTANCE • IN THE UNITED STATES AND UNITED KINGDOM, STRAINS OF CARBAPENEM- RESISTANT ENTERIC BACTERIA HAVE BEEN ISOLATED FROM PATIENTS HAVING RECEIVED RECENT MEDICAL CARE IN PAKISTAN, BANGLADESH, AND INDIA. THESE STRAINS CARRY A GENE CALLED NEW DELHI METALLO-Β-LACTAMASE (SHORTENED NDM- 1) THAT IS RESPONSIBLE FOR THE PRODUCTION OF A METALLO-Β-LACTAMASE ENZYME THAT HYDROLYSES CARBAPENEM. Dr.T.V.Rao MD 21
  22. 22. KPC’S IN ENTEROBACTERIACEAE Species Comments Klebsiella spp. K. pneumoniae-cause of outbreaks K. oxytoca-sporadic occurrence Enterobacter spp. Sporadic occurrence Escherichia coli Salmonella spp. Citrobacter freundii Serratia spp. Pseudomonas aeruginosa – Columbia & Puerto Rico
  23. 23. MECHANISMS OF RESISTANCE • A CLINICAL ISOLATE OF E. COLI FROM THE SPUTUM SAMPLE OF A PATIENT ADMITTED TO A BEIJING HOSPITAL WAS FOUND TO SHOW UNUSUAL RESISTANCE TO CARBAPENEM THAT DOES NOT RELY ON THE PRESENCE OF CARBAPENEMASE. THE ISOLATE WAS DETERMINED TO HAVE FOUR SEPARATE MUTATIONS TO ACQUIRE THE RESISTANCE TO CARBAPENEMS. TWO MUTATIONS REMOVED THE OUTER MEMBRANE PROTEINS OMPF AND OMPC TO PREVENT THE ANTIBIOTICS FROM REACHING THE PBPS (PENICILLIN BINDING PROTEINS) IN THE INNER MEMBRANE.[8] A REGULATOR GENE MARR WAS MUTATED AND A NORMALLY NON-TRANSLATED MEMBRANE PROTEIN YEDS WAS EXPRESSED; BOTH WERE DEMONSTRATED TO HAVE EFFECTS ON THE ABILITY OF THIS STRAIN OF E.COLI TO RESIST CARBAPENEMS. THE BACTERIA ALSO INCREASED THE EXPRESSION OF A MULTIDRUG EFFLUX PUMP.Dr.T.V.Rao MD 23
  24. 24. MECHANISMS OF RESISTANCE • FOUND TO SHOW UNUSUAL RESISTANCE TO CARBAPENEM THAT DOES NOT RELY ON THE PRESENCE OF CARBAPENEMASE. THE ISOLATE WAS DETERMINED TO HAVE FOUR SEPARATE MUTATIONS TO ACQUIRE THE RESISTANCE TO CARBAPENEMS. TWO MUTATIONS REMOVED THE OUTER MEMBRANE PROTEINS OMPF AND OMPC TO PREVENT THE ANTIBIOTICS FROM REACHING THE PBPS (PENICILLIN BINDING PROTEINS) IN THE INNER MEMBRANE.[8] A REGULATOR GENE MARR WAS MUTATED AND A NORMALLY NON-TRANSLATED MEMBRANE PROTEIN YEDS WAS EXPRESSED; BOTH WERE DEMONSTRATED TO HAVE EFFECTS ON THE ABILITY OF THIS STRAIN OF E.COLI TO RESIST CARBAPENEMS. THE BACTERIA ALSO INCREASED THE EXPRESSION OF A MULTIDRUG EFFLUX PUMP. Dr.T.V.Rao MD 24
  25. 25. MAJOR TYPES OF CARBAPENEM-RESISTANT ENTEROBACTERIACEAE (CRE) • TYPES OF CRE ARE SOMETIMES KNOWN AS KPC (KLEBSIELLA PNEUMONIAE CARBAPENEMASE) AND NDM (NEW DELHI METALLO- BETA-LACTAMASE). KPC AND NDM ARE ENZYMES THAT BREAK DOWN CARBAPENEMS AND MAKE THEM INEFFECTIVE. Dr.T.V.Rao MD 25
