carbapenamases facts and detecction
TRANSCRIPT
-
8/7/2019 Carbapenamases Facts and Detecction
1/68
CARBAPENAM
ASESFacts, Controversies,DetectionDr.T.V.Rao MD
-
8/7/2019 Carbapenamases Facts and Detecction
2/68
Dr.T.V.Rao MD 2
ang ng an scape orNumbers of Approved Antibacterial
Agents
We have more resistant Microbes
Bars represent number of new antimicrobial agents approved by the FDA during the.p eri od l is te d
002468
1012141618
-1983 87 -1988 92 -1993 97 -1998 02 -2003 05 2008
.Infectious Diseases Society of America ,Bad Bugs No Drugs. ; .July 2004 Spellberg B et al Clin Infect Dis. ; : - ;2004 38 1279 1286.New antimicrobial agents Antimicrob Agents Chemother. ; :2006 50 1912
-
8/7/2019 Carbapenamases Facts and Detecction
3/68
Dr.T.V.Rao MD 3
Carbapenems x
PenicillinThe carbapenems arestructurally verysimilar to thepenicillins, but thesulphur atom in
position 1of thestructure has been
replaced with acarbon atom, andhence the name ofthe group, the
carbapenem
-
8/7/2019 Carbapenamases Facts and Detecction
4/68
Dr.T.V.Rao MD 4
What are carbapenems
Carbapenems are a class ofbeta-lactam antibiotics with abroad spectrum of
antibacterial activity. Theyhave a structure that rendersthem highly resistant to beta-
lactamases. Carbapenemantibiotics were originallydeveloped from thienamycin,
a naturally-derived product of
-
8/7/2019 Carbapenamases Facts and Detecction
5/68
Spectrum of activity
Broad spectrum activity GPC & GNB
Aerobic & Anaerobic bacteria
Active against MDR isolates
Active against ESBL +ve GNB
Active against Ps aeruginosa &Acinetobacter spp.
Not active against MRSA
Enterococcus spp.
Stenotrophomonas maltophilia
-
8/7/2019 Carbapenamases Facts and Detecction
6/68
Dr.T.V.Rao MD 6
Carbapenems inCommon Use
Imipenem Broad spectrum, covers Gram-positive,
Gram-negative (including ESBL-producing strains), Pseudomonas and
anaerobes Meropenem
Less seizure-inducing potential, canbe used to treat CNS infections
Ertapenem Lacks activity vs. Acinetobacter and
Pseudomonas Has limited activity against penicillin-
resistant pneumococci
-
8/7/2019 Carbapenamases Facts and Detecction
7/68
Dr.T.V.Rao MD 7
Carbapenems effective onseveral common isolates
Staph(notMRSA), Strep(highlyresistant),Neisseria,Haemophilus,Proteus,
Pseudomonas,Klebseilla,Bacteroides,anaerobes(excluding C.dif)
-
8/7/2019 Carbapenamases Facts and Detecction
8/68
Dr.T.V.Rao MD 8
Spectrum of Activity
Drug Strep spp. &MSSA
Entero-bacteriaeae
Non-fermentors
Anaerobes
Imipenem + + + +
Meropenem + + + +
Ertapenem + + Limitedactivity
+
Doripenem + + + +
-
8/7/2019 Carbapenamases Facts and Detecction
9/68
Dr.T.V.Rao MD 9
Carbapenems
Drug Route of Administration
FDA Status
Imipenem IV Cleared
Meropenem IV Cleared
Ertapenem IM, IV Cleared
Doripenem IV Application Submitted
-
8/7/2019 Carbapenamases Facts and Detecction
10/68
Dr.T.V.Rao MD 10
Enterobacteriaceae are realproblamatic microbes
The rapid anddisturbing spreadof:
ESBL extended-spectrum -lactamases
AmpC enzymes carbapenem
resistance metallo--
lactamases
0 1 0
-
8/7/2019 Carbapenamases Facts and Detecction
11/68
:0 1 0 Distribution of lactamases according to fu
Most Carbapenemases canHydrolyzeALLBeta lactam antibiotics
-
8/7/2019 Carbapenamases Facts and Detecction
12/68
Discovery ofCarbapenamases
In 1996, the first isolate of KPC-producing bacteria was discovered ina clinical specimen ofK pneumoniae
from a hospital in North Carolinainvolved in the Intensive CareAntimicrobial ResistanceEpidemiology (ICARE) surveillance
program. KPCs were infrequentlyisolated until 2001, when KPC-producing Enterobacteriaceae werereported in several extended
outbreaks in metropolitan hospitals ofNew York and New Jerse .
