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.

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Here is your comprehensive teaching note covering all the chapters you listed, drawn directly from 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 & Classification Nocardia are aerobic actinomycetes - gram-positive, weakly acid-fast, branching filamentous bacteria. They are environmental saprophytes found in soil, water, and decaying organic matter worldwide. Key pathogenic species include N. asteroides complex, N. brasiliensis, N. farcinica, N. nova, and N. cyriacigeorgica. N. brasiliensis is the most common cause of cutaneous/subcutaneous disease (mycetoma). N. farcinica tends to be most drug-resistant.

Epidemiology

~1,000 cases/year in the USA
Predominantly affects immunocompromised patients: organ transplant recipients, long-term corticosteroid users, patients with HIV/AIDS, those with chronic granulomatous disease, and patients on anti-TNF therapy
Inhalation is the primary route; cutaneous inoculation is secondary
Not transmitted person-to-person

Clinical Forms

Form	Features
Pulmonary nocardiosis	Most common (>75%). Subacute/chronic pneumonia with nodules, cavities, infiltrates. Mimics TB or fungal infection
Disseminated/CNS	Brain abscess in ~1/3 of pulmonary cases. Any organ can be seeded
Cutaneous/Subcutaneous	Mycetoma (painless, draining sinuses with granules), cellulitis, lymphocutaneous disease
Bacteremia	Rare, mostly in severely immunosuppressed

Diagnosis

Gram stain: beaded, branching gram-positive filaments
Modified acid-fast stain: weakly positive (key differentiator from Actinomyces, which is acid-fast negative)
Culture: slow growth on standard media (days to weeks); requires prolonged incubation
Molecular typing for species identification

Treatment

Drug of choice: TMP-SMX (trimethoprim-sulfamethoxazole) - dose: TMP 5-10 mg/kg/day
Severe/disseminated disease: combination of TMP-SMX + imipenem + amikacin (triple therapy)
CNS disease: add imipenem or amikacin
Duration: immunocompromised patients require 12 months or longer; immunocompetent patients 3-6 months
Alternatives: imipenem, amikacin, linezolid, minocycline, amoxicillin-clavulanate

Chapter 180 - Actinomycosis (referred to as "Mycosis" - actually Actinomycosis)

Organism Actinomyces israelii is the classic pathogen - a gram-positive, non-acid-fast, anaerobic-to-microaerophilic, filamentous bacterium. Normal oral, GI, and genital flora. Disease occurs only when normal mucosal barriers are disrupted.

Key Features

NOT a true fungal infection despite the name "actinomycosis"
Produces characteristic sulfur granules (yellow-white granules visible in drainage) - these are compact colonies of organisms, not true sulfur
Spreads by direct extension across tissue planes, ignoring anatomical boundaries
Causes chronic, indurated, slowly progressive suppurative lesions

Clinical Forms

Form	Site	Trigger
Cervicofacial ("lumpy jaw")	Jaw, neck, face	Dental procedure, trauma, poor dentition (most common form - 50-60%)
Thoracic	Lungs, pleura, chest wall	Aspiration, esophageal disease
Abdominal/Pelvic	Abdomen, IUD-related pelvic disease	Abdominal surgery, trauma, appendicitis, IUD use
CNS	Brain abscess	Hematogenous spread

Diagnosis

Identification of sulfur granules in pus or tissue
Anaerobic culture - slow growth
Histology: branching gram-positive filaments with surrounding neutrophilic microabscesses

Treatment

High-dose penicillin G IV (18-24 million units/day) for 2-6 weeks, then amoxicillin orally
Total duration: 6-12 months (to prevent relapse)
Surgical drainage of large abscesses when required
Alternatives: doxycycline, erythromycin, clindamycin

Chapter 181 - Plague (Yersinia pestis)

(Note: "Peoples disease" in your list refers to Plague - Chapter 181)

Organism Yersinia pestis - gram-negative coccobacillus. Shows bipolar staining ("closed safety pin" appearance) with Wayson or Wright-Giemsa stain. It is a clone derived from Y. pseudotuberculosis within the last 7,000-50,000 years. Two key plasmid acquisitions (pla and ymt) enabled the shift from fecal-oral to arthropod-mammal transmission.

Epidemiology

Zoonosis maintained in wild rodent reservoirs; transmitted to humans via flea bite (primarily Xenopsylla cheopis)
Endemic: sub-Saharan Africa (Democratic Republic of Congo, Madagascar), western USA
USA: 744/913 documented cases were bubonic (82%), 10% septicemic, 8% pneumonic
Pre-antibiotic mortality: 66%; post-antibiotic: 8-16%
Pneumonic plague mortality: 17% (treated) vs. 98% (untreated)

Pathogenesis

Flea ingests blood meal containing bacteria -> Y. pestis multiplies in flea proventriculus -> forms biofilm, blocks blood feeding -> inoculates bacteria at each bite
ymt gene (phospholipase D, on pFra plasmid): required for flea colonization from most hosts
pla gene (plasminogen activator): facilitates systemic spread from inoculation site
Bacteria survive intracellularly in macrophages; temperature shift from 21°C to 37°C upregulates virulence factors (Yops - Yersinia outer proteins that inhibit phagocytosis)

Clinical Manifestations

Form	Features
Bubonic plague	Most common (82%). Sudden fever, chills, headache, 1-10 days after bite. Bubo (extremely tender, enlarged lymph node in groin/axilla/neck) develops within hours-days. Septicemia can follow
Septicemic plague (primary)	No bubo; bacteremia without lymphadenopathy. Fever, hypotension, DIC; may present with purpura ("Black Death" appearance from peripheral gangrene)
Pneumonic plague	Most fatal. Primary: inhalation exposure. Secondary: hematogenous seeding. Presents with fulminant pneumonia; bloody sputum; person-to-person transmission possible
Pharyngeal plague	Rare; from consumption of raw camel/goat meat

