#!/usr/bin/env python3
"""
Fosfomycin Pocket Reference Guide - PDF Generator
Uses ReportLab for a professional, clinically formatted pocket guide
"""

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.units import mm, cm
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether, PageBreak
)
from reportlab.platypus.flowables import BalancedColumns
from reportlab.pdfbase import pdfmetrics
from reportlab.pdfbase.ttfonts import TTFont
from reportlab.graphics.shapes import Drawing, Rect, String, Line
from reportlab.graphics import renderPDF
import os

# ── Colour palette ──────────────────────────────────────────────────────────
NAVY       = colors.HexColor("#0D2B55")   # header / section bars
TEAL       = colors.HexColor("#007C91")   # sub-headers
AMBER      = colors.HexColor("#E8871A")   # warning / caution
GREEN      = colors.HexColor("#1A7A4A")   # susceptible / positive
RED        = colors.HexColor("#C0392B")   # resistant / negative
LIGHT_BLUE = colors.HexColor("#D6EAF8")   # alternate row
LIGHT_GREY = colors.HexColor("#F2F3F4")   # section bg
WHITE      = colors.white
DARK_TEXT  = colors.HexColor("#1C1C1C")

# ── Page setup ───────────────────────────────────────────────────────────────
OUTPUT = "/tmp/workspace/fosfomycin-guide/Fosfomycin_Pocket_Reference.pdf"
PAGE_W, PAGE_H = A4
MARGIN = 15 * mm

doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=MARGIN,
    rightMargin=MARGIN,
    topMargin=12 * mm,
    bottomMargin=12 * mm,
    title="Fosfomycin Pocket Reference Guide",
    author="Clinical Reference",
    subject="Fosfomycin Drug Profile",
)

# ── Styles ────────────────────────────────────────────────────────────────────
styles = getSampleStyleSheet()

def style(name, **kw):
    return ParagraphStyle(name, **kw)

COVER_TITLE = style("CoverTitle", fontSize=28, textColor=WHITE,
                    fontName="Helvetica-Bold", alignment=TA_CENTER, leading=34)
COVER_SUB   = style("CoverSub", fontSize=13, textColor=colors.HexColor("#AED6F1"),
                    fontName="Helvetica", alignment=TA_CENTER, leading=18)
COVER_BADGE = style("CoverBadge", fontSize=10, textColor=WHITE,
                    fontName="Helvetica-Bold", alignment=TA_CENTER)

SEC_HEAD    = style("SecHead", fontSize=11, textColor=WHITE,
                    fontName="Helvetica-Bold", alignment=TA_LEFT,
                    leftIndent=4, spaceBefore=6, spaceAfter=2)
SUBSEC_HEAD = style("SubSecHead", fontSize=10, textColor=NAVY,
                    fontName="Helvetica-Bold", spaceBefore=5, spaceAfter=2)
BODY        = style("Body", fontSize=8.5, textColor=DARK_TEXT,
                    fontName="Helvetica", leading=12, spaceAfter=2)
BODY_BOLD   = style("BodyBold", fontSize=8.5, textColor=DARK_TEXT,
                    fontName="Helvetica-Bold", leading=12)
SMALL       = style("Small", fontSize=7.5, textColor=colors.HexColor("#555555"),
                    fontName="Helvetica", leading=10)
TABLE_HDR   = style("TableHdr", fontSize=8, textColor=WHITE,
                    fontName="Helvetica-Bold", alignment=TA_CENTER)
TABLE_CELL  = style("TableCell", fontSize=8, textColor=DARK_TEXT,
                    fontName="Helvetica", leading=11)
TABLE_CELL_B= style("TableCellB", fontSize=8, textColor=DARK_TEXT,
                    fontName="Helvetica-Bold", leading=11)
FOOTER_ST   = style("Footer", fontSize=7, textColor=colors.HexColor("#888888"),
                    fontName="Helvetica", alignment=TA_CENTER)
NOTE_ST     = style("Note", fontSize=7.5, textColor=colors.HexColor("#555555"),
                    fontName="Helvetica-Oblique", leading=10)
WARN_ST     = style("Warn", fontSize=8, textColor=colors.HexColor("#7D3C00"),
                    fontName="Helvetica-Bold", leading=11)
GREEN_ST    = style("GreenSt", fontSize=8, textColor=GREEN,
                    fontName="Helvetica-Bold", leading=11)

