Title: Antimicrobial Agents
1Antimicrobial Agents
- Martin Votava
- Olga Kroftová
2Overview
- If bacteria make it past our immune system and
start reproducing inside our bodies, they cause
disease. - Certain bacteria produce chemicals that damage or
disable parts of our bodies. - Antibiotics work to kill bacteria.Antibiotics are
specific to certain bacteria and disrupt their
function.
3What is an Antibiotic?
- An antibiotic is a selective poison.
- It has been chosen so that it will kill the
desired bacteria, but not the cells in your body.
Each different type of antibiotic affects
different bacteria in different ways. - For example, an antibiotic might inhibit a
bacteria's ability to turn glucose into energy,
or the bacteria's ability to construct its cell
wall. Therefore the bacteria dies instead of
reproducing.
4Antibiotics
- Substances produced by various species
- of microorganisms bacteria, fungi,
actinomycetes- to suppress the growth of other
microorganisms and to destroy them. - Today the term ATB extends to include synthetic
antibacterial agents sulfonamides and quinolones.
5History
- The German chemist Paul Ehrlich developed the
idea of selective toxicity that certain
chemicals that would be toxic to some organisms,
e.g., infectious bacteria, would be harmless to
other organisms, e.g., humans. - In 1928, Sir Alexander Fleming, a Scottish
biologist, observed that Penicillium notatum, a
common mold, had destroyed staphylococcus
bacteria in culture.
6Sir Alexander Fleming
7Flemings Petri Dish
8Zone of Inhibition
- Around the fungal colony is a clear zone where no
bacteria are growing - Zone of inhibition due to the diffusion of a
substance with antibiotic properties from the
fungus
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10History
- Penicillin was isolated in 1939, and in 1944
Selman Waksman and Albert Schatz, American
microbiologists, isolated streptomycin and a
number of other antibiotics from Streptomyces
griseus.
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12Susceptibility vs. Resistanceof microorganisms
to Antimicrobial Agents
- Success of therapeutic outcome depends on
- Achieving concentration of ATB at the site of
infection that is sufficient to inhibit
bacterial growth. - Host defenses maximally effective MI effect is
sufficient bacteriostatic agents (slow protein
synthesis, prevent bacterial division) - Host defenses impaired- bactericidal agents
- Complete ATB-mediated killing is necessary
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14Susceptibility vs. Resistance(cont.)
- Dose of drug has to be sufficient to produce
effect inhibit or kill the microorganism - However concentration of the drug must remain
below those that are toxic to human cells - If can be achieved microorganism susceptible to
the ATB - If effective concentration is higher than toxic-
microorganism is resistant
15Susceptibility vs. Resistance(cont.)
- Limitation of in vitro tests
- In vitro sensitivity tests are based on
non-toxic plasma concentrations cut off - Do not reflect concentration at the site of
infection - E.g. G- aer.bacilli like Ps.aeruginosa inhibited
by 2 4 ug/ml of gentamycin or tobramycin.
Susceptible !?
16Antibiotic Susceptibility Testing
17Susceptibility vs. Resistance(cont.)
- Plasma concentration above 6-10 ug/ml may result
in ototoxicity or nephrotoxicity - Ration of toxic to therapeutic concentration is
very low agents difficult to use. - Concentration in certain compartments vitreous
fluid or cerebrospinal fluid much lower than
those in plasma. - Therefore can be only marginally effective or
ineffective even those in vitro test states
sensitive.
18Susceptibility vs. Resistance(cont.)
- Therefore can be only marginally effective or
ineffective even those in vitro test states
sensitive. - Conversely concentration of drug in urine may
be much higher than in plasma , so resistant
agents can be effective in infection limited to
urine tract
19Resistance
- To be effective ATB must reach the target and
bind to it. - Resistance
- Failure to reach the target
- The drug is inactivated
- The target is altered
20Resistance (cont.)
- Bacteria produce enzymes at or within the cell
surface inactivate drug - Bacteria possess impermeable cell membrane
prevent influx of drug. - Transport mechanism for certain drug is energy
dependent- not effective in anaerobic
environment. - ATB as organic acids penetration is pH
dependent.
