Antifungal therapy
Cryptococcus is susceptible to polyenes, flucytosine, and azoles. Among these drugs, azoles exhibit the least fungicidal activity. Antifungal treatment for cryptococcosis varies according to the disease extent, severity, as well as host immune status. Although there are some clinical distinctions between cryptococcosis due to
C. neoformans and
C. gattii, recommended treatment regimens for both species are currently identical. Some experts suggest that a longer duration of induction and consolidation therapy should be used in
C. gattii infection [
71,
72]. Fluconazole monotherapy is recommended for mild-to-moderate pulmonary disease. In contrast, treatment of disseminated disease, severe pulmonary disease, and meningitis/meningoencephalitis consists of three phases: induction, consolidation, and maintenance. A combination of two drugs is preferred in the induction phase. Fluconazole monotherapy is recommended during consolidation and maintenance phases (Table
1) [
2].
Table 1
Antifungal therapy for cryptococcosis in HIV-infected patients
Meningitis/meningoencephalitis, disseminated disease, severe pulmonary diseasea
|
Induction phase |
Amphotericin B deoxycholateb (0.7–1 mg/kg/day) plus flucytosine (100 mg/kg/day) | 2 weeks |
Alternative regimens |
Amphotericin B deoxycholate (0.7–1 mg/kg/day) plus fluconazole (800 mg/day) | 2 weeks |
Amphotericin B deoxycholateb (0.7–1 mg/kg/day) | 4–6 weeks |
Fluconazole (≥800 mg/day, preferably 1200 mg/day) plus flucytosine (100 mg/kg/day) | 6 weeks |
Fluconazole (800–2000 mg/day, preferably ≥1200 mg/day) | 10–12 weeks |
Itraconazole (400 mg/day) | 10–12 weeks |
Consolidation phase |
Fluconazole (400 mg/day) | 8 weeks |
Alternative regimens |
Itraconazole (400 mg/day) | 8 weeks |
Maintenance phase |
Fluconazole (200 mg/day) | ≥1 yearc
|
Alternative regimens |
Itraconazole (400 mg/day) | ≥1 yearc
|
Amphotericin B deoxycholate (1 mg/kg/week) | ≥1 yearc
|
Mild-to-moderate pulmonary disease |
Fluconazole (400 mg/day) | 6–12 months |
Amphotericin B plus flucytosine has been shown to be the most potent and advocated regimen for the induction phase [
2,
9,
73‐
77]. Intravenous amphotericin B deoxycholate should be given at a dose of 0.7–1 mg/kg/day [
2,
9]. Liposomal amphotericin B at a dose of 3–4 mg/kg/day or amphotericin B lipid complex at a dose of 5 mg/kg/day can be used as a substitute for amphotericin B deoxycholate, as these formulations cause less nephrotoxicity and infusion reaction, while demonstrating similar, if not better, efficacy [
78,
79]. Flucytosine should be used at a dose of 100 mg/kg/day, given in four divided doses. Alternative regimens for the induction phase include amphotericin B plus fluconazole, amphotericin B monotherapy, fluconazole plus flucytosine, and high-dose fluconazole monotherapy [
2,
9]. Unfortunately, flucytosine is not available in many countries in resource-limited settings and cannot be used in patients with bone marrow suppression and liver enzyme elevations. Amphotericin B deoxycholate at a dose of 0.7 mg/kg/day plus 800 mg/day of fluconazole might have better efficacy than amphotericin B alone [
73,
79‐
81]. A high fluconazole dosage at 800 mg/day is also associated with high serum and CSF fluconazole concentration and appears to be associated with increased survival and treatment success [
82]. Moreover, no additional toxicity was observed [
73,
79‐
81]. If the patient cannot tolerate amphotericin B or the drug is not available, the induction phase can be achieved by fluconazole plus flucytosine, or high-dose fluconazole monotherapy (Table
1) [
2,
9]. However, these two regimens have lowered efficacy. As a result, higher doses of fluconazole and longer durations of treatment are suggested [
2,
9,
83]. Fluconazole plus flucytosine has proven better than fluconazole monotherapy [
84‐
86].
