Download Penicillin

PENICILLINS
CEPHALOSPORINS & OTHER
β-LACTUM ANTIBIOTICS
Dr. Rajendra Nath
Professor
PENICILLINS CEPHALOSPORINS &
OTHER β-LACTUM ANTIBIOTICS
• Useful & frequently prescribed AM
agents .
• Share a common structure & mech.
of action i.e. – inhibition of synth. of
the bact. peptidoglycan cell wall .
PENICILLINS CEPHALOSPORINS &
OTHER β-LACTUM ANTIBIOTICS
• β- lactums - include Cephalosporin
antibiotics which are classified by
generations .
PENICILLINS CEPHALOSPORINS &
OTHER β-LACTUM ANTIBIOTICS
• β- lactamase inhibitors e.g.Clavulanate , Sulbactum etc. are
used to extend the spectrum of
Penicil. against β- lactamase prod.
organisms.
PENICILLINS CEPHALOSPORINS &
OTHER β-LACTUM ANTIBIOTICS
• Other β- lactums include –
- Carbapenems including Meropenem
& Imipenem which have broadest AM
spect. of any antibiotics .
• Monobactums – e.g.- Aztreonam has
G-ve spect. resembling that of Amino
-glycosides .
PENICILLINS CEPHALOSPORINS &
OTHER β-LACTUM ANTIBIOTICS
Bact. resist. against the β- lactum
antb.s continues to ↑at high rate.
Mech. - by β –lactamase that destroy the antb
- alteration in or acquisition of novel
penicil. binding proteins ( PBPs) .
- Decreased entry & / or efflux of antb.s
.
PENICILLINS
-One of the most important gp of
antibiotics.
- However numerous other AM agents
have been prod. since the first penicil.
become available.
- These are still used widely & many of
these are currently the DOC for a
large no. of infectious diseases .
PENICILLINS
- In 1928 in laboratory of St mary’s
hosp. London , A. Fleming observed
that a mold contaminating one of the
bact. cultures caused the bact. in its
vicinity to undergo lysis. Because the
the mold belonged to the genus
Penicillium , Fleming named the antb.
PENICILLINS
substance as Penicillin .
Chemistry :
Basic struct. consists of
1. Thiazolidine ring (A) connected to
2. β- lactum ring (B) to which attach
3. Side chain (R) .
PENICILLINS
O
R C
2
S
NH
CH
CH
B
O= C
Amidase
CH3
C
A
N
1
CH3
CH COOH
Penicillin
Penicillinase site of action
PENICILLINS
A. Thiazolidine ring
B. β- lactam ring
1. Site of action of penicillinase
2. Site of action of amidase
PENICILLINS
- The penicillin nucleus itself is the
chief struct. requirement for biologic.
activity . Metabolic transformation/
chem. alteration of this portion of the
mol. causes loss of all sig. AB activity
- Side chain determine many of the AB
& pharmacol. character of a particular
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type of Penicillin.
- Penicil. G ( benzyl penicil. ) has the
greatest AM activity of these & is the
only natural penicil. used clinically.
Semi-synthetic Penicillins :
It has been discovered that 6- aminopenicillanic acid could be obtained from
PENICILLINS
cultures of P. chrysojenum lead to the
dev. of the semi-synth. Penicil.s .by
adding different side chains in this .
-6-aminopenicillanic acid is now prod.
in large quantities with the aid of the
amidase from P. chrysojenum .
PENICILLINS
Unitage of Penicillin :
- one Int. unit ≡ 0.6 μg of the cryst. sod.
salt of Penicil. G.
-1mg of pure Penicil. G ≡ 1667 units.
Mech. of Penicillins :
-The cell walls of bact. are essential for
their normal growth & development.
PENICILLINS
- Peptidoglycan is a heteropolymeric
component of the cell wall that
provides rigid mech. stability .
- Cell wall is 50-100 mols thick in G+ve
& ½ molecule thick in G-ve bacteria .
- Peptidog. is composed of glycan
chains having linear strands of two
PENICILLINS
alternating amino sugar (N-acetyl –
glucosamine & N- acetyl muramic acid)
& they are cross-linked by peptide
chain .
Biosynth. of Peptidoglycan :
involves three stages
PENICILLINS
Final stage involves completion of the
cross link .This accomplished by a
transpeptidation react. that occurs outside
the cell memb.( with the help of
Transpeptidase enz. which is memb.
bound ). These enz.s & related proteins
are now called as Penicillin Binding
Proteins ( PBPs).
PENICILLINS
It is this last step in peptidoglycan
synth. that is inhibited by the β- lactum
antb.s & glycopeptide antb.s
(e.g.Vancomyc.)
PENICILLINS
- Main target for the action of penicil.s
& cephalosporins are these
Penicil. Binding Proteins (PBPs) .All
bact. have such entities e.g.- E .coli
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has 7 & S. aureus has 4 PBPs .
The PBPs vary in their affinity for diff.
β – lactum antb.s , although interact.
become covalent .
- ↓ of transpept.( PBP-I) causes formation of
spheroplast & rapid lysis.
