Advances in the treatment of invasive fungal disease.

With over 300 million severe cases and 1.5 million deaths annually, invasive fungal diseases (IFDs) are a major medical burden and source of global morbidity and mortality. The World Health Organization (WHO) recently released the first-ever fungal priority pathogens list including 19 fungal pathogens, considering the perceived public health importance. Most of the pathogenic fungi are opportunistic and cause diseases in patients under immunocompromised conditions such as HIV infection, cancer, chemotherapy, transplantation, and immune suppressive drug therapy. Worryingly, the morbidity and mortality caused by IFDs are continuously on the rise due to the limited available antifungal therapies, the emergence of drug resistance, and the increase of population that is vulnerable to IFDs. Moreover, the COVID-19 pandemic worsened IFDs as a globe health threat as it predisposes the patients to secondary life-threatening fungi. In this mini-review, we provide a perspective on the advances and strategies for combating IFDs with antifungal therapies.

Liposomal amphotericin B-the future.

Advances in medicine have led to a growing number of people with compromised or suppressed immune systems who are susceptible to invasive fungal infections. In particular, severe fungal infections are becoming increasingly common in ICUs, affecting people within and outside of traditional risk groups alike. This is exemplified by the emergence of severe viral pneumonia as a significant risk factor for invasive pulmonary aspergillosis, and the recognition of influenza-associated pulmonary aspergillosis and, more recently, COVID-19-associated pulmonary aspergillosis. The treatment landscape for haematological malignancies has changed considerably in recent years, and some recently introduced targeted agents, such as ibrutinib, are increasing the risk of invasive fungal infections. Consideration must also be given to the risk of drug-drug interactions between mould-active azoles and small-molecule kinase inhibitors. At the same time, infections caused by rare moulds and yeasts are increasing, and diagnosis continues to be challenging. There is growing concern about azole resistance among both moulds and yeasts, mandating continuous surveillance and personalized treatment strategies. It is anticipated that the epidemiology of fungal infections will continue to change and that new populations will be at risk. Early diagnosis and appropriate treatment remain the most important predictors of survival, and broad-spectrum antifungal agents will become increasingly important. Liposomal amphotericin B will remain an essential therapeutic agent in the armamentarium needed to manage future challenges, given its broad antifungal spectrum, low level of acquired resistance and limited potential for drug-drug interactions.

Contribution of voriconazole N-oxide plasma concentration measurements to voriconazole therapeutic drug monitoring in patients with invasive fungal infection.

BACKGROUND: Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter- and intra-individual pharmacokinetic variability. The main metabolite voriconazole N-oxide (NOX) can provide information on the patient's drug metabolism capacity. OBJECTIVES: Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage-adjustment algorithm. PATIENTS AND METHODS: Sixty-one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC-MS/MS. A mixed logistic model on repeated measures was implemented to analyse risk factors for the patient's concentration to be outside the therapeutic range. RESULTS: Based on 225 measurements, the median and interquartile range were 2.4 µg/ml (1.2; 4.2), 2.1 µg/ml (1.5; 3.0) and 1.0 (0.6; 1.9) for VRC, NOX and the MR, respectively. VRC Cmin <2 µg/ml were associated with a higher MR during the previous visit. MR values >1.15 and <0.48 were determined to be the best predictors for having a VRC Cmin lower than 2 µg/ml and above 5.5 µg/ml, respectively, at the next visit. CONCLUSIONS: Measurement of NOX resulted useful for TDM of patients treated with VRC. The MR using NOX informed interpretation and clinical decision-making and is very interesting for complex patients. VRC phenotyping based on the MR is now performed routinely in our institution. A dosing algorithm has been suggested from these results.

Secondary invasive fungal infection in hospitalised patients with COVID-19 in the United States.

