Antimicrobial Agents
History
• Antimicrobial chemotherapy started
• Clinical use of sulfonamide 1936
• Golden age – 1941 production of
penicillin
• 30% of hospitalized patients 1 or more
ATB
• Among most misused agents in practice
• Wide spread use- emerging resistance
Antibiotics
• Substances produced by various
species
of microorganisms: bacteria, fungi,
actinomycetes- to supress the growth of
other microorganisms and to destroy
them.
• Today the term ATB extends to include
synthetic antibacterial agents:
sulphonamides and quinolones.
Classification
on chemical structure and
mechanism of action
• Inhibition of synthesis of bacterial cell
wall
• Acting directly on cell membrane,
permeability, leakage
• Inhibition of protein synthesis
• Inhibition of DNA gyrase, RNA
polymerase
• Inhibiton of folic acid metabolism
Classification
on mechanism of action
• Inhibition of synthesis of bacterial cell wall
(PEN, CEP, MONOBACT. VANCO, BACIT,
imidazol antifungal agents:miconazol,
ketokonazol, clotrimazol)
• Directly on cell membrane, permeability,
leakage
(Polymixins, antifugals: nystatin, amfotericin
B-binds to cell wall sterols)
Classification
on mechanism of action (cont.)
• Inhibition of protein synthesis
• Affecting function of 30S and 50S
ribosomal subunits-reversibal inhibition
of protein synthesis . Bacteriostatic:
(Chloramphenicol, TTC, ERY,
Clindamycin)
• Bind to 30S subunit, alter protein
synthesis, cell death (Aminoglycoside)
Classification
on mechanism of action (cont.)
• Affecting Nucleic Acid metabolism:
DNA-dependent RNA polymerase
(rifamycins)
DNA gyrase (quinolones)
• Inhibiton of folic acid metabolism
• Antimetabolites :(Trimethoprim,
sulphonamides)
• Nucleic acid analogues (zidovudin,
ganciclovir, vidarabine, acyclovir)
Classification of Antibiotics
• Bacteriostatic
• Bactericidal
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 nontoxic 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 !?
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.
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 judgement, 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
Rational ATB therapy
• Precise diagnosis (clinical./microbiology)
• Regional sensitivity/resistance patterns
– ATB centre / Narional reference lab
• Clinical state (renal, liver functions)
• PK / PD relations
– To reach the effectice concentration in the
infection site
Pk/PD of antibiotics
dose
conc. in the site
of infection
Antimicrobial
effect
conc. in other
tissues
other effects
Conc. in the
blood
ADME
PHARMACOKINETICS
PHARMACODYNAMICS
PK/PD classif. of ATB
• T>MIC (maximum exposure time) – TIME DEPENDENT
– peniciliny, cefalosporiny, karbapenemy, eryth, clarith,
clindamycin, linezolid
• Cmax : MIC (maximum safe concentration; PAE)
• = CONCENTRATION DEPENDENT
– fluorochinolony, aminoglykosidy, metronidazol
aminoglycosides
1x vs. 2-3x daily
PK / PD...-lactams
co-amoxicillin BID vs. TID
Penicillins
• Penicillins contain a -lactam ring which
inhibits the formation of peptidoglycan
crosslinks in bacterial cell walls
(especially in Gram-positive organisms)
• Penicillins are bactericidal but can act
only on dividing cells
• They are not toxic to animal cells which
have no cell wall
Penicillins (cont.)
Clinical Pharmacokinetics
• Penicillins are poorly lipid soluble and do
not cross the blood-brain barrier in
appreciable concentrations unless it is
inflammed (so they are effective in
meningitis)
• They are actively excreted unchanged by
the kidney, so the dose should be reduced
in severe renal failure
• This tubular secretion can be blocked by
probenecid to potentiate penicillins`s
action
Penicillins (cont.)
Resistance
• This is the result of production of lactamase in the bacteria which destroys
the -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 -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 -laclamase sensitive
Penicillins (cont.)
Examples
• Amoxicillin is similar but better absorbed
orally
• It is sometimes combined with
clavulanic acid, which is a -lactam with
little antibacterial effect but which binds
strongly to -lactamase and blocks the
action of -lactamase in this way
• It extends the spectrum of amoxycillin
Penicillins (cont.)
Examples
• Antistaphyloccocal penicilins
• Flucloxacillin is acid stable and is given
orally or parenterally
• It is -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
• Piperacillin the most potent and popular
• It is -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.)
