INTRODUCTION:

Mucormycosis is caused by the fungi belonging to the order Mucorales. Humans acquire theinfection predominantly by inhalation of sporangiospores, occasionally by ingestion of contaminated food or traumatic inoculation. The fungi under Mucorales are ubiquitous, and morphologically appear as broad, aseptate or sparsely septate ribbon-like hyphae. Eleven genera and ~27 species under Mucorales are associated with human infections. Rhizopusarrhizus is the most common agent causing mucormycosis across the globe, followed by Lichtheimia, Apophysomyces, Rhizomucor, Mucorand Cunningham Ella species.¹ Mucormycosis are a group of invasive infections caused by filamentous fungi of the Mucoraceae family. Throughout the present paper we will refer to infections caused by Mucorales as mucormycosis in contrast to the term zygomycosis.

The latter is sometimes used in the relative literature due to the previous classification of the involved fungi and encompasses infections by both Mucorales and Entomophthorales. Mucormycosis is a rare but serious infection due to filamentous fungi of the division of Mucorales, the class Zygomycetes. They occur most often in immuno compromised patients with diabetes or hematological malignancies with prolonged neutropenia they represent the third cause of fungal infection in these patients after invasive candidiasis and aspergillosis.² 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. Invasivpulmonary aspergillosis complicating the course of COVID-19 is widely recognized; however, mucormycosis is uncommonly suspected or diagnosed. They occur most often in immuno compromised patients with diabetes or hematological malignancies with prolonged neutropenia they represent the third cause of fungal infection in these patients after invasive candidiasis and aspergillosis.³

Fig. No. 1: Fungal Structure of the Order Mucorales

Fig. No. 2: Microscopic Morphologies of Mucorales Genera

History and Other Name:

In 1885, the German pathologist Paltauf, reported the first case of Mucormycosis and described it as Mycosis Mucorina. During 1980s and 1990s Mucormycosis was increasingly seen among immuno compromised individuals.³Based on the prevalence rate, a study carried out in France reported amplification by 7.4% per year.Worldwide occurrence along with the possibility of seasonal variation of mucorales infection hasbeen reported.⁴

Other names:

1. Zygomycosis black fungus

2. Periorbital mucormycosis

Types:

1. Rhinocerebral (sinus and brain) mucormycosis

2. Pulmonary (lung) pkmucormycosis

3. Gastrointestinal mucormycosis

4. Cutaneous (skin)Mucormycosis

5. Disseminated mucormycosis.

· Rhinocerebral (sinus and brain) mucormycosis:

Is an infection in the sinuses that can spread to the brain. This form of mucormycosis is most common in people with uncontrolled diabetes and in people who have had a kidney transplant.

· Pulmonary (lung) mucormycosis:

Is the most common type of mucormycosis in people with cancer and in people who have had an organ transplant or a stem cell transplant.

· Gastrointestinal mucormycosis:

Is more common among young children than adults, especially premature and low birth weight infants less than 1 month of age, who have had antibiotics, surgery, or medications that lower the body’s ability to fight germs and sickness.

· Cutaneous (skin) mucormycosis:

It occurs after the fungi enter the body through a break in the skin (for example, after surgery, a burn, or other type of skin trauma). This is the most common form of mucormycosis among people who do not have weakened immune systems.

· Disseminated mucormycosis:

Occurs when the infection spreads through the bloodstream to affect another part of the body. The infection most commonly affects the brain, but also can affect other organs such as the spleen, heart, and skin.⁵

Classification:

Table No. 1: Classification of the aetiological agents responsible for mucormycosis.⁶

Family	Genus	Species
Mucoraceae	Obsidian Apophysomyces Macro Rhizopus	A.corymbifera A. elegans M. circinelloides M. hiemalis M. racemosus M. ramosissimus M. rouxianus R. pusillus R. arrhizus R. azygosporus
Cunninghamellaceae	Cunninghamella	C. bertholletiae
Mortierellaceae	Mortierella
Saksenaceae	Saksenaea	S. vasiformis
Syncephalastraceae	Syncephalastrum	S. racemosum
Thamnidaceae	Cokeromyces	C. recurvatus

