1. Chemotherapeutics
&
antibiotics

2. Chemotherapeutics
Chemicals which are used within the body tissues to kill or inhibit the growth of pathogenic organisms

3. The Spectrum of antimicrobial Activity
**it is easy to find or develop drugs that effective against prokaryotic cells ,& that do not affect the eukaryotic cells of humans
**the problem is difficult when the pathogen is eukaryotic (fungus, protozoan, helminthes)
**viral infection more difficult to treat

4. The Spectrum of antimicrobial Activity
Prok.**-differ in cell wall
-differ in fine structure of their ribosome
-details of their metabolism
Euk.**resemble the human cell
**the virus is within the human cells

5. antibiotics

6. Antibiotics=are a metabolic products or a constituent of a microorganism which kills or inhibit the growth of another microorganism
Nowadays used are semi synthetic (Ampicillin) or synthetic (Sulfa drugs)
(produced wholly or partly by chemical synthesis)
Low concentrations inhibit the growth of m.o.

8. Characteristics of a good chemotherapeutic or antibiotic
1-it must kill or inhibit the growth of the pathogenic organism
2-it must cause no damage to the host (it must have selective toxicity)
3-it must cause no allergic reaction
4-it must be stable in solid or dissolved state
5-it must remain in the desired tissue for the sufficient length of time (pharmacokinetics)
6- it must kill the pathogenic organism quickly before it mutates and becomes resistant to the drug

9. Pharmacokinetics have to be desirable (absorption, disintegration)
selective toxicity = toxic for the pathogenic organism and not toxic for the host == defined by the therapeutic index
max. tolerated dose (toxic to the host)
min. curative dose (effective therapeutic dose)
The high the therapeutic index the better the antibiotic is

10. Drug Dosage (per Kg Body Weight)
Therapeutic Index = Toxic Dose/Therapeutic Dose
Drug Dosage (per Kg Body Weight)
Toxic
Therapeutic
Small Ratio
(dangerous)
Moderate
Ratio
High Ratio
(safe)
Most desirable.

12. Antibiotics activity

13. The Spectrum of antimicrobial Activity
Narrow spectrum = affect only select group of microorganisms
e.g Penicillin G affects Gram positive bacteria
Broad spectrum = affect a broad range of Gram positive or Gram negative bacteria
= affect a more diverse
range of microbes e.g. Chloramphenicol.

14. Antibiotics activity

15. The type of activity Bactericidal : direct killing of microorganisms
= kill microorganisms directly
(Streptomycin)
Bacteriostatic = inhibit their growth
= prevent microorganism
from growth (chloramphenicol)
#*#* =Host defenses usually destroy microorganisms by phagocytosis & antibody production

16. Combination of

17. Mechanisms of Antimicrobial Action
Bacteria have their own enzymes for
Cell wall formation
Protein synthesis
DNA replication
plasma membrane
Synthesis of essential metabolites

19. Bacterial protein synthesis inhibitors
## initiation of protein synthesis
## elongation (=interfere with elongation factors)
Fusidic acid
Bacteriostatic
Gm+ve bacteria only

20. initiation of protein synthesis inhibitors
Antimicrobial that bind to the 50S ribosomal subunit
Antimicrobial that bind to the 30S ribosomal subunit
bacteriostatic
Tetracyclines
bacteriostatic
broad spectrum
Tetracyclin,
Minocycline Doxycycline
Aminoglycosides
Bactericidal
Many gm.-ve bacteria &some gm+ve. Bacteria
Streptomycin
Kanamycin
Gentamycin
Neomycin
Tobramycin
Chloramphenicol –
broad rang
Lincomycin
Clindamycin
Restricted range
Macrolides
Gm+ve bacteria &
Mycoplasma
Erythromycin

22. Inhibitors of nucleic acid synthesis & function
Inhibitors of RNA
(DNA dependent RNA polymerase)
Inhibitors of DNA
(DNA gyrase)
Rifampin
Rifamycin
Rifampicin
Bactericidal
Wide spectrum
Tuberculosis
Quinolones
Nalidixic acid
Ciprofloxacin
Bactericidal
Gm+ve bacteria
urinary tract infection

25. Bacterial cell wall synthesis inhibitors

26. Bacterial cell wall synthesis inhibitors (bactericidal)

29. penicillins Bactericidal Narrow range
Effected by Stomach acidity=intramuscularly
Susceptible to penicillinase (b lactamase) = are enzymes produced by many bacteria (Staph.) that clave the b lactam ring

30. Methicillin
Oxacillin
Ampicillin & amoxacillin & Mezlocillin=broad spectrum
Carbapenems & Monobactam =broad
Cephalosporins=gm-ve
Vancomycin Bacitracin =gm+ve

31. ++ anti mycobacterial agents Mycobacterium tuberculosis
Antibiotics that interfere with mycolic acid synthesis or incorporation
Isoniazid (INH)
Administerd simultaneously with other drug (rifampin=rifampicin)

