Antifungal drugs

Antifungal drugs

J.K. Aronson 27 ALLYLAMINES [SEDA-31, 457; SEDA-32, 491; SEDA-33, 541] Terbinafine [SED-15, 3316; SEDA-31, 457; SEDA-32, 491; SEDA-33, 541] Skin A p...

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J.K. Aronson

27 ALLYLAMINES

[SEDA-31, 457; SEDA-32, 491; SEDA-33, 541]

Terbinafine [SED-15, 3316; SEDA-31, 457; SEDA-32, 491; SEDA-33, 541] Skin A photosensitivity reaction has been attributed to terbinafine [1A]. • A 60-year-old man took oral terbinafine for onychomycosis starting on a sunny day in September. After 6 days he developed a pruritic rash on the forehead and the backs of the hands, which gradually worsened. He stopped taking the terbinafine, but the erythema, edema, and scaling continued to progress on his face, upper chest, and the back of the neck, with moderate malaise and a slightly raised body temperature. Covered areas of the skin were not involved. Local and oral glucocorticoids produced significant improvement overnight and complete clearance within 2 days. Photopatch tests were positive only with terbinafine.

Antifungal drugs took terbinafine and had another episode of AGEP within 2 days; the pustules resolved spontaneously after withdrawal. Two years later she took an aminopenicillin for erysipelas and 2 days later developed a similar pustular eruption, arising on edematous and pruritic erythema, predominantly in the intertriginous areas, with a positive Nikolsky’s sign. After withdrawal of the aminopenicillin, the rash cleared within 10 days. The next year, 2 days after starting a course of pristinamycin for erysipelas, she had a similar eruption, and a skin biopsy suggested AGEP.

Immunologic A 71-year-old man developed a hypersensitivity syndrome associated with terbinafine and later had peritonitis due to ileal perforation [3A]. Cytomegalovirus-specific IgG antibodies were significantly increased and pathological examination of the resected ileum confirmed cytomegalovirus infection. The authors attributed the hypersensitivity reaction and the ileal perforation to cytomegalovirus reactivation by terbinafine.

Acute generalized exanthematous pustulosis (AGEP) has been attributed to various drugs in the same patient, including terbinafine [2A]. • A 79-year-old woman took terbinafine for intertrigo and 2 weeks later she developed widespread erythema over the trunk with superficial pustules. The erythema intensified, the pustules became confluent and spread all over her body, and she had a fever and a leukocytosis. Liver function tests, urea and creatinine were normal. Biopsy showed acute generalized exanthematous pustulosis (AGEP). Terbinafine was withdrawn and the eruption subsided gradually over the next 10 days. Eight years later she again

Side Effects of Drugs, Annual 34 J.K. Aronson (Editor) ISSN: 0378-6080 http://dx.doi.org/10.1016/B978-0-444-59499-0.00027-1 # 2012 Elsevier B.V. All rights reserved.

AMPHOTERICIN

[SED-15, 192; SEDA-31, 458; SEDA-32, 493; SEDA-33, 542] Systematic reviews In a systematic review and meta-analysis of 39 randomized controlled trials in more than 8000 patients, the incidence rates of treatment discontinuation owing to adverse reactions in general and liver damage in particular associated with antifungal therapy varied widely [4M]. The pooled risks of treatment withdrawal because of adverse reactions were over 10% for amphotericin B and itraconazole and 2.5–3.8% for fluconazole, caspofungin, and micafungin. 427

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In a systematic review of the risk of nephrotoxicity induced by two different lipid formulations of amphotericin, amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AmB), 11 studies were identified and 8 were included [5M]. There was a higher probability of nephrotoxicity in patients who received ABLC versus LAmB (OR ¼ 1.75; RR ¼ 1.55), but there was a significant lack of homogeneity across these studies. Restricted analyses, omitting different studies that contributed to the heterogeneity, showed that the risks were more similar between the two formulations. Drug–drug interactions Vancomycin In 35 patients, mean age 59 years being treated in an ICU 76 drug–drug interactions and 60 adverse events were recorded [6C]. There was a significant association for acute renal failure due to the combined use of amphotericin with vancomycin.

Amphotericin B deoxycholate (DAMB) Observational studies Adverse reactions to amphotericin B deoxycholate have been studied in a retrospective analysis of 39 courses of treatments in 33 Chilean patients [7c]. On average, therapy lasted 12 (range 2–39) days and the cumulative dose was 600 (100–1950) mg. In 63% of cases 24-hour infusions were used and 36% received a 4to 6-hour infusion. In addition, 37% received daily an infusion of saline before amphotericin. There were adverse reactions in 40% of treatments; fever was the most common (25%). Nephrotoxicity was relatively infrequent (9.4%), and it affected only patients without previous renal disease and not requiring dialysis. Hypokalemia developed in 22% of treatments. In a multivariate analysis, age over 60 years was an independent factor for infusion-related adverse reactions and a Sequential Organ Failure Assessment (SOFA) score over 3 and glucocorticoid administration at the same time as amphotericin were independently associated with fatal outcomes.

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Amphotericin B lipid complex (ABLC) Drug administration route In a prospective study of the disposition of nebulized amphotericin B lipid complex, 1 mg/kg every 24 hours for 4 days in 35 lung transplant recipients, satisfactory concentrations were achieved in the bronchial epithelial lining fluid with only low concentration in the plasma [8c]. Adverse reactions to nebulized amphotericin included wheezing, coughing, and a 12% fall in FEV1.

