Section 7, miscellaneous bacterial infections, 179 chapter nocardia is 180 at mycosis, 181 peoples disease, 182 infections due to mixed aerobic organisms. Section 8 micro bacterial diseases chapter number 183, tuberculosis 184 x 185 non-tuberculous bacterial infections, 186 antimicrobial anti Mico bacterial agents, section 9, Phairo diseases, 187, syphilis 188, hematosis 189 la pyrosis, 190 lapsing fever, 191 lines disease section 10 disease is caused by cricket, CA micro plasma and club idea. Chapter number 192 cricket CL is 193 infections due to mycoplasma 194 loml disease section number 11 viral diseases, general considerations, 195 principles of medical virology, 196 anti-viral haemotherapy, excluding antiretroviral drugs. These are the chapters from Harrisons 22nd edition teach me in detail about these topics.
I'll read the medical library skill first, then systematically cover all these chapters.
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Now let me search the database for the Harrison's textbook and all relevant chapters in parallel:
Finding Sources
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Good - Harrison's is in the database. Now let me search specifically within Harrison's for all the chapter topics:
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Finding Sources
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I can see the key blocks. Block 21 has Syphilis, Leptospirosis, Relapsing Fever. Block 21 also has TB chapter reference. Let me now read the major blocks in parallel:
Finding Sources
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Block 21 covers pages 1457-1522. I need to read through the specific chapters. Let me read the key sections now - Syphilis starts at line 596, TB chapter at 21, Mycoplasma at 2115, Virology at 2541, and also read block 22 for antiviral drugs:
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I now have substantial content from Harrison's 22E. Let me also read key sections on TB, Nocardia/mixed anaerobes, and the rickettsia/chlamydia sections:
Reading File
Reading File
I now have a very strong foundation of content directly from Harrison's 22E. Let me now compile and present the comprehensive teaching notes.Here is your complete, detailed teaching guide based directly on Harrison's Principles of Internal Medicine, 22nd Edition (2025):
Harrison's 22E - Sections 7 to 11: Complete Teaching Notes
SECTION 7 - MISCELLANEOUS BACTERIAL INFECTIONS
Chapter 179 - Nocardia
Organism: Nocardia species are aerobic actinomycetes (filamentous gram-positive bacteria) found in soil. Key pathogens: N. asteroides complex, N. brasiliensis, N. farcinica.
Who gets it: Primarily affects immunocompromised patients (steroids, transplant, lymphoma, HIV with CD4 <100, chronic granulomatous disease). Can rarely affect immunocompetent hosts.
Pathogenesis: Inhalation of aerosols or direct skin inoculation. The organism resists killing within phagolysosomes.
Clinical Forms:
- Pulmonary nocardiosis - Most common (>80%). Presents as subacute/chronic pneumonia with nodules, cavities, or consolidation. May mimic TB or lung abscess.
- CNS nocardiosis - Brain abscess (single or multiple). Can occur even without lung disease. Always do CT/MRI of brain in pulmonary nocardiosis.
- Cutaneous/lymphocutaneous - Sporotrichoid spread up lymphatics; more common with N. brasiliensis.
- Disseminated - Spreads to skin, kidneys, eyes, joints.
Diagnosis:
- Modified acid-fast stain (weakly acid-fast, unlike Mycobacteria which are strongly acid-fast)
- Gram stain: gram-positive, beaded, branching filaments
- Culture: slow growing on routine media; must alert lab
Treatment:
- Drug of choice: TMP-SMX (sulfamethoxazole/trimethoprim)
- Severe/CNS: triple therapy - TMP-SMX + imipenem + amikacin
- Duration: 6-12 months; immunocompromised may need indefinite suppression
- Alternatives: amikacin, imipenem, ceftriaxone, linezolid, amoxicillin-clavulanate
Chapter 180 - Actinomycosis (Mycosis)
Organism: Actinomyces israelii - anaerobic, gram-positive, non-acid-fast, filamentous bacterium. Part of normal oral flora.
Key feature: "Sulfur granules" - yellow granular clumps of organisms in pus - pathognomonic.
Clinical Forms:
- Cervicofacial (most common ~50%) - "Lumpy jaw." Hard, painless swelling at mandible after dental extraction/trauma. Draining sinuses form.
- Thoracic - Lung involvement mimicking carcinoma or TB. Can penetrate chest wall - "chest wall fistula crossing pleural space" is classic.
- Abdominal/pelvic - After bowel surgery or perforation. Can mimic Crohn's disease or appendicitis. Pelvic actinomycosis associated with IUD use.
- CNS - Brain abscess; rare.
Diagnosis:
- Biopsy showing sulfur granules histologically
- Anaerobic culture (rarely grows on routine aerobic culture)
- Gram stain of granules: gram-positive branching filaments
Treatment:
- Penicillin G IV x 2-6 weeks, then amoxicillin PO x 6-12 months total
- Alternatives: doxycycline, erythromycin
- Surgical drainage of large abscesses
Chapter 181 - Whipple's Disease (Peoples Disease)
Organism: Tropheryma whipplei - gram-positive actinomycete.
Epidemiology: Rare; predominantly middle-aged white men. Organism in soil and wastewater.
Classic Tetrad:
- Diarrhea / malabsorption / weight loss
- Arthralgias (migratory, non-destructive - may precede GI symptoms by years)
- Fever
- Lymphadenopathy
Other features: Hyperpigmentation of skin, oculomasticatory myorhythmia (pathognomonic - pendular eye movements + jaw movement), uveitis, CNS involvement (dementia, supranuclear gaze palsy).
Diagnosis:
- Small bowel biopsy - PAS-positive macrophages in lamina propria filled with bacilli (diastase-resistant PAS staining)
- PCR of tissue/CSF/blood
- Electron microscopy shows trilamellar bacterial wall
Treatment:
- Ceftriaxone 2g IV x 2 weeks, then TMP-SMX x 1 year (or longer for CNS disease)
- Relapse common without prolonged treatment
- If untreated: uniformly fatal
Chapter 182 - Infections Due to Mixed Aerobic-Anaerobic Organisms
Key concept: Polymicrobial infections with both aerobes and anaerobes working synergistically, typically at sites with endogenous flora.
Common Syndromes:
1. Aspiration Pneumonia / Lung Abscess
- Organisms: oral anaerobes (Prevotella, Fusobacterium, Peptostreptococcus) + streptococci
- Risk: aspiration, impaired swallowing, alcoholism
- Treatment: amoxicillin-clavulanate or clindamycin + metronidazole
2. Intraabdominal Sepsis (Peritonitis, Abscess)
- Organisms: E. coli, Bacteroides fragilis, enterococci
- B. fragilis - most virulent anaerobe; produces polysaccharide capsule and resists phagocytosis; produces beta-lactamase
- Treatment: metronidazole + cephalosporin, or piperacillin-tazobactam, or carbapenems
3. Necrotizing Fasciitis
- Type I: Polymicrobial (aerobes + anaerobes) - more common in diabetics, elderly
- Type II: Group A streptococcus alone
- Presents: pain out of proportion to skin findings, crepitus, systemic toxicity
- Treatment: immediate surgical debridement + broad-spectrum antibiotics (carbapenems + clindamycin + linezolid)
4. Bacterial Vaginosis
- Gardnerella vaginalis + anaerobes replacing normal lactobacilli
- Clue cells on wet prep, "fishy" amine odor with KOH (Whiff test), pH >4.5
- Treatment: metronidazole or clindamycin
B. fragilis special properties:
- Produces beta-lactamase (resistant to penicillin alone)
- Requires metronidazole, carbapenems, or beta-lactam/beta-lactamase inhibitor combos
SECTION 8 - MYCOBACTERIAL DISEASES
Chapter 183 - Tuberculosis
Organism: Mycobacterium tuberculosis - obligate aerobic, acid-fast bacillus (Ziehl-Neelsen stain).
