CARBAPENEM RESISTANCE IN CLINICAL CARE

DR.T.V.RAO MD

Dr.T.V.Rao MD

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
Dr.T.V.Rao MD 2

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 Dr.T.V.Rao MD OR PAKISTAN.( REF PUBLIC HEALTH ENGLAND) INDIA

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
Dr.T.V.Rao MD 4

USED TO TREAT SEVERE INFECTIONS.

WHAT ARE CARBAPENEMS

CARBAPENEMS ARE A CLASS OF -LACTAM ANTIBIOTICS WITH A BROAD SPECTRUM OF ANTIBACTERIAL ACTIVITY. THEY HAVE A STRUCTURE THAT RENDERS THEM HIGHLY RESISTANT TO MOST LACTAMASES.[1] CARBAPENEM ANTIBIOTICS WERE ORIGINALLY Dr.T.V.Rao MD DEVELOPED FROM THE CARBAPENEM THIENAMYCIN, A

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 6 HAS BEEN INTRODUCED HENCE THE NAME OF THE

Dr.T.V.Rao MD

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--LACTAMASE, NDM1. THERE ARE CURRENTLY NO NEW ANTIBIOTICS IN DEVELOPMENT TO COMBAT BACTERIA RESISTANT TO CARBAPENEMS, AND WORLDWIDE SPREAD OF THE RESISTANCE Dr.T.V.Rao MD GENE IS CONSIDERED A POTENTIAL NIGHTMARE SCENARIO

SPECTRUM OF ACTIVITY
Drug
Strep spp. & MSSA

Entero-bacteriaeae

Nonfermentors

Anaerobes

Imipenem

+ + + +

+ + + +

+ +
Limited activity

+ + + +

Meropenem

Ertapenem

Doripenem

CARBAPENEMASES
Classification Class A Enzyme KPC, SME, IMI, NMC, GES Most Common Bacteria Enterobacteriaceae
(rare reports in P. aeruginosa)

Class B (metallo-b-lactamse)

IMP, VIM, GIM, SPM

P. aeruginosa Enterobacteriacea Acinetobacter spp. Acinetobacter spp.

Class D

OXA

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)
Dr.T.V.Rao MD DORIPENEM (FDA APPROVAL 2007) PANIPENEM/BETAMIPRON (JAPANESE APPROVAL 1993) 10

SPECTRUM OF USE
THESE AGENTS HAVE THE BROADEST ANTIBACTERIAL SPECTRUM COMPARED TO OTHER -LACTAM CLASSES SUCH AS PENICILLINS AND CEPHALOSPORINS. IN ADDITION, THEY ARE GENERALLY RESISTANT TO THE TYPICAL BACTERIAL ENZYME, -LACTAMASE, WHICH IS ONE OF THE PRINCIPAL -LACTAM RESISTANCE MECHANISMS OF BACTERIA. CARBAPENEMS CIRCUMVENT 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 Dr.T.V.Rao MD INTRACELLULAR BACTERIA (ATYPICALS), SUCH AS THE

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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

Dr.T.V.Rao MD

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SELECTION FOR ANTIMICROBIAL-RESISTANT STRAINS Resistant Strains

Rare

Antimicrobial Exposure

Resistant Strains Dominant

Dr.T.V.Rao MD 13

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 Dr.T.V.Rao MD 14 KLEBSIELLA

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 Dr.T.V.Rao MD PART OF THE HUMAN GUT BACTERIA, THAT CAN BECOME

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KLEBSIELLA PNEUMONIAE CARBAPENEMASE

KPC IS A CLASS A B-LACTAMASE
CONFERS RESISTANCE TO ALL B-LACTAMS INCLUDING EXTENDEDSPECTRUM 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

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Carbapenems: Resistance Issues

Carbapenem nucleus

Ertapenem

Mutated or missing D2 porin

Imipenem
D2 Porin (OprD)

Outer membrane

Periplasm
Penicillin-binding proteins (PBPs) Cytoplasmic Dr.T.V.Rao MD membrane
PBP 1 PBP 2 PBP 3 PBP 4 PBP 5

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Courtesy of John Quinn, MD.

MECHANISMS OF CARBAPENEM RESISTANCE: IMPERMEABILITY

OPRD FORMS NARROW TRANSMEMBRANE CHANNELS THAT ARE NORMALLY ACCESSIBLE ONLY TO CARBAPENEMS, NOT TO OTHER LACTAMS LOSS OF OPRD PORIN IS ASSOCIATED WITH DECREASED PERMEABILITY OF CARBAPENEMS AND INCREASED CARBAPENEM MICS, WHEREAS OTHER -LACTAMS REMAIN ACTIVE
Dr.T.V.Rao MD

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KPC ENZYMES
LOCATED ON PLASMIDS; CONJUGATIVE AND NONCONJUGATIVE BLAKPC IS USUALLY FLANKED BY TRANSPOSON SEQUENCES BLAKPC REPORTED ON PLASMIDS WITH:
NORMAL SPECTRUM BDr.T.V.Rao MD LACTAMASES EXTENDED SPECTRUM BLACTAMASES
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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

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 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-LACTAMASE (SHORTENED NDM-1) Dr.T.V.Rao MD THAT IS RESPONSIBLE FOR THE

EMERGENCE OF BACTERIAL RESISTANCE

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KPCS IN ENTEROBACTERIACEAE
Species Comments

Klebsiella spp.
Enterobacter spp. Escherichia coli Salmonella spp. Citrobacter freundii

K. pneumoniae-cause of outbreaks K. oxytoca-sporadic occurrence

Sporadic occurrence

Serratia spp.
Pseudomonas aeruginosa Columbia & Puerto Rico

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 Dr.T.V.Rao MD EXPRESSED; BOTH WERE DEMONSTRATED TO HAVE EFFECTS ON THE 23 ABILITY OF THIS STRAIN OF E.COLI TO RESIST CARBAPENEMS. THE

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 Dr.T.V.Rao MD 24 OF A MULTIDRUG EFFLUX PUMP.

