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Dennis Neofytos, M.D. and Paul G. Auwaerter, M.D.
08-17-2009
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Aspergillus is a ubiquitous organism and considered endemic in Zambia.
- No published reports of aspergillosis in Zambia, but has been reported in neighboring countries.
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Aspergillus spp. have been detected in maize products in Zambia.
- Capacity to make definitive Dx of aspergillosis in Zambia challenging due to limited Bx, bronchoscopy, and Cx resources.
- If Dx is made, management is as recommended below, though treatment options in Zambia are more limited.
- Voriconazole, posaconazole, liposomal amphotericin preparations, G-CSF, 5-FC, and the echinocandins are generally not available in Zambia.
Zambia Information Author: Larry William Chang, MD, MPH
- Ubiquitous filamentous mold, hyphae (2-5 µm) usually septated with 45° angle branching.
- Diagnosis mainly based on colony morphology on solid media and specific microscopic features.
- Non-invasive diagnostic tests now available: galactomannan antigen in serum and BAL (good sensitivity/specificity in the right patient population), PCR (not well studied), beta-D-glucan (not specific).
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A. fumigatus most common cause of human disease. A. flavus next most common, followed by A. terreus, A. niger (usually a contaminant), A. versicolor, and A. nidulans,Recently, new Aspergillus spp. described (e.g. A. lentulus).
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A. terreus may be resistant to amphotericin products. A. fumigatus: azole-resistance reported. A. lentulus: may be resistant to itraconazole, voriconazole, caspofungin.
- Portal of entry:respiratory tract >skin. Aspergillus conidia inhaled and migrate to bronchi/lung parenchyma, germinate into hyphae, which can invade tissue. Alveolar macrophages and neutrophils important host defences.
- Broad spectrum of disease from non-invasive: colonization, allergic bronchopulmonary aspergillosis (ABPA), aspergilloma (lung nodule), to more invasive: chronic pulmonary necrotizing aspergillosis, invasive or disseminated aspergillosis.
- Invasive disease generally seen with immune suppression: transplant (bone marrow and organ) recipients, hematologic malignancy, neutropenia, corticosteroids, HIV/AIDS, chronic granulomatous disease.
- HIV: common risk factors include advanced HIV (CD4 <50), steroid use, prior OI and neutropenia. May present as sinusitis, tracheobronchitis, otitis or pneumonia, but colonization of respiratory tract common.
- Frequent bronchial colonizer in pts w/ structural lung disease (eg, bronchiectasis, carcinoma, sarcoid, prior TB).
- Invasive lung disease w/ pleuritic chest pain, cough, hemoptysis, dyspnea. Lung imaging w/ nodular/cavitary lesions, patchy infiltrates, "halo-sign" (hemorrhage), and "crescent-sign" (necrosis).
- Dx of invasive disease: proven: histopathological/Cx evidence; probable: host factors, clinical criteria and mycological criteria (microscopy/Cx/galactomannan antigen); possible (absence of mycological support).
- Lung: allergic bronchopulmonary aspergillosis (ABPA), tracheobronchitis w/ white plaques, aspergilloma, chronic necrotizing aspergillosis, invasive aspergillosis
- Sinuses: allergic, fungus ball, invasive disease.
- CNS: abscess (contiguously through sinuses or hematogenously), mycotic infarction.
- Skin: primary (inoculation, armboard-related, catheter-related) or secondary (disseminated) in heavily immunosuppressed pts.
- Heart: endocarditis (risk factors: prosthetic heart valve surgery, IV drug abuse, central line infection).
- Eye: endophthalmitis (hematogenous or direct inoculation). Keratitis from trauma.
- Disseminated: to kidney, liver, spleen, and CNS; blood Cx rarely positive.
- Preferred: voriconazole 6 mg/kg IV q12h x 2 then 4 mg/kg IV q12h.
- Alternative: amphotericin B 1.0-1.5 mg/kg/d IV or lipid formulation amphotericin 5.0 mg/kg/d IV.
- Salvage: caspofungin 70 mg IV x 1 dose, then 50 mg IV q24h.
- Salvage: posaconazole 200 mg PO q6h x 7 d, then 400 mg PO q8-12h with food.
- Combination therapy often employed (e.g., voriconazole + caspofungin, amphotericin + voriconazole) but limited data to support practice and cost high.
