torsades de pointes ( tdp ) is a rare , potentially fatal cardiac arrhythmia that is associated with both prolongation and dispersion of the corrected qt ( qtc ) interval of any cause . the causes of prolonged qtc are protean and include genetic susceptibility , many drugs , electrolyte disturbances , underlying cardiac abnormality and an increased predisposition if female . voriconazole , approved by the fda in 2002 , is the preferred treatment for invasive aspergillosis , where it confers a survival advantage and has increased tolerability over other antifungal drugs such as amphotericin - based formulations . a recognised side - effect of voriconazole is its inhibition of the rapid potassium rectifier channel ( ikr ) in the cardiac myocyte that can lead to a pathologically prolonged qtc . in congenital long qt syndrome , a qtc of greater than 500  ms is associated with a higher risk for tdp , with a 79% increase in risk for every 10  ms prolongation over this level . since 2004 , there have only been a handful of published reports of voriconazole - induced tdp , three in the adult population and three in the paediatric population , with the first dating back to 2004 [ 712 ] . our experience of two adult presentations with voriconazole - associated tdp in one centre adds to the literature for this uncommonly reported event . a 59 year old chinese man was admitted ( day 0 ) to commence treatment for natural killer ( nk ) cell lymphoma : his chemotherapeutic regimen was cyclophosphamide , doxorubicin , etoposide , vincristine and methylprednisolone . he was previously well , with no family history of syncope or sudden cardiac death . a gated cardiac blood pool scan prior to chemotherapy showed a normal left ventricular ejection fraction . an electrocardiograph ( ecg ) taken six days prior to commencing chemotherapy showed a prolonged qtc interval of 520  ms ( n=<470  ms ) . on day 1 , he suffered respiratory distress requiring intensive care support and commenced piperacillin / tazobactam and vancomycin as empirical treatment for hospital - acquired pneumonia . a high - resolution computer tomogram ( ct ) of the thorax three days prior had not shown any evidence of infection . over the following week the patients respiratory function improved ; however , he developed melena requiring multiple blood transfusions and was commenced on total parenteral nutrition ( tpn ) . on the ninth day of admission to the intensive care unit ( day 10 ) , his medications at the time of his arrest included voriconazole 200  mg iv twice a day , piperacillin / tazobactam 4.5  g intravenously ( iv ) twice a day , vancomycin 1  g iv daily , trimethoprim  sulfamethoxazole 180  mg/400  mg three times orally per week , frusemide 60  mg iv four times a day , prednisolone 7.5  mg orally daily , pantoprazole 40  mg iv daily , filgrastim 300  g subcutaneous daily and tranexamic acid 500  mg orally daily . his relevant blood test results at the time of arrest are shown in table 1 . an ecg performed soon after recovery from cardiac arrest showed a prolonged qtc interval of 579  ms ( n=<450  ms ) . voriconazole was ceased and not replaced with another antifungal , and electrolyte disturbances were corrected . with respect to antifungal prophylaxis , non - azole based treatment was used without incident . a 54 year old woman with relapsed diffuse large b - cell lymphoma with cerebral involvement , treated with intrathecal methotrexate , cytarabine and hydrocortisone , two episodes of tdp were documented on the following day in the intensive care unit , and the collapse is assumed to represent an episode of tdp that degenerated into vf . the patient had a pre - treatment qtc interval of 405  ms ( n480  ms ) but had no ecg recorded in the time before her arrest . her antifungal therapy was switched to liposomal amphotericin and a convalescent ecg showed a normalised qtc of 423  ms . the patient made a full recovery from this episode . at the time of her arrest , the patients medications included voriconazole 200  mg iv twice daily and caspofungin 50  mg iv daily , for presumed hepatic fungal abscess . she was also prescribed prednisolone 15  mg orally daily and metoclopramide 10  mg orally or intravenously three times a day . she was receiving tpn , had recurrent episodes of hypokalaemia and hypomagnesaemia and had biochemical evidence of hepatic impairment ( see table 1 ) . a 59 year old