21Resistance (cont.)
- Acquired by mutation and passed vertically by
selection to daughter cells. - More commonly horizontal transfer of resistance
determinant from donor cell, often another
bacterial species, by transformation,
transduction, or conjugation. - Horizontal transfer can be rapidly disseminated
- By clonal spread or resistant strain itself
- Or genetic exchange between resistant and further
susceptible strains.
22Resistance (cont.)
- Methicilin resistant strains of Staphylococcus
aureus clonally derived from few ancestral
strains with mecA gene - Encodes low-affinity penicillin-binding protein
that confers methicillin resistance. - Staphylococcal beta-lactamase gene, which is
plasmid encoded, presumambly transferred on
numerous occasions. Because is widely distributed
among unrelated strains, identified also in
enterococci
23Selection of the ATB
- Requires clinical judgment, detailed knowledge of
pharmacological and microbiological factors. - Empirical therapy initial infecting organism
not identified single broad spectrum agent - Definitive therapy- microorganism identified a
narrow spectrum low toxicity regiment to
complete the course of treatment
24Empirical and Definite Therapy
- Knowledge of the most likely infecting
microorganism and its susceptibility - Gram stain
- Pending isolation and identification of the
pathogen - Specimen for culture from site of infection
should be obtain before initiation of therapy - Definite therapy
25Penicillins
- Penicillins contain a b-lactam ring which
inhibits the formation of peptidoglycan
crosslinks in bacterial cell walls (especially in
Gram-possitive organisms) - Penicillins are bactericidal but can act only on
dividing cells - They are not toxic to animal cells which have no
cell wall
26Synthesis of Penicillin
- b-Lactams produced by fungi, some ascomycetes,
and several actinomycete bacteria - b-Lactams are synthesized from amino acids valine
and cysteine
27b Lactam Basic Structure
28Penicillins (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
29Penicillins (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
30Penicillins (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
31Penicillins (cont.)Examples
- Benzylpenicillin (Penicillin G) is acid labile
and b-lactamase sensitive and is given only
parenterally - 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
32Penicillins (cont.)Examples
- Phenoxymethylpenicillin (Penicillin V) is acid
stable and is given orally for minor infections - it is otherwise similar to benzylpenicillin
33Penicillins (cont.)Examples
- 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
34Penicillins (cont.)Examples
- 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
35Penicillins (cont.)Examples
- 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
36Penicillins (cont.)Examples
- 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
37Penicillins (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
38Penicillins (cont.)Drug interactions
- The use of ampicillin (or other broad-spectrum
antibiotics) may decrease the effectiveness of
oral conraceptives by diminishing enterohepatic
circulation
39Antistaphylococcus penicillins
- Oxacillin, cloxacillin
- Resistant against staphylococcus penicillinasis
40Cephalosporins
- 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
41Cephalosporins
- BACTERICIDAL- modify cell wall synthesis
- CLASSIFICATION- first generation are early
compounds - Second generation- resistant to ß-lactamases
- Third generation- resistant to ß-lactamases
increased spectrum of activity - Fourth generation- increased spectrum of activity
42Cephalosporins
- 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 enerobacteriaceae eg E. coli,
Klebsiella spp,proteus spp. May be active vs H
influenzae and N meningtidis
43Cephalosporins
- THIRD GENERATION- eg cefixime and other I.V.s
cefotaxime,ceftriaxone,ceftazidine. 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
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45Cephalosporins (cont.)Adverse effects
- Allergy (10-20 of patients wit penicillin
allergy are also allergic to cephalosporins) - Nephritis and acute renal failure
- Superinfections
- Gastrointestinal upsets when given orally
46Aminoglycosides (bactericidal)streptomycin,
kanamycin, gentamicin, tobramycin, amikacin,
netilmicin, neomycin (topical)
- Mode of action - The aminoglycosides irreversibly
bind to the 16S 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
ß-lactam antibiotics. The ß-lactams inhibit cell
wall synthesis and thereby increase the
permeability of the aminoglycosides.
47AminoglycosidesClinical 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.
48Aminoglycosides (cont.)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.
