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Diarrhoea: Investigations and Management with Pharmacology

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Definition

• Acute diarrhoea: onset and duration <14 days (usually infectious)
• Persistent/chronic diarrhoea: >14 days (requires full evaluation)

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Pathophysiology (Types of Diarrhoea)

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INVESTIGATIONS

A. Bedside / Initial Screening Tests

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B. Stool Microbiological Studies

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C. Blood Investigations

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D. Special/Hormonal Tests (Secretory/Endocrine Causes)

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E. Imaging

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F. Endoscopy

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G. Functional Tests (Chronic Diarrhoea)

• Hydrogen breath test - lactose/fructose malabsorption, small intestinal bacterial overgrowth (SIBO)
• SeHCAT scan (75Se-taurocholate) - bile acid malabsorption
• Secretin stimulation test - pancreatic exocrine insufficiency
• Faecal elastase - pancreatic insufficiency (non-invasive)
• D-xylose absorption test - small intestinal mucosal disease vs. luminal maldigestion

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MANAGEMENT

Step 1: Assessment of Dehydration (WHO Classification)

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Step 2: Oral Rehydration Therapy (ORT) - Cornerstone

• Sodium: 75 mmol/L
• Chloride: 65 mmol/L
• Glucose (anhydrous): 75 mmol/L
• Potassium: 20 mmol/L
• Citrate: 10 mmol/L
• Osmolarity: 245 mOsm/L (reduced osmolarity)

• Mild (3-5% dehydration): 30-50 mL/kg over 4 hours
• Moderate (6-9%): 60-80 mL/kg over 4 hours
• Replace ongoing losses: 10 mL/kg per stool; 2 mL/kg per emesis

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Step 3: Dietary Management

• Continue feeding - do NOT withhold food; age-appropriate diet
• BRAT diet (Banana, Rice, Applesauce, Toast) or soft diet
• Avoid lactose-containing products temporarily in acute gastroenteritis
• Zinc supplementation (10-20 mg/day for 10-14 days) in children in developing countries - reduces duration and severity

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PHARMACOLOGY OF DIARRHOEA

1. Oral Rehydration Salts (ORS)

• Mechanism: Exploits intact Na⁺-glucose cotransport in small intestine enterocytes; water follows osmotically
• Remains effective even when electrogenic Na⁺ absorption is impaired

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2. Antimotility Agents

Loperamide (Imodium)

• Class: Opioid receptor agonist (MOR - mu opioid receptor)
• Mechanism:
  • Binds peripheral MOR on enteric neurons - reduces peristalsis
  • Increases small intestinal and mouth-to-caecum transit time
  • Increases anal sphincter tone
  • Has antisecretory activity against cholera toxin and E. coli toxin (counters adenylyl cyclase stimulation via G-linked receptors)
  • 40-50 times more potent than morphine as antidiarrhoeal; poorly crosses the BBB
• ADME: Oral (capsule/solution/chewable tablet); peak plasma at 3-5 hours; t½ ~11 hours; extensive hepatic metabolism
• Dose: Adults: 4 mg initially, then 2 mg after each loose stool; max 16 mg/day. Children: 2-5 yr: 3 mg/day max; 6-8 yr: 4 mg/day; 8-12 yr: 6 mg/day; not recommended <2 years
• Adverse effects: Constipation, abdominal bloating, nausea
• Contraindications: Bloody diarrhoea or suspected invasive bacterial diarrhoea (may mask infection, delay clearance, increase risk of systemic invasion); avoid in C. difficile colitis; caution in young children

Diphenoxylate + Atropine (Lomotil)

• Mechanism: Diphenoxylate is a synthetic opioid (MOR agonist); reduces GI motility. Atropine added in subtherapeutic dose to deter abuse
• Use: Acute/chronic non-inflammatory diarrhoea
• Penetrates CNS more than loperamide - more CNS side effects

Codeine phosphate

• Opioid with antidiarrhoeal and analgesic effects; used for refractory diarrhoea; risk of dependence

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3. Antisecretory Agents

Bismuth Subsalicylate (Pepto-Bismol)

• Mechanism: Antisecretory + anti-inflammatory + antimicrobial effects; in stomach low pH forms bismuth oxychloride; clay component may adsorb toxins; salicylate component has anti-inflammatory activity
• Uses: Traveller's diarrhoea (prevention and treatment), acute gastroenteritis, non-ulcer dyspepsia
• Dose: 30 mL or 2 tablets every 30-60 min, up to 8 times/day; each dose contains ~262 mg each of bismuth and salicylate
• Adverse effects: Black stools (bismuth sulfide - not melena), black tongue; salicylate absorbed - carries Reye's syndrome warning in children; tinnitus, CNS effects
• Note: 99% of bismuth unabsorbed; salicylate is absorbed

Racecadotril (Acetorphan)

• Mechanism: Prodrug - converted to thiorphan, an enkephalinase inhibitor (NEP inhibitor). Inhibits breakdown of enkephalins → increased enkephalin activity → reduced cAMP-driven intestinal secretion via delta opioid receptors (DOR). Pure antisecretory - does not affect motility
• Advantage: Does not cause rebound constipation; preferred in children
• Use: Acute secretory diarrhoea, especially in children

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4. Antibiotics (Empiric and Targeted)

• Moderate-to-severe traveller's diarrhoea
• Suspected bacterial dysentery (Shigella, Campylobacter)
• C. difficile colitis
• Giardia, Entamoeba histolytica
• Immunocompromised patients

• Enterohemorrhagic E. coli (EHEC/O157:H7) - risk of HUS
• Uncomplicated viral gastroenteritis
• Mild, self-limiting bacterial diarrhoea

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5. Probiotics

• Mechanism: Restore commensal microflora; compete with pathogens; modulate immune response
• Evidence-based strains:
  • Lactobacillus GG - effective in acute infectious diarrhoea, antibiotic-associated diarrhoea
  • Saccharomyces boulardii - effective in antibiotic-associated and infectious diarrhoea
• Uses: Antibiotic-associated diarrhoea, C. difficile (adjunct), acute gastroenteritis

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6. Drugs for Specific Syndromes

Diarrhoea-Predominant IBS (IBS-D)

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7. Anti-parasitic Drugs

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8. Zinc Supplementation

• WHO recommendation: 10 mg/day (<6 months); 20 mg/day (>6 months) for 10-14 days in children with acute diarrhoea
• Reduces severity, duration, and recurrence risk

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Summary Algorithm

Acute Diarrhoea (<14 days)
├── Mild/No dehydration → ORS + continue diet + zinc (children)
├── Bloody/fever/severe → Stool culture + antibiotics (targeted)
├── Traveller's diarrhoea → Fluoroquinolone or Azithromycin
├── Antibiotic-associated → Check C. difficile; vancomycin/fidaxomicin
└── Suspected viral → Supportive only; no antibiotics

Chronic Diarrhoea (>14 days)
├── Osmotic gap → check for osmotic cause (dietary, laxative)
├── Fecal leukocytes/calprotectin ↑ → Colonoscopy; consider IBD
├── Steatorrhea → Malabsorption workup (biopsy, ERCP, breath tests)
├── Secretory (hormonal) → Serum VIP, gastrin, 5-HIAA, calcitonin
└── IBS-D → Loperamide / Alosetron / Eluxadoline / Rifaximin

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• Henry's Clinical Diagnosis and Management by Laboratory Methods - Table 23.4 (Lab investigations)
• Harrison's Principles of Internal Medicine 22E - Chronic diarrhoea chapter
• Rosen's Emergency Medicine - Acute diarrhoea, dehydration management
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Antidiarrheal pharmacology (loperamide, bismuth, racecadotril, alosetron, eluxadoline, antibiotics)
• Goldman-Cecil Medicine - Postoperative diarrhoea, C. difficile

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Dysentery: Complete Clinical Guide

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1. DEFINITION

• Stools are small in volume (not watery and large)
• Visible blood + mucus in stool
• Tenesmus - painful ineffectual urge to defecate
• Systemic features: fever, malaise, toxaemia

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2. TYPES / CLASSIFICATION

A. By Causative Agent

B. By Duration

C. By Severity

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3. CAUSES (Aetiology)

Bacterial

Parasitic

Other

• Clostridioides difficile - Antibiotic-associated pseudomembranous colitis
• Ulcerative colitis - Non-infectious inflammatory cause of bloody diarrhoea mimicking dysentery
• Ischaemic colitis - Particularly in elderly

