from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import BaseDocTemplate, Frame, PageTemplate
from reportlab.lib.colors import HexColor

OUTPUT = "/home/daytona/workspace/antimicrobial-studyguide/Antimicrobial_Study_Guide.pdf"

# ─── Colour Palette ──────────────────────────────────────────────────────────
NAVY     = HexColor("#1A237E")
TEAL     = HexColor("#00695C")
ORANGE   = HexColor("#E65100")
CRIMSON  = HexColor("#B71C1C")
PURPLE   = HexColor("#4A148C")
BLUE     = HexColor("#1565C0")
LGRAY    = HexColor("#F5F5F5")
MGRAY    = HexColor("#ECEFF1")
DGRAY    = HexColor("#546E7A")
WHITE    = colors.white
BLACK    = colors.black
GOLD     = HexColor("#F9A825")
GREEN    = HexColor("#2E7D32")

# ─── Page Setup ──────────────────────────────────────────────────────────────
PAGE_W, PAGE_H = A4

def header_footer(canvas, doc):
    canvas.saveState()
    # Header bar
    canvas.setFillColor(NAVY)
    canvas.rect(0, PAGE_H - 1.5*cm, PAGE_W, 1.5*cm, fill=1, stroke=0)
    canvas.setFillColor(WHITE)
    canvas.setFont("Helvetica-Bold", 9)
    canvas.drawString(1.5*cm, PAGE_H - 0.95*cm, "ANTIMICROBIAL PHARMACOLOGY — COMPREHENSIVE STUDY GUIDE")
    canvas.setFont("Helvetica", 8)
    canvas.drawRightString(PAGE_W - 1.5*cm, PAGE_H - 0.95*cm, f"Page {doc.page}")
    # Footer bar
    canvas.setFillColor(NAVY)
    canvas.rect(0, 0, PAGE_W, 0.8*cm, fill=1, stroke=0)
    canvas.setFillColor(GOLD)
    canvas.setFont("Helvetica-Oblique", 7)
    canvas.drawCentredString(PAGE_W/2, 0.25*cm, "Questions 24–47 | Anti-Protozoal & Antimicrobial Drug Short Notes")
    canvas.restoreState()

doc = BaseDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=1.8*cm, rightMargin=1.8*cm,
    topMargin=2.2*cm, bottomMargin=1.5*cm,
)
frame = Frame(doc.leftMargin, doc.bottomMargin,
              doc.width, doc.height, id="main")
doc.addPageTemplates([PageTemplate(id="main", frames=frame, onPage=header_footer)])

# ─── Styles ──────────────────────────────────────────────────────────────────
base = getSampleStyleSheet()

def style(name, **kwargs):
    s = ParagraphStyle(name, **kwargs)
    return s

S_TITLE = style("Title2",
    fontName="Helvetica-Bold", fontSize=22,
    textColor=WHITE, alignment=TA_CENTER, spaceAfter=6)

S_SUBTITLE = style("Sub",
    fontName="Helvetica-Oblique", fontSize=11,
    textColor=GOLD, alignment=TA_CENTER, spaceAfter=4)

S_Q_HEADER = style("QHead",
    fontName="Helvetica-Bold", fontSize=13,
    textColor=WHITE, alignment=TA_LEFT,
    leftIndent=6, spaceAfter=2, spaceBefore=10)

S_SECTION = style("Sec",
    fontName="Helvetica-Bold", fontSize=10,
    textColor=NAVY, spaceAfter=2, spaceBefore=4)

S_BODY = style("Body2",
    fontName="Helvetica", fontSize=8.5,
    textColor=BLACK, spaceAfter=2, leading=13, alignment=TA_JUSTIFY)

S_BULLET = style("Bul",
    fontName="Helvetica", fontSize=8.5,
    textColor=BLACK, leftIndent=14, bulletIndent=4,
    spaceAfter=1, leading=12)

S_NOTE = style("Note",
    fontName="Helvetica-Oblique", fontSize=8,
    textColor=DGRAY, leftIndent=10, spaceAfter=3, leading=11)

S_TOC_ITEM = style("TOC",
    fontName="Helvetica", fontSize=9,
    textColor=NAVY, leftIndent=10, spaceAfter=2)

S_TOC_HEAD = style("TOCHead",
    fontName="Helvetica-Bold", fontSize=11,
    textColor=NAVY, spaceAfter=6, spaceBefore=4)

# ─── Helper builders ─────────────────────────────────────────────────────────
def q_banner(num, title, color=NAVY):
    data = [[Paragraph(f"Q{num} — {title}", S_Q_HEADER)]]
    t = Table(data, colWidths=[doc.width])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), color),
        ("ROWBACKGROUNDS", (0,0), (-1,-1), [color]),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING", (0,0), (-1,-1), 8),
        ("RIGHTPADDING", (0,0), (-1,-1), 8),
        ("ROUNDEDCORNERS", [4,4,4,4]),
    ]))
    return t

def section_label(text, color=TEAL):
    return Paragraph(f'<font color="#{color.hexval()[2:]}"><b>▶ {text}</b></font>', S_SECTION)

def body(text):
    return Paragraph(text, S_BODY)

def bullet(text):
    return Paragraph(f"• {text}", S_BULLET)

def note(text):
    return Paragraph(f"<i>★ {text}</i>", S_NOTE)

def sp(h=4):
    return Spacer(1, h)

def hr(color=TEAL, thickness=0.5):
    return HRFlowable(width="100%", thickness=thickness, color=color, spaceAfter=4, spaceBefore=2)

def simple_table(headers, rows, col_widths=None, header_color=NAVY):
    if col_widths is None:
        col_widths = [doc.width / len(headers)] * len(headers)
    h_style = ParagraphStyle("th", fontName="Helvetica-Bold", fontSize=8,
                              textColor=WHITE, alignment=TA_CENTER)
    c_style = ParagraphStyle("td", fontName="Helvetica", fontSize=7.8,
                              textColor=BLACK, alignment=TA_LEFT, leading=11)
    table_data = [[Paragraph(h, h_style) for h in headers]]
    for row in rows:
        table_data.append([Paragraph(str(c), c_style) for c in row])
    t = Table(table_data, colWidths=col_widths, repeatRows=1)
    ts = TableStyle([
        ("BACKGROUND",   (0,0), (-1,0),  header_color),
        ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, LGRAY]),
        ("GRID",         (0,0), (-1,-1), 0.4, HexColor("#B0BEC5")),
        ("TOPPADDING",   (0,0), (-1,-1), 3),
        ("BOTTOMPADDING",(0,0), (-1,-1), 3),
        ("LEFTPADDING",  (0,0), (-1,-1), 5),
        ("RIGHTPADDING", (0,0), (-1,-1), 5),
        ("VALIGN",       (0,0), (-1,-1), "TOP"),
    ])
    t.setStyle(ts)
    return t

def tag_box(text, bg=TEAL):
    d = [[Paragraph(f"<b>{text}</b>",
          ParagraphStyle("tag", fontName="Helvetica-Bold", fontSize=8,
                         textColor=WHITE, alignment=TA_CENTER))]]
    t = Table(d, colWidths=[doc.width])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), bg),
        ("TOPPADDING",(0,0),(-1,-1),3),
        ("BOTTOMPADDING",(0,0),(-1,-1),3),
    ]))
    return t

# ─── Content ─────────────────────────────────────────────────────────────────
story = []

# ══════════════════════ COVER PAGE ══════════════════════
cover_bg = Table([[""]], colWidths=[PAGE_W - 3.6*cm], rowHeights=[3.5*cm])
cover_bg.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), NAVY),
    ("ROUNDEDCORNERS", [8,8,8,8]),
]))
story.append(sp(20))
story.append(cover_bg)
story.append(sp(8))

title_data = [[Paragraph("ANTIMICROBIAL PHARMACOLOGY", S_TITLE)]]
title_t = Table(title_data, colWidths=[doc.width])
title_t.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), NAVY),
    ("TOPPADDING",(0,0),(-1,-1),10),
    ("BOTTOMPADDING",(0,0),(-1,-1),4),
]))
story.append(title_t)

sub_data = [[Paragraph("Comprehensive Study Guide — Questions 24 to 47", S_SUBTITLE)]]
sub_t = Table(sub_data, colWidths=[doc.width])
sub_t.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), NAVY),
    ("TOPPADDING",(0,0),(-1,-1),2),
    ("BOTTOMPADDING",(0,0),(-1,-1),10),
]))
story.append(sub_t)
story.append(sp(16))

# Cover info box
info_style = ParagraphStyle("inf", fontName="Helvetica", fontSize=9.5,
                             textColor=NAVY, alignment=TA_CENTER, leading=16)
cover_info = [
    [Paragraph("📋  Format: Disease | Class | MOA | P/K | Uses | ADRs | C/I | Drug Interactions", info_style)],
    [Paragraph("🎯  Coverage: 24 Drug Topics — Anti-Microbial &amp; Anti-Protozoal Pharmacology", info_style)],
    [Paragraph("📅  Date: 30 June 2026", info_style)],
]
ci_t = Table(cover_info, colWidths=[doc.width])
ci_t.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), MGRAY),
    ("TOPPADDING",(0,0),(-1,-1),6),
    ("BOTTOMPADDING",(0,0),(-1,-1),6),
    ("LEFTPADDING",(0,0),(-1,-1),12),
    ("GRID",(0,0),(-1,-1),0.5, HexColor("#CFD8DC")),
]))
story.append(ci_t)
story.append(PageBreak())

# ══════════════════════ TABLE OF CONTENTS ══════════════════════
story.append(sp(6))
story.append(Paragraph("TABLE OF CONTENTS", S_TOC_HEAD))
story.append(hr(NAVY, 1.5))
story.append(sp(4))

toc_items = [
    ("Q24", "Antimicrobials Inhibiting Protein Synthesis"),
    ("Q25", "3rd Generation Cephalosporins"),
    ("Q26", "Drug Resistance"),
    ("Q27", "Chloramphenicol"),
    ("Q28", "Beta-Lactam Antibiotics"),
    ("Q29", "Sulfamethoxazole + Trimethoprim (Co-trimoxazole)"),
    ("Q30", "Amoxicillin Preferred Over Ampicillin"),
    ("Q31", "Azithromycin — Once Daily Dosing"),
    ("Q32", "Classification of Cephalosporins"),
    ("Q33", "Narrow Spectrum Preferred Over Broad Spectrum"),
    ("Q34", "Drugs for Pseudomonas Infection"),
    ("Q35", "Tuberculosis — First-Line Pharmacotherapy"),
    ("Q36", "MDR-TB — Pharmacotherapy"),
    ("Q37", "Artemisinin-Based Combination Therapy (ACT)"),
    ("Q38", "Metronidazole"),
    ("Q39", "Imipenem + Cilastatin"),
    ("Q40", "Fixed Dose Combinations — Advantages & Disadvantages"),
    ("Q41", "Penicillin G vs Ampicillin"),
    ("Q42", "Drug Therapy of Anaerobic Infections"),
    ("Q43", "Superinfection"),
    ("Q44", "Pharmacotherapy of Typhoid Fever"),
    ("Q45", "Pharmacotherapy of Pulmonary TB"),
    ("Q46", "E. coli-Induced UTI"),
    ("Q47", "Pyridoxine with Isoniazid — Rationale"),
]
toc_rows = [[q, t] for q, t in toc_items]
toc_t = simple_table(["#", "Topic"], toc_rows,
                     col_widths=[1.4*cm, doc.width - 1.4*cm], header_color=NAVY)
story.append(toc_t)
story.append(PageBreak())

# ═══════════════════════════════════════════════════════
# ─── Q24 ───────────────────────────────────────────────
story.append(q_banner(24, "Antimicrobials Inhibiting Protein Synthesis", NAVY))
story.append(sp(4))
story.append(section_label("Overview"))
story.append(body("Bacteria use 70S ribosomes (30S + 50S subunits). Drugs that target these subunits selectively inhibit bacterial protein synthesis without affecting human 80S ribosomes."))
story.append(sp(3))
story.append(simple_table(
    ["Ribosomal Target", "Drug Class", "Key Drugs", "Mechanism"],
    [
        ["30S subunit", "Aminoglycosides", "Gentamicin, Tobramycin, Amikacin, Streptomycin", "Bind 16S rRNA → mRNA misreading → faulty proteins → bactericidal"],
        ["30S subunit", "Tetracyclines", "Doxycycline, Minocycline, Tetracycline", "Block aminoacyl-tRNA attachment to acceptor site → bacteriostatic"],
        ["50S subunit", "Chloramphenicol", "Chloramphenicol", "Inhibits peptidyl transferase → blocks peptide bond formation → bacteriostatic"],
        ["50S subunit", "Macrolides/Azalides", "Erythromycin, Azithromycin, Clarithromycin", "Bind 23S rRNA → block translocation → bacteriostatic"],
        ["50S subunit", "Lincosamides", "Clindamycin", "Similar to macrolides — bind 23S rRNA 50S → bacteriostatic"],
        ["50S subunit", "Oxazolidinones", "Linezolid", "Block 70S initiation complex formation → bacteriostatic"],
        ["50S subunit", "Streptogramins", "Quinupristin-Dalfopristin", "Dual-site 50S inhibition → bactericidal in combination"],
    ],
    col_widths=[2.2*cm, 2.8*cm, 4.8*cm, 6.2*cm]
))
story.append(note("Mnemonic — '30S': Amino-GLUE-cosides stick wrong amino acids; Tetras block the Tray (A-site). '50S': ChloroMAC-LinLin block Peptide transfer."))
story.append(PageBreak())

# ─── Q25 ───────────────────────────────────────────────
story.append(q_banner(25, "3rd Generation Cephalosporins", TEAL))
story.append(sp(4))
rows_25 = [
    ["Disease", "Meningitis, Typhoid, Gonorrhoea, Septicaemia, Hospital-acquired pneumonia, Complicated UTI"],
    ["Class", "Beta-lactam antibiotics — 3rd generation cephalosporins"],
    ["Drugs", "Cefotaxime, Ceftriaxone, Ceftazidime*, Cefoperazone*, Cefixime (oral), Cefpodoxime (oral) [*=antipseudomonal]"],
    ["MOA", "Bind PBPs (transpeptidases) → inhibit peptidoglycan cross-linking → bactericidal. Resistance: ESBLs, altered PBPs, efflux pumps"],
    ["P/K", "IV/IM route (mostly). Ceftriaxone T½ ~8 hrs → once daily. Good CSF penetration (meningitis). Renal excretion (except Cefoperazone — biliary)"],
    ["Uses", "Meningitis (ceftriaxone/cefotaxime), Typhoid (ceftriaxone), Gonorrhoea (ceftriaxone single dose), HAP, Septicaemia, Pseudomonas (ceftazidime/cefoperazone)"],
    ["Adverse Effects", "Hypersensitivity (cross-reactivity with penicillin ~1-2%), Diarrhoea, Superinfection (Candida, C. difficile), Ceftriaxone: biliary sludge (pseudolithiasis), Cefoperazone: disulfiram-like reaction with alcohol"],
    ["C/I", "Hypersensitivity to cephalosporins; caution if severe penicillin allergy"],
    ["Drug Interactions", "Probenecid ↑ levels; Aminoglycosides — synergistic effect; Cefoperazone + alcohol → disulfiram reaction"],
]
t = Table(rows_25, colWidths=[3.2*cm, doc.width - 3.2*cm])
t.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (0,-1), MGRAY),
    ("FONTNAME", (0,0), (0,-1), "Helvetica-Bold"),
    ("FONTSIZE", (0,0), (-1,-1), 8.5),
    ("FONTNAME", (1,0), (1,-1), "Helvetica"),
    ("TEXTCOLOR", (0,0), (0,-1), NAVY),
    ("GRID", (0,0), (-1,-1), 0.4, HexColor("#B0BEC5")),
    ("ROWBACKGROUNDS", (1,0), (1,-1), [WHITE, LGRAY]*10),
    ("VALIGN", (0,0), (-1,-1), "TOP"),
    ("TOPPADDING", (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING", (0,0), (-1,-1), 6),
]))
story.append(t)
story.append(PageBreak())