# ── Helper functions ──────────────────────────────────────────────────────────
def section_header(text, color=NAVY):
    """Coloured section bar with white text."""
    tbl = Table([[Paragraph(text, SEC_HEAD)]], colWidths=[PAGE_W - 2*MARGIN])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), color),
        ("TOPPADDING",    (0,0), (-1,-1), 4),
        ("BOTTOMPADDING", (0,0), (-1,-1), 4),
        ("LEFTPADDING",   (0,0), (-1,-1), 6),
        ("RIGHTPADDING",  (0,0), (-1,-1), 6),
        ("ROUNDEDCORNERS", [3,3,3,3]),
    ]))
    return tbl

def two_col_table(rows, col1w=60*mm, col2w=None, header=None, alt=True):
    """Generic two-column table with optional header and alternating rows."""
    if col2w is None:
        col2w = PAGE_W - 2*MARGIN - col1w
    data = []
    if header:
        data.append([Paragraph(header[0], TABLE_HDR), Paragraph(header[1], TABLE_HDR)])
    for i, (k, v) in enumerate(rows):
        kp = Paragraph(str(k), TABLE_CELL_B)
        vp = Paragraph(str(v), TABLE_CELL)
        data.append([kp, vp])
    style_cmds = [
        ("GRID",       (0,0), (-1,-1), 0.4, colors.HexColor("#CCCCCC")),
        ("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"),
    ]
    if header:
        style_cmds += [
            ("BACKGROUND", (0,0), (-1,0), TEAL),
            ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
        ]
        start = 1
    else:
        start = 0
    if alt:
        for i in range(start, len(data), 2):
            style_cmds.append(("BACKGROUND", (0,i), (-1,i), LIGHT_GREY))
    tbl = Table(data, colWidths=[col1w, col2w])
    tbl.setStyle(TableStyle(style_cmds))
    return tbl

def three_col_table(rows, widths, header=None):
    data = []
    if header:
        data.append([Paragraph(h, TABLE_HDR) for h in header])
    for row in rows:
        data.append([Paragraph(str(c), TABLE_CELL) for c in row])
    style_cmds = [
        ("GRID",       (0,0), (-1,-1), 0.4, colors.HexColor("#CCCCCC")),
        ("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"),
    ]
    if header:
        style_cmds += [
            ("BACKGROUND", (0,0), (-1,0), TEAL),
            ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
        ]
        for i in range(1, len(data), 2):
            style_cmds.append(("BACKGROUND", (0,i), (-1,i), LIGHT_GREY))
    tbl = Table(data, colWidths=widths)
    tbl.setStyle(TableStyle(style_cmds))
    return tbl

def sp(h=3):
    return Spacer(1, h*mm)

def hr():
    return HRFlowable(width="100%", thickness=0.5, color=colors.HexColor("#CCCCCC"), spaceAfter=3)

def bullet(text, color=TEAL):
    return Paragraph(f'<font color="#{color.hexval()[1:]}">&#9654;</font> {text}', BODY)

def note(text):
    return Paragraph(f'<i>{text}</i>', NOTE_ST)

def warning_box(text):
    data = [[Paragraph(f"⚠ {text}", WARN_ST)]]
    tbl = Table(data, colWidths=[PAGE_W - 2*MARGIN])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), colors.HexColor("#FEF9E7")),
        ("LEFTBORDER_COLOR", (0,0), (-1,-1), AMBER),
        ("BOX",        (0,0), (-1,-1), 1.5, AMBER),
        ("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 tbl

def green_box(text):
    data = [[Paragraph(f"✔ {text}", GREEN_ST)]]
    tbl = Table(data, colWidths=[PAGE_W - 2*MARGIN])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), colors.HexColor("#EAFAF1")),
        ("BOX",        (0,0), (-1,-1), 1.5, GREEN),
        ("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 tbl

# ── Cover page helper ─────────────────────────────────────────────────────────
def cover_page():
    """Returns a Table that acts as a full-page cover."""
    content_w = PAGE_W - 2*MARGIN

