Infection and Drug Resistance Dovepress open access to scientific and medical research Open Access Full Text Article C A S E R E P O RT Osteoarticular Cryptococcosis Successfully Treated with High-Dose Liposomal Amphotericin B Followed by Oral Fluconazole This article was published in the following Dove Press journal: Infection and Drug Resistance Guillem Deus 1 Background: Skeletal involvement of Cryptococcus neoformans is infrequent and usually Silvia Gómez-Zorrilla 1 associated with disseminated cryptococcosis or underlying predisposing conditions. We Daniel Echeverria-Esnal 2 present an atypical case of osteoarticular cryptococcosis in an immunocompetent patient. Ana Siverio 3 Case Presentation: We herein report a case of bone and soft tissue cryptococcal infection in a 42-year-old male from Pakistan with well-controlled diabetes without other associated Robert Güerri-Fernandez 1 immunodeficiencies treated with antifungal therapy without surgical debridement. Jesús Ares 4 Furthermore, the patient developed toxidermia due to fluconazole use, so a fluconazole Nuria Campillo 2 desensitization was performed. Therapeutic management also included the performance of Emili Letang 1,5 therapeutic drug monitoring of fluconazole plasma concentrations. Hernando Knobel 1 Conclusion: To our knowledge, this is the first case of osteoarticular cryptococcosis treated Santiago Grau 2 with this treatment regimen. This strategy may be of interest to try to reduce hospital stay Juan Pablo Horcajada 1 and associated complications. 1 Infectious Diseases Service, Hospital del Keywords: Cryptococcus neoformans, osteoarticular cryptococcosis, immunocompetent, Mar, Infectious Pathology and liposomal amphotericin B, fluconazole desensitization Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain; Case Report 2 Pharmacy Service, Hospital del Mar, A 42-year-old male from Pakistan was admitted to hospital in July 2018 complain­ Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital ing of chronic lumbar pain. The patient, who had been living in Barcelona since del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de 2003, was recently diagnosed with type 2 diabetes mellitus, established with two Barcelona (UAB), Barcelona, Spain; hemoglobin A1C tests of over 6.5%, and was well controlled on diet. He had no 3 Microbiology Service, Laboratori de Referència de Catalunya, Hospital del other medical conditions. He worked in public works water and sewer maintenance Mar, Barcelona, Spain; 4Department of and claimed to have had no prior contact with animals. The patient reported Radiology, Hospital del Mar, Universitat Autònoma de Barcelona (UAB), a 6-month history of mechanical lumbar pain, without any previous trauma. The Barcelona, Spain; 5ISGlobal, Barcelona only symptoms reported during this time were 5 kg weight loss and 24-hr fever. Institute for Global, Universitat de BarcelonaHealth, Barcelona, Spain After five months of pain, nodular lesions in the right gluteal region were noticed and antibiotic treatment was initiated by his general practitioner (amoxicillin- clavulanate 1g/200mg TID for 10 days and thereafter ciprofloxacin 500 mg BID for 10 days). Despite antibiotic treatment, pain and inflammatory signs increased Correspondence: Silvia Gómez-Zorrilla and spontaneous drainage of the gluteal abscess occurred. A sample was taken for Hospital del Mar, Infectious Diseases microbiological cultures and Cryptococcus neoformans was isolated. The patient Department, Passeig Maritim 25-29 I, Barcelona, 08003, Spain was hospitalized for further study. Physical examination at admission revealed two Tel +34 932483468 indurated areas without inflammatory signs in the right gluteus and right lumbar Fax +34 93248325 Email sgomezzorrilla@psmar.cat area. The rest of the exploration was unremarkable. Laboratory tests showed renal submit your manuscript | www.dovepress.com Infection and Drug Resistance 2021:14 719–722 719 DovePress © 2021 Deus et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php http://doi.org/10.2147/IDR.S294299 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Deus et al Dovepress and liver function values within the normal range (total [minimum inhibitory concentration (MIC) of 2 mg/L] and bilirubin 0.36 mg/dl, GOT 31 UI/L, GPT 29 UI/L, FA 67 amphotericin B. UI/L), hemoglobin 15.3 g/dl, white cell count 6940 cells/ Since the patient refused to remain in hospital due to µL (44.2% neutrophils, 44.5% lymphocyte). The plasma family and work responsibilities, a treatment regimen was cryptococcal antigen latex agglutination test (CLAT) was planned based on a single-dose of liposomal amphotericin positive (1:100), suggesting a disseminated infection. B (L-AmB) (10 mg/kg, total dose 870 mg), infused over A lumbar puncture was performed with normal results, 3h, followed by outpatient therapy with oral fluconazole including a