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4. PATHOLOGY

A. Bacillary Dysentery (Shigella) - Detailed Pathogenesis

1. Entry via M cells: Shigella selectively adheres to and transcytoses through follicle-associated M cells (lack brush border) overlying mucosal lymphoid nodules
2. Macrophage apoptosis: Bacteria enter subepithelial macrophages, escape the phagosome, and activate caspase-1 via IpaB - inducing macrophage apoptosis (releases IL-18 and IL-1β)
3. Basolateral invasion of enterocytes: Released bacteria contact the basolateral surface of enterocytes; Type III secretion system injects IpaA, IpaB, IpaC, IpaD proteins into the host cell
4. Actin polymerization and intracellular spread: IcsA (VirG) protein on the bacterial surface recruits N-WASP to polymerize actin, propelling bacteria through cytoplasm and into neighbouring cells (cell-to-cell spread)
5. Massive inflammatory response: Infected epithelial cells release IL-8, massively recruiting PMNs, which further destabilize the epithelial barrier, exacerbating inflammation
6. NF-κB activation: Intracellular NLR (NOD-like receptor) activation + IL-1β drives NF-κB signalling → acute colitis

• Phase 1 (watery): Active secretion/abnormal water reabsorption in jejunum - due to enterotoxin ShET-1 and early mucosal inflammation
• Phase 2 (dysenteric): Colonic mucosal invasion - bloody, mucopurulent stools with tenesmus

• Acute purulent proctitis with multiple small shallow ulcers (bacillary dysentery - Bailey & Love)
• Edematous, hemorrhagic colonic mucosa
• Ulcerations with overlying exudates (pseudomembrane-like)
• Mainly affects distal colon and rectum

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B. Amoebic Dysentery - Pathology

1. Ingestion of cysts via contaminated water/food
2. Cysts excyst in small intestine → trophozoites in large intestine
3. Trophozoites invade colonic mucosa via proteolytic enzymes (cysteine proteases) and amoebapores (pore-forming peptides) → lysis of epithelial cells, goblet cells, and mucosal glands
4. Flask-shaped (bottleneck) ulcers: Trophozoites burrow through epithelium, creating ulcers with markedly undermined edges and a yellow necrotic floor with blood and pus
5. Trophozoites may be seen ingesting erythrocytes (erythrophagocytosis - pathognomonic)
6. Distribution: mainly distal sigmoid colon and rectum; can involve entire colon

• Hepatic amoebiasis (liver abscess) - most common extraintestinal complication
• Amoeboma: granulation tissue mass (mimics colonic carcinoma)
• Toxic megacolon (0.5% of cases)
• Haemorrhage, stricture formation, perforation
• Pericolitis with adhesions → intestinal obstruction
• Intussusception and necrotizing colitis (in children)

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5. CLINICAL FEATURES

Bacillary Dysentery (Shigellosis) - Four Phases:

• HUS (S. dysenteriae type 1): Microangiopathic haemolytic anaemia + thrombocytopenia + acute renal failure
• Toxic megacolon: Severe inflammation extending transmurally; colon dilatation
• Rectal prolapse - especially in malnourished children
• Hypoglycaemia, hyponatraemia (metabolic)
• Bacteraemia (rare; <5%; mainly malnourished/HIV patients)
• Ekiri syndrome (toxic encephalopathy in Japanese children)
• Reactive arthritis (post-dysentery HLA-B27 associated)
• Seizures, delirium, coma (children <5 years)

Amoebic Dysentery Features:

• Slower onset (3-4 weeks after infection) vs. bacterial (1-2 days)
• Lower fever or no fever (fever present in minority)
• Abdominal tenderness + increasingly severe diarrhoea
• Proctoscopy and sigmoidoscopy not painful (contrast to bacillary)
• More often chronic course with exacerbations after prolonged symptom-free periods

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6. DIAGNOSTIC APPROACH

Step 1: History

• Travel history, food/water source, contact history
• Antibiotic use (C. difficile)
• Duration, character of stool (blood, mucus, volume)
• Onset speed - bacterial: 1-2 days; amoebic: weeks

Step 2: Physical Examination

• Temperature, dehydration signs
• Abdominal tenderness (LIF/suprapubic)
• Rectal examination / proctoscopy / sigmoidoscopy

Step 3: Stool Investigations

• Shigellosis: Many PMNs per field; no trophozoites
• Amoebiasis: Erythrophagocytic trophozoites; very few PMNs

Step 4: Blood Investigations

Step 5: Endoscopy / Imaging

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7. MANAGEMENT

General / Supportive

1. Oral rehydration therapy (ORT) - WHO ORS (245 mOsm/L) is the mainstay; IV fluids only for severe dehydration/coma/shock
   • Shigellosis rarely causes significant dehydration - but remains important in endemic settings
2. Nutrition: Start as early as possible; malnutrition is the primary risk factor for death
3. Isolation: Source isolation; strict hand hygiene; sodium hypochlorite decontamination
4. Zinc supplementation (children): 10-20 mg/day × 10-14 days
5. AVOID antimotility agents (loperamide, diphenoxylate) in dysentery - risk of toxic megacolon, prolonged fever, increased HUS risk in EHEC

Management of Complications

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8. PHARMACOLOGY

A. Antibiotics for Bacillary Dysentery

IMPORTANT: As an invasive disease, shigellosis requires antibiotic treatment. However, multidrug resistance is now a dominant factor in treatment decisions.

First-Line: Fluoroquinolones

Alternative/Second-Line

Antibiotics by Organism (Goldman-Cecil Table 265-7)

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B. Treatment of Amoebic Dysentery

Step 1: Tissue Amoebiasis (Active Dysentery/Invasive Disease)

• Rapidly absorbed orally; t½ 8 hours; >50% hepatic metabolism; excreted in urine
• Adverse effects: Nausea, vomiting, diarrhoea, metallic taste (very common), headache, dizziness, vertigo, numbness
• Disulfiram-like reaction with alcohol (avoid alcohol during and 48h after course)
• Can cause peripheral neuropathy in high doses / prolonged use

• Longer half-life → shorter dosing regimen
• Less GI side effects
• Same alcohol warning (disulfiram-like reaction)

Step 2: Luminal Amoebiasis (Eradication of Cysts - MANDATORY after tissue therapy)

Neither metronidazole nor tinidazole reliably eradicates intraluminal cysts - therefore a luminal amoebiocide MUST always follow tissue therapy to prevent relapse.

1. Metronidazole or Tinidazole (tissue) THEN
2. Paromomycin or Diloxanide furoate (luminal cyst eradication)

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C. Treatment of Schistosomal Dysentery

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D. Treatment of C. difficile Colitis (Antibiotic-Associated Dysentery)

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E. Drugs to AVOID in Dysentery

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Summary: Bacillary vs. Amoebic Dysentery

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• Harrison's Principles of Internal Medicine 22E - Shigellosis chapter (Chapters 172, 230)
• Goldman-Cecil Medicine - Amebic Dysentery, Table 265-7
• Bailey and Love's Short Practice of Surgery 28th Ed - Bacillary and Amoebic dysentery pathology
• Sherris & Ryan's Medical Microbiology 8th Ed - Shigella pathogenesis
• Robbins & Kumar Basic Pathology - Infectious Enterocolitis
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Metronidazole, antiprotozoal drugs

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Irritable Bowel Syndrome (IBS): Complete Clinical Guide

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1. DEFINITION

• Functional constipation (chronic idiopathic constipation)
• Functional diarrhoea
• Functional abdominal bloating/distension
• Functional dyspepsia

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2. EPIDEMIOLOGY

• Global prevalence: 4.1% (Rome IV criteria); up to 9% using older Rome III criteria
• More common in women (5.2%) than men (2.9%) - odds ratio ~1.7
• More prevalent in patients under 50 years and those with lower socioeconomic status
• Up to 50% of individuals with IBS symptoms do not seek healthcare
• Generates ~4.4 million annual physician visits in the US alone
• Associated with significant work absenteeism and impaired productivity
• IBS-D and IBS-M each account for 35-40% of cases; IBS-C ~25%; IBS-U <5%

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3. TYPES / SUBTYPES

• Women with IBS are more likely to have IBS-C (OR 2.38)
• Men with IBS are more likely to have IBS-D (OR 0.45 in women, i.e., men predominate)
• Women's symptoms can worsen premenstrually when oestrogen and progesterone decline

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4. CAUSES AND RISK FACTORS

A. Predisposing Factors

B. Precipitating Factors

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5. PATHOBIOLOGY (Pathophysiology)

