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HARRISON'S 22E - SECTION 6: DISEASES CAUSED BY GRAM-NEGATIVE BACTERIA

Complete Study Guide

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CHAPTER 160 - MENINGOCOCCAL INFECTIONS

Organism

• Gram-negative aerobic diplococcus, humans are the only host
• Catalase- and oxidase-positive; utilizes glucose and maltose (key: does NOT use lactose, unlike gonococci which uses only glucose)
• Capsule determines serogroup - 12 serogroups total; A, B, C, X, Y, W cause most invasive disease
• Group B capsule = α-2,8-N-acetylneuraminic acid (mimics human neural tissue - poor immunogen)
• Group A = major cause of epidemic disease in sub-Saharan Africa (Meningitis Belt)
• Group W = outbreaks at mass gatherings (Hajj pilgrimage)

Epidemiology

• Colonizes nasopharynx asymptomatically in 5-10% of healthy adults (up to 25% in outbreaks)
• Invasive disease rate: ~0.3-3 per 100,000; highest in infants, adolescents, young adults
• Spread by respiratory droplets and direct contact
• Risk factors: complement deficiencies (especially terminal complement C5-C9), asplenia, properdin deficiency, crowded living (military recruits, college dorms), active/passive smoking
• Adolescents/young adults: important reservoir and vaccine target group

Pathogenesis

• Colonization → nasopharyngeal attachment via pili → mucosal invasion → bacteremia → seeding meninges
• Lipooligosaccharide (LOS) = major virulence factor; triggers cytokine storm
• Factor H binding protein allows immune evasion
• Meningococcemia: bacteria replicate in blood, LOS triggers TNF-α, IL-1, IL-6 → DIC, capillary leak → septic shock

Clinical Manifestations

1. Meningococcal Meningitis

• Most common presentation of invasive disease
• Fever, headache, neck stiffness, photophobia, vomiting
• Kernig's and Brudzinski's signs
• Petechial/purpuric rash in 50-80% (pathognomonic when present)

2. Meningococcemia (Septicemia)

• Fever, rigors, myalgia, malaise
• Petechial rash - initially blanching; progresses to non-blanching purpura (purpura fulminans)
• Rapidly evolving to hypotension, DIC, multiorgan failure
• Waterhouse-Friderichsen syndrome = bilateral adrenal hemorrhage → adrenal insufficiency

3. Other Presentations

• Occult bacteremia (especially young children)
• Pneumonia (serogroup Y associated)
• Septic arthritis
• Conjunctivitis
• Chronic meningococcemia (rare) - intermittent fever, rash, arthritis for weeks

Diagnosis

• Blood cultures (positive in ~75% of untreated cases)
• CSF - turbid, elevated WBC (neutrophils), elevated protein, low glucose; Gram stain shows gram-negative diplococci; culture; PCR
• Do NOT delay antibiotics for LP if raised ICP suspected
• Serum meningococcal PCR useful even after antibiotics started

Treatment

• Immediate IV penicillin G or ceftriaxone (third-generation cephalosporins are first-line)
• Adults: ceftriaxone 2g IV q12h
• Duration: 7 days for uncomplicated meningococcal meningitis
• Supportive: IV fluids, vasopressors for shock, FFP/platelets for DIC
• Dexamethasone 0.15 mg/kg q6h x4 days (reduces hearing loss and neurologic sequelae in meningitis)
• Rifampicin for close contacts (chemoprophylaxis): 600mg BD x2 days; alternatives = ciprofloxacin single dose or ceftriaxone single IM dose

Vaccines

• MenACWY conjugate vaccines - for all adolescents (US: 11-12 years, booster at 16)
• MenB vaccines (Bexsero, Trumenba) - for high-risk groups (complement deficiency, asplenia, outbreaks)
• MenACWY required for Hajj pilgrims
• MenAfriVac (Group A conjugate) - dramatically reduced Group A disease in the Meningitis Belt

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CHAPTER 161 - HAEMOPHILUS AND MORAXELLA INFECTIONS

Haemophilus influenzae

Organism

• Gram-negative coccobacillus; requires factor X (hemin) and factor V (NAD) for growth
• Grows on chocolate agar (heated blood agar releases both factors)
• 6 capsular types (a-f); type b (Hib) = most virulent
• Nontypeable H. influenzae (NTHi) = no capsule = major cause of mucosal infections

Diseases

Diagnosis

• Gram-negative coccobacilli in CSF = strong evidence for Hib meningitis
• Blood cultures, CSF culture, PCR
• NTHi: gram-negative coccobacilli predominating with PMNs in sputum Gram stain

