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CEPHALOSPORINS

Teaching Basics
Dr.T.V.Rao MD

Dr.T.V.Rao MD 1
Cephalosporins
Cephalosporin discovery credited to
Brotzu in 1945 in sewer water off coast of
Sardinina
Several compounds isolated from mold
Acremonium chrysogenum with
cephalosporin C as basic nucleus for
future drugs
First introduced into clinical use in 1964
(cephalothin)
Dr.T.V.Rao MD 2
What are Cephalosporins
The cephalosporins
structurally related
to the penicillin's
consist of a beta
lactam ring
attached to a
dihydrothiazoline
ring. Substitutions of
chemical groups result
in varying
pharmacologic
properties and
antimicrobial activities .
Dr.T.V.Rao MD 3
History of Cephalosporins
Cephalosporin compounds were first isolated
from cultures of Cephalosporium acremonium
from a sewer in Sardinia in 1948 by Italian
scientist Giuseppe Brotzu. He noticed that these
cultures produced substances that were
effective against Salmonella typhi, Researchers
at the Sir William Dunn School of Pathology at
the University of Oxford isolated
cephalosporin C, which had resistance to
-lactamases but was not sufficiently potent for
clinical use.
Dr.T.V.Rao MD 4
Resembles Penicillin
The cephalosporin nucleus,
7-aminocephalosporanic acid (7-ACA),
was derived from cephalosporin C and
proved to be analogous to the penicillin
nucleus 6-aminopenicillanic acid.
Modification of the 7-ACA side-chains
resulted in the development of useful
antibiotic agents, and the first agent
cephalothin (cefalotin) was launched by
Eli Lilly in 1964.
Dr.T.V.Rao MD 5
How Cephalosporins work
Cephalosporins are bactericidal and have the same
mode of action as other beta-lactam antibiotics (such as
penicillins). Cephalosporins disrupt the synthesis of the
peptidoglycan layer of bacterial cell walls. The
peptidoglycan layer is important for cell wall structural
integrity. The final transpeptidation step in the synthesis
of the peptidoglycan is facilitated by transpeptidases
known as penicillin binding proteins (PBPs). PBPs bind
to the D-Ala-D-Ala at the end of muropeptides
(peptidoglycan precursors) to crosslink the
peptidoglycan. beta-lactam antibiotics mimic this site and
competitively inhibit PBP crosslinking of peptidoglycan.

Dr.T.V.Rao MD 6
Cephalosporins
Mechanism of action: binds to penicillin binding
proteins and inhibition of formation of cell wall
Mechanisms of resistance:
Changes in drug target of penicillin binding proteins -
methicillin-resistant Staphylococcus aureus
Lack of access of the drug to the penicillin binding protein
target
Efflux pumps MexAB-OprM efflux pump in Pseudomonas
aeruginosa
Decreased permeability of cell wall less common for
cephalosporins
Alteration of drug itself by hydrolysis by beta-lactamases
Numbers and types of beta-lactamases increasing
Can be chromosomally or extra-chromosomally (more easily
transmitted to other organisms) mediated

Dr.T.V.Rao MD 7
Cephalosporins
Resistance to one
cephalosporin can
result in resistance
others depending on
mechanism
Resistance to
cephalosporins can
confer resistance to
other beta-lactam
drugs like penicillins
as well Dr.T.V.Rao MD 8
Generation of Cephalosporins
Cephalosporin
drugs fall into five
classes or
generations. Each
subsequent
generation of these
drugs demonstrates
greater efficacy
against gram-
negative bacteria.

