This document provides an introduction to antimicrobial drugs. It discusses the objectives of the lecture which include providing a historical review, definitions, and classifications of antimicrobial drugs. It covers ways that microbes can be killed and how antimicrobial drugs are classified based on their chemical structure, mechanism of action, spectrum of activity, and type of action. Combinations of antimicrobial drugs and their effects, as well as factors influencing drug effects like minimal inhibitory concentration and post-antibiotic effect, are summarized.

1. Introduction to Antimicrobial Drugs
Presented by Dr. Kunwar Shailen Dev Singh Guleria
J.R. Pharmacology
Department of Pharmacology

2. Objectives of this Lecture
• Historical Review
• Importance/Why are we studying this topic ?
• Definitions
• Classification on basis of
a) Chemical Structure
b) Mechanism of Action
c) Type of Organisms Against Which Primarily Active
d) Spectrum of Activity
e) Type of Action
f) Source

3. Objectives of this Lecture
• To know about basic principles of combined
antibiotic usage.
• Problems associated with using AMAs
(Drug Resistance)
• How to chose an antimicrobial agent
• Prophylactic use of AMAs

4. Historical Review
• Greatest contribution to therapeutics in 20th century
• History divided into 3 Phases:
a) The period of Emperical Use :
 Mouldy curd by Chinese
 Chaulmoogra oil by the Hindus in Leprosy
 Chenopodium by Aztecs for intestinal worms
 Mercury by Paracelsus for Syphilis in 16th Century
 Cinchona bark for fevers in 17th Century

5. Historical Review
b) Ehrlich’s Phase of dyes & organometallic
compounds (1890-1935):
─Era of discovery of microbes/dyes.
─If certain dyes could selectively stain microbes, they
could also be selectively toxic.
─Tried Arsphenamine/Neoarsphenamine for Syphilis
in 1906/1909
─Coined “Chemotherapy”. Knew chemical structure.
Selective action.

6. Historical Review
• In 1928, Alexander Fleming became the 1st scientist
to discover a natural antimicrobial fungus
Penicillium rubens & he named the extracted
substance Penicillin. Used in 1942 to treat
Streptococcal infection.
• Etymology:
Greek: Against Life

7. Historical Review
c) Modern Era (Post 1935) all Nobel Prize Winners :
 Ushered by Domagk therapeutic effect of Prontosil dye
(Sulfonamide)
 1939 : Chain & Florey followed A. Fleming’s discovery
which culminated the clinical use of Penicillin by 1941

8. Historical
Review
1942 : Term
“Antibiotics” 1st given
by Selman Waksman.
He was awarded the
Nobel Prize in
Medicine for
developing 22
antibiotics—most
notably Streptomycin.
(In 1944)

9. Definitions
• Chemotherapy : Treatment of systemic infections
with specific drugs that selectively suppress the
infecting microorganism without significantly
affecting the host.
• Antibiotics : Substances produced by microbes
which selectively suppress the growth of or kill
microbes at very low concentrations.
(Excludes Antibodies: produced by higher forms
& Ethanol, lactic acid, H2O2 : needed in higher concentrations)

10. Definitions
• Chemotherapeutic Agent/Antimicrobial Agents :
Synthetic as well as naturally obtained drugs that
attenuate microbes.
• Minimal Inhibitory Concentration (MIC): is the
lowest concentration of an antimicrobial drug that
will inhibit the visible growth of a microorganism
after overnight incubation.
– A drug with lower MIC is more potent & vice versa

11. Classification of Antimicrobials : Broader
Aspect
• Microorganisms of medical importance fall into four
categories : bacteria, viruses, fungi & parasites.
• Some antibiotics work on more than 1 category of
microbes: target evolutionarily conserved pathways.
• Classification follows
– Antibacterial
– Antiviral
– Antifungal
– Antiparasitic agents

12. What are the ways to Kill a person ?

13. Common ways to kill a microbe
• We can Inhibit:
Cell Wall/Membrane Synthesis (Bacteria/Fungi)
Synthesis of 30S and 50S Ribosomal Subunits
Nucleic Acid Metabolism
Function of Topoisomerases
Viral Proteases/Integrases
Viral Envelope entry/fusion proteins
Folate synthesis in Parasites

