This document provides information on chemotherapeutic drugs and antimicrobial mechanisms of action and resistance. It begins by outlining the learning objectives which are to describe the principles of chemotherapy, mechanisms of antimicrobial drug action and resistance, specific drug classes and their effects. It then discusses the basic principles of chemotherapy and antimicrobials before explaining various mechanisms of antimicrobial action and how selective toxicity is achieved. The document closes by discussing antimicrobial resistance and complications of drug therapy.

1. CHEMOTHERAPEUTIC DRUGS
Teshome G.
1

2. Learning Objectives
 At the end this section the student will able to:
• Describe the general principles chemotherapy and mechanisms
of action of antimirobial drugs.
• Illustrate the mechanims of antimicrobial drug resistance.
• Describe the mechanims of action and the adverse effects of
antituberculois drugs.
• Classify antifungal drugs.
• HIV treatment in neonates
• Describe the clinical uses, and the major adverse effects of
Antiprotosal drugs
2

3. BASIC PRINCIPLES OF CHEMOTHERAPY

4. Chemotherapy
• Is the use of chemical agents (either
synthetic or natural) to destroy
infective agents (microorganisms’ i.e
bacteria, fungus and viruses, protozoa,
and helminthes) and to
• inhibit the growth of malignant or
cancerous cells.
4

5. An antimicrobial
Is any substance of natural, semi-
synthetic, or synthetic origin that
kills or inhibits the growth of a
microorganism, but causes little or
no host damage.
5

6. An antibiotic
• Is a substance produced by a microorganism
(bacteria, fungi and actinomycetes) that, at low
concentrations, inhibits or kills other
microorganisms. (Antimicrobial and antibiotic will
often be used interchangeably)
• Antibiotics differ markedly in chemical, and
pharmacological properties, in antimicrobial
spectra, and in mechanisms of action.
6

7. Classification of antimicrobials
A) By susceptible organisms
• Antibacterial
• Antifungal
• Antiviral
• Antiprotozoal
• Miscellaneous (Parasites, worms…)
B) By mechanism of actions
I. Bacteria cell wall synthesis inhibitor
• Penicillins
• Cephalosporins
• Cycloserin
• vancomycin
7

8. II – Protein synthesis inhibitors:
• Chloramphenicol
• Tetracycline
• Macrolides
• Aminoglycosides
8

9. III – Agents that interfere with nucleic acid synthesis.
• Rifamcin (rifampin) – inhibits DNA – dependent
RNA polymerase.
IV – Antimetabolites
• Sulfonemides
• trimethoprim
V – Inhibitors of viral replicalion
• ZDV
• Acyclovir
9

10. Modes of Antimicrobial Action
10

11. Antimicrobial Activity
 Describe the nature of the effect of the antimicrobial
against microorganisms.
 Bacteriostatic: - agents that interfere with growth
or replication of the bacteria, but do not kill it.
The body’s immune system attacks, immobilizes
and eliminates the pathogens.
 Bacteriocidal: - agents that kill the bacteria
choice form bacteriostatic and bactericidal depends
up on bacterial susceptibility and/ or host status. 11

12. Antimicrobial Spectrum
• Is a description of the GENERAL
activity of an antimicrobial against
micro-organisms.
• Narrow spectrum
• Is usually imply activity against
some limited subset of bacteria.
12

13. Spectrum…
 Broad Spectrum
• Iimplies activity against a wide range of
bacteria (perhaps even all genre) and may
imply activity against mycoplasma, rickettsia,
and chlamydia
• It is much better to know the bacteria
causing an infection than to rely on the
broadness of an antimicrobial's spectrum. 13

14. How can a drug be highly toxic to microbes
but harmless to the host?
• The key lies with differences in the cellular
chemistry of mammals and microbes.
• There are biochemical processes critical to
microbial well-being that do not take place in
mammalian cells.
• Hence, drugs that selectively interfere with these
unique microbial processes can cause serious
injury to microorganisms while leaving
mammalian cells intact 14

15. Selective toxicity
• The term selective toxicity is defined as
the ability of a drug to injure a target cell or
target organism without injuring other cells
or organisms that are in intimate contact
with the target.
• As applied to antimicrobial drugs, selective
toxicity indicates the ability of an antibiotic
to kill or suppress microbial pathogens
without causing injury to the host. 15

