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Aspergillosis

• 1. Invasive pulmonary aspergillosis

• Preferred regimen: Voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h)
• Alternative regimen: Liposomal amphotericin B(L-AMB) 3–5 mg/kg/day IV OR Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV OR Caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter) OR Micafungin (IV 100–150 mg/day; dose not established ), Posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of disease )OR Itraconazole (dosage depends upon formulation)

• 2. Invasive sinus aspergillosis

• Preferred regimen: Voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h)
• Alternative regimen: Liposomal amphotericin B(L-AMB) 3–5 mg/kg/day IV OR Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV OR Caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter) OR Micafungin (IV 100–150 mg/day; dose not established ), Posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of disease )OR Itraconazole (dosage depends upon formulation)

• 3. Tracheobronchial aspergillosis

• Preferred regimen: Voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h)
• Alternative regimen: Liposomal amphotericin B(L-AMB) 3–5 mg/kg/day IV OR Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV OR Caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter) OR Micafungin (IV 100–150 mg/day; dose not established ), Posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of disease )OR Itraconazole (dosage depends upon formulation)

• 4. Chronic necrotizing pulmonary aspergillosis

• Preferred regimen: Voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h)
• Alternative regimen: Liposomal amphotericin B(L-AMB) 3–5 mg/kg/day IV OR Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV OR Caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter) OR Micafungin (IV 100–150 mg/day; dose not established ), Posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of disease )OR Itraconazole (dosage depends upon formulation)

• 5. Aspergillosis of the CNS

• Preferred regimen: Voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h)
• Alternative regimen: Liposomal amphotericin B(L-AMB) 3–5 mg/kg/day IV OR Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV OR Caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter) OR Micafungin (IV 100–150 mg/day; dose not established ), Posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of disease )OR Itraconazole (dosage depends upon formulation)

• 6. Aspergillus infections of the heart (endocarditis, pericarditis, and myocarditis)

• Preferred regimen:
• Alternative regimen:

• 7. Aspergillus osteomyelitis and septic arthritis

• Preferred regimen:
• Alternative regimen:

• 8. Aspergillus infections of the eye (endophthalmitis and keratitis)

• Preferred regimen:
• Alternative regimen:

• 9. Cutaneous aspergillosis

• Preferred regimen:
• Alternative regimen:

Yellow Fever Virus

• 1. Yellow fever

• 1.1. Summary

• Yellow fever was one of the most lethal diseases before the development of the vaccine. It is a major health concern for unvaccinated travellers to tropical regions in South America and Africa. It is transmitted by mosquitoes (Aedes aegypti) bites in a cycle which involve these mosquitoes biting also monkeys and human beings, which act as hosts for the virus. The yellow fever virus is a member of the Flaviviridae family, which comprises about 70 viruses, most of which are arthropod-borne.

• 1.2. Epidemiology

• Up to 5000 cases are reported annually in Africa and 300 annually in South America, although it is believed that numbers are underestimated. In Africa the human population is seasonally exposed in and around villages and small cities so the highest risk of disease are children without naturally acquired immunity. In South America the virus is transmitted in poorly populated forested areas and it occurs mainly with workers and farmers in the borders of the forested areas.

• 1.3. Clinical Manifestations

• Yellow fever can present itself in three forms: subclinical infection, nonspecific abortive febrile disease and fatal hemorrhagic fever. The incubation time for the disease is 3-6 days. After this period, the onset of fever, myalgia, lower back pain, irritability, nausea, malaise, headache, fotofobia and dizziness is oftenly abrupt. These findings are not specific to Yellow Fever and can be found in any acute infection. During this period the patient can be a source of virus for mosquitoes.
• On physical examination the liver can be enlarged with tenderness, Faget sign (slow pulse rate despite high fever) can be found. Skin might appear flushed with reddening of conjunctivae and gums. Between 48-72h after onset and before the jaundice, hepatic enzymes starts to rise. Laboratory studies may show leukopenia with relative neutropenia. This is called period of infection and may last for several days and may be followed by a remission period which last about 48h, with the disappearance of the fever and the symptoms. Patients with the abortive form of the disease recover at this stage.
• After the third to sixth day of the onset of the symptoms the patient may present return of the fever, vomiting, renal failure (oliguria), jaundice, epigastric pain and hemorrhagic diathesis. The viremia terminates during this stage and the antibodies appear in the blood. The patient may evolve with multiorgan failure during this phase. Also in this stage, AST concentrations might exceed ALT, probably due to myocardial and skeletal muscle damage. Serum creatinine and bilirubin levels also rise at this stage. Hemorrhagic manifestations may include petechiae, ecchymoses, epistaxis, melena, metrorrhagia, haematemesis. Laboratory studies may show thrombocytopenia, reduced fibrinogen levels, presence of fibrin split products, reduced factors II, V, VII, VIII, IX and X, which suggest a multifactorial cause for the bleeding with a consumption coagulopathy. Myocardial disfunction may be demonstrated by abnormalities in the ST-T segment in the electrocardiogram. Encephalitis is very rare.
• 20-50% of the patients with the hepatorenal disease die after 7-10 days of the onset.