-
8/7/2019 Carbapenamases Facts and Detecction
13/68
Carbapenems used asimportant life saving option
Carbapenems are often used asantibiotics of last resort for treatinginfections due to multidrug-resistant
gram-negative bacilli, because theyare stable even in response toextended-spectrum and AmpC -lactamases. However, gram-
negative bacilli producing theacquired metallo--lactamases (MBLs)IMP and VIM have been increasinglyreported in Asia and Europe and
more recently, they have beendetected in Canada and the United
-
8/7/2019 Carbapenamases Facts and Detecction
14/68
Carbapenemases
The most versatile family of -lactamases
Two major groups based on the hydrolytic
mechanism at the active site Serine at the active site: class A and D
Zinc at the active site : class B
All carbapenemases hydrolyze penicillin's,extended spectrum cephalosporins, andcarbapenems
-
8/7/2019 Carbapenamases Facts and Detecction
15/68
-
8/7/2019 Carbapenamases Facts and Detecction
16/68
Dr.T.V.Rao MD 16
Carbapenamases arespreading faster
A new class of bacterial enzymescapable of inactivatingCarbapenems, known as
Klebsiella pneumoniaeCarbapenamases (KPCs), hasrapidly spread in the United States
and continues to be extensivelyreported elsewhere in the world.KPCs are class A Carbapenamasesthat reside on transferableplasmids and can hydrolyze all
-
8/7/2019 Carbapenamases Facts and Detecction
17/68
Dr.T.V.Rao MD 17
Carbapenemases withinthe Enterobacteriaceae
KPC carbapenemase Difficult todetect using current MICbreakpoints.
Isolates that have an MIC of 2 g/mlto ertapenem or an MIC of 2-4 g/ml to meropenem or Imipenem.
Modified Hodge test isconfirmatory..PCR is gold standard.
-
8/7/2019 Carbapenamases Facts and Detecction
18/68
Dr.T.V.Rao MD 18
KPC(K. pneumoniaecarbapenemase)
KPCs are the mostprevalent of thisgroup of enzymes,
found mostly ontransferable
plasmidsinK.
pneumoniae
Substratehydrolysis
spectrum
-
8/7/2019 Carbapenamases Facts and Detecction
19/68
Dr.T.V.Rao MD 19
KPCs in
EnterobacteriaceaeSpecies CommentsKlebsiella spp. K.pneumoniae-cause of outbreaks
K.oxytoca-sporadic occurrence
Enterobacterspp. Sporadic occurrenceEscherichia coli
Salmonella spp.
Citrobacter freundii
Serratia spp.
-
8/7/2019 Carbapenamases Facts and Detecction
20/68
-
8/7/2019 Carbapenamases Facts and Detecction
21/68
Dr.T.V.Rao MD 21
Pseudomonas aeruginosaCarbapenamases
KPC resistance hasbeen reported ininherently resistantorganisms such as
Pseudomonasfrom Trinidad, an
isolate of multidrug-resistantPseudomonasaeruginosa that
harboured a novel
-
8/7/2019 Carbapenamases Facts and Detecction
22/68
-
8/7/2019 Carbapenamases Facts and Detecction
23/68
Enzyme Ambler
Class
Country Spectrum of activity Organisms
IMP (18)ImipenemJapan
B Japan All lactams Ps., Acinetobacter
VIM (12)Verona
B Italy Pan R, may be S toaztreonam
Ps. , Acinetobacte
SPMSao Paulo
B Brazil Pan R Ps
GIM German B Germany Pan R Ps.
SIMSouel
B SouthKorea
Pan R Acinetobacter, Ps.