16. Mechanism of Action of
Antimicrobials
16

17. 1. Disruption of the Bacterial Cell Wall
• Unlike mammalian cells, bacteria are enclosed
in a rigid cell wall.
• The protoplasm within this wall has a high
conc. of solutes, making osmotic pressure
within the bacterium high.
• If it were not for the cell wall, bacteria
would absorb water, swell, and then burst.
17

18. Inhibition of the Bacterial Cell Wall…
• Several families of drugs (eg,
penicillins, cephalosporins) weaken the
cell wall and thereby promote bacterial
lysis.
• Because mammalian cells have no cell
wall, drugs directed at this structure do
not affect us.
18

19. 2. Inhibition of an Enzyme Unique to
Bacteria
or Nucleic acid synthesis inhibitors or
Antimetabolites
• The sulfonamides represent antibiotics that are
selectively toxic because they inhibit an enzyme
critical to bacterial survival but not to our survival.
• Specifically, sulfonamides inhibit an enzyme needed
to make folic acid, a compound required by all cells,
both mammalian and bacterial to make DNA.
19

20. Bacterial Enzyme Inhibition…
• If we need folic acid, why don't
sulfonamides hurt us?
• Because we can use folic acid from dietary
sources.
• In contrast, bacteria must synthesize folic
acid themselves (because, unlike us, they
can't take up folic acid from the
environment). 20

21. Bacterial Enzyme Inhibition…
• Hence, to meet their needs, bacteria first take
up para-aminobenzoic acid (PABA), a precursor
of folic acid, and then convert the PABA into
folic acid.
• Sulfonamides block this conversion.
• Since mammalian cells do not make their own
folic acid, sulfonamide toxicity is limited to
microbes. 21

22. 3. Disruption of Bacterial Protein Synthesis
• In bacteria as in mammalian cells, protein
synthesis is done by ribosomes.
• However, bacterial and mammalian ribosomes
are not identical, and hence we can make drugs
that disrupt function of one but not the other.
• As a result, we can impair protein synthesis in
bacteria while leaving mammalian protein
synthesis untouched.
22

23. Antibiotics Resistance
23

24. ANTIBIOTIC PARADIGM
Excessive / inappropriate
antibiotic use
Failure of antibiotic
treatment
Antibiotic
resistance

25. Mechanisms of resistance to antibiotics
• Production of enzymes that inactivate
the drug:
− β -lactamase, which inactivates beta
lactam antibiotics
− acetyl transferases, which inactivate
chloramphenicol
− kinases and other enzymes, which
inactivate aminoglycosides. 25

26. Mechanisms of resistance to antibiotics…
• Reduction of drug uptake by the
bacterium: eg. Tetracyclines
• Alteration of enzymes: eg.
Dihydrofolate reductase becomes
insensitive to trimethoprim
26

27. Delaying the emergence of resistance
• Use anti microbial agents only when needed.
• Use narrow – spectrum antibiotics whenever
possible.
• Newer antibiotics should be reserved for
situations in which older drugs are dangerous
or no longer effective.
27

28. Selection of antibiotics…
 Selection of antibiotics depends on :
 The identity of the organism and its sensitivity
to a particular agents.
 The site of infection .
 The safety of the agents .
 Patient factors : immune system , renal
dysfunction ,hepatic dysfunction , pregnancy ,
lactation & age.
28

29. Definitions of terms
• Empiric therapy: treatment of an infection before
specific culture information.
• Definitive therapy :treatment of an infection after
the identification of an organism and its sensitivity
to a particular agent is made.
• Prophylactic therapy : using antimicrobials to
prevent infection.
29

30. Indications for antimicrobial combinations
 For treatment of mixed bacterial infection
 For severe infection where the causative agent is
unknown
 To prevent emergency of resistant strains of organisms
 To enhance antimicrobial activity
Disadvantages of antibiotic combinations
 Increased cost.
 Increased risk of allergic reactions and toxicity
 Increased risk of super infection.
 Possible antagonism of antimicrobial effects.
30

31. Misuses of Antimicrobial Drugs
A. Attempted Treatment of Untreatable Infection.
B. Treatment of Fever of Unknown Origin.
C. Improper Dosage—Too low or too high.
D. Treatment in the Absence of Adequate Bacteriologic
Information.
E. Omission of Surgical Drainage—Have limited
efficacy in presence of foreign material, necrotic
tissue, or pus 31

