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 2
 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 3
 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 4
 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 5
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 6
 1 st
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 7
 The 1st generation
cephalosporins are:
Cefadroxil


Cephalexin
Cephaloridine
Cephalothin
Cephapirin
Cefazolin
Cephradine
Dr.T.V.Rao MD 8
 1 st 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 9
 2 nd
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 10
 2nd 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 11
2 nd Generation Cephalosporins
..


Cefoxitin
Cefuroxime
Cefuroxime axetil
Cefaclor
Cefprozil

Dr.T.V.Rao MD 12
 3 rd
generation
Cephalosporins


They have an
extended spectrum
of action against
gram -ve
organisms
Resistant to beta-
lactamases
Dr.T.V.Rao MD 13
 3 rd 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 14
 Third Generation Cephalosporins

Ceftriaxone
Cefotaxime
Ceftazidime
Cefoperazone
Cefixime

Dr.T.V.Rao MD 15
 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 16
 4 th
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 17
 4 th
Generation
Cephalosporins...


Cefepime
Cefluprenam
Cefozopran
Cefpirome
Cefquinome
Dr.T.V.Rao MD 18
 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 19
 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 20
 Why Cephalosporins are Widely
Prescribed Antibiotics
Broad spectrum of

activity
Stability to β-lactamase
Oral and parenteral preparations
Widely accepted
Treats ‘day to day’ as well as
‘serious infections’
High safety profileDr.T.V.Rao MD 21
 Cephalosporins
-Limitations
 Emerging resistance


patterns

 III & IV generation

cephalosporins were
available only as
parenteral formulations

 Pharmacoeconomics

Dr.T.V.Rao MD 22
 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 23
 Detection Strategy: step 1

with :
Screen Enterobacteriaceae
• 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 24
 Detection of ESBLs: step 2


Seek ceph/clav
synergy in ceph R
isolates
Double
disc
Combinati
on disc
Etest
Dr.T.V.Rao MD Ref http://www.hpa.org.uk 25
Double Disk Method

Dr.T.V.Rao MD 26
 Etest for ESBLs
Cefotaxime

Cefotaxime
+
Clavulanate
Dr.T.V.Rao MD 27
 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 28
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 29
 Bacteria not to test for ESBLs

Acinetobacter
–Often S to clavulanate alone
S. maltophilia
–+ve result by inhibition of L-2
chromosomal β-lactamase,
ubiquitous in the species
Dr.T.V.Rao MD 30
 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 31
 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 32
 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 33
 Enterobacteriaceae -
Rapid Spread of resistance
 The rapid and disturbing

spread of:

extended-spectrum ß-
lactamases

AmpC enzymes

carbapenem resistance
 metallo-β-lactamases
 KPC and OXA-48 β-
lactamases

quinolone resistance

Dr.T.V.Rao MD 34
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 35
 Extended-Spectrum β-
Lactamases


 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 β-
lactamases (TEM-1, TEM-2, and SHV-1)

differ from their progenitors by as few as one AA
Dr.T.V.Rao MD 36
CTCTX-M-type ESBLs X-
M-type ESBLs


 Until 2000, most ESBL producers were hospital Klebsiella
spp. with TEM and SHV mutant β-lactamases
 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 37
Livermore, DM J. Antimicrob. Chemother 2009
 Enterobacteriaceae: Revised
Breakpoints for Cephalosporins
CLSI 2009
CLSI 2010
Agent

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
Dr.T.V.Rao MD ≤8 16 ≥32
38
 Disk diffusion breakpoints (mm):


 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.

Dr.T.V.Rao MD 39
Following MIC breakpoints were reevaluated for
Enterobacteriaceae but were not revised


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

Dr.T.V.Rao MD 40
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 41
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., false-negative 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 46