Dr.T.V.Rao MD 9
Cephalosporins
Divided into generations for convenience
but many drugs in same generation not
chemically related and different spectrum of
activity
Currently five generations of cephalosporins
but which generation a particular drug
belongs often a matter of debate
Generalization that with increasing generation activity in
vitro against Gram positive organisms decreases while
activity against Gram negatives increases (but an
oversimplification)
Dr.T.V.Rao MD 10
Usage of Cephalosporins in
Human Medicine
3rd and 4th generation cephalosporins used
in hospital setting in seriously ill patients for
serious and life-threatening diseases
Many of these diseases due to organisms
that reside in the gastrointestinal tract
Drugs of last resort for serious infections
due to food-borne pathogens Salmonella
and Shigella
These organisms may be resistant to other drugs
Quinolones may be effective but avoid in children due to
potential for toxicities
Dr.T.V.Rao MD 11
Important I st Generation
Cephalosporins
Cefacetrile (cephacetrile)
Cefadroxil (cefadroxyl; Duricef)
Cefalexin (cephalexin; Keflex)
Cefaloglycin (cephaloglycin)
Cefalonium (cephalonium)
Cefaloridine (cephaloradine)
Cefalotin (cephalothin; Keflin)
Cefapirin (cephapirin; Cefadryl)
Cefatrizine
Cefazaflur
Cefazedone
Cefazolin (cephazolin; Ancef, Kefzol)
Cefradine (cephradine; Velosef)
Cefroxadine
Ceftezole

Dr.T.V.Rao MD 12
Classification of Cephalosporin
Cefaclor
1. First generation Cephalosporins
Loracarbef Cefprosil
Cefazolin
Cephradine

Cephalexin

Cefadroxil Cefoxitin Na
Cefoperazone
Cefuroxime Na

Cefixime
Dr.T.V.Rao MD 13 Cefotetan
Disodium
Advantages of I st generation
Cephalosporins
Very active against Gram + ve cocci
Including penicillin senstive Pneumococci,
Viridians streptococci
Group A hemolytic streptococci
Staphylococcus aureus
Not useful against Enterococci, Methicillin
resistant Staphylococcus
Activity against H.influenzae, and Pencillin
resistant Streptococci is poor
Effective against gram ve as E.coli,Klebsiella
pneumonia, Proteus mirabilis
But not effective
Dr.T.V.Rao MD 14
Clinical uses
Orally useful in Urinary tract infection.
Intravenous preparations are useful in
surgical prophylaxis in clean cases
But 2nd and 3rd generation drugs are more
useful in colorectal surgeries and
Hysterectomy cases
Ist Generation drugs are not useful in
Meningitis.
Dr.T.V.Rao MD 15
Second Generation
Cephalosporins
The are heterogeneous group with
Individual differences
Against Gram Negative organisms as like
Ist generation Cephalosporins with
extended spectrum of activity against
Indole positive Proteus,
Klebsiella, Moraxella catarrhalis
Neisseria species
Dr.T.V.Rao MD 16
Effective against Anaerobes
Second generation
cephalosporins
with antianaerobial
activity
Cefmetazole
Cefotetan
Cefoxitin

Dr.T.V.Rao MD 17
Second generation Cephalosporins

Cefuroxime useful in H influenza including Beta


lactam producing strains
Lesser in activity against Serratia and B.fraglilis
Cefoxitin and Cefotetan active against B.fraglilis
Majority of 2nd generations are less active
against Gram + ve organism than Ist generation
compounds except cefuroxime
Not active against P aeruginosa

Dr.T.V.Rao MD 18
Classification of Cephalosporin
Second generation Cephalosporins

> have a greater Gram-negative


spectrum while retaining some activity
against Gram-positive cocci. They are
also more resistant to beta-lactamase.

Cefaclor (Ceclor, Distaclor, Keflor, Ranicl


Cefonicid (Monocid)
Cefprozil (cefproxil; Cefzil)
Cefuroxime (Zinnat, Zinacef, Ceftin, Biofur
Cefuzonam
Dr.T.V.Rao MD 19
Clinical Uses
2nd generation cephalosporins are more useful
in Beta lactamases producing H influenza,
Moraxella catarrhalis
Apart from Aerobic infections Cefoxitin,
Cefmetazole, and Cefotetan can be used to treat
mixed anaerobic infections, including peritonitis,
and diverticulitis
However it is proved that in life threating
infections better to choose alternative antibiotics
Cefoxitin and Cefotenan are useful as
prophylaxis in colorectal surgeries,vaginal or
abdominal hysterectomies and appendicitis ,
because of activity against B.fraglilis.20
Dr.T.V.Rao MD
Antipseudomonal activity

