Co-trimoxazole

1. SULFONAMIDES
COTRIMOXAZOLE &
URINARY ANTISEPTICS
Dr. Jeena M Joy
BIMS,Belagavi

2. QUESTIONS ASKED IN UNIVERSITY EXAMS
• Topically used sulphonamides. (5mark)
• Two side effects & two clinical uses of sulphonamides.
• Why sulphonamides are less effective in presence of pus?
• Sequential blockage (5marks)
• Give two examples for sequential blockage.
• Rationale for combining trimethoprim & sulfamethoxazole.
• MOA & indications for cotrimoxazole.
• Drugs used in UTI.

3. TOPIC CONTENT SLIDE NUMBER
SULFONAMIDES INTRODUCTION 5
CHEMISTRY 6
CLASSIFICATION 7
MECHANISM OF ACTION 8-9
PHARMACOKINETICS 10
ANTIMICROBIAL SPECTRUM 11
MECHANISM OF RESISTANCE 12
USES 13
ADVERSE EFFECTS 14
INDIVIDUAL DRUGS 15-19
COTRIMOXAZOLE INTRODUCTION 20
INDIVIDUAL DRUGS 21
MECHANISM OF ACTION 22
WHY THE DRUGS ARE COMBINED? 23
BACTERIAL RESISTANCE 24
ADVERSE EFFECTS 25

4. TOPICS CONTENT SLIDE NUMBER
COTRIMOXAZOLE C/I & INTERACTION 26
USES 27
URINARY ANTISEPTICS INTRODUCTION 28
CLASSIFICATION OF DRUGS USED IN UTI 29
INDIVIDUAL DRUGS 30-32

5. INTRODUCTION SULFONAMIDES
 Discovered by Domagk, who investigated use of dyes as antibiotics .
 He discovered use of Prontosil Red effective against streptococcus
in mice, found to be highly effective & treated his own daughter with
it from Streptococcal Septicemia.
In 1937, it was found that prontosil was broken down in body to
sulfonamides with was the active antibacterial agent.
First antimicrobial agent effective against pyogenic bacterial
infection.
Act by inhibiting bacterial folate synthase .

6. CHEMISTRY
All sulphonamides are derivatives of sulfanilamides.
4
1
SULFANILAMIDE

7. CLASSIFICATION
TYPES DOA DRUGS
SHORT ACTING 4-8 HOURS Sulfadiazine
INTERMEDIATE ACTING 8-12 HOURS Sulfamethoxazole
LONG ACTING >7 DAYS Sulfadoxine
Sulfamethopyrazine
SPECIAL PURPOSE Sulfacetamide Sod.*
Sulfasalazine#
Silver Sulfadiazine*
Mafenide*
*Topical #Orally nonabsorbable

8. MECHANISM OF ACTION
1. Folic acid is essential for nucleic acid synthesis in bacteria.
2. Few bacteria produce their own folic acid
from PABA & cannot take folic acid from surrounding media.
3. Sulfonamides are structural analogues of PABA
and inhibit bacterial folate synthase enzyme.
a. It competitively inhibits union of PABA with pteridine residue to form
dihydropteroic acid which conjugates with glutamic acid to form dihydrofolic
acid. No folic acid No protein synthesis
No cell multiplication
b. It get incorporated to form an altered folic acid that is
metabolically injurious.
/folate
synthase
Dihydrofolate
Reductase
Dihydrofolate
synthase

9. MOA
4. Humans absorb folic acid directly from diet, hence sulphonamides are
selectively toxic to bacteria only and not to host cell
5.Pus and tissue extracts contain PABA, purines and thymidine
which decreases bacterial requirement for folic acid and
antagonizes sulphonamide action.

10. PHARMACOKINETICS
A- Rapidly & completely absorbed orally
D- Widely distributed in the body- enters serous cavities easily
Crosses BBB and placenta
Extend of plasma protein binding differs- Longer action are highly protein
bound.
M-Acetylation at N4 in liver. Acetylated derivative is inactive, but.It precipitates
& cause crystalluria in acidic urine -Renal toxicity.
E-By kidney via glomerular filtration. More lipid-soluble members are highly
reabsorbed (Longer acting agents).