Epidemiology
- Leading infectious disease killer globally
- 10+ million new cases/year; highest burden in South/Southeast Asia and sub-Saharan Africa
- HIV co-infection dramatically increases risk (40x lifetime risk vs. 5-10% in immunocompetent)
Pathogenesis
- Inhalation of droplet nuclei (<5 μm, carries 1-3 bacilli)
- Phagocytosed by alveolar macrophages
- If innate immunity fails, spreads to regional lymph nodes (Ghon focus + lymph node = Ranke complex/primary complex)
- Granuloma formation - hallmark: macrophages, epithelioid cells, Langhans giant cells, lymphocytes, central caseous necrosis
- 90% develop latent TB infection (LTBI); 10% progress to active disease
Primary vs Post-primary TB
| Feature | Primary TB | Post-primary (Reactivation) TB |
|---|---|---|
| Age | Children/first exposure | Adults |
| Location | Lower/middle lobe | Upper lobe apical/posterior segments |
| Cavitation | Rare | Common |
| Lymphadenopathy | Prominent | Less common |
Clinical Presentations
Pulmonary TB:
- Cough >3 weeks, hemoptysis, weight loss, night sweats, low-grade fever
- Chest X-ray: apical/posterior upper lobe infiltrates, cavitation, tree-in-bud pattern
Extrapulmonary TB (more common in HIV):
- TB Meningitis - basilar meningitis; CSF: lymphocytes, high protein, very low glucose; ADA elevated
- TB Pericarditis - constrictive pericarditis if untreated
- TB Pleuritis - exudative pleural effusion; ADA >40 IU/L
- Miliary TB - hematogenous dissemination; millet-seed pattern on CXR
- Pott's disease - vertebral TB (T10-L1 most common); gibbus deformity, paraplegia
- TB Lymphadenitis - most common extrapulmonary form; cervical nodes (scrofula)
- Renal TB - sterile pyuria; IVP shows "moth-eaten" calyx
Diagnosis
- AFB Smear and Culture - gold standard; culture takes 3-6 weeks (solid media) or 2 weeks (liquid MGIT)
- Tuberculin Skin Test (TST/Mantoux) - 5 TU PPD; read at 48-72 hours; induration (not erythema)
- ≥5 mm: HIV+, close contacts, immunosuppressed, fibrotic changes on CXR
- ≥10 mm: Recent immigrants, IV drug users, healthcare workers, high-risk settings
- ≥15 mm: Low-risk individuals
- IGRA (QuantiFERON-TB Gold, T-SPOT) - Preferred over TST; not affected by BCG vaccination; detects IFN-γ release to ESAT-6 and CFP-10 antigens
- Xpert MTB/RIF (GeneXpert) - Rapid molecular test; detects TB + rifampin resistance simultaneously; WHO-recommended first-line test
- ADA (Adenosine Deaminase) - Useful in pleural/pericardial/CSF TB
Treatment - Active Drug-Susceptible TB (Harrison's Table 186-2)
Standard 6-month regimen:
- Intensive phase (2 months): HRZE (Isoniazid + Rifampin + Pyrazinamide + Ethambutol)
- Continuation phase (4 months): HR (Isoniazid + Rifampin)
- Extend continuation to 7 months (9 months total) for: cavitary disease, culture-positive at 2 months
Newer 4-month regimen (2020 trial): Rifapentine + Isoniazid + Pyrazinamide + Moxifloxacin x 8 weeks, then Rifapentine + Moxifloxacin x 9 weeks - noninferior to standard 6-month regimen.
LTBI Treatment (Harrison's Table 186-1)
| Regimen | Duration | Notes |
|---|---|---|
| Isoniazid + Rifapentine (3HP) | 3 months weekly | Preferred for all adults & children >2 yr |
| Rifampin (4R) | 4 months daily | Preferred over INH 6-9 months |
| Isoniazid + Rifampin (3HR) | 3 months daily | Alternative |
| Isoniazid (9H) | 9 months daily | Older regimen, still used |
Drug Side Effects
| Drug | Key Side Effect | Monitoring |
|---|---|---|
| Isoniazid (H) | Hepatotoxicity, peripheral neuropathy (B6 deficiency) | LFTs; give pyridoxine |
| Rifampin (R) | Orange discoloration of secretions, induces CYP450, hepatotoxicity | Drug interactions |
| Pyrazinamide (Z) | Hepatotoxicity, hyperuricemia, arthralgias | LFTs, uric acid |
| Ethambutol (E) | Optic neuritis (color vision loss, decreased acuity) | Monthly visual acuity & color vision |
Chapter 184 - Leprosy (Hansen's Disease)
Organism: Mycobacterium leprae - obligate intracellular pathogen; cannot be cultured in vitro; grows best at 27-30°C (hence peripheral skin, nerves, eyes).
Transmission: Prolonged close contact; droplets from nasal secretions; low transmissibility.
Ridley-Jopling Classification (based on immune response):
| Type | Immunity | Bacillary Load | Skin Lesions | Nerve Involvement |
|---|---|---|---|---|
| Tuberculoid (TT) | Strong CMI | Low (paucibacillary) | 1-5 lesions, well-defined, hypopigmented, anesthetic, dry | Severe, asymmetric |
| Borderline Tuberculoid (BT) | Good | Paucibacillary | Similar to TT but more lesions | Moderate |
| Mid-Borderline (BB) | Intermediate | Intermediate | Multiple unstable lesions | Variable |
| Borderline Lepromatous (BL) | Poor | Multibacillary | Many lesions | Moderate |
| Lepromatous (LL) | Absent CMI | High (multibacillary) | Nodules, plaques (leonine facies), bilateral, symmetric, loss of eyebrows/eyelashes | Bilateral, glove & stocking |
WHO Classification (practical):
- Paucibacillary (PB): ≤5 skin lesions, smear-negative
- Multibacillary (MB): >5 skin lesions, or smear-positive
Diagnosis:
- Slit-skin smear (Ziehl-Neelsen): bacillary index (0-6+)
- Skin biopsy: granulomas with AFB
- Lepromin test: positive in tuberculoid (indicates immunity), negative in lepromatous
Reactions (immune-mediated complications):
- Type 1 (Reversal reaction): Borderline forms; sudden worsening of existing lesions + new ones + nerve pain; treat with prednisolone 40-60 mg/day
- Type 2 (Erythema Nodosum Leprosum/ENL): Lepromatous/BL forms; painful red nodules + fever + systemic; treat with thalidomide (men/non-fertile women) or prednisolone
Treatment (WHO MDT):
| Type | Regimen | Duration |
|---|---|---|
| Paucibacillary | Rifampin 600 mg monthly (supervised) + Dapsone 100 mg/day | 6 months |
| Multibacillary | Rifampin 600 mg + Clofazimine 300 mg monthly + Dapsone 100 mg + Clofazimine 50 mg/day | 12 months |
Dapsone side effects: Hemolytic anemia (especially G6PD deficiency), methemoglobinemia
Clofazimine side effects: Red-brown skin pigmentation, GI symptoms
Rehabilitation: ISSO (Inspect, Soak, Scrape, Oil) self-care routine for insensate limbs.