A. Visceral Hypersensitivity (Central Mechanism)

• Patients have lowered pain thresholds to luminal distension (balloon distension studies show pain at lower volumes than healthy controls)
• Allodynia: Perception of pain with normally non-painful stimuli
• Central sensitization: Altered brain processing of visceral afferent signals
• Brain imaging shows activation of emotional arousal centres (amygdala, anterior cingulate cortex) during rectal distension rather than the pain inhibitory areas (prefrontal cortex) seen in controls
• Endogenous pain modulation is impaired: Reduced activation of descending inhibitory pathways; reduced activation of PFC during rectal distension
• Structural brain changes: Greater volume/cortical thickness of sensorimotor cortex correlating with symptom severity

B. Altered GI Motility

• Colonic transit is slower in IBS-C and faster in IBS-D
• Exaggerated colonic responses to meals (gastrocolic reflex), cholecystokinin (CCK), and mechanical stimuli
• Increased high-amplitude propagating contractions (HAPCs) in some patients

C. Mucosal Immune Activation

• Increased mast cells adjacent to sensory neurons in colonic mucosa
• Mast cells release histamine → activate afferent nerves → peripheral sensitization → increased abdominal pain
• Increased T lymphocytes in colonic mucosa
• Elevated mucosal colonic nerves expressing substance P, TRPV1 cannabinoid receptors, and protease-activated receptors

D. Increased Intestinal Permeability (Leaky Gut)

• Some patients have decreased tight junction protein expression in jejunum and colon
• Increased permeability linked to greater visceral hyperalgesia, abdominal pain severity, and altered bowel habits
• Likely mediated by immune activation (mast cells + T cells) and food allergens
• Also linked to non-classical food allergies and postprandial symptoms

E. Dysbiosis (Gut Microbiota Imbalance)

• IBS fecal microbiota shows:
  • Increased: Enterobacteriaceae, Lactobacillaceae, Bacteroides (produce organic acids, reduce mucosal glycoproteins)
  • Decreased: Clostridiales, Faecalibacterium prausnitzii, Bifidobacterium (produce butyrate - anti-inflammatory, epithelial energy source)
• ~25% of IBS patients have bile acid diarrhoea (BAD) due to impaired ileal bile acid reabsorption

F. Serotonin (5-HT) Dysregulation

• ~95% of body's serotonin is in enterochromaffin cells of the gut
• Serotonin regulates motility, secretion, and visceral sensation
• Altered serotonin transporter (SERT) expression in IBS:
  • Low SERT expression → excess 5-HT → IBS-D (increased secretion and motility)
  • High SERT expression → rapid 5-HT reuptake → IBS-C
• This forms the basis for 5-HT-targeted pharmacotherapy

G. Dysregulated Stress Response

• Hyperactivated hypothalamic-pituitary-adrenal (HPA) axis in IBS compared to controls
• Stress increases visceral sensitivity, gut motility, gut permeability, and mucosal immune responses
• Explains worsening of IBS during periods of psychological stress

H. Genetic/Epigenetic Factors

• Polymorphisms in 5-HTTLPR, CRF-1R, cannabinoid receptors, COMT
• Alterations in gene methylation and non-coding microRNA expression

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6. CLINICAL FEATURES

Core Symptoms (Required for Diagnosis)

• Recurrent abdominal pain: Crampy, lower abdominal, often related to defecation
• Altered bowel habits: Diarrhoea, constipation, or alternating
• Associated with defecation: Pain relieved or worsened by passing stool
• Bloating/abdominal distension: Very common; often worsens through the day

Supportive Symptoms

Extraintestinal Manifestations (Frequent Comorbidities)

• Functional: Functional dyspepsia, functional heartburn (coexist in ~1/3)
• Pain syndromes: Fibromyalgia, chronic pelvic pain, chronic fatigue syndrome
• Urological: Interstitial cystitis, painful bladder syndrome
• Neurological: Migraine headaches, temporomandibular joint disorder
• Gynaecological: Dysmenorrhoea
• Psychological: Anxiety, depression, somatization (major comorbidities)
• Sleep disturbances: Especially when GI symptoms are severe

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7. DIAGNOSTIC APPROACH

Rome IV Diagnostic Criteria (2016) - Gold Standard

1. Related to defecation
2. Associated with a change in frequency of stool
3. Associated with a change in form (appearance) of stool

IBS Diagnostic Algorithm (Goldman-Cecil, Fig. 123-1):

Alarm Features (Red Flags) - REQUIRE FURTHER INVESTIGATION

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Investigations

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8. MANAGEMENT

Step 1: Patient Education and Reassurance

• Explain the functional nature of IBS; reassure no malignancy
• Set realistic expectations - IBS is chronic but not progressive or life-threatening
• Address psychological concerns; validate symptoms

Step 2: Dietary Modification (First-Line)

Step 3: Psychological Therapies (Highly Effective)

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9. PHARMACOLOGY

A. Drugs for PAIN AND SPASM

1. Antispasmodics (First-Line for Abdominal Pain)

2. Peppermint Oil

• Mechanism: L-menthol - acts as calcium channel antagonist on gut smooth muscle → relaxation; also TRPV1 agonist → reduces visceral hypersensitivity; mild local anaesthetic effect
• Dose: ≥200 mg TDS (enteric-coated capsules to prevent lower oesophageal sphincter relaxation and heartburn)
• NNT: 4 (3-6) for abdominal pain and global IBS symptoms
• Recommended by: ACG, CAG, AGA, NICE
• Adverse effects: Heartburn/reflux (if non-enteric-coated), perianal burning

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B. Drugs for IBS-D (Diarrhoea-Predominant)

1. Loperamide

• Mechanism: Peripheral mu-opioid receptor (MOR) agonist → reduces intestinal motility + increases anal sphincter tone + antisecretory activity
• Dose: 2-4 mg as needed; max 16 mg/day
• Evidence: Reduces stool frequency and improves consistency; does NOT significantly reduce abdominal pain - used as an adjunct to other IBS-D therapies
• Caution: Do not use in IBS as monotherapy for pain

2. Alosetron (Lotronex) - 5-HT3 Antagonist

• Mechanism: Potent antagonist of 5-HT3 receptors on enteric neurons; reduces colonic contractility, decreases colonic transit, increases fluid and electrolyte absorption, reduces visceral hypersensitivity
• Dose: 0.5-1 mg BD; start at 0.5 mg BD × 4 weeks; max 1 mg BD
• Indication: FDA-approved for severe IBS-D in women who have failed conventional therapy
• Adverse effects: Ischaemic colitis (3/1000 patients - serious adverse effect), severe constipation, nausea, GI discomfort
• Restricted access: Requires physician certification and detailed patient consent/education protocol due to risk of ischaemic colitis (discontinued treatment required immediately if symptoms develop)

3. Eluxadoline (Viberzi) - Mixed Opioid Receptor Agent

• Mechanism: MOR agonist + DOR antagonist + KOR agonist - acts locally in enteric nervous system; reduces abdominal pain and diarrhoea without causing rebound constipation
• Dose: 100 mg BD with food (gallbladder intact); 75 mg BD (no gallbladder)
• Adverse effects: Pancreatitis (especially in patients without a gallbladder - sphincter of Oddi spasm), constipation, nausea, abdominal pain
• Contraindicated in: Biliary duct obstruction, sphincter of Oddi disease/dysfunction, pancreatitis history, absent gallbladder (relative), severe constipation, alcohol dependence

4. Rifaximin - Non-absorbable Antibiotic

• Mechanism: Non-absorbed rifamycin-class antibiotic; inhibits bacterial RNA polymerase β subunit → bactericidal effect within GI lumen without systemic absorption; reduces dysbiosis and SIBO
• Dose for IBS-D: 550 mg TDS × 14 days (may repeat up to 2 courses)
• Evidence: Reduces bloating, abdominal discomfort, and diarrhoea in non-constipating IBS; ~40% response rate
• Advantage: Minimal systemic side effects; low risk of Clostridium difficile
• ACG recommendation: Strong recommendation for non-constipating IBS

5. Bile Acid Sequestrants (for IBS-D with BAD)

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C. Drugs for IBS-C (Constipation-Predominant)

1. Osmotic Laxatives

• Polyethylene glycol (Macrogol/Movicol): Improves stool frequency and consistency but does NOT reduce abdominal pain; safe, OTC, inexpensive; side effects: bloating, abdominal pain, nausea

2. Lubiprostone (Amitiza)

• Mechanism: Chloride channel (ClC-2) activator on intestinal epithelium → increased luminal chloride secretion → fluid secretion into intestinal lumen → softens stool and increases motility
• Dose: 8 µg BD for IBS-C (lower dose than for chronic idiopathic constipation)
• Evidence: Improves constipation, stool consistency, straining, abdominal pain, bloating
• Adverse effects: Nausea (most common; reduced by taking with food), diarrhoea, dyspepsia
• Contraindicated in pregnancy (possible foetal harm - category C)

