Infection DOI 10.1007/s15010-013-0552-6
CASE REPORT
Successful isavuconazole salvage therapy in a patient with invasive mucormycosis J. Ervens • M. Ghannoum • B. Graf S. Schwartz
•
Received: 25 April 2013 / Accepted: 28 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract A 45-year-old male with rhinocerebral mucormycosis (Rhizopus oryzae), refractory to liposomal amphotericin B and posaconazole, received isavuconazole salvage therapy. Initial isavuconazole plasma and tissue levels were 0.76–0.86 lg/mL and 1.09–1.38 lg/g. Plasma levels increased to 1.3–3.24 lg/mL with reduced comedication. Isavuconazole was well tolerated, and the patient has remained disease-free 24 months post-antifungal therapy. Keywords Mucormycosis Rhizopus oryzae Isavuconazole Drug monitoring
J. Ervens Department of Oral and Maxillofacial Surgery, Charite´–Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany M. Ghannoum Center for Medical Mycology, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH, USA B. Graf Institute of Medical Microbiology, Charite´–Universita¨tsmedizin Berlin, Berlin, Germany Present Address: B. Graf Fachbereich Mikrobiologie, Labor Berlin Charite´ Vivantes GmbH, Berlin, Germany S. Schwartz (&) Department of Hematology and Oncology, Charite´–Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany e-mail: [email protected]
A 45-year-old male presented with a 2-week history of progressive left facial pain. Previous dentist examination was unremarkable. Conventional X-rays showed left-sided maxillary sinusitis, and the patient was admitted for presumed odontogenous bacterial sinusitis (day 1). Prior to admission, the patient had received prednisolone therapy (80 mg/day for 3 weeks) for a flare-up of ulcerative colitis. The medical history further revealed unilateral renal loss after trauma 20 years previously and a mild degree hypertension. The physical examination showed a slight, left-sided facial swelling. There was no visual impairment, but an enhanced, left-sided sensitivity to light and numbness of the maxillary branch of the trigeminal nerve were present. Laboratory testing showed a markedly elevated white blood cell count (20.6/nL) and creatinine level (1.5 mg/dL). Antibacterial therapy with cefuroxime and clindamycin was started. On day 4, deterioration of the clinical condition required intensive care with mechanical ventilation. Facial swelling progressed to left-sided periorbital swelling with chemosis and absence of the pupillary reflex. The following day, the left part of the hard palate showed large areas of necrosis, and hyphae, with morphological features indicative of mucormycosis, were identified in sinonasal lavage fluid. A computed tomography scan disclosed left-sided maxillary sinusitis and orbital cellulitis with bone destruction and extended soft tissue infection of the left facial area. This prompted emergency surgical resection on day 5 which consisted of tracheostomy with left-sided maxillectomy and orbital exenteration that included the infratemporal fossa, resection of the nasal septum, left-sided turbinates and left-sided ethmoidal cells extended to the anterior skull base. The infected anterior skull base and dura were partially resected, and dural defects were covered with dura mater sealers as well as with muscle and local flaps.