32. Complications of antibiotic therapy
 Hypersensitivity
 Hypersensitivity reactions to antimicrobial drugs or
their metabolic products frequently occur.
 For example, the penicillins, despite their almost
absolute selective microbial toxicity, can cause
serious hypersensitivity problems, ranging from
urticaria (hives) to anaphylactic shock.
32

33.  Direct toxicity
High serum levels of certain antibiotics may
cause toxicity by directly affecting cellular
processes in the host.
For example, aminoglycosides can cause
ototoxicity by interfering with membrane
function in the hair cells of the organ of
Corti.
33

34.  Super infection:
Drug therapy, particularly with broad-spectrum
antimicrobials or combinations of agents, can
lead to alterations of the normal microbial flora
of the upper respiratory, intestinal, and
genitourinary tracts, permitting the overgrowth
of opportunistic organisms, especially fungi or
resistant bacteria.
These infections are often difficult to treat.
34

35. Monitoring
• Efficacy and toxicity of antimicrobials
• Clinical assessment
– Improvement in signs and symptoms
• Fever curve,  WBC
•  erythema, pain, cough, drainage, etc.
• Antimicrobial regimen
– Serum levels
– Renal and/or hepatic function
– Other lab tests as needed
– Consider IV to PO switch
• Microbiology reports
– Modify antimicrobial regimen to susceptibility results if necessary
• Resistance?
– “Narrow” spectrum of antimicrobial if appropriate

36. Cell wall synthesis inhibitors
Members the group: Beta-lactam antibiotics,
vancomycin, bacitracine, and cycloserine
36

37. Inhibition of cell wall synthesis
• (“Beta-lactams”)
 Penicillin
.Amoxicillin
.Ampicillin
 Cephalosporins
 etc.
Varies (and can be
modified)
ß-_______
ring
37

38. Beta-lactam antibiotics
• Penicillins, cephalosporins, carbapenems, and
monobactams are members of the family.
• All members of the family have a beta-lactam
ring and a carboxyl group resulting in
similarities in the pharmacokinetics and
mechanism of action of the group members.
38

39. Penicillins
39

40. Benzylpenicillin and congeners
Benzylpenicillin (Penicillin G)
Crystallin penicillin
Procain penicillin
Bezanthin penicillin
Spectrum: Against Gram +ve cocci and Gram –ve.
Destroyed by Beta-lactamases
• Penicillin G is bactericidal to a number of gram-
positive bacteria as well as to some gram-negative
bacteria.
• Despite the introduction of newer antibiotics,
penicillin G remains a drug of choice for many
infections
40

41. Benzylpenicillin and congeners
Benzylpenicillin (Penicillin G)
• Penicillin G is active against
− most gram-positive bacteria (except penicillinase-producing
staphylococci)
− gram-negative cocci (Neisseria meningitidis and non–
penicillinase-producing strains of Neisseria gonorrhoeae)
− anaerobic bacteria, and spirochetes with few exceptions
gram-negative bacilli are resistant.
• Although many organisms respond to penicillin G, the drug
is considered a narrow-spectrum agent (compared with
other members of the penicillin family).
41

42. Beta-lactamase resistant penicillins
Cloxacillin, Flucloxacillin, Methicillin, Nafcillin
Spectrum: As benzylpenicillin but less
potent.
• Preferred drug for those few strains of
Staph. aureus that do not produce
penicillinase.
42

43. Broad-spectrum penicillins
Ampicillin, Amoxicillin
Spectrum: Benzylpenicillin + some Gram –ve
bacteria. Destroyed by Beta-lactamases.
• have the same spectrum and activity, but amoxicillin is
better absorbed from the gut.
• These drugs are given orally to treat urinary tract
infections, sinusitis, otitis, and lower respiratory tract
infections.
• Ampicillin IV is useful for treating serious infections caused
by penicillin-susceptible organisms 43

44. Pharmacokinetics of penicillin
• Penicillin G is unstable in acid media, hence
destroyed by gastric juice.
• Ampicillin, amoxicillin, and cloxacillin are acid-
stable and relatively well absorbed after oral
adminstraion.
• Oral penicillins should be given 1-2 hours before
or after meals to minimize binding to food
proteins and acid inactivation (except ampicilin).
44

