Thyroid Physiology_Dr.E. Muralinath_ Associate Professor
ANTIBIOTICS-1.ppt
1. 1
ANTIBIOTICS
Antibiotics
Antibiotics are chemical substances
produced by microorganisms (fungi,
actinomycetes, bacteria ) that suppress
the growth of other microorganisms, and
may eventually destroy them.
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ANTIBIOTICS
Classification
1. According to the source
Antibiotics have been isolated from
three types of microorganisms.
(i) Antibiotics from fungi:
Penicllin from Penicillium notatum and
penicillin chrysogenum;
griseofulvin from Penicillium greseofulvin
and others.
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ANTIBIOTICS
(ii) Antbiotics from actinomycetes
Streptomycin from Streptomyces griseus;
chlortetracycline from Streptomyces aureofacines;
oxytetracycline from Streptomyces rimosus;
chloramphenicol from Streptomyces venezuelae;
erythromycin from Streptomyces erythreus
9. 9
Cell membrane
THFA
PABA
Cell wall
DNA
MRA
Inhibitors of
Metabolism
-Sulphonamide
-Trimethoprim
Inhibitors of
cell wall synthesis
-beta lactams
-vancomycin
Inhibitors of
protein synthesis
-tetracycline
-aminoglycosides
-macrolides
-clindamycin
-chloramphenicol
Inhibitors of DNA
synthesis or function
-fluoroquinolones, griseofulvin
-rifampicin,
Site of action of antibiotics
Inhibitors of cell
membrane function
-polymixins
-nystatin
-amphotericin -B
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ANTIBIOTICS
3. According to the Antibacterial
Spectrum
(i) Narrow – spectrum antibiotics
penicillins, streptomycin. erythromycin,
lincomycin, polymixin B, vancomycin and
others.
(ii) Broad – spectrum antibiotics
chloramphenicol, tetracyclines, kanamycin,
cephalosporins, ampicillin, amoxycillin and
others.
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ANTIBIOTICS
INHIBITORS OF BACTERIAL CELL WALL
SYNTHESIS
The most important of this group are the
penicillins and the cephalosporins,
designated as Beta-lactam antibiotics (see
fig).
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ANTIBIOTICS
PENICILLINS
• Comprise of substances some of which are
natural products while others are
semisynthetic compounds.
• They have a common chemical nucleus, 6-
aminopenicillanic acid (6-APA), and a common
mode of antibacterial action, i e by the inhibition
of cell wall mucopeptide synthesis.
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ANTIBIOTICS
HISTORY
• Penicilin was discovered by Sir Alexander
Fleming in 1928 when he saw that colonies of
staphylcocci were lysed when contaminated by a
mould.
• The mould was later classified as penicillium
notatum.
• Crude penicillin G became available for limited
therapeutic trials in 1941.
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ANTIBIOTICS
• Up to 1959 biosynthesis of penicillins
depended upon growth of Penicillium
notatum and Penicillium chrysogenum.
• The natural penicilin G has several
shortcomings:
(i) It is acid labile therefore destroyed
on oral administration.
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ANTIBIOTICS
(ii) It is destroyed by beta-lactamase
enzymes.
(iii) Has a narrow bacterial spectrum.
(iv) Is rapidly excreted from the body.
(v) It poorly penetrates into
compartments like the CSF.
(vi) It is antigenic.
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ANTIBIOTICS
• These factors led to the search for better
compounds.
• In 1958 the basic penicillin nucleus, 6-
aminopenicillanic acid was isolated.
• It is possible to synthetically add side chains to
produce a range of penicillins that collectively
overcome the first four shortcomings of penicillin
G.
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ANTIBIOTICS
Chemistry
• The basic structure is a sulphur containing
thiazolidine ring fused to a beta-lactam
ring, forming 6-aminopenicillinic acid (6-
APA), the so called penicillin nucleus,
upon which the antibacterial activity
depends (see Fig).
• The side chain determines the individual
penicillin characteristics.
18. 18
H H H S CH3
R N C C C
CH3
C N C H
O COOH
Beta – lactam ring
6 – aminopenicillanic acid
R – group determines the drug’s stability
to enzymatic or acidic hydrolysis
and affects its bacterial spectrum
Structure of beta-lactam antibiotics
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ANTIBIOTICS
• Bacterial beta-lactamase (penicillinase)
and acids such as gastric acid hydrolyse
penillin to Penicilloic acid by breaking the
beta-lactam ring.
• Penicilloic acid has no antibacterial
activicity, but is allergenic.
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ANTIBIOTICS
• Penicillin G has benzyl side chain,
substituting it with phenoxymethyl or
phenoxyethyl groups increased acid
stability, hence oral penicillins.
• The addition of an alpha-NH3 group led to
production of broad spectrum penicillins
like ampicillin, amoxycillin.
