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HARRISON'S SECTION 5: DISEASES CAUSED BY GRAM-POSITIVE BACTERIA

Chapters 151-159 — Complete Study Notes

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CHAPTER 151 — PNEUMOCOCCAL INFECTIONS

The Organism

• Optochin-sensitive (distinguishes from other α-hemolytic streptococci)
• Bile soluble
• Fastidious: needs 5% CO₂ and a catalase source (blood) for agar growth
• 100 recognized serotypes in 21 serogroups, identified by the Quellung reaction (capsular swelling with specific antiserum)
• Encapsulated strains = mucoid/smooth colonies; unencapsulated = rough colonies

Virulence Factors

Epidemiology

• ~317,000 deaths/year in children 1-59 months globally
• Highest IPD rates: children <2 years (188/100,000) and adults ≥65 years (60/100,000)
• Nasopharyngeal carriage: 20-50% in children <5 yrs (developed world); up to 70-90% in LMICs
• Risk factors for pneumococcal disease:
  • Asplenia/splenic dysfunction (sickle cell disease, celiac disease)
  • Chronic respiratory disease (COPD, CF, bronchiectasis)
  • Chronic heart, kidney, or liver disease
  • Diabetes mellitus requiring medication
  • Immunocompromise: HIV, leukemia/lymphoma, transplant, glucocorticoids ≥20 mg/day for >1 month
  • Cochlear implants; CSF leaks
  • Alcoholism; malnutrition; cigarette smoking; day-care attendance

Pathogenesis

1. Colonizes nasopharynx - downregulates capsule there (rough phenotype), upregulates on tissue invasion (smooth)
2. Spreads via bloodstream to brain, joints, peritoneum OR locally → otitis media, pneumonia
3. Innate defense: mucociliary escalator, CRP (binds phosphorylcholine → complement), splenic function
4. Acquired immunity: capsule-specific serum IgG (T-cell independent, serotype-specific, poor in children <1-2 years)
5. IRAK-4 deficiency → unusual susceptibility to encapsulated bacteria
6. Inflammatory cascade: peptidoglycans → IL-1, IL-6, TNF → PMN infiltration

Clinical Manifestations

• Abrupt onset: cough (dry → purulent/blood-tinged), dyspnea, fever, shaking chills, pleuritic chest pain
• Elderly: may present atypically - confusion/malaise without fever or cough
• CXR: classic lobar/segmental consolidation; "round pneumonia" in children
• Blood cultures positive in <30%
• Lab: WBC >15,000 (up to 40,000); leukopenia in <10% (poor prognosis sign)
• Empyema <5% of cases; pleural pH ≤7.1 indicates empyema → aggressive drainage
• CFR: <5% in 18-44 year olds; >12% in those >65

• Clinically indistinguishable from other bacterial meningitis
• Severe headache, fever, stiff neck, photophobia, seizures, altered consciousness, Kernig's/Brudzinski's signs
• Now most common bacterial meningitis in children AND adults (alongside N. meningitidis)
• Mortality ~20%; up to 50% of survivors have sequelae (deafness, hydrocephalus, cerebrovascular complications)
• CSF: turbid, elevated protein, elevated WBC, reduced glucose, positive culture/Gram's stain

• Acute otitis media - most common pneumococcal syndrome overall
• Sinusitis, bronchitis (usually in pre-existing lung disease)

Diagnosis

• Sputum Gram stain + culture (most cases of adult pneumonia)
• Blood cultures positive <30% in pneumonia
• Urinary pneumococcal antigen - highly specific in adults (not useful in children - high colonization)
• CSF examination for meningitis
• Rapid antigen tests, PCR

Treatment

• Vancomycin + cefotaxime OR ceftriaxone (first-line empirical)
  • Adults: vancomycin 30-60 mg/kg/day; cefotaxime 8-12 g/day in 4-6 divided doses OR ceftriaxone 4 g/day
  • Children: vancomycin 60 mg/kg/day; cefotaxime 225-300 mg/kg/day
• Penicillin-sensitive isolate: switch to penicillin alone
• Penicillin-resistant + cephalosporin-resistant: vancomycin + high-dose cephalosporin ± rifampin
• Dexamethasone: give BEFORE or WITH first antibiotic dose - reduces mortality, hearing loss, neurologic sequelae in adults

• Oral amoxicillin 45-90 mg/kg/day (q8h) - best worldwide option
• Levofloxacin 500-750 mg/day or moxifloxacin 400 mg/day
• Azithromycin or clarithromycin effective in ~80%
• Duration: at least 5 days once afebrile (5 days total usually sufficient in adults)

• <6 months AND 6-23 months bilateral: amoxicillin 80-90 mg/kg/day
• Observation (no antibiotics): nonsevere illness, uncertain diagnosis in 6 months - 2 years
• Duration: 10 days (younger children/severe); 5-7 days for children >6 years mild disease