123
J. Ervens et al.
Histopathological examination of resected tissue revealed the presence of extended necroses and infiltration by filamentous fungal elements that showed morphological characteristics of mucormycosis. Cultures grew a fungus with morphological features compatible with mucormycosis. The isolate was identified as Rhizopus oryzae species (MRL 19448) by molecular methodology using the 5.8 s internal transcribed spacer 1 and referenced to accession no. HM753610, with 100 % identity and a sequence length of 605 bp [1]. The minimum inhibitory concentrations (MIC) of the isolate using Etest according to the manufacturer’s instructions (bioMe`rieux, Marcy l’Etoile, France) were 0.5 lg/mL for amphotericin B, 3 lg/mL for posaconazole and 1 lg/mL for isavuconazole (isavuconazole test strips were provided by Basilea Pharmaceutica International Ltd., Basel, Switzerland). However, isavuconazole in vitro susceptibility against this R. oryzae strain varied by methodology. Although the MIC measured by Etest agar diffusion was relatively low (1 lg/mL), the MIC values obtained by both CLSI (Clinical and Laboratory Standards Institute, Wayne, PA) and EUCAST (European Committee on Antimicrobial Susceptibility Testing) microdilution were 8 to[16 lg/mL as determined by two different reference laboratories. These in vitro data indicate possible resistance to isavuconazole, although there are no interpretive breakpoints established for this novel antifungal. The mechanism of resistance studies performed at the Center for Medical Mycology further supported the fact that this strain is resistant to isavuconazole. The fungal cellular target for azoles is a 14-a
demethylase enzyme involved in sterol synthesis leading to ergosterol formation, and alteration in sterol composition is linked to antifungal resistance [2]. Our data showed that squalene, the first intermediate in the ergosterol biosynthetic pathway, was elevated in this Rhizopus strain (17.06 vs. 9.95 % in the control susceptible strain). Similarly, zymosterol levels were greatly elevated (68.70 vs. 0.00 %). In contrast, the ergosterol level in the resistant strain was significantly reduced relative to that in a isavuconazolesusceptible control strain (2.3 vs. 76.93 % in the control strain). The accumulation of these ergosterol precursors and the lower levels of ergosterol observed in this strain are suggestive of azole resistance. Liposomal amphotericin B (5 mg/kg/day) and posaconazole (C200 mg administered four times daily via a nasogastric tube after high-fat-containing tube feeding) were started immediately after emergency resection on day 5 and given for 92 and 52 days, respectively. Posaconazole plasma concentrations remained \0.2 lg/mL throughout the treatment (Table 1). In addition, the concentration of posaconazole in a soft tissue specimen (muscle, fat) that was obtained during surgical debridement was below the MIC of the fungal isolate despite 24 days of posaconazole therapy (0.03 lg/g; Table 1). Worsening of renal failure during therapy with liposomal amphotericin B required intermittent hemodialysis between days 23 and 28. However, filamentous fungal elements were recovered from tissue biopsies on day 61 (no cultures performed), despite 52 and 57 days of therapy with posaconazole and liposomal amphotericin B, respectively. Therefore, therapy with
Table 1 Plasma trough and soft tissue concentrations of posaconazole and isavuconazole during therapy Daya
Posaconazole trough level: plasma (lg/mL)
Daya
Isavuconazole trough level: plasma (lg/mL)
Isavuconazole level: soft-tissue (lg/g)
10
\0.16
112
0.86
1.09–1.38b
12
\0.19
113
0.76
13
0.09
117
0.82
19
0.12
141c
1.3
26
0.10
148
1.65
29
ND
155
1.76
32
0.19
Posaconazole level: soft-tissue (lg/g)
0.03
187
2.34
217
2.83
250
2.85
285
3.24
313
3.02
ND not done Posaconazole and isavuconazole concentrations were measured by combined high-performance liquid chromatography (HPLC)/mass spectroscopy and HPLC, respectively a
Day 1: day of admission; day 5: start of posaconazole; day 104: start of isavuconazole (see text for dosages)
b
Isavuconazole levels in 3 soft tissue biopsies (muscle, fat), simultaneously obtained 3 h after dosing, were 1.09, 1.27 and 1.38 lg/g (corresponding plasma level: 0.85 lg/mL)
c
Reduction of comedication prior to day 141 (see text for details)
123
Successful isavuconazole salvage therapy in a patient
