2. • To be covered;
• Sulphonamides
• Chloramphenical
• Azoles
• Oxazolidinones
3. ANTIFOLATE DRUGS
• Sulfonamides
• Antimicrobial Activity
• Because sulfonamides are structural analogs of
PABA, they inhibit dihydropteroate synthase and
folate production.
• Sulfonamides inhibit both gram-positive and gram-
negative bacteria, nocardia, Chlamydia trachomatis,
and some protozoa.
• Some enteric bacteria, such as Escherichia coli,
klebsiella, salmonella, shigella, and enterobacter, are
also inhibited
• Activity is poor against anaerobes.
4. SULFONAMIDES
• These are among the first antibacterial drugs to
be discovered in 1935.
• Examples of sulphonamides include:
sulphadiazine, Sulfisoxazole, sulphadimidine,
Sulfasazine, sulfametopyrazine,
sulfamethoxazole, and Sulphaloxate among
others.
• Combination of a sulfonamide with an inhibitor
of dihydrofolate reductase (trimethoprim or
pyrimethamine) provides synergistic activity
because of sequential inhibition of folate
synthesis
5. Pharmacokinetics
Sulfonamides can be divided into three major groups:
(1) oral, absorbable;
(2) oral, nonabsorbable;
(3) topical.
The oral, absorbable sulfonamides can be classified as short-
, intermediate-, or long-acting on the basis of their half-lives
absorbed from the stomach and small intestine and
distributed widely to tissues and body fluids (including the
central nervous system and cerebrospinal fluid), placenta,
and fetus.
Sulfonamides and inactive metabolites are then excreted
into the urine, mainly by glomerular filtration.
In significant renal failure, the dosage of sulfonamide must
be reduced.
6. Clinical Uses
• Sulfonamides are infrequently used as single
agents.
• Many strains of formerly susceptible species,
including meningococci, pneumococci,
streptococci, staphylococci, and gonococci, are
now resistant.
• The fixed-drug combination of trimethoprim-
sulfamethoxazole is the drug of choice for
infections such as Pneumocystis jiroveci (formerly
P carinii) pneumonia, toxoplasmosis, nocardiosis,
and occasionally other bacterial infections.
7. Adverse Reactions
• The most common adverse effects are fever,
skin rashes, exfoliative dermatitis,
photosensitivity, urticaria, nausea, vomiting,
diarrhea, and difficulties referable to the
urinary tract .
• Stevens-Johnson syndrome, although relatively
uncommon (ie, < 1% of treatment courses), is a
particularly serious and potentially fatal type of
skin and mucous membrane eruption
associated with sulfonamide use.
8. • Sulphonamides can also cause mental
depression, cyanosis, bone marrow depression,
hepatitis, convulsions and ataxia.
• A serious adverse effect called crystalluria may
occur in which case you should stop the
treatment.
• This is due to precipitation of acetylated
sulphonamide metabolite in urine.
9. • A lot of resistance for all other sulphonamides
has developed, particularly for systemic use.
• The mechanism for development of resistance is
production of altered dihydropteroate
synthetase or by overproduction of para-
aminobenzoic acid which overcomes
sulphonamide inhibition.
• Other than co-trimoxazole which is used for
systemic effects, most other sulphonamides are
used for topical purposes.
10. TRIMETHOPRIM & TRIMETHOPRIM-
SULFAMETHOXAZOLE MIXTURES
• Trimethoprim, selectively inhibits bacterial
dihydrofolic acid reductase, which converts
dihydrofolic acid to tetrahydrofolic acid, a step
leading to the synthesis of DNA.
• Trimethoprim or pyrimethamine in combination
with a sulfonamide blocks sequential steps in folate
synthesis, resulting in marked enhancement
(synergism) of the activity of both drugs.
• The combination often is bactericidal, compared
with the bacteriostatic activity of a sulfonamide
alone.
11. Clinical Uses
• ORAL TRIMETHOPRIM
• Trimethoprim can be given alone (100 mg
twice daily) in acute urinary tract infections.
