Fungal infections remain a major cause of illness and death, especially in immunocompromised patients. Voriconazole is a broad-spectrum triazole antifungal that is effective against a wide range of fungi including Aspergillus and Candida. Studies have shown voriconazole to have higher response and survival rates compared to amphotericin B for invasive aspergillosis. It is also as effective as fluconazole for esophageal candidiasis. Voriconazole can be used alone or in combination with other antifungals as salvage therapy for refractory infections.

2.  Fungal infections remain a significant cause of morbidity and
mortality despite advances in medicine and the emergence of new
antifungal agents.
 Immunocompromised patients are particularly at risk of developing
these infections, with Candida and Aspergillus spp. being the mycoses
most commonly identified.
 Patients who develop candidemia have a greater chance of prolonged
hospitalization and have a mortality rate as high as 60%.

3.  In addition, the prevalence of Candida spp. that are resistant to
triazole antifungal agents is increasing, making treatment options a
concern.
 Aspergillosis carries a 100% mortality rate if left untreated.
 Although there are numerous treatment options, no broad-spectrum
antifungal agents with an acceptable safety profile and with both
intravenous and oral formulations are available at this time.

4.  Amphotericin B
 Liposomal amphotericin B
 ECHINOCANDINS
 Azole compounds

5.  Amphotericin B is currently the drug of choice for the treatment of
systemic infections caused by Aspergillus and Candida spp.
However, the high incidence of toxicity associated with amphotericin
B has limited its use in many patients.
 Lipid formulations of amphotericin B are better tolerated than
conventional amphotericin B and have similar efficacy. However,
these agents are costly and are generally reserved for second-line
therapy in patients who did not respond to or could not tolerate
conventional amphotericin B therapy.

6.  Broad spectrum triazole antifungal
 Structure related to that of fluconazole and a spectrum of activity
comparable to that of itraconazole.
 Voriconazole was approved by the Food and Drug Administration in
May 2002.(VFEND, Pfizer)
 Available in oral and intravenous form

8.  Like the other triazole antifungals, voriconazole exerts its
antifungal activity by inhibition of 14-alpha-lanosterol
demethylation, which is mediated by fungal cytochrome P450
enzymes.
 The accumulation of 14-alphamethyl sterols results in a decrease
in ergosterol, which is an essential component of fungal cell wall
formation.
 The resulting cell wall abnormalities are thought to be responsible
for voriconazole’s antifungal activity.

9. Indicated in adults and children aged 2 years and above as follows:
 Treatment of invasive aspergillosis.
 Treatment of candidaemia in non-neutropenic patients.
 Treatment of fluconazole-resistant serious invasive Candida infections
Treatment of serious fungal infections caused by Scedosporium spp. and
Fusarium spp.
 Should be administered primarily to patients with progressive, possibly
life-threatening infections.
 Prophylaxis of invasive fungal infections in high risk allogeneic
hematopoietic stem cell transplant (HSCT) recipients.

12.  Oral administration leads to rapid and almost complete absorption
 2 h after single 400 mg dose, serum concentrations of ~2 mg
achieved
 Disproportionate increase in blood levels with increasing oral and
parenteral dosage
 Non-linear pharmacokinetics in high-risk patients: may indicate
monitoring levels
 Mean time to maximum plasma concentration: 1–2 h post-dose
 Bioavailability >96%

13.  Best when not administered within 1 h of food intake
 Widely distributed throughout tissues
 Protein binding 58%
 Large volume of distribution: 4.6 l/kg
 Elimination by metabolic clearance
 Extensively metabolized by cytochrome P450 isoenzymes: may affect
delivery across intestinal mucosa
 Elimination half-life is dose-dependent: 6–9 h after a 3 mg/kg
parenteral dose or 200 mg oral dose

14.  200 mg every 12 h >40 kg / 100 mg every 12 h <40kg
 If patient response inadequate, increase to 300 mg every 12h (or 150
mg every 12 h for patients <40 kg)
 1 h before or 1 h following a meal
 No adjustment required in patients with abnormal liver function tests
(up to 5-fold upper limit of normal) but continued monitoring is
recommended
 No adjustment of oral dose required for patients with renal
impairment
 Hemodialysis (4 h session) does not remove a sufficient amount of drug
– no dosage adjustment required
Treatment duration depends on the patient’s clinical and mycological
response.

