Oesophageal candidiasis

Mark Kelly: Armidale Rural and Referral Hospital, NSW

Epidemiology

Oesophageal candidiasis is the third most common AIDS-defining infection in Australia accounting for 10% of all Australian AIDS cases.[1] The incidence of oesophageal candidiasis has reduced dramatically since the introduction of combination antiretroviral therapy (cART). More than 100 cases per year were reported in 1993-1994 in Australia whereas there were approximately 20 cases per year reported in 2004-2006. Similar decreases in the incidence of oesophageal candidiasis have been reported in the USA since the introduction of cART.[2] Most patients with oesophageal candidiasis have CD4 T-lymphocyte (CD4) cell counts < 100 cells/μL. Less than 15% of cases occur in patients with CD4 cell counts > 200 cells/μL.[3]

Microbiology

Candida species are ubiquitous yeasts and commensal agents found in the gastrointestinal tract, female genital tract and oropharynx. Candida albicans is the most common cause of oesophageal candidiasis and accounts for more than 90% of cases.[4] Non-albicans isolates are often present with C. albicans. These include C. tropicalis, C. parapsilosis, C. krusei and C. glabrata. The pathogenicity of non-albicans isolates in this context is unknown as most patients respond to standard doses of fluconazole.[5]

Clinical presentation

Patients with oesophageal candidiasis present with dysphagia, odynophagia or retrosternal discomfort. Characteristically the pain is diffuse, unlike the focal pain which is more common in patients with non-Candida oesophagitis. Weight loss is common. Oral thrush is present in up to 80% of cases of oesophageal candidiasis.[6] The diagnosis of oesophageal candidiasis should be reassessed if oral candidiasis is not present. Fever and oral ulceration are uncommon. Occasionally oesophageal candidiasis may be asymptomatic.

Diagnosis

A clinical diagnosis of oesophageal candidiasis is usually made in immunodeficient patients who present with odynophagia, dysphagia and oral candidiasis.[7] Endoscopy is indicated only in those patients who fail to respond to an empirical trial of fluconazole. Macroscopically, the oesophageal lesions typically comprise both pseudomembranous and ulcerative elements. Speciation of Candida isolates assists in identifying non-albicans infection that may be inherently resistant to fluconazole.

Management

Many agents have demonstrated similar efficacy in the management of oesophageal candidiasis. Fluconazole however remains the preferred first-line agent where resistance is not suspected.[8] Fluconazole therapy is associated with a rapid response, is well tolerated and is associated with few drug interactions. The dose of 100-200 mg daily is continued after a loading dose of 200 mg and is continued for 14-21 days. Intravenous fluconazole may be administered in patients who cannot swallow capsules. Maintenance therapy is required until cART-induced immune reconstitution occurs. Suppressive therapy is recommended for patients with recurrent disabling episodes. Long-term suppressive therapy with fluconazole 100 mg daily is effective at reducing relapses but may be associated with the development of resistance.[9]

Itraconazole solution (200 mg daily) is regarded by some to be an alternative first-line agent,[10] however this agent has variable absorption especially in those on gastric acid blockers and is associated with significantly more drug-drug interactions than fluconazole (Table 1). Voriconazole has been shown to be non-inferior to fluconazole (400 mg loading dose and 200 mg daily) in the treatment of oesophageal candidiasis but remains second-line treatment as it is associated with greater toxicity.[11] Posaconazole oral suspension 400 mg orally twice a day for one day then 400 mg daily is an alternative. It has been shown to be equally as efficacious as fluconazole in achieving a successful response and more effective in sustaining a clinical response after therapy was discontinued.[12] Posaconazole has been shown to be effective in fluconazole-refractory oesophageal candidiasis.[13]

Echinocandins have shown similar efficacy to fluconazole in the treatment of oesophageal candidiasis. Caspofungin (50 mg per day after a loading dose of 70 mg), has been demonstrated to be as effective as fluconazole.[14] However the role of this agent as first-line treatment is limited because of the need for intravenous administration. Higher relapse rates have been reported with the use of echinocandins.[15]

Most patients will experience substantial clinical improvement within 72 hours of commencing fluconazole. Those patients who do not will require endoscopy to confirm the diagnosis, exclude other diagnoses and to permit fungal speciation and antifungal susceptibility testing. Up to 30% of patients may have Candida isolates with a fluconazole minimum inhibitory concentration (MIC) of ≥ 16 μg/mL. These isolates are likely to respond to increased doses of fluconazole.[16]

A clinical response is expected in up to or about 90% of cases even if the fluconazole MIC is ≥ 64 μg/mL. Patients with a pure growth of a non-albicans Candida isolate with known intrinsic fluconazole resistance (e.g. C. krusei) should receive alternative therapy and discontinue fluconazole (Figure 1).

