beta lactam antibiotics by Dr. Swaroopa

1. Dr.Swaroopa, 2nd yr Pg
Department of Pharmacology,
Rangaraya Medical College
1
Inhibitors of bacterial cell wall synthesis

2. 2
QUESTIONS FROM THIS TOPIC
1. Glycopeptide antibiotics
2. Fourth generation cephalosporins
3. Extended spectrum Penicillins
4. Carbapenems
5. Drugs effective against Methicillin resistant staph.aureus
6. Vancomycin resistant enterococcal infections
7. Antipseudomonal beta lactams
8. 3rd generation cephalosporins

3. CONTENTS
3
1. INTRODUCTION
2. CLASSIFICATION
3. PENCILLINS
4. CEPHALOSPORINS
5. MONOBACTAMS
6. CARBAPENEMS
7. GLYCOPEPTIDE ANTIBIOTICS
8. CONCLUSION
9. REFERENCES

4. 4

5. 5
BACTERIAL CELL WALL SYNTHESIS
• The bacterial cell wall presents unique antibacterial targets.
• This structure consists of a three-dimensional mat of cross-
linked peptide-sugar polymers called murein and is synthesized
in three stages:
1. synthesis of murein monomers,
2. polymerization of monomers into murein polymers, and
3. cross-linking of polymers to complete the wall.

6. 6

7. 7
INTRODUCTION
 PENICILLINS, CEPHALOSPORINS,
MONOBACTAMS and CARBAPENEMS,
all of them share a common feature i.e.,
having a β-lactam ring in their chemical
structure.(BETA-LACTAM ANTIBIOTICS)
 They all have same mechanism of action i.e.,
Inhibition of Bacterial cell wall Synthesis.
 Other Antibiotics that inhibit cell wall
synthesis include Vancomycin, Teicoplanin,
Daptomycin, Bacitracin, Fosfomycin and
Cycloserine.

8. 8
PENICILLINS
High yielding source of Penicillin is Penicillium chrysogenum.
The active moiety of the Penicillin structure is
6-amino penicillanic acid (6-APA).
The nature of the side chain at position 6
determines the pharmacokinetics and also the
antimicrobial spectrum.

9. 9
Beta lactam ring
Pencilloic acid
Degraded by beta lactamase
enzyme.
or
Can be hydrolysed by
Gastric acid
Doesn’t have any
antibacterial activity.

10. 10
MECHANISM OF ACTION OF PENICILLINS
• Penicillins are bactericidal drugs acting through the
inhibition of cell wall synthesis (inhibition of murein
polymer cross-linking)and lysis of the bacteria.
• Penicillins are lethal in multiplying phase rather than
the dormant phase of bacteria.
• Bactericidal activity of Penicillins is greater against
gram-positive compared to gram-negative bacteria.

11. 11

12. 12
CLASSIFICATION OF PENICILLINS
Narrow Spectrum Penicillins Extended Spectrum Penicillins
Beta lactamase
sensitive
(natural Penicillins)
Beta lactamase
resistant
(antistaphylococcal
Penicillins)
Aminopenicillins
(Acid Stable)
Antipseudomonal
Penicillins
(Acid Labile)
Acid Stable Acid Labile
Acid Stable Acid Labile

13. 13
Beta lactamase Sensitive (Natural) Penicillins
Acid Stable
• Penicillin-V
(Phenoxymethyl Penicillin)
Acid Labile
• Penicillin- G
(Benzyl penicillin)
(I.V , I.M)
• Procaine penicillin-G
(I.M., Depot inj)
• Benzathine Penicillin-G
(I.M., depot inj)

14. 14 Beta lactamase Resistant(Antistaphylococcal) Penicillins
Acid Stable
• Cloxacillin (oral, I.M)
• Dicloxacillin (oral, I.M)
• Flucloxacillin (oral, I.M)
Acid Labile
• Methicillin (I.M., I.V)
• Nafcillin (I.M., I.V)

15. 15
Extended Spectrum Penicillins
Acid Stable(Aminopenicillins)
• Ampicillin (oral/parenteral)
• Bacampicillin
(oral/parenteral)
• Talampicillin (oral/parenteral)
• Amoxycillin (oral/parenteral)
Acid Labile(Antipseudomonal Penicillins)
• Carbenicillin (parenteral)
• Ticarcillin (parenteral)
• Piperacillin (parenteral)
• Mezlocillin (parenteral)
• Azlocillin (parenteral)
All are
sensitive
to beta
lactamase
carboxypenicillins
ureidopenicillins

