Dr.T.V.Rao MD
Dr.T.V.Rao MD
1
Introduction to Cephalosporins..
Cephalosporins were
first isolated from
cultures of
Cephalosporium
acremonium from a
sewer in 1948 by
Italian scientist,
Giuseppe Brotzu

The first agent cephalothin
(cefalotin) was launched
by Eli Lilly in 1964
Dr.T.V.Rao MD
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Cephalosporins ….

B-Lactam antibiotics ( similar to
penicillin's)
Broad spectrum in action.
Act by inhibition of cell wall synthesis
Bactericidal
Inactive against : enterococci, MRSA,
legionella , mycoplasma, chlamydia
spp.
Widely used in surgical procedures to
reduce the risk of post operative infections
Dr.T.V.Rao MD
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Antimicrobial activity of
Cephalosporins

 The site of action of beta-lactam antibiotics is the
penicillin binding proteins (PBPs) on the inner
surface of the bacterial cell membrane that are
involved in the synthesis of the cell wall
Cephalosporins are bactericidal agents
All bacterial cells have a cell wall that protects them.
Cephalosporins disrupt the synthesis of the
peptidoglycan layer of bacterial cell walls, which
causes the walls to break down and eventually the
bacteria die.
Dr.T.V.Rao MD
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Classification is based on
spectrum of activity

Cephalosporins are grouped
into "generations"
based on their spectrum
of antimicrobial activity.
The first cephalosporins
were designated first
generation while later,
more extended spectrum
cephalosporins were
classified as second
generation
cephalosporins.
So continued Generations
Dr.T.V.Rao MD
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Basis of Classification
…
 Each newer generation
of cephalosporins has
significantly greater
gram-negative
antimicrobial
properties than the
preceding generation
Fourth generation
cephalosporins,
however, have true
broad spectrum activity
Dr.T.V.Rao MD
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st
1
generation
Cephalosporins

First generation cephalosporins
are moderate spectrum
agents
Effective against gram +ve
aerobes
They are effective for treating
staphylococcal and
streptococcal infections and
therefore are alternatives
for skin and soft-tissue
infections, as well as for
streptococcal pharyngitis.
Dr.T.V.Rao MD
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The 1st generation
cephalosporins are:
Cefadroxil
Cephalexin
Cephaloridine
Cephalothin
Cephapirin
Cefazolin
Cephradine

Dr.T.V.Rao MD
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st
1
Generation

Active against G+ cocci ( except. Enterococci &
MRSA ):
s.pneumoniae, s.pyogenes,s. aureus,
S. epidermidis
Indicated for streptococcal pharyngitis ( e.g.
cephalexin)
Commonly used ( eg. Cefazolin) as prophylactic
for surgical procedures.
Modest activity against G- bacteria
Dr.T.V.Rao MD
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nd
2
generation
Cephalosporins

 Their antibacterial
spectrum is broader than
that of 1st generation
cephalosporins and
includes some gram -ve
pathogens
 They are also more
resistant to beta-lactamase
 They are useful agents
for treating upper and
lower respiratory tract
infections and sinusitis
Dr.T.V.Rao MD
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nd
2
generation cont...

These agents are also
active against E. coli,
Klebsiella and
Proteus, which makes
them potential
alternatives for
treating urinary tract
infections caused by
these organisms
Dr.T.V.Rao MD
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nd
2
Generation
Cephalosporins ..
Cefoxitin
Cefuroxime

Cefuroxime axetil
Cefaclor
Cefprozil
Dr.T.V.Rao MD
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rd
3
generation
Cephalosporins

They have an
extended
spectrum of
action against
gram -ve
organisms
Resistant to betalactamases
Dr.T.V.Rao MD
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rd
3
generation cont...

 The parenteral third
generation
cephalosporins
(ceftriaxone and
cefotaxime) have excellent
activity against most
strains of Streptococcus
pneumoniae, including
the vast majority of those
with intermediate and
high level resistance to
penicillin
Dr.T.V.Rao MD
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Third Generation Cephalosporins
Ceftriaxone
Cefotaxime
Ceftazidime
Cefoperazone
Cefixime

Dr.T.V.Rao MD
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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 in
neonates (interferes with bilirubin
metabolism )
Cefotaxime preferred in neonate ( does not
interfere with bilirubin metabolism ), as may
ceftriaxone.
Ceftazidime & cefoperazone have excellent
activity against P.aeruginosa.
Cefixime has similar activity to amoxicillin &
Cefaclor for actute otitis media
Dr.T.V.Rao MD
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th
4
generation
cephalosporins

 4th generation
cephalosporins are extended
spectrum agents with
similar activity against
gram-positive organisms as
first generation
cephalosporins.
 They also have a greater
resistance to beta-lactamases
than the third generation
cephalosporins.
 Many can cross blood brain
barrier and are effective in
meningitis.
Dr.T.V.Rao MD
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th
4
Generation
Cephalosporins...

