[Translated article] Paradoxical interaction between nirmatrelvir/ritonavir and voriconazole in a patient with COVID-19.

This case is based on a drug interaction between nirmatrelvir/ritonavir (approved drug for COVID-19) and voriconazole is presented, possibly derived from the bidirectional effect of ritonavir on the 2 main voriconazole metabolizing enzymes (cytochrome P450 3A and 2C19) ritonavir inhibits the former and induces the latter respectively. According to the main pharmacotherapeutic information databases, in the interaction between both drugs, a decrease in the area under the curve of voriconazole is expected due to the inducing effect of its metabolism; however, in the case we present, unexpectedly, a paradoxical effect occurs, according to what is described in literature, with the result of sustained supratherapeutic levels of voriconazole. Given the short treatment period with nirmatrelvir/ritonavir (5 days), the induction effect of ritonavir proposed in the studies on which the recommendations are based, where treatment with ritonavir is longer, does not occur.

Post-COVID-19 fatal Aspergillus endocarditis: A case report.

BACKGROUND: Aspergillus endocarditis (AE) is a rare fatal infection. The infection is often reported in patients with prosthetic heart valves, immunosuppressed, broad-spectrum antimicrobial use regimens, and drug abusers. METHODS: Herein, we report a rare case of native mitral valve AE in a 63-year-old man, with a probable COVID-19-associated invasive pulmonary aspergillosis nine months ago treated with antifungals. RESULTS: In the last admission, the lethargy, neurological deficit, and septic-embolic brain abscess in brain MRI led to suspicion of infective endocarditis. Transesophageal two-dimensional echocardiography and color Doppler flow velocity mapping showed a large highly mobile mass destroying leaflet and severe mitral regurgitation. The Surgical valve replacement is performed. The surgical valve replacement is performed. Direct microscopic examination and culture of the explanted and vegetative mass revealed Aspergillus section Fumiagati confirmed by molecular method. Despite the administration of voriconazole and transient improvement the patient expired. CONCLUSION: As AE is a late consequence of COVID-19-associated invasive pulmonary aspergillosis, therefore, long-term follow-up of invasive aspergillosis, and prompt diagnosis of surgical and systemic antifungal therapy treatment, are warranted to provide robust management.

Invasive cerebral aspergillosis in non-neutropenic patients: A case series from Western India.

PURPOSE: Invasive cerebral aspergillosis (ICA) is a rare but fatal infection affecting neutropenic immunocompromised patients. Recently cases have been reported in non-neutropenic settings also. We hereby present a series of ICA cases in non-neutropenic patients diagnosed at our tertiary care centre in Western India between March to October 2021. METHODS: All patients with clinico-radiological suspicion of CNS infections were analysed. Data regarding Clinico-radiological features, diagnosis, treatment and outcome were collected. After ruling out bacterial, viral and mycobacterial causes, appropriate samples were sent for KOH (potassium hydroxide) wet mount, fungal culture, histopathology and serum/CSF galactomannan. RESULTS: A total of four patients were diagnosed with ICA with a mean age of 43.5 years. Three patients had significant comorbidities; Diabetes mellitus, chronic liver disease and COVID-19 pneumonia treated with dexamethasone, respectively. One patient had no known predisposing factor. Radiologically, one patient presented with a frontal brain abscess and two patients had multiple subcortical hyperintensities. Three patients were diagnosed based on CSF galactomannan (Platelia™ Aspergillus antigen, Bio-Rad, France) with OD >1 and one patient had high serum galactomannan (OD >2). CSF culture grew Aspergillus species in two patients. All patients were treated with Voriconazole. One patient recovered, and the remaining three succumbed due to delayed presentation and extensive cerebral involvement. CONCLUSION: Even in non-neutropenic patients, a high index of suspicion is warranted for cerebral aspergillosis. CSF galactomannan can be considered a reliable marker for diagnosing ICA in non-neutropenic settings. Early diagnosis allows timely antifungal therapy, which could be a key to improving the outcomes.

Endogenous Fungal Endophthalmitis following COVID-19 Hospitalization: Evidence from a Year-Long Observational Study.

