PENICILLINS CEPHALOSPORINS & OTHER β-LACTUM ANTIBIOTICS Dr. Rajendra Nath Professor.

PENICILLINS PENICILLINS CEPHALOSPORINS & OTHER CEPHALOSPORINS & OTHER

ββ-LACTUM ANTIBIOTICS-LACTUM ANTIBIOTICS

Dr. Rajendra Nath Dr. Rajendra Nath ProfessorProfessor

PENICILLINS CEPHALOSPORINS & PENICILLINS CEPHALOSPORINS & OTHER OTHER ββ-LACTUM ANTIBIOTICS-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 .


• β- lactums - include Cephalosporin antibiotics which are classified by generations .


• β- lactamase inhibitors e.g.-

Clavulanate , Sulbactum etc. are

used to extend the spectrum of

Penicil. against β- lactamase prod.

organisms.


• 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 .


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

.

PENICILLINSPENICILLINS -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 .

PENICILLINSPENICILLINS- 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.

PENICILLINSPENICILLINS substance as PenicillinPenicillin .Chemistry : Basic struct. consists of 1. Thiazolidine ring (A) connected to 2. β- lactum ring (B) to which attach 3. Side chain (R) .

PENICILLINSPENICILLINS O S CH3 R C NH CH CH C 2 B A CH3

O = C N CH COOH Amidase 1 Penicillin

Penicillinase site of action

PENICILLINSPENICILLINS

A. Thiazolidine ring

B. β- lactam ring

1. Site of action of penicillinase

2. Site of action of amidase


- 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

PENICILLINSPENICILLINS 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- amino-penicillanic acid could be obtained from


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 .

PENICILLINSPENICILLINSUnitage of PenicillinUnitage 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 PenicillinsMech. of Penicillins :-The cell walls of bact. are essential for their normal growth & development.


- 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

PENICILLINSPENICILLINSalternating amino sugar (N-acetyl –glucosamine & N- acetyl muramic acid)& they are cross-linked by peptide chain .Biosynth. of Peptidoglycan : involves three stages

PENICILLINSPENICILLINS 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.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

PENICILLINS

PENICILLINS

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 penicillinMech. of bact . Resist. to penicillin ( & Cephalosporins )( & 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 Cephalo- sporins 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

PENICILLINS

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 forStaphylococcal penicillinase is encodedIn a plasmid & this may be transferredby 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 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 anti- Pseudomonal 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 generalPharmacological 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 micro- org. (but penicil. G is 5-10 times morebut penicil. G is 5-10 times more active against Neisseria sp. & againstactive against Neisseria sp. & against certain anaerobescertain anaerobes). They are narrow spect. & enz. sens. Penicil.s

PENICILLINS

Spectrum :

effective against Pneumococci.

streptococci, Meningococci , non β-

lactamase prod. gonococci & staphy.

(> 90% strains of staphyl. Isolated (> 90% strains of staphyl. Isolated from individuals inside or outside from individuals inside or outside

hospitals are now resisthospitals 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 None of the Penicil.s are effective against Amoeba , Plasmodium ,against Amoeba , Plasmodium , Rikettsia , fungi or virusesRikettsia , 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 hencePenicil. V is more stable in acid hence

better absorbedbetter 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 mins30 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 testH/S test

is done by I.D. test of 0.1 ml of proc.)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 benz. penicil. has got longest duration of detectable antbof 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 daysavg. 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 meningitisincrease 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 :1.1.Pneumococcal inf.-Pneumococcal inf.-Penicil. G (DOC) -Pneumococcal Pneumonia – (Penicil. G- 24 million U dailyPenicil. G- 24 million U daily

Penicil. V – 500 mg orally 6 hrlyPenicil. 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 isif sensitive - penicil. G is

given -20-24 mill. U/day x 14 daysgiven -20-24 mill. U/day x 14 days)

2. Streptococ. InfStreptococ. Inf.. – in scarlet fever

( Streptococ. pharyngitis ) – penicil. V. -500 mg 6 hrly x 10 dayspenicil. V. -500 mg 6 hrly x 10 days

penicil. G. – 6 lacks U OD x 10 dayspenicil. G. – 6 lacks U OD x 10 days

PENICILLINS

or single inj. of Benz. Penicil. 1.2 mill U stat.)or single inj. of Benz. Penicil. 1.2 mill U stat.) , also effective in –Streptococcal

pneumonia , arthritis , meningitis & endocarditis .

