eMedicine Specialties > Pulmonology > Infectious Lung Diseases
Pneumonia, Fungal: Treatment & Medication
Updated: Sep 17, 2009
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Treatment
Medical Care
In persons with endemic mycoses, spontaneous recovery usually occurs without treatment, especially in patients who are mildly affected and immunocompetent without dissemination; otherwise, administer treatment as outlined in the Table below.
If aspergillosis, mucormycosis, and candidiasis occur in an immunocompromised host, reverse the factors affecting the patient's immune status, which is linked to successful recovery from the infection. Attempt the following ancillary events, which may help to promote recovery from the opportunistic infection:
- With the use of growth factors, ensure neutropenia recovery in patients receiving chemotherapy and bone marrow transplants.
- Withdraw or taper immunosuppressive drugs and steroids.
- Remove infected or highly colonized catheters in patients with candidiasis.
[#target1] Medical treatment
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Table
| Fungal Pathogen | Indication for Antifungal Therapy | Surgical Care and Other Treatments | Antifungal Drugs Used |
|---|---|---|---|
| Histoplasmosis | Acute pulmonary histoplasmosis with hypoxia; prolonged moderate symptoms for more than 1 month; disseminated disease; immunosuppressed host Mortality rate for untreated disseminated disease at 80%; reduced to 25% with treatment | Significant hemoptysis; recurrent pneumonia; repair of bronchopleural fistula Corticosteroids in severe hypoxia Anti-inflammatory agents to treat rheumatologic syndromes | Amphotericin B induces rapid response in patients who are severely ill Azoles/triazoles in patients with milder illness |
| Coccidioidomycosis | Disseminated disease; chronic pulmonary disease; acute pulmonary infection with hypoxia or protracted morbidity (>1-2 mo); immunosuppressed host (worst outcome, 70% mortality) | Surgical debridement or resection of infective tissue often necessary adjunct to antifungal treatment Anti-inflammatory agents for rheumatologic syndromes | Amphotericin B effective in more than 90% of cases Fluconazole or itraconazole after improvement Treatment less effective than in other endemic mycoses |
| Persistent or recurrent symptoms of acute or chronic pulmonary disease or with pleural involvement; disseminated disease | N/A | Amphotericin B response rates of 77-90% Itraconazole successful in 90% Ketoconazole response of 80%; poor outcome in patients who are immunosuppressed Fluconazole less effective, 65% response rate Chronic maintenance treatment essential for all patients with AIDS or meningitis | |
| Cryptococcosis | Patients who are immunosuppressed and symptomatic; patients who are immunocompetent with disease progression; any patients with meningitis or disseminated disease | N/A | Amphotericin B in patients who are severely ill Fluconazole in milder cases or after clinical response to amphotericin B Lifelong maintenance therapy in AIDS patients may not be necessary as long as the patient's CD4 count is maintained above 100 cells/µL with HAART 13 |
All patients with invasive disease; in patients who are immunosuppressed, early diagnosis and empiric treatment for persistent fever not responding to broad-spectrum antibiotics; high mortality once infiltrates and symptoms appear; prognosis ultimately linked to severity and outcome of underlying disease Mortality rate of 50-60% in patients with AIDS; mortality rate as high as 85% in patients with prior bone marrow transplantation | Aggressive surgical debridement of necrotic tissue important in mucormycosis, especially if confined to lungs Rapid tapering of immunosuppressive agents and corticosteroids and reversal of neutropenia (if possible) | Voriconazole is the new standard of care for invasive aspergillosis based on superiority over amphotericin B in primary therapy Lipid formulations of amphotericin B have at least equal efficacy but less toxicity compared with amphotericin B desoxycholate Oral voriconazole can be used to complete treatment with initial response to IV voriconazole or amphotericin B; Mucor species generally resistant to azoles Caspofungin useful as salvage therapy | |