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ANTIBIOTICS
Units of Penicillin
• IU of penicillin is the specific penicillin
activity contained in 0.6mcg of the
crystalline sodium salt of penicillin G
(benzyl penicillin).
• One milligram of pure sodium penicillin G
is equivalent to 1667 units (for penicillins
derived from 6-APA).
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ANTIBIOTICS
Mode of Action
• Beta-lactam antibiotics (penicillins,
cephalosporins) prevent the normal
synthesis of the bacterial cell wall.
• By selectively inhibiting the synthesis of
mucopeptide in the bacterial wall of
multiplying bacteria.
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ANTIBIOTICS
• The bacteria cell wall construction and cell
division continues, but the resulting cells have
defective cell walls.
• The defective cells with defective walls are
subject to lysis as result of osmotic forces.
• Bacterial resistance to penicillins is due to beta-
lactamases which split the beta-lactam ring,
rendering penicillin inactive.
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ANTIBIOTICS
Pharmacokinetics of Penicillin G
Preparations
Absorption
Three main types of penicillin G are available:
(i) Penicillin G for oral use
(ii) Aqueous penicillin G for parenteral use
(iii) Depot preparations as suspensions for
parenteral use
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ANTIBIOTICS
• Penicillin G is erratically absorbed from GIT
(15-20%).
• Most of it destroyed by gastric acid before
reaching the duodenum, site of maximum
absorption.
• Should be taken on an empty stomach to
minimise destruction by acid, and prevent
delay in absorption.
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ANTIBIOTICS
• Parenteral administration is preferably by
IM injection.
• Is rapidly absorbed from site of injection,
peak plasma levels attained within 20
mins.
• Intravenous injection used in life
threatening infections.
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ANTIBIOTICS
Distribution, Metabolism and Excretion
• Penicillin G is highly bound to plasma
proteins.
• High concentration is achieved in kidney
and urinary tract.
• 90% of drug is excreted unchanged by the
kidneys. Is also excreted in milk.
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ANTIBIOTICS
Probenecid (Benemid)
• Was developed to delay rapid renal
excretion of penicillin when administered
together.
• Probenecid competes with penicillin for the
tubular transport system that transports
the antibiotic from blood to tubular fluid
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ANTIBIOTICS
Therapeutic Use of Penicillin G and
Phenoxypenicillins (Penicillin V)
• Penicillin G 250,000U/5ml or procaine
penicillin G 300,000U/ml are drugs of
choice in pneumonia, given by IM 300,000
– 600,000 units 12 hourly for 7-10 days.
• Penicillin V 125/ 250/500mg tablets: useful
in tonsillitis, pharyngitis, and endocarditis
given orally, 500mg qid for 10 days.
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ANTIBIOTICS
• Penicillin V 125mg/5ml powder: 25-
50mg/kg/day in 3-6 divided doses in
children
• Penicillin G given intravenously is drug of
choice in pneumococcal menengitis
300,000 – 8 mil U per day.
• In gas gangrene Penicillin G is drug of
choice 10 -20 mil U per day.
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ANTIBIOTICS
• In gonorrhoea Benzylpenicillin 600/1200mg/vial
is used 4.8 mil U as single dose together with 1g
Probenecid orally.
• In syphilis Benzathine penicillin G (long acting
penicillin G) 300,000/600,000U/lm: is used 2.4
mil U IM as single dose or aqueous penicillin G
600,000 U IM daily for 8 days
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ANTIBIOTICS
Toxicity
• Penicillins are least toxic of all antibiotics 10-
15 % incidence.
• Hypersensitivity reactions – 1- 5 %, it is
unpredictable mainly due to exposure to
penicillin dust, topical application, oral and
parenteral preparations of penicillin
– urticaria, angioedema, anaphlactic
shock, asthma, hypotension.
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ANTIBIOTICS
• Should be assumed that once
hypersensitivity reaction occurs patient will
react to all other drugs in the class.
• Hypersensitivity reactions are treated
using adrenaline, or antihistamines or
corticosteriods
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ANTIBIOTICS
Broad-spectrum Penicillins
The main ones are Ampicillin and Amoxycillin.
Ampicillin
• Apart form those covered by Penicillin G, ampicllin is
also active against E.coli, Proteus mirabilis, H. Fluenza,
and Salmonella.
• Ampicillin taken orally is poorly and slowly absorbed.
• Should be taken on empty stomach.
• After normal dose peak blood levels attained after 2hrs.
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ANTIBIOTICS
Preparations and dosage:
• Ampicillin capsules 250/500mg: 250 mg every
6hours.
• Powder for suspension 125/250mg/5ml:
50mg/kg/day in divided doses 6hrly.
• Powder for Injection 125/250mg; 1,2,10g/vial
IV/IM 25-50mg/kg/day in divided doses.
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ANTIBIOTICS
• The half life is between 1-1.5hrs and distributes
to 40% of body weight.
• Within 6hrs 30% of dose is excreted mostly
unchanged in urine.