posaconazole and liposomal amphotericin B was discontinued on days 52 and 96, respectively, and the patient was enrolled into a clinical phase 3 trial exploring the safety and efficacy of monotherapy with the novel triazole, isavuconazole (ClinicalTrials.gov Identifier: NCT00634049). Antifungal treatment was resumed on day 104 with isavuconazole. Initially, isavuconazole was administered intravenously (days 104–105: 200 mg t.i.d. daily; day 106–107: 200 mg daily q.d.) with a switch to oral therapy on day 108 (200 mg q.d.). During 14 days of isavuconazole therapy, the plasma trough concentration did not exceed 0.86 lg/mL, and the concentration in soft tissue samples ranged from 1.09 to 1.38 lg/g (Table 1), which although higher than the MIC of the infecting isolate was still lower than the trough concentration expected from the isavuconazole dose given (C2 lg/mL). To enhance isavuconazole concentrations, which might have been limited by yet unknown drug–drug interactions, concomitant therapy with various drugs was either terminated between days 117 and 141 or limited to this period, while treatment with amlodipine, mesalazine (both prior to isavuconazole—ongoing after end of isavuconazole), ranitidine (terminated on day 174) and heparin (dalteparin: given prior to treatment to day 113 and on days 119–174; unfractioned heparin: days 114–118) was maintained. The drugs terminated were ciprofloxacin eardrops (days 121–127), clindamycine (days 114–118), fentanyl (days 112, 119), loperamide (days 118–119), lorazepam (days 121–132), lormetazepam (days 119–120, 124), metamizole (days 113–119), mirtazapine (prior isavuconazole—day 125), morphine (day 119), ondansetron (day 117), paracematol (days 113–118), propofol (days 112, 119), tramadol (days 120–132) and valproate (prior isavuconazole—day 133). There were no comedications during isavuconazole therapy which were terminated before day 117. The following drugs were administered after day 141: amoxicillin/clavulanate (days 663–669), cefuroxime (days 320–326, 357–363, 504–516), ciprofloxacin eardrops (days 293–299) and flucloxacillin (days 660–662). Continued drug monitoring showed an increase in plasma isavuconazole trough levels, first evident on day 141, to 1.3–3.24 lg/mL. However, there was no evidence for drug accumulation (Table 1). The patient was discharged from hospital on day 174. Oral isavuconazole (200 mg q.d.) was given as monotherapy until day 609 (total duration of isavuconazole therapy: 506 days). The patient received isavuconazole as study therapy for a total duration of 84 days and for the remaining treatment period under compassionate use authorization granted by the German health authorities. Isavuconazole was well tolerated without adverse effects except for a transient grade I skin rash, which was associated with prolonged sunlight exposure. Early follow-up biopsies, obtained 16 days after the switch to isavuconazole, still
showed filamentous fungal elements, but subsequent biopsies and fungal cultures (obtained for the last time more than 1 year after termination of isavuconazole therapy) gave negative results. The appearance of the facial skull cavity was without any specific evidence of an ongoing invasive fungal infection during isavuconazole therapy, with largely a similar appearance throughout. However, contrast media enhancement of the cavernous sinus was detectable by magnetic resonance imaging; this enhancement decreased during isavuconazole therapy. Two early attempts of reconstructive surgery (days 49 and 112) were unsuccessful due to ischemia of the muscle free grafts. Six months after the completion of antifungal therapy (day 796), the patient resettled in his home country, the UK, where he later received final reconstructive surgery (microvascular free fibular osteocutaneous flap as well as dental and orbital implants). At last follow-up, 2 years after the termination of isavuconazole therapy (day 1,333), the patient was well and without any signs of recurrence of the invasive fungal infection. Invasive mucormycosis (formerly termed zygomycosis) is a devastating infection which is increasingly recognized in patients with various types of predisposing conditions (e.g. poorly controlled diabetes, iron overload, chemotherapy and hematopoietic stem cell transplantation). However, invasive mucormycosis has been reported less frequently in patients with corticosteroid-induced immunosuppression as the sole risk factor [3]. The available data on this disease have been comprehensively reviewed by Dr. Walsh and other experts, and a guideline from the third European Conference on Infections in Leukemia has been published very recently [4, 5]. The prognosis of this type of fungal infection has improved to some extent in recent years, but mortality rates in patients with pulmonary, rhinocerebral or disseminated infection still range from 48 to 100 % [6, 7]. Early therapy with amphotericin B (lipid preparations preferred) and resection of infected/necrotic areas, whenever feasible, is considered to be the treatment of choice [7–9]. Fungi of the order Mucorales are notoriously resistant to antifungal drugs other than amphotericin B, with the exception of posaconazole. Posaconazole shows clinical activity in mucormycosis, but this azole is currently available only as an oral solution and displays limited absorption and variable bioavailability [10, 11]. In our patient, liposomal amphotericin B caused nephrotoxicity, requiring hemodialysis, and the fungus persisted despite prolonged therapy with liposomal amphotericin B and posaconazole. Isavuconazole is a novel azole that shows in vitro activity against mucorales comparable to that of posaconazole [12]. A water-soluble prodrug, isavuconazonium sulfate, which is suitable for intravenous and oral administration, is under clinical development and is rapidly cleaved into the isavuconazole active moiety
