Melioidosis, Glanders, Lyme Disease & Skin Disease caused by NTM (L)
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Melioidosis, Glanders, Lyme Disease & Skin Disease Caused by NTM
1. GLANDERS
Causative organism: Burkholderia mallei (formerly Pseudomonas mallei) - a non-motile, strictly aerobic, facultative intracellular, Gram-negative bacillus. Historically also known as equinia, farcy, and malleus.
Epidemiology & Risk:
- Primarily a disease of horses, mules, and donkeys
- Human infection occurs in those handling infected animals and laboratory personnel
- Not reported naturally in the US since 1934; still endemic in East Asia, South America, Eastern Europe, North Africa, and the Middle East
- Both B. mallei and B. pseudomallei are considered bioterrorism threats
Pathogenesis: Tissue damage results from exotoxins including pyocyanin (interferes with electron transfer), lecithinase (causes cell lysis), collagenase, lipase, and hemolysin.
Clinical Forms (4):
| Form | Features |
|---|---|
| Septicemic (Acute) | Malaise, chills, fever, diarrhea, joint pain; disseminated pustular eruption, cellulitis, lymphangitis, erythroderma, cyanosis, jaundice; multi-organ failure; mortality ~50% (>90% without treatment) |
| Localized | Nodule/pustule/vesicle surrounded by hemorrhagic edema at inoculation site after 1-5 days; superficial sloughing produces ulcer with gray-brown base; can involve nasal mucosa, causing epistaxis, mucoid discharge, or septal/palatal perforation |
| Pulmonary | After inhalation; catarrhal symptoms, then epistaxis/mucoid nasal discharge (characteristic) |
| Chronic | Malaise, myalgias, fevers; painful subcutaneous/intramuscular abscesses; "farcy buds" - multiple nodules along draining lymphatics; "farcy pipes" - firm cords from lymphatic involvement |
Skin Lesion Pattern:
- Inflammatory papule/vesicle at inoculation site
- Rapidly progresses: nodular → pustular → ulcerative
- Irregular excavation with undermined edges, purulent and sanguineous exudate
- "Farcy buds" develop along lymphatics in days to weeks, then break down
Diagnosis:
- Culture: Isolation of B. mallei from skin ulcers or nasal discharge is definitive
- Serum agglutination to confirm
- Also: serological tests, PCR-based assays, indirect hemagglutination assay
Treatment:
| Disease Extent | Regimen |
|---|---|
| Localized (skin) | Amoxicillin-clavulanate, doxycycline, or TMP-SMX for 60-150 days |
| Severe/septic | IV ceftazidime (parenteral) |
| Other options | Ciprofloxacin, streptomycin, gentamicin |
| Infected lab worker (reported cure) | Imipenem + doxycycline in combination |
Note: Bovine farcy (a related but distinct condition) is caused by Mycobacterium farcinogenes and M. senegalense in sub-Saharan Africa, presenting as suppurative granulomatous inflammation of skin and lymphatics.
- Andrews' Diseases of the Skin, p. 326; Dermatology 2-Volume Set 5e
2. MELIOIDOSIS (Whitmore Disease)
Causative organism: Burkholderia pseudomallei - a motile, obligately aerobic, intracellular, non-spore-forming Gram-negative bacillus found in soil and water.
- Name derived from Greek: melis (donkey distemper) + eidos (resembles) - i.e., "resembles glanders"
Epidemiology:
- Endemic in Southeast Asia and northern Australia; also Africa, Middle East, Central and South America
- B. pseudomallei identified along Gulf Coast of the US; contaminated imported products (e.g., aromatherapy spray from India) have caused US outbreaks
- Cases peak during rainy season (aerosolization of bacteria)
- Transmission: direct contact with contaminated soil/water (through abraded/lacerated skin), ingestion, inhalation, or sexual intercourse
Risk factors for severe disease: Diabetes mellitus (highest risk), alcohol use, chronic lung disease, chronic kidney disease, chronic renal failure
Clinical Forms:
| Form | Features |
|---|---|
| Acute localized | Cellulitis, subcutaneous abscesses, granulomatous lesions |
| Acute pulmonary | Pneumonia; often confused with TB in subacute form |
| Acute septicemic | Multiple miliary abscesses in viscera; rapid death |
| Cutaneous manifestations | Cellulitis, subcutaneous abscesses, granulomatous lesions, ecthyma gangrenosum, purpura, pustules, Sweet syndrome, urticaria |
| Chronic | Abscesses and granulomas in multiple sites |
| Uncommon complications | Severe urticaria, necrotizing fasciitis |
Key clinical features: Similar to glanders, disseminated fungal infections, and tuberculosis. Can remain latent for decades and recrudesce.
