Inhibitors of bacterial cell wall synthesis are bactericidal drugs targeting the peptidoglycan structure unique to bacteria, effective during rapid bacterial growth. Key classifications include beta-lactam drugs (like penicillins and cephalosporins) and non-beta-lactam drugs (such as vancomycin and daptomycin). Penicillins, discovered by Alexander Fleming, are among the most widely used antibiotics and have various therapeutic applications, but may lead to allergic reactions in some patients.

2. Inhibitors of Bacterial Cell
Wall Synthesis

3. Inhibitors of Bacterial Cell Wall Synthesis
A group of Bactericidal drugs which selectively interfere with
synthesis of bacterial cell wall.
The bacterial cell wall is composed of peptidoglycans.
(a structure not present in mammalian cells)
• They are maximally effective when bacteria are rapidly
growing & synthesizing cell wall, also called cell wall active
drugs
• They have no effect on bacteria that are not growing &
dividing.
• Includes important drugs like Penicillins, Cephalosporins,
Vancomycin & others.

4. Classification
Inhibitors of Bacterial Cell Wall Synthesis
or Membrane-active drugs
I. Beta Lactam drugs
II. Non Beta Lactam drugs
I. Beta Lactam drugs
a. Penicillins
b. Cephalosporins & Cephamycins
c. Monobactam --- Aztreonam

5. d. Beta lactamase inhibitors
 Sulbactam Sodium
 Tazobactam Sodium
 Clavulanate potassium.
e. Carbapenems
 Ertapenem
 Imipenem
 Meropenem

6. II. Non-Beta Lactam drugs
a. Vancomycin
b. Teicoplanin
c. Daptomycin
d. Fosfomycin
e. Bacitracin
f. Cycloserine

7. PENICILLINS

8. PENICILLINS
• Penicillins are the most widely effective & the least toxic drugs.
(High margin of safety)
• They lack organ toxicity, but acute anaphylaxis is important
adverse effect.
• Many members of this group of antibiotics are currently the drugs
of choice for a large number of infectious diseases.

9. PENICILLINS - HISTORY
Discovered in 1928 by Alexander Fleming .
• While studying Staphylococcus variants in the laboratory at St. Mary's
Hospital in London.
• He observed that a mold contaminating one of his cultures caused the
bacteria in its vicinity to undergo lysis.
• Broth in which the fungus was grown was markedly inhibitory for many
microorganisms.
• Because the mold belonged to the genus Penicillium, Fleming named the
antibacterial substance penicillin .
• In 1941 Penicillin was developed as systemic therapeutic agent & tested
on an old terminally ill lady having cancer.
• Penicillin used in 1944 on war soldier having multiple wounds .

10. Classification of Penicillins
Natural Penicillin & its Congener
Penicillin G/ Benzylpenicillin
Penicillin V /Phenoxymethylpenicillin.
Repository preparations of Benzylpenicillin :
Procaine Penicillin G
Benzathine Penicillin G
Semi-synthetic Penicillins
a.  lactamase Resistant Penicillins
i. Methicillin
ii. Nafcillin
iii. Isoxazolyl Penicillins
Oxacillin, Cloxacillin
Di-cloxacillin, Flucloxacillin.

11. Extended Spectrum Penicillins
i. Aminopenicillins
 Amoxicillin,
Ampicillin
 Ampicillin prodrugs: Piv, Bac & Tal-ampicillin
Antipseudomonal Penicillins
a. Carboxypenicillins
Carbenicillin , Ticarcillin
b. Ureidopenicillins
Azlocillin , Mezlocillin , Piperacillin

12. Combinations of Penicillins with - Lactamase
Inhibitors
• Amoxicillin / Clavulanate ( Augmentin)
• Ampicillin / Sulbactum
• Piperacillin / Tazobactum
• Ticarcillin / Clavulanate

13. Penicillins
• Bactericidal drugs
• Bacterial cell wall synthesis Inhibitors
• Only act when bacteria are rapidly growing & synthesizing
cell wall.
• Have time dependent (Concentration independent killing)
• Entry in to G+ve bacteria through bacterial cell wall & G –
ve bacteria through porins in the outer cell wall, which is
absent in G+ve bacteria.

16. Mechanism of Action Penicillins…
Penicillins act by following steps
1.Binding to their receptors (specific enzymes, PBPs)
2. Inhibition of transpeptidation reaction / cross linking of
linear peptidoglycans chains of the cell wall.
So synthesis of bacterial cell wall is inhibited
3. Activation of autolysins, disruption of cell morphogenesis
& Cell death.