    # Title block
    title_data = [
        [Paragraph("FOSFOMYCIN", COVER_TITLE)],
        [Paragraph("Pocket Reference Guide", COVER_SUB)],
        [Spacer(1, 6*mm)],
        [Paragraph("For Clinical Use", COVER_SUB)],
    ]
    title_tbl = Table(title_data, colWidths=[content_w])
    title_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), NAVY),
        ("TOPPADDING",    (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
        ("LEFTPADDING",   (0,0), (-1,-1), 10),
        ("RIGHTPADDING",  (0,0), (-1,-1), 10),
        ("ROUNDEDCORNERS", [4,4,4,4]),
    ]))

    # Badges row
    badges = [
        ("BACTERICIDAL", GREEN),
        ("UNIQUE MOA", TEAL),
        ("ESBL-ACTIVE", NAVY),
        ("SINGLE DOSE", AMBER),
    ]
    badge_cells = []
    for label, col in badges:
        p = Paragraph(label, COVER_BADGE)
        badge_cells.append(p)
    badge_tbl = Table([badge_cells], colWidths=[content_w/4]*4)
    badge_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (0,0), GREEN),
        ("BACKGROUND", (1,0), (1,0), TEAL),
        ("BACKGROUND", (2,0), (2,0), NAVY),
        ("BACKGROUND", (3,0), (3,0), AMBER),
        ("TOPPADDING",    (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("ALIGN",      (0,0), (-1,-1), "CENTER"),
        ("GRID",       (0,0), (-1,-1), 1, WHITE),
    ]))

    # Quick facts
    qf_rows = [
        ("Class", "Phosphonic acid antibiotic (unique structural class)"),
        ("Target", "MurA — enolpyruvyl transferase (step 1 of peptidoglycan synthesis)"),
        ("Formulations", "Oral: 3 g sachet (Monurol) | IV: 6 g vial (Contepo, FDA 2025)"),
        ("Primary Use", "Uncomplicated cystitis (oral) | cUTI / pyelonephritis (IV)"),
        ("Key Advantage", "Active against ESBL-producers, VRE, MRSA; no cross-resistance"),
    ]
    qf_tbl = two_col_table(qf_rows, col1w=42*mm)

    elements = [
        sp(4),
        title_tbl,
        sp(5),
        badge_tbl,
        sp(5),
        Paragraph("AT-A-GLANCE", style("AG", fontSize=9, textColor=TEAL,
                  fontName="Helvetica-Bold", spaceBefore=2, spaceAfter=3)),
        qf_tbl,
        sp(4),
        note("Sources: Harrison's 22E | Goodman & Gilman's | Lippincott Pharmacology | "
             "Rosen's Emergency Medicine | Merck Manual Apr 2025 | Drugs.com Dec 2025"),
    ]
    return elements

# ── BUILD CONTENT ─────────────────────────────────────────────────────────────
story = []

# ─── COVER ────────────────────────────────────────────────────────────────────
story.extend(cover_page())
story.append(PageBreak())

# ─── PAGE 2: MECHANISM + SPECTRUM ─────────────────────────────────────────────
story.append(section_header("1.  MECHANISM OF ACTION"))
story.append(sp(2))
moa_rows = [
    ("Target", "MurA (UDP-GlcNAc enolpyruvyl transferase) — catalyzes step 1 of peptidoglycan synthesis"),
    ("Binding", "Covalent, irreversible alkylation of Cys115 in MurA active site via epoxide ring"),
    ("Effect", "Blocks N-acetylmuramic acid (NAM) formation → no peptidoglycan → cell lysis"),
    ("Extra Effect", "Reduces bacterial adherence to uroepithelial cells (anti-adhesin activity)"),
    ("Type", "Bactericidal | Concentration-dependent killing"),
    ("Uniqueness", "No cross-resistance with ANY other antibiotic class (unique structural scaffold)"),
    ("Testing Note", "Susceptibility testing requires glucose-6-phosphate media supplementation"),
]
story.append(two_col_table(moa_rows, col1w=38*mm))
story.append(sp(3))

story.append(section_header("2.  ANTIMICROBIAL SPECTRUM"))
story.append(sp(2))