• Mostly indicated for chronic bronchitis, otitis
media, urinary tract infections and menengitis
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ANTIBIOTICS
Amoxycillin
• Is a derivative of amplicillin with same
antibacterial spectrum but is more active against
Strep. faecalis and Salmonella species.
• Twice as well absorbed orally than ampicillin,
and twice peak plasma levels
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ANTIBIOTICS
• Presence of food does not interfere with
absorption.
• Peak blood levels reached within 2hrs
• The half-life and plasma protein binding is same
as ampicillin.
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ANTIBIOTICS
Preparations and dosage:
• Capsules 250/500mg: 250-500mg every 8
hrs.
• Powder for oral suspension
125/250mg/5ml:
25-50mg/kg/day every 8 hrs.
• Injection powder 500mg and 1g vials. IM
or IV 500mg tid.
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ANTIBIOTICS
Pinicillinase-resistant Penicillins
• Most staphylococci resistant to Penicillin G
because they produce penicillinases which
disrupt the beta-lactam ring.
• In penicillinase-resistant penicillins the
access of this enzyme to beta-lactam ring is
hindered by the molecular geometry of the drug.
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ANTIBIOTICS
• The drugs in this group include Methicillin,
Cloxacillin, Flucloxacillin. .
• Dosage: Methicillin 1,4,6,10g/vial: IM/IV 4-
6g/day in divided doses every 4-
6hrs.
Cloxacillin capsules 250mg– Oral
250mg-1g every 6hrs on empty
stomach.
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ANTIBIOTICS
Powder for oral suspension
125mg/ml: 50-100mg/kg/day in
divided doses 6hrly.
Powder for Injection
250/500mg/vial: 250-500mg 4-6
hourly
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ANTIBIOTICS
Flucloxacillin capsules 250mg: Oral
250mg-500mg every 6hrs, is better
absorbed than cloxacillin.
Powder for suspension 125mg/ml: 25-
50mg/kg/day 6hrly.
Powder for Injection 250/500mg/vial:
250/500mg 6hourly
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ANTIBIOTICS
Cephalosporins
• They are structurally and
pharmacologically related to penicillins.
• They are water soluble, broad spectrum,
semi-synthetic, bactericidal antibiotics.
• Derived from 7-aminocephalosporanic
acid (7-ACA).
45. 45
H H
S H
R1 C N C C H
O C N C CH2 R2
C
O
COOH
7- amino-cephalosporanic acid
Semi-synthetic cephalosporins are prepared by
attaching different chemical groups at R1 and R2
Structural features of cephalosporins
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ANTIBIOTICS
Antibacterial spectrum
• Cephalosporins and related compounds
are divided into first, second, and third
generation agents.
• Differentiation is primarily based on their
pharmacokinetics and antibacterial
spectrum.
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ANTIBIOTICS
• From first to third generation exhibits:
- broadening gram-ve spectrum
- loss of efficacy against gram +ve
organisms
- greater efficacy against resistant
organisms
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Mode of action
• They inhibit mucopeptide synthesis in the
bacterial cell wall, making it defective and
osmotically unstable.
• They are usually bactericidal depending
on dose, tissue concentration, and
organism susceptibility.
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ANTIBIOTICS
• Cephalosporins are widely distributed in
most tissues and fluids, with maximum
concentration in liver and kidney.
• First and second generation agents do not
readily diffuse into CSF except
cefuroxime.
• Most of them and their metabolites are
excreted via the kidneys.
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ANTIBIOTICS
Beta-lactam resistance
• First generation cephalosporins are
inactivated by beta-lactamase producing
organisms.
• Newer agents cefuroxime, ceftriaxone,
cefotaxime, cefotetan etc show high
stability in presence of pencillinases and
cephalosporinases.
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ANTIBIOTICS
Therapeutic uses
Cephalosporins are indicated for:
preoperative, intraoperative, and
postoperative prophylaxis to reduce
incidence of infection in surgery likely to
be contaminated e g gasrointestinal
surgery, cesarean section, vaginal
hysterectomy etc
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ANTIBIOTICS
• They are alternatives in patients who
cannot tolerate penicillins.
• They are also drug of choice in menengitis
caused by gram –ve bacteria because of
their good penetration of the CSF.
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ANTIBIOTICS
Adverse reactions
• Gasrointestinal disturbances and
hypersensitivity can occur.
• Cross sensitivity with penicillins.
• Agranulocytosis, haemolytic anaemia,
leucopenia, thrombocytopenia have been
reported.
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ANTIBIOTICS
• They are nephrotoxic and cause acute
tubular necrosis.
• Treatment alters normal flora in the colon
and can cause and can permit overgrowth
of Clostridia.
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ANTIBIOTICS
Drug interactions
• Bacteriostatic agents interfere with the
bactericidal action of cephalosporins.