45. Clinical uses of penicillin
Meningitis
Pharyngitis
Otitis media
Broanchitis
Phnemonia
UTI
Gonorrhoea
Syphilis
Endocarditis
45

46. Clinical uses of penicillin
• In addition to treating active infections,
penicillin G has important prophylactic
applications.
• The drug is used to prevent syphilis in sexual
partners of individuals who have this infection.
• Benzathine penicillin G (administered monthly
for life) is employed for prophylaxis against
recurrent attacks of rheumatic fever
46

47. ADRs penicillin
 Hypersensitivity reactions
(Acute anaphylactic shock)
• Penicillins are the most common cause of drug
allergy.
• Between 0.4% and 7% of patients who receive
penicillins experience an allergic reaction.
• Severity can range from a minor rash to life-
threatening anaphylaxis.
• Because of cross sensitivity, patients allergic to one
penicillin should be considered allergic to all
penicillins.
47

48. ADRs penicillin
• Other ADR to penicillins are generally less
sever than anaphylaxis.
Interstitial nephritis
Electrolyte disturbance
Thrombocytopenia, Platelate dysfunction
Seizure and Hepatitis
48

49. Cephalosporins
49

50. • Classification –can be classified into
four generations depending mainly on
the spectrum of antimicrobial activity.
• First-generation compounds have better
activity against gram-positive
organisms and the later compounds
exhibit improved activity against gram-
negative aerobic organisms.
50

51. First Generation
Cefadroxil, Cefalexin, Cefazolin, Cefapirin,
Cefradine, cephalothin
• Very active against Gram +ve and
some Gram –ve
• Iv penetrate most tissues well – choice
for surgical prophylaxis
51

52. First Generation…
• Cephalexin, and cefadroxil are absorbed
from the gut to a variable extent.
• Clinical Uses: Oral drugs may be used for
the treatment of urinary tract infections,
for minor staphylococcal lesions, or for
minor polymicrobial infections such as
cellulitis or soft tissue abscess.
52

53. Second Generation
Cefaclor, Cefuroxime, Cepfotetan, Cefoxitin,
Cefprozil
• All are less active against Gram +ve bacteria than
the first-generation drugs; however, they have an
extended Gram –ve coverage.
• Clinical Uses: Sinusitis, otitis, or lower
respiratory tract infections, mixed anaerobic
infections, and community-acquired pneumonia.
53

54. Third Generation
Cefotaxime, Ceftriaxone,
Ceftizoxime, Cefdinir, Cefepime,
Cefixime, Cefpodoxime,Ceftazidime,
Expanded to Gram –ve + aemophilus and
Neisseria (beta lactamase producing) +
Enterobacter + P.aeruginosa
Reach well in CNS
54

55. Third Generation
• They can be given orally or IM or IV.
• They penetrate body fluids and tissues well.
• Cefotaxime, ceftazidim, and ceftriaxone
crosses blood brain barrier, hence inhibit
most pathogens, including gram-negative
rods
• Ceftazidime is effective in pseudomonas
infections. 55

56. Third Generation..
• Clinical uses: Gonorrhea (ceftriaxone
and cefixime), meningitis (pneumococci,
meningococci, H influenzae, and
susceptible enteric gram-negative rods),
penicillin-resistant strains of
pneumococci (ceftriaxone, cefotaxime),
and sepsis
56

57. Fourth-generation cephalosporins
(e.g.cefepime)
• It is similar to third-generation
agents; however, it is more
resistant to hydrolysis by
betalactamases.
• It has good activity against P.aeruginosa.
57

58. Adverse Effects of Cephalosporins
• Cephalosporins are sensitizing and may
elicit a variety of hypersensitivity
reactions that are identical to those of
penicillins (cross reactions with
penicillins)
• Nephrotoxicity – Cefradine
58

59. Vancomycin
• Spectrum: Bactericidal; Gram
+ve, MRSA, Clostridium difficile.
• Mechanism: Inhibits cell wall
synthesis.
• ADRs: Nephrotoxicity, Ototoxicity
59