Diagnosis

Appropriate samples: bubo aspirate (bubonic), blood (septicemic), BAL/sputum (pneumonic)
Bubo aspiration: inject 1 mL saline, aspirate blood-tinged fluid
Bipolar staining, culture, F1 antigen detection, species-specific PCR
Seroconversion (fourfold rise in anti-F1 antibody in paired sera ≥2 weeks apart)
Y. pestis is a Tier 1 Select Agent - strict biosafety protocols required

Treatment (WHO/CDC 2021 Guidelines)

First-line: Gentamicin (preferred) or streptomycin IM
Alternatives: doxycycline, ciprofloxacin, levofloxacin (fluoroquinolones increasingly recommended by WHO)
Chloramphenicol for plague meningitis (CNS penetration)
Duration: 10-14 days
Post-exposure prophylaxis: doxycycline or TMP-SMX for 7 days
Pneumonic plague requires strict respiratory isolation

Chapter 182 - Infections Due to Mixed Aerobic Organisms

This chapter covers polymicrobial infections involving combinations of aerobic and anaerobic organisms:

Key Conditions

1. Animal & Human Bites

Cat bites: infect >50% of cases (deeper puncture wounds); highest risk of septic arthritis and osteomyelitis
Key organism: Pasteurella multocida (narrow gram-negative coccobacillus, rapid onset <24h)
Dog bites: polymicrobial (Pasteurella, Capnocytophaga, Staphylococcus, anaerobes)
Human bites: Streptococcus, Staphylococcus aureus, Eikenella corrodens, anaerobes
Treatment: amoxicillin-clavulanate (drug of choice for most bites)
Tetanus and rabies prophylaxis to be considered

2. Synergistic Polymicrobial Infections

Infections where mixed flora (aerobes + anaerobes) act synergistically
Examples: Fournier's gangrene (necrotizing fasciitis of perineum), Ludwig's angina, intraabdominal abscesses, diabetic foot infections
Broad-spectrum coverage required; surgical debridement essential

3. Bartonella Infections (Chapter 177 overlap)

Bartonella species: fastidious, facultative intracellular, gram-negative bacteria
40 species; key pathogens: B. henselae (cat-scratch disease, bacillary angiomatosis), B. quintana (trench fever, bacillary angiomatosis), B. bacilliformis (Carrión's disease)
Cause cat-scratch disease, trench fever, Carrión's disease, bacillary angiomatosis (in HIV), peliosis hepatis
Long-term intraerythrocytic and endothelial parasitism; evade immunity by modifying LPS and flagella

SECTION 8: MYCOBACTERIAL DISEASES

Chapter 183 - Tuberculosis

Organism Mycobacterium tuberculosis (MTB) - obligate aerobe, non-spore-forming, non-motile, acid-fast bacillus. Doubling time 15-20 hours (slow). Cell wall: high lipid content (mycolic acids, arabinogalactan, lipoarabinomannan) - responsible for acid-fastness and resistance to desiccation, disinfectants, and many antibiotics.

Epidemiology (2024 data from Harrison's 22E)

Globally: ~10 million new cases/year; 1.5 million deaths/year (2nd leading cause of death from a single infectious agent after COVID-19)
HIV/TB co-infection is especially prevalent in sub-Saharan Africa
Incidence was declining but has increased again in the context of the COVID-19 pandemic
One-quarter of the world's population is estimated to have latent TB infection (LTBI)

Transmission

Airborne - droplet nuclei (<5 μm); can remain suspended in air for hours
Pulmonary TB patients with cavitary disease are most infectious
One infectious case can transmit to 10-20 contacts

Pathogenesis

Inhaled droplet nuclei reach the alveoli -> engulfed by alveolar macrophages
Bacteria survive intracellularly by inhibiting phagosome-lysosome fusion
Granuloma formation: key host defense mechanism (Th1, IFN-γ, TNF-α mediated)
Primary TB: usually asymptomatic; Ghon complex (parenchymal focus + hilar adenopathy)
Latent TB infection (LTBI): bacteria contained but not eliminated
Reactivation TB: 5-10% lifetime risk in immunocompetent; greatly increased in HIV, TNF-α inhibitor use, diabetes, malnutrition

Clinical Forms

Form	Features
Primary TB	Often asymptomatic; Ghon focus, hilar adenopathy; miliary TB in young children
Reactivation/Secondary TB	Upper lobe infiltrates, cavitation, hemoptysis, night sweats, weight loss, fever
Miliary TB	Hematogenous dissemination; "millet seed" CXR pattern; fever, pancytopenia, hepatosplenomegaly
Extrapulmonary TB	Lymphadenitis (most common extrapulmonary form), pleural effusion, pericarditis, meningitis, spine (Pott's disease), genitourinary, peritoneal
TB meningitis	Most severe extrapulmonary form; high mortality; basilar meningitis, cranial nerve palsies

Diagnosis

Sputum AFB smear (ZN stain) - sensitivity 40-60%
Sputum culture (gold standard) - Lowenstein-Jensen medium; 6-8 weeks
GeneXpert MTB/RIF (NAAT): rapid, also detects rifampin resistance; WHO-recommended first-line
TST (tuberculin skin test)/IGRA (interferon-gamma release assay) for LTBI
CXR: infiltrates, cavities, upper lobe predominance; miliary pattern

Treatment - Latent TB Infection (LTBI)

Regimen	Schedule	Duration
Isoniazid + Rifapentine (3HP)	900 mg each, weekly	3 months (DOT)
Rifampin alone	600 mg daily	4 months
Isoniazid + Rifampin	300 mg + 600 mg daily	3 months
Isoniazid alone	300 mg daily or 900 mg twice weekly	6-9 months

(Source: MMWR 2020 - CDC/NTCA Guidelines)

Treatment - Active TB (Drug-Susceptible) Standard regimen: 2 months HRZE + 4 months HR

H = Isoniazid (INH): inhibits mycolic acid synthesis (InhA pathway); hepatotoxic; add pyridoxine
R = Rifampin (RIF): inhibits RNA polymerase (rpoB gene); turns body fluids orange; many drug interactions
Z = Pyrazinamide (PZA): active in acidic pH; useful against intracellular/dormant bacilli; hyperuricemia
E = Ethambutol: inhibits arabinosyl transferase (arabinan synthesis); optic neuritis (monitor visual acuity)

