Classification of antibiotics ,Antibiotics modes of actions , Antibiotics clinical uses

1. Pharmacology of
the Antibiotics
Pharma. Amr Rafat
Neuropsychiatry hospital
Tanta university
1

2. The anti-infective drugsThe anti-infective drugs
Anti-infective agents are drugs that
are designed to act selectively on
foreign organisms that have invaded
and infected the body
2

3. Infectious bacteria
3

4. Microbial
Sources of
Antibiotics
4

5. General Mechanisms of Action of anti-
infective agents
The mechanisms are:
1.Inhibition the biosynthesis of bacterial
cell WALL
2.Inhibition of protein synthesis
3.Some change the cell membrane
permeability
4.Some inhibit DNA synthesis
5

6. The Action of Antimicrobial Drugs
6

7. Modes of Antimicrobial Action
7

8. Inhibition of Protein Synthesis by Antibiotics
8

9. Examples
CELL WALLCELL WALL
INHIBITORSINHIBITORS
penicillin,penicillin,
cephalosporin,cephalosporin,
vancomycinvancomycin
PROTEINPROTEIN
SYNTHESISSYNTHESIS
INHIBITORSINHIBITORS
Macrolides,Macrolides,
aminogylcosidesaminogylcosides
CELL WALLCELL WALL
PermeabilityPermeability
KetoconazoleKetoconazole
DNA SYNTHESISDNA SYNTHESIS
INHIBITORSINHIBITORS
QuinolonesQuinolones
9

10. Features of Antimicrobial Drugs
• Selective toxicity: Drug kills pathogens without damaging
the host.
• Therapeutic index: ratio between toxic dose and
therapeutic dose – or ratio of LD50 to ED50
High therapeutic index ⇒ less toxic
• Antimicrobial action – Bacteriostatic vs. bactericidal
• Activity Spectrum – Broad-spectrum vs. narrow- spectrum
• Tissue distribution, metabolism, and excretion – BBB;
Unstable in acid; half-life duration
10

11. Antibiotic Spectrum of Activity
No antibiotic is effective against all microbes
11

12. Spectrum of Activity of Anti-infectives
Antibiotics agents can also be:
• Bacteriostatic
Erythromycin, tetracyclines,clindamycin,
chloramphenicol, spectinomycin, sulfonamides
• Bactericidal
Penicillins, Cephalosphorins, Metronidazole,
Aminoglycosides, Vancomycin, Polymyxin
12

13. Spectrum of Activity of Anti-infectives
• Anti-infectives that interfere with the
ability of the cell to reproduce/replicate
without killing them are called
BACTERIOSTATIC drugs.
• Tetracycline is an example.
13

14. Spectrum of Activity of Anti-infectives
• Antibiotics that can aggressively cause
bacterial death are called BACTERICIDAL.
• These properties (-cidal and –static) can also
depend on the antibiotic concentration in the
blood.
• (e.g. Erythromycin and Clindamycin may be
bactericidal at higher blood levels)
14

15. Factors That Determine the Likehood Of a
microorganism Causing an Infection:
Factors That Determine the Likehood Of a
microorganism Causing an Infection:
1. Virulence of the microorganism
2. Number of the microorganism
present
3. Resistance of the host
15

16. Antimicrobial activity
DrugConcentration
Time
Peak (Peak/MIC)
Area Under the Curve (AUC/MIC)
Time above
MIC
MIC
16

17. Pharmacodynamic properties of
antibiotics
Type of bactericidal
profile
Important
parameter
Dosage optimization
Dose-dependent
Aminoglycosides,
quinolones
Cmax / MIC
Prolonged PAE
Single daily dose
Time-dependent
Penicillin, cephalosporins
T > MIC No PAE
Multiple DD or
continuous infusion
Cumulative-dose
dependent
Clarithromycin,
clindamycin
AUC / MIC
Prolonged PAE
Total dose and
duration
PAE: Post-Antibiotic Activity17

18. S. aureus
Penicillin
[1950s
]
Penicillin-resistant
S. aureus
Evolution of Drug Resistance inEvolution of Drug Resistance in S.S.
aureusaureus
Methicillin
[1970s]
Methicillin-
resistant
S. aureus (MRSA)
Vancomycin-resistant
enterococci (VRE)
Vancomycin
[1990s]
[1997]
Vancomycin
intermediate-
resistant
S. aureus
(VISA)
[ 2002 ]
Vancomycin-
resistant
S. aureus
18

19. Antibiotic Resistance
• A variety of mutations can lead to antibiotic resistance
• Mechanisms of antibiotic resistance
1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3. Alteration of drug's target site
4. Rapid ejection of the drug
• Resistance genes are often on plasmids or transposons
that can be transferred between bacteria.
19

20. Resistance to Antibiotics
20

21. Antibiotic Resistance
21

22. Only three of the
approved antibiotics in
the last 10 years (25%
of total) have of new
mode of action
Superbugs, is the situation really that bad?
22

23. Lots of drugs Not so many
Superbugs, is the situation really that bad?
23

24. 24

25. Common Adverse Reactions to
Anti-infective Therapy
The most common adverse effects are due to
the direct action of the drugs in the following
organ system- Neuro, nephro and GI system
25

26. Common Adverse Reactions to Anti-
infective Therapy
1. Nephrotoxicity
• Antibiotics that are metabolized and
excreted in the kidney most frequently
cause kidney damage..
26