After the Induction phase of treatment, the consolidation phase commences. Longer durations of induction should be considered if clinical improvement is not evident and/or CSF culture at 2 weeks is still positive [
2,
9]. Patients who fail to achieve negative CSF culture after 2 weeks were shown to have higher risks for treatment failure at 10 weeks [
87]. Fluconazole is the drug of choice during this phase (Table
1). It is noted that 800 mg/day, rather than 400 mg/day, of fluconazole should be used if amphotericin B plus fluconazole regimen is selected for induction. The consolidation phase continues for at least 8 weeks. Then, the fluconazole dose should be reduced to 200 mg/day during the maintenance phase. As long as the patients’ CD4 cell counts remain low, they are still at high risk for relapse. The maintenance phase can be safely discontinued in patients who have been treated for at least 12 months, have suppressed or very low viral load, and have CD4 counts >100 cells/µL for at least 3 months [
88‐
92].
Other azoles, such as itraconazole, voriconazole, posaconazole, and isavuconazole, also possess anti-cryptococcal activity. However, given the scarcity of studies of clinical efficacy, potential drug interactions, CNS penetration, and bioavailability, they are reserved for refractory cases only [
2,
9,
75,
93‐
99].
Resistance to antifungal drugs was previously rare. However, recent reports described increased MICs of
C. neoformans isolates to fluconazole and, to a lesser extent, amphotericin B over the past decade [
100,
101]. Whether this has an impact on clinical outcomes is not known. Furthermore, clinical breakpoints of
Cryptococcus spp. to antifungal drugs are not yet established. Some small studies suggested that worse treatment outcomes might be associated with higher MICs to antifungal drugs, although this is still controversial [
100‐
105]. Currently, testing for antifungal susceptibility might be considered only in patients with persistent or relapse disease [
2,
9]. An MIC of ≥16 µg/mL for fluconazole may be considered resistant, and alternative treatment is suggested, e.g. intravenous amphotericin B deoxycholate at a dose of 1 mg/kg/day until CSF, blood, and/or other sites are sterile [
2]. An MIC of ≥32 µg/mL for flucytosine may be considered resistant, and the induction phase with non-flucytosine-containing regimen may be selected [
2].
Cerebral cryptococcoma should be treated with the same regimen used for cryptococcal meningitis, but with an extended duration of therapy (Table
1) [
2]. This should also be guided by clinical response and imaging during treatment. The recommended dose of fluconazole during consolidation is 400–800 mg/day [
2]. Surgery is rarely necessary, except when other etiologies are suspected and histopathological diagnosis is required, or mass effect is observed. It is noteworthy that an MRI of the brain may not show a decrease in lesion size for many months [
106]. Adjunctive treatment with corticosteroids with gradual tapering might be considered in patients with significant perilesional edema [
2].
Pulmonary cryptococcosis in HIV-infected patients is frequently a manifestation of disseminated disease. Hence, these patients should be evaluated for CNS involvement and disease dissemination, even if they are asymptomatic. A CSF examination, culture, as well as testing for cryptococcal antigen in the CSF and serum should be performed. Disseminated disease should be treated with the same regimen as that of cryptococcal meningitis [
2,
9]. For isolated pulmonary cryptococcosis, treatment varies according to severity. Pulmonary cryptococcosis with severe symptoms and/or diffuse pulmonary infiltrates should be treated with regimens identical to those for disseminated disease and meningitis [
2,
9]. For pulmonary cryptococcosis with mild-to-moderate symptoms, a dosage of 6 mg/kg/day of oral fluconazole for 12 months is recommended [
2,
9]. Surgical removal and drainage of pleural effusion caused by
Cryptococcus are rarely required [
107].
Similar to pulmonary cryptococcosis, cryptococcal infection of other organs is often a manifestation of disseminated disease, especially in HIV-infected patients. These patients should be evaluated for CNS involvement and disease dissemination as well [
2,
9]. For ocular cryptococcosis, combined antifungal agents using systemic amphotericin B with high-eye penetration drugs, such as flucytosine or fluconazole, are recommended [
2].
Positive serum cryptococcal antigen has been shown to be associated with subsequent cryptococcal disease [
108‐
110]. Screening for serum cryptococcal antigen in asymptomatic HIV-infected patients with CD4 counts <100 cells/µL and preemptive treatment of those who test positive lead to more favorable outcomes and more cost-effectiveness [
63‐
65,
108,
109,
111‐
113]. Antifungal regimens have been proposed [
9,
114] although sparse data exist: (1) oral fluconazole at the dose of 800 mg/day for 2 weeks, followed by 400 mg/day for 8 weeks, and 200 mg/day thereafter until CD4 count is >200 cells/µL [
65], or (2) oral fluconazole at the dose of 400 mg/day for 1 year. HIV-infected patients with serum antigen titer ≥1:512 may be treated as CNS disease [
2].
