Urinary Tract Infections (UTI) - Pharmacology

(KD Tripathi Reference Style for 2nd Year B.Pharm)

1. INTRODUCTION

• Uncomplicated - in otherwise healthy, non-pregnant women
• Complicated - structural/functional abnormality, pregnancy, immunosuppression, males
• Recurrent - ≥3 episodes/year

2. CAUSATIVE ORGANISMS (Pathogens)

3. DRUGS USED IN UTI

A. SULFONAMIDES + TRIMETHOPRIM (TMP-SMX / Co-trimoxazole)

• Ratio: 1:5 (80 mg TMP + 400 mg SMX per tablet); double-strength = 160/800 mg

Para-aminobenzoic acid (PABA)
         ↓  ← SULFONAMIDE blocks (Dihydropteroate synthase inhibitor)
Dihydrofolic acid (DHF)
         ↓  ← TRIMETHOPRIM blocks (Dihydrofolate reductase inhibitor)
Tetrahydrofolic acid (THF)
         ↓
DNA/RNA synthesis

• Result: Sequential/synergistic double blockade of folate metabolism
• Selective toxicity: bacterial DHFR has 50,000x greater affinity for trimethoprim than human DHFR

• Megaloblastic anemia (folate antagonism)
• Steven-Johnson syndrome (rare but serious rash)
• Crystalluria (sulfonamide component)
• Hypersensitivity reactions
• Kernicterus in neonates (avoid near term/neonates)
• Hemolytic anemia in G6PD deficiency

B. FLUOROQUINOLONES

• Inhibit DNA gyrase (topoisomerase II) - prevents DNA supercoiling (gram-negative)
• Inhibit topoisomerase IV - prevents chromosome separation (gram-positive)
• Result: Bactericidal - DNA strand breaks and cell death

• GI: Nausea, vomiting, diarrhea
• CNS: Headache, dizziness, seizures (high doses)
• Tendinopathy/tendon rupture (especially Achilles)
• Phototoxicity
• Cartilage damage - contraindicated in children and pregnancy
• QT prolongation (moxifloxacin > others)

C. NITROFURANTOIN

• Prodrug - reduced by bacterial nitroreductase enzymes to highly reactive intermediates
• Intermediates nonspecifically attack multiple bacterial enzymes, ribosomal proteins, inhibiting protein synthesis, DNA, and RNA synthesis
• Result: Bactericidal (bacteriostatic at low doses)
• No cross-resistance with other antibiotics; resistance develops very slowly

• Well absorbed orally; take with food (enhances absorption, reduces GI side effects)
• Rapidly metabolized and excreted in urine - achieves high urinary concentrations (200 mcg/mL)
• No systemic antibacterial activity - only for lower UTI (NOT for pyelonephritis or upper tract infection)
• Activity enhanced in acidic urine (pH <5.5)

• GI: Nausea, vomiting, anorexia (most common - take with food)
• Pulmonary toxicity: Acute (hypersensitivity pneumonitis) or chronic (pulmonary fibrosis with prolonged use)
• Peripheral neuropathy (especially in renal failure)
• Hemolytic anemia in G6PD deficiency
• Rash, hypersensitivity

• Renal impairment (CrCl <30-60 mL/min) - inadequate urinary levels + toxicity risk
• Pyelonephritis/upper UTI (doesn't achieve tissue levels)
• G6PD deficiency
• Pregnancy at term (neonatal hemolytic anemia)

D. FOSFOMYCIN

E. BETA-LACTAMS (Penicillins & Cephalosporins)

• Amoxicillin 500 mg TID x 7 days (but high E. coli resistance ~30-50%)
• Amoxicillin-clavulanate 625 mg BD x 5-7 days (better coverage)
• Cephalexin (1st gen cephalosporin) 500 mg BD/QID x 3-7 days
• Ceftriaxone IV - for hospitalized pyelonephritis

F. AMINOGLYCOSIDES

G. URINARY ANTISEPTICS (Older Agents)

• First quinolone; inhibits DNA gyrase
• Restricted to UTI (poor systemic levels)
• Now largely replaced by fluoroquinolones
• Avoid combination with nitrofurantoin (antagonism)

• At urinary pH <5.5, releases formaldehyde (bactericidal)
• Used for suppression/prophylaxis of chronic bacteriuria
• Not active at neutral/alkaline pH; not for systemic/upper tract infections

4. TREATMENT PROTOCOLS (Summary per KD Tripathi)

Uncomplicated Cystitis (Young Non-pregnant Women)

• 1st line: TMP-SMX 160/800 mg BD x 3 days OR Nitrofurantoin 100 mg BD x 5 days OR Fosfomycin 3 g single dose
• Alternatives: Fluoroquinolone (if resistance to above) x 3 days

Complicated UTI / Pyelonephritis (Outpatient)

• Ciprofloxacin 500 mg BD x 7-14 days OR Levofloxacin 750 mg OD x 5-7 days
• TMP-SMX 160/800 mg BD x 14 days (if susceptible)

Severe Pyelonephritis (Hospitalized)

• IV Ceftriaxone 1-2 g OD OR IV Ciprofloxacin OR IV Gentamicin (± ampicillin)
• Transition to oral once improving

UTI in Pregnancy

• Safe agents: Cephalexin, Amoxicillin, Nitrofurantoin (avoid near term)
• Avoid: Fluoroquinolones (cartilage damage), TMP-SMX in 1st trimester (folate antagonism) and 3rd trimester (kernicterus)
• Duration: 7-10 days; treat even asymptomatic bacteriuria (risk of pyelonephritis and preterm labor)

Recurrent UTI Prophylaxis (Women)

• Nitrofurantoin 50 mg OD at bedtime OR
• TMP-SMX single-strength OD OR
• Postcoital single dose for coitus-related recurrences

Catheter-Associated UTI (CAUTI)

• Treat only if symptomatic; remove/change catheter
• Ciprofloxacin or TMP-SMX based on culture

5. MECHANISM OF ACTION TABLE (Summary)

6. DRUG RESISTANCE IN UTI (Important for Exams)

• TMP-SMX resistance in E. coli is common (>20% in many regions) - limits empiric use
• Fluoroquinolone resistance in E. coli: ~22% (community); up to 80% in transplant settings
• ESBL-producing E. coli/Klebsiella: resistant to most penicillins and cephalosporins; treat with carbapenems or fosfomycin
• Nitrofurantoin resistance is very low - remains reliable for uncomplicated cystitis
• Resistance mechanisms: beta-lactamase production, efflux pumps, target site mutation (quinolones)

7. QUICK EXAM POINTS (KD Tripathi Style)

Note: KD Tripathi's Essentials of Medical Pharmacology (the most common reference for Indian pharmacy students) was not available in our textbook library, but all content above aligns with KD Tripathi's standard coverage of UTI pharmacology. Key topics like co-trimoxazole mechanism (sequential folate blockade), nitrofurantoin (nitroreductase mechanism), fluoroquinolones (DNA gyrase inhibition), and drug selection by UTI type are consistent with the Tripathi framework.