SULPHONAMIDES

Introduction

• Sulphonamides were the first effective antibacterial agents used systemically in humans.
• Introduced by Domagk in 1935; many variants were synthesized and widely used in the following years.
• Their role today is limited due to:
  • Toxicity
  • Development of bacterial resistance
  • Availability of safer, more effective drugs
• Chemistry: They are structural analogs of para-aminobenzoic acid (PABA) - synthetic agents that contain a sulfonamide group.

Classification

Antibacterial Spectrum

• Many gram-positive bacteria
• Some gram-negative bacteria including:
  • Streptococci, H. influenzae, H. ducreyi, Nocardia, E. coli, Salmonella, Shigella, Proteus, V. cholerae
  • Some staphylococci, gonococci, meningococci, pneumococci
• Also effective against Chlamydia, P. falciparum, Toxoplasma gondii

Mechanism of Action

• Folic acid is essential for nucleic acid synthesis. Bacteria must synthesize their own folic acid from PABA using the enzyme folic acid synthetase.
• Sulphonamides are structurally similar to PABA and competitively inhibit folic acid synthetase.
• This causes folic acid deficiency → inhibition of bacterial growth and cell injury.
• Sulphonamides are bacteriostatic.
• Important limitation: Pus, blood, and tissue breakdown products are rich in PABA, which renders sulphonamides ineffective in such environments (e.g., abscesses).

PABA → [Folic acid synthetase] → blocked by Sulfonamides → Dihydrofolic acid

Resistance

1. Mutations causing overproduction of PABA
2. Using an alternative metabolic pathway for folic acid synthesis, producing a folate synthetase with low affinity for sulphonamides
3. Decreased permeability to sulphonamides (drug cannot enter the cell)

Adverse Effects

1. Renal toxicity - Renal irritation, haematuria, albuminuria, and crystalluria (precipitation of drug in acidic urine). Prevented by drinking large volumes of fluids and alkalinizing the urine with sodium bicarbonate. Nephrosis and allergic nephritis can also occur.
2. Allergic reactions - Rashes, fever, hypersensitivity, urticaria, photosensitivity, anaphylactoid reactions, exfoliative dermatitis. Rarely, Stevens-Johnson Syndrome (SJS) - which can be fatal. Nephritis may also have an allergic basis.
3. GI effects - Anorexia, nausea, stomatitis, abdominal pain, conjunctivitis, and arthritis.
4. Blood disorders - Haemolytic anaemia, decreased granulocyte and thrombocyte count. Haemolytic anaemia is precipitated in patients with G6PD deficiency.
5. Kernicterus - Sulphonamides displace bilirubin from plasma protein binding sites. Free bilirubin crosses the Blood-Brain Barrier (BBB) in newborns → kernicterus (brain damage from bilirubin). Therefore, sulphonamides are contraindicated in pregnancy and in infants.

Clinical Uses

1. Urinary Tract Infections (UTI) - Uncomplicated acute UTI in areas where resistance is low; Sulfisoxazole 1g QID or Sulfamethoxazole 1g TDS.
2. Nocardiosis - High doses as an alternative treatment.
3. Toxoplasmosis - Sulfadoxine + Pyrimethamine is the treatment of choice for T. gondii. They act synergistically by blocking sequential steps in folate synthesis. Dose: Sulfadoxine 4g/day + Pyrimethamine 75 mg bolus then 25 mg daily for 4-6 weeks. Leucovorin rescue (10 mg folinic acid daily) is required to prevent severe folic acid deficiency.
4. Trachoma, Inclusion Conjunctivitis, Lymphogranuloma Venereum (LGV), Chancroid - Alternatives to tetracyclines.
5. Malaria - Sulfadoxine is used with Pyrimethamine for chloroquine-resistant malaria.
6. Prophylaxis - In penicillin-allergic patients, for prophylaxis of streptococcal pharyngitis in rheumatic fever.
7. Topical uses:
   • Sulfacetamide eye drops for bacterial conjunctivitis
   • Mafenide and Silver sulfadiazine ointments used in burns to prevent infection (silver sulfadiazine is preferred)
8. Ulcerative Colitis - Sulfasalazine is useful in ulcerative colitis and rheumatoid arthritis.

COTRIMOXAZOLE

What is it?

• Cotrimoxazole = Trimethoprim + Sulfamethoxazole (combined drug)
• Trimethoprim alone is effective against gram-positive and gram-negative organisms, but resistance develops rapidly when used alone.
• Combination is preferred because:
  • Cotrimoxazole has a broader spectrum
  • Effective against Staph. aureus, streptococci, meningococci, C. diphtheriae, E. coli, Proteus, H. influenzae, Salmonella, Shigella, and Pneumocystis jiroveci

Mechanism of Action (Cotrimoxazole)

• Sulphonamides block the conversion of PABA → Dihydrofolic acid (DHF) by inhibiting folic acid synthetase
• Trimethoprim blocks the next step: DHF → Tetrahydrofolic acid (THF) by inhibiting dihydrofolate reductase (DHFR)
• Together, they block two sequential steps in folate synthesis → synergistic effect

PABA → [Folic acid synthetase ⊖ by sulfonamide] → Dihydrofolic acid → [Dihydrofolate reductase ⊖ by Trimethoprim] → Tetrahydrofolic acid

• Both drugs individually are bacteriostatic, but the combination is bactericidal
• Trimethoprim has high selective affinity for bacterial DHFR vs. human DHFR - that's why it's relatively safe for humans