- ↓ of PBP-II & III ( Carboxypeptidase &
endopeptidase enz.s) cause delayed lysis
or production
PENICILLINS
of spherical cells & large filamentous
form of bacterium.
Penicil.↓ synth. of cell wall & thereby
expose the org.s to the lethal external
environment which is not matching
with internal osmotic –pressure &
bact . swells & lysis occurs .
PENICILLINS
Death of the bact. also occurs due to
activation of autolysing enz.s called
autolysins or murein -hydrolase .
-Lethality of penicil. involve both lysis
or nonlytic mech.
PENICILLINS
Mech. of bact . Resist. to penicillin
( & Cephalosporins ) :
1.Micro-org may be intrinsically resist.
because of structural diff. in the PBPs
that are the targets of these drugs
(A sensitive strain may acquire resist.
of this type by the dev. of high mol.
PENICILLINS
wt. PBPs that have ↓ affinity for the
antb. e.g.- Penicil. resistance in
Streptococcus gp. emerged
as a result of replacement of its PBPs
with resist. PBPs from S. pneumoniae.
PENICILLINS
2. Other way of bact. resist. is caused
by the inability of the agent to
penetrate to its site of action e.g.G-ve bact.
PENICILLINS
- in G+ve bact . the peptidoglycan
polymer is very near the cell surface ,
some G+ve bact. have polysacch.
capsule that are external to the cell
wall but they are not the barrier to the
diffusion of β- lactums .
PENICILLINS
-
In G-ve bact. the inner memb. is
analog. to the cytoplasmic memb.
of G+ve bact. & is covered by outer
memb. of Lipopolysaccharide &
capsule ,it functions as a
impermeab. barrier for some antb.s
PENICILLINS
Some small hydrophilic antb.s diffuse
through aqueous channels in the out.
memb. that are formed by protein
called porins .
-Broad spect. Penicil.s e.g. – Ampicill.
& Amoxycill. & most of the Cephalosporins diff. through the pores in the
PENICILLINS
E.coli outer memb. more rapidly than
can Penicill. G ( the no. & size of the
pores vary e.g.- Pseudomonas aeru.
lack the classical high permeability
porins .)
3. Active efflux pumps serve as another
mech. of resist. removing the antb.s
PENICILLINS
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from its site of action before it can act
e.g.-β- lactum resist. in P.aerug. ,E.coli
& N. gonorrheae .
4.Bact. can also destroy β- lactum antb.
enzymatically by β- lactamases which
inactivates certain of these antb.s .
PENICILLINS
-diff. micro-orgs elaborate a no. of
distinct β- lactamase which often are
described as Penicillinases or Cepha linases . These are grouped into 4
clases ( A-D) .
- Class A β- lactamases include the
extend. spect. β –lactamases which
PENICILLINS
degrade Penicil.s , some Cephalospor.
and in some instances ,Carbapenems.
-Class B: β-lactamases are Zn++ dep.
enz. that destroy all β- lactams except
Aztreonam .
- Class C: β- lactamases are active
against Cephalosporins.
PENICILLINS
-Class D : include Cloxacillin deg. enz.s
- G+ve bact. prod. & secrt. a large
amount of β- lactmases . Most of these
are Penicillinases . The information for
Staphylococcal penicillinase is encoded
In a plasmid & this may be transferred
by bacteriophage to other bact.
PENICILLINS
-
-
In G-ve bact. β-lactamases are
found in relatively small amounts .
they are encoded either in chromos.
or in plasmids & may be constitutive
or inducible .
The plasmids can be transferred
between bact. by conjugation .
PENICILLINS
-
-
Other factors : micro-org.s adhering
to implanted prosthetic devices
( e.g.- catheters , artific. Joints ,
prosth. heart valves etc.) prod.
biofilms & are much less sens. to
antb.s .
The presence of proteins & other
PENICILLINS
constituents of pus, low pH or low
oxyg. tension does not appreciably
↓ the ability of β-lactum antb.s to kill
bact. However bact. that survive
inside visible cells of the host gener.
are protected from the action of the
β- lactum antb.s .
PENICILLINS
Classification :
According to their spectrum of AM act.
I Narrow spectrum
A. Penicillinase sensitive
i) Penicillin G ( parenteral ) – highly
active against sensitive strains of
G+ve cocci hydrolyzed by
PENICILLINS
penicillinase , not effective against
most strains of S. aureus e.g.-Crystalline or Benzyl Penicil. or
Penicil. G.
- Procaine Penicil.
- Benzathine Penicil.
ii) Phenoxy methyl Penicil. or Penicil. V
PENICILLINS
( orally active )
B. Penicillinase resist. Penicil. -e.g.Methicillin , Naficillin , Cloxacillin
Oxacillin , Flucloxacillin etc.
have less potent AM activity against
micro-org. sensitive to Penicil. G .
but agent of first choice for
PENICILLINS
penicillinase prod. S. aureus & S. epid
-ermidis .
C. Penicillinase inhibitors .
e.g.- Clavulanic acid ( comb. with
Amoxycil.)