Prevention/Vaccines

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CHAPTER 152 — STAPHYLOCOCCAL INFECTIONS

The Organism

• Gram-positive cocci forming grape-like clusters, ~1 μm diameter
• Catalase-positive (unlike streptococci); aerobic and facultatively anaerobic
• S. aureus identification:
  • Coagulase-positive (converts fibrinogen → fibrin) - most important test
  • Ferments mannitol; protein A positive; DNAse positive
  • Golden β-hemolytic colonies on blood agar
• Coagulase-negative staphylococci (NSaS/CoNS):
  • S. epidermidis = most common pathogen
  • S. saprophyticus = novobiocin-resistant, common UTI pathogen in young women
  • S. lugdunensis and S. schleiferi = more virulent; native-valve endocarditis

Epidemiology

• ~20-40% of healthy persons colonized; ~10% persistently
• Colonization sites: anterior nares, oropharynx, damaged skin, axilla, vagina, perineum
• Transmission: primarily from person's own commensal flora; direct contact
• Most common cause of surgical wound infections
• MRSA epidemiology:
  • Nosocomial MRSA: 40-50% of S. aureus isolates in many US hospitals
  • CA-MRSA (community-associated): Dramatic rise since 1990s-2000s
    • US predominant clone: ST8 (PFGE type USA300)
    • SCCmec types 4-6 in CA-MRSA (vs. types 1-3 in nosocomial)
    • 5-10% of CA-MRSA infections are invasive/life-threatening

Virulence Factors

• Clumping factor, collagen-binding protein → adhere to fibrinogen, collagen, fibronectin
• Critical for endocarditis and septic arthritis pathogenesis

• Antiphagocytic polysaccharide microcapsule (types 5 and 8)
• Protein A: Fc receptor for IgG → prevents opsonophagocytosis
• CHIPS (chemotaxis inhibitory protein), EAP → inhibit PMN migration
• α-toxin: Pore formation; initiates inflammatory cascade
• Panton-Valentine Leukocidin (PVL): Cytolytic to PMNs and monocytes; linked to CA-MRSA SSTIs and necrotizing pneumonia
• Intracellular survival → sanctuary from host defenses; small-colony variants in osteomyelitis/CF
• Biofilm formation (ica locus) → device-related infections

• mecA gene (on SCCmec pathogenicity island) encodes PBP2a → methicillin resistance
• ACME (arginine catabolic mobile element) aids host defense evasion
• VRSA (2002): Acquired vanA from VRE via conjugal transfer; vanA → D-Ala-D-Lac (vancomycin cannot bind)

Clinical Syndromes

• Folliculitis, furuncle (true abscess in moist/hairy areas), carbuncle (coalescent, lower neck)
• Cellulitis, impetigo, mastitis (1-3% of nursing mothers, 2-3 weeks postdelivery)
• Surgical wound infections (most common cause)

• Septic arthritis - most common cause in native joints; joint fluid >50,000 PMNs/μL
• Osteomyelitis: hematogenous in children = long bones; adults = vertebral
• Vertebral osteomyelitis: hemodialysis, endocarditis, diabetes, IDU; epidural abscess = emergency
• Pyomyositis (tropical; HIV-infected)

• Newborns/infants: respiratory failure, pneumatoceles on CXR, pneumothorax, empyema
• Adults: nosocomial (ICU/intubated); post-influenza (post-viral): bloody sputum, midlung-field pneumatoceles, multiple patchy infiltrates

• S. aureus = leading cause of endocarditis worldwide (25-35% of cases); mortality 20-40%
• Bacteremia complications: endocarditis (~25% with catheter-associated bacteremia), metastatic seeding (up to 31%)
• Four clinical settings of endocarditis:
  1. Right-sided (tricuspid) in IDU: High fever, toxic appearance, pleuritic chest pain, purulent/bloody sputum, septic pulmonary emboli (peripheral circular lesions on CXR that may cavitate)
  2. Left-sided native-valve: Older patients, worse prognosis, peripheral emboli, CNS involvement
  3. Prosthetic-valve: Fulminant early postoperative; often requires valve replacement
  4. Nosocomial: Intravascular devices; often blood culture-negative at presentation
• Signs: new/changing murmur, Osler's nodes, Janeway lesions, Roth spots; Duke criteria used

• Food Poisoning: Incubation 1-6 hours; nausea/vomiting ± diarrhea/hypotension; fever absent; resolves 8-10 hours; supportive treatment only
• Staphylococcal TSS (menstrual and non-menstrual):
  • Criteria: Fever ≥38.9°C + diffuse macular erythroderma + desquamation (1-2 weeks post-rash) + hypotension + ≥3 organ systems involved (GI, muscular, mucous membranes, renal, hepatic, hematologic, CNS)