spectrum_rows = [
    ("Gram-Negative", "Susceptibility", "Notes"),
    ("E. coli", "✔ Susceptible", "Primary uropathogen target"),
    ("Proteus spp.", "✔ Susceptible", "—"),
    ("Klebsiella pneumoniae", "~ Variable", "Most ESBL-producers susceptible"),
    ("Enterobacter spp.", "~ Variable", "Check MIC"),
    ("Serratia marcescens", "~ Variable", "Check MIC"),
    ("Pseudomonas aeruginosa", "✘ Resistant", "Intrinsic resistance"),
    ("Acinetobacter baumannii", "✘ Resistant", "Intrinsic resistance"),
    ("Burkholderia spp.", "✘ Resistant", "Intrinsic resistance"),
]
gn_header = spectrum_rows[0]
gn_data = spectrum_rows[1:]
w3 = [60*mm, 40*mm, PAGE_W - 2*MARGIN - 100*mm]
gn_tbl = three_col_table(gn_data, w3, header=list(gn_header))

gp_rows = [
    ("Gram-Positive", "Susceptibility", "Notes"),
    ("Enterococcus faecalis", "✔ Susceptible", "Including VanA VRE"),
    ("Enterococcus faecium (VRE)", "✔ Susceptible", "—"),
    ("S. saprophyticus", "✔ Susceptible", "—"),
    ("S. aureus / MRSA", "✔ Often susceptible", "Resistance may emerge on monotherapy"),
]
gp_data = gp_rows[1:]
gp_tbl = three_col_table(gp_data, w3, header=list(gp_rows[0]))

story.append(gn_tbl)
story.append(sp(2))
story.append(gp_tbl)
story.append(sp(2))
story.append(green_box(
    "ESBL-PRODUCING Enterobacterales: the vast majority remain susceptible — "
    "fosfomycin is one of the few oral options available (Harrison's 22E)"
))
story.append(sp(3))

# ─── PAGE 3: PHARMACOKINETICS + DOSING ────────────────────────────────────────
story.append(section_header("3.  PHARMACOKINETICS"))
story.append(sp(2))

pk_header = ["Parameter", "Oral (Tromethamine)", "IV (Disodium)"]
pk_data = [
    ("Bioavailability",    "~40%",                   "100% (IV)"),
    ("Peak serum conc.",   "~26 µg/mL at 2 h (3 g)", "High (dose-dependent)"),
    ("Urinary conc.",      "1,000–4,000 µg/mL",      "Very high"),
    ("Urine active time",  "Up to 48 h (single dose)","Continuous during infusion"),
    ("Protein binding",    "Negligible",              "Negligible"),
    ("Vd",                 "Wide (kidney, bladder, prostate)", "Wide"),
    ("Metabolism",         "None — excreted unchanged","None — excreted unchanged"),
    ("Elimination",        "Renal (GFR + tubular secretion)", "Renal"),
    ("Half-life (t½)",     "5–8 hours",               "4–8 hours"),
    ("Activity in urine",  "Greater in acidic pH",    "Greater in acidic pH"),
]
pk_tbl_data = [[Paragraph(pk_header[0], TABLE_HDR),
                Paragraph(pk_header[1], TABLE_HDR),
                Paragraph(pk_header[2], TABLE_HDR)]]
for i, row in enumerate(pk_data):
    pk_tbl_data.append([Paragraph(row[0], TABLE_CELL_B),
                        Paragraph(row[1], TABLE_CELL),
                        Paragraph(row[2], TABLE_CELL)])
pk_widths = [52*mm, 60*mm, PAGE_W - 2*MARGIN - 112*mm]
pk_tbl = Table(pk_tbl_data, colWidths=pk_widths)
pk_style = TableStyle([
    ("BACKGROUND", (0,0), (-1,0), TEAL),
    ("GRID",       (0,0), (-1,-1), 0.4, colors.HexColor("#CCCCCC")),
    ("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"),
])
for i in range(1, len(pk_tbl_data), 2):
    pk_style.add("BACKGROUND", (0,i), (-1,i), LIGHT_GREY)
pk_tbl.setStyle(pk_style)
story.append(pk_tbl)
story.append(sp(3))

story.append(section_header("4.  DOSING & FORMULATIONS"))
story.append(sp(2))