Examples
• Timentin is a combination of of ticarcillin
and clavulanic acid ( a beta lactamase
inhibitor) designed to overcome the
problems of beta-lactamase formation
by Pseudomonas
• It is used intravenously for lifethreatening infections, given i.v. every 46 hours , half-life 1 – 1.5 hours, renally
excreted
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
Cephalosporins
• They also owe their activity to -lactam
ring and are bactericidal.
• They are broad-spectrum antibiotics.
• They are relatively expensive but 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
• Some cephalosporins (e.g.cefotaxime)
may be indicated for empirical use to
treat life-threatening infections where
the organism is probably sensitive
Cephalosporins
Examples and pharmacokinetics
• Cephradine and cephalexin are well
absorbed orally
• Cephradine can be also given
parenterally.
• They cover mostly Gram-positive
organism, such as Streptococcus
pyogenes, S. pneumoniae and
Staphylococcus aureus, as well as
some Gram-negative bacteria,
Cephalosporins (cont.)
Examples and pharmacokinetics
• alhough they are less effective in this
than later cephalosporins.
• They are excreted by the kidney
(reduce dose in renal failure)
Cephalosporins (cont.)
Examples and pharmacokinetics
• Cefuroxime can be given parenterally or
as an oral prodrug.
• It has a broader spectrum, including
many Gram-negative bacilli.
• Cefotaxime is given parenterally.
• It has an even broader spectrum,
including many Enterobacter, E.coli,
Proteus strains.
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
• They cause misreading of mRNA by the
ribosome, leading to abnormal protein
production.
• They are bactericidal.
• To enter the bacterium, they need to be
actively transported across the cell
membrane.
• Anaerobic organisms are resistant.
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
dmage) 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 concentrationrelated.
• 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 doserelated, and are relatively rare, e.g.
allergies, eosinophilia.
Macrolides
• These are broad-spectrum antibiotics
which are relatively non-toxic but to
which the resistance develops rapidly.
• They inhibit protein synthesis by binding
to the ribosome
• They are bacteriostatic at usual doses
but bactericidal in high doses.
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, Haemophilus infections.
Macrolides (cont.)
Examples and clinical pharmacokinetics
• Newer macrolides such as
clarithromycin and azithromycin may
have fewer adverse effects. They have
immunomodulatory effects which
improves the clinical outcome.
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)
Sulfoamides and trimethoprim
• Sulfoamides are rarely used alone
today.
• Trimethoprim is not chemically related
but is considered here because their
modes of action are complementary.
Sulfoamides and trimethoprim
Mode of action
• Suphoamides are competitive
antagonists of paraaminobenzoic acid
(PABA), a precursor of folic acid that is
essential for the synthesis of purine
nucleotides for DNA and RNA.
• Animals do not manufacture folate,
depending on absorbed folate and so
are unaffected.
Sulfoamides 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
animals, as the animal enzyme is far
less sensitive than that in bacteria.
Sulfoamides and trimethoprim
Mode of action
• Individually, these drugs are
bacteriostatic; but a combination,
cotrimoxazole, of a sulphonamide
(sulphamethoxazole) and trimethoprim
is bactericidal.
Sulfoamides and trimethoprim
Clinical pharmacokinetics
• Most sulhpoamides are well absorbed
orally and they are widely distributed
including to the CNS.
• Most are excreted by the kidney
unchanged.
• They are effective against Grampositive and many Gram-negative
organism but are rarely used alone now.
Sulfoamides 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.
Sulfoamides and trimethoprim
Clinical pharmacokinetics
• It is the drug of choice for the treatment
and prevention of pneumonia caused by
Pneumocystis carinii in
immunosuppressed 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.
Sulfoamides and trimethoprim
Adverse effects
• Gastrointestinal upsets
• Less common but more serious:
-sulphoamides: allergy, rash, fever,
agranulocytosis, renal toxicity
• -trimethoprim: macrocytis anemia,
thrombocytopenia
-cotrimoxazole: aplastic anemia
Sulfoamides and trimethoprim
Drug intereactions
• Sulphoamides can decrease
metabolism of phenytoin, warfarin and
some oral hypoglycaemics, increasing
their effects.
Quinolones
• The quinolones are effective but
expensive antibiotics.
• With increased use, resistance to these
drugs is becoming more common.
• They should not be a first-line
treatment.
• They inhibit DNA gyrase and prevent
recoiling of DNA after replication.
• This is bactericidal for dividing cells.