| Candidiasis | All patients with invasive disease or dissemination; important to reverse factors affecting immune status | Rapid tapering of immunosuppressive agents and corticosteroids; important to remove indwelling infected intravenous lines or urinary catheters in setting of hematogenous spread | Amphotericin B is mainstay Flucytosine may be of benefit when added to amphotericin B Fluconazole use in pulmonary disease not studied but is effective in hepatosplenic candidiasis and candidemia Echinocandins may be useful alternatives |
| Fungal Pathogen | Indication for Antifungal Therapy | Surgical Care and Other Treatments | Antifungal Drugs Used |
|---|---|---|---|
| Histoplasmosis | Acute pulmonary histoplasmosis with hypoxia; prolonged moderate symptoms for more than 1 month; disseminated disease; immunosuppressed host Mortality rate for untreated disseminated disease at 80%; reduced to 25% with treatment | Significant hemoptysis; recurrent pneumonia; repair of bronchopleural fistula Corticosteroids in severe hypoxia Anti-inflammatory agents to treat rheumatologic syndromes | Amphotericin B induces rapid response in patients who are severely ill Azoles/triazoles in patients with milder illness |
| Coccidioidomycosis | Disseminated disease; chronic pulmonary disease; acute pulmonary infection with hypoxia or protracted morbidity (>1-2 mo); immunosuppressed host (worst outcome, 70% mortality) | Surgical debridement or resection of infective tissue often necessary adjunct to antifungal treatment Anti-inflammatory agents for rheumatologic syndromes | Amphotericin B effective in more than 90% of cases Fluconazole or itraconazole after improvement Treatment less effective than in other endemic mycoses |
| Persistent or recurrent symptoms of acute or chronic pulmonary disease or with pleural involvement; disseminated disease | N/A | Amphotericin B response rates of 77-90% Itraconazole successful in 90% Ketoconazole response of 80%; poor outcome in patients who are immunosuppressed Fluconazole less effective, 65% response rate Chronic maintenance treatment essential for all patients with AIDS or meningitis | |
| Cryptococcosis | Patients who are immunosuppressed and symptomatic; patients who are immunocompetent with disease progression; any patients with meningitis or disseminated disease | N/A | Amphotericin B in patients who are severely ill Fluconazole in milder cases or after clinical response to amphotericin B Lifelong maintenance therapy in AIDS patients may not be necessary as long as the patient's CD4 count is maintained above 100 cells/µL with HAART 13 |
All patients with invasive disease; in patients who are immunosuppressed, early diagnosis and empiric treatment for persistent fever not responding to broad-spectrum antibiotics; high mortality once infiltrates and symptoms appear; prognosis ultimately linked to severity and outcome of underlying disease Mortality rate of 50-60% in patients with AIDS; mortality rate as high as 85% in patients with prior bone marrow transplantation | Aggressive surgical debridement of necrotic tissue important in mucormycosis, especially if confined to lungs Rapid tapering of immunosuppressive agents and corticosteroids and reversal of neutropenia (if possible) | Voriconazole is the new standard of care for invasive aspergillosis based on superiority over amphotericin B in primary therapy Lipid formulations of amphotericin B have at least equal efficacy but less toxicity compared with amphotericin B desoxycholate Oral voriconazole can be used to complete treatment with initial response to IV voriconazole or amphotericin B; Mucor species generally resistant to azoles Caspofungin useful as salvage therapy | |
| Candidiasis | All patients with invasive disease or dissemination; important to reverse factors affecting immune status | Rapid tapering of immunosuppressive agents and corticosteroids; important to remove indwelling infected intravenous lines or urinary catheters in setting of hematogenous spread | Amphotericin B is mainstay Flucytosine may be of benefit when added to amphotericin B Fluconazole use in pulmonary disease not studied but is effective in hepatosplenic candidiasis and candidemia Echinocandins may be useful alternatives |
Surgical Care
- Indications for surgery in invasive aspergillosis are as follows14 :
- In patients with documented fungal infection treated with antifungal agents but with residual lesions to prevent disease relapse when additional immunosuppression is required
- To prevent or treat massive bleeding especially when the lung lesion is contiguous to a large blood vessel
Consultations
- A pulmonologist may perform diagnostic procedures (eg, bronchoscopy, lavage).
