Mucormycosis: The hidden and forgotten disease

Mucormycosis is a rare but serious fungal infection caused by a group of moulds called mucormycetes. More attention has recently been paid to it due to its association with coronavirus disease 2019 (COVID-19). Thus, it is important to review the progress of studies on mucormycosis and highlight the important findings in relation to epidemiology, clinical manifestation, major risk factors, diagnostic strategies and management. An electronic literature search was performed in PubMed using the keywords: Rhizopus, Mucorales, mucormycosis, zygomycosis, zygomycetes, COVID-19, the drugs (azoles, posaconazole, isavuconazole, amphotericin B pharmaceutical preparations and caspofungin), combination therapy, diagnosis and clinical manifestations. Studies written in the English language from January 1960 to 2021 were considered for this review article. All search results were reviewed, and the relevance of each article was determined by the authors independently. The review emphasized the fact that the diagnosis of mucormycosis is difficult, it is necessary to have a high index of suspicion to identify it, surgical debridement should be done prior to the dissemination of infection to improve clinical outcomes and identifying underlying risk factors is important for proper treatment. Moreover, antifungal therapeutic options are few with polyenes and their combinations should be appropriate for empirical therapy while posaconazole and isavuconazole are best reserved for de-escalation, refractory cases or patients intolerant to amphotericin B.     

Antifungal Therapy for Invasive Fungal Diseases in Allogeneic Stem Cell Transplant Recipients: An Update

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. While the most common pathogens are Candida spp. and Aspergillus spp., the incidence of infections caused by non-albicans Candida species as well as molds such as Zygomycetes has increased. For many years, amphotericin B deoxycholate (AMB-D) was the only available antifungal for the treatment of IFDs. Within the past decade, there has been a surge of new antifungal agents developed and added to the therapeutic armamentarium. Lipid-based formulations of amphotericin B provide an effective and less nephrotoxic alternative to AMB-D. Voriconazole has now replaced AMB-D as first choice for primary therapy of invasive aspergillosis (IA). Another extended-spectrum triazole, posaconazole, also appears to be a promising agent in the management of zygomycosis, refractory aspergillosis, and for prophylaxis. Members of the newest antifungal class, the echinocandins, are attractive agents in select infections due to their safety profile, and are a more attractive option compared to AMB-D as initial treatment for invasive candidiasis and (based on one study) challenge fluconazole for superiority in management with this mycoses. However, challenges do exist among these newer agents in very high-risk individuals like allogeneic SCT recipients, which may include adverse drug events, drug–drug interactions, variability in oral absorption, and availability of alternative formulations. The addition of newer agents has also stimulated interest in the potential application of combination therapy in serious, life-threatening infections. However, adequate studies are not available for most IFDs; thus, the clinical use of combination therapy is not evidenced based on most cases and preciseness in its use is uncertain. Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses.     

Activity of Combined Antifungal Agents Against Multidrug-Resistant <Emphasis Type="Italic">Candida glabrata</Emphasis> Strains

In this study, we evaluated the in vitro activity of echinocandins, azoles, and amphotericin B alone and in combination against echinocandin/azole-sensitive and echinocandin/azole-resistant Candida glabrata isolates. Susceptibility tests were performed using the broth microdilution method in accordance with the Clinical and Laboratory Standards Institute document M27-A3. The checkerboard method was used to evaluate the fractional inhibitory concentration index of the interactions. Cross-resistance was observed among echinocandins; 15% of the isolates resistant to caspofungin were also resistant to anidulafungin and micafungin. Synergistic activity was observed in 70% of resistant C. glabrata when anidulafungin was combined with voriconazole or posaconazole. Higher (85%) synergism was found in the combination of caspofungin and voriconazole. The combinations of caspofungin with fluconazole, posaconazole and amphotericin B, micafungin with fluconazole, posaconazole and voriconazole, and anidulafungin with amphotericin B showed indifferent activities for the majority of the isolates. Anidulafungin combined with fluconazole showed the same percentage of synergism and indifference (45%). Antagonism was detected in 50% of isolates when micafungin was combined with amphotericin B. Combinations of echinocandins and antifungal azoles have great potential for in vivo assays which are required to evaluate the efficacy of these combinations against multidrug-resistant C. glabrata strains.     

Cutaneous zygomycosis caused by Rhizopus arrhizus in a surgical wound.

