Beta lactam antibiotics

1. BETA – LACTAM ANTIBIOTICS
or
Inhibitors of Bacterial cell wall
Y.Durga priyanka
M.Pharmacy( pharmacology)
Y18MPHPY446

2. what is β-lactam :- are a class of antibiotic consisting of all antibiotic agents that contain a beta-lactam ring in
their molecular structures.
What is antibiotic :-Antimicrobial agent made from microorganisms, and can kill and inhibit the growth of
microorganisms, especially those that are infectious or disease-causing.

4. Gram –ve Bacteria Gram +ve Bacteria

5. PEPTIDOGLYCAN STRUCTURE & SYNTHESIS
•Hence, majority of bacteria are surrounded by a thick cell wall that confers stability
and rigidity of their cell structure.
•Their cell wall is composed of peptidoglycan layer.
• Glycan means polysaccharide chain and peptido means peptide chains.
• Hence the term peptidoglycan
•This peptidoglycan layer which envoleps the cell, does not allow bacteria to swell and
prevents its death due to lysis.
•The glycan chain consists of the repeating units of the two aminosugars:-
• N-acteyl muramic acid(NAcM)
&
N-acetylglucosamine(NAcG)
•The pentapeptide side chain( L-alanyl-D-glutamyl-L-lysyl-D-alanyl-D-alanine) is
linked to NAcM.

6. These peptide chains are cross linked to other
peptide chains by a pentaglycine bridge
which extends from L- lysine residue of one
peptide chain to D-alanine residue of another
peptide chain.
• These cross bridging between the
peptidoglycan strands provides necessary
strength to the bacterial cell wall.
• The process of cross- bridging is called as the
TRANSPEPTIDATION reaction catalyzed by
PENCILLIN BINDING PROTEIN (PBPs) which are
transmembrane surface enzymes present in
the every bacteria.

7. BETA Lactam –DRUGS
• The beta lactam are comprised of FOUR different group of Antibiotics:-
pencillins cephalosporins
Carbapenems

8. PENCILLINS.
• Pencillins( 6- aminopencillinic acid) was orginially
obtained from the fungus pencillium notatum, but at
present high-yielding source of pencillin now a days is
from another fungus called
pencillium
chrysogenum.
• The active moiety of the pencillin structure is
6-amino penicillianic acid which consists of intact
beta lactam ring having a amine group at position -6
joined to thiazolide ring .
• obviously therfore pencillins are classified as
Beta lactam antibiotics.
In natural pencillin( pencillin-G), the R in the side chain in
benzyl(CH2C6H5); but in semisynthetic pencillins, this R is
anything other than Benzyl moeity.
6 – Amino pencillianic acid
Pencillins

9. • The nature of the side chain governs mainly the
pharmacokinetics but also the antimicrobial
spectrum.
• Most of the pencillins are available as their Na+
or K+ salts formed at the COOH group at
position-3 of the thiazolidine ring. However
some amine.
• The beta lactam ring of pencillins can be
degraded by beta-lactamase enzyme produced
by the invading bacteria.
• Beta lactam ring can also be hydrolyzed by
Gastric acid. The resultant product is pencilloic
acid is devoid of any antibacterial activity.
However, it combines with the host proteins
and acts as antigenic determinant of pencillin
induced hypersensitivity.

10. Classification of pencillins
• Pencillins are classified according to their Antimicrobial spectrum.
• Within each of these groups some are stable to gastric acid( given orally), while some are acid liable(given
parentrally).
• Similarly some are resistant to β lactmase degradation while others are β lactmase sensitive.
1) Narrow spectrum pencillins:-
A) β lactmase sensitive(Natural pencillins)
Acid stable:- Pencillin V.
Acid liable:- Pencillin G.
B) β lactmase Resistant(Antistaphylococcus pencillins):-
Cloxacillin, Dicloxacillin, Methicillin & Nafcillin
2) Extended spectrum pencillins:-
A) Aminopencillins:- Ampicillin & Amoxycillin.
B) Carboxypencillins:- Carbenicillin & Ticarcillin.
C) Ureidopencillins:- Piperacillin, Mezlocillin & Azlocillin.