Diagnosis:
- Bacterial culture - gold standard, but sensitivity only ~60%
- Multiplex PCR - more sensitive and species-specific
- Complement-fixing and agglutinating antibodies appear 4-6 weeks after infection (serologic testing alone inadequate in endemic regions)
Treatment:
| Phase | Regimen |
|---|---|
| Intensive phase (acute/septicemic) | IV ceftazidime or carbapenem (meropenem/imipenem) for at least 10-14 days |
| Eradication phase | Oral TMP-SMX or amoxicillin/clavulanate for ≥3 months (up to 3-6 months) |
| Chronic cutaneous only | Oral treatment alone usually effective |
Resistance: B. pseudomallei shows intrinsic resistance to quinolones, macrolides, and aminoglycosides.
Prognosis: Sepsis mortality 50-90%; with intensive supportive care lowers to ~20%. Relapse rate ~10%.
- Andrews' Diseases of the Skin, p. 326; Dermatology 2-Volume Set 5e, p. 1541
3. LYME DISEASE
Causative organisms: Borrelia burgdorferi sensu lato species complex; transmitted by Ixodidae (hard ticks).
- B. burgdorferi sensu stricto - United States
- B. garinii - European Lyme neuroborreliosis
- B. afzelii - acrodermatitis chronica atrophicans, lymphocytoma (Europe)
- Borrelia lonestari - STARI (Southern Tick-Associated Rash Illness) via Lone Star tick (Amblyomma americanum)
Skin Manifestations
Stage 1 - Early Localized: Erythema Migrans (EM)
- ~50% of patients recall tick bite (leaves small red macule/papule)
- Sites: legs, groin, axilla (adults: lower extremity; children: trunk more common)
- 3-32 days (median 7) after bite: gradual expansion of redness
- Advancing border: slightly raised, warm, red to bluish-red, no scale
- Center may clear (bull's-eye/annular appearance) or remain red, indurated, vesicular, or necrotic
- US pattern: usually homogeneous central redness
- European pattern: large annular variety most common
- Median diameter 15 cm (range 3-68 cm)
- Burning sensation in ~50%; rarely pruritic; localized alopecia may develop
Fig. 14.50A - Erythema migrans: early expanding erythema
Fig. 14.50B - Erythema migrans: large annular pattern
Stage 2 - Early Disseminated (European features):
- Borrelia-induced lymphocytoma: B-cell proliferations presenting as red, indurated papules and plaques, most commonly on areola or earlobe; occurs from time of EM until 10 months later
Stage 3 - Late/Chronic (European, B. afzelii):
- Acrodermatitis chronica atrophicans (ACA): late cutaneous sequela
- Also: morphea, atrophoderma of Pasini and Pierini, anetoderma, lichen sclerosus et atrophicus
- Some morphea-type lesions: interstitial granulomatous dermatitis with histiocytic pseudorosettes
Systemic Manifestations
| System | Features |
|---|---|
| Musculoskeletal | Chronic arthritis of knees in ~10% of untreated US patients; half progress to severe disability |
| Cardiac | Fluctuating AV block or complete heart block (3 days - 6 weeks); dilated cardiomyopathy (Europe) |
| Neurologic | Stiff neck, headache, meningitis, Bell palsy, optic neuritis, radiculopathy, cranial/peripheral neuropathies; Bannworth syndrome in Europe (radicular pains + lymphocytic meningitis + cranial nerve paralysis) |
| Transplacental | Rare; infant deaths reported |
Histopathology of EM
- Superficial and deep perivascular and interstitial mixed-cell infiltrate
- Lymphocytes, plasma cells, eosinophils (especially at center)
- Warthin-Starry stain may reveal spirochetes in upper dermis
Diagnosis
| Test | Detail |
|---|---|
| Clinical | EM recognition is most sensitive for early infection |
| Serologic conversion | 27% at <7 days symptoms; 41% at 7-14 days; 88% at >2 weeks |
| ELISA (screening) | 89% sensitive, 72% specific |