  • 90% menstrual cases due to TSST-1; non-menstrual often due to enterotoxin B

  • Onset 2-3 days into menses; rapid progression to vomiting, diarrhea, confusion, myalgias, multiorgan dysfunction
  • Recurrence possible if anti-TSST-1 antibody fails to develop
• SSSS (Scalded-Skin Syndrome):
  • Primarily newborns and children
  • Thin-walled fluid-filled bullae; Nikolsky's sign positive; mucous membranes SPARED
  • Significant fluid losses in extensive disease

Diagnosis

• Gram stain and culture: S. aureus rarely a blood culture contaminant (unlike CoNS)
• PCR/point-of-care tests for MRSA screening
• CoNS interpretation: Only 10-20% of positive blood cultures = true bacteremia
  • True bacteremia criteria: fever, local infection signs, leukocytosis, same strain in separate cultures, growth within 48 hours
• TEE mandatory to rule out endocarditis in all S. aureus bacteremia

Treatment

• Endocarditis (MRSA): Vancomycin AUC-based dosing OR daptomycin 6-10 mg/kg q24h × 6 weeks
• Prosthetic-valve endocarditis: Vancomycin/β-lactam + gentamicin 1 mg/kg q8h × 2 weeks + rifampin 300 mg q8h × ≥6 weeks; usually requires surgery
• TSS: Fluids + pressors; remove tampon/packing; clindamycin + semi-synthetic penicillin (MSSA) OR clindamycin + vancomycin (MRSA); IVIG uncertain benefit; clindamycin preferred (inhibits toxin production)
• Prosthetic joint infections: Rifampin + ciprofloxacin (biofilm activity); almost always requires prosthesis removal

• Daptomycin: Bactericidal membrane disruptor; NOT effective for respiratory infections (inactivated by surfactant); monitor CPK
• Linezolid: Bacteriostatic; excellent oral bioavailability; adverse effects: thrombocytopenia, peripheral/optic neuropathy (prolonged use)
• Ceftaroline: 5th-gen cephalosporin; bactericidal vs. MRSA including VISA/VRSA
• Dalbavancin/oritavancin: Long-acting lipoglycopeptides; once-weekly dosing for SSTIs
• Delafloxacin: Fluoroquinolone with MRSA activity

• Hand washing; isolation; universal/targeted MRSA screening
• Decolonization: topical mupirocin (nasal) + chlorhexidine body washes
• Community/recurrent: household decolonization + bleach baths (½ cup bleach in half-filled bathtub, 15 min, 3×/week)
• Vaccines: capsular polysaccharide-protein conjugate and clumping factor antibody strategies have NOT been successful in trials

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CHAPTER 153 — STREPTOCOCCAL INFECTIONS

Classification of Streptococci

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GROUP A STREPTOCOCCUS (GAS) - S. pyogenes

• M protein (major surface protein): anti-phagocytic; binds fibrinogen → blocks complement; >200 emm types; M protein-specific antibodies are protective (serotype-specific)
• Hyaluronic acid capsule: Anti-phagocytic; binds CD44 on pharyngeal epithelium; weak immunogen
• Streptolysin S and O: β-hemolysis; cell membrane damage; ASO antibody = useful serodiagnosis for ARF/PSGN
• Streptokinase: Fibrinolysis
• DNases (A-D): Anti-DNase B antibody used for serodiagnosis of recent infection
• SpyCEP (serine protease): Cleaves IL-8 → inhibits neutrophil recruitment
• Pyrogenic exotoxins A, B, C: Cause scarlet fever rash; function as superantigens → invasive infections, necrotizing fasciitis, TSS

• Most common bacterial infection of school-age children; 20-40% of exudative pharyngitis in children; rare under age 3
• Transmission: respiratory droplets; incubation 1-4 days
• Signs: purulent exudate on posterior pharynx/tonsillar pillars; enlarged tender anterior cervical lymph nodes
• Diagnosis unreliable on clinical grounds alone
• Rapid antigen test: Specificity >95% (positive = definitive); sensitivity 70-90% (negative → confirm by culture in higher-risk)
• Gold standard: Throat culture

• Suppurative (rare with antibiotics): peritonsillar/retropharyngeal abscess, sinusitis, otitis media, meningitis, bacteremia
• Non-suppurative (post-infectious): ARF (Chap. 370), PSGN (Chap. 326)
  • Penicillin treats pharyngitis → reduces ARF risk but NOT PSGN risk

• Streptococcal infection (usually pharyngitis) + characteristic rash from pyrogenic exotoxins
• Rash: begins day 1-2 on upper trunk → spreads to extremities, spares palms/soles
• "Sandpaper" texture; circumoral pallor; "strawberry tongue"; Pastia's lines (accentuation in skin folds)
• Desquamation of palms/soles at 6-9 days
• Recent large outbreaks in China and UK; M1 UK strain implicated