16. 16
PHARMACOKINETICS :-
Acid stable penicillins
Cloxacillin
Dicloxacillin
Flucloxacillin
Given orally
Acid Labile penicillins – given parenterally
Penicillin-G
Procaine penicillin-G
Benzathene penicillin-G
Methicillin
Nafcillin
Intramuscular depot formulations
sustained absorption
Prolonged half-life

17. 17
 Penicillins have poor penetration in eye, prostrate and CNS
( if meninges are inflamed, permeability of Penicillins increases)
 Except Amoxycillin, all oral Penicillins should be given 1-2 hrs before
or after meals as food interferes with absorption
Excretion :
Penicillin-G excreted by Kidneys
(Half-life of Penicillin-G is 30 min)
**Probenecid blocks tubular secretion of Penicillin plasma conc
90% via tubular secretion
10% via glomerular filtrate
Half-life of Penicillins
may increase up to
10hrs.
0.5g, every 6hrs, orally

18. 18
Renal Failure --- the half-life of Penicillin so dose must be reduced
accordingly.
Cloxacillin excreted by both renal and Biliary route
Dicloxacillin
Nafcillin Excreted primarily by Biliary route
No dose adjustments are required in Renal
failure Patients.

19. 19
USES
A)
Penicillin-G Drug of Choice for • Streptococci
• Meningococci
• Some Enterococci
• Penicillin susceptible Pneumococci
• Staphylococci
• Treponema pallidum
• Clostridium species
• Actinomyces
• Non beta lactamase producing gram
negative anaerobic organisms.
Effective doses range
between 4 to24 million units
per day I.V in 4 to 6 divided
doses.

20. 20
Penicillin-V :- • Oral form
• Indicated for minor infections
• It has narrow antibacterial spectrum
• Relatively poor bioavailability
Benzathine Penicillin :- 1.2 million units, I.M
Effective treatment for beta haemolytic Streptococcal Pharyngitis,
rheumatic fever.
• Once in every 3-4 weeks for 5yrs as Prophylaxis.
 2.4 million units I.M once a week for 1-3 weeks
Effective for Syphillis

21. 21
B)
Oxacillin
Nafcillin
8-12 g/day, given intermittent I.V infusion of 1-2 g
every 4-6 hrs
DOC for serious Staphylococcus infections such as
Endocarditis
Dicloxacillin (Isoxazolyl penicillin)
0.25-0.5g, orally every 4-6 hrs
Rx of mild to moderate localised Staphylococcal infections

22. 22
Methicillin
Nafcillin
Dicloxacillin
Sensitive
• Beta lactamase
producing
staphylococci
• Penicillin
susceptible strains of
streptococci,
pneumococci
Resistant
• Listeria
monocytogenes
• Enterococci
• Methicillin
resistant strains
of staphylococci
DOC for Methicillin susceptible and Penicillin resistant strains of
Staphylococci.

23. 23
C) EXTENDED SPECTRUM PENICILLINS
Amoxycillin :- 250-500mg TID, orally
To treat bacterial sinusitis
otitis
lower respiratory tract infections
• Also used in multidrug regimen for eradication of Helicobacter pylori
in duodenal and gastric ulcers.
Amoxycillin
Ampicillin
Effective against Pneumococci

24. 24
Ampicillin • Effective against
susceptible strains
of Shigella
Dose 4-12 g/day I.V
For Rx of infections of
• Anaerobes
• Enterococci
• L.monocytogenes
• E.coli
• Salmonella
• Non beta lactamase
producing strains of
H.influenza
Not active against
• UTI
• Typhoid fever
• Klebseilla species
• Enterobacter species
• P.aeruginosa
• Citrobacter species
• Serratia
• Indole positive proteus species
• Hospital acquired infections.

