Therapeutics

1. Antimicrobial Agents and their
Classification
Tejpal DAHIYA
Dept. of zoology

2. PRESENTATION LAYOUT
 Introduction to antimicrobial
drugs
 Classification of antimicrobial
drugs
 Antibacterial drugs:
- Classification
- Indications
- Side effects
 Antibacterial Resistance

4.  Antimicrobial drugs are
chemotherapeutic drugs
 Two categories:
–Antibiotics : Antimicrobial drugs
produced by microorganisms
–Synthetic drugs :
Antimicrobial drugs
synthesized in the lab

5. Have highly selective toxicity to the
pathogenic microorganisms in host body
Have no or less toxicity to the host
Low propensity for development of
resistance
Not induce hypersensitivies in the host
Have rapid and extensive tissue
distribution
Be free of interactions with other drugs
Be relatively inexpensive
Ideal antimicrobial drug

6. Where do antibiotics come
from
 Several species of fungi including Penicillium and
Cephalosporium
E.g. penicillin, cephalosporin
 Species of actinomycetes, Gram +ve filamentous
bacteria
 Many from species of Streptomyces
 Also from Bacillus, Gram +ve spore formers
 A few from myxobacteria, Gram -ve bacteria
 New source explored : plants, fish

7. Sourcesof some common antibiotics and semisynthetics

8.  Ehrlich (1854–1915) coined the term
chemotherapy
 1929 Penicillin discovered by Alexander Fleming
History of Antimicrobial Therapy
 1940 Florey and Chain mass produced penicillin for war
time use becomes available to the public
 1935 sulfa drugs “prontosil” was discovered by Gerhard
Domagk
 1943 streptomycin discovered by Waksman from
Streptomyces griseus

9. Classification of antimicrobial agent
Chemical
structure
Type of
organism to
be killed
Antimicrobial
agent

10. Based on chemical structure
Group Examples
Sulfonamide sulfadiazine, dapsone, paraminosalicylic acid
B-lactam penicillins, cephalosporins, monobactams
tetracycline oxytetracycline, doxycycline
aminoglycoside streptomycin, gentamycin, neomycin
Macrolide erythromycin, azithromycin, clarithromycin
polypeptide polymyxin-B, bacitracin
glycopeptide vancomycin
Quinolones ciprofloxacin, ofloxacin, moxifloxacin, gatifloxacin
Azole derivative miconazole, clotrimazole, ketoconazole, fluconazole
nitroimidazole Metronidazole, tinidazole

12. Antibacterial drugs
 Drugs active against bacteria
 Natural or synthetic
 Naturally, obtained from
microorganisms which suppress the
growth or kill other microorganisms
 Synthetics are made in lab by
bioengineering
 The term antibiotic was first used
by Selman Waksman

13. classification
Spectrum of activity
Type of action
Mechanism of action

14. Bacteriostatic
Sulphonamides
Tetracycline
Chloramphenicol
Macrolides
Bactericidal
Penicillins
Aminoglycosides
Cephalosporins
Vancomycin
Type of action

15. Narrow spectrum
Penicillin G
Streptomycin
Erythromycin
Broad spectrum
Tetracyclin
Chloramphenicol
Cephalosporins
Spectrum of activity

16. • Inhibit cell wall synthesis
• Cause leakage from cell membranes
• Inhibit protein synthesis
• Inhibit DNA gyrase
• Action as antimetabolite
Mechanism of action

17. Mechanism of action

18. Inhibit cell wall synthesis
These are the drugs that interfere
with the cell wall synthesis process
These drugs consist β-Lactam
rings so called β-lactam antibiotics
Bactericidal in nature

19. Penicillin
Cephalosporin
Vancomycin
Inhibitor of cell wall synthesis

20. First antibiotic to be used
clinically
Obtained from fungus
Penicillium notatum
Structure
β-lactam is responsible for
antimicrobial activity
Properties like antimicrobial
spectrum, stability to stomach
acid and susceptibility to
bacterial degradative enzymes
(β-lactamases) depends upon
the side chain
Also, differ in structure by the
side chain
Penicillin