Drug-Resistant TB

MDR-TB: resistant to at least isoniazid AND rifampin
XDR-TB (now "pre-XDR" and "XDR" per 2021 WHO redefinition): additional resistance to fluoroquinolones ± bedaquiline/linezolid
New/repurposed drugs:
- Bedaquiline: inhibits mycobacterial ATP synthase (atpE subunit c); 400 mg/d x 2 weeks, then 200 mg thrice weekly x 6 months; QT prolongation (black box warning); metabolized by CYP3A4 (avoid with rifampin/efavirenz)
- Linezolid (oxazolidinone): inhibits 50S ribosome; ~80% success in MDR-TB when added to individualized regimens; side effects: optic/peripheral neuropathy, pancytopenia, lactic acidosis; weak MAO inhibitor (serotonin syndrome risk)
- Delamanid: inhibits mycolic acid synthesis
- Pretomanid: used in BPaL regimen (Bedaquiline + Pretomanid + Linezolid) for XDR-TB
- Clofazimine: anti-inflammatory; cross-resistance with bedaquiline via MmpS5-MmpL5 efflux pump
- Sutezolid: modified oxazolidinone with higher early bactericidal activity than linezolid

Chapter 184 - Leprosy (Mycobacterium leprae)

Organism M. leprae - cannot be cultured in vitro; can be grown in armadillos and mouse footpads. Obligate intracellular organism with tropism for peripheral nerves (Schwann cells) and skin macrophages. Prefers cooler body areas (skin, peripheral nerves, anterior eye).

Transmission

Via respiratory droplets (nasal secretions from lepromatous patients)
Long incubation period: 2-10 years (can be up to 20 years)
Low infectivity; >95% of exposed individuals are naturally immune

Classification (Ridley-Jopling)

Type	Immunity	Bacteria	Skin Lesions	Nerve
Tuberculoid (TT)	Strong (Th1)	Few (paucibacillary)	1-5 hypopigmented, anesthetic patches	Thickened, damaged
Borderline tuberculoid (BT)	Good	Low	More lesions
Borderline (BB)	Unstable	Moderate	Many lesions
Borderline lepromatous (BL)	Poor	High
Lepromatous (LL)	Poor (Th2)	Many (multibacillary)	Diffuse infiltration, nodules (leonine facies), loss of eyebrows/lashes	Diffuse damage

WHO Classification (Practical)

Paucibacillary: ≤5 skin lesions
Multibacillary: >5 skin lesions

Reactions

Type 1 (Reversal): DTH reaction during treatment; inflammation of skin lesions; treat with prednisolone
Type 2 (ENL - Erythema Nodosum Leprosum): Multibacillary; immune complex deposition; painful red nodules, fever, iritis; treat with thalidomide or prednisolone

Nerve Involvement

Peripheral neuropathy is hallmark; sensory loss precedes motor
Classic affected nerves: ulnar (claw hand), median, radial, common peroneal (foot drop), posterior tibial, facial (lagophthalmos), great auricular, radial cutaneous
Rehabilitation: ISSO routine (Inspect, Soak, Scrape, Oil) for hands and feet

Treatment (WHO MDT)

Paucibacillary: Rifampin 600 mg monthly (supervised) + Dapsone 100 mg/day - 6 months
Multibacillary: Rifampin 600 mg monthly + Clofazimine 300 mg monthly + Dapsone 100 mg/day + Clofazimine 50 mg/day - 12 months

Chapter 185 - Nontuberculous Mycobacterial (NTM) Infections

Overview

180 species identified; most are environmental organisms (soil, water, biofilms)
Exposure is essentially universal but disease is rare - requires specific host susceptibility
Key NTM in North America: M. avium complex (MAC), M. kansasii, M. abscessus complex
In northern Europe: M. xenopi, M. malmoense are prominent
M. ulcerans causes Buruli ulcer (tropical zones, especially West Africa)
M. marinum: cutaneous/tendon infections in coastal regions, fish tank/swimming pool exposures

Host Susceptibility Factors

HIV/AIDS (CD4 <50 cells/μL - risk for disseminated MAC)
TNF-α inhibitors (infliximab, adalimumab, etanercept) - inhibit granuloma formation
Cystic fibrosis/bronchiectasis (3-15% have NTM clinical infection)
Mutations in the IFN-γ/IL-12 synthesis and response pathway
Autoantibodies to IFN-γ

Pathobiology (IL-12/IFN-γ Axis) Macrophages phagocytose mycobacteria -> produce IL-12 (IL-12p70 heterodimer: IL-12p35 + IL-12p40) -> binds IL-12R (IL-12Rβ1 + IL-12Rβ2/IL-23R) -> phosphorylates STAT4 -> IFN-γ secretion -> activates macrophages and neutrophils to kill mycobacteria via reactive oxidants. Mutations at any point in this pathway (IL-12p40, IL-12Rβ1, IFN-γR1/R2, STAT1) cause susceptibility to disseminated NTM.

Clinical Forms

Form	Key Organism	Features
Pulmonary	MAC, M. kansasii, M. abscessus	Chronic cough, nodules, bronchiectasis; Lady Windermere syndrome (right middle lobe + lingula)
Lymphadenitis	MAC, M. scrofulaceum	Children; unilateral cervical adenopathy
Cutaneous	M. marinum, M. ulcerans, M. abscessus	Fish-tank granuloma, Buruli ulcer, post-injection abscesses
Disseminated	MAC (in HIV)	Fever, weight loss, diarrhea, hepatosplenomegaly, anemia; CD4 <50

Diagnosis

Must distinguish active disease from commensal harboring (ATS/IDSA criteria used)
Culture x2 positive sputum samples + compatible clinical and radiologic findings
Speciation by HPLC, PCR probes, or sequencing