- Sulbactum ( + Ampicillin )
- Tazobactum ( + Piperacillin)
PENICILLINS
They are given with broad spectrum
antb.s to prevent hydrolysis by broad
spect. β- lactamases ( in G-ve bact.
e.g. E.coli .)
II Broad spect. Penicillins :
A. Carboxypenicil. e.g.- Carbenicillin
Carbenicil. Indanyl ,Ticarcillin .
PENICILLINS
their AM activity is extended to include
Pseudomonas , Enterobacter &
Proteus gp. (inferior to Ampicil.against
G+ve cocci & L.monocytogenes &
less active than Piperacil. against
Pseudomonas.& also known as antiPseudomonal penicillins )
PENICILLINS
B. Aminopenicillins : e.g.- Ampicillin ,
Amoxycillin, etc.. They are also
effective against G- ve org.s e.g. –
H. influenzae , E. coli , Proteus mira bilis . etc. . But they are sensitive to
penicillinase enzyme. (They are used
now with β- lactamase inhib.s e.g. Clavulanic acid
which further extends their spectrum )
PENICILLINS
C. Uriedopenicillins ( extended spect.
penicil.) : e.g.- Azlocillin , Mezlocillin
& Piperacillin .
Excellent activity against
Pseudomonas ,Klebsiella & other
G-ve org.s
PENICILLINS
Pharmacological propert. in general:
- Following abs. of orally administered
penicil. these agents are distributed
widely through out the body.
- Therapeutic conc. attain readily in
tissues & in secret. e.g. joint fluid ,
pleural fluid ,pericardial fluid & bile
PENICILLINS
-Low conc. in prostatic fluid ,brain
tissue ,intra-ocular fluid & in CSF (conc
of penicil. is < 1% of those in plasma ,
but in inflammed meninges conc. may
↑ upto 5% of plasma ) .
- Eliminated rapidly by glomerular filtr.
& renal tubular secrt. (t½ -30-90 min.)
PENICILLINS
Penicil.G & Penicil. V :
The AM spect. of penicil. G &V are
very similar for aerobic G+ve microorg. (but penicil. G is 5-10 times more
active against Neisseria sp. & against
certain anaerobes). They are narrow
spect. & enz. sens. Penicil.s
PENICILLINS
Spectrum :
effective against Pneumococci.
streptococci, Meningococci , non βlactamase prod. gonococci & staphy.
(> 90% strains of staphyl. Isolated
from individuals inside or outside
hospitals are now resist.)
PENICILLINS
- Treponima pallidum , bacil. anthracis
& vast majority of strain of C. diphther.
are senst. but some are resist.
- Actinomyces , Clostridium sp.
(anaer. micro-org.) are highly senst.
PENICILLINS
( Bact. fragilis is exception ) .
- None of the Penicil.s are effective
against Amoeba , Plasmodium ,
Rikettsia , fungi or viruses .
Absorption : Oral about ⅓rd of oral dose is absorbed
in favorable cond. not destroyed by
PENICILLINS
gastric juice ( 2/3rd destroyed by GJ) .
Penicil. V is more stable in acid hence
better absorbed .
-Food may interfere with abs. of all Penicil.s
-Parenteral – after I.M. inj. peak conc.
of Penicil.G reached with in 15-30
mins .
PENICILLINS
( vol. declines as half life of Penicil. G
is 30 mins ) . Different measures are
there to prolong its existence in body
e.g.
1. Repository prep. -Procain Penicil.
& Benzathine Penicil. they release
PENICILLINS
penicil. G. slowly from the area in
which they are injected & prod. relativ.
low but persistent conc. of antb. in
blood .
Penicil.G. Procaine susp. is an aquous
prep. of the crystalline salt ( H/S test
is done by I.D. test of 0.1 ml of proc.)
PENICILLINS
-
It is a painless inj.
Benzath. Penicil. susp. of the salt
obtained by the comb. of 1 mol. of
an ammonium base & 2 mol. of
penicil. G. . The long persistence of
penicil. conc. in blood after I.M. inj.
reduces cost , need for repeated inj.
PENICILLINS
and local trauma.
benz. penicil. has got longest duration
of detectable antb. A dose of 1.2 mill.
unit I.M. → conc. of 0.09 μg/ml on the
1st , 0.02 μg/ml on 14th & 0.002 μg/ml
on 32nd day (avg. duration is 26 days)
2. Use of Probenecid that blocks renal
PENICILLINS
tubular secr. of penicil. & thus exct. ,is
also used to increase the dur. of action
- It also ↑ the conc. of penicil. in CSF
as it does not readily enter the CSF
normally (increase abs. in meningitis)
- Penicil. is secrt. rapidly from the CSF
into blood stream by an active
PENICILLINS
transport process & probenecid compe
-titively ↓ this transport & thus↑ the
conc. of penicil. in CSF.
Excretion :
Penicil. G. is eliminated rapidly from
the body mainly by the kidney ,but
small part in the bile & other routes .
PENICILLINS
Therapeutic Uses :
1.Pneumococcal inf.-Penicil. G (DOC)
-Pneumococcal Pneumonia –
(Penicil. G- 24 million U daily
Penicil. V – 500 mg orally 6 hrly).