• Probenecid administered concurrently with
cephalosporins increases and prolongs plasma
levels by competitively inhibiting renal secretion.
• Concomitant administration with
aminoglycosides increases nephrotoxicity.
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ANTIBIOTICS
Other Inhibitors of Bacterial Wall
Synthesis
Apart from penicilins and cephalosporins
other agents like bacitracin, cycloserine,
and vancomycin also inhibit the
synthesis of bacterial cell wall.
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ANTIBIOTICS
Bacitracin
• Bacitracin is a generic name for a group of
at least four separate bactericidal
polypeptide antibiotics.
• Originally isolated from Bacillus subtilis.
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ANTIBIOTICS
• Effective against gram +ve organisms,
especially common skin pathogens like
staphylcocci, streptococci and neisseria.
• Inactive against most gram –ve bacteria.
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ANTIBIOTICS
• Bacitracin interferes with bacterial wall
synthesis by preventing the formation of
the peptidoglycon chains that are crossed
to form rigid bacterial cell wall.
• No longer used parenterally because of
nephrotoxicity.
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ANTIBIOTICS
• It is safe when used topically, but
hypersensitivity reactions like allergic
dermatitis may occur.
• For topical use combination of bacitracin
with neomycin or polymyxin B widens
spectrum of activity.
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ANTIBIOTICS
• Such combinations are effective in the
treatment of topical ulcers, sycosis
(inflammation of hair follicles), external
otitis, pyodermas (any septic skin lesions),
infected traumatic and surgical wound and
impetigo (acute infection of the skin).
• Ophthalmic preparations are useful in
treating superficial eye infections like
conjuctivitis and infected corneal ulcers.
66. 66
ANTIBIOTICS
Cycloserine
• A broad spectrum bactericidal antibiotic
produced by Streptomyces archidaceous.
• Its use is restricted to treatment of
tuberculosis.
• Orally cycloserine is rapidly absorbed and
freely distributed to the tissues and CSF.
.
67. 67
ANTIBIOTICS
• Limitation of its use is potential CNS
toxicity.
• In prolonged therapy plasma drug levels
should be periodically checked.
• Given in doses of 15mg/kg body weight,
orally with 250mg increments to reach
serum levels of 15-35mcg/ml
68. 68
ANTIBIOTICS
Vancomycin
• Is a bactericidal glycopeptide antibiotic obtained
from Streptomyces orientalis.
• Effective against gram +ve organisms.
• Most potent antibiotic against Staphylcocci in
colitis (inflammation of colon).
69. 69
ANTIBIOTICS
• Because of toxicity only used when less
toxic antibiotics have failed.
• Allergic skin rashes and anaphylactic
reactions may occur.
• Administered in doses of 1g IV twice aday.
70. 70
ANTIBIOTICS
Beta-lactamase Inhibitors
• Some molecules can bind to beta-
lactamases and inactivate them.
• Thus preventing destruction of beta-lactam
which are substrates to these enzymes.
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ANTIBIOTICS
i) Clavulanic acid - produced by Streptomyces
clavuligerus.
• Well absorbed orally, and can also be given
parenterally.
• It has been combined with Amoxycillin (as jn
Augmentin; Co-Amoxiclav) for oral use and with
Ticarcillin for parenteral administration.
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ANTIBIOTICS
Doses: expressed as Amoxycillin
By mouth: 250mg tid, doubled in
severe infection.
Children: 125 – 250mg tid.
Injection: IV or Infusion 1g tid: children
25mg/kg tid.
77. 77
ANTIBIOTICS
• Usual dose is 1-2g of ampicillin with 0.5-1g
sulbactam every 6 hours.
• Combination successfully used in mixed
intra-abdominal and pelvic infection.
78. 78
ANTIBIOTICS
Inhibitors of Protein Synthesis
The antibiotics which inhibit bacterial
protein synthesis include
aminoglycosides, tetracyclines,
chloramphenicol, maclorides, the
lincosamides. etc.
80. 80
ANTIBIOTICS
• Most aminoglycosides prepared by natural
fermentation from various species of
Streptomyces, exception is gentamicin
which is fermented from
Micromonospora purpurea.
• Aminoglycosides include: gentamicin,
streptomycin, kanamycin, neomycin,
tobramycin, framycetin
81. 81
ANTIBIOTICS
Antibacterial Spectrum
• All aminoglycosides are bactericidal, and
active against gram +ve and mainly gram
–ve organisms.
• Streptomycin and Kanamycin are also
active against Mycobacterium
tuberculosis.
82. 82
ANTIBIOTICS
Bacterial Resistance
Bacteria frequently develop permanent
resistance to aminoglycosides by any of the
following:
- the resistance (R) factor transmitted between
bacteria
- development of ribosomes which do not
bind aminoglycosides
- acquisition of inactivating enzymes.
- reduced permeability to the drug
84. 84
ANTIBIOTICS
Mode of Action
• Aminoglycosides inhibit bacterial protein
synthesis and are bactericidal.