Treatment

• Hib meningitis: ceftriaxone (75-100 mg/kg/day in 2 doses) or cefotaxime
• Adults: ceftriaxone 2g q12h or cefotaxime 2g q4-6h
• Add dexamethasone (0.6 mg/kg/day in 4 doses x2 days) for children >2 months with Hib meningitis
• Epiglottitis: airway management is CRITICAL + ceftriaxone 50 mg/kg/day
• Rifampicin chemoprophylaxis for household contacts

Vaccine

• Hib conjugate vaccine = dramatic reduction in Hib invasive disease (routine childhood immunization)
• Does NOT protect against NTHi

Haemophilus ducreyi

• Causes chancroid - painful genital ulcer with painful inguinal lymphadenopathy (bubo)
• Soft, undermined edges (vs hard, painless chancre of syphilis)
• STI, common in developing countries, co-factor for HIV transmission
• Treatment: azithromycin 1g single dose, or ceftriaxone 250mg single IM dose, or ciprofloxacin

Moraxella catarrhalis

• Gram-negative diplococcus (resembles Neisseria)
• Causes otitis media in children, sinusitis, exacerbations of COPD (pneumonia in elderly)
• Nearly all strains are beta-lactamase positive - resistant to ampicillin
• Treatment: amoxicillin-clavulanate, second/third-gen cephalosporins, or trimethoprim-sulfamethoxazole

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CHAPTER 162/163 - HACEK GROUP AND OTHER FASTIDIOUS GRAM-NEGATIVES

HACEK Organisms

• Fastidious gram-negatives, part of normal oral/upper respiratory flora
• Classically associated with subacute bacterial endocarditis (SBE) - especially in patients with structural heart disease or poor dental hygiene
• Blood cultures may require prolonged incubation (now usually detected by standard BACTEC systems within 5 days)
• Treatment: ceftriaxone 2g/day x4 weeks (preferred); ampicillin-sulbactam is an alternative

Individual HACEK Members

• Aggregibacter aphrophilus: periodontitis, endocarditis, brain abscess
• Cardiobacterium hominis: endocarditis (mostly aortic/mitral valves)
• Eikenella corrodens: human bite wounds, periodontal abscess, neck infections, endocarditis - resistant to clindamycin and metronidazole
• Kingella kingae: children <4 years - septic arthritis, osteomyelitis, bacteremia; occupies respiratory tract

Other Miscellaneous Gram-Negatives

• Capnocytophaga canimorsus: dog and cat bites → severe sepsis (especially in asplenic patients), DIC, gangrene; treatment: penicillin or amoxicillin-clavulanate
• Chromobacterium violaceum: freshwater/soil → skin/soft tissue infections; produces violet pigment; treatment: fluoroquinolones or carbapenems
• Pasteurella multocida: animal bites (especially cats > dogs) → rapidly progressing cellulitis; treatment: amoxicillin-clavulanate

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CHAPTER 165 - PERTUSSIS AND OTHER BORDETELLA INFECTIONS

Organism

• Gram-negative pleomorphic aerobic bacillus
• B. pertussis - humans only; B. parapertussis - milder illness; B. bronchiseptica - animals (kennel cough in dogs)
• Slow-growing, fastidious; grows on Bordet-Gengou agar (selective)
• Key virulence factor: pertussis toxin (PT) - ADP-ribosylates G proteins; also filamentous hemagglutinin (FHA), adenylate cyclase toxin

Clinical Stages

1. Catarrhal stage (1-2 weeks): rhinorrhea, mild cough, low fever - most infectious stage
2. Paroxysmal stage (2-6 weeks): paroxysmal coughing bursts followed by inspiratory whoop; post-tussive vomiting; apnea in infants; leukocytosis (lymphocytosis)
3. Convalescent stage (weeks to months): gradual improvement - the "100-day cough"

Diagnosis

• Nasopharyngeal PCR = most sensitive (gold standard now)
• Culture on Bordet-Gengou agar - takes 5-7 days, lower sensitivity
• Serology (anti-PT IgG) useful >3 weeks into illness
• Lymphocytosis on CBC (counts can exceed 50,000-100,000/μL in infants)

Treatment

• Macrolides are first-line (reduce duration and transmission if given early)
  • Azithromycin 10mg/kg/day x5 days (preferred for infants and children)
  • Clarithromycin or erythromycin alternatives
• TMP-SMX if macrolide intolerant
• Antibiotics in paroxysmal stage: do NOT shorten illness but prevent spread

Vaccine

• DTaP (diphtheria, tetanus, acellular pertussis) - routine childhood series
• Tdap booster for adolescents and adults; every pregnancy (3rd trimester)
• Acellular vaccine replaced whole-cell vaccine (lower side effects; immunity wanes faster)

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CHAPTER 168 - HELICOBACTER PYLORI INFECTIONS

Organism

• Gram-negative spiral bacillus; flagellated (motile in gastric mucus)
• Microaerophilic; produces abundant urease (key virulence factor - neutralizes stomach acid)
• Lives in gastric mucus layer; mucosal (not systemic) distribution