-Pneumococ. mening. – until it is
established that penicil.G .is sens.
PENICILLINS
it is treated with Vancomycin + III gen
Cephalosporin ( if sensitive - penicil. G is
given -20-24 mill. U/day x 14 days)
2. Streptococ. Inf. – in scarlet fever
( Streptococ. pharyngitis ) –
penicil. V. -500 mg 6 hrly x 10 days
penicil. G. – 6 lacks U OD x 10 days
PENICILLINS
or single inj. of Benz. Penicil. 1.2 mill U stat.)
also effective in –Streptococcal
pneumonia , arthritis , meningitis &
endocarditis .
3. Inf. with Anaerobes :
mixt . of org.s most are sens. to
penicil. G. exception is B. fragilis gp.
,
PENICILLINS
-Penicil.G. + Metronidazole or Chlora
- mphenicol .
4. Staphylococ inf. – penicil. resist
penicil. e.g.Naficillin or Oxacillin
5. Meningococ. Inf. – Penicil G. ( DOC)
given I.V. high dose
PENICILLINS
6. Gonococ. Inf. – resist. to penicil. G
& they are no longer the therapy of
choice ( IIIgen. Cephalosporins Ceftriaxone is given ) .
7. Syphilis –
penicil.G. is highly effective in primary,
second. & latent syphilis of < 1 y dur.
PENICILLINS
(Proc. Penicil. -2.4 mill. U /day I.M. + Probenecid
1 gm/ day orally x 10 days or
Benz. Penicil. G. 2.4 mill. U I.M. 1 -3 weekly ).
Pts with late latent syph., neurosyph ,
cardiovas. syph. – 20 mill. U of penicil G.
daily x10 days (child.-50,000 U/kg of Penicil. G
. in two div. doses.)
PENICILLINS
most pts dev. Jerisch Herxheimer reac.
(several hrs after the 1st inj of penicil. G) Chills with fever, headach, myalgia &
arthralgia may dev. & syph. lesion
may become more prominent . It fades
with in 48 hrs & does not recur with 2nd
PENICILLINS
inj. ( due to Spirochaetal antigens ).
8. Actinomycosis – Penicil. G. – DOC
( 12 -20 mill. U I.V. /day x 6 wks)
9. Diphtheriaspecific antitoxin (antidiphtheritic serum)
is the only effective tt. however penicil. G
eliminate the carrier state -
PENICILLINS
( Proc. Penicil. 2-3 mill. U / day x 10-12 days.)
10. Anthrax -now resist. in most of the cases
11. Clostridial inf. – penicil. G. is DOC in
(i) Gas gangrene (by C.perfringens,12-20
mill. U/day), debridement of inf. area is
necessary apart from the drug .
(ii) No effect on ultimate outcome of
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Tetanus ( C. tetani ) ,hence tetanus immunoglob.
(ATS ) is indicated along with debridement of
dead tissue + Penicil G (10-20 mill. U /day I.M.) to
eradicate the bact.
- Fusospiroch. Inf. - Gingivo-stomatitis
e.g.-Trench mouth (Penicil. V.-500 mg 6 hrly x7 d)
12. Rat bite fever : by Spirillium minor senst. to
penicil.( G -12-15 mill. U/d x 3-4 wks)
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13. Listeria inf. – Ampicillin 1-2 gm 4
hrly. ( +Gentamycin in immuno -comp. host &
pt with meningitis.) & penicil.G(15-20 mill.
U/d) are DOC.
14. Erysepilas –Pasteurella multocida wound inf. after dog / cat bite .
senst. to penicil. & Ampicil.s
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Prophylactic use – was effective in
previous inf.s but still used in
1. Streptococcal inf. & cases of deep
burn.
Single inj. of Benz. Penicil.-1.2 mill.U
2.Recurence of Rheumatic fever –
oral –penicil. V or
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Benz. Penicil. G – (1.2 mill. U once a
month.)
3. Syphilis – prophyl. for contacts .
4. Surg. procedure in pts with valvular
heart dis.( Dental extractions ).
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2. Penicillinase resist penicil.:
This type of penicil. is resist. to
hydrolysis by Staphy. penicillinase
(their use should be restricted to the
tt of inf. which are caused by staphy.
that secrete this enz.)
-these are less sens. than is penicil. G
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against other penicil. senst. micro-org
-Methicil. resist. micro-org.s are
resist. to all the penicil. resist.Penicil.s
& Cephalosp.s .
-Hospital acquired inf. are also resist to
these penicil.
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e.g.Isoxazolyl Penicil.:
Oxacillin , Cloxacillin & Dicloxacillin –
-These are congeneric semi –synth.
Penicil.s .
- These are similar pharmacologically,
abs. adequately after oral administ.
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( abs. is more effective on empty
stomach) .
Naficillin :
This semisynth. Penicil. is highly resist.
to penicillinase & effective against inf.
caused by penicillinase prod. strains
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of S. aureus .
- abs. in GIT is irregular ( inactivated
in acid medium ) therefore given
parenteraly ( 1 gm I.M. ) .