• 1.4. Diagnosis

• Diagnosis can be made by serology, detection of viral genome by polymerase chain reaction, immunohistochemistry on postmortem tissues, viral isolation or histopathology. No commercial test is available and diagnostic capabilities are restricted to selected laboratories only. Serologic diagnosis is made by dosing IgM antibodies with ELISA. The virus might be isolated by inoculating it in mice, cell cultures or mosquitoes. PCR is generally used to detect viral genome in clinical samples that were negative by virus isolation or other method.

• 1.5. Treatment

• Preferred regimen: No specific treatment is available for yellow fever. In the toxic phase, supportive treatment includes therapies for treating dehydration and fever. Ribavirin has failed in several studies in the monkey model.

• Note: An international seminar held by WHO in 1984 recommended maintenance of nutrition, prevention of hypoglycemia, maintenance of the blood pressure with fluids and vasoactive drugs, prevention of bleeding with fresh-frozen plasma, dialysis if renal failure, correction of metabolic acidosis, administration of cimetidine IV to avoid gastric bleeding and oxygen if needed.

• 1.6. Prevention

• The Yellow fever 17D is highly effective, safe, attenuated vaccine that has been used for over 60 years. It should be taken my travellers who are going to endemic areas of the disease. Revaccination is needed after 10 years from the first dose. The side effects of the vaccines are rare but they include yellow fever associated viscerotropic disease and neurotropic disease. Immunization is contraindicated during pregnancy and in patients with immunodeficiency due to cancers, HIV/AIDS, or treatment with immunosuppressive agents.

Chikungunya Fever

Chikungunya Fever

• Preferred regimen: no specific therapeutics agents are available and there are no licensed vaccines to prevent Chikungunya Fever.

• Note: Anti inflammatory drugs can be used to control joint swelling and arthritis.

Rabies

Rabies

• Preferred regimen: no specific therapeutics agents are available once the disease is established.

• Note: There are vaccines and immune globulins available for postexposure prophylaxis:

• Postexposure Prophylaxis for non immunized individuals: Wound cleansing, human rabies immune globulin - administer full dose infiltrated around any wound. Administer any remaining volume IM at other site anatomically distant from the wound. Administer vaccine 1,0ml, IM at deltoid area one each on days 0, 3, 7 and 14.
• Postexposure Prophylaxis for immunized individuals: Wound cleansing, do not administer human rabies immune globulin. Administer vaccine 1,0ml, IM at deltoid area one each on days 0 and 3.

Cryptococcus

1. Cryptococcus neoformans

1.1. Cryptococcus neoformans meningitis in HIV infected patients

• 1.1.1. Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 0.7-1.0 mg/kg per day IV (consider using lipid formulations for patients with renal dysfunction - Liposomal AmB 3-4mg/kg per day IV or Amphotericin B lipid complex (ABLC) 5mg/kg IV per day) plus Flucytosine 100mg/kg PO or IV divided in 4 doses for at least 2 weeks followed by fluconazole 400mg (6mg/kg) per day PO for at least 8 weeks.
• 1.1.2. Alternative regimen for induction and consolidation: Amphotericin B deoxycholate 0.7-1.0 mg/kg per day IV, Liposomal AmB 3-4 mg/kg per day IV or AmB lipid complex 5mg/kg IV per day for 4-6 weeks.
• 1.1.3. Alternative regimen for induction and consolidation: Amphotericin B deoxycholate 0.7 mg/kg IV per day plus fluconazole 800mg PO daily for 2 weeks, followed by fluconazole 800mg PO daily for at least 8 weeks.
• 1.1.4. Alternative regimen for induction and consolidation: Fluconazole (>800 mg per day PO, 1200mg daily is favored) plus flucytosine (100mg/kg PO per day, divided in 4 doses) for 6 weeks.
• 1.1.5. Alternative regimen for induction and consolidation: Fluconazole 800-2000mg PO per day for 10-12 weeks.
• 1.1.6. Preferred regimen for maintenance and prophylactic therapy: Initiate HAART 2-10 weeks after commencing initial antifungal therapy, Fluconazole 200mg/day PO.
• 1.1.7. Alternative regimen for maintenance and prophylactic therapy: Itraconazole 200mg twice per day PO - monitor drug-level ; Amphotericin B deoxycholate (1mg/kg) per week IV (should be used in azole-intolerant patients).
• Note: Consider discontinuing supressive therapy if CD4 count is higher than 100 cells/uL and undetectable or very low HIV RNA level for more than 3 months. Consider reinstitution of maintenance therapy if CD4 count <100 cels/uL.
• Note: Do not use Acetazolamide, mannitol or corticosteroids to treat increased intracranial pressure, instead it should be used lombar puncture in the absence of focal neurologic signs or impaired mentation (which, if present, patient must be submitted to CT or MRI scan first).