17. Mech. of bacterial resistance to penicillin
Bacteria can acquire resistance by:
I.Enzymatic hydrolysis of drug by;
− beta lactamases
II.Altered target PBPs
−Basis of Methicillin resistance in Staph (MRSA) & Penicillin
resistance in Pneumococci & enterococci

18. III. Impaired penetration of drug to target PBPs
• Only in G-ve bacteria due to resistant outer cell membrane–
porins may be absent or decreased
• This is more important if bacteria is also beta lactamase
producing.
IV. Active efflux pump: May be produced in G-ve bacteria,
transport the drug from the periplasm back across the outerwall.
Natural resistance to penicillins occurs in organisms who lack
peptidoglycan cell wall---- Mycoplasma.

19. Benzyl penicillin
(Penicillin G)
• Natural penicillin
• Acid labile – not effective orally
Source
Obtained from fermentation of mold Penicillium chrysogenum in
huge tanks.
For penicillin G, the side chain is a phenyl-methyl substituent

20. Pharmacokinetics - Benzyl Penicillin
Route of Administration
Acid labile, so given I/V.
• Never intrathecally--- convulsions
• Topical application avoided –risk of allergy
• I/M Injection only Repository preparations
• Procaine Penicillin – 1ml-2ml inj /d
• Benzathine Penicillin 1.2 million units every 3-4 wks-for
prophylaxis
2.4 million units once a week for 1-3 wks for treatment of syphilis.

21. Distribution:
• Distributed in body fluids but poor concentration in the cells as
it is polar.
• Crosses BBB only if meninges are inflamed.
• Crosses placental barrier, but not teratogenic.
• Secreted in breast milk & sputum.
• PPB: low
Metabolism: Not significant in host.
Bacteria may hydrolyze 6APA to Penicilloic acid which has no
bacterial activity but is antigenic.

22. Excretion: Rapid excretion by kidneys—10% GF
90% --Active tubular secretion via organic acid transporter,
competitively inhibited by Probenecid.
So co-administration of 0.5g Probenecid can raise the blood levels
& ↓the frequency of injections.
Elimination less effective in neonates.
Plasma half life (t1/2)
Short—30 minutes prolonged in renal failure—10 hrs.
Dosage adjustment according to renal function.

23. Spectrum Of Activity of Penicillin G
Penicillin G has antimicrobial activity against following
susceptible organisms:
• Streptococci: pyogenes & viridans
• Meningococci
• Pneumococci
• Gonococci (Non –  lactamase producing)
• Staphylococci (Non –  lactamase producing)
• Treponema Pallidum & other spirochetes
• Clostridium perfringes
• Actinomyces
• Non β-lactamase producing G-ve anaerobic organisms.

24. Uses of benzylpenicillin
Dose 4 – 24 million units/d I/V 4-6 divided doses.
I/V infusion may be given—for large doses
1. -Haemolytic Streptococcal (Strept. pyogenes) infections
such as:
• Acute Tonsillitis & Pharyngitis
• Scarlet fever
• Pneumonia
• Arthritis
• Meningitis
• Endocarditis.

25. Uses Of Benzylpenicillin…
2. Strep. viridans Endocarditis (The viridans streptococci are the
most common cause of infectious endocarditis )
3. Pneumococcal Pneumonia , Pneumococcal Meningitis
4. Meningococcal meningitis (Massive doses).
5. Staphylococcal Infections (non -lactamase producing strains
only).
6. Enterococcal endocarditis with aminoglycosides
7. Syphilis: Single inj of Benzathine Penicillin G I/M 2.4 million
units once a week for 1-3 wks. No antibiotic resistance has been
reported.
8. Actinomycosis
9. Clostridial infections (gas gangrene)

26. Prophylactic Uses of Penicillin G
Benzathine Penicillin I/M 1.2 million units once /3-4 wks is given
for prophylaxis of Streptococcal infections in:
• Recurrences of rheumatic fever
• Surgical/ dental procedures in patients with valvular heart
disease.

27. PHENOXY METHYL PENICILLIN
(Penicillin V)
Differences from Penicillin G
1. Gastric acid resistant--- Orally effective, but poor bioavailability.
2. Narrow antibacterial spectrum.
3. Less potent
Therapeutic Uses
 Only for mild streptococcal & pneumococcal infections
Pharyngitis , Sinusitis , Otitis media.

