1. Principles of Antibiotic
Therapy
1

2. Definition -Antibiotic
An antibiotic is a substance produced by
various species of living microorganisms
(e.g. bacteria and fungi)
Inhibit pathogens by interfering with
intracellular processes
Term antibiotic includes synthetic
antimicrobial agents i.e. sulphonamides
Antibiotics do not kill viruses -not effective
in treating viral infections.
2

3. Selection of Antimicrobial Agent
Empiric therapy - prior to identification of
organism – critically ill patients
Organism’s susceptibility to the antibiotic
Patient factors - immune system,
renal/hepatic function
Effect of site of infection on therapy –blood
brain barrier
Safety of the agent
Cost of therapy
3

4. Properties Influencing Frequency of
Dosing
Concentration dependent killing –
antimicrobials including aminoglycosides =
significant increase in rate of bacterial killing as
the drug concentration increases
Time-dependent killing – β-lactams,
glycopeptides, macrolides, clindamycin &
linezoid – dependent on the % of time that
blood concentrations remain above minimum
inhibitory concentration (MIC)
4

5. 5

6. Properties Influencing Frequency of
Dosing
Post-antibiotic effect (PAE)– persistent
suppression of microbial growth after levels
of antibiotic have fallen below MIC
Antibiotics with a long PAE – aminoglycosides
and fluroquinolines
Minimum bacterial concentration (MBC) is
the lowest concentration of antibiotic that
kills 99.9% of bacteria
6

7. MIC
INHIBITS
Figure 30.2 (part 2)
7
Chapter 30 MENU >

8. MBC
KILLS
Figure 30.2 (part 3)
8
Chapter 30 MENU >

9. Chemotherapeutic Spectra
Narrow-spectrum Antibiotics:
Act on a single / limited group of micro-organisms;
e.g., isoniazid given for mycobacterium
Extended-spectrum Antibiotics:
Effective against gram-positive organisms and a
significant number of gram-negative organisms; e.g.,
ampicillin
Broad-spectrum Antibiotics:
Effective against a wide variety of microbial species;
e.g., tetracycline & chloramphenicol.
Can alter the nature of intestinal flora = super infection
9

10. Combinations of Antimicrobial Drugs
Advantages
Synergism; the combination is more effective
than either drug used separately; β-lactams and
aminoglycosides
Infections of unknown origin
Disadvantages
Bacteriostatic (tetracycline) drugs may interfere
with bactericidal ( penicillin and cephalosporin)
drugs
10

11. Complications of Antibiotic Therapy
Resistance – inappropriate use of antibiotics
Hypersensitivity – penicillin
Direct toxicity – aminoglycosides = ototoxicity
Super infections – broad spectrum
antimicrobials cause alteration of the normal
flora; often difficult to treat
11

12. Drug Resistance
1. Alteration of the target site of the antibiotic
One of the most problematic antibiotic resistances worldwide,
methicillin resistance among Staphylococcus aureus.
2. Enzyme inactivation of the antibiotic
β-lactam antibiotics (penicillins & cephalosporins) can be
inactivated by β-lactamases.
3. Active transport of the antibiotic out of the bacterial cell
(efflux pumps)
Removal of some antibiotics (i.e. tetracyclines, macrolides, &
quinolones)
4. Decreased permeability of the bacterial cell wall to the
antibiotic
Alteration in the porin proteins that form channels in the cell
membrane – Resistance of Pseudomonas aeruginosa to a variety
of penicillins and cephalosporins
12

13. Antibiotic
Resistance 4.
2.
1.
3.
13

14. Resistance - β-lactamase
Some bacteria secrete an enzyme called β-
lactamase which destroys the beta lactam
ring, rendering beta-lactam antibiotics
ineffective.
Solution - add clavulanic acid - a β-
lactamase inhibitor - i.e. co-amoxiclav
(Augmentin) or the combination of
piperacillin and tazobactam (Tazocin).
14

15. Resistance –
Decreased Permeability of the Drug
Prevents the drug reaching the target
penicillin binding proteins (PBPs)
Presence of an Efflux pump also reduces the
amount of the intracellular drug
15

