Radboud University Nijmegen Medical Centre

Patients with advanced dementia and suspected pneumonia are at high risk of death. Antibiotics are commonly prescribed for these patients; however, there is little evidence that treatment meaningfully prolongs life, improves quality of life, or promotes comfort. At the same time, treatment with antibiotics in this population has potential side effects, contributes to antibiotic overuse, and may be burdensome for these frail patients who are near the end of life. This Tomorrow’s Trial reviews the existing evidence, and the article proposes a trial to address the question, “Do Antibiotics Improve Survival, Quality of Life, and Comfort in Patients with Advanced Dementia and Pneumonia?”

Candida tropicalis frequently causes invasive infections in immunocompromised hosts. Mortality rates are high compared to other yeasts, while antifungal resistance varies between countries. To date, multicenter studies regarding C. tropicalis infections in Türkiye are limited. The current study therefore characterized C. tropicalis infections in Türkiye. In this retrospective study, 120 invasive C. tropicalis isolates were collected from four hospitals in Türkiye, mostly from blood. In vitro antifungal susceptibility testing (AFST) was performed for eight common antifungals, and short tandem repeat (STR) genotyping was applied to investigate genetic relatedness within the current population and previously genotyped isolates. Patients with invasive C. tropicalis candidiasis were mostly elderly, with a central venous line (CVL) and cancer or diabetes as underlying disease, and an overall mortality rate of 37%. Except for a single isolate from blood being resistant to fluconazole and voriconazole, no resistance to common antifungals was found. Finally, nosocomial transmission within hospitals was limited as nearly all isolates displayed unique genotypes. When compared to 605 previously investigated isolates from 12 diverse countries, only few clusters were present, indicating an overall high genetic diversity for C. tropicalis. While isolates from the current study did not form a single monophyletic branch, there were 27 isolates that formed a distinct pan-susceptible clade together with isolates of other Middle Eastern countries. To conclude, we described a retrospective multicenter study on invasive C. tropicalis infections in Türkiye characterized by a high mortality rate for untreated patients, while isolates showed little antifungal resistance and high genetic diversity.

This study documents the first reported cases of Candida (Candidozyma)auris in the Dominican Republic, isolated from both a critically ill human patient and a captive dolphin. Antifungal susceptibility testing from dolphin isolate showed elevated minimum inhibitory concentrations (MIC) of fluconazole but low MICs of other antifungals, including the novel drugs rezafungin, ibrexafungerp and manogepix. Whole genome sequencing (WGS) of the dolphin isolate allocated it to clade I, but surprisingly did not show any known mutations that confer azole resistance, suggesting a mechanism different from mutations in the genes studied. The concurrent emergence of C. auris in human and animal hosts underscores the importance of a One Health approach, emphasizing the interconnectedness of human, animal, and environmental health, and the need for strengthened surveillance and rigorous infection control measures across medical and veterinary settings.

In high tuberculosis (TB)-burden countries, considerable transmission of Mycobacterium tuberculosis (M. tb) likely occurs outside of households. We aimed to estimate the TB prevalence and incidence in households and neighbourhoods around known TB cases and to understand transmission patterns. Household and neighbourhood contacts of pulmonary TB index cases from contiguous areas in Bandung, Indonesia, were screened and followed up for 12 months. Sputum samples underwent smear microscopy, M. tb culture, Xpert MTB/RIF, DNA isolation and whole-genome sequencing (WGS). Pairwise single-nucleotide polymorphism (SNP) distance ≤12 defined transmission for pairs with known epidemiological links, or SNP≤3 for pairs without epidemiological link. An SNP=12 cut-off was used to characterise transmission clusters. From 213 index cases, 514 household and 4141 neighbourhood contacts underwent TB screening: 19 household (3.70%, 95% CI 2.24 to 5.71) and 45 neighbourhood (1.09%, 95% CI 0.79 to 1.45) contacts were identified with TB, of whom 18 (3.50%, 95% CI 2.20 to 5.48) and 38 (0.92%, 95% CI 0.65 to 1.13) respectively, were bacteriologically confirmed. During follow-up, 11 household and 13 neighbourhood contacts were identified with TB (incidence per 100 000 person-years: 2286 (95% CI 1286 to 4148) and 350 (95% CI 190 to 563)), of whom 6 and 8, respectively, were bacteriologically confirmed (incidence per 100 000 person-years: 1247 (95% CI 560 to 2776) and 201 (95% CI 101 to 402)). A total of 223 patient M. tb isolates underwent WGS. Of 15 intra-household pairs, 8 (53.3%) were transmission pairs. Of 24 neighbour to index case pairs, 1 (4.2%) was a transmission pair. 11 of 19 transmission pairs shared no epidemiological link. We identified 25 M. tb genetic clusters from 205 mono-TB isolates overall. Neighbours have lower prevalence and incidence of TB than household contacts, but twice as many cases. Very few received M. tb from their index case, suggesting uncontrolled community-wide transmission. Whole population active case finding may be necessary in high TB-burden settings.