28. Semi-synthetic Penicillins
a.  lactamase Resistant Penicillins:
Resistant to hydrolysis by beta lactamase (Penicillinase) produced
by Staphylococcus aureus . They include:
i. Nafcillin
ii. Isoxazolyl Penicillins
Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin
iii. Methicillin ---- not used; due to renal toxicity -
interstitial nephritis

29. • All are acid stable; Effective orally except Nafcillin
• Well absorbed, absorption is delayed by food so given 1-2 hrs
before of after meals. Flucloxacillin– best absorbed
• Elimination:
Nafcillin – only biliary excretion & highly PPB
All others: Eliminated both by renal & biliary excretion

30. Therapeutic Uses of  lactamase Resistant Penicillins
Used in infections by beta lactamase (Penicillinase)
producing staphylococcus aureus & Streptococci
(except methicillin resistant Staph-aureus ---- MRSA).
• For mild Infection
Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin orally.
• For severe Infection
Oxacillin or Nafcillin by intermittent I/V infusion.
No activity against gram negative infections.

31. Extended spectrum Penicillins
Aminopencillins
Amoxicillin, Ampicillin & Prodrugs
•Extended spectrum penicillins.
•Acid stable.
•Retain the antibacterial spectrum of penicillin G
•Have improved activity against gram negative organisms.
Enhanced ability to penetrate outer membrane of Gram –
ve bacteria
•Susceptible to hydrolysis by Beta-lactamases

32. Pharmacokinetics
• All are acid stable, effective orally. Can be used I/M or I/V
• Absorption: Well absorbed, delayed by food (except
amoxicillin) so given 1-2 hrs before or after meals.
• Amoxicillin better abs than Ampicillin,
• As Ampicillin is less completely absorbed so is effective in
Shigella dysentery & can disturb the normal flora also—
chances of superinfection.
• Elimination: Renal—10% GF & 90% --Active tubular
secretion Ampicillin also excreted in feces.
• Amoxicillin 250-500 mg 8 hrly = Ampicillin 250-500 mg given
6 hrly

33. Antibacterial spectrum - Aminopenicillins
Have antibacterial spectrum of penicillin G, but more active
against G-ve bacilli ---extended spectrum
• Resistance due to plasmid –mediated penicillinases is a major
problem
• Combined with a beta lactamase inhibitor -- Clavulanic acid
/ sulbactum
• Pneumococci (resistant to Pen. G)
• Listeria monocytogenese -- Ampicillin is the DOC
• H-influanzae (Non-  lactamase producing---resistance
developing)
• Salmonella
• Shigella
• E-coli
• Gonococci
• Helicobacter pylori

34. Therapeutic Uses - Aminopenicillins
• Respiratory Tract Infections
Specially Streptococcal , Pneumococcal & H- Influenzae infections:
• Sinusitis
• Otitis media in children.
• Bronchitis , Pneumonia .
• Bacterial Meningitis
Specially in children by S. Pneomonias or N. Meningitidis
• In immunocompromised persons by Listeria.
monocytogenes (Ampicillin)
• Uncomplicated UTI by E. Coli : Ampicillin
(Fluoroquinolones / co-trimoxazole are preferred because of
resistance)
• Gonorrhea (Amoxicillin + clavulanate)

35. • Bacillary dysentery by Shigella ---Ampicillin
• (but Should not be used for Salmonella diarrhea as
it may prolong the carrier state)
• Typhoid fever (Amoxicillin).
• Prophylaxis of Sub-acute bacterial endocarditis in
abnormal valves by dentists before extensive oral
surgery.
• E. Coli Septicaemia with gentamicin.
• Eradication of H-pylori as a part of regimen in peptic
ulcer (Amoxicillin).

36. Antipseudomonal Penicillins
Carboxypenicillins: Carbenicillin, Ticarcillin
Ureidopenicillins: Azlocillin, Mezlocillin, Piperacillin
•As they are susceptible to penicillinases --- combined
with Beta lactamase inhibitors
• Synergistic with an Aminoglycosides

37. Carboxypenicillins
Carbenicillin –First carboxy penicillin ; is obsolete
Now Carbenicillin Indanyl sodium is used orally -
congener is the indanyl ester of carbenicillin
Ticarcillin– I/V
Antibacterial spectrum
•Pseudomonas aeruginosa & Proteus
Therapeutic Uses
•UTI caused by pseudomonas aeruginosa / Proteus
•In other pseudomonal infections with
Aminoglycosides

38. Ureidopenicillins
Antibacterial spectrum
•Klebsiella pneumoniae , Proteus & Pseudomonas
aeruginosa
Therapeutic Uses
•Serious infections by sensitive G -ve Bacteria
• UTI
• Infections after burns
• Bacteremia
• In neutropenic & immunocompromised Patients
• May be combined with Aminoglycosides

39. Adverse Reactions - Penicillins
Penicillins are remarkably safe, no marked direct
toxicity.
In 5% patients some form of Hypersensitivity /
Allergic reactions occur.
• Major antigenic determinant: Metabolite Penicilloic
acid - act as haptens after covalent reaction with
proteins --causes immunological reaction.
• Cross allergenic with Beta lactams.
• Desensitization may be done.

