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Sulfonamides, Cotrimoxazole, Quinolones & Urinary Tract Antiseptics

Complete Pharmacological Reference

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PART 1: SULFONAMIDES

Pathology / What They Treat

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Mechanism of Action

Harrison's Principles of Internal Medicine, 21st Ed., p. 4372

PABA → [Dihydropteroate synthetase] → Dihydropteroate → Dihydrofolate
         ↑ BLOCKED by Sulfonamides

• Humans obtain folate from diet (not synthesized endogenously), so human cells are unaffected.

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Drug Names — Sulfonamides

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Clinical Uses of Sulfonamides (Alone)

• Sulfadiazine + pyrimethamine → Toxoplasmosis (1st line)
• Silver sulfadiazine → Burn wound infections
• Sulfasalazine → Ulcerative colitis, Crohn's disease, rheumatoid arthritis
• Dapsone → Leprosy (with rifampicin), PCP prophylaxis in HIV

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Toxicity / Adverse Effects

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Contraindications

• Neonates / premature infants (kernicterus risk)
• Pregnancy (near term — displaces bilirubin; 1st trimester — folate antagonism)
• Severe renal/hepatic failure
• G6PD deficiency (hemolysis)
• Hypersensitivity to sulfa drugs

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Resistance Mechanisms

• Mutation of dihydropteroate synthetase
• Plasmid-encoded resistant enzymes bypassing the inhibited step
• Increased PABA production by bacteria

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PART 2: COTRIMOXAZOLE (TMP-SMX)

What It Is

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Mechanism of Action (Double Blockade)

Harrison's Principles of Internal Medicine, 21st Ed., p. 4372

PABA
  ↓  ← STEP 1: SMX blocks Dihydropteroate Synthetase
Dihydropteroate
  ↓
Dihydrofolate
  ↓  ← STEP 2: TMP blocks Dihydrofolate Reductase
Tetrahydrofolate (THF)
  ↓
DNA precursors (thymidine, purines)

• SMX blocks step 1 (dihydropteroate synthetase)
• TMP blocks step 2 (dihydrofolate reductase)
• Together: 20–100x more potent than either alone → bactericidal combination

TMP has ~50,000x greater affinity for bacterial dihydrofolate reductase than human enzyme.

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Spectrum of Activity

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Clinical Uses of Cotrimoxazole (TMP-SMX)

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Pharmacokinetics

• The half-lives are matched to maintain the 1:20 ratio in plasma.

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Adverse Effects of Cotrimoxazole

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Drug Interactions — Cotrimoxazole

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Diet / Food Interactions

• Avoid high PABA foods (yeast extracts) — can theoretically reduce efficacy
• Take with plenty of water (at least 2L/day) to prevent crystalluria
• Folate supplementation (folic acid) does NOT reverse antibacterial activity because bacteria cannot take up exogenous folate — but humans can. Folinic acid (leucovorin) can rescue human cells in toxicity.

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Contraindications — Cotrimoxazole

• Neonates < 2 months (kernicterus)
• Pregnancy — especially 1st trimester (folate antagonism → neural tube defects) and near term (neonatal jaundice)
• Severe renal failure (dose adjustment required; avoid if CrCl <15)
• Megaloblastic anemia from folate deficiency
• G6PD deficiency (hemolytic anemia)
• Hypersensitivity to sulfonamides

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PART 3: QUINOLONES / FLUOROQUINOLONES

Overview

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Mechanism of Action

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Generations of Quinolones

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Individual Drug Profiles

Ciprofloxacin (Cipro)

• Best quinolone for Pseudomonas aeruginosa
• Uses: UTI, anthrax (prophylaxis/treatment), typhoid, gonorrhea, bone/joint infections, intra-abdominal (with metronidazole), TB (2nd line)
• NOT for community-acquired pneumonia (poor pneumococcal coverage)

Norfloxacin

• Concentrated in urine — mainly used for uncomplicated UTI
• Low systemic bioavailability

Ofloxacin

• UTI, STIs (chlamydia, gonorrhea), respiratory infections, tuberculosis (2nd line)

Levofloxacin (Levaquin)

• "Respiratory quinolone" — Community-acquired pneumonia (CAP), sinusitis, bronchitis
• Covers Streptococcus pneumoniae well
• Also: UTI, prostatitis, inhalational anthrax

Moxifloxacin (Avelox)

• Best anaerobic coverage of all fluoroquinolones
• CAP, ABECB, skin infections, intra-abdominal infections
• NOT for UTI — inadequate urinary concentration

Nalidixic acid (1st generation)

• Historical — urinary antiseptic only
• Gram-negatives in urinary tract
• Now mostly replaced

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Spectrum of Activity — Fluoroquinolones

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Clinical Uses Summary

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Pharmacokinetics — Fluoroquinolones

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Adverse Effects / Toxicity — Fluoroquinolones

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Black Box Warnings (FDA) — Fluoroquinolones

