Pub Date : 2026-02-01DOI: 10.1016/j.lanmic.2025.101236
Marjorie J Gibbon PhD , Natacha Couto PhD , Keira Cozens MSc , Samia Habib PhD , Lauren Cowley PhD , Prof David M Aanensen PhD , Prof Jukka Corander PhD , Harry A Thorpe PhD , Marit A K Hetland MSc , Davide Sassera PhD , Cristina Merla PhD , Marta Corbella MSc , Carolina Ferrari MSc , Prof Katy M E Turner PhD , Kwanrawee Sirikanchana PhD , Punyawee Dulyayangkul PhD , Nisanart Charoenlap PhD , Prof Visanu Thamlikitkul MD , Prof Matthew B Avison PhD , Prof Edward J Feil PhD
<div><h3>Background</h3><div><em>Klebsiella pneumoniae</em> is an important pathogen of humans and animals. In the past five years, increasing reports of convergent strains that carry both virulence factors and antimicrobial resistance genes (ARGs) have raised serious public health concerns. The aim of this study is to describe the global diversity of plasmids carrying <em>iuc3</em> (a key virulence factor in <em>K pneumoniae</em> associated with pigs and clinical isolates) from diverse settings, and their role in the emergence of convergent strains through hybridisation with plasmids carrying ARGs.</div></div><div><h3>Methods</h3><div>This population genomic analysis study was designed to describe both the global and local diversity of <em>iuc3</em>-carrying plasmids from diverse sources, and the co-occurrence of <em>iuc3</em> with ARGs. We used all 4148 <em>Klebsiella</em> spp isolates from two large One-Health studies (SpARK, Italy, and OH-DART, Thailand), including 191 <em>Klebsiella</em> isolates from pigs, 635 from clinical isolates, 1040 from hospital and community carriage, and 2282 from other sources. Short-read sequencing of <em>Klebsiella</em> isolates was performed as part of the SpARK study. We sequenced <em>Klebsiella</em> isolates from the OH-DART (MicrobesNG, Birmingham, UK; HiSeq and NovaSeq, Illumina San Diego, CA, USA; GridION, Oxford Nanopore Technologies, Oxford, UK) and SpARK (MinION or GridION, Oxford Nanopore Technologies, Oxford, UK) studies. We also retrieved plasmid sequences carrying <em>iuc3</em> from the National Centre for Biotechnology Information (NCBI). To ascertain the degree of diversity, evolutionary dynamics, and structuring across ecological and geographical axes, we detected ARGs and virulence loci, analysed clustering patterns and generated approximate maximum-likelihood phylogenetic trees.</div></div><div><h3>Findings</h3><div>We identified 48 <em>K pneumoniae</em> isolates with <em>iuc3</em> in the SpARK data and 79 in the OH-DART data. Three (2·4%) of these 127 isolates were from clinical sources, 73 (57·5%) were from pig or pork meat. <em>iuc3</em> isolates corresponded to multiple (n=47) host sequence types (STs), with ST35, ST45, ST881, ST25, and ST967 harbouring <em>iuc3</em> in both datasets. We generated hybrid assemblies for 44 (SpARK) and 36 (OH-DART) isolates, plus a single <em>iuc3</em> isolate from Germany. 53 (65·4%) of these isolates were from pigs, three (3·7%) from clinical sources, and 25 (30·9%) from other sources. There were an additional 48 <em>iuc3</em> positive isolates from our collections for which only short read data was available. A single <em>iuc3</em>-positive <em>Klebsiella oxytoca</em> isolate from a pig farm was detected in the SpARK data, which was also sequenced. We identified 330 <em>iuc3</em>-positive isolates and 58 <em>iuc3</em>-carrying plasmid assemblies from NCBI, of which 83 (21·4%) were from clinical sources, 120 from pigs (30·9%), and 185 (47·7%) from other sou
{"title":"Convergence and global molecular epidemiology of Klebsiella pneumoniae plasmids harbouring the iuc3 virulence locus: a population genomic analysis","authors":"Marjorie J Gibbon PhD , Natacha Couto PhD , Keira Cozens MSc , Samia Habib PhD , Lauren Cowley PhD , Prof David M Aanensen PhD , Prof Jukka Corander PhD , Harry A Thorpe PhD , Marit A K Hetland MSc , Davide Sassera PhD , Cristina Merla PhD , Marta Corbella MSc , Carolina Ferrari MSc , Prof Katy M E Turner PhD , Kwanrawee Sirikanchana PhD , Punyawee Dulyayangkul PhD , Nisanart Charoenlap PhD , Prof Visanu Thamlikitkul MD , Prof Matthew B Avison PhD , Prof Edward J Feil PhD","doi":"10.1016/j.lanmic.2025.101236","DOIUrl":"10.1016/j.lanmic.2025.101236","url":null,"abstract":"<div><h3>Background</h3><div><em>Klebsiella pneumoniae</em> is an important pathogen of humans and animals. In the past five years, increasing reports of convergent strains that carry both virulence factors and antimicrobial resistance genes (ARGs) have raised serious public health concerns. The aim of this study is to describe the global diversity of plasmids carrying <em>iuc3</em> (a key virulence factor in <em>K pneumoniae</em> associated with pigs and clinical isolates) from diverse settings, and their role in the emergence of convergent strains through hybridisation with plasmids carrying ARGs.