Cephalosporins
with
Antipseudomonal
activity
Cefoperazone
(Cefobid)
Ceftazidime
(Fortum, Fortaz)

Dr.T.V.Rao MD 21
Classification of Cephalosporin
Third generation
Third-generation Cephalosporins
cephalosporins have a broad spectrum of
activity and further increased activity against Gram-negative
organisms.

They may be particularly useful in treating hospital-acquired


infections, although increasing levels of extended-spectrum
beta-lactamases are reducing the clinical utility of this class of
antibiotics.
They are also able to penetrate the CNS, making them useful
against meningitis caused by pneumococci, meningococci, H.
influenzae, and susceptible E. coli, Klebsiella, and penicillin-
resistant N. gonorrhoeae.
Dr.T.V.Rao MD 22
Classification of
Cephalosporin
Third generation Cephalosporins
Cefcapene Cefixime (Suprax)
Cefdaloxime Cefmenoxime
Cefdinir (Omnicef, Cefdiel) Cefodizime
Cefditoren Cefotaxime (Claforan)
Cefetamet Cefpimizole

Cefpodoxime (Vantin,)
Cefteram Ceftiolene
Ceftibuten (Cedax) Ceftizoxime (Cefizox)
Ceftiofur Ceftriaxone (Rocephin)

Dr.T.V.Rao MD 23
Third Generation - Ceftriaxone
Lower Respiratory Tract Infections caused by
Streptococcus pneumoniae, Staphylococcus
aureus, Haemophilus influenza, Haemophilus
Parainluenza, Klebsiella pneumoniae,
Escherichia coli, Enterobacter aerogenes,
Proteus mirabilis or Serratia marcescens.
Acute Bacterial Otitis Media caused by
Streptococcus pneumoniae,
Haemophilus influenza (including beta-
lactamase producing strains) or
Moraxella catarrhalis (including beta-
lactamase producing strains).
Dr.T.V.Rao MD 24
Third Generation - Ceftriaxone
Skin and Skin Structure Infections caused
by Staphylococcus aureus,
Staphylococcus epidermidis,
Streptococcus pyogenes, Viridans group
streptococci, Escherichia coli,
Enterobacter cloacae, Klebsiella oxytoca,
Klebsiella pneumoniae, Proteus mirabilis,
Morganella morganii*, Pseudomonas
aeruginosa, Serratia marcescens,
Acinetobacter calcoaceticus, Bacteroides
fragilis * or Peptostreptococcus
Dr.T.V.Rao MD species.
25
Preferred in cases of UTI
Urinary Tract
Infections
(complicated and
uncomplicated)
caused by
Escherichia coli,
Proteus mirabilis,
Proteus vulgaris,
Morganella morganii
or Klebsiella
pneumoniae.
Dr.T.V.Rao MD 26
Third Generation Ceftriaxone
in Gonorrhoea's
Uncomplicated
Gonorrhoea
(cervical/urethral and
rectal) caused by
Neisseria gonorrhoea,
including both
penicillinase- and
nonpenicillinase-
producing strains, and
pharyngeal
gonorrhoea caused
by nonpenicillinase-
Dr.T.V.Rao MD 27
Third Generation - Ceftriaxone
Pelvic Inflammatory Disease caused
by Neisseria gonorrhea. Rocephin,
like other cephalosporins, has no
activity against Chlamydia
trachomatis. Therefore, when
cephalosporins are used in the
treatment of patients with pelvic
inflammatory disease and
C. trachomatis is one of the
suspected pathogens,
appropriate anti chlamydial
coverage should be added.
Dr.T.V.Rao MD 28
In Bacterial Septicaemia
Bacterial Septicaemia
caused by
Staphylococcus
aureus,
Streptococcus
pneumoniae,
Escherichia coli,
Haemophilus
influenza or Klebsiella
pneumoniae.
Dr.T.V.Rao MD 29
In Bone and Joint Infections
Bone and Joint
Infections caused by
Staphylococcus
aureus,
Streptococcus
pneumoniae,
Escherichia coli,
Proteus mirabilis,
Klebsiella