NDMNew Delhi
B India, UK Pan R Kleb pneu, E.
coli
M e ta llo (lactamases Zn at)a ctiv e site
-
8/7/2019 Carbapenamases Facts and Detecction
24/68
-
8/7/2019 Carbapenamases Facts and Detecction
25/68
Dr.T.V.Rao MD 25
Carbapenemase Class A
First identified 1982 in UK
Four major families
Chromosomally encoded Serratia marcescens enzyme (SME)
Not metalloenzyme carbapenemases (NMC)
Imipenem-hydrolyzing -lactamases (IMI)
Plasmid encoded
Klebsiella pneumoniae carabapenemases (KPC)
Guiana Extended-Spectrum (GES)
-
8/7/2019 Carbapenamases Facts and Detecction
26/68
Dr.T.V.Rao MD 26
Emerging CarbapenemResistance in Gram-Negative
Bacilli
Significantly limits treatment optionsfor life-threatening infections
No new drugs for gram-negative bacilli
Emerging resistance mechanisms,carbapenemases are mobile,
Detection of carbapenemases andimplementation of infection controlpractices are necessary to limit
spread
E b i B k i
-
8/7/2019 Carbapenamases Facts and Detecction
27/68
Dr.T.V.Rao MD 27
Enterobacteriaceae: Breakpointsrevised so need for other newer
drugs, may be carbapenms ?
AgentCLSI 2009 CLSI 2010
S I R S I R
Cefazolin 8 16 32 1 2 4
Cefotaxime 8 16-32 64 1 2 4
Ceftriaxone 8 16-32 64 1 2 4
Ceftazidime 8 16 32 4 8 16
Aztreonam 8 16 32 4 8 16
Cefipime 8 16 32 8 16 32
-
8/7/2019 Carbapenamases Facts and Detecction
28/68
Laboratory Detection: &al and Laboratory Standards Institute breakpoints 2009 201Revised Break Points 2010Agent MIC breakpoint (ug/ml) DD breakpoints (mm)
S MHT I R S MHT I R
IPM < 1< 1
2-4 82
>16>4
>16>23
NA 14-1520-22
4
>22>23
16-21 14-1520-22
1
> 22>23
19-21 16-1820-22
-
8/7/2019 Carbapenamases Facts and Detecction
29/68
Dr.T.V.Rao MD 29
Class ACarbapenemases
K. p neumoniae carbapenemase( - ) -KPC type possess carbapenemhydrolyzing enzymes most
. .common on East Coast of U S Enzymes are capable ofefficiently hydrolyzing
, ,penicillins Cephalosporins,aztreonam and carbapenems
and are inhibited byclavulanic acid andtazobactam
To date 4 KPC enzymes have
: - , - ,been identified KPC 1 KPC 2- - Cl A
-
8/7/2019 Carbapenamases Facts and Detecction
30/68
Dr.T.V.Rao MD 30
Class ACarbapenemases
K. p neumoniae carbapenemase( - ) -KPC type possess carbapenemhydrolyzing enzymes most
. .common on East Coast of U S Enzymes are capable ofefficiently hydrolyzing
, ,penicillins Cephalosporins,aztreonam and carbapenems
and are inhibited byclavulanic acid andtazobactam
To date 4 KPC enzymes have
: - , - ,been identified KPC 1 KPC 2- -
-
8/7/2019 Carbapenamases Facts and Detecction
31/68
Dr.T.V.Rao MD 31
Located on plasmids; conjugativeand nonconjugative
blaKPC is usually flanked bytransposon sequences
blaKPC reported on plasmids with:
Normal spectrum -lactamases Extended spectrum -lactamases Aminoglycoside resistance
KPC Enzymes
-
8/7/2019 Carbapenamases Facts and Detecction
32/68
Dr.T.V.Rao MD 32
When to Suspect a KPC-Producer
Enterobacteriaceae especiallyKlebsiella pneumoniae that areresistant to extended-spectrum
cephalosporins: MIC range for 151 KPC-producing
isolates Ceftazidime 32 to >64 g/ml
Ceftriaxone 64 g/ml
Cefotaxime 64 g/ml
Variable susceptibility to cefoxitin and
cefepime
-
8/7/2019 Carbapenamases Facts and Detecction
33/68
Modified Hodge Test
for CarbapenemaseDetection in
Enterobacteriaceae
-
8/7/2019 Carbapenamases Facts and Detecction
34/68
Laboratory Detection ofKPC-Producers
Problems: 1) Some isolates demonstrate low-level
carbapenem resistance
2) Some automated systems fail to
detect low-level resistance
Th M difi d H d
-
8/7/2019 Carbapenamases Facts and Detecction
35/68
The Modified HodgeTest
The Modified Hodge Test is aphenotypic confirmatory test forCarapnemase activity and is
indicated when there is a positivescreening test and resistance to oneor more agents in cephalosporin
subclass III (i.e., cefoperazone,cefotaxime, ceftazidime,ceftizoxime, and ceftriaxone) Beaware that imipenem disk tests
perform poorly as a screen for
Phenotypic Tests for
-
8/7/2019 Carbapenamases Facts and Detecction
36/68
Phenotypic Tests forCarbapenemase
Activity
Modified Hodge Test
100% sensitivity in detecting KPC; alsopositive when other carbapenemasesare present
100% specificity
. , , - .Procedure described by Lee et al CMI 7 88 102
.2001
Th M difi d H d
-
8/7/2019 Carbapenamases Facts and Detecction
37/68
The Modified HodgeTest (MHT)
The Modified Hodge Test (MHT)detects carbapenemase production
in isolates of Enterobacteriaceae Carbapenemase production is
detected by the MHT when the test
isolate produces the enzyme andallows growth of a carbapenemsusceptible strain (E.coli ATCC25922) towards a carbapenem disk
Step 1 and 2 of
-
8/7/2019 Carbapenamases Facts and Detecction
38/68
Step 1 and 2 of
MHT Prepare a 0.5McFarlanddilution of the
E.coli ATCC25922 in 5 ml ofbroth or saline.