49Aminoglycosides (cont.)Resistance
- Resistance results from bacterial enzymes which
break down aminoglycosides or to their decreased
transport into the cells.
50Aminoglycosides (cont.)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.
51Aminoglycosides (cont.)Examples
- In addition to treating known sensitive
organisms, it is used often blindly with other
antibiotics in severe infections of unknown
cause. - Streptomycin was formerly the mainstay of
antituberculous therapy but is now rarely used in
the developed world.
52Aminoglycosides (cont.)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.
53Aminoglycosides (cont.)Adverse 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.
54Aminoglycosides (cont.)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,
eosinophilia.
55Macrolides (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
56Macrolides (cont.)Examples and clinical
pharmacokinetics
- Erythromycin is acid labile but is given as an
enterically coated tablet - Absorption is erratic and poor.
- It is excreted unchanged in bile and is
reabsorbed lower down the gastrointestinal tract
(enterohepatic circulation). - It may be given orally or parenterally
57Macrolides (cont.)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.
58Macrolides (cont.)Examples and clinical
pharmacokinetics
- Newer macrolides such as clarithromycin and
azithromycin may have fewer adverse effects.
59Macrolides side effects
- Nauzea, vomitus
- Allergy
- Hepatitis, ototoxicity
- Interaction with cytochrome P450 3A4 (inhibition)
60Chloramphenicol, 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.
61Clindamycin
- 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.
62ClindamycinAdverse effects
- Diarrhoea is common.
- Superinfection with a strain of Clostridium
difficile which causes serious inflammation of
the large bowel (Pseudomembranous colitis)
63Chloramphenicol
- 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 limitid by its serious toxicity.
64Chloramphenicol (cont.)
- 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).
65Chloramphenicol (cont.)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
66Sulfonamides and trimethoprim
- Sulfonamides are rarely used alone today.
- Trimethoprim is not chemically related but is
considered here because their modes of action are
complementary.
67Sulfonamides, 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.
68Trimethoprim, 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.
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70Sulfonamides and trimethoprimMode 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.
71Sulfonamides and trimethoprimClinical
pharmacokinetics
- Most sulfonamides are well absorbed orally and
they are widely distributed including to the CNS. - Most are excreted by the kidney unchanged.
- They are effective against Gram-positive and many
Gram-negative organism but are rarely used alone
now.
72Sulfonamides and trimethoprimClinical
pharmacokinetics
- Trimethoprim is also well absorbed and excreted
by the kidneys, with similar spectrum. - Cotrimoxazole is widely used for urinary and
upper respiratory tract infections but should not
be the drug of choice because of its adverse
effects.
73Sulfonamides and trimethoprimClinical
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.
74Sulfonamides and trimethoprimAdverse effects
- Gastrointestinal upsets
- Less common but more serious -sulfonamides
allergy, rash, fever, agranulocytosis, renal
toxicity -trimethoprim macrocytis anemia,
thrombocytopenia -cotrimoxazole
aplastic anemia
75Sulfonamides and trimethoprimDrug intereactions
- Sulfonamides can decrease metabolism of
phenytoin, warfarin and some oral hypoglycaemics,
increasing their effects.
76Quinolones (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
77Quinolones
- The quinolones are effective but expensive
antibiotics. - With increased use, resistance to these drugs is
becoming more common. - They should in general be reverse drugs and not
first-line treatment.
78Quinolones (cont.)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,
79Quinolones (cont.)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 as peritonitis and Salmonella. - Activity against anaerobic organism is poor and
it should not be first choice for respiratory
tract infections.
80Quinolones (cont.)Adverse effects
- Gastrointestinal upsets
- Fluoroquinolones may block the inhibitory
neurotransmitter GABA, and this may cause
confusion in the elderly and lower the fitting
threshold. - They are also contraindicated in epileptics.
- Allergy and anaphylaxis
81Quinolones (cont.)Adverse effects
- Possibly damage to growing cartilage not
recommended for pregnant women and
children Drug interaction - Ciprofloxacin is a liver enzyme inhibitor and may
cause life-threatening interaction with
theophylline.
82Tetracyclines (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.
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84Tetracyclines (cont.) 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 portly absorbed.