MAJOR TYPES OF CARBAPENEMRESISTANT ENTEROBACTERIACEAE (CRE)

TYPES OF CRE ARE SOMETIMES KNOWN AS KPC (KLEBSIELLA PNEUMONIAE CARBAPENEMASE) AND NDM (NEW DELHI METALLO-BETALACTAMASE). KPC AND NDM ARE ENZYMES THAT BREAK DOWN CARBAPENEMS AND MAKE THEM INEFFECTIVE.

Dr.T.V.Rao MD

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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.
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Dr.T.V.Rao MD PEOPLE USUALLY DO HEALTHY NOT GET CRE INFECTIONS.

WHEN TO SUSPECT A KPCPRODUCER

ENTEROBACTERIACEAE ESPECIALLY KLEBSIELLA PNEUMONIAE THAT ARE RESISTANT TO EXTENDEDSPECTRUM CEPHALOSPORINS:
MIC RANGE FOR 151 KPC-PRODUCING ISOLATES
CEFTAZIDIME CEFTRIAXONE
Dr.T.V.Rao MD

32 TO >64 MG/ML 64 MG/ML 64 MG/ML

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CEFOTAXIME

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 28 RECEIVING TREATMENT FOR OTHER CONDITIONS.

Dr.T.V.Rao MD

PATIENTS AT RISK WITH CARBAPENEMRESISTANT ENTEROBACTERIACEAE (CRE) INFECTION

Dr.T.V.Rao MD

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

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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 30 CONTACT WITH WOUNDS OR STOOL

Dr.T.V.Rao MD

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
Dr.T.V.Rao MD

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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 32 SOME CRE THAT WAS FIRST IDENTIFIED IN THE UNITED

Dr.T.V.Rao MD

KPC BREAKS DOWN CARBAPENEM

KPC BREAKS DOWN CARBAPENEM MAKING THEM INEFFECTIVE. IN ADDITION TO KPC, OTHER ENZYMES, SUCH AS NDM1, VIM, AND IMP, CAN BREAKDOWN CARBAPENEMS AND LEAD
Dr.T.V.Rao MD

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CDC INFORMS
SOME CRE BACTERIA HAVE BECOME RESISTANT TO ALMOST ALL AVAILABLE ANTIBIOTICS AND CAN BE DEADLYONE REPORT CITES THEY CAN CONTRIBUTE TO DEATH IN UP TO 50% OF PATIENTS WHO BECOME INFECTED.

Dr.T.V.Rao MD

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KPC QUESTIONS
IF I HAVE DETECT KPCPRODUCTION, SHOULD I CHANGE SUSCEPTIBLE CARBAPENEM RESULTS TO RESISTANT?
NOT ENOUGH DATA TO MAKE A CLEAR RECOMMENDATION
Dr.T.V.Rao MD

CLINICAL OUTCOMES DATA WILL BE NECESSARY

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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
Dr.T.V.Rao MD

RESISTANT 8 MG/ML

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TESTING OTHER DRUGS

POLYMIXIN B OR COLISTIN
COULD TEST EITHER, BUT COLISTIN USED CLINICALLY

DISK DIFFUSION TEST DOES NOT WORK DONT USE!

ETEST WORKS WELL, BUT NOT FDA CLEARED

BROTH MICRODILUTION REFERENCE LABS

BREAKPOINTS
Dr.T.V.Rao MD

- NONE

MIC 2 MG/ML, NORMAL MIC RANGE

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MIC 4 MG/ML INDICATES INCREASED

PROTECT YOUR PATIENTS FROM CRE.

FOLLOW CONTACT PRECAUTIONS AND HAND HYGIENE RECOMMENDATIONS WHEN TREATING PATIENTS WITH CRE.
Dr.T.V.Rao MD

DEDICATE ROOMS, STAFF, AND EQUIPMENT TO PATIENTS WITH CRE. PRESCRIBE ANTIBIOTICS WISELY. REMOVE TEMPORARY MEDICAL DEVICES SUCH AS CATHETERS AND 38 VENTILATORS FROM PATIENTS AS SOON AS POSSIBLE.

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

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

Dr.T.V.Rao MD

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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
Dr.T.V.Rao MD

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IF WE DO NOT STOP MISUSE OF ANTIBIOTICS AND PRACTICE ANTIBIOTIC POLICY WE ARE WALKING INTO DARKNESS

Dr.T.V.Rao MD

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VISIT ME FOR MORE ARTICLES OF INTEREST ON INFECTIOUS DISEASES ON ..

Dr.T.V.Rao MD

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 PROGRAMME CREATED AND DESIGNED BY DR.T.V.RAO MD FOR MEDICAL AND PARAMEDICAL PROFESSIONAL FOR GLOBAL EDUCATION ON ANTIBIOTIC RESISTANCE
EMAIL
Dr.T.V.Rao MD

DOCTORTVRAO@GMAIL.COM

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