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1. Malformations of the Musculoskeletal System in Children: Muscular Torticollis

Definition

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Etiology & Pathogenesis

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Classification

1. Postural torticollis – No palpable mass; only positional preference; most benign
2. Muscular torticollis (SCM tightness) – Tight SCM band without mass
3. SCM mass (sternocleidomastoid tumor/pseudotumor) – Palpable fibrotic mass within SCM; most common form; identified in first few weeks of life

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Clinical Features

• Head tilt to the affected side, chin rotated to opposite side
• Palpable firm, non-tender mass within SCM (in the mass type), usually 1–3 cm, appearing at 2–4 weeks of age and typically regressing by 6 months
• Limited range of motion of the neck
• Facial asymmetry (plagiocephaly): if untreated, facial flattening on the ipsilateral side (due to sleeping on same side), orbital and zygomatic asymmetry
• Associated anomalies: developmental dysplasia of the hip (DDH) (2–3%), foot deformities (metatarsus adductus), obstetric brachial plexus palsy

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Diagnosis

• Ultrasound (USG) of neck: gold standard for soft tissue — confirms SCM thickening/fibrosis vs. other masses
• X-ray cervical spine / AP skull: to exclude osseous anomalies (Klippel-Feil syndrome, atlanto-axial instability, cervical hemivertebra)
• MRI: reserved for atypical or non-resolving cases

Differential diagnoses: Klippel-Feil syndrome (bony fusion), atlantoaxial rotatory subluxation, ocular torticollis (squint), Sandifer syndrome (GERD), cervical lymphadenitis, osseous tumors

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Treatment

Conservative (First-line, <1 year of age)

• Passive stretching exercises by physiotherapist and trained parents: lateral tilt and rotation stretches, 3–4 sessions/day
• Active repositioning: encourage the child to turn toward the affected side
• Botulinum toxin A injections: adjunct in resistant cases to temporarily relax SCM
• Success rate: ~90% if started within first 3 months of life

Surgical (Indicated when conservative fails or age > 1 year with significant restriction)

• Distal release (most common): SCM release from clavicular and sternal heads
• Bipolar release: origin (mastoid) + insertion for severe cases
• Endoscopic release: minimally invasive option
• Post-operative: collar/brace + physiotherapy

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Complications of Untreated CMT

• Permanent facial asymmetry / cranial plagiocephaly
• Scoliosis (compensatory)
• Cervical osteoarthritis in adulthood
• Psychosocial effects

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2. Hernias of the Anterior Abdominal Wall & Inguinal Hernias

Definition

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Anatomy of the Anterior Abdominal Wall

1. Skin
2. Subcutaneous fat (Camper's fascia)
3. Scarpa's fascia (deep membranous layer)
4. External oblique aponeurosis
5. Internal oblique muscle
6. Transversus abdominis
7. Transversalis fascia
8. Extraperitoneal fat
9. Peritoneum

• Inguinal canal
• Umbilicus
• Linea alba (epigastric region)
• Femoral canal
• Incisional scars
• Spigelian line

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General Hernia Anatomy

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Types of Anterior Abdominal Wall Hernias

1. Umbilical Hernia

• In infants: due to failure of umbilical ring to close; very common; most close spontaneously by age 3–4 years; repair if still present at 4–5 years
• In adults: due to raised intra-abdominal pressure (obesity, ascites, multiparity)
• Repair: Mayo repair (vest-over-pants technique) or mesh repair

2. Paraumbilical Hernia

• Through the linea alba just above/below umbilicus
• Common in obese, multiparous women
• Does NOT spontaneously resolve → surgical repair advised
• High strangulation risk

3. Epigastric Hernia

• Through defects in linea alba between xiphoid and umbilicus
• Often contains extraperitoneal fat (no true sac)
• Small but painful; surgical repair

4. Incisional / Ventral Hernia

• Through previous surgical scars
• Risk factors: wound infection, obesity, poor technique, malnutrition, steroids
• Management: mesh repair (open or laparoscopic); recurrence rate higher than primary hernias

5. Spigelian Hernia

• Through semilunar line (lateral border of rectus sheath) at level of arcuate line
• Interparietal hernia (lies between layers) — clinically occult; diagnosed by USS or CT
• Surgical repair required

6. Lumbar Hernia

• Petit's triangle (inferior lumbar) or Grynfelt's triangle (superior lumbar)
• Rare; repair needed

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Management Principles (Abdominal Wall Hernias)

• Not all hernias need immediate repair
• Surgery is recommended when:
  • Complications are likely (strangulation, obstruction) — especially narrow-necked hernias
  • All femoral hernias should be repaired
  • Symptomatic or irreducible hernias
  • Increasing difficulty in reduction or increasing size
  • Younger adult patients (lifetime complication risk)
• Surgery may be deferred only if coexisting medical factors create prohibitive surgical risk

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Inguinal Hernias — Detailed

Anatomy of the Inguinal Canal

Hesselbach's Triangle (Direct Hernia site)

• Laterally: inferior epigastric vessels
• Medially: lateral border of rectus abdominis
• Inferiorly: inguinal ligament

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Classification: Direct vs. Indirect vs. Femoral

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Indirect Inguinal Hernia — Special Considerations in Children

• Most common hernia in children and infants
• Due to patent processus vaginalis (PPV): failure of obliteration after testicular descent
• Right > left (right testis descends later)
• Bilateral in ~10% (higher in premature infants)
• Associated conditions: undescended testis, hydrocele
• Risk of incarceration/strangulation is highest in infancy (<1 year)
• Treatment: elective herniotomy (high ligation of sac) — NOT herniorrhaphy (no repair of floor needed in children)
• In infants: surgery within days of diagnosis due to strangulation risk