Epidemiology

• Colonizes ~40% of world's population; essentially lifelong unless eradicated
• Prevalence: <30% in US/Europe/Oceania vs >60% in Africa, South America, West Asia
• US: ~18% adults, ~14% children; prevalence declining with socioeconomic development
• Transmission: human-to-human; fecal-oral or oral-oral route (especially child-to-child in developing countries)
• Risk factors: childhood crowding, poor sanitation, low socioeconomic status

Pathogenesis

• CagA-positive strains (cytotoxin-associated gene A): more virulent; associated with peptic ulcer and gastric cancer
• VacA (vacuolating cytotoxin A): disrupts epithelial cells
• Urease → ammonia → neutralizes acid → allows survival → mucosal injury
• Chronic inflammation → atrophic gastritis → intestinal metaplasia → dysplasia → gastric adenocarcinoma
• Type I antrum-predominant gastritis → duodenal ulcer (increased acid)
• Type II corpus-predominant gastritis → gastric ulcer and gastric cancer (decreased acid)

Associated Diseases

1. Peptic ulcer disease (most common): ~95% of duodenal ulcers, ~70-80% of gastric ulcers
2. Gastric adenocarcinoma - H. pylori is WHO Group 1 carcinogen
3. Gastric MALT lymphoma - eradication achieves remission in low-grade MALT lymphoma
4. Possible protection against GERD and esophageal adenocarcinoma (controversial)
5. Possible extra-gastric associations (ITP, iron deficiency anemia, ischemic heart disease - less established)

Diagnosis

• Non-invasive (no endoscopy needed):
  • Urea breath test (UBT): gold standard non-invasive test; uses 13C or 14C-labelled urea; H. pylori urease cleaves it → labelled CO2 exhaled
  • Stool antigen test: similar accuracy to UBT; useful for diagnosis and test-of-cure
  • Serology (IgG antibody): useful for epidemiology; cannot confirm eradication (antibody persists)
• Invasive (endoscopy-based):
  • Rapid urease test (CLO test) on biopsy - quick, cheap
  • Histology (Giemsa or Warthin-Starry silver stain)
  • Culture (for antibiotic sensitivity testing)
• Important: Stop PPIs 2 weeks before testing, antibiotics 4 weeks before - to avoid false negatives on UBT/stool antigen/urease tests

Treatment - Eradication Regimens

• First-line (where clarithromycin resistance <15%): Triple therapy x14 days:
  • PPI + clarithromycin + amoxicillin (or metronidazole if penicillin allergy)
• Bismuth quadruple therapy (where resistance higher or first-line fails):
  • PPI + bismuth subsalicylate + metronidazole + tetracycline x10-14 days
• Concomitant therapy: PPI + clarithromycin + amoxicillin + metronidazole x14 days
• Test of cure: UBT or stool antigen at ≥4 weeks after completing therapy
• Eradication of H. pylori permanently cures peptic ulcer disease in most cases

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CHAPTER 169 - CAMPYLOBACTER AND RELATED ORGANISMS

Key Organisms

• Campylobacter jejuni = most common cause of bacterial gastroenteritis in developed world
• Also: C. coli, C. fetus (systemic disease in immunocompromised), Arcobacter, Helicobacter (non-pylori)

Organism

• Gram-negative curved/spiral motile bacilli; microaerophilic
• Darting "corkscrew" motility on darkfield microscopy
• Reservoir: poultry (major), cattle, unpasteurized milk, pets
• Transmission: undercooked poultry (most common in developed countries), contaminated water, unpasteurized milk, contact with infected animals

Clinical Manifestations - C. jejuni

• Enteritis: watery or bloody diarrhea (dysentery-like), fever, cramping abdominal pain
• Incubation 1-7 days; self-limiting in 5-7 days in immunocompetent
• Complications: reactive arthritis, Guillain-Barré syndrome (GBS) - C. jejuni most common identifiable trigger of GBS (molecular mimicry between LOS and gangliosides GM1/GD1a)
• Bacteremia rare in immunocompetent; more common with C. fetus

Diagnosis

• Stool culture on selective media (Skirrow's or CCDA agar) at 42°C, microaerophilic conditions
• PCR becoming standard

Treatment

• Most cases: self-limiting, supportive care (oral rehydration)
• Antibiotics (azithromycin or fluoroquinolone) for severe disease, dysentery, immunocompromised, or prolonged illness
• Note: increasing fluoroquinolone resistance (especially in Asian strains)
• C. fetus bacteremia: ampicillin or imipenem + aminoglycoside

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CHAPTER 170 - PSEUDOMONAS AERUGINOSA AND OTHER PSEUDOMONAS INFECTIONS

Organism

• Gram-negative aerobic rod; non-fermenter
• Produces blue-green pigment (pyocyanin + pyoverdin) → blue-green pus
• Sweet, grape-like/corn tortilla odor
• Oxidase-positive; grows on most media including minimal nutrient agar
• Ubiquitous in moist environments (water, soil, plants, hospital equipment)

Virulence Factors

• Exotoxin A (inhibits EF-2 - protein synthesis like diphtheria toxin)
• Alginate capsule (mucoid strains in CF patients - biofilm formation)
• Exoenzymes S, T, U, Y (type III secretion system)
• Elastases, proteases, phospholipase C

Who Gets Pseudomonas Infections?

