Just Accepted by Leukemia & Lymphoma
Voriconazole toxicity masquerading as septic shock P. Chandrasekar, Priscilla Rupali, Dhaval Patel
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
Doi: 10.3109/10428194.2014.955023
© 2014 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Voriconazole toxicity masquerading as septic shock
P. Chandrasekar, Priscilla Rupali, Dhaval Patel Christian Medical College, Department of Medicine, India; Karmanos Cancer Center, Pharmacy, United States
ED
Short Title:Voriconazole Toxicity
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Keywords: Voriconazole; CYP2C19; Aspergillosis
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
Corresponding Author: P. Chandrasekar, Karmanos Cancer Center, Pharmacy, United States. Email: [email protected]
We wish to highlight the case history of a patient in whom voriconazole toxicity resulted in leukocytosis, and adrenal insufficiency mimicking “septic shock.” A 41-year-old woman with acute myeloid leukemia, underwent induction chemotherapy with cytarabine and daunocrubicin. She subsequently developed febrile neutropenia that was treated empirically with
ED
vancomycin and imipenem initially, then changed to oral therapy with Augmentin and ciprofloxacin at hospital discharge, to complete an additional
PT
the complaints of low grade fever, mild dry cough, fatigue, and poor appetite, but no breathing difficulty or chest pain. She had a history of smoking tobacco, alcoholism and drug abuse including injecting heroin and snorting
CC E
cocaine. Physical examination was unremarkable. Laboratory tests revealed WBC 400/mm3 (absolute neutrophil count 100/mm3; Platelet count 19000/mm3; Blood Urea Nitrogen 15mg/dl; Serum Creatinine 0.9mg/dl; normal liver function tests; Blood cultures: no growth ; Chest Xray: Bilateral
ST A
rounded infiltrates in upper zones. High resolution CT chest showed multiple > 1 cm nodules with surrounding ground glass opacity consistent with halo sign. Serum galactomannan was 1.02, serum Beta-D-glucan 178pcg/ml, bronchoalveolar lavage galactomannan 5.1, all of which strongly suggested the diagnosis of invasive aspergillosis. Therapy was initiated with voriconazole at a dose of 400mg PO BID (based on a dose of 4mg/kg).
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
week of therapy. Four days later, while still neutropenic, she returned with
Serum trough voriconazole level (after 7 days of treatment) was 5.1µg/ml. Her symptoms improved, and chemotherapy-induced neutropenia resolved. About 2 weeks later, while receiving oral voriconazole, she presented to the emergency room with vomiting, diarrhea and abdominal pain. On examination, she was afebrile but hypotensive (80/60 mm mercury),
tachycardic (110/min pulse) with mild tenderness in the right upper and lower quadrants of the abdomen. Rest of the examination was normal. Laboratory tests revealed WBC 43800/mm3 (80% polymorphonuclear forms; no blast forms) with normal hemoglobin level and platelet count. Serum Sodium was 128mEg/L and potassium 5mEg/L. Other laboratory
ED
abnormalities noted were serum transaminitis (ALT = 26; AST = 157) elevated serum alkaline phosphatase 409u/ml and serum creatinine 1.9mg/L.
PT
intensive care unit, she was treated for ‘septic shock’ with empiric
antibiotics, vasopressors and IV fluids. A random voriconazole level during an earlier clinic visit was 10μg/ml. After careful clinical and laboratory
CC E
evaluation, voriconazole toxicity, and not sepsis, was deemed to be the cause of her clinical features. With no evidence of infection on physical exam and laboratory tests, all antimicrobials including voriconazole were discontinued; her clinical condition steadily improved with supportive care, and all
ST A
laboratory abnormalities reversed.
Absence of fever, the patient’s stable/comfortable appearance despite hypotension, no evident focus of infection, good urine output, transient hypotension requiring only a small dose of vasopressors and negative microbiologic cultures strongly suggested sepsis as un unlikely etiology for the hypotension. Serum elecrolyte abnormalities and hypotension suggested
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
A CT scan of the abdomen did not reveal any source of infection. In the
adrenal insufficiency. Subsequently, a Synacthen test demonstrated primary adrenal insufficiency (baseline cortisol =17.8 which only increased to 23.5 after synthetic ACTH). While the common side effects of voriconazole include abnormal vision change, photophobia, visual hallucinations, fever, nausea, and liver function abnormalities 1, rarely, endocrine dysfunction
including adrenal insufficiency, and leukocytosis may occur. Similar drugs, ketoconazole and, to a lesser degree fluconazole are known to cause adrenal hypofunction; the former has been used for adrenal suppression in Cushing’s syndrome and metastatic prostate cancer. As of July 2013, FDA has limited the use of ketoconazole due to fatal liver injury, drug interactions and adrenal
ED
gland problems 2. Azoles inhibit the CYP3A4 isozyme and, in addition, are strong inhibitors of
PT
homozygous poor metabolizers of CYP2C19, the Cmax and AUC values of voriconazole are 2-5 times higher than those in extensive metabolizers 3. The prevalence of CYP2C19 genotypic variation leading to poor metabolism of
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voriconazole is seen in 15-20% of Asians and in 2-3% of Caucasians and hence checking for this polymorphism may help predict toxicity 4. In this instance, our patient was not tested for genetic polymorphism as her condition improved promptly after discontinuation of voriconazole.