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Clinical Features of Inguinal Hernia

• Reducible: lump in groin that disappears on lying down or manual pressure; expansile cough impulse
• Irreducible (incarcerated): lump that cannot be reduced; tender; no cough impulse
• Strangulated: irreducible + signs of bowel obstruction + ischemia (severe pain, vomiting, absent bowel sounds, peritonism) — surgical emergency

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Diagnosis

• Primarily clinical
• Ultrasound: for occult or uncertain cases
• CT/MRI: for complex, recurrent, or bilateral cases

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Surgical Repair (Hernioplasty)

Open Techniques

Laparoscopic Techniques

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Complications of Inguinal Hernia Repair

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Summary Table: Key Points

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Treatment of Acute Hematogenous Osteomyelitis (AHO) in Children

Based on PIDS/IDSA Clinical Practice Guidelines, Harrison's Principles of Internal Medicine (21st ed., p. 3948), and Bailey & Love's Surgery.

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Overview of Treatment Approach

1. Antibiotic therapy — to eradicate the causative organism
2. Surgical intervention — when indicated (abscess, non-response, complications)

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Step 1: Initial Assessment Before Treatment

Key principle: Obtain cultures before starting antibiotics whenever possible, but do not delay antibiotics if the child is septic.

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Step 2: Empirical Antibiotic Therapy

Most Common Causative Organisms by Age

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Empirical Antibiotic Selection

If MRSA prevalence is LOW (<10–15%) or community MSSA suspected:

If MRSA prevalence is HIGH (>10–15%) or MRSA suspected:

Neonates: Broad-spectrum coverage

• Oxacillin + Gentamicin or Ampicillin-sulbactam + Gentamicin
• Add anti-MRSA coverage if community MRSA risk

Sickle cell disease:

• Cover both Salmonella and S. aureus: Ceftriaxone + Oxacillin (or Vancomycin if MRSA concern)

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Step 3: IV-to-Oral (Sequential) Therapy

Criteria for Oral Switch (PIDS/IDSA Guidelines):

• Clinical improvement (afebrile, pain decreasing, improved mobility)
• CRP trending down significantly
• Organism identified and susceptible to oral agent with high bioavailability
• No surgical drainage required / procedure completed
• Child can tolerate oral medications
• Reliable follow-up assured

Timing of Switch:

• Typically after 2–4 days of IV therapy in uncomplicated AHO
• Some centers switch as early as 48–72 hours if criteria are met

Oral Antibiotic Options:

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Step 4: Total Duration of Antibiotic Therapy

CRP normalization is a useful guide — therapy can often be stopped safely once CRP returns to normal and the child is clinically well.

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Step 5: Surgical Treatment

Indications for Surgery

Surgical Procedures

1. Needle aspiration / bone aspiration
   • Diagnostic + therapeutic
   • Performed under imaging guidance or in theatre
   • Useful for subperiosteal collections
2. Surgical drainage and debridement
   • Cortical windowing (drilling or creating a bone window to drain pus)
   • Thorough curettage of necrotic tissue
   • Irrigation of the cavity
   • Closed suction drainage may be placed
3. Sequestrectomy
   • Removal of dead bone (sequestrum) in subacute/chronic cases
   • Only after involucrum is sufficiently formed
4. Joint washout / arthrotomy
   • If concurrent septic arthritis: emergency surgical washout of the joint
   • Hip joint septic arthritis in children = surgical emergency (risk of avascular necrosis of femoral head)

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Step 6: Monitoring Response to Treatment

Failure to improve within 48–72 hours = reassess: wrong antibiotic? abscess requiring drainage? resistant organism? wrong diagnosis?

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Special Situations

Neonatal AHO

• Often presents subtly (pseudoparalysis, irritability, swelling)
• High risk of spreading to adjacent growth plate and joint
• Multi-focal in up to 40%
• Requires aggressive IV therapy + early surgical drainage
• Prolonged course: 4–6 weeks

Pelvic Osteomyelitis

• Uncommon; involves ilium, ischium, pubis
• Often misdiagnosed (mimics septic hip, appendicitis)
• MRI is key for diagnosis
• Usually responds to antibiotics alone (less often requires surgery)

Vertebral Osteomyelitis (Discitis in Children)

• Most common at lumbar spine
• S. aureus most common; often hematogenous
• Presents with back pain, refusal to walk
• Usually treated with antibiotics alone; surgery if epidural abscess

MRSA-associated AHO (Severe)

• Community-acquired MRSA (especially USA300 strain) can cause deep vein thrombosis, pulmonary septic emboli, multi-focal disease
• Consider Vancomycin + Clindamycin (for anti-toxin effect) in severe presentations
• Higher surgical rate

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Imaging Modalities for Monitoring

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Treatment Algorithm Summary

Suspected AHO in Child
        ↓
Blood cultures + CRP/ESR/WBC + CXR
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MRI (preferred) or bone scan
        ↓
Abscess / collection identified?
    YES → Surgical drainage + antibiotics
    NO  → IV antibiotics empirically
        ↓
48–72 h: Clinical & CRP response?
    NO → Reassess; consider surgery / change antibiotics
    YES → Continue; plan IV→oral switch
        ↓
Switch to oral when criteria met (2–4 days)
        ↓
Total duration: 3–6 weeks guided by CRP + clinical response

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Key Take-Home Points

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Acute Hematogenous Osteomyelitis (AHO) in Children

Sources: PIDS/IDSA Guidelines; Bailey & Love's Surgery (28th ed., p. 656); Harrison's Principles of Internal Medicine (21st ed., p. 3948); Guide to Utilization of the Microbiology Laboratory (p. 80)

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Definition

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Epidemiology

• Incidence: ~8 per 100,000 children per year
• Peak age: 2–12 years (prepubertal); neonates form a separate high-risk group
• Sex: Boys > Girls (2:1), likely due to greater trauma exposure
• Most common sites: Distal femur > Proximal tibia > Proximal humerus > Proximal femur
• Majority (~85%) affect a single bone; multi-focal disease seen in neonates and immunocompromised

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Etiology / Causative Organisms

S. aureus is the single most common causative pathogen at all pediatric ages. MRSA strains (especially community-acquired USA300) are increasingly prevalent and associated with more severe disease.