27. Common Adverse Reactions to Anti-
infective Therapy
2. Gastro-intestinal toxicity
• Direct toxic effect to the cells of the GI tract
can cause nausea, vomiting, stomach pain
and diarrhea.
• Some drugs are toxic to liver cells and can
cause hepatitis or liver failure.
27

28. Common Adverse Reactions to Anti-
infective Therapy
3. CNS toxicity
• When drugs can pass through the brain
barrier and accumulate in the nervous
tissues, they can interfere with neuronal
function.
28

29. Common Adverse Reactions to Anti-
infective Therapy
4. Hypersensitivity
• Most protein antibiotics can induce the
body’s immune system to produce allergic
responses.
• Drugs are considered foreign substances and
when taken by the individual, it encounters
the body’s immune cells.
29

30. Common Adverse Reactions to Anti-
infective Therapy
5. Super-infections
• Opportunistic infections that develop during
the course of antibiotic therapy are called
SUPERINFECTIONS.
30

31. 31

32. 32

33. The PENICILLINS
33

34. Penicillin
Penicillin is a beta-lactam drug, with a
beta-lactam ring.
The group of penicillins is called beta
lactam antibiotics.
34

35. Penicillin
The action of Penicillins
The penicillin and penicillinase-resistant
penicillins produce BACTERICIDAL effects
by interfering with the ability of susceptible
bacteria from biosynthesizing the
framework of the cell wall.
The bacterium will have weakened cell
wall, will swell and then burst from the
osmotic pressure within the cell. 35

36. 36

37. Typical therapeutic applications of penicillinTypical therapeutic applications of penicillin
37

38. Penicillin cont.
Penicillinase (β-lactamase): bacterial enzyme that
destroys natural penicillins
Penicillinase resistant penicillins: methicilin replaced by
oxacilin and nafcilin due to MRSA
Extended-spectrum penicilins: Ampicilin, amoxicilin; new:
carboxypenicilins and ureidopenicillins (also good against
P. aeruginosa)
Fig 20.8
38

39. Penicillin
Pharmacokinetics:
Amoxicillin is well absorbed in the GIT. This
in NOT affected by food intake!!
39

40. Retention of Penicillin G
Figure 20.7
40

41. Penicillin
Therapeutic Indications of penicillin:-
No other class of antibacterial drugs
provides as wide a spectrum of antimicrobial
activity as the penicillins.
As a class, they cover gram-positive, gram-
negative, and anaerobic organisms, although
specific penicillins are more effective against
specific organisms.
41

42. Adverse Effects of Penicillins
• GI system effects- the major adverse effects of
penicillin therapy involve the GIT.
• Nausea, vomiting, diarrhea, abdominal pain,
glossitis, stomatitis, gastritis, sore mouth and
furry tongue.
• The reason for some of these effects
(superinfection) is associated with the loss of
bacterial flora.
42

43. Summary of the
adverse effects of
penicillin
Summary of the
adverse effects of
penicillin
43

44. Adverse Effects of Penicillins
• Hypersensitivity reactions- rashes, pruritus,
fever and urticaria
• Anaphylaxis can also happen leading to shock
or death. It occurs in 5-10% of those receiving
penicillins.
• Pain and inflammation on injection sites
44

45. 45

46. 46

47. Cephalosporins
Fungi of genus
Cephalosporium ⇒ 4
Generations of
cephalosporins
1. First-generation: Narrow spectrum, gram-positive
2. Second-generation: Extended spectrum includes gram-
negative
3. Third-generation: Includes pseudomonads; mostly
injected, some oral.
4. Fourth-generation: Most extended spectrum
47

48. Cephalosporins cont.
Structure and mode of action resembles penicilins
1. More stable to
bacterial β-
lactamases than
penicilins
2. Broader spectrum
⇒ used against
penicillin-resistant
strains
48

49. 49

50. THE CEPHALOSPORINS
• First Generation cephalosporins- are largely
effective against the same gram-positive
organisms affected by penicillin.
• Second generation cephalosporins- are
effective against those strains as well as
Haemophilus influenza, Entreobacter
aerogenes and Nesseria sp. These drugs are
less effective against gram positive bacteria
50

51. THE CEPHALOSPORINS
• Third Generation cephlosporins- are relatively
weak against gram-positive bacteria but more
potent against gram-negative bacteria, to
include Serratia marcescens.
• Fourth generation cephalosporins- are
developed to fight against the resistant gram-
negative bacteria. The first drug is cefepime.
51

52. Cephalosporin
The mechanism of action:-
• The cephalosporins are primarily bactericidal .
• They interfere with the cell-wall building ability
of bacteria when they divide.
• They prevent the bacteria from biosynthesizing
the framework of their cell wall.
• The weakened cell wall will swell and burst
causing cell death. 52

53. Administration and fate of the
cephalosporins
Administration and fate of the
cephalosporins
53

54. Cephalosporin
• Pharmacokinetics
–Only a few cephalosporins are administered
orally, most are administered parenterally.
– Their half-lives are short and they are
excreted mainly in the urine.
• Contraindications and Precautions
–The drugs are contraindicated in patients
with known allergies to cephalosporins and
penicillins.
54

55. 55

56. Cephalosporin
Adverse Effects
• GI system- Nausea, vomiting, diarrhea,
anorexia, abdominal pain and flatulence are
common effects.
• CNS – headache, dizziness, lethargy and
paresthesias have been reported.
• Renal system- nephrotoxicity in individuals
with pre-existing renal disease
• Hypersensitivity
56

