INTRODUCTION:

MUCORMYCOSIS:

American pathologist R.D. Baker coined the term Mucormycosis. It is also known as Zygomycosis. It can be defined as an insidious fungal infection caused by members of Mucorales and zygomycotic species1.Mucormycotina are the common saprobes originating from the rotten matter or soils. Infections with Mucorales are categorized by rapid progression.²Mucormycosis (sometimes called zygomycosis) is a serious but rare fungal infection caused by a group of molds called mucormycetes.¹¹These fungi live throughout the environment, particularly in soil and in decaying organic matter, such as leaves, compost piles, or rotten wood.People get mucormycosis by coming in contact with the fungal spores in the environment. For example, the lung or sinus forms of the infection can occur after someone breathes in spores. These forms of mucormycosis usually occur in people who have health problems or take medicines that lower the body’s ability to fight germs and sickness. Mucormycosis can also develop on the skin after the fungus enters the skin through a cut, scrape, burn, or other type of skin trauma.Mucormycosis is a rare, emerging fungal infection, with high morbidity and mortality. Mucormycetes belong to the order Mucorales, subphylum Mucoromycotina. Due to the rarity of the disease, it is almost impossible to conduct large, randomized clinical trials, and most of the available data regarding epidemiology, diagnosis, and treatment, originate from case reports and case series. The first effort to analyze all the available literature was made by Roden et al. in 2005. Relatively large epidemiological studies were performed either on a national level or in patients with selected underlying diseases, for example, hematopoietic stem cell transplantation (HSCT). Registries are another source of valuable information, despite their inherent limitations. The Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) and the International Society of Human and Animal Mycology (ISHAM) constructed such a registry in 2004.^[1]The mortality of mucormycosis remains high. Treatment includes antifungal agents in combination with surgical intervention. The only new agent with activity against Mucorales is isavuconazole, but it does not seem to offer significant advantages over historical first line therapy of amphotericin B-based drugs or posaconazole. The aim of many researchers is to find new methods for making the diagnosis of mucormycosis earlier, as early diagnosis of mucormycosis leads to improved survival. This review will outline the various fields of research targeting diagnosis, as well as the modalities used either as primary or as adjunctive treatment of this frequently lethal disease.^[1]

Types of Mucormycosis:

1. Rhinocerebral (sinus and brain) mucormycosis

2. Pulmonary (lung) mucormycosis

3. Gastrointestinal mucormycosis

4. Cutaneous (skin) mucormycosis

5. Disseminated mucormycosis

Treatment of Mucormycosis:

Approach to treatment:

Involves a combination of surgical debridement of involved tissues and antifungal therapy ^18,20.

Elimination of predisposing factors for infection, such as hyperglycemia, metabolic acidosis, deferoxamine administration, immunosuppressive drugs, and neutropenia.

1. Surgery:

Aggressive surgical debridement of involved tissues should be considered as soon as the diagnosis of any form of mucormycosis is suspected. Surgical intervention with removal of necrotic tissue and debulking infection has been associated with improved survival in anecdotal clinical reviews of rhinocerebral and pulmonary infection. In the case of rhinocerebral infection, debridement to remove all necrotic tissue can often be disfiguring, requiring removal of the palate, nasal cartilage, and the orbit. However, more recent experience shows that endoscopic debridement with limited tissue removal can be accomplished ^10.

2. Antifungal drugs:

Early diagnosis of mucormycosis is critical to enable early initiation of therapy.

2.1. Initial therapy:

Amphotericin B is the drug of choice for initial therapy; most clinicians use a lipid formulation of amphotericin B (rather than amphotericin B deoxycholate) in order to deliver a high dose with less nephrotoxicity. The usual starting dose is 5 mg/kg daily of liposomal amphotericin B and may be increased as high as 10 mg/kg daily in an attempt to control this infection.

There have been apparent cures of isolated renal mucormycosis using amphotericin B deoxycholate alone ^[96,106] or combined with nephrectomy.If nephrectomy is not performed, amphotericin B deoxycholate is the agent of choice for initial therapy as the lipid formulations of amphotericin B do not penetrate the kidney or achieve measurable concentrations in the urine.

2.2. Step-down thearpy:

Posaconazole and isavuconazole are broad-spectrum azoles that are active in vitro against the agents of mucormycosis and that are available in both parenteral and oral formulations.

When switching to oral posaconazole, we favor the use of posaconazole delayed-release tablets (300 mg every 12 hours on the first day, then 300 mg once daily) taken with food if possible.

We do not use the oral suspension of posaconazole since it is not highly bioavailable and requires fatty food for absorption. A serum trough concentration of posaconazole should be checked after one week of therapy; we suggest a goal trough concentration >1 mcg/mL, but higher levels are preferred for treatment of this serious infection (see "Pharmacology of azoles", section on 'Posaconazole').

When using isavuconazole, loading doses are necessary for the first 48 hours; of 200 mg (ie, two capsules) should be given every 8 hours for six doses, followed by 200 mg orally once daily starting 12 to 24 hours after the last loading dose [114].Median treatment duration was 102 days for patients with primary mucormycosis, 33 days for those with refractory mucormycosis, and 85 days for those with intolerance to other antifungal therapy. All-cause mortality through day 42 was 38 percent, and overall complete or partial response rate at the end of treatment was 32 percent for primary treatment and 36 percent for treatment of mucormycosis refractory to other antifungals.

2.3. Salvage therapy:

We use posaconazole or isavuconazole as salvage therapy for patients who do not respond to or cannot tolerate amphotericin B. Posaconazole (both IV and delayed-release formulations) is given as a loading dose of 300 mg every 12 hours on the first day, followed by a maintenance dose of 300 mg every 24 hours thereafter.