Cefepime
Cefluprenam
Cefozopran
Cefpirome
Cefquinome
Dr.T.V.Rao MD
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Fourth Generation
Cefipime
Active against G+
bacteria > than
Cefazolin against s.
pyogenes,
S.pneumoniae but
lower against s.
aureus.
Similar to cefotaxime
against E.coli & K.
pneumoniae but < for
p. aeruginosa.

Dr.T.V.Rao MD
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Pharmacokinetic
consideration

 They are organic acids and are hydrophilic
 They generally have poor oral bioavailability as they
unstable in acid environments
 They are readily excreted by the kidneys, via tubular
secretion in the proximal convoluted tubule. This
results in high concentrations of the drug in urine.
 Exceptions are:
 Cephalexin which is stable in acid and so suitable for
oral dosing.
 Cefoperazone is excreted in bile rather than in urine.
Dr.T.V.Rao MD
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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 as
‘serious infections’
High safety profile
Dr.T.V.Rao MD
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Cephalosporins
 Emerging resistance
patterns

-Limitations
 III & IV generation
cephalosporins were
available only as
parenteral formulations
 Pharmacoeconomics
Dr.T.V.Rao MD
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Why detect ESBL producers?
 may:
ESBL producers
• Appear Sensitive to some
cephalosporins in vitro
• Show major inoculum effects
• Fail in therapy, despite appearing
susceptible
Dr.T.V.Rao MD
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Detection Strategy: step 1

Screen Enterobacteriaceae
with :
• Cefpodoxime- best general ESBL substrate
• Cefotaxime & ceftazidime- good substrates
for CTX-M & TEM/SHV, respectively
Spread of CTX-M into community means
screening must be wider than before
Dr.T.V.Rao MD
Ref http://www.hpa.org.uk
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Detection of ESBLs: step 2
Seek ceph/clav
synergy in ceph R
isolates

Double
disc
Combina
tion disc
Etest
Dr.T.V.Rao MD
Ref http://www.hpa.org.uk
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Double Disk Method

Dr.T.V.Rao MD
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Etest for ESBLs
Cefotaxime
Cefotaxime
+
Clavulanate
Dr.T.V.Rao MD
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Pitfalls in ESBL detection

• 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
Dr.T.V.Rao MD
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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
with TEM-24 in Belgium & France
 Sensitivity for weak ESBLs remains to be
proven
 Cefpirome & cefepime products need
comparison
Dr.T.V.Rao MD
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Bacteria not to test for ESBLs

Acinetobacter
–Often S to clavulanate alone
S. maltophilia
–+ve result by inhibition of L-2
chromosomal -lactamase,
ubiquitous in the species
Dr.T.V.Rao MD
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Role of CLSI in Revising Breakpoints in
Antibiotic Resistance

 Briefly, revising breakpoints involves systematic
review of microbiological, pharmacologic, and
clinical data. Recognized experts, sponsors
(pharmaceutical industry), and regulators participate
in the process which includes discussions at public
meetings of the CLSI Subcommittee on
Antimicrobial Susceptibility Testing that take place
twice a year. When establishing original breakpoints
for new agents, controlled clinical trial data are
required
Dr.T.V.Rao MD
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Follow the New
Guidelines CLSI 2010
 Guidelines for
cephalospins for
Enterobacteriaceae in
accordance with the
2010 Clinical
Laboratory Standards
Institute (CLSI)
recommendations. The
following changes will
be made to comply
with the CLSI.

Dr.T.V.Rao MD
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Why do breakpoints sometimes
need to be
revised?

 Breakpoints need to be
revised due to changing
resistance mechanisms
and bacterial population
distributions, changing
science leading to a better
understanding of the
pharmacologic
determinants of clinical
response, and adoption of
“best practices” by
clinicians.
Dr.T.V.Rao MD
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Enterobacteriaceae Rapid Spread of resistance

 The rapid and
disturbing spread of:
 extended-spectrum ßlactamases
 AmpC enzymes
 carbapenem resistance
 metallo-β-lactamases
 KPC and OXA-48 βlactamases
 quinolone resistance
Dr.T.V.Rao MD
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What breakpoints were revised in
2010?

