Volume 2 - Issue 3

Oral posaconazole as a first-line antifungal for rhinocerebral mucormycosis

Sheelu Srinivas*, Mohammed Saifulla

Department of ENT, Kauvery Hospital, Bengaluru, Karnataka, India

*Correspondence: drsheelusrinivas@gmail.com

Abstract

Background: Mucormycosis is a rare opportunistic invasive fungal infection. The most commonly reported form of the disease is rhinocerebral mucormycosis. Early diagnosis of the disease and aggressive medical and surgical intervention prevent the high morbidity and mortality associated with mucormycosis.

Case presentation: A 45-year-old male with transient diabetes (steroid induced) presented with left frontal headache, left facial swelling and retro-orbital pain of three days' duration. On examination, the patient was conscious and oriented with a blood pressure of 130/89 mm Hg. Left frontal and maxillary sinus tenderness was present. Anterior rhinoscopy showed central septum and left nasal mucosal congestion. Eye examination revealed normal vision without any periorbital swelling. MRI brain/PNS with contrast showed no significant intracranial abnormality but showed T1 isointense and T2 mixed intensity lesion with restricted diffusion and absent contrast enhancement in the posterior ethmoids obliterating the left spheno-ethmoidal recess and also in right middle meatus, indicating likely acute invasive fungal sinusitis. Both orbits and intraorbital contents were normal. The patient underwent bilateral extensive sinonasal debridement with Left Denkers and tissue sampling. Following this antifungal therapy with only oral posaconazole was initiated since KOH-fungal stain from sinus mucosa was positive (aseptate hyphae). The patient responded well to extensive endoscopic sinus surgical evacuation of the fungal debris and posaconazole and has done well on follow-up.

Conclusion: This case report emphasizes the fact that posaconazole, the only available oral antifungal, can be used as a first-line agent in the management of mucormycosis, even in immunocompromised individuals.

Keywords: Posaconazole, Mucormycosis, Covid-19, Fungal infections

Background

Mucormycosis (also known as phycomycosis and zygomycosis) is a rare opportunistic invasive infection caused by fungi belonging to the order Mucorales and the family Mucoraceae [1,2] It is recognized as one of the most rapidly progressive lethal forms of fungal infection in human beings with a high mortality rate of 70 to 100% [3]. The incidence of mucormycosis is approximately 1.7 cases per 100,000 population per year [4]. The most commonly reported form of the disease is rhinocerebral mucormycosis, characterized by progressive fungal invasion of the hard palate, paranasal sinuses, orbit, and the brain.5 The conditions predisposing to mucormycosis are diabetes mellitus, malnutrition, burns, long-term steroid therapy, cirrhosis, immunosuppressive therapy, and hematological malignancies [5].

The pandemic coronavirus disease 2019 (COVID-19) continues to be a significant problem worldwide. While several treatment options have been evaluated, none except systemic glucocorticoids have been shown to improve survival in COVID-19. Unfortunately, the widespread use of glucocorticoids can lead to secondary bacterial or fungal infections. We report the case of a patient with COVID-19 infection, who, during the course of the treatment, developed rhino-orbital mucormycosis.

Extensive use of steroids/monoclonal antibodies/broad-spectrum antibiotics may lead to the development/exacerbation of fungal disease. A high index of suspicion and aggressive management is required to improve outcomes.