3. Linaclotide (Linzess)

• Mechanism: Guanylate cyclase-C (GC-C) receptor agonist on intestinal epithelium → increases intracellular cGMP → activates CFTR chloride channel → secretion of chloride and bicarbonate into intestinal lumen → increased fluid and motility. Also decreases firing of visceral sensory C-fibres via cGMP → reduces abdominal pain (dual action)
• Dose: 290 µg OD (30 min before first meal of day) for IBS-C
• Adverse effects: Diarrhoea (most common; dose-dependent), abdominal pain
• FDA approved for IBS-C and chronic idiopathic constipation

4. Plecanatide (Trulance)

• Mechanism: Structurally similar to uroguanylin; GC-C receptor agonist (same mechanism as linaclotide but pH-sensitive - greater activity in the alkaline small intestine)
• Dose: 3 mg OD
• Evidence: Similar benefits to linaclotide in IBS-C
• Adverse effects: Diarrhoea

5. Tenapanor (Ibsrela)

• Mechanism: Minimally absorbed inhibitor of Na⁺/H⁺ exchanger isoform 3 (NHE3) in the gut → blocks sodium (and therefore water) reabsorption → increased luminal fluid → softer stools and increased motility
• Dose: 50 mg BD for IBS-C
• Adverse effects: Diarrhoea

6. Prucalopride (Resolor)

• Mechanism: Selective, high-affinity 5-HT4 receptor agonist on enteric neurons → triggers prokinetic activity throughout the colon; stimulates peristaltic reflex
• Dose: 1-2 mg OD
• Primarily approved for chronic constipation; used off-label in IBS-C
• Adverse effects: Headache, nausea, diarrhoea, abdominal pain

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D. Brain-Gut Neuromodulators (for PAIN in ALL IBS subtypes)

1. Tricyclic Antidepressants (TCAs)

• Drugs: Amitriptyline, imipramine, doxepin, desipramine, nortriptyline
• Mechanism: Block serotonin and noradrenaline reuptake → enhance descending pain inhibition; also anticholinergic effects → slow gut transit (beneficial in IBS-D)
• Dose for IBS: Low doses, 10-25 mg at bedtime (sub-antidepressant doses for pain modulation); can titrate up to 75-100 mg
• Evidence: NNT = 4.5 (3.5-7) for global IBS symptoms; especially effective for abdominal pain
• Preferred agents: Desipramine or nortriptyline (less sedation, less constipation, less dry mouth than amitriptyline)
• Especially useful: IBS-D (anticholinergic slows transit); also for sleep disturbance
• Adverse effects: Dry mouth, sedation, constipation (problematic in IBS-C), blurred vision, urinary retention, weight gain, cardiac arrhythmia (at higher doses)
• Recommended by: ACG (1A), CAG (1A) - highest quality evidence

2. Selective Serotonin Reuptake Inhibitors (SSRIs)

• Drugs: Fluoxetine, sertraline, paroxetine, citalopram
• Mechanism: Block serotonin reuptake transporter (SERT) → increased synaptic serotonin → modulates gut motility (accelerates transit) and CNS pain processing; enhances descending inhibitory pathways
• Dose: 10-100 mg daily (standard antidepressant doses)
• Evidence: NNT = 5 (3-16.5) for global IBS symptoms; less effective than TCAs for abdominal pain reduction; may be useful in IBS-C (prokinetic effect); fewer side effects than TCAs
• Adverse effects: Nausea, insomnia, sexual dysfunction, GI side effects, serotonin syndrome (rare)
• Recommended by: ACG (2C), CAG (2C)

3. Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)

• Drugs: Duloxetine, venlafaxine
• Mechanism: Dual reuptake inhibition of serotonin and noradrenaline → enhanced descending pain inhibition; especially effective for comorbid pain conditions (fibromyalgia, chronic pelvic pain)
• Use: Patients with IBS + chronic pain who cannot tolerate TCAs
• Adverse effects: Nausea, sweating, hypertension, serotonin syndrome risk

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E. Probiotics

• Mechanism: Restore commensal gut microbiota; improve dysbiosis; produce short-chain fatty acids (butyrate); modulate mucosal immune response; reduce visceral hypersensitivity
• Evidence: NNT = 7 (5-12) for global IBS symptoms (37 RCTs, n=4403); most useful for bloating
• Best-studied strains: Bifidobacterium infantis 35624, Lactobacillus plantarum, Lactobacillus GG, Saccharomyces boulardii
• Recommended by: ACG (2C), CAG (2C)
• Combination products may be more effective than single strains (NNT 19 for combinations, though CI wide)

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F. Summary Pharmacology by Subtype

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Summary: IBS at a Glance

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• Goldman-Cecil Medicine - Chapters 123 (IBS), including Rome IV criteria table and diagnostic algorithm
• Yamada's Textbook of Gastroenterology 7th Ed - Chapter 67 (comprehensive IBS pathobiology, treatment tables, NNT data)
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease - Functional bowel disorders
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Alosetron, eluxadoline, linaclotide, rifaximin, lubiprostone pharmacology

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Intestinal Worm Infestation (Intestinal Helminthiasis): Complete Clinical Guide

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1. DEFINITION

• Unlike protozoa, helminths are macroscopic multicellular organisms
• They cannot multiply within the human host (except Strongyloides and Capillaria) - disease severity is related to worm burden (intensity of infection)
• They produce eggs/larvae passed in faeces to continue the life cycle in soil or water
• Most infections are asymptomatic in low worm burdens; symptoms increase proportionately with worm load

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2. CLASSIFICATION / TYPES

A. By Organism Type

B. Common Intestinal Nematodes (Focus of This Guide)

C. Common Intestinal Cestodes (Tapeworms)

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3. CAUSES AND TRANSMISSION

Fecal-Oral Route (Most Common)

Skin Penetration Route

Meat Consumption

Special Routes

• Anisakiasis: Ingestion of raw saltwater fish (sushi/sashimi)
• Capillaria: Raw freshwater fish

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4. PATHOLOGY (Organ-by-Organ)

A. ASCARIS LUMBRICOIDES

1. Ingestion of embryonated eggs from contaminated soil/food
2. Larvae hatch in small intestine → penetrate intestinal mucosa → portal venules → liver → right heart → pulmonary capillaries
3. Too large for pulmonary capillaries → rupture into alveolar spaces → coughed up → swallowed → reach small intestine
4. Mature into adults in small intestine (2-3 months from ingestion to oviposition)
5. Adults live 1-2 years, survive by muscular swimming against intestinal flow (do NOT burrow into mucosa)

• Intestinal phase: Abdominal pain, nausea, vomiting; obstruction with heavy loads (bolus of worms in small intestine); malnutrition and growth stunting in children
• Larval migration phase (Loeffler's syndrome): Cough, wheezing, eosinophilia, transient pulmonary infiltrates on CXR
• Complications: Intestinal obstruction, biliary obstruction (worms migrating into bile duct/pancreatic duct), cholangitis, pancreatitis, perforation, volvulus, appendicitis
• Eosinophilia is prominent during larval migration phase

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B. TRICHURIS TRICHIURA (Whipworm)

1. Unembryonated eggs passed in stool → embryonate in soil (15-30 days)
2. Infective eggs ingested → hatch in small intestine → larvae mature and establish as adults in caecum and ascending colon
3. Anterior thin ends thread through and anchor in colonic mucosa; posterior ends remain free in lumen
4. Adults live ~1 year; females produce eggs 60-70 days after infection

• Light infections: Asymptomatic
• Moderate infections: Nausea, abdominal pain, diarrhoea, growth stunting
• Heavy infections (>800 worms): Entire colonic lumen parasitized → significant mucosal damage, blood loss, anaemia; "dysentery syndrome" with bloody diarrhoea mimicking Shigella; tenesmus; rectal prolapse (hallmark of heavy Trichuris load)
• Moderate eosinophilia in heavy infections (adults anchored in mucosa present antigens to GALT)

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C. ENTEROBIUS VERMICULARIS (Pinworm/Threadworm)

1. Eggs ingested (hand-to-mouth, fomites, bedding, inhalation) → hatch in small intestine → mature in large intestine
2. Female migrates nocturnally to perianal area to deposit 10,000-11,000 eggs in perianal skin folds
3. Eggs are immediately infective (no soil maturation required)
4. Reinfection: scratching → eggs under fingernails → fecal-oral transmission