11. 1) Narrow spectrum pencillins
Beta lactmase sensitive (Natural
pencillin):-
Pencillin-V(Phenoxymethyl pencillin) :-
• Is acid stable & Hence can be given orally.
• Peak blood level is reached in 1 hour and plasma
t1/2 is 30-60 min.
• Pencillin- G(Benzyl pencillin) :-
Dose:- 0.5-5units/I.M/I.V/6-12hrs
Is acid liable & suitable for I.M or I.V route.
• It is excreted by the kidneys 90% elimination occurs via
tubular secretion while only 10% is excreted via glomerular
filteration.
• PROBENCID blocks tubular secretion of pencillin and has
been used to increases the plasma conc & to prolong the
half- life of pencillins.
• UNITS:-
• 1u of crystalline sodium Benzyl pencillin= 0.6ug of
the std preparation.
Thus 1g=1.6 million units or 1MU= O.6g.
Pencillin-v

12. • PROCAINE PENCILLIN-G and BENZATHINE
PENCILLIN-G are the depot formulations of Pencillin-G
that are used Intramuscularly. They have a delayed but a
sustained adsorption and consequently have a prolonged
half- life.
PROCAINE PENCILLIN-G:-
A single 0.5-1 million unit of i.m/i.v dose of procaine
pencillin-G yields clinically effective concentration for 12-24
hrs.
Similarly a single I.M dose of 0.6-2.4 million unit of Benzathine
pencillin-G can provide plasma levels which are sufficient to
protect against Beta haemolytic streptococcal infections for 3
weeks.
A single injection of BENZATHINE pencillin –G (1.2 million units
i.m) , is satisfactory for treating Rheumatic fever as it
prevents colonisation of Beta haemolytic streptococci.
The same dose given I.M once every 3-4 weeks for 5 years
after the attack, provide satisfactory prophylaxis against
reinfection with beta- haemolytic streptococcal
pharyngitis(Rheumatic fever).
BENZATHINE PENCILLIN-G:-

13. • Use of Natural pencillins:-
Natural pencillins are highly active against Gram+ve cocci & Gram+ve Bacilli, Gram-ve cocci & Equally effective
against spirochetes and Actinomycetes.
Pencillin-G has insignificant activity against Bacteroids and Gram-Ve Bacilli.
Gram +ve Cocci Gram +ve Bacilli
Streptococcus
pyrogenes(otitis.m,phar
yyngitis)
Clostridium Tetani
Streptococcus
Pneumonia
Clostridium perfringens
Streptococcus Viridans Corynebacterium diphtheria
Streptococcus Faecalis Bacillus Anthraecis
Enterococcus Faecalis Listeria Monocytogenes
Gram –Ve Cocci
Neisseria meningitidis
Neisseria Gonorrhoeae
Spirochetes
Trepnoma Palladium
Actinomycetes
Actinomyces israelii

14. 1.Narrow spectrum pencillins
• B) Beta- lactamase resistant Group or Antistaphylococal pencillins:-
Cloxacillin, Dicloxacillin, Methacillin & Nafcillin.
• Have antimicrobial spectrum similar to pencillin-G as described above, but these are additionally effective against Beta
lactmase producing Staphylococci and hence called Antistaphylococcal pencillins.
CLOXACILLIN:-
Cloxacillin has an isooxazolyl side chain is acid stable, well absorbed and can be given orally; but their absorption is impaired
by food. Hence these should be administered 1-2 hrs before or after food.
It is greater than 90% plasma protein Bound.
Eliminated through kidney also partly by Liver. Plasma t1/2 is about 1 hour.
DOSE:- cap or inj :- 0.25,0.5 g .syrup:- 125mg/3 gms.
USES:-
Cloxacillin, in addition, can also be used to treat mild Staphylococcal skin infections such as impetigo. ( A highly contagious skin
infection that causes red sores on the face.)

15. • DICLOXACILLIN:-
• Dicloxacillin also isooxazolyl pencillin which is acid stable, well absorbed can be given orally; but their absorption is
impaired by food.
Hence these should be administered 1-2 hrs before or after food.
• METHICILLIN:-
• Methicillin is acid-liable, hence these are not suitable for oral administration.
• Methicillin Resistant streptococcus aureus- MRSA have emerged in many areas.
• The drug of choice for these organism is Vancomycin/linezolid/ciprofloxacin/cloxacillin/nafcillin.
• Methicillin use has been declined because of Haematuria, albuminuria and revesible interstitial nephritis.