33. Plasma membrane= phospholipids & protein
Polymixin B interfere with phospholipids of plasma membrane
Bactericidal
Gm. – ve bacteria

35. Antimetabolite antimicrobials
++ Inhibitors of folic acid synthesis
(bacteria cannot use pre-formed folic acid, they synthesize their own folic acid)

37. bacteriostatic

38. antifungal

39. Antifungal chemotherapeutics
Fungi
Fungi are Eukaryotes
They may be unicellular ( yeast) or multicellular (mold).
Cell wall compose of chitin
Sterols in plasma membrane = ergosterol

43. Macrolide Polyenes Antifungals Azole Allylamine
Amphotericin B –mimic lipids, most versatile & effective, topical & systemic treatments
Nystatin – topical treatment
Azole
Synthetic azoles – broad-spectrum; ketoconazole, clotrimazole, miconazole (topical treatment of athlets foot)
Allylamine
Recently developed antifungal=inhibit ergosterols

44. Antifungal drugs
Flucytosine – analog of cytosine; coetaneous mycoses or in combination with amphotericin B for systemic mycoses
**interfere with RNA biosynthesis 44

45. Antiviral drugs

46. Antiviral drugs Attachment Penetration Uncoating
Nucleic acid synthesis (polymerases inhibitors)
Assembly
release

47. Nucleoside & nucleotide analoges
(acyclovir, ribavirin, lamavudine)
Lamavudine ==nucleoside analog=cytidine
Hepatitis B virus
Reverse transcriptase inhibitor==HIV

48. Antiviral drugs Acyclovair=Zovirax=acycloguanosine=ACV
Guanosine analogus
**Herpes simplex virus infection
(Genital, oral & eye)
**varicilla zoster virus
(Shingles & Chickenpox in immunocompromised patients)
###viral thymidine kinase phosphorelate the drug
==this inactivate DNA polymerase
only inside virally infected

49. Ribavirin==guanosin analoge
stop viral RNA synthesis & mRNA
===nucleoside inhibitor
***hepatitis C virus
***respiratory syncytial virus

50. HIV inhibitors Amantadine ==symmetrel ***uncoating of influenza virus
Tamiflue…..neuraminidase
HIV inhibitors
Reveres transcriptase enzyme inhibitors=retrovirus= nucleoside analoge
Protease inhibitors
(Indinavir, saquinavir, ritonavir)
Zidovidine=rv.tr. inhibitor

52. Antiviral Drugs
Interferon=protein(cytokines) produced by virally infected cells, that inhibit spread of the virus & protect other cells
***by the activation of the cell to produce certain enzyme
==prevent viral protein
synthesis
==kill virally infected cells
==the same way in which cancer
cells be killed (cancers)
(Viral hepatitis)

53. Anti protozoa chemotherapeutics
Protozoa are unicellular Eukaryotic microbes
Have variety of shapes,
Lives free or as parasite
They absorb or ingest organic compounds from their environment

55. Anti malaria
Malaria is an entirely preventable & treatable disease
treatment==rapid & complete elimination of the parasite chronic & anemia
prevention== of the spread & emerging resistance

56. Drugs used for malaria prophylaxis can work in one of three ways:
Kill parasites in the liver
Causal prophylaxis
primaquine ++++
malarone ++
Kill asexual parasites in RBCs Suppressive prophylaxis
chloroquine ++++
malarone ++++
mefloquine ++++
doxycycline ++++
Mosquito
Human
Kill sexual parasites (gametocytes) in RBCs
Gametocytocidal prophylaxis
primaquine ++++ 56

57. Antihelminthic Drugs
Praziquantel
Albendazole
Surgery
Helminths are macroscopic multicellular eukaryotic organisms: tapeworms, roundworms, pinworms, hookworms 57 57

58. Clinical uses of antimicrobial drugs

59. Clinical uses of antimicrobial drugs
Inappropriate Antimicrobial Use
Prescription not taken correctly
Antibiotics for viral infections
Antibiotics sold without medical supervision
Spread of resistant microbes in hospitals due to lack of hygiene

60. **-the identity of the pathogen **-potential toxicity to the patient
Proper selection of antimicrobial agent is based on a number of factors
**-the identity of the pathogen
**-potential toxicity to the patient
**-pharmacokinetics & pharmacodynamics of the agent
**-site of infection
**-rout of administration
**-drug resistance
**-possible drug interaction
**-host factors
**-cost

61. Drug selection should be based on it’s activity against infecting pathogen
pathogen may be predictably susceptible to a particular drug
Therefore lab. guidance is essential for safe prescribing
Culture & sensitivity test

62. Susceptibility Tests Agar diffusion = disk-diffusion test
(cont’d)
Agar diffusion = disk-diffusion test
 Kirby-Bauer Disk Diffusion Test
Sensitive
Intermediate
resistant 62

63. Minimal Inhibitory Concentration (MIC)=the lowest concentration of drug capable of preventing bacterial growth
vs.
Minimal Bactericidal Concentration (MBC)=the lowest concentration of chemotherapeutic agent that kills bacteria
32 ug/ml
16 ug/ml
8 ug/ml
4 ug/ml
2 ug/ml
1 ug/ml
Sub-culture to agar medium
MIC = 8 ug/ml
MBC = 16 ug/ml

65. Minimum inhibitory concentration (MIC) is determined when
**a patient does not respond to treatment
**thought to be adequate,
**relapses while being treated
**when there is immunosuppression.

