Failure of artemether-lumefantrine therapy in travellers returning to Belgium with Plasmodium falciparum malaria: an observational case series with genomic analysis.

BACKGROUND: Failure of artemisinin-based combination therapy is increasingly reported in patients with Plasmodium falciparum malaria in sub-Saharan Africa. We aimed to describe the clinical and genomic characteristics of recent cases of P. falciparum malaria failing artemether-lumefantrine in Belgium. METHODS: Travel-related cases of malaria confirmed at the national reference laboratory of the Institute of Tropical Medicine, Antwerp, Belgium, were reviewed. All cases for which attending clinicians reported persistence (beyond Day 3 post-treatment initiation, i.e. early failure) or recrudescence (from Day 7 to 42, i.e. late failure) of P. falciparum parasites despite adequate drug intake were analysed. Both initial and persistent/recurrent samples were submitted to next generation sequencing to investigate resistance-conferring mutations. RESULTS: From July 2022 to June 2023, eight P. falciparum cases of failure with artemether-lumefantrine therapy were reported (early failure = 1; late failure = 7). All travellers were returning from sub-Saharan Africa, most (6/8) after a trip to visit friends and relatives. PfKelch13 (PF3D7_1343700) mutations associated with resistance to artemisinin were found in two travellers returning from East Africa, including the validated marker R561H in the patient with early failure and the candidate marker A675V in a patient with late failure. Additional mutations were detected that could contribute to decreased susceptibility to artemisinin in another three cases, lumefantrine in six cases and proguanil in all eight participants. Various regimens were used to treat the persistent/recrudescent cases, with favourable outcome. CONCLUSION: Within a 12-month period, we investigated eight travellers returning from sub-Saharan Africa with P. falciparum malaria and in whom artemether-lumefantrine failure was documented. Mutations conferring resistance to antimalarials were found in all analysed blood samples, especially against lumefantrine and proguanil, but also artemisinin. There is a pressing need for systematic genomic surveillance of resistance to antimalarials in international travellers with P. falciparum malaria, especially those experiencing treatment failure.

Using risk factors and markers to predict bacterial respiratory co-/superinfections in COVID-19 patients: is the antibiotic steward's toolbox full or empty?

BACKGROUND: Adequate diagnosis of bacterial respiratory tract co-/superinfection (bRTI) in coronavirus disease (COVID-19) patients is challenging, as there is insufficient knowledge about the role of risk factors and (para)clinical parameters in the identification of bacterial co-/superinfection in the COVID-19 setting. Empirical antibiotic therapy is mainly based on COVID-19 severity and expert opinion, rather than on scientific evidence generated since the start of the pandemic. PURPOSE: We report the best available evidence regarding the predictive value of risk factors and (para)clinical markers in the diagnosis of bRTI in COVID-19 patients. METHODS: A multidisciplinary team identified different potential risk factors and (para)clinical predictors of bRTI in COVID-19 and formulated one or two research questions per topic. After a thorough literature search, research gaps were identified, and suggestions concerning further research were formulated. The quality of this narrative review was ensured by following the Scale for the Assessment of Narrative Review Articles. RESULTS: Taking into account the scarcity of scientific evidence for markers and risk factors of bRTI in COVID-19 patients, to date, COVID-19 severity is the only parameter which can be associated with higher risk of developing bRTI. CONCLUSIONS: Evidence on the usefulness of risk factors and (para)clinical factors as predictors of bRTI in COVID-19 patients is scarce. Robust studies are needed to optimise antibiotic prescribing and stewardship activities in the context of COVID-19.

Presumed Urinary Tract Infection in Patients Admitted with COVID-19: Are We Treating Too Much?

Despite the low rates of bacterial co-/superinfections in COVID-19 patients, antimicrobial drug use has been liberal since the start of the COVID-19 pandemic. Due to the low specificity of markers of bacterial co-/superinfection in the COVID-19 setting, overdiagnosis and antimicrobial overprescription have become widespread. A quantitative and qualitative evaluation of urinary tract infection (UTI) diagnoses and antimicrobial drug prescriptions for UTI diagnoses was performed in patients admitted to the COVID-19 ward of a university hospital between 17 March and 2 November 2020. A team of infectious disease specialists performed an appropriateness evaluation for every diagnosis of UTI and every antimicrobial drug prescription covering a UTI. A driver analysis was performed to identify factors increasing the odds of UTI (over)diagnosis. A total of 622 patients were included. UTI was present in 13% of included admissions, and in 12%, antimicrobials were initiated for a UTI diagnosis (0.71 daily defined doses (DDDs)/admission; 22% were scored as 'appropriate'). An evaluation of UTI diagnoses by ID specialists revealed that of the 79 UTI diagnoses, 61% were classified as probable overdiagnosis related to the COVID-19 hospitalization. The following factors were associated with UTI overdiagnosis: physicians who are unfamiliar working in an internal medicine ward, urinary incontinence, mechanical ventilation and female sex. Antimicrobial stewardship teams should focus on diagnostic stewardship of UTIs, as UTI overdiagnosis seems to be highly prevalent in admitted COVID-19 patients.

Normocalcemic Primary Hyperparathyroidism: A Comparison with the Hypercalcemic Form in a Tertiary Referral Population.

Normocalcemic primary hyperparathyroidism (NPHPT) is a formally recognized variant of primary hyperparathyroidism (PHPT), characterized by normal total and ionized serum calcium concentrations and elevated parathyroid hormone (PTH) levels, in the absence of secondary causes for hyperparathyroidism. NPHPT has been studied previously, but data are limited and confounded. We aimed to compare the clinical and biochemical data of normocalcemic and hypercalcemic subjects in a hospital-based population.We retrospectively analysed the medical records of 131 subjects diagnosed with PHPT at the university hospital Brussels (UZ Brussel) between January 1st 2007 and December 31st 2016, including 25 normocalcemic and 106 hypercalcemic subjects.The mean values of age, BMI, sex, serum 25-OH vitamin D levels and urinary phosphate excretion were comparable between both groups. Subjects diagnosed with NPHPT had significantly lower plasma PTH levels, lower urinary calcium excretion and lower serum creatinine levels compared to the hypercalcemic subjects with PHPT. Corresponding eGFR values were higher in the normocalcemic group. Normocalcemic subjects (NPHPT) presented with a high prevalence of nephrolithiasis (36%), fragility fractures (12%) and osteoporosis (25%). Clinical manifestations and BMD measurements revealed no statistically significant differences between both groups.Our data show a relative prevalence of 19% NPHPT in PHPT. NPHPT may present the earliest form of PHPT with an extension in time, but is not an indolent disease state. Normocalcemic subjects should be managed as hypercalcemic subjects with PHPT. Further research regarding the pathophysiology and natural course of NPHPT is required.