11. ANTIBACTERIAL SPECTRUM
• Primerly bacteriostatic. (Both GPB &GNB)
• Bactericidal concentration may be attained in urine
• Anaerobic bacteria not susceptible
Sensitive organisms
Strept. pyogenes
H.Inflenzae & H.Ducreyi
Caly. Granulomatis( causing Donovaniosis)
Vibrio Cholerae
Chlamydiae
Actinomyces & Nocardia
Toxoplasma

12. MECHANISM OF ANTIBACTERIAL RESISTANCE
Resistance developed by
Staph. Aureus
Gonococci
Meningococci
Pneumococci
E.Coli
Shigella
Anaerobes
 Organism produce increased amount of PABA
or
 Their folate synthase enzyme has low affinity
for sulphonamides.
or
 Adopt alternative pathway for folate
metabolism

13. USES
• Systemic use of sulphonamides alone is obsolete now.
• Combined with trimethoprim (as cotrimoxazole) sulfamethoxazole is
used for many bacterial infections
• Along with pyrimethamine used for malaria & toxoplasmosis.
• Ocular sulfacetamide sod is a cheap alternative in trachoma/inclusion
conjunctivitis.
• Topical silver sulfadiazine or mafenide are use for burns patients.

14. ADVERSE EFFECTS
• Nausea, vomiting & epigastric pain.
• Crystalluria is dose related, but infrequent now.
• Hepatitis, unrelated to dose, occurs in 0.1 % patients.
• Haemolysis can occur in G-6-PD deficient individuals with high doses of
sulfonamides.
• Hypersensitivity in 2-5%cases-rashes, urticaria and drug fever. Stevens-Johnson
syndrome and exfoliative dermatitis are serious reactions reported with the long
acting agents.
• Kernicterus in premature newborns.

15. FEW FEATURES OF INDIVIDUAL DRUGS
Sulfamethoxazole –
Combined with trimethoprim (cotrimoxazole)
 High fraction is acetylated-crystalluria can occur.

16. Sulfadoxine, Sulfamethopyrazine-
1. Combination with pyrimethamine in the treatment of CQ resistant P. falciparnm malaria.
2. Pneumocysris jiroveci pneumonia in AIDS patients
3. Toxoplasmosis.

17. Sulfacetamide sod.
• After topical instillation it attains high concentrations in anterior segment & aqueous humour
• Used for ocular infections due to susceptible bacteria and chlamydia, including ophthalmia
neonatorum .

18. Mafenide
Used topically as 1% cream
Active in the presence of pus and against Pseudomonas & clostridia.
Used for burns dressing

19. Silver sulfadiazine
Used topically as 1% cream,
Active against a large number of bacteria (even Pseudomonas) and fungi.
 It slowly releases silver ions which appear to be largely responsible for the
antimicrobial action.
It is considered to be one of the most effective drugs for preventing infection of
burnt surfaces and chronic ulcers.
Local side effects are-burning sensation and itch. Released sulfadiazine may be
absorbed systemically and produce its own adverse effects.

20. INTRODUCTION COTRIMOXAZOLE
• Introduced in 1969
• Rational fixed dose combination of trimethoprim & sulfamethoxazole
in the dose ratio 1: 5.
• Bacteriocidal

21. TRIMETHOPRIM SULFAMETHOXAZOLE
Diaminopyrimidine related to the antimalarial
drug pyrimethamine
Intermediate acting PABA structural analogue
Selectively inhibits bacterial dihydrofolate
reductase
Inhibit bacterial folate synthase.
Bacteriostatic Bacteriostatic
Pharmacokinetics:
A-More rapidly absorbed(more lipid soluble)
D-40% plasma protein bound, wider VOD* and
attain lower plasma concentration.
M-Partly metabolized in liver.
E-Excreted in urine
Pharmacokinetics:
A-Rapidly absorbed
D-65% plasma protein bound
M-Acetylation in liver
E-Renal excretion by glomerular filtration

22. MECHANISM OF ACTION
• Sequential blockage of bacterial folate metabolism.
SULFAMETHOXAZOLE
TRIMETHOPRIM
DHFRase

23. WHY ARE THESE DRUG COMBINED?
1. Both compounds have similar half life (10hours)
2. Both are bacteriostatic, but the combination in bacteriocidal.
3. MIC of each compound reduced by 3-6 times in concentration ratio 20:1
(sulfa. : tri.)
4. Have wider antibacterial spectrum than when used as individual drugs.
5. Delays the development of bacterial resistance .
6. Trimethoprim being more lipid soluble, easily enter tissues ; cross BBB
and placenta unlike sulfamethoxazole

