Antibiotic principles

1. Principles of Antibiotic
Therapy
1

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

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

4. Properties Influencing Frequency of
Dosing
P
Concentration dependent killing –
antimicrobials including aminoglycosides=
significant increase in rate of bacterial killing a s
the drug concentration increases
P
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
P
Post-antibiotic effect (PAE)– persistent
suppression of microbial growth after levels
of antibiotic have fallen below MIC
P
Antibiotics with a long PAE
–
aminoglycosides
P
Antibiotics with a long PAE
–
aminoglycosides
and fluroquinolines
P
Minimum bacterial concentration (MBC) is
the lowest concentration of antibiotic that
kills 99.9% of bacteria 6

7. M
I
C
INHIBITS
Figure 30.2 (part 2) Chapter 30 MENU >
7

8. M
B
C
KILLS
Figure 30.2 (part 3) Chapter 30 MENU >
8

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

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

11. Complications of Antibiotic Therapy P
Resistance –inappropriate use of antibiotics
P
Hypersensitivity–penicillin Direct toxicity
–
aminoglycosides
=
ototoxicity
P
Direct toxicity
–
aminoglycosides
=
ototoxicity
P
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
β
One of the most problematic antibiotic resistances worldwi de,
methicillin resistance amongStaphylococcus aureus.
2.
Enzyme inactivation of the antibiotic
β
β-lactam antibiotics (penicillins & cephalosporins) can be
inactivated by β-lactamases.
3.
Active transport
of the antibiotic out of the bacterial cell
3.
Active transport
of the antibiotic out of the bacterial cell
(efflux pumps)
β
Removal of some antibiotics (i.e. tetracyclines, macrolides, &
quinolones)
4.
Decreased permeability of the bacterial cell wall to the
antibiotic
β
Alteration in the porin proteins that form channels in the cell
membrane – Resistance of Pseudomonas aeruginosato a variety
of penicillins and cephalosporins
12

13. Antibiotic
Resistance
2.
4.
131.
3.

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

15. Resistance –
Decreased Permeability of the Drug
R
Prevents the drug reaching the target
penicillin binding proteins (PBPs)
R
Presence of an Efflux pump also reduces the
R
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 orgram-pos
Mechanism of action / site of action ;
P
Inhibitors of cell metabolism; (Sulfonamides, Trime thoprim)
P
Cell wall inhibitors; (β-Lactam, Vancomycin)
P
Protein synthesis inhibitors; (Tetrecyclines, Amini glycosides,
Macrolides, Clindamycin, Chloramphenicol)
P
Nucleic acid inhibitors; (Floroquinolones, Rifampin )
P
Cell membrane inhibitors; (Isoniazid, AmphotericinB )
16

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

18. 1. CELL WALL INHIBITORS
β
Interfere with the synthesis of the bacterial cell
wall
β
Little or no effect on bacteria that are not growin g
and dividing
βlactamgroup Other antibiotics Penicillins
Vancomycin
CephalosporinsBacitracin
CarbapenemsDaptomycin
MonobactamsTelavancin
RecβnoβmatdabaolP fh
antibiotic combinations
18

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

20. PENICILLINS (bactericidal) P
Most widely effective and least toxic
P
Limited use -increased resistance
P
Mechanism of action P
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
Figure 31.7 (still) Chapter 31 MENU >
21
•
Others oral, IV or IMI
Absorption
• Decreases by food in the stomach –
administer before meals 30-60min
Distributionto bone and CSF
insufficient
Excretion- Kidneys

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

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

24. Mechanism of Action P
Bactericidal, inhibit cell wall synthesis.
P
Cephalosporins are also beta-lactams so can be
degraded by beta-lactamase secreting bacteria.
P
Good to know:
P
Good to know: P
Classified by generation, based on general features
pertaining to activity;
P
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
Figure 31.10 (part 1) Chapter 31 MENU >
•
Resistant to staph penicillinase
25

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

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

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

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

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

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

32. Other βLactam Antiobiotics Monobactams R
Activity restricted to Gram –ve aerobic
bacteria
R
Aztreonam
R
Aztreonam
32

33. βLACTAMASE INHIBITORS
β
Recβnoβmβ ifatdabaolP fu
clavulanic acid –sulbactam and
tazobactam
β
Do not have significant antibacterial activity antibacterial activity
β
MatOfolfβtOfatβnoagβoifodifRe
lactamases –protect the
antibiotics
β
Formulated in combination with
Recβnoβmβ iff it aoagifβtoabaloan
β
Clavulanic acid and amoxicillin
33
Growth of E. Coli in presence of
amoxicillin with and without
clavulanic acid