1.2. Cerebral cryptococcomas

• 1.2.1. Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 0.7-1.0 mg/kg per day IV (consider using lipid formulations for patients with renal dysfunction - Liposomal AmB 3-4mg/kg per day IV or AmB lipid complex (ABLC) 5mg/kg IV per day) plus Flucytosine 100mg/kg PO or IV divides in 4 doses for at least 6 weeks followed by fluconazole 400-800mg per day PO for 6-18 months; corticosteroids might be useful for surrounding edema and mass effect.
• Note: Consider surgery if lesions are larger than 3cm, accessible lesions with mass effect or lesions that are enlarging and not explained by IRIS.

1.3. Cryptococcus neoformans meningitis in HIV negative patients

• 1.3.1. Preferred regimen: Amphotericin B deoxycholate 0.7-1.0 mg/kg per day IV plus Flucytosine 100mg/kg PO or IV divides in 4 doses for at least 4 weeks (which may be extended to 6 weeks if there is any neurological complications) followed by fluconazole 400mg per day PO for 8 weeks. If there's toxicity to AmBd, consider changing to LFAmB in the second 2 weeks.
• Note: After induction and consolidation therapy, start fluconazole 200mg (3mg/kg) per day, PO for 6-12 months.
• Note: If flucytosine is not given, consider lengthening the induction therapy for at least 2 weeks.

1.4. Cryptococcus neoformans pulmonary disease - immunosupressed

• 1.4.1. Preferred regimen: for mild-moderate symptoms, no severe immunosupression, absence of diffuse pulmonary infiltrates - Fluconazole 400mg per day orally for 6-12 months.
• 1.4.2. Preferred regimen: for 6-12 months. If there's severe pneumonia, disseminated disease or CNS infection, treat like CNS cryptococcosis.
• Note: In HIV- infected patients, treatment should be stopped after 1 year if CD4 count is >100 and a cryptococcal antigen titer is <1:512 and not increasing.
• Note: Consider corticosteroid if ARDS is present in a context which it might be attributed to IRIS.

1.5. Cryptococcus neoformans pulmonary disease - non-immunosupressed

• 1.5.1. Preferred regimen: for mild-moderate symptoms, no severe immunosupression, absence of diffuse pulmonary infiltrates - Fluconazole 400mg per day orally for 6-12 months.
• 1.5.2. Alternative regimen: if fluconazole is unavailable or contraindicated, Itraconazole PO 200 mg twice per day, voriconazole PO 200 mg twice per day, and posaconazole PO 400 mg twice per day.
• 1.5.3. Preferred regimen: for 6-12 months. If there's severe pneumonia, disseminated disease or CNS infection, treat like CNS cryptococcosis.

1.6. Cryptococcus neoformans non-lung, non-CNS infection

• 1.6.1. Preferred regimen: If cryptococcemia or disseminated (involvement of at least 2 noncontiguous sites or cryptococcal antigen titer >1:512) disease treat like CNS infection.
• 1.6.2. Preferred regimen: If infection occurs at a single site and no immunosupressive risk factors, consider: fluconazole 400mg PO per day for 6-12 months.

1.7. Cryptococcosis in Children

• 1.7.1. Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 1.0 mg/kg per day IV plus Flucytosine 100mg/kg PO or IV divided in 4 doses for 2 weeks followed by fluconazole 10-12mg/kg per day PO for 8 weeks.
• 1.7.2. Alternative regimen: patients with renal dysfunction: change Amphotericin B deoxycholate by Liposomal AmB 5mg/kg per day IV or Amphotericin B lipid complex (ABLC) 5mg/kg IV per day).
• 1.7.3. Preferred regimen for maintenance: fluconazole 6mg/kg PO per day
• 1.7.4. Preferred regimen for cryptococcal pneumonia: fluconazole 6-12mg/kg PO per day for 6-12 months.