We report a case of cutaneous zygomycosis caused by Rhizopus arrhizus in a surgical wound following colostomy. The patient was a diabetic and in addition presented others risk factors. Zygomycosis was suspected when a necrotic wound surface appeared in the appropiate clinical setting. Diagnosis was confirmed on a combined histological and microbiological study. Extensive surgical resection, high doses of amphotericin B and treatment of the underlying conditions permitted the control of the infection.     

In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature

The echinocandins anidulafungin and micafungin and the triazole posaconazole are currently undergoing phase III clinical trials. Caspofungin and voriconazole have recently been licensed for the treatment of aspergillosis (both agents), other less common mould (voriconazole) and candidal (caspofungin) infections. This review summarizes the published in vitro data obtained by NCCLS or NCCLS modified methods on the in vitro fungistatic and fungicidal activities of these five agents for yeasts and moulds in comparison to the established agents, amphotericin B, fluconazole, itraconazole, and flucytosine. Among the yeasts, the echinocandins have less activity for Candida parapsilosis and Candida guilliermondii, no activity for Cryptococcus neoformans and Trichosporon spp., but good fungistatic and fungicidal activity in vivo and in vitro for most of the other Candida spp.; this fungicidal activity has been reported by minimum fungicidal concentrations (MFCs) or time kill curve results. The new triazoles exhibit good fungistatic activity (but not fungicidal) for most Candida spp., C. neoformans, and Trichosporon spp. For the Aspergillus spp. evaluated, the echinocandins have similar or better fungistatic activity than those of amphotericin B and the triazoles, but fungicidal activity has been demonstrated only with amphotericin B and the triazoles, with the exception of fluconazole. Most studies showed posaconazole and voriconazole minimum inhibitory concentrations (MICs) ranging from 0.25 to 8 microg/ml for non-solani Fusarium spp., while MIC and minimum effective concentration (MEC) endpoints of the echinocandins were >8 microg/ml. The fungistatic activity of the triazoles is also superior to that of the echinocandins for most of the dimorphic fungi and the Zygomycetes. However, micafungin has activity for the mould phase of most dimorphic fungi, but not for the parasitic or yeast phase of Paracoccidioides brasiliensis. The echinocandins appear to have variable and species dependent fungistatic activity for the dematiaceous fungi, but all agents have poor or no activity against most isolates of Scedosporium prolificans. Only amphotericin B exhibit good fungistatic activity against the Zygomycetes. The combination of caspofungin with some triazoles, amphotericin B or liposomal amphotericin B has been synergistic in vitro, in animal models and in patients. Breakpoints are not available for any mould and antifungal agent combination. In vitro/in vivo correlations should aid in the interpretation of these results, but standard testing conditions are needed for the echinocandins, especially for mould testing, to obtain reliable results.     

A Mucormycosis Case in a Cirrhotic Patient Successfully Treated with Posaconazole and Review of Published Literature

Mucormycosis is an invasive fungal infection associated with a high mortality rate, especially in immunocompromised hosts. Mucormycosis rarely occurs in cirrhotic patients. Here, we report a case of mucormycosis with underlying liver cirrhosis and diabetes mellitus. The patient suffered from maxillary sinusitis and osteomyelitis, and the infection was successfully treated with antifungal agents, surgical debridement, and hyperbaric oxygen therapy. The antifungal treatments used were liposomal amphotericin B, itraconazole, and posaconazole. Although our patient had liver cirrhosis (Child-Pugh classification B), no hepatic decompensation was developed during the treatment course of posaconazole. This is the first report of the safe and effective use of posaconazole for the treatment of mucormycosis in a cirrhotic patient.     

Clinical efficacy of new antifungal agents

Several new options are now available for treating serious fungal infections. All three echinocandin agents currently available have been shown in randomized, blinded clinical trials to be efficacious in treating candidemia and invasive candidiasis. By contrast, the demonstrated efficacy of the echinocandins for the treatment of invasive aspergillosis has been based on historically controlled salvage treatment trials in patients failing or intolerant of other therapies. The new triazole agents, voriconazole and posaconazole, have a broad spectrum of antifungal activity. Voriconazole has become the agent of choice for invasive aspergillosis. On the basis of compassionate treatment data, posaconazole appears to be effective for treatment of zygomycosis. These agents have also been shown to be effective in the treatment of non-Aspergillus mould infections, several of the endemic mycoses and serious Candida infections.     