• Perianal pruritus (especially nocturnal) - cardinal symptom
• Vulvovaginitis in girls (ectopic migration)
• Insomnia, irritability, restlessness
• Appendicitis (rare; ectopic worms in appendix)
• Light infections usually asymptomatic
• No eosinophilia (adults confined to intestinal lumen; no tissue invasion)

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D. HOOKWORM (Necator americanus and Ancylostoma duodenale)

1. Eggs passed in faeces → hatch in soil within 48 hours → rhabditiform larvae (free-living) → develop into infective filariform larvae within 1 week
2. Filariform larvae penetrate bare skin (usually feet)
3. Lymphohematogenous transport → right heart → lungs → rupture into alveoli → coughed up → swallowed → small intestine
4. Attach to small bowel mucosa using teeth/cutting plates; suck blood and villous tissue
5. Prepatent period: 6-8 weeks

• Ancylostoma duodenale: 0.2 mL/worm/day (more serious)
• Necator americanus: 0.03 mL/worm/day
• Additional blood loss from migration and old attachment sites

• Skin (ground itch): Pruritic maculopapular rash at larval entry site; serpiginous tracks
• Pulmonary (Loeffler's): Transient cough, eosinophilia, mild pneumonitis (less severe than Ascaris)
• Intestinal phase: Epigastric pain, nausea, bloating 1-2 months after heavy infection
• Chronic heavy infection: Iron-deficiency anaemia (hypochromic microcytic) - the major clinical consequence; hypoproteinaemia/hypoalbuminaemia with oedema (face, extremities, abdomen); fatigue, weakness, dyspnoea
• "Wakana disease" (Ancylostoma): Nausea, vomiting, dyspnoea after oral larval ingestion
• Eosinophilia peaks at 5-9 weeks (when adults appear in intestine)

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E. STRONGYLOIDES STERCORALIS

1. Filariform larvae penetrate skin → lungs → swallowed → embed in duodenojejunal mucosa
2. Parthenogenetic female worms (1-2 mm; no males in humans) produce eggs in mucosa → rhabditiform larvae pass in faeces OR
3. Autoinfection: Rhabditiform larvae → filariform larvae in bowel → penetrate colonic wall or perianal skin → re-enter circulation and repeat the cycle

• Uncomplicated strongyloidiasis: Often asymptomatic; cutaneous larva currens (serpiginous, erythematous, pruritic, moves up to 10 cm/h); midepigastric pain resembling peptic ulcer disease; nausea, diarrhoea, alternating constipation
• Hyperinfection syndrome (immunocompromised patients - steroids, HTLV-1, immunosuppression): Massive larval dissemination throughout body; gram-negative bacteraemia (larvae carry gut bacteria through intestinal wall); meningitis; hepatitis; can be fatal
• Eosinophilia characteristic; may be absent in hyperinfection

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F. TAPEWORMS (Cestodes)

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G. INTESTINAL FLUKES (Trematodes)

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5. CLINICAL FEATURES SUMMARY

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6. DIAGNOSTIC APPROACH

Step 1: History

• Geographic origin / travel history (tropical, endemic areas)
• Barefoot outdoor exposure (hookworm, Strongyloides)
• Dietary habits (raw fish, pork, beef, vegetables)
• Contact with soil / playing in dirt
• Household contacts with similar symptoms
• Perianal itch (Enterobius)
• Immunosuppression status (critical for Strongyloides hyperinfection)

Step 2: Clinical Examination

• Growth assessment in children (stunting, weight)
• Pallor (iron deficiency / B12 deficiency anaemia)
• Oedema (hypoalbuminaemia in hookworm)
• Abdominal tenderness
• Rectal prolapse (heavy Trichuris)
• Skin: perianal excoriation (Enterobius), ground itch, larva currens

Step 3: Stool Examination (Primary Diagnostic Tool)

Step 4: Special Tests by Organism

Step 5: Additional Investigations

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7. MANAGEMENT

General Principles

1. Anthelmintic therapy - mainstay
2. Nutritional rehabilitation - iron, protein, vitamins
3. Treat household contacts (Enterobius - all members simultaneously)
4. Sanitation and hygiene measures - prevent reinfection
5. Mass Drug Administration (MDA) programs in endemic areas - albendazole/mebendazole annually for school-aged children (WHO-recommended deworming)

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8. PHARMACOLOGY OF ANTHELMINTICS

A. BENZIMIDAZOLES

Albendazole (Albenza, Zentel) - Broad-spectrum, Drug of Choice

• Mechanism of Action:
  • Binds to β-tubulin of helminth → inhibits tubulin polymerization → disrupts microtubule assembly → impairs glucose uptake and transport → depletes glycogen stores → immobilization and death of worm
  • Also inhibits fumarate reductase (helminth mitochondrial enzyme) → impairs energy production
  • Absorbed systemically → reaches worm's head buried in gut wall (superior to mebendazole for Trichuris)
  • Active metabolite: Albendazole sulphoxide - pharmacologically active; penetrates blood-brain barrier (useful for cysticercosis)
• Spectrum and Doses (Goldman-Cecil Table 327-1):

• ADME: Well absorbed with fatty meals; extensive first-pass hepatic metabolism to albendazole sulphoxide (active); t½ 8-12 hours; biliary excretion
• Adverse Effects: Generally well tolerated; nausea, abdominal pain; elevated liver enzymes (monitor in prolonged courses); bone marrow suppression (rare, with prolonged use); teratogenic - contraindicated in pregnancy (Category D); alopecia

Mebendazole (Vermox)

• Mechanism: Same as albendazole - binds β-tubulin → inhibits microtubule polymerization → blocks glucose uptake
• Poorly absorbed from GI tract (acts locally in intestinal lumen) - therefore less effective when the worm's head is embedded in mucosa (e.g., Trichuris)
• Doses:
  • Ascaris: 500 mg single dose or 100 mg BD × 3 days
  • Hookworm: 500 mg OD or 100 mg BD × 3 days
  • Trichuris: 100 mg BD × 3 days (albendazole preferred)
  • Enterobius: 100 mg single dose, repeat in 2 weeks
• Adverse Effects: Generally well tolerated; mild GI upset; teratogenic (avoid in first trimester)

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B. MACROCYCLIC LACTONES

Ivermectin (Stromectol) - Drug of Choice for Strongyloides

• Mechanism of Action:
  • Binds to glutamate-gated chloride ion channels (invertebrate-specific) in nerve and muscle cells of helminths
  • Also potentiates GABA-gated chloride channels → hyperpolarization → paralysis → death of parasite
  • Does NOT cross the human blood-brain barrier at therapeutic doses (BBB excludes ivermectin via P-glycoprotein)
• Spectrum and Doses:

• ADME: Oral; peak concentration 4 hours; t½ ~18 hours; hepatic metabolism; fecal excretion
• Adverse Effects: Generally very well tolerated; Mazzotti reaction (fever, pruritus, rash, hypotension) in microfilaraemic patients with onchocerciasis; CNS toxicity if BBB compromised (avoid in meningitis, concurrent CNS disease, Loa loa co-infection with high microfilaraemia)
• Note: Contraindicated in pregnancy; caution in children <15 kg

Moxidectin

• Newer macrocyclic lactone; similar mechanism to ivermectin
• Ascaris: 8 mg single dose
• Trichuris: 8 mg OD × 3 days (in combination with albendazole)

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C. PYRANTEL PAMOATE (Combantrin)

• Mechanism: Depolarising neuromuscular blocking agent - acts as nicotinic acetylcholine receptor agonist → persistent activation → spastic paralysis of worm → expelled by normal intestinal peristalsis
• Poorly absorbed from GI tract - acts locally
• Doses:
  • Ascaris, Enterobius: 11 mg/kg single dose (max 1 g)
  • Hookworm (heavy burden): 11 mg/kg × 3 days
  • Trichostrongylus: 11 mg/kg single dose
  • Enterobius: Repeat after 2 weeks
• Adverse Effects: Mild nausea, vomiting, diarrhoea, headache; generally very safe
• Contraindication: Do NOT combine with piperazine (antagonistic - piperazine causes flaccid paralysis vs. pyrantel's spastic paralysis)

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D. PIPERAZINE

• Mechanism: GABA agonist → opens Cl⁻ channels → flaccid paralysis of worm musculature → worm expelled alive by peristalsis
• Used for Ascaris and Enterobius when other agents unavailable
• Largely replaced by safer agents

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E. PRAZIQUANTEL (Biltricide) - Drug of Choice for Cestodes and Trematodes