# ─── Q26 ───────────────────────────────────────────────
story.append(q_banner(26, "Drug Resistance", CRIMSON))
story.append(sp(4))
story.append(section_label("Types of Resistance", CRIMSON))
story.append(simple_table(
    ["Type", "Description", "Example"],
    [
        ["Natural/Intrinsic", "Inherent lack of target or permeability barrier", "Mycoplasma: no cell wall → resistant to penicillin"],
        ["Acquired", "Previously sensitive organism develops resistance via mutation or gene transfer", "MRSA, ESBL-producing organisms"],
    ],
    col_widths=[3*cm, 6*cm, 7*cm], header_color=CRIMSON
))
story.append(sp(4))
story.append(section_label("Mechanisms of Resistance", CRIMSON))
story.append(simple_table(
    ["Mechanism", "Description", "Example"],
    [
        ["Enzymatic inactivation", "Enzyme destroys or modifies drug", "Beta-lactamases (destroy penicillin ring); acetyltransferases (aminoglycosides)"],
        ["Altered target site", "Drug cannot bind its target", "Modified PBPs (MRSA); altered DNA gyrase (fluoroquinolones); altered 23S rRNA (macrolides)"],
        ["Decreased permeability", "Reduced uptake of drug into cell", "Reduced porin expression in gram-negative bacteria"],
        ["Efflux pumps", "Active transport of drug out of cell", "Tetracycline resistance; fluoroquinolone resistance"],
        ["Bypass/alternative pathway", "Acquire different enzyme not inhibited by drug", "MRSA acquires PBP2a (mecA gene) — low affinity for beta-lactams"],
    ],
    col_widths=[3.5*cm, 6*cm, 6.5*cm], header_color=CRIMSON
))
story.append(sp(4))
story.append(section_label("Transfer of Resistance", CRIMSON))
story.append(simple_table(
    ["Method", "Mechanism"],
    [
        ["Conjugation", "Direct cell-to-cell contact via pili — transfer of R-plasmids (most important)"],
        ["Transduction", "Bacteriophage-mediated DNA transfer"],
        ["Transformation", "Uptake of free naked DNA from environment"],
        ["Transposons", "'Jumping genes' — move resistance genes between plasmids/chromosomes"],
    ],
    col_widths=[3.5*cm, doc.width - 3.5*cm], header_color=CRIMSON
))
story.append(PageBreak())

# ─── Q27 ───────────────────────────────────────────────
def drug_note_table(rows, accent=NAVY):
    t = Table(rows, colWidths=[3.2*cm, doc.width - 3.2*cm])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (0,-1), MGRAY),
        ("FONTNAME", (0,0), (0,-1), "Helvetica-Bold"),
        ("FONTSIZE", (0,0), (-1,-1), 8.5),
        ("FONTNAME", (1,0), (1,-1), "Helvetica"),
        ("TEXTCOLOR", (0,0), (0,-1), accent),
        ("GRID", (0,0), (-1,-1), 0.4, HexColor("#B0BEC5")),
        ("ROWBACKGROUNDS", (1,0), (1,-1), [WHITE, LGRAY]*10),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
        ("TOPPADDING", (0,0), (-1,-1), 4),
        ("BOTTOMPADDING", (0,0), (-1,-1), 4),
        ("LEFTPADDING", (0,0), (-1,-1), 6),
    ]))
    return t

story.append(q_banner(27, "Chloramphenicol", ORANGE))
story.append(sp(4))
story.append(drug_note_table([
    ["Disease", "Typhoid fever, Bacterial meningitis, Rickettsial infections (scrub typhus), Anaerobic infections, Eye/ear infections (topical)"],
    ["Class", "Broad-spectrum antibiotic — inhibits 50S ribosomal subunit (peptidyl transferase inhibitor)"],
    ["MOA", "Binds 23S rRNA of 50S subunit → inhibits peptidyl transferase → prevents peptide bond formation. Bacteriostatic (bactericidal for H. influenzae, N. meningitidis, S. pneumoniae). Resistance: Acetyltransferase (CAT) inactivates the drug — plasmid mediated"],
    ["P/K", "Excellent oral bioavailability. Widely distributed — excellent CSF penetration (45–90% of plasma). Metabolised in liver (glucuronidation). T½ ~4 hours. Renal excretion of inactive metabolites"],
    ["Uses", "Typhoid (alternative to fluoroquinolones); Bacterial meningitis (when beta-lactams contraindicated); Brain abscess; Rickettsial infections; Anaerobic infections; Topical: eye (conjunctivitis), ear"],
    ["Adverse Effects", "1. BONE MARROW SUPPRESSION: (a) Dose-dependent reversible: leukopenia, thrombocytopenia, anaemia (b) Idiosyncratic APLASTIC ANAEMIA — 1:25,000–40,000; irreversible, fatal risk\n2. GREY BABY SYNDROME: Neonates lack glucuronyl transferase → drug accumulates → vomiting, hypotension, grey cyanosis, cardiovascular collapse (40% mortality)\n3. GI disturbances\n4. Optic & peripheral neuritis (prolonged use)\n5. Herxheimer reaction (typhoid)"],
    ["C/I", "Neonates (Grey baby syndrome); Pregnancy and lactation; Liver disease; Pre-existing blood dyscrasias; Concurrent myelosuppressants"],
    ["Drug Interactions", "Inhibits CYP2C9 and CYP3A4 → ↑ phenytoin, warfarin, tolbutamide levels. Phenobarbitone/Rifampicin → ↓ chloramphenicol levels. Avoid with other myelosuppressants"],
], ORANGE))
story.append(PageBreak())

# ─── Q28 ───────────────────────────────────────────────
story.append(q_banner(28, "Beta-Lactam Antibiotics", BLUE))
story.append(sp(4))
story.append(simple_table(
    ["Group", "Examples", "Key Feature"],
    [
        ["Penicillins", "Pen G, Amoxicillin, Ampicillin, Piperacillin, Ticarcillin", "Narrow to extended spectrum; acid-labile (Pen G) vs acid-stable"],
        ["Cephalosporins", "Cefazolin (1G), Cefuroxime (2G), Ceftriaxone (3G), Cefepime (4G), Ceftaroline (5G)", "Generation-based expanded gram-negative coverage"],
        ["Carbapenems", "Imipenem-Cilastatin, Meropenem, Ertapenem, Doripenem", "Broadest spectrum; stable to most beta-lactamases"],
        ["Monobactams", "Aztreonam", "Gram-negative only; safe in penicillin allergy"],
        ["Beta-lactamase inhibitors", "Clavulanic acid, Sulbactam, Tazobactam, Avibactam", "No/weak antibacterial activity alone; protect partner drug from beta-lactamase"],
    ],
    col_widths=[3.2*cm, 5.5*cm, 7.3*cm], header_color=BLUE
))
story.append(sp(4))
story.append(drug_note_table([
    ["MOA", "Bind PBPs (transpeptidases) on bacterial cell membrane → inhibit cross-linking of peptidoglycan → structural weakness → bactericidal (autolysins cause lysis)"],
    ["Resistance", "Beta-lactamase production; Altered PBPs (MRSA: mecA → PBP2a); Reduced permeability; Efflux pumps"],
    ["P/K", "Most parenteral (IV/IM); some oral (amoxicillin, cephalexin, cefixime). Poor CSF penetration at normal doses. Mostly renal excretion"],
    ["Adverse Effects", "Hypersensitivity (most common) — maculopapular rash to anaphylaxis (IgE-mediated); Diarrhoea; Superinfection; Nephrotoxicity (rare); Seizures (imipenem, high-dose pen G)"],
    ["C/I", "Known hypersensitivity. Caution with cross-allergy between penicillins and cephalosporins (~1–2%)"],
    ["Drug Interactions", "Probenecid blocks tubular secretion → ↑ drug levels. Aminoglycosides — synergistic but physically incompatible in same syringe"],
], BLUE))
story.append(PageBreak())

# ─── Q29 ───────────────────────────────────────────────
story.append(q_banner(29, "Sulfamethoxazole + Trimethoprim (Co-trimoxazole)", TEAL))
story.append(sp(4))
story.append(section_label("Why Combined? — Sequential Blockade of Folate Synthesis"))
story.append(body("PABA → [Dihydropteroate synthase ← SULFONAMIDE] → Dihydrofolic acid → [DHFR ← TRIMETHOPRIM] → Tetrahydrofolic acid (THF)"))
story.append(body("Combined ratio: Sulfamethoxazole : Trimethoprim = 5:1. Together = bactericidal; individually = bacteriostatic. Synergistic effect reduces resistance development."))
story.append(sp(3))
story.append(drug_note_table([
    ["Disease", "UTI, PCP (Pneumocystis jirovecii pneumonia), Nocardiosis (DOC), Typhoid, Shigellosis, Traveller's diarrhoea, Toxoplasma prophylaxis"],
    ["Class", "Sulfonamide (SMX) + DHFR inhibitor (TMP)"],
    ["MOA", "SMX: Inhibits dihydropteroate synthase (competes with PABA). TMP: Inhibits dihydrofolate reductase (DHFR). Sequential blockade → ↓ THF → ↓ nucleotide synthesis → bactericidal"],
    ["P/K", "Oral and IV available. Both T½ ~10 hours (matched kinetics). Good tissue/CSF distribution. Renal excretion"],
    ["Adverse Effects", "Stevens-Johnson syndrome; Bone marrow suppression (megaloblastic anaemia, leukopenia); Kernicterus (neonates); Nephrotoxicity/crystalluria (drink plenty of water); Hyperkalaemia (TMP blocks renal K+ excretion); Photosensitivity"],
    ["C/I", "Pregnancy (near term); Neonates <2 months; Severe renal/hepatic failure; G6PD deficiency"],
    ["Drug Interactions", "Warfarin (↑ anticoagulant effect); Phenytoin (↑ levels); ACE inhibitors/K+-sparing diuretics (↑ hyperkalaemia risk)"],
], TEAL))
story.append(PageBreak())

# ─── Q30 ───────────────────────────────────────────────
story.append(q_banner(30, "Amoxicillin Preferred Over Ampicillin", GREEN))
story.append(sp(4))
story.append(simple_table(
    ["Property", "Amoxicillin", "Ampicillin"],
    [
        ["Oral bioavailability", "~90% (excellent)", "~40% (poor, variable)"],
        ["Food effect", "Absorption NOT affected by food", "Absorption REDUCED by food"],
        ["Acid stability", "More acid-stable", "Less acid-stable"],
        ["Serum/urinary levels", "Higher levels achieved", "Lower levels"],
        ["Dosing frequency", "TDS (3x/day)", "QID (4x/day)"],
        ["GI side effects", "Less diarrhoea", "More diarrhoea (unabsorbed drug irritates colon)"],
        ["Spectrum", "Identical (same antibacterial spectrum)", "Identical"],
        ["Beta-lactamase", "Both susceptible", "Both susceptible"],
        ["Preferred use", "Oral therapy (H. pylori, LRTI, otitis, sinusitis)", "IV therapy (Listeria, empirical sepsis); Shigella (oral)"],
    ],
    col_widths=[4.5*cm, 5.5*cm, 6*cm], header_color=GREEN
))
story.append(sp(4))
story.append(note("Key: Ampicillin remains preferred IV and for Shigella (oral amoxicillin is less effective for Shigella despite in vitro similarity)."))
story.append(PageBreak())

# ─── Q31 ───────────────────────────────────────────────
story.append(q_banner(31, "Azithromycin — Once Daily Dosing", PURPLE))
story.append(sp(4))
story.append(drug_note_table([
    ["Disease", "Atypical pneumonia (Mycoplasma, Chlamydia, Legionella), CAP, STIs (Chlamydia trachomatis), Typhoid, MAC in HIV, Otitis media"],
    ["Class", "Azalide — sub-class of macrolide antibiotics"],
    ["MOA", "Binds 23S rRNA of 50S ribosomal subunit → inhibits translocation step of protein synthesis → bacteriostatic (bactericidal at high tissue concentrations)"],
    ["Why Once Daily?", "1. Very long T½ = 68 hours (vs erythromycin T½ 1.5–2 hrs)\n2. Enormous Vd (~31 L/kg) — concentrates in phagocytes & tissues (tissue levels 10–100x serum)\n3. Concentration-dependent PAE (Post-Antibiotic Effect) maintains inhibition long after serum levels fall\n4. Prolonged intracellular accumulation in lysosomes and phagocytes — released at infection site"],
    ["P/K", "Oral (good absorption, not affected by food for capsules); also IV. T½ 68 hrs. Vd 31 L/kg. Biliary excretion primarily"],
    ["Uses", "CAP (typical + atypical coverage); Chlamydia (single dose 1g); MAC prophylaxis in HIV (1.2g once weekly); Typhoid alternative; STIs; Pharyngitis (pen-allergic)"],
    ["Adverse Effects", "GI disturbances (most common); Reversible sensorineural hearing loss (high doses); QT prolongation; Hepatotoxicity (rare); Interactions via mild CYP3A4 inhibition"],
    ["C/I", "QT prolongation syndromes; Severe hepatic dysfunction; Hypersensitivity"],
    ["Drug Interactions", "Antacids reduce absorption (take 1 hr before); QT-prolonging drugs (risk of Torsades de Pointes); Warfarin (↑ anticoagulant effect)"],
], PURPLE))
story.append(PageBreak())

# ─── Q32 ───────────────────────────────────────────────
story.append(q_banner(32, "Classification of Cephalosporins", NAVY))
story.append(sp(4))
story.append(simple_table(
    ["Generation", "Key Drugs", "Spectrum", "Primary Uses"],
    [
        ["1st Generation", "Cephalexin (PO), Cefazolin (IV), Cephradine", "Gram-positive (Staph, Strep) + limited gram-negative (E. coli, Klebsiella, Proteus mirabilis)", "Skin/soft tissue, surgical prophylaxis, UTI"],
        ["2nd Generation", "Cefuroxime (IV/PO), Cefaclor (PO), Cefoxitin*, Cefotetan*\n*= anaerobic cover", "Extended gram-negative + anaerobes (cefoxitin/cefotetan)", "LRTI, Sinusitis, Otitis media, Mixed pelvic infections"],
        ["3rd Generation", "Cefotaxime, Ceftriaxone, Ceftazidime†, Cefoperazone†, Cefixime (PO)\n†= antipseudomonal", "Excellent gram-negative including Pseudomonas (ceftaz/cefop); reduced gram-positive", "Meningitis, Typhoid, Gonorrhoea, Septicaemia, HAP"],
        ["4th Generation", "Cefepime", "Broad: gram-positive AND gram-negative + Pseudomonas; stable to AmpC beta-lactamases", "Hospital-acquired infections, Febrile neutropenia, Pseudomonas"],
        ["5th Generation", "Ceftaroline, Ceftobiprole", "MRSA coverage + broad gram-negative; bind PBP2a", "MRSA infections, Complicated skin/soft tissue infections"],
    ],
    col_widths=[2.5*cm, 4.5*cm, 5*cm, 4*cm], header_color=NAVY
))
story.append(sp(4))
story.append(note("All cephalosporins: Beta-lactam MOA (PBP inhibition); hypersensitivity ADR (1–2% cross-reactivity with penicillin); disulfiram reaction with alcohol for cefoperazone/cefotetan."))
story.append(PageBreak())

# ─── Q33 ───────────────────────────────────────────────
story.append(q_banner(33, "Narrow Spectrum Preferred Over Broad Spectrum", GREEN))
story.append(sp(4))
story.append(simple_table(
    ["Reason", "Explanation"],
    [
        ["1. Preserves normal flora", "Broad-spectrum agents disrupt commensal microbiome (gut, vagina, skin) → risk of Candida overgrowth and C. difficile colitis"],
        ["2. Reduces resistance", "Broad-spectrum drugs exert selective pressure on many species simultaneously → faster emergence of MDROs"],
        ["3. Lowers superinfection risk", "Eliminating commensal bacteria creates ecological niches for resistant opportunistic pathogens"],
        ["4. Targeted therapy more effective", "Adequate drug concentration against specific pathogen; no waste of spectrum"],
        ["5. Fewer adverse effects", "Narrow-spectrum agents often have better safety profiles than broad-spectrum agents"],
        ["6. Cost-effective", "Narrow-spectrum drugs (penicillins, cephalexin) are generally cheaper than carbapenems or broad-spectrum agents"],
        ["7. Epidemiological responsibility", "Preserves antimicrobial effectiveness at a community/public health level (antimicrobial stewardship)"],
    ],
    col_widths=[4*cm, doc.width - 4*cm], header_color=GREEN
))
story.append(sp(4))
story.append(section_label("Exceptions — When Broad Spectrum is Acceptable"))
for exc in [
    "Empirical therapy in sepsis (causative organism unknown)",
    "Polymicrobial infections (intra-abdominal abscess, diabetic foot)",
    "Immunocompromised patients (neutropenic fever)",
    "Life-threatening infections where delay is dangerous",
]:
    story.append(bullet(exc))
story.append(PageBreak())