Case presentation

A 45-year-old transient diabetic (steroid induced - 15 days' post covid treatment) presented with left frontal headache, left facial swelling and retro-orbital pain, aggravated on bending down, of three days duration. There was one episode of epistaxis three days back. There was no history of any nasal/eye discharge, vomiting, diplopia, loosening of teeth or blurring of vision. On examination, patient was conscious and oriented with a blood pressure of 130/89 mmHg. There were no meningeal signs and he did not have any other focal neurological deficits. Left Frontal and maxillary sinus tenderness was present. Anterior rhinoscopy showed central nasal septum and left nasal mucosal congestion. Eye examination revealed normal vision without any periorbital swelling. Diagnostic nasal endoscopy showed normal right nasal cavity but thickened mucosa over the osteomeatal complex and necrosed mucosa over the anterior wall of left sphenoid. Laboratory investigations of blood revealed hemoglobin, 12.7 g%; white blood cells, 9700/mm3; with 88% polymorphs, 6% lymphocytes, 6% monocytes, and platelets of 220,000. Liver function revealed serum bilirubin 0.5 mg/dL (total) and 0.1 mg/dL (direct) with aspartate transaminase/alanine transaminase: 21/38 and alkaline phosphatase: 53. Renal function showed blood urea 28 mg/dL and serum creatinine 0.7 mg/dL. Magnetic resonance imaging of brain/PNS with contrast was done. Coronal T1-weighted image (Fig. 1a and b) showed T1 intermediate to high-signal soft tissue in bilateral ethmoids. Coronal post contrast image (Fig. 1c and d) showed heterogeneously enhancing soft tissue in the middle and posterior ethmoid air cells on both sides. Similar signal tissues seen in left sphenoid. Axial T1-weighted image (Fig. 2a and b) showed T1 intermediate to high-signal soft tissue in bilateral ethmoids. Axial post contrast image (Fig. 2c and d) showed heterogeneously enhancing soft tissue in the middle and posterior ethmoid air cells on both sides, also in left sphenoid.

The patient underwent bilateral functional endoscopic sinus surgery (FESS) with complete sinonasal debridement and Left Denkers, following which antifungal therapy with only oral posaconazole was initiated because biopsy from sinus mucosa showed acute on chronic inflammatory pathology. Tissue culture showed no growth. Fungal culture showed Rhizopus. GMS stain - fungal elements were not identified although the initial KOH fungal stain was positive for aseptate hyphae. Also due to limited availability of IV Amphotericin B at the beginning of the mucor pandemic, decision was taken to use the available resources for patients with orbital and cerebral spread. The patient responded well to extensive endoscopic sinonasal surgical evacuation of the fungal debris and oral Posaconazole for two weeks, following which symptoms subsided. Repeat MRI brain/PNS done at the time of discharge showed no significant intracranial abnormality. Post-operative changes following debridement in the left sinonasal cavity were retained secretions in the residual sinuses and hemorrhagic contents. Bilateral orbits and intraorbital contents were normal. He was discharged with oral Posaconazole for four more months with serial LFT monitoring, and is doing well on follow-up.

Fig. 1(a and b). Coronal T1-weighted images showed T1 intermediate to high-signal soft tissue in bilateral ethmoids. (c) Coronal post contrast images showed heterogeneously enhancing soft tissue in the middle and posterior ethmoid air cells on both sides. (d) Coronal post contrast image showed similar signal tissues seen in left sphenoid.

Fig. 2(a and b). Axial T1-weighted images showed T1 intermediate to high-signal soft tissue in bilateral ethmoids. (c and d) Axial post contrast images showed heterogeneously enhancing soft tissue in the middle and posterior ethmoid air cells on both sides, also in left sphenoid.

Discussion

Mucormycosis was first described by Paultauf in 1885 [2]. Based on the clinical presentation and the involvement of a particular anatomic site, mucormycosis can be classified into six clinical categories

  • Rhinocerebral
  • Pulmonary
  • Cutaneous
  • Gastrointestinal
  • Disseminated
  • Miscellaneous

Chakrabarti et al [6] observed that rhino-orbito-cerebral type (44.2%) was the commonest presentation in their retrospective analysis for 10 years in India. It accounts for one-third to one-half of all cases of mucormycosis. Rhino-orbito-cerebral mucormycosis can be subdivided into rhinomaxillary and rhino-oculocerebral forms, the latter being characterized by a high mortality rate. In a case described of severe COVID-19 associated with fungal coinfection, cell counts revealed that there was a progressive increase in white blood cell count and neutrophils while lymphocytes progressively decreased [7]. It is hypothesised that SARS-CoV-2 infection may affect CD4+ and CD8+ T-cells, which are highly involved in the pathological process of COVID-19 infection. It has been shown that in severe COVID-19 cases, there is a reduction in the absolute number of lymphocytes and T-cells, which is associated with the adverse outcomes. Mucorales-specific T-cells (CD4+ and CD8+) produce cytokines such as interleukin (IL) 4, IL-10, IL-17 and interferon-gamma (IFN-γ) that damage the fungal hyphae. Such specific T-cells were seen only in patients affected by invasive mucormycosis, and they concluded that they could be a useful surrogate diagnostic marker of an invasive fungal disease. It might be speculated that lymphopenia could increase the risk of developing invasive mucormycosis, while the recovery of lymphocyte count could improve the adaptive immune system and induce the production of Mucorales-specific T-cells, which might have a role in controlling the invasive infection.