- If neutropenic, use G-CSF. Decrease/stop corticosteroids/other immunosuppression if possible.
- Avoid IV voriconazole if Cr Cl<50 because cyclodextrin accumulates, although no good data.
- Often requires no intervention. Must be distinguished from necrotic mass in cavity due to invasive pulmonary aspergillosis.
- Significant hemoptysis: consider pulmonary artery embolization, partial lung resection (if adequate PFTs).
- Medical treatment of unclear benefit; main conundrum: is there invasive/progressive disease? Some data suggest itraconazole may be helpful, but rate of invasive disease low, despite risk factors.
- Medical therapy as in invasive disease.
- Surgery to remove necrotic tissue, active infection eg: brain, bone, heart valve, skin, sinuses.
- Prednisone 0.5 mg/kg/d x 1 wk then 0.5 mg/kg every other day x 5 wks with taper.
- Itraconazole 200 mg PO twice-daily x 16 wks leads to quicker steroid taper and improved pulmonary parameters. Role of voriconazole not studied.
| Drug | Recommendations/Comments |
| Amphotericin B | Prior standard therapy, now replaced by voriconazole. If used, many clinicians favor the higher dose (1.5 mg/kg/d) for aspergillosis. A. terreus may be more resistant to amphotericin B. |
| Amphotericin B liposomal | May be preferred over standard amphotericin B for reasons of toxicity, but no compelling data to suggest clinical superiority. |
| Caspofungin acetate | FDA approved for salvage therapy, but lack of larger clinical trials makes this a 2nd-tier choice compared to voriconazole; would not use alone. A. lentulus may be resistant to caspofungin. |
| Itraconazole | Older azole with some activity; would not use. |
| Voriconazole | Preferred drug for serious infections, but numerous drug interactions (calcineurin inhibitors, rifampin, PIs, EFV etc). Excellent bioavailability makes parenteral to oral switch easy. In severe invasive disease would use IV formulation. Beware of increasing azole-resistance among A. fumigatus isolates. A. lentulus may be resistant. |
| Posaconazole | Good in vitro activity, FDA approved for prevention of aspergillosis in high-risk populations, but little treatment data (can use off label as salvage therapy). Only available in oral formulation. |
| Anidulafungin | Echinocandin with spectrum similar to caspofungin; does not have indication for aspergillosis, but should work similarly. |
| Micafungin | Echinocandin with spectrum similar to caspofungin; does not have indication for aspergillosis, but should work similarly. |
- Voriconazole 4mg/kg mg PO twice-daily once clinically stable.
- Duration uncertain, but usually until no clinical evidence of active disease and reduced immunosuppression.
- Treatment failure: some define as no response within 96 hrs or persistent fever. Beware of "transient" worsening of chest CT findings upon resolution of neutropenia and possibly immune reconstitution. Consider adding caspofungin (70 mg IV x 1dose, then 50 mg IV once daily) or voriconazole. Limited data available for combination therapy.
- Very limited data to correlate galactomannan assay titers with response.
- Serious disease remains difficult to treat. However, outcomes have improved due to a number of factors (risk factor identification, high clinical suspicion, non-invasive diagnostic tests, effective/safe antifungal agents).
- Walsh T, Anaissie E, denning D, et al. ;
Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. ;
Clin Infect Dis ;
2008 ; Vol.
46 ; pp.
327-60 ;
Rating:
Basis for recommendation
Comments:Revised treatment guidelines for treatment of aspergillosis.
- De Pauw B, Walsh TJ, Donnelly JP, et al. ;
Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. ;
Clin Infect Dis ;
2008 ; Vol.
46 (12) ; pp.
1813-21 ;
PUBMED: 18462102
Rating:
Basis for recommendation
Comments:Revised definitions of invasive fungal infections, including invasive aspergillosis. Important assitions: galactomannan assay in serum/BAL.
- Herbrecht R, Denning DW, Patterson TF, et al.;
Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.;
N Engl J Med;
2002; Vol.
347; pp.
408-15;
ISSN:
1533-4406;
PUBMED: 12167683
Rating:
Basis for recommendation
Comments:Important paper that has made voriconazole preferred treatment for aspergillosis based on randomized trial of 277 pts w/ invasive aspergillosis (most had hematological malignancies). Voriconazole response rate 53% vs. 32% for amphotericin B. Survival also superior: 71 vs. 58%.
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