2. • Antibiotics - antibacterial substances produced by
various species of microorganisms (bacteria, fungi, and
actinomycetes) - suppress the growth of other
microorganisms.
Drugs that destroy microbes, prevent their
multiplication or growth or prevent their
pathogenic action.
Differ in their physical, chemical, and
pharmacological properties.
Differ in their antibacterial spectrum of activity
and their mechanism of action.
3. Antibiotics = “against life”
Antibiotics can be either natural products or man-
made synthetic chemicals.
Old : An antibiotic is a chemical substance
produced by various species of microorganisms
that is capable of inhibiting the growth of other
microorganisms in small concentrations.
New: An antibiotic is a product produced by a
microorganism or a similar substance produced
wholly or partially by chemical synthesis, which
in low concentrations, inhibits the growth of
other microorganisms.
4. • Antibiotics (i.e., anti-infective or antimicrobial
drugs) may be directed at one of several disease-
producing organisms including bacteria, viruses,
fungi, helminthes, etc.
• The vast majority of antibiotics are bacteria
fighters; although there are millions of viruses,
there are only about half a dozen antiviral drugs.
• Bacteria are more complex than viruses (while
viruses must “live” in a host (us), bacteria can
live independently, and so are easier to kill.
5. Where do antibiotics come from?
• Several species of fungi including Penicillium and
Cephalosporium
• E.g. penicillin, cephalosporin
– Species of actinomycetes, Gram positive filamentous
bacteria
• Many from species of Streptomyces
– Also from Bacillus, Gram positive spore formers
– A few from myxobacteria, Gram negative bacteria
– New sources explored: plants, herbs, fish
6.
7. Microbes in History
• Date Event
• 300Bc Aristotle, Greek philosopher and scientist, studied and
wrote about living organisms.
• 1675 Antony van Leeuwenhoek discovered bacteria.
• 1796 Edward Jenner laid the foundation for developing
vaccines.
• 1848 Ignác Fülöp Semmelweis discovered simple handwashing
could prevent passage of infection from one patient to another.
• 1857 Louis Pasteur introduced the germ theory of disease.
• 1867 Joseph Lister showed evidence that microbes caused
disease and pioneered the use of antiseptics during surgery to
kill germs.
• 1876 Robert Koch, by studying anthrax, showed the role of
bacteria in disease.
• 1928 Alexander Fleming is credited with discovering penicillin.
8. History of Antimicrobial Therapy
• 1909 Paul Ehrlich
– Differential staining of tissue, bacteria
– Search for magic bullet that would attack bacterial
structures, not ours.
– Developed salvarsan, used against syphilis ultimately
proved to be too toxic for human use.
• Arsphenamine was the opening event in the
chemotherapeutic revolution for the treatment of human
infections.
10. • In 1891, the Russian Romanovsky – suggested
that usage of quinine to cure malaria.
• Ehrlich (1854–1915) coined the term
chemotherapy.
• Ehrlich defined chemotherapy as “the use of
drugs to injure an invading organism without
injury to the host.”
11. Fleming and Penicillin
Alexander Fleming was first to
characterize penicillin’s activity.
He found mold contaminating
his culture plates, with clearing
of staphylococcal colonies all
around the mold. Fleming then
isolated penicillin from the mold.
13. Thanks to work by Alexander Fleming (1881-1955),
Howard Florey ( 1898-1968) and Ernst Chain (1906-
1979), penicillin was first produced on a large scale for
human use in 1943.
A. Fleming E. Chain H. Florey
14. • Florey developed penicillin during WWII when it was
much needed; tons of mold was grown to produce it, and
was even collected from the urine of people that had first
been treated with it (because it is eliminated unchanged
by the kidneys).
• 1935- Sulfa drugs discovered.
• 1943 -Streptomycin discovered.
• Gerhard Domagk
– Discovered sulfanilamide
• Selman Waksman
– Antibiotics
• Antimicrobial agents produced naturally by organisms
22. Selective toxicity means safer for host
• Antibiotics generally have a low MIC
– Minimum inhibitory concentration
– Effective at lower doses
• Good therapeutic index ( Ti)
– Safer; larger quantity must be administered before
harmful side effects occur.