25. 25
Carboxypenicillins - Carbenicillin
Ticarcillin
Against gram negative pathogens including P.aeruginosa
Ureidopenicillins – Piperacillin
Mezlocillin
Azlocillin
Active against Klebseilla pneumonia, Pseudomonas

26. 26
BETA LACTAMASE INHIBITORS • Sulbactam
• Clavulanic acid
• Tazobactam
• Avibactam
• Vaborbactam
• Relebactam
Structurally resemble beta lactam
antibiotics but do not possess any
significant antimicrobial action.
MOA:- bind irreversibly to the catalytic site of susceptible
beta-lactamases to prevent hydrolysis of penicillins
(suicide inhibitors)
Can inhibit plasmid mediated beta-lactamases which
are responsible for transferred drug resistance.

27. 27
 Clavulanic acid is absorbed Orally
 Remaining all are used parenterally (I.V / I.M)
Available Fixed Drug Combinations
1. Amoxycillin 250/500mg + Clavulanic Acid 125mg Tab/Cap
2. Injection Ampicillin 1g + Sulbactam 0.5g I.V/I.M
3. Injection Piperacillin 2g + Tazobactam 0.25g I.M/I.V
4. Ceftazidime + Avibactam
5. Meropenem + Vaborbactam
6. Imipenem/Cilastatin + Relebactam

28. 28
ADVERSE DRUG REACTIONS TO PENICILLINS
1. Hypersensitivity Reactions:-
• Incidence – 5-8% of patients receiving penicillins
• Major antigenic determinant – Penicilloic acid
• Minor antigenic determinant – benzyl penicillin itself
or sodium benzylpenicilloate
Immediate
Accelerated
Late Hypersensitivity

29. 29 Immediate :- • Occurs within 20min of administration of Penicillin
• Mediated by IgE antibodies against minor determinants
Manifestations :- • Urticaria
• Pruritus
• Wheezing
• Sneezing
• Rhinitis
• Anaphylaxis
• Diffused pruritus
• Hypotensive shock
• Angioneuritic oedema
• Choking
• Finally loss of
consciousness & death.

30. 30
Management :-
1) Adrenaline SC/IM
2) Corticosteroids IV/IM
3) Antihistamines IM
4) Supportive measures – O2 inhalation, iv
fluids or plasma expanders
If necessary desensitization can be accomplished with gradually increasing
doses as in case of Enterococcal Endocarditis or Neurosyphillis with serious
penicillin allergy.

31. 31
Accelerated :- • Occurs within 72 hrs
• Mediated by IgE antibodies against major
antigenic determinant
Manifestations :- Rash
Fever
Urticaria
Rarely angoineurotic oedma

32. 32
Late hypersensitivity:- occurs after 72 hrs
Mediated by IgE & IgM antibodies against major antigenic
determinant.
Manifestations :- • Morbiliform,
• Urticarial or erythematous eruptions
• Local inflammatory reactions
• Lymphadenopathy
• Splenomegaly
• Serum sickness
• Coombs positive haemolytic anaemia

33. 33 2) GI side effects :- • Diarrhoea – mc with Ampicillin
• Glossitis
• Stomatitis
• Abnormal taste sensation after
oral use
3) Others :-
• Oxacillin – reversible increase in SGOT & SGPT levels
• Methicillin – interstitial nephritis
• Carbenicillin – at higher doses produce
1. reversible increase in prothrombin time leading to
bleeding problems
2. Neurotoxicity

34. 34 Penicillin injected in a Syphilitic patient may produce
Jarisch-Herxheimer reaction
Lasts upto 72 hrs
• Shivering
• Fever
• Myalgia
• Collapse due to sudden release of
spirochaetal breakdown products

35. 35
CEPHALOSPORINS
 Cephalosporins and Cephamycins consists of dihydrothiazine ring fused
to a beta-lactam ring containing an appropriate side chain at position 7.
 The nucleus of the Cephalosporins :- 7 –aminocephalosporanic acid
 Cephalosporins are similar to Penicillins but are more stable to many
bacterial beta lactamases, have a broader spectrum of activity.