Chapter 185 - Non-Tuberculous Mycobacteria (NTM)
Definition: All mycobacteria except M. tuberculosis complex and M. leprae. Also called atypical mycobacteria, MOTT (mycobacteria other than TB).
Runyon Classification:
| Group | Growth | Pigment | Examples |
|---|---|---|---|
| I - Photochromogens | Slow | Only in light | M. kansasii, M. marinum |
| II - Scotochromogens | Slow | Light & dark | M. scrofulaceum, M. gordonae |
| III - Nonchromogens | Slow | None | M. avium complex (MAC), M. xenopi, M. malmoense, M. ulcerans |
| IV - Rapid growers | Fast (<7 days) | Variable | M. abscessus, M. chelonae, M. fortuitum |
Key Species & Clinical Syndromes:
MAC (M. avium complex):
- Lung disease: resembles TB (nodular bronchiectatic form in postmenopausal women - Lady Windermere syndrome; fibrocavitary form in smokers/COPD)
- Disseminated MAC in HIV (CD4 <50): fever, weight loss, diarrhea, hepatosplenomegaly, anemia; blood cultures positive; treat with clarithromycin + ethambutol ± rifabutin
- MAC lymphadenitis in children: most common NTM adenitis; cervical nodes; treat surgically
M. kansasii: Similar to TB clinically; treat with rifampin + isoniazid + ethambutol
M. marinum: "Swimming pool/fish tank granuloma" - skin nodules along lymphatics; traumatic inoculation; treat with clarithromycin + ethambutol
M. ulcerans: Buruli ulcer - painless destructive ulcers; Africa; treat with rifampin + clarithromycin or streptomycin
M. abscessus: Lung disease (especially cystic fibrosis); catheter infections; very difficult to treat (macrolide-based regimen)
Chapter 186 - Antimycobacterial Agents
First-Line Anti-TB Drugs
| Drug | Mechanism | Key Toxicity | Notes |
|---|---|---|---|
| Isoniazid (INH) | Inhibits mycolic acid synthesis (InhA enzyme) | Hepatotoxicity, peripheral neuropathy, seizures (B6 deficiency), SLE-like | Bactericidal; give pyridoxine prophylactically |
| Rifampin | Inhibits RNA polymerase (rpoB gene) | Hepatotoxicity, drug interactions (CYP450 inducer), orange secretions, flu-like syndrome | Bactericidal; most important TB drug |
| Pyrazinamide | Unknown (targets fatty acid synthase?) | Hepatotoxicity, hyperuricemia, arthralgia | Only active in acidic environment (intracellular); sterilizing activity |
| Ethambutol | Inhibits arabinosyl transferase (arabinogalactan synthesis) | Optic neuritis | Bacteriostatic; not for children <5 yr |
| Streptomycin | Inhibits 30S ribosome | Ototoxicity (vestibular > auditory), nephrotoxicity | First anti-TB drug; not in standard regimen now |
Second-Line Anti-TB Drugs (MDR-TB)
| Drug | Class | Notes |
|---|---|---|
| Moxifloxacin, levofloxacin | Fluoroquinolones | Inhibit DNA gyrase; key MDR-TB drugs |
| Bedaquiline | Diarylquinoline | Inhibits mycobacterial ATP synthase; approved for MDR-TB |
| Delamanid | Nitroimidazo-oxazole | Inhibits mycolic acid synthesis; MDR-TB |
| Linezolid | Oxazolidinone | Inhibits 50S ribosome; effective but toxic (myelosuppression, neuropathy) |
| Clofazimine | Riminophenazine | Used in MDR-TB and leprosy |
| Cycloserine | Analog of D-alanine | CNS toxicity (psychosis, seizures) |
| Kanamycin/Amikacin | Aminoglycosides | Injectable; ototoxic/nephrotoxic |
MDR-TB and XDR-TB
- MDR-TB: Resistant to at least isoniazid + rifampin
- Pre-XDR-TB (2021 WHO definition): MDR-TB + resistance to any fluoroquinolone
- XDR-TB: Pre-XDR + resistance to bedaquiline or linezolid
- Treatment: BPaL regimen (Bedaquiline + Pretomanid + Linezolid) - approved 2019-2022
Anti-Leprosy Drugs
- Dapsone (DDS): Inhibits folate synthesis (like sulfonamides); bacteriostatic
- Rifampin: Bactericidal against M. leprae
- Clofazimine: Anti-inflammatory + weakly bactericidal; causes skin pigmentation
SECTION 9 - SPIROCHETAL DISEASES
Chapter 187 - Syphilis
Organism: Treponema pallidum subsp. pallidum - thin spiral spirochete; cannot be cultured in vitro (historically); now long-term propagation possible in complex medium with eukaryotic cells.
Structure: Cell body + trilaminar cytoplasmic membrane + peptidoglycan layer + lipid-rich outer membrane + endoflagella in periplasmic space.
Stages of Syphilis
Primary Syphilis (3-90 days after exposure):
- Chancre - painless, indurated, clean-based genital/anal/oral ulcer with raised borders
- Regional lymphadenopathy - firm, non-tender
- Heals spontaneously in 3-6 weeks
Secondary Syphilis (6-8 weeks after chancre):
- Generalized rash: maculopapular, involves palms and soles (classic)
- Condylomata lata: broad, moist, flat warts in perianal/vulval area (highly infectious)
- Mucous patches in mouth (highly infectious)
- Systemic: fever, malaise, generalized lymphadenopathy, alopecia (moth-eaten), hepatitis, nephritis
Latent Syphilis:
- Early latent: <1 year (seropositive, no symptoms, 25% may relapse to secondary)
- Late latent: >1 year (non-infectious except to fetus)
Tertiary Syphilis (years-decades later; ~1/3 of untreated):
- Cardiovascular syphilis: Aortitis → aortic root dilatation → aortic regurgitation, aneurysm (ascending aorta); "tree-bark" appearance of aorta
- Gummatous syphilis: Granulomatous lesions in skin, bone, liver; "punched out" lesions; respond rapidly to penicillin
- Neurosyphilis:
- Meningovascular (strokes, headache)
- Tabes dorsalis: degeneration of posterior columns and dorsal nerve roots; lightning pains, Argyll Robertson pupils (accommodate but don't react), ataxia, Charcot joints, Romberg sign
- General Paresis: dementia, personality change, Argyll Robertson pupils; "PARESIS" mnemonic (Personality, Affect, Reflexes, Eye-Argyll Robertson, Sensorium, Intellect, Speech)
Congenital Syphilis:
- Early (<2 yr): snuffles (bloody nasal discharge), maculopapular rash, condylomata lata, hepatosplenomegaly, hemolytic anemia
- Late (>2 yr): Hutchinson's teeth (notched incisors), interstitial keratitis, eighth nerve deafness (Hutchinson's triad), saddle nose, saber shins, Clutton joints
Neurosyphilis: Any stage; CSF: lymphocytes, elevated protein, reactive VDRL.