• Most community-acquired organisms tend to
be susceptible to the high concentrations that
are found in the urine
12. ORAL TRIMETHOPRIM-
SULFAMETHOXAZOLE (TMP-SMZ)
• A combination of trimethoprim-sulfamethoxazole
is effective treatment for a wide variety of
infections including P jiroveci pneumonia,
shigellosis, systemic salmonella infections, urinary
tract infections, prostatitis, and some non-
tuberculous mycobacterial infections.
• Sulphamethoxazole (400mg) plus trimethoprim
(80gms) makes co-trimoxazole (septrin).
13. ORAL TRIMETHOPRIM-SULFAMETHOXAZOLE
• One double-strength tablet ( trimethoprim 160 mg
plus sulfamethoxazole 800 mg)
• It is given every 12 hours is effective treatment for
urinary tract infections and prostatitis.
• One half of the regular (single-strength) tablet given
three times weekly for many months may serve as
prophylaxis in recurrent urinary tract infections of
some women.
• Infections with P jiroveci and some other pathogens
can be treated orally with high doses of the
combination (dosed on the basis of the trimethoprim
component at 15–20 mg/kg).
• This can be prevented in immunosuppressed
patients by one double-strength tablet daily or three
times weekly.
14. INTRAVENOUS TRIMETHOPRIM-SULFAMETHOXAZOLE
• A solution of the mixture containing 80 mg
trimethoprim plus 400 mg sulfamethoxazole
per 5 mL diluted in 125 mL of 5% dextrose in
water can be administered by intravenous
infusion over 60–90 minutes.
• It is the agent of choice for moderately severe
to severe pneumocystis pneumonia.
15. • Others are used for topical applications for
prophylaxis/treatment of Burns; legs ulcers
pressure sores etc because of their wide
antibacterial spectrum.
16. Adverse Effects
• Trimethoprim produces the predictable
adverse effects of an anti-folate drug,
especially megaloblastic anemia, leukopenia,
and granulocytopenia.
• The combination trimethoprim-
sulfamethoxazole may cause all of the
untoward reactions associated with
sulfonamides.
17. Drug interactions
Several drugs interact with sulphonamides such
interactions include:
• Sulphonamides displace warfarin from protein
binding sites and also inhibit its metabolism,
hence warfarin toxicity may result.
• Sulphonamides inhibit metabolism of phenytoin,
hence increase the chances of phenytoin toxicity.
• Procaine antagonizes the effects of
sulphonamides because it’s an ester of PABA.
18. CHLORAMPHENICOL
• It is soluble in alcohol but poorly soluble in
water.
• Chloramphenicol succinate, which is used for
parenteral administration, is highly water-
soluble.
• It is hydrolyzed in vivo with liberation of free
chloramphenicol.
19. Pharmacokinetics
• The usual dosage of chloramphenicol is 50–
100 mg/kg/d.
• After oral administration, crystalline
chloramphenicol is rapidly and completely
absorbed.
• A 1-g oral dose produces blood levels between
10 and 15 mcg/mL.
• Chloramphenicol palmitate is a prodrug that is
hydrolyzed in the intestine to yield free
chloramphenicol.
20. Antimicrobial Activity
• Chloramphenicol is a potent inhibitor of microbial
protein synthesis.
• It binds reversibly to the 50S subunit of the
bacterial ribosome and inhibits the peptidyl
transferase step of protein synthesis.
• Chloramphenicol is a bacteriostatic broad-
spectrum antibiotic that is active against both
aerobic and anaerobic gram-positive and gram-
negative organisms.
21. Clinical Uses
• Because of potential toxicity, bacterial resistance,
and the availability of many other effective
alternatives, chloramphenicol is rarely used.
• It may be considered for treatment of serious
rickettsial infections such as typhus and Rocky
Mountain spotted fever.
• It is an alternative to a B-lactam antibiotic for
treatment of meningococcal meningitis occurring in
patients who have major hypersensitivity reactions
to penicillin or bacterial meningitis caused by
penicillin-resistant strains of pneumococci.