16. Classifying Antimicrobial Agents
Mode of action
BACTERICIDAL (kills the bug)
BACTERIOSTATIC (stops the bug multiplying)
Spectrum of activity
BROAD (e.g. effective a variety of gram-neg & gram-pos bacteria)
NARROW (e.g. effective only against gram-neg or gram-pos
Mechanism of action / site of action;
Inhibitors of cell metabolism; (Sulfonamides, Trimethoprim)
Cell wall inhibitors; (β-Lactam, Vancomycin)
Protein synthesis inhibitors; (Tetrecyclines, Aminiglycosides,
Macrolides, Clindamycin, Chloramphenicol)
Nucleic acid inhibitors; (Floroquinolones, Rifampin)
Cell membrane inhibitors; (Isoniazid, Amphotericin B)
16

17. Classification of Antimicrobials by Site
of Action
Figure 30.13 (still)
17
Chapter 30 MENU >
Wolters Kluver

18. 1. CELL WALL INHIBITORS
Interfere with the synthesis of the bacterial cell
wall
Little or no effect on bacteria that are not growing
and dividing
β-lactam group Other antibiotics
Penicillins Vancomycin
Cephalosporins Bacitracin
Carbapenems Daptomycin
Monobactams Telavancin
β-lactam inhibitors +
antibiotic combinations
18

19. Antimicrobial Agents
Affecting Cell Wall
Synthesis
Figure 31.1 (still)
19
Chapter 31 MENU >

20. PENICILLINS (bactericidal)
Most widely effective and least toxic
Limited use - increased resistance
Mechanism of action
Inactivates various proteins on bacterial
cell wall
20

21. Administration and Fate of
PENICILLIN
Routes of Administration
• Oral only –Pen V, Amoxicillin &
amoxicillin combined with clavulanic
acid
• IV / IM- Tiracillin, piperacillin,
ampicillin with sulbactam, tiracillin
with clavulanic acid and piperacillin
with tozobactam
• Others oral, IV or IMI
Absorption
• Decreases by food in the stomach –
administer before meals 30-60min
Distribution to bone and CSF
insufficient
Excretion - Kidneys
Figure 31.7 (still)
21
Chapter 31 MENU >

22. Adverse Effects of Penicillin
Figure 31.9 (still)
22
Chapter 31 MENU >

23. CEPHALOSPORINS (bactericidal)
Semi-synthetic antibiotics
β-lactam antibiotics closely related functionally
and structurally to penicillins
Mode of action - inhibit the synthesis of the cell
wall
More resistant than penicillins to certain β –
lactamases
Classified as 1st, 2nd, 3rd and 4th generation – based
on spectrum of antimicrobial activity
23

24. Mechanism of Action
Bactericidal, inhibit cell wall synthesis.
Cephalosporins are also beta-lactams so can be
degraded by beta-lactamase secreting bacteria.
Good to know:
Classified by generation, based on general features
pertaining to activity;
The higher the generation, the broader the
spectrum. E.g. ceftriaxone (3rd generation) is
effective against more gram negative bacteria than
cephalexin (1st generation).
24

25. • Gram +ve and moderate
Gram –ve activity
• Act as penicillin G
substitutes
• Resistant to staph
penicillinase
Figure 31.10 (part 1)
25
Chapter 31 MENU >

26. Greater activity against
Gram -ve organisms;
• H influenza
• Enterobacter aerogenes
• Neisseria species
Activity against gram +ve
organisms is weaker
Some agents with activity
against anaerobes
Figure 31.10 (part 2)
26
Chapter 31 MENU >

27. • Activity against Gram +ve
organisms
• Increased activity against
Enterobacteriaceae and
pseudomonas aeruginosa
• Important in the treatment
of infectious diseases
• Inferior to 1st generations
in activity against MSSA
(meticillin-sensitive
S. Aureus)
Figure 31.10 (part 3)
27
Chapter 31 MENU >

28. 4th Generation Cephalosporins
Spectrum similar to 3rd
Generation
Have increased stability
Cefepime ;
28

29. Administration and fate
of cephalosporins
• Resistance same as
that for penicillins
Figure 31.11 (still) 29
Chapter 31 MENU >

30. Most Common Side Effects –
Cephalosporins
• Diarrhoea • Individuals
• Nausea hypersensitive to
• Abdominal pain penicillins may also be
• Vomiting hypersensitive to
• Headache cephalosporins
• Dizziness • Like almost all
• Skin rash antibiotics, may cause
• Fever mild or severe cases of
• Abnormal liver tests pseudomembranous
• Vaginitis colitis
30