123
J. Ervens et al.
with an oral bioavailability in humans that approaches 100 % [13]. The first measured isavuconazole plasma levels in our patient were approximately 0.8 lg/mL (Table 1), with a higher tissue to plasma ratio (1.3–1.6) compared to posaconazole (0.2–0.3). The subsequent increase in isavuconazole plasma levels with reduced comedication was possibly associated with higher tissue levels, but it did not indicate drug accumulation. The longterm isavuconazole therapy for more than 16 months was well tolerated in this particular patient, with only one minor, transient side-effect. There were no remaining measurable fungal lesions after extensive resection, which precluded a radiological response assessment. However, the improved clinical condition, the transition from positive to negative biopsies after therapy switch to isavuconazole and the observed long-term survival without any further systemic antifungal therapy suggests that the treatment success was at least in part due to isavuconazole, albeit diverging susceptibility test results. This first case report on the clinical use of isavuconazole demonstrates the beneficial clinical and pharmacokinetic properties of isavuconazole and suggests that this novel azole could be an attractive option in the future for patients with deep-seated fungal infections, including invasive mucormycosis. However, more data from ongoing phase 3 clinical trials are needed before isavuconazole might extend the limited therapeutic armamentarium for patients with invasive mucormycosis. Conflict of interest M.G. has received speaker honoraria and grants from Astellas. B.G. has received speaker honoraria from Pfizer. S.S. has received speaker honoraria and travel grants from Gilead, Pfizer and MSD. J.E. declares that he has no conflict of interest.
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References 1. Dannaoui E, Schwarz P, Slany M, et al. Molecular detection and identification of zygomycetes species from paraffin-embedded tissues in a murine model of disseminated zygomycosis: a collaborative European Society of Clinical Microbiology and
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Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) evaluation. J Clin Microbiol. 2010;48:2043–6. Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12:501–17. Dojcinovic I, Richter M. Mucormycoses: serious complication of high-dose corticosteroid therapy for traumatic optic neuropathy. Int J Oral Maxillofac Surg. 2008;37:391–4. Walsh TJ, Bloom BE, Kontoyiannis DP. Meeting the challenges of an emerging pathogen: the Henry Schueler 41&9 Foundation International Forum on Mucormycosis. Clin Infect Dis. 2012;54:S1–4. Skiada A, Lanternier F, Groll AH, et al. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica. 2013;98:492–504. Lanternier F, Dannaoui E, Morizot G, et al. A global analysis of mucormycosis in France: the RetroZygo Study (2005–2007). Clin Infect Dis. 2012;54:S35–43. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634–53. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis. 2008;47:503–9. Skiada A, Pagano L, Groll A, et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011;17:1859–67. Cornely OA, Vehreschild JJ, Ruping MJ. Current experience in treating invasive zygomycosis with posaconazole. Clin Microbiol Infect. 2009;15:S77–81. Nagappan V, Deresinski S. Reviews of anti-infective agents: posaconazole: a broad-spectrum triazole antifungal agent. Clin Infect Dis. 2007;45:1610–7. Verweij PE, Gonzalez GM, Wiederhold NP, et al. In vitro antifungal activity of isavuconazole against 345 mucorales isolates collected at study centers in eight countries. J Chemother. 2009;21:272–81. Schmitt-Hoffmann A, Roos B, Heep M, et al. Single-ascendingdose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother. 2006;50:279–85.
