Sulphonamides

Mechanism of action
These are bacteriostatic agents. Sulphonamides are structural analogs of PABA. They compete
with PABA for enzyme dihydropteroate synthetase (DHPS), which is essential for synthesis of
folic acid in bacteria. Folate is required for synthesis of precursors of DNA and RNA in both
bacteria and mammals.
Both humoral and cellular defence mechanisms of host are essential to eradicate infection.

Sulfonamides trimethoprim
Pteridine+ PABA Æ Dihydropteroic acid(+glutamate)Æ dihydrofolicacidÆ Tetrahydrofolic acid

Antagonists of sulfonamides Synergists of sulfonamides

• Local anesthetics like procaine • Trimethoprim
• Pus and tissue break down products. • Pyrimethamine
• Excess of PABA

Resistance may occuar due to mutations (plasmid mediated) that

• Cause overproduction of PABA
• Production of a folic acid synthesizing enzyme that has low affinity for sulfonamides.
• Impair permeability

Antibacterial spectrum
Usually susceptible organisms:
• Gram +ve, gram –ve, enterobactericeriacea (active against E.coli, proteus, enterobacter,
poor for indole +ve proteus, Klebsiella), inactive against pseudomonas and serratia
• Also effective for Nocardia, Chlamydia spp, Toxoplasma gondii, Chloroquine resistant
P. falciparum.

ADME:
• Absorption- 70-100% from small intestine.
• Protein binding to albumin varies (20-90%). Distribution to tissues and body fluids (pleural,
peritoneal, synovial, ocular, CSF-50% -80% ); crosses placenta.
• Metabolism in liver by acetylation, acetylated metabolite has no antibacterial activity but
retains its toxic activity. Excretion occurs mainly through kidney- partly unchanged and partly
as metabolites. T ½ depends on the renal function.

1
 Classification
I. Rapidly absorbed and rapidly eliminated:
Sulfisoxazole T ½ 6 hours, sulfadiazine T ½ -10 hours
sulfamethoxazole - T ½ 11 hours;
II. Long acting sulfonamides
Sulfadoxine T ½ 7-9 days; used with pyrimethamine (fansidar) for treatment of
chloroquine resistant P. falciparum malaria. Adverse reactions with long
acting – Stevens Johnson syndrome.
III. Poorly absorbed sulphonamide
Sulfasalazine: used for ulcerative colitis and regional enteritis. It is broken down by
intestinal bacteria to sulfapyridine (absorbed and excreted), and 5 aminosalicylate,
(not absorbed) which acts as local anti inflammatory agent. Sulfapyridine is toxic
(may produce heinz body reaction, acute hemolytic anemia in G6PD deficiency, and
agranulocytosis). With sulfasalazine rash, fever, arthralgia and decrease in sperm no.
and morphology leading to reversible infertility may occur.

IV. Sulphonamide for topical use

a. Eye: sulfacetamide sodium. Its sodium salt has the pH of 7.4, 30% is used
for ophthalmic conditions, is not irritating and penetrates ocular fluid tissues
easily.
. b. Skin:
• Silver sulfadiazine – it inhibits the growth of all pathogenic bacteria and
fungi., used to prevent infection of wound from burns. Silver, released
slowly, is toxic to microorganisms.
• Mafenide acetate cream- prevents colonization of burn by gram positive and
negative bacteria. Superinfections with candida may occur.

Adverse reactions
1. Disturbances of urinary tract: crystalluria, hematuria, obstruction due to
precipitation of acetylated form.. To prevent damage to kidney by crystalluria,
maintain a urine output of 1500 ml/d and alkalinize the urine (sulphonamides
are soluble in alkaline urine).
2. Disorders of hematopoietic system
• Acute hemolytic anemia due to sensitization, or in a G6PD deficient
patient.
• Agranulocytosis
• Aplastic anemia- due to direct myelotoxic effect – may be fatal ..
3. Hypersensitivity reactions: common
• Various skin rashes, erythema multiforme, erythema nodosum,
Stevens-Johnson syndrome, exfoliative dermatitis and
photosensitivity.
• Fever, malaise and pruritus, serum sickness, drug fever.
• Focal or diffuse necrosis of liver.- acute yellow atrophy
4. Miscellaneous:
ƒ Kernicterus They should not be given to pregnant women at term as
they pass through placenta, and are secreted in milk.
ƒ GIT and CNS disturbances
Drug interactions:
With oral anticoagulants, oral hypoglycemics (sulfonylureas), hydantoin.