There are a significant number of reports showing alterations in cell-mediated immunity, such as chemotaxis, phagocytosis and cytokine secretion in both type 1 and type 2 diabetics. Individuals with diabetes have been described to have alterations in innate immune system components. Natural killer cell activity is reduced in individuals with diabetes, and more pro-inflammatory M1 macrophages are present. Furthermore, T-cell activity is skewed. Disease severity in patients is due to not only the viral infection but also the host response. Elevated glucose levels may also suppress the antiviral response. In the context of COVID-19, severe disease progression is described by a delay in IFN-γ response with a prolonged hyperinflammatory state and lower CD4 and CD8 cell numbers. Regardless of the involvement of the endothelial cells, the initial delay in IFN-γ response together with the hyperinflammatory response in individuals with diabetes may exacerbate the 'cytokine storm' and increase COVID-19 severity. Increased vascular lesions, endothelial inflammation and vasoconstriction associated with endothelial dysfunction put individuals with diabetes at a greater risk for endotheliitis in several organs. Change of vascular tone towards more vasoconstriction can lead to subsequent organ ischaemia, tissue oedema and a procoagulant state. Finally, dysregulated immune cell populations and activity observed in individuals with diabetes play a critical role in aggravating the severity [8].

Our patient was transiently diabetic, and uncontrolled diabetes can alter the normal immunologic response of patients to infections. Such patients have decreased granulocyte phagocytic ability with altered polymorphonuclear leukocyte response. Reports have suggested that the ability of serum of immunocompromised patients to inhibit fungus in vitro is reduced, which makes them suitable hosts to opportunistic infections [9]. The fungus invades the arteries, forms thrombi within the blood vessels that reduce blood supply, and causes necrosis of hard and soft tissues. Once entered into the arteries, the fungus can spread to orbital and intracranial structures [9]. Nasal congestion, headache, earache, and facial pains are some of the most common features, which are not at all characteristic. Depending on the affected site, adjacent structures like the orbit or the central nervous system may be involved. Periorbital edema, ophthalmoplegia, and deterioration of eye are of high probability. Extension into cavernous sinus may cause cavernous sinus thrombosis. Through the cribriform plate of the ethmoid bone or the supraorbital fissure, the infection may spread intracranially, affect cranial nerves, and cause abscesses or sagittal sinus thrombosis. Perineural invasion has also been reported [10]. A histopathological diagnosis is generally considered more precise than simple culture due to the depth of invasion of the infection [11]. Four factors are critical for treating mucormycosis:

  • Rapidity of diagnosis
  • Reversal of underlying predisposing factors (if possible)
  • Appropriate surgical debridement of infected tissue, and
  • Appropriate antifungal therapy [12].

Surgical resection and debridement are associated with improved outcomes. Amphotericin B and posaconazole are the only antifungal agents currently available that are active against Mucorales [13]. Considering the safety profile in terms of nephrotoxicity, liposomal amphotericin remains a better option in treating mucormycosis. Posaconazole is a relatively new broad-spectrum triazole with in vitro activity against various fungal pathogens like Aspergillus, Candida, Mucor, and Fusarium sp. The formulation is a 100 mg oral tablet taken 300 mg bd on day one followed by 300 mg od or 40 mg/ml oral suspension containing polysorbate 80 as an emulsifying agent. It is administered at a dosage of 800 mg per day, in two or four divided doses. It has a long elimination half-life of 35 h, and its steady-state is reached in 7-10 days. Its absorption is promoted by nutritional supplements and high-fat meals and hence it should be administered with a full meal whenever possible, to ensure optimal absorption. There is no requirement of dose titration even in cases of renal dysfunction as the kidneys have insignificant role in its excretion. None of our patients showed any side effect with this drug. Posaconazole has low risk of adverse effects, does not require parenteral administration and hence there is no need for hospitalization [14]. It can also be used as a step-down treatment after initial therapy with Amphotericin B. Two case series and more than 20 case reports of successful treatment with Posaconazole have been published and all conclude a significantly good and complete response [15,16]. Posaconazole is the only antifungal formulation available as an oral preparation. It has been used as an oral step-down agent after successful response with Amphotericin B or for salvage therapy in case of refractory disease or intolerance to side effects of Amphotericin B [13].

