1) The document discusses antimicrobial agents and provides an overview of their classification, mechanisms of action, development of resistance, and appropriate usage. 2) Key points include the differences between human and bacterial cells that allow antimicrobials to selectively target bacteria, the different mechanisms of antimicrobials including inhibition of cell wall synthesis, membrane disruption, and inhibition of protein and DNA/RNA synthesis. 3) Resistance is a major issue discussed due to overuse and misuse of antimicrobials. Proper use and development of new agents is important to maintain effectiveness.

1. Antimicrobial Agents
(General Considerations)
Prof. R. K. Dixit
Pharmacology and Therapeutics
K.G.M.U. Lucknow
dixitkumarrakesh@gmail.com
9415089880

4. Objectives
• After this lecture students will be able to answer
– What are antimicrobials, antibiotics, chemotherapeutic agents
(Terminologies used in antimicrobial treatment)
– Classification of antimicrobials (chemicals, mechanism, spectrum)
– Mechanisms of action of antimicrobials
– Resistance development in antimicrobials
– General adverse effects of antimicrobials
– General drug interactions related to antimicrobials
– Uses of antimicrobials (Therapeutic and Prophylaxis)
– Selection of appropriate antimicrobials
– Precautions while prescribing antimicrobials and failure

5. A naturopath tells
“One should never take antibiotics
Except in
Pneumonia, GIT infections, boils, meningitis,
encephalitis, osteomyelitis, occular infections, or
other serious illness……………………………………….”

6. Allopath is Lucky to have the help of Antimicrobials
But
This Luck may not last long due to reasons……
–Inappropriate use,…
–Overuse…..
–Antimicrobial resistance
–Reduced immunity
–Worsening of environment
–Co morbid illnesses like diabetes, malnutrition……
–Less interest of pharmaceuticals in this field
–New antimicrobials generally expensive

7. Antimicrobials , Antimicrobials , Antimicrobials ,
Antimicrobials, Antimicrobials , Antimicrobials
Antimicrobials!!!
Penicillin, ampicillin, amoxycillin, ticarcillin, piperacillin,
flucloxacillin, dicloxacillin, oxacillin, methicillin, nafcillin,
carbenicillin, eryhtromycin, clindamycin, roxythromycin
clarithromycin, tetracycline, doxycycline, minocycline,
vancomycin, teicoplanin, augmentin, gentamicin, tobramycin,
amikacin, streptomycin, azithromycin, aztreonam, cephalexin,
cefotaxime, cephamandole, cefepime, ceftriaxone,
ceftazidime, cefpirome, imipenem, chloramphenicol,
cotrimoxazole, ciprofloxacin, norfloxacin, trimethoprim,…….
………………………………………………………………………………………………
………………………………………………….. hundreds of different
antimicrobial agents on the market.

8. What are the two basic causes of diseases
• Abnormality in (Biochemistry, Anatomy and
Physiology (BAP) of the body) the body’s self
environment or cells or tissues or organs.
Reasons may be anything including deficiency
of essential elements, vitamins etc or
abnormality in CNS, CVS, ANS etc.
• Attack on the body by
–Real invaders (Viruses, Bacteria, Protozoa,
Helminthes, Fungus etc)
–Pseudo invaders- Malignant cells

9. What are the two basic types of therapies
in modern medical science
• Pharmacotherapy against
– Abnormality in (Anatomy, Biochemistry and
Physiology of the body) the body’s self environment
or cells or tissues or organs. Reasons may be anything
including deficiency of essential elements, vitamins
etc or abnormality in CNS, CVS, ANS etc.
• Chemotherapy against
– Real invaders (Viruses, Bacteria, Protozoa,
Helminthes, Fungus etc)
– Pseudo invaders- Malignant cells

10. Terminology
11
Chemotherapy –
Use of drugs to treat infections and malignancy
Antimicrobials and Antineoplastic agents (Beware of using this)
Pharmacodynamic agents-
Drugs regulating physiological process of body and act on the body cells.
Chemotherapeutic agents-
Selectively acting against microbes or malignant cells. (Don’t touch body cells)
Prophylactic therapy-
To prevent the occurrence of disease (May be chemo may be pharmacotherapy)
Antimicrobials –
Used in treating infectious microbial diseases.
Antibiotics –
Produced from microbes to inhibit or kill other microbes in low concentration
(Antimicrobials from microbes)
All antibiotics are antimicrobials
But
All antimicrobials are NOT antibiotics

11.  Bacteriostatic-
 Stop the growth of bacteria
 Bactericidal-
 Kill the bacteria
 PAE-
 Post antibiotic effect
 Minimum Inhibitory Concentration (MIC)-
 Which stops the growth
 Minimum Bactericidal Concentration (MBC)-
 Which kills by 99.99%
Which concentration will be more MIC or MBC
What about MBC-MIC value regarding cidal or static activity
MBC – MIC Less = Bactericidal
MBC – MIC More = Bacteristatic
What comes first
•Stopping
Or
•Killing

12. • Bacteriostatic drugs
–Kill (MBC)
– This is your last chance to
stop
– Again I warn please stop
– Please this is serious stop
– Stop please I request
– Please stop
–Stop (MIC)
• Bactericidal
– if don’t obey Kill (MBC)
– Stop (MIC)
Bacteriostatic drugs (Police)
show more patience
Bactericidal are to kill
(Commandos)