3. Inf. with AnaerobesInf. 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.Staphylococ inf. – penicil. resist penicil. e.g.-

Naficillin Naficillin or OxacillinOxacillin

5. Meningococ. InfMeningococ. Inf. – Penicil G. ( DOC)

given I.V. high dose

PENICILLINS

6. Gonococ. Inf.Gonococ. Inf. – resist. to penicil. G & they are no longer the therapy of choice ( IIIgen. Cephalosporins -IIIgen. Cephalosporins - Ceftriaxone is givenCeftriaxone is given ) .7. SyphilisSyphilis – penicil.G. is highly effective in primary, second. & latent syphilis of < 1 y dur.

PENICILLINS

(Proc. Penicil. -2.4 mill. U /day I.M. + ProbenecidProc. Penicil. -2.4 mill. U /day I.M. + Probenecid

1 gm/ day orally x 10 days or1 gm/ day orally x 10 days or

Benz. Penicil. G. 2.4 mill. U I.M. 1 -3 weeklyBenz. 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. 20 mill. U of penicil G.

daily x10 daysdaily x10 days (child.-50,000 U/kg of Penicil. G

. in two div. doses.)

PENICILLINS

most pts dev. Jerisch Herxheimer reac.Jerisch Herxheimer reac.

(several hrs after the 1several hrs after the 1stst inj of penicil. G 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 antigensdue to Spirochaetal antigens ).

8. ActinomycosisActinomycosis – Penicil. G. – DOC

( 12 -20 mill. U I.V. /day x 6 wks12 -20 mill. U I.V. /day x 6 wks)

9. DiphtheriaDiphtheria-

specific 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 daysProc. Penicil. 2-3 mill. U / day x 10-12 days.)

10. AnthraxAnthrax -now resist. in most of the cases

11. Clostridial inf.Clostridial inf. – penicil. G. is DOC in

(i) Gas gangrene (by C.perfringens,12-20 by C.perfringens,12-20

mill. U/daymill. U/day), debridement of inf. area is necessary apart from the drug .

(ii) No effect on ultimate outcome of

PENICILLINS

Tetanus ( C. tetaniC. tetani ) ,hence tetanus immunoglob.

(ATSATS ) is indicated along with debridement of

dead tissue + Penicil G (10-20 mill. U /day I.M.)10-20 mill. U /day I.M.) to eradicate the bact.

- Fusospiroch. Inf.Fusospiroch. Inf. - Gingivo-stomatitis

e.g.-Trench mouth (Penicil. V.-500 mg 6 hrly x7 dPenicil. V.-500 mg 6 hrly x7 d)

12. Rat bite feverRat bite fever : by Spirillium minor senst. to penicil.( G -12-15 mill. U/d x 3-4 wksG -12-15 mill. U/d x 3-4 wks)

PENICILLINS

13. Listeria inf.Listeria inf. – Ampicillin 1-2 gm 4

hrly. ( +Gentamycin in immuno -comp. host & +Gentamycin in immuno -comp. host &

pt with meningitispt with meningitis.) & penicil.G(15-2015-20 mill. mill.

U/dU/d) are DOC.14. ErysepilasErysepilas –Pasteurella multocida - wound inf. after dog / cat bite . senst. to penicil. & Ampicil.s

PENICILLINS

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.U1.2 mill.U

2.Recurence of Rheumatic fever –

oral –penicil. V or

PENICILLINS

Benz. Penicil. G – (1.2 mill. U once a1.2 mill. U once a

monthmonth.)