• Chloramphenicol is used topically in the treatment of
eye infections because of its broad spectrum and its
penetration of ocular tissues and the aqueous humor
22. Adverse Reactions
• Gastrointestinal disturbances
• Adults occasionally develop nausea, vomiting,
and diarrhea. This is rare in children.
• Oral or vaginal candidiasis may occur as a
result of alteration of normal microbial flora
23. BONE MARROW DISTURBANCES
• Chloramphenicol commonly causes a dose-
related reversible suppression of red cell
production at dosages exceeding 50 mg/kg/d
after 1–2 weeks.
• Aplastic anemia, a rare consequence (1 in 24,000
to 40,000 courses of therapy) of chloramphenicol
administration by any route, is an idiosyncratic
reaction unrelated to dose, although it occurs
more frequently with prolonged use.
• It tends to be irreversible and can be fatal.
24. TOXICITY FOR NEWBORN INFANTS
• Newborn infants lack an effective glucuronic
acid conjugation mechanism for the
degradation and detoxification of
chloramphenicol.
• Consequently, when infants are given dosages
above 50 mg/kg/d, the drug may accumulate,
resulting in the gray baby syndrome, with
vomiting, flaccidity, hypothermia, gray color,
shock, and collapse.
25. Azoles
• These include several classes of drugs e.g.
Metronidazole and tinidazole which have anti
bacterial and anti protozoal activity.
• Others are fluconazole, itraconazole,
clotrimazole, econazole, ketoconazole, and
miconazole which are anti fungal drugs.
• Others include mebendazole, thiabendazole
which are anti helminthic drugs.
26. Metronidazole
• It’s very active against anaerobic bacteria and
also protozoa
Pharmacodynamics
• Metronidazole is converted to an active form by
reduction of its nitro group, which binds to DNA
and prevents nucleic acid formation which
consequently interferes with bacterial replication.
• Hence, it is bacteriostatic.
27. Pharmacokinetics
• Well absorbed after oral or rectal
administration.
• Distributions are wide and metabolism in the
liver.
• It is excreted in urine partly unchanged and
partly as metabolite.
• Half life is 8 hrs
28. Indications
• Metronidazole is active against anaerobic bacteria and
protozoa.
• It is used for treatment of sepsis caused by organisms like
Bacteroids species and anaerobic cocci,
• Intra-abdominal infections and septicemia, wounds and
pelvic infections, osteomylits, and infections of the brain
/lungs.
• Also used in prevention of postoperative infections
especially after bowel surgery, antibiotic- related colitis e.g.
pseudomembraneous colitis, amoebiasis (entamoeba
histolytica) whether in symptomless carriers and cysts or
intestinal and extra-intestinal infections.
• Other indications include Giardias, acute ulcers, gingivitis
and dental infections, and Aerobic vaginosis.
29. Dosage and routes of administration-
• Established Aerobic infections are usually treated
for 7 days.
• The dose by mouth is 800gm initially for 3 days
then 400gm every 4 days or 500gm every 8 hours
or just 400gms 8 hrs for 7 days.
• By rectum: 1gm every 8hours for 3 days, then
1gm 12 hourly.
• By IV infusion: 500gm every 8 hours. In children:
7.5mg per 1kg every 8 hours by any route.
30. • For surgical prophylaxis: By mouth- 400mg
every 8 hrs started 24 hrs before surgery then
continued postoperative by IV infusion by
rectum until oral administration can be
resumed for 2 days.
31. Unwanted effects:
• Vomiting and nausea, diarrhea, furred tongue,
unpleasant metallic taste in the mouth,
Headache, dizziness and ataxic,-Rashes, urticaria,
angiodema, peripheral neuropathy if treated is
prolonged.
• Epileptiform seizure if the dose is high,
Disulfiram-like effect occurs with alcohol
metronidazole inhibits aldehyde dehydrogenate
which metabolises alcohol.