# ─── Q34 ───────────────────────────────────────────────
story.append(q_banner(34, "Drugs for Pseudomonas Infection", CRIMSON))
story.append(sp(4))
story.append(body("<b>Organism:</b> Pseudomonas aeruginosa — opportunistic gram-negative rod; intrinsically resistant to many antibiotics (outer membrane impermeability, efflux pumps, AmpC beta-lactamase)."))
story.append(sp(3))
story.append(simple_table(
    ["Drug Class", "Key Drugs", "Route", "Notes"],
    [
        ["Antipseudomonal penicillins", "Piperacillin-tazobactam (PipTazo)", "IV", "First choice for many Pseudomonas infections"],
        ["3rd gen cephalosporins", "Ceftazidime, Cefoperazone", "IV", "Only 3G cephalosporins with Pseudomonas cover"],
        ["4th gen cephalosporins", "Cefepime", "IV", "Broad spectrum including Pseudomonas"],
        ["Carbapenems", "Imipenem-Cilastatin, Meropenem, Doripenem", "IV", "For serious/resistant infections; NOT Ertapenem"],
        ["Monobactams", "Aztreonam", "IV", "Gram-negative only; safe in penicillin allergy"],
        ["Aminoglycosides", "Tobramycin (most active), Gentamicin, Amikacin", "IV/IM", "Combined with beta-lactam for synergy; monitor ototoxicity/nephrotoxicity"],
        ["Fluoroquinolones", "Ciprofloxacin", "PO/IV", "Only oral antipseudomonal quinolone; first choice for uncomplicated Pseudomonas UTI"],
        ["Polymyxins", "Colistin (Polymyxin E), Polymyxin B", "IV/inhaled", "Last resort for MDR/XDR Pseudomonas; nephrotoxic"],
    ],
    col_widths=[4*cm, 4.5*cm, 1.8*cm, 5.7*cm], header_color=CRIMSON
))
story.append(sp(4))
story.append(note("ALWAYS use combination therapy (2 antipseudomonal drugs from different classes) for serious infections to prevent emergence of resistance. De-escalate once C&S results available."))
story.append(PageBreak())

# ─── Q35 ───────────────────────────────────────────────
story.append(q_banner(35, "Tuberculosis — First-Line Pharmacotherapy", ORANGE))
story.append(sp(4))
story.append(section_label("Standard DOTS Regimen (WHO/RNTCP)"))
story.append(body("<b>Intensive phase (2 months):</b> HRZE — Isoniazid + Rifampicin + Pyrazinamide + Ethambutol daily"))
story.append(body("<b>Continuation phase (4 months):</b> HR — Isoniazid + Rifampicin daily"))
story.append(body("<b>Total duration: 6 months</b> for new pulmonary TB"))
story.append(sp(3))
story.append(simple_table(
    ["Drug", "Abbrev", "Daily Dose", "Mechanism", "Key ADRs"],
    [
        ["Isoniazid", "H", "5 mg/kg (max 300 mg)", "Inhibits InhA (enoyl-ACP reductase) → blocks mycolic acid synthesis → bactericidal (replicating bacilli)", "Peripheral neuropathy (↑ by B6 deficiency) → Give Pyridoxine! Hepatotoxicity, Lupus-like syndrome"],
        ["Rifampicin", "R", "10 mg/kg (max 600 mg)", "Inhibits DNA-dependent RNA polymerase (beta subunit) → no mRNA → bactericidal (replicating + semi-dormant)", "Orange secretions, Hepatotoxicity, CYP450 inducer (many drug interactions), Flu-like syndrome (intermittent dosing)"],
        ["Pyrazinamide", "Z", "25 mg/kg (max 2000 mg)", "Active at acidic pH (inside macrophages/caseous lesions) → disrupts membrane potential; sterilizing activity → reduces treatment duration to 6 months", "Hyperuricaemia (gout), Hepatotoxicity, Arthralgia, Flushing"],
        ["Ethambutol", "E", "15–20 mg/kg (max 1600 mg)", "Inhibits arabinosyl transferase → blocks arabinogalactan synthesis → prevents initial resistance emergence", "Optic neuritis (dose-related, monitor visual acuity/colour vision), Rash"],
    ],
    col_widths=[2.3*cm, 1.3*cm, 2.4*cm, 5.5*cm, 4.5*cm], header_color=ORANGE
))
story.append(PageBreak())

# ─── Q36 ───────────────────────────────────────────────
story.append(q_banner(36, "MDR-TB — Pharmacotherapy", CRIMSON))
story.append(sp(4))
story.append(body("<b>MDR-TB definition:</b> Resistant to at least Isoniazid + Rifampicin (the two most potent first-line drugs)"))
story.append(body("<b>XDR-TB definition:</b> MDR-TB + resistant to any fluoroquinolone AND at least one injectable second-line agent"))
story.append(sp(3))
story.append(section_label("New WHO 2022 Preferred Regimen — BPaL/BPaLM", CRIMSON))
story.append(simple_table(
    ["Regimen", "Drugs", "Duration", "Use"],
    [
        ["BPaL", "Bedaquiline + Pretomanid + Linezolid", "6 months", "Pre-XDR and XDR-TB"],
        ["BPaLM", "Bedaquiline + Pretomanid + Linezolid + Moxifloxacin", "6 months", "MDR-TB (if moxifloxacin susceptible)"],
    ],
    col_widths=[2*cm, 6*cm, 2.5*cm, 5.5*cm], header_color=CRIMSON
))
story.append(sp(4))
story.append(section_label("Second-Line Drug Groups (Conventional Regimen)", CRIMSON))
story.append(simple_table(
    ["Group", "Drugs", "Key ADR"],
    [
        ["Fluoroquinolones", "Levofloxacin, Moxifloxacin (preferred)", "QT prolongation"],
        ["Injectable agents", "Amikacin, Kanamycin, Capreomycin", "Ototoxicity, Nephrotoxicity"],
        ["New agents", "Bedaquiline (ATP synthase inhibitor), Delamanid, Pretomanid", "QT prolongation (bedaquiline)"],
        ["Repurposed", "Linezolid (oxazolidinone), Clofazimine, Cycloserine", "Linezolid: myelosuppression, neuropathy"],
        ["Older backup", "Ethionamide, PAS (para-aminosalicylic acid)", "GI intolerance; hypothyroidism (ethionamide)"],
    ],
    col_widths=[3.5*cm, 5.5*cm, 7*cm], header_color=CRIMSON
))
story.append(note("Conventional MDR-TB treatment: 18–24 months with ≥4–5 effective drugs. BPaL/BPaLM shortens this to 6 months."))
story.append(PageBreak())

# ─── Q37 ───────────────────────────────────────────────
story.append(q_banner(37, "Artemisinin-Based Combination Therapy (ACT)", TEAL))
story.append(sp(4))
story.append(drug_note_table([
    ["Disease", "Plasmodium falciparum malaria (uncomplicated and severe); P. vivax (in some regions)"],
    ["Class", "Sesquiterpene lactone endoperoxide (artemisinin) + partner drug (combination)"],
    ["MOA", "Artemisinin activated by haem iron (Fe2+) inside parasite → generates free radicals (reactive oxygen species) → alkylate and damage parasite proteins and membranes → rapid parasite killing. Acts on ALL parasite stages including gametocytes (reduces transmission). Resistance: Kelch-13 gene mutations in P. falciparum → delayed clearance (Southeast Asia)"],
    ["Why Combination?", "Artemisinin has very short T½ (1–3 hrs) → cannot be used alone (residual parasites). Partner drug kills remaining parasites after artemisinin's rapid kill. Reduces selection pressure for resistance"],
    ["Common ACTs", "Artemether + Lumefantrine (Coartem) — global standard uncomplicated falciparum. Artesunate + Mefloquine — SE Asia. Artesunate + Amodiaquine — Africa. Dihydroartemisinin + Piperaquine — Asia. Artesunate IV/IM — Severe malaria"],
    ["P/K", "Artemether: oral/IM → rapidly converted to active DHA. Artesunate: oral/IV/IM/rectal → hydrolysed to DHA. T½ ~1–3 hours (very short). Partner drugs have longer T½"],
    ["Adverse Effects", "Generally well tolerated. Neurotoxicity (animal studies — not significant clinically at therapeutic doses). QT prolongation (lumefantrine). Embryotoxic (avoid in 1st trimester)"],
    ["C/I", "1st trimester pregnancy (use quinine + clindamycin instead). Hypersensitivity to artemisinins"],
    ["Drug Interactions", "Lumefantrine: QT-prolonging drugs. Artemether: CYP3A4 substrate; rifampicin reduces levels. Avoid with other QT-prolonging drugs"],
], TEAL))
story.append(PageBreak())

# ─── Q38 ───────────────────────────────────────────────
story.append(q_banner(38, "Metronidazole", PURPLE))
story.append(sp(4))
story.append(drug_note_table([
    ["Disease", "Amoebic dysentery (DOC), Amoebic liver abscess (DOC), Giardiasis (DOC), Trichomoniasis (DOC), Bacterial vaginosis (DOC), Anaerobic infections, C. difficile colitis, H. pylori eradication"],
    ["Class", "Nitroimidazole — antiprotozoal + antianaerobic antibiotic"],
    ["MOA", "Enters cells and is reduced by ferredoxin/electron transport systems (present ONLY in anaerobes/protozoa, NOT aerobic bacteria) → nitro radical anion generated → damages DNA (strand breaks, loss of helical structure) → selective cell death. Selective toxicity: only anaerobes/microaerophiles can activate the prodrug. Resistance: Reduced nitroreductase activity; efflux; DNA repair"],
    ["P/K", "Excellent oral bioavailability (~100%). Widely distributed — crosses BBB (brain abscess), placenta, breast milk. Metabolised by CYP450 in liver. T½ ~8 hours. Renal excretion of metabolites"],
    ["Uses", "DOC: Amoebic liver abscess, amoebic dysentery, giardiasis, trichomoniasis, BV; Anaerobic infections (intra-abdominal, pelvic, brain abscess); C. difficile (mild-moderate); H. pylori triple/quadruple therapy; Surgical prophylaxis (colorectal/gynaecological); Dracunculiasis (guinea worm)"],
    ["Adverse Effects", "Metallic taste (very common); Nausea, vomiting, anorexia; DISULFIRAM-LIKE REACTION with alcohol; Peripheral neuropathy (prolonged use); CNS: headache, dizziness, seizures (high doses); Dark/reddish-brown urine (harmless)"],
    ["C/I", "1st trimester of pregnancy (teratogenic concern); Alcohol consumption (disulfiram reaction); Severe hepatic disease"],
    ["Drug Interactions", "ALCOHOL — disulfiram-like reaction (avoid alcohol during Rx and 48 hrs after); Warfarin — ↑ anticoagulant effect (inhibits CYP2C9); Lithium — ↑ lithium toxicity; Phenobarbitone/Rifampicin — ↓ metronidazole levels; Cimetidine — ↑ metronidazole levels"],
], PURPLE))
story.append(PageBreak())

# ─── Q39 ───────────────────────────────────────────────
story.append(q_banner(39, "Imipenem + Cilastatin", BLUE))
story.append(sp(4))
story.append(section_label("Why is Cilastatin Added?"))
story.append(simple_table(
    ["Aspect", "Explanation"],
    [
        ["What is Cilastatin?", "NOT an antibiotic. It is a specific inhibitor of renal tubular brush border enzyme Dehydropeptidase-I (DHP-I)"],
        ["Problem without Cilastatin", "Imipenem is rapidly hydrolysed and inactivated by DHP-I in renal tubules → (1) Very low urinary imipenem levels (insufficient for UTI treatment), (2) Hydrolysis produces a nephrotoxic metabolite causing proximal tubular damage"],
        ["Solution — Cilastatin", "Blocks DHP-I → prevents metabolism of imipenem in kidney → achieves adequate urinary imipenem levels → treats UTI effectively AND prevents nephrotoxicity"],
        ["Combination ratio", "Imipenem : Cilastatin = 1:1 (equal parts)"],
        ["Meropenem comparison", "Meropenem is stable to DHP-I (not a substrate) → does NOT need cilastatin"],
    ],
    col_widths=[3.5*cm, doc.width - 3.5*cm], header_color=BLUE
))
story.append(sp(4))
story.append(drug_note_table([
    ["Disease", "Hospital-acquired pneumonia, Intra-abdominal infections, Febrile neutropenia, Polymicrobial infections, ESBL-producing organisms, Complicated UTI"],
    ["Class", "Carbapenem — beta-lactam antibiotic (broadest spectrum beta-lactam)"],
    ["MOA", "Binds PBP1 and PBP2 → inhibits cell wall synthesis. Active against gram-positive, gram-negative, anaerobes. Stable to most beta-lactamases including ESBLs. NOT stable to metallo-beta-lactamases (NDM-1 = New Delhi Metallo-beta-lactamase). NOT active against MRSA, Stenotrophomonas maltophilia, VRE"],
    ["Adverse Effects", "Seizures (CNS penetration — dose-related, more than meropenem); Nausea/vomiting; Hypersensitivity; Superinfection"],
    ["C/I", "Hypersensitivity; Epilepsy (caution — lower seizure threshold); Dose reduction in renal failure"],
    ["Drug Interactions", "Valproate: Imipenem reduces serum valproate levels → seizures (significant, avoid combination); Probenecid: ↑ imipenem levels"],
], BLUE))
story.append(PageBreak())

# ─── Q40 ───────────────────────────────────────────────
story.append(q_banner(40, "Fixed Dose Combinations (FDCs) — Advantages & Disadvantages", ORANGE))
story.append(sp(4))
story.append(section_label("ADVANTAGES", GREEN))
story.append(simple_table(
    ["Advantage", "Example"],
    [
        ["Synergism — enhanced efficacy", "Co-trimoxazole: SMX + TMP → sequential folate blockade → bactericidal (vs bacteriostatic individually)"],
        ["Reduced resistance", "TB HRZE tablet: 4 drugs simultaneously → prevents selection of resistant mutants"],
        ["Improved compliance", "One tablet vs 4 separate tablets (TB regimen); HIV ART single pill regimens"],
        ["Pharmacokinetic synergy", "Augmentin: Clavulanate inhibits beta-lactamase → protects amoxicillin from destruction"],
        ["Prevents monotherapy", "HIV ART — ensures patient receives complete regimen even if non-adherent to some pills"],
        ["Cost-effective", "Single FDC tablet cheaper than multiple individual tablets"],
        ["Reduced pill burden", "Critical in HIV management — improves long-term adherence"],
    ],
    col_widths=[5*cm, doc.width - 5*cm], header_color=GREEN
))
story.append(sp(4))
story.append(section_label("DISADVANTAGES", CRIMSON))
story.append(simple_table(
    ["Disadvantage", "Example"],
    [
        ["Individual dose adjustment difficult", "Cannot titrate rifampicin dose alone in TB FDC (e.g., for hepatic disease)"],
        ["ADR attribution difficult", "Rash with Co-trimoxazole — is it sulfa or trimethoprim?"],
        ["Not suitable if organism resistant to one component", "If resistant to sulfamethoxazole, TMP alone insufficient"],
        ["Pharmacokinetic mismatch", "Different T½ of partner drugs (artemether T½ 1–3 hrs vs lumefantrine T½ 3–6 days)"],
        ["Contraindication to one component stops entire FDC", "Ethambutol FDC — optic neuritis forces stopping all 4 drugs"],
        ["Formulation challenges", "Chemical incompatibility, degradation, stability issues"],
    ],
    col_widths=[5*cm, doc.width - 5*cm], header_color=CRIMSON
))
story.append(sp(3))
story.append(note("Key FDCs: Co-trimoxazole (5:1) | Augmentin (amox+clavulanate) | Pip-Tazo | HRZE tablet | Lopinavir/Ritonavir (Kaletra) | Artemether/Lumefantrine (Coartem)"))
story.append(PageBreak())

# ─── Q41 ───────────────────────────────────────────────
story.append(q_banner(41, "Penicillin G vs Ampicillin — Comparison", NAVY))
story.append(sp(4))
story.append(simple_table(
    ["Property", "Penicillin G", "Ampicillin"],
    [
        ["Class", "Natural penicillin", "Aminopenicillin (semi-synthetic)"],
        ["Spectrum", "Narrow: gram-positives (Staph-sensitive, Strep) + Spirochetes + gram-negative cocci (N. meningitidis, N. gonorrhoeae)", "Extended: same as Pen G + gram-negatives (H. influenzae, E. coli, Proteus mirabilis, Salmonella, Shigella, Listeria)"],
        ["Oral route", "NO — acid labile; IV/IM only", "YES — acid stable; oral bioavailability ~40%"],
        ["Food effect", "N/A (parenteral only)", "Absorption reduced by food (take 30 min before meals)"],
        ["Beta-lactamase", "Susceptible (destroyed)", "Susceptible (destroyed)"],
        ["Pseudomonas", "No activity", "No activity"],
        ["DOC for", "Syphilis (Treponema pallidum), GAS pharyngitis, Streptococcal endocarditis, Rheumatic fever prophylaxis, Gas gangrene (C. perfringens), Actinomycosis, Tetanus", "Listeria monocytogenes meningitis, H. influenzae infections (susceptible), Ampicillin-sensitive enterococcal endocarditis"],
        ["Unique ADR", "High Na+/K+ load with IV forms", "Ampicillin rash (non-allergic maculopapular rash in viral illness — EBV, CMV, CLL)"],
        ["Probenecid", "↑ levels (blocks tubular secretion)", "↑ levels (blocks tubular secretion)"],
    ],
    col_widths=[3.5*cm, 6*cm, 6.5*cm], header_color=NAVY
))
story.append(PageBreak())