Medical and Adjunctive Treatment of Mucormycosis in Children: Scientific Rationale and Analysis of Cases Reported in the Literature

Mucormycosis is associated with significant morbidity and mortality in both children and adults. Studies have shown an increase in the incidence of mucormycosis, particularly among hematopoietic stem cell transplant (HSCT) recipients, patients with hematologic malignancies, and those with diabetic ketoacidosis. The infection typically presents as soft tissue, rhinoorbitocerebral, pulmonary, or disseminated disease and is characterized by rapid clinical progression and high mortality rates. Treatment with amphotericin B lipid formulations in combination with surgery offers the best option for treatment and survival; posaconazole, a relatively new antifungal triazole, is increasingly used for consolidation or salvage therapy. Because of the poor prognosis of zygomycosis, particularly in immunocompromised cancer patients, adjunctive treatments such as hyperbaric oxygen therapy, use of immunomodulatory cytokines, and in vivo iron chelation continue to be explored. Thus far, it is unclear how these adjunctive treatments can be harnessed to impact outcomes and which patients may benefit from them.     

Zygomycosis (absidiomycosis) in an AIDS patient

Absidia corymbifera is rarely cited as a cause of zygomycosis in the human host. Presented here is a case of absidiomycosis in a 29 year old construction worker hospitalized with a 6 year history of intravenous drug abuse, serological evidence for HIV infection, and the symptomatology of AIDS. ACT scan and gallium uptake imaging identified a nonfunctioning right kidney. Following a biopsy and a nephrectomy, histopathology revealed hyphal components consistent with zygomycosis. Culture of the biopsy and surgical specimens yielded A. corymbifera. Clinically the patient responded well to amphotericin B therapy.     

Zygomycosis Caused by Rhizopus microsporus and Rhizopus oryzae in Madhya Pradesh (M.P.) Central India: A Report of Two Cases

Zygomycosis encompasses infections due to two distinct orders of fungi, Mucorales and Entomophthorales. With rare exception, Entomophthorales are restricted to tropical areas. By contrast, mucorales are ubiquitous opportunistic fungi, which play a crucial part in the natural decay process. In human pathology, they may be opportunistic agents and be responsible for rare infection called (Mucormycosis) zygomycosis. We report two cases of zygomycosis from Madhya Pradesh, Central India, one caused by Rhizopus oryzae in a diabetic patient and another caused by Rhizopus microsporus in an apparently healthy patient. The cases were diagnosed by direct microscopy, histopathological examination and culture. Both the patients were successfully treated with liposomal amphotericin B. Rhizopus microsporus is, for the first time reported from Madhya Pradesh, India, causing rhino-maxillary orbital zygomycosis.     

Farmacología de los antifúngicos en el tratamiento de la aspergilosis

The treatment of invasive aspergillosis requires the use of drugs that characteristically have complex pharmacokinetic properties, the knowledge of which is essential to achieve maximum efficacy with minimal risk to the patient. The lipid-based amphotericin B formulations vary significantly in their pharmacokinetic behaviour, with very high plasma concentrations of the liposomal form, probably related to the presence of cholesterol in their structure. Azoles have a variable absorption profile, particularly in the case of itraconazole and posaconazole, with the latter very dependent on multiple factors. This may also lead to variations in voriconazole, which requires considering the possibility of monitoring plasma concentrations.The aim of this article is to review some of the most relevant aspects of the pharmacology of the antifungals used in the prophylaxis and treatment of the Aspergillus infection. For this reason, it includes the most relevant features of some of the azoles normally prescribed in this infection (itraconazole, posaconazole and voriconazole) and the amphotericin B formulations.     

Antifungal Dosing in Critically Ill Patients

This article reviews appropriate dosing for antifungals and emphasizes factors specific to the critically ill patient, along with drug pharmacokinetics and pharmacodynamics. The rationale for doses of the echinocandins (caspofungin, micafungin, anidulafungin), triazoles (fluconazole, voriconazole, itraconazole, posaconazole), amphotericin B (including lipid formulations), and flucytosine are discussed.     