- conc. of drug is adequate in CSF for
the tt of S. meningitis .
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Aminopenicillins :
Ampicillin , Cloxacillin & their cong.s
- these are known as broad spect. antb
have similar AM activity .
-they all are destroyed by β- lactamase
- they are bactericidal for both G+ve &
G-ve bact.
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- N. gonorrhoeae , E. coli , P. mirabilis,
Salmonella & Shigella were highly
senst. to these when they are first
used but now resist. is increasing.
(Pseudomonas & Klebsiella are
resist.)
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( however concurrent administ. of a βlactamase inhib. e.g.- Clavulanate or
Sulbactum markedly expands the
Spect. of activity of these drugs )
dose – 500mg QID or 0.5 – 1 gm sod.
Ampicil. Inj. I.M. ( adjustment
is req . in cases of renal dysf.)
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Amoxycillin :
- abs. is more complete & rapid than
Ampicil. & stable in acid & given
orally.
- spect. similar ( except less senst. in
Shigellosis )
- food does not interfere with abs.
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- Incidence of diarrhea is less
- Effective conc. of orally administ.
Amoxy. are detectable in plasma
twice as long as with Ampicil.
- Probenecid delays exct. of drug .
Uses -1. URTI against S. pyog. & S.
pneumonia & H. influenzae .
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-effective for sinusitis , otitis media &
acute exacer. of chr. Bronchitis &
epiglottitis
- Addition of β –lactamase inhib.
( Amoxy + Clavulanate & Ampicil +
Sulbactum ) extends the spect. to
H. influenzae & enterobacteriaceae.
PENICILLINS
2. UTI
3. Meningitis – not alone but in comb.
with Vancomycin + 3rd gen. cephalo.
4. Salmonella inf. – bacteremia &
enteric fever ( Typhoid) synd.
respond well to these . Fluoroq. ,
/ Ceftriaxone are DOC but Trimeth.
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+ Sulfamethoxazole or high doses of
Ampicil. also are effective ( 12 gm/d for
adults) .
Antipseudomonal Penicil.s :
Carboxypenicillins – e.g.Carbenicillin ,Carbenicillin indanyl
( indanyl ester of carbenicilin which
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is acid stable & used orally) &
Ticarcillin .
- They are active against some
strains of Pseudomonas aeruginosa
& certain sp. of Proteus ( that are
resist. to Ampicil.& congener ).
- Hypokalemia may occur.
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Ureidopenicillins :
e.g.- Mezlocillin & Piperacillin have
superior activity against P.aerug.
- they are also used against Klebsiella
- they are senst. to destruction by β –
lactamases .
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(In comb. with a β – lactamase
inhib. Piperacil. &Tazobactum has
the broadest AM spect. of the
penicil.s )
Uses – serious inf. caused by G-ve
bacteria.
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( esp. in pts of impaired immuno logical defenses & inf.s acquired in
hospitals)
so greater use in bacteremias ,Pneum.
inf. following burns & UTI .
( in neutropenic pts )
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Side effects :
1. Hypersenst. React. – they are the
most common ADRs noted in
penicil.s & most comm. cause of
drug allergy – include
maculopap. rash ,urticarial rash
fever , bronchospasm ,vasculitis
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serum sickness ,exfol. dermatitis,
St. Johnson’s synd. & anaphylaxis.
- It may occur with any dosage form
of penicil.
- Cross allergy occur between diff. gps. of
penicil.s
(occurrence of untoward effects does not
necessarily imply repetitions on
PENICILLINS
.)
- H/S react. may appear in the
absence of a previous known
exposure to drugs
(may be due to prev. unrecognized exposure to
subsequent exposure
penicil. in the environment e.g.- foods of animal
origin or from the fungus prod. penicil.)
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- Although H/S clears after stopping
antb. but may persist for 1-2 wks or
longer after therapy has been
stopped .
- In few instances , it is necessary to
stop the future use of penicil.
PENICILLINS
because of risk of death ( pts should
be warned for this).
Mech.penicil. & their breakdown prod.s act
as haptens after covalent react. with
proteins . major breakdown moiety is
penicilloyl moiety which is the major
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determinant moiety ( MDM) .
- IgE med. react. occur due to MDM
( in 25% other breakdown prod.s are
responsible)
- The most serious H/S react.s are
angioedema ( marked swelling of
lips , tongue ,face, peri-orbital tissue
PENICILLINS
frequently accomp. by asthamatic
breathing.)
- H/S react. can occur with small testing
dose ( intradermal inj. )
2. Serum sickness :
mild fever , rash , leukopenia ,
arthralgia ,purpura, lymphadenopathy
PENICILLINS
spleenomegaly, mental changes ,ECG
abnormalities , albuminuria ,hematuria.
It is mediated by IgG antibodies.
( it occurs when penicil. is continued for a wk or
more but is rare ).
- fever may be the only symptom
- eosinophilia & rarely int. nephritis
PENICILLINS
Management :
- pts history is most practical.