# ─── Q42 ───────────────────────────────────────────────
story.append(q_banner(42, "Drug Therapy of Anaerobic Infections", TEAL))
story.append(sp(4))
story.append(body("<b>Common anaerobes:</b> Bacteroides fragilis, Clostridium spp. (perfringens, difficile, tetani, botulinum), Peptostreptococcus, Fusobacterium, Actinomyces"))
story.append(sp(3))
story.append(simple_table(
    ["Drug", "Spectrum/Feature", "Key Uses"],
    [
        ["Metronidazole", "Excellent B. fragilis coverage; crosses BBB", "DOC: amoebic, giardia, BV, C. difficile (mild), brain abscess, intra-abdominal"],
        ["Clindamycin", "Excellent gram-positive anaerobes; bone penetration", "Aspiration pneumonia, Dental infections, Bone/joint infections (anaerobic), Toxoplasma (+ pyrimethamine)"],
        ["Carbapenems (Imipenem, Meropenem)", "Broadest including anaerobes", "Severe polymicrobial infections (intra-abdominal, diabetic foot)"],
        ["Piperacillin-Tazobactam", "Broad including anaerobes", "Intra-abdominal, Polymicrobial sepsis"],
        ["Amoxicillin-Clavulanate", "Mixed aerobic/anaerobic oral option", "Dental, Aspiration pneumonia (outpatient)"],
        ["Cefoxitin/Cefotetan", "2G cephs with anaerobic cover", "Pelvic inflammatory disease, Intra-abdominal"],
        ["Penicillin G (high dose)", "Clostridial species", "Gas gangrene (C. perfringens) + surgical debridement; Tetanus; Actinomycosis"],
        ["Vancomycin (oral)", "C. difficile", "C. difficile colitis (moderate-severe) — preferred over metronidazole"],
        ["Fidaxomicin", "C. difficile — minimal systemic absorption", "C. difficile colitis (preferred — lower recurrence rate)"],
    ],
    col_widths=[4*cm, 4.5*cm, 7.5*cm], header_color=TEAL
))
story.append(note("Combination therapy: Metronidazole + Cephalosporin (or Pip-Tazo) covers both anaerobes and aerobic gram-negatives simultaneously."))
story.append(PageBreak())

# ─── Q43 ───────────────────────────────────────────────
story.append(q_banner(43, "Superinfection", GREEN))
story.append(sp(4))
story.append(section_label("Definition & Mechanism"))
story.append(body("<b>Superinfection:</b> Development of a new infection caused by a different, usually resistant organism during or after antibiotic therapy for the original infection."))
story.append(sp(2))
story.append(body("<b>Mechanism:</b> Antibiotics (especially broad-spectrum) eliminate sensitive commensal flora → creates ecological niche (no competition for nutrients/adhesion sites) → resistant or opportunistic organisms proliferate and cause new infection."))
story.append(sp(4))
story.append(simple_table(
    ["Superinfecting Organism", "Clinical Presentation", "Most Commonly After"],
    [
        ["Candida albicans", "Oral thrush (white plaques), Vaginal candidiasis (itching, discharge)", "Any broad-spectrum antibiotic"],
        ["Clostridium difficile", "Profuse watery/bloody diarrhoea, abdominal pain, fever; pseudomembranous colitis → toxic megacolon", "Clindamycin, 3G cephalosporins, Fluoroquinolones, Ampicillin"],
        ["MRSA", "Skin/soft tissue, wound infections, pneumonia", "Broad-spectrum antibiotics clearing competing flora"],
        ["Resistant gram-negatives (Pseudomonas, Klebsiella)", "Hospital-acquired pneumonia, UTI, septicaemia", "Carbapenems, cephalosporins (paradoxically)"],
        ["Enterococcus", "UTI, endocarditis", "Cephalosporins (enterococci are intrinsically resistant)"],
    ],
    col_widths=[3.5*cm, 6*cm, 6.5*cm], header_color=GREEN
))
story.append(sp(3))
story.append(section_label("Prevention & Treatment"))
for pt in [
    "Use narrow-spectrum antibiotics whenever possible (antimicrobial stewardship)",
    "Shortest effective course of antibiotic therapy",
    "Probiotics may reduce C. difficile risk (Lactobacillus, Saccharomyces boulardii)",
    "Treatment: Antifungals for Candida (fluconazole, nystatin topical); Oral vancomycin or fidaxomicin for C. difficile",
]:
    story.append(bullet(pt))
story.append(PageBreak())

# ─── Q44 ───────────────────────────────────────────────
story.append(q_banner(44, "Pharmacotherapy of Typhoid Fever", ORANGE))
story.append(sp(4))
story.append(body("<b>Causative organism:</b> Salmonella typhi (and S. paratyphi A/B/C)"))
story.append(sp(3))
story.append(simple_table(
    ["Drug", "Route", "Duration", "Notes/Indication"],
    [
        ["Ciprofloxacin 500 mg BD", "PO/IV", "10–14 days", "DOC for sensitive strains; excellent intracellular penetration; avoid if resistance suspected"],
        ["Ofloxacin 400 mg BD", "PO", "7–14 days", "Alternative fluoroquinolone"],
        ["Ceftriaxone 2–3 g OD", "IV/IM", "10–14 days", "DOC for MDR typhoid, severe typhoid, and pregnant women; most reliable current option"],
        ["Azithromycin 500–1000 mg OD", "PO", "7 days", "Preferred for uncomplicated typhoid; increasing use for fluoroquinolone-resistant strains"],
        ["Chloramphenicol", "PO/IV", "14 days", "Original DOC; still used in resource-limited settings; risk of aplastic anaemia"],
        ["Ampicillin/Amoxicillin", "PO/IV", "14 days", "For sensitive strains only; rarely used now"],
        ["Co-trimoxazole", "PO", "14 days", "Alternative for sensitive strains"],
        ["Cefixime", "PO", "7–14 days", "Oral alternative (less effective than parenteral ceftriaxone)"],
    ],
    col_widths=[3.5*cm, 1.5*cm, 2.5*cm, 8.5*cm], header_color=ORANGE
))
story.append(sp(3))
story.append(simple_table(
    ["Resistance Pattern", "Treatment"],
    [
        ["MDR typhoid (resistant to chloramphenicol, ampicillin, co-trimoxazole)", "Fluoroquinolones or Ceftriaxone"],
        ["XDR typhoid (MDR + resistant to fluoroquinolones + 3G cephalosporins)", "Azithromycin or Carbapenems (meropenem)"],
    ],
    col_widths=[6.5*cm, 9.5*cm], header_color=CRIMSON
))
story.append(PageBreak())

# ─── Q45 ───────────────────────────────────────────────
story.append(q_banner(45, "Pharmacotherapy of Pulmonary TB", NAVY))
story.append(sp(4))
story.append(section_label("Standard DOTS Regimen — New Case"))
story.append(body("<b>2 months HRZE → 4 months HR</b> (Total 6 months)"))
story.append(sp(3))
story.append(simple_table(
    ["Drug", "Dose", "Mechanism (simplified)", "Critical ADR", "Monitoring"],
    [
        ["Isoniazid (H)", "5 mg/kg/day (max 300 mg)", "Inhibits mycolic acid synthesis (InhA enzyme) — bactericidal for rapidly dividing bacilli", "Peripheral neuropathy, Hepatotoxicity, Drug-induced lupus", "LFTs, Neurological exam; Give Pyridoxine 10–25 mg/day"],
        ["Rifampicin (R)", "10 mg/kg/day (max 600 mg)", "Inhibits RNA polymerase — bactericidal for replicating + semi-dormant bacilli", "Orange-red secretions, Hepatotoxicity, Flu-like syndrome (intermittent), Many drug interactions (CYP450 inducer)", "LFTs, Drug interactions (OCP, ARVs, warfarin, phenytoin reduced)"],
        ["Pyrazinamide (Z)", "25 mg/kg/day (max 2g)", "Active at acidic pH — kills bacilli inside macrophages (caseous lesions) — sterilising activity", "Hyperuricaemia (gout), Hepatotoxicity, Arthralgia", "Uric acid levels, LFTs, Gout symptoms"],
        ["Ethambutol (E)", "15–20 mg/kg/day (max 1.6g)", "Inhibits arabinosyl transferase — prevents resistance; used to protect other drugs in initial phase", "OPTIC NEURITIS — colour vision loss, visual acuity reduction (dose-related, reversible if stopped early)", "Monthly visual acuity and colour vision; Avoid in children <5 years (cannot report visual changes)"],
    ],
    col_widths=[2.3*cm, 2.5*cm, 4.5*cm, 4.2*cm, 2.5*cm], header_color=NAVY
))
story.append(sp(3))
story.append(section_label("Special Situations"))
story.append(simple_table(
    ["Situation", "Modification"],
    [
        ["TB + HIV", "Start ART 2–8 weeks after anti-TB therapy. Rifampicin ↑ CYP450 → reduces ARV levels → use rifabutin instead of rifampicin (less CYP induction) or adjust ARV doses"],
        ["TB in pregnancy", "HRZE safe in 1st trimester. AVOID streptomycin (ototoxic to fetus). Pyridoxine supplementation essential"],
        ["TB in liver disease", "Avoid/delay pyrazinamide; reduce INH dose; use ethambutol + rifampicin + streptomycin with close LFT monitoring"],
        ["TB in renal failure", "Reduce ethambutol, pyrazinamide doses; INH and rifampicin: standard dose (hepatic elimination)"],
    ],
    col_widths=[3.5*cm, doc.width - 3.5*cm], header_color=TEAL
))
story.append(PageBreak())

# ─── Q46 ───────────────────────────────────────────────
story.append(q_banner(46, "E. coli-Induced UTI", PURPLE))
story.append(sp(4))
story.append(body("<b>Organism:</b> Escherichia coli — most common cause of UTI (~80% community-acquired). Virulence factors: Type 1 and P fimbriae (adhesion), haemolysin, aerobactin."))
story.append(sp(3))
story.append(section_label("Treatment by Type", PURPLE))
story.append(simple_table(
    ["Type", "Drug", "Dose/Duration", "Notes"],
    [
        ["Uncomplicated Lower UTI (cystitis)", "Nitrofurantoin (1st choice)", "100 mg SR BD × 5 days", "Concentrated in urine; low systemic absorption; avoid in renal impairment"],
        ["Uncomplicated Lower UTI", "Fosfomycin", "3g single dose", "Excellent for uncomplicated cystitis; growing use for ESBL E. coli"],
        ["Uncomplicated Lower UTI", "Co-trimoxazole", "960 mg BD × 3 days", "Only if local resistance <20%"],
        ["Uncomplicated Lower UTI", "Ciprofloxacin", "250 mg BD × 3–7 days", "Reserve — increasing resistance; avoid unnecessary use"],
        ["Complicated UTI/Pyelonephritis", "Ciprofloxacin", "500 mg BD × 7–14 days", "Drug of choice for pyelonephritis if sensitivity confirmed"],
        ["Complicated UTI/Pyelonephritis", "Ceftriaxone", "1–2g OD IV", "Hospitalized/severe pyelonephritis"],
        ["ESBL-producing E. coli", "Ertapenem or Meropenem", "IV", "Carbapenem required for ESBL; fosfomycin/nitrofurantoin may be options for lower UTI"],
        ["Pregnancy — Asymptomatic bacteriuria (TREAT!)", "Cephalexin / Nitrofurantoin", "5–7 days", "Avoid: Fluoroquinolones (cartilage), Tetracyclines (teeth), Nitrofurantoin at term (haemolytic anaemia in neonate), Co-trimoxazole near term"],
    ],
    col_widths=[3.5*cm, 3.5*cm, 3*cm, 6*cm], header_color=PURPLE
))
story.append(note("Amoxicillin NOT recommended for empirical UTI therapy — resistance rates typically >50% in E. coli community strains. Always send MSU C&S before treating complicated/recurrent UTI."))
story.append(PageBreak())

# ─── Q47 ───────────────────────────────────────────────
story.append(q_banner(47, "Pyridoxine (Vitamin B6) Given with Isoniazid — Rationale", GREEN))
story.append(sp(4))
story.append(section_label("Mechanism of Isoniazid-Induced Peripheral Neuropathy"))
story.append(simple_table(
    ["Step", "Event"],
    [
        ["1", "Isoniazid is structurally similar to pyridoxine (Vitamin B6)"],
        ["2", "INH competes with pyridoxal-5-phosphate (active B6) for enzyme apotryptophanase"],
        ["3", "INH reacts with pyridoxal phosphate → forms inactive hydrazones → excreted in urine"],
        ["4", "Result: Functional pyridoxine deficiency despite adequate dietary intake"],
        ["5", "Pyridoxine is a cofactor for synthesis of GABA (inhibitory neurotransmitter) and other amino acids"],
        ["6", "GABA deficiency → CNS excitability; PLP deficiency → peripheral nerve dysfunction"],
        ["7", "Clinical: 'Glove and stocking' peripheral neuropathy (numbness, tingling, burning in hands and feet)"],
    ],
    col_widths=[0.8*cm, doc.width - 0.8*cm], header_color=GREEN
))
story.append(sp(4))
story.append(section_label("Who Especially Needs Pyridoxine Supplementation?"))
story.append(simple_table(
    ["High-Risk Group", "Reason"],
    [
        ["Malnourished patients", "Already B6 deficient → additive deficiency with INH"],
        ["Alcoholics", "Chronic alcohol depletes B6; also poor diet"],
        ["HIV-positive patients", "Concurrent nutritional deficiencies; neuropathy risk from ARVs too"],
        ["Diabetics", "Pre-existing peripheral neuropathy risk; accelerated by INH"],
        ["Pregnant and lactating women", "Increased B6 requirements; fetal risk"],
        ["Elderly", "Reduced dietary intake and absorption"],
        ["Renal failure patients", "Altered B6 metabolism"],
        ["Slow acetylators of INH", "Higher drug levels → greater B6 depletion"],
    ],
    col_widths=[5*cm, doc.width - 5*cm], header_color=GREEN
))
story.append(sp(3))
story.append(drug_note_table([
    ["Dose", "Prophylaxis: 10–25 mg/day with every INH-containing regimen. Treatment of established neuropathy: up to 100 mg/day"],
    ["Other INH ADRs (not prevented by pyridoxine)", "Hepatotoxicity (monitor LFTs — stop if ALT/AST >3x normal with symptoms or >5x without). Drug-induced lupus (antinuclear antibodies, arthralgia). Pellagra (INH inhibits tryptophan → NAD conversion → give nicotinamide). Psychosis and seizures (INH overdose — give high-dose pyridoxine IV as antidote)"],
], GREEN))
story.append(sp(6))
story.append(hr(NAVY, 1.5))
story.append(sp(4))

# End page
end_style = ParagraphStyle("end", fontName="Helvetica-Bold", fontSize=13,
                            textColor=NAVY, alignment=TA_CENTER)
story.append(Paragraph("— END OF STUDY GUIDE —", end_style))
story.append(sp(4))
end_note = ParagraphStyle("en2", fontName="Helvetica-Oblique", fontSize=9,
                          textColor=DGRAY, alignment=TA_CENTER)
story.append(Paragraph("All 24 questions (Q24–Q47) answered in Drug Short Note format", end_note))
story.append(Paragraph("Disease | Class | MOA | P/K | Uses | Adverse Effects | C/I | Drug Interactions", end_note))

# ─── BUILD ────────────────────────────────────────────────────────────────────
doc.build(story)
print(f"PDF saved: {OUTPUT}")

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import ParagraphStyle
from reportlab.lib.units import cm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import BaseDocTemplate, Frame, PageTemplate
from reportlab.lib.colors import HexColor

OUTPUT = "/home/daytona/workspace/antimicrobial-set2/Antimicrobial_StudyGuide_Set2.pdf"