pneumoniae or
Enterobacter species.
Dr.T.V.Rao MD 30
Intra-Abdominal Infections
Intra-Abdominal
Infections caused by
Escherichia coli,
Klebsiella
pneumoniae,
Bacteroides fragilis,
Clostridium species
(Note: most strains of
C. difficle are
resistant) or
Peptostreptococcus
Dr.T.V.Rao MD 31
species.
In Meningitis
Meningitis caused by Haemophilus
influenza, Neisseria meningitidis or
Streptococcus pneumoniae. Rocephin has
also been used successfully in a limited
number of cases of meningitis and shunt
infection caused by Staphylococcus
epidermidis* and Escherichia coli.*
* Efficacy for this organism in this organ system
was studied in fewer than ten infections.
Surgical Prophylaxis
Dr.T.V.Rao MD 32
Classification of
Cephalospor in
4. Fourth generation Cephalosporins
Fourth-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
Cefozopran cephalosporins.
Cefpirome (Cefrom)
Many can cross the
Cefquinome
Cefclidine blood-brain barrier and are effective
Cefepime (Maxipime)in meningitis.
Cefluprenam They are also used against
Cefoselis
Dr.T.V.Rao MD
Pseudomonas 33
aeruginosa.
Fourth Generation -
Cefepime
FDA approved indications
Pneumonia (moderate to severe) caused by
Streptococcus pneumoniae , including cases
associated with concurrent bacteremia, Pseudomonas
aeruginosa , Klebsiella pneumoniae , or Enterobacter
species.
Empiric Therapy for Febrile Neutropenia Patients.
Uncomplicated and Complicated Urinary Tract
Infections (including pyelonephritis) caused by
Escherichia coli or Klebsiella pneumoniae , when the
infection is severe, or caused by Escherichia coli ,
Klebsiella pneumoniae , or Proteus mirabilis , when the
infection is mild to moderate, including cases
associated with concurrent bacteremia with these
microorganisms. Dr.T.V.Rao MD 34
Fourth Generation -
Cefepime
FDA approved indications
Uncomplicated Skin and Skin Structure
Infections caused by Staphylococcus
aureus (methicillin-susceptible strains
only) or Streptococcus pyogenes .
Complicated Intra-abdominal Infections
(used in combination with metronidazole)
caused by Escherichia coli , viridans group
streptococci, Pseudomonas aeruginosa,
Klebsiella pneumoniae, Enterobacter
species, or Bacteroides
Dr.T.V.Rao MD fragilis 35
Classification of
Cephalosporin
Ceftobiprole has been described as "fifth
generation" though acceptance
5. Fifth generation for this
Cephalosporins
terminology is not universal.

Ceftobiprole (and the soluble prodrug


medocaril) are on the FDA fast-track.

Ceftobiprole has powerful Antipseudomonal


characteristics and appears to be less
susceptible to development of resistance.

Dr.T.V.Rao MD 36
What are 5th generation
Cephalosporins
Fifth generation
cephalosporins were
developed in the lab to
specifically target
against resistant
strains of bacteria.
In particular,
ceftobiprole is
effective against
methicillin-resistant
Staphylococcus
aureus (MRSA).
Dr.T.V.Rao MD 37
Fifth Generation
Cephalosporin
5. Fifth generation Cephalosporins
Ceftobiprole has been described as "fifth
generation" though acceptance for this
terminology is not universal.
Ceftobiprole (and the soluble prodrug
medocaril) are on the FDA fast-track.
Ceftobiprole has powerful antipseudomonal
characteristics and appears to be less
susceptible to development of resistance.