3. Syphilis – prophyl. for contacts .

4. Surg. procedure in pts with valvular heart dis.( Dental extractions ).

PENICILLINS

2. Penicillinase resist penicil.: This type of penicil. is resist. to hydrolysis by Staphy. penicillinase (their use should be restricted to thetheir use should be restricted to the tt of inf. which are caused by staphy.tt of inf. which are caused by staphy. that secrete this enzthat secrete this enz.) -these are less sens. than is penicil. G

PENICILLINS

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.

PENICILLINS

e.g.-

Isoxazolyl PenicilIsoxazolyl Penicil.:

Oxacillin , CloxacillinOxacillin , Cloxacillin & DicloxacillinDicloxacillin –

-These are congeneric semi –synth. Penicil.s .

- These are similar pharmacologically,

abs. adequately after oral administ.

PENICILLINS

( abs. is more effective on empty stomach) .

NaficillinNaficillin :

This semisynth. Penicil. is highly resist.

to penicillinase & effective against inf.

caused by penicillinase prod. strains

PENICILLINS

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 .

PENICILLINS

Aminopenicillins : Ampicillin Ampicillin , , CloxacillinCloxacillin & 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.

PENICILLINS

- 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 arePseudomonas & Klebsiella are

resistresist.)

PENICILLINS

( however concurrent administ. of a however concurrent administ. of a ββ- - lactamase inhib. e.g.- Clavulanate orlactamase inhib. e.g.- Clavulanate or Sulbactum markedly expands theSulbactum markedly expands the Spect. of activity of these drugsSpect. of activity of these drugs ) dose – 500mg QID or 0.5 – 1 gm sod.500mg QID or 0.5 – 1 gm sod.

Ampicil. Inj. I.M.Ampicil. Inj. I.M. ( adjustment is req . in cases of renal dysf.)

PENICILLINS

AmoxycillinAmoxycillin :

- 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.

PENICILLINS

- 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. URTIURTI against S. pyog. & S.

pneumonia & H. influenzae .

PENICILLINS

-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.

PENICILLINS

+ Sulfamethoxazole or high doses of Ampicil. also are effective ( 12 gm/d for adults) .Antipseudomonal Penicil.s : Carboxypenicillins – e.g.- Carbenicillin Carbenicillin ,,Carbenicillin indanylCarbenicillin indanyl ( indanyl ester of carbenicilin which

PENICILLINS

is acid stable & used orally) &

TicarcillinTicarcillin .

- They are active against some strains of Pseudomonas aeruginosa

& certain sp. of Proteus ( that are

resist. to Ampicil.& congener ).

- Hypokalemia may occur.

PENICILLINS

Ureidopenicillins :

e.g.- MezlocillinMezlocillin & PiperacillinPiperacillin have

superior activity against P.aerug.

- they are also used against Klebsiella

- they are senst. to destruction by β –lactamases .

PENICILLINS

(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.

PENICILLINS

( esp. in pts of impaired immuno -esp. in pts of impaired immuno -

logical defenses & inf.s acquired inlogical defenses & inf.s acquired in

hospitals)hospitals)

so greater use in bacteremias ,Pneum.

inf. following burns & UTI .

( in neutropenic pts )

PENICILLINS

Side effects : 1. Hypersenst. ReactHypersenst. 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

PENICILLINS

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 doesoccurrence of untoward effects does notnot

necessarily imply repetitions on necessarily imply repetitions on

PENICILLINS

subsequent exposuresubsequent exposure .)

- H/S react. may appear in the H/S react. may appear in the absence of a previous known absence of a previous known exposure to drugs exposure to drugs

(may be due to prev. unrecognized exposure tomay be due to prev. unrecognized exposure to

penicil. in the environment e.g.- foods of animalpenicil. in the environment e.g.- foods of animal

origin or fromorigin or from the fungus prod. penicilthe fungus prod. penicil.).)