- They bind avidly to heavy metal ions and so
absorption is greatly reduced if taken with food,
milk, antacids or iron tablets.
85Tetracyclines (cont.) 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.
86Tetracyclines (cont.) Examples and clinical
pharmacokinetics
- Resistance is frequent.
- They are specially indicated for Mycoplasma,
Rikettsia, Chlamydia and Brucella infections. - Their most common use today is for acne, given
either orally or topically.
87Tetracyclines (cont.) Adverse effects
- Gastrointestinal upsets
- Superinfection
- Discolouration and deformity in growing teeth and
bones (contraindicated in pregnancy and in
children lt 12 years) - Renal impairment (should be also avoided in renal
disease)
88Metronidazole
- 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.
89Metronidazole (cont.)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 and can be used to treat
pseudomembranous colitis.
90Metronidazole (cont.)Uses
- Increasingly, it is used as part of treatment of
Helicobacter pyloris infestion of the stomach and
duodenum associated with peptic ulcer disease. - It is used also to treat a variety of dental
infections, particularly dental abscess.
91Metronidazole (cont.)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. - Possibly teratogenic if taken in the first
trimester of pregnancy
92Nitrofurantoin
- This is used as a urinary antiseptic and to treat
Gram-negative infections in the lower urinary
tract. - It is taken orally and is well absorbed and is
excreted unchanged in the urine. - It only exerts its antimicrobial effect when it
is concentrated in the urine and so has no
systemic antibacterial effect.
93Nitrofurantoin (cont.)
- It is ineffective in renal failure because of
failure to concentrate. - Resistance develops relatively quickly.
94Nitrofurantoin (cont.)Adverse effects
- Gastrointestinal upsets
- Allergy
- Polyneuritis
95Fucidin
- 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
96Fucidin (cont.)
- It can be given orally or parenterally.
- It is metabolized in the liver. Adver
se effects - Gastrointestinal upsets
- Hepatitis and jaundice
97Vancomycin
- 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.
98Vancomycin (cont.)
- It is given orally to treat pseudomembranous
colitis - teicoplanin is similar but less toxic
99Vancomycin (cont.)Adverse effects
- Its toxicity is similar to aminoglycoside and
likewise monitoring of plasma concentrations is
essential. - Nephrotoxicity
- Ototoxicity
- Allergy
100Antibiotics 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.
101Antibiotics for leprosy
- Rifampicin is used and dapsone, which is related
to the sulphoamides. - Its adverse effects include haemolysis,
gastrointestinal upsets and rashes.
102Chemotherapy for viruses
103Antiviral drugs
- Antiviral chemotherapy is still in its infancy.
- Viruses are more difficult targets than
bacteria they are most vulnerable during
reproduction, but all use host cell organelles
and enzymes to do this, so that antiviral
compounds are often as toxic to host cells as to
virus.
104Antiviral drugs (cont.)
- Viruses have assumed increasing importance in the
setting of immunosuppression - both drug induced
and AIDS.
105Antiviral drugs (cont.)
- Current antiviral drugs are thought to work in
one of the following ways - inhibition of
viral uncoating shortly after penetration into
the cell they are best for prophylaxis or very
early in the disease course (e.g.amantadine) -
interference with viral RNA synthesis and
function (e.g. ribavirin)
106Antiviral drugs (cont.)
- interference with DNA synthesis (e.g.
cytarabine) - inhibition of viral DNA polymerase (e.g.aciclovir
and gancyclovir) - inhibition of reverse transcriptase at
retroviruses such as HIV (e.g.zidovudine) - use of complex natural antiviral defences by
employing interferon
107AciclovirMode of action
- It is active against Herpes simplex and Herpes
zoster. - Aciclovir targets virus-infected cells quite
specifically, and this explains the drugs
relatively low toxicity.
108Aciclovir (cont.)Clinical pharmacokinetics
- The drug is used topically, orally and i.v.
- Little drug is absorbed from topical
formulations, and the bioavailability of the oral
drug is low (about 20). - It is widely distributed and crosses the
blood-brain barrier. - It is excreted in the urine and in lactating
women in the breast milk.
