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Dr.T.V.Rao MD
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Introduction to Cephalosporins..
Cephalosporins werefirst isolated fromcultures of
Cephalosporiumacremonium from asewer in 1948 byItalian scientist,Giuseppe Brotzu
The first agent cephalothin
(cefalotin) was launched by
Eli Lilly in 1964 Dr.T.V.Rao M
D 2
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B-Lactam antibiotics ( similar topenicillin's)Broad spectrum in action.Act by inhibition of cell wall synthesisBactericidal
Inactive against : enterococci, MRSA,legionella , mycoplasma, chlamydia spp.Widely used in surgical procedures to reduce
the risk of post operative infections
Cephalosporins .
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The site of action of beta-lactam antibiotics is thepenicillin binding proteins (PBPs) on the inner surface ofthe bacterial cell membrane that are involved in thesynthesis of the cell wall
Cephalosporins are bactericidal agentsAll bacterial cells have a cell wall that protects them.
Cephalosporins disrupt the synthesis of the
peptidoglycan layer of bacterial cell walls, which causesthe walls to break down and eventually the bacteria die.
Antimicrobial activity ofCephalosporins
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Classification is based onspectrum of activity
Cephalosporins are groupedinto "generations" basedon their spectrum ofantimicrobial activity.
The first cephalosporins were
designated first generationwhile later, more extendedspectrum cephalosporinswere classified as secondgeneration cephalosporins.
So continued Generations
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Basis of Classification
Each newer generation ofcephalosporins hassignificantly greatergram-negative
antimicrobial propertiesthan the precedinggeneration
Fourth generationcephalosporins, however,have true broad spectrumactivity
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1st
generationCephalosporins
First generation cephalosporinsare moderate spectrum agents
Effective against gram +ve aerobes
They are effective for treating
staphylococcal andstreptococcal infections andtherefore are alternatives forskin and soft-tissue infections,as well as for streptococcal
pharyngitis.
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Dr.T.V.Rao MD 8
CefadroxilCephalexin
Cephaloridine
Cephalothin
Cephapirin
Cefazolin
Cephradine
The 1st
generationcephalosporins are:
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Active against G+ cocci ( except. Enterococci & MRSA):s.pneumoniae, s.pyogenes,s. aureus,
S. epidermidisIndicated for streptococcal pharyngitis ( e.g.
cephalexin)Commonly used ( eg. Cefazolin) as prophylactic for
surgical procedures.Modest activity against G- bacteria
1st Generation
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2nd
generationCephalosporins
Their antibacterial spectrumis broader than that of 1st
generation cephalosporinsand includes some gram -ve
pathogens They are also more resistant
to beta-lactamase
They are useful agents for
treating upper and lowerrespiratory tract infectionsand sinusitis
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2nd generation cont...
These agents are alsoactive against E. coli,Klebsiella and Proteus,
which makes thempotential alternativesfor treating urinary tract
infections caused bythese organisms
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Dr.T.V.Rao MD 12
2nd Generation Cephalosporins
..
CefoxitinCefuroxime
Cefuroxime axetilCefaclor
Cefprozil
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3rd
generationCephalosporins
They have anextended spectrum
of action againstgram -veorganisms
Resistant to beta-lactamases
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3rd generation cont...
The parenteral thirdgeneration cephalosporins(ceftriaxone and cefotaxime)have excellent activity
against most strains ofStreptococcus pneumoniae,including the vast majorityof those with intermediateand high level resistance topenicillin
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Third Generation Cephalosporins
CeftriaxoneCefotaxime
CeftazidimeCefoperazoneCefixime
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THIRD GENERATION
They have enhanced G- activity, H. influenza, N.meningitidis, N.gonorrhea, P. aeruginosae, M.catarrhalis, E.coli, most Klebsiella
Ceftriaxone has long half-life . Not advised inneonates (interferes with bilirubin metabolism )
Cefotaxime preferred in neonate ( does not interferewith bilirubin metabolism ), as may ceftriaxone.Ceftazidime & cefoperazone have excellent activity
against P.aeruginosa.Cefixime has similar activity to amoxicillin &
Cefaclor for actute otitis media
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4th
generationcephalosporins
4th
generation cephalosporinsare extended spectrum agentswith similar activity againstgram-positive organisms asfirst generation cephalosporins.