Dilute 1:10 byadding 0.5 ml ofthe 0.5McFarland to 4.5
ml of MHB or
-
8/7/2019 Carbapenamases Facts and Detecction
39/68
Step 3 and 4 of MHT
Streak a lawn ofthe 1:10 dilutionofE.coli ATCC25922 to a
Mueller Hintonagar plate andallow to dry 35minutes.
Place a 10 gmeropenem orertapenem
susceptibility disk
-
8/7/2019 Carbapenamases Facts and Detecction
40/68
Protocols in ModifiedHodge Test
-
8/7/2019 Carbapenamases Facts and Detecction
41/68
Step 5 and 6 of MHT
In a straight line, streak testorganism from the edge of thedisk to the edge of the plate.Up to four organisms can betested on the same plate withone drug.
Incubate overnight at 35C 2OCin ambient air for 1624 hours
-
8/7/2019 Carbapenamases Facts and Detecction
42/68
Detection
Anderson KF et al. Evaluation of methods to identify KPC inenterobacteriaceae. JCM 2007; 45: 2723 2725.
Modified Hodge Test (MHT) Carbapenem Inactivation Assay
Carbapenem Disk
SusceptibleE. coli
Test Isolate
M difi d H d T
-
8/7/2019 Carbapenamases Facts and Detecction
43/68
Modified Hodge Test
Lawn ofE. coliATCC 259221:10 dilution of a0.5 McFarland suspension
Imipenem disk
Test isolates
. , , -Described by Lee et al CMI 7 88. .102 2001
serva on or
-
8/7/2019 Carbapenamases Facts and Detecction
44/68
serva on orCarbapenamases
detection by HMT After 1624 hours
of incubation,
examine theplate for a cloverleaf-typeindentation atthe intersection
of the testorganism and theE. coli 25922,within the zone
of inhibition of
Q li l i i
-
8/7/2019 Carbapenamases Facts and Detecction
45/68
Quality control strains inModified Hodge test
Perform quality control of theCarbapenems disks according to
CLSI guidelines.
Perform quality control with each run.
