Treatment of paracoccidioidomycosis

INTRODUCTION — Paracoccidioidomycosis is a systemic endemic mycotic disease caused by the thermally dimorphic fungi of the genus Paracoccidioides. Two species are recognized to cause paracoccidioidomycosis: Paracoccidioides brasiliensis and Paracoccidioides lutzii. The fungus has a geographic distribution limited to Central and South America, and paracoccidioidomycosis is the most frequent systemic endemic mycosis in this region. Primary infection is usually transient and almost always devoid of clinical manifestations. If the infection is not contained by the host, the disease may evolve into one of two patterns: the chronic form, which represents reactivation of the primary infection and is most common, and the acute/subacute form [1].

The treatment of paracoccidioidomycosis will be reviewed here. The mycology, epidemiology, clinical manifestations and diagnosis of paracoccidioidomycosis are discussed separately. (See "Mycology and epidemiology of paracoccidioidomycosis" and "Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis" and "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis".)

ANTIFUNGAL AGENTS — Paracoccidioides spp are sensitive to most antifungal agents, including amphotericin B, the azoles (ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole), terbinafine, and even sulfonamides [2,3]. Of these agents, itraconazole has been studied the most extensively and is most commonly used. Sulfonamides, such as trimethoprim-sulfamethoxazole, are used in some cases but require prolonged therapy to prevent relapse. Amphotericin B is reserved for patients with severe disease (eg, respiratory failure, central nervous system involvement, clinical instability due to severe forms of acute or chronic disseminated paracoccidioidomycosis). Response to treatment seems to be similar regardless of whether paracoccidioidomycosis is caused by P. brasiliensis or P. lutzii [4]. Even though paracoccidioidomycosis has a high incidence and morbidity in Central and South America, few studies have been conducted to define its optimal treatment. Only two randomized trials have been published, neither of which had sufficient power to assess response or cure rates [5,6].

Itraconazole — Itraconazole has been used extensively in the treatment of paracoccidioidomycosis and results in high response rates. (See 'Choice of therapy' below.)

Efficacy — The efficacy of itraconazole was first shown in a single-center noncomparative study in which 47 patients (45 with chronic disease) received itraconazole for a median duration of six months (range 3 to 24 months) [7]. The overall response rate (complete resolution or marked improvement) was 91 percent. Of 15 patients who were followed for 12 months post-therapy, none had a relapse.

In a randomized trial that included 42 patients with paracoccidioidomycosis (35 with chronic disease, 7 with acute disease), itraconazole capsules (50 to 100 mg per day) were compared with ketoconazole (200 to 400 mg per day) or sulfadiazine (100 to 150 mg/kg per day) [5]. One of these agents was given for four to six months as determined by clinical response, followed by slow release sulfa (sulfamethoxypyridazine) until serologic testing became negative. The mean duration of therapy with the initial antifungal agent was 170 days for the itraconazole group, 164 days for the sulfadiazine group, and 154 days for the ketoconazole group. The mean total duration of therapy (including maintenance sulfa therapy) was 24, 28, and 31 months, respectively. Clinical responses were observed in all patients receiving itraconazole or sulfadiazine, and in all but one patient receiving ketoconazole. As expected with such a small sample size, no differences were observed among the three agents.

Toxicity — Itraconazole is generally well tolerated. Adverse effects include hepatotoxicity, hypokalemia, pedal edema, and, rarely, heart failure. (See "Pharmacology of azoles", section on 'Adverse effects'.)

Pharmacokinetics — There are important pharmacokinetic differences between the capsule and liquid preparations of itraconazole. Absorption of the capsule formulation is highly variable, requires gastric acidity, and is enhanced when the agent is taken with food. Thus, in patients who receive concomitant medications that decrease gastric acidity, blood levels are reduced. In contrast, the liquid formulation has better bioavailability, does not require an acidic environment, and is taken on an empty stomach. (See "Pharmacology of azoles", section on 'Pharmacokinetics'.)

The factors that affect itraconazole pharmacokinetics, including drug interactions, absorption, and drug formulation, are discussed in detail separately. (See "Pharmacology of azoles", section on 'Drug interactions'.)