Quinolones (cont.)
Examples and clinical pharmacokinetics
• Nalidixic acid, the first quinolone, is
used as a urinary antiseptic and for
lower urinary tract infestions, as it has
no systemic antibacterial effect.
• Ciprofloxacin is a fluoro quinolone with
a broad spectrum against Gramnegative 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
• These bind to the ribosome and interfere with
protein synthesis
• They are bacteriostatic.
• Tetracycline, oxytetracycline have short halflives.
• Doxycycline has a longer half-life and can be
given once per day.
• These drugs are only poorly absorbed.
• They bind avidly to heavy metal ions and so
absorbtion 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 concenrate 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 avoid
in renal disease)
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.
• Adverse effects
– Gastrointestinal upsets
– Allergy
– Polyneuritis
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 penicillinallergic people.
Vancomycin (cont.)
• It is given orally to treat pseudomembranous
colitis
• teicoplanin is similar but less toxic
• Adverse effect
• Its toxicity is similar to aminoglycoside and
likewise monitoring of plasma concentrations
is essential.
– Nephrotoxicity
– Ototoxicity
– Allergy
Chloramphenicol
• This inhibits bacterial protein synthesis.
• It is well absorbed and widely
distributed , including to the CNS.
• It is metabolized by glucoronidation in
the liver.
• Although an effective broad-spectrum
antibiotics, its uses are limited by its
serious toxicity.
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
Antibiotics for tuberculosis
• Tuberculosis (TB) is a major cause of
death in many parts of the world. In the
developed world, TB is currently
undergoing a resurgence, partly
because of infection in
immunosupressed patients.
• The tubercle bacillus ( Mycobacterium
tuberculosis) is intracellular organism
which may survive for months in
dormant forms.
Antibiotics for tuberculosis
• Therapy, therefore, needs to be
prolonged. Drug-resistant mutants are
often present and will proliferate if only
single drug therapy is used; hence
several drug are used simuntaneously
to avoid resistance.
• Failure of therapy is most often the
result of poor compliance with the drugs
rather than drug resistance.
Antibiotics for tuberculosis
Isoniazid
• Isoniazid is bactericidal,
• It is the most active of the antiTB drugs.
• It is well absorbed after oral
administration and widely distributed,
including into the CNS.
Antibiotics for
tuberculosis(cont.)
Isoniazid
• It is acetylated by the liver prior to
excretion, this shows genetic
polymorfism in different population.
• Acetylation ability may effect efficiency
and toxicity in an individual.
Antibiotics for
tuberculosis(cont.)
Isoniazid
– Adverse effects
– Periphetal neuropathy
Hepatitis
Rashes
Drug-induced lupus syndrome
– Drug interactions
Isoniazid is a liver enzyme
inhibitor(caution with phenytoin and
warfarin)
Antibiotics for
tuberculosis(cont.)
Rifampicin
• Rifampicin inhibits RNA syntesis in
bacteria but not in humans
• It is bactericidal.
• As well as its use in TB, it is also a
valuable broad-spectrum antibiotic but it
should avoid the contact with
meningococcal meningitis, and the
treatment of Legionella pneumoniae
and S. aureus
Antibiotics for
tuberculosis(cont.)
Rifampicin
• Adverse effects
Malaise, headache
Fever, rashes
Hepatitis
Invariability, all body secretions
becone an orange-red colour.
Antibiotics for
tuberculosis(cont.)
Pyrazinamide
• Pyrazinamide it is bactericidal.
• It is well absorbed and widely
distributed, in particular achieving good
penetration of the CNS.
• Adverse effects
Hepatitis
Hyperuricaemia
Antibiotics for
tuberculosis(cont.)
Ethambutol
• Ethambutol is bacteriostatic but its
mode of action is unknown.
• It is excreted by the kidneys.
• Adverse effects
Optic neuritis, which is dose related
and
rare
Antibiotics for
tuberculosis(cont.)
•
•
•
•
•
Other drugs
Thiacetazone
ethionamide
paraaminosalicylate
capreomycin
streptomycin
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.