• Superficial skin infection; young children; warmer months; poor hygiene
• Red papules → vesicular → pustular → honeycomb-like amber crusts; predominantly face and legs; no fever
• GAS colonizes skin first; S. aureus appears as secondary flora
• Bullous impetigo = S. aureus
• Sequela: PSGN may follow; ARF generally does NOT follow skin infection (exception: indigenous Australia/Pacific Islands)

• Erysipelas: Bright red, sharply demarcated from surrounding normal skin; warm, tender, shiny; "peau d'orange" texture; blebs/bullae at 2-3 days; classic on malar face or lower extremities; recurrence common
• Almost always β-hemolytic streptococci (GAS or Group C/G)
• Portal of entry may be distant (e.g., tinea pedis fissures → leg cellulitis)

• Two types:
  1. Polymicrobial (bowel flora): anaerobes + gram-negative bacilli; from bowel surgery
  2. GAS (alone or with S. aureus): ~60% of cases
• Inoculation site may be distant from clinical involvement
• Presentation: severe pain, malaise, fever, toxic appearance; pain disproportionate to skin appearance (key warning sign); evolves to dusky/mottled erythema, edema; anesthesia develops as cutaneous nerves infarcted
• Management: Early surgical exploration is BOTH diagnostic AND therapeutic (necrosis along fascial planes) → extensive debridement + antibiotics

• Previously healthy individuals; abrupt onset; ~50% have empyema (nearly always infected, unlike pneumococcal effusions)
• Empyema volume increases rapidly → drain early (loculates → chronic fibrosis → may need thoracotomy)

• Criteria: I - isolation of GAS from sterile site (definite) or non-sterile (probable); II - Hypotension AND ≥2 of: renal impairment, coagulopathy, liver impairment, ARDS, generalized erythematous macular rash, soft tissue necrosis
• Most patients are bacteremic (contrast with staphylococcal TSS)
• Lab: marked left shift, hypocalcemia, hypoalbuminemia, thrombocytopenia worsening day 2-3
• Most common associated infection: soft tissue infection (necrotizing fasciitis, myositis, cellulitis)
• Mortality ≥30% from shock and respiratory failure
• Pathogenesis: pyrogenic exotoxin A = superantigen → T-cell cytokine storm; IVIG may neutralize these effects

• Clindamycin resistance: ≥30% of invasive GAS in US since ~2021; must confirm susceptibility; linezolid is alternative
• Macrolide resistance: >30% among invasive GAS in US; avoid unless susceptibility confirmed
• Full 10 days of pharyngitis treatment required (even though symptoms resolve in 3-5 days) to prevent ARF by eradicating organism
• Clindamycin rationale for necrotizing fasciitis/TSS: Protein synthesis inhibitor → terminates toxin production; retains activity at high bacterial density (β-lactams less effective at stationary growth phase)
• No commercially available GAS vaccine yet

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GROUP B STREPTOCOCCUS (GBS) - S. agalactiae

• Sodium hippurate hydrolysis (+), bile esculin hydrolysis (-), bacitracin (resistant)
• CAMP factor (phospholipase): synergistic hemolysis with S. aureus β-lysin
• 10 antigenically distinct capsular polysaccharides (major virulence factor)

• Maternal vaginal/rectal carriage: 5-40% of women
• Neonatal incidence fell from ~2-3/1000 to ~0.6/1000 after prenatal screening in 1990s
• Adults now account for a larger proportion of invasive GBS than newborns

• Peripartum: fever, endometritis/chorioamnionitis
• Non-peripartum (elderly/chronically ill): cellulitis, UTI, pneumonia, endocarditis, septic arthritis, meningitis, osteomyelitis

• Drug of choice: penicillin
• Empirical: ampicillin + gentamicin until cultures available
• Meningitis duration: ≥14 days (risk of relapse with shorter courses)
• Bacteremia/soft tissue: penicillin 200,000 units/kg/day

• Serious infections: ~12 million units/day penicillin G
• Endocarditis/meningitis: 18-24 million units/day
• Vancomycin for penicillin allergy

• Screen at 35-37 weeks: lower vaginal + anorectal swab
• Intrapartum chemoprophylaxis: Penicillin 5 million units loading → 2.5 million units q4h until delivery
• Indications: culture-positive, previous GBS infant, GBS bacteriuria, unknown status + premature labor/prolonged rupture >18h/intrapartum fever
• Penicillin allergy (low anaphylaxis risk): cefazolin
• Penicillin allergy (high anaphylaxis risk): clindamycin (if susceptible) or vancomycin

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GROUPS C AND G STREPTOCOCCI (SDSE)