Treatment

MAC pulmonary: Clarithromycin/azithromycin + ethambutol + rifamycin (18 months, culture-negative for 12 months)
M. kansasii: Isoniazid + rifampin + ethambutol (12 months)
M. abscessus: Most drug-resistant; amikacin + imipenem/cefoxitin + macrolide

Chapter 186 - Antimycobacterial Agents

Key drug summary (beyond what is covered under TB treatment above):

First-Line Anti-TB Drugs

Drug	Mechanism	Key Toxicity	Notes
Isoniazid (INH)	Inhibits InhA (mycolic acid synthesis); prodrug activated by KatG catalase-peroxidase	Hepatotoxicity, peripheral neuropathy (give pyridoxine), lupus-like syndrome	Resistance: katG or inhA mutations
Rifampin (RIF)	Inhibits β-subunit of DNA-dependent RNA polymerase (rpoB)	Hepatotoxicity, drug interactions (potent CYP450 inducer), turns body fluids orange	Colors secretions red-orange; contraceptive failure
Pyrazinamide (PZA)	Converted to pyrazinoic acid by bacterial pyrazinamidase; disrupts membrane energetics	Hepatotoxicity, hyperuricemia/gout, arthralgia	Active in acidic environment (macrophage phagosome)
Ethambutol (EMB)	Inhibits arabinosyl transferase; blocks arabinogalactan synthesis	Optic neuritis (monitor visual acuity/color vision monthly)	Resistance: embB mutations
Streptomycin	Inhibits 30S ribosome (protein synthesis)	Ototoxicity, nephrotoxicity	Injection only; resistance: rrs mutations

Second-Line & Newer Drugs

Drug	Mechanism	Notes
Bedaquiline	Inhibits mycobacterial F0F1 ATP synthase (atpE subunit c); bactericidal	MDR/XDR-TB; QT prolongation (black box); avoid with rifampin (50% level reduction)
Linezolid	Binds 50S ribosome; inhibits protein synthesis	MDR-TB; 80% success; optic neuropathy, myelosuppression
Delamanid	Inhibits mycolic acid synthesis (different from INH pathway)	MDR-TB in children and adults
Clofazimine	Anti-inflammatory; disrupts mycobacterial membrane	MDR-TB, also leprosy; cross-resistance with bedaquiline via efflux pump
Fluoroquinolones (levofloxacin, moxifloxacin)	Inhibit DNA gyrase (topoisomerase II and IV)	Backbone of MDR-TB treatment regimens

SECTION 9: SPIROCHETAL DISEASES

Chapter 187 - Syphilis (Treponema pallidum)

Organism Treponema pallidum subsp. pallidum - thin, tightly coiled spirochete; cannot be cultured in vitro (obligate intracellular); too thin to be seen on Gram stain (visualized by darkfield microscopy).

Transmission

Sexual contact (most common)
Vertical (congenital syphilis)
Blood transfusion (rare)

Stages & Clinical Features

Stage	Timing	Features
Primary	10-90 days after exposure	Single, painless, indurated chancre at inoculation site; heals in 3-6 weeks without treatment; regional lymphadenopathy
Secondary	2-8 weeks after chancre	Disseminated disease: maculopapular rash on palms and soles (pathognomonic), condylomata lata, mucous patches, generalized lymphadenopathy, fever, malaise; highly infectious
Latent	After secondary resolves	No symptoms; early latent (<1 year), late latent (>1 year); not infectious (except vertically)
Tertiary	Years after initial infection	Cardiovascular syphilis (aortitis, aortic regurgitation), gummatous syphilis, neurosyphilis
Neurosyphilis	Any stage	Meningitis, meningovascular disease, general paresis, tabes dorsalis; can occur early or late

Congenital Syphilis

Hutchinson's triad: Hutchinson's teeth (notched incisors), interstitial keratitis, sensorineural deafness
Saddle nose, saber shins, rhagades

Diagnosis

Primary: darkfield microscopy (chancre scraping)
Nontreponemal tests (screening): RPR, VDRL - titres correlate with disease activity
Treponemal tests (confirmatory): FTA-ABS, TPPA, TPHA - remain positive for life after treatment
Reverse sequence screening now used: treponemal test first (EIA/CIA), then nontreponemal

Treatment

Primary, secondary, early latent: Benzathine penicillin G 2.4 million units IM single dose
Late latent, cardiovascular: Benzathine penicillin G 2.4 MU IM weekly x 3 doses
Neurosyphilis: Aqueous penicillin G 18-24 million units/day IV x 10-14 days
Penicillin allergy (non-pregnant): Doxycycline 100 mg BID x 14 days
Jarisch-Herxheimer reaction: fever, chills, myalgia within 24h of first penicillin dose; treat with antipyretics; not a reason to stop therapy

Chapter 188 - Endemic Treponematoses (Haematosis/Yaws, Bejel, Pinta)

These non-venereal treponematoses are caused by T. pallidum subspecies/variants:

Disease	Organism	Transmission	Geography	Primary Lesion	Key Features
Yaws	T. pallidum subsp. pertenue	Skin contact (not sexual)	Tropical (Africa, Americas, Pacific)	Papilloma (mother yaw) - raspberry-like on leg	Bone involvement (osteitis); gangosa (destroyed nose/palate)
Bejel (Endemic syphilis)	T. pallidum subsp. endemicum	Contact with mucous membranes	Arid regions (Africa, Middle East)	Oropharyngeal mucous patches	Bone involvement; no cardiovascular/neurological disease
Pinta	T. carateum	Skin contact	Central/South America	Red papule (pintid)	Skin only (dyschromia - hyperchromia then achromia); no systemic involvement

Treatment: Single dose benzathine penicillin; azithromycin as alternative (WHO mass treatment campaigns)

Chapter 189 - Leptospirosis

Organism Leptospira interrogans - thin, tightly coiled spirochete with characteristic hooked ends ("shepherd's crook"); aerobic; >300 serovars.