- Intradermal test
-Desensitization is recomm.. Low dose
penicil. in ICU ( 1, 5, 10, 100 & 1000
Unit / day )
- Adrenaline ( S.C. inj.)
PENICILLINS
Antihistaminic ( injectable)
- Glucocorticoids ( inj.)
3. Other reactions –
-Bone marrow depression leads to
granulocytopenia
-Hepatitis (Oxacil. & Naficillin.)
- inj. can cause local pain & inflammation
-
(Intrathecal inj. can cause arachinoiditis & severe
encephalopathy .)
CEPHALOSPORINS
History & Source –
First source – Cephalosporium –
acremonium isolated in 1948 by
Brotzu . Crude filtrates from cultures
of this fungus were found to inhibit
the growth of S. aureus to cure
staphylococ. inf. & Typhoid fever
CEPHALOSPORINS
caused by Salmonella sp.
- Cultures shows three distinct antb.s
which were named Cephalosp. P, N,
C.
- With isolation of the active nucleus
of Cephalosp. C. i.e. 7 amino
cephalosporanic acid & with addition
CEPHALOSPORINS
of the side chains it become possible
to prod. synthetic comp.s having equiv.
AM activity or greater activity than
parent comp.
Chemistry :
Cephalosp. C contains a side chain
derived from D-α aminoadipic acid
CEPHALOSPORINS
condensed with a dihydrothiazide βlactam ring syst. ( 7- aminocephalospo
-ranic acid ).
-- comp.s containing 7- aminocephalo.
acid are relatively stable in dilute
acid & are highly resist. to
penicillinases .
CEPHALOSPORINS
CHEMISTRY:
1
S
R1
C
NH–7
3
O
N
R2
COO ˉ
- Alteration in position 7 of the β- lactum ring changes the
AB activity & alteration at post. 3 of di-hydrothiazine
ring is associated with changes in metabolic &
pharmacokinetic prop.s .
CEPHALOSPORINS
Mech. –
↓ cell wall synthesis ≡ Penicillins
Classification :
Well accepted syst. of classif. by
generation is very useful based on gen.
features of AM activity . ( Cephal. Having
A after Cef or Ceph are Ist Gen.
CEPHALOSPORINS
First Generation :
Name
Cephazolin
Dose
Spectrum
1-1.5 gm 6 hrly well effective against
( t½ -2 hr )
G+ve but less active
Cephalexin (O) 1 gm 6 hrly
against G-ve bacterias
( t½ - 0.9 hr)
Streptococ.( except
Cephadroxyl (O) 1gm 12hrly
Penicillin resist str.)
( t½ -1.1 hr )
Staphylococ. aureus
Cephalothin ( N)
(except. Methicillin.
Cephaloridine (N)
resist strains ) + PEK
(Cephal. having A after Cef or Ceph are Ist Gen. )
CEPHALOSPORINS
FIRST GENERATION
Cephalexin , po
Cefazolin
Cephalothin
Cephradine , po
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
( Minimal activity against G-cocci & G +ve bacilli )
These do not cross BBB ( not suitable for treating brain abcess /
meningitis ) & all are sensitive to β- lactamase enz. Degradation .
CEPHALOSPORINS
Second Generation :
Cefoxitin (BF*) inj. -2gm 4 hrly
(t½ - 0.9 hr )
Cefaclor (O)
1gm 8 hrly
(t½ - 0.7 hr )
Cefamandole
( bl , A )
Cefuroxime
3gm 8hrly
( * ,BB)
(t½ - 1.7hr)
Cefotetan
inj. 2-3gm 12hrly
( BF, bl ,A )
They are in between
1st & 3rd gen. little less
effect. against G+ve &
little more against
G- ve ( HNPEK )
but not as active
against G+ve org.
as 1st gen. cephalosp.
Loracarbef (O)
( Cephal. Containing PI are 4th gen. )
CEPHALOSPORINS
SECOND GENERATION
Cefoxitin ( mefoxin )
Cefuroxime ( zinacef )
Cef. axetil ( zinnat )
Cefaclor ( ceclor )
Cefprozil ( cefzil )
Mainly effective against G- bacteria ( cocci & bacilli )
Modest activity against G+ bacteria & anaerobes
Cefoxitin active against bowel anaerobes (B. fragilis )
Cefuroxim active against H. influenzae, M. catarrhalis, S. pneumoniae
crosses BBB .
Cef. Axetil- oral form of cefuroxim
Cefaclor active against H. influenzae, M. catarrhalis &E.coli
Cefprozil- similar to cefaclor, c. axetil and augmentin - Liked by children
Second Generations are used primarily for URTIs ( acute otitis media,
sinusitis ) and Lower RTIs ( acute exacerbation of chronic bronchitis)
(These drugs are more stable to β-lactamase degradation )
LORACARBEF: ≡ Cefaclor, can be given orally , overdose can cause seizures
CEPHALOSPORINS
Third Generation :
Cefotaxime
inj. 2gm 4-8hrly
They are much more
(t-½ -1.1 hr )
act. against G-ve org.