BACKGROUND: Invasive fungal infections (IFIs) have been identified as a complication in patients with Coronavirus disease 2019 (COVID-19). To date, there are few US studies examining the excess humanistic and economic burden of IFIs on hospitalised COVID-19 patients. OBJECTIVES: This study investigated the incidence, risk factors, clinical and economic burden of IFIs in patients hospitalised with COVID-19 in the United States. PATIENTS/METHODS: Data from adult patients hospitalised with COVID-19 during 01 April 2020-31 March 2021 were extracted retrospectively from the Premier Healthcare Database. IFI was defined either by diagnosis or microbiology findings plus systemic antifungal use. Disease burden attributable to IFI was estimated using time-dependent propensity score matching. RESULTS: Overall, 515,391 COVID-19 patients were included (male 51.7%, median age: 66 years); IFI incidence was 0.35/1000 patient-days. Most patients did not have traditional host factors for IFI such as hematologic malignancies; COVID-19 treatments including mechanical ventilation and systemic corticosteroid use were identified as risk factors. Excess mortality attributable to IFI was estimated at 18.4%, and attributable excess hospital costs were $16,100. CONCLUSIONS: Invasive fungal infection incidence was lower than previously reported, possibly due to a conservative definition of IFI. Typical COVID-19 treatments were among the risk factors identified. Furthermore, diagnosis of IFIs in COVID-19 patients may be complicated because of the several non-specific shared symptoms, leading to underestimation of the true incidence rate. The healthcare burden of IFIs was significant among COVID-19 patients, including higher mortality and greater cost.

Invasive Mucormycosis and Aspergillosis Coinfection Associated with Post-COVID-19 Pneumonia in a Tertiary Care Hospital.

Acute invasive fungal rhinosinusitis is a rare infection primarily affecting patients with co-morbidities like immunosuppression and poorly controlled diabetes. Mucormycosis is increasingly being reported in patients with SARS-CoV-2 (COVID-19). However, reports of coinfection of aspergillosis and mucormycosis involving nose, paranasal sinuses, orbit, and brain are rare in literature. We aimed to evaluate the patient demographics, clinical presentation, and management of cases presenting with mixed infection. We carried out retrospective analysis of 12 patients with confirmed diagnosis of mixed invasive fungal infections post-COVID-19 disease out of 70 cases of COVID-19-associated mucormycosis (CAM) presenting to a tertiary-level hospital in North India from May to June 2021. All patients had diabetes mellitus; the mean age was 48 years. The common presenting features were headache, nasal congestion, palatal ulcer, and vision loss accompanied by facial pain and swelling. Two patients developed cerebral abscess during the course of treatment; three patients had concurrent COVID-19 pneumonia. All patients received systemic liposomal amphotericin B and serial surgical debridements. The overall mortality rate was 16.7%. Our study demonstrates that mucormycosis and aspergillosis are angioinvasive mycoses that are clinically and radiologically identical. KOH direct mount of clinical sample showing septate hyphae should be extensively searched for aseptate hyphae after digestion and clearing of the tissue. A high index of suspicion of mixed infection post-COVID-19 and early initiation of liposomal amphotericin B followed by prompt surgical intervention can reduce the overall morbidity and mortality among patients with this condition.

Indications that the Antimycotic Drug Amphotericin B Enhances the Impact of Platelets on Aspergillus.

Platelets are currently thought to harbor antimicrobial functions and might therefore play a crucial role in infections, e.g., those caused by Aspergillus or mucormycetes. The incidence of invasive fungal infections is increasing, particularly during the coronavirus disease 2019 (COVID-19) pandemic, and such infections continue to be life-threatening in immunocompromised patients. For this reason, the interaction of antimycotics with platelets is a key issue to evaluate modern therapeutic regimens. Amphotericin B (AmB) is widely used for the therapy of invasive fungal infections either as deoxycholate (AmB-D) or as a liposomal formulation (L-AmB). We showed that AmB strongly activates platelets within a few minutes. AmB concentrations commonly measured in the blood of patients were sufficient to stimulate platelets, indicating that this effect is highly relevant in vivo. The stimulating effect was corroborated by a broad spectrum of platelet activation parameters, including degranulation, aggregation, budding of microparticles, morphological changes, and enhanced adherence to fungal hyphae. Comparison between the deoxycholate and the liposomal formulation excluded the possibility that the liposomal part of L-Amb is responsible for these effects, as no difference was visible. The induction of platelet activation and alteration by L-AmB resulted in the activation of other parts of innate immunity, such as stimulation of the complement cascade and interaction with granulocytes. These mechanisms might substantially fuel the antifungal immune reaction in invasive mycoses. On the other hand, thrombosis and excessive inflammatory processes might occur via these mechanisms. Furthermore, the viability of L-AmB-activated platelets was consequently decreased, a process that might contribute to thrombocytopenia in patients.