Figure 1 Management of oesophageal candidiasis that fails to respond to 72 hours of fluconazole 200 mg daily 

Note a [17]

Up to 5% of cases of HIV-associated oesophageal candidiasis do not respond to fluconazole.[18][19] Risk factors for fluconazole resistance include a low CD4 cell count and prior use of fluconazole.[20] Failure to respond to fluconazole may be secondary to several factors apart from drug resistance. These other factors include poor absorption, drug interactions and non-adherence. Conversely these factors may lead to the development of drug resistance. Fungal factors such as increased adherence to oesophageal mucosa of non-albicans species may also play a role.[21] Two orally administered agents have been demonstrated to be efficacious in the treatment of fluconazole-refractory oesophageal candidiasis. These include itraconazole solution (200 mg daily)[22]and posaconazole.[23] A number of intravenously administered agents have also been demonstrated to be effective in the treatment of fluconazole-refractory oesophageal candidiasis. These include voriconazole (200 mg twice a day)[24] and caspofungin (50 mg daily after a loading dose of 70 mg).[25][26] Approximately 75% of patients with fluconazole-refractory oesophageal candidiasis will respond to second-line agents. Antifungal susceptibility testing may be useful in fluconazole-refractory disease.

Refractory cases may be treated with intravenous amphotericin (0.3-0.5 mg/kg daily), or liposomal amphotericin (0.9-1.5 mg/kg/day).[27][28] Some isolates demonstrate cross-resistance between voriconazole and fluconazole, so efficacy of voriconazole as a single agent may be limited.[29] Combination oral antifungal agents with documented in vitro synergy may also be used in this context. These include the combination of terbinafine and either itraconazole[30] or voriconazole[31] (Table 1). Immune reconstitution with cART has been demonstrated to improve refractory oesophagitis.[32]

Table 1 Drugs used to treat oesophageal candidiasis
Drug DailyDose Side-effect Drug interactions Comment
Fluconazole Induction 200mg (a)

Gastrointestinal (GI) intolerance

Hepatitis

Alopecia

Dizziness

Hypokalaemia

Headache

Thrombocytopenia

Fluconazole increases levels of: Atovaqoune, benzodiazepines, clarithromycin, opiates, warfarin, saquinavir, phenytoin, oral hypoglycaemics, rifabutin (increases risk of uveitis), cyclosporine, cisapride

Co-administration of fluconazole and cisapride may cause life-threatening arrhythmias

Fluconazole can be used with protease inhibitors and non-nucleoside reverse transcriptase inhibitors without dose modification

Non- responders 400mg  Fluconazole levels are decreased by: Rifabutin and rifampicin
Maintenance (prior to immune recovery) 50-100 mg (b)

Itraconazole 

solution

200mg (loading dose of 200mg twice a day followed by 200mg/day)

Same as fluconazole but more frequent rash and GI intolerance 

Hypokalaemia

Hypertension

Oedema

Ventricular fibrillation

Hepatitis

Itraconazole increases levels of: Terfenadine, cisapride, astemizole, triazolam, lovastatin, simvastatin, rifabutin, rifampicin, phenytoin, phenobarbital Owing to variable absorption, potential drug interactions and potential cardiactoxicity, therapeutic drug monitoring of Itraconazole may guide management
Indinavir, saquinavir2
Itraconazole levels are decreased by: Decreased itraconazole absorption-Antacids, sucralfate, H2 blockers, omeprazole
Increased Itraconazole metabolism: Rifabutin, rifampicin, phenobarbital, carbamazepine, didanosine isoniazid and phenytoin
Voriconazole 200mg twice a day

Hepatitis

Visual disturbance

Voriconazole increases levels of: Terfenadine, astemizole, cisapride, pimozide, quinidine, ergotalkaloids1  
Cyclosporine, warfarin, statins, benzodiazepines, calcium channel antagonists, sulfonylureas, vincaalkaloids3
Voriconazole levels are decreased by: Rifampicin, rifabutin, carbamazepine, phenobarbital1
Phenytoin4 Increase voriconazole dose from 200mg to 400mg twice a day
Omeprazole Omeprazole dose should be halved
  1. May load with 200mg for one day then reduce induction dose to 100mg daily
  2. In the presence of immune recovery, maintenance therapy may be omitted to avoid the development of azole resistance
  1. Co-administration is contraindicated
  2. Reduced dose of second drug
  3. Monitor second drug
  4. Careful monitoring
Note: For therapeutic drug monitoring, a specimen should be taken two hours post-dosing and at least 5 days after initiation of therapy. Target level for itraconazole is> 1μg/mL
Source: Adapted from http://www.mosbysdrugconsult.com/DrugConsult/003556.html

Prophylaxis

Although fluconazole has been demonstrated to prevent oesophageal candidiasis, primary prophylaxis is not recommended.[33] Reasons for this approach include the cost of prophylaxis, the possibility of drug interactions, the potential for antifungal resistance, the low mortality associated with the disease, and the relative ease with which oesophageal candidiasis responds to treatment.[34]

Discontinuing maintenance therapy

In patients who achieve CD4 cell counts > 100 cells/μL following the initiation of cART, maintenance therapy for oesophageal candidiasis can be stopped.[35] Cases of primary and relapsed oesophageal candidiasis have been reported in patients on cART who have achieved undetectable viral load. These patients all had CD4 cell counts of < 100 cells/μL. These infections generally occurred during the first 2 months of cART, but some occurred later. Therefore, patients on maintenance azole therapy for oesophageal candidiasis should continue until they have experienced a CD4 cell count rise to > 100 cells/μL for at least 2 months.[36]

 

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