24. • What is the ideal antimicrobial drug ?
• Have highly selective toxicity to the
pathogenic microorganisms in host body
• Have no or less toxicity to the host.
• Low propensity for development of resistance.
• Not induce hypersensitivies in the host.
• Have rapid and extensive tissue distribution
• Be free of interactions with other drugs.
• Be relatively inexpensive
25. • Antimicrobial drugs are chemotherapeutic drugs.
• Two categories:
• – Antibiotics : Antimicrobial drugs produced by
microorganisms.
• – Synthetic drugs : Antimicrobial drugs
synthesized in the lab.
• Antibacterial synthetic drugs
• Antifungal synthetic drugs
• Antiviral agents
26. Definitions
• Chemotherapeutic Index (CI): the ratio of median
lethal dose (LD50) to median effective dose (ED50)
of infective animals.
LD50/ED50 or LD5/ ED95
• Generally the bigger the CI of a drug is, the lower its
toxicity, the better its curative effect and the greater
its value of clinical application.
However, a drug with big CI does not mean that it is
definitely safety.
• Penicillin G has almost no toxicity and its CI is big, can
cause anaphylactic shock and lead to death.
27. Definitions
• Antimicrobial spectrum : the scope that
a drug kills or suppresses the growth of
microorganisms.
• Narrow-spectrum: The drugs that only act
on one kind or one strain of bacteria.
(isoniazid )
• Broad-spectrum: The drugs that have a
wide antimicrobial scope.
(tetracycline,chloramphenicol )
28. Definitions
• Antimicrobial activity: the ability that a drug
kills or suppresses the growth of microorganisms.
• Potency- AMA activity per mg/µg.
• Expressed as MIC, MBC, MAC
• The minimal inhibitory concentration (MIC)
the minimum amount of a drug required to
inhibit the growth of bacteria in vitro.
• The minimal bactericidal concentration (MBC)
• the minimum amount of a drug required to kill
bacteria in vitro.
29. • MIC 90- inhibit 90 % m/o tested
• MBC- to kill m/o
• MAC- Conc of AMA, reduces the growth of m/o in
vitro by a factor of 10. It may be 1 quarter or 1/10th
of the MIC depends on the drug and organism.
• PAE – persistence of AMA for longer period
( few hrs) after brief exposure to or in absence of
detectable conc of AMA.
• Biphasic (Eagle’s) effect- phenomenon , Low dose-
cidal whereas High dose - No effect
• Common in BLA because of differential sensitivity
of the PBPs to high doses of BLA.
30.
31.
32. • The molecular basis of chemotherapy
• The biochemical reactions that are potential targets
for antibacterial drugs
•
• There are three groups.
• Class I: Utilization of glucose / carbon source for the
generation of energy (ATP) and synthesis of simple
carbon compounds used as precursors in the next
class of reactions.
• Class II: Utilization of these precursors in an energy-
dependent synthesis of all the amino acids,
nucleotides, phospholipids, amino sugars,
carbohydrates and growth factors required by the
cell for survival and growth.
33. • Class III: Assembly of small molecules into
macromolecules- proteins, RNA, DNA,
polysaccharides and peptidoglycon.
• Other potential targets are the formed structures
e.g., cell membrane
microtubules
other specific tissues muscle tissue in helminths).
36. Antimicrobial Agents
• Effect on microbes:
• Cidal (killing) effect
• Static (inhibitory) effect
• Spectrum of action
• Broad Spectrum – effective against procaryotes which kill or inhibit a
wide range of Gram+ and Gram- bacteria
• Narrow spectrum – effective against mainly Gram+ or Gram- bacteria
• Limited spectrum – effective against a single organism or disease
37.