- Interventional radiologists can perform needle aspirations, when necessary, for diagnosis.
- Patients who are severely ill and progressively hypoxic may require intensive care, ventilatory support, and pressor support in the ICU under the care of a critical care intensivist.
- Consultations with surgeons are required as indicated above and the Table in Medical Care.
- Rheumatologists can assist with the rheumatologic syndromes manifesting with the endemic mycoses.
- Infectious disease consultants may assist with the intricacies of antifungal treatment, especially with respect to the exact drugs, dose, duration, therapy length, maintenance treatment, and even follow-up studies.
Medication
When treatment is indicated, initiate antifungal agents as appropriate. Amphotericin B is the mainstay of initial therapy in many cases, especially for patients who are acutely ill. More expensive liposomal preparations of amphotericin B offer equal efficacy with less toxicity. In patients with invasive aspergillosis, including pulmonary aspergillosis, voriconazole is the new standard of care based on superiority over amphotericin B as primary therapy.15,16,17 Vary the dose and treatment duration depending on the underlying pathogen causing the pneumonia.
Amphotericin B is available in the following formulations:
- Conventional amphotericin B injection contains amphotericin B and sodium deoxycholate as the solvent vehicle.
- Amphotericin B cholesteryl sulfate complex (ABCD, Amphotec) consists of a 1:1 molar ratio of amphotericin B to cholesteryl sulfate in a colloidal dispersion, forming a bilayer in microscopic disk-shaped particles that have a diameter of approximately 115 nm and a thickness of 4 nm.
- Amphotericin B lipid complex (ABLC, Abelcet) is composed of amphotericin B and phospholipid complex, with a microscopic ribbonlike structure having a diameter of approximately 2-11 µm.
- Liposomal amphotericin B (L-AmB, AmBisome) contains amphotericin B intercalated in a unilamellar bilayer liposomal membrane; has a liposomal membrane diameter less than 100 nm; and consists of hydrogenated soy phosphatidylcholine, cholesterol, distearoyl phosphatidylglycerol, and alpha-tocopherol.
Prophylactic therapy (suppressive therapy) with amphotericin B is used against recurrence or relapse of coccidioidomycosis, cryptococcosis, or histoplasmosis in individuals infected with HIV who have received adequate treatment of the infection. Other formulations, however, are starting to replace amphotericin B because of their ease of use (oral formulations) and less toxicity for more long-term suppression. Posaconazole is used in the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients receiving hematopoietic stem cell transplants with graft versus host disease or those with hematologic malignancies with chemotherapy-induced neutropenia.
Other antifungal agents used in the treatment of fungal pneumonia are fluconazole (Diflucan), itraconazole (Sporanox), flucytosine (Ancobon), and ketoconazole (Nizoral). Newer antifungal agents such as the third-generation triazoles or the echinocandins are more tolerable than amphotericin B or its liposomal preparations and may even be more effective in first- or second-line treatment.
Caspofungin is approved for the treatment of invasive Aspergillus infections in patients unresponsive to or unable to receive amphotericin B. Combinations of a triazole with an echinocandin with or without amphotericin B have been anecdotally reported to be effective in some cases of resistant organisms such as Mucor or Zygomycetes species. Echinocandins such as caspofungin, micafungin, and anidulafungin18,19,20 offer a broad spectrum of activity for the many Candida species, including fluconazole-resistant strains. They also show effectiveness in Aspergillus infections alone or in combination with an azole. Because of these new safer and possibly more potent agents and the ability to combine them together, the outlook for patients with invasive pulmonary infections, especially immunocompromised hosts, may be improving.