13. MBC – MIC is More MBC – MIC is Less
What about MBC – MIC in this

14. • Prebiotics-
–Chemicals which stimulate the growth of
intestinal commensals and prevent multiplication
and establishment of pathogenic bacteria
• Inulin, Lactulose, Lactitol (ILL)
• Probiotics-
–Live microbs used as supplements to maintain
the intestinal bacterial flora.
• Lactobacilli and Bifidobacteria

15. Terminology Summary
 Chemotherapy –
 Pharmacodynamic agents-
 Chemotherapeutic agents-
 Antimicrobials –
 Antibiotics –
 Bacteriostatic-
 Bactericidal-
 PAE-
 Minimum Inhibitory Concentration (MIC)-
 Minimum Bactericidal Concentration (MBC)-
• Prebiotics-
• Probiotics-
• Prophylaxis-

16. Beware of term Chemotherapy
Presently it is used only for Antineoplastic agents

17. History of Antimicrobials

18. Historical perspectives
• Pasteur- (1877)
– Phenomenon of antibiosis
• Paul Ehrlich- (1906)
– Father of Chemotherapy,
– Coined term chemotherapy
• Domagk- (1935)
– Discovery of sulfonamides (Prontosil to sulphanilamide)
• Fleming, Chain, Florey-
– Penicillin (1929, 39, 41) from penicillium
• Waksman-
– Streptomycin, from actinomycetes,
– Coined term antibiotic

20. Invaders And Agents Acting Against
• Viruses
• Bacteria
– Gram Positive
– Gram Negative
– Acid fast
• Fungi
• Protozoa infections
– Amoeba
– Malarial parasite
– Others
• Helminthes
• Neoplastic cells
• Antiviral
• Antibacterial
– Against gram positive
– Against gram negative
– Antitubercular/Leprotic
• Antifungal
• Antiprotozoal
– Antiamoebic
– Antimalarial
– Other antiprotozoals
• Anthelmintics
• Antineoplastic /
Chemotherapeutic agents

21. What are the most important factors to be good
Antimicrobial or Chemotherapeutic Agent?
• Selectivity and Specificity (Don’t Touch
Human Cells)
• Safety
• Stability
• Availability
• Feasibility & Affordability
• Efficacy
SAFE

22. Here onwards we will focus on
Antibacterials only

23. How bacteria are identified
• Gram staining
• Developed by Hans
Christian Gram in 1884
• Based on structural
characters of cell wall
• Gram positive has thick
layers of peptidoglycan
and stain purple
• Gram negative contains
thin and stain pink
• Reagents used are gention
violet, iodine, alcohol,
safarin
• Acid fast or Ziehl-Neelsen
staining
• Described by Franz Ziehl and
Friedrich Neelsen
• Acid fast organisms contain
large amounts of lipid
substance within cell walls
called MYCOLIC ACIDS which
resist staining by gram stains.
Reagents used are Ziehl-
Neelsen carbol fuchsin, acid
alcohol and metylene blue. Acid
fast bacteria appear red
– Mycobacteria
– Nocardia
By structure and culture and Colony characters

25. Human Vs Bacteria
HUMAN CELLS ARE LAZY WHILE BACTERIAL CELLS ARE CRAZY
Who’s Cells
are more
Lazy???
Exploring Selectivity and Specificity

26. Human Cell Vs Bacterial Cell
Use Preformedfolic acid
for synthesis of DNA
Use precursor PABA of folic acid and
synthesize Folic acid by themselves to be used for synthesis
of DNA
Topoisomerase II
during DNA replication
Topoisomerase IV and DNA
Gyrase during DNA replication
Sterols
Hopanoids
Different DNA dependent
RNA Polymerase

27. Differences between human cells Vs Bacterial Cells
(Makes the antibacterial selective)
• Human cells don’t posses wall
– (Peptidoglycans = peptides + sugar)
• Human cell membrane is different
– ( Bacteria Contain HOPANOIDS (with extra ring) in place of
Sterol)
• Human cells take preformed dihydrofolic acid
– (no need of PABA in human)
• Dihydrofolic acid reducatase enzyme is different
• Topoisomerases are different
– (in bacteria topoisomerase IV, DNA Gyrase)
• DNA dependent RNA polymerase is different
• Ribosome 60S subunit (in bacteria 50S)
• Ribosome 40S subunit (in bacteria 30S)
Human Cells
are more lazy
than Bacterial
Cells

28. Gram Positive Gram Negative

29. Gram positive & Gram Negative
• Gram positive bacteria have
– Thick cell wall
– Peptidoglycan directly accessible from environment
• Gram negative bacteria have
– Thin cell wall
– Surrounded by inner and outer membrane
– Of lipopolysaccharide, phospholipids, and proteins
– Outer membrane is a barrier to diffusion of antibiotics
• Limited antibiotics may diffuse through porins

30. Organism affected
• Anti-viral
• Anti-bacterial
• Anti-fungal
• Anti-protozoal
• Anthelmintic
• Antitubercular
• Antileprotic
Sources
• Fungi-
– Penicillin
– Cephalosporins
– Griseofulvin
• Bacteria-
– Polymyxin B
– Colistin
– Bacitracin
• Actinomycetes-
– Most common
– Aminoglycosides
– Tetracyclines
– Chloramphenicol
– Macrolides