31. OTHER β-LACTAM ANTIOBIOTICS
Carbapenems:
Imipenem – broad spectrum of activity
against Gram +ve and Gram –ve aerobic
and anaerobic bacteria
Meropenem – Important for empirical
mono therapy of serious infections
31

32. Other β-Lactam Antiobiotics
Monobactams
Activity restricted to Gram –ve aerobic
bacteria
Aztreonam
32

33. β-LACTAMASE INHIBITORS
β-lactamase inhibitors –
clavulanic acid – sulbactam and
tazobactam
Do not have significant
antibacterial activity
Bind to and inactivate the β-
lactamases – protect the
antibiotics
Formulated in combination with
β-lactamase sensitive antibiotics
Clavulanic acid and amoxicillin
Growth of E. Coli in presence of
33 amoxicillin with and without
clavulanic acid

34. VANCOMYCIN;
• Tricyclic glycopeptide
• Effective against multiple
drug resistant organisms
(MRSA) & enterococci
• Resistance is becoming a
problem
• Enterococcus faecium
• Enterococcus faecalis
Figure 31.17 (still)
34
Chapter 31 MENU >

35. Vancomycin Adverse Effects – Serious problem
Figure 31.18 (still)
35
Chapter 31 MENU >

36. DAPTOMYCIN
Cyclic lipopeptide – linezolid and quinupristin /
dalfopristin
Treatment of infections caused by resistant
gram +ve
MRSA – methicillin S. Aureus
MSSA - methillin susceptible S. Aureus
VRE - vancomycin- resistant enterococci
Daptomycin is bactericidal
Concentration dependent
Inactivated by surfactant – never used in
treatment of pneumonia
36

37. Adverse Effects
Constipation
Nausea
Headache
Myalgias
Insomnia
Increased hepatic transaminases
Elevation of creatine phosphokinases
37

38. TELAVANCIN
Semi-synthetic lipoglycopeptide
antibiotic
Synthetic derivative of Vancomycin
Treatment of complicated skin and
skin structure infections caused by
resistant gram +ve organisms
including MRSA
38

39. Mechanism of
Action
• Inhibits bacterial cell
wall synthesis
• Also involves
disruption of
bacterial cell
membrane
• Bactericidal against
MRSA
Figure 31.20 (still)
Chapter 31 MENU >

40. Cautions & Adverse Effects Telavancin
Prolonged QT
interval
Figure 31.21 (still)
Chapter 31 MENU >

41. 2. PROTEIN SYNTHESIS INHIBITORS
• Target the bacterial
ribosome
• High levels of drugs i.e.
Chloramphenicol or the
tetracyclines may
cause toxic effect
•Interaction with the
host mitochondrial
ribosomes
41

42. TETRACYCLINES –
Antibacterial spectrum
Broad-spectrum bacteriostatic
antibiotic
Effective against:
Gram+ve and Gram-ve bacteria
Organisms other than bacteria
42

43. Tetracyclines – drug of choice
43

44. Absorption
Adequately but
incomplete oral
absorption
Taking with dairy
foods decreases
absorption
Resistance
Widespread
resistance limits
44
clinical use

45. Administration
of
Tetracyclines
Distribution –
• Liver, kidneys, liver
and skin
• Bind to tissue
undergoing
calcification; bones
and teeth, tumours
with high calcium
• Penetrate most body
Figure 32.5 (still)
fluids
Chapter 32 MENU >

46. Tetracycline - Adverse Effects
Figure 32.6 (still)
46 Adverse effects have restricted their usefulness
Chapter 32 MENU >

47. GLYCYLCYCLINES
(Pronunciation: gli-sil-sī-klēns)
Tigecycline – a derivative of minocycline
Similar to tetracycline
Broad-spectrum activity against
Multidrug-resistant Gram +ve pathogens
Some Gram –ve organisms
Aerobic organisms
Treatment of complicated skin and soft tissue
infections and complicated intra-abdominal
infections
Mechanism of action – bacteriostatic
47

48. GLYCYLCYCLINES Adverse Effects
Associated with nausea and vomiting and
other adverse effects similar to tetracyclines
Drug interactions
Inhibits the clearance of warfarin
Oral contraception with Glycylcyclines –
less effective
48