PENICILLINS

- 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).MechMech.- penicil. & their breakdown prod.s act as haptenshaptens after covalent react. with proteins . major breakdown moiety is penicilloyl moiety which is the major

PENICILLINS

determinant moiety ( MDM) .

- IgE med. react.IgE med. react. occur due to MDM

( in 25% other breakdown prod.s are

responsible)

- The most serious H/S react.s are

angioedemaangioedema ( 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 sicknessSerum sickness : mild fever , rash , leukopenia , arthralgia ,purpura, lymphadenopathy

PENICILLINS

spleenomegaly, mental changes ,ECG abnormalities , albuminuria ,hematuria. It is mediated by IgG antibodiesIgG antibodies.( it occurs when penicil. is continued for a wk orit occurs when penicil. is continued for a wk or

more but is raremore 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 & 10001, 5, 10, 100 & 1000

Unit / dayUnit / day )

- Adrenaline ( S.C. inj.)

PENICILLINS - Antihistaminic ( injectable) - Glucocorticoids ( inj.)3. Other reactions – -Bone marrow depression leads to

granulocytopenia -Hepatitis (Oxacil. & Naficillin.)Oxacil. & Naficillin.) - inj. can cause local pain & inflammation (Intrathecal inj. can cause arachinoiditis & severe Intrathecal inj. can cause arachinoiditis & severe

encephalopathyencephalopathy .)

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 amino7 amino

cephalosporanic acidcephalosporanic 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 β- lactam ring syst. ( 7- aminocephalospo7- aminocephalospo -ranic acid-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 R 2

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.

CEPHALOSPORINSFirst Generation : Name Dose Spectrum Cephazolin 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 GENERATIONFIRST GENERATION Cephalexin , po Cefazolin Cephalothin Cephradine , poActive against G+ cocci ( except. enterococci & MRSA ): s. pneumoniae, s. pyogenes, s. aureus, &

s. epidermidis Indicated for streptococcal pharyngitisIndicated for streptococcal pharyngitis ( e.g. cephalexin) Commonly used (eg. Cefazolin) as prophylactic for surgical proceduresCommonly 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 .

CEPHALOSPORINSSecond Generation : Cefoxitin (BF*) inj. -2gm 4 hrly They are in between (t½ - 0.9 hr ) 1st & 3rd gen. little less Cefaclor (O) 1gm 8 hrly effect. against G+ve & (t½ - 0.7 hr ) little more against Cefamandole G- ve ( HNPEK ) ( bl , A ) but not as active Cefuroxime 3gm 8hrly against G+ve org. ( * ,BB) (t½ - 1.7hr) as 1st gen. cephalosp. Cefotetan inj. 2-3gm 12hrly ( BF, bl ,A )

Loracarbef (O)( Cephal. Containing PI are 4th gen. )

CEPHALOSPORINSSECOND GENERATIONSECOND GENERATIONCefoxitin ( mefoxin )Cefuroxime ( zinacef ) Cef. axetil ( zinnat )Cefaclor ( ceclor ) Cefprozil ( cefzil ) Mainly effective against G- bacteria ( cocci & bacilli )Modest activity against G+ bacteria & anaerobesCefoxitin active against bowel anaerobes (B. fragilis ) Cefuroxim active against H. influenzae, M. catarrhalis, S. pneumoniae crosses BBB .Cef. Axetil- oral form of cefuroximCefaclor active against H. influenzae, M. catarrhalis &E.coliCefprozil- similar to cefaclor, c. axetil and augmentin - Liked by childrenSecond Generations are used primarily for URTIs ( acute otitis media, Second Generations are used primarily for URTIs ( acute otitis media,

sinusitis ) and Lower RTIs ( acute exacerbation of chronic sinusitis ) and Lower RTIs ( acute exacerbation of chronic bronchitis)bronchitis)

(These drugs are more stable to (These drugs are more stable to ββ-lactamase degradation )-lactamase degradation )

