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THE FOLATE ANTAGONISTSSulfonamides
Are synthetic anti-microbial agents derived from
 sulfanilamide.
They are structural analogs of para-aminobenzoicacid (PABA), a factor required by bacteria for folicacid synthesis.
Mechanism of Action
Inhibit competitively with the conversion of PABAto folic acid mediated by the enzymedihydropteroate synthetase
 
H
2
NCOOHp- Aminobenzoic acid (PABA)Pteridine precursor
-
H
2
N S NHRDihydropteroatesynthetaseSulfanilamide(and other sulfonamides)Folic Acid
Competitive inhibition of folic acidsynthesis by sulfonamides
Antibiotic Activity:
Bacteriostatic
Antimicrobial Spectrum:
a. Staph. Aureus b.Non enterococcal Streptococeusc.Listeria monocytogenesd.Nocardiae.Neisseriaf.H. influenzag.E. colih.Proteus mirabilis
Sulfonamides: For systemic use
1. Sulfamethizole – short acting2. Sulfisoxazole – short acting3. Sulfadiazine – short acting4. Sulfamerazine – short acting5. Sulfamethazine - short acting6. sulfacetamide- (ophthalmic infections)7.Sulfisomidine8.Sulfachloropyridazine- short acting9.Sulfamethoxypyridazine10.Sulfamethoxazole - intermediate acting11. Sulfamethazine- short acting12. Sulfadoxine- long acting
Combination of:
1.Sulfadiazine2.Sulfamerazine Trisulfapyrimidine
 
3. Sulfamethazine
Uses of Sulfonamides
* Sulfadiazine + Pyrimethamine – effective againstToxoplasmosis* Sulfadoxine + Pyrimethamine – (Fansidar)effective for Chloroquine resistant P. Falcifarum.* Sulfamethoxazole + Trimethoprim - producesSynergistic action =useful in respiratory, urinary.Ear and sinuses infection[
For instestinal Use: (Long acting)]
1.Succinylsulfathiazole2.Phthalysulfathiazole* Topically use Sulfonamide – silver sulfadiazine,mafemide ,sulfacetamide= use astopical treatment for burns* Sulfasalazine (A Sulfidine) – use in treatment of ulcerative colitis and rheumatoid arthritis.* For ocular infections =sulfacetamide – use in thetreatment of trachoma ( chlamydia trachoma)
Untoward Effects:
1. 75% involves the skin with sensitization often being responsible conditions prod. Include:a.Exfoliative Dermatitis, photosensitivity b.Steven – Johnson syndrome (fever,malaise and erythema multiforme).2. Drug fever (due to sensitization)3. Blood dyscrasias rare but can occur. But the drugshould be stopped if any of the following occurs:a.Acute hemolytic anemia (seen in patients with Glucose – 6 – Phosphatedehydrogenase def.) b.Aplastic anemiac.Agranulocytosisd.Thrombocytopeniae. Eosinophilia4.Crystalluria (rare with sulfisoxazole- moresoluble) occurs with more newer agents,Sulfamethaxazole and long acting agents especiallyin acidic urine.5.Hepatitis6. Kernicterus in newborn
Drug Interactions
Sulfonamides inhibit the metabolism of a.Warfarin b.Phenytoinc.Tolbutamided.ChlorpropamideSTEVEN JOHNSON SYNDROME
Trimethoprim (TMP)
Trimethoprim is a synthetic antimicrobial cpd.Which is available as a single agent and in a fixedcombination with sulfamethoxazole (TMP-SMX)
Mechanism of Action
It interferes with the action of dihydrofolatereductase, the enzyme that reduces dihydrofolic totetrahydrofolic acid. An essential step in purine andultimately DNA synthesis.
 
PABA(Dihydrofolic)folic Acid(Tetrahydrofolic)folinic AcidPrecursorsCoFSulfonamidecompetes withPABADihydrofolatereductaseAdenineGuanineThymineInhibited byTrimethoprim21Sequential blockade - results in a higher degree ofsynergistic activity against a wide spectrum ofmicroorganism
Antibiotic activity of Trimethoprim:
 bacteriostaticAntibiotic activity of Trimethoprim +Sulfamethoxazole = Broad spectrum , Bactericidaldue to synergistic action of the two drug.
Antimicrobial Spectrum of Trimethoprim1. Gram positive Aerobic Bacteria
a.S. aureus (including penicillin – resistant andsome methicillin resistant strain) b.Staph. Epidermidisc.Streptococcusd.Listeria monocytogenes
2. Gram (-) Aerobic Bacteria
a. E. coli b. Enterobacter c. Klebsiellad. Providenciae.Morganellaf.Serratia marcescensg.Citrobacter h.Salmonellai.Shigella j.Yersiniak.Acinetobacter l.Vibriom.Aeromonasn.Ps. maltophilao.Ps cepacia (but not Ps. Aeruginasa- resistant) p.H. influenzae (including ampicillin – resistantstrains)q.Neiseria (Meningococci and Gonococci)r.Branhamella catarrhalis – sensitive to TMP-SMX combination
TMP-SMX Combination – other Sensitiveorganisms
1.Anaerobic organisms2.Pneumocytis carinii
Adverse Effects
1.Nausea, diarrhea – most common adverse effect2.hypersensitivity3.Hematologic disorders in persons withsuboptional folate nutrition-megaloblastic anemia
Clinical Use: TMP-SMX ( Co-trimoxazole)
1.UTI; prostates; epididymo – orchitis2. Drug of choice for:a.Nocardia asteroids infections b.Pneumocystis cariniic.Shigellosisd.Travelers diarrhea (E. coli)e.Yersinia entercolitica3.2
nd
line of choice for a.Listeria meningitis b.Legionella infectionc.Typhoid fever 4. Meningitis due to Acinetobacter ; Ps maltophila;Enterobacter 
Mechanism of Bacterial Resistance 
SulfonamideTrimethoprim1. Over productionof PABA bymicroorganisms2.Altereddihydropteroatesynthetase3. Plasmid that codefor the production of drug resistance1. Inability of drug to penetrate cell(membrane) envelope2. Presence of unsusceptibledihydrofolate reductase3. Over production of dihydrofolate reductase4. Mutation
THE BROAD SPECTRUM ANTIBIOTICS
A
. CHLORAMPHENICOL
First isolated from cultures of Streptomycesvenezuelae – Contains a nitrobenzene moiety and derivative of dichloroacetic acid
Mechanism of Action :
inhibits protein synthesis –  binds to 50s ribosomal subunit and prevent peptide bond formation by blocking the action of peptidyltransferase.(High conc. it will inhibit eukaryote proteinsynthesis and may affect mitochondrial proteinsynthesis).
Antimicrobial spectrum – 
broad spectrum
Bactericidial against:
1.H. influenza2.Strep. Pneumonia3. N. meningitides
More commonly it is BacteriostaticHighly active against
1.Methicillin – sensitive staph. Aureus2.Strep. Pneumoniae3.Listeria monocytogenes4.N. gonorrhea5.H. influenza6.Bordotella pertusis7.Salmonella8. Brucella9.E. Coli10.Proteus mirabilis11.Klebsiella12.Shigella13.Anaerobic bacteriaa.Peptococcus, peptostreptococcus b.Clostridiumc.Actinomycesd.Bacteroides14.Spirochetes15.Mycoplasma16. Chlamydia (effective only in vitro although notclinically effective)17.Rickettsia
Pharmacokinetics:-
well absorb from the GIT (can also be administeredIV -chloramphenicol succinate)-it is lipid soluble and diffuses well into tissues and body fluids, and it also crosses the placenta.
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