Microbiology:

Fungi are eukaryotic organisms that evolved shortly before plants and animals. Fortunately, only a few hundred species are implicated in human disease, of which only a few dozen fungi cause 90% of human infections. Most pathogenic fungi are exogenous, residing in water, soil, and organic debris. They can cause disease by inducing an allergic response, elaborating toxin, establishing an infection or invading tissues. Most of the fungal rhino sinusitis is caused by species of Aspergillus, dematiaceous (i.e., melanized) moulds, or Zygomycetes which are part of the normal microbial flora.Most fungi are obligate or facultative aerobes.The size of the fungal particles, which influences the depth to which they penetrate the nasal or respiratory passages; the integrity of the nonspecific and specific host defences.⁷

Epidemiology:

Epidemiology Precise information on the prevalence of mucormycosis is lacking due to difficulties in clinical diagnosis. However, according to the current worldwide autopsy reports, it is the third most common cause of invasive fungal infections following Aspergillosis and Candidiasis with an increase of mucormycosis in the adult population and in infants less than 1 year old. According to documented literature, mucormycosis is at least 5–10-fold less common than other fungal infections like aspergillosis. Differences in the epidemiology of mucormycosis seem to exist between developed and developing countries.While hematologic malignancies and hematopoietic stem cell transplantation (HSCT) are the leading causes of mucormycosis in the developed countries, uncontrolledDM or trauma are the major causes in the developing countries, especially in India.⁸

Signs and symptoms:

The symptoms of mucormycosis depend on where in the body the fungus is growing. Contact your healthcare provider if you have symptoms that you think are related to mucormycosis.

Fig. No. 3: Signs and symptoms

1. Facial pain, pain over sinuses, pain in teeth and gums

2. Paraesthesia/decreased sensation over half of face.

3. Blackish discolouration of skin over nasolabial groove/alae nasii.

4. Nasal crusting and nasal discharge which could be blackish or blood tinged.

5. Conjunctival injection or chemosis.

6. Periorbital swelling.

7. Blurring of vision/diplopia.

8. Loosening of teeth/discoloration of palate/ gangrenous inferior turbinates.

9. Worsening of respiratory symptoms, hemoptysis, chest pain, alteration of consciousness, headache.

Symptoms of mucormicosis as pre types:

1. Symptoms of rhino cerebral (sinus and brain) mucormycosis include:

· One-sided facial swelling

· Headache

· Nasal or sinus congestion

· Black lesions on nasal bridge or upper inside of mouth that quickly become more severe

· Fever

2. Symptoms of pulmonary (lung) mucormycosis include:

· Fever

· Cough

· Chest pain

· Shortness of breath

3. Symptoms of Cutaneous (skin) mucormycosis include:

· Can look like blisters or ulcers, and the infected area may turn black.

· Other symptoms; include pain, warmth, excessive redness, or swelling around a wound.

4. Symptoms of gastrointestinal mucormycosis include:

· Abdominal pain

· Nausea and vomiting

· Gastrointestinal bleeding

5. Disseminated mucormycosis typically occurs in people who are already sick from other medical conditions, so it can be difficult to know which symptoms are related to mucormycosis.

Patients with disseminated infection in the brain can develop mental status changes or coma.⁹

Pathogenesis:

Pathogenesis The host-pathogen interaction is crucial in developing disease. To cause disease, fungal spores need to enter, evade the host immune system and germinate, leading to angioinvasion and dissemination.

1. Host defense against mucormycosis A healthy host with intact skin/mucosal barrier and innate immunity is usually resistant to develop disease even though the spores are present ubiquitously. The mucus layer of sinus/lung has anti-microbial properties and poor in nutrients. Moreover, the host keeps the essential nutrient iron firmly bound to the serum proteins to restrict access to pathogens in a process called nutrient immunity and keeps an iron poor environment as a defense strategy against fungal invasion. Mononuclear cells provide the host defense. Tissue macrophages phagocytose the inhaled spores and kill them. If any spores escape the macrophages and germinate, the hyphae induce chemotaxis of neutrophils, which damage the hyphae and phagocytose them. Neutrophils produce reactive oxygen metabolites, perforin, cationic peptides, and enzymes and kill the spores and hyphae by oxidative cytotoxic effect. The phagocytes express pattern recognition receptors like toll-like receptors (TLR) which identify and bind to the pathogen-associated molecular patterns (PAMP) on the fungi. This recognition activates intracellular signaling and mediates inflammation. Platelets play an important role in host immunity due to their antimicrobial and anti-fungal properties.¹⁰