Liposomal amphotericin (L-AmB) Electrolyte balance Of 25 Japanese subjects with fungal infections treated with L-AmB, one had a raised serum creatinine and six had hypokalemia; there was a positive relation between the fall in serum potassium and the dose of amphotericin, and the serum potassium tended to fall after 5–6 days [9c]. Skin A 72-year-old man developed a postoperative infection with candidiasis, for which he was given liposomal amphotericin 75 mg/day [10A]. After 4 days he developed a generalized exudative reaction. The amphotericin was withdrawn and the rash subsided within a week.

ANTIFUNGAL AZOLES [SED-15, 301; SEDA-31, 459; SEDA-32, 497; SEDA-33, 545] For metronidazole see Chapter 28.

Drug–drug interactions with antifungal azoles All-trans retinoic acid A 21-year-old woman with acute promyelocytic leukemia took alltrans retinoic acid (ATRA) for 5 months, after which she was given voriconazole for

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persistent fever and pancytopenia; after 15 days she complained of blurred vision, longsightedness, and dry skin with pruritus, due to pseudotumor cerebri, which resolved after withdrawal of ATRA [11A]. The authors attributed this adverse reaction to inhibition of the metabolism of ATRA. Axitinib Axitinib, a selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by CYP3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. In a single-blind, 2-way, randomized, placebo-controlled crossover study in 32 healthy volunteers axitinib exposure was significantly increased by ketoconazole [12C]. Adverse events were predominantly mild, the most common treatment-related adverse events being headache and nausea. Bortezomib In a retrospective medical record review of six adults with relapsed multiple myeloma who received intravenous bortezomib þ oral dexamethasone, three who also took itraconazole had new or worsening peripheral neuropathy and grade 4 thrombocytopenia [13c]. One patient who took lansoprazole alone and two who did not take itraconazole or lansoprazole had no such reactions. The authors noted that itraconazole inhibits CYP3A4 and lansoprazole inhibits CYP2C19. Casopitant The effects of ketoconazole and rifampicin on the pharmacokinetics of single doses of the neurokinin-1 receptor antagonist casopitant, which is metabolized primarily by CYP3A4, have been investigated in phase I studies in 131 healthy subjects [14c]. Ketoconazole increased the Cmax of single-dose casopitant 2.7-fold, the AUC0 ! t 12-fold, and the AUC0 ! t 4.3-fold and increased the Cmax of casopitant 2.5-fold. Similar results were found after administration of casopitant for 3 days. There were no effects on either safety signals or the Fredericia-corrected QT interval. Repeat-dose rifampicin reduced the Cmax and AUC0 ! t of casopitant by 96% and 90% respectively. These clinical studies confirm the role of CYP3A in the metabolism of casopitant. Co-administration of casopitant with

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potent inhibitors of CYP3A is likely to increase plasma exposure of casopitant, and co-administration with potent inducers is likely to reduce exposure and compromise efficacy. Ebastine In a 3-way crossover sequential study with 2-week washouts, 10 healthy participants took itraconazole for 6 days, rifampicin for 10 days, or neither, followed by oral 20 mg ebastine [15c]. Itraconazole reduced the oral clearance of ebastine to 10% and increased the AUC of its active metabolite, carebastine, threefold. Rifampicin reduced the AUC of carebastine to 15%, markedly reduced the oral availability of ebastine, and significantly reduced histamine-induced skin reactions. Echinocandins In a phase I study of the effects of posaconazole on the pharmacokinetics of caspofungin and micafungin in 67 healthy subjects no interaction was observed. Adverse events, clinical laboratory tests, vital signs, and electrocardiograms were unaffected [16c]. Glimepiride Glimepiride is metabolized by CYP2C9, which is inhibited by voriconazole. In one case co-administration led to persistent hypoglycemia for 48 hours in a 69-year-old man [17A]. HMG Co-A reductase inhibitors A 58-yearold man who was taking simvastatin was given itraconazole for onychomycosis, and the simvastatin was replaced by pravastatin to prevent drug interactions [18A]. He ran out of pravastatin and started to take simvastatin again. He developed myalgia and muscle weakness after 1 week, with a greatly raised serum creatine kinase activity, and then severe rhabdomyolysis. Oxycodone In 12 healthy subjects who took 200 mg itraconazole or placebo orally for 5 days in a crossover study, oxycodone was administered on day 4, intravenously (0.1 mg/kg) in the first part of the study and orally (10 mg) in the second part [19C]. Itraconazole increased the AUC and reduced the plasma clearance of intravenous oxycodone by 51% and 32% respectively and increased the AUC of oral oxycodone by 144%. The Cmax of oxycodone increased by 45%. The

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AUC0 ! 48h of noroxycodone fell by 49% and that of oxymorphone was increased by 359% after oral oxycodone. However, the pharmacodynamic effects of oxycodone were increased by itraconazole only modestly. Phenytoin A 59-year-old woman with Behçet’s disease who was taking high doses of phenytoin developed ataxia, tremor, fatigue, slurred speech, and somnolence, suggestive of phenytoin intoxication, when she took fluconazole; the serum phenytoin concentration rose to 138 mmol/l; she was a CYP2C9 ultrarapid metabolizer [20A]. Superwarfarins Superwarfarins have very long half-lives and reversal of their effects can be slow [21A]. • Hemoperitoneum occurred in a patient who was taking the superwarfarin brodifacoum after fluconazole administration for 1 week. The prothrombin time and partial thromboplastin time were markedly prolonged, although a mixing study with normal plasma showed that the corrected values were in the reference ranges. The vitamin K-dependent coagulation factors (II, VII, IX, and X) and anticoagulation factors (protein C and protein S) were reduced. After administration of fresh frozen plasma and oral vitamin K1 for 5 days, and following drainage of the hemoperitoneum, his bleeding tendency stopped and the prothrombin time and partial thromboplastin time slowly normalized.