• They act on the bacterial 30S ribosomal subunits
(but not human ribosomes) and distort the
messenger ribonucleic acid (mRNA) translation
of the genetic code.
• Thereby preventing the formation of the normal
complex required to initiate protein synthesis.
.
85. 85
ANTIBIOTICS
• Aminoglycosides also have strong
cationic charges which combine with
anionic membrane groups and damage
the bacterial cell wall membranes.
• Potency is increased in alkaline pH,
therefore in UTI treatment, alkalinization of
urine is advisable
86. 86
ANTIBIOTICS
Pharmacokinetics
• Aminoglycosides are poorly absorbed following
oral administration because they are charged
molecules.
• The are given by injection to treat systemic
infections.
• They are poorly bound to plasma protein (20-
30%) and are widely distributed through out the
body except the CNS and the eye.
88. 88
ANTIBIOTICS
Adverse Reactions
• The adverse reactions to aminoglycosides
are ototoxicity, nephrotoxicity and
neuromuscular blockade.
• In ototoxicity both auditory and vestibular
divisions of the 8th cranial narve are
affected.
89. 89
ANTIBIOTICS
Nephrotoxicity is dose related and tends to
occur first week of therapy. Neomycin is
the most nephrotoxic.
Neuromuscular blockade can lead to
paralysis, and respiratory arrest.
Contraindicated in renal and liver
insufficiency.
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ANTIBIOTICS
Therapeutic uses
1. Streptomycin – major indication is in the
treatment of tuberculosis in combination with
Isoniazid, Ethambutol or Rifampicin.
Also used in combination with Penicillin G or
Ampicillin in treatment of enterococci, surgical
infections and mixed UTIs.
Dosage: In TB treatment is 0.5-2.0g IM/day.
Available as 1g vial.
91. 91
ANTIBIOTICS
2. Kanamycin – Useful in treating urinary
and biliary infections, pre-operative bowel
sterilization and tuberculosis.
Dosage: Mostly given by IM but orally for
bowel sterilization.
IM 15mg/Kg body weight in two
equally divided doses every12hrs.
Orally up to 8g daily in divided doses.
92. 92
ANTIBIOTICS
3. Gentamicin
• Most important member of the group and
used widely in serious infections.
• Is a broad spectrum bactericidal antibiotic
chemically related to streptomycin.
93. 93
ANTIBIOTICS
• First isolated from Micromonospora
purpurae in 1963.
• Highly water soluble and stable in solution,
• Effective against Salmonella,
H. Influenza, E. Coli, Shigella,
Pseudomonas aeruginosa etc.
94. 94
ANTIBIOTICS
• Suited for treatment of UTIs. Alkalinisation
of urine increases efficacy of gentamicin.
• Also used topically for skin infections and
in eye infections.
95. 95
ANTIBIOTICS
• But main use is in septicemia and
neonatal sepsis, menengitis and other
CNS infections.
• Main adverse reactions of gentamicin are
vestibular damage and nephrotoxicity.
96. 96
ANTIBIOTICS
Gentamicin products and doses:
Injection: 40 and 80mg/ml IM or IV 3-5mg/kg
body daily in divided doses.
Eye drops: 0.3% as sulphate single dose
(minims) or multi-dose: one
drop every 2 hours reduce
frequency as infection is
controlled.
97. 97
ANTIBIOTICS
Ear Drops: 0.3% as sulphate; 2-3 drops tid
and at night.
Skin ointments/cream: used in various
combinations with antifungal and
corticosteroids.
For use in mixed skin
infections.
98. 98
ANTIBIOTICS
4. Neomycin Sulphate
• Because of toxicity used orally or topically.
• Used for bowel sterilization prior to surgery or
infections of the eye, ear, nose or skin.
Dosage:
Oral: Neomycin Sulphate tablets
500mg: 1g hourly for 4hrs
( bowel sterilization)
99. 99
ANTIBIOTICS
Cream: Neomycin Sulphate 0.5% for bacterial skin
infection; 2-4 times daily for not more than 7
days.
Eye drops/ointment: 0.5% neomycin sulphate; 2-3
drops 2-4 times aday.
Is also used in different combinations with
antifungals and corticosteroids in ear and nose
drops and skin preparations,
100. 100
ANTIBIOTICS
Tetracyclines
• The first member of this family was
Chlortetracycline derived from the soil
organism Streptomyces aureofaciens,
followed by Oxytetracycline produced from
Streptomyces rimosus.
• Molecular modification of Chlortetracycline
produced Tetracycline.
101. 101
ANTIBIOTICS
• These three agents formed the first group
of broad-spectrum bacteriostatic
antibiotics.
• Farther investigations of mutant strains of
Streptomyces aureofaciens led to
discovery of a new group of antibiotics, the
demethlytetracyclines such as
minocycline, doxycycline known as
‘newer’ tetracyclines.