# ── Palette ───────────────────────────────────────────────────────────────────
NAVY    = HexColor("#1A237E")
TEAL    = HexColor("#00695C")
ORANGE  = HexColor("#E65100")
CRIMSON = HexColor("#B71C1C")
PURPLE  = HexColor("#4A148C")
BLUE    = HexColor("#1565C0")
GREEN   = HexColor("#2E7D32")
LGRAY   = HexColor("#F5F5F5")
MGRAY   = HexColor("#ECEFF1")
DGRAY   = HexColor("#546E7A")
GOLD    = HexColor("#F9A825")
WHITE   = colors.white
BLACK   = colors.black

PAGE_W, PAGE_H = A4

# ── Header / Footer ───────────────────────────────────────────────────────────
def header_footer(canvas, doc):
    canvas.saveState()
    canvas.setFillColor(NAVY)
    canvas.rect(0, PAGE_H - 1.5*cm, PAGE_W, 1.5*cm, fill=1, stroke=0)
    canvas.setFillColor(WHITE)
    canvas.setFont("Helvetica-Bold", 9)
    canvas.drawString(1.5*cm, PAGE_H - 0.95*cm, "ANTIMICROBIAL PHARMACOLOGY — STUDY GUIDE SET 2  (Q1–Q23)")
    canvas.setFont("Helvetica", 8)
    canvas.drawRightString(PAGE_W - 1.5*cm, PAGE_H - 0.95*cm, f"Page {doc.page}")
    canvas.setFillColor(NAVY)
    canvas.rect(0, 0, PAGE_W, 0.8*cm, fill=1, stroke=0)
    canvas.setFillColor(GOLD)
    canvas.setFont("Helvetica-Oblique", 7)
    canvas.drawCentredString(PAGE_W/2, 0.25*cm,
        "Penicillins | Cephalosporins | Fluoroquinolones | Aminoglycosides | Macrolides | Antimalarials | TB | UTI")
    canvas.restoreState()

doc = BaseDocTemplate(OUTPUT, pagesize=A4,
    leftMargin=1.8*cm, rightMargin=1.8*cm,
    topMargin=2.2*cm, bottomMargin=1.5*cm)
frame = Frame(doc.leftMargin, doc.bottomMargin, doc.width, doc.height, id="main")
doc.addPageTemplates([PageTemplate(id="main", frames=frame, onPage=header_footer)])

# ── Style helpers ─────────────────────────────────────────────────────────────
def S(name, **kw):
    return ParagraphStyle(name, **kw)

S_QTITLE = S("qt", fontName="Helvetica-Bold", fontSize=13, textColor=WHITE,
             alignment=TA_LEFT, leftIndent=6, spaceAfter=2, spaceBefore=8)
S_SECTION= S("sec", fontName="Helvetica-Bold", fontSize=10, textColor=NAVY,
             spaceAfter=2, spaceBefore=4)
S_BODY   = S("bd", fontName="Helvetica", fontSize=8.5, textColor=BLACK,
             spaceAfter=2, leading=13, alignment=TA_JUSTIFY)
S_BULLET = S("bl", fontName="Helvetica", fontSize=8.5, textColor=BLACK,
             leftIndent=14, bulletIndent=4, spaceAfter=1, leading=12)
S_NOTE   = S("nt", fontName="Helvetica-Oblique", fontSize=8, textColor=DGRAY,
             leftIndent=10, spaceAfter=3, leading=11)
S_TOC    = S("tc", fontName="Helvetica", fontSize=9, textColor=NAVY,
             leftIndent=10, spaceAfter=2)
S_TOCH   = S("tch", fontName="Helvetica-Bold", fontSize=11, textColor=NAVY,
             spaceAfter=6, spaceBefore=4)
S_COVER1 = S("cv1", fontName="Helvetica-Bold", fontSize=22, textColor=WHITE,
             alignment=TA_CENTER, spaceAfter=6)
S_COVER2 = S("cv2", fontName="Helvetica-Oblique", fontSize=11, textColor=GOLD,
             alignment=TA_CENTER, spaceAfter=4)

DW = doc.width  # usable width

# ── Builder functions ─────────────────────────────────────────────────────────
def qbanner(num, title, color=NAVY):
    t = Table([[Paragraph(f"Q{num} — {title}", S_QTITLE)]],
              colWidths=[DW])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0),(-1,-1), color),
        ("TOPPADDING",(0,0),(-1,-1),5),("BOTTOMPADDING",(0,0),(-1,-1),5),
        ("LEFTPADDING",(0,0),(-1,-1),8),("RIGHTPADDING",(0,0),(-1,-1),8),
    ]))
    return t

def slabel(txt, color=TEAL):
    hx = color.hexval()[2:]
    return Paragraph(f'<font color="#{hx}"><b>▶ {txt}</b></font>', S_SECTION)

def body(t): return Paragraph(t, S_BODY)
def bul(t):  return Paragraph(f"• {t}", S_BULLET)
def note(t): return Paragraph(f"<i>★ {t}</i>", S_NOTE)
def sp(h=4): return Spacer(1, h)
def hr(c=TEAL, th=0.5): return HRFlowable(width="100%", thickness=th, color=c,
                                           spaceAfter=4, spaceBefore=2)

TH = ParagraphStyle("th2", fontName="Helvetica-Bold", fontSize=8,
                    textColor=WHITE, alignment=TA_CENTER)
TD = ParagraphStyle("td2", fontName="Helvetica", fontSize=7.8,
                    textColor=BLACK, alignment=TA_LEFT, leading=11)

def tbl(headers, rows, cw=None, hc=NAVY):
    if cw is None:
        cw = [DW/len(headers)]*len(headers)
    data = [[Paragraph(h, TH) for h in headers]]
    for row in rows:
        data.append([Paragraph(str(c), TD) for c in row])
    t = Table(data, colWidths=cw, repeatRows=1)
    t.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(-1,0), hc),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[WHITE,LGRAY]),
        ("GRID",(0,0),(-1,-1),0.4, HexColor("#B0BEC5")),
        ("TOPPADDING",(0,0),(-1,-1),3),("BOTTOMPADDING",(0,0),(-1,-1),3),
        ("LEFTPADDING",(0,0),(-1,-1),5),("RIGHTPADDING",(0,0),(-1,-1),5),
        ("VALIGN",(0,0),(-1,-1),"TOP"),
    ]))
    return t

def drug_rows(rows, accent=NAVY):
    """Two-column key:value table for drug short notes."""
    t = Table(rows, colWidths=[3.2*cm, DW-3.2*cm])
    t.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(0,-1), MGRAY),
        ("FONTNAME",(0,0),(0,-1),"Helvetica-Bold"),
        ("FONTSIZE",(0,0),(-1,-1),8.5),
        ("FONTNAME",(1,0),(1,-1),"Helvetica"),
        ("TEXTCOLOR",(0,0),(0,-1), accent),
        ("GRID",(0,0),(-1,-1),0.4, HexColor("#B0BEC5")),
        ("ROWBACKGROUNDS",(1,0),(1,-1),[WHITE,LGRAY]*20),
        ("VALIGN",(0,0),(-1,-1),"TOP"),
        ("TOPPADDING",(0,0),(-1,-1),4),("BOTTOMPADDING",(0,0),(-1,-1),4),
        ("LEFTPADDING",(0,0),(-1,-1),6),
    ]))
    return t

# ═══════════════════════════════════════════════════════════════════════════════
story = []

# ── COVER ─────────────────────────────────────────────────────────────────────
story += [sp(20)]
for txt, sty in [
    ("ANTIMICROBIAL PHARMACOLOGY", S_COVER1),
    ("Comprehensive Study Guide — Set 2  (Questions 1–23)", S_COVER2),
]:
    row = [[Paragraph(txt, sty)]]
    bg = NAVY
    pad_t = 10 if sty == S_COVER1 else 2
    pad_b = 4  if sty == S_COVER1 else 10
    cover_t = Table(row, colWidths=[DW])
    cover_t.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(-1,-1),bg),
        ("TOPPADDING",(0,0),(-1,-1),pad_t),
        ("BOTTOMPADDING",(0,0),(-1,-1),pad_b),
    ]))
    story.append(cover_t)

story += [sp(16)]
INF = ParagraphStyle("inf", fontName="Helvetica", fontSize=9.5,
                     textColor=NAVY, alignment=TA_CENTER, leading=16)
ci = Table([
    [Paragraph("📋  Format per question: Drug Short Note | Disease | Class | MOA | P/K | Uses | ADRs | C/I | Drug Interactions", INF)],
    [Paragraph("🎯  23 Topics — Penicillins · Cephalosporins · Fluoroquinolones · Aminoglycosides · Macrolides · Antimalarials · TB · UTI", INF)],
    [Paragraph("📅  Date: 30 June 2026", INF)],
], colWidths=[DW])
ci.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1),MGRAY),
    ("TOPPADDING",(0,0),(-1,-1),6),("BOTTOMPADDING",(0,0),(-1,-1),6),
    ("LEFTPADDING",(0,0),(-1,-1),12),
    ("GRID",(0,0),(-1,-1),0.5, HexColor("#CFD8DC")),
]))
story += [ci, PageBreak()]

# ── TOC ───────────────────────────────────────────────────────────────────────
story += [sp(6), Paragraph("TABLE OF CONTENTS", S_TOCH), hr(NAVY, 1.5), sp(4)]
toc_items = [
    ("Q1",  "MOA of Penicillins"),
    ("Q2",  "Difference Between Ampicillin and Amoxicillin"),
    ("Q3",  "Penicillin (Imipenem) Combined with Cilastatin"),
    ("Q4",  "Tetracycline Not Preferred in Children and Pregnant Women"),
    ("Q5",  "Advantages & Disadvantages of Antimicrobial Fixed Dose Combinations"),
    ("Q6",  "Amoxicillin + Clavulanic Acid (Augmentin) in Bacterial Infections"),
    ("Q7",  "Difference Between Cefuroxime and Ceftriaxone"),
    ("Q8",  "Difference Between Penicillin G and Amoxicillin"),
    ("Q9",  "Beta-Lactam Antibiotics — Short Note"),
    ("Q10", "Cephalosporins — Short Note"),
    ("Q11", "Empirical and Prophylactic Therapy"),
    ("Q12", "Remdesivir — Short Note"),
    ("Q13", "Concentration-Dependent vs Time-Dependent Killing"),
    ("Q14", "Antimalarial Drugs — Classification"),
    ("Q15", "Pharmacotherapy of Category II TB"),
    ("Q16", "Pharmacotherapy of UTI"),
    ("Q17", "Ciprofloxacin — Short Note"),
    ("Q18", "Difference Between Aminoglycosides and Macrolides"),
    ("Q19", "Vancomycin — Short Note"),
    ("Q20", "Isoniazid Resistance → Cross-Resistance to Ethionamide"),
    ("Q21", "Difference Between Macrolides and Chloramphenicol"),
    ("Q22", "Aminoglycosides — Gentamicin and Streptomycin"),
    ("Q23", "Urinary Antiseptics"),
]
story.append(tbl(["#","Topic"],
    [[q,t] for q,t in toc_items],
    cw=[1.4*cm, DW-1.4*cm], hc=NAVY))
story.append(PageBreak())

# ═══════════════════════════ Q1 ═══════════════════════════════════════════════
story += [qbanner(1,"MOA of Penicillins", NAVY), sp(4),
    slabel("Mechanism of Action"),
    body("Penicillins bind to <b>Penicillin-Binding Proteins (PBPs)</b> — transpeptidase enzymes on the bacterial cell membrane."),
    body("PBPs normally catalyse <b>cross-linking (transpeptidation)</b> of peptidoglycan strands. Penicillin binding → inhibition → structurally weak cell wall → bacterial <b>autolysins</b> lyse the cell → <b>bactericidal</b>."),
    body("Active only against dividing bacteria (no active wall synthesis in static bacteria). Selective toxicity: human cells have NO cell wall/PBPs."),
    sp(3),
    tbl(["Resistance Mechanism","Description","Example"],
    [
        ["Beta-lactamase production","Enzyme opens and destroys the beta-lactam ring","S. aureus, E. coli producing penicillinase"],
        ["Altered PBPs (low affinity)","Drug cannot bind; PBP has modified active site","MRSA: acquires PBP2a via mecA gene"],
        ["Reduced permeability","Porin channel loss or modification","Gram-negative outer membrane changes"],
        ["Efflux pumps","Active transport of drug out of cell","AcrAB-TolC system in E. coli"],
    ], cw=[3.5*cm,6*cm,6.5*cm], hc=NAVY),
    note("Mnemonic: Penicillin Prevents Peptidoglycan → bacteria Pop. All beta-lactams share this PBP-binding MOA."),
    PageBreak()]

# ═══════════════════════════ Q2 ═══════════════════════════════════════════════
story += [qbanner(2,"Difference Between Ampicillin and Amoxicillin", TEAL), sp(4),
    tbl(["Property","Ampicillin","Amoxicillin"],
    [
        ["Type","Aminopenicillin (semi-synthetic)","Aminopenicillin (semi-synthetic)"],
        ["Oral bioavailability","~40% (poor, variable)","~90% (excellent)"],
        ["Food effect","Absorption reduced — take on empty stomach","NOT affected by food"],
        ["Acid stability","Less acid-stable","More acid-stable"],
        ["Serum levels","Lower for same oral dose","Higher"],
        ["Dosing frequency","QID (4 times daily)","TDS (3 times daily)"],
        ["GI side effects","More diarrhoea (unabsorbed drug irritates colon)","Less diarrhoea"],
        ["Spectrum","Identical","Identical"],
        ["Beta-lactamase","Susceptible (destroyed by penicillinase)","Susceptible"],
        ["Unique ADR","Ampicillin rash — non-allergic maculopapular rash in EBV/CMV/CLL","Same rash possible"],
        ["Preferred IV use","Yes — Listeria meningitis, empirical sepsis","IV amoxicillin available but less common"],
        ["Preferred oral DOC","Shigella (PO), Listeria","H. pylori triple therapy, LRTI, otitis, sinusitis"],
    ], cw=[4.2*cm,5.5*cm,6.3*cm], hc=TEAL),
    note("Key: Amoxicillin preferred orally — better absorption, less GI upset, convenient dosing. Ampicillin preferred IV and for Shigella (oral amoxicillin less effective for Shigella despite identical in vitro spectrum)."),
    PageBreak()]

# ═══════════════════════════ Q3 ═══════════════════════════════════════════════
story += [qbanner(3,"Imipenem Combined with Cilastatin", ORANGE), sp(4),
    slabel("Why Cilastatin?", ORANGE),
    tbl(["Aspect","Explanation"],
    [
        ["What is Cilastatin?","NOT an antibiotic — it is a specific inhibitor of renal brush-border enzyme Dehydropeptidase-I (DHP-I)"],
        ["Problem without it","Imipenem hydrolysed & inactivated by DHP-I → (1) Urinary levels too low for UTI treatment, (2) Hydrolysis produces NEPHROTOXIC metabolite → proximal tubular damage"],
        ["Solution","Cilastatin blocks DHP-I → imipenem preserved in urine → adequate UTI treatment AND nephrotoxicity prevented"],
        ["Ratio","Imipenem : Cilastatin = 1:1 (equal parts)"],
        ["Meropenem comparison","Meropenem is DHP-I stable → does NOT need cilastatin"],
    ], cw=[3.5*cm, DW-3.5*cm], hc=ORANGE),
    sp(4),
    drug_rows([
        ["Disease","Hospital-acquired pneumonia, Intra-abdominal infections, Febrile neutropenia, Complicated UTI, Polymicrobial/ESBL infections"],
        ["Class","Carbapenem — broadest-spectrum beta-lactam antibiotic"],
        ["MOA","Binds PBP1 and PBP2 → inhibits cell wall synthesis → bactericidal. Stable to most beta-lactamases incl. ESBLs. NOT active vs MRSA, VRE, Stenotrophomonas maltophilia"],
        ["P/K","IV only. Good tissue distribution. Renal excretion (intact drug, protected by cilastatin). T½ ~1 hr"],
        ["Adverse Effects","Seizures (dose-related, lowers threshold — more than meropenem); Nausea/vomiting; Hypersensitivity; Superinfection"],
        ["C/I","Epilepsy (caution); Hypersensitivity; Dose reduction in renal failure"],
        ["Drug Interactions","Valproate: imipenem dramatically ↓ valproate levels → breakthrough seizures (AVOID combination); Probenecid: ↑ imipenem levels"],
    ], ORANGE),
    PageBreak()]