• Streptococcus dysgalactiae ssp. equisimilis; extensive genomic overlap with GAS
• Infections: pharyngitis, cellulitis, pneumonia, bacteremia, endocarditis, septic arthritis, meningitis
• Most often affects elderly/chronically ill
• Bacteremia without obvious focus → likely endocarditis
• Zoonotic species (S. equi): from horses/cattle or unpasteurized milk
• Treatment: Penicillin (all sensitive; nearly all inhibited by ≤0.03 μg/mL); ± gentamicin for endocarditis

S. gallolyticus (formerly S. bovis, Group D non-enterococcal)

• Strongly associated with colon carcinoma/polyps - GI workup mandatory in all cases of bacteremia/endocarditis
• Treatment: penicillin as single agent (reliably killed, unlike enterococci)

Viridans Streptococci

• Normal oral flora; S. salivarius, S. mitis, S. sanguis, S. mutans
• Most important cause of bacterial endocarditis (transient bacteremia from eating, toothbrushing)
• Neutropenic patients (bone marrow transplant/high-dose chemo): high fever, shock; treat presumptively with vancomycin (often penicillin-resistant)

S. milleri Group (S. intermedius/anginosus group)

• Suppurative (abscess-forming) infections: brain abscess, abdominal visceral abscess, peritonsillar abscess, subdural/epidural abscess

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CHAPTER 154 — ENTEROCOCCAL INFECTIONS

• Normal flora of GI and genitourinary tracts
• Intrinsically resistant to cephalosporins, penicillinase-resistant penicillins, and low-level aminoglycosides
• VRE (Vancomycin-Resistant Enterococcus): Major nosocomial problem
  • vanA: High-level vancomycin resistance; resistance to teicoplanin
  • vanB: Moderate vancomycin resistance; susceptible to teicoplanin
• E. faecium has greater intrinsic resistance than E. faecalis; more commonly vancomycin-resistant in hospitals

• UTI (most common); nosocomial bacteremia; endocarditis; intraabdominal/pelvic infections; wound infections; rarely meningitis
• Endocarditis: typically subacute; often affects damaged native valves; prosthetic valve endocarditis also common

• UTI: Ampicillin (oral amoxicillin) if susceptible
• Bacteremia: Ampicillin IV if susceptible
• Endocarditis: Penicillin/ampicillin + aminoglycoside synergy (gentamicin) - requires both agents for bactericidal activity
  • High-level aminoglycoside resistance (HLAR): if gentamicin-resistant, try streptomycin; if both resistant, aminoglycoside cannot be used
  • VRE endocarditis: linezolid or daptomycin (high dose 8-12 mg/kg q24h) ± ampicillin
• VRE treatment: Linezolid 600 mg q12h; daptomycin (high dose); tigecycline; quinupristin-dalfopristin (E. faecium only, not E. faecalis)
• Duration endocarditis: 4-6 weeks (native valve); 6 weeks (prosthetic valve)

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CHAPTER 155 — INFECTIONS CAUSED BY OTHER GRAM-POSITIVE BACTERIA

• Gram-positive club-shaped (Chinese-letter arrangement) non-spore-forming rod; aerobic
• Toxin-producing strains cause disease; toxin encoded by tox gene from bacteriophage β
• Diphtheria toxin: Inhibits protein synthesis by ADP-ribosylation of elongation factor 2 (EF-2); single molecule can kill a cell
• Clinical: Pharyngeal diphtheria: sore throat, low-grade fever, "bull neck" (cervical lymphadenopathy), tough adherent grayish-white pseudomembrane on tonsillar/pharyngeal surfaces that bleeds when removed; risk of airway obstruction
• Myocarditis (weeks 1-2): heart block, arrhythmias; neuropathy (palatal paralysis, oculomotor palsy, peripheral neuropathy; delayed complication)
• Diagnosis: culture on Loeffler's medium, tellurite medium; toxin detection
• Treatment: Diphtheria antitoxin (equine) + penicillin/erythromycin (antibiotics eliminate organism but do NOT neutralize toxin already released)
• Prevention: DTP/DTaP vaccination (diphtheria toxoid)

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CHAPTER 156 — LISTERIA MONOCYTOGENES INFECTIONS

The Organism

• Gram-positive rod; facultative intracellular pathogen; motile at room temperature (tumbling motility) but not at 37°C
• Grows well at refrigerator temperatures (4°C) - allows survival and multiplication in refrigerated foods
• ActA surface protein: Recruits actin cytoskeleton for intracellular movement and cell-to-cell spread without exposure to extracellular environment
• Primarily a T-cell-mediated (cell-mediated) immune pathogen → explains why immunosuppressed patients and neonates (T-cell deficiency) are most vulnerable