PURPOSE: To describe cases of endogenous fungal endophthalmitis (EFE) post-recovery from or hospitalization for coronavirus disease 2019 (COVID-19). METHODS: This prospective audit involved patients with suspected endophthalmitis referred to a tertiary eye care center over a one-year period. Comprehensive ocular examinations, laboratory studies, and imaging were performed. Confirmed cases of EFE with a recent history of COVID-19 hospitalization±intensive care unit admission were identified, documented, managed, followed up, and described. RESULTS: Seven eyes of six patients were reported; 5/6 were male, and the mean age was 55. The mean duration of hospitalization for COVID-19 was approximately 28 days (14-45); the mean time from discharge to onset of visual symptoms was 22 days (0-35). All patients had underlying conditions (5/6 hypertension; 3/6 diabetes mellitus; 2/6 asthma) and had received dexamethasone and remdesivir during their COVID-related hospitalization. All presented with decreased vision, and 4/6 complained of floaters. Baseline visual acuity ranged from light perception (LP) to counting fingers (CF). The fundus was not visible in 3 out of 7 eyes; the other 4 had "creamy-white fluffy lesions" at the posterior pole as well as significant vitritis. Vitreous taps were positive for Candida species in six and Aspergillus species in one eye. Anti-fungal treatment included intravenous amphotericin B followed by oral voriconazole and intravitreal amphotericin B. Three eyes underwent vitrectomy; the systemic health of two patients precluded surgery. One patient (with aspergillosis) died; the others were followed for 7-10 months - the final visual outcome improved from CF to 20/200-20/50 in 4 eyes and worsened (hand motion to LP) or did not change (LP), in two others. CONCLUSION: Ophthalmologists should maintain a high index of clinical suspicion for EFE in cases with visual symptoms and a history of recent COVID-19 hospitalization and/or systemic corticosteroid use - even without other well-known risk factors.

Characterization of Aspergillus spp. isolated from patients with coronavirus disease 2019.

INTRODUCTION: Invasive pulmonary aspergillosis (IPA) is an important complication of coronavirus disease 2019 (COVID-19), and while there are case reports and epidemiological studies, few studies have isolated Aspergillus strains from patients. Therefore, we analyzed the strains, sensitivities, and genetic homology of Aspergillus spp. Isolated from patients with COVID-19. METHODS: We investigated the Aspergillus strains detected from patients with COVID-19 hospitalized in Osaka Metropolitan University Hospital from December 2020 to June 2021. A molecular epidemiological analysis of Aspergillus spp. was performed using drug susceptibility tests and TRESPERG typing, and data on patient characteristics were collected from electronic medical records. RESULTS: Twelve strains of Aspergillus were detected in 11 of the 122 patients (9%) with COVID-19. A. fumigatus was the most common species detected, followed by one strain each of Aspergillus aureolus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus. A. aureolus was resistant to voriconazole, and no resistance was found in other strains. All A. fumigatus strains were genetically distinct strains. Six of the 11 patients that harbored Aspergillus received antifungal drug treatment and tested positive for ß-D-glucan and/or Aspergillus galactomannan antigen. The results indicated that Aspergillus infections were acquired from outside the hospital and not from nosocomial infections. CONCLUSION: Strict surveillance of Aspergillus spp. is beneficial in patients at high-risk for IPA. When Aspergillus is detected, it is important to monitor the onset of IPA carefully and identify the strain, perform drug sensitivity tests, and facilitate early administration of therapeutic agents to patients with IPA.

Paradoxical interaction between nirmatrelvir/ritonavir and voriconazole in a patient with COVID-19. / Interacción paradójica entre nirmatrelvir/ritonavir y voriconazol en un paciente con COVID-19.

This case is based on a drug interaction between nirmatrelvir/ritonavir (approved drug for COVID-19) and voriconazole is presented, possibly derived from the bidirectional effect of ritonavir on the 2 main voriconazole metabolising enzymes (cytochrome P450 3A and 2C19) ritonavir inhibits the former and induces the latter respectively. According to the main pharmacotherapeutic information databases, in the interaction between both drugs, a decrease in the area under the curve of voriconazole is expected due to the. inducing effect of its metabolism; however, in the case we present, unexpectedly, a paradoxical effect occurs, according to what is described in literature, with the result of sustained supratherapeutic levels of voriconazole. Given the short treatment period with nirmatrelvir/ritonavir (5 days), the induction effect of ritonavir proposed in the studies on which the recommendations are based, where treatment with ritonavir is longer, does not occur.

Impact of COVID-19 pandemic on antifungal consumption: a multicenter retrospective analysis.

BACKGROUND: In the context of COVID-19 pandemic, antifungal overuse may have occurred in our hospitals as it has been previously reported for antibacterials. METHODS: To investigate the impact of COVID-19 on antifungal consumption, a multicenter retrospective study including four medical sites and 14 intensive care units (ICU) was performed. Antifungal consumption and incidences of invasive fungal diseases before and during COVID-19 pandemic, for non-COVID-19 patients and COVID-19 patients, were described. RESULTS: An increase in voriconazole consumption was observed in 2020 compared with 2019 for both the whole hospital and the ICU (+ 40.3% and + 63.7%, respectively), whereas the incidence of invasive aspergillosis significantly increased in slightly lower proportions in the ICU (+ 46%). Caspofungin consumption also increased in 2020 compared to 2019 for both the whole hospital and the ICU (+ 34.9% and + 17.0%, respectively) with an increased incidence of invasive candidiasis in the whole hospital and the ICU but in lower proportions (+ 20.0% and + 10.9%, respectively). CONCLUSIONS: We observed an increased consumption of antifungals including voriconazole and caspofungin in our hospital during the COVID-19 pandemic and explained in part by an increased incidence of invasive fungal diseases in COVID-19 patients. These results are of utmost importance as it raises concern about the urgent need for appropriate antifungal stewardship activities to control antifungal consumption.