Tacrolimus An interaction of voriconazole with tacrolimus has been described [22A]. • A 43-year-old man with a renal transplant taking long-term immunosuppressive agents, including mycophenolate and tacrolimus, developed recurrent cryptococcal meningitis and was given oral voriconazole. After 6 days the trough concentration of tacrolimus markedly increased and hyponatremia developed.

Fluconazole

[SED-15, 1377; SEDA-31, 462; SEDA-32, 502; SEDA-33, 551] Sensory systems Vision Bilateral cystoid macular edema has been reported in a 76-year-old woman with longstanding Coccidioides infection treated with high-dose

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fluconazole; as the dose of fluconazole was reduced her visual acuity improved [23A]. Skin A 64-year-old woman developed a fixed drug eruption, with eight ovoid hyperpigmented patches on the arms, palms and lower legs on multiple occasions while taking fluconazole, confirmed by oral rechallenge [24A]. Stevens–Johnson syndrome has been attributed to fluconazole [25Ar].

Itraconazole [SED-15, 1932; SEDA-31, 463; SEDA-32, 504; SEDA-33, 552] Respiratory A 53-year-old man with chronic pulmonary aspergillosis developed near-fatal diffuse alveolar hemorrhage after receiving intravenous itraconazole; a lymphocyte stimulation test was positive; he did not respond to methylprednisolone but responded dramatically to hemoperfusion using a polymyxin B-immobilized fiber column [26A]. Nervous system Five patients developed fine bilateral tremor in the hands after taking itraconazole for 2 weeks to 12 months; in all cases the tremor resolved after withdrawal [27A]. Pancreas Four cases of pancreatitis in patients taking relatively high doses of itraconazole have been reported to the Netherlands Pharmacovigilance Centre Lareb. In two cases, recurrent use of itraconazole resulted in recurrent symptoms [28A].

Ketoconazole

[SED-15, 1269;

SEDA-30, 326] Skin A 12-year-old girl developed acute generalized exanthematous pustulosis after taking oral ketoconazole [29A].

Posaconazole [SED-15, 2905; SEDA31, 463; SEDA-32, 504; SEDA-33, 553] Endocrine A 4-year-old boy developed repeated seizures after taking posaconazole for about 3 weeks after having been lethargic

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for a few days; the serum sodium concentration was 99 mmol/l, potassium 2.8 mmol/l, and serum osmolality 243 mosm/kg, with high urinary osmolality and urinary sodium (415 mosm/kg and 125 mmol/l), confirming a diagnosis of inappropriate secretion of ADH (SIADH) [30A]. Posaconazole was withdrawn and he gradually recovered.

Voriconazole

[SED-15, 3688; SEDA31, 463; SEDA-32, 505; SEDA-33, 554] Nervous system A 71-year-old man with polyarteritis developed a peripheral axonal neuropathy after taking voriconazole for 1 month for chronic cavitary pulmonary aspergillosis; after withdrawal of voriconazole and a switch to posaconazole, the neuropathy partly improved [31A].

Sensory systems Vision A 56-year-old woman developed photopsia and color changes in the left eye from the start of therapy with voriconazole; 20 months after withdrawal of voriconazole she had persistent visual complaints, including photopsia and “additional sources of light” in her left eye [32A]. Electrolyte balance Hyponatremia in a 74year-old man with nephrotic syndrome due to a salt-losing nephropathy was attributed to voriconazole. The serum antidiuretic hormone (ADH) concentration and plasma renin activity were raised, and there was a high urine sodium concentration, despite volume depletion and a low serum osmolality [33A]. Liver In a retrospective review of 200 adult and pediatric recipients of hemopoietic stem cell transplants who took more than two consecutive doses of voriconazole, clinical hepatotoxicity was defined as any rises in liver enzymes (aminotransferases and alkaline phosphatase) that led to withdrawal of voriconazole and biochemical hepatotoxicity as a rise in one or more liver enzymes to more than three times the upper limit of the reference range or more than three times the baseline value if abnormal at

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baseline [34c]. The median duration of voriconazole therapy was 72 (range 1–804) days. There was biochemical hepatotoxicity in 51 patients and clinical hepatotoxicity in 17. In 35 patients hepatotoxicity was severe enough to require withdrawal. Acute graftversus-host disease was a susceptibility factor for hepatotoxicity and receipt of a T cell-depleted allograft was protective. Immunologic An infant with chronic granulomatous disease developed lupus-like lesions, with desquamation and erythematous annular scaly patches on the forehead and periorbital region, while receiving voriconazole for chronic invasive aspergillosis; the lesions disappeared after withdrawal [35A]. Histology showed vacuolar degeneration of the basal layer, superficial and deep perivascular inflammatory cell infiltrates of lymphocytes, and dermal mucin deposition between collagen bundles; immunofluorescence staining showed C3 and granular IgM deposition along the epidermodermal junction.

Voriconazole: Photosensitivity and tumorigenicity Voriconazole has often been reported to have caused photosensitivity [36R], and this adverse effect has been linked to a risk of tumors in light-exposed areas. The EIDOS and DoTS descriptions of this reaction are shown in Figure 1. The exact mechanisms of voriconazoleassociated photosensitivity are unknown, but inhibition of retinoid metabolism or a direct phototoxic effect of voriconazole or its N-oxide main metabolite, formed by the action of CYP2C19, has been implicated. There was no significant correlation between the incidence of photosensitivity and voriconazole serum concentrations in six children with allergic bronchopulmonary aspergillosis [37c]. In a retrospective study of 24 lung transplant recipients with cystic fibrosis who took voriconazole, heterozygous carriers of the CYP2C19*2 allele required lower maintenance doses than

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Chapter 27 Extrinsic species (E) Voriconazole