MHT Positive Klebsiellapneumoniae ATCC BAA-1705
MHT Negative Klebsiellapneumoniae ATCC BAA-1706
y es ng w
-
8/7/2019 Carbapenamases Facts and Detecction
46/68
y es ng wErtapenem or
Meropenem The procedure described by
Landman et al. describes using a
10-g imipenem disk for step 1.However, there are species ofEnterobacteriaceae which haveintrinsic mechanisms of resistance
to imipenem other than acarbapenemase (See CLSIdocument M100, Appendix G).Therefore, ertapenem ormeropenem may provide more
specific selection for acquired
What Labs Should Do
-
8/7/2019 Carbapenamases Facts and Detecction
47/68
What Labs Should DoNow
Look for isolates ofEnterobacteriaceae (especially K.pneumoniae), with carbapenem MIC
2 g/ml or nonsusceptible toErtapenem by disk diffusion
Consider confirmation by ModifiedHodge Test
Alert clinician and infection controlpractitioner to possibility of mobilecarbapenemase in isolate
Newer
-
8/7/2019 Carbapenamases Facts and Detecction
48/68
NewerCarbapenemases
As of June 2010, there werethree reported cases ofEnterobacteriaceae isolatesbearing this newly describedresistance mechanism in theUS, the CDC stated that "Allthree U.S. isolates werefrom patients who receivedrecent medical care in
"
-
8/7/2019 Carbapenamases Facts and Detecction
49/68
K. pneumoniae containing NDM-1was first discovered in 2008. By2009, a study in Mumbai revealed
24 carbapenem-resistantEnterobacteriaceae, 22 of whichwere NDM-1 producers. Of these 22organisms, 10 were klebsiella
species, 9 were Escherichia coli, 2were enterobacter species, and 1was Morganella morganii illustrating the ability of the
plasmid to spread rapidly among
NDM-1
CDC t th
-
8/7/2019 Carbapenamases Facts and Detecction
50/68
CDC reports the newgenetic mechanisms
The isolate, Klebseilla pneumoniae05-506, was shown to possess ametallo-beta-lactamase (MBL)
but was negative for previouslyknown MBL genes. Gene librariesand amplification of class 1integrons revealed three
resistance-conferring regions; thefirst contained bla(CMY-4) flanked by ISEcP1and blc. The second region of 4.8 kbcontained a complex class 1 integron
with the gene cassettes arr-2, a new
N D lhi t ll b t
-
8/7/2019 Carbapenamases Facts and Detecction
51/68
NDM-1, which stands for New Delhimetallo-beta-lactamase 1 and actuallyrefers not to a single bacterial speciesbut to a transmissible geneticelement encoding multiple resistancegenes that was initially isolated froma strain of Klebsiella obtained from apatient who acquired the organism inNew Delhi, India
Subsequently, organisms in theEnterobacteriaceae family containing thisgenetic element (or variants thereof) have
been found widely throughout India,
New Delhi metallo-beta-lactamase 1
-
8/7/2019 Carbapenamases Facts and Detecction
52/68
NDM-1 NDM-1 symptoms are reported to
be associated with the bacteria itattaches to. The currently knownbacteria's hosting this gene are E.Coliand Klebsiella pneumoniae. Themajority of the patients treated todate who are positive for NDM-1 werethose with urinary tract infections,bacteraemia, or pneumonia NDM-1 isthe gene responsible for the newestsuperbug. NDM-1 genes can live
inside different bacteria and is
w
-
8/7/2019 Carbapenamases Facts and Detecction
53/68
wDelhi creates
Controversy The gene was named after New Delhi, thecapital city of India, as it was firstdescribed by Yong et al. in 2009 in aSwedish national who fell ill with an
antibiotic-resistant bacterial infection thathe acquired in India . The infection wasunsuccessfully treated in a New Delhihospital and after the patient's
repatriation to Sweden, a carbapenem-resistant Klebsiella pneumoniae strainbearing the novel gene was identified. Theauthors concluded that the new resistancemechanism "clearly arose in India, but
there are few data arising from India to
-
8/7/2019 Carbapenamases Facts and Detecction
54/68
CDC reportsThree Enterobacteriaceae isolates
carrying a newly described resistancemechanism, the New Delhi metallo-
beta-lactamase (NDM-1) , wereidentified from three U.S. states atthe CDC antimicrobial susceptibility
laboratory. This is the first report ofNDM-1 in the United States, and thefirst report of metallo-beta-lactamasecarriage among Enterobacteriaceae
in the United States
Blame on India Is it
-
8/7/2019 Carbapenamases Facts and Detecction
55/68
Blame on India Is itjustified ?
As of June 2010, there werethree reported cases of
Enterobacteriaceae isolatesbearing this newly describedresistance mechanism in the
US, the CDC stated that "Allthree U.S. isolates werefrom patients who received
recent medical care in
CDC reports the new
-
8/7/2019 Carbapenamases Facts and Detecction
56/68
CDCreports the newgenetic mechanisms
The isolate, Klebseilla pneumoniae05-506, was shown to possess ametallo-beta-lactamase (MBL) but
was negative for previously knownMBL genes. Gene libraries andamplification of class 1 integronsrevealed three resistance-
conferring regions; the first containedbla(CMY-4) flanked by ISEcP1 and blc. Thesecond region of 4.8 kb contained acomplex class 1 integron with the gene
cassettes arr-2, a new erythromycin
Molecular configuration
-
8/7/2019 Carbapenamases Facts and Detecction
57/68
Molecular configurationof NDM-1
NDM-1 also has an additional insertbetween positions 162 and 166 notpresent in other MBLs. NDM-1 has a
molecular mass of 28 kDa, ismonomeric, and can hydrolyze allbeta-lactams except aztreonam.
