1.
Primarily bacteriostatic:
Inhibit growth of
organisms :
e.g.,sulfonamides
and body’s immune system
eliminates the pathogens.
Not used in
immunocompromised patients
or in life threatening infections.
Primarily bactericidal:
kill microorganisms;
e.g.- β lactams, quinolones.
Used in the treatment of meningitis,
endocarditis, and to treat bacteremia
in neutropenic patients.
ANTIBIOTICS
ANTIMICROBIAL AGENTS

2.
Antimicrobial drugs
Antibiotics
Antibiotics are chemical substances produced by bacteria, fungi,
actinomyces that suppress the growth of other microorganisms and may
destroy them, e.g. penicillin, streptomycin, etc.
Antimicrobials include synthetic compounds, e.g. quinolones,
sulfonamides and natural compounds, e.g penicillin.

3.
COMPETENCY &
SPECIFIC LEARNING OBJECTIVES
COMPETENCY - PH1.42, PH1.43
The student should able to
Describe the Antibacterial spectrum, MOA, resistance,
Uses & adverse effects of Sulphonamides and
Cotrimoxazole

4.
SPECIFIC LEARNING OBJECTIVES
At the end of the class, the student should able to:
Classify Sulphonamides with examples.
Describe the mechanism, spectrum, resistance and
pharmacokinetics of Sulphonamides.
Describe the clinical uses, adverse effects, interactions and
contraindications of Sulphonamides.
Mention the constituents of Cotrimoxazole and describe its
mechanism, spectrum, uses, adverse effects and
contraindications.

5.
Introduction
• The first antimicrobial agent used systemically effective against
pyogenic bacterial infections
PRONTOSIL RED
A dye used to treat experimental
streptococcal infections in mice
(Sulfonamido – chrysoidine)
Was found to be HIGHLY EFFECTIVE
Used to cure infants with staphylococcal septicemias
LATER - Puerperal sepsis & Meningococcal infection

6.
• In 1937: Prontosil was broken down in the body to release
sulfanilimide
The active
antibacterial agent
GERHARD DOMAGK -- PRONTOSIL DYE.
was awarded Nobel prize in medicine -- 1938

7.
SULFONAMIDES
Compounds with sulfonamido (So2NH2) group
PARA AMINO BENZENE

8.
• After this, a large number of synthetic sulfonamides were
produced
• Bacteriostatic
• Extensively used in following years to come
HOWEVER
Use of sulfonamides became limited
Cont……
Rapid emergence of
BACTERIAL RESISTANCE
Availability of safe &
more effective drugs

9.
Components:
•p-aminobenzene ring
•N1 substitution – solubility, potency
and PK property
•N4 free amino group – required for
antibacterial activity
Structure

10.
Structure
*Structural Analogue of
PABA*

11.
CLASSIFICATION
(1) Short acting : (4-8 HOURS) sulfadiazine.
(2) Intermediate acting : (8-12 HOURS) sulfamethoxazole.
(3) Long acting : (~7 days) sulfamethopyrazine, sulfadoxine
(4) Special purpose sulfonamides : Sulfasalazine, Mefenide , silver
sulfadiazine, sulfacetamide sodium.

12.
FOLIC ACID
PURINE PRECURSORS PYRIMIDINE PRECURSORS
NUCLEOTIDES
DEOXYNUELEOTIDES
DNA
RNA
PROTEIN SYNTHESIS

13.
Mechanism of Action
* Humans absorb folic acid directly from diet,
hence sulfonamides are SELECTIVELY TOXIC
TO THE BACTERIA ONLY and not to the host
cells!

14.
PABA pteridine residue
dihydropteoric acid
Dihydrofolic acid
Tetrahydrofolic acid
Dihydropteroate synthase
SULFONAMIDE
Dihydrofolate reductase
TRIMETHOPRIM
Glutamic acid

15.
Antibacterial Spectrum
•Primarily bacteriostatic
•Bactericidal concentrations can be attained
in the URINE
•Effective against Gram positive +Gram
negative bacteria

16.
ANTIBACTERIAL SPECTRUM
Gram Positive, Gram Negative and certain Chlamydia.
(a) Streptococci, staphylococci(some), gonococci, pneumococci &
meningococci.
strep.fecalis – resistant.
(b) Clostridia, B.anthracis, H. influenza, H.ducreyi, vibrio, E.coli.
Pasoturella pestis, shigella, Donovania granulomatosis.
(c) Nocardia, actinomyces, toxoplasmosis & malaria.
(d) Chlamydia - LGV, psittacosis & trachoma.