16. • NAFCILLIN:-
Is preferred for parentral use.
It is cleared by biliary excretion.
USES OF BETA LACTAMASE RESISTANT GROUP:- used to treat
Osteomyelitis Inflammation of bone caused by infection, generally in the legs, arm or spine.
septicaemia
Septicaemia is another term used to describe blood poisoning. It is an infection caused by large amounts of
bacteria entering the bloodstream. It is a potentially life-threatening infection that affects thousands of
patients every year.
endocarditis Endocarditis is inflammation of your heart's inner lining, called the endocardium. It's usually caused by
bacteria. When the inflammation is caused by infection, the condition is called infective endocarditis.
cellulitis Cellulitis is a common bacterial skin infection. Cellulitis may first appear as a red, swollen area that feels hot
and tender to the touch. The redness and swelling often spread rapidly. Cellulitis is usually painful.

17. 2) EXTENDED SPECTRUM PENCILLINS
• Amino pencillins:- Ampicillin and Amoxycillin. Which are acid stable
Carboxy pencillins:- Carbenicillin and Ticarcillin &
Ureido pencillins:- Piperacillin, Mezlocillin. Which are acid liable
• AMINO PENCILLINS:-
AMPICILLIN/0.5-2g/Oral/i.m/i.v/6hrs/children 25-50 mg/kg/day:-
Ingestion of food decreases the bioavailability of Ampicillin.
So administered 1hr before or after meal.
Ampicillin acheives therapeutic concentration in CSF during inflammatory conditions. Hence used in treatment of Meningitis
therapy. Excretion through Kidney.
PRODRUGS:- Bacampicillin and Talampicillin.
Active against Gram-ve Bacteria:- Bordetella pertusis (Whooping cough)
Haemophilus influenza ( pneumonia, otitis media, Sinusitis)
E.coli
Salmonella typhi UTIs
Proteus mirabilis
Shigella. (Bacillary dysentry)
Presently, Fluroquinolones have replaced Ampicillin for treating UTI, for treating typhoid fever

18. • AMOXYCILLIN/0.25-1gTDS Oral/i.m:-
It is a close cogner of ampicillin(but not a prodrug): similar to all aspects.
Amoxycillin is used in multidrug regimen for eradication of Helicobacter pylori in duodenal and gastric
ulcers.
• Carboxy pencillins:- Carbenicillin indanyl sodium and Ticarcillin
Ureido pencillins:- Piepracillin, Mezlocillin
The special features of these pencillins is their activity against Pseudomonas aeruginosa. Hence ,these
are called Antipseudomonal Pencillins also. And also active against Klebsellia pneumonia.

19. β lactamase inhibitors• Currently three Beta lactam inhibitors are available:-
Clavulanic acid ( derived from streptomyces clavligerus)/orally
Salbactam ( semisynthetic)i.v/i.m and
Tazobactam ( analogue of salbactam)/i.v/i.m
• Pharmacokinetics:-
clavulanic acid /125mg + Amoxycillin/250/500mg,
salbactam /0.5g/i.v or i.m + Ampicillin /1g and
Tazobactam /0.25g/i.v or i.m + Piperacillin/2g .
• Excreted through kidney.
• Mechanism of action:- Active against beta lactamase producing Bacteria
e.g:- Streptococcus pneumonia,
H.influenza and
Moraxella(otitis media,sinusitis and respiratory tract infections ),
MSSA,
klebsiella pneumoniae,
pencillinase producing Neisseria gonorrhoeae,
E.coli,
proteus and
β lactamse producing anaerobes.

20. MECHANISM OF ACTION OF PENCILLINS
• Pencillins compete for and inhibit this PBPs catalysed
process of Transpeptidation.
• The formation of imperfect cell wall leads to an osmotic
drive of the fluid from outside of the environment to
the inside of the bacteria which then swells and burst to
die.
• The death of bacterisa , however , is not solely due to
osmotic drive but also results from the activation of
Autolysing enzymes called Murein hydrolase or
Autolysins.
• Pencillins, i.e., are bactericidal drugs acting through the
inhibition of cell wall synthesis and lysis of bacteria.
• Since rapid cell wall synthesis takes place when bacteria
are multiplying, pencillins are lethal in the multiplying
phase rather than dormant phase of the bacteria.