Diagnosis
Nontreponemal tests (VDRL, RPR):
- Screening + monitoring treatment response
- Titers decline with treatment; should decline 4-fold at 6 months post-treatment
- Biological false positives: SLE, pregnancy, antiphospholipid syndrome, viral infections, malaria
Treponemal tests (FTA-ABS, TPPA, EIA):
- Confirmatory; remain positive for life even after treatment ("serofast")
- Cannot monitor treatment response
Reverse algorithm: EIA treponemal first → if positive → RPR → if discordant → TPPA
Treatment
| Stage | Treatment | Alternative |
|---|---|---|
| Primary, Secondary, Early latent | Benzathine penicillin G 2.4 MU IM x 1 dose | Doxycycline 100 mg PO bid x 14 days |
| Late latent, Unknown duration | Benzathine PCN G 2.4 MU IM x 3 doses (weekly) | Doxycycline x 28 days |
| Neurosyphilis | Aqueous PCN G 18-24 MU IV/day x 10-14 days | Ceftriaxone 2g IV/IM x 10-14 days |
Jarisch-Herxheimer reaction: Fever, chills, myalgias, hypotension 2-8 hours after first dose of treatment; due to cytokine release from dying organisms; treat supportively (antipyretics, fluids); not an allergy.
Chapter 188 - Endemic Treponematoses (Yaws, Bejel, Pinta)
Organisms: Non-venereal treponematoses caused by T. pallidum subspecies:
- Yaws (T. pallidum subsp. pertenue) - tropical Africa, Asia, S. America; transmitted by direct contact
- Bejel (T. pallidum subsp. endemicum) - dry savanna Africa/Middle East; oral transmission
- Pinta (T. carateum) - Central/South America; skin only
| Feature | Yaws | Bejel | Pinta |
|---|---|---|---|
| Transmission | Skin-skin contact | Oral mucosa | Skin-skin |
| Primary lesion | "Mother yaw" - papilloma on leg | Oral mucosa patch | Papule on skin |
| Secondary | Raspberry-like papillomas (framboesia), crab yaws (palmo-plantar) | Mucous patches, condylomata | Pintides (pigmented lesions) |
| Tertiary | Gangosa (destructive rhinopharyngitis), goundou, bone lesions | Gummas of bone/skin; no cardiovascular/neuro | Achromic/dyschromic patches |
| Cardiovascular/Neuro? | No | No | No |
Diagnosis: Same serologic tests as venereal syphilis (cannot distinguish clinically)
Treatment: Benzathine penicillin G 1.2 MU IM x 1; or azithromycin (increasingly preferred due to ease)
Chapter 189 - Leptospirosis
Organism: Leptospira interrogans complex - thin, tightly coiled spirochetes with hooked ends.
Epidemiology: Zoonosis; rodents are major reservoir (rats shed in urine). Humans infected through: contaminated water/soil entering skin abrasions or conjunctiva, or ingestion. Occupational: farmers, sewer workers, soldiers; recreational: swimmers, triathletes.
Pathogenesis: Spirochetemia phase → systemic dissemination → immune phase with organ damage.
Clinical Presentation:
Anicteric Leptospirosis (90%):
- Incubation 2-20 days
- Phase I - Leptospiremic (days 1-7): Abrupt fever, severe headache, myalgias (especially calves), conjunctival suffusion (injection without discharge - important sign), rash; spirochetes in blood/CSF
- Brief improvement
- Phase II - Immune phase (days 7-28): Antibodies develop; aseptic meningitis common; uveitis, rash; organisms in urine
Icteric Leptospirosis / Weil's Disease (~10%):
- Severe jaundice + renal failure + hemorrhage (especially pulmonary) = Weil's syndrome
- Jaundice - hepatocellular damage; may be severe
- Renal failure - acute tubular necrosis; non-oliguric initially
- Pulmonary hemorrhage - ARDS-like syndrome; high mortality
- Myocarditis, uveitis (may occur months later)
Diagnosis
- Serology: MAT (Microscopic Agglutination Test) - gold standard; serovar-specific; rise of 4x titer
- Culture (Fletcher's medium): blood (first week), urine (second week) - slow, 4-6 weeks
- PCR - most sensitive early
- Dark-field microscopy of blood: poor sensitivity/specificity
Treatment (Harrison's Table 189-1)
| Severity | Treatment |
|---|---|
| Mild | Doxycycline 100 mg PO bid x 7 days; or amoxicillin 500 mg PO tid |
| Moderate/Severe | Penicillin G 1.5 MU IV/IM q6h; or Ceftriaxone 2g IV/day; or Cefotaxime 1g IV q6h |
| Prophylaxis | Doxycycline 200 mg PO once/week; or Azithromycin 250 mg once/twice weekly |
- Supportive care critical: aggressive fluid resuscitation, hemodialysis for oliguric renal failure, ventilatory support for pulmonary hemorrhage
- Jarisch-Herxheimer reaction can occur
Chapter 190 - Relapsing Fever
Organisms: Multiple Borrelia species
Three clinical/epidemiologic forms:
- Louse-Borne Relapsing Fever (LBRF) - B. recurrentis; body louse (Pediculus humanus corporis); humans only reservoir; northeastern Africa, migrants
- Soft Tick Relapsing Fever (STRF) - multiple Borrelia spp.; soft Ornithodoros ticks; Africa, Central Asia, western N. America; rapid bite (painless, feeding 20-30 min)
- Hard Tick Relapsing Fever (HTRF) - B. miyamotoi, B. lonestari; Ixodes ticks; overlaps with Lyme disease geography
Pathogenesis: Antigenic variation of surface lipoproteins (Vlp/Vsp proteins) explains relapsing course. Each relapse results from a new antigenic variant overwhelming existing antibodies.
Structure: Helix-shaped, 10-20 μm long, 0.2-0.3 μm diameter; too narrow for Gram stain; technically gram-negative; flagella between two membranes.
Clinical Features:
- Sudden fever, rigors, headache, myalgias, arthralgia, hepatosplenomegaly
- Petechiae, epistaxis, conjunctival hemorrhage (especially LBRF)
- Febrile episodes last 3-7 days; afebrile periods 4-14 days; 2-10 relapses (STRF has more)
- CNS involvement: meningitis, cranial nerve palsies, uveitis (especially STRF)
- Pregnancy: high rates of miscarriage, premature labor
Diagnosis:
- Blood smear (Giemsa/Wright stain) - thick and thin smears; spirochetes visible in blood during febrile episodes (high spirochetemia)
- Peripheral blood is ideal during fever
- Serology less reliable due to cross-reactivity with Borrelia burgdorferi
Treatment:
| Type | Regimen |
|---|---|
| LBRF | Single dose: Doxycycline 100 mg PO or Tetracycline 500 mg PO or Erythromycin 500 mg PO |
| STRF/HTRF | Doxycycline 100 mg PO bid x 7-10 days; or Tetracycline x 10 days |
| CNS involvement | Ceftriaxone 2g IV x 14 days |
| Pregnancy/children | Erythromycin or penicillin G |
Jarisch-Herxheimer reaction: Very common (80% in LBRF) after first dose; can be severe with hypotension, rigors; higher mortality in LBRF; pretreat with meptazinol or hydrocortisone.