49. AMINOGLYCOSIDES
Similar antimicrobial spectrum to Macrolides
Relatively toxic but still useful in treatment of
infections caused by anaerobic Gram –ve bacteria
Ototoxicity = main limitation
Inhibit bacterial protein synthesis
Have a PAE
Good to know: Only available IV
Not absorbed by gut
49

50. Aminoglycosides
Antibacterial spectrum – effective in
combination for empirical treatment of
aerobic Gram –ve bacilli infections –
Pseudomonas aeruinosa
Combines with a β-lactam i.e.
Vancomycin Aminoglycosides and
bactericidal amikacin,gentamycin,
tobramycin and streptomycin
50

51. Figure 32.9 (still)
Chapter 32 MENU >

52. Adverse Effects of Aminoglycosides
Figure 32.10 (still)
Chapter 32 MENU >

53. MACROLIDES (bacteriostatic)
May also be bacteicidal
Large group of antibacterials
Low toxicity
Similar spectrum of activity
PAE – antibacterial activity continues after
concentrations have dropped
Good to know: Take on an empty stomach
53

54. Macrolides – Antibacterial Spectrum
Erythromycin – effective against the
same organisms as penicillin G
Clarithromycin - spectrum of activity
similar to erythromycin also Chlamidia,
Legionella, Moraxella & Ureaplasma
species & Helicobacter pylori
54

55. Macrolides – Antibacterial Spectrum
Azithromycin – less active to strep and
staph. More active against H. Influenzae,
Moraxella catarrhalis.
Preferred therapy for urethritis caused by
chlamydia trachomatis.
Also activity against Mycobacterium avium-
intracellularae complex in patients with AIDS
Telithromycin (ketolite) – spectrum similar
to azithromycin, resistance lower = more
55
effective

56. Therapeutic Applications of Macrolides
Most strains of staphylococci in hospitals are resistant
Figure 32.12 (still)
Chapter 32 MENU >

57. Macrolides
• Absorption
• food interferes with
absorption
• IV = increased
thrombophlebitis
• Distribution
• High in all body fluids &
prostatic fluids - except
CSF
• Elimination
• Erythromycin &
telithromycin interfere with
metabolism of drugs such
as theophylline &
Figure 32.13 (still) carbamazepine
Chapter 32 MENU >

58. Macrolides - Adverse Effects
Interactions –
Erythromycin, telithromycin and clarithromycin inhibit
metabolism of a number of drugs = toxic accumulation
Figure 32.15 (still)
Chapter 32 MENU >

59. OTHERS
Chrolamphenical - Chrolomycetin
Clindamycin- Cleocin, Dalacin C
Linezolid - Zyvox
Quinupristin / dalfopristin -
Synercid
59

60. Chloramphenicol
Active against a wide range of
Gram +ve and Gram –ve organisms
High toxicity – bone marrow
toxicity
Restricted for life-threatening
infections where no alternative
exists
60

61. Chloramphenicol - Spectrum
Broad spectrum antibiotic
Active against bacteria, Rickettsia,
Mot affected against - Pseudomonas
Aeruginosa and chlamydiae
Excellent activity against anaerobes
Both bactericidal and Bacteriostatic
61

62. Adverse Effects
• Clinical use limited to life
threatening infections – serious
side effects, GI upsets,
overgrowth of Candida albicans
• Anaemias – haemolytic
anaemia
• Gray baby syndrome – poor
feeding, depressed breathing,
cardiovascular collapse,
cyanosis and death
• Interactions – blocks the
metabolism of warfarin,
phenytoin, tolbutamide &
chlopropamide = increased
effects of the drugs
Figure 32.18 (still)
Chapter 32 MENU >
• Bone Marrow depression

63. CLINDAMYCIN
Mechanism of action same as
erythromycin
Treatment of infections caused by
anaerobic bacteria – Bacteriodes
fragilis (infections associated with
trauma) & MRSA
Resistance same as erythromycin
63

64. Clindamycin Administration
• Well absorbed by oral
route
• Adequate levels not
achieved in the brain
• Penetration into bone -
good
Accumulation of drug in
patients with compromised
renal function or hepatic
failure
Side Effects
Fatal pseudomembraneous
Figure 32.20 (still)
colitis
Chapter 32 MENU >