Transmission

Zoonosis; reservoir: rodents (especially rats), dogs, cattle, pigs
Transmission: contact with infected animal urine-contaminated water/soil through skin abrasions or mucous membranes
Occupational: farmers, sewer workers, veterinarians
Recreational: water sports (swimming, white-water rafting)
Weil's syndrome is the most severe form

Clinical Features Two-phase illness (classic, though often not clearly distinct):

Phase 1 - Leptospiremic (days 1-7)

Abrupt fever, severe headache, myalgia (especially calves), conjunctival suffusion (redness without exudate - pathognomonic), nausea, vomiting
Bacteria present in blood and CSF

Phase 2 - Immune Phase (days 7-14)

Antibodies develop; bacteria disappear from blood
Most patients recover
Severe form (Weil's disease): hepatorenal failure
- Jaundice + acute renal failure + hemorrhage + cardiovascular collapse
- Thrombocytopenia, coagulopathy
- Pulmonary hemorrhage syndrome (severe pulmonary hemorrhage - high mortality)
- Uveitis can occur late (post-illness)

Diagnosis

Culture: Fletcher's or EMJH medium; blood/CSF in first week, urine in second week
Serology: MAT (microscopic agglutination test) - gold standard; need paired sera (4-fold rise)
PCR in acute phase
CBC: leukocytosis, thrombocytopenia; LFTs elevated

Treatment

Mild: Doxycycline 100 mg BID x 7 days
Severe: IV Penicillin G (1.5 million units IV q6h) or IV ceftriaxone
Prophylaxis: doxycycline 200 mg once weekly for occupational/recreational exposure

Chapter 190 - Relapsing Fever (Borrelia species)

Types

Type	Organism	Vector	Distribution
Louse-borne (LBRF)	Borrelia recurrentis	Body louse (Pediculus humanus)	Africa (Ethiopia), displaced populations
Tick-borne (TBRF)	Multiple Borrelia spp. (e.g., B. hermsii)	Soft ticks (Ornithodoros spp.)	Worldwide (western USA, Africa, Europe, Asia)

Pathogenesis

Borrelia undergoes antigenic variation (VMP - variable major proteins): explains the relapsing nature of the fever
Each febrile episode corresponds to a new antigenic variant that escapes prior immunity; resolved when antibodies catch up, then re-emerges with new antigenic variant

Clinical Features

Abrupt onset: high fever, chills, severe headache, myalgia, arthralgia, hepatosplenomegaly
Fever lasts 3-7 days, then spontaneously resolves (crisis: severe rigor/chill followed by drenching sweat)
After 5-10 afebrile days, relapse occurs (LBRF: 1-2 relapses; TBRF: 3-10 relapses)
Jarisch-Herxheimer reaction is common (and can be severe) after treatment in LBRF

Diagnosis

Blood smear during febrile episode: spirochetes visible on Giemsa or Wright stain (spirochetemia)

Treatment

LBRF: single dose doxycycline 100 mg or tetracycline (or erythromycin if pregnant)
TBRF: doxycycline 100 mg BID x 7-10 days; tetracycline alternatives

Chapter 191 - Lyme Disease (Borrelia burgdorferi)

Organism & Transmission

Borrelia burgdorferi (in USA), B. afzelii and B. garinii (in Europe/Asia)
Tick vector: Ixodes scapularis (black-legged/deer tick) in eastern USA; I. pacificus in western USA; I. ricinus in Europe
Tick must be attached for >36-48 hours for transmission
Primary reservoir: white-footed mouse (Peromyscus leucopus)

Stages of Lyme Disease

Stage	Timing	Features
Stage 1 (Early Localized)	3-30 days	Erythema migrans (EM): pathognomonic expanding "bull's-eye" rash at bite site; may have flu-like symptoms; >90% sensitive for diagnosis
Stage 2 (Early Disseminated)	Weeks to months	Multiple secondary EM; neurological (Lyme neuroborreliosis: facial palsy, meningitis, radiculopathy - "Bannwarth's syndrome" in Europe); cardiac (AV block - most common manifestation, temporary pacemaker may be needed)
Stage 3 (Late)	Months to years	Lyme arthritis (oligoarticular, large joints, especially knee); chronic neurological disease (encephalopathy, peripheral neuropathy)

Post-Treatment Lyme Disease Syndrome (PTLDS)

Persistent fatigue, pain, cognitive symptoms >6 months after treatment
Not a persistent infection; prolonged antibiotics not recommended

Diagnosis

Clinical (EM rash alone sufficient)
Two-tier serology: ELISA (screening) then Western blot (confirmatory) - may be negative in early stage
PCR: useful for synovial fluid in Lyme arthritis
CSF analysis in neurological Lyme

Treatment

Early localized/disseminated: Doxycycline 100 mg BID x 14-21 days (first-line; also treats other tick-borne co-infections)
Lyme arthritis: Doxycycline or amoxicillin x 28 days; IV ceftriaxone if fails
Cardiac/neurological Lyme: IV ceftriaxone 2g/day x 14-28 days
Children <8 years: amoxicillin (avoid doxycycline)

SECTION 10: DISEASES CAUSED BY RICKETTSIAE, MYCOPLASMA, AND CHLAMYDIA

Chapter 192 - Rickettsial Diseases

Overview Rickettsiae are obligate intracellular, gram-negative bacteria transmitted by arthropod vectors. They cannot be grown on standard media.