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Pathogenesis

Why Does Infection Localize to the Metaphysis?

1. Terminal capillary loops in the metaphysis form sharp hairpin turns → sluggish blood flow → bacterial lodgment
2. These sinusoidal vessels lack phagocytic lining cells → bacteria evade early clearance
3. High metabolic activity of growth plate provides favorable environment for bacterial proliferation
4. Trauma (even minor) may cause microhematomas in metaphysis → bacterial colonization during transient bacteremia

Stages of Progression

Bacteremia → Metaphyseal seeding
        ↓
Acute inflammation (hyperemia, edema, WBC infiltration)
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Pus formation within medullary cavity (INTRAMEDULLARY ABSCESS)
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Rising intraosseous pressure → pus tracks through Volkmann's canals
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SUBPERIOSTEAL ABSCESS (periosteum stripped from bone)
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Periosteum ruptures → SOFT TISSUE ABSCESS
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Interruption of periosteal blood supply → BONE NECROSIS (SEQUESTRUM)
        ↓
Periosteum lays down new bone → INVOLUCRUM (reactive new bone shell)
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CHRONIC OSTEOMYELITIS

Special Anatomical Considerations (Bailey & Love, p. 656)

• Intracapsular metaphyses: The proximal femur, proximal humerus, proximal radius, and distal fibula have their metaphyses within the joint capsule → metaphyseal infection can directly spread into the adjacent joint → septic arthritis
• A sympathetic (sterile) joint effusion may occur adjacent to metaphyseal osteomyelitis — requires differentiation from true septic arthritis
• In neonates: the epiphyseal cartilage is crossed by transphyseal vessels → infection readily spreads to epiphysis and joint → growth plate destruction and joint sepsis are common

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Clinical Features

Symptoms

Signs

• Point tenderness over metaphysis — hallmark sign
• Local warmth, erythema, swelling (later finding)
• Restricted active and passive movement of adjacent joint
• Neonates: often subtle — irritability, reduced limb movement, swelling only

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Investigations

Laboratory Tests

Imaging

1. Plain X-ray

• First-line but insensitive early — changes appear only after 10–21 days
• Early: soft tissue swelling, loss of fat planes
• Late: lytic lesion in metaphysis, periosteal reaction, cortical erosion
• Role: exclude fracture, tumor; baseline for comparison

2. Ultrasound

• Detects subperiosteal fluid/abscess early (within days)
• Guides needle aspiration
• Cannot assess bone marrow or cortex

3. MRI — Gold Standard

• Most sensitive and specific modality for early AHO
• Detects bone marrow edema, intramedullary abscess, subperiosteal collection, soft tissue extension and transphyseal spread
• T1: low signal marrow; T2/STIR: high signal edema; Gd-contrast: rim-enhancing abscess

4. Bone Scintigraphy (Tc-99m)

• Sensitive early (within 24–48 h)
• Useful for multi-focal disease (whole-body scan)
• Less specific than MRI; involves radiation
• May be falsely negative in neonates (due to vascular compromise)

5. CT Scan

• Best for cortical destruction, sequestrum, involucrum detail
• Guides surgical planning in chronic/complicated cases
• Radiation concern limits use in children

Imaging Accuracy Comparison (PIDS/IDSA Guidelines, p. 13):

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Differential Diagnosis

Kocher criteria help differentiate septic arthritis from transient synovitis of the hip: fever, non-weight-bearing, ESR >40, WBC >12,000 — 4/4 criteria = ~99% probability of septic arthritis.

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Complications

Early

• Septic arthritis — especially hip, shoulder (intracapsular metaphyses)
• Pathological fracture — due to cortical weakening
• Septicemia / multi-organ failure — in severe cases

Late / If Inadequately Treated

• Chronic osteomyelitis — sequestrum formation, persistent sinus tracts, recurrent flares
• Growth disturbance — damage to physis → limb length discrepancy, angular deformity
• Avascular necrosis — particularly femoral head when hip joint involved
• Garre's sclerosing osteomyelitis — chronic non-suppurative form
• Brodie's abscess — walled-off chronic intraosseous abscess

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Treatment

Principles

1. Early empirical antibiotics based on likely organism and local MRSA prevalence
2. IV-to-oral switch early once criteria met
3. Surgical drainage when abscess present or medical failure
4. Monitor with serial CRP

Antibiotic Therapy

Empirical Selection

IV-to-Oral Switch (after 2–4 days if criteria met):

• Afebrile, CRP declining, tolerating oral intake
• Oral agents: Cephalexin (MSSA), Clindamycin / TMP-SMX (MRSA)

Total Duration:

• Uncomplicated AHO: 3–4 weeks
• Complicated (abscess, neonatal, delayed): 4–6 weeks

Surgical Indications

• Subperiosteal or intraosseous abscess
• No clinical improvement after 48–72 h of antibiotics
• Septic arthritis (emergency joint washout)
• Sequestrum formation
• Neonatal AHO (early drainage often needed)

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Summary

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Introduction to Clinical Pharmacology: General Issues & Fundamentals of Rational Pharmacotherapy

Based on: Harrison's Principles of Internal Medicine, 21st Ed. (p. 1880); core pharmacology principles from Goodman & Gilman's, Rang & Dale's, and WHO rational use of medicines framework.