65. Quinupristin / Dalfopristin
• Reserved for Vancomycin-
resistant Enterococcus
faecium (VRE)
• Active against Gram +ve cocci
including those resistant to
other antibiotics, including
MRSA
• Primary use treatment of
E.faecium infections + VRE
strains
Adverse Effects
• Venous irritation,
Arthralgia & myalgia,
Hyperbilirubinaemia, drug
Figure 32.21 (still)
interactions
Chapter 32 MENU >

66. LINEZOLID
Adverse effects
• GI upset
• Diarrhoea
• Headaches
• Rash
• Thrombocytopenia
• Inhibits MAO activity
• Precipitate serotonin
syndrome in patients
taking SSRI’s
Figure 32.24 (still)
Chapter 32 MENU >

67. 3. NUCLEIC ACID INHIBITORS -
QUINOLONES
Not recommended for children
May prolong QT interval, not to be used in patients
with arrhythmias
Limited therapeutic utility and rapid development
of resistance
Interfere with absorption
Antacids containing aluminium or magnesium
Dietary substances containing iron or zinc
Calcium , milk or yogurt
67

68. Newer compounds, Ciprofloxacin &
ofloxacin,
• Greater potency
• Broader spectrum of antimicrobial
activity
• Greater efficacy against resistant
organisms
• Active against Gram–ve bacilli &
cocci, mycobacteria, mycoplasmas
& rikettsiae
• Some cases better safety profile
than older quinolones
Respiratory quinolones
• Levofloxacin, gemifloxacin &
moxifloxacin
• Active against Gram +ve, typical,
Figure 33.5 (still)
atypical & anaerobic pathogens
Chapter 33 MENU >

69. Therapeutic Applications of Fluroquinolones
Figure 33.4 (still)
Chapter 33 MENU >

70. Adverse Reactions to Floroquinolones
Figure 33.7 (still)
Chapter 33 MENU >

71. Sulfonamides –Cell Membrane
Inhibitors
• Seldom prescribed on their own
• Resistance limits spectrum of
antimicrobial activity
• Trimethoprim -similar activity to
sulphonamides – in combination
with sulphonamides is synergistic
Adverse effects:
• Nephrotoxicity
• Hypersensitivity
• Haemopoeitic disturbances
• Kernicterus
• Displaces warfarin & Methotrexate
Figure 33.10 (still)
from binding sites
Chapter 33 MENU >

72. Therapeutic application of Cotrimoxazole
(sulfamethoxazole plus trimethoprim)
Figure 33.14 (still)
Chapter 33 MENU >

73. Adverse Effects Cotrimoxazole
Figure 33.16 (still)
Chapter 33 MENU >

74. 4. ANTIMYCOBACTERIALS
Figure 34.1 (still)
Chapter 34 MENU >

75. Figure 34.10 (still)
Chapter 34 MENU >

76. 5. ANTIFUNGAL DRUGS
Amphotericin B
Flucytosine
Ketoconazole
Flucanozole
Itraconazole
Variconazole
Posaconazole
Echinocandins
76

77. Drugs for Cutaneous and Mycotic
Infections
Terbinafine
Neftifine
Butenafine
Griseofulvin
Nystatin
Imidazole
Ciclopirox
Tolnaftate
77

78. The Top Ten Rule
1. All cell wall inhibitors are Beta-lactams
(penicllins, cephalosporins etc) except
vancomycin.
2. All penicllins are water soluble except nafcillin.
3. All protein synthesis inhibitors are bacteriostatic,
except for the aminoglycosides
4. All cocci are gram positive, except Neisseria spp.
5. All bacilli are gram negative, except anthrax,
tetanus, botulism and diphtheria bugs
6. All spirochaetes are gram negative
78

79. The Top Ten Rule
7. Tetracylcines and macrolides are used for
intracellular bacteria
8. Beware pregnant women and tetracylcines,
aminoglycosides, fluoroquinolones and
sulfonamides.
9. Antibitoics beginning with 'C' are particularly
associated with pseudomembranous colitis i.e.
Cephalosporins, Clindamycin and Ciprofloxacin.
10. While the penicillins are the most famous for
causing allergies, a significant proportion of people
with penicillin allergies may also react to
cephalosporins. These should therefore also be
avoided.
79

80. 80

81. 81