ObjectivesThere are substantial barriers to initiate advance care planning (ACP) for persons with chronic-progressive disease in primary care settings. Some challenges may be disease-specific, such as communicating in case of cognitive impairment. This study assessed and compared the initiation of ACP in primary care with persons with dementia, Parkinson’s disease, cancer, organ failure and stroke.DesignLongitudinal study linking data from a database of Dutch general practices’ electronic health records with national administrative databases managed by Statistics Netherlands.Setting and participantsData from general practice records of 199 034 community-dwelling persons with chronic-progressive disease diagnosed between 2008 and 2016.Outcome measureIncidence rate ratio (IRR) of recorded ACP planning conversations per 1000 person-years in persons with a diagnosis of dementia, Parkinson’s disease, organ failure, cancer or stroke, compared with persons without the particular diagnosis. Poisson regression and competing risk analysis were performed, adjusted for age, gender, migration background, living situation, frailty index and income, also for disease subsamples.ResultsIn adjusted analyses, the rate of first ACP conversation for persons with organ failure was the lowest (IRR 0.70 (95% CI 0.68 to 0.73)). Persons with cancer had the highest rate (IRR 1.75 (95% CI 1.68 to 1.83)). Within the subsample of persons with organ failure, the subsample of persons with dementia and the subsample of stroke, a comorbid diagnosis of cancer increased the probability of ACP. Further, for those with organ failure or cancer, comorbid dementia decreased the probability of ACP.ConclusionsConsidering the complexity of initiating ACP for persons with organ failure or dementia, general practitioners should prioritise offering it to them and their family caregivers. Policy initiatives should stimulate the implementation of ACP for people with chronic-progressive disease.

ObjectivesAdvance care planning (ACP) is important but complex with people living with dementia. This study aims to explore ethical considerations of physicians around ACP for dementia in two high-income countries (the United States and the Netherlands).MethodsIn this qualitative study, semistructured interviews were conducted with Dutch and American physicians from specialties that provide end-of-life care for people with living dementia. Their considerations regarding ACP for people living with dementia were solicited after short animation video vignettes on two approaches to ACP, one focused on concrete treatment orders, and the other on setting global care goals. Interview transcripts were analyzed using thematic analysis with elements of reflexive thematic analysis to identify ethical considerations.ResultsInterviews with 50 Dutch physicians and 47 American physicians and 3 nurse practitioners generated three themes of ethical considerations: (1) Respecting the autonomy of the person with dementia, (2) Rationality as the basis for decisions and subsequent actions, and (3) Minimizing burden and suffering.DiscussionThe complexity of ACP for people living with dementia is reflected in the challenges within each ethical consideration and the tensions between them, especially between autonomy and rationality. We recommend an approach to ACP that balances the ethical considerations, focusing on the values of the people living with dementia and allowing flexibility in future decision-making to take the current best interest of the person into account.

Surgical esophageal atresia (EA) repair is a complex operation with high risk of perioperative complications. Infants born with very low or extreme low birth weight (VLBW or ELBW) might be even at higher risk for developing perioperative complications. However, studies about this specific patient group are scarce, resulting in a knowledge gap on the outcomes of these infants. This hampers identifying the optimal treatment strategy, but also good counselling of parents. The aim of this study was to evaluate the mortality and surgery-related complication rates of VLBW and ELBW infants with EA after surgical esophageal repair in a multi-center cohort. A multi-center retrospective cohort study was performed in five academic hospitals in the Netherlands. Data was extracted from the medical record of patients born with EA and birthweight 1000-1500 g (VLBW) or <1000 g (ELBW) between 2000 and 2019. The main outcomes were overall mortality and specific surgery-related morbidity 90 days postoperative. Only descriptive analyses were performed. In total, 44 children were born with EA and VLBW/ELBW, of which 39 were included who underwent EA repair, 10 ELBW and 29 VLBW. Of the 39 infants, 25 had additional congenital anomalies. Six out of 29 VLBW infants and three out of 10 ELBW infants deceased. Complications occurred in 17 VLBW and two ELBW infants. Anastomotic stricture was the most frequent complications (VLBW n = 12, ELBW n = 1), others were anastomotic leakage (VLBW n = 5, ELBW n = 0), pneumothorax (VLBW n = 5, ELBW n = 0), surgical site infection (VLBW n = 1, ELBW n = 1) and recurrent fistula (VLBW n = 0, ELBW n = 1). Mortality and surgery-related complication rates in VLBW/ELBW infants after surgical EA repair in this large cohort are in line with previous studies. However, outcomes after surgical repair of EA are worse compared to infants born with a normal birthweight. This information is important to consider during parent counseling and multidisciplinary consultation.