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1. What Is Clinical Pharmacology?

1. To describe the conditions under which drug actions vary among human subjects
2. To determine the mechanisms underlying this variability, with the aim of improving therapy with available drugs and identifying new therapeutic targets

Relationship to Adjacent Disciplines

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2. Core Subdivisions of Pharmacology

2.1 Pharmacokinetics (PK) — "What the body does to the drug"

A — Absorption

• Process by which a drug moves from its site of administration into the systemic circulation
• Bioavailability (F): fraction of administered dose that reaches systemic circulation unchanged
  • IV administration: F = 100%
  • Oral: reduced by first-pass hepatic metabolism, gut wall metabolism, incomplete absorption
• Factors affecting absorption: drug solubility, formulation, GI motility, food, pH, surface area
• Routes of administration and their implications:

D — Distribution

• Movement of drug from blood into tissues
• Volume of Distribution (Vd): apparent volume into which drug is distributed
  • Vd = Dose / Plasma concentration at time 0
  • Small Vd (e.g., 5–10 L): drug confined to plasma (large MW, highly protein-bound)
  • Large Vd (e.g., hundreds of litres): extensive tissue binding (lipophilic drugs)
• Plasma protein binding: albumin (acidic drugs), α1-acid glycoprotein (basic drugs)
  • Only free (unbound) drug is pharmacologically active
• Blood-brain barrier (BBB): limits CNS entry; lipophilic, non-ionized drugs cross more readily
• Placental transfer: lipophilic, low MW, non-ionized drugs cross freely — critical in pregnancy

M — Metabolism (Biotransformation)

• Primarily hepatic; also gut wall, lung, kidney, plasma
• Goal: convert lipophilic drugs into more polar (water-soluble) metabolites for excretion
• Phase I reactions: Oxidation, reduction, hydrolysis — introduce/unmask functional groups
  • Mainly via CYP450 enzymes (CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2)
  • May produce active metabolites (e.g., codeine → morphine via CYP2D6)
  • May produce toxic metabolites (e.g., paracetamol → NAPQI)
• Phase II reactions: Conjugation (glucuronidation, sulfation, acetylation, methylation) → inactive, polar products
• First-pass effect: drugs absorbed orally pass through portal circulation → hepatic metabolism before reaching systemic circulation → reduced bioavailability (e.g., morphine, GTN, propranolol)
• Enzyme induction (e.g., rifampicin, carbamazepine, phenytoin): increases CYP activity → reduces drug levels → therapeutic failure
• Enzyme inhibition (e.g., fluconazole, erythromycin, grapefruit juice): reduces CYP activity → increases drug levels → toxicity

E — Elimination (Excretion)

• Primary route: renal (glomerular filtration, tubular secretion, tubular reabsorption)
• Also: biliary/fecal, pulmonary (volatile agents), sweat, saliva, breast milk
• Clearance (CL): volume of plasma cleared of drug per unit time (mL/min)
  • Total clearance = Hepatic clearance + Renal clearance + Other
• Half-life (t½): time for plasma drug concentration to halve
  • t½ = 0.693 × Vd / CL
  • Clinical importance: determines dosing interval; ~5 half-lives to reach steady state; ~5 half-lives to eliminate drug after stopping
• Steady state: achieved when rate of drug input = rate of elimination; reached after ~5 × t½
• Accumulation: drugs with long t½ or renal/hepatic impairment → dose adjustment required

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2.2 Pharmacodynamics (PD) — "What the drug does to the body"

Drug Receptors and Mechanisms of Action

Dose-Response Relationships

• Graded dose-response curve: increasing dose → increasing effect (up to maximum = Emax)
• Quantal dose-response: proportion of population showing a defined effect at each dose
• Key parameters:
  • Emax (Efficacy): maximum effect a drug can produce regardless of dose
  • EC50: concentration producing 50% of Emax — measure of potency
  • Potency: dose required to produce a given effect (lower dose = more potent)
  • Efficacy ≠ Potency: a drug can be highly potent but have low efficacy

Therapeutic Index (TI) / Therapeutic Window

• TD50: dose toxic in 50% of population
• ED50: dose effective in 50% of population
• Wide TI (e.g., penicillin): large safety margin
• Narrow TI (e.g., digoxin, warfarin, lithium, aminoglycosides, phenytoin): small margin between therapeutic and toxic → requires therapeutic drug monitoring (TDM)

Agonists and Antagonists

Tolerance and Tachyphylaxis

• Tolerance: decreased response to drug over time (requires dose escalation)
  • Mechanisms: receptor downregulation, enzyme induction, physiological adaptation
• Tachyphylaxis: rapid tolerance developing within minutes-hours (e.g., nitrates, ephedrine)
• Desensitization: receptor becomes unresponsive despite continued agonist presence
• Physical dependence: physiological adaptation → withdrawal syndrome on cessation (e.g., opioids, benzodiazepines, alcohol)

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2.3 Pharmacogenomics

• Study of how genetic variation affects drug response
• Key examples:
  • CYP2D6 polymorphism: poor metabolizers → codeine toxicity; ultra-rapid metabolizers → inadequate analgesia
  • CYP2C19: clopidogrel activation — poor metabolizers get inadequate antiplatelet effect
  • TPMT deficiency: azathioprine toxicity (bone marrow suppression)
  • G6PD deficiency: hemolysis with primaquine, nitrofurantoin
  • HLA-B*5701: abacavir hypersensitivity (test before prescribing)
• Guides personalized/precision medicine