Pregnant women with cryptococcosis represent a special population. Amphotericin B can be used safely without risk of teratogenicity in humans (FDA pregnancy category B) [
2,
9,
115]. Use of other antifungal agents, however, should be considered when the benefits outweigh fetal risks. Flucytosine is classified as category C by the FDA. Although animal studies showed teratogenic effect of flucytosine, limited studies in humans showed no adverse fetal outcomes after exposure [
112]. Fluconazole is classified as category D. There are few reports of fetal anomalies in pregnant women who had received ≥400 mg/day of fluconazole [
116]. Use of fluconazole, as well as other azoles, is thereby discouraged during pregnancy, especially in the first trimester [
2,
9,
112]. Neonates born to patients receiving amphotericin B at delivery should be evaluated for renal function and electrolytes [
9].
Intracranial pressure management for cryptococcal meningitis
In cryptococcal meningitis, intracranial pressure rises along with CSF fungal burden and is associated with morbidity and mortality [
10‐
12]. Increased intracranial pressure may be more prominent in cerebral cryptococcoma. Aggressive control of intracranial pressure should be done [
2,
9]. Management options include therapeutic lumbar puncture, lumbar drain insertion [
117], ventriculostomy, or ventriculoperitoneal shunt. Therapeutic lumbar puncture is usually selected in most cases. CSF opening pressure should be measured before treatment, and therapeutic lumbar punctures to achieve closing pressure below 20 cm H
2O or 50% of initial opening pressure are recommended [
2,
9]. Brain imaging before the procedure should be considered for patients with alteration of consciousness and/or focal neurological deficits. Lumbar puncture should be performed whenever symptoms of increased intracranial pressure arise. Persistently increased intracranial pressure should be managed by daily lumbar puncture until symptoms abate and normal opening pressure is obtained for >2 days [
2,
9]. Interestingly, a recent study showed far less deaths in patients who received at least one therapeutic lumbar puncture, compared to those who did not, regardless of baseline opening pressure [
118]. This finding underscores the importance of therapeutic lumbar puncture. Failure to control intracranial pressure with lumbar puncture warrants the need of lumbar drain insertion, ventriculostomy, or CSF shunt placement. This can be performed without a need for CSF sterilization before the procedure [
2,
9]. Patients who experience increased intracranial pressure as a manifestation of IRIS should be managed alike.
Medical treatment such as corticosteroids, mannitol, and acetazolamide are ineffective and should not be used [
2,
9]. A recent randomized controlled trial showed that routine use of corticosteroids in cryptococcal meningitis might do harm to the patients. This study was terminated prematurely, because there was no difference in mortality or the rate of IRIS between the two groups at 10 weeks [
119]. Additionally, the use of steroids was associated with higher risks of disability, higher adverse events, and reduced sterilizing power of amphotericin B plus fluconazole during the induction phase. Therefore, its use is limited to patients with CNS IRIS and cerebral cryptococcoma with significant edema [
2,
9]. Table
2 summarizes intracranial pressure management for cryptococcal meningitis.
Table 2
Intracranial pressure management for cryptococcal meningitis in HIV-infected patients
Meningitis/meningoencephalitis |
Aggressive control of intracranial pressurea
|
Management options |
Therapeutic lumbar punctureb (usually selected in most cases) |
Lumbar drain insertion |
Ventriculostomy |
Ventriculoperitoneal shuntc
|
Medical treatment i.e. corticosteroidd, mannitol, and acetazolamide are ineffective |
Cryptococcoma |
Management as in meningitis/meningoencephalitis |
Corticosteroids may be used in cryptococcoma with significant brain edema |
Cryptococcal IRIS |
Management as in meningitis/meningoencephalitis |
Corticosteroids may be used in severe IRIS |
Treatment monitoring and treatment failure of cryptococcosis
After appropriate treatment, clinical improvement should be observed, usually within 2 weeks. In patients with cryptococcal meningitis, increased intracranial pressure usually resolves. Follow-up CSF cultures gradually turn negative. It is recommended by several experts that a CSF culture at 2 weeks should be sent to determine CSF sterility after induction phase [
2,
9]. A persistently positive CSF culture at 2 weeks after treatment is associated with morbidity and mortality, higher risk for treatment failure at 10 weeks, relapse, and paradoxical IRIS [
76,
87,
120‐
123]. Serial CSF quantitative cultures have been used as a determinant of fungicidal activity of given treatment regimens, and have been shown to be correlated with morbidity and mortality [
9,
73,
75‐
77,
84,
124]. However, a quantitative culture is rarely done merely for clinical purposes.