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

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

36. DAPTOMYCIN
P
Cyclic lipopeptide–linezolidandquinupristin/
dalfopristin
P
Treatment of infections caused by resistant
gram +ve
P
MRSA –methicillinS. Aureus
P
MSSA
-
methillin
susceptible S.
Aureus
P
MSSA
-
methillin
susceptible S.
Aureus
P
VRE -vancomycin-resistant enterococci
P
Daptomycinis bactericidal
P
Concentration dependent
P
Inactivated by surfactant –never used in
treatment of pneumonia
36

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

38. TELAVANCIN
P
Semi-synthetic lipoglycopeptide
antibiotic
P
Synthetic derivative of Vancomycin
P
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
Figure 31.20 (still) Chapter 31 MENU >
disruption of bacterial cell
membrane
• Bactericidal against
MRSA

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

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

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

43. Tetracyclines –drug of choice
43

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

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

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

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

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

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

50. Aminoglycosides
P
Antibacterial spectrum –effective in
combination for empirical treatment of
aerobic Gram –vebacilli infections –
Pseudomonas aeruinosa
Combines with a
β
-
lactam
i.e.
P
Combines with a
β
-
lactam
i.e.
VancomycinAminoglycosidesand
bactericidal amikacin,gentamycin,
tobramycinand 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) P
May also be bacteicidal
P
Large group of antibacterials
P
Low toxicity
P
Similar spectrum of activity PAE
–
antibacterial activity continues after
P
PAE
–
antibacterial activity continues after
concentrations have dropped
P
Good to know: Take on an empty stomach
53

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

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

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

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

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

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

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

61. Chloramphenicol -Spectrum P
Broad spectrum antibiotic
P
Active against bacteria, Rickettsia,
P
Mot affected against -Pseudomonas Aeruginosa and chlamydiae Aeruginosa and chlamydiae
P
Excellent activity against anaerobes
P
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,
Figure 32.18 (still) Chapter 32 MENU >
feeding, depressed breathing, cardiovascular collapse,
cyanosis and death
•Interactions–blocks the
metabolism of warfarin,
phenytoin, tolbutamide&
chlopropamide= increased
effects of the drugs
•Bone Marrow depression

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

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

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

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

67. 3. NUCLEIC ACID INHIBITORS -
QUINOLONES
P
Not recommended for children
P
May prolong QT interval, not to be used in patients
with arrhythmias
P
Limited therapeutic utility and rapid development of resistance of resistance
P
Interfere with absorption P
Antacids containing aluminium or magnesium
P
Dietary substances containing iron or zinc
P
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–vebacilli & cocci
,
mycobacteria
,
mycoplasmas
Figure 33.5 (still) Chapter 33 MENU >
cocci
,
mycobacteria
,
mycoplasmas
& rikettsiae
• Some cases better safety profile
than older quinolones
Respiratory quinolones • Levofloxacin, gemifloxacin&
moxifloxacin
• Active against Gram +ve, typical,
atypical & anaerobic pathogens

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
Figure 33.10 (still) Chapter 33 MENU >
with sulphonamides is synergistic
Adverse effects
:
• Nephrotoxicity
• Hypersensitivity
• Haemopoeitic disturbances
• Kernicterus
• Displaces warfarin & Methotrexate
from binding sites

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 P
Amphotericin B
P
Flucytosine
P
Ketoconazole
P
Flucanozole
P
Flucanozole
P
Itraconazole
P
Variconazole
P
Posaconazole
P
Echinocandins
76

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

78. The Top Ten Rule 1.
All cell wall inhibitors are Beta-lactams
(penicllins, cephalosporinsetc) except
vancomycin.
2.
All penicllinsare water soluble exceptnafcillin.
3.
All protein synthesis inhibitors are
bacteriostatic
,
3.
All protein synthesis inhibitors are
bacteriostatic
,
exceptfor the aminoglycosides
4.
All cocciare grampositive, exceptNeisseriaspp.
5.
All bacilli are gram negative, exceptanthrax,
tetanus, botulism and diphtheria bugs
6.
All spirochaetesare gram negative
78

79. The Top Ten Rule 7.
Tetracylcinesand macrolidesare used for
intracellular bacteria
8.
Beware pregnantwomen and tetracylcines,
aminoglycosides, fluoroquinolonesand
sulfonamides.
9.
Antibitoics
beginning with 'C' are particularly
9.
Antibitoics
beginning with 'C' are particularly
associated with pseudomembranouscolitis i.e.
Cephalosporins, Clindamycinand Ciprofloxacin.
10.
While the penicillins are the most famous for
causing allergies, a significant proportion of peop le
with penicillin allergies may also react to
cephalosporins. These should therefore also be
avoided.
79

80. 80

81. 81