21. ADVERSE EFFECTS OF PENCILLINS
• HYPERSENSITIVITY REACTIONS:-
• Allergic reactions of pencillins can be classified as:- Immediate, with in 20 min
Accelarated , with in 72 hrs
&
late hypersensitivity reactions, after 72hrs
• GIT SIDE EFFECTS:- Diarrhoea is more common with ampicillin but less with
amoxycillin,bacampicillin or talampicillin.
• MISCELLANEOUS EFFECTS:- Pencillin- Jarish-Herxheimer reaction
Methicillin- cause interstitial nephritis.
Carbenicillin- High dose are neurotoxic and may produce reversible increase
in prothrombin time leading to bleeding problem

23. INTRODUCTION
• The core of the basic cephalosporin molecule consists of a two rings which include:-
1) Beta lactam ring
2) which is condensed with dihydrothiazine ring.
• It is referred to as 7-Aminocephlosporanic acid.
• The active nucleus of the cephalosporins is isolated from the fungus called
cephalosporinium acremonium
& from
streptomyces lactamdurans.
• The most of the drugs in use today are semisynthetic or synthetic and are obtained by chemical modification from position -3
or 7.
• Cephalosporins are similar to pencillins chemically , in mechanism of their action, and in adverse effects.

24. CLASSIFICATION OF CEPHALOSPORINS
First generation Second generation Third generation Fourth generation Fifth generation
Cephalexin Cefaclor Cefixime Cefepime Ceftaroline
Cefadroxil Cefuroxime axetil Cefpodoxime Cefpirome Ceftobiprole
Cephradine Cefprozil Ceftibuten Cefozopran
Cefazolin Cefotetan Cefdinir
Cefamandole Cefditoren
Cefoxitin Ceftolozane
Cefoperazone
Ceftriaxone
Cefotaxime
Ceftazidime
Ceftizoxime

25. FIRST GENERATION CEPHALOSPORINS
Drug Structure R.O.A Dose
CEPHALEXIN Orally O.25-1g/6-8hrs
children:- 25-
100mg/kg/day
CEFADROXIL Orally 0.5-1gBD/12hrs
CEPHADRINE Oral/I.M/I.V 0.25-1g/6-12hrs
CEFAZOLINE I.M/I.V 0.25g/8hr
1g/6hrs

26. • PHARMACOKINETICS:-
Oral cephalosporins are generally well absorbed.
These do not cross BBB.
Metabolism is not a major elimination path for these cephalosporins.
These are primarily excreted through Kidney.
As usual PROBENCID increases their plasma concentration and prolongs their half- life by inhibiting their renal
tubular secretion.
• USES OF First generation cephalosporins:-
Highly active against Gram +ve Bacteria :- Streptococci
Pneumococci
&
MSSA(Methicillin suspectible streptococcus aureus), but not inhibit MRSA and Entercoccus faecalis.
Moderately activity against Gram-ve bacteria:-
E.coli,
Klebseilla pneumonia.
These have insignificant activity against Gram+ve Bacilli.

27. SECOND GENERATION CEPHALOSPORINS
• CEFACLOR/ Oral/0.25-1.0g
It is given orally and have good bioavailability.
USES:-
It is more active than the first generation compounds
against H.influenza, E.coli, and Proteus mirabilis and are
primarily used to treat Upper respiratory tract infections.
CEFUROXIME AXETIL/ Oral,I.MorI.V/250-
500mgBD/8hrs:-
It is an ester prodrug formulation in which the ester is hydrolysed
during passage through the intestinal mucosa.
• The free cefuroxime then enters the systemic circulation.
• Among these drugs only cefuroxime crosses BBB and
achieve therapeutic concentrations in CSF.
• This drug is more stable to Beta lactmase degradation.
• Excreted through Kidney.
USES:-
Used to treat meningitis, Gram-ve:-
Neisseria gonorrhoeae, klebsiella pneumonia.
Gram+ve:-Streptococcus pneumonia and s.pyogenes but not
against s.aureus

28. Third generation cephalosporins
Drug name R.O.A Dose uses Active against
Cefixime ORAL 200-400mg Resiratory, urinary and Biliary Tract
infections
Enterobacteriacea,
H.influenza.
Cefpodoxime
proxetil
ORAL 200mg BD Respiratory, urinary, skin and soft tissue
infections.
Enterobacteriacea,
Streptococci.
Cefdinir ORAL 300mg BD Pneumonia, chronic bronchitis, ENT and
Skin infections
Gram +ve Cocci.
Ceftibuten ORAL 200mg or 400mg BD Respiratory, urinary and gastrointestinal
infections
Gram+ve and Gram –ve.
Ceftamet
(cefditoren)
pivoxil
ORAL 400mg BD-TDS Respiratory, Skin-soft tissue
infections,etc.
Gram-ve,especially
Enterobacteriaceae and
N. gonorrhoea.
Ceftazimide i.m or i.v 0.5-2g/8hrs
children: 30mg/kg/day
Pseudomonal meningitis. Highly active against
Pseudomonas.