1.8. Cryptococcosis in Pregnant Women

• 1.8.1. Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 0.7-1.0 mg/kg per day IV (consider using lipid formulations for patients with renal dysfunction - Liposomal AmB 3-4mg/kg per day IV or Amphotericin B lipid complex (ABLC) 5mg/kg IV per day). Consider using flucytosine in relationship to benefit risk basis, since it is a Category C drug for pregnancy. Start fluconazole after delivery. Avoid use during first trimester and consider use in the last 2 trimesters with the need for continuous antifungal therapy during pregnancy.
• 1.8.2. Preferred regimen for pulmonary cryptococcosis: perform close follow-up and administer fluconazole after delivery.

2. Cryptococcus gatti

• 2.1. Preferred regimen: If disseminated or CNS disease, the treatment is the same as C. neoformans.
• 2.2. Preferred regimen:For pulmonary disease: single and small cryptococcoma suggest fluconazole 400mg per day PO.
• 2.3. Preferred regimen:If very large or multiple cryptococcomas, administer flucytosine and AmB deocycholate for 4-6 weeks, followed by fluconazole for 6-18 months.
• Note: Surgery should be considered if there is compression of vital structures or failure to reduce the size of the cryptococcoma after 4 weeks of therapy.

Dermatophytosis

• Dermatophytosis

• 1. Tinea Cruris

• 1.1. Preferred regimen: Interdigital: Topical cream/ointment: terbinafine, imidazoles (miconazole, econazole, clotrimazole), Griseofulvin 250mg tid PO for 14 days should be used in resistant to topic therapy cases.

• 2. Tinea Corporis

• 2.1. Preferred regimen: Small, well-defined lesions: Topical cream/ointment: terbinafine, imidazoles (miconazole, econazole, clotrimazole).
• 2.2. Preferred regimen: Larger lesions: terbinafine PO 250mg/day for 2 weeks; itraconazole PO 200mg/day for 1 week, fluconazole PO 250mg weekly for 2-4 weeks.

• 3. Tinea Pedis

• 3.1. Preferred regimen: Interdigital: Topical cream/ointment: terbinafine, imidazoles (miconazole, econazole, clotrimazole), undecenoic acid, tolnaftate.
• 3.2. "Dry type": Oral: terbinafine PO 250mg/day for 2-4 weeks, itraconazole PO 400mg/day for 1 week per month (repeat if necessary), fluconazole PO 200mg weekly for 4-8 weeks.

• 4. Tinea Capitis

• 4.1. Preferred regimen: Griseofulvin PO 10-20mg/kg/day for at least 6 weeks (Preferred for children).
• 4.2. Alternative regimens: Terbinafine PO 62.5mg/day if <20kg; 125 mg/day if 20-40kg; 250mg/day if >40kg. Itraconazole PO 4-6mg/kg pulsed dose weekly.
• Note: Nistatin is not effective in the treatment of dermatophytosis.

• 5. Tinea Barbae

• 5.1. Preferred regimen: Terbinafine PO 250mg/day for 4 weeks.
• 5.2. Alternative regimen: Itraconazole PO 200mg/day for 2 weeks.

• 6. Tinea Incognito

• 6.1. Preferred regimen: Stop topical steroids and treat with topical 1% terbinafine cream for 6 weeks.

• 7. Tinea Manuum

• 7.1. Preferred regimen: topical or systemic terbinafine PO 250 mg/day por 2-4 weeks.

• 8.Tinea Versicolor

• 8.1. Preferred regimen: Itraconazole 200mg daily for a week.
• 8.2. Alternative regimen: Ketoconazole 200mg daily for 4 weeks.

• 9. Majocchi's Granuloma

• 9.1. Preferred regimen: Terbinafine PO 250mg/day for 2-4 weeks or Itraconazole 200mg PO bid for 1 week, per month for 2 months.

• 10. Onychomycosis

• 10.1. Preferred regimen: Fingernails Terbinafine PO 250mg/day for 6 weeks.
• 10.2. Preferred regimen: Toenails Terbinafine PO 250mg/day for 12 weeks.
• 10.3. Preferred regimen: Toenails Itraconazole PO 200mg/day for 12 weeks (U.S. guidelines).
• 10.4. Preferred regimen: Fingernails Itraconazole PO 200mg twice a day for a week a month for 2 months (European guidelines).
• 10.5. Preferred regimen: Toenails Itraconazole PO 200mg twice a day for a week a month for 3 months (European guidelines).

• Note: There is no evidence that combining systemic and topic treatments has any benefit to the patient.