Anti-fungal resistance in candida isolated from oral and diaper rash candidiasis in neonates

The purpose of the present study is to evaluate the sensitivity of Candida species isolated from oral candidiasis and diaper dermatitis infections in children. The children referring to private and public clinics in Ilam, Iran were exmined for oral candidiasis and diaper dermatitis. In this study, 248 oral candidiasis and diaper dermatitis samples were collected and cultured.Candida species were identified by using standard methods. Resistance and sensitivity to amphotericin B, nystatin, ketoconazole, fluconazole, itraconazole, clotrimazole, and posaconazole were determined using the CLSI M44-A standard disk diffusion method. From the 248 studied samples, 149 were positive for Candida, among which the Candida albicans was the most prevalent (64.4%). The resistance of different Candida species to nystatin, itraconazole, fluconazole, ketoconazole, clotrimazole, voriconazole, and posaconazole were 4, 43, 34.2, 34.9, 21.5, 6, and 6.7%, respectively. No resistance to amphotericin B was observed. Considering rather low resistance to nystatin, this drug is the best choice for oral candidiasis and diaper dermatitis.     

Successful posaconazole salvage therapy for rhinocerebral mucormycosis in a child with leukemia. Review of the literature

BackgroundMucormycosis is a fungal infection caused by species of the Mucorales order. These microorganisms are angioinvasive, with rapid disease progression and potentially lethal in its rhinocerebral form.Case reportWe present the case of a 12-year-old female with trisomy 21, acute lymphoblastic leukemia and diabetes, with fever and neutropenia who developed rhinocerebral mucormicosis. After treatment with amphotericin B lipid complex and extensive surgery, disease progressed and posaconazole was added as salvage treatment with full remission of the infection. Four years after diagnosis the patient continues without relapse of mucormycosis or leukemia.ConclusionsThis case highlights the use of posaconazole as either monotherapy or combined therapy. Although it is still debated, it can be considered an option for salvage treatment in children with non-responding mucormycosis, despite lack of standard dosage in pediatric patients.     

Antifungal drug resistance pattern of Candida. spp isolated from vaginitis in Ilam-Iran during 2013-2014

Vaginal Candidiasis is the most common and important opportunistic fungal infection in women. By increasing use of antifungal drugs in recent years, it has caused drug resistance. This study aims to evaluate antifungal drugs susceptibility of Candida. spp isolated of women with vaginitis from Ilam-Iran during 2013-2014. samples were collected and cultured from 385 women with vaginitis, then Candida.spp was diagnosed by standard method. Antifungal drug susceptibility test for nystatin 100 unit/disk, fluconazole 10µg/disk, itraconazole 10µg/disk, ketoconazole 10µg/disk, amphotericinB 20µg/disk, clotrimazole 10µg/disk, posaconazole 5µg/disk, and voriconazole 1µg/disk were carried out by M44-A method(CLSI). From all culture positive samples, 150 isolates were Candida albicans and 89 isolates were non-albicans. The resistance to fluconazole, itraconazole, ketoconazole, clotrimazole, voriconazole, posaconazole, nystatin and amphotericin B was 76%, 62%, 72%, 55%, 6%, 7%, 1% and 0%. The highest resistance was seen for fluconazole , itraconazole, and the highest susceptible was seen for nystatin and amphotericin B. These results indicate nystatin and amphotericin B can be used as the first line for empirical therapy of vaginal candidiasis in the district.     

中国大陆肺接合菌病102例回顾性分析

目的 总结与探讨中国大陆地区近25 a肺接合菌病的流行病学特点及诊疗情况.方法 检索分析重庆维普、CNKI系列数据库、万方数据库、中国医师协会全文期刊库及Pubmed等数据库中1988年以来的中国大陆地区肺接合菌病的相关文献资料.结果 共检索文献73篇,病例102例.患者的平均发病年龄为48.4岁,男女比例为2.46∶1,总死亡率为40.82％.我国肺接合菌病多见于糖尿病、HIV感染、病毒性肝炎、长期使用糖皮质激素和（或）免疫抑制剂等伴基础疾病的人群.其临床及影像学检查无特异性,诊断主要依赖于真菌学及组织病理学检查.治疗方法首选两性霉素B,联合手术治疗较之单独抗真菌药物疗效更好.结论 近年来中国大陆地区肺接合菌病发病率呈上升趋势.对高度怀疑肺接合菌感染的患者,宜尽早启动抗真菌治疗,及时联合病灶切除者疗效更佳.     