36. 36
MECHANISM OF ACTION :-
Inhibition of transpeptidation process leading to the
formation of imperfect cell wall
Osmotic drive from outside environment to inside
bacterial cytoplasm
Activation of the autolysin enzyme
Lysis of bacteria

37. 37

38. 38
CLASSIFICATION OF CEPHALOSPORINS
Classified into generations based on the spectrum of
antibacterial activity & stability to beta-lactamases.
FIRST GENERATION CEPHALOSPORINS
SECOND GENERATION CEPHALOSPORINS
THIRD GENERATION CEPHALOSPORINS
FOURTH GENERATION CEPHALOSPORINS
FIFTH GENERATION CEPHALOSPORINS

39. 39
FIRST GENERATION CEPHALOSPORINS • Cefazolin (parenteral)
• Cefadroxil (oral)
• Cephalexin (oral)
• Cephalothin
• Cephapirin
• Cephradine (O/P)
Pharmacokinetics:-
• Orally well absorbed
• Do not cross BBB
• Primarily excreted through kidney
• Probenecid increases plasma conc and
increases half life
• All are sensitive to beta lactamase
degradation
Doses
• Cephalexin 0.25-0.5g QID, orally
• Paeds Dose- 25-50mg/kg/d, 4
doses
• Cefazolin 0.5 – 2g 8hourly, i.v
• Paeds dose 25-100mg/kg/d in 3 or
4 doses

40. 40 Clinical uses:- Oral drugs may be used for
• UTI
• Staphylococcal or Streptococcal infections including cellulitis or
soft tissue abscess
• Cefazolin -- DOC for surgical prophylaxis & infections due to
E.coli or K.pneumonia
Antimicrobial spectrum
+cocci > -Bacilli > +Bacilli > -cocci

41. 41
SECOND GENERATION CEPHALOSPORINS • Cefaclor (oral)
• Cefamandole (parenteral)
• Cefonicid
• Cefuroxime (O/P)
• Cefprozil (oral)
• Cefotetan (parenteral)
• Cefoxitin (parenteral)
• Loracarbef
Pharmacokinetics:-
• Oral drugs have good
bioavailability
• Cefuroxime is an ester prodrug
Only drug that crosses BBB
• All drugs are stable to beta-
lactamase except Cefaclor
• Excreted unchanged through
kidney
Probenecid increases half-life.

42. 42
Doses • Cefoxitin 1-2g, 6-8 hrly, IV
Paeds dose 75-150mg/kg/d in 3 or 4 doses
• Cefotetan 1-2g, 12th hourly
• Cefuroxime 0.75-1.5g 8hrly, IV
Paeds dose 50-100mg/kg/d in 3-4 doses
Antimicrobial spectrum
-- Cocci
-- Bacilli
anaerobes
>> +cocci > +Bacilli
 All second generation drugs
are less active against gram-
positive cocci and bacilli
 Have an extended coverage of
gram-negative cocci & bacilli
including anaerobes

43. 43
USES • Against H.influenza or Moraxella catarrhalis
• To treat sinusitis, otitis & lower respiratory tract
infections.
Cefoxitin & Cefotetan:- • Peritonitis
• Diverticulitis
• Pelvic inflammatory
disease
Cefuroxime :- To treat community-acquired
pneumonia

44. 44
THIRD GENERATION CEPHALOSPORINS • Cefixime (oral)
• Cefpodoxime (oral)
• Cefibuten (oral)
• Cefdinir (oral)
• Cefditoren (oral)
• Ceftolozane (oral)
• Cefoperazone (P)
• Ceftriaxone (P)
• Cefotaxime (P)
• Ceftazidime (P)
• Ceftizoxime (P)
Pharmacokinetics:-
• All drugs cross BBB
• Ceftriaxone long half-life(7-8hrs) & high
protein binding
• Cefotaxime – metabolised to an active
metabolite desacetyl Cefotaxime
• Cefoperazone & Ceftriaxone are excreted
through bile
• Others are excreted through kidney

45. 45
• Cefotaxime 1-2g, 6hrly, I.V
Paeds dose 50-200 mg/kg/d in 4-6 doses
• Ceftazidime 1-2g 8-12hrly, I.V
Paeds dose 75-150 mg/kg/d in 3 doses
• Ceftriaxone 0.5-2g 24hrly I.V
Paeds dose 50-100mg/kg/d in 1 or 2 doses
Doses :

46. 46 USES:- Ceftriaxone & Cefotaxime:
Treatment of meningitis caused by • Pneumococci
• Meningococci
• H.influenza
• Susceptible enteric
gram negative rods
Treatment of Sepsis in both immunocompetent and
immunocompromised patients
Antimicrobial spectrum
-cocci
-Bacilli
anaerobes
>
+cocci
+Bacilli