38. VI. Antibacterial Agents
• A. Inhibitors of cell wall synthesis
• 1. Penicillins
• 2. Cephalosporins
• 3. Other antibacterial agents that act on cell walls
• B. Disrupters of cell membranes
• 1. Polymyxins
• 2. Tyrocidins
• C. Inhibitors of protein synthesis
• 1. Aminoglycosides
• 2. Tetracyclines
• 3. Chloramphenicol
• 4. Other antibacterial agents that affect protein synthesis
• a. Macrolides
• b. Lincosamides
• D. Inhibitors of nucleic acid synthesis
• 1. Rifampin
• 2. Quinolones
• E. Antimetabolites and other antibacterial agents
• 1. Sulfonamides
• 2. Isoniazid
• 3. Ethambutol
• 4. Nitrofurans
39. Inhibition of cell
wall synthesis
Penicillins
Cephalosporins
Vancomycin
Bacitracin Inhibition of
Isoniazid protein synthesis
Inhibition of pathogen’s Ethambutol Aminoglycosides
attachment to, or Echinocandins Tetracyclines
recognition of, host (antifungal) Chloramphenicol
Arildone Macrolides
Pleconaril
Disruption of
Inhibition of DNA cytoplasmic
or RNA synthesis membrane
Actinomycin Polymyxins
Nucleotide Polyenes
analogs (antifungal)
Quinolones
Rifampin
Inhibition of general
metabolic pathway
Sulfonamides
Trimethoprim
Dapsone
40.
41.
42.
43. Inhibitors of Cell Wall Synthesis
Penicillin G
(benzylpenicillin)
Cephalosporin
47. Mechanisms of antimicrobial agents
• Inhibition of cell wall synthesis
• – Penicillins and cephalosporins stop synthesis of
wall by preventing cross linking of peptidoglycan
units.
• – Bacitracin and vancomycin also interfere here.
• – Excellent selective toxicity
48.
49. Vancomycin also inhibits cell wall synthesis but it is not a β lactam
AMA. It does by interfering with the production of Peptidoglycan.
It binds to D-Ala-D-Ala terminals of peptido glycan precursors on
the outer surface membrane. As a result precursors cannot
incorporate into the peptidoglycan.
Bacitracin inhibits secretion of NAG and NAM subunits
53. “Penicillin Home”
• Looks like a house with a new room added to
the side
• Think of the R-group as of a funky antenna
• Changing “antennae” and or finishing the
“basement” will create better “homes”
(penicillins)
54.
55. [Penicillin] Home Improvement Project
• Adding a new antenna creates broad
spectrum penicillins
– Example: Ampicillin
• Adding additional antennae and finishing the
basement creates cephalosporins
– Example: 1st, 2nd, 3rd, & 4th generation
cephalosporins
56.
57.
58.
59. Penicillins
• Penicillins contain a b-lactam ring which inhibits the
formation of peptidoglycan crosslinks in bacterial cell
walls (especially in Gram-positive organisms)
• Penicillins are bactericidal but can act only on dividing
cells
• They are not toxic to animal cells which have no cell
wall
60.
61. Synthesis of Penicillin
b-Lactams produced by fungi, some
ascomycetes, and several actinomycete bacteria
b-Lactams are synthesized from amino acids
valine and cysteine
62. Penicillins (cont.)
Clinical Pharmacokinetics
• Penicillins are poorly lipid soluble and do not
cross the blood-brain barrier in appreciable
concentrations unless it is inflamed (so they
are effective in meningitis)