103. 103
ANTIBIOTICS
Mode of Action
• Tetracyclines enter bacterial cells by either
passive diffusion through pores or by an active
transport system.
• Inside the cell they bind specifically to 30S
ribosomes, thereby blocking binding of transfer
RNA to the messenger RNA-ribosome complex,
thus inhibiting protein synthesis.
104. 104
ANTIBIOTICS
• Tetracyclines also bind magnesium,
manganese and calcium and this chelating
action is probably also responsible for their
antibacterial action.
105. 105
ANTIBIOTICS
Bacterial Resistance
• An increasing number of pathogens have
developed resistance such as
streptococci, pneumococci, staphylcocci.
• Cross resistance develops within the
group. As a result their usefulness has
decreased.
106. 106
ANTIBIOTICS
Pharmacokinetics
• Tetracyclines are usually given orally but can be
given by IV or IM and by local application to eye
and skin.
• Absorption from stomach and intestine is
variable and incomplete partially due to low
solubility and partially due to binding to Ca++,
Al+++, Fe+++, and Mg++ in food or drugs in the
GIT.
107. 107
ANTIBIOTICS
• Thus (except for doxycycline) absorption is
depressed by food.
• There is a varying degree of plasma binding.
• Plasma concentration shows a slow rise, a
prolonged plateau and a slow fall due to slow
absorption, high protein binding and
enterohepatic circulation of the drugs.
108. 108
ANTIBIOTICS
• Body tissue and cavities penetration is
good but CSF levels are 20-25% of
plasma levels (for doxy and minocycline),
other tetracyclines do not penetrate into
CSF.
• Tetracyclines are laid down in growing
bones and teeth probably because of their
chelating with calcium.
109. 109
ANTIBIOTICS
• On IV administration, are excreted
primarily in urine by glomerular filtration
the remainder is excreted in bile and
enterohepatic circulation.
• Also excreted in milk during lactation.
110. 110
ANTIBIOTICS
Therapeutic Uses
Clinical usefulness is due to their broad-
spectrum activity.
The main indications are:
I. First-line choice for:
1. Acute chronic bronchitis
2 .Non-specific urethritis
3. Primary atypical pneumonia.
4. Rickettsial infections (typhus).
113. 113
ANTIBIOTICS
• Because of their colour are used in several
yellow fluorescence diagnostic tests for
gastric and colonic cancer.
• Also used to determine the rate of bone
turnover utilizing their calcium chelating
property.
114. 114
ANTIBIOTICS
• When used orally tetracyclines depress
bacterial flora in the colon.
• Riboflavin and folic acid deficiency can
occur with prolonged use, multivitamins
should be given.
116. 116
ANTIBIOTICS
Adverse Reactions
• Generally have low toxicity at normal dose
level, side effects related to dose and
length of treatment.
• In about 10% of patients, anorexia, GIT
upset, heartburn, nausea and vomiting,
flatulence, diarrhoea may be experienced.
117. 117
ANTIBIOTICS
• In 20-30% of patients get, black hairy
tongue, cheilosis (lips and angles of mouth
condition), anogenital pruritus, glossitis.
• Superinfections can occur due to
depression of normal body flora, especially
if used simultaneously with
immunosuppressive agents.
118. 118
ANTIBIOTICS
• Long continued IV use may cause generalized
candidiasis, especially pulmonary candidiasis.
• Hypersensitive reactions such as skin rashes of
all types, dermatitis and anaphylactic shock may
occur.
• Because of deposition in growing bones and
teeth, can get brown staining of teeth and nails
and cause stunted growth in children.
120. 120
ANTIBIOTICS
Dosage and preparations:
Tetracycline, oxytet. and chlortet: 250mg
tablets or capsules: 250-500mg qid for 7days
orally.
Skin Ointment: tetracycline hydrochloride 3%, for
cuts and bruises.
Eye ointment: tetracycline hydrochloride 1%
Doxycycline : 100mg capsules: 200mg first day,
then 100mg daily for 5-7 days orally.
122. 122
ANTIBIOTICS
Chloramphenicol
• Chloramphenicol was isolated from
Streptomyces venezuelae ( a soil organism) in
1947.
• It is a potent, potentially toxic, broad spectrum
antibiotic.
• Reserved for life-threatening infections caused
by H. Influenza, or K. Pneumoniae and typhoid
fever.
123. 123
ANTIBIOTICS
Antibacterial spectrum
• Has a broad-spectrum of activity like
tetracyclines.
• It is effective against many gram –ve and
gram +ve organisms and also exhibits
activity against Rickettsiae and
Salmonelloses
124. 124
ANTIBIOTICS
Mode of action
• Chloramphenicol is primarily
bacteriostatic, and works by inhibiting
bacteria protein synthesis.