17.
BACTERIOSTATIC
high concentrations - urinary tract - BACTERIOCIDAL

18.
RESISTANCE
Gonococci
Pneumococci
Staph.aureus
Meningococci
E.coli
Shigella
Strepto. pyogenes (some).
(1) Increased production of PABA.
(2) Folate synthetase has low affinity for sulfonamides.
(3) Adopt alternate pathway – folate metabolism.

19.
PHARMACOKINETICS
Rapid absorption from GIT OBA 10 – 95%
Bound to albumin – 50%
Differ with various compounds.
The importance are
(1) Bound sulfa – bacterial activity
Tissue concentration LESS
BBB concentration
(2) Bound sulfa not available for renal excretion – Long acting.
(3) Not effective for acute infections.

20.
Penetrate into aqueous humour.
Peak plasma concentration – 2 to 4 hrs.
CONCENTRATED IN KIDNEYS
Excretion – by Acetylation Rapid - 62 – 90%
Slow - 40 – 53%
THE ACETYLATE FORM
No antibacterial activity
Possess toxic potentialities of parent drug.
Certain products – poorly soluble in acidic urine
- crystalluria
- Renal complications.
Elimination – Glomerular filteration.
Sweat, bile & saliva- small amounts.

21.
SULFADIAZINE
Rapid absorption / Excretion
50% plasma protein bound
20 – 40% acetylated
Acetylated compound - less soluble in urine
- Crystalluria
Good CSF penetration
Dose 500 mg – 2 gms TDS / QID.

22.
(2) SULFAMETHOXAZOLE
10 – 12hrs.
Intermediate acting
With trimethoprim
Acetylation – High crystalluria
Dose – 1 gm BD.
(3) SULFAMOXOLE
Dose 0.5 – 1gm BD.

23.
(4) SULFADOXINE
SULFAMETHOPYRAZINE
Ultra long acting
DOA > 1 week.
not suitable for acute pyogenic infections
With pyrimethamine – malaria,
pneumocystis jiroversi – AIDS,
Toxoplasmosis.

24.
(5) SULAFACETAMIDE SODIUM
Highly soluble
Topical – eye infections (Chlamydia ophthalmia neonatorum)
10% , 20% 30% eye drops. 6% eye ointment.
(6)SULFASALAZINE (5ASA & sulfapyridine)
In ulcerative colitis
Rheumatoid arthritis.

25.
MEFENIDE
Not a typical sulfonamide.
Only topically – Burn dressing
Burning sensation & severe pain absorbed from raw surface.
Mefenide & metabolites – CA inhibitors
alkalinization of urine – Acidosis
Hyperventilation
Allergy common.

26.
(8) SILVER SULFADIAZINE
Topical 1% cream.
Against bacteria, fungi
Active against other sulfa resistant strains (Pseudomonas)
MOA - Release silver ions
Antibacterial action
For burn dressing
For chronic ulcers.
Local effects – burning sensation, Itching

27.
ADVERSE EFFECTS
(1) Hypersensitivity Reactions
Allergy - Common.
Drug fever, rash, eosinophillia.(rash associated with conjunctivitis).
Severe exfoliative dermatitis, high fever – RARE
Serum sickness
Uncommon – cutaneous photosensitization
Fatal necrotizing arteritis
Acute toxic hepatitis
fatal hepatic necrosis (Rare).
Toxic nephrosis
Acute hemolytic anaemia.

28.
Stevens Johnsons syndrome – long acting sulfonamides
Exudative form of erythema multiforme.
Skin & mucus membrane lesions
Rare, self limiting
fatal – occasionally
Cross sensitivity - Common
(2) GIT – nausea, vomiting

29.
(3) Renal toxicity + Crystalluria
drug is precipitated in acidic urine (Dose related)
acetylated form -- CT & calyces cause renal irritation, obstruction &
renal colic.
Crystalluria, albuminuria, & hematuria.
Reduced by
Adequate urinary output (>1L/d)
Alkalinize the urine - solubility of conjugation products.
Use sulfa soluble in acidic urine – (e.g) sulfisoxazole.