CASE REPORT
Successful isavuconazole salvage therapy in a patient with invasive mucormycosis J. Ervens • M. Ghannoum • B. Graf S. Schwartz
•
Received: 25 April 2013 / Accepted: 28 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract A 45-year-old male with rhinocerebral mucormycosis (Rhizopus oryzae), refractory to liposomal amphotericin B and posaconazole, received isavuconazole salvage therapy. Initial isavuconazole plasma and tissue levels were 0.76–0.86 lg/mL and 1.09–1.38 lg/g. Plasma levels increased to 1.3–3.24 lg/mL with reduced comedication. Isavuconazole was well tolerated, and the patient has remained disease-free 24 months post-antifungal therapy. Keywords Mucormycosis Rhizopus oryzae Isavuconazole Drug monitoring
J. Ervens Department of Oral and Maxillofacial Surgery, Charite´–Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany M. Ghannoum Center for Medical Mycology, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH, USA B. Graf Institute of Medical Microbiology, Charite´–Universita¨tsmedizin Berlin, Berlin, Germany Present Address: B. Graf Fachbereich Mikrobiologie, Labor Berlin Charite´ Vivantes GmbH, Berlin, Germany S. Schwartz (&) Department of Hematology and Oncology, Charite´–Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany e-mail: [email protected]
A 45-year-old male presented with a 2-week history of progressive left facial pain. Previous dentist examination was unremarkable. Conventional X-rays showed left-sided maxillary sinusitis, and the patient was admitted for presumed odontogenous bacterial sinusitis (day 1). Prior to admission, the patient had received prednisolone therapy (80 mg/day for 3 weeks) for a flare-up of ulcerative colitis. The medical history further revealed unilateral renal loss after trauma 20 years previously and a mild degree hypertension. The physical examination showed a slight, left-sided facial swelling. There was no visual impairment, but an enhanced, left-sided sensitivity to light and numbness of the maxillary branch of the trigeminal nerve were present. Laboratory testing showed a markedly elevated white blood cell count (20.6/nL) and creatinine level (1.5 mg/dL). Antibacterial therapy with cefuroxime and clindamycin was started. On day 4, deterioration of the clinical condition required intensive care with mechanical ventilation. Facial swelling progressed to left-sided periorbital swelling with chemosis and absence of the pupillary reflex. The following day, the left part of the hard palate showed large areas of necrosis, and hyphae, with morphological features indicative of mucormycosis, were identified in sinonasal lavage fluid. A computed tomography scan disclosed left-sided maxillary sinusitis and orbital cellulitis with bone destruction and extended soft tissue infection of the left facial area. This prompted emergency surgical resection on day 5 which consisted of tracheostomy with left-sided maxillectomy and orbital exenteration that included the infratemporal fossa, resection of the nasal septum, left-sided turbinates and left-sided ethmoidal cells extended to the anterior skull base. The infected anterior skull base and dura were partially resected, and dural defects were covered with dura mater sealers as well as with muscle and local flaps.
123
J. Ervens et al.
Histopathological examination of resected tissue revealed the presence of extended necroses and infiltration by filamentous fungal elements that showed morphological characteristics of mucormycosis. Cultures grew a fungus with morphological features compatible with mucormycosis. The isolate was identified as Rhizopus oryzae species (MRL 19448) by molecular methodology using the 5.8 s internal transcribed spacer 1 and referenced to accession no. HM753610, with 100 % identity and a sequence length of 605 bp [1]. The minimum inhibitory concentrations (MIC) of the isolate using Etest according to the manufacturer’s instructions (bioMe`rieux, Marcy l’Etoile, France) were 0.5 lg/mL for amphotericin B, 3 lg/mL for posaconazole and 1 lg/mL for isavuconazole (isavuconazole test strips were provided by Basilea Pharmaceutica International Ltd., Basel, Switzerland). However, isavuconazole in vitro susceptibility against this R. oryzae strain varied by methodology. Although the MIC measured by Etest agar diffusion was relatively low (1 lg/mL), the MIC values obtained by both CLSI (Clinical and Laboratory Standards Institute, Wayne, PA) and EUCAST (European Committee on Antimicrobial Susceptibility Testing) microdilution were 8 to[16 lg/mL as determined by two different reference laboratories. These in vitro data indicate possible resistance to isavuconazole, although there are no interpretive breakpoints established for this novel antifungal. The mechanism of resistance studies performed at the Center for Medical Mycology further supported the fact that this strain is resistant to isavuconazole. The fungal cellular target for azoles is a 14-a