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3. Drug Variability — Sources of Interindividual Differences

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4. Drug Interactions

Pharmacokinetic Interactions

Pharmacodynamic Interactions

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5. Adverse Drug Reactions (ADRs)

Classification (Rawlins & Thompson — ABC System)

WHO-UMC Causality Assessment

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6. Fundamentals of Rational Pharmacotherapy

Definition

The WHO 5-Step Prescribing Model (P-Drug Concept)

Core Principles of Rational Prescribing

1. Correct Diagnosis

• Drug therapy must be guided by an accurate diagnosis
• Empirical treatment is appropriate only when diagnosis is uncertain and delay is harmful (e.g., sepsis, meningitis)

2. Indication

• A drug should only be prescribed when there is a clear clinical indication
• Avoid polypharmacy — each drug must have a justified indication

3. Drug Selection Criteria (STEP approach)

• Safe — acceptable risk-benefit ratio for this patient
• Tolerable — acceptable adverse effect profile
• Effective — proven efficacy for the condition
• Price — affordable; least costly among equally effective options

• Evidence base: prefer drugs with RCT-level evidence; use guidelines
• Formulation: appropriate for the patient (age, swallowing ability, route)
• Spectrum: narrowest spectrum antibiotic; most specific drug

4. Correct Dosing

• Right dose: based on body weight (mg/kg), age, renal/hepatic function, pharmacogenomics
• Right interval: based on t½; too frequent → toxicity; too infrequent → subtherapeutic
• Loading dose: used when rapid steady state is needed (e.g., digoxin, amiodarone, phenytoin)
  • Loading dose = Target concentration × Vd
• Maintenance dose: sustains steady state
  • Maintenance dose = Target concentration × CL × dosing interval
• Dose reduction: required in renal/hepatic impairment, elderly, neonates

5. Route of Administration

• Determined by: urgency, drug properties (bioavailability, stability), patient factors (vomiting, unconscious), site of action
• "Start IV, switch oral as soon as possible" — reduces hospital stay, cost, line infections

6. Duration of Therapy

• Must be defined at the time of prescribing
• Too short: therapeutic failure, relapse, resistance (antibiotics)
• Too long: ADRs, drug dependence, unnecessary cost
• Chronic conditions: review regularly; step-down when possible

7. Monitoring

• Therapeutic Drug Monitoring (TDM): mandatory for narrow TI drugs

• Clinical monitoring: efficacy endpoints (BP, glucose, pain score)
• Safety monitoring: LFTs (statins, anti-TB), renal function (ACEi, metformin), CBC (azathioprine, methotrexate)

8. Patient Adherence (Compliance)

• Non-adherence is the leading cause of therapeutic failure
• Causes: complex regimens, side effects, cost, poor understanding, cognitive impairment
• Strategies to improve adherence:
  • Simplify regimens (once-daily dosing; fixed-dose combinations)
  • Clear verbal and written instructions
  • Patient education about purpose and expected effects
  • Blister packs, pill organizers
  • Regular follow-up

9. Special Populations

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7. Prescription Writing — Elements of a Valid Prescription

1. Patient details: name, age, weight (pediatrics), date
2. Drug name: preferably generic (INN) name
3. Dose: amount per administration
4. Route: oral, IV, topical, etc.
5. Frequency: once daily, q8h, PRN, etc.
6. Duration: number of days/weeks; total quantity
7. Instructions: with food/without, special precautions
8. Prescriber signature & details

Generic prescribing is preferred: reduces cost, avoids brand confusion, allows pharmacist substitution with bioequivalent products.

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8. Polypharmacy and Deprescribing

• Polypharmacy: use of ≥5 drugs simultaneously (problematic polypharmacy = inappropriate drugs)
• Risks: ADRs, drug interactions, non-adherence, falls (elderly), hospitalization
• Deprescribing: systematic, supervised process of tapering/stopping drugs that are no longer needed or causing harm
• Tools: STOPP criteria (drugs to stop), START criteria (drugs to start that may be omitted), Beers criteria (potentially inappropriate medications in elderly)

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9. Pharmacovigilance and Drug Safety Monitoring

• Ongoing surveillance of drug safety after market approval (post-marketing surveillance)
• Methods: spontaneous reporting (yellow card system), prescription event monitoring, database studies, case-control studies
• WHO Programme for International Drug Monitoring — global ADR reporting
• Goal: detect rare, delayed, or long-term adverse effects not captured in pre-marketing trials

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Summary Table: Key Concepts

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Drug Contraindications in Pregnancy

Based on: FDA Pregnancy and Lactation Labeling Rule (2015); Harrison's Principles of Internal Medicine (21st ed.); Goodman & Gilman's Pharmacology; Management of Arrhythmias During Pregnancy (p. 12); clinical teratology references.

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Background: FDA Pregnancy Classification

Old System (pre-2015): Letter Categories

Key Principle: Trimester Sensitivity

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Absolutely Contraindicated Drugs (Former FDA Category X)

1. Thalidomide

• Effect: Phocomelia (limb reduction defects), internal organ malformations, ear/eye defects
• Mechanism: Inhibits angiogenesis, TNF-α, affects cereblon protein in limb development
• Trimester: 1st (days 20–36 of gestation = most critical)
• Historical significance: 1950s–60s disaster leading to modern drug safety regulation
• Current use: Multiple myeloma, leprosy — requires mandatory pregnancy prevention program (REMS)

2. Isotretinoin (13-cis-retinoic acid)

• Effect: Retinoic acid embryopathy — craniofacial defects, CNS malformations (hydrocephalus, microcephaly), cardiac defects (conotruncal), thymic aplasia
• Risk: Even brief exposure in 1st trimester causes severe teratogenicity
• Contraception: Requires two forms of contraception; mandatory iPLEDGE program in USA
• Avoidance: Stop ≥1 month before conception