2. Iron uptake and mucormycosis pathogenesis In addition to host factors that predispose patients to mucormycosis, Mucorales possess virulence factors that enable the organism to cause disease. One such trait is the ability to acquire iron from the host. Iron is an essential element for cell growth and development, contributing to many vital processes of the cell. Therefore, successful pathogens use multiple processes for obtaining iron from the host. Recent data demonstrate that the level of available, unbound iron in serum plays a critical factor in uniquely predisposing patients with DKA to mucormycosis. In mammalian hosts, iron is bound to host carrier proteins, such as transferrin, ferritin, and lactoferrin. This sequestration avoids toxic effect of free iron. This strategy of limiting iron availability is also a major universal host defense mechanism against microbes and against Mucorales in particular, because R.oryzae grows poorly in normal serum unless exogenous iron is added.

3. Host-pathogen interactions Mucormycosis infections are characterized by extensive angioinvasion that results in vessel thrombosis and subsequent tissue necrosis. Ischemic necrosis of infected tissues can prevent delivery of leukocytes and antifungal agents to the foci of infection. This angioinvasion likely contributes to the capacity of the organism to hematogenously disseminate to other target organs. Therefore, understanding the mechanisms by which these processes occur may lead to new approaches to prevent and/or treat mucormycosis.

Fig. No. 4: Proposed mechanisms of iron uptake by Mucorales during mucormycosis.¹¹Risk factors:

There are several risk factors are present including:

· Uncontrolled Diabetes Mellitus, hematological malignancy,

· Solid organ and bone marrow transplantation,

· Immuno compromised status,

· Neutropenia, chronic steroid usage,

· Trauma,

· Metabolic acidosis,

· Previous fungal prophylaxis,

· Extensive antibiotic therapy,

· Aluminum and iron overload,

· Deferoxamine therapy,

· Illicit intravenous drug use,

· Malnourishment, neonatal prematurity,

· Nosocomial spread etc.^12,13

Pathway of spread:

The spores enter the body by

a. Inhalation

b. Ingestion of contaminated food

c. Implantation in injured skin by trauma/ burns/ surgery, or

d. Percutaneous route by contaminated needles or catheters

Fig. No 5: Mucormycosis: modes of spread and clinical forms with common pathologic process¹⁰

Diagnosis and treatment:

Diagnosis:

Physical examination, swab test, tissue biopsy, imaging tests like CT or MRI scans to understand about the severity.¹⁴

Drugs used in treatment:

Antifungal Agents for Mucormycosis:

· Amphotericin B deoxycholate (AmB)

· New Triazoles

· Posaconazole

· Isavuconazole

Amphotericin B deoxycholate (AmB):

Remains the only licensed antifungal agent for the treatment of mucormycosis.

However, lipid formulations of AmB (LFABs) are significantly less nephrotoxic and can be safely administered at higher doses for a longer period of time than AmB.

In one study, amphotericin B lipid complex (ABLC) resulted success rate as salvage therapy for mucormycosis.

New Triazoles:

Triazoles act by depleting ergosterol from the fungal cell membrane. Among triazole antifungals, fluconazole, itraconazole, and voriconazole have little or no activity against Mucorales.

Newer triazoles, namelyposaconazole and isavuconazole, have better in vitro activity against Mucorales and clinicaldata supporting their use in mucormycosis.

Posaconazole:

It has variable in vitro activity against Mucorales, which is species-dependent. Until recently, posaconazole was available only as oral suspension, administered three or fourtimes daily, with food (preferably a high-fat meal) or with an acidic carbonated beverage, in orderto enhance bioavailability.

These food requirements make difficult the use of the oral solution in critically ill patients, as they might not be able to eat or they might be nauseous.