Epidemiology and Risk Factors

• High-risk groups:
  • Pregnant women (risk 18× higher than general population)
  • Neonates
  • Adults ≥65 years
  • Immunocompromised: HIV infection, solid organ transplants, malignancy (especially hematologic), glucocorticoids, anti-TNF therapy, alemtuzumab
  • Patients on antacid therapy (decreased gastric acidity increases susceptibility)
• Foodborne transmission is the predominant route
  • Common vehicles: deli meats, hot dogs, soft cheeses (unpasteurized), smoked fish, raw vegetables, cantaloupe
  • Listeria grows at refrigerator temperatures - unlike most pathogens
• Seasonal variation: more common in summer/autumn

Clinical Syndromes

• Most cases are non-invasive GI illness in healthy individuals
• Incubation: ~24 h
• Fever, diarrhea, nausea/vomiting; self-limiting

• Most common manifestation in immunocompromised adults
• Fever, malaise, myalgias, arthralgias; may lack obvious source
• Mortality ~30% (higher with delayed treatment)
• Risk of metastatic seeding (endocarditis, osteomyelitis, abscesses)

• Onset sudden or subacute over several days
• Symptoms similar to other bacterial meningitides
• CSF features distinct: ~60-75% have WBC <1,000/μL (less pronounced pleocytosis than other bacterial meningitides); ~30-40% have low glucose
• Gram's stain: may show gram-positive rods but commonly shows no organisms - sometimes shows gram-positive cocci or diphtheroids (mimics other bacteria)
• Listeria causes <5% of community-acquired bacterial meningitis in US adults

• Encephalitis of the cerebellum and brainstem
• Disproportionately affects otherwise healthy older adults
• Biphasic presentation: fever + headache → days later brainstem/cerebellar signs (asymmetric cranial nerve palsies, ataxia, tremor, hemiparesis)
• Nearly half experience respiratory failure
• MRI is superior to CT for diagnosis
• CSF often only minimally abnormal (diagnosis may be delayed)

• Risk during pregnancy increased due to impaired maternal cell-mediated immunity
• Most common in third trimester
• Pregnant women: often asymptomatic or mild flulike illness (fever, headache, myalgias); neurolisteriosis and death rare in women without other risk factors
• Outcomes in infected pregnancies (French cohort, 107 pregnancies): 24% fetal loss, 45% premature birth, 6% late-onset neonatal listeriosis, 21% term delivery with complications
• Granulomatosis infantiseptica: Severe in utero infection; disseminated microabscesses and granulomas in skin, liver, spleen; most infants stillborn or die soon after birth
• Neonatal early-onset disease (first week): bacteremia, respiratory distress, rash
• Neonatal late-onset disease (1-4 weeks): meningitis (most common)
• Mortality 30% for neurolisteriosis overall; nearly half of survivors have long-term neurologic impairment

Diagnosis

• Blood cultures are the most reliable method
• CSF culture and Gram's stain (often negative - low sensitivity)
• Culture of placenta, amniotic fluid, neonatal blood/CSF in pregnancy-related cases
• MRI for rhombencephalitis

Treatment

• Drug of choice: Ampicillin IV (most bactericidal; for serious infections)
• Meningitis/serious infection: Ampicillin 2 g q4h IV; add gentamicin 1-1.7 mg/kg q8h for synergy (aminoglycoside adds bactericidal activity)
• Penicillin allergy: TMP-SMX (trimethoprim-sulfamethoxazole) - good intracellular penetration; excellent alternative
• Duration:
  • Bacteremia: 2 weeks
  • Meningitis: 3 weeks
  • Rhombencephalitis or brain abscess: 4-6 weeks
• Cephalosporins are ineffective - intrinsic resistance; never use empirically when Listeria is suspected
• Vancomycin has poor intracellular activity - not preferred
• Dexamethasone associated with increased mortality in neurolisteriosis (contrasts with pneumococcal/other bacterial meningitis)

Prevention

• Cook foods thoroughly; avoid soft cheeses, unpasteurized products, deli meats (especially for high-risk individuals: pregnant women, immunocompromised, elderly)
• No vaccine available
• Prophylaxis with TMP-SMX in severely immunocompromised patients may provide some protection

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CHAPTERS 157-158 — TETANUS, BOTULISM

• Spore-forming anaerobic rod; tetanospasmin (tetanus toxin) = second most potent toxin known
• Toxin mechanism: cleaves synaptobrevin (VAMP) → blocks inhibitory neurotransmitter (GABA/glycine) release at Renshaw cells → disinhibition → spastic paralysis
• Clinical: trismus ("lockjaw"), risus sardonicus (spastic facial contraction), opisthotonus (back arching), autonomic instability, laryngospasm
• Treatment: tetanus immunoglobulin (TIG) 3000-5000 units IM (neutralize unbound toxin); wound debridement; metronidazole 500 mg IV q6h (drug of choice; better than penicillin, which is a GABA antagonist); diazepam/sedation for spasms; magnesium sulfate for autonomic instability; mechanical ventilation
• Prevention: DTP/DTaP vaccination (active immunization with toxoid)

