Transcript Antimicrobial Agents

Antimicrobial Agents
Martin Votava
Olga Kroftová
Overview
• 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.
What 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.
Antibiotics
• 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.
History
• 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.
Sir Alexander Fleming
Fleming’s Petri Dish
Zone 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
History
• 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.
Susceptibility vs. Resistance
of 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
Susceptibility 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 toxicmicroorganism is resistant
Susceptibility 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 !?
Antibiotic Susceptibility Testing
Disk Diffusion Test
Determination of MIC
Str
Tet
8
4
2
1
Tetracycline (μg/ml)
MIC = 2 μg/ml
0
Ery
Chl
Amp
Susceptibility 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.
Susceptibility 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
Resistance
• 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
Resistance (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.
Resistance (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.
Resistance (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
Selection 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
Empirical 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
Penicillins
• 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
Synthesis of Penicillin


b-Lactams produced by fungi, some ascomycetes,
and several actinomycete bacteria
b-Lactams are synthesized from amino acids
valine and cysteine
b Lactam Basic Structure
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
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
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
Penicillins (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
Penicillins (cont.)
Examples
• Phenoxymethylpenicillin (Penicillin V) is
acid stable and is given orally for minor
infections
• it is otherwise similar to benzylpenicillin
Penicillins (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
Penicillins (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 blactamase in this way
• It extends the spectrum of amoxycillin
Penicillins (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
Penicillins (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
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
Penicillins (cont.)
Drug interactions
• The use of ampicillin (or other broadspectrum antibiotics) may decrease the
effectiveness of oral conraceptives by
diminishing enterohepatic circulation
Antistaphylococcus penicillins
• Oxacillin, cloxacillin
– Resistant against staphylococcus penicillinasis
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
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
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 enerobacteriaceae eg
E. coli, Klebsiella spp,proteus spp. May be
active vs H influenzae and N meningtidis
Cephalosporins
• 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
Cephalosporins (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
Aminoglycosides (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-mRNAtRNA) 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.
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.
Aminoglycosides (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.
Aminoglycosides (cont.)
Resistance
• Resistance results from bacterial enzymes
which break down aminoglycosides or to
their decreased transport into the cells.
Aminoglycosides (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.
Aminoglycosides (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.
Aminoglycosides (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.
Aminoglycosides (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.
Aminoglycosides (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.
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
Macrolides (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
Macrolides (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.
Macrolides (cont.)
Examples and clinical pharmacokinetics
• Newer macrolides such as clarithromycin
and azithromycin may have fewer adverse
effects.
Macrolides – side effects
• Nauzea, vomitus
• Allergy
• Hepatitis, ototoxicity
• Interaction with cytochrome P450 3A4
(inhibition)
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.
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.
Clindamycin
Adverse effects
• Diarrhoea is common.
• Superinfection with a strain of Clostridium
difficile which causes serious inflammation
of the large bowel (Pseudomembranous
colitis)
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 limitid by its serious
toxicity.
Chloramphenicol (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).
Chloramphenicol (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
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.
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 grampositive 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.
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 grampositive 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.
p-aminobenzoic acid + Pteridine
Pteridine
synthetase
Sulfonamides
Dihydropteroic acid
Dihydrofolate
synthetase
Dihydrofolic acid
Dihydrofolate
reductase
Trimethoprim
Tetrahydrofolic acid
Methionine
Thymidine
Purines
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.
Sulfonamides and trimethoprim
Clinical 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.
Sulfonamides and trimethoprim
Clinical 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.
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.
Sulfonamides and trimethoprim
Adverse effects
• Gastrointestinal upsets
• Less common but more serious:
-sulfonamides: allergy, rash, fever,
agranulocytosis, renal toxicity
-trimethoprim: macrocytis anemia,
thrombocytopenia
-cotrimoxazole: aplastic anemia
Sulfonamides and trimethoprim
Drug intereactions
• Sulfonamides can decrease metabolism of
phenytoin, warfarin and some oral
hypoglycaemics, increasing their effects.
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
Quinolones
• 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.
Quinolones (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,
Quinolones (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.
Quinolones (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
Quinolones (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.
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.
Tetracyclines (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.
Tetracyclines (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.
Tetracyclines (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.
Tetracyclines (cont.)
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)
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.
Metronidazole (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.
Metronidazole (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.
Metronidazole (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
Nitrofurantoin
• 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.
Nitrofurantoin (cont.)
• It is ineffective in renal failure because of
failure to concentrate.
• Resistance develops relatively quickly.
Nitrofurantoin (cont.)
Adverse effects
• Gastrointestinal upsets
• Allergy
• Polyneuritis
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
Fucidin (cont.)
• It can be given orally or parenterally.
• It is metabolized in the liver.
Adverse effects
• Gastrointestinal upsets
• Hepatitis and jaundice
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.
Vancomycin (cont.)
• It is given orally to treat
pseudomembranous colitis
• teicoplanin is similar but less toxic
Vancomycin (cont.)
Adverse effects
• Its toxicity is similar to aminoglycoside and
likewise monitoring of plasma
concentrations is essential.
• Nephrotoxicity
• Ototoxicity
• Allergy
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.
Antibiotics for leprosy
• Rifampicin is used and dapsone, which is
related to the sulphoamides.
• Its adverse effects include haemolysis,
gastrointestinal upsets and rashes.
Chemotherapy for viruses
Antiviral 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.
Antiviral drugs (cont.)
• Viruses have assumed increasing
importance in the setting of
immunosuppression - both drug induced
and AIDS.
Antiviral 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)
Antiviral 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
Aciclovir
Mode of action
• It is active against Herpes simplex and
Herpes zoster.
• Aciclovir targets virus-infected cells quite
specifically, and this explains the drug`s
relatively low toxicity.
Aciclovir (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.
Aciclovir (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.
Aciclovir (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
Aciclovir (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
Zidovudine (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 cell`s DNA, thereby
allowing viral replication.
• Synthesis of the initial DNA transcript
involves the enzyme reverse transcriptase.
Zidovudine (AZT) cont.
Mode of action
• Zidovudine is a potent inhibitor of reverse
transcriptase.
• It has relatively specific toxicity for the
virus.
Zidovudine (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
Zidovudine (AZT) cont.
Clinical pharmacokinetics
• In patients with renal or liver impairment,
the drug may accumulate, and doses are
usually adjusted in these disease states
Zidovudine (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.
Zidovudine (AZT) cont.
Adverse effects
• Bone marrow toxicity
• Polymyositis
• Headache and insomnia
Zidovudine (AZT) cont.
Drug interactions
• Paracetamol: the risk of bone marrow
suppression may increased
• Probenecid
Purine and pyrimidine analogues
Mode 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.
Purine and pyrimidine analogues
Examples 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
Purine and pyrimidine analogues
Therapeutic 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 lifethreatening systemic Herpes infections
Purine and pyrimidine analogues
Adverse effects
• Idoxuridine: because it is used only
topically, severe adverse effects are unusual
• Vidarabine: anorexia, nausea, vomiting,
diarroea and bone marrow suppression
Purine and pyrimidine analogues
Drug interactions
• The metabolism of vidarabine is inhibited
by the xanthine oxidase inhibitor
allopurinol, and toxicity may result
Ribavirin
• 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.
Ribavirin (cont.)
• The drug is eliminated by both metabolism
and renal excretion, with a terminal half-life
of about 2 weeks
Ribavirin (cont.)
Therapeutic uses
• Respiratory syncytial virus (RSV)
infections: bronchiolitis and pneumonia at
young children
• Influenza A and B
• Lassa fever