31. Spectrum
• Narrow
– Penicillin G
– Aminoglycosides
– Isoniazide
• Broad
– Tetracycline
– Chloramphenicol
• Extended
– Ampicillin
– Amoxicillin
– Sulphonamides
– Fluoroquinolones
– Most……..
Bacteristatic
– Sulfonamides and Trimethoprim (alone)
– Tetracyclines
– Macrolides (Erythromycin)
– Chloramphenicol
– Ethambutol
– Nitrofurantoin
Bactericidal
– Cotrimoxazol
– Penicillins
– Cephalosporins
– Aminoglycosides
– Vancomycin, Daptomycin
– Fluroquinolones (ciprofloxacin)
– INH, Rifampicin, Pyrazinamide
– Polymixins, Bacitracin
– Metronidazole

32. Differences Between Human Cells Vs
Bacterial Cells To Use As Selective
Targets For The Antibacterial Agents

33. Differences between human cells Vs Bacterial Cells
(Makes the antibacterial selective)
• Human cells don’t posses wall
– (Peptidoglycans = peptides + sugar)
• Human cell membrane is different
– ( Bacteria Contain HOPANOIDS (with extra ring) in place of Sterol)
• Human cells take preformed dihydrofolic acid
– (no need of PABA in human)
• Dihydro folic acid reducatase enzyme is different
– (thousand time affinity)
• Topoisomerase II are different
– (in bacteria topoisomerase IV, DNA Gyrase)
• DNA dependent RNA polymerase is different
• Ribosome 60S subunit (in bacteria 50S)
• Ribosome 40S subunit (in bacteria 30S)
1
2
3
4
5
6
7
8
Human Cells
are more lazy
than
Bacterial
Cells

34. Mechanism of action (Targets)
• Cell Wall synthesis inhibition-
– Beta-lactams, Vancomycin, Cycloserines
• Cell membrane Leakage-
– Polypeptides, Polyenes
• Folate Synthesis inhibition-
– Sulfonamides
– Pyrimethamine
• DNA gyrase and Topoisomerase (IV) inhibition-
– Fluroquinolones
• RNA polymerase inhibition-
– Rifampicin,,
• Protein Synthesis Inhibition- (ATT)
– Inhibition of 50S ribosome-Chloramphenicol, Macrolides, Clindamycin,
Linezolid
– Inhibition of 30S ribosome -Aminoglycosides, tetracyclines
7
8
1
2
3
4
5
6
Human Cells are more lazy
than Bacterial Cells

35. 1
2
3
4 5
6
7
8
Human Cells are more lazy
than Bacterial Cells

36. Folate Metabolism and sequence of
Protein synthesis in bacteria

37. PABA
Dihydrofolic acid
Tetrahydrofolic acid
Purines and Pyrimidines
DNA And RNA
DNA unwinding and thread separation (DNA
gyrase / Topoisomerase IV)
DNA dependent RNA Polymerase
tRNA +Amino Acids
Ribosome unit (50S)
Ribosome unit (30S)
Protein Synthesis
Dihydro-folic acid Synthetase
Dihydro-folic acid reductase
DNA multiplication
mRNA
Sulphonamides (PABA analogue and inhibitor of DHFAS)
Trimethoprim and Pyrimethamine (inhibitor of
DHFAR)
Quinolones
(Inhibitor of DNA gyrase
and Topoisomerase IV)
Rifampicin
(inhibitor of DNA dependant RNA Polymerase)
Chloramphenicol, Macrolides (50S)
Aminoglycosides, Tetracyclines (30S)

38. DNA unwinding and thread separation (DNA
gyrase / Topoisomerase IV)
PABA
Dihydrofolic acid
Tetrahydrofolic acid
Purines and Pyrimidines
DNA And RNA
Dihydro-folic acid Synthetase
Dihydro-folic acid reductase
RNA Polymerase
tRNA +Amino Acids
Ribosome unit (50S)
Ribosome unit (30S)
Protein Synthesis
mRNA
Sulphonamides (PABA analogue and inhibitor of DHFAS)
Trimethoprim and Pyrimethamine (inhibitor of
DHFAR)
Quinolones
(Inhibitor of DNA gyrase
and Topoisomerase IV)
Rifampicin (inhibitor of DNA dependant RNA Polymerase)
Chloramphenicol, Macrolides (50S)
Aminoglycosides, Tetracyclines (30S)
3
4
5
6
7
8

39. Cell Wall synthesis inhibition-
Beta-lactams, Vancomycin, Cycloserines
Cell membrane Leakage-
Polypeptides, Polyenes
PABA
Dihydrofolic acid
Tetrahydrofolic acid
Purines and Pyrimidines
DNA And RNA
DNA unwinding (DNA gyrase)
Threads sepeartion (Topoisomerase IV)
RNA Polymerase
mRNA
tRNA + Amino Acids
Ribosome unit (50S)
Ribosome unit (30S)
Protein Synthesis
Dihydro-folic acid Synthetase
Dihydro-folic acid reductase
DNA multiplication
Sulphonamides (PABA analogue and inhibitor of DHFAS)
Trimethoprim and Pyrimethamine (inhibitor of DHFAR)
Quinolones
(Inhibitor of DNA gyrase and Topoisomerase IV)
Rifampicin (inhibitor of RNA Polymerase)
Chloramphenicol, Macrolides (50S)
Aminoglycosides, Tetracyclines (30S)
1
2
3
4
5
6
7
8

40. 1
2
3
4 5
6
7
8

41. Which of the following will have effect for longer time on
the control of notorious activities of baby
Post Pityai Effect
(Post Antibiotic effect)

42. Post-Antibiotic Effect
• Capacity to inhibit the growth of bacteria after
removal of the drug from the culture (body)
• Provides additional time for the immune
system to remove bacteria that might have
survived
Post Pityai Effect