 Select cephalosporin
and aztreonam
breakpoints for
Enterobacteriaceae
were revised as noted
below (for comparison,
the old breakpoints are
included):
Dr.T.V.Rao MD
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Extended-Spectrum βLactamases

 β-lactamases capable of conferring bacterial
resistance to




the penicillin's
first-, second-, and third-generation cephalosporins
aztreonam
(but not the cephamycins or carbapenems)
 These enzymes are derived from group 2b βlactamases (TEM-1, TEM-2, and SHV-1)
 differ from their progenitors by as few as one AA
Dr.T.V.Rao MD
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CTCTX-M-type ESBLs
X-M-type ESBLs

 Until 2000, most ESBL producers were hospital
Klebsiella spp. with TEM and SHV mutant βlactamases
 Now, the dominant ESBLs across most of Europe
and Asia are CTX-M enzymes, which originated as
genetic escapes from Kluyvera spp
 Currently recognized as the most widespread and
threatening mechanism of antibiotic resistance, both
in clinical 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
Dr.T.V.Rao MD
Livermore, DM J. Antimicrob. Chemother 2009
37
Enterobacteriaceae: Revised
Breakpoints for Cephalosporins

CLSI 2009
Agent
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
Dr.T.V.Rao MD
≥32
≤8
16
≥32
38
Disk diffusion breakpoints (mm):

 Agent






Cefazolin
Cefotaxime
Ceftizoxime
Ceftriaxone
Ceftazidime
Aztreonam
Old (M100-S19)
S
≥18
≥23
≥20
≥21
≥18
≥22
I
15-17
15-22
15-19
14-20
15-17
16-21
R
≤14
≤14
≤14
≤13
≤14
≤15
Revised (M100-S20)
S
I
R
NA
NA
NA
≥26
23-25 ≤22
≥25
22-24 ≤21
≥23
20-22 ≤19
≥21
18-20 ≤17
≥21
18-20 ≤17
 S – susceptible
 I – Intermediate
 R – Resistant.
Dr.T.V.Rao MD
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Following MIC breakpoints were reevaluated
for Enterobacteriaceae but were not revised

Agent
M100-S19
S
 Cefuroxime ≤8
 Cefepime ≤8
 Cefotetan ≤16
 Cefoxitin ≤8
M100-S20
I
R
S
I
R
16
16
32
16
≥32
≥32
≥64
≥32
≤8
≤8
≤16
≤8
16
16
32
16
≥32
≥32
≥64
≥32
 S – susceptible
 I – Intermediate
 R – Resistant
Dr.T.V.Rao MD
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Why were the breakpoints for cefepime
and cefuroxime (parenteral) not revised?

 The cefepime breakpoints
were not revised based
upon clinical trial data
and PK-PD evaluations.
The clinical trial data
showed cefepime efficacy
for patients infected with
isolates that tested
cefepime susceptible
(MIC ≤8 μg/ml), but
produced an ESBL
Dr.T.V.Rao MD
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Why are there no disk diffusion
breakpoints for Cefazolin?

 Studies have not yet been
completed to identify the
zone diameter
breakpoints that correlate
with the revised MIC
breakpoints for Cefazolin.
Initial studies did not
reveal clear zone diameter
breakpoints and disk
diffusion testing of
Cefazolin may require a
new disk with alternate
disk content.
Dr.T.V.Rao MD
42
Cephalothin group

 Cephalothin is now
classified under
Test/Report Group U for
Enterobacteriaceae.
Results for cephalothin
can be used to represent
activities of several other
oral FDA-approved
agents for treatment of
urinary tract infections
which include cefadroxil,
cefpodoxime, cephalexin,
and loracarbef.
Dr.T.V.Rao MD
43
Need for Changing
Recommendations

 The ESBL testing recommendations were to be a
short term solution to address a new mechanism of
resistance. Subsequently, additional mechanisms of
resistance have been identified (e.g., new types of
ESBLs and AmpC-like enzymes) and with increased
frequency multiple enzymes are identified in a single
isolate which can complicate ESBL testing (1). These
issues coupled with improved understanding of the
PK-PD determinants of efficacy with cephalosporins
and monobactams resulted in the decision to revise
the breakpoints.
Dr.T.V.Rao MD
44
Measuring the Revised
Zones is Advantageous

 The revised breakpoints eliminate the need to
perform ESBL screen and confirmatory tests for
making treatment decisions. Phenotypic tests for
ESBL detection and confirmation are less accurate
when multiple enzymes are present (e.g., falsenegative results occur when isolates express both
ESBLs and AmpC-type enzymes) (13) and the
presence of multiple enzymes are more common in
contemporary isolates (4, 8). The MIC of an isolate
correlates better with clinical outcome than
knowledge of resistance mechanisms (e.g., ESBLs)
Dr.T.V.Rao MD
45
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
Dr.T.V.Rao MD
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