# ═══════════════════════════ Q4 ═══════════════════════════════════════════════
story += [qbanner(4,"Tetracycline Not Preferred in Children & Pregnant Women", CRIMSON), sp(4),
    drug_rows([
        ["Drug","Tetracyclines: Tetracycline, Doxycycline, Minocycline"],
        ["Class","Broad-spectrum antibiotic — 30S ribosomal inhibitor (blocks aminoacyl-tRNA binding)"],
    ], CRIMSON),
    sp(4),
    slabel("In Children (< 8 years)", CRIMSON),
    tbl(["Complication","Mechanism","Consequence"],
    [
        ["Teeth discolouration (PERMANENT)","Tetracyclines chelate Ca²⁺ → deposits in developing teeth → enamel hypoplasia","Yellow-brown-grey permanent discolouration; structural weakening"],
        ["Bone growth retardation","Deposits in growing long bones → reversible growth inhibition","Potential height/growth impact during critical development"],
    ], cw=[3.5*cm,6*cm,6.5*cm], hc=CRIMSON),
    sp(3),
    slabel("In Pregnant Women", CRIMSON),
    tbl(["Complication","Mechanism"],
    [
        ["Fetal teeth/bone damage","Crosses placenta freely → affects ALL primary teeth (form in utero) + fetal bone development"],
        ["Maternal hepatotoxicity","Severe acute fatty liver of pregnancy (esp. IV tetracycline) — potentially fatal; pregnant women disproportionately susceptible"],
        ["Fetal liver toxicity","Hepatotoxicity in developing fetus"],
        ["Breast milk","Excreted in breast milk → affects nursing infant's developing teeth and bones"],
    ], cw=[4*cm, DW-4*cm], hc=CRIMSON),
    sp(3),
    note("Exception: Doxycycline is used in pregnancy for life-threatening Rocky Mountain Spotted Fever when no safer alternative exists. Risk-benefit decision."),
    note("Additional CI: Renal failure (except doxycycline — hepatically eliminated); outdated tetracycline → Fanconi syndrome (nephrotoxic epitetracycline)."),
    PageBreak()]

# ═══════════════════════════ Q5 ═══════════════════════════════════════════════
story += [qbanner(5,"Fixed Dose Combinations (FDCs) — Advantages & Disadvantages", PURPLE), sp(4),
    slabel("ADVANTAGES", GREEN),
    tbl(["Advantage","Example"],
    [
        ["Synergism — enhanced killing","Co-trimoxazole (SMX+TMP): sequential folate blockade → bactericidal (vs bacteriostatic individually)"],
        ["Reduced resistance","TB HRZE: 4 drugs simultaneously prevent selection of resistant mutants"],
        ["Better compliance — fewer tablets","4-in-1 TB tablet vs 4 separate tablets; HIV single-pill regimens"],
        ["Pharmacokinetic synergy","Augmentin: Clavulanate irreversibly inhibits beta-lactamase → protects amoxicillin"],
        ["Prevents monotherapy in HIV","Atripla (TDF+FTC+EFV): ensures complete ART even with partial adherence"],
        ["Cost-effective","Single FDC cheaper than multiple individual drugs"],
        ["Reduces pill burden","Critical for long-term TB/HIV therapy adherence"],
    ], cw=[5*cm, DW-5*cm], hc=GREEN),
    sp(4),
    slabel("DISADVANTAGES", CRIMSON),
    tbl(["Disadvantage","Example"],
    [
        ["Individual dose adjustment impossible","Cannot reduce rifampicin dose alone in hepatic disease (TB FDC)"],
        ["ADR attribution difficult","Rash with Co-trimoxazole — sulfa or trimethoprim?"],
        ["Resistance to one component = ineffective FDC","SMX-resistant organism → TMP alone may be insufficient"],
        ["Pharmacokinetic mismatch","Artemether T½ 1–3 hrs vs Lumefantrine T½ 3–6 days (Coartem)"],
        ["C/I to one component stops entire FDC","Ethambutol causes optic neuritis → forced to stop all 4 TB drugs"],
        ["Formulation incompatibility","Chemical degradation or physical instability when combined"],
    ], cw=[5*cm, DW-5*cm], hc=CRIMSON),
    note("Key FDC examples: Co-trimoxazole | Augmentin | Pip-Tazo | TB HRZE | Coartem (ACT) | Kaletra (LPV/r) | Atripla"),
    PageBreak()]

# ═══════════════════════════ Q6 ═══════════════════════════════════════════════
story += [qbanner(6,"Amoxicillin + Clavulanic Acid (Augmentin)", TEAL), sp(4),
    slabel("Why Combined?"),
    body("<b>Amoxicillin</b>: Broad-spectrum aminopenicillin; susceptible to beta-lactamase destruction."),
    body("<b>Clavulanic acid</b>: Suicide inhibitor of beta-lactamase — binds irreversibly, inactivating the enzyme → protects amoxicillin. Minimal antibacterial activity alone. Ratio: 500:125 mg or 875:125 mg."),
    sp(3),
    drug_rows([
        ["Disease","LRTI, Sinusitis, Otitis media (beta-lactamase producing H. influenzae, M. catarrhalis), Skin/soft tissue, UTI, Diabetic foot, Animal/human bites (Pasteurella), Dental abscesses"],
        ["Class","Aminopenicillin + Beta-lactamase inhibitor combination"],
        ["MOA","Clavulanate: suicide substrate for beta-lactamase → irreversible inhibition → amoxicillin restored to activity. Amoxicillin: binds PBPs → blocks peptidoglycan cross-linking → bactericidal"],
        ["P/K","Both well absorbed orally. Matched T½ ~1 hr. Take WITH FOOD (↓ GI side effects; does not reduce amoxicillin absorption). Renal excretion"],
        ["Uses","Beta-lactamase producing organisms (MSSA, H. influenzae, E. coli, Klebsiella, M. catarrhalis); Animal/human bites; Aspiration pneumonia; Sinusitis; Otitis media; H. pylori (alternate); Dental abscess"],
        ["Adverse Effects","Diarrhoea (most common — clavulanate irritates GI tract); Nausea; Hypersensitivity; CHOLESTATIC JAUNDICE (hepatotoxicity — clavulanate implicated, more common than with amoxicillin alone); C. difficile (prolonged use)"],
        ["C/I","Penicillin/cephalosporin hypersensitivity; Prior cholestatic jaundice with co-amoxiclav; Severe hepatic disease"],
        ["Drug Interactions","Warfarin (↑ anticoagulation); Allopurinol (↑ rash frequency); Probenecid (↑ amoxicillin levels); Methotrexate toxicity (↓ renal excretion)"],
    ], TEAL),
    PageBreak()]

# ═══════════════════════════ Q7 ═══════════════════════════════════════════════
story += [qbanner(7,"Difference Between Cefuroxime and Ceftriaxone", BLUE), sp(4),
    tbl(["Property","Cefuroxime","Ceftriaxone"],
    [
        ["Generation","2nd generation cephalosporin","3rd generation cephalosporin"],
        ["Gram-positive cover","Good (Staph, Strep)","Reduced vs 2G"],
        ["Gram-negative cover","Extended (H. influenzae, E. coli, Klebsiella, Neisseria)","Excellent — broader than cefuroxime"],
        ["Pseudomonas","NO","NO (need ceftazidime/cefepime)"],
        ["CSF penetration","Moderate (meningitis option)","EXCELLENT — DOC for bacterial meningitis"],
        ["Route","IV/IM AND oral (cefuroxime axetil — prodrug)","IV/IM only (no oral form)"],
        ["Half-life","~1.3 hours → 2–3x daily dosing","~8 hours → ONCE DAILY dosing"],
        ["Protein binding","~50%","~95% (highest among cephalosporins)"],
        ["Elimination","Renal","DUAL: biliary + renal"],
        ["Biliary sludge","No","YES — pseudolithiasis (esp. children/neonates/prolonged use)"],
        ["Key DOC uses","Surgical prophylaxis, LRTI, Lyme disease (mild), UTI, Sinusitis","Meningitis, Typhoid, Gonorrhoea (single dose DOC), Septicaemia, MDR infections"],
        ["Cost","Lower","Higher"],
    ], cw=[4*cm,5.5*cm,6.5*cm], hc=BLUE),
    PageBreak()]

# ═══════════════════════════ Q8 ═══════════════════════════════════════════════
story += [qbanner(8,"Difference Between Penicillin G and Amoxicillin", ORANGE), sp(4),
    tbl(["Property","Penicillin G","Amoxicillin"],
    [
        ["Type","Natural penicillin","Aminopenicillin (semi-synthetic)"],
        ["Spectrum","NARROW: gram-positives (Staph-sensitive, Strep, Enterococcus) + Spirochetes + gram-negative cocci (N. meningitidis, N. gonorrhoeae)","EXTENDED: Pen G spectrum + H. influenzae, E. coli, Proteus mirabilis, Salmonella, Listeria monocytogenes"],
        ["Oral route","NO — acid labile; IV/IM only","YES — acid stable; 90% oral bioavailability"],
        ["Food effect","N/A (parenteral)","NOT affected by food"],
        ["Beta-lactamase","Susceptible","Susceptible (both need clavulanate protection)"],
        ["Antipseudomonal","No","No"],
        ["Formulations","Pen G Na/K (IV); Benzathine Pen G (IM depot, long-acting); Procaine Pen G (IM, intermediate)","Oral capsules/suspension; IV available"],
        ["DOC for","Syphilis (Treponema pallidum), GAS pharyngitis, Streptococcal endocarditis, Gas gangrene, Tetanus, Rheumatic fever prophylaxis, Actinomycosis","H. pylori triple therapy, LRTI, Otitis media, Sinusitis, Listeria meningitis"],
    ], cw=[3.5*cm,6*cm,6.5*cm], hc=ORANGE),
    PageBreak()]

# ═══════════════════════════ Q9 ═══════════════════════════════════════════════
story += [qbanner(9,"Beta-Lactam Antibiotics", NAVY), sp(4),
    tbl(["Group","Examples","Key Feature"],
    [
        ["Penicillins","Pen G, Amoxicillin, Ampicillin, Piperacillin, Oxacillin","Narrow to broad; acid-labile (Pen G) vs acid-stable"],
        ["Cephalosporins","Cefazolin (1G), Cefuroxime (2G), Ceftriaxone (3G), Cefepime (4G), Ceftaroline (5G)","Generation-based expanded gram-negative coverage; 5G covers MRSA"],
        ["Carbapenems","Imipenem-Cilastatin, Meropenem, Ertapenem, Doripenem","Broadest spectrum; stable to most beta-lactamases incl. ESBLs"],
        ["Monobactams","Aztreonam","Gram-negative ONLY; safe in penicillin allergy (different ring structure)"],
        ["BL inhibitors","Clavulanic acid, Sulbactam, Tazobactam, Avibactam","Protect partner drug from beta-lactamase; weak/no activity alone"],
    ], cw=[3.2*cm,5.5*cm,7.3*cm], hc=NAVY),
    sp(4),
    drug_rows([
        ["MOA","Bind PBPs (transpeptidases) → inhibit peptidoglycan cross-linking → cell wall lysis → BACTERICIDAL. Requires active cell division"],
        ["Resistance","Beta-lactamase production (most common); Altered PBPs (MRSA - mecA); Reduced permeability; Efflux pumps"],
        ["P/K","Most parenteral (IV/IM). Some oral: amoxicillin, cephalexin, cefixime. Poor CNS penetration (adequate in meningitis with inflamed BBB). Mostly renal excretion"],
        ["Adverse Effects","Hypersensitivity (most common: rash → anaphylaxis); Diarrhoea/C. difficile; Seizures (imipenem, high-dose Pen G); Superinfection; Electrolyte load (Na+/K+ with IV penicillins)"],
        ["C/I","Known hypersensitivity. Cross-allergy penicillin-cephalosporin ~1–2%"],
        ["Drug Interactions","Probenecid: blocks tubular secretion → ↑ levels. Aminoglycosides: synergistic but physically incompatible in same syringe"],
    ], NAVY),
    PageBreak()]

# ═══════════════════════════ Q10 ══════════════════════════════════════════════
story += [qbanner(10,"Cephalosporins", TEAL), sp(4),
    tbl(["Generation","Key Drugs","Spectrum","Primary Uses"],
    [
        ["1st Gen","Cephalexin (PO), Cefazolin (IV), Cephradine","Gram-positive > gram-negative (E. coli, Klebsiella, Proteus — basic)","Surgical prophylaxis, Skin/soft tissue, UTI"],
        ["2nd Gen","Cefuroxime, Cefaclor (PO), Cefoxitin*, Cefotetan*\n*= anaerobic cover","Extended gram-negative + anaerobes","LRTI, Sinusitis, Otitis media, PID"],
        ["3rd Gen","Cefotaxime, Ceftriaxone, Ceftazidime†, Cefoperazone†, Cefixime (PO)\n†= antipseudomonal","Excellent gram-negative; Pseudomonas (ceftaz/cefop); reduced gram-positive","Meningitis, Typhoid, Gonorrhoea, Septicaemia"],
        ["4th Gen","Cefepime","Broad: gram-positive AND gram-negative + Pseudomonas; AmpC-stable","HAP, Febrile neutropenia, Pseudomonas"],
        ["5th Gen","Ceftaroline, Ceftobiprole","MRSA (binds PBP2a) + broad gram-negative","MRSA infections, Complicated SSTI"],
    ], cw=[2.2*cm,4.2*cm,5*cm,4.6*cm], hc=TEAL),
    sp(4),
    drug_rows([
        ["MOA","Bind PBPs → inhibit transpeptidation → bactericidal. Resistance: ESBLs, AmpC beta-lactamases, altered PBPs, reduced permeability"],
        ["Adverse Effects","Hypersensitivity (cross with penicillin 1–2%); Diarrhoea; Biliary sludge (ceftriaxone, esp. in children); Disulfiram-like reaction with alcohol (cefoperazone, cefotetan); C. difficile"],
        ["C/I","Hypersensitivity; caution if severe penicillin allergy"],
        ["Drug Interactions","Probenecid ↑ levels; Alcohol + cefoperazone/cefotetan → disulfiram reaction; Aminoglycosides: synergistic + nephrotoxic (monitor)"],
    ], TEAL),
    PageBreak()]

# ═══════════════════════════ Q11 ══════════════════════════════════════════════
story += [qbanner(11,"Empirical and Prophylactic Therapy", GREEN), sp(4),
    slabel("A) Empirical Therapy", GREEN),
    body("<b>Definition:</b> Treatment started <b>before</b> causative organism is identified, based on clinical syndrome and likely pathogens. De-escalate once C&S results available."),
    sp(3),
    tbl(["Clinical Scenario","Empirical Regimen","Target Organisms"],
    [
        ["Community-acquired pneumonia","Amoxicillin + Azithromycin (oral); Ceftriaxone + Azithromycin (hospitalised)","S. pneumoniae, H. influenzae, Atypicals"],
        ["Bacterial meningitis","Ceftriaxone + Ampicillin + Dexamethasone","S. pneumoniae, N. meningitidis, Listeria"],
        ["Sepsis (hospital-acquired)","Pip-Tazo or Carbapenem ± Vancomycin (if MRSA risk)","Gram-negatives, MRSA, mixed flora"],
        ["Febrile neutropenia","Cefepime or Pip-Tazo (± vancomycin)","Gram-negatives, Pseudomonas, MRSA"],
        ["PID","Ceftriaxone + Doxycycline + Metronidazole","N. gonorrhoeae, Chlamydia, Anaerobes"],
    ], cw=[4*cm, 5.5*cm, 6.5*cm], hc=GREEN),
    sp(4),
    slabel("B) Prophylactic Therapy", GREEN),
    body("<b>Definition:</b> Use of antibiotics to <b>prevent</b> infection before it occurs in high-risk patients."),
    sp(3),
    tbl(["Type","Indication","Drug"],
    [
        ["Surgical prophylaxis","Before incision (30–60 min prior); single dose usually sufficient","Cefazolin (most surgeries); Metronidazole (colorectal/gynaecological)"],
        ["Rheumatic fever prophylaxis","Previous rheumatic fever — prevent GAS recurrence","Benzathine Pen G 1.2M units IM monthly × 5–10 years"],
        ["PCP prophylaxis (HIV)","CD4 < 200 cells/μL","Co-trimoxazole 960 mg daily"],
        ["MAC prophylaxis (HIV)","CD4 < 50 cells/μL","Azithromycin 1.2 g once weekly"],
        ["Meningococcal contacts","Household/close contacts of N. meningitidis","Rifampicin 600 mg BD × 2 days or Ciprofloxacin 500 mg single dose"],
        ["Malaria prophylaxis","Travel to endemic areas","Chloroquine / Mefloquine / Doxycycline / Atovaquone-proguanil (Malarone)"],
    ], cw=[3.5*cm,4.5*cm,8*cm], hc=GREEN),
    PageBreak()]