The Management of Chronic Pulmonary Aspergillosis: The UK National Aspergillosis Centre Approach

Purpose of Review

Chronic pulmonary aspergillosis (CPA) is a serious long-term fungal disease of the lung with a worldwide prevalence. Treatment of CPA is not straightforward given the often-multiple associated co-morbidities, complex clinical picture, drug interactions, toxicities and intolerances.

Recent Findings

First line treatment is oral itraconazole or voriconazole. In the event of intolerance or toxicity, patients may be swapped from itraconazole to voriconazole or vice versa. In the event of resistance or further intolerance, third line treatment with posaconazole could be initiated. In those with pan-azole resistance, short-term courses of intravenous liposomal amphotericin B or micafungin are fourth line therapy, keeping in mind the nephrotoxic effects of amphotericin B.

Summary

The available evidence for current treatments in CPA is limited and based mostly on retrospective cohort studies. There is a real need to raise awareness of this devastating disease to enable early treatment as well as prospective drug trials and studies to identify potential patient factors that correlate with progression, severity and overall outcomes in order to target future therapies.

     

How I Treat Blastomycosis

Blastomyces dermatitidis, a dimorphic fungus endemic to the Midwestern, South Central and Northeastern United States, causes the disease blastomycosis. Aerosolized spores from the environment are inhaled into the lungs where primary infection may be asymptomatic or subclinical. Pneumonia, the most common presentation of symptomatic blastomycosis, can be acute, subacute or chronic. Cutaneous, osteoarticular, genitourinary or central nervous system involvement may result from extra-pulmonary dissemination. The Infectious Diseases Society of America has published treatment guidelines for blastomycosis Chapman (Clin Infect Dis 46:1801-1812, 2008). Oral itraconazole has been the mainstay of therapy for mild to moderate infection, while amphotericin B, or alternatively a lipid formulation, is reserved for more severe infection. Newer triazoles, such as voriconazole and posaconazole, have shown clinical potential and expand available treatment options.     

中国大陆地区接合菌病流行现状的回顾性分析

目的了解中国大陆地区近30 a接合菌病流行情况及诊治现状。方法通过CNKI和Pubmed数据库搜索1976年来中国大陆地区接合菌病相关文献,进行数据分析和总结。结果病例报告206篇,共428例患者。感染类型以胃溃疡基础上合并胃肠毛霉菌病为主,其他常见感染类型为肺部、鼻眶脑和皮肤软组织。继发于糖尿病、消化道溃疡、外伤手术烧伤和其他无基础疾病患者多见。病原学诊断主要依赖镜检、培养和病理,仅35株菌鉴定至种的水平,其中6例进行分子生物学鉴定。单独系统抗真菌药物治疗为主,体外药敏试验少,两性霉素B和两性霉素B脂质体为首选用药。428例患者中共死亡126例,占发病总人数的29.43%;其中以全身播散型感染死亡率最高,占此型感染人数的83.34%。结论中国大陆地区接合菌病感染率有上升趋势。感染类型以胃溃疡基础上合并胃肠毛霉菌病为主。应该提高形态学诊断水平,并积极开展分子鉴定,同时有条件情况下应进行菌种的体外药物敏感性检测,为临床提供更为准确的参考信息。     

Five cases of zygomycosis.

Combined histological and mycological study of tissue specimens established a proven diagnosis of cutaneous zygomycosis in four patients. All patients had been treated with wide spectrum antibiotics and one patient (liver transplantation) was in addition also treated with cyclosporine. All had acidosis and cutaneous breaks and four had also been treated with systemic corticosteroids. The infecting organisms were Absidia corymbifera (n=2), Rhizopus stolonifer (n=1) and Mucor circinelloides (n=1). Combined treatment with i.v. conventional and liposomal formulations of amphotericin B and surgical treatment lead to a favourable clinical and mycological cure in three patients (A. corymbifera and R. stolonifer infections). One lymphoma patient with suspected Rhizopus pusillus infection of the lungs (presence of hyphae in sputum and positive culture) had an unfavourable outcome. The patient had been treated with wide spectrum antibiotics, corticosteroids and showed severe neutropenia and acidosis. The clinical presentations are outlined, including the outcomes and predisposing factors and focus on the diagnostic procedures, treatment and preventive measures.