• Mechanism:
  • Increases Ca²⁺ permeability of parasite cell membrane → influx of calcium → tetanic spasm/paralysis of worm musculature
  • Also damages worm tegument → exposes worm surface to immune attack
• Doses:
  • Taenia (tapeworms): 5-10 mg/kg single dose
  • Intestinal flukes (Fasciolopsis, Heterophyes): 25 mg/kg TDS × 1 day
  • Schistosoma: 40 mg/kg in 2 divided doses (S. mansoni/haematobium); 60 mg/kg in 3 doses (S. japonicum)
  • Clonorchis/Opisthorchis: 25 mg/kg TDS × 1 day
• ADME: Well absorbed orally; extensive first-pass hepatic metabolism; t½ ~1.5 hours
• Adverse Effects: Nausea, headache, dizziness, abdominal pain (Mazzotti-like reactions); generally transient; caution in neurocysticercosis (may trigger inflammatory reaction around dying cysts - use corticosteroids)

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F. TRICLABENDAZOLE (Egaten)

• Mechanism: Benzimidazole that uniquely inhibits tubulin in Fasciola (not nematodes)
• Treats fascioliasis: 10 mg/kg × 2 doses on consecutive days
• Also used for paragonimiasis

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G. NICLOSAMIDE

• Mechanism: Inhibits mitochondrial ATP synthesis in tapeworms by uncoupling oxidative phosphorylation → kills worm scolex (head) → worm detaches
• Used for tapeworms (Taenia, D. latum, H. nana): 2 g single dose (chewed)
• Now largely replaced by praziquantel

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H. DILOXANIDE FUROATE (Luminal Amoebiocide - also used for some protozoa)

• Not for helminths; cross-referenced as it may appear in parasite tables

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I. TREATMENT SUMMARY TABLE (Goldman-Cecil, Table 327-1)

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J. Adjunct Pharmacological Treatments

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9. PREVENTION AND PUBLIC HEALTH

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• Harrison's Principles of Internal Medicine 22E - Chapters 236-240 (all intestinal helminths); Table 327-1 (treatment doses)
• Goldman-Cecil Medicine - Table 327-1 Oral Treatment of Intestinal Nematodes
• Sherris & Ryan Medical Microbiology 8th Ed - Chapter 54 (Ascaris, Trichuris, Enterobius, Hookworm, Strongyloides life cycles and pathogenesis)
• Yamada's Textbook of Gastroenterology 7th Ed - Chapter 147 (hookworm clinical manifestations, diagnosis, treatment)
• Goodman & Gilman's - Anthelmintic pharmacology (benzimidazoles, ivermectin, praziquantel, pyrantel pamoate)

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Urinary Tract Infection (UTI): Complete Clinical Guide

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1. DEFINITION

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2. TYPES / CLASSIFICATION

A. By Anatomical Location

B. By Complexity

C. By Course

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3. CAUSES AND RISK FACTORS

Causative Organisms

Risk Factors

• Short urethra (anatomical - opens near vulva and perirectal area)
• Sexual activity, new sexual partner
• Spermicide use (disrupts vaginal flora, promotes E. coli colonisation)
• Prior UTI; family history of UTI (possible inherited urethral anatomy)
• Postmenopausal status (oestrogen deficiency → loss of Lactobacillus protection)
• Pregnancy (physiological urinary stasis; dilated ureters; progesterone smooth muscle relaxation)
• Diabetes mellitus
• High postvoid residual (incomplete emptying)

• Urological abnormalities (BPH, urethral stricture)
• Unretracted foreskin
• Male homosexuality (rectal E. coli)
• Lack of circumcision

• Urinary tract obstruction (calculi, stricture, tumour, BPH)
• Urinary instrumentation (catheterisation, cystoscopy)
• Vesicoureteral reflux
• Neurogenic bladder
• Immunosuppression (HIV, steroids, transplant)
• Hospital/nursing home setting
• Diabetes mellitus

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4. PATHOPHYSIOLOGY AND PATHOLOGY

Route of Infection

1. Colonisation of periurethral/perirectal area by enteric/vaginal flora (predominantly E. coli)
2. Colonisation of urethra → bladder ascent (facilitated by short female urethra; sexual intercourse; instrumentation)
3. Bladder infection (cystitis) → may ascend ureters to renal pelvis → pyelonephritis
4. The most common mechanism in pregnancy is ascending infection from perineal bacteria with fimbriated E. coli attaching to uroepithelial cells

Virulence Factors of Uropathogens (E. coli)

Host Defence Mechanisms (and their Failure)

• Urine flow (mechanical flushing) - impaired by obstruction, incomplete voiding
• Urinary pH, osmolality, organic acids
• Tamm-Horsfall protein (uromodulin) - binds bacteria; first-line defence
• Urothelial tight junctions - barrier
• Secretory IgA in urine
• Vaginal Lactobacillus flora in women - maintains acidic pH, produces H₂O₂

Pathology

• Mucosal erythema, oedema, petechiae
• Superficial infection of bladder mucosa - hence no systemic fever
• Microscopy: epithelial cell vacuolation, submucosa oedema, neutrophilic infiltrate

• Gross: kidney swollen, focal yellow-white abscesses on cortex (wedge-shaped)
• Micro: suppurative (neutrophilic) infiltrate in interstitium, tubules, collecting ducts; tubular necrosis; glomeruli relatively spared; pus-filled tubules
• Cortical abscesses when severe → renal carbuncle
• Complications: perinephric abscess, emphysematous pyelonephritis (gas-forming organisms in diabetics - life-threatening)

• Gross: coarse irregular corticomedullary scars; deformed calyces
• Micro: interstitial fibrosis, tubular atrophy, mononuclear infiltrate; "thyroidisation" (colloid casts in atrophic tubules resembling thyroid tissue)
• Occurs with vesicoureteric reflux (reflux nephropathy) or obstruction

• Xanthogranulomatous pyelonephritis: Lipid-laden macrophages (foam cells) replace renal parenchyma; associated with Proteus or E. coli + obstructing calculus; can mimic renal carcinoma
• Malacoplakia: Soft yellowish plaques of macrophages containing Michaelis-Gutmann bodies (calcified bacterial remnants); rare
• Emphysematous cystitis/pyelonephritis: Gas in bladder wall or renal parenchyma by glucose-fermenting organisms (E. coli, Klebsiella); mainly diabetics

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5. CLINICAL FEATURES

Uncomplicated Cystitis (Lower UTI)

• Dysuria (burning/stinging on micturition) - single most reliable symptom
• Urinary frequency (voiding small amounts frequently)
• Urgency (sudden, compelling desire to void)
• Suprapubic pain or pressure
• Haematuria (visible or microscopic)
• Nocturia
• Foul-smelling or cloudy urine (non-specific)
• NO fever, chills, or systemic symptoms
• Combination of dysuria + frequency predicts UTI in >90% of cases (in absence of vaginal discharge)

Acute Pyelonephritis (Upper UTI)

• Fever (≥38°C) - often high-spiking with rigors
• Flank/loin pain (unilateral or bilateral)
• Costovertebral angle tenderness (CVAT) on examination
• Nausea, vomiting
• Lower urinary tract symptoms (dysuria, frequency) - may precede or accompany
• Systemic toxaemia: malaise, myalgia, headache
• In pregnancy: right-sided predominance (right ureter more dilated)
• May progress to urosepsis → septic shock (10-20% mortality)

Prostatitis

• Acute bacterial prostatitis: Fever, chills, perineal/pelvic pain, dysuria, urinary retention, tender boggy prostate on PR (do NOT massage - bacteraemia risk)
• Chronic bacterial prostatitis: Voiding symptoms, low back and perineal pain, myalgias; recurrent UTIs in men

Asymptomatic Bacteriuria (ASB)

• No symptoms; detected on routine screening
• Treat in: Pregnant women, immunosuppressed, prior to urological procedures
• Do NOT treat in: Elderly, catheterised patients, diabetics (unless symptomatic) - treatment increases resistant organisms without clinical benefit

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6. DIAGNOSTIC APPROACH

Step 1: History

• Symptoms (onset, duration, character)
• Previous UTIs, recurrence pattern
• Sexual activity, spermicide use
• Pregnancy status
• Prior urological procedures, catheterisation
• Antibiotic use history (resistance risk)
• Comorbidities: DM, immunosuppression, renal disease

Step 2: Physical Examination

• Temperature (fever → upper UTI)
• Abdominal palpation - suprapubic tenderness
• CVA tenderness (CVAT) - hallmark of pyelonephritis
• PR examination in men (prostate tenderness/size)
• Pelvic examination in women (to exclude vaginitis, cervicitis)

Step 3: Urinalysis (Primary Diagnostic Test)