23. Working of penicillin
NAM-NAG-NAM-NAG
Pep Pep
Pep Pep
NAM-NAG-NAM-NAG
Pep side chains are cross linked as the
final step in synthesis of peptidoglycan in
the presence of penicillin binding protein
(PBPs).Penicillin drugs inhibit this
process after binding with PBPS.
Pep=peptide linkage
NAM &NAG =N-acetyl muramic acid and N-
acety glucosamine
Penicillin
Binds to PBPs
Inhibition of cross
linkage
Blockage of
peptidoglycan
synthesis
Cell dies

24. Penicillin
G
Penicillinase
resistant
penicillins
Extended
spectrum
penicillins
-Have side chain of benzyl
group
-Active against Gram
+ve bacteria than
Gram -ve
-Resistant against
penicillinase/β-
lactamase producing
bacteria
eg. Methicillin,
Cloxacillin
 The latter two are semisynthetic in
-Sensitive against wide
range of bacteria(Gram
+ve/-ve)
eg. Ampicillin,
Amoxicillin
Types

25. Coverage of Penicillins
• Penicillin G
• Gram Positive cocci:
• Streptococcus pneumonia
Streptococcus pyogens
• Gram Positive bacilli:
• Bacillus
Corynebacterium,
Clostridia, Listeria
Spirochetes
• Gram Negative cocci:
• Neisseria
Penicillinase
resistant
penicillins
Penicillinase
producing
Staphylococcus
Extended
spectrum
penicillins
Sensitive against all
Gram positive as well
following Gram
negative bacteria

26.  Hypersensitivity reaction (rash, itching)
 Pain at i.m. injection site, thrombophlebitis
of injected vein
 Oral penicillin can cause nausea, vomiting or
diarrhea
 Toxicity to the brain: mental confusion,
convulsions & coma
Side Effects

27. Beta-lactamase inhibitors
 Some of the bacteria produces β-lactamase enzyme.
This enzyme causes hydrolysis of β-lactam ring so
that the antibiotic activity of penicillin/ β-lactam drug
is destroyed
 This can be prevented by two inhibitors i.e. clavulanic
acid and sulbactam
 These are the enzyme with β-lactam ring but has no
antibacterial activity. It combines with the lactamase
enzyme and thus prevent the destruction of lactam
ring of antibiotic making it potent to show action

28. Cephalosporins
Have similar action to penicillin (bactericidal)
Semisynthetic antibiotics derived from
cephalosporin-C obtained from fungus
Cephalosporium

29. Cephalosporins
Classification

30. Cefazolin Cephalexin
Cephradine Cephadroxil
 Exhibits good activity against Gram positive
cocci like Staph.sps, Strep. sps & Gram –ve
rods like E.coli, Klebseilla
Includes
First Generation

31. Cefuroxim
e
Cefoxiti
n
Cefaclor Cefuroxime Axetil
rod
H.influenza
Second Generation
 Shows somewhat enhanced activity towards
Gram –ve bacteria compared to 1st generation
Coverage:
 Coverage of 1st generation &
 Additional -ve cocci like Neisseria & -ve
Includes

32. Cefotaxime Ceftriaxone
Ceftizoxime Cefixime
Third Generation
 More potent than 2nd generation
 Shows augmented activity
against:
 Enterobacteria
 β-lactamases producing
bacteria
 Pseudomonas
Includes

33. Cefepime
Cefpirome
Fourth Generation
 Similar to 3rd generation
 Shows increased resistance to β-
lactamase producing bacteria
Includes

34.  Alternative to penicillin allergic host
 Respiratory , urinary and soft tissue
infection caused by Gram –ve organism
 Septicaemia by Gram –ve bacteria
Indications

35.  Pain on intramuscular injection
 Diarrhoea due to alteration of gut
ecology
 Hypersensitivity reaction
 Nephrotoxicity
Side effect