57. Cephalosporin
Drug-Drug interactions
• ALCOHOL- many patients experience a
disulfiram-like reactions when taken with
some specific cephlosporins ( cefamandole,
cefoperazone or moxalactam).
• The patient may experience flushing,
headache, nausea, vomiting and muscular
cramps. This may occur even up to 72
hours of cephalosporin discontinuance.
57

58. Carbapenems are a class of beta-
lactam antibacterials that includes:
1.ertapenem
2.imipenem-cilastatin sodium (a
combination drug)
3.meropenem.
Carbapenems
58

59.  The antibacterial spectrum of activity for imipenem-cilastatin is
broader than that of any other antibacterial studied to date.
 Because of this broad spectrum of activity, it’s used for serious or
life-threatening infection, especially gram-positive and gram-
negative health-care acquired infections
Pharmacodynamics
• Imipenem-cilastatin, ertapenem, and meropenem are
bactericidal.
• They exert antibacterial activity by inhibiting bacterial cell-wall
synthesis.
Pharmacotherapeutics
Imipenem has the broadest spectrum of activity of currently
available beta-lactam antibiotics:-
1. It’s effective against aerobic gram-positive species, such as
Streptococcus, S. aureus, and S. epidermidis.
2. It inhibits most Enterobacter species.
3. It also inhibits P. aeruginosa (including strains resistant to
59

60. Common adverse reactions to ertapenem, imipenem-
cilastatin, and meropenem include:
nausea and vomiting
diarrhea.
Hypersensitivity reactions, such as rashes, may occur,
particularly in the patient with a known hypersensitivity
to penicillins.
Kidney conditions (In the patient with decreased or
impaired renal function, the dosage may need to be
adjusted).
Adverse reactions to carbapenems
60

61.  Aztreonam is the first member in the class of
monobactam antibiotics and the only one currently
available.
 It’s a synthetic monobactam with a narrow spectrum
of activity that includes many gram-negative aerobic
bacteria.
Pharmacokinetics
• After parenteral administration, aztreonam is rapidly
and completely absorbed and widely distributed
throughout the body.
• It’s metabolized partially and excreted primarily in
urine as unchanged drug.
Monobactams
61

62. Pharmacodynamics
Aztreonam’s bactericidal activity
results from inhibition of bacterial
cell-wall synthesis.
It binds to the PBP-3 of susceptible
gram-negative bacterial cells,
inhibiting cell-wall division and
resulting in lysis.
62

63. Pharmacotherapeutics
Aztreonam is indicated in a range of therapeutic situations:-
1)It’s effective against a wide variety of gram-negative aerobic
organisms, including P. aeruginosa.
2)It’s effective against most strains of the following organisms: E.
coli, Enterobacter, Klebsiella pneumoniae, K. oxytoca, Proteus
mirabilis, Serratia marcescens, H. influenzae, and Citrobacter.
3)It’s also used to treat complicated and uncomplicated UTIs,
septicemia, and lower respiratory tract, skin and skin-structure,
intra-abdominal, and gynecologic infections caused by susceptible
gram-negative aerobic bacteria.
4)It’s usually active against gram-negative aerobic organisms that
are resistant to antibiotics hydrolyzed by beta-lactamases.
63

64. Aztreonam can cause some adverse reactions
including:-
diarrhea
hypersensitivity and skin reactions
hypotension
nausea and vomiting
transient electrocardiogram changes (including
ventricular arrhythmias)
transient increases in serum liver enzyme levels.
Adverse reactions to aztreonam
64

65. Vancomycin
– Glycopeptide from Streptomyces
– Inhibition of cell wall synthesis
– Used to kill MRSA
– Emerging Vancomycin
resistance: VRE and VRSA
65

66. Pharmacodynamics
Vancomycin inhibits bacterial cell-wall synthesis, damaging the
bacterial plasma membrane.
When the bacterial cell wall is damaged, the body’s natural
defenses can attack the organism.
Pharmacotherapeutics
Vancomycin is active against gram-positive organisms, such as S.
aureus, S. epidermidis, S. pyogenes, Enterococcus, and S.
pneumoniae.
In the I.V. league
I.V. vancomycin is the therapy of choice for the patient with a
serious resistant staphylococcal infection who’s hypersensitive to
penicillins.
66

67. Pharmacokinetics
Because vancomycin is not absorbed from the GI tract, it must be
given I.V. to treat systemic infections.
an oral form of vancomycin is used to treat pseudomembranous
colitis.
Vancomycin diffuses well into pleural, pericardial, synovial joint
ascitic fluids.
Normal T ½ of vancomycin is 6 to 10 hr , compared to over 200 hr
in end-stage renal disease.
No switching!
Remember that I.V. vancomycin can’t be used in place of oral
vancomycin and vice versa. The two forms aren’t interchangeable.
Metabolism and excretion
The metabolism of vancomycin is minimal .
About 90% of the dose is excreted unchanged in urine within 24
hours.
67

68. Antimicrobial spectrum of vancomycinAntimicrobial spectrum of vancomycin
Some adverse effects of vancomycinSome adverse effects of vancomycin
68

