Jean-Pierre Gangneux

Background: Surveillance for serious fungal diseases (SFDs) relies on the capacity to recognize them and request and accurately perform diagnostic investigations. However, knowledge in resource-limited settings is suboptimal. This study evaluated the impact of a training intervention on the diagnosis and management of SFDs among clinicians and laboratory scientists in Nigerian tertiary hospitals. Methods: Clinicians in 6 hospitals were purposively selected and trained in 6 SFDs using standardized modules developed by international medical mycology experts. A quasi-experimental design assessed performance using a pretest and posttest. Designated laboratory scientists received hands-on training with pretraining and posttraining assessments. Paired t tests were used to assess differences in mean scores. An impact assessment of the laboratory mycology records was performed 1 year after intervention using analysis of variance. Results: A total of 149 clinicians and 8 laboratory scientists participated. Mean performance scores of participants improved significantly after training, with the following percentage increases: invasive aspergillosis (25.4%), chronic pulmonary aspergillosis (13.0%), invasive candidiasis (23.8%), Pneumocystis pneumonia (22.6%), mucormycosis (29.5%), and histoplasmosis (20.6%) (all P < .001). There was also a significant improvement in the laboratory scientists’ posttraining performance (59.1%; P < .001). The laboratory mycology records reviewed 1 year later indicated a significant increase in the number of samples sent to the laboratory for mycological testing (P < .001) and the number and distribution of fungal isolates identified (P < .001). Conclusions: Training significantly improved SFD diagnosis and enhanced surveillance and patient care. Expanding this model across other low-resource settings is recommended.

Background: Treating Candida spp. urinary tract infections (UTIs) are challenging when isolates have reduced susceptibility to fluconazole. Voriconazole may be a therapeutic alternative despite its low urinary excretion as an unchanged compound. Objectives: To quantify voriconazole and its main metabolite, voriconazole N-oxide, in urine and plasma, determine minimum inhibitory concentrations (MICs) of voriconazole and voriconazole N-oxide, and assess the antifungal activity of urine from voriconazole-treated patients. Methods: Sixty patients receiving oral voriconazole were prospectively included. Voriconazole and voriconazole N-oxide concentrations in urine (12-h urine volume) and plasma were measured by liquid chromatography-tandem mass spectrometry. MICs were determined by broth microdilution according to EUCAST guidelines. Urinary antifungal activity was assessed using a disk diffusion bioassay, including against N. glabratus. A pharmacokinetic/pharmacodynamic target concentration/MIC >1 in urine was defined. Results: Median voriconazole urinary concentration was 1.9 mg/L [1.1–3.1], similar to plasma trough concentration (2.2 mg/L) and positively correlated (R2 = 0.82). Voriconazole N-oxide urinary concentrations (median 20.4 mg/L) were substantially higher than plasma trough concentrations (median 2.1 mg/L). Voriconazole MICs ranged from 0.155 to 0.75 mg/L, while voriconazole N-oxide MICs were 32–48 mg/L for reduced susceptibility to fluconazole isolates. Urine with voriconazole concentrations above 3 mg/L was more likely to inhibit N. glabratus. The median urinary voriconazole concentration/MIC ratio of 4.75 supports potential clinical efficacy. Conclusions: Voriconazole can achieve therapeutically relevant urinary concentrations for treating UTIs with reduced susceptibility to fluconazole. Therapeutic drug monitoring may facilitate individualized dosing and optimize treatment outcomes.

Candidemia displays significant clinical heterogeneity in critically ill patients. This study aimed to identify distinct clinical phenotypes and to assess

The seroprevalence of toxoplasmosis is well-described in French pregnant women, but no data are available in the general population. This study investigated 1,995 blood donors (sex ratio = 1), aged 18 to > 70 years (mean 44.8). The seroprevalence was 50.9% and increased with age, reaching almost 90% in blood donors > 70. Men exhibited a higher seroprevalence than women in age group 30–39 (41.1% vs 27.6%, p = 0.033). Multivariate analysis confirmed that men were more likely to be infected than women (OR = 1.234, p = 0.036). The highest prevalences for Toxoplasma were observed in the Northern and South-Western regions of France (55.2 to 60.5%). The lowest prevalence was observed in the East (41.4%), and was significantly higher in men < 40 years compared to women. These data are consistent with prevalence studies conducted in French pregnant women, but shows for the first time that females are less frequently infected than males, particularly in some regions, which could motivate further epidemiological investigations.

ECMM-Candida III was a pan-European, multicentre observational study of adult patients with blood culture-proven candidemia. Among a total of 632 patients with candidemia across 64 institutions in 20 European countries, a sub-analysis of 396 (63%) cases occurring outside the intensive care unit (ICU) was conducted. Compared with ICU-patients, non-ICU patients had a higher comorbidity burden (median Charlson Comorbidity Index [CCI] 6 vs. 5 in ICU patients, p=0.006). Hematologic and oncologic malignancies were more frequent among non-ICU cases (45.5%, vs 28.4%, pCandida scores were associated with lower mortality risk in the multivariable Cox regression models. In conclusion, despite higher co-morbidity rates, non-ICU patients with candidemia had higher survival rates.