36. Vancomycin
 Highly effective against Gram +ve
cocci
 Uses : used for serious infections
 Drug of choice for treating:
 Methicillin resistant
staphylococci
 Penicillin resistant S.
pneumoniae

37.  Nephrotoxic drug, can cause impaired renal
function and lead to permanent deafness
 Contradicated in hypersensitivity reaction
Side effect

38. Drugs
inhibiting
Protein
synthesis
Tetracycline
Chlorem-
phenicol
Macrolide
Aminoglycoside

39. Mechanism of action

40. Tetracycline
 Broad spectrum antibiotics
 Have nucleus of four cyclic rings, so
named tetracycline
 1st tetracycline to be obtained
was chlortetracycline
 Bacteriostatic in nature

41. Class I
• Tetracycline
• Oxytetracycline
Class II
• Methacycline
Class III
• Doxycycline
• Minocycline
Gram -ve Gram +ve Spirochaetes Chlamydiae
Rickettsiae Entamoeba Mycoplasm
Division of Tetracycline
Coverage of Tetracycline

42. Vibriosis
Brucellosis
Drug of first choice
Atypical coccus infection
(S.iniae)
Drug of second choice
To penicillin for Clostridium,
actinomyces
Indications
Rickettsial infection
To azithromycin for chlamydial
infection

43.  Liver toxicity
 Renal toxicity
 Tetracycline get deposited in bone
Side effects

44. Chloramphenicol
 Broad spectrum
 Nitrobenzene substitute
 Bacteriostatic in nature
 Initially obtained from Streptomyces,
now synthesized chemically

45. Though static in nature, its high concn
can be cidal too
Active against
Gram +ve cocci & bacilli
Chlamydia
Gram –ve cocci & bacilli
Coverage of chloramphenicol

46.  Because of serious bone marrow toxicity use of this
drug has been reduced much
 Not used for infection that can be treated by
other antibiotics. However, some of its use
are:
- Enteric infection
- Haemophilus infection
 the topical application is less hazardous than
systemic use
 blepharitis etc.
Indications

47.  Bone marrow depression
 thrombocytopenia
 Hypersensitivity reaction
 It occurs due to poor renal development in
neonate which results in accumulation of drug
Side effects

48. Aminoglycosides
 Bactericidal in nature
 Includes neomycin,
gentamicin, tobramycin,
amikacin, streptomycin
 good coverage for Gram
–ve bacilli like P.
aeruginosa, Proteus,
Klebseilla, E. coli

49. Neomycin
 Broad spectrum among all
the aminoglycoside
 But, cannot show effectivity
against P. aeruginosa
 Eyedro
p
0.5
%

50. Gentamicin
 Mainstay in the
treatment of serious
Gram –ve bacilli
infection
 Frequently used for
empiric therapy in
presumed Gram –ve
bacilli infection
 Ointment 0.3%

51. Tobramycin
 Same coverage
as gentamicin
 Also effective
against
Staphylococci
 Potent to P.
aeruginosa
 Eyedrop 0.3%nt
0.3%

52. Amikacin
It is
semisynthetic
Preferred in
Gram –ve
infection
resistant to
gentamycin
and tobramycin

53.  Gram –ve bacillary infection
 Septicaemia, abdominal sepsis
 Bacterial endocarditis
Indications

54. Nephrotoxicity: retention of these
drugs in proximal tubular cells
disrupts Ca mediated transport
system and cause renal damage
Neuromuscular paralysis: these
drugs cause decrease in release of
AchAllergic reaction: Contact
dermatitis
Side effects

55. Macrolides
 Bacteriostatic in nature
 Protein synthesis inhibitor
 Are compounds having a
macrocyclic lactone ring to
which deoxy sugars are
attached
 Includes
erythromycin,
clarithromycin and
azithromycin

56. Erythromycin
 First member of this group
 Effective against many of the same
organism as penicillin G
 So, used if host allergic to penicillin
 Ointment
0.5
%