60. 60
Aminoglycosides
Protien Synthesis Inhibitors

61. 61
Members of Aminoglycosides
Streptomycin Kanamycin
Neomycin Amikacin
Tobramycin Paromomycin
Gentamicin

62. 62
Aminoglycosides (AGs)
• Not absorbed adequately after oral
administration
• Widely used but serious ADRs – major
limitation
• Clinical spectrum – Gram negative aerobes
• Rapidly bactericidal – dose dependent

63. 63
AGs: Mechanism of action
• Protein synthesis inhibitors – 30 S ribosomal
subunit
• They interfere with the "initiation complex"
of peptide formation and
• Induce misreading ribosomal proteins

64. 64
Pharmacokinetics
• Highly polar cations – poorly absorbed
from the GIT
• Distribution is limited due to polarity
and negligible plasma binding
• High conc. – renal cortex & endolymph
/perilymph of the inner ear

65. 65
Adverse Drug Effects
• Ototoxicity – irreversible –accumulate
in perilymph and endolymph
• Nephotoxicity –reversible – accumulate
in proximal tubular cells (Neomycin)
• Neuromuscular blockade – inhibition of
Ach release!

66. 66
66
AGs : Clinical uses
 Streptomicin - Bacterial endocarditis (AG +
Penicillin G), TB
 Tobramycin - Similar with Gentamicin but
superior against P. aeruginosa

67. 67
AGs : Clinical uses
 Gentamicin
• Low cost and active against
―all resistant Gram –ve aerobes
―Gram –ve bacillary infections
―P. aeruginosa, Enterobacter, and Klebsiella
• Used for UTI, Pneumonia, Meningitis,
Peritonitis, Septicemia due to P. aeruginosa

68. 68
Tetracyclines

69. Structure and derivatives of tetracycline
69

70. 70
Tetracyclines
• Are a large group of drugs with a common basic
structure and activity
• Broad spectrum including activity against
some protozoa.
• Bacteriostatic
• Tetracycline (TTC) is a prototype but short
acting.
• Doxycycline a new generation and long-

71. 71
Members
Tetracycline, Oxytetracycline,
Demeclocycline, Minocycline, Doxycycline,
Chlorotetracyline

72. 72
Mechanism of action
• Inhibit protein synthesis – binds to 30S
subunit of ribosome
• Higher concentrations affect mammalian
ribosomes

73. 73
TTCs: Adverse Drug Effects
• GI irritation – Nausea / Vomiting
• Deposition in calcified tissues – in teeth enamel
 CI for children < 12 years, pregnancy &
lactation.
• Liver Toxicity - pre-existing insufficiency
• Kidney Toxicity – Except doxycyline
• Antianabolic effect – Decreased protein
synthesis
• Photosensitivity

74. 74
Clinical uses of TTCs
 Bacterial and protozoans
• Gram –ve and Gram +ve bacteria -
Mycoplasmas and Chlamydia
• Malaria and Ameobiasis
• Rickettisial infections
• STI: Uncomplicated gonococcal infections

75. 75
Chloramphenicol

76. 76
Chloramphenicol…
• Bacteriostatic and Broad spectrum
• Because of potential toxicity, bacterial
resistance, and the availability of other
effective drugs
Reserved for patients with serious
infections
o Meningitis, Typhus, Typhoid fever

77. 77
Mechanism of action
• Protein synthesis inhibition – binds to
50s ribosomal subunit

78. 78
Adverse Drug Effects of chloramphenicol
• Hypersensitivity reactions
• Hemato-toxicity (dose-related)– anemia,
agranulocytosis, thrombocypenia
• Idiosyncratic response – Aplastic anemia
• Gray Baby Syndrome
• N/V/D

79. 79
Clinical uses Chloramphenicol
• Typhiod fever – Salmonella typhi
• Bacterial meningitis – H.inflenzae; 2nd
choice N.meningitidis and Strep.
pnemoniae
• Anaerobic inflections – Bacteroide spp.
• Rickettsiae

80. 80
Macrolides
• Erythromycin, Clarithromycin, Azithromycin,
Roxithromycin
•Are broad-spectrum antibiotics that inhibit
bacterial protein synthesis.