• Pyuria: ≥10 WBCs/mm³ (haemocytometer) - present in nearly all UTIs from coliforms
• Bacteria on microscopy: Most reliable test; Gram stain may identify organism class
• WBC casts: Highly specific for pyelonephritis (casts formed in renal tubules)
• RBC casts: Glomerulonephritis (distinguish from UTI)

• Positive culture: ≥10⁵ CFU/mL (conventional); ≥10³ CFU/mL acceptable with classic symptoms
• Identifies organism and antibiotic sensitivities (C&S)
• When to send culture:
  • Pyelonephritis
  • Complicated UTI
  • Recurrent or relapsing UTI
  • Pregnant women
  • Suspected multidrug-resistant organism
  • Men with UTI
  • No improvement after 48-72 hours of treatment
  • NOT required for uncomplicated cystitis in young women with typical symptoms

• Mid-stream clean catch (MSCC) urine - most common
• Catheter specimen (for inpatients/catheterised patients)
• Suprapubic aspiration (gold standard for infants and equivocal cases - any growth significant)

Step 4: Blood Tests (for Pyelonephritis/Complicated UTI)

Step 5: Imaging

• Previous urinary trauma/surgery
• Previous bladder/renal calculi
• Gross haematuria after resolution of infection
• Obstructive symptoms; high PVR
• Urea-splitting organisms on culture
• Immunocompromise/DM
• Repeated pyelonephritis
• Bacterial persistence despite sensitivity-based therapy

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7. MANAGEMENT

General Measures (All UTIs)

• Increased fluid intake (2-3 L/day) - dilutes urine, flushes bacteria
• Urinary analgesic: Phenazopyridine (bladder-specific local anaesthetic) for dysuria symptom relief (colours urine orange; max 2 days)
• Complete the full antibiotic course
• Treat underlying risk factors (calculi, obstruction, DM control)
• Remove/change urinary catheters where possible
• Follow-up culture (test of cure) for pregnant women, recurrent UTI, pyelonephritis

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8. PHARMACOLOGY

A. Treatment of Uncomplicated Cystitis (Lower UTI)

1. Nitrofurantoin (Macrobid, Macrodantin)

• Mechanism: Complex mechanism not fully understood; rapidly reduced intracellularly by bacterial nitroreductases to highly reactive intermediates → damage bacterial DNA, ribosomes, and multiple enzyme systems; both bacteriostatic and bactericidal (concentration-dependent)
• Spectrum: Gram-negatives (E. coli, Klebsiella, Enterobacteriaceae), Enterococci; NOT effective against Proteus, Pseudomonas, or Serratia
• Dose: Nitrofurantoin macrocrystals (Macrobid): 100 mg BD × 5 days (uncomplicated cystitis)
• ADME: Rapidly absorbed; concentrates only in urine (not in serum or tissues) → NOT suitable for upper UTI, pyelonephritis, bacteraemia, or systemic infections
• Advantages: Minimal effects on bowel or vaginal flora; exceedingly low acquired resistance in E. coli; inexpensive
• Adverse Effects: GI upset (take with food); pulmonary reactions (acute hypersensitivity pneumonitis or chronic pulmonary fibrosis - with prolonged use); peripheral neuropathy (long-term); hepatotoxicity (rare); haemolytic anaemia in G6PD deficiency
• Contraindications: eGFR <30 mL/min (inadequate urinary concentrations; accumulation of toxic metabolites); pregnancy at term (≥38 weeks) and first trimester when alternatives available; G6PD deficiency
• Avoid in: Pyelonephritis (does NOT achieve adequate tissue levels)

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

• Mechanism:
  • Sulfamethoxazole: Structural analogue of PABA → competitively inhibits dihydropteroate synthase → blocks dihydrofolic acid synthesis
  • Trimethoprim: Inhibits dihydrofolate reductase → blocks conversion of dihydrofolate to tetrahydrofolate (active form)
  • Sequential blockade of the same folate pathway = synergistic bactericidal effect (50:1 ratio in SMX:TMP in co-trimoxazole)
  • Human cells unaffected because they use dietary preformed folate
• Dose: 160/800 mg (one DS tablet) BD × 3 days (uncomplicated cystitis)
• Spectrum: E. coli, Klebsiella, Enterobacteriaceae; Staphylococci; Listeria; Pneumocystis
• Adverse Effects: GI upset; Stevens-Johnson syndrome (severe - rare); bone marrow suppression; hyperkalaemia (trimethoprim blocks renal K⁺ secretion); crystalluria; megaloblastic anaemia (folate deficiency with prolonged use)
• Contraindications: Pregnancy (first trimester - sulfonamides may cause foetal haemolysis and hyperbilirubinaemia; third trimester - risk of kernicterus); G6PD deficiency; severe renal failure
• Note: Rising resistance (up to 20-30% in some regions); check local antibiogram before empirical use

3. Fosfomycin Trometamol (Monurol)

• Mechanism: Inhibits MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) → blocks the first step in peptidoglycan cell wall synthesis; bactericidal
• Dose: 3 g sachet as a SINGLE ORAL DOSE (uncomplicated cystitis); single dose is highly effective and improves compliance
• Spectrum: E. coli, Enterococcus faecalis; active against some ESBL-producers and VRE
• ADME: Well absorbed; concentrates in urine; urinary concentrations maintained for 24-48 hours after single dose
• Advantages: Single-dose therapy; active against multidrug-resistant organisms; safe in pregnancy
• Adverse Effects: Diarrhoea, nausea; headache
• Not effective for: Pyelonephritis (inadequate tissue levels)

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B. Treatment of Uncomplicated Pyelonephritis (Upper UTI - Outpatient)

4. Fluoroquinolones (First-Line for Outpatient Pyelonephritis)

Ciprofloxacin

• Mechanism: Inhibits bacterial DNA gyrase (topoisomerase II) and topoisomerase IV → prevents DNA supercoiling, replication, and repair → stabilises DNA-enzyme complex → lethal double-strand DNA breaks; bactericidal
• Dose: Ciprofloxacin XR 500-1000 mg OD × 7 days (pyelonephritis); or Ciprofloxacin 500 mg BD × 7 days
• Spectrum: Excellent against gram-negatives (E. coli, Klebsiella, Proteus, Pseudomonas); Staphylococci
• Advantages: Excellent tissue penetration including prostate (first-line for prostatitis); excellent urinary concentrations
• Adverse Effects: GI disturbances; CNS effects (dizziness, headache, seizures - rare); tendinopathy/tendon rupture (especially Achilles; risk with age >60, steroids); peripheral neuropathy; prolonged QT interval; photosensitivity; cartilage damage (avoid in children and pregnancy); Clostridioides difficile
• Resistance: Chromosomal mutations in DNA gyrase/topoisomerase IV; plasmid-mediated PMQR genes; up to 20-30% resistance in some regions; 80% resistance in transplant units using prophylactic fluoroquinolones
• Contraindications: Pregnancy, children, myasthenia gravis; caution with QT-prolonging drugs

Levofloxacin

• Third-generation fluoroquinolone; enhanced gram-positive activity vs. ciprofloxacin
• Dose: 250-500 mg OD × 7-10 days (uncomplicated pyelonephritis); 750 mg OD × 5 days (complicated)

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C. Treatment of Complicated UTI / Severe Pyelonephritis (Inpatient IV Therapy)

5. Third/Fourth-Generation Cephalosporins

Ceftriaxone

• Mechanism: Beta-lactam; binds Penicillin-Binding Proteins (PBPs) → inhibits transpeptidation step in peptidoglycan cross-linking → cell wall synthesis blocked → osmotic lysis
• Dose: 1-2 g IV once daily (pyelonephritis, urosepsis); first IV dose for severe pyelonephritis requiring admission
• Spectrum: Excellent gram-negative coverage (E. coli, Klebsiella, Proteus); limited Pseudomonas; Staphylococci (not MRSA)
• Adverse Effects: Hypersensitivity; GI disturbance; biliary sludge; cholecystitis (with high doses or prolonged use)

Cefepime (4th gen)

• Extended gram-negative coverage including Pseudomonas
• Dose: 1-2 g IV every 8-12 hours
• Used for complicated UTI/pyelonephritis

6. Aminoglycosides

Gentamicin / Amikacin

• Mechanism: Binds irreversibly to 30S ribosomal subunit → inhibits protein synthesis → causes mRNA misreading → insertion of wrong amino acids → dysfunctional proteins; also disrupts cell membrane
• Dose: Gentamicin 3-5 mg/kg/day IV (once-daily dosing preferred; monitor trough levels); Amikacin 15 mg/kg/day
• Advantages: Excellent urinary concentrations; bactericidal; active against Pseudomonas
• Adverse Effects: Nephrotoxicity (tubular necrosis; monitor creatinine); ototoxicity (vestibular > cochlear); avoid in pre-existing renal failure
• Use: Second-line; complicated UTI; hospital-acquired UTI