Key Rickettsial Diseases

Disease	Organism	Vector	Geographic Distribution	Key Features
Rocky Mountain Spotted Fever (RMSF)	Rickettsia rickettsii	Dog tick (Dermacentor)	USA (Southeast, South Central)	Petechial rash starts peripherally (wrists/ankles), spreads centrally; involves palms/soles; high mortality if untreated
Epidemic typhus	Rickettsia prowazekii	Body louse	Overcrowded, poor hygiene conditions	Maculopapular rash starting on trunk; Brill-Zinsser disease = recurrence
Endemic (murine) typhus	Rickettsia typhi	Rat flea	Worldwide	Milder than epidemic typhus; rat exposure
Scrub typhus	Orientia tsutsugamushi	Trombiculid mite (chigger)	Asia-Pacific ("Tsutsugamushi triangle")	Eschar at bite site; rash; lymphadenopathy; can cause CNS involvement
Rickettsialpox	Rickettsia akari	Mouse mite	USA (urban), Eastern Europe	Vesicular rash (pox-like); eschar; self-limited
Q Fever	Coxiella burnetii	Inhalation (not arthropod bite)	Worldwide	Sheep/cattle/goats; acute: atypical pneumonia/hepatitis; chronic: culture-negative endocarditis
Human monocytic ehrlichiosis	Ehrlichia chaffeensis	Lone Star tick	Eastern USA	Leukopenia, thrombocytopenia; morulae in monocytes
Human granulocytic anaplasmosis	Anaplasma phagocytophilum	Ixodes tick	Northern USA, Europe	Leukopenia, thrombocytopenia; morulae in granulocytes; often co-transmitted with Lyme

Key Points

RMSF triad: fever + headache + rash (rash may be absent initially - do not wait for rash to treat)
Eschar (tache noire) = painless black necrotic ulcer at bite site - seen in scrub typhus, some spotted fever group rickettsiae
Lab: thrombocytopenia, elevated LFTs, hyponatremia common
Weil-Felix reaction (historical agglutination test with Proteus) - replaced by specific serology
IFA (indirect immunofluorescence) is gold standard serology

Treatment

Doxycycline is the drug of choice for ALL rickettsial diseases, including in children
- Adults: 100 mg BID x 7-14 days (minimum 3 days after fever resolves)
- Children: benefits outweigh risks of dental staining for life-threatening illness
Alternatives: chloramphenicol (limited availability), azithromycin for some
Delay in treatment = major cause of death

Chapter 193 - Mycoplasma Infections

Organism Mycoplasmas are the smallest self-replicating bacteria; lack a cell wall (therefore resistant to beta-lactam antibiotics and not visible on Gram stain). Key human pathogens: Mycoplasma pneumoniae, M. hominis, M. genitalium, Ureaplasma urealyticum.

M. pneumoniae - Atypical Pneumonia

Incubation: 2-3 weeks
Most common cause of community-acquired pneumonia (CAP) in young adults (5-35 years)
Spreads via respiratory droplets; closed communities (schools, military barracks)

Clinical Features

Gradual onset (vs. abrupt in typical pneumonia)
Prominent: dry, nonproductive cough; headache; malaise; sore throat
Low-grade fever; minimal physical findings (classic "walking pneumonia")
CXR: patchy interstitial infiltrate out of proportion to clinical findings
Extrapulmonary manifestations: Stevens-Johnson syndrome, autoimmune hemolytic anemia (cold agglutinins - anti-i antibodies), myocarditis, pericarditis, encephalitis, transverse myelitis, polyarthritis, erythema multiforme, bullous myringitis

Diagnosis

Cold agglutinins: present in 50-75% of M. pneumoniae pneumonia cases (but not specific)
Serology: IgM antibodies (paired sera 4-fold rise)
PCR of nasopharyngeal swab: most sensitive and specific
Culture: possible but very slow and impractical

Treatment

Macrolides: azithromycin (drug of choice - 5-day course)
Alternatives: doxycycline, fluoroquinolones (levofloxacin, moxifloxacin)
Beta-lactams and glycopeptides are INEFFECTIVE (no cell wall target)
Duration: 5-14 days depending on severity

M. genitalium

Emerging pathogen; causes urethritis, cervicitis, PID
Rising resistance to azithromycin; moxifloxacin used for resistant cases
Treatment: doxycycline + azithromycin or moxifloxacin

Chapter 194 - Chlamydial Infections (Legionella - "loml disease" = Legionella)

Note: Your list says "loml disease" for Chapter 194, which corresponds to Legionella infections in Harrison's. Chlamydia is covered in Chapter 194 in some editions.

Chlamydial Infections

Chlamydia are obligate intracellular bacteria with a unique biphasic life cycle:

Elementary body (EB): extracellular, infectious, metabolically inactive; binds to host cell
Reticulate body (RB): intracellular, replicating, metabolically active; non-infectious

Key Chlamydial Pathogens

Species	Serovars	Disease
C. trachomatis	D-K	Urethritis, cervicitis, PID, epididymitis; neonatal conjunctivitis and pneumonia
C. trachomatis	A, B, Ba, C	Trachoma (leading cause of preventable blindness worldwide)
C. trachomatis	L1-L3	Lymphogranuloma venereum (LGV) - inguinal buboes, rectal strictures
C. pneumoniae	-	Atypical pneumonia, pharyngitis, bronchitis (TWAR strain)
C. psittaci	-	Psittacosis/ornithosis - from birds; atypical pneumonia, hepatitis, endocarditis

Trachoma: Repeated infection -> conjunctival scarring -> entropion -> trichiasis -> corneal abrasion -> blindness (WHO SAFE strategy: Surgery, Antibiotics, Facial cleanliness, Environmental improvement)

Treatment

Urogenital chlamydia: Doxycycline 100 mg BID x 7 days or azithromycin 1 g single dose
LGV: Doxycycline 100 mg BID x 21 days
Trachoma: azithromycin 1 g single dose or tetracycline eye ointment
Psittacosis: doxycycline 100 mg BID x 14+ days

Legionella pneumophila (Chapter 194 in some Harrison's editions)

Gram-negative intracellular rod; grows on BCYE (buffered charcoal yeast extract) agar
Source: water systems (cooling towers, hospital water, showers, hot tubs)
Two forms:
- Legionnaires' disease: severe pneumonia with relative bradycardia, confusion, hyponatremia, high LDH, diarrhea; Pontiac fever (milder, non-pneumonic form)
- Diagnosis: urinary antigen (Lp serogroup 1 - most cases); culture on BCYE; PCR
Treatment: Fluoroquinolones (levofloxacin, moxifloxacin) - first choice; macrolides; rifampin as adjunct
NOT treated with beta-lactams (intracellular organism)