The role of combination therapy has only been studied in small retrospective trials with very unclear results. Combination therapy is usually not indicated in first-line treatment. In rare cases, it might be offered with a great deal of caution as second-line or salvage treatment.21
Antifungal Agent, Systemic
The mainstay of therapy for fungal pneumonias must include antifungal agents. The type of antifungal drug to be used must be tailored based on the particular pathogen isolated or clinically suspected. Many classes of antifungal agents are now available, including the classic antibiotics; first-, second-, and third-generation triazoles; and the echinocandins. The establishment of neutrophil recovery or engraftment and the reduction of immunosuppression in certain patients who are at risk for fungal infections are likely to improve the chances of a successful treatment outcome. Granulocyte-macrophage colony-stimulating factor can theoretically augment pulmonary host defenses against Aspergillus fumigatus infection .
Voriconazole (VFEND)
Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal CYP450–mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.
Adult
Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses
Maintenance: 4 mg/kg IV q12h infused over 2 h; when able to tolerate PO, may switch to 200 mg PO q12h (administer PO 1 h ac or pc)
Note: For inadequate response, may increase to 300 mg PO q12h; <40 kg administer oral maintenance dose of 100 mg PO q12h (may increase to 150 mg PO q12h)
Pediatric
<12 years: Not established
>12 years: Data limited; administer as in adults
CYP450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitors; CYP450 inducers (eg, rifampin) decrease steady-state peak plasma levels by up to 93%; may increase serum levels of drugs metabolized by CYP450 2C19 or 2C9, of which some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids); others may require more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG-CoA inhibitors, benzodiazepines, calcium channel blockers)
Documented hypersensitivity; CrCl <50 mL/min (decreased excretion of IV vehicle) if administering IV; coadministration with rifampin, rifabutin, carbamazepine, barbiturates, sirolimus, pimozide, quinidine, cisapride, or ergot alkaloids
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Decrease maintenance dose in hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, rash (including Stevens-Johnson syndrome and phototoxicity), and respiratory disorder; rare cases of severe hepatotoxicity reported; administer PO dosage form 1 h ac or pc
Amphotericin B, conventional (Amphocin, Fungizone)
Antifungal antibiotic produced by Streptomyces nodosus. Has a broad spectrum of activity against pathogenic fungi, including yeasts, except Fusarium species. Exerts antifungal activity, principally by binding to sterols in fungal cell membrane.
Adult
0.25-1.5 mg/kg/d IV; not to exceed 1.5 mg/kg/d
Test dose: 1 mg in 20 mL of D5W infused IV over 20-30 min; monitor pulse, respiration rate, temperature, and blood pressure q30min for 2 h
Invasive aspergillosis: 0.5-0.6 mg/kg/d IV (1-1.5 mg/kg/d in patients who are neutropenic for rapidly progressing, potentially fatal infections); duration uncertain; cumulative dose of 1.5-4 g has been administered over 11 mo
Zygomycosis or mucormycosis: 1-1.5 mg/kg/d IV for 2-3 mo; cumulative dose of 3-4 g
Invasive candidiasis: 0.4-0.6 mg/kg/d IV (1-1.5 mg/kg/d for candidemia or rapidly progressing potentially fatal infections); treat for 7-14 d in low-risk patients (6 wk or longer in high-risk patients)
Blastomycosis: 0.5-1 mg/kg/d IV; cumulative dose of 1.5 g for patients who are very ill
Coccidioidomycosis: 0.5-1 mg/kg/d IV (1.5 mg/kg/d in rapidly progressing, potentially fatal infections); treat for 4-12 wk; treat for at least 8 wk in patients with HIV
Histoplasmosis: 0.5-1 mg/kg/d IV for 7 d; then, 0.8 mg/kg IV qod; total dose of 10-15 mg/kg in patients with HIV
Paracoccidioidomycosis: 0.4-0.5 mg/kg/d IV; total dose of 1.5-2.5 g
Cryptococcosis: 0.3-1 mg/kg/d IV (with or without flucytosine) until response, usually 2-4 wk to several mo; then, change to fluconazole 400 mg PO/IV for 8-10 wk; in patients with HIV infection, follow with indefinite suppressive treatment with fluconazole at 200 mg/d