Monoclonal Antibodies and Invasive Aspergillosis: Diagnostic and Therapeutic Perspectives.

Invasive aspergillosis (IA) is a life-threatening fungal disease that causes high morbidity and mortality in immunosuppressed patients. Early and accurate diagnosis and treatment of IA remain challenging. Given the broad range of non-specific clinical symptoms and the shortcomings of current diagnostic techniques, most patients are either diagnosed as "possible" or "probable" cases but not "proven". Moreover, because of the lack of sensitive and specific tests, many high-risk patients receive an empirical therapy or a prolonged treatment of high-priced antifungal agents, leading to unnecessary adverse effects and a high risk of drug resistance. More precise diagnostic techniques alongside a targeted antifungal treatment are fundamental requirements for reducing the morbidity and mortality of IA. Monoclonal antibodies (mAbs) with high specificity in targeting the corresponding antigen(s) may have the potential to improve diagnostic tests and form the basis for novel IA treatments. This review summarizes the up-to-date application of mAb-based approaches in assisting IA diagnosis and therapy.

Invasive fungal infections in critically ill COVID-19 patients in a large tertiary university hospital in Israel.

An increasing number of studies have tried to determine the incidence of invasive fungal infections (IFIs) in COVID-19 patients. Challenges in the diagnosis of pulmonary aspergillosis in these patients have led to new definitions of COVID-19-associated pulmonary aspergillosis (CAPA). The aim of this study was to determine the incidence and outcomes of and risk factors for IFIs in critically-ill COVID-19 patients, using the new definitions, in a tertiary center in Israel. METHODS: A case-controlled study (from 1 September 2020 to 31 March 2021) in which data from COVID-19 critically-ill patients with a diagnosis of IFI were collected and compared to a control group without IFI. RESULTS: The incidence of IFI amongst 311 COVID-19 critically-ill patients was 6.1%. 3.5% had CAPA and 3.5% had candidemia. In-hospital mortality was higher amongst patients with IFI compared to those without IFI (89.4% vs 60%, p < 0.03). The most significant predictors of IFI were cardiovascular co-morbidity and carbapenem use. CONCLUSIONS: The low incidence of CAPA in our group of COVID-19 critically-ill patients was consistent with recent reports, underscoring the importance of differentiating between true infection and colonization. Awareness and timely diagnosis of IFIs in COVID-19 critically-ill patients are imperative considering the associated high mortality.

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin.

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.

A case report of rhino-facial mucormycosis in a non-diabetic patient with COVID-19: a systematic review of literature and current update.

BACKGROUND: COVID-19 disease may be associated with a wide range of bacterial and fungal infections. We report a patient with COVID-19 infection who developed rhino-facial mucormycosis during treatment with corticosteroids. CASE PRESENTATION: A 59-year-old non-diabetic male patient was admitted with a diagnosis of COVID-19 based on positive RT-PCR and CT of the lungs. Due to sever lung involvement, he was treated with methylprednisolone. The patient was re-admitted to hospital, due to nasal obstruction and left side facial and orbital swelling, several days after discharge. In sinus endoscopic surgery, debridement was performed and the specimens were sent to pathology and mycology laboratories. A nasal biopsy showed wide hyphae without septa. The sequenced PCR product revealed Rhizopus oryzae. Despite all medical and surgical treatment, the patient died. In addition, the characteristics of patients with COVID-19-associated mucormycosis were reviewed in 44 available literatures. In most studies, diabetes mellitus was the most common predisposing factor for mucormycosis. CONCLUSION: Our report highlights the need for assessing the presence of mucormycosis in patients with COVID-19 and also it shows that physicians should consider the potential for secondary invasive fungal infections in COVID-19 cases.