Prevention (STRF): Post-exposure doxycycline (100-200 mg day 1, then 100 mg/day x 4 days) - efficacious in placebo-controlled trial.
Chapter 191 - Lyme Disease
Organism: Borreliella burgdorferi sensu lato complex (note: reclassified from Borrelia to Borreliella)
- USA: B. burgdorferi sensu stricto
- Europe: B. afzelii, B. garinii (cause more neurologic/arthritic disease)
Vector: Ixodes ticks (I. scapularis - northeast/midwest USA; I. pacificus - west coast; I. ricinus - Europe). Transmission requires tick attachment for >36 hours (nymphal stage most dangerous).
Clinical Stages:
Stage 1 - Early Localized (days 3-30):
- Erythema migrans (EM): Expanding annular rash with central clearing ("bull's-eye"); ≥5 cm; pathognomonic; at bite site; warm, not painful
- Flu-like symptoms: fever, malaise, headache, myalgias
Stage 2 - Early Disseminated (weeks-months):
- Cardiac: AV block (most common: complete heart block; may need temporary pacemaker), myopericarditis
- Neurologic (Lyme neuroborreliosis): Lymphocytic meningitis, cranial neuropathies (bilateral facial palsy is classic), radiculopathy; Europe: Bannwarth syndrome (painful radiculopathy)
- Multiple EM lesions
Stage 3 - Late Disseminated (months-years):
- Lyme Arthritis: Oligoarticular, intermittent; large joints (knee); may persist; anti-CCP negative
- Chronic neurologic Lyme: Encephalopathy, cognitive difficulties, peripheral neuropathy
Diagnosis:
- Standard two-tier testing: ELISA first → if positive/equivocal → Western blot (IgM + IgG)
- IgM Western blot: ≥2 of 3 bands (23, 39, 41 kDa)
- IgG Western blot: ≥5 of 10 bands
Treatment:
| Stage | Treatment |
|---|---|
| Early localized EM | Doxycycline 100 mg bid x 10-21 days; or Amoxicillin x 14-21 days |
| Early disseminated - Carditis (1st/2nd degree AV block) | Oral doxycycline |
| Carditis with high-degree AV block | IV Ceftriaxone 2g/day x 14 days; may need temporary pacemaker |
| Neurologic (meningitis, cranial nerve, radiculopathy) | IV Ceftriaxone 2g/day x 14-28 days; or IV Penicillin G |
| Lyme arthritis (no neuro) | Doxycycline 100 mg bid x 28 days |
| Antibiotic-refractory arthritis | NSAIDs, DMARDs, synovectomy |
SECTION 10 - DISEASES CAUSED BY RICKETTSIAE, MYCOPLASMA, AND CHLAMYDIA
Chapter 192 - Rickettsial Diseases
Key biology: Obligate intracellular gram-negative bacteria transmitted by arthropod vectors. Target endothelial cells (except Coxiella). Weil-Felix reaction historically (now replaced by serology).
Major Rickettsioses:
Spotted Fever Group (SFG)
Rocky Mountain Spotted Fever (RMSF) - Rickettsia rickettsii:
- Vector: Dermacentor variabilis (dog tick, eastern USA), D. andersoni (western USA)
- Most severe rickettsial disease; 5-10% mortality even treated
- Classic triad: fever + headache + rash (maculopapular → petechial) beginning on wrists/ankles and spreading centrally including palms and soles
- Rash appears day 2-5; may be absent in early disease
- Pathogenesis: endothelial invasion → vasculitis → vascular leakage → petechiae, edema, shock
- Labs: thrombocytopenia, elevated LFTs, hyponatremia; WBC normal or low
- Diagnosis: serology (IFA); skin biopsy PCR/immunohistochemistry for early rapid diagnosis
- Treatment: Doxycycline 100 mg bid (drug of choice, even in children); never delay for lab confirmation
- "Never await lab results before treating RMSF"
Mediterranean Spotted Fever - R. conorii: Tache noire (eschar at bite site); Rhipicephalus tick
Rickettsialpox - R. akari: Mite; eschar; vesicular rash; self-limited; New York City urban setting
Typhus Group
Epidemic (Louse-borne) Typhus - R. prowazekii:
- Vector: body louse (P. humanus); reservoir: flying squirrels in USA
- Epidemic in overcrowding, wars, refugee camps
- Rash spares face, palms, soles (opposite of RMSF)
- Brill-Zinsser disease: Reactivation years later; milder illness; person served as reservoir
- Treatment: Doxycycline
Endemic (Murine) Typhus - R. typhi:
- Vector: rat flea (Xenopsylla cheopis); reservoir: rats
- Milder than epidemic typhus
- Treatment: Doxycycline
Scrub Typhus - Orientia tsutsugamushi:
- Vector: larval trombiculid mites (chiggers)
- Endemic: Asia-Pacific ("tsutsugamushi triangle")
- Eschar (painless) at bite site - key diagnostic clue
- Fever, lymphadenopathy, hepatosplenomegaly
- Complications: myocarditis, ARDS, meningoencephalitis
- Treatment: Doxycycline; azithromycin if pregnant
Ehrlichioses and Anaplasmosis
Human Monocytotropic Ehrlichiosis (HME) - Ehrlichia chaffeensis:
- Vector: Amblyomma americanum (lone star tick)
- Intracellular inclusions in monocytes called morulae
- Fever, headache, leukopenia, thrombocytopenia, elevated LFTs
- Rash in ~30% (unlike RMSF, rash less prominent)
- Diagnosis: blood smear (morulae), PCR, serology
- Treatment: Doxycycline (not susceptible to chloramphenicol in vitro)
Human Granulocytotropic Anaplasmosis (HGA) - Anaplasma phagocytophilum:
- Vector: Ixodes scapularis/pacificus - same tick as Lyme disease; northeastern/upper Midwest USA
- Morulae in granulocytes (neutrophils)
- Similar clinical picture to HME; rash uncommon
- 64,225 cases reported to CDC as of November 2023
- Treatment: Doxycycline; rifampin alternative
"Candidatus Neoehrlichia mikurensis": Identified in immunocompromised patients; venous thrombosis predilection; Europe/China; Ixodes ticks.
Q Fever - Coxiella burnetii
Unique features: Does NOT require arthropod vector; transmitted by aerosol from infected animal products (cattle, sheep, goats), especially parturient fluids. Highly resistant - forms spore-like structures.
Acute Q fever: Pneumonia (atypical), hepatitis (granulomatous), fever; self-limited in most.
Chronic Q fever: Endocarditis (most serious; vegetations often absent; diagnosis by serology - phase I IgG titer ≥1:800); occurs in valvular disease patients.
Treatment:
- Acute: Doxycycline x 14-21 days
- Chronic/Endocarditis: Doxycycline + Hydroxychloroquine x 18 months (at least)
Chapter 193 - Infections Due to Mycoplasma
Key Biology: Smallest free-living organisms; no cell wall (hence: no Gram stain, natural resistance to beta-lactams and glycopeptides); pleomorphic; cannot be seen by standard light microscopy well.