• Cystic fibrosis patients - chronic airway colonization/infection (mucoid strains)
• Burn patients
• Neutropenic/immunocompromised patients (bacteremia, pneumonia)
• ICU patients on mechanical ventilation (VAP)
• Diabetics (malignant otitis externa, osteomyelitis of foot)
• Hot tub/swimming pool users (folliculitis, otitis externa)
• Contact lens wearers (corneal ulcers/keratitis - vision-threatening)
• IV drug users (endocarditis)

Key Clinical Syndromes

• Ecthyma gangrenosum: pathognomonic skin lesion - begins as erythematous papule → black necrotic ulcer with surrounding erythema; occurs in bacteremia in neutropenic patients
• Malignant (necrotizing) otitis externa: diabetics/elderly; severe, progressive; involves temporal bone; treat with ciprofloxacin (IV or oral)
• Pneumonia: in mechanically ventilated and CF patients; carries high mortality
• Bacteremia: in neutropenic patients - high mortality; "septicemic" presentation

Treatment

• Always use combination therapy for serious infections (anti-pseudomonal beta-lactam + aminoglycoside or fluoroquinolone)
• Anti-pseudomonal beta-lactams: piperacillin-tazobactam, ceftazidime, cefepime, imipenem, meropenem
• Aminoglycosides: tobramycin, amikacin
• Fluoroquinolones: ciprofloxacin (most active quinolone against Pseudomonas)
• Colistin/polymyxin B for MDR/XDR strains
• CF chronic management: inhaled tobramycin, azithromycin (immunomodulatory)

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CHAPTER 171 - SALMONELLA INFECTIONS (TYPHOID FEVER / ENTERIC FEVER)

Two Major Diseases:

1. Enteric (Typhoid) Fever - caused by S. Typhi and S. Paratyphi A, B, C (humans only host)
2. Non-typhoidal Salmonella (NTS) - many serotypes (e.g., S. Typhimurium, S. Enteritidis) - causes gastroenteritis and bacteremia

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TYPHOID FEVER

Epidemiology

• 9.2-21 million cases/year globally; 110,000-280,000 deaths/year
• Highest incidence: India, Pakistan, Bangladesh, Nepal, Eastern Africa
• Fecal-oral transmission; waterborne or food-borne from chronic carriers
• Multidrug-resistant (MDR) strains emerged 1980s (resistance to chloramphenicol, ampicillin, TMP); now widely prevalent
• XDR-S. Typhi (extensively drug-resistant): resistance to above + fluoroquinolones + third-gen cephalosporins; emerged in Pakistan 2016

Clinical Stages (Week by Week)

Complications

• Intestinal perforation (~3% in endemic areas, peak week 3)
• GI hemorrhage
• Hepatitis, cholecystitis (chronic carrier state in bile)
• Neurological (encephalopathy, meningitis, cerebellar ataxia)
• Myocarditis
• Relapse in ~10% (usually milder)
• Chronic carrier state: ~3% after acute illness; gallbladder colonization; associated with gallstones; slight increase in gallbladder carcinoma risk

Diagnosis

• Blood culture: positive in 60-80% of first week (most sensitive early)
• Bone marrow culture: gold standard, positive in ~90% even after antibiotics started
• Stool culture: positive weeks 2-3
• Widal test (serology): historical, poor specificity and sensitivity - not recommended
• PCR (blood/urine) emerging

Treatment

• Dexamethasone for severe disease with encephalopathy/shock (0.3 mg/kg then 0.1 mg/kg q6h x2 days)
• Chronic carrier: ciprofloxacin 750mg BD x28 days (if susceptible); cholecystectomy for gallstone-associated carriers

Vaccines

• Vi polysaccharide vaccine (ViCPS): single IM dose; adults and children >2 years; 50-80% efficacy
• Ty21a oral live attenuated vaccine: 3-4 capsules on alternate days; children >6 years
• Typhoid conjugate vaccine (TCV): newer; Vi polysaccharide conjugated to carrier protein; children ≥6 months; WHO recommended for endemic countries

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NON-TYPHOIDAL SALMONELLA (NTS)