Emerging Fungal Infections.

Various uncommon fungal pathogens have been increasingly identified as causes of disseminated and invasive fungal disease (IFD) worldwide. Growing recognition and clinical knowledge of these emerging fungal pathogens has occurred through improved molecular diagnostics, nucleic sequence databases, and taxonomic reclassification of medically significant fungi. However, emerging fungal diseases carry significant morbidity and mortality and, due to a paucity of published literature, the collective clinical experience with these fungi is often limited. In this review, we focus on unusual emerging fungal pathogens not extensively covered elsewhere in this issue of Infectious Diseases Clinics of North America.

Mucormycosis after Coronavirus disease 2019 infection in a heart transplant recipient - Case report and review of literature.

Mucormycosis is an invasive fungal infection (IFI) due to several species of saprophytic fungi, occurring in patients with underlying co-morbidities (including organ transplantation). During the ongoing Coronavirus disease 2019 (COVID-19) pandemic, there have been increasing reports of bacterial and fungal co-infections occurring in COVID-19 patients, including COVID-19 associated pulmonary aspergillosis (CAPA). We describe a case of mucormycosis occurring after COVID-19, in an individual who received a recent heart transplant for severe heart failure. Two months after heart transplant, our patient developed upper respiratory and systemic symptoms and was diagnosed with COVID-19. He was managed with convalescent plasma therapy and supportive care. Approximately three months after COVID-19 diagnosis, he developed cutaneous mucormycosis at an old intravascular device site. He underwent extensive surgical interventions, combined with broad-spectrum antifungal therapy. Despite the aggressive therapeutic measures, he died after a prolonged hospital stay. In this case report, we also review the prior well-reported cases of mucormycosis occurring in COVID-19 patients and discuss potential mechanisms by which COVID-19 may predispose to IFIs. Similar to CAPA, mucormycosis with COVID-19 may need to be evaluated as an emerging disease association. Clinicians should be vigilant to evaluate for invasive fungal infections such as mucormycosis in patients with COVID-19 infection.

Fatal disseminated aspergillosis in an immunocompetent patient with COVID-19 due to Aspergillus ochraceus.

Aspergillus infection is a well-known complication of severe influenza and severe acute respiratory syndrome coronavirus (SARS-CoV), and these infections have been related with significant morbidity and mortality even when appropriately diagnosed and treated. Recent studies have indicated that SARS-CoV-2 might increase the risk of invasive pulmonary aspergillosis (IPA). Here, we report the first case of Aspergillus ochraceus in a SARS-CoV-2 positive immunocompetent patient, which is complicated by pulmonary and brain infections. Proven IPA is supported by the positive Galactomannan test, culture-positive, and histopathological evidence. The patient did not respond to voriconazole, and liposomal amphotericin B was added to his anti-fungal regimen. Further studies are needed to evaluate the prevalence of IPA in immunocompetent patients infected with SARS-CoV-2. Consequently, testing for the incidence of Aspergillus species in lower respiratory secretions and Galactomannan test of COVID-19 patients with appropriate therapy and targeted anti-fungal therapy based on the primary clinical suspicion of IPA are highly recommended.

Optimal management of acute kidney injury in critically ill patients with invasive fungal infections being treated with liposomal amphotericin B.

Critically ill patients are at risk of developing both acute kidney injury (AKI) and invasive fungal infections (IFIs). Prompt and efficient treatment of the IFI is essential for the survival of the patient. This article examines three distinct clinical situations where liposomal amphotericin B, a broad-spectrum antifungal agent, was successfully used in the setting of AKI. The first was Aspergillus infection in a 63-year-old man with bleeding oesophageal varices related to advanced liver disease. The second was gastrointestinal mucormycosis in a 74-year-old man who developed a small bowel obstruction following an autologous stem cell transplant for mantle cell lymphoma. The third was a Fusarium infection in a 32-year-old woman on immunosuppression for a bilateral lung transplant for cystic fibrosis. In all three cases, liposomal amphotericin B was required for urgent management of the patient's IFI. We discuss the rationale for treatment with a potentially nephrotoxic agent in this setting.