EIDOS

Intrinsic species (I) Elements of the skin; DNA

Distribution Skin

Manifestations (clinical) Erythema, vesicles, and blisters Pseudoporphyria and porphyria cutanea tarda Risk of skin tumors

DoTS

Dose-responsiveness Collateral

J.K. Aronson

Modifying factors Sunlight (especially UVA)

Outcome (the adverse effect) Free radical-induced damage

Sequela (the adverse reaction) Photosensitivity (?phototoxic)

Time-course Early permanent

Susceptibility factors Genetic (?CYP2C19 polymorphisms) Age Physiology (skin type) Drugs (immunosuppressants; ?vitamin A) Diseases (HIV-AIDS)

Figure 1 The EIDOS and DoTS descriptions of voriconazole-induced photosensitivity.

those with the wild-type allele and CYP2C19*17 allele carriers [38c]. The time to achieve concentrations in the target range and the proportion of out-of-range concentrations were significantly higher in the CYP2C19*2 carriers. However, there was no relation between voriconazole toxicity and CYP2C19 status. It is not known whether this genetic polymorphism is related to the risk of photosensitivity. Photosensitivity can be due to either a photoallergic or a phototoxic effect. In photoallergy light modifies a molecule in the skin and causes it to bind to a carrier molecule, usually a protein; a cell-mediated immune response then occurs in the skin. In phototoxicity the absorption and reemission of light energy (especially UVA) by a molecule present in the skin causes thermal damage and free radicals are generated. Repeated damage causes chronic lesions such as lentigines (freckles) and actinic keratosis; the DNA of affected cells can be altered, with effects that include breakage, the formation of photoadducts, and dimerization of bases. Photosensitivity due to voriconazole clinically and histologically resembles phototoxicity [39R].

Reports of photosensitivity Severe retinoidlike photosensitivity (erythema, desquamation, and ulceration of light-exposed skin) occurred in two children with chronic granulomatous disease who took voriconazole 200 mg bd for chronic invasive aspergillosis [40A]. Histopathological examination in one of the patients showed superficial and deep perivascular dermatitis with epidermal necrosis, compatible with a photo-induced drug eruption. Although strict sun protection and sun avoidance led to resolution of the acute lesions while voriconazole was continued, dark pigmented lentigines developed over previously involved areas. In the second patient, the lesions completely resolved after withdrawal of the drug. There were similar phototoxic manifestations in two adults who took long-term voriconazole [41A]. In both patients, voriconazole was withdrawn and the lesions resolved within 2 weeks. Seven patients with photosensitivity during treatment with voriconazole had severe immunosuppression and were taking voriconazole for fungal infections [42c]. The photosensitivity reactions occurred within 5 weeks to 14 months after the start of

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treatment and in all cases followed exposure to the sun, occasionally at low levels. The lesions disappeared rapidly on withdrawal of voriconazole. Five patients who were initially thought to be having a flare of cutaneous chronic graftversus-host disease were actually exhibiting phototoxicity due to voriconazole [43c]. Three cases of voriconazole-induced photosensitivity occurred in immunocompromised children, a 1-month-old boy, a 3-year-old boy, and a 16-year-old girl [44A]. Erythematous lesions, some vesicular, appeared on the face and other sun-exposed areas. In a retrospective study of six children with cystic fibrosis who took voriconazole, five developed photosensitivity and all six reported visual disturbances [45A]. Among them, a 7-year-old boy developed striking erythema on the face and upper thorax and a 16-year-old girl reported unexpected visual disturbances, including scotomas and tunnel vision. The authors speculated that these effects may have been due to inhibition of the hepatic enzymes that are involved in the metabolism of all-trans retinoic acid (ATRA), coupled with vitamin A supplementation in cystic fibrosis. They suggested that vitamin A supplementation might be reduced during voriconazole treatment. Other cases have been reported, including some in which photoageing was a feature. • Phototoxicity occurred in a 60-year-old man, who took voriconazole for 15 days and developed erythroderma 30 minutes after exposure to intense sunlight, with papulopustular pruriginous lesions, vesicles, and bullae [46A]. • A 50-year-old male heroin user developed Candida parapsilosis infection and was given amphotericin followed by long-term oral voriconazole 200 mg bd; after 5 months he developed a non-pruritic, non-tender, erythematous, macular eruption on sun-exposed skin areas, particularly on the face, neck, and hands [47A]. The photosensitivity reaction resolved over 6 weeks after fluconazole was substituted for voriconazole. • An 8-year-old boy developed severe phototoxicity after taking voriconazole for treatment and prophylaxis after pulmonary aspergillosis for 1 year; he developed blistering eruptions on his face after minimal sunlight exposure [48A]. • A 10-year-old boy with X-linked chronic granulomatous disease developed photoageing and photosensitivity associated with voriconazole

433 exposure; a broad-spectrum sunscreen, topical steroids, and withdrawal of voriconazole produced significant improvement [49A]. • A 15-year-old girl developed cheilitis and erythema over the sun-exposed areas of her body after taking voriconazole for 5 weeks for a severe fungal infection [50A]. The lesions improved transiently before subsequent photodamage occurred to the backs of her forearms, the backs of her hands, and face. Voriconazole was withdrawn once the fungal infection had completely resolved and her blisters, erythema, and cheilitis resolved. However, she was left with solar elastosis, multiple lentigines, and ephelides on sun-exposed areas. • A 59-year-old man with acute myeloid leukemia developed fungal pneumonia after unrelated donor stem cell transplantation and was given posaconazole then voriconazole 200 mg bd, and soon after began working outside and developed photodistributed, macular erythema on the head, neck, and upper chest [51A].