• Botulinum toxin = most potent toxin known (lethal dose 0.2-10 ng/kg); 7 serotypes (A-G)
• Mechanism: cleaves SNAP-25 or synaptobrevin → blocks acetylcholine release at neuromuscular junction → flaccid paralysis (descending, symmetric)
• Types of botulism:
  • Foodborne: Home-canned foods; incubation 12-36 hours; nausea/vomiting → descending flaccid paralysis; diplopia, dysarthria, dysphagia (cranial nerves first), then limb weakness; no fever; mental status intact
  • Wound botulism: Injection drug users; no GI symptoms
  • Infant botulism: Honey ingestion or environment; constipation first → hypotonia ("floppy baby"), poor feeding, weak cry
• Diagnosis: mouse inoculation bioassay (gold standard); ELISA for toxin
• Treatment: heptavalent botulinum antitoxin (HBAT) - equine (give early before toxin binds irreversibly); supportive care/mechanical ventilation; antibiotics do not help foodborne/infant botulism
• Infant botulism: BabyBIG (human-derived botulinum immune globulin)

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CHAPTER 159 — GAS GANGRENE AND OTHER CLOSTRIDIAL INFECTIONS

The Genus Clostridium

• 60 species; gram-positive pleomorphic rod-shaped bacteria; obligately anaerobic (mostly); form endospores resistant to heat, desiccation, chemicals

• May appear gram-negative or gram-variable in older cultures or infected tissue specimens
• C. septicum swarms on solid media; most species motile via peritrichous flagella; C. perfringens, C. ramosum, C. innocuum are non-motile
• Produce more protein toxins than any other bacterial genus: >25 lethal toxins identified; include neurotoxins, enterotoxins, cytotoxins, collagenases, permeases, phospholipases, hemolysins, DNases, neuraminidases

• Botulinum and tetanus neurotoxins = most potent toxins known; lethal doses 0.2-10 ng/kg for humans
• Epsilon toxin (C. perfringens types B and D): causes edema/hemorrhage in brain, heart, spinal cord, kidneys; considered potential bioterrorism agent

• Clostridial spores widespread in nature: soil, feces, sewage, marine sediments
• Ecology of C. perfringens in soil influenced by degree/duration of animal husbandry (explains higher incidence in agricultural regions of Europe vs. Sahara)
• C. septicum causes spontaneous (non-traumatic) gas gangrene associated with occult malignancy and neutropenia

Gas Gangrene (Clostridial Myonecrosis)

• C. perfringens produces α-toxin (phospholipase C/lecithinase) - major virulence factor; destroys cell membranes, activates platelet aggregation, causes hemolysis, cardiovascular collapse
• θ-toxin (perfringolysin O): Synergizes with α-toxin; causes massive tissue destruction
• Together: systemic effects including hypotension, decreased cardiac output, tachycardia, and cardiovascular collapse
• Gas production from fermentation → crepitus (characteristic finding)

• Usually follows traumatic wound contamination (soil contamination) or bowel surgery
• Incubation typically <24 hours from onset to diagnosis
• Sudden onset of severe, disproportionate pain at wound site (pain out of proportion to appearance - key feature)
• Wound: tense, edematous; bronze/dusky discoloration; thin, watery, foul-smelling ("mousey/sweet") exudate
• Skin becomes pale, then bronzed, then black as necrosis progresses
• Crepitus on palpation (gas in tissue) - characteristic but may be absent early
• Gas on X-ray/CT in tissue planes (feathering pattern along muscle fascial planes)
• Systemic toxicity: profound tachycardia, disproportionate tachycardia to fever (heart rate may exceed 140 with only mild/moderate fever)
• Bacteremia in 15% of cases
• Rapid deterioration: Shock, renal failure, hemolytic anemia, DIC, multiorgan failure within hours

• No obvious wound; sudden onset; most commonly in cecum/terminal ileum area
• Associated with colorectal carcinoma, leukemia, neutropenia (especially chemotherapy-induced)
• Rapidly fatal; mortality >50% even with treatment

• Clinical diagnosis (cannot wait for laboratory confirmation)
• Wound Gram stain: large gram-positive rods; few or no PMNs (characteristic - organisms not killed by neutrophils)
• Imaging: CT/X-ray showing gas in deep tissue planes
• Blood cultures (positive in ~15%)

