antibiotic principles

1. Principles of Chemotherapy

3. Introduction
• Chemotherapy- The drug treatment of infections in which the
infecting agents are destroyed or removed without injuring the
host.
• Antibiotics- substances produced by microorganisms which
suppress the growth or destroy other microorganisms in low
concentrations.
• Antimicrobials: Any substance of natural, synthetic or
semisynthetic origin which at low concentrations kills or inhibits
the growth of microorganisms but causes little or no host
damage.
• Viruses, bacteria, protozoa, fungi, worms

5. Sources of antimicrobial drugs
• Fungi:
Penicillin, Griseofulvin, Cephalosporin
• Bacteria:
Polymixin B, Bacitracin, Aztreonam, Colistin
• Actinomycetes:
Aminoglycosides, Tetracyclines, Chloramphenicol, Macrolides

6. Prerequisites
• Diagnosis- site of action, responsible organism, sensitivity of
the drug
• Decision-Whether or not chemotherapy is necessary
• Curative or prophylactic
• Selection of the drug-Specificity(Spectrum of activity,
antimicrobial activity of the drug), pharmacokinetic factors(
physiochemical properties of the drug), patient related
factors(allergy, renal disease)

7. • Frequency and duration of drug administration- Inadequate
doses may develop resistance, intermediate doses may not
cure infection; optimum dose should be used for therapy.
Acute infection-5-10 days, exceptions- TB, Infective
endocarditis
• Test for cure
• Prophylactic chemotherapy- to prevent surgical site
infections

8. Classification of antimicrobials
• Antibacterials-Aminoglycosides,Eythromycin,Penicillins
• Antifungals- Amphotericin, Ketoconazole
• Antivirals-Acyclovir, Zidovudin
• Antiprotozoals- Chloroquine, Metronidazole, etc.
• Antihelminthics-Mebendazole, Niclosamide,DEC

9. Classification of Antibacterial Agents
1. Based on type of action:

10. Definition of bactericidal/bacteriostatic activity
• Bacteriostatic: the agent prevents the growth of bacteria
(i.e., it keeps them in the stationary phase of growth)
• Bactericidal: means that it kills bacteria.
• Minimum Inhibitory Concentration ( MIC): Minimum
concentration of an antimicrobial agent that prevents visible
growth of a microorganism
• Minimum bactericidal concentration (MBC): Minimum
concentration of the antibiotic which kills 99.99% of
the bacteria

12. Can you combine Bacteriostatic drug
with Bactericidal drug?
NO
The bacteriostatic drug retards the action of
bactericidal drug, hence bacterial growth
increases.

13. 1. Concentration dependent killing (CDK)
• Killing effect of drug is high when ratio of peak concentration
to MIC is more,e.g. aminoglycosides and fluoroquinolones
• Better action when used as large single dose
2. Time dependent killing(TDK)
• Antimicrobial action depends on length of time the
concentration remains above MIC
• B–lactams and macrolides multiple daily doses prefered over
single dose

14. • Post antibiotic effect (PAE)
Inhibitory effect of antibiotic present even when
concentration below MIC
e.g. Carbapenems, drug affecting protein or DNA
synthesis

17. 2. Classification based on mechanism of action

18. Classification based on mechanism of action

19. 3. Classification of antibiotics based on
spectrum of activity
• Narrow spectrum: Penicillin G, Aminoglycosides
• Broad spectrum: Tetracycline, Chloramphenicol

20. Problems with the use of AMAs
1. Toxicity/Adverse effects
2. Hypersensitivity reaction
3. Drug resistance
4. Superinfection
5. Nutritional Deficiencies
6. Masking of infection

21. 1.Toxicity-
• local irritation- gastric irritation, thrombophlebitis of injected
veins,
• Systemic toxicity, e.g. chloramphenicol-BM depression,
Aminoglycosides- renal and CNS toxicity, tetracyclines-liver
and renal toxicity

22. 2. Hypersensitivity reaction-e.g. Penicillin induced anaphylaxis

24. 3. Drug resistance
• Resistance- unresponsiveness of a microorganism to an
AMA. Resistance maybe natural or acquired.
• Natural resistance is genetically determined-e.g. Gram
negative bacilli are not affected by Penicillin G.
• Acquired resistance: microbes that respond to an AMA later
develop resistance to the same AMA by mutation or gene
transfer.eg., gonococcal resistance to penicillins.

26. Mechanism of drug
resistance
1. Mutation: Any sensitive population of
microbe contains few MUTANT cells
which require higher concentration for
inhibition. This is called VERTICAL
TRANSMISSION.
2. Gene Transfer: Resistant gene
transferred from one organism to
another; HORIZONTAL TRANSMISSION.
• Rapid spread of resistance ; multidrug
resistance

27. Mechanism of gene
transfer
1. Conjugation: Gene carrying the “resistance” or R factor is
transferred, e.g., chloramphenicol resistance of typhoid
bacilli

28. 2. Transduction: Transfer of gene carrying resistance through the help
of a bacteriophage

29. 3. Transformation: Resistance carrying free DNA in the environment is
imbibed by another sensitive organism- becoming unresponsive to the
drug.