SECTION 11: VIRAL DISEASES - GENERAL CONSIDERATIONS

Chapter 195 - Principles of Medical Virology

Classification of Viruses

Not formally placed in any kingdom; classified by ICTV into realms, orders, families, genera, species
Classification criteria: type of nucleic acid (RNA/DNA), strand polarity (ss+, ss-, ds), capsid symmetry (icosahedral, helical, complex), envelope presence, replication mode, tropism
Genome sequencing has refined traditional classifications

Key Viral Families of Medical Importance

Genome	Family	Examples
dsDNA	Herpesviridae	HSV-1/2, VZV, CMV, EBV, HHV-6/7/8
dsDNA	Adenoviridae	Adenoviruses
dsDNA	Poxviridae	Smallpox, monkeypox, vaccinia
ssDNA	Parvoviridae	B19 parvovirus
ssRNA (+)	Picornaviridae	Poliovirus, HAV, rhinovirus, enteroviruses
ssRNA (+)	Flaviviridae	Dengue, Zika, WNV, HCV, Yellow fever
ssRNA (+)	Togaviridae	Rubella, chikungunya
ssRNA (+)	Coronaviridae	SARS-CoV-2, MERS-CoV
ssRNA (-)	Orthomyxoviridae	Influenza A, B, C
ssRNA (-)	Paramyxoviridae	Measles, mumps, RSV, parainfluenza, hMPV
ssRNA (-)	Rhabdoviridae	Rabies
ssRNA (-)	Filoviridae	Ebola, Marburg
dsRNA	Reoviridae	Rotavirus, Reovirus
ssRNA-RT	Retroviridae	HIV, HTLV
dsDNA-RT	Hepadnaviridae	HBV

Viral Replication Cycle Steps: Attachment -> Entry -> Uncoating -> Transcription -> Translation -> Replication -> Assembly -> Egress

1. Attachment

Virus binds specific receptors on host cell surface (viral tropism is determined here)
Example: HIV binds CD4 + CCR5/CXCR4; influenza binds sialic acid; adenovirus binds CAR

2. Entry (3 Pathways)

Fusion with plasma membrane (enveloped viruses - e.g., HIV)
Endocytosis followed by endosomal membrane fusion (influenza - acidification triggers HA conformational change)
Endosomal lysis or pore formation

3. Replication Strategies by Genome Type

Genome Type	Strategy	Examples
ssRNA (+)	Direct translation as mRNA; polyprotein cleavage	Picornaviruses, flaviviruses, coronaviruses
ssRNA (-)	Must first transcribe RNA to (+) mRNA using packaged RNA-dependent RNA polymerase	Influenza, RSV, rabies
dsRNA	Transcribed to (+) mRNA by packaged polymerase inside particles	Rotavirus, reovirus
dsDNA (nuclear)	Transcription in nucleus using host RNA polymerase	Herpesviruses, adenoviruses
Retroviruses (ssRNA-RT)	Reverse transcriptase converts RNA -> DNA -> integrates as provirus	HIV, HTLV
Hepadnaviruses (dsDNA-RT)	Partially dsDNA; replicates via RNA intermediate (pregenomic RNA)	HBV

Host Immune Responses to Viral Infection

Innate Immunity (First Line - Rapid) Pattern recognition receptors (PRRs) detect PAMPs:

TLR7/TLR8: recognize viral ssRNA -> Type I IFN induction
TLR3: recognizes dsRNA -> Type I IFN
RIG-I / MDA5 (cytoplasmic): recognize ssRNA/dsRNA -> Type I IFN
TLR2/TLR4: recognize viral glycoproteins
cGAS (cytoplasmic): recognizes viral DNA -> activates STING -> Type I IFN
IFI16 (nuclear): recognizes viral DNA -> IFN expression or epigenetic silencing

IFNs act autocrine and paracrine to induce antiviral ISGs (IFN-stimulated genes).

Adaptive Immunity (Specific - Slower but More Targeted)

CD4+ T cells (Th): help B cells produce neutralizing antibodies; activate CD8+ cells
CD8+ T cells (CTL): kill infected cells presenting viral peptides on MHC I
Antibodies: neutralize virions (prevent receptor binding, block entry); promote ADCC, phagocytosis, complement lysis
Memory T and B cells provide long-term protection

Viral Evolution

RNA viruses: error-prone RNA-dependent RNA polymerases (no editing) -> high mutation rates -> quasispecies
Antigenic drift: gradual point mutations (drives annual influenza vaccine updates)
Antigenic shift: reassortment of segmented genomes (influenza pandemics)
Drug resistance: emerges via selection of preexisting variants

Long-Term Effects / Post-Acute Infection Syndromes (PAIS)

Long COVID (SARS-CoV-2), post-EBV fatigue, post-dengue syndrome, post-polio syndrome
Mechanisms: (1) persistent viral replication/antigens; (2) autoimmune activation; (3) alterations in microbiome/endogenous viruses; (4) irreparable tissue damage

Viral Pathogenesis Mechanisms

Cytopathic effect: direct cell killing by viral replication
Immune-mediated: immunopathology (hepatitis B, dengue hemorrhagic fever)
Transformation: oncogenesis (HPV, EBV, HHV-8, HTLV-1)
Immune evasion: latency (herpesviruses), downregulation of MHC I (CMV), antigenic variation (influenza, HIV)

Chapter 196 - Antiviral Chemotherapy (Excluding Antiretrovirals)