• Reservoir: poultry, eggs, reptiles, livestock
• Transmission: undercooked eggs/poultry, unpasteurized dairy, produce contaminated with animal feces; reptile contact (turtles - important in US children)
• Most common: S. Enteritidis, S. Typhimurium

Clinical Syndromes

1. Gastroenteritis (most common): watery or bloody diarrhea, fever, cramps; 6-72 hours incubation; self-limiting 3-7 days
2. Bacteremia: elderly, infants, immunocompromised (HIV, sickle cell anemia - predisposition due to opsonization defect), malnutrition
3. Focal infections: osteomyelitis (sickle cell disease - S. Typhimurium is the most common cause of osteomyelitis in sickle cell patients), endovascular infections (atherosclerotic plaques/aneurysms), meningitis in infants

Treatment NTS

• Gastroenteritis: supportive (do NOT use antibiotics routinely - prolongs carriage)
• Antibiotics for: infants <3 months, elderly, immunocompromised, bacteremia, severe disease
• Drugs: ciprofloxacin, ceftriaxone, azithromycin

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CHAPTER 172 - SHIGELLOSIS

Organism

• Gram-negative non-motile rod; facultative anaerobe
• 4 species (serogroups):
  • S. dysenteriae type 1 (Group A): most severe; produces Shiga toxin (Stx1); epidemic dysentery
  • S. flexneri (Group B): most common in developing countries
  • S. boydii (Group C): rare
  • S. sonnei (Group D): most common in developed countries; mildest disease

Epidemiology

• Humans are the only reservoir (unlike Salmonella)
• Very low infectious dose: 10-200 organisms (extremely contagious)
• Fecal-oral transmission; waterborne and foodborne; person-to-person (daycare, institutions)
• Global burden: ~188 million cases/year; responsible for ~200,000 deaths, mostly children <5

Pathogenesis

• Invades colonic epithelium via M cells of Peyer's patches → intracellular spread → mucosal ulceration
• Intracellular motility via actin polymerization (APC/N-WASP/Arp2/3 complex)
• Shiga toxin (Stx1 from S. dysenteriae type 1): inhibits protein synthesis (cleaves 28S rRNA) → cell death; can cause HUS (hemolytic-uremic syndrome)

Clinical Features

• Incubation 1-4 days
• Watery diarrhea initially → progresses to dysentery: small-volume bloody mucoid stools with tenesmus, fever, cramps
• "Paradoxical": fever + small bloody stools + tenesmus (vs. large watery stools in cholera)
• Severe: febrile seizures in children, toxic megacolon, perforation (rare)
• S. dysenteriae type 1: can cause HUS (microangiopathic hemolytic anemia + thrombocytopenia + renal failure)

Diagnosis

• Stool culture: selective media (XLD, MacConkey agar); non-lactose fermenting colonies
• PCR for gastrointestinal pathogens (multiplex panels)
• Stool wet prep: PMNs + RBCs

Treatment

• Avoid antidiarrheal agents (loperamide) - may worsen disease and predispose to toxic megacolon
• ORS for hydration; nutritional support

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CHAPTER 173 - CHOLERA

Organism

• Vibrio cholerae - gram-negative curved rod (comma-shaped); highly motile (single polar flagellum)
• O1 and O139 serogroups cause epidemic cholera
• O1 has 2 biotypes: Classical and El Tor (currently dominant globally)
• El Tor biotype: 2 serotypes - Ogawa and Inaba
• The ongoing 7th pandemic (since 1961) is due to El Tor biotype

Virulence

• Cholera toxin (CT): ADP-ribosylates Gs → permanently activates adenylyl cyclase → massive ↑cAMP → chloride secretion, sodium absorption inhibited → massive watery diarrhea
• CT gene on the filamentous bacteriophage CTXφ
• Toxin-coregulated pili (TCP): colonization factor; receptor for CTXφ

Clinical Features

• Incubation: hours to 5 days
• Classic presentation: sudden onset "rice-water" diarrhea (large volume, watery, white flecks of mucus, no blood, fishy odor) + vomiting
• Fluid loss up to 1 liter/hour → severe dehydration, electrolyte imbalance
• Rapid progression to: sunken eyes, dry mouth, poor skin turgor, hypotension, hypovolemic shock, "washerwoman's hands"
• Death from hypovolemia and metabolic acidosis if untreated; case fatality rate can reach 50% untreated vs <1% with treatment

Diagnosis

• Clinical in endemic areas
• Stool dark-field microscopy: "shooting star" motility
• Culture on TCBS agar (thiosulfate-citrate-bile salts-sucrose agar): yellow colonies (O1 ferments sucrose)
• PCR

Treatment

• ORAL REHYDRATION SOLUTION (ORS) = cornerstone of treatment; WHO/UNICEF ORS = glucose + Na + K + citrate
• Severe dehydration: IV Ringer's lactate
• Antibiotics: shorten duration and reduce shedding (do not replace ORS):
  • Doxycycline 300mg single dose (adults) - first-line
  • Azithromycin 1g single dose (preferred in pregnant women and children)
  • Ciprofloxacin 1g single dose alternative
• Zinc supplementation in children reduces duration