30.
(4) Haematopoietic toxicity
Agranulocytosis
Thrombocytopenia - Haemorrhage.
Aplastic anaemia – (RARE)
Methhemoglobenemia – oxidize Hb
In G6PD deficiency – Hhemolysis
(5) Nervous system
confusion, depression, ataxia, tinnitus, fatique,
psychotic episodes, Peripheral neuritis – rare.

31.
(6) Kernicterus in Neonates -- Bilirubin Metabolism
Compete with bilirubin for albumin binding sites.
sulfa displaces bilirubin from albumin binding sites.
Bilirubin cross BBB
Kernicterus [Deposited in Basal Ganglia
+ Subthalamic nuclei]
In newborn, premature infants, in G6PD deficiency.
C/I pregnancy, neonates
Rh incompatibility, premature delivery.

32.
(7) Miscellaneous
Hypothyroidism
Goitre – chronic use.
DRUG INTERACTIONS
Sulfonylureas
Anticoagulants
MTX - Activity enhanced.
phenytoin

33.
THERAPEUTIC USES
Cheap drug.
Not used commonly now because of RESISTANCE
Not used for Streptococcal
Staphylococcal
Pneumococcal / Gonococcal infections.

34.
THERAPEUTIC USES
Systemic use of sulfonamides ALONE is RARE now
(1) UTI.
(2) Meningococcal meningitis.
(3) Ulcerative colitis – SULFASALAZINE
(Sulfapyridine + 5 Aminosalicylic acid )
(4)Toxoplasmosis & malaria - With pyrimethamine
(5) Acute bacillary dysentery.
(6) Trachoma & inclusion conjunctivitis.(Ophthalmic solution/ointment
)

35.
COTRIMOXAZOLE
INHIBIT DHF REDUCTASE
C.diphtheria, E.coli, salmonella, shigella
H.influenza, K. pneumoniae,
Less effective – Neisseria
Cl. welchlii
B. Pertusis
TRIMETHOPRIM + SULFAMETHOXAZOLE (1:5)

36.
Mechanism ofAction
(Cotrimoxazole)
Cotrimoxazole inhibits Nucleic Acid Synthesis
by…
…. causing SEQUENTIAL BLOCKADE of Folic Acid Sy
in bacterial organisms

37.
Rationale
(Cotrimoxazole)
• Both compounds have a similar half life (~10 hours)
• Two bacteriostatic drugs produces bactericidal action when
combined [ 80mg : 400 mg (1:5) ]
• The combination has a wider antibacterial spectrum
• The combination delays the development of bacterial
resistance
• The MIC of each component can be reduced 3-6 times
• Trimethoprim enters many tissues and has a larger volume
of distribution

38.
ADVERSE EFFECTS
Nausea, vomiting, skin rashes, glossitis, stomatitis, anaemia,
leucopenia, thrombocytopenia.
Aplastic anaemia.
Precipitate megaloblastic anaemia. (folic acid deficiency)
AVOID – pregnancy (teratogenicity).
Dose 80 : 400mg 2 tab BD X 10 days.
IV/IM every 12 hrs
Pediatric 20 + 100 mg tab.
40 + 200mg suspension / 5ml.

39.
THERAPEUTIC USES
1) UTI – due to E.coli, proteus. – acute, chronic
2) Prostatitis
3) Typhoid fever
4) STD – Gonorrhoea, chancroid
5) RTI- bronchitis, sinusitis & otitis media
6) GI infections – shigellosis

40.
7) Serous infection - Meningitis, osteomyelitis. (Gm -ve organisms)
8) Pneumocystis jiroverci – High doses 15- 20 mg /kg .
Immunocompramised patients
cotrimaxazole + carbencillin
Neutropenic patients
(9) Miscellaneous – plague , brucellosis & nocardiosis.
ADVANTAGES
Broad spectrum
Safe & well tolerated
Cost effective.

41.
Summary…….
Primarily bacteriostatic drugs, cidal in some
Inhibit bacterial Folic acid synthesis
Activity – Gm positive , negative, clamydia & Plasmodium
Not in common use except Few
Rapid resistance
ADR – common ( Hypersensitivity , crystalluria)
UTI, RTI
TOPICAL USE
Cotrimoxazole