1. Immediate surgical debridement - most critical intervention; aggressive; repeat operations often needed
2. Antibiotics: High-dose penicillin G + clindamycin (same rationale as for GAS necrotizing fasciitis: toxin inhibition)
   • Penicillin G 3-4 MU IV q4h (24 MU/day)
   • Clindamycin 600-900 mg IV q8h
   • C. septicum is susceptible to penicillin, clindamycin, metronidazole
3. Hyperbaric oxygen (HBO): Adjunctive; inhibits anaerobic metabolism; may help demarcate viable tissue; use after initial surgical stabilization; do NOT delay surgery for HBO
4. ICU supportive care: Fluids, vasopressors; management of DIC, renal failure, hemolytic anemia

Other Clostridial Infections

• Leading cause of nosocomial diarrhea
• Toxins A (enterotoxin) and B (cytotoxin): disrupt colonic epithelial tight junctions
• Clinical spectrum: mild diarrhea → pseudomembranous colitis → toxic megacolon → colonic perforation
• Risk factors: antibiotic use (clindamycin, cephalosporins, fluoroquinolones most implicated), hospitalization, PPI use, age ≥65
• Diagnosis: stool toxin EIA, PCR (GDH antigen screening + toxin confirmation)
• Treatment: Fidaxomicin 200 mg bid × 10 days (preferred over vancomycin for non-severe initial episode due to lower recurrence); vancomycin oral 125 mg qid × 10 days; metronidazole (less effective, reserved for mild cases where others unavailable); bezlotoxumab (monoclonal antibody against toxin B; reduces recurrence); FMT (fecal microbiota transplant) for recurrent CDI; discontinue offending antibiotic

• Often transient; arises from GI tract (especially bowel malignancy)
• C. septicum bacteremia: search for occult malignancy (colon cancer, hematologic malignancy)
• C. perfringens bacteremia: often from GI/biliary/GU source; may cause massive hemolysis (rare)

• Second most common cause of food poisoning in US (after Salmonella)
• Typically from cooked meat/poultry dishes that cool slowly → spores survive → germinate → toxin produced
• Incubation: 8-16 hours; watery diarrhea + crampy abdominal pain; NO vomiting; NO fever (contrast with staphylococcal food poisoning)
• Self-limiting (24 hours); supportive treatment only; spores also cause necrotizing enteritis (pigbel) in Papua New Guinea (type C strains)

• Clostridia contaminate >30% of battle wounds without causing gas gangrene
• Simple wound contamination: no treatment beyond wound debridement
• Localized infection (cellulitis): penicillin + debridement; different from myonecrosis

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KEY SUMMARY AND CLINICAL PEARLS

Antibiotic Quick Reference

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High-Yield Clinical Pearls (Exam Essentials)

1. Pneumococcus: Optochin-sensitive + bile soluble = S. pneumoniae. Add dexamethasone WITH/BEFORE first antibiotic for meningitis. Empirical meningitis = vancomycin + 3rd-gen cephalosporin.
2. S. aureus: Always get TEE to rule out endocarditis in bacteremia. Vancomycin is less effective than β-lactams for MSSA - always de-escalate if MSSA. Daptomycin is inactivated by pulmonary surfactant - never use for pneumonia.
3. GAS: Pain disproportionate to appearance = necrotizing fasciitis until proven otherwise → surgical emergency. Clindamycin used WITH penicillin to stop toxin production. Macrolide and clindamycin resistance now >30% in invasive GAS in US - confirm susceptibility.
4. GBS: Screen all pregnant women at 35-37 weeks. Early-onset neonatal GBS = first week of life. Cefazolin for penicillin allergy with low anaphylaxis risk.
5. S. gallolyticus bacteremia/endocarditis = always colonoscopy (associated with colon carcinoma).
6. Enterococcus: Intrinsically resistant to cephalosporins. Endocarditis requires penicillin + aminoglycoside synergy. VRE = use linezolid or high-dose daptomycin.
7. Listeria: Grows at refrigerator temperature (unique). Cephalosporins are INEFFECTIVE (intrinsic resistance). Ampicillin + gentamicin = treatment of choice. Dexamethasone increases mortality in neurolisteriosis (opposite of other bacterial meningitis). CSF Gram stain often negative - may show cocci/diphtheroids (confusing). Rhombencephalitis = biphasic with respiratory failure.
8. Gas Gangrene: Large gram-positive rods + few or no PMNs on Gram stain (pathognomonic impression). Incubation <24 hours. C. septicum spontaneous gangrene = search for occult malignancy/neutropenia. HBO is adjunctive - do NOT delay surgery for HBO.
9. C. difficile: Fidaxomicin preferred over vancomycin (lower recurrence). Metronidazole only if others unavailable. FMT for recurrent disease.
10. Botulism vs. tetanus: Botulism = flaccid paralysis (blocks ACh release, descending); Tetanus = spastic paralysis (blocks inhibitory GABA/glycine release). Antitoxin helps both but must be given early.

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