| Western blot (confirmatory) | IgM: 2 of 3 bands positive; IgG: 5 of 10 bands positive |
| False positives | Syphilis, pinta, yaws, leptospirosis, relapsing fever, EBV, autoantibody diseases |
| VDRL | Negative in B. burgdorferi infection |
| PCR | Specific but not sensitive; not widely available |
Treatment
| Population | Drug | Dose/Duration |
|---|---|---|
| Adults (EM/early) | Doxycycline | 100 mg BID × 3 weeks |
| Alternative (adults) | Amoxicillin | 500 mg TID |
| Children / pregnant | Amoxicillin | 500 mg TID |
| Pregnant women | Penicillin | preferred alternative |
| Cardiac (complete heart block) | IV ceftriaxone | 2 g/day |
| Late neurologic/arthritis | IV ceftriaxone | 2 g/day × 30 days |
| ACA / late skin | Doxycycline or penicillin | 3-4 weeks |
- Andrews' Diseases of the Skin, pp. 334-336
4. SKIN DISEASES CAUSED BY NONTUBERCULOUS MYCOBACTERIA (NTM)
NTM are acid-fast mycobacteria that do not cause tuberculosis. >190 species are now known. Human skin disease is increasing due to: cosmetic procedures, expanding immunocompromised populations, improved identification techniques.
Classification by growth rate:
- Rapidly growing mycobacteria (RGM): subcultured within 1 week - M. fortuitum, M. chelonae, M. abscessus
- Slowly growing mycobacteria:
- Photochromogens (pigment only with light): M. marinum, M. kansasii
- Scotochromogens (pigment regardless of light): M. gordonae, M. scrofulaceum
- Nonchromogens (no pigment): MAC organisms, M. ulcerans
Diagnostic approach: Culture at both high and low temperatures on special media; AFB stain; PCR from fresh or paraffin-fixed tissue; molecular identification.
A. Mycobacterium marinum - Fish Tank Granuloma / Swimming Pool Granuloma
Source: Fresh and salt water; kills aquarium fish. Grows optimally at 30°C (photochromogen).
Exposure: Home aquariums, fishermen, fish sellers, aquaculture. A preceding injury with water exposure is usually present. Males 60% of cases.
Skin lesions:
- Start ~3 weeks after exposure as indolent papule/nodule on hands, knees, elbows, or feet
- Keratotic or warty surface
- Sporotrichoid pattern (ascending nodules up the arm) is very common
- Immunosuppressed: ulcers and abscesses
- Deep structures: tenosynovitis, bursitis, arthritis, osteitis; tendon sheath involvement limiting range of motion
Fig. 16.27 - M. marinum infection in a sporotrichoid pattern (Andrews' Diseases of the Skin)
Treatment: Combination of macrolide + ethambutol + rifamycin. Therapy continued 1-2 months after clinical resolution; longer for tendon/bone involvement. Also active: sulfonamides, TMP-SMX, doxycycline, minocycline, clarithromycin.
B. Mycobacterium ulcerans - Buruli Ulcer
Geography: West and Central Africa, Australia, Papua New Guinea, Southeast Asia.
Transmission: Contact with contaminated soil or water (abraded skin); in Australia, mosquito bites are associated.
Skin lesions:
- Starts as painless nodule, plaque, or edema (preulcerative)
- Progresses to massive, undermined ulcer - destroys skin, subcutaneous tissue, and fascia
- Histotoxin mycolactone causes tissue necrosis and immune suppression
Diagnosis: AFB smear (up to 80% positive), culture, PCR, histology; at least one test positive in 94% when all three done simultaneously.
Treatment: Daily observed therapy for 8 weeks with streptomycin + rifampin; ciprofloxacin may substitute for streptomycin. Healing is slow (half healed by 24 weeks). Surgical excision with delayed grafting for those refusing/intolerant to antibiotics.
Complications: Severe scarring, contracture deformity, amputation; periocular involvement may require enucleation; metastatic skin lesions; rarely bone lesions (75% distant from primary ulcer).