Pseudoporphyria is an uncommon blistering disorder. It has clinical and histological similarities to porphyria cutanea tarda but without changes in urine and serum porphyrin concentrations and has been attributed to voriconazole [52A,53A,54A]; in one case it was controlled with a sunscreen during continued voriconazole exposure [55A]. However, phototoxic reactions due to voriconazole can also result in true porphyria cutanea tarda, with superficial cheilitis [56A]. • A 65-year-old man with a history of excessive alcohol consumption developed typical features of porphyria cutanea tarda associated with mild superficial desquamating cheilitis after he had taken oral voriconazole for 12 days for cavitary aspergillosis. Laboratory tests confirmed porphyria cutanea tarda. Withdrawal of voriconazole resulted in complete disappearance of the cheilitis but incomplete remission of the porphyria.

Reports of skin tumors Because of photosensitivity voriconazole has been implicated as a cause of melanomas [57c] and nonmelanoma tumors. Squamous cell carcinoma occurred after prolonged use of voriconazole in an HIVinfected patient [58A] and a 69-year-old renal transplant patient [59A]. • A 32-year-old woman who took long-term voriconazole for recurrent aspergillosis associated with chronic granulomatous disease developed

434 a severe photosensitivity reaction, and continued exposure led to the development of multifocal facial squamous cell carcinomas; the photosensitivity reaction resolved after the patient changed therapy to posaconazole [60A].

In a retrospective review of patients who developed one or more squamous cell neoplasms during long-term treatment with voriconazole, 51 lesions were identified in eight patients, median age 34 years, taking long-term voriconazole for a median duration 46 months [61c]. Underlying diagnoses included graft-versus-host disease, HIVAIDS, and Wegener’s granulomatosis. Signs of chronic phototoxicity and accelerated photoageing included erythema, actinic keratoses, and lentigo formation. The authors commented that these preliminary results suggest that voriconazole may be associated with an increased risk of photosensitivity and squamous cell neoplasms when it is used in immunosuppressed patients. In a case–control study in 543 lung transplant recipients, 17 (3.1%) developed squamous cell carcinomas after a median follow-up of 36 months [62C]. The median time to development was 19 months after transplantation. Risk factors by univariate analysis included older age, residence in locations with high levels of sun exposure, single-lung transplantation, and duration and cumulative dose of voriconazole. The duration of voriconazole therapy and residence in locations with high sun exposure were independent risk factors by multivariate analysis. The lesions were located on the head and neck in 94% of cases and 53% had multiple lesions. After surgery at least one further independent lesion developed in 47% of patients. There was local spread and distant metastases in 7% of cases. There were no deaths. This association has been supported by other anecdotal observations. • Four immunocompromised patients developed multiple squamous cell carcinomas while taking voriconazole for 2–3 years, preceded by photosensitization lesions and predominately found in photoexposed area, particularly the face [63c]. • A 56-year-old immunosuppressed woman developed a poorly differentiated squamous cell carcinoma of the left forearm [64A].

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• A 54-year-old immunosuppressed woman developed numerous non-melanoma skin cancers [64A]. • A 55-year-old man with pulmonary aspergillosis developed a phototoxic reaction after taking voriconazole for a few months, followed by multiple squamous cell carcinomas on sun-exposed skin areas [65A]. After voriconazole withdrawal, no new carcinomas were observed. Exploration of gene mutations involved in skin carcinogenesis showed two variants of the MICR gene.

The authors of the last case suggested that several factors, including voriconazole uptake, immunosuppression, and genetic background, could explain the occurrence of fast-developing skin carcinomas. Conclusions The mechanisms by which voriconazole predisposes to skin cancers are not clear, but susceptibility factors include immunosuppression, ultraviolet exposure, advanced age, and skin type. Voriconazole should be used carefully, particularly in patients with susceptibility factors for skin cancer; if prolonged voriconazole therapy is required, it is advisable to carry out frequent diligent skin examinations, to avoid excess sunlight, and to use UV protectants liberally [66R].

ECHINOCANDINS [SED-15, 1197; SEDA-31, 464; SEDA-32, 507; SEDA-33, 556] Drug–drug interactions Posaconazole See above.

Caspofungin

[SEDA-32, 508;

SEDA-33, 556] Skin Fatal toxic epidermal necrolysis has been attributed to caspofungin [67A]. • An 86-year-old man was given intravenous caspofungin 70 mg and immediately developed a rash, which resolved after withdrawal of the drug and treatment with intravenous diphenhydramine 30 mg and methylprednisolone 40 mg; 6 days later he was again given caspofungin 70 mg and on the next day developed

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erythematous purpuric macules and plaques, which rapidly progressed to extensive erythema, exfoliation, blisters, and skin erosions. Despite intravenous hydrocortisone 100 mg every 8 hours and diphenhydramine 30 mg every 8 hours the skin lesions progressed and he died of refractory shock 6 days later.

Micafungin

[SEDA-31, 464; SEDA-32, 510; SEDA-33, 558] Hematologic Acute hemolytic anemia has been attributed to micafungin [68A]. • A 60-year-old man with myelodysplastic syndrome was given micafungin and within 4 hours developed general fatigue, vertigo, vomiting, and hemoglobinuria; on the next day, his hemoglobin fell from 8.6 to 7.3 g/dl and the reticulocyte count was 19%; he had multiorgan failure and increased total bilirubin,

435 lactate dehydrogenase, serum creatinine, and aspartate and alanine aminotransferases, and reduced haptoglobin. Drug–anti-drug immune complexes to micafungin were detected.

FLUCYTOSINE [SED-15, 1388; SEDA-32, 497; SEDA-33, 000] Combination studies In 41 HIV-positive patients with cryptococcal meningitis combination therapy with flucytosine þ fluconazole was more effective than fluconazole alone, with fewer deaths; however, more patients had grade 3 or 4 neutropenia with combination therapy, although there was no increase in infection-related adverse events [69c].