3. Methotrexate

• Effect: Folic acid antagonist → neural tube defects, skeletal abnormalities, spontaneous abortion, fetal death
• Trimester: All (abort at any stage)
• Uses: RA, psoriasis, ectopic pregnancy, cancer
• Note: Also used therapeutically to terminate ectopic pregnancy
• Washout: Stop ≥3 months before conception; supplement folic acid

4. Warfarin

• Effects by trimester:
  • 1st trimester: Warfarin embryopathy — nasal hypoplasia, stippled epiphyses, chondrodysplasia punctata
  • 2nd–3rd trimester: CNS defects (Dandy-Walker, agenesis of corpus callosum), optic atrophy
  • Near delivery: Fetal/neonatal hemorrhage (fetus cannot reverse anticoagulation)
• Safe alternative: Low-molecular-weight heparin (LMWH) — does not cross placenta
• Exception: Mechanical heart valves may require warfarin in 2nd trimester under specialist guidance (risk-benefit decision)

5. Valproic Acid (Sodium Valproate)

• Effects:
  • Neural tube defects (spina bifida, anencephaly) — 1–2% risk (10× background)
  • Fetal valproate syndrome: midface hypoplasia, long philtrum, thin lips, digital anomalies
  • Cognitive impairment: children exposed in utero have significantly lower IQ scores; autism spectrum disorder
• Mechanism: Inhibits histone deacetylase; folate antagonism
• Trimester: 1st most critical; cognitive effects across all trimesters
• UK MHRA: Valproate is banned in women of childbearing age unless Pregnancy Prevention Programme is in place

6. Carbamazepine

• Effects: Neural tube defects (spina bifida ~1%), craniofacial defects, fingernail hypoplasia, developmental delay
• Safer than valproate but still teratogenic
• Alternative: Lamotrigine or levetiracetam (relatively safer in pregnancy)

7. Phenytoin

• Effects: Fetal hydantoin syndrome — hypertelorism, broad nasal bridge, digital/nail hypoplasia, cleft lip/palate, cardiac defects, cognitive impairment
• Mechanism: Folate antagonism, toxic epoxide metabolites

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Cardiovascular Drugs

8. ACE Inhibitors & ARBs

• Safe in 1st trimester (debated, but generally used if needed)
• Contraindicated from 2nd trimester onward:
  • ACE inhibitor fetopathy: oligohydramnios, renal tubular dysgenesis, anuria, neonatal renal failure, skull ossification defects (calvaria hypoplasia), limb contractures, pulmonary hypoplasia
  • Mechanism: Fetal RAA system blockade → fetal hypotension → renal ischemia
• Drugs: Enalapril, lisinopril, ramipril; Losartan, valsartan, candesartan (ARBs)
• Alternative for hypertension: Methyldopa, labetalol, nifedipine (preferred in pregnancy)

9. Statins (HMG-CoA reductase inhibitors)

• Effect: Cholesterol essential for fetal development; statins may cause CNS and limb defects
• Historically FDA Category X; evidence is still evolving (some newer data suggest lower risk)
• Current recommendation: Discontinue during pregnancy
• Drugs: Atorvastatin, simvastatin, rosuvastatin, lovastatin

10. Amiodarone

• Effects: Neonatal hypothyroidism/hyperthyroidism (contains 37% iodine by weight), neonatal bradycardia, QT prolongation, IUGR, premature birth
• Use only when no alternative for life-threatening arrhythmia
• Monitor neonatal thyroid function

11. Aldosterone Antagonists (Spironolactone)

• Effect: Anti-androgenic → feminization of male fetus; genital ambiguity
• Contraindicated throughout pregnancy

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Antimicrobials

12. Tetracyclines

• Effect: Chelate calcium → deposited in developing teeth and bones
  • Yellow-brown tooth discoloration (deciduous teeth) — permanent
  • Bone growth inhibition
  • Maternal hepatotoxicity at high doses (IV)
• Contraindicated after week 14 (tooth bud development); avoid throughout pregnancy as precaution
• Drugs: Tetracycline, doxycycline, minocycline
• Alternative: Amoxicillin, azithromycin, erythromycin (base)

13. Fluoroquinolones

• Effect: Arthropathy in weight-bearing joints of developing animals (cartilage damage); theoretical risk of tendinopathy in fetus
• Human data relatively reassuring but avoid as precaution
• Drugs: Ciprofloxacin, levofloxacin, moxifloxacin
• Alternative: Beta-lactams, azithromycin

14. Aminoglycosides

• Effect: Ototoxicity — 8th cranial nerve damage → irreversible sensorineural hearing loss in neonate
• Drugs: Streptomycin (highest risk), gentamicin, tobramycin, amikacin
• Use only if essential (life-threatening infection with no alternative); monitor levels

15. Chloramphenicol (near term)

• Effect: Gray baby syndrome — cardiovascular collapse, cyanosis, abdominal distension, death
• Mechanism: Immature neonatal hepatic glucuronyl transferase → drug accumulation
• Avoid especially in 3rd trimester and near delivery

16. Sulfonamides (near term)

• Effect: Neonatal hyperbilirubinemia / kernicterus — compete with bilirubin for albumin binding → free bilirubin crosses BBB
• Avoid in 3rd trimester and near delivery

17. Metronidazole

• Avoid in 1st trimester (some evidence of mutagenicity in bacteria; human teratogenicity not established but precautionary)
• Generally safe in 2nd–3rd trimester when clearly indicated (e.g., bacterial vaginosis, Trichomonas)