Antiherpesvirus Drugs

Drug	Mechanism	Spectrum	Key Notes
Acyclovir	Nucleoside analogue; activated by viral thymidine kinase (TK) -> inhibits viral DNA polymerase	HSV-1/2, VZV	IV for severe HSV/VZV; oral for genital herpes suppression; nephrotoxicity with IV (hydrate well)
Valacyclovir	Oral prodrug of acyclovir; higher bioavailability	HSV-1/2, VZV	Preferred oral formulation for HSV/VZV
Famciclovir	Prodrug of penciclovir	HSV-1/2, VZV	Used for genital herpes and zoster
Ganciclovir	Activated by CMV UL97 kinase -> inhibits DNA polymerase	CMV	IV for CMV retinitis, colitis, pneumonitis; bone marrow suppression (neutropenia, thrombocytopenia)
Valganciclovir	Oral prodrug of ganciclovir	CMV	CMV prophylaxis in transplants; same side effects as ganciclovir
Foscarnet	Directly inhibits viral DNA polymerase at pyrophosphate binding site (does NOT require activation by TK)	CMV, HSV, VZV, HHV-6	IV only; used for TK-deficient acyclovir-resistant HSV; nephrotoxicity, electrolyte imbalances
Cidofovir	Nucleotide analogue; activated independently (no viral kinase needed)	CMV, HSV, adenovirus, poxviruses	IV; severe nephrotoxicity (give with probenecid and IV saline)
Letermovir	CMV terminase complex inhibitor (UL56 subunit)	CMV only	Prophylaxis in CMV-seropositive allogeneic HSCT recipients; no bone marrow toxicity
Maribavir	CMV UL97 kinase inhibitor	CMV	Treatment of refractory/resistant CMV in transplant patients

Anti-Influenza Drugs

Drug	Mechanism	Notes
Oseltamivir (oral)	Neuraminidase inhibitor	Treatment (within 48h) and prophylaxis of influenza A and B; nausea, vomiting; resistance via neuraminidase or HA mutations; 15% resistance in children
Zanamivir (inhaled)	Neuraminidase inhibitor	Treatment and prophylaxis; can cause bronchospasm - avoid in asthma/COPD; 10 mg BID x 5 days
Peramivir (IV)	Neuraminidase inhibitor	Single IV dose 600 mg; for hospitalized or unable to take oral
Baloxavir (oral)	PA endonuclease inhibitor (inhibits cap-snatching RNA transcription)	Single dose (40 mg or 80 mg if >80 kg); active against neuraminidase inhibitor-resistant strains
Amantadine / Rimantadine	M2 ion channel blockers	Most circulating influenza A strains are resistant - use ONLY if known susceptible

Anti-RSV / Respiratory Drugs

Drug	Use	Notes
Ribavirin (inhaled)	RSV bronchiolitis	Nucleoside analogue; broad spectrum; teratogenic; inhaled form for severe RSV in premature infants
Nirsevimab	RSV prevention in infants/young children	Extended half-life anti-RSV monoclonal antibody (F-protein target); single IM injection; replaced palivizumab as first choice
Palivizumab	RSV prevention (high-risk infants)	Anti-RSV monoclonal antibody; monthly injections during RSV season

Anti-Hepatitis Drugs (Non-ARV)

Drug	Target	Notes
Interferon-α (pegylated)	Immunomodulatory + antiviral	Used for HBV and HCV (prior to DAAs); subcutaneous injection; flu-like side effects, depression, cytopenias
Tenofovir, Entecavir, Adefovir, Lamivudine, Telbivudine	HBV DNA polymerase (reverse transcriptase)	For chronic HBV; tenofovir and entecavir are preferred (high barrier to resistance)
Direct-Acting Antivirals (DAAs) for HCV:
- Protease inhibitors (suffix -previr)	NS3/4A protease	Glecaprevir, grazoprevir, voxilaprevir
- Polymerase inhibitors (suffix -buvir)	NS5B RdRp	Sofosbuvir
- NS5A inhibitors (suffix -asvir)	NS5A replication complex	Ledipasvir, velpatasvir, pibrentasvir
Combination regimens		Sofosbuvir/ledipasvir (Harvoni); Sofosbuvir/velpatasvir (Epclusa); Glecaprevir/pibrentasvir (Mavyret) - >95% SVR rates; 8-12 week courses

Early-Generation/Historical Antivirals

Idoxuridine: topical for HSV keratitis (corneal ulcers) - first antiviral approved
Trifluridine: topical for HSV keratitis; more potent than idoxuridine
Vidarabine (Ara-A): IV for HSV encephalitis (replaced by acyclovir)
Methisazone: prophylaxis against poxviruses (largely historical)

KEY COMPARATIVE SUMMARY TABLE

Disease	Key Organism	Unique Feature	Drug of Choice
Nocardia	Nocardia spp.	Weakly acid-fast; brain abscess in 1/3	TMP-SMX
Actinomycosis	Actinomyces israelii	Sulfur granules; crosses tissue planes	Penicillin G (long course)
Plague	Y. pestis	Bipolar "safety pin" staining; bubo	Gentamicin or streptomycin
TB	M. tuberculosis	Acid-fast; Ghon complex	HRZE x 2 months + HR x 4 months
Leprosy	M. leprae	Cannot culture; nerve tropism	Rifampin + Dapsone (± Clofazimine)
NTM	M. avium complex etc.	IL-12/IFN-γ axis defects	Macrolide + ethambutol + rifamycin
Syphilis	T. pallidum	Darkfield microscopy; Jarisch-Herxheimer	Benzathine penicillin G
Leptospirosis	L. interrogans	Conjunctival suffusion; Weil's disease	Penicillin G (IV) or doxycycline
Relapsing fever	Borrelia spp.	Antigenic variation; spirochetemia on smear	Doxycycline
Lyme disease	B. burgdorferi	Bull's-eye rash; AV block; arthritis	Doxycycline
RMSF	R. rickettsii	Rash spreads from periphery to center	Doxycycline
Mycoplasma	M. pneumoniae	No cell wall; cold agglutinins	Azithromycin
Chlamydia	C. trachomatis	EB/RB life cycle; no cell wall	Doxycycline or azithromycin
Legionella	L. pneumophila	BCYE agar; urinary antigen; hyponatremia	Levofloxacin
Influenza	Influenza A/B	Neuraminidase inhibition	Oseltamivir
HSV/VZV	Herpesviruses	Viral TK activation required	Acyclovir/Valacyclovir
CMV	Cytomegalovirus	UL97 kinase activation	Ganciclovir/Valganciclovir

All content drawn from Harrison's Principles of Internal Medicine, 22nd Edition (McGraw Hill, 2025) - Sections 7-11, Chapters 179-196.

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