Therapeutic uses
Number of indications has sharply declined due to development of other antibiotics and
increased resistance of bacteria.

2
• Acute uncomplicated UTI, .
• Toxoplasmosis- sulfadiazine + pyrimethamine
• Chloroquine resistant P. falciparum malaria- sulfadoxine + pyrimethamine- fansidar.
• Nocardiosis
• Topically silver sulfadiazine cream- prophylaxis against pseudomonas aeru, which colonises
burn, less effective for staph.
• Topical sulfacetamide 30% solution- for bacterial conjunctivitis and trachoma.
• Sulfasalazine for ulcerative colitis.

Trimethoprim
A pteridine analogue. It inhibits dihydrofolate reductase (DHFR), mammalian is 20,000 to 60,000
times less susceptible.
May be used as sole therapy for UTI. Concentrates in prostatic and vaginal fluid.
Adverse reactions: megaloblastic anemia, leukopenia and granulocytopenia.

Trimethorpim and sulfamethoxazole.

Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole in a ratio of 1:5. Both
the drugs by themselves are bacteriostatic but the combination in this ratio is bactericidal
(synergistic action).
Antibacterial spectrum : gram + ve and –ve organisms especially enterobactericeae but not for
pseudo, anaerobes , MRSA, enterococci.

Resistance:
• Altered DHFR
• Increased production of DHFR by bacteria
• Decreased permeability.

Kinetics
Well absorbed, enters CSF, crosses placenta, enters milk, metabolized and excreted in urine,
reduce dose in moderate to severe renal dysfunction.

Uses:
Treatment of genitourinary, respiratory and GI infections caused by suspected bacteria- E. coli,
enterococci, P. mirabilis, indole positive proteus, Klebsiella.
1. UTI: Acute uncomplicated UTI, chronic and recurrent UTI- chemoprophylaxis
2. GI infections: shigella, salmonella: typhoid fever and for carrier of salmonella typhi,
traveler’s diarrhea.- E.coli.
3. RTI: otitis media, acute exacerbation of chronic bronchitis
4. Pneumocystis jiroveci penumonia
5. G –ve bacterial sepsis- administered IV
6. Others: gonorrhea, brucellosis, chancroid, nocardia, MRSA, prophylaxis in neutropenic
patients.

Adverse reactions:
• Megaloblastotic anemia, leukopenia and granulocytopenia
• All adverse effects produced by sulfonamides like hypersensitivity reactions, CNS
symptoms, GI upsets and renal and hepatic toxicity.
• Patients with AIDS and pneumocystosis: fever, rash, leukopenia, diarrhea, raised
aminotransferases, hyperkalemia and hyponatremia.

C/I: pregnancy- neural tube defects, hepatic disease, renal disease.

3
 Quinolones
Broad spectrum antibiotics.
Play an important role in the treatment of multidrug resistant bacterial infections.
May be used in patients allergic to or intolerant to penicillins, cephalosporins, sulfonamides,

Mechanism of action:
They inhibit topoisomerase II (DNA gyrase ) (in G-ve organism) and topoisomerase IV(
in G +ve). DNA gyrase has a strand cutting function to prevent supercoiling of DNA strands
during separation and replication of mirror strand. Fluoroquinolones act on this.
Topoisomerase IV which is responsible for separation of daughter cells – is also inhibited by
quinolones.
These are bactericidal- unable to repair DNA damage. Killing is concentration
dependent so there is a long PAE.
macrolides, etc.
Resistance:
• Mutation in DNA gyrase
• Alteration in porins (-ve bacteria)
• Increased efflux.