They also have a greaterresistance to beta-lactamasesthan the third generationcephalosporins.
Many can cross blood brain
barrier and are effective inmeningitis.
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4th
GenerationCephalosporins...
Cefepime
CefluprenamCefozopran
CefpiromeCefquinome
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Fourth Generation
Cefipime
Active against G+ bacteria> than Cefazolin againsts. pyogenes,S.pneumoniae but lower
against s. aureus.Similar to cefotaximeagainst E.coli & K.pneumoniae but < for p.aeruginosa.
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They are organic acids and are hydrophilic
They generally have poor oral bioavailability as theyunstable in acid environments
They are readily excreted by the kidneys, via tubularsecretion in the proximal convoluted tubule. This resultsin high concentrations of the drug in urine.
Exceptions are:
Cephalexin which is stable in acid and so suitable for oraldosing.
Cefoperazone is excreted in bile rather than in urine.
Pharmacokineticconsideration
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Why Cephalosporins are Widely
Prescribed Antibiotics
Broad spectrum of activity
Stability to -lactamase
Oral and parenteral preparations
Widely accepted
Treats day to day as well asserious infections
High safety profileDr.T.V.Rao MD 21
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Dr.T.V.Rao MD 22
Cephalosporins-Limitations
Emerging resistancepatterns
III & IV generation
cephalosporins wereavailable only as
parenteral formulations
Pharmacoeconomics
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Why detect ESBL producers?
ESBL producers may:
Appear Sensitive to some cephalosporins in
vitro
Show major inoculum effects
Fail in therapy, despite appearingsusceptible
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Detection Strategy: step 1
Ref http://www.hpa.org.uk
Screen Enterobacteriaceae with : Cefpodoxime- best general ESBL substrate
Cefotaxime & ceftazidime- good substrates for
CTX-M & TEM/SHV, respectively
Spread of CTX-M into community meansscreening must be wider than before
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Detection of ESBLs: step 2
Seek ceph/clavsynergy in ceph Risolates
DoublediscCombinati
on discEtest
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Double Disk Method
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Etest for ESBLs
Cefotaxime
Cefotaxime+
ClavulanateDr.T.V.Rao MD 27
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Methods optimised for E. coli & Klebsiella
More difficult with Enterobacter
clavulanate induces AmpC; hides ESBL
Best advice is to do synergy test (NOT
SCREEN) with 4th gen cephalosporins
Pitfalls in ESBL detection
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Synergy tests with 4-gen cephalosporins
Cefepime/clav (Mast & AB Biodisk)
Cefpirome clav (Oxoid)
Devt. driven by spread of clonal E. aerogenes withTEM-24 in Belgium & France
Sensitivity for weak ESBLs remains to be proven
Cefpirome & cefepime products need comparison
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Bacteria not to test for ESBLsAcinetobacter
Often S to clavulanate alone
S. maltophilia+ve result by inhibition of L-2
chromosomal -lactamase,ubiquitous in the species
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Briefly, revising breakpoints involves systematic reviewof microbiological, pharmacologic, and clinical data.Recognized experts, sponsors (pharmaceutical industry),and regulators participate in the process which includesdiscussions at public meetings of the CLSI Subcommitteeon Antimicrobial Susceptibility Testing that take placetwice a year. When establishing original breakpoints for
new agents, controlled clinical trial data are required
Role of CLSI in Revising Breakpoints in AntibioticResistance
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Follow the New GuidelinesCLSI 2010
Guidelines forcephalospins forEnterobacteriaceae inaccordance with the 2010
Clinical LaboratoryStandards Institute (CLSI)recommendations. Thefollowing changes will be
made to comply with theCLSI.
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Why do breakpoints sometimesneed to be revised?
Breakpoints need to berevised due to changingresistance mechanisms andbacterial population
distributions, changingscience leading to a betterunderstanding of thepharmacologic determinantsof clinical response, and
adoption of best practicesby clinicians.
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Enterobacteriaceae -Rapid Spread of resistance The rapid and disturbing
spread of:
extended-spectrum -lactamases
AmpC enzymes carbapenem resistance
metallo--lactamases
KPC and OXA-48 -
lactamases quinolone resistance
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What breakpoints were revised in 2010?