Determinants of fluconazole resistance and echinocandin tolerance in C. parapsilosis isolates causing a large clonal candidemia outbreak among COVID-19 patients in a Brazilian ICU.

Patients presenting with severe COVID-19 are predisposed to acquire secondary fungal infections such as COVID-19-associated candidemia (CAC), which are associated with poor clinical outcomes despite antifungal treatment. The extreme burden imposed on clinical facilities during the COVID-19 pandemic has provided a permissive environment for the emergence of clonal outbreaks of multiple Candida species, including C. auris and C. parapsilosis. Here we report the largest clonal CAC outbreak to date caused by fluconazole resistant (FLZR) and echinocandin tolerant (ECT) C. parapsilosis. Sixty C. parapsilosis strains were obtained from 57 patients at a tertiary care hospital in Brazil, 90% of them were FLZR and ECT. Although only 35.8% of FLZR isolates contained an ERG11 mutation, all of them contained the TAC1L518F mutation and significantly overexpressed CDR1. Introduction of TAC1L518F into a susceptible background increased the MIC of fluconazole and voriconazole 8-fold and resulted in significant basal overexpression of CDR1. Additionally, FLZR isolates exclusively harboured E1939G outside of Fks1 hotspot-2, which did not confer echinocandin resistance, but significantly increased ECT. Multilocus microsatellite typing showed that 51/60 (85%) of the FLZR isolates belonged to the same cluster, while the susceptible isolates each represented a distinct lineage. Finally, biofilm production in FLZR isolates was significantly lower than in susceptible counterparts Suggesting that it may not be an outbreak determinant. In summary, we show that TAC1L518F and FKS1E1393G confer FLZR and ECT, respectively, in CAC-associated C. parapsilosis. Our study underscores the importance of antifungal stewardship and effective infection control strategies to mitigate clonal C. parapsilosis outbreaks.

Consensus guidelines for the diagnosis and management of invasive aspergillosis, 2021.

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.

Impact of COVID-19 on the antifungal susceptibility profiles of isolates collected in a global surveillance program that monitors invasive fungal infections.

Studies demonstrated the impact of the COVID-19 pandemic in the prevalence and susceptibility profiles of bacterial and fungal organisms. We analyzed 4821 invasive fungal isolates collected during 2018, 2019, and 2020 in 48 hospitals worldwide to evaluate the impact of this event in the occurrence and susceptibility rates of common fungal species. Isolates were tested using the CLSI broth microdilution method. While the percentage of total isolates that were C. glabrata (n = 710 isolates) or C. krusei (n = 112) slightly increased in 2020, the percentage for C. parapsilosis (n = 542), A. fumigatus (n = 416), and C. lusitaniae (n = 84) significantly decreased (P < .05). Fluconazole resistance in C. glabrata decreased from 5.8% in 2018-2019 to 2.0% in 2020, mainly due to fewer hospitals in the US having these isolates (5 vs. 1 hospital). Conversely, higher fluconazole-resistance rates were noted for C. parapsilosis (13.9 vs. 9.8%) and C. tropicalis (3.5 vs. 0.7%; P < .05) during 2020. Voriconazole resistance also increased for these species. Echinocandin resistance was unchanged among Candida spp. Voriconazole susceptibility rates in A. fumigatus were similar in these two periods (91.7% in 2018 and 2019 vs. 93.0% in 2020). Changes were also noticed in the organisms with smaller numbers of collected isolates. We observed variations in the occurrence of organisms submitted to a global surveillance and the susceptibility patterns for some organism-antifungal combinations. As the COVID-19 pandemic is still ongoing, the impact of this event must continue to be monitored to guide treatment of patients affected by bacterial and fungal infections. LAY SUMMARY: Secondary infections were documented in COVID-19 patients. We compared the prevalence of invasive fungal isolates consecutively collected in 48 worldwide hospitals and their susceptibility patterns between 2020, the year of the global COVID-19 pandemic, and the two prior years.

A 67-Year-Old Male Patient With COVID-19 With Worsening Respiratory Function and Acute Kidney Failure.