69. Oral history
Oral vancomycin is used for the patient with antibiotic-associated
Clostridium difficile colitis who can’t take or has responded poorly to
metronidazole.
The 1 in the 1-2 punch
Vancomycin, when used with an aminoglycoside, is also the
treatment of choice for E. faecalis endocarditis in the patient who’s
allergic to penicillin.
Drug interactions
Vancomycin may increase the risk of toxicity when administered with
other drugs toxic to the kidneys and organs of hearing, such as
aminoglycosides, amphotericin B, bacitracin, cisplatin, colistin, and
polymyxin B.
69

70. Adverse reactions to vancomycin, although rare, include:
1)hypersensitivity and anaphylactic reactions
2)drug fever
3)eosinophilia (an increased number of eosinophils)
4)neutropenia
5)hearing loss (transient or permanent), dose dependent ototoxicty
s (as when it’s given with other ototoxic drugs).
Rash behavior(red man’s syndrome):-
Severe hypotension may occur with rapid I.V. administration of
vancomycin and may be accompanied by a red rash with flat and
raised lesions on the face, neck, chest, and arms
Infusion of 1 g or less should be given over 1 hour.
Adverse reactions to vancomycinAdverse reactions to vancomycin
70

71. 71
Daptomycin is a cyclic lipopeptide antibiotic that is an alternative
to other agents, such as linezolid and quinupristin/dalfopristin, for
treating infections caused by resistant gram-positive organisms,
including MRSA and vancomycin-resistant enterococci (VRE).
Mode of action
Upon binding to the bacterial cytoplasmic membrane,
daptomycin induces rapid depolarization of the membrane, thus
disrupting multiple aspects of membrane function and inhibiting
intracellular synthesis of DNA, RNA, and protein.
Daptomycin is bactericidal, and bacterial killing is concentration
dependent.
DaptomycinDaptomycin

72. 72
Antibacterial spectrum
Daptomycin has a spectrum of activity limited
to gram-positive organisms, which includes:-
methicillin-susceptible
methicillin-resistant S. aureus
penicillin resistant Strept.pneumoniae
Streptococcus pyogenes
Corynebacterium jeikeium
E. faecalis
E. faecium (including VRE)

73. 73
Adverse effects
•The most common adverse effects reported in clinical trials
included:-
constipation,
nausea,
headache
insomnia.
Increased hepatic transaminases
elevations in creatin phosphokinases
•Although no clinically significant interactions have been
identified, it is recommended to temporarily discontinue 3-
hydroxy-3-methylglutary coenzyme A reductase inhibitors
(statins) while receiving daptomycin due to the potential for
additive muscle toxicity.

74. 74
 Quinupristin/dalfopristin is a mixture of two
streptogramins in a ratio of 30 to70, respectively.
 They are derived from a streptomycete and then
chemically modified.
 The drug is normally reserved for the treatment of
vancomycin-resistant Enterococcus faecium (VRE).
Mechanism of action
 Each component of this combination drug binds to a
separate site on the 50S bacterial ribosome, forming a
stable ternary complex.
 Thus, they synergistically interrupt protein synthesis.
 The combination drug is bactericidal and has a long
postantibiotic effect.
Quinupristin/DalfopristinQuinupristin/Dalfopristin

75. 75
Administration and fate of
quinupristin/dalfopristin

76. 76
Antibacterial spectrum
The combination drug is active primarily against gram-positive cocci,
including those resistant to other antibiotics (for example, methicillin-
resistant staphylococci).
Its primary use is in the treatment of E. faecium infections, including
VRE strains.
The drug is not effective against Enterococcus faecalis.
Pharmacokinetics
Quinupristin/dalfopristin is injected intravenously in a 5 percent
dextrose solution (the drug is incompatible with saline medium).
The combination drug penetrates macrophages and
polymorphonucleocytes, a property that is important, because VRE
are intracellular.

77. 77
Adverse effects
1.Venous irritation: This commonly occurs when
quinupristin/dalfopristin is administered through a
peripheral rather than a central line.
2.Arthralgia and myalgia: These have been reported when
higher levels 2. of the drugs are employed.
3.Hyperbilirubinemia: Total bilirubin is elevated in about
25 percent of patients, resulting from a competition with
the antibiotic for excretion.
Interactions:
1.Because of the ability of quinupristin/dalfopristin to inhibit the
cytochrome P450 (CYP3A4)isozyme,
2.drug interaction with digoxin appears to occur by the same
mechanism as that caused by erythromycin (lead to toxicities ).

78. 78

79. 79
Linezolid is a totally synthetic oxazolidinone
It was introduced recently to combat resistant gram-
positive organisms, such as :-
methicillin and vancomycin-resistant Staphylococcus
aureus,
vancomycin-resistant E. faecium and E. faecalis,
Penicillin-resistant streptococci.
Mechanism of action
•The drug inhibits bacterial protein synthesis by inhibiting
the formation of the 70S initiation complex.
•Linezolid binds to a site on the 50S subunit near the
interface with the 30S subunit.
LinezolidLinezolid

80. 80
Antimicrobial spectrum of linezolid.

81. 81
Adverse effects
Linezolid is well-tolerated, with some reports of
gastrointestinal upset
Nausea
Diarrhea
headaches
rash
Thrombocytopenia was found to occur in
longer than 2 weeks use .