Select cephalosporin andaztreonam breakpoints
for Enterobacteriaceaewere revised as notedbelow (for comparison,the old breakpoints are
included):
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-lactamases capable of conferring bacterialresistance to the penicillin's
first-, second-, and third-generation cephalosporins aztreonam
(but not the cephamycins or carbapenems)
These enzymes are derived from group 2b -lactamases (TEM-1, TEM-2, and SHV-1) differ from their progenitors by as few as one AA
Extended-Spectrum -Lactamases
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Until 2000, most ESBL producers were hospital Klebsiella
spp. with TEM and SHV mutant -lactamasesNow, the dominant ESBLs across most of Europe and
Asia are CTX-M enzymes, which originated as genetic
escapes from Kluyvera sppCurrently recognized as the most widespread and
threatening mechanism of antibiotic resistance, both inclinical and community settings 80% of ESBL-positive E. coli from bacteraemias in the UK and
Ireland are resistant to fluoroquinolones 40% are resistant to gentamicin
CTCTX-M-type ESBLs X-M-type ESBLs
Livermore, DM J. Antimicrob. Chemother2009
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Agent
CLSI 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
Enterobacteriaceae: RevisedBreakpoints for Cephalosporins
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Agent Old (M100-S19) Revised (M100-S20)
S I R S I R
Cefazolin 18 15-17 14 NA NA NA
Cefotaxime 23 15-22 14 26 23-25 22
Ceftizoxime 20 15-19 14 25 22-24 21 Ceftriaxone 21 14-20 13 23 20-22 19
Ceftazidime 18 15-17 14 21 18-20 17
Aztreonam 22 16-21 15 21 18-20 17
S susceptible I Intermediate
R Resistant.
Disk diffusion breakpoints (mm):
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Agent M100-S19 M100-S20
S I R S I R
Cefuroxime 8 16 32 8 16 32
Cefepime 8 16 32 8 16 32
Cefotetan 16 32 64 16 32 64
Cefoxitin 8 16 32 8 16 32
S susceptible I Intermediate
R Resistant
Following MIC breakpoints were reevaluated forEnterobacteriaceae but were not revised
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Dr.T.V.Rao MD 41
Why were the breakpoints for cefepime andcefuroxime (parenteral) not revised?
The cefepime breakpointswere not revised based uponclinical trial data and PK-PD
evaluations. The clinical trialdata showed cefepimeefficacy for patients infectedwith isolates that testedcefepime susceptible (MIC8 g/ml), but produced anESBL
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Dr.T.V.Rao MD 42
Why are there no disk diffusion
breakpoints for Cefazolin?
Studies have not yet beencompleted to identify thezone diameter breakpointsthat correlate with the
revised MIC breakpoints forCefazolin. Initial studies didnot reveal clear zonediameter breakpoints anddisk diffusion testing of
Cefazolin may require a newdisk with alternate diskcontent.
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Cephalothin group
Cephalothin is nowclassified under Test/ReportGroup U forEnterobacteriaceae. Resultsfor cephalothin can be usedto represent activities ofseveral other oral FDA-approved agents fortreatment of urinary tractinfections which include
cefadroxil, cefpodoxime,cephalexin, and loracarbef.
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The ESBL testing recommendations were to be a shortterm solution to address a new mechanism of resistance.Subsequently, additional mechanisms of resistance havebeen identified (e.g., new types of ESBLs and AmpC-likeenzymes) and with increased frequency multipleenzymes are identified in a single isolate which cancomplicate ESBL testing (1). These issues coupled withimproved understanding of the PK-PD determinants of
efficacy with cephalosporins and monobactams resultedin the decision to revise the breakpoints.
Need for ChangingRecommendations
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The revised breakpoints eliminate the need toperform ESBL screen and confirmatory tests formaking treatment decisions. Phenotypic tests for ESBLdetection and confirmation are less accurate when
multiple enzymes are present (e.g., false-negative resultsoccur when isolates express both ESBLs and AmpC-typeenzymes) (13) and the presence of multiple enzymes aremore common in contemporary isolates (4, 8). The MIC of
an isolate correlates better with clinical outcome thanknowledge of resistance mechanisms (e.g., ESBLs)
Measuring the Revised Zones isAdvantageous
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