• It binds to 50S subunit of the bacterial 70S
ribosomes, inhibiting peptidyltransferase
enzyme thereby blocking protein
synthesis
126. 126
ANTIBIOTICS
Pharmacokinetics
• The drug is well absorbed from the intestine
when given orally.
• Peak plasma levels reached after 2-5hrs and
t1/2 is 1.5 – 3.0hrs.
• In neonates peak plasma levels are reached
after 6-12hrs and t1/2 is 24-48hrs, because the
immature‘s reduced levels of enzyme
glucuronyl transferase responsible for
chloramphenicol conjugation.
127. 127
ANTIBIOTICS
• Plasma levels obtained from IV and IM
administration are similar as from oral.
• Is 60% bound to plasma proteins and penetrates
tissue better than any other antibiotic.
• Enters eye, foetus, saliva, and sputum. CSF
levels are 30-50% of those of the plasma.
128. 128
ANTIBIOTICS
• Mostly metabolised in the liver by reduction, or
by conjugation to glucuronide.
• Interacts with barbiturates which induce liver
microsomal enzymes and hence lower
chloramphenicol blood levels.
• Chloramphenicol itself depresses microsomal
function and may impair metabolism of
phenytoin and tolbutamide increasing their
action.
129. 129
ANTIBIOTICS
• Chloramphenicol is mainly (90%) excreted
in the urine and 10% as unchanged.
• About 3% undergoes biliary excretion as
conjugated chloramphenicol and enters
enterohepatic circulation.
130. 130
ANTIBIOTICS
Therapeutic uses
• Because of incidence of serious bone marrow
depression Chloramphenicol is restricted to
infections not treatable with other agents.
• Accepted indications are enteric fever and H.
influenzae meningitis.
Is also used topically for eye and infections on
skin.
131. 131
ANTIBIOTICS
Adverse reactions
• Bone marrow depression due to haemotoxicity
as a result of inhibition of mitochondrial protein
synthesis and is dose related, reversible on
stoppage of therapy.
• Irreversible aplastic anaemia may occur and
may be fatal and unpredictable and is not
dose related.
132. 132
ANTIBIOTICS
• Hypersensitivity reactions may occur such
as skin rushes, fever, angioedema,
urticaria.
• GIT disturbances such as nausea,
vomiting, glossitis, diarrhoea, etc.
• Neonates and prematures my develop
‘grey syndrome’ due to cyanosis leading
to death within 4-5 days.
133. 133
ANTIBIOTICS
Dosage and preparations
• Capsules 250mg for oral use 1.5-3.0g daily in
divided doses every 6-8hrs.
• Chloramphenicol palmitate suspension
125mg/5ml given as 50mg/kg/day in divided
doses 6-8hrly.
• Chloramphenicol sodium succinate 1g vials for
parenteral use. 50mg/kg/day in divided doses.
134. 134
ANTIBIOTICS
• Chloramphenicol 3% skin ointment for cuts
and bruises.
• Eye ointment: Chloramphenicol 1% for
bacterial conjuctivitis.
• Eye drops: Chloramphenicol 0.5% single
dose or multi-dose.
135. 135
ANTIBIOTICS
Macrolides
This group includes erythromycin, azithromycin,
clarithromycin etc.
1.Erythromycin
Isolated from Streptomyces erythreus in 1952.
Currently its use diminished due to bacterial
resistance.
Primarily effective against gram +ve cocci, H.
influenza, rickettsiae etc and mycoplasma
pneumoniae
136. 136
ANTIBIOTICS
Mode of Action
• Erythromycin is bound to the 50S subunit of the
ribosome and blocks the execution of
instructions coded by mRNA
• Macrolides do not attach to human ribosome.
• Erythromycin is a bacteriostatic drug, but in high
concentrations exerts bactericidal effect.
137. 137
ANTIBIOTICS
Pharmacokinetics
• Erythromycin base is destroyed by gastric acid.
• The acid resistant salts such as stearate or
estolate are well absorbed and produce good
plasma levels.
• The stearate has to be sugar coated to protect
from gastric acid.
138. 138
ANTIBIOTICS
• Peak plasma levels attained after 2-4hrs.
• Distributed to most of the tissues except the
brain within 6hrs.
• The t1/2 is 1.5-3.0hrs.
• Only 20% of drug excreted by the kidneys, the
remainder is metabolised by demethylation, or
appears in the bile.
139. 139
ANTIBIOTICS
Therapeutic uses
• Used as an alternative in penicillin-allergic
patients or in penicillin resistant gram +ve
pathogens.
• Also useful in atypical pneumonia caused
by Mycoplasma pneumonia, syphilis or
infections with Haemophilus influenza.
140. 140
ANTIBIOTICS
• First line choice as alternative to
penicillin in syphilis, gonorrhea,
pneumococcal infections.
• Second line choice in bronchitis, otitis
media and sinusitis, and chronic
prostatitis.
141. 141
ANTIBIOTICS
Adverse Reactions
• One of the safer antibiotics.