Dr.T.V.Rao MD 38
FDA approves ceftaroline fosamil
On October 29th, FDA has approved Ceftaroline Fosamil under
the trade name Teflaro. Ceftaroline Fosamil (previously known by
the research code TAK-599, the parent drug, Ceftaroline is also
known as T-91,825) is an antibiotic indicated for the treatment of
adults with acute bacterial skin and skin structure infections
(ABSSSI) caused by susceptible Gram-positive and Gram-
negative microorganisms, such as Staphylococcus aureus
(including methicillin-susceptible and -resistant isolates),
Streptococcus pyogenes Streptococcus agalactiae,
Escherichia coli, Klebsiella pneumoniae, and Klebsiella
oxytoca, and also for the treatment of community-acquied
bacterial pneumonia (CABP) caused by susceptible Gram-
positive and Gram-negative bacteria, such as Streptococcus
pneumoniae (including cases with concurrent bacteremia),
Staphylococcus aureus (methicillin-susceptible isolates
only), Haemophilus influenzae,
Dr.T.V.Rao MD Klebsiella pneumoniae,
39
Klebsiella oxytoca, and Escherichia coli.
Ceftaroline is modified from cefozopran
Ceftaroline was developed by
modifying the structure of the
fourth-generation cephalosporin
cefozopran The prodrug,
ceftaroline fosamil, which
contains a phosphono group to
increase water solubility, is
rapidly converted in plasma into
the bioactive agent, ceftaroline
The 1,3-thiazole ring attached
to the 3-position of the
cephalosporin nucleus and the
oxime group in the C7 acyl
moiety are responsible for the
enhanced anti-MRSA activity
observed with ceftaroline.
Dr.T.V.Rao MD 40
Advantage of Ceftaroline
Ceftaroline is an
injectable
cephalosporin active
against MRSA & MSSA
[ & RTI pathogens]
It is approved for use
in cSSSI & CABP
Its use may be
extended when
combined with NXL
104 to include ESBL
+ve GNB strains
It is inactive against Non
fermenters GNB &
Carbapenemases Dr.T.V.Rao MD 41
producers.
Fifth generation Ceftobiprole

Ceftobiprole has been


described as "fifth
generation",] though
acceptance for this
terminology is not universal.
Ceftobiprole (and the
soluble prodrug
medocaril) are on the FDA
fast-track. Ceftobiprole
has powerful
Antipseudomonal
characteristics and
appears to be less
susceptible to
development of
resistance.
Dr.T.V.Rao MD 42
CLSI puts on the list of unnamed
class
Currently,
ceftaroline and
ceftobiprole are on
an unnamed
subclass of
cephalosporins by
the Clinical and
Laboratory
Standards
Institute (CLSI).
Dr.T.V.Rao MD 43
5th generation cephalosporins are not ultimate
solutions for antibiotic resistance
Antimicrobial stewardship programmes can be
implemented to reduce inappropriate use of
antimicrobials, thereby controlling the
development of resistance. These
programmes are also useful in limiting toxicity
and overgrowth of pathogenic organisms such
as C. difficile. Typical stewardship
programmes target antimicrobials that pose a
risk of development of resistance, are
associated with significant toxicity, require
therapeutic drug monitoring, have the potential
to select for pathogenic
Dr.T.V.Rao MD organisms or
44 have a
high cost.
Conclusions
Cephalosporins one of most widely
used drug classes in the US and
worldwide
Mechanisms of resistance to
cephalosporins may confer resistance
to other beta-lactam agents
Ranking of 4th generation
cephalosporins as highly important
and 3rd generation agents as critically
important in Guidance 152; both
critically important in WHO criteria
Dr.T.V.Rao MD 45
Programme Created by
Dr.T.V.Rao MD for Medical and
Paramedical Students in the
Developing World
Email
doctortvrao@gmail.com

Dr.T.V.Rao MD 46