7. Piperacillin-Tazobactam

• Mechanism: Piperacillin (anti-pseudomonal penicillin) + tazobactam (beta-lactamase inhibitor) → protects from enzymatic inactivation
• Dose: 4.5 g IV every 6-8 hours
• Spectrum: Broad gram-negative including Pseudomonas; gram-positive; anaerobes
• Use: Complicated/hospital UTI; Pseudomonas UTI; ESBL-producing organisms (some strains)

8. Carbapenems

Meropenem / Imipenem-Cilastatin / Ertapenem

• Mechanism: Beta-lactam with broadest spectrum; stable to most beta-lactamases including ESBLs; binds PBPs → cell wall synthesis inhibition
• Use: Multidrug-resistant UTI (ESBL producers, carbapenem-sensitive Klebsiella); last resort for complicated UTI
• Dose: Meropenem 500 mg-1 g IV every 8 hours; Ertapenem 1 g IV once daily

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D. Treatment of Specific UTI Types

Trimethoprim (alone - used in UK)

• Mechanism: Inhibits dihydrofolate reductase alone
• Dose: 200 mg BD × 3 days (uncomplicated cystitis); or 100 mg ON for prophylaxis
• Commonly used in the UK as first-line for uncomplicated UTI

Nitrofurantoin vs Trimethoprim for Uncomplicated Cystitis (Efficacy)

• Both have ~85-90% clinical cure rates for uncomplicated cystitis
• Nitrofurantoin preferred when TMP-SMX resistance is >20% locally

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E. Antibiotic Selection by UTI Type - Treatment Summary

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F. Drugs for Recurrent UTI Prophylaxis

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G. Non-Antibiotic Approaches for Recurrent UTI Prevention

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9. SPECIAL POPULATIONS

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• Rosen's Emergency Medicine - Chapter 85 (UTI in adults and pregnancy; drug tables; diagnostic approach)
• Campbell-Walsh-Wein Urology 3-Volume Set - Chapter 55 (Nitrofurantoin, fluoroquinolone pharmacology; antimicrobial formulary; recurrent UTI management)
• Comprehensive Clinical Nephrology 7th Ed - Chapter definitions, pathogenesis, pregnancy UTI
• Harrison's Principles of Internal Medicine 22E - Antibiotic mechanisms (nitrofurantoin, quinolones)
• Goldman-Cecil Medicine - Complicated UTI, Pseudomonas UTI management

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What This Guide Covers

1. Definition

2. Types of Stones (with distribution pie chart)

• Calcium oxalate (~60-70%) - most common; radiopaque; monohydrate (dumbbell) and dihydrate (envelope) crystal forms
• Calcium phosphate (~10-20%) - includes brushite; alkaline urine; associated with RTA and hyperparathyroidism
• Struvite (~15-20%) - infection stones; magnesium ammonium phosphate; form staghorn calculi; need urease-producing bacteria
• Uric acid (~5-10%) - radiolucent; acidic urine; dissolvable with alkalinisation
• Cystine (~2%) - autosomal recessive; hexagonal crystals; COLA amino acids
• Drug-induced - indinavir, triamterene, topiramate, acyclovir, loop diuretics

3. Causes and Risk Factors

4. Pathophysiology + Flowcharts

• Master flowchart: Predisposing factors → Supersaturation → Nucleation (homogeneous/heterogeneous) → Crystal growth → Aggregation → Randall plaque anchoring → Stone growth → Ureteral migration → Colic
• Stone-specific pathways: CaOx (enteric hyperoxaluria), Struvite (urease cascade: urea → NH₃ → alkaline urine → MgNH₄PO₄), Uric acid (acidic urine + hyperuricosuria), Cystine (genetic transporter defect)
• Key inhibitors: citrate, magnesium, pyrophosphate, Tamm-Horsfall protein, glycosaminoglycans

5. Clinical Features

• Acute renal colic: abrupt onset severe colicky flank pain with location-dependent radiation (loin → groin → testis/labia); haematuria; nausea/vomiting; patient writhes
• Other presentations: asymptomatic, recurrent UTI, chronic loin pain, AKI, urosepsis

6. Diagnostic Approach (with flowchart)

• Urinalysis: pH, crystals (hexagonal = cystine pathognomonic; coffin-lid = struvite; envelope = CaOx)
• Blood: Ca, PTH, uric acid, eGFR, FBC/CRP
• NCCT (gold standard): 98%/97% sensitivity/specificity; all stone types; low-dose CT preferred
• Radiopacity table: uric acid is radiolucent; drug stones may be invisible even on CT
• 24-hour urine collection targets table for recurrent stone formers

7. Management (with flowchart)

• Emergency: Infected obstructed kidney → immediate decompression (DJ stent or PCN) + IV antibiotics
• Conservative: Stones ≤7 mm with controlled pain; hydration, analgesia, MET, strain urine
• Surgical: ESWL (≤2 cm, non-cystine); URS + laser lithotripsy (all ureteral stones, renal ≤2 cm); PCNL (>2 cm, staghorn); open surgery (last resort)
• Chemolysis: uric acid stones dissolve with urinary alkalinisation

8. Pharmacology

• Analgesia: NSAIDs first-line (diclofenac - COX inhibition → ↓PGE₂ → ↓ureteral spasm); opioids second-line
• MET: Tamsulosin 0.4 mg OD (α₁A-blocker → relax distal ureteral smooth muscle); Nifedipine (CCB) as alternative
• Prevention: Potassium citrate (↑citrate, alkalinise); Thiazides (↑distal tubular Ca reabsorption → ↓calciuria); Allopurinol (xanthine oxidase inhibitor → ↓uric acid); Penicillamine/Tiopronin (thiol chelators for cystine); Acetohydroxamic acid (urease inhibitor for struvite); Antibiotics for struvite eradication

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Guide Summary

Section A: Foundations

• Body fluid compartments (ICF 67%, ECF 33% - plasma + interstitial)
• Normal electrolyte distribution with ranges
• AVP/ADH, RAAS, natriuretic peptides, Starling forces
• The key principle: ECF osmolality drives transcellular water movement

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Section B: Water Imbalance (Sodium Disorders)

• 3-type classification: Hypovolaemic (GI losses, Addison's, diuretics) / Euvolaemic (SIADH - most common type, drugs, hypothyroidism) / Hypervolaemic (CHF, cirrhosis, nephrotic syndrome)
• Pathophysiology: Free water excess → ↓ osmolality → water INTO brain → cerebral oedema → symptoms
• SIADH criteria + full causes (CNS, pulmonary, malignancy, drugs - SSRIs, carbamazepine, cyclophosphamide)
• Osmotic Demyelination Syndrome (ODS/CPM): Over-rapid correction >8-10 mmol/L/24h → pontine demyelination → paraparesis, locked-in syndrome
• Diagnostic flowchart: Serum osm → volume status → urine Na⁺ → urine osm
• Management by type: NS (hypovolaemic) / Fluid restriction + tolvaptan (euvolaemic/hypervolaemic) / 3% NaCl bolus (severe acute)

• Causes: Diabetes Insipidus (central vs nephrogenic), dehydration, GI losses, inadequate intake
• Pathology: Water OUT of brain → cell shrinkage → vascular tearing → SDH
• DDAVP test to distinguish Central vs Nephrogenic DI
• Free water deficit formula + correction: Max 10 mmol/L/24h
• Treatment: D5W or 0.45% NS; DDAVP for central DI; thiazides paradoxically for nephrogenic DI

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Section C: Potassium Disorders

• ECG: Flat T waves → U waves (characteristic) → ST depression
• Potentiates digoxin toxicity
• Urine K⁺ differentiates renal vs extra-renal loss
• Management: Oral KCl (40-100 mmol/day); IV for severe (never bolus); correct Mg²⁺ first

• ECG: Peaked T waves (first sign) → absent P waves → wide QRS → sine wave → VF
• Three-step treatment: (1) Calcium gluconate - cardiac membrane stabilisation; (2) Insulin/glucose + salbutamol + NaHCO₃ - shift K⁺ into cells; (3) SZC/Patiromer/Kayexalate/dialysis - remove K⁺ from body

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Section D: Calcium Disorders

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Section E: Magnesium Disorders

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Section F: Phosphate Disorders

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Section G: 16 Drug Pharmacology Profiles