demethylase enzyme involved in sterol synthesis leading to ergosterol formation, and alteration in sterol composition is linked to antifungal resistance [2]. Our data showed that squalene, the first intermediate in the ergosterol biosynthetic pathway, was elevated in this Rhizopus strain (17.06 vs. 9.95 % in the control susceptible strain). Similarly, zymosterol levels were greatly elevated (68.70 vs. 0.00 %). In contrast, the ergosterol level in the resistant strain was significantly reduced relative to that in a isavuconazolesusceptible control strain (2.3 vs. 76.93 % in the control strain). The accumulation of these ergosterol precursors and the lower levels of ergosterol observed in this strain are suggestive of azole resistance. Liposomal amphotericin B (5 mg/kg/day) and posaconazole (C200 mg administered four times daily via a nasogastric tube after high-fat-containing tube feeding) were started immediately after emergency resection on day 5 and given for 92 and 52 days, respectively. Posaconazole plasma concentrations remained \0.2 lg/mL throughout the treatment (Table 1). In addition, the concentration of posaconazole in a soft tissue specimen (muscle, fat) that was obtained during surgical debridement was below the MIC of the fungal isolate despite 24 days of posaconazole therapy (0.03 lg/g; Table 1). Worsening of renal failure during therapy with liposomal amphotericin B required intermittent hemodialysis between days 23 and 28. However, filamentous fungal elements were recovered from tissue biopsies on day 61 (no cultures performed), despite 52 and 57 days of therapy with posaconazole and liposomal amphotericin B, respectively. Therefore, therapy with
Table 1 Plasma trough and soft tissue concentrations of posaconazole and isavuconazole during therapy Daya
Posaconazole trough level: plasma (lg/mL)
Daya
Isavuconazole trough level: plasma (lg/mL)
Isavuconazole level: soft-tissue (lg/g)
10
\0.16
112
0.86
1.09–1.38b
12
\0.19
113
0.76
13
0.09
117
0.82
19
0.12
141c
1.3
26
0.10
148
1.65
29
ND
155
1.76
32
0.19
Posaconazole level: soft-tissue (lg/g)
0.03
187
2.34
217
2.83
250
2.85
285
3.24
313
3.02
ND not done Posaconazole and isavuconazole concentrations were measured by combined high-performance liquid chromatography (HPLC)/mass spectroscopy and HPLC, respectively a
Day 1: day of admission; day 5: start of posaconazole; day 104: start of isavuconazole (see text for dosages)
b
Isavuconazole levels in 3 soft tissue biopsies (muscle, fat), simultaneously obtained 3 h after dosing, were 1.09, 1.27 and 1.38 lg/g (corresponding plasma level: 0.85 lg/mL)
c
Reduction of comedication prior to day 141 (see text for details)
123
Successful isavuconazole salvage therapy in a patient
posaconazole and liposomal amphotericin B was discontinued on days 52 and 96, respectively, and the patient was enrolled into a clinical phase 3 trial exploring the safety and efficacy of monotherapy with the novel triazole, isavuconazole (ClinicalTrials.gov Identifier: NCT00634049). Antifungal treatment was resumed on day 104 with isavuconazole. Initially, isavuconazole was administered intravenously (days 104–105: 200 mg t.i.d. daily; day 106–107: 200 mg daily q.d.) with a switch to oral therapy on day 108 (200 mg q.d.). During 14 days of isavuconazole therapy, the plasma trough concentration did not exceed 0.86 lg/mL, and the concentration in soft tissue samples ranged from 1.09 to 1.38 lg/g (Table 1), which although higher than the MIC of the infecting isolate was still lower than the trough concentration expected from the isavuconazole dose given (C2 lg/mL). To enhance isavuconazole concentrations, which might have been limited by yet unknown drug–drug interactions, concomitant therapy with various drugs was either terminated between days 117 and 141 or limited to this period, while treatment with amlodipine, mesalazine (both prior to isavuconazole—ongoing after end of isavuconazole), ranitidine (terminated on day 174) and heparin (dalteparin: given prior to treatment to day 113 and on days 119–174; unfractioned heparin: days 114–118) was maintained. The drugs terminated were ciprofloxacin eardrops (days 121–127), clindamycine (days 114–118), fentanyl (days 112, 119), loperamide (days 118–119), lorazepam (days 121–132), lormetazepam (days 119–120, 124), metamizole (days 113–119), mirtazapine (prior isavuconazole—day 125), morphine (day 119), ondansetron (day 117), paracematol (days 113–118), propofol (days 112, 119), tramadol (days 120–132) and valproate (prior isavuconazole—day 133). There were no comedications during isavuconazole therapy which were terminated before day 117. The following drugs were administered after day 141: amoxicillin/clavulanate (days 663–669), cefuroxime (days 320–326, 357–363, 504–516), ciprofloxacin eardrops (days 293–299) and flucloxacillin (days 660–662). Continued drug monitoring showed an increase in plasma isavuconazole trough levels, first evident on day 141, to 1.3–3.24 lg/mL. However, there was no evidence for drug accumulation (Table 1). The patient was discharged from hospital on day 174. Oral isavuconazole (200 mg q.d.) was given as monotherapy until day 609 (total duration of isavuconazole therapy: 506 days). The patient received isavuconazole as study therapy for a total duration of 84 days and for the remaining treatment period under compassionate use authorization granted by the German health authorities. Isavuconazole was well tolerated without adverse effects except for a transient grade I skin rash, which was associated with prolonged sunlight exposure. Early follow-up biopsies, obtained 16 days after the switch to isavuconazole, still