43. ANTIMICROBIALS
Dose-dependent (With PAE) Time-dependent
Antibacterial effect directly
depends on their concentrations
in the locus of infection
(high doses 1-2 times/24h)
•Aminoglycosides
•Fluoroqinolones
•Metronidazol
•Amphotericin B
Effectiveness depends on a
period of time, during which
concentration in blood
overwhelms MIC for a particular
causative agent
(constant i.v. infusion or 3-6
times/24h)
•Beta-lactames
•Glycopeptides
•Macrolides
•Tetracyclines
•Vancomycin
Post Pityai Effect

44. Summary
• Human cells are…………while bacterial cells are…..
• Human cells use ………………………..folic acids
• Gram positive cells contain …………………….
• Gram negative bacteria contain two………………..
• High quantity of Mycolic acid is present in……….
• If Post antibiotic effect is more then frequency is
• There are eight targets for Antibacterials to act. These
are…………..
• Antibacterials can be classified according to………………..

45. Relax and Revise

46. What is this?????

47. Antimicrobial Resistance
Resistance
Intrinsic Acquired
Mutation
Conjugation
Transformation
Transduction
Not Dangerous/
less clinical importance
Transmitted vertically only
Dangerous/
clinical
importance
Can be
transferred
Horizontally and
Vertically

48. Inherent Resistance
(Not Much of clinical importance)
• Bacteria naturally resistant
– e.g., Gram-negative bacteria resistant to penicillins
– Genes transferred to the bacterial progeny
• Bacteria may be resistant because
– No mechanism to transport the drug into the cell
– Do not contain antibiotic’s target process or protein

49. Acquired Resistance
• Due to exposure of antimicrobials
• Horizontal evolution:
–Resistance genes pass from resistant to
nonresistant strain,
–Antibiotics- a selective pressure.
–Gene transfer mechanisms:
• Conjugation.
• Transduction.
• Transformation.

50. Resistance Transfer Horizontal

51. Antibiotic Produces Selection Pressure

53. Resistance to Antibiotics
5. Adaptation of
alternate metabolic
pathway

54. Factors favoring Resistance
•Prescription related factors:
•Overuse and Underuse
•Early discontinuation
•Over continuation
•Less dose, duration
•Livestock doping:
•Animals exposure

58. Adverse Drug Reactions of Antimicrobials
• General
– Hypersensitivity reactions
– CNS
– GIT
– Injectable S/E
– Vitamin Deficiency
– Super infections
– Teratogenic
– Masking of infections
– Intolerance
– Drug induced fever
• Specific

59. General-Adverse effects of antimicrobials
•Hypersensitivity reaction-
•Penicllins, Sulphonamides
•Skin rashes , Angioedema, Bronchospasm
•Anaphylaxis,
•Management with OASIS
•Oxygen,
•Adrenaline {Physiological antagonist of histamine}
•Antihistaminics
•Steroid,
•IV fluid
•Supportive,

60. •Gastrointestinal symptoms-
•Nausea,
•Anorexia,
•Gastric irritation,
•Flatulence, indigestion,
•Altered GI motility,
•Mouth ulcers, Glossititis, Stomatitis, Chelitis
•Esophagitis,
•Mal-absorption syndrome
•Tetracyclines, Chloramphenicol, Quinolones,
Ampicilline, Metronidazole

61. •Injectable Side effects-
•Pain, Abscess formation,
•Thrombo-phlebitis in case of IV
•Flushing, redness in case of rapid IV

62. • Deficiency of Vitamins-
• Vitamin Bcomplex and Vitamin K,

63. Reduced Efficacy
of other drugs
• Drugs which
need entero-
hepatic
recirculation for
their effect like
Oral
contraceptives

64. Super infections
New infection
• Most common organisms
• Pseudomonas, Candida, Proteus
• Clostridium difficle- Pseudomembranous Colitis
• Due to removal of inhibitory mechanisms (Bacteriocins
and competition for nutrition)
– Common in immunocompromised, Diabetic, Surgical patients
– Common drugs causing super infections (CAT)
• Clindamycin, Cotrimoxazole, Chloramphenicol
• Ampicillin
• Tetracyclines
Treated by Metronidazole, Vancomycin, Bacitracin

65. •CNS-
•Headache,
•Irritability,
•Sedation,
•Tinnitus ,
•Ataxia,
•Forgetfulness
•Slurred speech,
•Blurring of vision
•Convulsions in high dose of cephalosporins

66. •Masking of infections-
•eg. Tt Gonorrhea mask Syphilis
•Idiosyncratic and Intolerance-
•Drug Fever-
•Electrolyte imbalance-

67. • Teratogenic effects-
• No antimicrobial is absolutely safe during pregnancy
• No one is Category A
• Category B, C and D can be given under special situation
• Category X absolutely contraindicated to pregnant

68. Antibiotics in Pregnancy
FDA Category Antibiotics in Category
A
B Penicillins, Cephalosporins, Carbapenems (except Imipenem),
Daptomycin, Vancomycin (oral), Clindamycin, Erythromycin,
Azithromycin, Metronidazole (avoid first trimester), Nitrofurantoin,
Acyclovir, Amphoterocin B, Ethambutol
C Quinolones, Chloramphenicol, Clarithromycin, Imipenem, Linezolid,
Trimethoprim/Sulfa (D if used near term), Vancomycin (IV),
Rifampin, INH, PZA, PAS, Fluconazole, Caspofungin
D Tetracyclines (Doxy, Tige, Mino), Voriconazole, Aminoglycosides
(some put gentamicin as a category C)
X Ribavarin
Betalactam
(Penicillins and
Cephalosporins)
Macrolides
Quinolones
Sulphonamides
Tertracylines
Aminoglycosides