Amphotericin B cholesteryl sulfate complex: 3-4 mg/kg/d IV for invasive aspergillosis; 3-6 mg/kg/d IV for invasive Candida species or cryptococcal infections in patients unresponsive to or intolerant of conventional IV amphotericin B; dosages of as high as 7.5 mg/kg are used in BMT patients
Amphotericin B lipid complex: 5 mg/kg/d for aspergillosis at median duration of 25 d; as long as 6 wk for cryptococcosis in patients with HIV infection; then, 12 wk of fluconazole PO
Liposomal amphotericin B: 3-5 mg/kg/d IV for systemic fungal infections (eg, Aspergillus, Candida, and Cryptococcus species)
Pediatric
Administer as in adults
Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; renal toxicity risk increases with cyclosporine
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Monitor renal function, serum electrolyte values (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients who are neutropenic and receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion)
Amphotericin B, liposomal (AmBisome)
Novel lipid formulations of amphotericin B that deliver higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity. Produced from a strain of S nodosus. Antifungal activity of amphotericin B results from its ability to insert itself into fungal cytoplasmic membrane at sites containing ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium). At low concentrations, main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, pores of 40-105 nm in cytoplasmic membrane are produced, leading to large losses of ions and other molecules. A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. Main fungicidal activity of amphotericin B may reside in ability to cause auto-oxidation of cell membranes.
Adult
3-5 mg/kg/d IV for systemic fungal infections (eg, Aspergillus, Candida, and Cryptococcus species)
Pediatric
Administer as in adults
Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity increased with cyclosporine
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Monitor renal function, serum electrolyte levels (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock
Amphotericin B lipid complex (Abelcet)
Amphotericin B in phospholipid complexed form. Produced from a strain of S nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death. Has a broad spectrum of activity against pathogenic fungi, including yeasts, except Fusarium species. Exerts antifungal activity, principally by binding to sterols in fungal cell membrane.
Drug of third choice when conventional amphotericin B therapy is failing and renal function is not impaired.
Adult
5 mg/kg/d IV for aspergillosis at median duration of 25 d; as long as 6 wk for cryptococcosis in patients with HIV infection; then, 12 wk of fluconazole PO
Pediatric
Administer as in adults
Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity increased with cyclosporine
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Infusion-related adverse effects are common and may require pretreatment with acetaminophen, diphenhydramine, and hydrocortisone; dose-limiting renal toxicity limits use; monitor renal function, serum electrolyte levels (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients who are neutropenic and receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion)
Caspofungin (Cancidas)
Used to treat refractory invasive aspergillosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.
Adult
70 mg IV over 1 h on day 1; 50 mg IV qd thereafter
Pediatric
Not established
Coadministration with cyclosporine may increase risk of hepatotoxicity; carbamazepine, nelfinavir, efavirenz, or dexamethasone may decrease levels; may decrease levels of tacrolimus; rifampin decreases levels by 30% (ie, adjust dose to 70 mg/d)
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in moderate hepatic dysfunction (ie, decrease dose to 35 mg/d); may exacerbate preexisting renal dysfunction or myelosuppression
Anidulafungin (Eraxis)
Antifungal agent of the echinocandin class. Inhibits synthesis of 1,3-beta-D-glucan, an essential component of fungal cell walls. Indicated to treat esophageal candidiasis, candidemia, and other forms of candidal infections (eg, intraabdominal abscesses, peritonitis).