showed filamentous fungal elements, but subsequent biopsies and fungal cultures (obtained for the last time more than 1 year after termination of isavuconazole therapy) gave negative results. The appearance of the facial skull cavity was without any specific evidence of an ongoing invasive fungal infection during isavuconazole therapy, with largely a similar appearance throughout. However, contrast media enhancement of the cavernous sinus was detectable by magnetic resonance imaging; this enhancement decreased during isavuconazole therapy. Two early attempts of reconstructive surgery (days 49 and 112) were unsuccessful due to ischemia of the muscle free grafts. Six months after the completion of antifungal therapy (day 796), the patient resettled in his home country, the UK, where he later received final reconstructive surgery (microvascular free fibular osteocutaneous flap as well as dental and orbital implants). At last follow-up, 2 years after the termination of isavuconazole therapy (day 1,333), the patient was well and without any signs of recurrence of the invasive fungal infection. Invasive mucormycosis (formerly termed zygomycosis) is a devastating infection which is increasingly recognized in patients with various types of predisposing conditions (e.g. poorly controlled diabetes, iron overload, chemotherapy and hematopoietic stem cell transplantation). However, invasive mucormycosis has been reported less frequently in patients with corticosteroid-induced immunosuppression as the sole risk factor [3]. The available data on this disease have been comprehensively reviewed by Dr. Walsh and other experts, and a guideline from the third European Conference on Infections in Leukemia has been published very recently [4, 5]. The prognosis of this type of fungal infection has improved to some extent in recent years, but mortality rates in patients with pulmonary, rhinocerebral or disseminated infection still range from 48 to 100 % [6, 7]. Early therapy with amphotericin B (lipid preparations preferred) and resection of infected/necrotic areas, whenever feasible, is considered to be the treatment of choice [7–9]. Fungi of the order Mucorales are notoriously resistant to antifungal drugs other than amphotericin B, with the exception of posaconazole. Posaconazole shows clinical activity in mucormycosis, but this azole is currently available only as an oral solution and displays limited absorption and variable bioavailability [10, 11]. In our patient, liposomal amphotericin B caused nephrotoxicity, requiring hemodialysis, and the fungus persisted despite prolonged therapy with liposomal amphotericin B and posaconazole. Isavuconazole is a novel azole that shows in vitro activity against mucorales comparable to that of posaconazole [12]. A water-soluble prodrug, isavuconazonium sulfate, which is suitable for intravenous and oral administration, is under clinical development and is rapidly cleaved into the isavuconazole active moiety
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with an oral bioavailability in humans that approaches 100 % [13]. The first measured isavuconazole plasma levels in our patient were approximately 0.8 lg/mL (Table 1), with a higher tissue to plasma ratio (1.3–1.6) compared to posaconazole (0.2–0.3). The subsequent increase in isavuconazole plasma levels with reduced comedication was possibly associated with higher tissue levels, but it did not indicate drug accumulation. The longterm isavuconazole therapy for more than 16 months was well tolerated in this particular patient, with only one minor, transient side-effect. There were no remaining measurable fungal lesions after extensive resection, which precluded a radiological response assessment. However, the improved clinical condition, the transition from positive to negative biopsies after therapy switch to isavuconazole and the observed long-term survival without any further systemic antifungal therapy suggests that the treatment success was at least in part due to isavuconazole, albeit diverging susceptibility test results. This first case report on the clinical use of isavuconazole demonstrates the beneficial clinical and pharmacokinetic properties of isavuconazole and suggests that this novel azole could be an attractive option in the future for patients with deep-seated fungal infections, including invasive mucormycosis. However, more data from ongoing phase 3 clinical trials are needed before isavuconazole might extend the limited therapeutic armamentarium for patients with invasive mucormycosis. Conflict of interest M.G. has received speaker honoraria and grants from Astellas. B.G. has received speaker honoraria from Pfizer. S.S. has received speaker honoraria and travel grants from Gilead, Pfizer and MSD. J.E. declares that he has no conflict of interest.
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