82. 82

83. The Aminoglycosides
The following are the aminoglycosides:-
1) Amikacin sulfate
2) Gentamicin sulfate
3) Kanamycin sulfate
4) Neomycin sulfate
5) Paromomycin sulfate
6) Streptomycin sulfate
7) Tobramycin sulfate
83

84. The Aminoglycosides
Mechanism of action
• These are BACTERICIDAL.
• They inhibit protein synthesis in
susceptible strains of gram-negative
bacteria, leading to loss of functional
integrity of the bacterial cell membrane,
which causes cell death.
84

85. Typical therapeutic applications of
aminoglycosides
Typical therapeutic applications of
aminoglycosides
85

86. The Aminoglycosides
Therapeutic Use of the Aminoglycosides:-
infections caused by gram-negative bacilli
serious nosocomial (hospital-acquired) infections,
such as gram-negative bacteremia, peritonitis, and
pneumonia, in critically ill patients
urinary tract infections (UTIs) caused by enteric
bacilli that are resistant to less toxic antibiotics,
such as penicillins and cephalosporins
infections of the central nervous system (CNS) and
the eye (treated with local instillation).
86

87. 87

88. The Aminoglycosides
Serious adverse reactions limit the
use of aminoglycosides include:
1.neuromuscular reactions, ranging from
peripheral nerve toxicity to
neuromuscular blockade
2.ototoxicity
3.renal toxicity.
Oral history
Adverse reactions to oral
aminoglycosides include:
1.nausea and vomiting
2.diarrhea.
88

89. The Aminoglycosides
Drug to drug interactions
• Diuretics- increased incidence of ototoxicity,
nephrotoxicity and neurotoxicity.
• Anesthetics and Neuromusular blockers-
increased neuromuscular blockage and paralysis
may be possible
• Penicillin- synergistic action
• These drugs are contraindicated in known
allergies to aminoglycosides, in patients with
renal failure, hepatic disease, pre-existing
hearing loss, myasthenia gravis, Parkinson’s,
pregnancy and lactation.
89

90. The Macrolides
The macrolides are
 Azithromycin
 Clarithromycin
 Erythromycin
 Telithromycin
90

91. The Macrolides
Mechanism of Action of the Macrolides
–They exert their effect by binding to the
bacterial cell ribosomes and changing or
altering protein production/function
–This will lead to impaired cell metabolism
and division.
91

92. The Macrolides
•Pharmacokinetics
–Erythromycin is destroyed by the
gastric juice, which is why slats
are added to stabilize the drug.
–Food does not interfere with the
absorption of the macrolides.
92

93. Administration and fate of the
macrolide antibiotics
Administration and fate of the
macrolide antibiotics properties of the macrolide antibioticsproperties of the macrolide antibiotics
93

94. Typical therapeutic applications of macrolidesTypical therapeutic applications of macrolides
94

95. The Macrolides
Therapeutic Use of Macrolides:-
• It provides a broad spectrum of antimicrobial activity
against gram-positive and gram-negative bacteria,
including Mycobacterium, Treponema, Mycoplasma, and
Chlamydia.
• It’s also effective against pneumococci and group A
streptococci. Staphylococcus aureus is sensitive to
erythromycin; however, resistant strains may appear
during therapy.
• Erythromycin is the drug of choice for treating
Mycoplasma pneumoniae infections as well as
pneumonia caused by Legionella pneumophila.
95

96. The Macrolides
Adverse Effects of Macrolides
• GI system- abdominal cramping, anorexia, diarrhea,
vomiting and pseudomembranous colitis.
HEPATOTOXICITY can occur if the drug is taken in
high doses with other hepatotoxic drugs.
• CNS- confusion, abnormal thinking and
uncontrollable emotions.
• Hypersensitivity reactions
96

97. Some adverse effects of macrolide antibioticsSome adverse effects of macrolide antibiotics
Inhibition of the cytochrome P450 system
by erythromycin, clarithromycin, and
telithromycin.
Inhibition of the cytochrome P450 system
by erythromycin, clarithromycin, and
telithromycin. 97

98. The Macrolides
Contraindications and Precautions in the Use of
Macrolides:-
These agents are contraindicated in the
presence of known allergy to any macrolide,
because cross-sensitivity occurs.
Caution should be used in patients with hepatic
dysfunction that could alter the metabolism of
the drug;
In lactating women because of drug excretion in
breast milk and in pregnant women because
potential adverse effects on the developing
fetus. 98

99. The Lincosamides
 These agents are similar to the Macrolides but are
more toxic.
1. Clindamycin
2. Lincomycin
 Lincomycin is less effective than clindamycin and is
rarely used.
 Lincomycin shouldn’t be used in the treatment of
minor infections but would be used to treat serious
respiratory or skin infections in the patient who’s
allergic to other antibiotics indicated for the infection.
99

100. The Lincosamides
Pharmacokinetics
Clindamycin is absorbed well orally and distributed widely
throughout the body.
It’s metabolized by the liver and excreted by the kidneys and
biliary pathways.
The bioavilability of lincomycin is about 20% to 30% .food
delays its absorption.
Lincomycin is partially metabolized in the liver and is excreted
in the urine, stool, and bile.
Pharmacodynamics
Clindamycin and lincomycin inhibit bacterial protein synthesis
by inhibiting the binding of bacterial ribosomes.
At therapeutic concentrations, clindamycin is primarily
bacteriostatic against most organisms.
100