References [1] Spiewak R. Systemic photoallergy to terbinafine. Allergy 2010; 65(8): 1071–2. [2] Coquart N, Kupfer-Bessaguet I, Staroz F, Plantin P. Acute generalized exanthematous pustulosis (AGEP) induced by terbinafine and two different antibiotics: four recurrences. Eur J Dermatol 2010; 20(5): 638–9. [3] Sano S, Ueno H, Yamagami K, Yakushiji Y, Isaka Y, Kawasaki I, Takemura M, Inoue T, Hosoi M. Isolated ileal perforation due to cytomegalovirus reactivation during management of terbinafine hypersensitivity. World J Gastroenterol 2010; 16(26): 3339–42. [4] Wang JL, Chang CH, Young-Xu Y, Chan KA. Systematic review and metaanalysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection. Antimicrob Agents Chemother 2010; 54(6): 2409–19. [5] Safdar A, Ma J, Saliba F, Dupont B, Wingard JR, Hachem RY, Mattiuzzi GN, Chandrasekar PH, Kontoyiannis DP, Rolston KV, Walsh TJ, Champlin RE, Raad II. Drug-induced nephrotoxicity caused by amphotericin B lipid complex and liposomal

amphotericin B: a review and meta-analysis. Medicine (Baltimore) 2010; 89(4): 236–44. [6] Plaza J, Alamo M, Torres P, Fuentes A, López F. Interacciones de medicamentos y eventos adversos en farmacos utilizados en una unidad de cuidados intensivos. [Drug interactions and adverse events induced by drugs used in an intensive care unit.] Rev Med Chil 2010; 138(4): 452–60. [7] Quinteros AR, Fica CA, Abusada AN, Muñoz CL, Novoa MC, Gallardo AC. Uso de anfotericina B deoxicolato y sus reacciones adversas en un hospital universitario en Chile. [Amphotericin B deoxycholate prescription and adverse events in a Chilean university hospital.] Rev Chilena Infectol 2010; 27(1): 25–33. [8] Husain S, Capitano B, Corcoran T, Studer SM, Crespo M, Johnson B, Pilewski JM, Shutt K, Pakstis DL, Zhang S, Carey ME, Paterson DL, McCurry KR, Venkataramanan R. Intrapulmonary disposition of amphotericin B after aerosolized delivery of amphotericin B lipid complex (Abelcet; ABLC) in lung transplant recipients. Transplantation 2010; 90(11): 1215–9.

436 [9] Hamada Y, Komatsu T, Seto Y, Matsubara H, Kume H, Sunakawa K, Yago K. [Liposomalamphotericin B efficacy and safety.] Kansenshogaku Zasshi 2010; 84(2): 193–8. [10] de Miguel-Bouzas JC, Herrero-Poch L, Piñeiro-Corrales G. Toxicodermia generalizada secundaria a la administración de anfotericina B liposomal. [Generalised toxicoderma secondary to administering liposomal amphotericin B.] Farm Hosp 2010; 34(4): 211–2. [11] Dixon KS, Hassoun A. Pseudotumor cerebri due to the potentiation of all-trans retinoic acid by voriconazole. J Am Pharm Assoc 2010; 50(6): 742–4. [12] Pithavala YK, Tong W, Mount J, Rahavendran SV, Garrett M, Hee B, Selaru P, Sarapa N, Klamerus KJ. Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers. Invest New Drugs 2012; 30(1): 273–81. [13] Iwamoto T, Ishibashi M, Fujieda A, Masuya M, Katayama N, Okuda M. Drug interaction between itraconazole and bortezomib: exacerbation of peripheral neuropathy and thrombocytopenia induced by bortezomib. Pharmacotherapy 2010; 30(7): 661–5. [14] Johnson BM, Adams LM, Zhang K, Gainer SD, Kirby LC, Blum RA, Apseloff G, Morrison RA, Schutz RA, Lebowitz PF. Ketoconazole and rifampin significantly affect the pharmacokinetics, but not the safety or QTc interval, of casopitant, a neurokinin-1 receptor antagonist. J Clin Pharmacol 2010; 50(8): 951–9. [15] Shon JH, Yeo CW, Liu KH, Lee SS, Cha IJ, Shin JG. Itraconazole and rifampin alter significantly the disposition and antihistamine effect of ebastine and its metabolites in healthy participants. J Clin Pharmacol 2010; 50(2): 195–204. [16] Krishna G, Vickery D, Ma L, Yu X, Noren C, Power E, Beresford E, Medlock M. Lack of pharmacokinetic drug interaction between oral posaconazole and caspofungin or micafungin. J Clin Pharmacol 2011; 51(1): 84–92. [17] Shobha JC, Muppidi MR. Interaction between voriconazole and glimepiride. J Postgrad Med 2010; 56(1): 44–5. [18] Tiessen RG, Lagerwey HJ, Jager GJ, Sprenger HG. Geneesmiddelinteractie door