15.  Voriconazole increased tacrolimus Cmax and AUCs by 117% and
221%, respectively. When initiating voriconazole in patients
already receiving tacrolimus, it is recommended that the
Tacrolimus dose be reduced to a third of the original dose and that
the tacrolimus level be carefully monitored.
 Increased tacrolimus levels have been associated with
nephrotoxicity.
 When voriconazole is discontinued, tacrolimus levels must be
carefully monitored and the dose increased as necessary.
Coadministration of voriconazole and sirolimus is contraindicated

16.  In stable renal transplant recipients, voriconazole increased
cyclosporine Cmax and AUCs by at least 13% and 70%,
respectively.
 When initiating voriconazole in patients already receiving
cyclosporine, it is recommended that the cyclosporine dose be
halved and that the cyclosporine level be carefully monitored.
 Increased cyclosporine levels have been associated with
nephrotoxicity.
 When voriconazole is discontinued, cyclosporine levels must be
carefully monitored and the dose increased as necessary.

17.  >30% transient visual disturbances, but no anatomical
correlates of the disturbances
 Headache
 Gastrointestinal upset
 Rare cases of severe exfoliative cutaneous reactions, eg.
Stevens–Johnson syndrome
 Elevation in liver function tests in ~13% patients

18.  An open, non-comparative study of 116 patients with invasive
aspergillosis resulted in an overall efficacy of 48% (56 complete
⁄ partial responses)
 Fifty (60%) of the 84 patients with pulmonary infection
responded well to treatment with voriconazole, 6 mg⁄ kg twice
a day on the first day, followed by 3 mg⁄ kg twice daily for 6–27
days and 200 mg twice daily, given orally for up to 24 weeks.

19.  A 12 week comparative study on 391 patients between voriconazole
(two 6 mg⁄ kg infusions 12 h apart on the first day, followed by 4 mg⁄ kg
every 12 h for at least 7 days, after which treatment could be
continued orally 200 mg every 12 h) and intravenous amphotericin B
(1–1.5 mg⁄ kg ⁄ day).
 A satisfactory response (complete or partial resolution of all
attributable symptoms and signs and of radiographic or bronchoscopic
abnormalities present at baseline) was recorded for 76 (53%) of the 144
patients treated with voriconazole but only for 42 (32%) of the 133
patients treated with amphotericin B

21.  The 12-week survival rate was also higher for the voriconazole
group (71%, compared with 58%for amphotericin B group).
 More than twice as many patients (29%) randomised to
amphotericin B died from invasive aspergillosis as those
randomised to voriconazole (13%).
 Treatment with voriconazole was sustained longer, with a
median duration of 77 days (range 2–84 days), compared with 10
days (range 1–84 days) for patients receiving amphotericin B.
 Fewer adverse events compared to ampho. B arm

22.  The efficacy, safety, and tolerability of voriconazole and fluconazole
were compared in 391 immunocompromised patients with mycology-
and biopsy-proven esophageal candidiasis.
 Primary efficacy analysis (256 patients) of esophageal treatment as
assessed by esophagoscopy revealed success rates of 98.3% with
voriconazole and 95.1% with fluconazole.

23. Voriconazole (200 mg, b.i.d.) was shown to be at least as effective as
fluconazole in the treatment of biopsy proven esophageal candidiasis in
immunocompromised patients.

24.  Prospective, multicentre, open-labelled, randomized, controlled trial, renal
transplant recipients with invasive fungal infections in china for 2 years
 65 patients, of whom 31 were treated with micafungin, and 34 with voriconazole.
 There was no significant difference between the two groups in terms of efficacy,
survival beyond 10 days and discontinuation of treatment because of lack of
efficacy.
 Mortality rates in the micafungin and voriconazole groups were 9.7% (3/31) and
12.1% (4/33), respectively.
 Rates of adverse effects in the two groups were 41.9% and 51.6%, respectively.
This is the first comparison of micafungin and voriconazole in renal
transplant patients. Study shows that the effectiveness of micafungin was
similar to that of voriconazole in patients.

27. Salvage=who have failed or were intolerant to standard antifungal therapy

29. Salvage therapy with the combination of voriconazole and caspofungin was
associated with reduced mortality, compared with voriconazole
monotherapy

31.  Drug of choice for invasive aspergilosis
 Available as oral and intravenous form
 Established superiority over amphotericin B in terms of both efficacy
and patient survival.
 Life-saving drug for patients with infections caused by less-common
fungal pathogens.
 Can be used in combination with echinocandins in refractory cases
 Salvage therapy