ST A
Monitoring of serum voriconazole levels, and ensuring trough concentrations between > 1 and 5μg/ml have been associated with good response and improved survival in the treatment of invasive aspergillosis, while adverse events are associated with levels > 5μg/ml. It is possible that dosing of voriconazole based on actual body weight may have led to voriconazole toxicity in our patient, as was found in a previous
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
CYP2C9 and CYP2C19. Voriconazole is a substrate for CYP2C19 and in
retrospective series 5. In case of obese and overweight patients, it is prudent
to choose voriconazole dose based on adjusted rather than actual body weight to prevent adverse events.
REFERENCES 1. VFEND (voriconazole) injection, powder, lyophilized, for solution as accessed from
ST A
CC E
PT
ED
3. Roger J. M. Bru¨ggemann,1,4 Jan-Willem C. Alffenaar,5 Nicole M. A. Blijlevens et al. Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents. Clinical Infectious Diseases 2009; 48:1441–58. 4. Balian JD, Sukhova N, Harris JW, et al. The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Clin Pharmacol Ther 1995; 57:662–9. 5. Davies-Vorbrodt S, Ito JI, Tegtmeier BR et al. Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review. Pharmacotherapy. 2013 Jan;33(1):22-30. doi: 10.1002/phar.1156.
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=dac26bcd-7a59-401f-9f66a0649767cece#section-6 on 30 th November 2013. 2. FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems on 7/26/2013. Accessed from http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm on 12/29/2013
Voriconazole toxicity masquerading as septic shock P. Chandrasekar, Priscilla Rupali, Dhaval Patel
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
Doi: 10.3109/10428194.2014.955023
© 2014 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Voriconazole toxicity masquerading as septic shock
P. Chandrasekar, Priscilla Rupali, Dhaval Patel Christian Medical College, Department of Medicine, India; Karmanos Cancer Center, Pharmacy, United States
ED
Short Title:Voriconazole Toxicity
ST A
CC E
PT
Keywords: Voriconazole; CYP2C19; Aspergillosis
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
Corresponding Author: P. Chandrasekar, Karmanos Cancer Center, Pharmacy, United States. Email: [email protected]
We wish to highlight the case history of a patient in whom voriconazole toxicity resulted in leukocytosis, and adrenal insufficiency mimicking “septic shock.” A 41-year-old woman with acute myeloid leukemia, underwent induction chemotherapy with cytarabine and daunocrubicin. She subsequently developed febrile neutropenia that was treated empirically with
ED
vancomycin and imipenem initially, then changed to oral therapy with Augmentin and ciprofloxacin at hospital discharge, to complete an additional
PT
the complaints of low grade fever, mild dry cough, fatigue, and poor appetite, but no breathing difficulty or chest pain. She had a history of smoking tobacco, alcoholism and drug abuse including injecting heroin and snorting
CC E
cocaine. Physical examination was unremarkable. Laboratory tests revealed WBC 400/mm3 (absolute neutrophil count 100/mm3; Platelet count 19000/mm3; Blood Urea Nitrogen 15mg/dl; Serum Creatinine 0.9mg/dl; normal liver function tests; Blood cultures: no growth ; Chest Xray: Bilateral
ST A
rounded infiltrates in upper zones. High resolution CT chest showed multiple > 1 cm nodules with surrounding ground glass opacity consistent with halo sign. Serum galactomannan was 1.02, serum Beta-D-glucan 178pcg/ml, bronchoalveolar lavage galactomannan 5.1, all of which strongly suggested the diagnosis of invasive aspergillosis. Therapy was initiated with voriconazole at a dose of 400mg PO BID (based on a dose of 4mg/kg).