29. Drug name R.O.A Dose Uses Active against
Cefoperazone i.m/i.v 1-3 gm/8-12hrs Respiratory,Urinary,Biliary,Skin-soft
tissue infections, Meningitis and
Septicaemias
Pseudomonas
Ceftriaxone i.m 250mg Gonorrhoea and chancroid, UTIs,
abdominal sepsis, septicaemias, typhoid
fever.
H.influenza and
staph .aureus
Ceftizoxime i.m/i.v 0.5-2.0g/8 or 12 hrs - Bacteroides fragilis
Cefotaxime i.m 0.5-1g Meningitis, Respiratory,genitourinary ,
abdominal infections, septicaemia,
anaerobic , hospital acquired infections,
pneumonia and pneumonia.
Ceftolozane+Tazobacta
m( it is a novel 3rd gene)
i.v/1hr 2000+1000mg/
1000+500mg/
500+250mg
UTIs, skin and soft tissue infections,Bone
and joint infections,GIT infections and
variety of systemic infections,particularly
in patients with severe burns and in
cancer and AIDS patients
Pseudomonas
aeriginosa(PA) and other
Gram-ve Bacilli

30. Fourth generation cephalosporins
Drug name R.O.A Dose
Cefepime i.m/i.v 1-2g/8hrs
Cefpirome i.m/i.v 1-2g/12hrs
Cefozopran i.m/i.v 1-2g/12hrs
Highly active against
Gram-ve:-
p.aeruginosa
Enterobacteriaceae
Haemophilus.i
Proteus
Neisseria

31. Fifth generation cephalosporins
• Ceftaroline Fosamil :- has been approved fro the treatment of :- Bacterial pneumonia
Bacterial skin infections including MRSA
• Ceftobiprole /i.v/30min infusion of 500mg:- used to treat pneumonia, skin infections and skin structure
infections including non-limbic threatening diabetic foot infection with out bone involvement.
It is a broad spectrum antibiotic active against
Gram+ve cocci:- MRSA Gram-ve Bacilli:- E.coli and p.aerguinosa
MRSE
PRSP
Enterococcus
Enterococcus faecalis.
And limited activity against Bacteroides Fragilis.
• MECHANISM OF ACTION:-
Although they also inhibit cell wall synthesis, they have different mode of action and a unique microbial spectrum.
• They effectively bind to and inhibit an altered pencillin binding protein-2a(PBP-2a) produced by MRSA and pencillin
resistant Streptococcus pneumoniae, which is not inhibited by majority of cephalosporins in clinical use.

32. MECHANISM OF ACTION OF CEPHALOSPORINS
• Cephalosporins posses a mechanism of action identical to pencillins,i.e., Inhibition of
transpeptidation process leading to the formation of imperfect cell wall; osmotic drive from the
outside isotonic environment of the host cell to the inside of the hypertonic bacterial cytoplasm; and finally
activation of the autolysin enzyme leading to lysis of bacteria.
• Hence the cephalosporins are also bactericidal drugs.

33. ADVERSE EFFECTS OF CEPHALOSPORINS
• HYPER SENSITIVITY:-
Is very less compared to pencillins, yet fever(1%),skin rash(1-4%),eosinophilia(3-8%) and haemotological abnormalities(1-
2%) can occur.
The anaplylactic reactions to cephalosporins are rare(less than 0.02%).
• SUPERINFECTION,PSEUDOMEMBRANOUS COLITIS(PMC) and DIARRHOEA :- could result from
the use of 3rd,4th,5th generation cephalosporins.
• COAGULATON ABNORMALITIES :- may be an uncommon but serious side effect of some cephalosporins like
Cefamandole,Cefoperazone & Cefotetan.
They cause hypo-prothrombinaemia and bleeding disorders by destruction of vitamin-k producing colonic bacteria and by reducing
the synthesis of vit-k dependent clotting factors.Administration of vitamin-k can prevent this problem.
• Local irritaion can produce severe pain after I.M injection of many cephalosporins.
• CEFTRIAXONE:-
can result into PSEUDOLITHIASIS( gall bladder sludge) which disappears after discontinuation of the therapy.
Ignorance of this effect usually leads to uncalled for laparotamy

34. DRUG INTERACTIONS
• PROBENCID enhances plasma levels and duration of action of these cephalosporis which are secreted
through renal tubule.
• Antacid decrease the absorption of CEFACLOR,CEFDINIR and CEFPODOXIME.
• Food decrease the oral absorption of CEFUROXIME and CEFPODOXIME.
• Aminoglycosides should not be mixed, in the same syringe, with cephalosporins