Voriconazole — Although voriconazole has excellent in vitro activity against Paracoccidioides spp [8], it has only been evaluated for the treatment of paracoccidioidomycosis in one small randomized open-label trial [6]. Thirty-five patients with paracoccidioidomycosis received voriconazole (400 mg twice daily on the first day and 200 mg twice daily thereafter) and 18 received itraconazole capsules (100 mg twice daily). All but one patient had the chronic form of paracoccidioidomycosis. The median duration of treatment was 169 days for patients treated with voriconazole and 200 days for patients treated with itraconazole. The response rates were similar in patients who received at least one dose of treatment (89 percent with voriconazole versus 94 percent with itraconazole) and in patients receiving >6 months of treatment (100 percent in both groups). Thus, voriconazole appears to be as effective as itraconazole for the treatment of chronic paracoccidioidomycosis, although the small size of the study limits these findings.

Toxicity — Common toxicities of voriconazole include hepatotoxicity, photosensitivity skin rash, and transient visual disturbances. (See "Pharmacology of azoles".)

Isavuconazole — Data on treatment of paracoccidioidomycosis with isavuconazole are scarce. In one study, ten patients with paracoccidioidomycosis received primary treatment with isavuconazole for an average of 180 days (range 27 to 182) [3]. Clinical response was observed in eight patients (one complete, seven partial) while the other two patients died.  

Trimethoprim-sulfamethoxazole

Efficacy — Trimethoprim-sulfamethoxazole (TMP-SMX) has been used extensively for the treatment of paracoccidioidomycosis [9]; however, there are no randomized trials evaluating its use. In addition, several retrospective studies have found that more prolonged treatment is required with TMP-SMX (usually two years) compared with itraconazole [1,10-12]. As examples:

●One study compared treatment outcomes in 71 patients with paracoccidioidomycosis who received TMP-SMX and 19 who received itraconazole [10]. The groups were comparable with regards to age, sex, and the form of disease (acute or chronic). The cure rates were similar (94 and 95 percent for patients receiving TMP-SMX and itraconazole, respectively), but the median duration of treatment was shorter in patients receiving itraconazole (7 versus 24 months). Furthermore, compliance was better in patients receiving itraconazole, as no patients receiving itraconazole discontinued treatment early, compared with 23 patients receiving TMP-SMX.

●Similar results were observed in another study comparing 47 patients who received itraconazole with 130 who received TMP-SMX [11]. The efficacy was similar (100 versus 98 percent); however, among those who received itraconazole, the time to clinical cure was significantly shorter (105 versus 159 days), and side effects were significantly less frequent (6 versus 20 percent).

●In a different study that compared 81 itraconazole recipients with 119 patients who received TMP-SMX, the median duration of treatment was also shorter with itraconazole (12 versus 23 months), and treatment was discontinued less frequently (6.2 versus 18.5 percent) [12]. However, in this study, cure rates were significantly lower in those who received TMP-SMX (51 percent versus 86 percent).

Toxicity — TMP-SMX is generally well tolerated in non-HIV-infected patients in whom adverse reactions occur in approximately 6 to 8 percent. In comparison, the adverse reaction rate is as high as 25 to 50 percent in HIV-infected patients, with many of the reactions being severe.

The more common adverse reactions to TMP-SMX involve the gastrointestinal tract (nausea, vomiting) and skin (rash, Steven-Johnson syndrome, and pruritus). (See "Trimethoprim-sulfamethoxazole: An overview", section on 'Adverse effects and precautions'.)

Amphotericin B — Given the toxicity of amphotericin B deoxycholate as well as the good clinical results obtained with itraconazole and trimethoprim-sulfamethoxazole, amphotericin B is used infrequently. Amphotericin B deoxycholate is generally given only to patients with severe infection (eg, respiratory failure, central nervous system involvement, clinical instability due to severe forms of acute or chronic disseminated paracoccidioidomycosis) [13].

Efficacy — Evaluation of amphotericin B deoxycholate for paracoccidioidomycosis has been limited to small observational studies [14,15]. Amphotericin B deoxycholate is often avoided due to nephrotoxicity and the availability of less toxic agents. However, amphotericin B is the drug of choice for treating patients with sepsis due to Paracoccidioides spp (occasionally seen with the acute or subacute form of paracoccidioidomycosis) and patients with respiratory failure. It is not possible to estimate the response rate to amphotericin B in patients with severe paracoccidioidomycosis because there are inadequate data.