  26. 26. WHO ARE LIABLE TO GET CARBAPENEM-RESISTANT ENTEROBACTERIACEAE (CRE) • PATIENTS WHOSE CARE REQUIRES DEVICES LIKE VENTILATORS (BREATHING MACHINES), URINARY (BLADDER) CATHETERS, OR INTRAVENOUS (VEIN) CATHETERS, AND PATIENTS WHO ARE TAKING LONG COURSES OF CERTAIN ANTIBIOTICS ARE MOST AT RISK FOR CRE INFECTIONS. • HEALTHY PEOPLE USUALLY DO NOT GET CRE INFECTIONS.Dr.T.V.Rao MD 26
  27. 27. WHEN TO SUSPECT A KPC-PRODUCER • ENTEROBACTERIACEAE – ESPECIALLY KLEBSIELLA PNEUMONIAE THAT ARE RESISTANT TO EXTENDED-SPECTRUM CEPHALOSPORINS: • MIC RANGE FOR 151 KPC-PRODUCING ISOLATES • CEFTAZIDIME 32 TO >64 MG/ML • CEFTRIAXONE ≥ 64 MG/ML • CEFOTAXIME ≥ 64 MG/ML • VARIABLE SUSCEPTIBILITY TO CEFOXITIN AND CEFEPIME Dr.T.V.Rao MD 27
  28. 28. PATIENTS CARBAPENEM-RESISTANT ENTEROBACTERIACEAE (CRE) INFECTION • CRE INFECTIONS ARE MOST COMMONLY SEEN IN PEOPLE WITH EXPOSURE TO HEALTHCARE SETTINGS LIKE HOSPITALS AND LONG-TERM CARE FACILITIES, SUCH AS SKILLED NURSING FACILITIES, AND LONG- TERM ACUTE CARE HOSPITALS. IN HEALTHCARE SETTINGS, CRE INFECTIONS OCCUR AMONG SICK PATIENTS WHO ARE RECEIVING TREATMENT FOR OTHER CONDITIONS. Dr.T.V.Rao MD 28
  29. 29. PATIENTS AT RISK WITH CARBAPENEM-RESISTANT ENTEROBACTERIACEAE (CRE) INFECTION • PATIENTS WHOSE CARE REQUIRES DEVICES LIKE VENTILATORS (BREATHING MACHINES), URINARY (BLADDER) CATHETERS, OR INTRAVENOUS (VEIN) CATHETERS, AND PATIENTS WHO ARE TAKING LONG COURSES OF CERTAIN ANTIBIOTICS ARE AMONG THOSE AT RISK FOR CRE INFECTIONS.Dr.T.V.Rao MD 29
  30. 30. SPREAD OF CRE INFECTION • TO GET A CRE INFECTION, A PERSON MUST BE EXPOSED TO CRE BACTERIA. CRE BACTERIA ARE MOST OFTEN SPREAD PERSON-TO-PERSON IN HEALTHCARE SETTINGS THROUGH CONTACT WITH INFECTED OR COLONIZED PEOPLE, PARTICULARLY CONTACT WITH WOUNDS OR STOOL Dr.T.V.Rao MD 30
  31. 31. CRE CAN BE A IATROGENIC INFECTION • CRE CAN CAUSE INFECTIONS WHEN THEY ENTER THE BODY, OFTEN THROUGH MEDICAL DEVICES LIKE INTRAVENOUS CATHETERS, URINARY CATHETERS, OR THROUGH WOUNDS CAUSED BY INJURY OR SURGERY. Dr.T.V.Rao MD 31
  32. 32. MECHANISM OF RESISTANCE IN CRE • RESISTANCE TO CARBAPENEM CAN BE DUE TO A FEW DIFFERENT MECHANISMS. ONE OF THE MORE COMMON WAYS THAT ENTEROBACTERIACEAE BECOME RESISTANT TO CARBAPENEM IS THROUGH THE PRODUCTION OF KLEBSIELLA PNEUMONIAE CARBAPENEMASE (KPC). KPC IS AN ENZYME THAT IS PRODUCED BY SOME CRE THAT WAS FIRST IDENTIFIED IN THE UNITED STATES AROUND 2001.Dr.T.V.Rao MD 32
  33. 33. KPC BREAKS DOWN CARBAPENEM • KPC BREAKS DOWN CARBAPENEM MAKING THEM INEFFECTIVE. IN ADDITION TO KPC, OTHER ENZYMES, SUCH AS NDM-1, VIM, AND IMP, CAN BREAKDOWN CARBAPENEMS AND LEAD TO THE DEVELOPMENT OF Dr.T.V.Rao MD 33
  34. 34. CDC INFORMS • SOME CRE BACTERIA HAVE BECOME RESISTANT TO ALMOST ALL AVAILABLE ANTIBIOTICS AND CAN BE DEADLY—ONE REPORT CITES THEY CAN CONTRIBUTE TO DEATH IN UP TO 50% OF PATIENTS WHO BECOME INFECTED. Dr.T.V.Rao MD 34