• They are actively excreted unchanged by the
kidney, but the dose should be reduced in
severe renal failure
63. Penicillins (cont.)
Resistance
• This is the result of production of b-
lactamase in the bacteria which destroys the
b-lactam ring
• It occurs in e.g. Staphylococcus aureus,
Haemophilus influenzae and Neisseria
gonorrhoea
64. Penicillins (cont.)
Examples
• There are now a wide variety of penicillins,
which may be acid labile (i.e. broken down by
the stomach acid and so inactive when given
orally) or acid stable, or may be narrow or
broad spectrum in action
65. Penicillins (cont.)
Examples
• It is the most potent penicillin but has a relatively
narrow spectrum covering Strepptococcus
pyogenes, S. pneumoniae, Neisseria meningitis or
N. gonorrhoeae, treponemes, Listeria,
Actinomycetes, Clostridia
• Benzylpenicillin (Penicillin G) is acid labile and b-
lactamase sensitive and is given only parenterally
66. Penicillins (cont.)
Examples
• Phenoxymethylpenicillin (Penicillin V) is acid
stable and is given orally for minor infections
• it is otherwise similar to benzylpenicillin
67. • Ampicillin is less active than benzylpenicillin
against Gram-possitive bacteria but has a
wider spectrum including (in addition in those
above) Strept. faecalis, Haemophilus
influenza, and some E. coli, Klebsiella and
Proteus strains
• It is acid stable, is given orally or parenterally,
but is b-laclamase sensitive
68. • Amoxycillin is similar but better absorbed orally
• It is sometimes combined with clavulanic acid,
which is a b-lactam with little antibacterial
effect but which binds strongly to b-lactamase
and blocks the action of b-lactamase in this
way
• It extends the spectrum of amoxycillin
69. • Flucloxacillin is acid stable and is given orally
or parenterally
• It is b-lactamase resistant
• It is used as a narrow spectrum drug for
Staphylococcus aureus infections
70. • Azlocillin is acid labile and is only used
parenterally
• It is b-lactamase sensitive and has a broad
spectrum, which includes Pseudomonas
aeruginosa and Proteus species
• It is used intravenously for life-threatening
infections,i.e. in immunocompromised
patients together with an aminoglycoside
71. Penicillins (cont.)
Adverse effects
• Allergy (in 0.7% to 1.0% patients). Patient
should be always asked about a history of
previous exposure and adverse effects
• Superinfections(e.g.caused by Candida )
• Diarrhoea : especially with ampicillin, less
common with amoxycillin
• Rare: haemolysis, nephritis
72. Penicillins (cont.)
Drug interactions
• The use of ampicillin (or other broad-
spectrum antibiotics) may decrease the
effectiveness of oral conraceptives by
diminishing enterohepatic circulation
74. Cephalosporins
• They also owe their activity to b-lactam ring
and are bactericidal.
• Good alternatives to penicillins when a broad -
spectrum drug is required
• should not be used as first choice unless the
organism is known to be sensitive
75. Cephalosporins
• BACTERICIDAL- modify cell wall synthesis
• CLASSIFICATION- first generation are early
compounds
• Second generation- resistant to β-lactamases
• Third generation- resistant to β-lactamases &
increased spectrum of activity
• Fourth generation- increased spectrum of
activity
76. Cephalosporins
• FIRST GENERATION- eg cefadroxil, cefalexin,
Cefadrine - most active vs gram +ve cocci. An
alternative to penicillins for staph and strep
infections; useful in UTIs
• SECOND GENERATION- eg: cefaclor and
cefuroxime. Active vs Enterobacteriaceae eg E.
Coli, Klebsiella spp, proteus spp. May be active
vs H. influenzae and N. meningtidis
77. c
• THIRD GENERATION- eg cefixime and other
I.V.s cefotaxime,ceftriaxone,ceftazidime. Very
broad spectrum of activity inc gram -ve rods,
less activity vs gram +ve organisms.
• FOURTH GENERATION- cefpirome better vs
gram +ve than 3rd generation. Also better vs
gram -ve esp enterobacteriaceae &
pseudomonas aerugenosa. I.V. route only
78. Cephalosporins (cont.)
Adverse effects
• Allergy (10-20% of patients with penicillin
allergy are also allergic to cephalosporins)
• Nephritis and acute renal failure
• Superinfections
• Gastrointestinal upsets when given orally
79. Vancomycin
• This interferes with bacterial cell wall formation
and is not absorbed after oral administration
and must be given parenterally.
• It is excreted by the kidney.
• It is used i.v. to treat serious or resistant Staph.
aureus infections and for prophylaxis of
endocarditis in penicillin-allergic people.
80. Vancomycin
Adverse effects
• Its toxicity is similar to aminoglycoside and
likewise monitoring of plasma concentrations is
essential.