# ═══════════════════════════ Q12 ══════════════════════════════════════════════
story += [qbanner(12,"Remdesivir", PURPLE), sp(4),
    drug_rows([
        ["Disease","COVID-19 (SARS-CoV-2) — hospitalised patients requiring supplemental O₂; investigated in Ebola"],
        ["Class","Nucleoside analogue antiviral — adenosine analogue prodrug"],
        ["MOA","Remdesivir (prodrug) → metabolised intracellularly to active triphosphate (GS-443902). Active form incorporated into viral RNA by RNA-dependent RNA polymerase (RdRp) → acts as chain terminator (delayed termination after 3 nucleotides — evades exonuclease proofreading) → premature termination of viral RNA synthesis → prevents viral replication. Selective for viral RdRp over human polymerases"],
        ["P/K","IV infusion only (original formulation — prodrug not orally bioavailable). Rapidly converted to active metabolite. High lung concentrations. Hepatic metabolism; renal excretion of metabolites. T½ prodrug ~1 hr; active intracellular metabolite much longer"],
        ["Uses","COVID-19: adults and children ≥28 days (≥3 kg) requiring supplemental oxygen. Reduces time to clinical improvement. 5-day course (IV); oral formulation under investigation"],
        ["Adverse Effects","BRADYCARDIA (transient, within minutes of infusion — monitor HR); Elevated liver transaminases (hepatotoxicity — monitor LFTs); Nausea, vomiting; Infusion-related hypersensitivity reactions (flushing, sweating, tachycardia); Hypotension; Elevated creatinine (cyclodextrin vehicle — nephrotoxic in renal impairment)"],
        ["C/I","eGFR <30 mL/min (cyclodextrin vehicle accumulates — original IV form); ALT >5× ULN (hepatotoxicity risk); Hypersensitivity to remdesivir"],
        ["Drug Interactions","Chloroquine/Hydroxychloroquine — ANTAGONISES remdesivir antiviral activity (avoid combination); CYP3A4 inducers (rifampicin) → ↓ remdesivir levels; P-gp inducers ↓ absorption"],
    ], PURPLE),
    PageBreak()]

# ═══════════════════════════ Q13 ══════════════════════════════════════════════
story += [qbanner(13,"Concentration-Dependent vs Time-Dependent Killing", BLUE), sp(4),
    tbl(["Feature","Concentration-Dependent Killing","Time-Dependent Killing"],
    [
        ["Definition","Rate and extent of kill ↑ as drug concentration ↑ above MIC. Higher peak = greater kill","Bacterial killing depends on how LONG concentration stays above MIC. Raising concentration beyond 4×MIC gives no extra benefit"],
        ["Key PD parameter","Cmax/MIC ratio  OR  AUC/MIC","Time above MIC (T>MIC) — aim 40–70% of dosing interval"],
        ["Optimal dosing strategy","High peak doses — ONCE DAILY dosing (maximise Cmax)","FREQUENT dosing or CONTINUOUS INFUSION (maintain T>MIC)"],
        ["Post-Antibiotic Effect (PAE)","SIGNIFICANT — bacterial suppression continues after drug levels fall below MIC","MINIMAL — bacteria regrow rapidly when drug levels fall"],
        ["Examples","Aminoglycosides (gentamicin, tobramycin), Fluoroquinolones (ciprofloxacin), Metronidazole, Daptomycin","Beta-lactams (penicillins, cephalosporins, carbapenems), Vancomycin, Clindamycin, Macrolides"],
        ["Clinical implication","Once-daily aminoglycoside dosing (Extended Interval Dosing) maximises efficacy AND reduces toxicity (trough recovery time)","Beta-lactams by continuous infusion OR q4–6h dosing; carbapenem extended infusion (4-hr infusion instead of 30 min)"],
    ], cw=[3.5*cm,6*cm,6.5*cm], hc=BLUE),
    note("Vancomycin: AUC/MIC is now the preferred PD target (target AUC 400–600 mg·h/L for MRSA). Neither purely concentration- nor time-dependent — AUC-dependent."),
    PageBreak()]

# ═══════════════════════════ Q14 ══════════════════════════════════════════════
story += [qbanner(14,"Antimalarial Drugs — Classification", TEAL), sp(4),
    slabel("A) By Chemical Class"),
    tbl(["Class","Drugs","MOA (simplified)"],
    [
        ["Quinoline derivatives","Chloroquine, Quinine, Quinidine, Primaquine, Tafenoquine, Amodiaquine, Mefloquine","Accumulate in parasite food vacuole → inhibit haem polymerisation → toxic haem accumulates → parasite death"],
        ["Aryl amino alcohols","Mefloquine, Lumefantrine, Halofantrine","Accumulate in food vacuole; complex with haem → toxic to parasite"],
        ["Artemisinins (endoperoxides)","Artesunate, Artemether, Dihydroartemisinin (DHA)","Fe²⁺ activates endoperoxide bridge → free radicals → damage parasite proteins and DNA"],
        ["Antifolates","Pyrimethamine, Proguanil, Sulfadoxine-Pyrimethamine (SP/Fansidar)","Block folate synthesis: SP blocks dihydropteroate synthase; Pyrimethamine/Proguanil block DHFR"],
        ["Antibiotics","Doxycycline, Clindamycin, Azithromycin","Slow-acting; inhibit protein synthesis in parasite apicoplast"],
        ["Naphthoquinones","Atovaquone (+ proguanil = Malarone)","Inhibits mitochondrial electron transport (cytochrome bc1 complex); Proguanil synergises"],
    ], cw=[3.5*cm, 5*cm, 7.5*cm], hc=TEAL),
    sp(4),
    slabel("B) By Life Cycle Stage"),
    tbl(["Drug","Stage","Use"],
    [
        ["Chloroquine","Blood stage (erythrocytic)","Treatment + prophylaxis (sensitive P. vivax/malariae/ovale)"],
        ["Artesunate / ACT","Blood stage (all stages incl. gametocytes)","Standard treatment of P. falciparum malaria"],
        ["Primaquine / Tafenoquine","Liver hypnozoites + gametocytes","RADICAL CURE of P. vivax/ovale (prevents relapse); requires G6PD screening before use"],
        ["Proguanil / Doxycycline","Pre-erythrocytic (liver)","Causal prophylaxis"],
        ["SP (Fansidar)","Blood stage","IPTp (Intermittent Preventive Treatment in Pregnancy) for P. falciparum"],
    ], cw=[3.5*cm, 3.5*cm, 9*cm], hc=NAVY),
    sp(4),
    slabel("C) ACT Regimens (Current Standard)"),
    tbl(["ACT Combination","Region/Indication"],
    [
        ["Artemether + Lumefantrine (Coartem)","Global standard — uncomplicated P. falciparum"],
        ["Artesunate + Mefloquine","Southeast Asia"],
        ["Artesunate + Amodiaquine","Africa"],
        ["Dihydroartemisinin + Piperaquine","Asia"],
        ["IV/IM Artesunate (monotherapy)","Severe/complicated P. falciparum malaria (DOC)"],
    ], cw=[6*cm, DW-6*cm], hc=ORANGE),
    PageBreak()]

# ═══════════════════════════ Q15 ══════════════════════════════════════════════
story += [qbanner(15,"Pharmacotherapy of Category II TB (Retreatment)", ORANGE), sp(4),
    body("<b>Category II:</b> Retreatment cases — relapse, failure, or default from Category I. Requires C&S/DST before starting. If MDR confirmed → BPaL/BPaLM regimen."),
    sp(3),
    slabel("Regimen (WHO/RNTCP Category II)", ORANGE),
    body("<b>Intensive phase (3 months):</b> HRZES — Isoniazid + Rifampicin + Pyrazinamide + Ethambutol + Streptomycin (first 2 months only)"),
    body("<b>Continuation phase (5 months):</b> HRE — Isoniazid + Rifampicin + Ethambutol"),
    body("<b>Total duration: 8 months</b>"),
    sp(3),
    tbl(["Drug","Abbrev","Dose","Mechanism","Key ADR"],
    [
        ["Isoniazid","H","5 mg/kg/d (max 300 mg)","Inhibits InhA → blocks mycolic acid synthesis → bactericidal","Peripheral neuropathy (↑B6 deficiency) → give pyridoxine; Hepatotoxicity"],
        ["Rifampicin","R","10 mg/kg/d (max 600 mg)","Inhibits DNA-dependent RNA polymerase → bactericidal (replicating + semi-dormant)","Orange secretions; Hepatotoxicity; CYP450 inducer (↑↑ drug interactions); Flu-like (intermittent)"],
        ["Pyrazinamide","Z","25 mg/kg/d (max 2 g)","Active at acidic pH (macrophages/caseous lesions) → sterilising","Hyperuricaemia/gout; Hepatotoxicity; Arthralgia"],
        ["Ethambutol","E","15–20 mg/kg/d (max 1.6 g)","Inhibits arabinosyl transferase → blocks arabinogalactan synthesis","OPTIC NEURITIS (monitor visual acuity + colour vision monthly)"],
        ["Streptomycin","S","15 mg/kg IM (max 1 g)","Binds 30S (protein S12) → mRNA misreading → bactericidal","Vestibular ototoxicity > cochlear; Nephrotoxicity; AVOID in pregnancy (congenital deafness)"],
    ], cw=[2.3*cm,1.3*cm,2.2*cm,5*cm,5.2*cm], hc=ORANGE),
    note("Current WHO 2022: Category II regimen is DISCOURAGED without DST. Send sputum C&S first. If MDR-TB confirmed → BPaL (Bedaquiline + Pretomanid + Linezolid) or BPaLM (+Moxifloxacin) for 6 months."),
    PageBreak()]

# ═══════════════════════════ Q16 ══════════════════════════════════════════════
story += [qbanner(16,"Pharmacotherapy of UTI", GREEN), sp(4),
    body("<b>Most common pathogen:</b> E. coli (~80% community UTI). Others: Klebsiella, Staph. saprophyticus, Proteus mirabilis, Enterococcus, Pseudomonas (hospital/catheter)."),
    sp(3),
    tbl(["Type","First-line Drug","Dose & Duration","Key Notes"],
    [
        ["Uncomplicated cystitis","Nitrofurantoin","100 mg SR BD × 5 days","DOC in many guidelines; concentrated in urine; avoid if eGFR <30"],
        ["Uncomplicated cystitis","Fosfomycin","3 g single oral dose","Excellent for uncomplicated UTI incl. ESBL E. coli; growing use"],
        ["Uncomplicated cystitis","Co-trimoxazole","960 mg BD × 3 days","Only if local resistance <20%"],
        ["Pyelonephritis (mild-moderate)","Ciprofloxacin","500 mg BD PO × 7–14 days","DOC for pyelonephritis if sensitivity confirmed"],
        ["Pyelonephritis (severe/hospitalised)","Ceftriaxone → step-down to oral","1–2 g OD IV × 10–14 days","Step-down to oral ciprofloxacin once improving"],
        ["ESBL-producing E. coli","Ertapenem or Meropenem","IV × 10–14 days","Carbapenem required; fosfomycin/nitrofurantoin may work for lower UTI"],
        ["Enterococcal UTI","Amoxicillin","500 mg TDS × 7 days","Cephalosporins intrinsically inactive against Enterococcus"],
        ["CAUTI","Based on C&S results","7–14 days","Remove/change catheter if possible before treating"],
        ["Pregnancy (asymptomatic bacteriuria — TREAT!)","Cephalexin / Nitrofurantoin","5–7 days","AVOID: Fluoroquinolones, Tetracyclines, Nitrofurantoin at term, Co-trimoxazole near term"],
    ], cw=[3.5*cm, 3.5*cm, 3.2*cm, 5.8*cm], hc=GREEN),
    note("Amoxicillin NOT recommended empirically for UTI — community E. coli resistance typically >50%. Always send MSU C&S for complicated/recurrent/pregnant patients."),
    PageBreak()]

# ═══════════════════════════ Q17 ══════════════════════════════════════════════
story += [qbanner(17,"Ciprofloxacin", CRIMSON), sp(4),
    drug_rows([
        ["Disease","UTI (complicated, pyelonephritis), Respiratory infections (gram-negative/atypical), Pseudomonas infections, Typhoid, Anthrax (DOC), Gonorrhoea (if susceptible), Osteomyelitis, Traveller's diarrhoea"],
        ["Class","Fluoroquinolone (2nd generation quinolone)"],
        ["MOA","Inhibits bacterial DNA gyrase (topoisomerase II) — primary target in gram-negatives — and topoisomerase IV — primary target in gram-positives. Inhibition → DNA strand breaks → bactericidal. Concentration-dependent killing. Resistance: mutations in gyrA/parC (altered targets); efflux pumps (most common); reduced permeability"],
        ["P/K","Excellent oral bioavailability ~70–80%. Wide tissue distribution — penetrates bone, prostate, lungs well. Moderate CSF penetration. Vd ~2.5 L/kg. Metabolised hepatically. Renal + biliary excretion. T½ ~4–6 hours → twice daily dosing"],
        ["Uses","DOC: Anthrax (post-exposure prophylaxis + treatment), Typhoid (sensitive strains), Pseudomonas UTI (oral). Complicated UTI/pyelonephritis; Osteomyelitis/septic arthritis (excellent bone penetration); Traveller's diarrhoea; HAP; Meningococcal prophylaxis; Plague (alternative)"],
        ["Adverse Effects","TENDINOPATHY/TENDON RUPTURE — Achilles tendon (↑ risk: >60 yrs, corticosteroids, renal failure) — BLACK BOX WARNING; CARTILAGE DAMAGE in growing animals → avoid in <18 yrs (except anthrax, plague); QT PROLONGATION → Torsades de Pointes; CNS: headache, dizziness, seizures; GI: nausea, diarrhoea, C. difficile; Phototoxicity; Hepatotoxicity (rare); Blood glucose dysregulation"],
        ["C/I","Children <18 yrs (except specific life-threatening indications); Pregnancy and lactation; QT prolongation; Epilepsy; Hypersensitivity to quinolones"],
        ["Drug Interactions","Antacids/Ca²⁺/Fe²⁺/Zn²⁺ — chelation → ↓ absorption 50–90% (separate by 2–6 hrs); THEOPHYLLINE — inhibits CYP1A2 → theophylline toxicity (↓ dose by 50%); Warfarin — ↑ anticoagulant effect (monitor INR); QT-prolonging drugs — additive risk; NSAIDs — ↑ CNS seizure risk; Sucralfate — ↓ absorption"],
    ], CRIMSON),
    PageBreak()]

# ═══════════════════════════ Q18 ══════════════════════════════════════════════
story += [qbanner(18,"Difference Between Aminoglycosides and Macrolides", BLUE), sp(4),
    tbl(["Property","Aminoglycosides","Macrolides"],
    [
        ["Examples","Gentamicin, Tobramycin, Amikacin, Streptomycin, Neomycin","Erythromycin, Azithromycin, Clarithromycin, Roxithromycin"],
        ["Chemical class","Amino sugars linked by glycosidic bonds","Large macrolactone ring (14-, 15-, or 16-membered)"],
        ["Ribosomal target","30S subunit (16S rRNA) — irreversible binding","50S subunit (23S rRNA)"],
        ["Mechanism","Irreversible 30S binding → mRNA misreading → faulty proteins inserted → ↑ membrane permeability → bactericidal","Block translocation step of peptide chain elongation → bacteriostatic"],
        ["Bactericidal/static","BACTERICIDAL","BACTERIOSTATIC"],
        ["Killing type","Concentration-dependent (once-daily dosing optimal)","Time-dependent"],
        ["Spectrum","Gram-NEGATIVE aerobes (Pseudomonas, E. coli, Klebsiella, Enterobacter); gram-positives (limited synergy)","Gram-POSITIVE + Atypicals (Mycoplasma, Chlamydia, Legionella, Bordetella); limited gram-negatives"],
        ["Anaerobic activity","NONE — require oxygen for drug uptake (oxygen-dependent active transport)","Limited; azithromycin some activity"],
        ["Oral bioavailability","Poor (polar, ionised) — IV/IM only (except neomycin topical)","Good oral bioavailability (esp. azithromycin, clarithromycin)"],
        ["Intracellular activity","POOR","EXCELLENT (concentrate in phagocytes — ideal for intracellular pathogens)"],
        ["Key uses","Pseudomonas sepsis, Gram-negative septicaemia, TB (streptomycin), Endocarditis (synergy), Plague, Tularaemia","CAP, Atypical pneumonia, STIs (Chlamydia), H. pylori (clarithromycin), MAC in HIV, Whooping cough"],
        ["Key toxicity","OTOTOXICITY (irreversible — hair cell destruction); NEPHROTOXICITY; Neuromuscular blockade","GI disturbances; QT prolongation; Hepatotoxicity; Ototoxicity (azithromycin — reversible)"],
        ["CYP enzyme","No significant CYP inhibition","Erythromycin/Clarithromycin: strong CYP3A4 INHIBITORS; Azithromycin: mild"],
    ], cw=[3.5*cm, 6*cm, 6.5*cm], hc=BLUE),
    PageBreak()]