1. Tendinitis and tendon rupture (especially Achilles, risk ↑ with corticosteroids, age >60, renal failure)
2. Peripheral neuropathy (may be permanent)
3. CNS effects (seizures, toxic psychosis)
4. Myasthenia gravis exacerbation (neuromuscular blockade)
5. Aortic aneurysm/dissection

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Drug Interactions — Fluoroquinolones

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Diet / Food Interactions — Fluoroquinolones

• Dairy products, calcium-fortified foods/juices — reduce absorption (chelation of divalent cations)
• Antacids and iron supplements — take quinolone 2 hours before or 6 hours after
• Caffeine — ciprofloxacin reduces caffeine metabolism → jitteriness, insomnia
• Can be taken with or without food (food slows but doesn't prevent absorption)

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Contraindications — Fluoroquinolones

• Children < 18 years (cartilage toxicity — exceptions: anthrax, cystic fibrosis)
• Pregnancy and breastfeeding
• History of tendon disorders / on corticosteroids (high tendon rupture risk)
• Myasthenia gravis (worsens neuromuscular blockade)
• QT prolongation / electrolyte disturbances (hypokalemia, hypomagnesemia)
• Epilepsy / CNS disorders
• Hypersensitivity to quinolones

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Resistance Mechanisms

• Mutations in DNA gyrase (gyrA, gyrB) or topoisomerase IV (parC, parE)
• Efflux pumps (overexpression)
• Plasmid-mediated quinolone resistance (PMQR) — qnr genes
• Reduced outer membrane permeability (gram-negatives)

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PART 4: URINARY TRACT ANTISEPTICS

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4A. NITROFURANTOIN

Harrison's Principles of Internal Medicine, 21st Ed., p. 4352

Mechanism of Action

• Nitrofurantoin is reduced by bacterial nitroreductase enzymes to highly reactive electrophilic intermediates
• These intermediates damage bacterial DNA, ribosomes, cell wall proteins, and other macromolecules
• Bactericidal, concentration-dependent
• Because multiple bacterial targets are damaged simultaneously, resistance is rare

Spectrum

Clinical Uses

• Drug of choice for uncomplicated UTI (cystitis)
• Preferred in UTI during pregnancy (but avoid near term)
• Prophylaxis of recurrent cystitis
• UTIs caused by ESBL-producing E. coli (important emerging use)
• NOT suitable for pyelonephritis (inadequate tissue/blood levels)

Pharmacokinetics

• Oral only (no IV formulation)
• Rapidly absorbed, rapidly excreted into urine → high urinary concentrations, low serum levels
• Requires functioning kidneys to concentrate in urine
• Two formulations: macrocrystalline (less GI side effects) and microcrystalline

Adverse Effects

Contraindications

• Renal failure (GFR <45 mL/min / CrCl <30) — drug cannot concentrate in urine AND toxic metabolites accumulate → peripheral neuropathy
• Pregnancy at term (38–42 weeks) — hemolytic anemia in neonate (G6PD)
• Neonates < 1 month
• G6PD deficiency

Drug/Food Interactions

• Take with food or milk — significantly reduces GI side effects
• Antacids (Mg trisilicate) — reduce absorption
• Probenecid — blocks renal tubular secretion → reduces urinary levels (reduces efficacy)
• Quinolones — antagonism (avoid concurrent use)

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4B. NALIDIXIC ACID (1st generation quinolone)

• Mechanism: Inhibits DNA gyrase
• Use: Gram-negative UTI (E. coli, Klebsiella, Proteus)
• Limitations: Resistance develops rapidly, no systemic activity, now largely obsolete
• Side effects: GI upset, photosensitivity, hemolysis (G6PD), seizures in epilepsy
• Contraindications: Children <3 months, G6PD deficiency, epilepsy

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4C. METHENAMINE (Methenamine hippurate / Methenamine mandelate)

• Mechanism: In acidic urine (pH <5.5), methenamine hydrolyzes to formaldehyde, which is bactericidal by denaturing bacterial proteins
• Use: Long-term prophylaxis of recurrent UTIs
• NOT for acute infections (takes time to form formaldehyde)
• Requires acidic urine — co-administer with ascorbic acid or ammonium chloride
• Contraindications: Renal failure, hepatic failure, sulfonamide co-administration (precipitates in urine), metabolic acidosis

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4D. FOSFOMYCIN

• Mechanism: Inhibits MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) — first step of peptidoglycan synthesis
• Use: Single-dose treatment of uncomplicated UTI (E. coli, E. faecalis)
• Advantages: Single dose, useful in ESBL-producing organisms, safe in pregnancy
• Adverse effects: Diarrhea, nausea (generally well tolerated)

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MASTER COMPARISON TABLE

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QUICK CLINICAL MEMORY AIDS

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Sources

• Harrison's Principles of Internal Medicine, 21st Edition, pp. 4352, 4372
• Pharmacological knowledge synthesized from Katzung's Basic & Clinical Pharmacology, Goodman & Gilman's, and current clinical guidelines