• Nephrotoxicity
• Allergy
81. Ribosomes: site of protein synthesis
• Prokaryotic ribosome's are 70S;
– Large subunit: 50 S
• 33 polypeptides, 5S RNA, 23 S RNA
– Small subunit: 30 S
• 21 polypeptides, 16S RNA
• Eukaryotic are 80S
Large subunit: 60 S
• 50 polypeptides, 5S, 5.8S, and 28S RNA
– Small subunit: 40S
• 33 polypeptides, 18S RNA
82.
83. Ribosome Home Plate
Baseball player slides into
home
The ball is fielded by the
catcher who makes a CLEan
TAG
The word CLEean lies over
the base: these inhibit
50S
The word TAG lies beneath
the base: these inhibit 30S
84.
85. Antibiotics that Inhibit Protein
Synthesis
• Inhibitors of initiation – complex formation
and tRNA-ribosome interactions
Tetracyclines & Aminoglycosides
86. Antibiotics that Inhibit Protein
Synthesis
• Inhibitors of peptide bond formation &
translocation
• Chloramphenicol
• Erythromycin A
87. Tetracyclines
• Discovered in 1947
• Bacteriostatic (almost always)
• Enter via porins (G-) and by their lipophilicity in (G+).
• Low toxicity, broad spectrum for both Gram- and Gram+ bacteria
• Selectivity results from transfer into bacterial cells but not
mammalian cells
• Primary binding site is 30s ribosomal subunit. Prevents the
attachment of amino acyl-tRNA to the ribosome and protein
synthesis is stopped
• Resistance associated with ability of compound to permeate
membranes and alteration of the target of the antibiotic by the
microbe
88. Aminoglycosides (bactericidal)
streptomycin, kanamycin, gentamicin, tobramycin,
amikacin, netilmicin, neomycin (topical)
• Mode of action - The aminoglycosides irreversibly bind to
the 60S ribosomal RNA and freeze the 30S initiation
complex (30S-mRNA-tRNA) so that no further initiation can
occur. They also slow down protein synthesis that has
already initiated and induce misreading of the mRNA. By
binding to the 16 S r-RNA the aminoglycosides increase the
affinity of the A site for t-RNA regardless of the anticodon
specificity. May also destabilize bacterial membranes.
• Spectrum of Activity -Many gram-negative and some gram-
positive bacteria
• Resistance - Common
• Synergy - The aminoglycosides synergize with β-lactam
antibiotics. The β-lactams inhibit cell wall synthesis and
thereby increase the permeability of the aminoglycosides.
89. Aminoglycosides
Clinical pharmacokinetics
• These are poorly lipid soluble and, therefore, not
absorbed orally
• Parenteral administration is required for systemic
effect.
• They do not enter the CNS even when the
meninges are inflamed.
• They are not metabolized.
90. Aminoglycosides
Clinical pharmacokinetics
• They are excreted unchanged by the kidney
(where high concentration may occur, perhaps
causing toxic tubular demage) by glomerular
filtration (no active secretion).
• Their clearance is markedly reduced in renal
impairment and toxic concentrations are more
likely.
91. Aminoglycosides
Resistance
• Resistance results from bacterial enzymes
which break down aminoglycosides or to their
decreased transport into the cells.
92. Aminoglycosides
Examples
• Gentamicin is the most commonly used,
covering Gram-negative aerobes, e.g. Enteric
organisms (E.coli, Klebsiella, S. faecalis,
Pseudomonas and Proteus spp.)
• It is also used in antibiotic combination
against Staphylococcus aureus.
• It is not active against aerobic Streptococci.
93. Aminoglycosides
Examples
• Tobramycin: used for pseudomonas and for
some gentamicin-resistant organisms.
• Some aminoglycosides,e.g. Gentamicin, may
also be applied topically for local effect, e.g. In
ear and eye ointments.
• Neomycin is used orally for decontamination
of GI tract.
94. Aminoglycosides
Adverse effects
• The main adverse effects are:
Nephrotoxicity
Toxic to the 8th cranial nerve (ototoxic),
especially the vestibular division.