Clinical experience with the lipid formulations of amphotericin B is scarce, but they are expected to be at least as effective as amphotericin B deoxycholate and have the benefit of lower nephrotoxicity. A study described 28 patients who were treated with amphotericin B lipid complex (median dose of 3.35 mg/kg per day for a median of 14 days), and a treatment response was observed in all patients [16]. In addition, one of the lipid formulations (liposomal amphotericin B; AmBisome) had better central nervous system penetration in an animal model [17]. The lipid formulations of amphotericin B are given at a dose of 3 to 5 mg/kg intravenously daily. (See "Pharmacology of amphotericin B".)

Toxicity — Amphotericin B deoxycholate therapy is frequently complicated by significant toxicity, such as reduced renal function and/or infusion-related systemic reactions. The lipid formulations of amphotericin B are associated with less nephrotoxicity than amphotericin B deoxycholate. In the series of 28 patients treated with amphotericin B lipid complex, adverse events included hypomagnesemia, anemia, and chills, which occurred in more than 50 percent of patients, and acute renal failure occurred in three patients; however, no patient discontinued treatment due to side effects [16]. (See "Pharmacology of amphotericin B" and "Amphotericin B nephrotoxicity".)

Other drugs — Fluconazole and terbinafine are active against Paracoccidioides spp [18,19]. However, because of the very limited clinical experience with these drugs for the treatment of paracoccidioidomycosis, they cannot be recommended.

CHOICE OF THERAPY — Our recommendations are generally in keeping with the Brazilian guidelines for the management of paracoccidioidomycosis and the global guidelines for the diagnosis and management of endemic mycoses [13,20]. The approach to treatment depends upon the severity of disease. Most patients are treated as outpatients with oral antifungals.

Mild to moderate — Itraconazole (100 to 200 mg daily) is the drug of choice for the treatment of mild to moderate paracoccidioidomycosis in adults [13]. The 100 mg dose can be used for those with mild forms of disease, whereas those with a moderate clinical presentation should be treated with higher doses (200 mg once daily). We prefer itraconazole solution, rather than the capsules, because it has better bioavailability (see 'Pharmacokinetics' above). However, in many parts of Latin America where paracoccidioidomycosis is endemic, the solution is not available and the capsules can be used for treatment.

For children, the dose of itraconazole is 5 to 10 mg/kg once daily (maximum dose 200 mg). If the oral solution of itraconazole is not available, trimethoprim-sulfamethoxazole (TMP-SMX) suspension can be used for children who cannot swallow itraconazole capsules. The dose of TMP-SMX for paracoccidioidomycosis is 8 to 10 mg/kg per day based on the TMP component divided into two daily doses (maximum single dose 160 mg TMP).

In patients who cannot tolerate itraconazole, oral fluconazole (400 mg daily) is an alternative option.

Information on the duration of treatment is found below. (See 'Duration' below.)

Severe — For patients with severe paracoccidioidomycosis (hypotension, respiratory failure, severe malnutrition, central nervous system [CNS] involvement), we suggest amphotericin B deoxycholate (0.7 to 1 mg/kg per day). An alternative is intravenous TMP-SMX (8 to 10 mg/kg per day of the TMP component divided into three daily doses) or intravenous fluconazole (600 to 800 mg per day) [13].

Other options for severe disease are intravenous voriconazole or a lipid formulation of amphotericin B (3 to 5 mg/kg per day). However, there are few data on the use of these agents for the treatment of severe paracoccidioidomycosis. Although the optimal dose of voriconazole has not been determined for the treatment of severe paracoccidioidomycosis, it would be reasonable to use doses similar to those used for other invasive fungal infections in patients with contraindications to the other possible agents, or for step-down therapy.

Patients treated initially with an intravenous drug can be switched to an oral agent once significant improvement in the clinical condition has been observed (resolution of hypotension, reduction of ascites, improvement of respiratory function and nutritional status). Such improvements are usually achieved after 20 to 40 days of intravenous therapy. The transition to an oral regimen should be made cautiously in patients with extensive abdominal involvement because oral absorption can be impaired due to edema of the intestinal wall, involvement of abdominal lymph nodes, and fibrosis. In these cases, itraconazole capsules should be avoided because of their erratic oral absorption.

