Management of Urinary Tract Infection (UTI) - Pharmacology

Definition & Common Organisms

• Uncomplicated (lower UTI/cystitis) - otherwise healthy women
• Complicated (upper UTI/pyelonephritis, or in men, pregnancy, structural abnormality)

Drugs Used in UTI

1. Trimethoprim-Sulfamethoxazole (TMP-SMX / Co-trimoxazole)

• Mechanism: Synergistic sequential blockade of folate synthesis - sulfonamide inhibits dihydropteroate synthase; trimethoprim inhibits dihydrofolate reductase. Together, they block purine and nucleic acid synthesis, producing bactericidal activity.
• Use: First-line for uncomplicated UTI (where local resistance <20%). Also used for soft tissue infections and bone/joint infections.
• Dose: TMP 160 mg + SMX 800 mg (double strength) twice daily for 3-7 days for uncomplicated UTI.
• ADR: Nausea, rashes, Stevens-Johnson syndrome, folate deficiency, haemolytic anaemia in G6PD deficiency, megaloblastic anaemia.
• Note: Increasing resistance in E. coli limits its empiric use.

2. Fluoroquinolones (Ciprofloxacin, Norfloxacin, Levofloxacin)

• Mechanism: Inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, preventing DNA supercoiling and replication.
• Use: Effective in UTI caused by most gram-negatives including P. aeruginosa. Ciprofloxacin/levofloxacin preferred for complicated UTI and pyelonephritis. Norfloxacin - restricted to urinary tract (poor systemic levels).
• Dose: Ciprofloxacin 500 mg BD x 3 days (uncomplicated); 7-14 days for complicated UTI/pyelonephritis.
• ADR: Nausea, dizziness, QT prolongation, tendinitis/tendon rupture (avoid in <18 yrs), photosensitivity, cartilage damage in growing children.
• Caution: Absorption impaired by antacids, calcium, iron (chelation). Give 2 hrs before or 4 hrs after such agents.

3. Nitrofurantoin

• Mechanism: Reduced by bacterial reductases to reactive intermediates that react nonspecifically with ribosomal proteins, disrupting protein, RNA, and DNA synthesis. Bactericidal.
• Spectrum: Gram-positive and gram-negative bacteria; P. aeruginosa and most Proteus strains are inherently resistant.
• Pharmacokinetics: Rapidly metabolised after absorption; achieves urine concentrations ~200 mcg/mL - no systemic antibacterial action. Excreted by both glomerular filtration and tubular secretion.
• Use: Lower UTI only (cystitis). Not for pyelonephritis (insufficient upper tract drug levels). Important alternative as TMP-SMX and fluoroquinolone resistance increases. Single daily dose (100 mg) used for prophylaxis of recurrent UTI.
• Dose: 100 mg orally four times daily (7 days); macrocrystalline (Macrobid) 100 mg BD.
• ADR: Anorexia, nausea, vomiting; peripheral neuropathy and pulmonary fibrosis (prolonged use); haemolytic anaemia in G6PD deficiency; rashes.
• Contraindicated in significant renal insufficiency (CrCl <30 mL/min) - inadequate urine levels + accumulation causing toxicity.
• Acidic urine (pH <5.5) greatly enhances activity.

4. Methenamine (Mandelate / Hippurate) - Urinary Antiseptic

• Mechanism: At urinary pH <5.5, releases formaldehyde, which is bactericidal.
• Use: Long-term prophylaxis/suppression of recurrent UTI, not acute infection.
• Require urinary acidification for activity.

Summary: Drug of Choice by Situation