Isavuconazole should be given as a loading dose of 200 mg (equivalent to 372 mg of the prodrug isavuconazonium sulfate) IV or orally every 8 hours for the first six doses followed by 200 mg IV or orally every 24 hours thereafter.

The IV formulation should be avoided in patients with moderate or severe renal impairment (creatinine clearance <50 mL/minute).

The clinical efficacy of the oral suspension of posaconazole was shown in a salvage study that enrolled 91 patients who had failed or could not tolerate standard therapy¹¹⁵.Posaconazole led to complete or partial response in 60 percent of patients; 21 percent had stable disease. Although there are limitations to this salvage study, this series supports a potential role for oral posaconazole for the treatment of mucormycosis refractory to standard therapy.

3. Duration of therapy:

Therapy should continue until there is clinical resolution of the signs and symptoms of infection, as well as resolution of radiographic signs of active disease; therapy should also continue until reversal of underlying immunosuppression has been achieved, when feasible. Therapy often extends for months, and some patients remain on therapy for life if immunosuppression cannot be corrected.¹⁶

4. Combination Antifungal therapy:

Larger studies are needed to establish whether combination therapy is beneficial. Although the echinocandins (eg, caspofungin) have no in vitro activity against the agents of mucormycosis ¹⁷, R. oryzae, the most common cause of mucormycosis, expresses the target enzyme for echinocandins, suggesting that these agents may have clinical utility ¹⁵.

In a retrospective study of 21 patients with rhino-orbital mucormycosis and 20 patients with rhino-orbital-cerebral mucormycosis, all six patients who received combination therapy with amphotericin B and an echinocandin had successful outcomes, defined as surviving and not requiring hospice care, compared with only 14 of 31 patients who received amphotericin B monotherapy ^[14]. The benefit of combination therapy was most pronounced among patients with cerebral involvement; all four patients who received combination therapy survived compared with 4 of 16 patients who received amphotericin B monotherapy.

Other antifungal agents, including voriconazole, fluconazole, and flucytosine, are not effective against the Mucorales ²⁰.

5. Deferasirox:

In contrast with the iron chelator, deferoxamine, which increases the risk of mucormycosis, other iron chelating agents, such as deferasirox and deferiprone, do not act as siderophores and therefore do not increase the risk of mucormycosis. However, deferasirox as an adjunctive agent for mucormycosis has not been adequately studied in humans and it should therefore not be used.

In a small trial, 20 patients with proven or probable mucormycosis were randomly assigned to receive liposomal amphotericin B plus either deferasirox or placebo for the first 14 days of therapy ^[19].Death at 90 days after therapy was initiated was significantly more frequent in those who received deferasirox than in those who received placebo (82 versus 22 percent). Reported adverse events were similar between the groups. One possible reason for the worse outcomes in the patients who received deferasirox is that more patients with hematologic malignancy, neutropenia, and/or pulmonary involvement received this agent; all of these conditions are associated with poor outcomes.^[9]

6. Hyperbaric oxygen:

Hyperbaric oxygen has been used in some patients with mucormycosis, but the benefit of this therapy has not been established ¹⁷. It may be useful in health care centers with the appropriate technical expertise and facilities ¹⁶.

7. Proinflammatory cytokines:

Such as interferon-γ and granulocyte macrophage colony-stimulating factor, enhance the ability of granulocytes to damage the agents of mucormycosis ¹⁸.

Survival of patients with mucormycosis treated with adjunctive immune therapy with recombinant granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor, or with recombinant interferon-γ, in conjunction with LFAB ¹⁷ has been reported. The role of recombinant cytokines in the primary treatment of mucormycosis is not defined.

Granulocyte colony-stimulating factor–mobilized granulocyte transfusions have been increasingly used for refractory mycoses, including mucormycosis ^{15, 16}. Although the reported experience with granulocyte transfusions is limited, such transfusions may be life-saving for persistently neutropenic patients with mucormycosis.

Drug Used for Mucormicosis:

1. Amphotericin b

2. Posaconazole

3. Isavaconazole

Molecular Docking of Amphotericin B

CONCLUSION:

Mucormycosis is a rare but emerging fungal infection with a high mortality rate. Most of the existing epidemiological studies of mucormycosis are retrospective and limited. The incidence of mucormycosis seems to be increasing in leukemic patients and stem cell transplant recipients chronically exposed to Aspergillus-active agents, although the generalizability of this observation is controversial. Mucormycosis is an opportunistic life-threatening infection mostly occurring in the immunocompromised host. The order Mucorales comprises 261 species in 55 genera, 38 of which have been associated with human infections. The taxonomy of Mucorales is evolving; a total of 11 genera and 27 species were described as causative agents of mucormycosis. An ecological study on Mucorales in Indian soils documented the isolation of pathogenic species such as Rhizopus, Lichtheimia, Cunninghamella, Rhizomucor, and Apophysomyces. Rhizopus arrhizus is the most common agent causing mucormycosis in India and globally. Diagnosis of mucormycosis remains challenging. Histopathology, direct examination and culture remain essential tools, although the molecular methods are improving. New molecular platforms are being investigated and new fungal genetic targets are being explored. Molecular-based methods have gained acceptance for confirmation of the infection when applied to tissues. Methods on detection of Mucorales DNA in blood have shown promising results for earlier and rapid diagnosis and could be used as screening tests in high-risk patients, but have to be validated in clinical studies. More, much needed, rapid methods that do not require invasive procedures, such as serology-based point-of-care, or metabolomics-based breath tests, are being developed and hopefully will be evaluated in the near future.

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Received on 11.07.2023 Modified on 23.07.2023

Research J. Science and Tech. 2023; 15(3):145-152.

DOI: 10.52711/2349-2988.2023.00024