Chapter 27

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

J.K. Aronson

communicatieproblemen. Rabdomyolyse door de combinatie van itraconazol en simvastatine. [Drug interaction caused by communication problems. Rhabdomyolysis due to a combination of itraconazole and simvastatin.] Ned Tijdschr Geneeskd 2010; 154: A762. Saari TI, Grönlund J, Hagelberg NM, Neuvonen M, Laine K, Neuvonen PJ, Olkkola KT. Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone. Eur J Clin Pharmacol 2010; 66 (4): 387–97. Helldén A, Bergman U, Engström Hellgren K, Masquelier M, Nilsson Remahl I, Odar-Cederlöf I, Ramsjö M, Bertilsson L. Fluconazole-induced intoxication with phenytoin in a patient with ultra-high activity of CYP2C9. Eur J Clin Pharmacol 2010; 66(8): 791–5. Kim SY, Cho SY, Lee HJ, Suh JT, Oh SH, Lee WI, Park TS, Yoon HJ. Superwarfarin intoxication of unknown etiology accompanying hemoperitoneum in a patient on fluconazole therapy. Ann Clin Lab Sci 2010; 40(3): 300–3. Chang HH, Lee NY, Ko WC, Lee HC, Yang YH, Wu CJ, Chang CM. Voriconazole inhibition of tacrolimus metabolism in a kidney transplant recipient with fluconazoleresistant cryptococcal meningitis. Int J Infect Dis 2010; 14(4): e348–50. Magrath GN, Pulido JS, Montero J, Mason C, Wilson J. Cystoid macular edema secondary to fluconazole toxicity. Ocul Immunol Inflamm 2010; 18(6): 472–4. Walling HW, Swick BL. Cutaneous fixed drug eruption to fluconazole. J Drugs Dermatol 2010; 9(8): 1025–8. Thiyanaratnam J, Cohen PR, Powell S. Fluconazole-associated Stevens–Johnson syndrome. J Drugs Dermatol 2010; 9(10): 1272–5. Izumikawa K, Nakano K, Kurihara S, Imamura Y, Yamamoto K, Miyazaki T, Sakamoto N, Seki M, Ishimatsu Y, Kakeya H, Yamamoto Y, Yanagihara K, Tsuchiya T, Yamasaki N, Tagawa T, Mukae H, Nagayasu T, Kohno S. Diffuse alveolar hemorrhage following itraconazole injection. Intern Med 2010; 49(5): 497–500. Lestner JM, Denning DW. Tremor: a newly described adverse event with long-term

Antifungal drugs

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

Chapter 27

itraconazole therapy. J Neurol Neurosurg Psychiatry 2010; 81(3): 327–9. Passier JL, van Puijenbroek EP, Jonkers GJ, van Grootheest AC. Pancreatitis associated with the use of itraconazole. Neth J Med 2010; 68(6): 285–9. Miteva L, Kadurina M, Schwartz RA. Childhood acute generalized exanthematous pustulosis induced by oral ketoconazole. Acta Dermatovenerol Croat 2010; 18(4): 267–70. Jain S, Kapoor G. Severe life threatening neurotoxicity in a child with acute lymphoblastic leukemia receiving posaconazole and vincristine. Pediatr Blood Cancer 2010; 54(5): 783. Gendrot A, de La Blanchardière A, de La Gastine B, Fromager G, Massias L, Verdon R. Neuropathie périphérique sous voriconazole au cours d’une aspergillose pulmonaire cavitaire chronique. [Painful peripheral neuropathy associated with voriconazole during the treatment of chronic cavitary pulmonary aspergillosis.] Rev Med Interne 2010; 31(2): 163–6. Kadikoy H, Barkmeier A, Peck B, Carvounis PE. Persistent photopsia following course of oral voriconazole. J Ocul Pharmacol Ther 2010; 26(4): 387–8. Teranishi J, Nagatoya K, Kakita T, Yamauchi Y, Matsuda H, Mori T, Inoue T. Voriconazole-associated salt-losing nephropathy. Clin Exp Nephrol 2010; 14(4): 377–80. Amigues I, Cohen N, Chung D, Seo SK, Plescia C, Jakubowski A, Barker J, Papanicolaou GA. Hepatic safety of voriconazole after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2010; 16(1): 46–52. Gomez-Moyano E, Vera-Casaño A, Moreno-Perez D, Sanz-Trelles A, Crespo-Erchiga V. Lupus erythematosuslike lesions by voriconazole in an infant with chronic granulomatous disease. Pediatr Dermatol 2010; 27(1): 105–6. Drucker AM, Rosen CF. Drug-induced photosensitivity: culprit drugs, management and prevention. Drug Saf 2011; 34(10): 821–37. Markantonis SL, Katelari A, Pappa E, Doudounakis S. Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis. J Cyst Fibros 2012; 11(3): 246–52.

437 [38] Berge M, Guillemain R, Trégouet DA, Amrein C, Boussaud V, Chevalier P, Lillo-Lelouet A, Le Beller C, Laurent-Puig P, Beaune PH, Billaud EM, Loriot MA. Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients. Eur J Clin Pharmacol 2011; 67(3): 253–60. [39] Epaulard O, Leccia MT, Blanche S, Chosidow O, Mamzer-Bruneel MF, Ravaud P, Thiebaut A, Villier C, Lortholary O. Phototoxicity and photocarcinogenesis associated with voriconazole. Med Mal Infect 2011; 41(12): 639–45. [40] Rubenstein M, Levy ML, Metry D. Voriconazole-induced retinoid-like photosensitivity in children. Pediatr Dermatol 2004; 21: 675–8. [41] Vandecasteele SJ, Van Wijngaerden E, Peetermans WE. Two cases of severe phototoxic reactions related to long-term outpatient treatment with voriconazole. Eur J Clin Microbiol Infect Dis 2004; 23: 656–7. [42] Auffret N, Janssen F, Chevalier P, Guillemain R, Amrein C, Le Beller C. Photosensibilisation au voriconazole: 7 cas. [Voriconazole photosensitivity: 7 cases.] Ann Dermatol Venereol 2006; 133(4): 330–2. [43] Patel AR, Turner ML, Baird K, Gea-Banacloche J, Mitchell S, Pavletic SZ, Wise B, Cowen EW. Voriconazole-induced phototoxicity masquerading as chronic graft-versus-host disease of the skin in allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant 2009; 15: 370–6. [44] Frick MA, Soler-Palacín P, Martín Nalda A, Guarner ME, Nadal CF. Photosensitivity in immunocompromised patients receiving long-term therapy with oral voriconazole. Pediatr Infect Dis J 2010; 29(5): 480–1. [45] Cheng MP, Paquette K, Lands LC, Ovetchkine P, Théoret Y, Quach C. Voriconazole inhibition of vitamin A metabolism: are adverse events increased in cystic fibrosis patients? Pediatr Pulmonol 2010; 45(7): 661–6. [46] Serra Soler G, Delgado Sánchez O, Esteban Marcos E, Martínez-López I, Femenías Sureda M. Fototoxicidad asociada