Vaccines

• Oral cholera vaccines (OCV): Dukoral (WC-rBS), Shanchol, Euvichol-Plus
• Dukoral: also contains CTB subunit - provides some protection against ETEC
• 2-dose schedule; 85-90% efficacy for 2 years

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CHAPTER 174 - BRUCELLOSIS

Organism

• Gram-negative coccobacilli; intracellular pathogen (lives within macrophages)
• Four main species in humans:
  • B. melitensis (goats, sheep, camels) - most common and most virulent
  • B. abortus (cattle) - causes undulant fever
  • B. suis (pigs) - severe systemic disease
  • B. canis (dogs) - less common in humans
• Zoonosis: humans are accidental hosts

Epidemiology

• Endemic: Mediterranean, Middle East, Indian subcontinent, Latin America, sub-Saharan Africa
• Transmission routes: unpasteurized dairy products (most common worldwide), direct contact with infected animals or their products (placentas, aborted fetuses), inhalation of aerosols (lab workers, abattoir workers), rare: sexual transmission
• Occupational risk: veterinarians, farmers, abattoir workers, lab personnel

Clinical Features - "The Great Imitator"

• Incubation 2-4 weeks (can be up to months)
• Undulant fever (fever waves, rises in afternoon/evening then sweats and defervescence)
• Malaise, night sweats, arthralgia, myalgia, weight loss, depression
• Hepatosplenomegaly in 25%
• Osteoarticular disease (most common focal complication, ~30-40%):
  • Sacroiliitis (most common)
  • Spondylitis (lumbar spine most common; distinguish from TB - see table)
  • Peripheral arthritis (hip, knee)
• Endocarditis (~1% of cases; most serious complication; aortic valve; high mortality without surgery)
• Epididymo-orchitis in ~10% of men
• Neurobrucellosis: meningoencephalitis, cranial nerve palsies, cerebral abscess (rare)
• Respiratory (25%): dry cough, hilar adenopathy

Brucellosis vs TB Spinal Involvement (Table 174-1):

Diagnosis

• Blood culture: definitive but only 15-70% positive; prolonged incubation needed
• Serology: Standard Agglutination Test (SAT or Wright's test); titer ≥1:160 significant; rising titers diagnostic
• 2-mercaptoethanol (2-ME) test distinguishes IgG (active/chronic) from IgM (early/acute)
• Bone marrow culture: highest sensitivity (~90%)
• PCR increasingly used
• Biochemical findings: mild anemia, leukopenia, thrombocytopenia, elevated LFTs

Treatment - Must be combination + prolonged (intracellular organism)

• First-line: Doxycycline 200mg/day x6 weeks + Rifampicin 600-900mg/day x6 weeks
• Alternative (spondylitis, endocarditis, neurobrucellosis): Doxycycline x6 weeks + streptomycin or gentamicin x2-3 weeks (streptomycin preferred for spondylitis)
• Endocarditis: triple therapy + usually requires valve replacement
• Children and pregnancy: TMP-SMX + rifampicin (avoid doxycycline in pregnancy/children)
• Relapse is common if treatment is incomplete or short

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CHAPTER 175 - TULAREMIA

Organism

• Francisella tularensis - gram-negative coccobacillus; facultative intracellular (lives in macrophages)
• Two subspecies: tularensis (Type A - more virulent, North America) and holarctica (Type B - less virulent, Eurasia and North America)
• Potential bioterrorism agent (Category A); extremely low infectious dose (~10 organisms)

Epidemiology

• Reservoir: rabbits, hares, voles, muskrats, ticks, deer flies
• Transmission:
  • Tick bite (Dermacentor, Amblyomma) or deer fly bite - most common in US
  • Direct contact with infected animals (hunters, trappers) - handling rabbit carcasses
  • Ingestion of contaminated water or undercooked meat
  • Inhalation of aerosols (most dangerous - causes pneumonic form)

Clinical Forms (6 types)

Diagnosis

• Culture hazardous (BSL-3); require notifying lab
• Serology (agglutination test): titer ≥1:160 diagnostic; paired sera show 4-fold rise
• PCR (blood, lymph node aspirate)
• Intradermal skin test (historical)

Treatment

• Streptomycin 7.5-10 mg/kg IM q12h x10-14 days = drug of choice (best evidence)
• Gentamicin alternative (easier to use)
• Doxycycline or ciprofloxacin (oral options; higher relapse rate than aminoglycosides)
• Post-exposure prophylaxis (bioterrorism exposure): doxycycline or ciprofloxacin x14 days

