The rising burden of invasive fungal infections in COVID-19, can structured CT thorax change the game

Background The occurrence of invasive fungal infections in COVID-19 patients is on surge in countries like India. Several reports related to rhino-nasal-sinus mucormycosis in COVID patients have been published in recent times; however, very less has been reported about invasive pulmonary fungal infections caused mainly by mucor, aspergillus or invasive candida species. We aimed to present 6 sputum culture proved cases of invasive pulmonary fungal infection (four mucormycosis and two invasive candidiasis) in COVID patients, the clues for the diagnosis of fungal invasion as well as difficulties in diagnosing it due to superimposed COVID imaging features. Case presentation The HRCT imaging features of the all 6 patients showed signs of fungal invasion in the form of cavities formation in the pre-existing reverse halo lesions or development of new irregular margined soft tissue attenuating growth within the pre-existing or in newly formed cavities. Five out of six patients were diabetics. Cavities in cases 1, 2, 3 and 4 of mucormycosis were aggressive and relatively larger and showed relatively faster progression into cavities in comparison with cases 5 and 6 of invasive candidiasis. Conclusion In poorly managed diabetics or with other immunosuppressed conditions, invasive fungal infection (mucormycosis, invasive aspergillosis and invasive candidiasis) should be considered in the differential diagnosis of cavitary lung lesions.

Cost-effectiveness Analysis of Caspofungin and Fluconazole for Primary Treatment of Invasive Candidiasis and Candidemia in Ethiopia

Background: Caspofungin was shown to be more effective than fluconazole in treating patients with invasive candidiasis and/or candidaemia (IC/C). However, cost-effectiveness of caspofungin for treating IC/C in Ethiopia remains unknown. We aimed to assess the cost-effectiveness of caspofungin compared to fluconazole as primary treatment of IC/C in Ethiopia.Methods: A Markov cohort model was developed to compare the cost-utility of caspofungin versus fluconazole antifungal agents as first-line treatment for adult inpatients with IC/C from the Ethiopian health system perspective. Treatment outcome was categorized as either a clinical success or failure, with clinical failure being switched to a different antifungal medication. Liposomal amphotericin B (L-AmB) was used as a rescue agent for patients who had failed caspofungin treatment, while caspofungin or L-AmB were used for patients who had failed fluconazole treatment. Primary outcomes were expected quality-adjusted life years (QALYs), costs (US$2021), and the incremental cost-effectiveness ratio (ICER). QALYs and costs were discounted at 3% annually. Cost data was obtained from Addis Ababa hospitals while locally unavailable data were derived from the literature. Cost-effectiveness was assessed against the recommended threshold of 50% of Ethiopia’s gross domestic product/capita. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the findings.Results: In the base-case analysis, treatment of IC/C with caspofungin as first-line treatment resulted in better health outcomes (12.86 QALYs) but higher costs (US$7,714) compared to fluconazole-initiated treatment followed by caspofungin (12.30 QALYs; US$3,217) or L-AmB (10.92 QALYs; US$2,781) as second-line treatment. Caspofungin as primary treatment for IC/C was not cost-effective when compared to fluconazole-initiated therapies. Fluconazole-initiated treatment followed by caspofungin was cost-effective for the treatment of IC/C compared to fluconazole with L-AmB as second-line treatment, at US$316/QALY gained. Our findings were sensitive to medication costs, drug effectiveness, infection recurrence, and infection-related mortality rates. Probabilistic sensitivity analysis confirmed the stability of our findings.Conclusions: Our study showed that the use of caspofungin as primary treatment for IC/C in Ethiopia was not cost-effective when compared with fluconazole-initiated treatment alternatives. The findings supported the use of fluconazole-initiated therapy with caspofungin as a second-line treatment to treat IC/C in Ethiopia and other low-income countries.

Invasive Candidiasis in Hospitalized Patients with Major Burns

Background: Invasive candidiasis (IC) is a major cause of morbidities and mortality in patients hospitalized with major burns. This study investigated the incidence of IC in this specific population and analyzed the possible risk factors. Materials and Methods: We retrospectively analyzed data from the National Health Insurance Research Database (NHIRD) of Taiwan. We identified 3582 patients hospitalized with major burns on over 20% of their total body surface area (TBSA) during 2000–2013; we further analyzed possible risk factors. Result: IC was diagnosed in 452 hospitalized patients (12.6%) with major burns. In the multivariate analysis, patients older than 50 years (adjusted odds ratio (OR) = 1.96, 95% confidence interval (CI) 1.36–2.82), those of female sex (adjusted OR = 1.33, 95% CI 1.03–1.72), those with burns on the head (adjusted OR = 1.33, 95% CI 1.02–1.73), and those with burns over a greater TBSA had higher risks of IC. Conclusion: Treating IC is crucial in healthcare for major burns. Our study suggests that several risk factors are associated with IC in patients hospitalized with major burns, providing reliable reference value for clinical decisions.

STANDARDS OF MEDICAL CARE “INVASIVE CANDIDIASIS IN NEWBORNS”

Candida infection (candidiasis) is an important clinical problem in newborns who need treatment in modern intensive care units. Organ and/or systemic infections caused by these fungi are called invasive candidiasis (IC). Newborns are especially vulnerable to IC, and their incidence is 3-5 times higher than the corresponding rates in children or adults. Invasive fungal infections caused by Candida are the third most common late-onset infection in infants born with a birth weight <1500 g. IC in newborns is associated with approximately 20% mortality, and about half of survivors have serious long- term neurological damage. In recent years, new data have been obtained on the diagnosis, prevention and treatment of IC in newborns, which has determined a change in treatment recommendations. Accordingly, the need arose to ensure the compliance of our clinical practice with modern evidence-based approaches. Early diagnosis of candidiasis and prompt treatment with effective antifungal agents such as fluconazole, amphotericin B, and micafungin, when indicated, are critical to improving outcomes.

Drug Resistance and Novel Therapeutic Approaches in Invasive Candidiasis

Candida species are the leading cause of invasive fungal infections worldwide and are associated with acute mortality rates of ~50%. Mortality rates are further augmented in the context of host immunosuppression and infection with drug-resistant Candida species. In this review, we outline antifungal drugs already in clinical use for invasive candidiasis and candidaemia, their targets and mechanisms of resistance in clinically relevant Candida species, encompassing not only classical resistance, but also heteroresistance and tolerance. We describe novel antifungal agents and targets in pre-clinical and clinical development, including their spectrum of activity, antifungal target, clinical trial data and potential in treatment of drug-resistant Candida. Lastly, we discuss the use of combination therapy between conventional and repurposed agents as a potential strategy to combat the threat of emerging resistance in Candida.

Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy

We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40–140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5–1.0 μg/mL and 1.0–2.0 μg/mL for 200 mg/day and 1.0–2.0 μg/mL and 2.0–4.0 μg/mL for 400 mg/day, respectively. The recommended dose was 400–700 mg/day for the loading dose and 200–400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.