40. A: Acute anaphylaxis /Anaphylactic shock.
Immidiate/type –I hypersensitivity reaction, seen in 0.5%
The most serious ADR. May be fatal
B. Skin rashes of various types.maculopapular / urticarial rash
C. Serum sickness like syndrome —7-10 d after exposure.
D. Angioedema
E. Allergic Renal disturbances: Interstitial nephiritis----
methicillin.
F. Allergic Blood disturbances. Eosinophilia , hemolytic anemia
G. Vasculitis.

41. Adverse Reactions – Penicillins…
Other Adverse effects of Pen. G:
 Pain after IM injection.
 Thrombophlebitis after I/V injection.
 Seizures. With large doses in renal failure, epileptic pts are
at risk
 Arachnoiditis ---encephalopathy - after Intra-thecal inj.
 Dizziness, tinnitus, headache, hallucination, seizures –
With procaine penicillin .

42. Cation Toxicity: Penicillins are generally given as
Sodium or Potassium salts So when used in large
doses-- Sodium or Potassium toxicity may occur.
Hyperkalemia in renal dysfunction with large doses of
Pen. G potassium.
Hypokalemia with sodium excess.
It can be avoided by using the most potent drug – in lower
doses

43. Jerisch Herxhimier Reaction
Symptoms: Several hours after the first inj in
syphilis patient
--chills, fever, headache, myalgias, arthopathy &
prominence of cutaneous lesions.
Remedy: Discontinue penicillin
Give Inj Hydrocortisone
Cause: Due to killing of a large number of
spirochetes, libration of toxins

44. Nafcillin neutropenia
Oxacillin hepatitis
Methicillin interstitial nephritis
Ampicillin
• GIT upset , nausea, vomiting, and diarrhea.
• Super infection i.e. Pseudomembranous colitis ,
Vaginal candidiasis.
•Ampicillin and Amoxicillin can cause skin rashes that
are not allergic in nature. In petients of infectious
mononucleosis treated with Ampicillin ---- Incidence of
maculopapular rash is 100%

45. Beta lactamase inhibitors (Clavulanic acid,
Sulbactam, & Tazobactam)

46. Beta lactamase inhibitors (Clavulanic acid, Sulbactam,
& Tazobactam)
•Resemble β-lactam molecule.
•Almost NO antibacterial action.
•Potent inhibitors of many but not all β-lactamases.
•Protect hydrolyzable penicillins from inactivation

47. Most active against Ambler class A β-lactamases.
produced by staphylococci, H. influenzae, N.
gonorrhoeae, salmonella, shigella, E coli & K
Pneumoniae.
•Not good inhibitors of class C β-lactamases, which
typically are chromosomally encoded and inducible.
• Produced by enterobacter, citrobacter, serratia, and
pseudomonas.
•They do inhibit chromosomal β-lactamases of legionella,
bacteroides.

48. Available only in fixed combinations with specific
penicillins.
•Antibacterial spectrum --- determined by the
penicillin, not the β-lactamase inhibitors.
•Extend the spectrum of a penicillin.
Combinations of Penicillins with - Lactamase
Inhibitors
•Amoxicillin / Clavulanate ( Augmentin)
•Ampicillin / Sulbactum
•Piperacillin / Tazobactum
•Ticarcillin / Clavulanate

49. •Therapeutic indications for penicillin - β-lactamase
inhibitor combinations are:
•Empirical therapy for infections caused by a wide
range of potential pathogens in both
immunocompromised & immunocompetent patients.
•Treatment of mixed aerobic & anaerobic infections i.e.
intra-abdominal infections.
•Dosage adjustment according to the penicillin.

50. Monobactams: Drugs with β-lactam monocyclic ring
Aztreonam
Mechanism of Action: inhibition of bacterial cell wall
synthesis.
•Binds to PBP3 & synergistic with aminoglycosides.
•Resistant to β-lactamases
•Active only against G-ve rods including Pseudomonas &
Serretia.
•No cross allergenicity with penicillin.
So penicillin allergic patients tolerate Aztreonam very well.