Compared to VIM-2, NDM-1 displaystighter binding to mostCephalosporins.
NDM ti di diff f th
-
8/7/2019 Carbapenamases Facts and Detecction
58/68
NDM genetic coding differs from otherrecent isolates
Compared to VIM-2, NDM-1 displaystighter binding to mostcephalosporins, in particular,cefuroxime, cefotaxime, and
cephalothin (cefalotin), and also tothe penicillins. NDM-1 does not bindto the carbapenems as tightly as IMP-1 or VIM-2 and turns over thecarbapenems at a rate similar to thatof VIM-2. In addition to K. pneumoniae05-506, bla(NDM-1) was found on a140-kb plasmid in an Escherichia colistrain isolated from the patient's
feces, inferring the possibility of in
-
8/7/2019 Carbapenamases Facts and Detecction
59/68
CLSI guidelines for assessingthe antibiograms pattern
All patients colonized or infected withCRE or carbapenemase-producingEnterobacteriaceae should be placedon contact precautions. Acute carefacilities should establish a protocol,in conjunction with CLSI guidelines, todetect nonsusceptibility andcarbapenemase production inEnterobacteriaceae, particularlyKlebseilla spp. and Escherichia coli,and immediately alert epidemiologyand infection control staff members ifidentified
Ph t i d t ti ith H d
-
8/7/2019 Carbapenamases Facts and Detecction
60/68
Phenotypic detection with Hodgetest a Minimal requirement
Carbapenem resistanceand carbapenemaseproduction conferredby blaNDM-1 is
detected reliably withphenotypic testingmethods currentlyrecommended by the
Clinical andLaboratory StandardsInstitute , includingdisk diffusion testingand the modified
Hodge test
-
8/7/2019 Carbapenamases Facts and Detecction
61/68
CHROMagarESBL & KPC
Why is CRE a public health
-
8/7/2019 Carbapenamases Facts and Detecction
62/68
Why is CRE a public healthemergency ?
Significantly limits treatment optionsfor life threatening infections
No new drug for GNB in the pipeline
Resistant mechanism easilytransferable as it in now on atransposon
Rapid Detection & effective infectioncontrol measures essential tocontrol spread
-
8/7/2019 Carbapenamases Facts and Detecction
63/68
Testing Other Drugs
Polymyxin B or Colistin
Could test either, but colistin usedclinically
Disk diffusion test does not work dont use!
Etest works well, but not FDAcleared
Broth micro dilution reference labs
Breakpoints - none
MIC 2 g/ml, normal MIC range
MIC 4 g/ml indicates increased
Laboratories should
-
8/7/2019 Carbapenamases Facts and Detecction
64/68
Laboratories shouldcreate protocols for
detection of CRE The exact procedure for confirmation of
CRE or carbapenemase-production
should be laboratory-specific andchosen based upon laboratoryworkflow and the types of isolatescausing clinical infections in thepatient population served. It may behelpful to refer to the CLSI guidelinesfor identification of carbapenemase
production in isolates that test
u oma on as m e
-
8/7/2019 Carbapenamases Facts and Detecction
65/68
u oma on as m euse in Carbapenamases
detection Automated testingalone will notdetect all of theresistancepatterns that
occur via beta-lactamases andcarbapenemases.Failure to detectorganisms with
these enzymescan result inerroneous reportsthat wouldindicate an isolate
is susceptible to-
Become a Member of Alliance for
-
8/7/2019 Carbapenamases Facts and Detecction
66/68
Dr.T.V.Rao MD 66
the Prudent Use of Antibiotics(APUA) www.apua.org
An internationalorganization
dedicated tocurbingantibiotic
resistanceChapters exist
currently in
several Asian
an as ng an
-
8/7/2019 Carbapenamases Facts and Detecction
67/68
an as ng anReduce the Spread of
Microbes
-
8/7/2019 Carbapenamases Facts and Detecction
68/68
Created by Dr.T.V.Rao MD for e learning resources for theMedical Professionals in the
Developing Worldemail.