dose_data = [
    ["Indication", "Formulation", "Dose & Regimen", "Notes"],
    ["Uncomplicated cystitis\n(FDA-approved)", "Oral 3 g sachet\n(Monurol)", "Single 3 g dose\n(dissolved in water)", "First-line; avoid if pyelonephritis suspected"],
    ["Complicated UTI\n(off-label, oral)", "Oral 3 g sachet", "3 g every 48 h × 3 doses", "Off-label; consider IV if severe"],
    ["UTI prophylaxis\n(off-label)", "Oral 3 g sachet", "3 g every 10 days", "Recurrent UTI prevention"],
    ["Complicated UTI / APN\n(IV, FDA-approved 2025)", "IV 6 g vial\n(Contepo)", "6 g IV q8h × 7–14 days", "Adults ≥18 yr; E. coli or K. pneumoniae"],
    ["MDR/systemic infections\n(off-label, IV)", "IV formulation", "4–8 g q6–8h\n(PK/PD guided)", "Use IN COMBINATION; TDM in renal impairment"],
]
dose_widths = [38*mm, 28*mm, 42*mm, PAGE_W - 2*MARGIN - 108*mm]
dose_tbl_data = []
for i, row in enumerate(dose_data):
    cell_style = TABLE_HDR if i == 0 else TABLE_CELL
    dose_tbl_data.append([Paragraph(c, TABLE_HDR if i==0 else TABLE_CELL) for c in row])
dose_tbl = Table(dose_tbl_data, colWidths=dose_widths)
dose_style = TableStyle([
    ("BACKGROUND", (0,0), (-1,0), NAVY),
    ("GRID",       (0,0), (-1,-1), 0.4, colors.HexColor("#CCCCCC")),
    ("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"),
    ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, LIGHT_GREY]),
])
dose_tbl.setStyle(dose_style)
story.append(dose_tbl)
story.append(sp(2))
story.append(warning_box(
    "Oral fosfomycin achieves LOW SYSTEMIC concentrations — do NOT use for pyelonephritis, "
    "bacteremia, or deep-seated infections. Use IV formulation for systemic disease."
))
story.append(sp(3))

# ─── PAGE 4: ADRs + RESISTANCE + INTERACTIONS ─────────────────────────────────
story.append(section_header("5.  ADVERSE EFFECTS"))
story.append(sp(2))
adr_rows = [
    ("GI: nausea, diarrhea, dyspepsia", "Most common; usually mild and self-limiting"),
    ("Headache, dizziness", "Occasional; reversible"),
    ("Vaginitis", "Reported with oral use"),
    ("Asthenia", "Uncommon"),
    ("Sodium load (IV)", "Each gram fosfomycin disodium ≈ 0.32 mEq Na — monitor in CHF, fluid restriction"),
    ("Hypokalemia (IV)", "High-dose IV therapy; monitor electrolytes"),
]
story.append(two_col_table(adr_rows, col1w=65*mm,
             header=["Adverse Effect", "Clinical Note"]))
story.append(sp(2))
story.append(green_box(
    "Notably ABSENT: no hepatotoxicity, nephrotoxicity, QT prolongation, tendon rupture, "
    "peripheral neuropathy, or photosensitivity — a favorable safety profile vs. fluoroquinolones"
))
story.append(sp(3))

story.append(section_header("6.  RESISTANCE MECHANISMS"))
story.append(sp(2))
res_rows = [
    ("Reduced uptake (most common)",
     "Mutations in glpT (glycerol-3-phosphate transporter) or uhpT (hexose phosphate transporter); "
     "fosfomycin requires these carriers to enter the bacterial cell"),
    ("MurA target mutation",
     "Cys115 → Asp substitution in the MurA active site prevents covalent binding"),
    ("Enzymatic inactivation (plasmid)",
     "FosA (glutathione-S-transferase), FosB, FosC, FosX enzymes open the epoxide ring and "
     "inactivate the drug — transferable on plasmids"),
    ("Efflux pumps",
     "Minor contribution observed in some strains"),
]
story.append(two_col_table(res_rows, col1w=55*mm,
             header=["Mechanism", "Detail"]))
story.append(sp(2))
story.append(warning_box(
    "Resistance does NOT emerge during oral cystitis treatment. It HAS been documented during "
    "IV therapy for osteomyelitis and respiratory infections — ALWAYS combine IV fosfomycin "
    "with a second agent for systemic infections."
))
story.append(sp(3))

story.append(section_header("7.  DRUG INTERACTIONS"))
story.append(sp(2))
int_rows = [
    ("Metoclopramide / prokinetics",
     "Decreased serum conc. and urinary excretion of fosfomycin (accelerated GI transit)"),
    ("Antacids (Ca²⁺, Mg²⁺)",
     "May reduce oral absorption — separate dosing by ≥2 hours"),
    ("Meropenem (IV)",
     "In vitro synergy against E. coli — a useful combination for MDR infections"),
    ("Cimetidine",
     "No clinically significant effect on fosfomycin pharmacokinetics"),
    ("CYP450 substrates",
     "No interaction — fosfomycin is NOT hepatically metabolized"),
]
story.append(two_col_table(int_rows, col1w=55*mm,
             header=["Drug / Class", "Interaction"]))
story.append(sp(3))