66. **-circulating & tissue phagocyte activity
Host factors play an important part in proper selection of antimicrobial drug
**-age
**-circulating & tissue phagocyte activity
e.g. hematological malignancy=acute leukemia
Bactericidal= amino glycosides
broad spectrum penicillins
cephalosporin
quinolones

67. Pharmacological factors
By achieving satisfactory drug concentration at the site of infection
Standard pharmacokinetics =absorption
distribution
metabolism
excretion
Oral---- G.I. absorption should be satisfactory
interaction with food
vomiting (surgery)
***Parenteral agent will be required

68. Site of infection
---lipid solubility of the drug
Amino glycosides are poorly lipid –soluble =penetrate CSF poorly (bacterial meningitis)
Meningeal inflammation also affect drug penetration into the tissues
Beta-lactam agents achieve satisfactory concentration within CSF but the inflammation subsides drug concentration

69. super infection Normal flora (skin & mucous membrane)
Microbial overgrowth of resistant pathogen
Oral & vaginal candidiasis
Broad spactrum-(ampicillin or tetracycline)
Pseudo-membranous colitis
Toxin-producing strain of clostridium
Following the use of clindamycin
Managed by oral vancomycin
surgery

70. **-the identity of the pathogen **-potential toxicity to the patient
Proper selection of antimicrobial agent is based on a number of factors
**-the identity of the pathogen
**-potential toxicity to the patient
**-pharmacokinetics & pharmacodynamics of the agent
**-site of infection
**-rout of administration
**-drug resistance
**-possible drug interaction
**-host factors
**-cost

71. Drug resistance
Intrinsic= inherent properties of bac. are responsible for preventing antibiotic action ==always chromosomally mediated 0r
Acquired= occurs when bac. which were previously susceptible then become resistance
== occur by mutation in the chromosome or by acquisition of genes coding for resistance from external source (plasmid)

72. Plasmid mediated resistance has been recognized among Gm. -ve bact
Plasmid mediated resistance has been recognized among Gm.-ve bact.== can code for multiple resistant ##cephalosporins, chloromphinicol, amino glycosides
==enzymatic inactivation
hospitals & intensive care units

73. Multi-drug resistance
Methicillin resistant Staph.aureus (MRSA)
=resist to many antibiotics
Hospitals, intensive care units, burn ,cardiothoracic units
Glycopeptides , vancomycin

74. Mechanisms of Antibiotic Resistance
Enzymatic destruction of drug
(B lactamase) Drug inactivation – penicillinases
Prevention of penetration of drug to its target site within the bacteria (tetracycline resistance) Decreased permeability to drug or increased elimination of drug from cell 74 74 74

75. Mechanisms of Antibiotic Resistance
Alteration of drug's target site(a.a changes in the ribosome) Change in metabolic patterns
Rapid ejection of the drug Change in drug receptors
Efflux pump= antibiotic is rapidly extracted from the cell by an energy-dependent mechanism ( tetracyclines & macrolides)

76. ++ Inpaired cell wall or cell envelope penetration
++ Enzymatic inactivation
++ Altered binding sites
++ Efflux pump= antibiotic is rapidly extracted from the cell by an energy-dependent mechanism( tetracyclines & macrolides)

79. What Factors Promote Antimicrobial Resistance?
Exposure to sub-optimal levels of antimicrobial
Exposure to microbes carrying resistance genes 79 79 79

80. To lower Antimicrobial Resistance Development
Use more narrow spectrum antibiotics
Use antimicrobial cocktails
Effects of combinations of drugs
Synergism
Penicillin and streptomycin, Sulfa and trimethoprim
Antagonism
Penicillin and tetracycline
Addition 80 80 80

81. Combination of Drugs For antibiotics “A” and “B” used in combination:
Actual killing rate = A + B  Additive
Actual killing rate > A + B  Synergistic
Actual killing rate < A + B  Antagonistic
Typically bacteriostatic agents are antagonistic to bactericidal agents.
Bacteriocidal agents can be synergistic (think of the latter as one antibiotic weakens more bacteria than it kills, making the not-killed bacteria more susceptible to additional insult by the second antibiotic).
Additive means that the two (or more) antibiotics neither hinder nor help each other’s ability to kill.
Also relevant to rates of mutation to resistance.
Combination of Drugs 81

82. Second term exam.
Good luck