101. 101

102. Pharmacotherapeutics
Because of their potential for causing serious toxicity and
pseudomembranous colitis, these drugs are limited to a few
clinical situations in which safer alternative antibacterials
aren’t available.
1.Clindamycin is potent against most aerobic gram-positive organisms,
including staphylococci, streptococci (except Enterococcus faecalis), and
pneumococci.
2.Clindamycin is effective against most clinically important anaerobes
and is used primarily to treat anaerobic intraabdominal, pleural, or
pulmonary infections caused by Bacteroides fragilis.
3.It’s also used as an alternative to penicillin in treating Clostridium
perfringens infections.
4.Clindamycin and lincomycin may be used as alternatives to penicillin
in treating staphylococcal infections in a patient who’s allergic to
penicillin.
102

103. The Lincosamides
Side effects and Adverse Reactions:-
1. GIT- GI irritation, diarrhea
2. Nausea, vomiting and stomatitis
3. Allergic reactions
4. Pseudomembranous colitis (most serious reaction to
clindamycin)
Drug Interactions
• Lincomycin and clindamycin are incompatible with
aminophyline, phenytoin, barbiturates and ampicillin.
Pseudomembranous colitis syndrome can be fatal ,characterized by
severe diarrhea, abdominal pain, fever, and mucus and blood in
stool and requires prompt discontinuation of the drug as well as
aggressive fluid and electrolyte management
Pseudomembranous colitis syndrome can be fatal ,characterized by
severe diarrhea, abdominal pain, fever, and mucus and blood in
stool and requires prompt discontinuation of the drug as well as
aggressive fluid and electrolyte management
103

104. The Tetracyclines
These agents were first isolated from Streptomyces
The following are the tetracyclines:-
–Short-acting tetracyclines
tetracycline
oxytetracycline
–Intermediate acting tetracyclines
demeclocycline
methacycline
–Long acting tetracyclines
doxycycline
minocycline
104

105. Typical therapeutic applications of tetracyclinesTypical therapeutic applications of tetracyclines
105

106. The Tetracyclines
Pharmacodynamics:-
The tetracyclines inhibit protein
synthesis in susceptible bacteria
leading to the inability of the
bacteria to multiply.
106

107. The Tetracyclines
Contraindications and Precautions in the use
of Tetracyclines
 It is not recommended for use in pregnancy and
lactation because the drug can affect the bones
and teeth, causing permanent discoloration and
sometimes arrest of growth.
 Tetracyclines are also avoided in children less
than 8 (eight) years of age because of the
potential damage to the bones and permanent
discoloration of the teeth.
107

108. The Tetracyclines
Adverse Effects of the Tetracycline
• GI system- nausea, vomiting, diarrhea, abdominal pain, glossitis
and dysphagia.
• Fatal hepatotoxicity related to tetracycline’s irritating effect on
the liver cells has been reported.
• Musculoskletal- Tetracyclines have an affinity for teeth and
bones; they accumulate there, leading to weakening of the
bone/teeth and permanent staining and pitting.
• Skin- photosensitivity and rash are expected.
• Less frequent- bone marrow depression, hypersensitivity, super
infections, pain and hypertension
108

109. Some adverse effects of tetracyclineSome adverse effects of tetracycline
109

110. The Tetracyclines
Drug-Drug Interactions
• Penicillin- if taken with tetracyclines, will decrease
the effectiveness of penicillin.
• Oral contraceptives- if taken with tetracycline, will
have decreased effectiveness.
• Digoxin- digoxin toxicity rises when tetracyclines are
used together
110

111. The Tetracyclines
Drug-Food Interaction
• Dairy products- can complex with tetracycline
and render unabsorbable.
• Tetracyclines should then be given on an
EMPTY stomach 1 hour before meals or 2-3
hours after any meal or other medications.
111

112. 112
Tigecycline is the first available member of a new class
of antimicrobial agents called glycylcyclines.
Tigecycline, a derivative of minocycline, is structurally
similar to the tetracyclines and has a broadspectrum
activity against multidrug-resistant gram-positive
pathogens, some gram-negative organisms, and
anaerobic organisms.
Tigecycline is indicated for treatment of complicated
skin and soft tissue infections as well as complicated
intra-abdominal infections
Glycylcyclines

113. 113
Mechanism of action
Tigecycline exhibits bacteriostatic action by reversibly binding to the
30S ribosomal subunit and inhibiting protein translation.
Antibacterial spectrum
Tigecycline exhibits expanded broad-spectrum activity that includes
methicillin-resistant staphylococci
Multidrug-resistant Streptococcus pneumoniae
vancomycin-resistant enterococci
extended-spectrum B-lactamase producing gram-negative
bacteria
Acinetobacter baumannii
many anaerobic organisms.
N.B. tigecycline is not active against Proteus, Providencia,and
Pseudomonas species.

114. 114
Adverse effects
Tigecycline is well tolerated, with the main adverse
effects being similar to those of the tetracycline
class include:-
nausea and vomiting(most common)
photosensitivity
pseudotumor cerebri
discoloration of permanent teeth when used
during tooth development
fetal harm(teratogenic)

115. 115
• Chloramphenicol is active against a wide range of gram-
positive and gram-negative organisms.
• because of its toxicity, its use is restricted to life-threatening
infections for which no alternatives exist.
Mechanism of action
The drug binds to the bacterial 50S ribosomal subunit and
inhibits protein synthesis at the peptidyl transferase reaction
Because of the similarity of mammalian mitochondrial
ribosomes to those of bacteria, protein synthesis in these
organelles may be inhibited at high circulating chloramphenicol
levels, producing bone marrow toxicity.
Chloramphenicol

116. 116
Mechanism of action of chloramphenicol

117. 117

118. 118
Antimicrobial spectrum
Chloramphenicol, a broad-spectrum antibiotic, is active against
other microorganisms, such as rickettsiae.
Pseudomonas aeruginosa is not affected, nor are the chlamydiae.
Chloramphenicol has excellent activity against anaerobes.
The drug is either bactericidal or (more commonly) bacteriostatic,
depending on the organism.
Interactions:
•Chloramphenicol is able to inhibit some of the hepatic mixed-
function oxidases
•It blocks the metabolism of such drugs as warfarin, phenytoin,
tolbutamide, and chlorpropamide( elevating their concentrations
and potentiating their effects).