Penicillium, Talaromyces, and Purpureocillium species (so called Penicillium-like) are increasingly recognised as opportunistic fungal pathogens capable of causing a wide range of infections, from superficial to invasive. Although ocular infections caused by these environmental fungi have been reported in the literature, they remain relatively underrecognised. We conducted a multicentric retrospective study of Penicillium-like ocular cases reported in the RESeau de Surveillance des Infections Fongique (RESSIF) database of the French National Reference Center for Invasive Mycoses and Antifungals between 2012 and 2021. Among 55 cases of Penicillium-like invasive infections reported to the RESSIF network in France, a total of 24 cases (44%) were identified, which predominantly presented as keratitis (n = 22, 92%). Predisposing factors were as follows: contact lens wear (n = 11, 46%), topical corticosteroid use (n = 9, 37.5%), ocular trauma (n = 5, 21%), pre-existing corneal disease (n = 4, 17%), and previous ocular surgery (n = 2, 8%). Purpureocillium lilacinum was the predominant pathogen (n = 19, 79%), followed by four Penicillium species and one Talaromyces species. Direct examination of ocular samples was positive in 13 cases (54%). Antifungal susceptibility testing (European Committee on Antimicrobial Susceptibility Testing) revealed that all species exhibited high minimal inhibitory concentrations to amphotericin B (> 1 mg/l). Most patients were treated with a combination of topical voriconazole and amphotericin B (n = 15, 62.5%), which was administered alongside oral voriconazole in nine cases (37.5%). Surgical intervention was required in six cases (25%) and included keratoplasty (n = 4) and enucleation (n = 2). This study provides a valuable overview of Penicillium-like fungal ocular infections and highlights the importance of systematically surveilling filamentous fungal keratitis.

Background: Invasive aspergillosis (IA) is a leading cause of mortality despite antifungal therapy. Current biomarkers for treatment monitoring and outcome prediction are limited, with host biomarkers showing potential in other fungal diseases but not in IA yet. Methods: In this ECMM multicenter study, we prospectively evaluated a cohort of 51 patients with probable or proven IA with underlying hematological malignancies. Serial serum samples, collected over a 3-week period, were analyzed using the Olink Target 96 Inflammation panel. Differential expression analyses and survival analysis for outcome prediction were performed. Results: Early after treatment, all differentially expressed proteins were upregulated in patients showing clinical improvement compared with those with worsening disease, with the exception of CCL23. Multiple proteins significantly correlated with the need to switch from primary to salvage antifungal therapy. For late treatment response, matrix metalloproteinase-10 (MMP-10) emerged as predictor, with consistently lower expression during clinical improvement during Weeks 2 and 3. Moreover, low-serum concentrations of CXCL6 at Week 2 and MMP-10 at Week 3 were associated with higher survival probability. Conclusions: The dynamics of immune markers across disease states may help predicting responses to antifungal treatment. Future studies should establish their usefulness in clinical practice.

Background: The increasing incidence of resistant invasive mold infections (IMIs) has highlighted the need for novel antifungal agents. Olorofim, a first-in-class orotomide, has shown promising efficacy in a recent phase II study, but clinical data remain limited. Methods: We conducted a retrospective multicenter cohort study in France, including all patients who received olorofim under compassionate use for proven or probable non-Mucorales IMIs. Eligible patients had IMIs refractory to or intolerance to standard antifungals or no effective treatment options. Efficacy was defined as mycological and clinical control of infection; safety was also assessed. Results: Between January 2020 and December 2023, 17 patients (median age, 39 years) received olorofim. Underlying conditions included primary immunodeficiency (n = 4) and lung transplantation (n = 5). Sites of infection included the lung (88.2%) and the central nervous system (23.5%), with 5 cases of disseminated disease. In total, 23 strains were identified, mostly Aspergillus fumigatus (34.8%) and Microascus spp (13%). The median duration of prior antifungal therapy was 9.1 months. Olorofim was used primarily for refractory IMIs (70.6%) and in combination with other antifungals in 82.4% of cases. Olorofim minimum inhibitory concentrations were ≤0.5 mg/L in the 8 available isolates. Among 15 evaluable patients, 5 (33.3%) achieved clinical and mycological success, 7 (46.7%) had partial responses, and 3 (20%) experienced treatment failure. The 3-month mortality rate was 29.4% (5 of 17). No severe adverse events were reported. Conclusions: Olorofim exhibited potential efficacy and good tolerability in patients with refractory IMIs. Further data from ongoing clinical trials are needed to confirm these findings.