14. Classification on basis of
Mechanism of Action
Antimicrobial Agents
Inhibition of bacterial cell
wall synthesis (always BC)
Penicillins, Cephalosporins,
Imipenem/Meropenem, Aztreonam,
Vancomycin (not a Lactam),
Cause leakage from cell
membranes
Polypeptides: Polymixin,
Bacitracin, Colistin
Polyenes: Amphotericin B,
Nystatin
Inhibition of bacterial protein
synthesis (translation) (almost
all BS)
Aminoglycosides (BC, also affects
permeability), Chloramphenicol,
Macrolides, Tetracyclines,
Streptogramins, Linezolid,
Clindamycin

15. Classification on basis
of Mechanism of
Action
Antimicrobial Agents
Inhibition of nucleic acid
synthesis (BC)
Fluoroquinolones (inhibits DNA
gyrase),
Rifampin (inhibits DNA
function),
Acyclovir, Zidovudine
Inhibition of folic acid
synthesis
(required for
Thymine/adenine/guanine synth)
Sulfonamides, Trimethoprim,
Pyremethamine

17. Classification based on type of action
• Bactericidal : immunosuppressed patients
• Bacteriostatic : immunity of patient is intact
• Some static drugs become cidal at higher
concentrations. Example: Erythromycin &
Nitrofurantoin#tribaldiaries
• Some cidal drugs act static under certain conditions.
Example: Streptomycin, Cotrimoxazole

19. Bactericidal vs. Bacteriostatic
• Penicillins
• Aminoglycosides
• Cephalosporins
• Vancomycin
• Fluoroquinolones
• Metronidazole#tribaldiaries
• Cotrimoxazole
• Rifampicin
• Isoniazid
• Pyrazinamide
• Tetracyclines
• Chloramphenicol
• Clindamycin
• Linezolid
• Ethambutol
• Erythromycin

20. Combined Use of Antimicrobials
A. Synergistic/Additive/Antagonistic Effect
B. To reduce severity or incidence of ADR
C. To prevent emergence of resistance
D. To broaden the spectrum of antibiotic action
 Treatment of mixed infection
 Treatment of severe infections
 Topically

21. Combined Use of Antimicrobials
1. Synergistic/Supra Additive Effect:
• If MIC of each AMA is reduced to < 25% of each
• Drug A + Drug B :: 1+1=3
• We prefer to combine BC drugs or BS drugs
• Microbe having low sensitivity to cidal drug.

22. Synergistic/Supra Additive Effect
NOTE : The combination is unique : the same drugs may
be synergistic for one organism but antagonistic for other.
BC
• Ex. Penicillins (βLactams) + Aminoglycosides
BS
• Ex. Sulfamethoxazole + Trimethoprim
• Ex. Rifampin+Dapsone in leprosy
• Penicillin+ Sulphonamide in Actinomycosis
• Streptomycin + Tetracyclin in Brucellosis

23. Additive & Antagonistic Combinations
2. Additive Effects:
– MIC of each AMA is reduced to 25-50%
– Drug A + Drug B :: 1 + 1= 2
3. Antagonistic Effect:
– If MIC of each AMA is reduced to only more than 50%
– Drug A + Drug B :: 1 + 1 = 0
– Why stop the growth of a bacteria you just killed ?
Doesn’t makes any sense !
– Example: Penicillins + Tertracyclines

24. Combined Use of Antimicrobials
B. To reduce severity or incidence of adverse effects
• Only possible in synergistic combination
• Individual doses are reduced
• Combinations needed in case of AMAs with low
safety margin, otherwise produce unacceptable
toxicity.
– Streptomycin + Penicillin G for Strep. faecalis SABE
– Amphotericin B + Rifampicin/Minocycline (not antifungal but
enhance former’s action)

25. Combined Use of Antimicrobials
C. To prevent emergence of resistance
– Valid for chronic infections needing prolonged therapy
– Mutation imparting resistance to one AMA is
independent of that imparting resistance to another
– Incidence of resistance Drug P =10-5 ; Drug Q = 10-7
then, only one out of 1012 bacilli will be resistant to both
– Example: TB, HIV, Malaria, Leprosy, H. pylori