81. 81
Antimicrobial spectrum
 Gram +ve and some Gram –ve; Mycoplasma
pneumoniae, Chlamydia
• Macrolides are effective against especially
pneumococci, Mycoplasma, Chlamydia
trachomatis, and Helicobacter.
• Also useful as a penicillin substitute in
penicillin-allergic individuals with infections
caused by staphylococci, streptococci, or
pneumococci.

82. 82
Adverse Drug Effects
GI disturbances (epigastric pain), Liver toxicity
Increases GI motility – increase gastric
emptying

83. Clindamycin
• Spectrum: Bacteriostatic; Anaerobes,
Bacteroides, Some Gram +ve activity.
• Mechanism: Inhibits protein synthesis - bind to
50 S ribosomal subunit
• Clinical uses:
– Serious infections with aerobic Gram +ve
cocci
– Lung abscess, anaerobic lung and pleural
space infections
• ADRs: Nausea, diarrhea, Antibiotic-associated
colitis
83

84. Sulfonamides
Antimetabolites
84

85. Example Drugs
Sulfadiazine, Sulfisoxazole
Sulfasalazine, Sulfamethoxazole
Sulfadoxine
Topical Sulfa Drugs:
Sulfacetamide, Silver sulfadizine
85

86. Mechanism of action
• Block uptake of PABA - inhibit folic
acid synthesis.
• Bacteriostatic with slow onset of
action.
86

87. Antimicrobial Spectrum
• Broad spectrum but resistance is
common.
• Gram +ve and –ve, Chlamydia
trachomitis, Strep. pyrogens and
pneumonia,
87

88. Clinical uses [1]
Topical
• Sulfacetamide solution and oint for
conjunctivitis
• Silver sulfadiazine – burn
• Sulfasalazine - Ulcerative colitis, Enteritis
and IBD.
88

89. Clinical uses [2]
Oral
• Uncomplicated UTI - Sufisoxazole or Co-
trimoxazole
Chlamydia - genital tract, eye or respiratory tract.
• Sinusitis, Bronchitis, Pneumonitis, Otitis media.
• Bacillary dysentery
• Toxoplasmosis 89

90. Adverse Drug Effects
Hypersensitivity – (fever, skin rashes,
photosensitivity, urticaria) – cross allergenic rxns
Hemato-toxicity – Anemia (hemolytic or aplastic),
thrombocytopenia.
Nephrotoxicity – ppt in urine – producing
crystalluria, hematuria or obstruction.
Kernicterus in newborns – Never used in last-
90

91. Dihydrofolic Acid Reductase Inhibitors
Trimethoprim and Pyrimethamine
• Used in combination with sulfonamides –
sequential block in metabolic sequence
Trimethoprim - given orally alone or in
combination with sulfamethoxazole - Co-
trimoxazole
• .
91

92. Trimethoprim and
sulfamethoxazole
(Co-trimoxazole)
• The combination often is bactericidal,
compared to the bacteriostatic activity of a
sulfonamide alone.
• Clinical use
―Pneumocystis carinii pneumonia,
symptomatic Shigella enteritis, systemic
Salmonella, complicated UTIs and
prostatitis.
• ADRs: Antifolate effects – megaloblastic
anemia, leukopenia and granulocytopenia 92

93. Ciprofloxacin, Ofloxacin, Norfloxacin,
Nalidixic acid
Quinolones
and
Fluoroquinolones
93

94. Mechanism of action
• Inhibit DNA synthesis
• They inhibit normal transcription and
replication of bacterial DNA
• Bactericidal
Antimicrobial spectrum
Broad spectrum
94

95. Clinical uses
• Fluoroquinolones are effective in urinary
tract infections even when caused by
multidrug-resistant bacteria, eg,
Pseudomonas.
• Norfloxacin 400 mg, ciprofloxacin 500
mg, and given orally twice daily and all
are effective. 95

96. Clinical uses…
• Fluoroquinolones are also effective for
bacterial diarrhea caused by Shigella,
Salmonella, toxigenic E coli.
• Ciprofloxacin is effective for gonococcal infection.
• It can also used for infections of soft tissues,
bones and joints and in intraabdominal and
respiratory tract infections.
96

97. Adverse Effects
• Headache
• Tendonitis or tendon rupture
• V/N/D
• Phototoxicity
• May damage growing cartilage and cause
an arthropathy in young
97

98. THANK YOU!
98