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NSAIDs and Analgesics

18. NSAIDs (especially 3rd trimester)

• Effect:
  • Premature closure of ductus arteriosus → pulmonary hypertension of the newborn (PPHN)
  • Oligohydramnios (renal vasoconstriction → reduced fetal urine output)
  • Inhibit platelet function → fetal/neonatal bleeding
• Contraindicated from 30 weeks gestation onward (FDA 2020 warning extended to ≥20 weeks for oligohydramnios risk)
• Drugs: Ibuprofen, naproxen, diclofenac, indomethacin
• Safe alternative: Paracetamol (acetaminophen) — drug of choice for analgesia/antipyresis

19. Aspirin (high dose)

• High-dose aspirin: similar effects to NSAIDs (ductus arteriosus closure, bleeding)
• Low-dose aspirin (75–150 mg/day): safe and actually recommended in pre-eclampsia prevention from 12 weeks
• Avoid high-dose aspirin, especially in 3rd trimester

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Hormonal Drugs

20. Combined Oral Contraceptive Pill (COCP)

• Theoretical risk of virilization of female fetus (progestogen component)
• Generally associated with low risk in practice, but discontinue if pregnancy confirmed

21. Danazol / Androgenic Progestogens

• Effect: Virilization of female fetus — clitoral hypertrophy, labial fusion
• Absolutely avoid

22. Diethylstilbestrol (DES)

• Historical use (1940s–1970s) for miscarriage prevention
• Effect: Vaginal clear cell adenocarcinoma in female offspring (DES daughters); structural reproductive anomalies
• No longer used

23. Misoprostol (in 1st trimester)

• Prostaglandin E1 analogue; used for cervical ripening, post-partum hemorrhage, and medical abortion
• If used in 1st trimester without completing abortion: Möbius sequence (facial nerve palsy, limb defects)
• Contraindicated as anti-ulcer drug in 1st trimester

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CNS / Psychiatric Drugs

24. Lithium

• Effect: Ebstein's anomaly (tricuspid valve malformation, right heart defects) — risk ~2× background but absolute risk small
• Also: neonatal hypotonia, cyanosis, bradycardia ("floppy baby"), neonatal diabetes insipidus
• Use with caution; monitor levels; avoid if possible in 1st trimester
• Trimester: 1st (cardiac); all trimesters (neonatal toxicity)

25. Benzodiazepines

• 1st trimester: Possible association with oral cleft (controversial, small risk)
• 3rd trimester / near delivery: Neonatal withdrawal syndrome (jitteriness, hypotonia, respiratory depression) and floppy infant syndrome
• Use the lowest effective dose for the shortest possible time
• Drugs: Diazepam, lorazepam, clonazepam, alprazolam

26. MAO Inhibitors (MAOIs)

• Hypertensive crisis potential; fetal growth restriction; neonatal toxicity
• Generally avoid; switch to safer antidepressants (SSRIs relatively safer)

27. Sodium Valproate (repeated for emphasis)

• Highest teratogenic risk among antiepileptics — never use in women of childbearing potential without strict pregnancy prevention

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Cytotoxic / Immunosuppressive Drugs

28. Cyclophosphamide

• Effect: Fetal growth restriction, limb defects, eye abnormalities, cleft palate; miscarriage
• Alkylating agent — DNA damage in developing fetus
• Avoid especially in 1st trimester

29. Mycophenolate Mofetil (MMF)

• Effect: Miscarriage, ear abnormalities (microtia, atresia), facial clefts, limb/heart/kidney defects
• FDA Category D/X level risk; mandatory pregnancy prevention with this drug
• Stop ≥6 weeks before planned conception

30. JAK Inhibitors (Tofacitinib, Upadacitinib, Filgotinib)

• Per Management of Pregnancy in IBD guidelines (p. 28): animal data show teratogenicity and fetal death; limited human data
• Relatively contraindicated; discontinue ≥4 weeks before planned conception (tofacitinib, upadacitinib) or ≥1 week (filgotinib)

31. Leflunomide

• Effect: Teratogenic in animals; active metabolite (teriflunomide) persists for years
• Requires washout procedure with cholestyramine before conception can be attempted
• Absolute contraindication during pregnancy

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Miscellaneous

32. Radioactive Iodine (¹³¹I)

• Effect: Fetal thyroid ablation (thyroid begins concentrating iodine after 10–12 weeks) → permanent neonatal hypothyroidism
• Absolutely contraindicated from 2nd trimester onward

33. Retinoids (Acitretin, Tretinoin systemic)

• Similar to isotretinoin — vitamin A derivatives
• Acitretin: contraception required for 3 years after stopping (converts back to etretinate, which persists)

34. Ergotamine

• Effect: Uterotonic → placental vasoconstriction, fetal hypoxia, spontaneous abortion, premature labor
• Contraindicated throughout pregnancy
• Alternative for migraine: Paracetamol ± metoclopramide; sumatriptan (use with caution, limited data)

35. Quinine (high dose)

• High doses: uterotonic, auditory nerve damage, thrombocytopenia
• Low therapeutic doses for malaria: relatively safe when benefit outweighs risk

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Summary Reference Table

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Safe Alternatives for Common Conditions

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Acute Hematogenous Osteomyelitis (AHO) in Children

Sources: Bailey & Love's Short Practice of Surgery, 28th ed. (pp. 656–657); Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases (p. 80); Harrison's Principles of Internal Medicine, 21st ed. (p. 3948); PIDS/IDSA Guidelines.

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Definition

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Epidemiology

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Etiology

Causative Organisms by Age

S. aureus is the leading pathogen across all pediatric age groups. MRSA strains (especially community-acquired USA300) produce more severe, complicated disease with higher rates of deep vein thrombosis, multi-focal involvement, and surgical need.