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CHAPTER 176 - PLAGUE

Organism

• Yersinia pestis - gram-negative coccobacillus (bipolar staining "safety-pin" appearance on Wayson stain)
• Potential bioterrorism agent (Category A); historically caused Black Death pandemic

Epidemiology

• Natural reservoir: rodents (rats, prairie dogs, squirrels); fleas are vectors
• Transmission:
  • Flea bite (most common): Xenopsylla cheopis (rat flea)
  • Direct contact with infected animal tissues
  • Inhalation of respiratory droplets from pneumonic plague patients (human-to-human; only form of person-to-person transmission)
• Endemic: western US (New Mexico, Arizona, Colorado), sub-Saharan Africa, Central Asia, Peru

Three Clinical Forms

1. Bubonic Plague (most common, 80-85%)

• Flea bite → organisms travel to regional lymph nodes → massive lymph node swelling = BUBO
• Bubo most common in inguinal/femoral (flea bite on leg), then axillary, then cervical
• Painful, swollen, fluctuant lymph node (5-8 cm); surrounding edema
• Sudden high fever, chills, malaise, headache; incubation 2-8 days
• Can progress to septicemia and pneumonic plague

2. Septicemic Plague

• Bacteremia without visible bubo (primary) or from bubonic plague (secondary)
• High fever, shock, DIC, purpura fulminans (→ "Black Death")
• Highest untreated mortality

3. Pneumonic Plague (most dangerous, most feared bioterrorism form)

• Primary (inhalation) or secondary (spread from bacteremia)
• Severe pneumonia; watery, bloody sputum; rapid deterioration; near 100% fatal if untreated within 24 hours
• Can spread human-to-human (only form to do so) via respiratory droplets

Diagnosis

• Gram stain of bubo aspirate: safety-pin appearing gram-negative rods (Wayson or Giemsa better)
• Culture (BSL-3 facility required)
• Serology (passive hemagglutination)
• PCR
• Direct fluorescent antibody (DFA) staining

Treatment (time-critical)

• Streptomycin 15 mg/kg IM q12h x10 days = drug of choice
• Gentamicin is equally effective (preferred in many guidelines)
• Doxycycline or ciprofloxacin alternative
• Pneumonic plague: strict respiratory isolation + immediate antibiotics (death within 24-36h if untreated)
• Post-exposure prophylaxis: doxycycline or ciprofloxacin x7 days

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CHAPTER 177 - BARTONELLA INFECTIONS (INCLUDING CAT SCRATCH DISEASE)

Organism

• Gram-negative intracellular coccobacilli; facultative intracellular organisms
• Key species:
  • B. henselae - Cat scratch disease, bacillary angiomatosis, peliosis hepatis
  • B. quintana - Trench fever, bacillary angiomatosis (in homeless/immunocompromised)
  • B. bacilliformis - Oroya fever and Verruga peruana (South America - Carrion's disease)

CAT SCRATCH DISEASE (B. henselae)

Epidemiology

• Cats are reservoir; cat fleas (Ctenocephalides felis) maintain bacteremia in cats
• Humans infected via cat scratch or bite (flea feces contaminated onto wound)
• Children and young adults most commonly affected
• ~25,000 cases/year in US (September-February peak)

Clinical Features

• Primary inoculation site: papule/pustule at scratch site 3-10 days after injury
• Regional lymphadenopathy (2-8 weeks later): tender, swollen lymph nodes (axillary, cervical, submandibular, inguinal - depends on scratch site); nodes may suppurate
• Systemic symptoms: low-grade fever, malaise, headache in ~30%
• Parinaud's oculoglandular syndrome: granulomatous conjunctivitis + ipsilateral preauricular adenopathy (from conjunctival inoculation by contaminated hands)
• Self-limiting in immunocompetent (lymph nodes resolve in 2-4 months)

Severe/Atypical Manifestations

• Neuroretinitis: blurred vision, macular star on fundoscopy
• Encephalopathy (rare)
• Hepatosplenic CSD (bacillary peliosis in immunocompromised)
• Systemic disease: pneumonia, osteomyelitis (in immunocompromised/HIV)

BACILLARY ANGIOMATOSIS (in HIV/immunocompromised)

• B. henselae or B. quintana
• Vascular proliferative disease: red-to-purple papules/nodules resembling Kaposi's sarcoma
• Can involve skin, lymph nodes, liver (peliosis hepatis), spleen, bone
• Distinguished from KS histologically: lobular capillary proliferation with neutrophilic infiltrate + bacteria on Warthin-Starry silver stain

Diagnosis CSD

• Clinical diagnosis in immunocompetent with typical presentation
• Serology (anti-B. henselae IgG): titer ≥1:64 supportive; ≥1:256 diagnostic
• PCR on lymph node tissue
• Histology: stellate granulomas with central necrosis; Warthin-Starry silver stain shows pleomorphic bacilli