negative CLAT. Human immunodeficiency (800 mg/day). However, after the second dose of flucona­ virus (HIV), primary immunodeficiencies and zole, the patient developed a pruritic erythematous macu­ a lymphoproliferative disorder were ruled out. CD4 and lopapular rash. Given the lack of alternatives due to his CD8 counts were in the normal range. Except for diabetes, personal circumstances and based on previous data in no other predisposing factors were found. Thoraco- patients without HIV,1 a rapid oral desensitization protocol abdominal computed tomography ruled out lung involve­ was performed (Table 1). Desensitization was conducted ment and revealed a gluteal abscess and a 3 cm lytic lesion over 8 hours without complications, and the patient was on the right iliac crest (Figure 1). An ultrasound-guided discharged afterwards. He received 800 mg fluconazole fine-needle aspiration biopsy of the iliac crest was per­ daily for 14 days, followed by 400mg daily for one year. formed. No further surgical debridement was performed. The treatment was well tolerated with no adverse events. The sample was inoculated on Polyvitex and Sabouraud The pain resolved and plasma CLAT was undetectable at agar plates (Biomèrieux®) and incubated at 37°C. Growth the end of treatment. During follow-up, on-site monitoring was observed after 72h incubation and the strain was of fluconazole blood concentrations was conducted. While identified by matrix-assisted laser desorption ionization– patient was on 800 mg, the area under the curve (AUC)/ time of flight mass spectrometry (MALDI-TOF MS, MIC was 420 (objective >389). With the later 400 mg BrukerDaltonics®) as C. neoformans. Antifungal suscept­ dosage, a further 3 samples were obtained, yielding ibility testing was performed using the Sensititre AUC/MICs of 144, 180 and 156 (goal >100). At the end YeastOne® method, showing susceptibility to fluconazole of follow-up, a mild alteration in liver function was observed (total bilirubin 0.24 mg/dl, AST 41 UI/L, ALT 45 UI/L, GGT 62 UI/L and FA 67 UI/L), which was attributable to moderate liver steatosis confirmed by abdominal echography. After 20 months of follow-up, the patient continued asymptomatic without signs of recurrence. Discussion C. neoformans is a yeast normally found in soil. It causes opportunistic infection in immunocompromised patients, typically those with acquired immune deficiency syndrome.2 Although localized pulmonary disease is the main primary infection, extrapulmonary disease is com­ mon; especially central nervous system (CNS) infection.3 Osteoarticular cryptococcosis as the sole manifestation of extrapulmonary disease is rare, with an incidence of 5% in patients with cryptococcal disease.3 Hematogenous disse­ mination after the primary pulmonary infection may explain bone affectation.3 All of these findings are even rarer in immunocompetent patients.4 In our case, diabetes Figure 1 Transverse computed tomography image of the pelvis. mellitus was the only risk factor predisposing to crypto­ Notes: (A) Bone window: Osteolytic lesion with cortical bone destruction invol­ coccal infection. An exhaustive study ruled out other ving the right iliac bone (white arrow). (B) Soft tissue window: bulking of the right iliac and gluteus medius muscle with an abscess in the latter (*). immunodeficiencies. Although diabetes mellitus is 720 submit your manuscript | www.dovepress.com Infection and Drug Resistance 2021:14 DovePress Dovepress Deus et al Table 1 Protocol of Fluconazole Desensitization Step Fluconazole Dilution (mg/mL) Volume Administered (mL) Fluconazole Dose (mg) Cumulative Dose 1 0.002 10 0.02 0.02 2 0.005 10 0.05 0.07 3 0.01 10 0.1 0.17 4 0.02 10 0.2 0.37 5 0.04 10 0.4 0.77 6 0.08 10 0.8 1.57 7 0.16 10 1.6 3.17 8 2.0 5 4 7.17 9 2.0 3.13 6.25 13.42 10 2.0 6.25 12.5 25.92 11 2.0 12.5 25 50.92 12 2.0 25 50 100.92 13 2.0 50 100 200.92 14 – – 200 400.92 15 – – 400 800.92 16 – – 800 1600.92 Note: A time interval of 30 minutes between doses was established. a known risk factor for fungal infection, our patient had treatment, the plasma levels were considered therapeutic, non-severe diabetes, with glucose levels well controlled by since they achieved the recommended AUC/MIC of ≥389 in diet. We, therefore, considered low-grade immunosuppres­ induction therapy and AUC/MIC ≥100 during consolidation sion due to diabetes. The patient also denied exposure to therapy.12 other risk factors, such as avian guano. While exceptional, In conclusion, we present an atypical case of bone and other cases of cryptococcal infection with osteoarticular soft tissue cryptococcal infection in an immunocompetent involvement in seemingly healthy patients have been host, which was managed with antifungal treatment with­ reported.3–8 out surgical debridement. Induction therapy with a single Little is known about the optimal treatment of osteoarti­ high-dose of L-AmB followed by maintenance treatment cular cryptococcosis. Most cases reported in the literature with oral fluconazole appears to be effective. Fluconazole propose a wide variety of treatments, based on antifungal desensitization and therapeutic drug monitoring ensured drug therapy and surgical debridement.3,5 In contrast, more the proper application of treatment for twelve months evidence is available for the management of CNS infection. and suggests that results may be similarly effective when Recently, a Phase 2 non-inferiority clinical trial in HIV- applied to other patients. associated cryptococcal meningitis showed that a single high-dose of L-AmB plus high-dose oral fluconazole was Abbreviations non-inferior to 14 days of 3 mg/kg/day L-AmB in clearing L-AmB, liposomal amphotericin B; CNS, central nervous cerebrospinal fluid infection.9 In our case, although CNS system; CLAT, cryptococcal antigen latex agglutination test; infection was ruled out, high levels of cryptococcal antigen HIV, human immunodeficiency virus; MIC, minimum inhi­ in blood suggested disseminated cryptococcal infection. bitory concentration; AUC, area under the curve. Moreover, bone involvement requires high doses of anti­ fungal agents due to its poor vasculature. Consequently, Data Sharing Statement based on the latest IDSA guidelines10 and the evidence in All data (image and table) used in this study are included CNS infection,11 we treated this case with induction therapy in this published article. We do not have metadata sharing, consisting of a single high-dose of L-AmB followed by thus, it is not applicable to this article. maintenance treatment with oral fluconazole for twelve months. Remarkably, we report a successful desensitization Ethics Approval therapy that may be useful in other patients with fluconazole No institutional approval was required to publish the case allergy. Throughout the entire course of fluconazole details. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2021:14 721 DovePress Deus et al Dovepress Consent for Publication 2. Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006;20(3):507–544. The patient gave written informed consent to the publica­ 3. Medaris LA, Ponce B, Hyde Z, et al. Cryptococcal osteomyelitis: tion of his history and photographs. a report of 5 cases and a review of the recent literature. Mycoses. 2016;59(6):334–342. 4. Wood L, Miedzinski L. Skeletal cryptococcosis: case report and Author Contributions review of the literature. Can J Infect Dis. 1996;7:125–132. All authors made a significant contribution to the work 5. Zhou HX, Lu L, Chu T, et al. Skeletal cryptococcosis from 1977 to 2013. Front Microbiol. 2015;5:740. reported, whether that is in the conception, study design, 6. Ahn JH, Park C, Lee CW, Kim YC. Cryptococcal osteomyelitis of the execution, acquisition of data, analysis and interpretation, first metatarsal head in an immunocompetent patient. J Am Pediatr or in all these areas; took part in drafting, revising or Med Assoc. 2017;107(3):248–252. 7. Sang J, Yang Y, Fan Y, et al. Isolated iliac cryptococcosis in an critically reviewing the article; gave final approval of the immunocompetent patient. PLoS Negl Trop Dis. 2018;12(3): version to be published; have agreed on the journal to e0006206. 8. Li Z, Liang J, Shen J, Qiu G, Weng X. Thoracolumbar scoliosis due which the article has been submitted; and agree to be to cryptococcal osteomyelitis: a case report and review of the accountable for all aspects of the work. literature. Medicine. 2016;95(5):e2613. 9. Jarvis JN, Leeme TB, Mooketsi M, et al. Short-course high-dose liposomal amphotericin b for human immunodeficiency virus–asso­ Funding ciated cryptococcal meningitis: a phase 2 randomized controlled trial. The authors thank the Spanish Society of Infectious Clin Infect Dis. 2019;68(3):393–401. Diseases and Clinical Microbiology (SEIMC) which sup­ 10. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guide­ lines for the management of cryptococcal disease: 2010 update by the ports the research of Dr. Silvia Gómez-Zorrilla. infectious diseases society of America. Clin Infect Dis. 2010;50 (3):291–322. 11. Molloy SF, Kanyama C, Heyderman RS, et al. Antifungal combina­ Disclosure tions for treatment of cryptococcal meningitis in Africa. N Engl Juan Pablo Horcajada reports being a speaker with honor­ J Med. 2018;378(11):1004–1017. aria advisory boards for MSD, Pfizer, and Menarini. The 12. Chesdachai S, Rajasingham R, Nicol MR, et al. Minimum inhibitory concentration distribution of fluconazole against cryptococcus species authors report no conflicts of interest in this work. and the fluconazole exposure prediction model. Open Forum Infect Dis. 2019;6(10):ofz369. References 1. Randolph C, Kaplan C, Fraser B. Rapid desensitization to Fluconazole (Diflucan). 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