# ─── PAGE 5: SPECIAL POPULATIONS + CLINICAL USE ───────────────────────────────
story.append(section_header("8.  SPECIAL POPULATIONS"))
story.append(sp(2))
pop_rows = [
    ("Pregnancy",
     "Oral single-dose widely used for UTI in pregnancy; considered safe (Category B). "
     "Preferred when nitrofurantoin/TMP-SMX are contraindicated near term."),
    ("Breastfeeding",
     "Excreted in breast milk; avoid if alternatives available."),
    ("Pediatrics",
     "Emerging evidence supports use. Reviewed in Tran, Pharmacotherapy 2023 "
     "(PMID 36825460). No oral pediatric formulation widely approved in the US."),
    ("Renal impairment\n(CrCl <50 mL/min)",
     "IV: significant dose reduction required; TDM recommended in critically ill. "
     "Oral single-dose: generally safe but urinary concentrations may be lower."),
    ("Hepatic impairment",
     "No hepatic metabolism — no dose adjustment needed."),
    ("Elderly",
     "Oral single-dose appropriate. IV requires caution (sodium load, variable PK, "
     "increased risk of electrolyte disturbances)."),
    ("Immunocompromised / MDR",
     "Use in combination regimens. Clinical success ~75–80% for combination therapy "
     "against MDR pathogens (Frontiers Microbiology 2025)."),
]
story.append(two_col_table(pop_rows, col1w=48*mm,
             header=["Population", "Guidance"]))
story.append(sp(3))

story.append(section_header("9.  CLINICAL USE & COMBINATIONS FOR MDR INFECTIONS"))
story.append(sp(2))

combo_data = [
    ["Pathogen / Scenario", "Combination Partner", "Evidence / Notes"],
    ["ESBL-producing E. coli / K. pneumoniae (UTI)",
     "Fosfomycin ORAL alone",
     "One of few oral options; high susceptibility retained"],
    ["Carbapenem-resistant Enterobacterales (CRE)",
     "+ Meropenem or Imipenem",
     "Synergy shown in vitro and clinical reports; prevents resistance emergence"],
    ["MDR P. aeruginosa",
     "+ Aminoglycoside or β-lactam",
     "Note: P. aeruginosa has variable intrinsic resistance; IV only"],
    ["MRSA (bacteremia, endocarditis)",
     "+ Daptomycin or Rifampicin",
     "Off-label; case series show clinical benefit"],
    ["VRE infections",
     "+ Daptomycin or Linezolid",
     "Fosfomycin retains activity vs. vancomycin-resistant strains"],
    ["Carbapenem-resistant A. baumannii",
     "+ Colistin",
     "Synergy confirmed by time-kill assays (2025 data); A. baumannii has intrinsic resistance — check MIC"],
]
combo_widths = [52*mm, 46*mm, PAGE_W - 2*MARGIN - 98*mm]
combo_tbl_data = []
for i, row in enumerate(combo_data):
    combo_tbl_data.append([Paragraph(c, TABLE_HDR if i==0 else TABLE_CELL) for c in row])
combo_tbl = Table(combo_tbl_data, colWidths=combo_widths)
combo_style = TableStyle([
    ("BACKGROUND", (0,0), (-1,0), NAVY),
    ("GRID",       (0,0), (-1,-1), 0.4, colors.HexColor("#CCCCCC")),
    ("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"),
    ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, LIGHT_GREY]),
])
combo_tbl.setStyle(combo_style)
story.append(combo_tbl)
story.append(sp(3))