# ═══════════════════════════ Q19 ══════════════════════════════════════════════
story += [qbanner(19,"Vancomycin", NAVY), sp(4),
    drug_rows([
        ["Disease","MRSA infections (DOC), C. difficile colitis (oral form), Endocarditis (gram-positive, MRSA/VRE), Febrile neutropenia (MRSA risk), CNS infections (MRSA meningitis)"],
        ["Class","Glycopeptide antibiotic"],
        ["MOA","Binds D-Ala-D-Ala terminus of peptidoglycan precursors (NAM-NAG pentapeptide) → PHYSICALLY BLOCKS both transglycosylase AND transpeptidase → prevents cell wall synthesis → bactericidal. Entirely different binding site from beta-lactams → active against MRSA. Resistance (VRE): VanA/VanB genes change D-Ala-D-Ala to D-Ala-D-Lac → vancomycin affinity reduced 1000×"],
        ["P/K","IV for systemic infections (very poor oral absorption). Oral vancomycin acts ONLY in gut → used exclusively for C. difficile colitis. Vd ~0.7 L/kg; ~50% protein bound. Eliminated ENTIRELY by kidneys (dose-adjust in renal failure). T½ ~6 hours (normal); prolonged in renal failure. MANDATORY Therapeutic Drug Monitoring (TDM): target AUC/MIC 400–600 mg·h/L for serious MRSA (trough 15–20 mg/L for serious infections)"],
        ["Uses","DOC: All serious MRSA infections (bacteraemia, pneumonia, endocarditis, osteomyelitis, meningitis). Oral: C. difficile (moderate-severe). Gram-positive endocarditis (penicillin-allergic). Febrile neutropenia. Surgical prophylaxis (penicillin-allergic). CNS MRSA (+ rifampicin)"],
        ["Adverse Effects","NEPHROTOXICITY (concentration-related, additive with aminoglycosides); OTOTOXICITY (high levels — tinnitus, hearing loss); RED MAN SYNDROME (not true allergy) — rapid IV infusion → histamine release → facial/neck/upper body flushing, erythema, pruritus, hypotension; Prevention: infuse >60 min + antihistamine premedication; Thrombophlebitis at infusion site; Neutropenia (prolonged use)"],
        ["C/I","Severe hypersensitivity; Mandatory dose reduction in renal failure; Caution with other nephrotoxic/ototoxic drugs"],
        ["Drug Interactions","Aminoglycosides: synergistic antibacterial PLUS synergistic nephrotoxicity + ototoxicity; Loop diuretics (furosemide): ↑ ototoxicity; Other nephrotoxins (amphotericin, NSAIDs, contrast): additive nephrotoxicity; Neuromuscular blockers: enhanced blockade"],
    ], NAVY),
    PageBreak()]

# ═══════════════════════════ Q20 ══════════════════════════════════════════════
story += [qbanner(20,"Isoniazid Resistance → Cross-Resistance to Ethionamide", CRIMSON), sp(4),
    slabel("Explanation", CRIMSON),
    body("<b>Both INH and Ethionamide share the same ultimate target: InhA (enoyl-ACP reductase)</b> — an enzyme in mycolic acid synthesis pathway."),
    sp(3),
    tbl(["Step","Event"],
    [
        ["1","Isoniazid (prodrug): activated by KatG (catalase-peroxidase) → activated INH-NAD adduct → binds and inhibits InhA"],
        ["2","Ethionamide (prodrug): activated by EthA (monooxygenase) → activated ethionamide-NAD adduct → ALSO binds and inhibits InhA (same target)"],
        ["3","Most common INH resistance mechanism: mutations in inhA gene or its promoter → InhA with reduced affinity for drug-NAD adducts"],
        ["4","These inhA mutations affect BOTH activated INH AND activated ethionamide binding → CROSS-RESISTANCE"],
        ["5","Alternative INH resistance: katG mutations (reduced INH activation) → these do NOT cause ethionamide resistance (ethionamide uses different activating enzyme EthA, not KatG)"],
    ], cw=[0.8*cm, DW-0.8*cm], hc=CRIMSON),
    sp(4),
    tbl(["INH Resistance Mechanism","Cross-Resistance to Ethionamide?","Clinical Implication"],
    [
        ["inhA gene/promoter mutation","YES — both drugs share InhA target","Ethionamide will ALSO be ineffective — do not use"],
        ["katG gene mutation (no KatG enzyme)","NO — EthA still activates ethionamide","Ethionamide may STILL WORK"],
    ], cw=[5*cm, 4*cm, 7*cm], hc=NAVY),
    note("Clinical implication: Always perform molecular DST (e.g., GenoType MTBDRplus) to identify the specific mutation before prescribing ethionamide in MDR-TB regimens. Do NOT assume ethionamide active just because it's a different drug from INH."),
    PageBreak()]

# ═══════════════════════════ Q21 ══════════════════════════════════════════════
story += [qbanner(21,"Difference Between Macrolides and Chloramphenicol", PURPLE), sp(4),
    tbl(["Property","Macrolides","Chloramphenicol"],
    [
        ["Examples","Erythromycin, Azithromycin, Clarithromycin","Chloramphenicol"],
        ["Chemical class","Macrolactone ring (14/15/16-membered)","Nitrobenzene derivative"],
        ["50S binding site","23S rRNA — blocks TRANSLOCATION step","23S rRNA — inhibits PEPTIDYL TRANSFERASE"],
        ["Mechanism detail","Peptide chain elongation blocked (chain cannot move to next codon)","Peptide BOND FORMATION blocked (no new bond between incoming AA and growing chain)"],
        ["Bactericidal/static","Bacteriostatic","Bacteriostatic (bactericidal vs H. influenzae, N. meningitidis, S. pneumoniae)"],
        ["Spectrum","Gram-positive + atypical organisms (Mycoplasma, Chlamydia, Legionella, Bordetella, Rickettsia)","BROAD SPECTRUM: gram-positive, gram-negative, anaerobes, rickettsiae, Salmonella, spirochetes"],
        ["CSF penetration","Moderate (azithromycin limited)","EXCELLENT (45–90% of plasma) — ideal for meningitis/brain abscess"],
        ["Key uses","Atypical pneumonia, CAP, STIs, H. pylori, MAC, Whooping cough","Meningitis (beta-lactam alternative), Typhoid, Rickettsial infections, Brain abscess, Anaerobic infections"],
        ["Key toxicity","GI, QT prolongation, Hepatotoxicity, mild reversible ototoxicity","APLASTIC ANAEMIA (idiosyncratic 1:25,000–40,000; irreversible/fatal), Grey Baby Syndrome (neonates), Dose-related bone marrow suppression"],
        ["Resistance mechanism","erm genes: methylation of 23S rRNA (most common); Efflux (mef genes); Esterases","CAT (chloramphenicol acetyltransferase) enzyme inactivates drug; Efflux; Reduced permeability"],
        ["CYP enzymes","Erythromycin/Clarithromycin: strong CYP3A4 INHIBITORS; Azithromycin: mild","Inhibits CYP2C9 AND CYP3A4 → ↑ phenytoin, warfarin, tolbutamide, ciclosporin levels"],
        ["Pregnancy safety","Generally safe (avoid erythromycin estolate)","AVOID — Grey baby risk; fetal hepatotoxicity; teratogenic concerns"],
    ], cw=[3.5*cm, 6*cm, 6.5*cm], hc=PURPLE),
    PageBreak()]

# ═══════════════════════════ Q22 ══════════════════════════════════════════════
story += [qbanner(22,"Aminoglycosides — Gentamicin and Streptomycin", TEAL), sp(4),
    slabel("GENTAMICIN"),
    drug_rows([
        ["Disease","Gram-negative sepsis, Pseudomonas infections, Endocarditis (synergy), Plague, Tularaemia, PID, Neonatal sepsis"],
        ["Class","Aminoglycoside antibiotic"],
        ["MOA","Enters bacteria via oxygen-dependent active transport → irreversibly binds 30S ribosomal subunit (16S rRNA) → mRNA misreading → faulty proteins inserted into cell membrane → ↑ membrane permeability → more drug enters → accelerated bactericidal kill (concentration-dependent). Resistance: Aminoglycoside-modifying enzymes (acetyltransferases, phosphotransferases, nucleotidyltransferases); efflux; reduced uptake (anaerobes have no O₂-dependent transport — intrinsically resistant)"],
        ["P/K","IV/IM only (not oral — not absorbed). Hydrophilic → distributes extracellularly. Poor intracellular/CNS penetration. RENAL excretion (GFR-dependent). T½ ~2 hrs. MANDATORY TDM: Peak 5–10 mg/L; Trough <2 mg/L (conventional); or once-daily extended-interval dosing (10 mg/kg) with 18–24 hr trough monitoring"],
        ["Uses","Hospital-acquired gram-negative infections; Septicaemia; Pseudomonas (+ piperacillin-tazobactam); Endocarditis synergy (with penicillin for Enterococcus/Streptococcus); Neonatal sepsis; PID (+ clindamycin); Topical eye/ear drops"],
        ["Adverse Effects","NEPHROTOXICITY: Proximal tubular accumulation → ATN (reversible if detected early); OTOTOXICITY: Cochlear (high-frequency hearing loss) and vestibular (dizziness, ataxia) — often IRREVERSIBLE (hair cell destruction); NEUROMUSCULAR BLOCKADE: ↓ presynaptic Ca²⁺-dependent ACh release → apnoea in myasthenia gravis, post-anaesthesia; Avoid in pregnancy"],
        ["C/I","Renal failure (reduce dose/extend interval — use TDM); Myasthenia gravis; Pregnancy; Prior ototoxicity"],
        ["Drug Interactions","Loop diuretics (furosemide): ↑ ototoxicity; Vancomycin: ↑ nephrotoxicity + ototoxicity (synergistic toxicity); NSAIDs: ↑ nephrotoxicity; Neuromuscular blockers: enhanced blockade; Penicillins: synergistic antibacterial — do NOT mix in same syringe (physically incompatible)"],
    ], TEAL),
    sp(6), hr(NAVY),
    slabel("STREPTOMYCIN"),
    drug_rows([
        ["Disease","TB (Category II/retreatment), Plague (DOC), Tularaemia (DOC), Brucellosis (+ doxycycline), Streptococcal/enterococcal endocarditis (synergy)"],
        ["Class","Aminoglycoside antibiotic (first aminoglycoside discovered — Selman Waksman, 1943)"],
        ["MOA","Irreversibly binds protein S12 of 30S ribosomal subunit (16S rRNA) → mRNA misreading → bactericidal. Also active against Mycobacterium tuberculosis (used in TB regimen). Resistance: rpsL or rrs gene mutations (S12 protein change); 16S rRNA methylation; Aminoglycoside-modifying enzymes"],
        ["P/K","IM injection ONLY (not oral, not IV). Not absorbed orally. Poor CNS penetration. Renal excretion. T½ ~2–3 hours. TDM recommended"],
        ["Uses","TB (Category II regimen — intensive phase); Plague (Y. pestis) DOC; Tularaemia (F. tularensis) DOC; Brucellosis + doxycycline (synergistic); Endocarditis synergy with penicillin"],
        ["Adverse Effects","Vestibular ototoxicity > cochlear (dizziness, ataxia, vertigo MORE prominent than hearing loss — distinguishes from gentamicin/tobramycin); Nephrotoxicity (less than gentamicin); Neuromuscular blockade; Optic neuritis (rare); Pain at injection site"],
        ["C/I","PREGNANCY — ABSOLUTE CI (causes congenital sensorineural deafness); Renal failure; Myasthenia gravis; Prior ototoxicity"],
        ["Drug Interactions","Loop diuretics: ↑ ototoxicity; Vancomycin: ↑ nephrotoxicity + ototoxicity; Neuromuscular blockers: enhanced blockade"],
    ], CRIMSON),
    PageBreak()]

# ═══════════════════════════ Q23 ══════════════════════════════════════════════
story += [qbanner(23,"Urinary Antiseptics", GREEN), sp(4),
    body("<b>Definition:</b> Drugs that achieve high concentrations specifically in <b>urine</b> — used to treat/prevent UTI. NOT effective for systemic infections (insufficient blood/tissue levels)."),
    sp(3),
    slabel("1. Nitrofurantoin (Primary Urinary Antiseptic)", GREEN),
    drug_rows([
        ["Disease","Uncomplicated lower UTI (cystitis — E. coli, S. saprophyticus); Recurrent UTI prophylaxis"],
        ["Class","Nitrofuran antibiotic"],
        ["MOA","Reduced by bacterial nitroreductase enzymes (present in E. coli, absent in Pseudomonas) → reactive intermediates → simultaneously damages DNA, ribosomes, and multiple metabolic enzymes → bactericidal. Concentrates in urine (acidic urine ↑ activity)"],
        ["P/K","Oral only. Rapidly absorbed and rapidly excreted in urine. Blood/tissue levels negligible → ONLY effective for lower UTI (not pyelonephritis). T½ ~20 min plasma; prolonged urinary activity"],
        ["Uses","Uncomplicated cystitis (1st choice); Recurrent UTI prophylaxis (50–100 mg at bedtime); Safe in pregnancy (avoid at term — neonatal haemolysis risk)"],
        ["Adverse Effects","Nausea, vomiting (take with food, use SR form); PULMONARY TOXICITY: Acute (hypersensitivity pneumonitis — fever, eosinophilia, dyspnoea) and Chronic (pulmonary fibrosis with long-term use); PERIPHERAL NEUROPATHY (prolonged use); Haemolytic anaemia (G6PD deficiency); Brown urine discolouration (harmless); Hepatotoxicity (rare)"],
        ["C/I","eGFR <30 mL/min (insufficient urinary concentration + drug accumulation → toxicity); Near-term pregnancy (neonatal haemolysis); G6PD deficiency; Infants <1 month"],
        ["Drug Interactions","Antacids ↓ absorption; Probenecid/Sulfinpyrazone block tubular secretion → ↓ urinary concentration → ↓ efficacy"],
    ], GREEN),
    sp(5), hr(TEAL),
    slabel("Other Urinary Antiseptics — Summary", TEAL),
    tbl(["Drug","Class","MOA","Key Use","Key Caution"],
    [
        ["Fosfomycin","Phosphonic acid antibiotic","Inhibits MurA (first step in peptidoglycan synthesis — UDP-GlcNAc enolpyruvyl transferase) → bactericidal. Active vs ESBL E. coli, VRE in urine","3 g single oral dose for uncomplicated cystitis (incl. ESBL E. coli, VRE UTI) — growing use","Severe renal failure; not for pyelonephritis"],
        ["Methenamine hippurate","Formaldehyde-releasing prodrug","In ACIDIC urine (pH <6) decomposes → releases FORMALDEHYDE → non-specific bactericidal (denatures proteins, DNA)","PROPHYLAXIS only (NOT acute treatment) — recurrent UTI, neurogenic bladder, post-urological","NOT if sulfonamide co-administered (precipitate → haematuria); needs acid urine; hepatic/renal failure"],
        ["Norfloxacin","Fluoroquinolone","Inhibits DNA gyrase + topoisomerase IV → bactericidal","UTI — highest urinary vs serum ratio among quinolones; use sparingly (reserve quinolone class)","Children, pregnancy, QT prolongation, tendinopathy"],
        ["Trimethoprim (alone)","DHFR inhibitor","Inhibits bacterial dihydrofolate reductase → blocks folate synthesis → bacteriostatic/bactericidal","Uncomplicated UTI: 100 mg BD × 7 days (where sulfa allergy prevents co-trimoxazole)","G6PD deficiency; pregnancy (near term); hyperkalaemia"],
    ], cw=[2.5*cm, 2.8*cm, 4.5*cm, 3.5*cm, 2.7*cm], hc=TEAL),
    sp(6), hr(NAVY, 1.5), sp(4)]

# End note
END = ParagraphStyle("end", fontName="Helvetica-Bold", fontSize=13,
                     textColor=NAVY, alignment=TA_CENTER)
EN2 = ParagraphStyle("en2", fontName="Helvetica-Oblique", fontSize=9,
                     textColor=DGRAY, alignment=TA_CENTER)
story += [
    Paragraph("— END OF STUDY GUIDE —", END), sp(4),
    Paragraph("All 23 questions (Q1–Q23) answered in Drug Short Note format", EN2),
    Paragraph("Disease | Class | MOA (& Resistance) | P/K | Uses | Adverse Effects | C/I | Drug Interactions", EN2),
]

doc.build(story)
print("PDF saved:", OUTPUT)