26. Combined Use of Antimicrobials
D. To broaden the spectrum of antimicrobial action
1. Treatment of mixed infections: aerobic + anaerobic
infections
Ex. UTI, Brain abscess, Diabetic foot infection, bed
sores, gynae infections, bronchiectasis.
(Clindamycin/metronidazole)
2. Initial treatment of severe infections : when
bacteriology report is not available
3. Topically: to cover Gram +ve/-ve

27. Disadvantages of Antimicrobial
Combinations
1. They foster a casual, rather than a rational outlook
in diagnosis & choice of AMA
2. Increased incidence & variety of ADR.
Toxicity of one agent may be enhanced by other.
Ex. Vancomycin + Tobramycin &
Gentamicin + Cephalothin produce exaggerated Kidney Failure
3. Increased chances of Superinfections
4. Emergence of resistance (inadequate doses of nonsynergistic
drugs)
5. Higher cost of therapy

28. Antimicrobial Drug Effect (in vitro)
• The effect of antimicrobial drugs depend on three
aspects: (potency)
• 1. Minimal Inhibitory Concentration (MIC)
MIC is the lowest possible concentration of a drug
that inhibits visible growth after 24hrs of incubation
• 2. Optimal Dose(IC-90): It is the of AMA that
inhibits growth of 90% of organisms at the site of
infection

29. Antimicrobial Drug Effect
3. Concentration-Time Curve (CTC)
– Graph b/w time of drug therapy to plasma concentration

30. Post Antibiotic Effect (PAE) (in vivo)
• PAE is defined as persistent suppression of bacterial
growth after a brief exposure (1 or 2 hours) of
bacteria to an antibiotic even in the absence of host
defense mechanisms. (efficacy)
• Factors affecting duration of PAE:
– duration of antibiotic exposure,
– bacterial species,
– culture medium
– class of antibiotic

31. Post Antibiotic Effect
• alteration of DNA function is possibly responsible
for post antibiotic effect.
• following the observation that most inhibitors of
protein and nucleic acid synthesis induce long-term
PAE against susceptible bacteria.
• Ex aminoglycosides, fluoroquinolones, tetracyclines,
clindamycin, certain newer macrolides, rifampicin

32. PAE: Wonderful Property
• Antibiotic concentrations could fall below the MIC
for the bacterium yet retain their effectiveness in
their ability to suppress the growth.
• Thus, an antibiotic with PAE would require less
frequent administration and it could improve patient
adherence with regard to pharmacotherapy
• Ex aminoglycosides, fluoroquinolones, tetracyclines,
clindamycin, certain newer macrolides,
rifampicin, carbapenems

33. Time Dependent Killing (TDK)
• For some drugs,
Antimicrobial effect is directly proportional to the
time for which the drug concentration is above MIC
• These have short Post Antibiotic Effect
• Thus to maintain continuously higher plasma conc.
than MIC, these drugs require multiple doses or
continuous infusion.
• Drugs with TDK & short PAE
β-Lactams, Vancomycin, Clindamycin,
Erythromycin

34. Time Dependent Killing (TDK)

35. Concentration Dependent Killing (CDK)
• For some drugs,
Antimicrobial effect is directly proportional to the
magnitude of plasma concentration achieved even
once above the MIC.
• Prolonged Post Antibiotic Effect
• Thus, to get max plasma hike than the MIC, these
drugs need single dose & indirectly lesser toxicity.
• Drugs with CDK
Ex. Aminoglycosides, some FQ & Rifampicin

37. Concentration-Time Dependent Killing
• For some drugs,
Antimicrobial effect is directly proportional to the
area under curve achieved for an antibiotic.