Adult
Candidemia or other candidal infections: 200 mg IV on day 1; decrease dose on day 2 and thereafter to 100 mg/d IV; do not exceed infusion rate of 1.1 mg/min
Pediatric
Not established for <2 y
For >2 y, similar drug levels as in adults can be achieved using the following:
0.75 mg/kg/d = 50 mg/d in adults for esophageal candidiasis
1.5 mg/kg/d = 100 mg/d in adults for invasive candidiasis or aspergillosis
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include hypokalemia, diarrhea, elevated hepatic enzyme levels, and headache; rare reports of serious hepatotoxicity; infusion-related reactions (eg, rash, urticaria, flushing, pruritus, dyspnea, hypotension) may occur, particularly with rapid infusion; following reconstitution, dilute further with D5W or NS before administration
Micafungin (Mycamine)
Member of new class of antifungal agents, echinocandins, that inhibit cell wall synthesis. Inhibits synthesis of 1,3-beta-D-glucan, an essential fungal cell wall component not present in mammalian cells.
Indications include (1) prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and (2) treatment of esophageal candidiasis.
Adult
Candidiasis prophylaxis: 50 mg IV qd infused over 1 h
Esophageal candidiasis: 150 mg IV qd infused over 1 h
Pediatric
Not established
Increases sirolimus and nifedipine AUC approximately 20%
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects may include headache, nausea, vomiting, and abdominal pain; other adverse effects include rash, delirium, phlebitis, shock, leukopenia, and hyperbilirubinemia; rare cases of elevated hepatic enzyme, BUN, and creatine levels have been reported; transient acute intravascular hemolysis and hemoglobinuria may occur; do not mix or infuse in same IV line with other medications because precipitate forms with other commonly used medications (flush existing IV line with 0.9% NaCl before and after infusion); protect from light following dilution
Posaconazole (Noxafil)
Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus infections in patients at high risk because of severe immunosuppression.
Adult
200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption
Pediatric
<13 years: Not established
>13 years: Administer as in adults
Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor; UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk); inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine)
Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates likely to result in serious toxicities (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding
Fluconazole (Diflucan)
First of a new subclass of synthetic triazole antifungal agents is available as tab for oral administration, as a powder for oral susp, and as a sterile solution for IV use. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha demethylation. In general, a loading dose of twice the daily dose is recommended on first day of therapy to result in plasma concentrations close to steady state by second day of therapy. Base daily dose for treatment of infections other than vaginal candidiasis on infecting organism and patient response to therapy. Continue treatment until clinical parameters or laboratory test results indicate active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.
Adult
Systemic candidiasis: 400 mg PO/IV qd; continue for a minimum of 4 wk and for at least 2 wk after symptoms resolve
Cryptococcal meningitis: 400 mg PO/IV for 1 d; then 200-400 mg PO/IV qd; continue for 10-12 wk after cerebrospinal fluid becomes culture negative; 200 mg PO/IV qd for relapse in patients with AIDS
Coccidioidomycosis: 400 mg PO/IV for 1 d; then 200-400 mg PO/IV mg qd; 400-800 mg PO/IV qd for patients infected with AIDS
Blastomycosis/histoplasmosis: 400-800 mg PO/IV qd
Prophylaxis against candidiasis in patients undergoing bone marrow transplantation: 400 mg PO/IV qd; if patient is anticipated to have severe granulocytopenia (<500 neutrophils/m L), start fluconazole prophylaxis several days before anticipated onset of neutropenia; continue for 7 d after neutrophil count is >1000 cells/m L
Pediatric
Usual range: 3-12 mg/kg PO/IV qd; not to exceed 600 mg qd; dose of 3, 6, or 12 mg/kg qd in pediatric patients is equivalent to a dosage of 100, 200, or 400 mg qd, respectively, in adults; for neonates <2 wk, administer same daily dose as older children, but administer q72h
Systemic candidiasis: 6-12 mg/kg/d PO/IV
Cryptococcal meningitis: 12 mg/kg PO/IV for 1 d; then, 6-12 mg/kg PO/IV qd; for initial therapy, continue for 10-12 wk after cerebrospinal fluid becomes culture negative; give 6 mg/kg PO/IV qd for relapse in children with AIDS
Long-term suppressive therapy: 3-6 mg/kg PO/IV qd for cryptococcosis/histoplasmosis in children with HIV
Coccidioidomycosis: 6 mg/kg PO/IV qd
Long-term suppressive therapy for cryptococcosis or histoplasmosis in children with HIV: 3-6 mg/kg/d PO/IV
Levels may increase with hydrochlorothiazides; fluconazole levels may decrease with long-term coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Monitor closely if rashes develop, and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions (eg, AIDS, malignancy) and while taking multiple concomitant medications; not recommended during breastfeeding; weigh convenience and efficacy of single-dose regimen for treatment of vaginal yeast infections against difficulties resulting from a higher incidence of adverse reactions reported with oral fluconazole vs intravaginal agents
Itraconazole (Sporanox)
Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes. Fungistatic activity demonstrated against disseminated fungal infections caused by B dermatitidis, H duboisii, A fumigatus, C immitis, C neoformans, P brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes.