Central nervous system involvement — Both TMP-SMX and amphotericin B deoxycholate are effective for treating CNS infection. Thus, either one may be used for patients with CNS involvement. Intravenous fluconazole is an alternative.

DURATION AND MONITORING

Duration — The duration of treatment is a matter of debate, since no randomized trials have compared different treatment durations. It is generally accepted that azoles require a shorter treatment course than trimethoprim-sulfamethoxazole (TMP-SMX). Itraconazole and voriconazole are usually given for approximately 6 to 12 months, whereas TMP-SMX requires a longer period of treatment to prevent relapse (usually ≥2 years). Patients with severe disease often require longer courses of therapy (>2 years), even when itraconazole is used. Patients with central nervous system (CNS) involvement, as well as immunocompromised hosts (eg, HIV infection, cancer, transplantation) may also require a longer duration of therapy.

The main therapeutic challenges in the management of paracoccidioidomycosis are the long duration of treatment and the high frequency of relapse and sequelae (see 'Relapse' below and "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Sequelae'). In addition, patients may have comorbidities that complicate the management of the disease. These include tuberculosis (5.5 to 19 percent of patients with paracoccidioidomycosis) [21,22], enteric parasitic diseases, and others.

Treatment is usually continued until the clinical and radiologic signs of paracoccidioidomycosis have improved substantially or resolved (image 1 and image 2) and until there has been a significant reduction in antibody titers [13]. However, the presence of sequelae may complicate the interpretation of clinical and radiologic findings. In addition, the reproducibility of the quantitative double immunodiffusion and counterimmunoelectrophoresis assays can be poor [23]. (See 'Serologic testing' below.)

Serologic testing — Serial serologic testing by quantitative immunodiffusion is useful for monitoring the response to therapy since a good response to antifungal therapy is often associated with a reduction in the titer of serum antibodies [24].

●Serologic testing should be performed prior to the initiation of therapy, after three months of therapy, and every six months thereafter until the completion of therapy [13]. Serologies should also be requested if recurrence is suspected.

●Testing should be performed in the same reference laboratory to best monitor the serologic response to treatment since the reproducibility of quantitative tests performed by semiquantitative double immunodiffusion or counterimmunoelectrophoresis assays can be poor [23].

A typical serologic response involves a progressive reduction in the titers of antibodies after about three months of treatment until stabilization at a low titer [25]. However, antibodies titers do not always correlate with either the clinical status of the patient or with response to therapy. As an example, some patients exhibit a transient increase in antibody titers after starting antifungal therapy, despite a good clinical response. Thus, serologic testing should be used in combination with other factors, such as clinical and radiographic improvement, to determine the treatment response and total duration of antifungal therapy.

Laboratory studies — The need for laboratory studies during therapy depends upon the organs involved and the therapy used. Patients receiving an azole, for example, require close monitoring of liver function tests, given the risk of hepatotoxicity. (See "Pharmacology of azoles".)

When available, therapeutic drug monitoring can be used to monitor the levels of itraconazole and voriconazole. However, in many Latin American medical centers, access to monitoring is limited. Detailed information on how to monitor itraconazole and voriconazole levels is presented elsewhere. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)

Imaging — In patients with lung involvement, chest radiographs should be performed at the time of diagnosis and during follow-up evaluations (eg, every two months during the first six to nine months of therapy, and every six months thereafter until the completion of therapy) [13]. Chest computed tomography (CT) scanning is indicated when clinical response cannot be assessed adequately by chest radiograph (eg, in those with coexisting lung abnormalities, such as tuberculosis or chronic obstructive pulmonary disease) and for evaluation of pulmonary sequelae.

Follow-up CT scanning is also indicated in patients with abdominal and/or CNS involvement.

RELAPSE — The diagnosis of relapse should rely on clinical and radiologic parameters together with conventional mycologic methods, such as direct microscopy, culture, and histopathologic examination of clinical samples. Serology may lag behind clinical and radiologic deterioration [26]. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis", section on 'Diagnostic tests' and 'Serologic testing' above.)

Relapse typically occurs in patients with chronic paracoccidioidomycosis that has disseminated, especially if the treatment was discontinued earlier than recommended [1]. In contrast, relapse occurs in fewer than 5 percent of patients with chronic paracoccidioidomycosis who have received a full treatment course of itraconazole [27,28]. Relapse has also been seen with acute or subacute paracoccidioidomycosis [29]. (See "Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis".)