69. Specific Side effects of antimicrobials
•Bone marrow suppression-
•Chloramphenicol (Aplastic Anaemia)
•Thrombocytopenia-
•Sulphonamides
•Cephalosporins
Cefamandole
Cefoperazone
Cefotetan
Same which produce Disulfiram like reaction

70. • Renal toxicity-
• Aminoglycosides,
• Tetracyclines EXCEPT Doxycycline,
• Cephalothin,
• Talampicillin,
• Nitrofurantoin, Nalidixic acid, Amphotericin B,
• Vancomycin, Ethambutol, Flucytosine,
Methacillin,

71. •Hepatotoxicity-
•Rifampicin,
•Isoniazide (in fast acetylators due to accumulation of
Acetyl – isoniazide and acetyl – hydrazine)
•Pyrazinamide
•Tetracycline,
•Erythromycin estolate,
•Talampicillin, Nalidixic acid, Trovafloxacin
•Oxacillin,

72. • Photoxicity-
• Tetracyclines
• Demeclocycline
• Doxycycline
• Quinolones
•Sparfloxacin

73. •Ototoxicty-
•Aminoglycosides, Vancomycin
•Diabetes insipidus-
•Demeclocycline
Drugs producing Diabetes inspidus- Lithium, Demeclocycline
Drug used in treatment of Lithium induced Diabetes inspidus- Amiloride

74. • Neuromuscular block-
• Amino-glycosides
• Polymyxin- B
• Colistin
• Gaping of wound
• Respiratory paralysis in Myasthenia gravis

75. •Retinal damage-
•Chloroquine
•Neuropathy-
•Polypeptides
•Amphotericin B
•Nitrofurantoin
•Carbenicillin
•Dapsone
•Chloroquine
•Isoniazid- in slow acetylators
•Due to increased excretion of pyridoxine
•Accumulated INH inhibits pyridoxine-kinase
(Pyridoxine Kinase converts pyridoxine to active form)
Isoniazid in
•Slow Acetylators- Neuropathy
•Fast Acetylators- Hepatotoxicity

76. Isoniazid Side effect depends on
Acetylation status of Patient
• North Indians are
– 40% Fast
– 45% Intermediate
– 15% Slow Acetylators
Neurotoxicity
Hepatotoxicity
Hydrazonation
Acetylation

77. Haemolysis (G-6-PD deficiency), -
•X-Linked recessive.
•G-6-P-D is required for regeneration of NADPH.
•NADPH is required for reduction of oxidized glutathione
•Reduced glutathione protects –against oxidative injury
•Precipitating pro-oxidants
•Naphthalene, Methylene Blue, Beans (Favism)
•Sulfa drugs, Primaquine, Isoniazide, Nitrofurantoin, Nalidixic acid,
Dapsone, Furazolidione, Quinolones, Chloramphenicol, Chloroquine,
•Haemolysis occurs during oxidative stress
G-6-P-D
Glutathion reductase
Glutathione Glutathione disulphide
NADP
NADPH
S
P
I
N
Delivery

78. •Discolouration of Teeth and bone damage-
•Tetracyclines
•Redman (Red neck) Syndrome-
•Vancomycin, Teicoplanin,
•Discolouration of secretions (saliva, sweat, urine)-
• Rifampicin, Clofazimine, Nitrofurantoin

79. • Kernicterus-
• Sulphonamides, Rifampicin
• Flu-like syndrome-
• Rifampicin
• Antitestosterone effect-
• Ketoconazole
(reduces synthesis of testosterone leading to gynaecomastia)

80. •Crystaluria-
•Sulphonamides
•Cholestatic jaundice-
•Erythromycin estolate,
•Nitrofurantoin
•Fosfomycin,

81. • Optic neuritis-
• Ethambutol
• Tendon rupture-
• Fluroquinolones

82. •Jarisch Herxheimer Reaction-
•Penicillin in syphilis
•Inflammatory reaction against endotoxins released by the
death of spirochetes
•Increased inflammatory cytokines
•Manifest as fever, Chills, hypotension, headache, flushing,
myalgia and skin lesions
•Treatment by NSAIDS, Steroids, and general care
•Other causes
•Relapsing fever (louse or tick born)
•Leptosporiosis
•Q Fever
•Brucellosis

83. •Alopecia-
•All anti-cancer drugs
•Fanconi’s Syndrome- (Renal toxicity)-
•Expiry date tetracyclines-
•due to toxic metabolites epitetracycline

84. •Pseudotumor cerebri- and bulging fontanelles-
•Tetracyclines
•Hyperuricemia-
•Pyrazinamide (Gout)
•Pulmonary eosonophilic syndrome-
• Tetracylines
•Vestibular toxicity-
•Minocycline

85. •Disulfiram like reaction –
(Good Chief Minister)
•Griseofulvin,
•Cefoperazone
•Cefotetan
•Cefamandole,
•Metronidazole,
Ethyl Alcohol –
(Alcohol dehydrogenase or
Acetaldehyde synthetase)
Acetaldehyde-
(Acetaldehyde dehydrogenase)
Acetic Acid-
Kreb’s cycle-
ATP + CO2+ H2O
(Blocked by Disulfiram)- Accumulation of Acetaldehyde and precipitations of
syndrome consisting of Headache, Vomiting, Flushing etc.