Kingella kingae is a fastidious gram-negative rod that colonizes the upper respiratory tract in young children. It is frequently missed on routine blood cultures — requires specialized media (blood culture bottles inoculated with bone aspirate).

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Pathogenesis

Why the Metaphysis?

1. Terminal capillary loops in the metaphysis make sharp hairpin bends → sluggish, turbulent blood flow → bacteria settle and adhere
2. These sinusoidal capillaries lack phagocytic lining cells → bacteria evade early immune clearance
3. High metabolic rate of the growth plate provides a favorable environment for bacterial growth
4. Minor trauma (very common in active children) creates microhematomas in the metaphysis → bacteria colonize during episodes of transient bacteremia (e.g., from dental procedures, skin infections, upper respiratory tract infections)

Stages of Disease Progression

Bacteremia
    ↓
Metaphyseal seeding → Acute inflammation (hyperemia, edema, neutrophil infiltration)
    ↓
Pus formation within medullary cavity
(INTRAMEDULLARY / INTRAOSSEOUS ABSCESS)
    ↓
Rising intraosseous pressure → pus tracks through Volkmann's & Haversian canals
    ↓
Periosteum stripped from bone
(SUBPERIOSTEAL ABSCESS)
    ↓
Periosteum ruptures → pus enters soft tissues
(SOFT TISSUE ABSCESS)
    ↓
Disruption of periosteal blood supply → ischemic bone necrosis
(SEQUESTRUM — dead bone fragment)
    ↓
Periosteum lays down reactive new bone shell around sequestrum
(INVOLUCRUM) — Bailey & Love (p. 657)
    ↓
CHRONIC OSTEOMYELITIS (sinus tracts, recurrent flares)

Special Anatomical Considerations

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Clinical Features

Symptoms

Signs

• Point tenderness directly over the metaphysis — the hallmark sign
• Local warmth, erythema, and swelling (later finding as infection reaches periosteum/soft tissue)
• Restricted active and passive movement of adjacent joint
• Muscle spasm and guarding
• Neonates: often subtle — irritability, reduced spontaneous limb movement, swelling, feeding difficulties

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Investigations

Laboratory

Imaging

1. Plain X-ray

• First-line investigation — but insensitive in early disease
• Bone changes visible only after 10–21 days (requires 30–50% bone mineral loss)
• Early findings: soft tissue swelling, obliteration of fat planes
• Late findings: metaphyseal lytic lesion, periosteal reaction, cortical erosion, sequestrum
• Role: exclude fracture, tumor; establish baseline

2. Ultrasound

• Detects subperiosteal fluid and soft tissue abscess within days of onset
• Guides needle aspiration for culture
• Cannot assess bone marrow or cortex directly

3. MRI — Gold Standard

• Most sensitive and specific modality for early AHO
• Detects: bone marrow edema, intramedullary abscess, subperiosteal collection, soft tissue extension, transphyseal spread, joint involvement
• T1: low signal marrow (edema replaces fat)
• T2/STIR: hyperintense edema
• Gd-contrast T1 fat-sat: rim-enhancing abscess cavity

4. Bone Scintigraphy (Tc-99m)

• Sensitive within 24–48 hours of onset
• Useful for detecting multi-focal disease (whole-body survey)
• Less specific than MRI; involves ionizing radiation
• May be falsely negative in neonates (vascular compromise reduces uptake)

5. CT Scan

• Best for defining cortical destruction, sequestrum, and involucrum in subacute/chronic cases
• Guides surgical planning
• Not first-line due to radiation exposure in children

Comparative Imaging Accuracy vs. MRI (PIDS/IDSA Guidelines)

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Differential Diagnosis

Kocher criteria (hip): fever + non-weight-bearing + ESR >40 mm/hr + WBC >12,000/μL — 4/4 criteria gives ~99% probability of septic arthritis requiring emergency surgery.

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Treatment

General Principles (Bailey & Love, p. 657)

1. Rest and splintage of the affected limb — reduces pain and prevents pathological fracture
2. Analgesia — adequate pain control
3. Antibiotic therapy — parenteral initially, then oral
4. Surgical drainage — when pus is present
5. Treatment of underlying conditions — sickle cell disease, nutritional deficiency, immunodeficiency

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Antibiotic Therapy

Empirical Selection Based on MRSA Prevalence

IV-to-Oral Sequential Therapy

• Child is afebrile and clinically improving
• CRP trending down significantly
• Tolerating oral intake
• Organism identified and susceptible to an oral agent with high bioavailability

Total Duration

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Surgical Treatment

Indications for Surgery

Surgical Procedures

1. Needle aspiration / bone aspiration
   • Diagnostic + therapeutic
   • Drains subperiosteal collections
   • Performed under ultrasound guidance or in theater
2. Surgical drainage and debridement
   • Cortical windowing: drill holes / bone window to decompress and drain intramedullary pus
   • Curettage of necrotic tissue
   • Irrigation of the cavity
   • Closed suction drain placement
3. Sequestrectomy
   • Removal of dead bone (sequestrum) in subacute/chronic cases
   • Only performed once sufficient involucrum has formed to maintain structural integrity
4. Joint washout / arthrotomy
   • Emergency for concurrent septic arthritis
   • Hip joint = surgical emergency — delay risks avascular necrosis of femoral head

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Monitoring Response to Treatment

Failure to improve within 48–72 hours = reassess: wrong antibiotic? resistant organism? undrained abscess? wrong diagnosis?

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Complications

Early

Late (if inadequately treated)

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Special Situations

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Summary