Cefpodoxime 200-400mg 12hrly include. β -lactamase
proxetil ( O)
( t½ - 2.2 hr )
prod. less act against
Ceftriaxone
inj. 2gm 12-24hrly G+ve org.( Enterobac
(b½,ch,T,G) (t½ -8 hr )
P.aerug.exct penicilli-.
Cefoperazone inj.1.5-4 gm 8hrly
nase prod. ,Serratia ,
( P,b,D,A,T,bl) ( t½ - 2.1 hr )
N. gonor. are more
Cefexime (O) 200-400mg 12hrly sensitive to 3rd gen.)
CEPHALOSPORINS
Ceftazidime ( P)
Cefibuten ( O )
Cefdinir ( O)
inj. 2 gm 8 hrly
( t½ -1.8 hr )
400mg 4 hrly
( t½ - 2.4 hr )
300mg 12 hrly
( t½ - 1.7 hr )
( Cephal. ending with ME are 3rd gen. exceptCefuroxiME )
CEPHALOSPORINS
THIRD GENERATION
Ceftriaxone ( rocephin )
Cefotaxime ( claforan )
Cetazidime ( fortum )
Cefoperazone ( cefobid )
Cefixime ( suprax )
These are highly active against G-ve cocci, bacilli & anaerobes
They have enhanced G- activity, H. influenzae, N. meningitidis, N.gonorrhea,
P. aeruginosae, M. catarrhalis, E.coli, most Klebsiella are sensitive
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. aeruginosae.
Cefixime has similar activity to amoxicillin & cefaclor for actute otitis media
-These drugs are highly resist. to degradation by β- lactamases by G-ve org.s
-These can penetrate BBB ( Except-Cefoperazone & Cefixime )
CEPHALOSPORINS
Fourth Generation :
comp. to 3rd gen. but
more resist. to some
β – lactmases ( induc.
type I ) & not active
Cefpirome
against anaerobes
( Cephal. containing PI are 4th gen. )
o = orally , * = resist . to β- lactamases , BF = act. ag. B.
fragilis , P = act. Ag. P. aeruginosa , T = Typhoid , G =
gonorh. , A = alcohol intolerance , N = nephrotoxic
Cefepime
inj. 2 gm 8 hrly
( t½ -2 hr )
CEPHALOSPORINS
D = Diarrhea , BB = crosses BBB , b = exc. in bile , b½ =
half exct. in bile , bl = bleeding , ch = synd. mimicking
cholecystitis .
Now 5THGeneration has also came , although they inhibit the cell wall
synthesis but in a different way , they bind to & inhibit PBP-2 produced
by MRSA & Penicillin resist . S. pneumoniae which is not inhibited by
majority of antb.s .
-Also active against Enterococcus .& retain the activity of IV gent.
against G-ve bacilli ( esp. E.coli & Pseudomonas)
e.g.-Ceftaroline app. by FDA & Ceftobiprole ( phase III trial)
-Used for comm. aquired bact. Pneumonia & acute Bact. Skin inf. incl.
MRSA )
CEPHALOSPORINS
Mechanism of Bacterial Resistance :
Resist. to Cephalosp. may be related
to the :
-inability of the antb. to reach site of act.
or
- alteration in the PBPs that are targets of
the cephalosp. such
CEPHALOSPORINS
that the antb. bind to bact. enz.s ( β –
lactamases esp. inducible type I ) that can
hydrolyze the β- lactum ring & inactivates
the Cephalosp.s
CEPHALOSPORINS
General features :
Cephalosp.s are excrt. primarily by the
kidney , therefore dosage should be
altered in case of renal insufficiency.
- Probenecid slows the tubular secrt. of
most cephalosporins .
(Cefoperamide & Cefoperazone are
mainly excrt. in bile .)
CEPHALOSPORINS
- Cefotaxime is deacetylated in vivo &
half excrt. through kidney & half in
bile .
- Several of the Cephalosp.s penetrate
CSF in sufficient conc. to be useful
in meningitis (Cefuroxime ,2nd & 3rd
CEPHALOSPORINS
gen. cephalosp.s ) .
- Cephalosp.s cross the placenta &
also found in high conc. in synovial &
pericardial fluid .
- Penetr. in aq. humor of the eye is
good after syst. administ. of 3rd gen.
Cephalosp.s ( in vit. humor it is poor)
CEPHALOSPORINS
Side effects :
1. hypersenst. react. is most common
immed. react. e.g. anaphylaxis ,
bronchospasm & urticarial rash .
- most commonly maculopapular rash
dev. usually after several days of
CEPHALOSPORINS
-
therapy .
Cross reactivity occurs in between
Cephalosp.s & penicil.s due to the
structural similarity to the Penicillins
(about 20 % cases who are allergic to penicil.s
are also allergic to Cephalosp.s) .
CEPHALOSPORINS
-
Pts with mild react. to penicil.
appear to be at low risk of rashes
or other allergic react. following
administr. of Cephalosp.s . but pts
having recent severe allerg. react.
or anaphylaxis to penicil. should be
given Cephalosp. with great caution
CEPHALOSPORINS
-
Rarely causes bone marrow dep.
→ granulocytopenia .