438

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

Chapter 27

al voriconazol. [Voriconazole-associated phototoxicity.] Farm Hosp 2006; 30(6): 386–7. Malani AN, Aronoff DM. Voriconazoleinduced photosensitivity. Clin Med Res 2008; 6(2): 83–5. Vöhringer S, Schrum J, Ott H, Höger PH. Severe phototoxicity associated with longterm voriconazole treatment. J Dtsch Dermatol Ges 2011; 9(4): 274–6. Frisch S, Askari SK, Beaty SR, Burkemper CN. X-linked chronic granulomatous disease with voriconazole-induced photosensitivity/photoaging reaction. J Drugs Dermatol 2010; 9(5): 562–4. Racette AJ, Roenigk HH Jr, Hansen R, Mendelson D, Park A. Photoaging and phototoxicity from long-term voriconazole treatment in a 15-year-old girl. J Am Acad Dermatol 2005; 52(5 Suppl. 1): S81–5. Riahi RR, Cohen PR. Voriconazoleassociated phototoxicity. Dermatol Online J 2011; 17(2): 15. Sharp MT, Horn TD. Pseudoporphyria induced by voriconazole. J Am Acad Dermatol 2005; 53(2): 341–5. Dolan CK, Hall MA, Blazes DL, Norwood CW. Pseudoporphyria as a result of voriconazole use: a case report. Int J Dermatol 2004; 43(10): 768–71. Tolland JP, McKeown PP, Corbett JR. Voriconazole-induced pseudoporphyria. Photodermatol Photoimmunol Photomed 2007; 23(1): 29–31. Kwong WT, Hsu S. Pseudoporphyria associated with voriconazole. J Drugs Dermatol 2007; 6(10): 1042–4. Hickman G, Duval A, Picard C, Petit A. Porphyrie cutanée tardive révélée par le voriconazole. [Porphyria cutanea tarda revealed by voriconazole.] Ann Dermatol Venereol 2010; 137(1): 36–9. Miller DD, Cowen EW, Nguyen JC, McCalmont TH, Fox LP. Melanoma associated with long-term voriconazole therapy: a new manifestation of chronic photosensitivity. Arch Dermatol 2010; 146(3): 300–4. Brunel AS, Fraisse T, Lechiche C, Pinzani V, Mauboussin JM, Sotto A. Multifocal squamous cell carcinomas in an HIV-infected patient with a long-term voriconazole therapy. AIDS 2008; 22(7): 905–6.

J.K. Aronson

[59] Vanacker A, Fabré G, Van Dorpe J, Peetermans WE, Maes B. Aggressive cutaneous squamous cell carcinoma associated with prolonged voriconazole therapy in a renal transplant patient. Am J Transplant 2008; 8(4): 877–80. [60] McCarthy KL, Playford EG, Looke DF, Whitby M. Severe photosensitivity causing multifocal squamous cell carcinomas secondary to prolonged voriconazole therapy. Clin Infect Dis 2007; 44(5): e55–6. [61] Cowen EW, Nguyen JC, Miller DD, McShane D, Arron ST, Prose NS, Turner ML, Fox LP. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol 2010; 62(1): 31–7. [62] Vadnerkar A, Nguyen MH, Mitsani D, Crespo M, Pilewski J, Toyoda Y, Bermudez C, Kwak EJ, Silveira FP, Clancy CJ. Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients. J Heart Lung Transplant 2010; 29(11): 1240–4. [63] Epaulard O, Saint-Raymond C, Villier C, Charles J, Roch N, Beani JC, Leccia MT. Multiple aggressive squamous cell carcinomas associated with prolonged voriconazole therapy in four immunocompromised patients. Clin Microbiol Infect 2010; 16(9): 1362–4. [64] Ibrahim SF, Singer JP, Arron ST. Catastrophic squamous cell carcinoma in lung transplant patients treated with voriconazole. Dermatol Surg 2010; 36(11): 1752–5. [65] Morice C, Acher A, Soufir N, Michel M, Comoz F, Leroy D, Verneuil L. Multifocal aggressive squamous cell carcinomas induced by prolonged voriconazole therapy: a case report. Case Rep Med 2010; 2010: 351084. [66] Clancy CJ, Nguyen MH. Long-term voriconazole and skin cancer: is there cause for concern? Curr Infect Dis Rep 2011; 13 (6): 536–43. [67] Lee MC, Ni YW, Wang CH, Lee CH, Wu TW. Caspofungin-induced severe toxic epidermal necrolysis. Ann Pharmacother 2010; 44(6): 1116–8.

Antifungal drugs

Chapter 27

[68] Yoshizawa S, Gotoh M, Kitahara T, Kiguchi T, Akahane D, Sakuta J, Sunaga K, Ohyashiki K. Micafungin-induced hemolysis attack due to drug-dependent antibody persisting for more than 6 weeks. Leuk Res 2010; 34(2): e60–1. [69] Nussbaum JC, Jackson A, Namarika D, Phulusa J, Kenala J, Kanyemba C,

439 arvis JN, Jaffar S, Hosseinipour MC, Kamwendo D, van der Horst CM, Harrison TS. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin Infect Dis 2010; 50(3): 338–44.