Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

Cryptococcosis

Last Updated: November 6, 2013; Last Reviewed: November 6, 2013

Panel's Recommendations for Cryptococcosis
Panel's Recommendations
  • Routine use of antifungal medications is not recommended for primary prophylaxis of cryptococcal infections in children (BIII).
  • Combination therapy with amphotericin B deoxycholate (or liposomal amphotericin B) and flucytosine for 2 weeks (induction therapy) followed by fluconazole for a minimum of 8 weeks (consolidation therapy) is recommended for central nervous system disease (AI*). Amphotericin B lipid complex is another alternative to amphotericin B deoxycholate (BII*)
  • Liposomal amphotericin B is preferred over amphotericin B deoxycholate for patients with or at risk of renal insufficiency (AI*); amphotericin B lipid complex is an alternative (BII*).
  • In patients who cannot tolerate flucytosine or if flucytosine is unavailable, amphotericin B deoxycholate (or liposomal amphotericin B or amphotericin B lipid complex) with or without high-dose fluconazole can be used for initial therapy (BI*). Fluconazole plus flucytosine is superior to fluconazole alone and an option in patients who cannot tolerate any form of amphotericin (BII*)
  • Echinocandins are not active against cryptococcal infections and should not be used (AIII)
  • After a minimum of 2 weeks of induction therapy, if there is clinical improvement and a negative cerebrospinal fluid culture after repeat lumbar puncture, amphotericin B and flucytosine can be discontinued and consolidation therapy with fluconazole administered for a minimum of 8 weeks (AI*); itraconazole is a less preferable alternative to fluconazole (BI*).
  • Secondary prophylaxis with fluconazole (AI*) or itraconazole (less preferable) (BI*) is recommended for a minimum of 1 year. 
  • Discontinuing secondary prophylaxis (after receiving secondary prophylaxis for ≥ 1 year) can be considered for asymptomatic children aged ≥6 years with CD4 counts ≥100 cells/mm3 and an undetectable viral load on ≥3 months of combination antiretroviral therapy (CIII). Secondary prophylaxis should be reinitiated if the CD4 count decreases to <100 cells/mm3 (AIII). Most experts would not discontinue secondary prophylaxis for patients younger than age 6 years (CIII).
  • Patients with severe pulmonary disease or disseminated cryptococcosis should be treated with amphotericin B with or without the addition of flucytosine, as for CNS disease (AIII). Those with mild-to-moderate pulmonary illness or other localized disease can be managed with fluconazole monotherapy (AIII).
  • In antiretroviral-naive patients newly diagnosed with cryptococcal meningitis or disseminated disease, delay in initiation of potent antiretroviral therapy may be prudent until the end of the first 2 weeks of induction therapy (CIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion

Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents

Dosing Recommendations for Prevention and Treatment of Cryptococcosis
Indication First Choice Alternative Comments/Special Issues
Primary Prophylaxis
Not recommended
Not recommended
N/A
Secondary Prophylaxisa
Fluconazole 6 mg/kg body weight (maximum 200 mg) by mouth once daily Itraconazole oral solution 5 mg/kg body weight (maximum 200 mg) by mouth once daily  Secondary Prophylaxis Indicated:
  • Documented disease
Criteria For Discontinuing Secondary Prophylaxis
If All of the Following Criteria are Fulfilled: 
  • Age ≥6 years
  • Asymptomatic on ≥12 months of secondary prophylaxis
  • CD4 count ≥100 cells/mm 3 with undetectable HIV viral load on cART for >3 months
Criteria for Restarting Secondary Prophylaxis: 
  • CD4 count <100/mm3
Treatment CNS Disease
Acute Therapy (Minimum 2-Week Induction Followed by Consolidation Therapy):
  • Amphotericin B deoxycholate 1.0 mg/kg body weight (or liposomal amphotericin B 6 mg/kg body weight) IV once daily PLUS flucytosine 25 mg/kg body weight per dose by mouth given 4 times daily
Consolidation Therapy (Followed by Secondary Prophylaxis):
  • Fluconazole 12 mg/kg body weight on day 1, then 10–12 mg/kg body weight (max 800 mg) once daily IV or by mouth for a minimum of 8 weeks
CNS Disease
Acute Therapy (Minimum 2-Week Induction Followed by Consolidation Therapy)
If Flucytosine Not Tolerated or Unavailable
  • A. Liposomal amphotericin B, 6 mg/kg body weight IV once daily, or Amphotericin B Lipid Complex, 5 mg/kg body weight IV once daily, or Amphotericin B deoxycholate, 1.0–1.5 mg/kg body weight IV once daily alone or B. in combination with high-dose fluconazole (12 mg/kg body weight on day 1 and then 10–12 mg/kg body weight [max 800 mg] IV). Note: Data-driven pediatric dosing guidelines are unavailable for fluconazole with use of such combination therapy.
If Amphotericin B-Based Therapy Not Tolerated:
  • Fluconazole, 12 mg/kg body weight on day 1 and then 10–12 mg/kg body weight (maximum 800 mg) IV or by mouth once daily PLUS flucytosine, 25 mg/kg body weight per dose by mouth given 4 times daily