119. 119
1- Gastrointestinal upsets, overgrowth of Candida albicans
on mucous membranes.
2- Anemias:
Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate
dehydrogenase.
Aplastic anemia is independent of dose and may occur after therapy has ceased.
3- Gray baby syndrome:
Neonates have a low capacity to glucuronylate the antibiotic, and they have
underdeveloped renal function .
neonates have a decreased ability to excrete the drug, which accumulates to levels
that interfere with the function of mitochondrial ribosomes.
This leads to poor feeding, depressed breathing, cardiovascular collapse, cyanosis

120. The Fluoroquinolones
The fluoroquinolones are broad-spectrum antibiotics.
They are usually manufactured synthetically and are
associated with mild adverse reactions.
The examples are:
1)Nalidixic acid
2)ciprofloxacin
3)ofloxacin
4)norfloxacin
5)Levfofloxacin
6)Sparfloxacin
120

121. The Fluoroquinolones
Pharmacodynamics: Mechanism of action
of the Fluoroquinolones
 These agents enter the bacterial cell by
diffusion through cell channel.
 Once inside they interfere with the action
of DNA enzymes (DNA gyrase) necessary
for the growth and reproduction of the
bacteria. This will lead to cell death.
121

122. Administration and fate of the fluoroquinolonesAdministration and fate of the fluoroquinolones
122

123. Summary of antimicrobial spectrum of quinolones
123

124. Typical therapeutic applications of ciprofloxacinTypical therapeutic applications of ciprofloxacin
124

125. Fluoroquinolones
Adverse Effects of the
Fluoroquinolones
• CNS- dizziness, insomnia, headache,
and depression related to possible
effects on the CNS membrane.
• GI system- nausea, vomiting, diarrhea
and dry mouth related to the direct
effect on the GIT
• Hema- bone marrow depression
related to the direct effect of the drug
on the cells of the bone marrow that
rapidly turn over.
• Other effects- skin reactions, rash,
fever and photosensitivity 125

126. The Fluoroquinolones
• Contraindications and Precautions:-
a) Pregnancy and lactation are also
contraindications.
b) These agents are found to cause significant
damage to the cartilages such that they are
given cautiously to growing children and
adolescents less than 18 years of age
126

127. Sulfonamides
The following are the sulfonamides:
1.Sulfamethoxazole
2.Sulfadiazine
127

128. Inhibition of tetrahydrofolate synthesis by sulfonamides
and trimethoprim
Inhibition of tetrahydrofolate synthesis by sulfonamides
and trimethoprim
128

129. Sulfonamides
Pharmacodynamics
–The sulfa drugs competitively block
the para-amino benzoic acid to
prevent the synthesis of folic acid in
susceptible bacteria that synthesize
their own folates for the production of
RNA and DNA.
129

130. Some adverse reactions to sulfonamidesSome adverse reactions to sulfonamides
Administration and fate of the sulfonamidesAdministration and fate of the sulfonamides
130

131. Sulfonamides
Contraindications and precautions
– These agents are contraindicated to patients with
known allergy to sulfa drugs, sulfonylureas and thiazide
diuretics because they share similar structures.
– It is not recommended for use in pregnancy because it
can cross the placenta and cause birth defects and
kernicterus.
– Lactating women who take these drugs will excrete
them in the breast milk potentially causing kernicterus,
diarrhea and rash in the newborn.
131

132. Sulfonamides
Adverse Effects of the Sulfonamides
• GI system- nausea, vomiting, diarrhea, abdominal pain,
anorexia, stomatitis and hepatic injury, which are all
related to the direct irritation of the GIT and death of
normal flora.
• Renal system- crystalluria, hematuria and proteinuria
which can progress to a nephrotic syndrome.
• CNS- headache, dizziness, vertigo, ataxia, convulsions
and depression related to drug effects on the nerves
• Hema- bone marrow depression related to drug effects
on the cells of the bone marrow that turn over rapidly.
• Dermatologic effects- photosensitivity and rash and
hypersensitivity
132

133. Trimethoprim a potent inhibitor of
bacterial dihydrofolate reductase,
exhibits an antibacterial spectrum
similar to that of the sulfonamides.
Trimethoprim is most often
compounded with
sulfamethoxazole, producing the
combination called cotrimoxazole
Trimethoprim
Synergism between trimethoprim
and sulfamethoxazole133

134. Typical therapeutic applications of co-trimoxazole (sulfamethoxazole
plus trimethoprim).
134

135. 135

136. The anti tubercular
• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol
136

137. Mechanisms of action
Isoniazid Interferes with DNA
synthesis of bacterium
Rifampicin Interferes with RNA
synthesis
Pyrazinamide Interferes with bacterial
wall synthesis
Ethambutol Prevent multiplication
137