Classification
Generati Agents Antimicrobial spectrum Clinical indications
on
1st Nalidixic acid G-ve (not pseudomonas, Uncomplicated UTI.
proteus)
2nd Ciprofloxacin • G –ve including • Uncomplicated and complicated UTI
Antipseu Norfloxacin pseudomonas. and pyelonephritis.
domonal Lomefloxacin • Some G+ve including • Sexually transmitted disease
quinolon Enoxacin Staph aureus, but not (gonorrhea, PID)
es Ofloxacin Strep. Pneumoniae or • Prostatitis.
S. pyogenes • Skin and soft tissue infection
• Some atypical • GIT infections : typhoid, bacterial
pathogens diarrhoea ( shigella, campylobacter,
• Myco bacteriurm traveler’s)
tuberculosis and • Chronic G-ve infection: bones and
atypical mycobac. joints infections, osteomyelitis,
cholangitis, exacerbation of
pseudomonas infection in cystic fibrosis
• Anthrax.
• 2nd line for mycotuberculosis and good
for atypical myco (MAC)

4
3rd Levofloxacin • Beta lactamase • Acute otitis media, sinusitis,
respirato Sparfloxacin producing H. pharyngitis.
ry Gatifloxacin influenzae and • Acute exacerbation of chronic
quinolon Moxifloxacin Moraxella bronchitis
es Gemifloxacin catarrhalis. • Community acquired pneumonia.
• Expanded G+ve • Second line in TB.
coverage (penicillin
resistance S
pneumoniae, S.
pyogenes)
• Expanded atypical
pathogens coverage
4th Trovafloxacin • As 3rd generation. • Intraabdominal infections.
(associated. • + broad anaerobic • Nososcomial pneumonia
with coverage • Pelvic infections.
hepatotoxicity) • As 1st , 2nd , and 3rd generation (not
complicated UTI and pyelonephritis)

ADME- rapidly absorbed . Food does not affect bioavailability (BA 80-95%). Absorption
impaired by divalent cations (antacids). Widely distributed- CSF, bone, prostatic fluid, breast
milk, ascetic fluid. Half life 3-10 H, Levofloxacin, gatifloxacin, and moxifloxacin have longer
half lives , hence administered once daily.
Elimination occurs through GF and TS- modify dosage in patients with creatinine clearance <50
ml/min. Moxifloxacin is metabolized by glucuronidation, contraindicated in hepatic failure..

Adverse reactions
• GIT: N, V, D, abdominal pain
• CNS- drowsiness, weakness, headache, dizziness- severe cases convulsions and toxic
psychosis.
• Photosensitivity
• QT prolongation with gatifloxacin, moxifloxacin, gemifloxacin- avoid with class 1 and 3
antiarrhythmics and also erythromycin, TCA.
• With gatifloxacin- hyperglycemia in DM and hypoglycemia with oral hypoglycemics-
fatal- hence withdrawn from US.
• Bones and joins- damage to epiphyseal cartilage- contraindicated in children except
in patients with cystic fibrosis (arthropathy is reversible). Tendinitis and rupture
(adults).
• Hypersensitivity- rash, urticaria, eosinophilia.
• Liver- acute hepatic failure with trovafloxacin- used only in life threatening conditions.
• Nephrotoxicity
• Others: cholestatic jaundice, blood dyscrasia, hemolytic anemia,

Contraindications
• Children < 18 years
• Pregnant and lactating women

Cautions: .
• Patients with epilepsy.
• Dose to be reduced in renal impairment.

5
Interactions
• Synergistic affect with beta lactam antipseudomonal antibiotics and aminoglycosides.
• Inhibition of metabolism of certain drugs: theophylline, caffeine, sulfonylureas and warfarin.
• NSAIDs potentiate CNS toxicity- seizures .
• Antacids and sucralfate reduce their absorption.