• GIT disturbances and allergy are common
adverse reactions.
• With oral therapy can get nausea, anorexia,
diarrhoea, glossitis, stomatitis.
• Can get super infection with candida albicans
over prolonged therapy.
143. 143
ANTIBIOTICS
Resistance
Resistance to Erythromycin is becoming a serious
clinical problem because of:
(i) the inability of the organism to take up the antibiotic.
(ii) decreased affinity of the 50S ribosomal subunit for
the antibiotic.
(iii) a presence of a plasmid-associated erythromycin
esterase.
Both Clarithromycin and Azithromycin show cross-
resistance with Erythromycin.
144. 144
ANTIBIOTICS
Dosage
Erythromycin stearate 250mg capsules/tablets
given orally, 250-500mg qid for 7days
Erythromycin Ethyl Succinate 125mg/5ml
suspension, 4-6mg/kg/4-6hourly.
Erythromycin Lactobionate 1g/vial iv 300mg
6hrly.
145. 145
ANTIBIOTICS
2. Clarithromycin
– Has a spectrum of antibacterial activity
similar to that of Erythromycin.
– But is also effective against Haemophilus
influenza.
– Its activity against intracellular pathogens
such as Chlamydia, Legion Ella is higher.
146. 146
ANTIBIOTICS
Dose
Oral: Tablets : 250 - 500mg bid for 7 – 14
days.
Suspension: 125 – 250mg/5ml.
IV: 500mg bid.
Side effects: as for erythromycin.
147. 147
ANTIBIOTICS
3. Azithromycin
Is more effective against respiratory
infections due to H influenza and
Mirabella catarrhalis.
Is preferred treatment for urethritis
caused by Chlamydia trachomatis.
149. 149
ANTIBIOTICS
INHIBITORS OF CELL MEMBRANE
FUNCTION
• The bacterial cytoplasmic membrane serves as:
- the site for cell wall synthesis.
- an osmotic barrier.
- an organ for selective intercellular
transport of essential cell nutrients.
• Members of this group are polymyxins.
150. 150
ANTIBIOTICS
Polymixins
• Polymyxin is a generic name for six strongly
basic cyclic polypeptides (A, B, C, D, E and M).
• All differing in their amino acid content.
• Obtained from various strains of Bacillus
polymaxa.
151. 151
Only two, polymyxin B and E are
therapeutically useful.
Polymyxin B
Polymyxin B forms water soluble salts with
mineral acids.
The usual preparation is polymyxin B
sulphate.
ANTIBIOTICS
152. 152
ANTIBIOTICS
Antibacterial spectrum – polymyxin B
has a narrow spectrum limited to action
against gram –ve organisms.
Particularly active against Ps. Aeruginosa,
E. coli, H. influenza, K. pneumonia,
salmonella and shigella.
153. 153
ANTIBIOTICS
Mode of action
• Polymyxin B is bactericidal.
• Binds with the phospholipid components of the
cytoplasmic membrane of susceptible bacteria.
• It impairs the bacterial cell membrane function,
and causes leakage of small molecules ( e g
phosphate, nucleosides) from the bacteria.
154. 154
ANTIBIOTICS
Pharmacokinetics
• Usually administered topically with no absorption
from site.
• In CSF infection given by intrathecal injection,
can also be given by IV.
• No absorption from GIT in adults, appreciable in
children.
• Primarily cleared by the kidneys.
155. 155
ANTIBIOTICS
Therapeutic uses
Second line choice agents in the treatment
of P. aerugenosa infections particularly of
the UTI, external ear, conjuctiva,
meninges, and in septicaemia.
156. 156
ANTIBIOTICS
Adverse reactions
• Minimal on topical application.
• Oral therapy may cause nausea, vomiting,
and diarrhoea.
• On IM administration can get facial
flushing, drug fever, skin rushes, urticaria.
157. 157
ANTIBIOTICS
• The most serious adverse reaction after
parenteral administration is kidney
damage.
• It interacts with cephalosporins,
chloramphenicol, heparin, and
tetracyclines and should not be mixed with
them when given by IV.
158. 158
ANTIBIOTICS
Preparations and dosage
• Polymyxin B sulphate is available for local,
oral, or systemic administration.
• Frequently combined with other antibiotics
(bacitracin and neomycin), and with
hydrocortisone for topical use.
159. 159
ANTIBIOTICS
Oral dose: 4.0mg/kg daily in 3-4 divided
doses.
IM/IV dose: 1.2-2.5mg/daily in 3-4 divided
doses.
Intrathecally: 5mg/day with a 0.5 mg/ml
concentration.
Topically: 0.25% cream or ointment.
160. 160
ANTIBIOTICS
(iv) Inhibitors of nucleic acid (DNA)
synthesis and metabolism
fluoroquinolones, griseofulvin,
rifampicin etc
(Covered under other topics)