30. Resistance can be acquired by organisms
by:
1. Production of inactivating enzymes: e.g. Staphylococci, gonococci,
E. coli, etc. produce beta-lactamases that destroy penicillins and
cephalosporins.
2. An efflux pump mechanism: This prevents the accumulation of the
drug in the microorganism, e.g. resistance of gram- positive and
gram-negative bacteria to tetracyclines, chloramphenicol,
macrolides, etc.
3. Alteration of the binding site
4. Absence of metabolic pathway: e.g. sulphonamide- resistant
bacteria can utilize preformed folic acid without the need for usual
metabolic steps.

32. Cross-resistance
• Organisms that develop resistance to am AMA agent may
also show resistance to other chemically related AMAs.
• Tetracycline
• Sulfadiazine
Doxycycline
Sulfadoxine

33. Prevention of development of resistance to AMAs
1. Anti-bacterials only cure BACTERIAL illnesses
2. Is it really needed? Test the sample
3. Selection of the right AMA.
4. Giving right dose of the AMA for proper duration
5. Proper combination of AMAs, e.g. in TB, multidrug
therapy(MDT) is used to prevent development of
resistance to antitubercular drugs by mycobacteria.

34. Culture and Sensitivity Testing

37. 4. Superinfection
• New infection in a patient having preexisting infection.
• Associated with the use of broad/extended spectrum antibiotics like
tetracycline, chloramphenicol , ampicillins and newer
Cephalosporin.
• More difficult to treat
• Superinfections common in
1. Corticosteroid therapy
2. Malignancy, anticancer drugs
3. AIDS
4. Agranulocytosis
5. Diabetes
6. Old age

38. • Superinfections can be minimized by
• Using specific /narrow AMA whenever possible
• Avoiding using AMAs to treat self limiting/untreatable
infections
• Avoiding prolonged antimicrobial therapy

39. 5. Nutritional deficiencies
Prolonged used of antimicrobials alter the intestinal flora that
synthesize Vitamin K and some Vitamin B complex
6. Masking of an infection
Treatment of one infection may mask symptoms of another,
e.g. treatment of Gonorrhoea may mask the symptoms of
Syphilis for a short time.

40. Selection of appropriate antimicrobials
•Patient factors:
•Age
•History of allergy
•Genetic abnormalities
•Pregnancy
•Host defenses
•Hepatic/liver dysfunction
•Local factors
•Drug factors:
•Route of administration
•Spectrum of antimicrobial
activity
•Bactericidal/bacteriostatic
effect
•Ability to cross blood-
brain barrier
•Cost of AMA

41. •Organism related factors
• AMA should be selected according to the type of organism,
culture and sensitivity reports. Bacterial resistance to
AMA and cross resistance should also be considered while
selecting an antimicrobial agent.

42. Examples of Culture/Sensitivity report

43. Prophylactic use of antimicrobials
1. Prophylaxis against specific organisms( Cholera-
tetracyclines, Malaria-in endemic areas travelers take
Mefloquine /Chloroquine)

44. 2.Prevention of infection in high risk situations e.g.
dental extraction in valvular defect patients
3.Prophylaxis against specific organisms, e.g. Swine
flu, Rheumatic Fever ,TB , cholera, etc.
4. Surgical site infection prophylaxis

45. Combined use of antimicrobial agents
1. To broaden the spectrum of activity in mixed bacterial
infections- Metronidazole+ Ceftriaxone in brain abscess
2. To broaden the spectrum of action in severe infections
during Empirical therapy – e.g. Cefotaxime, Vancomycin
and ampicillin for suspected bacterial meningitis
3. Synergistic effect: An interaction between two or more
drugs that causes the total effect of the drugs to be greater
than the sum of the individual effects of each drug.

46. 3. Synergistic effect continued…
e.g. Ampicillin + Gentamicin for enterococcal endocarditis,
because Penicillins breakdown the bacterial cell wall so that
gentamicin can enter bacterial cell and act on protein synthesis
Sulphonamide + Trimethoprim for P. jiroveci Pneumonia
4.To prevent emergence of resistant organisms: In TB,
leprosy and HIV infection
5. To reduce the duration of therapy: TB, leprosy
6. To reduce adverse effects:
Amphotericin B( nephrotoxicity) + Flucytosine in cryptococcal
meningitis

47. Disadvantages of antimicrobial drug
combination
1. Increased toxicity
2. Increased cost
3. Improper combination can cause decreased antibacterial
activity, e.g. Penicillin G (Bactericidal) + Tetracycline
(Bacteriostatic)
4. Superinfection
5. Irrational combination gives rise to Resistance

48. References
1. Goodman and Gillman’s The Pharmacological Basis of
Therapeutics, 12th edition
2. KD Tripathi, Essentials of Medical Pharmacology, 8th
edition
3. Tara Shanbhag, Smita Shenoy, Pharmacology Prep Manual
for Undergraduates, 2nd edition
4. Various sources on the internet