- Nephrotoxicity occurs esp. with
Cephaloridine & Cephalothin .
- Diarrhea with Cephoperazone due to
biliary exc.
- Alcohol intolerance ( disulfiram like
CEPHALOSPORINS
react. in Cefamandole , Cefotetan &
Cefoperazone ).
- Bleeding related to hypoprothrombin –
emia ( Cefotetan & Cefoperazone )
- Superinfection by 3rd ,4th & 5th gent.
Therapeutic Uses :
Used widely- effective prophylactically
& therapeut.
CEPHALOSPORINS
1st Gen. Cephalosp.s –
- excellent for skin & soft tissue inf.s
- colorectal surgery.
- Prophylaxis for intracel. anaerobes .
2nd Gen. Cephalosp.s - they are displaced by 3rd gen.
Cephalosp.
CEPHALOSPORINS
- active for URTI , for Penicil. resist.
S. pneumoniae inf.
- Otitis media
- Diabetic foot inf.
3rd Gen. Cephalosp.s :
- with or without Aminoglycosides are
DOC for serious inf. caused by
CEPHALOSPORINS
Klebsiella , Enterobacter ,Proteus ,
Providencia , Serratia & haemophilus
sp.s
- Ceftriaxone is DOC for gonorrhea &
lyme disease & also for Salmonella
inf. ( Typhoid fever ) .
-Meningitis ( Ceftazidime + aminoglyc.
CEPHALOSPORINS
for Pseudomonas meningitis )
- Ceftriaxone & Cefotaxim are good
for community acquired pneumonia
4th Gen. Cephalosp.s :
The Nosocomial inf.s where antb.
resist. owing to extended spect. βlactamases
Other β- Lactum Antibiotics
With β –lactum structure that are
neither penicil. nor cephalosp.
Carbapenems
- It contain fused β- lactum by
unsaturated 5 nucleus ring syst. &
containing Carbon atom instead of
sulfur atom .
- have broader spect. of activity than
Other β- Lactum Antibiotics
do most other β –lactum antb.s
- These are synth. antibact. agents
Imipenems :
- marketed in comb. with Cilastatin a
drug that ↓ degradation of imipenem
by renal tubular dipeptidase .
- indicated against refractory nosocom.
Other β- Lactum Antibiotics
infections leading to -UTI , LRTI ,
-Gynecological inf.
-Joint inf. &
-Intra abdominal inf. caused by
Other β- Lactum Antibiotics
Enterobacter ,Pseudomonas ,
Acinetobacter & anaerobic inf.( by B.
fragilis & Clostr. difficil ).
-orally not abs. , rapidly hydrolyzed by
dipeptidase in renal tubules to
nephrotoxic metabolites
Other β- Lactum Antibiotics
Therefore Cilastatin is combined ( it ↓
dipeptidase enz.)
S/E – nausea , vomiting , seizures
& cross allergy .
Meropenem :
It is ≡ Imipenem but is not senst. to
renal dipeptidase & with less risk of
Other β- Lactum Antibiotics
of seizures .
Ertapenem :
-having longer t½ therefore given
once a day .
-effective in enterobacteriaceae &
anaerobes . Hence useful in abdom.
& pelvic inf.s.
Other β- Lactum Antibiotics
Monobactums :
Aztreonam - it is β- lactamase resist.
with spect. similar to Aminoglycoside
( G-ve aerobic bacilli ). G+ve & anaer.
org. are resist.
-no cross allergy to β –lactum antb.
-given I.M. or I.V. dose -2 gm/d 6-8 hrly
Other β- Lactum Antibiotics
β – lactamase inhibitors :
certain molecule can inactivate βlactamase & thus prev. the destruction
of β – lactam antb. that are substrates
of this enz. ( ↑ effectiveness of β –
lactum antb.s ).
Other β- Lactum Antibiotics
-most active against Plasmid encoded
β- lactamase e.g.Clavulanic acid ,
Sulbactum &
Tazobactum .
- They themselves have not any signif.
AM activity .
Other β- Lactum Antibiotics
- They do not inhibit inducible type I
β- lactamase induced in G-ve bacilli.
Useful comb.s are :
1. Amoxycil. + Clavulanic acid –
effective against β –lactamase prod.
strains of Staphylococ. ,H. influenz.
,Gonococci & E. coli .
Other β- Lactum Antibiotics
- indicated in resist. Otitis media,
sinusitis , animal bite wounds
cellulitis & diabetic foot.
2. Ticarcillin + Clavul. Acid :
≡ Imipenem
indicated in mixed nosocomial inf.
along with Aminoglyc.
Other β- Lactum Antibiotics
3. Ampicil + Sulbactum :
indicated in mixed intra abdominal
& pelvic inf.s .( exc. Pseud. & anaerobic inf.) .
4. Tazobactum + Piperacil.:
activity against Pseudomonas is not
enhanced but having broadest AM sp.
Bibliography
1.Goodman & Gilman’s ,The Pharmacological
Basis of Therapeutics (12th Edition).
2. Clinical Pharmacology by Lawrence (Latest
edition )