Treatment

• Immunocompetent CSD: usually self-limiting; azithromycin shortens duration (500mg day 1, 250mg days 2-5)
• Bacillary angiomatosis (HIV): doxycycline or erythromycin x3 months minimum; lifelong suppression in AIDS if CD4 <100
• Neuroretinitis: doxycycline + rifampicin

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TRENCH FEVER (B. quintana)

• Transmitted by body louse (Pediculus humanus corporis) via louse feces in skin abrasions
• Classic in WWI soldiers; now in homeless populations and refugees
• Relapsing fever (5-day fever/Quintan fever), bone pain (tibial pain classic), headache
• Treatment: doxycycline + gentamicin

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CARRION'S DISEASE (B. bacilliformis)

• Endemic to Andes mountains (Peru, Ecuador, Colombia) - transmitted by sandfly (Lutzomyia)
• Phase 1 - Oroya fever: acute hemolytic anemia; RBCs heavily parasitized; high mortality if untreated
• Phase 2 - Verruga peruana: chronic phase; vascular skin lesions (hemangioma-like nodules)
• Treatment: chloramphenicol (Oroya fever - also covers secondary Salmonella); rifampicin or azithromycin

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CHAPTER 178 - DONOVANOSIS (Granuloma Inguinale)

Organism

• Klebsiella granulomatis (formerly Calymmatobacterium granulomatis)
• Gram-negative intracellular bacillus; cannot be cultured on standard media

Epidemiology

• STI; low-to-moderate infectivity; requires repeated exposure
• Endemic: Papua New Guinea, parts of India, South Africa, Brazil, Caribbean
• Rare in US and Europe

Clinical Features

• Painless, progressive genital ulcers (vs. painful in chancroid and herpes)
• No regional lymphadenopathy (unlike LGV, syphilis, chancroid) - "pseudobuboes" = subcutaneous granulomata extending to skin, NOT true lymphadenopathy
• Four clinical types:
  1. Ulcerogranulomatous (most common): beefy-red, friable, bleeding granulation tissue
  2. Hypertrophic/verrucous: raised, dry, irregular ulcers
  3. Necrotic: destructive, foul-smelling, tissue destruction
  4. Sclerotic/cicatricial: fibrous scarring
• Extragenital spread (rare): mouth, liver, spleen, bone

Diagnosis

• Donovan bodies: intracellular "safety-pin" bacilli seen in Wright-Giemsa or Leishman stain of tissue biopsy or crush preparation from ulcer edge
• PCR available in reference labs
• Cannot culture on standard media

Treatment

• Azithromycin 1g weekly or 500mg daily x minimum 3 weeks (until lesions fully healed) = preferred
• Alternatives: doxycycline 100mg BD, TMP-SMX, erythromycin, ciprofloxacin - all x minimum 3 weeks

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QUICK REFERENCE COMPARISON TABLE

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HIGH-YIELD EXAM POINTS

• "Safety-pin" staining: Y. pestis (plague) AND K. granulomatis (donovanosis - both on Wayson/Giemsa)
• Streptomycin = drug of choice: Both plague AND tularemia
• Doxycycline + rifampicin x6 weeks: Brucellosis
• GBS post-infectious: C. jejuni (most common trigger), also CMV, EBV, HIV
• Ecthyma gangrenosum: Pseudomonas aeruginosa bacteremia in neutropenic patient
• Meningitis belt: Group A meningococcal disease in sub-Saharan Africa
• Chocolate agar (X and V factors): H. influenzae
• Bordet-Gengou agar: B. pertussis
• TCBS agar (yellow colonies): V. cholerae O1
• Widal test: Historical, unreliable; bone marrow culture is gold standard for typhoid
• Rifampicin chemoprophylaxis: Meningococcal (600mg BD x2 days) AND Hib contacts
• Vi polysaccharide vaccine: Typhoid (protects against S. Typhi only)
• Ty21a: Oral live typhoid vaccine; not for immunocompromised
• B. henselae vs B. quintana: both cause bacillary angiomatosis; quintana transmitted by lice (trench fever); henselae by cat scratch
• XDR typhoid from Pakistan: Resistant to everything including fluoroquinolones + cephalosporins → only azithromycin or carbapenems work
• Cholera toxin mechanism: ADP-ribosylates Gs protein → ↑cAMP → rice-water diarrhea
• Pertussis toxin mechanism: ADP-ribosylates Gi/inhibitory G protein (same enzyme but opposite target to cholera)
• H. pylori eradication: Always test for cure with UBT or stool antigen ≥4 weeks after finishing treatment
• Sickle cell + osteomyelitis: Think Salmonella (though Staph aureus is still overall most common)
• HACEK endocarditis: Subacute; prior dental work; treat with ceftriaxone x4 weeks

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