47. 47 FOURTH GENERATION CEPHALOSPORINS
• Cefipime (P)
• Cefpirome (P)
• Cefozopran (P)
Pharmacokinetics :-
• All are given parenterally
Cefipime
• half-life is 2hrs
• Crosses BBB
• Eliminated through kidney
Doses
• Cefipime 0.5-2g 12hrly, I.V
Paeds dose 75-120mg/kg/d in 2-3
doses

48. 48
USES • P.Aeruginosa
• Enterobacteriaceae
• Methicillin-susceptible S.aureus &
S.pneumonia
• UTI
• Resp tract infections
• Empiric therapy for febrile
neutropenic patients
Highly active against Haemophilus and Neisseria sps
Highly active against gram negative organisms

49. 49
FIFTH GENERATION CEPHALOSPORINS • Ceftaroline (P)
• Ceftobiprole (P)
Dose
Ceftaroline fosamil
600mg 12hrly i.v
MOA :-
It binds to penicillin-binding
protein2a (PBP2a) produced by
Methicillin Resistant Staphylococci
Inhibits cell wall synthesis
USES
• Community acquired bacterial pneumonia
• Bacterial skin and soft tissue infections

50. 50
SIDEROPHORE CEPHALOSPORIN
A Novel Cephalosporin called CEFIDEROCOL is approved for
treatment of resistant beta-lactamase producing gram negative
organisms.
MOA:- Binds to penicillin binding proteins, thus inhibiting
cell wall synthesis.
Is bound by active iron transporters and pumped
into the bacterial cell wall.
Cefiderocol is stable in presence of all types of beta-lactamases including
those responsible for multidrug resistance such as metallo-beta-lactamases.

51. 51
Cefoderocol has
potent invitro activity against aerobic gram negative organisms,
including drug resistant Enterobacteriaceae,
Pseudomonas aeruginosa and
Acinobacter baumannii

52. 52
MONOBACTAMS
• Aztreonam
• Tigemonam
• Carumonam
MOA:- prevents bacterial cell wall
synthesis by binding to and inhibiting
cell wall transpeptidases.
Effects :
Infections caused by aerobic, gram negative bacteria in patients
with immediate hypersensitivity to penicillins

53. 53
Pharmacokinetics :-
Its oral bioavailability is poor, hence given I.M or I.V
Dose : 1g 8hrly
The half-life is 1–2 hours and is greatly prolonged in renal
failure

54. 54
CARBAPENEMS
• Imipenem
• Meropenem
• Ertapenem
• Doripenem
• Faropenem
• Razupenem
These 4 are in use at present
Still in phase3 clinical trials
Pharmacokinetics :-
Given I.M/IV, poor oral bioavailability
Imipenem is hydrolysed by renal dehydropeptidase in renal brush border, cause low
urinary concentration, therefore administered along with Cilastin which inhibits
this enzyme and prevents its degradation.

55. 55 Dose
• Imipenem 0.25-0.5g, IV, 6-8hrly
• Meropenem 0.5 -1g, IV, 8hrly
• Doripenem 0.5g I.V infusion, 8hrly
• Ertapenem 1g IV/IM OD
• Faropenem 150-200mg, 6-8hrly, orally

56. 56
Antibacterial spectrum
They have a wider spectrum of antibacterial activity,
gram negative rods including pseudomonas aeruginosa,
Gram positive organisms and anaerobes.
These are resistant to many beta-lactamases
Carbapenems are drug of choice for infections by E.coli
K.pneumoniaeProteus
H.Influenza
Acinobacter
Enterobacter
Serratia
Bacteroides
MSSA
Streptococcus pneumoniae

57. 57
Razupenem
Is a novel carbapenem which has high activity against
multidrug resistant gram positive and gram negative bacteria

58. 58
GLYCOPEPTIDE ANTIBIOTICS
• Vancomycin
• Teicoplanin – a newer glycopeptide
• Telavancin
• Dalbavancin and Oritavancin
Vancomycin is an antibiotic isolated
from the bacterium known as
Amycolatopsis orientalis
VANCOMYCIN

59. 59
• Vancomycin inhibits cell wall synthesis by binding firmly to the d-Ala-d-
Ala terminus of nascent peptidoglycan pentapeptide.
• This inhibits the transglycosylase, preventing further elongation of
peptidoglycan and cross-linking
MOA