• 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
Life cycle of retrovirus
course of HIV infection
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 ti 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
•
Common fungal infections
• Pityriasis
versicolor
• Candidiasis intertrigo,
paranychia
stomatitis,
vulvovaginitis
• tenia- corpis,
cruris, barbae,
capatis, pedis,
manum, unguium
•
•
•
•
•
•
•
Histoplasmosis
coccidoiomycosis
blastomycosis
cryptococcosis
aspergillosis
mucormicosis
mycetoma
FUNGAL INFECTIONS
• Incidence - increasing trend
• Slow onset
• Difficult to diagnose &
eradicate
• Long duration of therapy
FUNGAL INFECTIONS
•
•
•
•
•
•
•
SYSTEMIC
HISTOPLASMOSIS
ASPERGILLOSIS
CRYPTOCOCCOSI
BLASTOMYCOSIS
MUCORMYCOSIS
CANDIDIASIS
•
•
•
•
•
•
LOCAL
DERMATOPHYTO.
SPOROTRICHIOSI.
ZYGOMYCOSIS
CHROMOMYCOSI.
RHINOSPOIDIOSIS
ANTIFUNGAL AGENTS
SYSTEMIC ANTIFUNGALS
TOPICAL ANTIFUNGALS
Systemic antifungals
1.
2.
3.
4.
5.
GRISEOFULVIN
AMPHOTERICIN- B
FLUCYTOSINE
IMIDAZOLES
TRIAZOLES
GRISEOFULVIN
• FUNGISTATIC - MICROSPORUM,
EPIDERMOPHYTON TRICHOPHYTONS
• MECHANISM - INHIBITION OF FUNGAL
MITOSIS , DISRUPTION OF MITOTIC
SPINDLES
• KINETICS - FATTY MEAL & MICROSIZED
PARTICLES - INCREASES ABSORPTION,
DEPOSITION IN KERATIN CELLS
GRISEOFULVIN
• INDICATIONS
• TENIA CAPITIS,
CORPORICRURIS
RUBRUM
• ATHLETS FOOT
[EPIDERMOPHYTO
SIS]
• DOSE-10-15 MG/Kg
• ADRs• HEADACHE - 15%
• PERIPHERAL
NEUROPATHY
• CONFUSION
• ANTABUSE
REACTION
• PHOTO
SENSITIVITY
• drug interactions
AMPHOTERICINE B
POLYENE MACROLIDE
• MECHANISMFORMS PORES,
BINDS TO
ERGOSTEROLS,
LEAKAGES OF
MOLECULES,
OXIDATIVE
DAMAGE.
• SPECTRUMCANDIDA, CRYPT.
BLASTOMYCES,
HISTOPLASMA,
ASPERGILLUS.
• LIMITED ACTIVITY
-LEISHMANIA.
• NO ANTIBACTIRIAL
AMPHOTERICINE B
• KINETICS - NO GIT
ABSORPTION,90%
BOUND TO
PROTEINS,
UN CHANGED
ELIMINATION,
ELIMINATION
HALF LIFE-15
DAYS
• PREPARATIONS • INJ. AMPHOTER.
LIOPHILISED 50MG,[DEOXYCHO
LATE +BUFFER]
• SUV
FORMULATION
• LIPID COMPLEX
FORMULATION.
AMPHOTERICINE B
• ADRschills & fever
[saline loadingbeneficial],
bronchospasm,
azotemia,
hypokalemia, renal
toxicity, [hydration
can decrease
toxicity]
• INDICATIONSDOSE-0.5-0.6
MG/kg
• mucormicosis
• aspergillosis
• sporotrichosis
• cryptococcosis
• neutropenia
FLUCYTOSINE
• SPECTRUMCANDIDA,
CRYPTOCOCCUS,
• MOA-INHIBITS
DNA,
• KINETICSWELL ABSORBED
ORALLY, GOOD
PENETRATION IN
CSF
• ADRs - leukopenia,
enterocolitis,
azotemia in AIDS
• LIVER-HEPATITIS
FLUCYTOSINE
• INDICATIONS
• USED ALONG WITH
AMPPHOTERICIN IN
BLASTOMICOSIS
• CANDIDA OF
URINARY BLADDER
• MENINGITIS
• DOSE
• 100-150 MG/KG
IN 4 DIVIDED
DOSES
AZOLE ANTIFUNGALS
• BROAD SPECTRUM OF ACTIVITY CANDIDA, CRYPTOCOCCUS,
BLASTOMYCES, HISTOPLASMA,
COCCIDIODES , DERMATOPHYTES.