Mycoplasma pneumoniae
Pathogenesis:
- Extracellular pathogen primarily
- Attaches to ciliated respiratory epithelium via P1 adhesin protein on terminal organelle
- Injury by hydrogen peroxide production + ADP-ribosylating vacuolating cytotoxin (similar to pertussis toxin)
- Lacks cell wall - no LPS/peptidoglycan; lipoproteins activate TLR2
- Lung biopsy: tracheobronchitis with monocytic infiltrate + PMN exudate
Epidemiology:
- Worldwide; major cause of atypical (walking) pneumonia
- Incubation: 2-4 weeks
- Most common atypical pathogen in CAP: 22.7% prevalence (vs. C. pneumoniae 11.7%, Legionella 4.6%)
- Outbreaks in military, schools, camps; epidemics every 4-7 years
Mycoplasma Pneumoniae Infections:
- Upper respiratory illness (20x more common than pneumonia)
- Tracheobronchitis, pharyngitis
- Atypical pneumonia: Gradual onset; non-productive cough; low-grade fever; normal WBC; bilateral diffuse infiltrates; patient "walks around" (walking pneumonia)
- Extrapulmonary: cold agglutinins (IgM anti-I antibodies causing hemolytic anemia - seen in ~50%), Stevens-Johnson syndrome, erythema multiforme, Raynaud's phenomenon, myocarditis, meningoencephalitis, transverse myelitis, hemolytic anemia
Diagnosis:
- Cold agglutinins titer ≥1:64 (non-specific but suggestive)
- PCR - most sensitive and specific
- Culture: very slow (weeks); specialized media; not practical
- Serology: complement fixation, ELISA - rise in paired sera
Treatment:
- Macrolides (azithromycin, clarithromycin) - first line; well-tolerated
- Doxycycline - alternative
- Fluoroquinolones (moxifloxacin, levofloxacin) - for macrolide-resistant strains
- NOT penicillins or cephalosporins (no cell wall)
- Duration: 5-14 days
Urogenital Mycoplasma Infections
Organisms: Mycoplasma hominis, Ureaplasma urealyticum (urealyticum/parvum)
- Ureaplasma produces urease (unique among mycoplasmas) → stone formation in catheterized patients
- M. hominis - associated with bacterial vaginosis, pelvic inflammatory disease, postpartum fever
- Ureaplasma - nongonococcal urethritis, infertility, chorioamnionitis, neonatal sepsis/meningitis
Treatment: Doxycycline; azithromycin for Ureaplasma; M. hominis often resistant to azithromycin
Chapter 194 - Legionella Disease (Legionellosis)
Organism: Legionella pneumophila (serogroup 1 - ~85% of disease); gram-negative rod; obligate intracellular pathogen of alveolar macrophages.
Reservoir: Freshwater environments; amplified in man-made water systems (cooling towers, hospital hot water, spa pools, decorative fountains).
Transmission: Inhalation of aerosols; NO person-to-person transmission.
Two clinical syndromes:
Pontiac Fever (non-pneumonic form):
- Self-limited flu-like illness: fever, myalgias, headache
- No pneumonia; no deaths; high attack rate (>90%)
- No treatment needed
Legionnaires' Disease (pneumonic form):
- Incubation: 2-10 days
- Severe pneumonia with systemic features
- Classic features: high fever, dry cough, confusion/encephalopathy, relative bradycardia (pulse-temperature dissociation), GI symptoms (diarrhea, abdominal pain), hyponatremia, elevated LFTs
- Chest X-ray: lobular/lobar consolidation; may progress to bilateral involvement
- Labs: lymphopenia, thrombocytopenia, hyponatremia, elevated creatinine, hematuria, elevated CK
- Hyponatremia - characteristic laboratory clue
Diagnosis:
- Urinary antigen test (UAT) - detects L. pneumophila serogroup 1; rapid, highly specific; remains positive for weeks; test of choice in acute illness
- Culture: BCYE (buffered charcoal yeast extract) agar - gold standard but slow; specimen from BAL/sputum
- PCR: urine, respiratory specimens
- Serology: 4-fold rise in IFA titer
Treatment:
- Fluoroquinolones (levofloxacin, moxifloxacin) - first line (superior outcomes)
- Azithromycin - alternative (macrolide)
- Duration: 5-10 days (mild); 10-21 days (severe, immunocompromised)
- Erythromycin historically used; now replaced by fluoroquinolones
Prevention: Regular maintenance and disinfection of water systems; hyperchlorination and superheating; ASHRAE guidelines.
SECTION 11 - VIRAL DISEASES: GENERAL CONSIDERATIONS
Chapter 195 - Principles of Medical Virology
(Harrison's 22E, p. 1521-1522 and block 21-22)
What is a Virus?
Viruses are obligate intracellular parasites that must enter cells to replicate. Unlike bacteria, they do not divide; they disassemble inside cells, replicate their genome using host machinery, then reassemble progeny virions. They depend on host ribosomes, organelles, and metabolic pathways.
The term "virus" derives from Latin for poison/toxin - infection injures host cells producing the cytopathic effect (CPE).
Distinguishing viruses from:
- Viroids: small circular ssRNA; no protein coat; infect plants only
- Virusoids: circular RNA; need helper virus for replication
- Prions: misfolded proteins; no nucleic acid; cause neurodegenerative disease
Virus Structure
- Minimum virion: Nucleic acid genome + protein capsid = nucleocapsid
- Capsids organized as: (1) Icosahedral symmetry (20 triangular faces, 2/3/5-fold axes) or (2) Helical symmetry
- Enveloped viruses: Lipid envelope surrounding capsid; derived from host cell membranes during budding
- Naked (non-enveloped) viruses: More resistant to detergent, drying, and acid
Viral Genomes
| Type | Examples |
|---|---|
| dsRNA | Reoviruses (rotavirus) |
| ss(+)RNA | Picornaviruses, flaviviruses, coronaviruses; genome directly translatable |
| ss(-)RNA | Influenza, rabies, measles; must be transcribed first (carry RNA polymerase within virion) |
| ssDNA | Parvoviruses |
| dsDNA | Herpesviruses, adenoviruses, poxviruses |
| Retrovirus (ssRNA → dsDNA via reverse transcriptase) | HIV |
Positive-strand RNA: Translated directly after uncoating
Negative-strand RNA: Must be transcribed; virion carries transcriptases (loaded onto genome prior to encapsulation)
Viral Replication Steps
- Binding - virus binds specific receptor on cell surface (charged molecule first, then specific protein/carbohydrate)
- Entry - fusion of envelope with plasma membrane; or endocytosis (clathrin-mediated, macropinocytosis, caveolar) → acidification of endosome → conformational change → fusion → release of nucleocapsid
- Uncoating - genome released
- Transport to replication site
- Transcription of mRNA
- Translation of viral proteins
- Genome replication
- Assembly of progeny particles
- Egress from cell
Viral Classification (Table 195-1, Harrison's)
Criteria: nucleic acid type, capsid symmetry, envelope, replication mode, tropism.
International Committee on Taxonomy of Viruses (ICTV) now uses genome sequencing for classification.