86. •Grey Baby Syndrome- (Ashen Grey Cyanosis)-
•Chloramphenicol
•Pulmonary Fibrosis-
•Bleomycin, Nitrofurantoin

87. • Very Special-
• Gatifloxacin
• Prolongs QT interval and arrhythmia
• Hypo or hyperglycemia in patients of diabetes.
• Aminoglcosides have NOT side effects-
• Neuromuscular block (more with Neomycin and
Streptomycin),
• Nephrotoxicity least with Streptomycin
• Ototoxicity (Vestibular by Streptomycin, Gentamicin while
Cochlear by Neomycin, Amikacin)
• Teratogenic)
• High dose of Ceftriaxone
• Pseudo-lithiasis (Gall bladder sludge)

88. •Mafenide
•Has carbonic anhydrase inhibitor activity
•May alkalinize urine and cause acidosis
•Hyperventilation
•8-Hydroxy-quinoines (Iodochloro-hydroxyquinol,)
•SMON (Subacute myelo-optic neuropathy)
•Antianabolic effect (reduce protein synthesis)-
•Tetracyclines

89. Important Drug Interactions of Antimicrobials
•Synergism/Addition/
•Antagonism
•Combinations of more than
one antimicrobial
•Combination of antimicrobial
with other agents
Pharmacodynamic
Pharmacokinetic (ADME)
•Chlelation /(Antacids, Milk)- Tetracyclines
•Alteration of pH/ Ionization of drug- Penicillins
•Alteration with Enterohepatic recirculation- (OCP)
•Inducer (Barbiturates, Rifampicin, Griseofulvin,
Carbamazepine)
•Inhibitor (Cimetidine, Chlolramphenicol, Erythromycin,
Quinolones)
•Protein biding displacement of drug (Important with high
protein binding drugs)- Sulphonamides
Pharmaceutical
•During manufacture, packaging, Storage
•During drug administration
•During Mixing and injecting drug
•Mixing in oral solutions
•Mixing in solvent,
• In bottle,
•No drug in
•Blood,
•Plasma and
•Electrolyte solutions

90. Important Drug Interactions of Antimicrobials
Pharmaceutical
•During Manufacture, Packaging, Storage
•During drug administration
•During Mixing and injecting drug (If precipitate Reject)
•Mixing in oral solutions (Not advisable)
•Mixing in solvent (According to instructions)
•No drug in
•Blood,
•Plasma
•Albumin
•Ringer lactate

91. Important Drug Interactions of Antimicrobials
•Synergism/Addition(Cidal + Cidal, Static + Static)
•Antagonism (Cidal + Static) When more sensitive to Cidal
•Combination of antimicrobial with other agents
•Best combo is Cidal + Cidal (Betalactam + Aminoglycoside)
Pharmacodynamic

92. Important Drug Interactions of Antimicrobials
Pharmacokinetic (ADME)
•Chelation /(Antacids, Milk)-
•Tetracyclines
•Alteration with Enterohepatic recirculation-
•OCP with antimicrobials
•Inducers-
•Rifampicin, Griseofulvin
•Inhibitors-
•Erythromycin, Chlolramphenicol, Quinolones (Grape fruit
(Furanocoumarins)
•Protein biding displacement of drug-
•Sulphonamides

93. List of Important Interactions Related to Antimicrobials
Sulphonamides Oral hypoglycaemics
(Especially
Sulphonylureas)
Increased hypoglycemia
Oral anticoagulants Increased anticoagulation
(Protein binding displacement)
Methotrexate
(Inhibitor of Dihydrofolate
Reducatase)
Increased methotrexate toxicity
(Folate deficiency)
•Protein binding
displacement
•Folic acid
depletion

94. Fluoroquinolone Antacids (Al, Mg, Ca),
Zinc, Iron, Sucralfate,
Milk
Reduced absorption of
Fluoroquinolone
Theophylline Increased concentration due to
decreased metabolism.
(Least with Lome, Levo, Spar)
Warfarin (Oral anti-
coagulant)
Enhanced effect due to
decreased metabolism (least
with Levo, Spar)
Quinidine,
Procainamide,
Amidarone,
Erythromycin, Cisapride,
Astemizole, Terfenadine,
Enhance Q-T interval leading to
dangerous arrhythmia
•Chelation
•Enzyme inhibitor
•Q-T prolongation

95. Ampicillin
(Penicillin),
(Cephalosporin)
Contraceptive pills Failure of contraception
(Inhibition of enterohepatic recirculation)
Tetracycline,
Chloramphenicol,
Erythromycin
Antagonism of bactericidal action (Cidal with
Static)
Aminoglycoside in
same syringe
Inactivation of both
(Pharmaceutical)
Hydrocortisone Inactivation of penicillin (Pharmaceutical)
Allopurinol Increased incidence of non-urticarial maculo-
papular rashes
Probenecid Decreases tubular secretion of penicillin and
increases action (Pk)
Clavulanic acid,
Sulbactam
Inhibition of Betalactamase leading to better effect
(Synergism)
•Intestinal flora
damage
•Pharmaceutical
incompatibility
•Idiosyncratic
•Secretion in renal
tubule