Here, we attempted to treat mucormycosis with posaconazole as the first-line agent following sinonasal debridement and the patient responded very well to it. It is also cost effective compared with Amphotericin B. A maximum dose of 3 g of lyophilized Amphotericin B in a month-long treatment will cost the patient approximately 200,000-300,000 INR (3000 USD approx.) for the drugs, frequent biochemical tests and hospitalization at the rate of 6500-8000 INR/day (100 USD approx.). This does not include the cost of the family attendant, loss of work and emotional trauma. Compared to this, a 3-month treatment with oral Posaconazole will cost the patient approximately 180,000 INR (2700 USD approx.) at the rate of 2000 INR/day (30 USD approx.). There is no loss of work and the patient can stay at home during the therapy period. The comparison leaves no doubt that oral therapy with Posaconazole is less burdening to the patient both economically and emotionally. Peet et al [17] and Singh et al had successfully used posaconazole as a first-line agent in the treatment of mucormycosis in systemic lupus erythematosus patients.

Conclusion

This report highlights the possibility of occurrence of this rapidly fatal condition even with normal-looking nasal mucosa. High index of suspicion is required to prevent the complications as the course of the disease is very rapid. In our patient with a very short history of symptoms of three days duration, the diagnosis was difficult with the disease involving predominantly the posterior group of sinuses. Surgical debridement of the fungal debris with strict diabetes control and prompt medical management with single drug oral posaconazole showed good clinical response. This case report also emphasizes the fact that posaconazole is the only available oral antifungal, which can be used as a first-line agent in the management of mucormycosis, even in an immunocompromised individual.

References

  • Spellberg B, Ibrahim A, Roilides E, Lewis RE, Lortholary O, Petrikkos G, et al. Combination therapy for mucormycosis: why, what, and how? Clin Infect Dis. 2012;54:S73-8.
  • Viterbo S, Fasolis M, Garzino-Demo P, Griffa A, Boffano P, Iaquinta C, et al. Management and outcomes of three cases of rhinocerebral mucormycosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112(6):e69-4.
  • Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41(5):634-53.
  • Bouza E, Munoz P, Guinea J. Mucormycosis: an emerging disease? Clin Microbiol Infect. 2006;12:7-23.
  • Elinav H, Zimhony O, Cohen MJ, Marcovich AL, Benenson S. Rhinocerbral mucormycosis in patients without predisposing medical conditions: a review of literature. Clin Microbiol Infect. 2009;15(7):693-7.
  • Chakrabarti A, Das A, Sharma A, Panda N, Das S, Gupta KL, et al. Ten years' experience in zygomycosis at a tertiary care centre in India. J Infect. 2001;42(4):261-6.
  • Asero D, Sanna S, Liperi C, et al. A challenging complication following SARS-CoV-2 infection: a case of pulmonary mucormycosis. Infection 2020:16.
  • Erener S. Diabetes, infection risk and COVID-19. Mol Metab. 2020;39:101044.
  • Zapico ADV, Rubio Suárez A, Mellado Encinas P, Morales Angulo C, Cabrera Pozuelo E. Mucormycosis of the sphenoidal sinus in an otherwise healthy patient - case report and literature review. J Laryngol Otol. 1996;110(5):471-3.
  • McLean FM, Ginsberg LE, Stanton CA. Perineural spread of rhinocerebral mucormycosis. Am J Neuroradiol. 1996;17(1):114-6.
  • Tryfon S, Stanopoulos I, Kakavelas E, Nikolaidou A, Kioumis I. Rhinocerebral mucormycosis in a patient with latent diabetes mellitus: a case report. J Oral Maxillofac Surg. 2002;60(3): 328-30.
  • Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation and management. Clin Microbiol Rev. 2005;18(3):556-69.
  • Greenberg RN, Mullane K, Van Burik JA, Raad I, Abzug MJ, Anstead G, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006;50(1):126-33.
  • Ullmann AJ, Cornely OA, Burchardt A, Hachem R, Kontoyiannis DP, Töpelt K, et al. Pharmacokinetics, safety, and efficacy of Posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection. Antimicrob Agents Chemother. 2006;50:658-66.
  • van Burik JA, Hare RS, Solomon HF, Corrado ML, Kontoyiannis DP. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis. 2006;42:61-5.
  • Greenberg RN, Mullane K, van Burik JA, Raad I, Abzug MJ, Anstead G, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006;50:126-33.
  • Peel T, Daffy J, Thursky K, Stanley P, Buising K. Posaconazole as first line treatment for disseminated zygomycosis. Mycoses 2008;51(6):542-5.