Example: Herpes simplex virus (HSV) = common name for Simplex virus human alpha 1.
Host Immune Responses
Innate Immunity (rapid, pattern-based):
- TLR7/8 - recognize ssRNA → Type I IFN genes
- TLR3 - recognizes dsRNA → Type I IFN
- RIG-I/MDA5 - cytoplasmic ss/dsRNA → Type I IFN
- TLR2/4 - viral glycoproteins
- cGAS - cytoplasmic viral DNA → Type I IFN
- IFI16 - nuclear DNA sensor → IFN + epigenetic silencing
- IFNs act in autocrine (on producing cell) + paracrine (surrounding cells) manner
Adaptive Immunity:
- APCs present viral peptides to CD4+ (helper) and CD8+ (cytotoxic) T cells
- CD8+ T cells kill virus-infected cells displaying MHC class I + viral peptide
- CD4+ T cells help B cells produce antibodies
- Antibodies: Neutralize virions (prevent receptor binding, entry, uncoating); promote phagocytosis; antibody-dependent cytotoxicity; complement-mediated lysis
Viral Evolution and Pathogenesis
- RNA polymerases are error-prone (lack editing functions) → high mutation rate
- Viral populations exist as "quasispecies" (diverse swarms)
- Drug pressure or immune selection → emergence of resistant variants
- Antigenic drift: Point mutations; gradual change (influenza yearly variation)
- Antigenic shift: Reassortment of gene segments from different strains; major change (influenza pandemic)
Post-Acute Infection Syndromes (PAIS):
Harrison's 22E highlights this as a priority topic. Long COVID brought attention to mechanisms:
- Persisting viral replication or antigens
- Autoimmune responses triggered by infection
- Alteration of microbiome/endogenous viruses
- Irreparable tissue damage
Prior examples: Post-EBV (infectious mononucleosis) fatigue, post-dengue fatigue, post-polio syndrome.
Viral Vaccines
- Inactivated virus: Salk polio vaccine - cannot replicate; safe in immunocompromised
- Live attenuated: Sabin polio vaccine; MMR, varicella; stronger/longer immunity; not for immunocompromised
- Recombinant proteins: Hepatitis B vaccine, HPV vaccine
- Viral vectors: VSV-based Ebola vaccine; adenovirus-based COVID-19/HIV vaccines
- mRNA vaccines: COVID-19; instructions for producing viral antigen
- Gene therapy: Retroviruses (stable integration), AAV (non-integrating, durable), adenoviruses; attenuated HSV expressing GM-CSF approved for melanoma (oncolytic)
Chapter 196 - Antiviral Chemotherapy (Excluding Antiretroviral Drugs)
(Harrison's 22E, pages 1528+, block 22)
General Principles:
- Antiviral drugs must target virus-specific events to avoid host toxicity (viruses use host cell machinery)
- Most successful drugs target viral enzymes (DNA polymerases, thymidine kinase, RNA polymerase, protease)
- Drugs do NOT eradicate latent infections - only suppress replication; virus reactivates when stopped
- RNA viruses have higher mutation rates → resistance develops more commonly in healthy hosts
- DNA viruses develop resistance mainly in immunocompromised patients
- Combination therapy preferred for RNA viruses (different mechanisms, different resistance patterns)
- Monitoring: Quantitative PCR for viremia (CMV, HBV, HCV)
Antiviral Drugs for Herpesvirus Infections
Acyclovir, Valacyclovir, Famciclovir, Penciclovir:
- Mechanism: Acyclovir = deoxyguanosine analogue; phosphorylated by viral thymidine kinase (HSV/VZV-encoded) → monophosphate; then by cellular kinases → triphosphate inhibits viral DNA polymerase + terminates replication when incorporated into viral DNA
- Selective activation in infected cells (viral TK) = safety for normal cells
- Valacyclovir = valine ester prodrug of acyclovir; 4x higher plasma levels after oral dosing
- Famciclovir = prodrug of penciclovir; similar mechanism to acyclovir
Indications (FDA-approved):
| Drug | Approved Indications |
|---|---|
| Acyclovir/Valacyclovir | Initial + recurrent genital herpes, varicella, zoster, herpes labialis; HSV suppression; genital HSV transmission reduction |
| Higher doses for VZV | VZV less susceptible than HSV to these drugs |
| IV acyclovir | Severe disease: HSV encephalitis, neonatal HSV, severe VZV |
Resistance: Due to mutations in TK (most common) or DNA polymerase; treat with foscarnet or cidofovir.
Ganciclovir, Valganciclovir:
- Active against CMV (and herpesviruses)
- Phosphorylated by CMV UL97 kinase (not TK) → inhibits CMV DNA polymerase
- Valganciclovir = oral prodrug; good bioavailability
- Indication: CMV retinitis, other CMV disease in immunocompromised; prophylaxis in transplant recipients
- Key toxicity: myelosuppression (leukopenia, thrombocytopenia); also teratogenic
Foscarnet:
- Pyrophosphate analogue; directly inhibits viral DNA polymerase WITHOUT need for phosphorylation (TK-independent)
- Active against CMV, HSV (including acyclovir-resistant strains), HBV
- Toxicity: nephrotoxicity (most serious), electrolyte disturbances (hypo- and hypercalcemia, hypomagnesemia, hypo/hyperphosphatemia), penile/vulvar ulcers; must be given with saline hydration
- Use: Acyclovir-resistant HSV/VZV; ganciclovir-resistant CMV
Cidofovir:
- Nucleoside analogue of cytosine; directly phosphorylated by cellular kinases (no viral kinase needed)
- Active against CMV, HSV, adenovirus, HPV, poxviruses
- Very long intracellular half-life (once-weekly/biweekly dosing)
- Toxicity: severe nephrotoxicity (proximal tubule); must give with probenecid and IV hydration
Antiviral Drugs for Influenza
Neuraminidase Inhibitors (NAIs):
- Oseltamivir (Tamiflu), Zanamivir (Relenza), Peramivir (IV)
- Mechanism: Inhibit influenza neuraminidase → prevent viral release from infected cells and spread
- Active against influenza A and B
- Must be given within 48 hours of symptom onset for maximum benefit
- Oseltamivir: oral; Zanamivir: inhaled (bronchospasm risk); Peramivir: single IV dose
- Resistance: NA H275Y mutation in influenza A(H1N1) - oseltamivir resistant; zanamivir still active
Baloxavir Marboxil:
- Inhibits cap-dependent endonuclease (PA subunit) of influenza RNA polymerase complex
- Novel mechanism; active against influenza A + B including oseltamivir-resistant strains
- Single oral dose
Amantadine, Rimantadine (M2 ion channel blockers):
- Active only against influenza A (NOT influenza B)
- Mechanism: Block M2 proton channel → prevent uncoating
- High rates of resistance; NOT recommended for current influenza A strains
- Side effects: CNS (confusion, insomnia) for amantadine; fewer CNS effects with rimantadine
Antiviral Drugs for Respiratory Viruses
Ribavirin:
- Guanosine analogue; broad spectrum; mechanism: inhibits RNA synthesis + mutational lethal mutagenesis
- Uses: Inhaled for severe RSV in infants; IV/oral for hemorrhagic fever viruses; HCV (with interferon, now largely replaced); hantavirus
- Toxicity: hemolytic anemia; teratogenic (Category X)
Nirmatrelvir/Ritonavir (Paxlovid):
- Nirmatrelvir: inhibits SARS-CoV-2 Mpro (main protease)
- Ritonavir: boosts nirmatrelvir levels by inhibiting CYP3A4
- Indicated for high-risk mild-moderate COVID-19 within 5 days of symptom onset
- Multiple drug interactions due to ritonavir
Remdesivir:
- Adenosine analogue; inhibits viral RNA-dependent RNA polymerase (RdRp); causes delayed chain termination
- Active against SARS-CoV-2, Ebola, filoviruses, RSV
- IV formulation; approved for hospitalized COVID-19
Molnupiravir:
- Ribonucleoside analogue; causes viral RNA mutagenesis (error catastrophe)
- Oral; COVID-19 treatment
Antiviral Drugs for Hepatitis B Virus (HBV)
(Entecavir, Tenofovir disoproxil/alafenamide, Adefovir, Lamivudine, Telbivudine) - covered under chronic hepatitis chapters; nucleos(t)ide analogues inhibiting HBV reverse transcriptase/DNA polymerase.