• Other adverse effects are not dose related,
and are relatively rare, e.g. Allergies.
95. Macrolides (bacteriostatic)
erythromycin, clarithromycin, azithromycin,
spiramycin
• Mode of action - The macrolides inhibit
translocation by binding to 50 S ribosomal
subunit
• Spectrum of activity - Gram-positive bacteria,
Mycoplasma, Legionella (intracellular
bacterias)
• Resistance - Common
96. Macrolides
Examples and clinical pharmacokinetics
• Erythromycin is acid labile but is given as an
enterically coated tablet
• It is excreted unchanged in bile and is
reabsorbed lower down the gastrointestinal
tract.
• It may be given orally or parenterally
97. Macrolides
Examples and clinical pharmacokinetics
• Macrolides are widely distributed in the body
except to the brain and cerebrospinal fluid
• The spectrum includes Staphylococcus aureus,
Streptococcuss pyogenes, S. pneumoniae,
Mycoplasma pneumoniae and Chlamydia
infections.
98. Macrolides – side effects
• Although effective, aminoglycosides are toxic,
and this is plasma concentration related.
• It is essential to monitor plasma
concentrations ( shortly before and after
administration of a dose) to ensure adequate
concentrations for bactericidal effects, while
minimising adverse effects, every 2-3 days.
99. Macrolides – side effects
• Nauzea, vomiting
• Allergy
• Hepatitis, ototoxicity
• Interaction with cytochrome P450 3A4
(inhibition)
100. Chloramphenicol, Lincomycin,
Clindamycin (bacteriostatic)
• Mode of action - These antimicrobials bind to the
50S ribosome and inhibit peptidyl transferase
activity.
• Spectrum of activity - Chloramphenicol - Broad
range; Lincomycin and clindamycin -
Restricted range
• Resistance - Common
• Adverse effects - Chloramphenicol is toxic (bone
marrow suppression) but is used in the treatment
of bacterial meningitis.
101. Clindamycin
• Clindamycin, although chemically distinct, is
similar to erythromycin in mode of action and
spectrum.
• It is rapidly absorbed and penetrates most
tissues well, except CNS.
• It is particularly useful systematically for S.
aureus (e.g.osteomyelitis as it penetrates
bone well) and anaerobic infections.
102. Clindamycin
Adverse effects
• Diarrhoea is common.
• Superinfection with a strain of Clostridium
difficile which causes serious inflammation of
the large bowel (Pseudomembranous colitis)
103. Chloramphenicol
• This inhibits bacterial protein synthesis.
• It is well absorbed and widely distributed ,
including to the CNS.
• It is metabolized by glucoronidation in the
liver.
• Although an effective broad-spectrum
antibiotics, its uses are limited by its serious
toxicity.
104. Chloramphenicol
• The major indication is to treat bacterial
meningitis caused by Haemophilus influenzae,
or to Neisseria menigitidis or if organism is
unknown.It is also specially used for Rikettsia
(typhus).
105. Chloramphenicol
Adverse effects
• A rare anemia, probably immunological in
origin but often fatal
• Reversible bone marrow depression caused by
its effect on protein synthesis in humans
• Liver enzyme inhibition
106. Tetracyclines (bacteriostatic)
tetracycline, minocycline and doxycycline
• Mode of action - The tetracyclines reversibly bind to
the 30S ribosome and inhibit binding of aminoacyl-
t-RNA to the acceptor site on the 70S ribosome.
• Spectrum of activity - Broad spectrum; Useful
against intracellular bacteria
• Resistance - Common
• Adverse effects - Destruction of normal intestinal
flora resulting in increased secondary infections;
staining and impairment of the structure of bone
and teeth.
107. Tetracyclines
Examples and clinical pharmacokinetics
• Tetracycline, oxytetracycline have short half-lives.
• Doxycycline has a longer half-life and can be
given once per day.
• These drugs are only partly absorbed.
• They bind avidly to heavy metal ions and so
absorption is greatly reduced if taken with food,
milk, antacids or iron tablets.