Management of patients who fail to achieve CSF sterility at 2 weeks awaits more data, but experts suggest induction therapy for another 2 weeks and a follow-up CSF culture obtained [
2,
9]. Nonetheless, the CSF cultures in some of these patients appear to become negative later with continued consolidation therapy [
77,
121,
122,
125]. Of note, despite a good correlation between quantitative CSF cultures and cryptococcal antigens at baseline, their kinetics of clearance after treatment differ [
126]. CSF cryptococcal antigens may persist for an extended period even if the culture is negative. Using cryptococcal antigen titer to make decisions during therapy is of limited value and is not advisable [
2,
9,
127,
128]. Likewise, continued presence of yeasts visualized by India ink does not indicate treatment failure or disease relapse.
Persistence is arbitrarily defined as lack of clinical improvement and continued positive cultures after 2–4 weeks of appropriate therapy [
2,
9]. In such a case, it should be assessed whether the treatment regimen, intracranial pressure management, as well as treatment adherence are optimal. Potential drug interaction should be sought. Brain imaging might be considered to rule out cryptococcoma. Although rare, concomitant opportunistic infections or malignancy is also possible, given the usually severe immunocompromised status of the patients [
129] and proper investigations should be sent. In addition, MICs of the persistent isolate should be checked and compared with those of the original isolate [
2,
9]. A ≥3-dilution increase suggests development of drug resistance [
2]. Re-induction, typically with combined antifungal agents, should be administered. A standard regimen should be used if a regimen with lowered efficacy was previously given. Higher dose and/or longer course (4–10 weeks) may be considered [
2,
9]. Although more clinical studies are required, MICs may be used to guide treatment regimen selection, as mentioned above. There are few case reports that describe a successful outcome of a combination of multiple antifungal agents, including newer azoles, or adjunctive treatment with recombinant interferon-γ1b [
95,
128,
130,
131].
Relapse is defined as a recurrence of symptoms, after an initial resolution, with a positive CSF culture after ≥4 weeks of treatment [
2,
9]. It remains challenging for clinicians taking care of patients who develop recurrent symptoms, as this may be secondary to several possible etiologies. These include disease relapse, paradoxical IRIS, new opportunistic conditions, drug toxicity, or a combination thereof. It is crucial to determine the etiology, as each requires a distinct management strategy. However, it is difficult to distinguish by clinical signs and symptoms of the patients alone. Thus, further investigations both for
Cryptococcus spp. and other potential pathogens are warranted. Disease relapse may be more likely if the patient has not yet received ART or has virologic failure. Patients who received inadequate induction treatment and/or had poor adherence to consolidation/maintenance therapy are also at high risk for disease relapse. Relapse was more frequent in cohorts using induction therapy with only fluconazole monotherapy [
45,
88]. Among patients without these clues, discriminating between disease relapse and IRIS is difficult. Limited data showed that patients with disease relapse returned later, were less likely to receive ART, had less CD4 count increases and less viral load declines in response to ART, and had lower CSF opening pressure than those with IRIS [
132]. Another recent study stated that no clinical features differentiated relapse from IRIS, but demonstrated lower CSF WBC counts and lower CSF interferon-γ, TNF-α, IL-4, IL-9, IL-12, and IL-17 [
52]. Yet another study showed that serum CRP levels were all normal in patients with disease relapse, while those of patients with IRIS were elevated in 76% [
44]. After all, a CSF culture remains the gold standard for diagnosing disease relapse [
2]. Of note, antifungal treatment might delay the yeast growth, and it may take up to 4 weeks to obtain the final result. In practice, induction therapy should be reinstituted, while CSF culture result is pending. If the disease relapse is confirmed, experts recommend management similar to that of persistent—re-induction, probably with a higher dose and longer course, and selecting the regimen according to MICs of the yeast [
2]. Newer azoles may be considered. If the isolate is fluconazole-susceptible and poor-adherence is a problem, prior suppressive doses of fluconazole may be used [
2]. Like newly diagnosed patients, those with persistence or relapse should be monitored for potential drug toxicity and appropriate intracranial pressure management should be exercised.