chinese man was admitted ( day 0 ) to commence treatment for natural killer ( nk ) cell lymphoma : his chemotherapeutic regimen was cyclophosphamide , doxorubicin , etoposide , vincristine and methylprednisolone . he was previously well , with no family history of syncope or sudden cardiac death . a gated cardiac blood pool scan prior to chemotherapy showed a normal left ventricular ejection fraction . an electrocardiograph ( ecg ) taken six days prior to commencing chemotherapy showed a prolonged qtc interval of 520  ms ( n=<470  ms ) . on day 1 , he suffered respiratory distress requiring intensive care support and commenced piperacillin / tazobactam and vancomycin as empirical treatment for hospital - acquired pneumonia . a high - resolution computer tomogram ( ct ) of the thorax three days prior had not shown any evidence of infection . over the following week the patients respiratory function improved ; however , he developed melena requiring multiple blood transfusions and was commenced on total parenteral nutrition ( tpn ) . on the ninth day of admission to the intensive care unit ( day 10 ) , his medications at the time of his arrest included voriconazole 200  mg iv twice a day , piperacillin / tazobactam 4.5  g intravenously ( iv ) twice a day , vancomycin 1  g iv daily , trimethoprim  sulfamethoxazole 180  mg/400  mg three times orally per week , frusemide 60  mg iv four times a day , prednisolone 7.5  mg orally daily , pantoprazole 40  mg iv daily , filgrastim 300  g subcutaneous daily and tranexamic acid 500  mg orally daily . his relevant blood test results at the time of arrest are shown in table 1 . an ecg performed soon after recovery from cardiac arrest showed a prolonged qtc interval of 579  ms ( n=<450  ms ) . voriconazole was ceased and not replaced with another antifungal , and electrolyte disturbances were corrected . with respect to antifungal prophylaxis , non - azole based treatment was used without incident . a 54 year old woman with relapsed diffuse large b - cell lymphoma with cerebral involvement , treated with intrathecal methotrexate , cytarabine and hydrocortisone , was admitted with febrile neutropaenia ( day 0 ) . on day 23 two episodes of tdp were documented on the following day in the intensive care unit , and the collapse is assumed to represent an episode of tdp that degenerated into vf . the patient had a pre - treatment qtc interval of 405  ms ( n480  ms ) but had no ecg recorded in the time before her arrest . her antifungal therapy was switched to liposomal amphotericin and a convalescent ecg showed a normalised qtc of 423  ms . at the time of her arrest , the patients medications included voriconazole 200  mg iv twice daily and caspofungin 50  mg iv daily , for presumed hepatic fungal abscess . she was also prescribed prednisolone 15  mg orally daily and metoclopramide 10  mg orally or intravenously three times a day . she was receiving tpn , had recurrent episodes of hypokalaemia and hypomagnesaemia and had biochemical evidence of hepatic impairment ( see table 1 ) . voriconazole is a synthetic second generation triazole and an effective drug for invasive mycoses , including aspergillosis , that has supplanted amphotericin - based formulations in the management of these life - threatening infections of the immunosuppressed . ketoconazole , an imidazole released in the 1980s , was first associated with tdp in 1990 . the first generation triazoles ( itraconazole and fluconazole ) were approved for use in the 1990s and several cases of tdp have been reported since , both in combination with other qt interval prolonging agents and without . a 5-year evaluation of the us fda adverse event reporting system database retrieved 75 cases of triazole antifungals associated with tdp , where fluconazole was the most commonly reported agent ( n=47 ) , followed by voriconazole ( n=17 ) , itraconazole ( n=8 ) and posaconazole ( n=3 ) , however , many of these cases involved other concomitant qt interval prolonging drugs or were duplicated reports . voriconazole was first identified in 2004 as the likely cause of tdp in a paediatric patient . since then , there have been five further reports ( three in adults ) of voriconazole contributing to tdp , with no deaths [ 712 ] . in all cases , including both described here , patients had additional risk factors for tdp . risk factors in prolonged qtc are additive and frequently cluster