108. Tetracyclines
Examples and clinical pharmacokinetics
• They should be taken at least half an hour
before food.
• Tetracyclines concentrate in bones and teeth.
• They are excreted mostly in urine, partly in bile.
• They are broad spectrum antibiotics, active
against most bacteria except Proteus or
Pseudomonas.
• Resistance is frequent
109. Tetracyclines
Adverse effects
• Gastrointestinal upsets
• Superinfection
• Discolouration and deformity in growing teeth
and bones (contraindicated in pregnancy and
in children < 12 years)
• Renal impairment (should be also avoided in
renal disease)
110. 3- Metabolic inhibitors
• Sulfonamides (sulfanilamide) are structural
analogs of PABA, a molecule crucial for Nucleic
acid synthesis
• humans do not synthesize dihydropteroic acid
from PABA
• Trimethoprim interferes in next step DHF -> THF
112. Sulfonamides and trimethoprim
• Sulfonamides are rarely used alone today.
• Trimethoprim is not chemically related but is
considered here because their modes of action
are complementary.
113. Sulfonamides, Sulfones (bacteriostatic)
• Mode of action - These antimicrobials are analogues of
para-aminobenzoic acid and competitively inhibit
formation of dihydropteroic acid.
• Spectrum of activity - Broad range activity against gram-
positive and gram-negative bacteria; used primarily in
urinary tract and Nocardia infections.
• Resistance - Common
• Combination therapy - The sulfonamides are used in
combination with trimethoprim; this combination blocks
two distinct steps in folic acid metabolism and prevents
the emergence of resistant strains.
114. Trimethoprim, Methotrexate, (bacteriostatic)
• Mode of action - These antimicrobials binds
to dihydrofolate reductase and inhibit
formation of tetrahydrofolic acid.
• Spectrum of activity - Broad range activity
against gram-positive and gram-negative
bacteria; used primarily in urinary tract and
Nocardia infections.
• Resistance - Common
• Combination therapy - These antimicrobials
are used in combination with the
sulfonamides; this combination blocks two
distinct steps in folic acid metabolism and
prevents the emergence of resistant strains.
116. Sulfonamides and trimethoprim
Mode of action
• Folate is metabolized by enzyme dihydrofolate
reductase to the active tetrahydrofolic acid.
• Trimethoprim inhibits this enzyme in bacteria
and to a lesser degree in animal s, as the animal
enzyme is far less sensitive than that in bacteria.
117. Sulfonamides and trimethoprim
Clinical pharmacokinetics
• It is the drug of choice for the treatment and
prevention of pneumonia caused by
Pneumocystis carinii in immunosupressed
patients.
• Trimethoprim is increasingly used alone for
urinary tract and upper respiratory tract
infections, as it is less toxic than the
combination and equally effective.
118. Sulfonamides and trimethoprim
Adverse effects
• Gastrointestinal upsets
• Less common but more serious:
sulfonamides: allergy, rash, fever,
renal toxicity trimethoprim:
anemia, thrombocytopenia
-cotrimoxazole: aplastic anemia
119. 4-Interference with nucleic acid
synthesis
• Bacterial DNA is negatively supercoiled
– Supercoiling is maintained by gyrase, a type II
topoisomerase.
– Inhibition of gyrase and type IV topoisomerase
interferes with DNA replication, causes cell death
– Eukaryotic topoisomerases differ in structure
120. Quinolones (bactericidal)
nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin,
levofloxacin, lomefloxacin, sparfloxacin
• Mode of action - These antimicrobials bind to the
A subunit of DNA gyrase (topoisomerase) and
prevent supercoiling of DNA, thereby inhibiting
DNA synthesis.
• Spectrum of activity - Gram-positive cocci and
urinary tract infections
• Resistance - Common for nalidixic acid;
developing for ciprofloxacin
122. Quinolones
Examples and clinical pharmacokinetics
• Nalidixic acid, the first quinolone, is used as a
urinary antiseptic and for lower urinary tract
infections, as it has no systemic antibacterial
effect.