• MECHANISM OF ACTION - IMPAIR
ERGOSTEROL SYNTHESIS, IMPAIR
ATPase FUNCTION
AZOLE ANTIFUNGALS
•
•
•
•
•
IMIDAZOLES
KETOCONAZOLE
MICONAZOLE
CLOTRIMAZOLE
ECONAZOLE
• BUTOCONAZOLE
• TRIAZOLES
• TERCONAZOLE
• ITRACONAZOLE
• FLUCONAZOLE
KETOCONAZOLE
• KINETICS
BIOAVAILABILIT
DECREASED BY
ANTACIDS,H-2
BLOKERS, HALF
LIFE -DOSE
DEPENDENT,80%BOUND TO PL.
PROTIENS,
REACHES
KERATINOCYTES
• ADRs-GIT ADRs,
rashes,gynaecoma
sti
• torsades de pontes
terfenadine&astem
iz.
• Menstrual
irregularity,
• liver toxicity
• teratogenic in
KETOCONAZOLE
• DOSE- 400 Mg
daily 3-6mg /kg
CHILD,
• VULVO VAGINITIS
5 DAYS,
• OESOPHAGITIS2 WEEKS ,
• DEEP MYCOSIS6-12 MONTHS.
• EFFICACY POOR
IN Pts. WITH AIDS.
• CSF CONC-POOR,
ITRACONAZOLE
• RELATED TO
KETOCONAZOLE,
• BETTER
TOLERATED,200400MG /DAY
• D .I. WITH RIFAMP,
PHENYTOIN,CARB
AMAZEPINE
• INDICATIONHISTOPLASMOSIS,
SPIROTRICHIOSIS
ASPERGILLOSIS ,
• ADRs- GIT
DISTRESS,
HEPATITIS.
FLUCONAZOLE
• KINETICS-FULL
ABSORPTION,
• PARENTERAL
ADMINISTRATIONNO ADVANTAGE.
• CSF CONC-.60%
• RENAL
EXCRETION.
• ADRs-• GIT SYMPTOMS
• HEADACHE,RASH.
• D I -PHENYTOIN,
ZIDOVUDINE,
RIFAMPIN
FLUCONAZOLE
• CANDIDIASIS-50-100MG OROPHARYNGEAL
• EOSOPHAGIAL-100-200MG/DAY
• VAGINAL- SINGLE DOSE-150MG
• CRYPTOCOCCOSIS-200MG /DAY
• DRUG OF CHOICE IN MENINGITIS
DUE TO COCCIDIOIDALS
• CHILDREN-3-6 MG/KG
TOPICAL ANTIFUNGAL
• AZOLES-CLOTRIMAZOLE,ECONAZOLE,
MICONAZOLE,TERCONAZOLE
.BUTOCONAZOLE
• CICLOPIROX OLAMINE
• HALOPROGIN,BENZOIC+SALICYLIC,TOL
NAFTATE,TERBINAFINE, NYSTATIN
• UNDECYLENIC ACID,
CLOTRIMAZOLE
• fungicidal,1% cream,lotion,vaginal
cream
• 100 mg -vaginal tab-o.d-7 days
• cure for dermatophytes
,vulvovaginitis,
• cut.candidiasis-80% success
• ADRs-erythema,pruritis,burning
sensations
Local antifugals
• MICONAZOLE CREAM,POWDER,LOTION
,100MG PESSARIES,
• TENIASIS,VULVOVAGINITIS,-80%
SUCCESS.
• TERCONAZOLE BUTOCONAZOLECICLOPIROX OLAMINE, HALOPROGIN ,
• TOLNAFTATE-TRICHOPHYTONS AND
MICROSPORUM.
• TERBINAFINE CREAM
Local antifugals
• DOSE- 400 Mg
daily 3-6mg /kg
CHILD,
• VULVO VAGINITIS
5 DAYS,
• OESOPHAGITIS2 WEEKS ,
• DEEP MYCOSIS6-12 MONTHS.
• EFFICACY POOR
IN Pts. WITH AIDS.
• CSF CONC-POOR,
NYSTATIN
• USEFUL ONLY FOR CANDIDIASISCUTANIOUS, ORAL OR VAGINAL
• 100,000 UNITS/GM CREAM,POWDER.
• VAGINAL TAB-TWICE A DAY-2WEEKS
• ADRs- RARE
Other local antifugals
• BENZOIC ACID 6% &SALICYLIC
ACID 3%-WHITFIELD OINTMENTTINEA PEDIS. KERTOLYTIC TOO,
• POTASSIUM IODIDE-1 GM/MLCUTANIOUS SPOROTRICHIOSIS
• GENTIAN VOILET,IODINE,SULPHUR