# ─── FINAL PAGE: QUICK REFERENCE SUMMARY ──────────────────────────────────────
story.append(section_header("10.  QUICK REFERENCE SUMMARY", color=NAVY))
story.append(sp(2))

summary_rows = [
    ("Drug class",          "Phosphonic acid antibiotic — unique class, no structural relatives"),
    ("Mechanism",           "Irreversible MurA inhibitor → blocks peptidoglycan synthesis (step 1)"),
    ("Bactericidal?",       "Yes — concentration-dependent killing"),
    ("Oral dose",           "3 g single dose (tromethamine salt, granules dissolved in water)"),
    ("Oral bioavailability","~40%"),
    ("Peak urinary conc.",  "1,000–4,000 µg/mL (maintained up to 48 h)"),
    ("t½",                  "5–8 h (oral); 4–8 h (IV)"),
    ("Protein binding",     "Negligible — 100% free drug"),
    ("Metabolism",          "None — excreted unchanged in urine"),
    ("Spectrum highlights", "E. coli, Proteus, Enterococcus (incl. VRE), MRSA, ESBL-producers"),
    ("Resistant organisms", "Pseudomonas, Acinetobacter, Burkholderia (intrinsic)"),
    ("FDA indications",     "Uncomplicated cystitis (oral, 1996) | cUTI / Pyelonephritis (IV, Oct 2025)"),
    ("Key ADRs",            "GI upset, headache, dizziness, vaginitis; sodium load (IV)"),
    ("Key interaction",     "Metoclopramide → decreased absorption"),
    ("Pregnancy safety",    "Category B — oral single-dose widely used in pregnancy"),
    ("Resistance warning",  "Use IV only in COMBINATION to prevent resistance emergence"),
]
story.append(two_col_table(summary_rows, col1w=48*mm))
story.append(sp(3))

story.append(warning_box(
    "ALWAYS confirm susceptibility before use. Fosfomycin resistance is increasing in "
    "nosocomial settings. For IV therapy, use in combination and monitor renal function / "
    "electrolytes regularly."
))
story.append(sp(2))
story.append(HRFlowable(width="100%", thickness=1, color=NAVY))
story.append(sp(2))
story.append(Paragraph(
    "<b>References:</b> Harrison's Principles of Internal Medicine 22E (2025) | "
    "Goodman &amp; Gilman's Pharmacological Basis of Therapeutics | "
    "Lippincott Illustrated Reviews: Pharmacology | Rosen's Emergency Medicine | "
    "Merck Manual Professional Apr 2025 | Drugs.com Monograph Dec 2025 | "
    "Kim &amp; Lees, <i>Biochemistry</i> 2025 (PMID 40127436) | "
    "Cai et al., <i>Int J Antimicrob Agents</i> 2023 (PMID 37748624)",
    SMALL
))
story.append(sp(1))
story.append(Paragraph(
    "<i>This reference is for educational and clinical support purposes. "
    "Always verify doses and guidelines against current institutional protocols "
    "and up-to-date prescribing information.</i>",
    NOTE_ST
))

# ── Page numbering callback ────────────────────────────────────────────────────
def add_page_number(canvas, doc):
    canvas.saveState()
    # Footer bar
    canvas.setFillColor(NAVY)
    canvas.rect(0, 0, PAGE_W, 10*mm, fill=1, stroke=0)
    canvas.setFillColor(WHITE)
    canvas.setFont("Helvetica", 7)
    canvas.drawCentredString(PAGE_W/2, 3.5*mm,
        f"FOSFOMYCIN POCKET REFERENCE  |  Page {doc.page}  |  Clinical Use Only")
    # Header stripe (pages 2+)
    if doc.page > 1:
        canvas.setFillColor(LIGHT_BLUE)
        canvas.rect(0, PAGE_H - 8*mm, PAGE_W, 8*mm, fill=1, stroke=0)
        canvas.setFillColor(NAVY)
        canvas.setFont("Helvetica-Bold", 7)
        canvas.drawString(MARGIN, PAGE_H - 5*mm, "FOSFOMYCIN — Pocket Clinical Reference")
        canvas.drawRightString(PAGE_W - MARGIN, PAGE_H - 5*mm,
                               "August 2026")
    canvas.restoreState()

# ── Build ─────────────────────────────────────────────────────────────────────
doc.build(story, onFirstPage=add_page_number, onLaterPages=add_page_number)
print(f"PDF generated: {OUTPUT}")
print(f"Size: {os.path.getsize(OUTPUT):,} bytes")