in cases of tdp   and strongly suggest the need for careful monitoring with baseline and post - treatment ecgs when instituting voriconazole therapy in patients with haematological malignancy . half of the previously reported cases of voriconazole - related tdp , and both cases presented herein , involved recent chemotherapy for haematological malignancy . anthracycline - based chemotherapy , in particular , is recognised to both prolong the qt and cause qt dispersion . furthermore , patients undergoing chemotherapy have an increased risk of receiving other qt interval - prolonging agents such as anti - emetics including 5ht3 antagonists or haloperidol , selective serotonin re - uptake inhibitors , other antimicrobials and diuretics . these patients are also at increased risk for the pro - arrythmic electrolyte disturbances due to drugs , altered oral intake , vomiting and diarrhoea . typically , at the time of our first patients episode of tdp , multiple risk factors for qtc prolongation , and therefore tdp were identified including voriconazole , baseline qt prolongation that may represent a genetic tendency , tpn , multi - organ failure and electrolyte imbalance . patients concomitant medications should also be carefully reviewed with respect to the mode of drug delivery . intravenous route of administration of qtc prolonging drugs is hypothesised to predispose to tdp through multiple mechanisms , including a higher peak concentration and a more rapid rise to peak concentration . of previously published case reports of tdp attributed partially to voriconazole it has also been hypothesised that metabolism of voriconazole by the cytochrome p450 pathway isoenzyme cyp2c19 ( as well as cyp2c9 and cyp3a4 ) is subject to significant inter - individual efficacy variation , with 1520% of people of asian extraction displaying a poor - metaboliser phenotype that can lead to increased drug levels , and therefore increased risk of dose - dependent side - effects , such as qtc prolongation . monitoring of voriconazole levels to guide therapy has been variably shown to reduce the commonly encountered non - cardiac adverse effects of voriconazole   but has not been proven to reduce the less common cardiac adverse reactions ; however , ikr channel inhibition is a dose - dependent effect . in both our cases , re - challenge of voriconazole was not conducted due to risk of further tdp . currently , there are no consensus recommendations about re - initiation of voriconazole or other azole antifungals in patients who have developed cardiac adverse reactions . in the previously described cases , voriconazole therapy was re - introduced in four of the reported six tdp cases with two cases of persistent qtc prolongation , one case without incident   and one case resulting in repeat tdp . tdp engendered by qtc prolongation is thought to be a rare complication of voriconazole therapy . however , two cases at our centre has raised our awareness of this potentially life - threatening condition and highlighted the need for a careful arrhythmia risk - assessment of patients commencing voriconazole therapy . the dearth of published case reports raises the possibility that this condition is under - recognised . in patients prescribed voriconazole , baseline ecg screening should be performed and a review of the patients concomitant medications and mode of delivery of other drugs that potentially affect qtc . ongoing intensive monitoring of the qtc interval should be performed in patients that are identified to be at increased risk of prolonged qtc and tdp due to underlying genetic tendency , potential cytochrome polymorphisms , recurrent electrolyte disturbance or drug interactions . monitoring of serum voriconazole levels has not been clearly demonstrated to reduce the cardiac side - effects of voriconazole .
voriconazole can prolong the qt interval contributing to life - threatening cardiac arrhythmia . 
 torsades de pointes is an uncommon but serious complication of voriconazole use which may be under - recognised . 
 we present torsades de pointes in two patients with underlying haematological malignancy being treated for invasive fungal infection with voriconazole . 
 patients receiving voriconazole should be screened and monitored for evidence of qt prolongation , and if prolongation detected , consideration given to alternative treatments or more intensive cardiac monitoring .