24. BACTERIAL RESISTANCE
• Plasmid mediated acquisition of a DHFRase having lower affinity for
the inhibitor.

25. ADVERSE EFFECTS
• All A/E seen with sulfonamides can occur.
• Nausea, vomiting, stomatitis, headache and rashes .
• Folate deficiency (megaloblastic anaemia) is infrequent, occurs only in patients with
marginal folate levels.
• AIDS patients with Pneumocystis jiroveci infection – fever, rash and bone marrow
hypoplasia
• Uremia- In renal disease .

26. CONTRAINDICATION
• In pregnancy-theoretical teratogenic risk, neonatal haemolysis and
methaemoglobinaemia can occur if it is given near term.
• The elderly –can cause bone marrow toxicity.
• Diuretics given with cotrimoxazole have produced a higher incidence
of thrombocytopenia
INTERACTION

27. • Pneumocystis jiroveci infection in AIDS
• Urinary tract infection-Acute uncomplicated and in chronic/recurrent
cases/prostatitis
• Respiratory tract infection-including chronic bronchitis, fascio maxillary
infection and otitis media by GP cocci.
• Bacterial diarrhoea and dysentery- In empirical therapy of infective diarrhoes.
• Chancroid
• Typhoid-Seldom used now.
USES

28. INTRODUCTION URINARY ANTISEPTICS
UTIs are prevalent in women of child-bearing age and in the elderly population.
E. coli is the most common pathogen, causing about 80% of uncomplicated upper
and lower UTIs. Staphylococcus saprophyticus is the second most common
bacterial pathogen causing UTIs.
Urinary antiseptics are oral drugs that are rapidly excreted into the urine and act
there to suppress bacteriuria.
Eg: Nitrofurantoin, Nalidixic acid and Methenamine mandelate.
These drugs lack systemic antibacterial effects but may be toxic.

29. CLASSIFICATION OF DRUGS USED IN UTI
Bacteriostatic agents Sulphonamides
Doxycycline
Nitrofurantoin
Bacteriocidal agents Cotrimoxazole
Ampicillin
Extended spectrum penicillin
Aminoglycosides
Fluroquinolones
Cephalosporins
Azithromycin

30. A. Nitrofurantoin
Active against many urinary tract pathogens (but not Proteus or Pseudomonas) and
resistance emerges slowly.–Not recommended for acute UTI
Poor tissue levels due to high plasma protein binding. ( Unsuitable for renal parenchymal
infection)
Given in the dose od 50-100mg/day for several weeks to months in chronic suppressive
therapy
Excreted mainly by tubular filtration & secretion- Toxic in case of kidney damage.
Use:1. Infection when other more commonly used drugs are resistant
2.Mixed infection
3.Infection accompanied by obstructive uropathy
Adverse effects : gastrointestinal irritation, skin rashes, phototoxicity, neuropathies, and
hemolysis in patients with G6PD deficiency.

31. B. Nalidixic Acid
This quinolone drug acts against many gram-negative organisms (Ecoli, shigella and
many strains of Proteus) by mechanisms that involve inhibition of bacterial DNA gyrase.
Rapid resistance can develop.
The drug is absorbed orally and 80% is excreted in the urine within 8hrs, partly
unchanged active form 20% and partly as the inactive glucuronide.
Nitrofurantoin shows therapeutic antagonism with nalidixic acid
Toxic effects : Allergic reactions, nausea, vomiting & diarrhoes. In children –
neurological toxicity( headache, drowsiness, vertigo, visual disturbances, and seizures. )

32. C. Methenamine Mandelate
Salt of mandelic acid and methenamine.
Rapidly absorbed from GIT and excreted in urine.
In pH of less than 5.5 methenamine liberate formaldehyde which act against many gram negative
pathogens & C.albicans.
Only used in chronic suppressive therapy.
A/E- Gastric discomfort, Large dose can cause acute inflammation of urinary tract.
Interaction: Sulphamethizole form insoluble complex with formaldehyde and so never used
together.

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