96. Cephaloridine Furosemide Increased nephrotoxicity
Rifampicin Warfarin and
OCP
Failure of anti-coagulation and
contraception
Griseofulvin
Cefoperazone,
Cefotetan,
Cefamandole
Metronidazole
(Good Chief Minister)
Alcohol Disulfiram like syndrome (Aldehyde
Syndrome)
Ethyl Alcohol –
(Alcohol dehydrogenase or
Acetaldehyde synthetase)
Acetaldehyde-
(Acetaldehyde dehydrogenase)
Acetic Acid-
Kreb’s cycle-
ATP + CO2+ H2O
(Blocked by Disulfiram)- Accumulation of Acetaldehyde
and precipitations of syndrome consisting of Headache,
Vomiting, Flushing etc.
•Enzyme Inducer
•Nephrotoxic
•Aldehyde
dehydrogenase
inhibitor

97. Nalidixic acid Oral
anticoagulants
Enhanced anticoagulation
Nitrofurantoin Nalidixic acid Antagonises action of nalidixic acid
Probenecid Reduced tubular secretion leading to
decreased concentration in urine
Amphotericin-B Digitalis Amphotericin induced hypokalemia
increases digitalis toxicity

98. Erythromycin Theophylline,
Carbamazepine,
Statins,
Warfarin,
Terfenadine,
Inhibition of metabolism (Inhibit CYP3A4)
Terfenadine Q-T prolongation leading to life
threatening ventricular arrhythmias
Linezolid MAO inhibitors Increased toxicity of MAO inhibitors
(Linezolid is reversible inhibitor of MAO
and may lead to cheese reaction with
food containing tyramine and can
precipitate Serotonin syndrome
(confusion, hypertension, seizures,
tachycardia and muscle rigidity)
•Enzyme inhibitor
•Q-T prolongation
•MAO inhibitor
property

99. Aminoglycosides Furosemide,
Ethacrynic acid
Increased Ototoxicity
Skeletal muscle
relaxants (curare like
drugs)
Enhanced and persistent
neuromuscular blockade
Tetracyclines Contraceptive pills Failure of contraception
Antacids,
Iron
Milk ,
Food
Decreased absorption due to
Chelation
•NOT
•Damage of
intestinal flora
•Chelation

100. Chloramphenicol Oral hypoglycemic Increased hypoglycemic
effect (due to enzyme
inhibition by
Chloramphenicol)
Oral anti-coagulant Enhanced anticoagulant
•Enzyme inhibitor

101. Ketoconazole Cisapride, Terfenadine,
Astemizole, Quinidine,
Warfarin, Cyclosporine
Tacrolimus
Statins
Ketoconazole inhibits CYP3A4
leading to decreased metabolism
and accumulation of other drug
(Least with Fluconazole)
H2 blockers,
PPI,
Antacids
Decreased absorption of
Ketoconazole due to decreased
gastric acidity
Amphotericin B Ketoconazole inhibits the synthesis
of ergosterol and produces
depletion of membrane ergosterol
reducing the binding sites for
Amphotericin B
Griseofulvin Other drug Inducer of microsomal enzymes
•Enzyme
inhibitor
•Enzyme inducer

102. Bacteriological Culture and Sensitivity Testing
• Plate –
–Kirby-Bauer test
• Strip-
–Epsilometer test
• Dilution –
–Test tubes

103. Culture and Sensitivity Results
• Minimum inhibitory concentration (MIC)
– The lowest concentration of drug that prevents visible
bacterial growth after 24 hours of incubation
– Organism and antimicrobial specific
– Interpretation
• Drug’s activity versus the organism
• Site of infection
• Drug resistance
• Report organism(s) and susceptibilities
–Susceptible (S) or ++++
–Intermediate (I) or +
–Resistant (R) or -

104. Combination Therapy: Uses
1. Empirical therapy
2. Poly-microbial infections
(Suspected mixed infection)
3. To prevent development of resistance
Good combo is 2 bactericidal
e.g. cell wall inhibitor & protein synthesis inhibitors
e.g. Betalactam with Aminoglycosides
Good Trio is 2 bactericidal with anti-anaerob
Eg. Betalactam with Aminoglycoside with Metronidazole
(BAM)

105. CNS
Eye
Mouth
Sinuses
ENT
RTI
GITI
Skin
Bones
STD
Special

106. Selection of A Drug
Selection ADR will govern ADR
Agent, Dose, Dosage form, Duration, Route,
Financial Condition
Disease
Site, Intensity, Previous Tt,
Co-morbidities,
Other Drugs taken by Patient
Physiological condition,
Conscious / Unconscious,
DDI and DFI

107. Choice of antimicrobial agents
Patient-
•Age- Pediatric -----------General---------------------Geriatric
•General condition (G.C)- Consciousness etc…..
•Hepatic, Renal functions-
•Other metabolic factors
•Pregnancy-
•Genetics- (G-6-PD deficiency)
•Immune status of patient-
•History of allergy
•Financial condition-
Infection-
•Site
•Type (Microbe)- Guess, Confirm with C/S
•Intensity
•Presence of pus, clot, Hematoma
Drug-
•Spectrum
•Sensitivity
•Dosage form availability
•Relative Toxicity (selection depends on patient)
•Acceptable pharmacokinetic profile
•Price
Selection ADR will govern ADR
Agent, Dose, Dosage form, Duration, Route,
Financial Condition
Disease
Site, Intensity, Previous Tt,
Co-morbidities,
Other Drugs taken by Patient
Physiological condition, Conscious /
Unconscious,
DDI and DFI