New IV formulation indicated for treatment of patients with pulmonary and extrapulmonary aspergillosis who are intolerant of or are refractory to amphotericin B therapy.
Adult
Aspergillosis
200-400 mg PO qd for 1 y
Blastomycosis
200-400 mg PO qd for 6 mo
Coccidioidomycosis
200 mg PO bid for 12-18 mo
Histoplasmosis
Moderate: 200 mg PO qd for 9 mo
Life-threatening: 200 mg PO tid for 3 d; then, 200 mg PO bid until response
Patients with HIV: 400 mg PO qd for 12 wk (85-90% response); then, 200 mg PO qd
Paracoccidioidomycosis
200 mg PO qd for 6 mo
Recommended IV dose: 200 mg IV bid for 4 doses; then, 200 mg IV qd for maximum of 14 d; each dose infused over 1 h
Pediatric
Not established; suggested dose of 100 mg/d for systemic fungal infections
Antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce levels (phenytoin metabolism may be altered)
Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects (possibly death)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in hepatic insufficiencies; do not use injection in patients with severe renal dysfunction (CrCl <30 mL/min)
Flucytosine (Ancobon)
Although exact mode of action is unknown, it is proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species and generally used in combination with amphotericin B.
Adult
50-150 mg/kg/d PO divided q6h
Pulmonary candidiasis or cryptococcosis: May be added to amphotericin B; 37.5 mg/kg PO qid for 6 wk; measure levels to get peaks of 70-80 mg/L and troughs of 30-40 mg/L
Pediatric
Not established; administration as in adults suggested
Amphotericin B may increase toxicity; cytosine may inactivate flucytosine
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in bone marrow suppression; adjust dose in renal impairment
Ketoconazole (Nizoral)
Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death
Adult
Histoplasmosis: 400 mg PO qd; less active and more poorly tolerated than itraconazole
Coccidioidomycosis: 400 mg PO qd; response rate of 28-76%; more than 50% relapses
Paracoccidioidomycosis: 400 mg PO qd for 6-18 mo
Blastomycosis: 400-800 mg PO qd for 6-18 mo
Pediatric
<2 years: Not established
>2 years: 3.3-6.6 mg/kg/d PO qd
Isoniazid may decrease bioavailability; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels
Documented hypersensitivity; immunosuppression; fungal meningitis; coadministration of cisapride and triazolam
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (adverse effects avoided with dose of 200-400 mg/d); administer antacids, anticholinergics, or H2-blockers at least 2 h after taking ketoconazole
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Further Reading
Keywords
fungal pneumonia, pulmonary mycosis, mycotic pneumonia, , endemic fungal pneumonia, aspergillosis, meningoencephalitis, cryptococcosis, acute leukemia, lymphoma, myeloablative chemotherapy, bone marrow transplantation, peripheral blood stem cell transplantation, allogeneic stem cell transplantation, unrelated donor transplantation, graft-versus-host disease, graft versus host disease, solid organ transplantation on immunosuppressive treatment, prolonged corticosteroid therapy, AIDS, congenital immune deficiency syndromes