Dr. Sheelu Srinivas

Dr. Mohammed Saifulla


Kauverian - Scientific Journals - Volume 1 - issue 1


Kauverian - Scientific Journals - Volume 1 - issue 2


Kauverian - Scientific Journals - Volume 1 - issue 3


Kauverian - Scientific Journals - Volume 1 - issue 4


Kauverian - Scientific Journals - Volume 1 - issue 5


Kauverian - Scientific Journals - Volume 1 - issue 6


Kauverian - Scientific Journals - Volume 1 - issue 7


Kauverian - Scientific Journals - Volume 1 - issue 8


Kauverian - Scientific Journals - Volume 1 - issue 9


Kauverian - Scientific Journals - Volume 2 - issue 1


Kauverian - Scientific Journals - Volume 2 - issue 2


Kauverian - Scientific Journals - Volume 2 - Issue 3


Kauverian - Scientific Journals - Volume 2 - Issue 4


Kauverian - Scientific Journals - Volume 2 - Issue 5


Kauverian - Scientific Journals - Volume 2 - Issue 6


Kauverian - Scientific Journals - Volume 2 - Issue 7


Kauverian - Scientific Journals - Volume 2 - Issue 8


Kauverian - Scientific Journals - Volume 2 - Issue 9


Kauverian - Scientific Journals - Volume 2 - Issue 10


Kauverian - Scientific Journals - Volume 2 - Issue 11


Kauverian - Scientific Journals - Volume 2 - Issue 12


Kauverian - Scientific Journals - Volume 3 - Issue 1


Kauverian - Scientific Journals - Volume 3 - Issue 2


Kauverian - Scientific Journals - Volume 3 - Issue 3


Kauverian - Scientific Journals - Volume 3 - Issue 4


Kauverian - Scientific Journals - Volume 3 - Issue 5


Kauverian - Scientific Journals - Volume 3 - Issue 6


Kauverian - Scientific Journals - Volume 3 - Issue 7


Kauverian - Scientific Journals - Volume 3 - Issue 8


Kauverian - Scientific Journals - Volume 3 - Issue 9


Kauverian - Scientific Journals - Volume 3 - Issue 10


Kauverian - Scientific Journals - Volume 3 - Issue 11-1


Kauverian - Scientific Journals - Volume 3 - Issue 11-2


Kauverian - Scientific Journals - Volume 3 - Issue 12


Kauverian - Scientific Journals - Volume 4 - Issue 1


Kauverian - Scientific Journals - Volume 4 - Issue 2


Kauverian - Scientific Journals - Volume 4 - Issue 3


Kauverian - Scientific Journals - Volume 4 - Issue 4


Kauverian - Scientific Journals - Volume 4 - Issue 5


Kauverian - Scientific Journals - Volume 4 - Issue 6


Kauverian - Scientific Journals - Volume 4 - Issue 7


Kauverian - Scientific Journals - Volume 4 - Issue 8


Kauverian - Scientific Journals - Volume 4 - Issue 9


Kauverian - Scientific Journals - Volume 5 - Issue 1


Kauverian - Scientific Journals - Volume 5 - Issue 2


Kauverian - Scientific Journals - Volume 5 - Issue 3


Kauverian - Scientific Journals - Volume 5 - Issue 4


Kauverian - Scientific Journals - Volume 5 - Issue 5


Kauverian - Scientific Journals - Volume 5 - Issue 6


Kauverian - Scientific Journals - Volume 5 - Issue 7


Kauverian - Scientific Journals - Volume 5 - Issue 8


Kauverian - Scientific Journals - Volume 5 - Issue 9


Kauverian - Scientific Journals - Volume 5 - Issue 10


Kauverian - Scientific Journals - Volume 5 - Issue 11


Kauverian - Scientific Journals - Volume 5 - Issue 12


Kauverian - Scientific Journals - Volume 5 - Issue 13

LOCATE US

Find a Doctor Teleconsultation Emergency