CASE PRESENTATION: A 67-year-old obese man (BMI 38.0) with type 2 diabetes mellitus (DM), chronic atrial fibrillation, and chronic lymphocytic leukemia stage II, stable for 8 years after chemotherapy, and a history of smoking presented to the ED with progressive dyspnea and fever due to SARS-CoV-2 infection. He was admitted to a general ward and treated with dexamethasone (6 mg IV once daily) and oxygen. On day 3 of hospital admission, he became progressively hypoxemic and was admitted to the ICU for invasive mechanical ventilation. Dexamethasone treatment was continued, and a single dose of tocilizumab (800 mg) was administered. On day 9 of ICU admission, voriconazole treatment was initiated after tracheal white plaques at bronchoscopy, suggestive of invasive Aspergillus tracheobronchitis, were noticed. However, his medical situation dramatically deteriorated.

Axillary Digital Thermometers uplifted a multidrug-susceptible Candida auris outbreak among COVID-19 patients in Brazil.

OBJECTIVES: To describe the first outbreak of Candida auris in Brazil, including epidemiological, clinical and microbiological data. METHODS: After the first Candida auris-colonised patient was diagnosed in a COVID-19 ICU at a hospital in Salvador, Brazil, a multidisciplinary team conducted a local C. auris prevalence investigation. Screening cultures for C. auris were collected from patients, healthcare workers and inanimate surfaces. Risk factors for C. auris colonisation were evaluated, and the fungemia episodes that occurred after the investigation were also analysed and described. Antifungal susceptibility of the C. auris isolates was determined, and they were genotyped with microsatellite analysis. RESULTS: Among body swabs collected from 47 patients, eight (n = 8/47, 17%) samples from the axillae were positive for C. auris. Among samples collected from inanimate surfaces, digital thermometers had the highest rate of positive cultures (n = 8/47, 17%). Antifungal susceptibility testing showed MICs of 0.5 to 1 mg/L for AMB, 0.03 to 0.06 mg/L for voriconazole, 2 to 4 mg/L for fluconazole and 0.03 to 0.06 mg/L for anidulafungin. Microsatellite analysis revealed that all C. auris isolates belong to the South Asian clade (Clade I) and had different genotypes. In multivariate analysis, having a colonised digital thermometer was the only independent risk factor associated with C. auris colonisation. Three episodes of C. auris fungemia occurred after the investigation, with 30-day attributable mortality of 33.3%. CONCLUSIONS: Emergence of C. auris in Salvador, Brazil, may be related to local C. auris clade I closely related genotypes. Contaminated axillary monitoring thermometers may facilitate the dissemination of C. auris reinforcing the concept that these reusable devices should be carefully cleaned with an effective disinfectant or replaced by other temperature monitoring methods.

Invasive pulmonary aspergillosis in a COVID-19 recovered patient: unravelling an infective sequalae of the SARS-CoV-2 virus.

Dear Editor, A 55-year-female, house wife, non-smoker, morbidly obese (BMI>35) with no other co-morbidities or pre-existing lung disease presented to the emergency room with complaints of highgrade fever, cough with minimal sputum, progressive breathlessness, streaky haemoptysis, and anorexia for the past 5 days. She was admitted in intensive care unit (ICU) for severe COVID-19 pneumonia three months back and had successfully recovered after 24 days of hospitalization....

Post COVID-19 opportunistic candida retinitis: A case report.

A 42-year-old male patient presented with profound impairment of vision in both eyes, just as he was recovering from COVID-19. A known diabetic and hypertensive, he suffered from COVID-19 pneumonia further complicated by ARDS, septicaemia and acute kidney injury. His vision on presentation was finger counting close to face bilaterally with multiple, yellowish lesions at the posterior pole. Based on the clinical findings and previous blood culture report, it was diagnosed as candida retinitis and treated with oral and intravitreal anti-fungals. The lesions were regressing at follow-up. This is a post COVID-19 presumed candida retinitis case report.

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.

COVID-19-Associated Pulmonary Aspergillosis, March-August 2020.

Pneumonia caused by severe acute respiratory syndrome coronavirus 2 emerged in China at the end of 2019. Because of the severe immunomodulation and lymphocyte depletion caused by this virus and the subsequent administration of drugs directed at the immune system, we anticipated that patients might experience fungal superinfection. We collected data from 186 patients who had coronavirus disease-associated pulmonary aspergillosis (CAPA) worldwide during March-August 2020. Overall, 182 patients were admitted to the intensive care unit (ICU), including 180 with acute respiratory distress syndrome and 175 who received mechanical ventilation. CAPA was diagnosed a median of 10 days after coronavirus disease diagnosis. Aspergillus fumigatus was identified in 80.3% of patient cultures, 4 of which were azole-resistant. Most (52.7%) patients received voriconazole. In total, 52.2% of patients died; of the deaths, 33.0% were attributed to CAPA. We found that the cumulative incidence of CAPA in the ICU ranged from 1.0% to 39.1%.

Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.

Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.