C. Rapidly Growing Mycobacteria (RGM): M. fortuitum, M. chelonae, M. abscessus
Exposure sources:
- Trauma, surgery, injections in immunocompetent patients
- Cosmetic procedures: laser resurfacing, laser hair removal, dermal fillers, botulinum toxin, mesotherapy, liposuction, Mohs surgery, acupuncture, tattoos, skin piercing
- Nail salon whirlpool footbaths (M. fortuitum leg abscess outbreaks)
- Renal transplant patients: tender nodular leg lesions
Skin lesions:
- Small erythematous papules, many spontaneously heal
- Others progress to large, fluctuant, painful abscesses that can ulcerate
- Sporotrichoid or disseminated disease in immunocompromised patients
- Deep extension into underlying bone possible
Fig. 16.13 - Mycobacterium fortuitum infection (Andrews' Diseases of the Skin)
Treatment:
| Organism | Treatment |
|---|---|
| M. chelonae / M. abscessus (skin) | Clarithromycin 500 mg BID × ≥6 months |
| M. chelonae / M. abscessus (severe/immunosuppressed) | Moxifloxacin + surgical debridement |
| M. fortuitum | Amikacin + cefoxitin + probenecid (6 weeks) then doxycycline or TMP-SMX up to 1 year; combination recommended |
| Pulmonary M. abscessus | Macrolide + IV amikacin, carbapenem, cefoxitin, or tigecycline (extremely difficult to cure) |
D. Mycobacterium haemophilum
Hosts: Primarily immunosuppressed patients (HIV, organ transplant, biologic agents, leukemia/lymphoma).
Growth requirement: Grows preferentially at 30-32°C (acral sites predominate - cooler body areas).
Skin lesions: Papules, plaques (cellulitis-like), dermal/subcutaneous nodules; break down to form painful draining ulcers. Also: septic arthritis, osteomyelitis, pulmonary nodules.
Special populations: Also reported in immunocompetent patients after acupuncture, permanent eyebrow makeup, and tattoos.
Culture: Requires special media (must notify the lab if suspected - not isolated on routine media).
Treatment: Ciprofloxacin + clarithromycin + rifabutin (all three in combination) for 1 year; adjunctive surgery may be needed.
E. Mycobacterium avium-intracellulare (MAC)
Skin involvement: Uncommon except in AIDS with disseminated infection (hematogenous spread).
- Presents as nodules, ulcers, pustules, or cellulitis-like appearance
- Rare cases of inoculation-type lesions in immunocompetent hosts
Treatment (disseminated): Clarithromycin or azithromycin + ethambutol + rifabutin (at least 3 drugs). Ensure adequate antiretroviral therapy in HIV patients.
F. Mycobacterium kansasii
Skin infection: Rare; usually after minor trauma; 75% in immunosuppressed persons.
Lesions: Papules, nodules, pustules, cellulitis, or sporotrichoid pattern.
Treatment: Isoniazid + rifampin + ethambutol until 12 months after culture clearance (15 months for HIV patients); surgical excision adjunctively.
Summary Table: NTM Skin Infections
| Organism | Setting | Characteristic Lesion | Key Treatment |
|---|---|---|---|
| M. marinum | Aquarium/water exposure | Papule/nodule → sporotrichoid ascending nodules | Macrolide + ethambutol + rifamycin |
| M. ulcerans | Africa, Australia | Massive undermined ulcer (Buruli ulcer) | Streptomycin + rifampin × 8 weeks |
| M. fortuitum | Trauma, nail salon, cosmetics | Subcutaneous abscess, cellulitis | Amikacin + cefoxitin → doxycycline/TMP-SMX |
| M. chelonae/abscessus | Surgery, cosmetics, trauma | Subcutaneous abscesses, erythematous papules | Clarithromycin ± moxifloxacin |
| M. haemophilum | Immunosuppressed, acral | Papules, nodules, draining ulcers at acral sites | Ciprofloxacin + clarithromycin + rifabutin |
| M. kansasii | Minor trauma, immunosuppressed | Papules, nodules, sporotrichoid | INH + rifampin + ethambutol |
| MAC | AIDS, disseminated | Nodules, ulcers, cellulitis-like | Clarithromycin/azithromycin + ethambutol + rifabutin |
- Andrews' Diseases of the Skin, pp. 388-395; Harrison's Principles of Internal Medicine 22E, pp. 1461-1470
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