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
week of therapy. Four days later, while still neutropenic, she returned with
Serum trough voriconazole level (after 7 days of treatment) was 5.1µg/ml. Her symptoms improved, and chemotherapy-induced neutropenia resolved. About 2 weeks later, while receiving oral voriconazole, she presented to the emergency room with vomiting, diarrhea and abdominal pain. On examination, she was afebrile but hypotensive (80/60 mm mercury),
tachycardic (110/min pulse) with mild tenderness in the right upper and lower quadrants of the abdomen. Rest of the examination was normal. Laboratory tests revealed WBC 43800/mm3 (80% polymorphonuclear forms; no blast forms) with normal hemoglobin level and platelet count. Serum Sodium was 128mEg/L and potassium 5mEg/L. Other laboratory
ED
abnormalities noted were serum transaminitis (ALT = 26; AST = 157) elevated serum alkaline phosphatase 409u/ml and serum creatinine 1.9mg/L.
PT
intensive care unit, she was treated for ‘septic shock’ with empiric
antibiotics, vasopressors and IV fluids. A random voriconazole level during an earlier clinic visit was 10μg/ml. After careful clinical and laboratory
CC E
evaluation, voriconazole toxicity, and not sepsis, was deemed to be the cause of her clinical features. With no evidence of infection on physical exam and laboratory tests, all antimicrobials including voriconazole were discontinued; her clinical condition steadily improved with supportive care, and all
ST A
laboratory abnormalities reversed.
Absence of fever, the patient’s stable/comfortable appearance despite hypotension, no evident focus of infection, good urine output, transient hypotension requiring only a small dose of vasopressors and negative microbiologic cultures strongly suggested sepsis as un unlikely etiology for the hypotension. Serum elecrolyte abnormalities and hypotension suggested
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
A CT scan of the abdomen did not reveal any source of infection. In the
adrenal insufficiency. Subsequently, a Synacthen test demonstrated primary adrenal insufficiency (baseline cortisol =17.8 which only increased to 23.5 after synthetic ACTH). While the common side effects of voriconazole include abnormal vision change, photophobia, visual hallucinations, fever, nausea, and liver function abnormalities 1, rarely, endocrine dysfunction
including adrenal insufficiency, and leukocytosis may occur. Similar drugs, ketoconazole and, to a lesser degree fluconazole are known to cause adrenal hypofunction; the former has been used for adrenal suppression in Cushing’s syndrome and metastatic prostate cancer. As of July 2013, FDA has limited the use of ketoconazole due to fatal liver injury, drug interactions and adrenal
ED
gland problems 2. Azoles inhibit the CYP3A4 isozyme and, in addition, are strong inhibitors of
PT
homozygous poor metabolizers of CYP2C19, the Cmax and AUC values of voriconazole are 2-5 times higher than those in extensive metabolizers 3. The prevalence of CYP2C19 genotypic variation leading to poor metabolism of
CC E
voriconazole is seen in 15-20% of Asians and in 2-3% of Caucasians and hence checking for this polymorphism may help predict toxicity 4. In this instance, our patient was not tested for genetic polymorphism as her condition improved promptly after discontinuation of voriconazole.
ST A
Monitoring of serum voriconazole levels, and ensuring trough concentrations between > 1 and 5μg/ml have been associated with good response and improved survival in the treatment of invasive aspergillosis, while adverse events are associated with levels > 5μg/ml. It is possible that dosing of voriconazole based on actual body weight may have led to voriconazole toxicity in our patient, as was found in a previous
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
CYP2C9 and CYP2C19. Voriconazole is a substrate for CYP2C19 and in
retrospective series 5. In case of obese and overweight patients, it is prudent
to choose voriconazole dose based on adjusted rather than actual body weight to prevent adverse events.
REFERENCES 1. VFEND (voriconazole) injection, powder, lyophilized, for solution as accessed from
ST A
CC E
PT
ED
3. Roger J. M. Bru¨ggemann,1,4 Jan-Willem C. Alffenaar,5 Nicole M. A. Blijlevens et al. Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents. Clinical Infectious Diseases 2009; 48:1441–58. 4. Balian JD, Sukhova N, Harris JW, et al. The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Clin Pharmacol Ther 1995; 57:662–9. 5. Davies-Vorbrodt S, Ito JI, Tegtmeier BR et al. Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review. Pharmacotherapy. 2013 Jan;33(1):22-30. doi: 10.1002/phar.1156.
JU
Leuk Lymphoma Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=dac26bcd-7a59-401f-9f66a0649767cece#section-6 on 30 th November 2013. 2. FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems on 7/26/2013. Accessed from http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm on 12/29/2013