60. 60 Antibacterial Activity :-
Vancomycin is bactericidal for Gram-positive bacteria in
concentrations of 0.5–10 mcg/ml.
Vancomycin is exclusively active against aerobic and anaerobic gram
positive species. • Streptococci
• Staphylococci
• Enterococci
• Peptostreptococci
• Corynebacterium
• Listeria clostridium
• Bacillus anthracis

61. 61 Clinical uses:
Infections caused by MRSA
Staph.epidermidis infections with use of intravascular catheters or with
continuous peritoneal dialysis.
Effective treatment staph.enterocolitis and endocarditis
Combination of vancomycin+Gentamycin is synergetic against enterococci
and is useful in enterococcal endocarditis.
 Orally effective in controlling pseudomembranous colitis(PMC)

62. 62 Pharmacokinetics:-
• Poorly absorbed orally.
• Preferred route is intravenous.
• Dose 500mg I.V, QiD or 1g IV BD.
• Excreted unchanged through
kidney.
Adverse effects:
• “Red neck Syndrome”
(due to histamine release)
• Ototoxicity
• Nephrotoxicity
• Skin rashes
• Reversible neutropenia
• Eosinophilia
• Chills and fever.

63. 63 OTHER CELL-WALL ACTIVE AGENTS
• Daptomycin
• Fosfomycin
• Bacitracin
• Cycloserine
DAPTOMYCIN
Daptomycin is a novel cyclic lipopeptide
MOA: Binds to cell membrane, causing depolarisation and
rapid cell death
Effects: Bactericidal activity against MRSA,
Vancomycin resistant enterococci as an alternative
to Linezolid and Quinupristin/Dalfopristim

64. 64 Clinical applications:-
Infections caused by gram positive bacteria including sepsis and
endocarditis.
Cannot be used to treat pneumonia as it inactivated by pulmonary
surfactant.
Pharmacokinetics:-
IV administration, once daily dose
Half-life 8hrs
Renal clearance

65. 65
• Antibacterial agents act in all three stages of cell wall synthesis:
• Fosfomycin and Cycloserine act in the first stage;
• vancomycin, Telavancin, Dalbavancin, Oritavancin, and bacitracin act
in the second stage; and
• The beta-lactams, the largest and most important group, act in the third
stage. Beta-Lactams—which include the penicillins, Cephalosporins,
monobactams, and carbapenems—are bactericidal; autolytic cell death
most likely results from the unopposed action of wall remodeling
proteins called autolysins.

66. 66
CONCLUSION
• Structural and chemical differences among the -lactams determine their spectra of
activity against bacteria with different cell wall architectures.
• Pharmacologists have addressed the mechanism of resistance by (1) developing new
beta-lactam agents, for example, the second- and thirdgeneration cephalosporins that are
resistant to degradation by many beta-lactamases, and (2) co-administering beta–lactam
“decoys”, such as clavulanic acid and sulbactam, that serve as beta-lactamase inhibitors
• Resistance to these agents is typically due to chromosomal mutation, but combination
therapy is critically important to avoid the development of mutational resistance.
• Future innovations will likely include the development of new agents directed against the
additional unique molecular targets that are presented by the biochemistry o the bacterial
cell wall.

67. 67
• The development of innovative therapeutic strategies appears to be
critical to achieving clinical success and, although resistance to these
new agents is uncommon, the emergence of resistant isolates reveals
the potential threat of resistance emergence in the future.
• The fight against resistant microorganisms is ongoing, as the high
adaptability of clinically important Gram positives will continue to
pose significant challenges for global medicine in the short and long
term.
• Antibiotic resistance is considered one of the world's
primary public health problems, as it is a challenge both in
terms of epidemiology and pharmacological treatment of
infectious diseases

68. 68 REFERENCES
1. Bertram G Katzung , Anthony J Trevor ;Basic and Clinical Pharmacology,
Beta-Lactam & other membrane active Antibiotics, 15th edition, Chapter
43; Pg no : 823- 840
2. David E Golan, Principles Of Pharmacology, 4th edition, chapter 35,
pharmacology of bacterial and mycobacterial infections: cell wall
synthesis, page no 622-655.

69. Thank you
69