Antiviral Drugs for Hepatitis C Virus (HCV)
Direct-Acting Antivirals (DAAs) - covered in hepatitis chapters; NS5B polymerase inhibitors (sofosbuvir), NS5A inhibitors (ledipasvir, velpatasvir), NS3/4A protease inhibitors (glecaprevir). Curative rates >95%.
Investigational Antiviral Drugs
Harrison's 22E notes ongoing development of:
- Broad-spectrum antivirals targeting conserved viral mechanisms
- Monoclonal antibodies for RSV (nirsevimab), Ebola
- CRISPR-based antiviral approaches
- Host-directed therapies targeting cellular factors required for viral replication
Summary: Key High-Yield Points for Examinations
| Topic | High-Yield Fact |
|---|---|
| Nocardia | Weakly acid-fast; TMP-SMX; always image CNS |
| Actinomycosis | Sulfur granules; penicillin x 12 months; IUD → pelvic actinomycosis |
| Whipple's disease | PAS+ macrophages; oculomasticatory myorhythmia; ceftriaxone → TMP-SMX |
| TB diagnosis | GeneXpert = first-line; IGRAs not affected by BCG |
| TB LTBI treatment | 3HP (isoniazid + rifapentine weekly x 3 months) = preferred |
| TB drug toxicity | Ethambutol → optic neuritis; INH → peripheral neuropathy; PZA → hyperuricemia |
| Leprosy | Tuberculoid = strong CMI, paucibacillary; Lepromatous = absent CMI, multibacillary |
| Syphilis | Chancre (primary); palm/sole rash + condylomata (secondary); Argyll Robertson pupil (late neuro); benzathine PCN G |
| Relapsing fever | Blood smear during fever; Jarisch-Herxheimer very common; doxycycline |
| Leptospirosis | Conjunctival suffusion; Weil's disease; MAT serology; IV penicillin/ceftriaxone |
| RMSF | Petechial rash wrists → palms/soles; doxycycline even in children; don't delay |
| HME/HGA | Morulae in monocytes/granulocytes; doxycycline; HGA shares Ixodes tick with Lyme |
| Mycoplasma pneumoniae | Cold agglutinins; walking pneumonia; azithromycin; no beta-lactam activity |
| Legionella | Hyponatremia; urinary antigen test; levofloxacin; no person-to-person spread |
| Medical Virology | ss(-)RNA viruses carry RNA polymerase; Acyclovir requires viral TK; RNA viruses mutate faster |
| Acyclovir resistance | Treat with foscarnet; mechanism: TK mutation |
| Antivirals: influenza | Oseltamivir within 48h; M2 blockers only influenza A; baloxavir - new mechanism (cap-endonuclease) |
*All content sourced from: Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw-Hill Medical), Sections 7-11, Chapters 179-196.*Here is your complete teaching guide - all chapters covered in detail directly from Harrison's Principles of Internal Medicine, 22nd Edition (2025). Here is a quick orientation of what was covered:
What Was Covered
Section 7 - Miscellaneous Bacterial Infections:
- Ch. 179 - Nocardia: Weakly acid-fast, TMP-SMX treatment, always image the brain
- Ch. 180 - Actinomycosis: Sulfur granules, penicillin x 12 months, IUD → pelvic actinomycosis
- Ch. 181 - Whipple's Disease: PAS+ macrophages in intestinal biopsy, oculomasticatory myorhythmia is pathognomonic, treat with ceftriaxone then TMP-SMX
- Ch. 182 - Mixed Aerobic-Anaerobic Infections: B. fragilis, necrotizing fasciitis, aspiration pneumonia, bacterial vaginosis
Section 8 - Mycobacterial Diseases:
- Ch. 183 - Tuberculosis: Full pathogenesis, diagnosis (IGRA, GeneXpert), LTBI and active TB regimens from Harrison's Tables 186-1 and 186-2, drug side effects
- Ch. 184 - Leprosy: Ridley-Jopling classification, WHO PB/MB, MDT regimens, Types 1 and 2 reactions
- Ch. 185 - NTM: Runyon classification, MAC, M. marinum, M. ulcerans, M. abscessus
- Ch. 186 - Antimycobacterial Agents: Mechanism and toxicity of all first- and second-line drugs, MDR/XDR definitions, BPaL regimen
Section 9 - Spirochetal Diseases:
- Ch. 187 - Syphilis: All stages, congenital syphilis, Argyll Robertson pupil, VDRL vs FTA-ABS, benzathine PCN treatment, Jarisch-Herxheimer reaction
- Ch. 188 - Endemic Treponematoses: Yaws, bejel, pinta - comparison table
- Ch. 189 - Leptospirosis: Conjunctival suffusion, Weil's disease, MAT, treatment table from Harrison's
- Ch. 190 - Relapsing Fever: LBRF vs STRF vs HTRF, antigenic variation, blood smear diagnosis, doxycycline
- Ch. 191 - Lyme Disease: EM rash, stages, two-tier serology, treatment by stage
Section 10 - Rickettsiae, Mycoplasma, Chlamydia:
- Ch. 192 - Rickettsial Diseases: RMSF, Typhus (epidemic/endemic/scrub), Ehrlichioses (HME/HGA - morulae), Q fever
- Ch. 193 - Mycoplasma Infections: M. pneumoniae (cold agglutinins, atypical pneumonia, azithromycin), urogenital mycoplasmas
- Ch. 194 - Legionella: Hyponatremia, urinary antigen test, BCYE culture, levofloxacin
Section 11 - Viral Diseases:
- Ch. 195 - Medical Virology: Virus structure, genome types, replication steps, immune responses (innate PRRs - TLR7/8/3, RIG-I, cGAS; adaptive - CD4/CD8/B cells), viral evolution, PAIS/Long COVID
- Ch. 196 - Antiviral Chemotherapy: Acyclovir mechanism (viral TK), valacyclovir, ganciclovir (CMV), foscarnet (TK-independent), neuraminidase inhibitors, baloxavir, ribavirin, Paxlovid (nirmatrelvir/ritonavir), remdesivir
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