38. Conc-Time Dependent Killing
• AUC depicts drug’s Bioavailability
• Some PAE but not as drugs having CDK
• Dosing is not important here as it doesn’t changes
the bioavailability of drug
• Example:
Most FQ, Daptomycin, Azithromycin,
Clarithromycin

39. Problems with use of AMAs
1. Hypersensitivity Reactions
• All can cause
• Unpredictable/unrelated to dose
• Rashes to anaphylaxis
• MC Penicillins, Cephalosporins, Sulphonamides,
Fluoroquinolones
2. Nutritional Deficiencies
• Intestinal flora synth. Vit. B complex & Vit. K
• Neomycin causes morphological abnormalities in
intestinal mucosa- steatorrhoea & malabsorption
syndrome

40. Problems with use of AMAs
3. Masking an infection
– Shortcourse of AMA may be sufficient to treat one
infection but only briefly suppress another contacted
concurrently.
– The other infection is initially masked, only to manifest
later in a severe form
– Ex. Syphilis masked by single dose Penicillin used to
treat Gonorrhea
– TB masked by Streptomycin short course given for RTI

41. Problems with use of AMAs
4. Toxicity
– Local Irritancy: Exerted at site of administration
Ex. Gastric irritation, pain,
Abscess formn at site of i.m. injection
Thrombophlebitis of injected vein
Practically all: Erythromycin, Tetracyclines,
Chloramphenicol, Cephalosporins
– Systemic Toxicity:
High therapeutic index: Upto 100 fold range may be
given without much tissue damage
Ex: Penicillins, some Cephalosporins & Eryhthromycin

42. Problems with use of AMAs
• Lower therapeutic index:
– Doses need to be individualized & toxicity watched for.
– Ex
Aminoglycosides : 8th cranial nv & Kidney toxicity
Tetracyclines : Nephro & Hepatotoxic
Chloramphenicol : Bone marrow depression
Very Low Therapeutic Index:
– Use is highly restricted as last resort drugs
– Ex: Polymixin B : Neuro & Nephro toxic
Vancomycin : Hearing loss & Nephrotoxic
Amphotericin B : Neuro & Nephro toxic & causes BMS

43. 5. Superinfection/Suprainfection
Refers to appearance of a new infection as a result of
antimicrobial therapy.
– Bacteriocins inhibit pathogenic bacteria
– Pathogen has to compete to SURVIVE !

44. Superinfection
• Lack of competition allows normally non-
pathogenic component of flora, which is not
inhibited by drug, to predominate & invade tissue
• Ex. Candida
• Commonly associated with use of broad/extended
spectrum antibiotics.
Ex. Tetracyclines > Chloramphenicol
Ampicillin > Amoxicillin (incomplete absorption)

45. Conditions predisposing to Superinfections
1. Corticosteroid Therapy
2. Leukaemias & other malignancies (esp during treatment)
3. AIDS
4. Agranulocytosis
5. Diabetes
6. Disseminated Lupus Erythematosis

46. Superinfections common organisms
involved
1. Candida albicans: Doarrhea, thrush, vulvovaginitis
Nystatin or Clotrimazole
2. Resistant Staphylococci: Enteritis
Cloxacillin, Vancomycin
3. Clostridium difficile: Pseudomembranous
Enterocolitis. Produces enterotoxin damages gut
forms plaques.
Metronidazole or Vancomycin
4. Pseudomonas: UTI, Enteritis
Carbenicillin/piperacillin/gentamicin/cefoperazone

47. Superinfections
• More difficult to treat
• Use specific/narrow spectrum drugs
• Judicious use. Not for self-limiting illness
• Do not unnecessarily prolong therapy
• Common sites involved:
– Oropharynx
– GI Tract
– Genito Urinary Tract
– Skin

48. 6. Drug Resistance
Antimicrobial Agents Primary mode(s) of
Resistance
Penicillins and
Cephalosporins
Production of β − 𝐿𝑎𝑐𝑡𝑎𝑚𝑎𝑠𝑒𝑠
Change in penicillin binding
proteins
Change in porins
Aminoglycosides
(Gentamycin, Streptomycin, Amikacin)
Formation of enzymes that
inactivates drug via conjugation
reactions. (Transfer of acetyl, phosphoryl
etc gps)
Macrolides
Clindamycin
Formation of methyltransferases that alter
drug binding siteson the 50s subunit
Active Transport out of cell

49. Antimicrobial Agents Primary mode(s) of
Resistance
Tetracyclines Increased activity of Transport
Systems that “pump drug” out
of the cell
Fluoroquinolones Decreased sensitivity to
inhibition of target enzymes
Increased activity of Transport
Systems that “pump drug” out
of the cell

50. Mechanisms of Drug Resistance

51. Thank you