138. Common Side effects
Isoniazid Interferes with B6
Peripheral neuritis
Rifampicin Red-orange discoloration of the
secretions
Hepatitis
Pyrazinamide Hyperuricemia
Ethambutol Optic neuritis
138

139. Precautions
Isoniazid Liver impairment
Rifampicin Liver impairment
Pyrazinamide Liver impairment
Gout
Pregnancy
Ethambutol Liver impairment
Children less than 6 years old
139

140. General Responsibilities
• Advise patient to take the DRUGS as
prescribed
• Multiple drugs are taken to prevent
RESISTANCE
• Periodically check the liver function tests
• Supplemental Intake of Vitamin B6
140

141. An elderly diabetic patient is admitted to the hospital with
pneumonia. The sputum culture stains for a gram-negative
rod. The patient is started on IV ampicillin. Two days later,
the patient is not improving, and the microbiology laboratory
reports the organism to be a B-lactamase producing H.
influenzae. What course of treatment is indicated?
A. Continue with the IV ampicillin.
B. Switch to IV cefotaxime.
C. Switch to oral vancomycin.
D. Add gentamicin to the ampicillin therapy.
Study Questions
141

142. A 70-year-old alcoholic male with poor dental hygiene is to
have his remaining teeth extracted for subsequent
dentures. He has mitral valve stenosis with mild cardiac
insufficiency and is being treated with captopril, digoxin,
and furosemide. The dentist decides that his medical
history warrants prophylactic antibiotic therapy prior to
the procedure and prescribes which of the following
drugs?
A. Vancomycin.
B. Amoxicillin.
C. Tetracycline.
D. Cotrimoxazole.
E. Imipenem. 142

143. A patient with degenerative joint disease is to
undergo insertion of a hip prosthesis. To avoid
complications due to postoperative infection, the
surgeon will pretreat this patient with an antibiotic.
This hospital has a significant problem with MRSA.
Which of the following antibiotics should the
surgeon select?
A. Ampicillin.
B. Imipenem/cilastatin.
C. Gentamicin/piperacillin.
D. Vancomycin.
E. Cefazolin 143

144. A 25-year-old male returns home from a holiday in
the Far East and complains of 3 days of dysuria
and a purulent urethral discharge. You diagnose
this to be a case of gonorrhea. Which of the
following is appropriate treatment?
A. Ceftriaxone IM.
B. Penicillin G IM.
C. Gentamicin IM.
D. Piperacillin/tazobactam IV.
E. Vancomycin IV.
144

145. A patient with a gunshot wound to the abdomen, which has
resulted in spillage of intestinal contents, is brought to the
emergency room. Which antibiotic would you select to effectively
treat an infection due to Bacteroides fragilis?
A. Aztreonam.
B. Clindamycin.
C. Gentamicin.
D. Azithromycin.
E. Doxycycline.
Children younger than 8 years of age should not receive
tetracyclines because these agents:
A. Cause rupture of tendons.
B. Do not cross into the CSF.
C. Are not bactericidal.
D. Deposit in tissues undergoing calcification.
E. Can cause aplastic anemia. 145

146. A pregnant woman was hospitalized and catheterized
with a Foley catheter. She developed a urinary tract
infection caused by Pseudomonas aeruginosa and was
treated with gentamicin. Which of the following adverse
effects was a risk to the fetus when the woman was on
gentamicin?
A. Skeletal deformity.
B. Hearing loss.
C. Teratogenesis.
D. Blindness.
E. Mental retardation.
146

147. A 46-year-old woman is in the intensive care unit for
treatment of a vancomycin-resistant strain of
Enterococcus faecium caused bacteremia. You want to
limit the risk of drug interactions in this woman, who
is receiving five other medications. Which one of the
following antibiotics would you choose?
A. Azithromycin.
B. Clindamycin.
C. Doxycycline.
D. Linezolid.
E. Quinupristin/dalfopristin.
147

148. A 30-year-old male is diagnosed to be human immunodeficiency
virus (HIV) positive. His CD4+ count is 200 cells/mm3 and his viral
load is 10,000 copies/mL. In addition to receiving antiviral therapy,
which of the following is indicated to protect him against
pneumonia due to Pneumocystis jiroveci?
A. Trimethoprim.
B. Ciprofloxacin.
C. Cotrimoxazole.
D. Clindamycin.
A 26-year-old young man presents with the symptoms of
gonorrhea. Because this condition is often associated with an
infection due to Chlamydia trachomatis, which of the following
quinolones would be the best choice for treating him?
A. Ciprofloxacin.
B. Nalidixic acid.
C. Norfloxacin.
D. Levofloxacin. 148

149. In which one of the following infections is ciprofloxacin ineffective?
A. Urinary tract infections due to a B-lactamase producing strain of
Klebsiella.
B. Pneumonia due to Streptococcus pneumoniae.
C. Exacerbation of chronic bronchitis due to Moraxella catarrhalis.
D. UTI due to Escherichia coli.
E. UTIs due to Pseudomonas aeruginosa.
Sulfonamides increase the risk of neonatal kernicterus, because
they:
A. Diminish the production of plasma albumin.
B. Increase the turnover of red blood cells.
C. Inhibit the metabolism of bilirubin.
D. Compete for bilirubin-binding sites on plasma albumin.
E. Depress the bone marrow.
149