Triazole resistance in Aspergillus spp. has therapeutic implications for managing chronic pulmonary aspergillosis (CPA) worldwide. However, antifungal susceptibility testing (AFST) is not routinely performed in Nigeria, a country with a high CPA burden. This study aimed to confirm the identity of Aspergillus spp. isolated from patients with CPA using molecular methods, determine their antifungal susceptibility profile, and ascertain phylogenetic relatedness. This study examined 47 Aspergillus isolates from sputum samples obtained in a prospective longitudinal study of CPA prevalence among 141 consenting symptomatic tuberculosis patients in Lagos, Nigeria, between June 2021 and May 2022. The preliminary phenotypically identified Aspergillus spp. were further identified by amplifying the calmodulin gene and performing AFST against seven antifungal agents using the Clinical Laboratory Standard Institute (CLSI) micro-dilution method, as well as determining their phylogenetic relatedness. The 51 patients who met the diagnostic criteria for CPA included 30 (59.0%) male and 21 (41.0%) female patients (age range: 17-68 years). Thirty-six (71.0%) had positive Aspergillus cultures. An isolate, initially identified phenotypically as A. fumigatus, was reidentified as A. pseudonomiae. Phylogenetic analysis on A. fumigatus and A. flavus isolates suggested the absence of clonal transmission. All isolates were susceptible to the tested antifungals. Clinical Aspergillus isolates from azole-naïve patients with CPA did not demonstrate triazole resistance. Nonetheless, AFST is required for patients on long-term azole therapy and systematic surveillance of clinical and environmental isolates is recommended to detect the emergence of azole-resistant phenotypes. This study underscores the importance of routine surveillance for antifungal resistance to detect the occurrence of resistance strains early in clinical settings, as this has therapeutic implications for patients harbouring resistant phenotypes.

Invasive fungal infections (IFI) are a major clinical challenge, particularly in immunocompromised patients, and are associated with high morbidity and mortality. With the increasing prevalence of immunosuppressive conditions and ageing populations, the incidence of IFI is rising globally. This survey aims to evaluate the diagnostic and therapeutic capacities for IFI in Belgium, the Netherlands, and Luxembourg (Benelux), a region of high azole-resistance among Aspergillus fumigatus isolates. A survey evaluating the diagnostic and therapeutic capacity for IFI was conducted in the Benelux. Data were collected from specialists via an online case report form between March and September 2023. The survey addressed patient characteristics, access to microbiology labs, diagnostic methods (microscopy, culture, molecular diagnostics, etc.), IFI incidence, and the availability of antifungal drugs and therapeutic drug monitoring. In total, 32 hospitals responded to the questionnaire (12 [38%] from the Netherlands, 19 [59%] from Belgium and one [3%] from Luxembourg). Antifungal susceptibility tests were available in 29 institutions (91%), constituting 84% of the centres in Belgium and 100% for the Netherlands (p = 0.265). Aspergillus PCR testing was available in 12 centres in Belgium (63%) while in 11 centres in the Netherlands (92%, p = 0.108). Mucorales PCR testing was available in 56% of centres. Treatment with at least one amphotericin B formulation was only available in 84% of the responding centres. Therapeutic drug monitoring (TDM), although recommended, was possible for voriconazole in 26 centres (81%) while for posaconazole in 24 centres (75%). Significantly more testing (diagnostic tests and TDM) was outsourced in Belgium compared to the Netherlands (p < 0.001). Antifungal susceptibility testing is widely available in Belgium and the Netherlands, but implementation in areas with high azole resistance for Aspergillus fumigatus is not yet universal, and techniques vary. Tests for coinfections, like Mucorales PCR, were only available in half of the centres. More testing is outsourced in Belgium, likely due to differences in reference centre organisation, country size, transport, and reimbursement. Delays in diagnosis can impact patient outcomes, so awareness of test availability and transport times is crucial.

Candida (Candidozyma) auris has distinct genetic clades. Clade distinction is relevant for infection control and epidemiological purposes. State-of-the-art typing methodologies for clade distinction are based on genomic approaches, such as short tandem repeat (STR) analysis and whole-genome sequencing (WGS). However, they are time-consuming and expensive. Fourier transform infrared spectroscopy (FT-IR) is an alternative tool for strain typing based on their unique biochemical spectral profiles. To apply FT-IR to differentiate C. auris clades and evaluate epidemiological relationships based on biochemical data among isolates from a multicenter C. auris outbreak in the state of Pernambuco, northeastern Brazil. Sixty-nine C. auris strains from clades I, II, III, and IV were analysed. Fifty-nine were clade IV strains obtained from three outbreaks that took place in Pernambuco state, northeastern Brazil. An adjusted FT-IR spectroscopy protocol was applied to obtain carbohydrates and lipid fingerprints. Short Tandem Repeat (STR) analysis was used in order to validate the spectroscopy approach. The adjusted preparation protocol for FT-IR analysis improved the spectral quality by 31.42% compared to standard protocol. FT-IR allowed us to discriminate C. auris clades I to IV. Moreover, important similarities were observed in C. auris clade IV strains obtained from two of the three hospitals, based on polysaccharides (1300-800 cm-1) plus lipids (3000-2800 cm-1 and 1500-1400 cm-1) spectra. STR confirmed the similarity results obtained by FT-IR, clustering the strains from two different hospitals. The IR Biotyper is fast, easy-to-use, and a promising alternative for moderate-to-high-complexity laboratories to differentiate C. auris clades. Furthermore, this technique has the potential for isolate-level source tracking, which could be valuable for monitoring transmission routes in clinical settings.