Other factors associated with relapse include the choice of agent and host factors. As examples:

●Therapy with trimethoprim-sulfamethoxazole has been associated with a rate of relapse of up to 25 percent [30]. In addition, amphotericin B is associated with a rate of relapse of approximately 20 to 30 percent unless followed by step-down therapy [30]. (See 'Antifungal agents' above.)

●Immunocompromised patients are at particular risk of relapse. In a retrospective case-control study of patients treated for paracoccidioidomycosis, relapse occurred in 5 of 27 (19 percent) of HIV-infected patients by 24 months after diagnosis compared with 2 of 61 (3 percent) HIV-uninfected patients [31].

PARADOXICAL REACTIONS — Two cases of acute paracoccidioidomycosis were reported in which immunocompetent adolescents exhibited persistent signs and symptoms of disease (fever, weight loss, and draining lymph nodes) despite long periods of treatment [32]. Examination of clinical material showed few or no fungal elements, and the patients improved with systemic glucocorticoids. While this report does not provide enough evidence to support a diagnosis of a paradoxical reaction, this entity should be considered in the differential diagnosis of patients with acute paracoccidioidomycosis who remain symptomatic despite appropriate treatment; paradoxical reactions have been likened to the immune reconstitution inflammatory syndrome seen in AIDS patients. Further studies will need to be performed before glucocorticoids can be recommended. (See "Immune reconstitution inflammatory syndrome".)

PROGNOSIS — The prognosis of paracoccidioidomycosis depends on the clinical form of the disease. In a series of 63 children with acute paracoccidioidomycosis who received trimethoprim-sulfamethoxazole as primary treatment, six patients died [33]. Five of these six patients were severely malnourished. In another study of 141 children with acute paracoccidioidomycosis, the mortality rate was 5.7 percent [34]. A low albumin serum level at baseline was predictive of mortality, with 99 percent survival in patients with an albumin value >2.18 g/dL. In adults with the chronic form of paracoccidioidomycosis, the mortality rate is lower, but the morbidity of patients with severe sequelae, especially in patients with extensive lung involvement, is high. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Sequelae'.)

SUMMARY AND RECOMMENDATIONS

●For patients with mild or moderate paracoccidioidomycosis, we suggest oral itraconazole rather than another azole or trimethoprim-sulfamethoxazole (TMP-SMX) (Grade 2C). The usual dose of itraconazole is 100 to 200 mg per day. (See 'Mild to moderate' above.)

●For patients with severe paracoccidioidomycosis, we suggest initial therapy with intravenous amphotericin B deoxycholate (Grade 2C). An alternative is TMP-SMX. The usual dose of amphotericin B deoxycholate is 0.7 to 1 mg/kg intravenously daily, and the usual dose of TMP-SMX is 8 to 10 mg/kg per day of the TMP component divided into three daily doses. (See 'Severe' above.)

●For patients with central nervous system involvement, we suggest either TMP-SMX or amphotericin B deoxycholate (Grade 2C). (See 'Central nervous system involvement' above.)

●Patients treated initially with an intravenous drug can be switched to an oral agent once significant improvement in the clinical condition has been observed. (See 'Severe' above.)

●Itraconazole and voriconazole are usually given for approximately 6 to 12 months, whereas TMP-SMX requires a longer period of treatment to prevent relapse (usually ≥2 years). Patients with severe disease often require longer courses of therapy. (See 'Duration' above.)

●Treatment is usually continued until the clinical and radiologic signs of paracoccidioidomycosis have improved substantially or resolved and there has been a significant reduction in antibody titers. (See 'Duration' above.)

●Patients with paracoccidioidomycosis should be monitored closely during therapy with laboratory studies including serologies, and imaging. (See 'Duration and monitoring' above.)

●Relapse typically occurs in patients with chronic paracoccidioidomycosis that has disseminated, especially if a long treatment course is not given. Relapse occurs in fewer than 5 percent of patients with chronic paracoccidioidomycosis who have received a full treatment course of itraconazole but is more common in patients receiving TMP-SMX or amphotericin B deoxycholate not followed by therapy with oral drugs. Relapse may also occur among patients with acute or subacute paracoccidioidomycosis. (See 'Relapse' above.)