51. Carbepenems
Ertapenem , Imipenem/cilasatin , meropenem:
β-lactam drugs
Resistant to most β-lactamases except Metallo β-
lactamases
Active against G-ve rods including Pseudomonas,
G+ve organisms. & anaerobes .
Cross allergenic with Penicillins

52. Therapeutic Uses of Carbepenems
•Enterobactor infection.
•Infections by Penicillin resistant pneumococci.
•Pseudomonal infection with Aminoglycoside.
Adverse Effects: Skin rashes ,Reaction at infusion site,
Seizures in renal failure. (imipenum)
Cross allergenic with Penicillins

53. Non-β-lactam Inhibitors of bacterial cell wall
synthesis
Vancomycin
Source: Glycopeptide Antibiotic --- Streptococcus
orientalis.
Antibacterial spectrum: Narrow ,against resistant micro-
org.
•G +ve bacteria, specially Staphylococcus, even MRSA
•Clostridium difficile.

54. Pharmacokinetics
• Poorly absorbed form intestine.
•Orally effective only for enterocolitis.
•For systemic infections--by I/V infusion.
• 90% excreted by GF.
•Drug is not removed by hemodialysis

55. Mechanism of Action
Bactericidal
•Binds to the D-Ala-D-Ala terminal of the nascent
peptidoglycan pentapeptide side chain
•Inhibits transglycosylation.
•So prevents elongation of the peptidoglycan chain &
interferes with cross linking.
Mechanism of Resistance
•Alteration of D-Ala-D-Ala binding site & loss of
affinity & activity.

56. Therapeutic uses of Vancomycin
Narrow spectrum , Serious infection by drug resistant
G +ve organisms.
•Sepsis or endocarditis by MRSA / severe penicillin
allergy. I/V
•Pneumococcal Meningitis with 3rd
gen .Cephalosporins
(Cefotaxine, Ceftriaxone) or Rifampin. I/V
•Antibiotic induced Enterocolitis by Clostridium difficile.
Orally for refractory cases.
First DOC -- Metronidazole

57. Adverse Effects of Vancomycin
• Rapid I/V infusion , “Redman” or “Red neck” syndrome due to
histamine release .
• Phlebitis
• Chills & fever ,
• Ototoxicity & Nephrotoxicity. (rare)
Teicoplanin
Similar to Vancomycin. Can be given I/M , I/V.
Dalbavancin & Telavancin are semisynthetic lipoglycopeptides
--- still inveatigational.

58. Daptomycin
Lipopeptide antibiotic
Source: Streptomyces roseoporus
•Cleared renally
•Spectrum of activity similar to vancomycin, even
effective against vancomycin resistant strains of
enteroccoci & S. aureus.
Mechanism of Action: Not clear.
•Binds to & depolarizes the cell membrane, potassium
efflux & cell death
Therapeutic Uses: Alternative to vancomycin, more
rapidly bactericidal than vancomycin. Useful in sepsis &
endocarditis caused by Gram positive bacteria.
Adverse effects: Myopathy.

59. Fosfomycin
Analog of Phosphoenolpyruvic acid.
Mechanism of Action: Inhibits early stage of
bacterial cell wall synthesis
•Inhibits cytoplasmic enolpyruvate transferase.
•Prevents formation of N-acetylmuramic acid ---
precursor of Peptidoglycan.
•Mechanism of Resistance: Inadequate transport into
bacteria.

60. Pharmacokinetics
Given orally, 40% bioavailability.
Half life 4 hrs. Renally excreted
Spectrum of activity: G +ve & G -ve
Therapeutic uses
Uncomplicated lower UTI in women– single 3 g dose.
•Safe in pregnancy.

61. Bacitracin
Source: Bacillus subtilis.
•No cross resistance with other Antimicrobial drugs.
•Markedly nephrotoxic.
Therapeutic Uses: Not used systemically
•Used topically as ointment on skin, with polymyxin &
neomycin for mixed bacterial flora.
•Saline solutions for irrigation of joints, wounds or
pleural cavity.

62. Cycloserine:
•Antibiotic -- Streptomyces orchidaceus.
Mechanism of Action: Structural analog of D-
alanine ,blocks the incorporation of D-Ala in to
Peptidoglycan chain.
Therapeutic Uses: 2nd
line anti TB drug.
Adverse Effects: Serious CNS toxicity ---- headache,
tremor, acute psychosis & convulsions.