109Aciclovir (cont.)Therapeutic uses
- It is the drug of first choice for Herpes simplex
and zoster infections, because of the great
efficacy and lower toxicity than the
alternatives. - The drug has little activity against
cytomegalovirus or Epstein-Barr virus.
110Aciclovir (cont.)Therapeutic uses
- Herpes simplex infections of skin, mucous
membranes and cornea - Life-threatening Herpes simplex infections
aciclovir i.v. reduces mortality - Herpes zoster that is less sensitive to aciclovir
than H. simplex .It is used for early topic or
oral treatment of zoster aciclovir i.v. is used
for life-threatening zoster infections as
pneumonia
111Aciclovir (cont.)Adverse effects
- Renal impairment mainly in high i.v. doses in
dehydrated patients - Local inflammation following extravascular
administration - Encephalopathy mainly in high i.v. doses
112Zidovudine (AZT)Mode of action
- HIV virus is an RNA virus capable of including
the synthesis of a DNA transcript of its genome,
which can then become integrated into the host
cells DNA, thereby allowing viral replication. - Synthesis of the initial DNA transcript involves
the enzyme reverse transcriptase.
113Zidovudine (AZT) cont.Mode of action
- Zidovudine is a potent inhibitor of reverse
transcriptase. - It has relatively specific toxicity for the virus.
114Zidovudine (AZT) cont.Clinical pharmacokinetics
- It is well absorbed from the gut but subject to
first-pass metabolism - Bioavailability is about 70
- The drug is widely distributed and crosses the
blood-brain barrier - Most of the drug is eliminated by hepatic
metabolism, unchanged zidovudine accounting for
about 10 of the dose
115Zidovudine (AZT) cont.Clinical pharmacokinetics
- In patients with renal or liver impairment, the
drug may accumulate, and doses are usually
adjusted in these disease states
116Zidovudine (AZT) cont.Therapeutic uses
- It is used to prolong life patients with AIDS and
AIDS-related complex (ACR) it probably does not
delay the onset of AIDS in HIV-positive patients - The drug usually produces a rise in CD4 cell
counts, but eventual deterioration is usual in
spite of zidovudine - In patients with late AIDS it is of little use.
117Zidovudine (AZT) cont.Adverse effects
- Bone marrow toxicity
- Polymyositis
- Headache and insomnia
118Zidovudine (AZT) cont.Drug interactions
- Paracetamol the risk of bone marrow suppression
may increased - Probenecid
119Purine and pyrimidine analoguesMode of action
- These drugs are effective against DNA viruses
- The compounds structurally resemble purine and
pyrimidine nucleosides - The resulting DNA molecule is more easily
fragmented, leading to transcription errors. - They also inhibit viral DNA polymerase.
120Purine and pyrimidine analoguesExamples and
clinical pharmacokinetics
- Idoxuridine it is not absorbed from the gut, and
is used topically - Vidarabine cannot be given orally because it is
metabolized in the gut - it is usually given
i.v. or topically
121Purine and pyrimidine analoguesTherapeutic uses
- Idoxuridine may be used topically for Herpes
simplex and zoster but is too toxic for systemic
use and has largely been supplanted by aciclovir - Vidarabine may be used for life-threatening
systemic Herpes infections
122Purine and pyrimidine analoguesAdverse effects
- Idoxuridine because it is used only topically,
severe adverse effects are unusual - Vidarabine anorexia, nausea, vomiting, diarroea
and bone marrow suppression
123Purine and pyrimidine analoguesDrug interactions
- The metabolism of vidarabine is inhibited by the
xanthine oxidase inhibitor allopurinol, and
toxicity may result
124Ribavirin
- It is effective against a wide range of DNA and
RNA viruses - The drug may be given by aerosol inhalation,
orally or i.v. - Oral biavailabity is about 40
- It readily crosses the blood-brain barrier and
has a very large volume of distribution, mainly
because of cellular uptake.
125Ribavirin (cont.)
- The drug is eliminated by both metabolism and
renal excretion, with a terminal half-life of
about 2 weeks
126Ribavirin (cont.)Therapeutic uses
- Respiratory syncytial virus (RSV) infections
bronchiolitis and pneumonia at young children - Influenza A and B
- Lassa fever