57. Fluoroquinolones
Drug interfering with
DNA

58. Fluoroquinolones
 Inhibit bacterial
DNA synthesis
 Are synthetic
fluorinated analogs
of quinolones
(Nalidixic acid)
 Bactericidal in
nature

59. Mechanism of action
 Fluoroquinolones block the bacterial DNA
synthesis by inhibiting bacterial
topoisomerase II (DNA gyrase) and
topoisomerase IV
 Inhibition of DNA gyrase prevents the
relaxation of positively supercoiled DNA that
is required for normal transcription and
replication
 Inhibition of topoisomerase IV interferes
with separation of replicated chromosomal
DNA into the respective daughter cells
during cell division

61. Classification
Ciprofloxacin Ofloxacin
Pefloxacin Cinafloxacin
Lomefloxacin
Norfloxacin
2
nd
Generation
1st Generation

62. Moxifloxacin Gatifloxacin
Trovafloxacin
Levofloxacin
3rd Generation
4
th
Generation

63. Ciprofloxacin
 Broad spectrum( most susceptible are
aerobic Gram –ve bacilli)
Widen use due to
 Rapid in action
 Relatively long post-antibiotic effect
 Low frequency of mutational resistance
 Active against many β-lactam and
aminoglycoside resistant bacteria

64. From first to fourth
generation
-ve +ve
covera
ge
Ofloxacin
 Active against gram negative
 Also shows more potency against gram +ve
cocci + chlamydia, mycoplasma too
Moxifloxacin
 Active against gram –ve bacilli, gram +ve
cocci, β- lactam and macrolide resistant ones
and anaerobic bacteria

65.  Prophylaxis and treatment of urinary tract
infection
 Septicaemia
 Respiratory infection
Indications

66. GI upset most
common
Hypersensitivity
reaction
rash,
photosensitivity
CNS disturbances
Side effects

67. Metabolic
inhibitors
Sulfonamides
 Bacteriostatic
 Binds and blocks enzymes mainly pteridine
synthetase,dihydrofolate reductase responsible
for folic acid synthesis
 Folic acid enzymes are nessary for the
synthesis of amino acids, hence necessary
for bacterial protein

68. Mode of action - These antimicrobials are analogues of
para- aminobenzoic acid (PABA) and competitively
inhibit formation of dihydropteroic acid
Spectrum of activity - Broad range activity against
Gram +ve and Gram -ve bacteria; used primarily in
Nocardia infections
Combination therapy - The sulfonamides are used in
combination with trimethoprim; this combination blocks
two distinct steps in folic acid metabolism and prevents
the emergence of resistant strains

69. p-aminobenzoic acid + Pteridine
Tetrahydrofolic acid
Pteridine
synthetase
Dihydropteroic acid
Dihydrofolate
synthetase
Dihydrofolic acid
Dihydrofolate
reductase
Thymidine
Purines
Methionine
Trimethoprim
Sulfonamides

70. A variety of mutations can lead to antibiotic
resistance
Mechanisms of antibiotic resistance
 Enzymatic destruction of drug
 Prevention of penetration of drug
 Alteration of drug's target site
 Rapid ejection of the drug
Resistance genes are often on plasmids or
transposons that can be transferred between
bacteria
Antibiotic
Resistance

71. Mechanism of Resistance
In cell wall
synthesis
inhibitor
Penicillinases: break the
beta lactam ring structure
( staphylococci)
Structural changes in PBP:
S.aureus, S. pneumococci
Change in porin
structure: concerns the
Gram Negative organism
In protein synthesis inhibitor
 A mutation of ribosomal binding
site
 Enzymatic modification of antibiotic
 An active efflux of antibiotic out of
cell
In nucleic acid synthesis
inhibitor
 An alteration of alpha subunit of
DNA gyrase (chromosomal)
 Beta subunit of RNA

72. oTextbook of microbiology by Ananthanarayan &
Paniker
o Essentials of Medical Pharmacology KD Tripathi
o Basic & Clinical Pharmacology by Bertram G.
Katzung
References