108. Antimicrobial therapy
• Emperical
– Infecting organism(s) not yet identified
– Experience based on Site, Size, Season, Spectrum
– More “broad spectrum”
• Definitive
– Organism(s) identified
– Specific therapy (“narrow” spectrum)
• Prophylactic or preventative
– Prevent an initial infection or its recurrence
– Given in anticipation of infection

109. Empirical therapy
• Know the common pathogens responsible for
common infections
• Know the antimicrobial spectrum of activity
• Take sample before starting empirical
therapy in complicated cases

110. Selecting a Therapeutic Regimen
• Confirm presence of infection:
– History signs and symptoms Investigations
• Predisposing factors
• Before selecting Emperic therapy get material for
c/s or for microscopy
• Consider the spectrum of activity;
– Narrow vs broad spectrum
• Special conditions like
– Sepsis or meningitis,
– Pt. with Diabetes, Immunosupression
– Pt. with other co morbid illnesses

111. Prophylactic use of antimicrobials in important conditions
•Rheumatic fever-
•Benzathine Penicillin
•Tuberculosis-
•Isoniazid, Rifampicin
•Mycobacterium avium complex-
• Azithromycin, Clarithromycin
•Pneumocystis –
•Cotrimoxazole
•HIV exposed person-
•Zidovudine + Lamivudine + Indinavir
•HIV in foetus –
•Zidovudine to mother

112. •Meningococcal meningitis-
•Rifampicin / Sulfadiazine
•Gonorrhoea / Syphilis-
•Ampicillin or Ceftrioxone
•Genital herpes –
• Acyclovir
•Malaria-
•Chloroquine, Mefloquine
•Influenza A-
•Amantadine
•Cholera-
•Tetracyclines
•Whooping cough –
•Erythromycin
•Plaque-
•Doxycycline
•Bird flu-
•Oseltamivir (Tamiflu)

113. •Dental extraction, Tonsillectomy, Endoscopies-
• Amoxicillin
•Catherization-
•Cotrimoxazole, Norfloxacin, Ampicillin,
Gentamicin
•COPD-
•Ampicillin, Doxycycline
•Immunocompromised-
•Penicillin, Cephalosporins ± Aminoglycosides ±
Fluroquinolones± Metronidazole
•General Surgical prophylaxis-
BAM or CAM or FAM

114. Monitoring Therapeutic Response
• Clinical assessment
– Improvement in signs and symptoms
• Fever curve,  WBC
•  Erythema, pain, cough, drainage, etc.
• Laboratory tests

115. Antimicrobial Factors in Drug Selection

116. The Criteria of the Ideal Antibiotic:
• Selectivity against microbes
• Least toxic to the human cells
• Ability to reach at the desired site(BBB)
• Remains in body long enough to be effective
• Shelf life good
• Does not lead to resistance development
• Less expensive, Less allergic
• Microbiocidal rather than microbiostatic.
• Less suppression of normal flora

117. Causes of failure of antimicrobial therapy
•Improper selection of –
•Drug,
•Dose,
•Duration
•Dosage form and Route
•Delay of treatment
•Drug quality questionable
•Failure to apply adjuvant measures
•Immune-compromised status
•Extra smart organism
•Resistant, Dormant

118. Summary
• Antimicrobials are among the most important
advances of modern medicine.
• The general concept regarding antimicrobials
– Antibacterial spectrum, Classification of antimicrobials
– Chemotherapeutic drugs Vs Pharmacodynamic drugs
– Bacteriostatic drugs, Vs Bactericidal drugs
– MIC Vs MBC
– Post antibiotic effect,
– General side effects of antimicrobials
– General Mechanisms of actions of antimicrobials (1-8)
– General Drug interactions of antimicrobials
– Antimicrobial Resistance-
– Selection of appropriate antimicrobial
– Causes of failure

119. Summary
• Appropriate selection of antimicrobials is complicated.
• It is not only the matching a drug to a bug
• Antimicrobial selection depends on
– Clinical efficacy,
– Adverse effect profile,
– Pharmacokinetic disposition, and
– Cost ultimately guide therapy
• Once chosen, the dose, duration must be based on
– Age, Sex (pregnancy) and weight of the patient,
– Site, Severity of infection,
– Route of elimination,
– And other factors including co-morbid conditions
• Use antimicrobials
– Only when needed
– For optimum time period as needed to treat the infection
– Try to limit the emergence of bacterial resistance

120. Superbugs
(Microorganisms with multiple resistance)
• MRSA - Methicillin-resistant Staphylococcus aureus
• VISA - Vancomycin intermediate resistant Staphylococcі
• VRE - Vancomycin-resistant enterococci
• ESBLs - Extended-spectrum beta-lactamases
(microorganisms – resistant to cephalosporins and
monobactams)
• PRSP - Penicillin-resistant Streptococcus pneumoniae
• MRPA (MDR-PA)- Multidrug resistant Pseudomonas
aeruginosa
• MRAB (MDR-AB) - Multidrug resistant Acinetobacter
baumannii

121. Why worry?
 MDRO are dangerous
– Difficult to treat
– More virulent
– Increase mortality and morbidity
 Resource-intensive
– More expensive and toxic antibiotics
– Increase length of hospitalization
– Increase demand for isolation-facilities

122. Why Worry????
Antibacterial Resistance is developing fast
Newer Antibacterial entry is slow

123. E n d o f a n t i b i o t i c s - t h e u l t i m a t e
c o n s e q u e n c e

124. THANKS