• Ciprofloxacin is a fluoroquinolone with a broad
spectrum against Gram-negative bacilli and
Pseudomonas,
123. Quinolones
Examples and clinical pharmacokinetics
• It can be given orally or i.v. to treat a wide range
of infections, including respiratory and urinary
tract infections as well as more serious infections,
such Salmonella.
• Activity against anaerobic organism is poor and it
should not be first choice for respiratory tract
infections.
124. Quinolones
Adverse effects
• Gastrointestinal upsets
• Fluoroquinolones may block the inhibitory
neurotransmitter, and this may cause
confusion in the elderly and lower the fitting
threshold.
• Allergy and anaphylaxis
125. Quinolones
Adverse effects
• Possibly damage to growing cartilage: not
recommended for pregnant women and
children
126. Metronidazole
• Metronidazole binds to DNA and blocks
replication.
Pharmacokinetics
• It is well absorbed after oral or rectal
administration and can be also given i.v.
• It is widely distributed in the body (including
into abscess cavities)
• It is metabolized by the liver.
127. Metronidazole
Uses
• Metronidazole is active against anaerobic
organisms (e.g. Bacteroides, Clostridia), which
are encountered particularly in abdominal
surgery.
• It is also used against Trichomonas, Giardia
and Entamoeba infections
128. Metronidazole
Uses
• Increasingly, it is used as part of treatment of
Helicobacter pylori infection of the stomach
and duodenum associated with peptic ulcer
disease.
• It is used also to treat a variety of dental
infections, particularly dental abscess.
129. Metronidazole
Adverse effects
• Nausea, anorexia and metallic taste
• Ataxia
• In patients, who drink alcohol, may occur
unpleasant reactions. They should be advised
not to drink alcohol during a treatment.
130. Nitrofurantoin
• This is used as a urinary antiseptic and to treat
Gram-negative infections in the lower urinary
tract. It is also used against Trypanosoma
infections.
• It is taken orally and is well absorbed and is
excreted unchanged in the urine.
132. Fucidin
• Fucidin is active only against Staphylococcus
aureus (by inhibiting bacterial protein
synthesis) and is not affected b-lactamase.
• It is usually only used with flucloxacillin to
reduce the development of resistance.
• It is well absorbed and widely distributed,
including to bone
• It can be given orally or parenterally.
• It is metabolized in the liver.
133. Antibiotics for leprosy
• Leprosy is caused by infection with
Mycobacteria leprae.
• A mixture of drugs are used to treat leprosy,
depending on the type and severity of the
infection and the local resistance patterns.
134. Antibiotics for leprosy
• Rifampicin is used, which is related to the
sulphoamides.
• Rifampicin and Rifamycin block synthesis of m-
RNA.
• Its adverse effects include haemolysis,
gastrointestinal upsets and rashes.
135. 5- Cell membranes as targets
• Bacterial cell membranes are essentially the
same in structure as those of eukaryotes
– Antibiotics also affect Gram neg. cell walls, ie.
Outer membrane together with cell membrane
– Anti-membrane drugs are less selectively toxic
than other antibiotics.
– Many antifungal drugs ( Polyenes as Amphotericin
B, Nystatin) make use of cell membrane
differences.
136. Cell membrane disruptors
• Amphotericin B binds to ergosterol of cell
membranes of fungi, causing lysis of cell
• Azoles (fluconazole) and allyamines
(terbinafine) block ergosterol synthesis
• Polymixin disrupts bacterial cell membranes,
but is toxic to people
137. Inhibition of the synthesis of the
nucleotides
Alteration of the base-pairing properties of the
template
Agents that intercalate in the DNA have this
effect.
e.g., Acridines (proflavine and acriflavine)-
topically as antiseptics.
The acridines double the distance between
adjacent base pairs and cause a frame shift
138. Synergy and Antagonism
• Synergy; If two antibiotics used in
combination have an antibacterial
effect much greater than either drug
alone
–Ex.; beta-lactams and aminoglycosides
• Antagonism; When two drugs in
combination have activity less than
the better of the two
–Ex.; bactericidal and bacteriostatic