  35. 35. KPC – QUESTIONS • IF I HAVE DETECT KPC-PRODUCTION, SHOULD I CHANGE SUSCEPTIBLE CARBAPENEM RESULTS TO RESISTANT? • NOT ENOUGH DATA TO MAKE A CLEAR RECOMMENDATION • CLINICAL OUTCOMES DATA WILL BE NECESSARY Dr.T.V.Rao MD 35
  36. 36. TESTING OTHER DRUGS •TIGECYCLINE: • TEST BY ETEST IF POSSIBLE – DISK DIFFUSION TENDS TO OVERCALL RESISTANCE • NO CLSI BREAKPOINT, BUT THERE ARE FDA BREAKPOINT • SUSCEPTIBLE ≤ 2 MG/ML • INTERMEDIATE = 4 MG/ML • RESISTANT ≥ 8 MG/ML Dr.T.V.Rao MD 36
  37. 37. TESTING OTHER DRUGS • POLYMIXIN B OR COLISTIN • COULD TEST EITHER, BUT COLISTIN USED CLINICALLY • DISK DIFFUSION TEST DOES NOT WORK – DON’T USE! • ETEST – WORKS WELL, BUT NOT FDA CLEARED • BROTH MICRODILUTION – REFERENCE LABS • BREAKPOINTS - NONE • MIC ≤ 2 MG/ML, NORMAL MIC RANGE • MIC ≥ 4 MG/ML INDICATES INCREASED RESISTANCE Dr.T.V.Rao MD 37
  38. 38. PROTECT YOUR PATIENTS FROM CRE. • FOLLOW CONTACT PRECAUTIONS AND HAND HYGIENE RECOMMENDATIONS WHEN TREATING PATIENTS WITH CRE. • DEDICATE ROOMS, STAFF, AND EQUIPMENT TO PATIENTS WITH CRE. • PRESCRIBE ANTIBIOTICS WISELY. • REMOVE TEMPORARY MEDICAL DEVICES SUCH AS CATHETERS AND VENTILATORS FROM PATIENTS AS SOON AS POSSIBLE.Dr.T.V.Rao MD 38
  39. 39. PATIENT ARE TOLD TO FOLLOW CLEAN YOUR OWN HANDS OFTEN, ESPECIALLY: BEFORE PREPARING OR EATING FOOD BEFORE TOUCHING YOUR EYES, NOSE, OR MOUTH BEFORE AND AFTER CHANGING WOUND DRESSINGS OR BANDAGES OR HANDLING MEDICAL DEVICES AFTER USING THE BATHROOM AFTER BLOWING YOUR NOSE, COUGHING, OR SNEEZING Dr.T.V.Rao MD 39
  40. 40. DOCTORS AND NURSES SHOULD CARE TO PREVENT CRE INFECTIONS • EXPECT ALL DOCTORS, NURSES AND OTHER HEALTHCARE PROVIDERS WASH THEIR HANDS WITH SOAP AND WATER OR AN ALCOHOL- BASED HAND RUB BEFORE AND AFTER TOUCHING YOUR BODY OR TUBES GOING INTO YOUR Dr.T.V.Rao MD 40
  41. 41. HEALTH CARE PROVIDERS CAN • KNOW IF PATIENTS IN YOUR FACILITY HAVE CRE. REQUEST IMMEDIATE ALERTS WHEN THE LAB IDENTIFIES CRE. ALERT THE RECEIVING FACILITY WHEN A PATIENT WITH CRE TRANSFERS, AND FIND OUT WHEN A PATIENT WITH CRE TRANSFERS INTO YOUR FACILITY. Dr.T.V.Rao MD 41
  42. 42. IF WE DO NOT STOP MISUSE OF ANTIBIOTICS AND PRACTICE ANTIBIOTIC POLICY – WE ARE WALKING INTO DARKNESS Dr.T.V.Rao MD 42
  43. 43. VISIT ME FOR MORE ARTICLES OF INTEREST ON INFECTIOUS DISEASES ON ….. Dr.T.V.Rao MD 43
  44. 44. • PROGRAMME CREATED AND DESIGNED BY DR.T.V.RAO MD FOR MEDICAL AND PARAMEDICAL PROFESSIONAL FOR GLOBAL EDUCATION ON ANTIBIOTIC RESISTANCE • EMAIL • DOCTORTVRAO@GMAIL.COM Dr.T.V.Rao MD 44
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