Voriconazole (Page 9 of 12)

14.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open-label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida , infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

The overall clinical and mycological success rates by Candida species in Study 150 to 608 are presented in Table 15.

Table 15: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen*,
Baseline Pathogen Clinical and Mycological Success (%)
Voriconazole Amphotericin B –> Fluconazole

C. albicans

46/107 (43%)

30/63 (48%)

C. tropicalis

17/53 (32%)

1/16 (6%)

C. parapsilosis

24/45 (53%)

10/19 (53%)

C. glabrata

12/36 (33%)

7/21 (33%)

C. krusei

1/4

0/1

*A few patients had more than one pathogen at baseline.

Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.

In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intra-abdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intra-abdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.

14.3 Esophageal Candidiasis (EC)

The efficacy of oral voriconazole 200 mg twice daily compared to oral fluconazole 200 mg once daily in the primary treatment of EC was demonstrated in Study 150 to 305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven EC. Patients were treated for a median of 15 days (range 1 to 49 days). Outcome was assessed by repeat endoscopy at end of treatment (EOT). A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score. For patients in the Intent-to-Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline. Voriconazole and fluconazole (200 mg once daily) showed comparable efficacy rates against EC, as presented in Table 16.

Table 16: Success Rates in Patients Treated for Esophageal Candidiasis
Population Voriconazole Fluconazole Difference % (95% CI)*

PP

113/115 (98.2%)

134/141 (95%)

3.2 (-1.1, 7.5)

ITT

175/200 (87.5%)

171/191 (89.5%)

-2 (-8.3, 4.3)

*Confidence Interval for the difference (Voriconazole – Fluconazole) in success rates.

PP (Per Protocol) patients had confirmation of Candida esophagitis by endoscopy, received at least 12 days of treatment, and had a repeat endoscopy at EOT (end of treatment).

ITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures.

Microbiologic success rates by Candida species are presented in Table 17.

Table 17: Clinical and Mycological Outcome by Baseline Pathogen in Patients with Esophageal Candidiasis (Study-150-305)
Pathogen* Voriconazole Fluconazole
Favorable endoscopic response Mycological eradication Favorable endoscopic response Mycological eradication
Success/Total (%) Eradication/Total (%) Success/Total (%) Eradication/Total (%)

C. albicans

134/140 (96%)

90/107 (84%)

147/156 (94%)

91/115 (79%)

C. glabrata

8/8 (100%)

4/7 (57%)

4/4 (100%)

1/4 (25%)

C. krusei

1/1

1/1

2/2 (100%)

0/0

*Some patients had more than one species isolated at baseline.

Patients with endoscopic and/or mycological assessment at end of therapy.

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