Consolidation Therapy (followed by secondary prophylaxis):
  • Itraconazole 5–10 mg/kg body weight by mouth given once daily, or 2.5–5 mg/kg body weight given twice daily (maximum 200 mg/dose) for a minimum of 8 weeks. A loading dose (2.5–5 mg/kg body weight per dose 3 times daily) is given for the first 3 days (maximum 200 mg/dose; 600 mg/day). See comment on itraconazole under Other Options/Issues.
In patients with meningitis, CSF culture should be negative prior to initiating consolidation therapy.

Overall, in vitro resistance to antifungal agents used to treat cryptococcosis remains uncommon. Newer azoles (voriconazole, posaconazole, ravuconazole) are all very active in vitro against C. neoformans, but published clinical experience on their use for cryptococcosis is limited.

Liposomal amphotericin and amphotericin B lipid complex are especially useful for children with renal insufficiency or infusion-related toxicity to amphotericin B deoxycholate.

Liposomal amphotericin and amphotericin B lipid complex are significantly more expensive than amphotericin B deoxycholate.

Liquid preparation of itraconazole (if tolerated) is preferable to tablet formulation because of better bioavailability, but it is more expensive. Bioavailability of the solution is better than the capsule, but there were no upfront differences in dosing range based on preparation used. Ultimate dosing adjustments should be guided by itraconazole levels.

Serum itraconazole concentrations should be monitored to optimize drug dosing.

Amphotericin B may increase toxicity of flucytosine by increasing cellular uptake, or impair its renal excretion, or both.

Flucytosine dose should be adjusted to keep 2-hour post-dose drug levels at 40–60 μg/mL

Oral acetazolamide should not be used for reduction of ICP in cryptococcal meningitis.

Corticosteroids and mannitol have been shown to be ineffective in managing ICP in adults with cryptococcal meningitis.

Secondary prophylaxis is recommended following completion of initial therapy (induction plus consolidation)—drugs and dosing listed above.
Localized Disease, Including Isolated Pulmonary Disease (CNS Not Involved)b:
  • Fluconazole 12 mg/kg body weight on day 1 and then 6–12 mg/kg body weight (maximum 600 mg) IV or by mouth once daily
Localized Disease Including Isolated Pulmonary Disease (CNS Not Involved)b:
  • Amphotericin B, 0.7–1.0 mg/kg body weight, or
  • Amphotericin liposomal 3–5 mg/kg body weight, or
  • Amphotericin lipid complex, 5 mg/kg body weight IV once daily
Disseminated Disease (CNS Not Involved) or Severe, Pulmonary Diseaseb:
  • Amphotericin B 0.7–1.0 mg/kg body weight, or 
  • Liposomal amphotericin, 3–5 mg/kg body weight, or
  • Amphotericin B lipid complex 5 mg/kg body weight IV once daily (± flucytosine)
Disseminated disease (CNS not involved) or severe, pulmonary diseaseb
  • Fluconazole, 12 mg/kg body weight on day 1 and then 6–12 mg/kg body weight (maximum 600 mg) IV or by mouth once daily
a Secondary prophylaxis is also referred to as maintenance therapy or suppressive therapy.
b Duration of therapy for non-CNS disease depends on site and severity of infection and clinical response

Key to Acronyms: cART = combination antiretroviral therapy; CNS = central nervous system; CSF = cerebrospinal fluid; ICP = intracranial pressure; IV = intravenous

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