• These effects can be lethal-e.g. tachycardia,
diaphoresis, vomiting, nausea and arrhythmias.
32. OXAZOLIDINONES
• Linezolid is a member of the oxazolidinones, a
new class of synthetic antimicrobials.
• It is active against gram-positive organisms
including staphylococci, streptococci,
enterococci, gram-positive anaerobic cocci, and
gram-positive rods such as corynebacteria and
Listeria monocytogenes.
• It is primarily a bacteriostatic agent except for
streptococci, for which it is bactericidal.
33. Linezolid
• The principal toxicity of linezolid is
hematologic—reversible and generally mild.
• Thrombocytopenia is the most common
manifestation (seen in approximately 3% of
treatment courses), particularly when the
drug is administered for longer than 2 weeks.
34. Linezolid
• Linezolid is 100% bioavailable after oral
administration and has a half-life of 4–6 hours.
• It is metabolized by oxidative metabolism,
yielding two inactive metabolites.
• Linezolid is approved for vancomycin-resistant E
faecium infections; nosocomial pneumonia;
community-acquired pneumonia; and skin
infections, complicated or uncomplicated.
• It should be reserved for treatment of infections
caused by multidrug-resistant gram-positive
bacteria.
35. GLYCOPEPTIDE ANTIBIOTICS
• Vancomycin
• With the single exception of flavobacterium, it
is active only against gram-positive bacteria,
particularly staphylococci.
• Vancomycin is a glycopeptide of molecular
weight 1500.
• It is water soluble and quite stable.
36. Antibacterial Activity
• Vancomycin is bactericidal for gram-positive
bacteria in concentrations of 0.5–10 mcg/mL.
• Most pathogenic staphylococci, including those
producing lactamase and those resistant to
nafcillin and methicillin, are killed by 2 mcg/mL
or less.
37. Pharmacokinetics
• Vancomycin is poorly absorbed from the
intestinal tract and is administered orally only for
the treatment of antibiotic-associated
enterocolitis caused by C difficile.
• Parenteral doses must be administered
intravenously.
• The drug is widely distributed in the body
• In the presence of renal insufficiency, striking
accumulation may occur.
• In functionally anephric patients, the half-life of
vancomycin is 6–10 days.
38. Adverse Reactions
• Vancomycin is irritating to tissue, resulting in
phlebitis at the site of injection.
• Chills and fever may occur.
• Ototoxicity is rare
• Nephrotoxicity is uncommon with current
preparations.
39. CARBAPENEMS
• The carbapenems are structurally related to b-
lactam antibiotics
• Doripenem, ertapenem, imipenem, and
meropenem
40. Imipenem
• Imipenem has a wide spectrum with good
activity against many gram-negative rods,
including P aeruginosa, gram-positive
organisms, and anaerobes.
• Enterococcus faecium, methicillin-resistant
strains of staphylococci, Clostridium difficile are
resistant.
• Imipenem is inactivated by dehydropeptidases in
renal tubules, resulting in low urinary
concentrations.
• Consequently, it is administered together with an
inhibitor of renal dehydropeptidase,
cilastatin, for clinical use.(TIENAM)
41. CARBAPENEMS
• Doripenem and meropenem are similar to
imipenem but have slightly greater activity
against gram-negative aerobes and slightly less
activity against gram-positives
• They are not significantly degraded by renal
dehydropeptidase and do not require an
inhibitor.
42. CARBAPENEMS
• Carbapenems penetrate body tissues and fluids
well, including the cerebrospinal fluid.
• All are cleared renally, and the dose must be
reduced in patients with renal insufficiency.
• The usual dosage of imipenem is 0.25–0.5 g given
intravenously every 6–8 hours (half-life 1 hour).
43. Adverse effects
• The most common adverse effects of
carbapenems—which tend to be more
common with imipenem—are nausea,
vomiting, diarrhea, skin rashes, and reactions
at the infusion sites.
• Excessive levels of imipenem in patients with
renal failure may lead to seizures.