LORACARBEFLORACARBEF: : ≡ Cefaclor, can be given orally , overdose can cause seizures≡ 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) inj. 2 gm 8 hrly

( t½ -1.8 hr )

Cefibuten ( O ) 400mg 4 hrly

( t½ - 2.4 hr )

Cefdinir ( O) 300mg 12 hrly

( t½ - 1.7 hr )

( Cephal. ending with ME are 3rd gen. except-CefuroxiME )

CEPHALOSPORINSTHIRD GENERATIONTHIRD GENERATIONCeftriaxone ( rocephin )Cefotaxime ( claforan )Cetazidime ( fortum )Cefoperazone ( cefobid )Cefixime ( suprax )These are highly active against G-ve cocci, bacilli & anaerobesThey have enhanced G- activity, H. influenzae, N. meningitidis, N.gonorrhea,

P. aeruginosae, M. catarrhalis, E.coli, most Klebsiella are sensitiveCeftriaxone 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 -These drugs are highly resist. to degradation by ββ- lactamases by G-ve org.s- lactamases by G-ve org.s-These can penetrate BBB ( Except-Cefoperazone & Cefixime )-These can penetrate BBB ( Except-Cefoperazone & Cefixime )

CEPHALOSPORINSFourth Generation : Cefepime inj. 2 gm 8 hrly comp. to 3rd gen. but

( t½ -2 hr ) 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

CEPHALOSPORINS D = Diarrhea , BB = crosses BBB , b = exc. in bile , b½ =

half exct. in bile , bl = bleeding , ch = synd. mimicking

cholecystitis .

Now 55THTHGenerationGeneration 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.-CeftarolineCeftaroline app. by FDA & app. by FDA & CeftobiproleCeftobiprole ( phase III trial) ( phase III trial)

-Used for comm. aquired bact. Pneumonia & acute Bact. Skin inf. incl. -Used for comm. aquired bact. Pneumonia & acute Bact. Skin inf. incl. MRSA )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 about 20 % cases who are allergic to penicil.s

are also allergic to Cephalosp.sare 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. β- lactamases

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


do most other β –lactum antb.s - These are synth. antibact. agentsImipenems : - marketed in comb. with Cilastatin a drug that ↓ degradation of imipenem by renal tubular dipeptidase . - indicated against refractory nosocom.


infections leading to -

-UTI , LRTI ,

-Gynecological inf.

-Joint inf. &

-Intra abdominal inf. caused by


Enterobacter ,Pseudomonas , Acinetobacter & anaerobic inf.( by B. fragilis & Clostr. difficil ).

-orally not abs. , rapidly hydrolyzed by

dipeptidase in renal tubules to nephrotoxic metabolites


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


of seizures .

Ertapenem :

-having longer t½ therefore given once a day .

-effective in enterobacteriaceae &

anaerobes . Hence useful in abdom.

& pelvic inf.s.


Monobactums :Aztreonam - it is β- lactamase resist. with spect. similar to Aminoglycoside ( G-ve aerobic bacilli ). G+ve & anaer.G+ve & anaer. org. are resist. org. are resist. -no cross allergy to β –lactum antb.-given I.M. or I.V. dose -2 gm/d 6-8 hrly


β – lactamase inhibitors :

certain molecule can inactivate β-

lactamase & thus prev. the destruction

of β – lactam antb. that are substrates of this enz. ( ↑ effectiveness of β –

lactum antb.s ).


-most active against Plasmid encoded β- lactamase e.g.- Clavulanic acid , Sulbactum & Tazobactum .- They themselves have not any signif. AM activity .


- 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 .


- 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.


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 )

PENICILLINS CEPHALOSPORINS & OTHER β-LACTUM ANTIBIOTICS Dr. Rajendra Nath Professor.

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Transcript of PENICILLINS CEPHALOSPORINS & OTHER β-LACTUM ANTIBIOTICS Dr. Rajendra Nath Professor.