Therefore, absorption of posaconazole oral suspension was often suboptimal leading to therapeutic failures.

To overcome the pharmacokinetic limitations of the oral solution a gastro-resistant tablet and anintravenous (IV) solution has been developed.

Isavuconazole

Isavuconazole is a new broad-spectrum triazole and is the biologically active agent of the prodrug isavuconazonium sulfate.

It is approved in the United States for the treatment of mucormycosis, and inEurope for the treatment of mucormycosis when amphotericin B is not feasible.

It is available in both intravenous and oral formulations and it is administered with a loading dose of 200 mg three times a day for two days and 200 mg daily thereafter.

Therapy:

Combination Therapy:

Despite the lack of solid clinical data therapy of mucormycosis in heavily immunosuppressed patients with a combination of antifungals has become an increasingly common practice. In one retrospective study among diabetic patients with rhino-orbital or rhino-cerebral mucormycosis, the combination of AMB+ echinocandin was successful 2 treated patients compared with 5 patients treated with ABLC monotherapy (p = 0.02). However, in patients with hematological malignancies, the combination was not so successful. Data on the efficacy of the AMB + triazole combination for the treatment of mucormycosis are contradictory. In vitro studies have shown synergy for the combination of a polyene and posaconazole, but in vivo studies in murine models of mucormycosis showed no benefit when the agents are used together. Similarly, a study in neutropenic mice infected with R. oryzae found that amphotericin B and posaconazole dose combination did not prolong survival or decrease organ fungal burden to agreater extent than AMB monotherapy. Human studies evaluating polyene-triazole combination for the treatment of mucormycosis are limited. The modest existing pre-clinical and clinical datado not support the use of combination therapy, with the possible exception of CNS mucormycosis, where a combination of high-dose LAMB and posaconazole or isavuconazole might be considered.

Surgery:

Surgical resection of necrotic tissues is the core of mucormycosis therapy. In pulmonarymucormycosis, surgical treatment along with appropriate systemic antifungal therapy has beenshown to significantly improve survival compared to antifungal therapy alone. In certain cases of localised disease surgery might be curative In patients with rhino-orbital mucormycosis, magnetic resonance imaging might have a role in staging the respectability of the lesions. Similarly, surgical removal of infected tissues is of paramount importance in the treatment of rhino-orbital-cerebral disease.

It should be underlined however, that the effect of surgery onoutcome is difficult to be defined, due to selection biases. An endoscopic approach is preferred over the open surgery in patients with early, limited disease, or with significant medical comorbidities. Open surgeries are preferred for extensive disease, and include maxillectomy, orbital exenterationand/or craniofacial resection; yet, no survival benefit has been proved for such radical approach, especially in patients with limited life expectancy. Researchers reported the outcome of surgical management in 5 patients with rhino-orbito-cerebral mucormycosis. Local controls of the disease with wide and repeated surgical debridemenath, not fungal-related, were relapsed and/or refractory malignancy and protracted neutropeniaLocal control was not obtained in the patients after radical surgery vs. in patients who had limited surgery.¹⁵ Finally, in our study of 5 patients with hematologic malignancy and/orHSCT and invasive fungal sinusitis, due to Mucoralesin 5cases, showed that early endoscopic surgerydid not improved overall outcome.

CONCLUSION:

Mucormycosis is an emerging infection associated with high mortality. The identification of risk factors, clinical features and radiological findings increase the possibility of an early diagnosis, which may prevent progressive tissue invasion, reduce extent of surgical resection and improve survival. The diagnosis of mucormycosis relies upon the identification of organisms in tissue by histopathology with culture confirmation. However, culture often yields no growth and histopathological identification of an organism with structural typical of mucorales may provide the only evidence of infection. A clinician must think of this entity in the appropriate clinical setting and pursue invasive testing in order to establish a diagnosis as early as possible. If any disease or genetic history was present it was also taken under consideration.After talking all these points under consideration the treatment given to the patient.

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Received on 30.09.2021 Modified on 10.11.2021

Asian J. Pharm. Tech. 2022; 12(1):41-46.

DOI: 10.52711/2231-5713.2022.00008