Drug Ratio & Pharmacokinetics

• The ratio of Trimethoprim : Sulfamethoxazole used is 1:5 to achieve the right plasma concentration
• Optimal peak plasma ratio of the combination is 1:20
• Sulfamethoxazole is specifically chosen among sulphonamides because its pharmacokinetic profile closely matches that of trimethoprim (they reach peak levels together)

Resistance

• Resistance develops slower with the combination than with either drug alone
• Bacteria may acquire resistance by:
  1. Mutation
  2. Acquisition of a plasmid coding for altered DHFR (plasmid-mediated resistance)

Adverse Effects

• Nausea, vomiting, headache, glossitis, stomatitis, and allergic skin rashes are common
• In folate-deficient patients: megaloblastic anaemia
• Haematological reactions (anaemia, granulocytopenia) are rare
• AIDS patients are more prone to adverse effects
• Renal disease patients may develop uraemia
• Contraindicated in pregnancy - it is an antifolate drug and could be teratogenic

Clinical Uses

1. Urinary Tract Infections
   • Acute uncomplicated UTI: Cotrimoxazole DS, twice daily for 7-10 days
   • Both drugs concentrate well in urine
   • Chronic/recurrent UTI: Low-dose prophylaxis (1 single-strength tab, thrice weekly)
   • Bacterial prostatitis: Trimethoprim achieves high concentration in prostatic fluid; Cotrimoxazole DS twice daily
2. Respiratory Tract Infections - Upper and lower respiratory infections including bronchitis, sinusitis, and otitis media
3. Bacterial Gastroenteritis - Shigella and E. coli infections respond to cotrimoxazole
4. Typhoid - Used as an alternative to fluoroquinolones
5. Pneumocystis jiroveci Infection (PCP)
   • Drug of choice for both prophylaxis and treatment
   • High dose: Trimethoprim 20 mg/kg + Sulfamethoxazole 100 mg/kg daily
   • Used in neutropenic and AIDS patients
   • Also protects against gram-negative bacteria
6. Chancroid - Cotrimoxazole DS, BD for 7 days is the drug of choice
7. Melioidosis (caused by Burkholderia pseudomallei)
   • Mild infections: Cotrimoxazole may be tried
   • Severe infections/septicaemia: Intensive phase = 2 weeks of ceftazidime or meropenem, then eradication = 3 months of cotrimoxazole + doxycycline
8. Toxoplasmosis - Used as an alternative to Pyrimethamine + Sulfadiazine
9. Intravenous Cotrimoxazole - Generally given orally; IV form is used in serious illness when oral route is not possible (e.g., severe PCP, typhoid, UTI caused by susceptible microbes)

Key Comparisons at a Glance

Classification of Fluoroquinolones

GENERATION 1 - Narrow Spectrum (Urinary Tract Only)

*Note: Some classifications place Norfloxacin in Gen 1 or early Gen 2 depending on the source.

• Active only against gram-negative organisms (Enterobacteriaceae: E. coli, Klebsiella, Proteus, etc.)
• Achieves only minimal serum levels - effective only in the urinary tract
• No systemic use

GENERATION 2 - Expanded Gram-Negative + Some Gram-Positive + Systemic Activity

• Good coverage of gram-negative rods (including Pseudomonas - ciprofloxacin is the most potent antipseudomonal quinolone)
• Some gram-positive coverage (limited against Streptococcus)
• Active against atypicals (Chlamydia, Mycoplasma) to a limited degree
• Systemic activity - adequate serum levels achieved

• UTI, pyelonephritis
• Gonorrhoea
• Enteric infections (Salmonella, Shigella, Campylobacter)
• Intra-abdominal infections
• Bone and joint infections
• Anthrax (ciprofloxacin)

GENERATION 3 - "Respiratory Fluoroquinolones" - Broad Spectrum + Enhanced Gram-Positive

• Expanded gram-positive coverage, especially penicillin-sensitive AND penicillin-resistant Streptococcus pneumoniae
• Expanded atypical pathogen coverage (Mycoplasma, Chlamydia, Legionella)
• Some Staphylococcal coverage

• Community-acquired pneumonia (CAP) - the main "respiratory quinolone"
• Acute exacerbation of chronic bronchitis (AECB)
• Sinusitis
• All Gen 2 indications

GENERATION 4 - Broadest Spectrum + Anti-Anaerobic Activity

• Anaerobic coverage (significant addition)
• Broad gram-positive including S. aureus
• Delafloxacin specifically active against MRSA (unique feature)
• Very broad atypical coverage
• Note: Minimal antipseudomonal activity (trade-off for broader gram-positive/anaerobic coverage)

• Community-acquired pneumonia
• Intra-abdominal infections (anaerobic coverage)
• Pelvic infections
• Nosocomial pneumonia
• Bacterial skin and soft tissue infections (delafloxacin - MRSA)
• All previous generation indications (except complicated UTI for some agents)

Summary Table

Mechanism of Action (All Generations)

1. DNA gyrase (topoisomerase II) - primary target in gram-negative bacteria
2. Topoisomerase IV - primary target in gram-positive bacteria

Important Notes

• Contraindicated in children (under 18 years) and pregnant women - cause cartilage damage in weight-bearing joints
• Avoid with antacids (aluminium/magnesium) - chelation reduces absorption significantly
• Tendon rupture risk - especially with concomitant corticosteroids; highest risk in elderly
• QT prolongation - especially moxifloxacin and sparfloxacin
• Resistance develops via mutations in DNA gyrase/topoisomerase IV genes, or efflux pumps