</div></div><div><h3>Methods</h3><div>This population genomic analysis study was designed to describe both the global and local diversity of <em>iuc3</em>-carrying plasmids from diverse sources, and the co-occurrence of <em>iuc3</em> with ARGs. We used all 4148 <em>Klebsiella</em> spp isolates from two large One-Health studies (SpARK, Italy, and OH-DART, Thailand), including 191 <em>Klebsiella</em> isolates from pigs, 635 from clinical isolates, 1040 from hospital and community carriage, and 2282 from other sources. Short-read sequencing of <em>Klebsiella</em> isolates was performed as part of the SpARK study. We sequenced <em>Klebsiella</em> isolates from the OH-DART (MicrobesNG, Birmingham, UK; HiSeq and NovaSeq, Illumina San Diego, CA, USA; GridION, Oxford Nanopore Technologies, Oxford, UK) and SpARK (MinION or GridION, Oxford Nanopore Technologies, Oxford, UK) studies. We also retrieved plasmid sequences carrying <em>iuc3</em> from the National Centre for Biotechnology Information (NCBI). To ascertain the degree of diversity, evolutionary dynamics, and structuring across ecological and geographical axes, we detected ARGs and virulence loci, analysed clustering patterns and generated approximate maximum-likelihood phylogenetic trees.</div></div><div><h3>Findings</h3><div>We identified 48 <em>K pneumoniae</em> isolates with <em>iuc3</em> in the SpARK data and 79 in the OH-DART data. Three (2·4%) of these 127 isolates were from clinical sources, 73 (57·5%) were from pig or pork meat. <em>iuc3</em> isolates corresponded to multiple (n=47) host sequence types (STs), with ST35, ST45, ST881, ST25, and ST967 harbouring <em>iuc3</em> in both datasets. We generated hybrid assemblies for 44 (SpARK) and 36 (OH-DART) isolates, plus a single <em>iuc3</em> isolate from Germany. 53 (65·4%) of these isolates were from pigs, three (3·7%) from clinical sources, and 25 (30·9%) from other sources. There were an additional 48 <em>iuc3</em> positive isolates from our collections for which only short read data was available. A single <em>iuc3</em>-positive <em>Klebsiella oxytoca</em> isolate from a pig farm was detected in the SpARK data, which was also sequenced. We identified 330 <em>iuc3</em>-positive isolates and 58 <em>iuc3</em>-carrying plasmid assemblies from NCBI, of which 83 (21·4%) were from clinical sources, 120 from pigs (30·9%), and 185 (47·7%) from other sou","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":"7 2","pages":"Article 101236"},"PeriodicalIF":20.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145946562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.lanmic.2025.101279
Cara Adolph PhD , Simon C Mendelsohn PhD , Laura E Via PhD , Leonardo Martinez PhD , Cecilia S Lindestam Arlehamn PhD , Prof David M Lewinsohn PhD , Jordi B Torrelles PhD , Prof Philip C Hill MD
Tuberculosis remains a leading cause of death, underscoring the urgent need for a new vaccine. Progress in vaccine development is hampered by incomplete understanding of how Mycobacterium tuberculosis causes infection and disease, and of protective immunity following natural infection and vaccination. Addressing these gaps requires biological samples from tuberculosis cases and contacts or healthy controls as well as from protected and unprotected vaccinated individuals. Numerous observational studies and clinical trials on tuberculosis are conducted each year, collecting and storing diverse samples—including blood derivatives, urine, sputum, saliva, and even radiographic images—from participants. In this Personal View, we suggest that pooling samples from these studies could enable the scientific community to address important and understudied research questions at an unprecedented scale. This approach could generate new insights into fundamental disease mechanisms and the requirements for an effective vaccine. We propose linking existing biorepositories from tuberculosis studies worldwide to facilitate large-scale studies and accelerate breakthroughs in tuberculosis vaccine development.
{"title":"The need for interconnected global biorepositories from tuberculosis studies to address fundamental questions at scale","authors":"Cara Adolph PhD , Simon C Mendelsohn PhD , Laura E Via PhD , Leonardo Martinez PhD , Cecilia S Lindestam Arlehamn PhD , Prof David M Lewinsohn PhD , Jordi B Torrelles PhD , Prof Philip C Hill MD","doi":"10.1016/j.lanmic.2025.101279","DOIUrl":"10.1016/j.lanmic.2025.101279","url":null,"abstract":"<div><div>Tuberculosis remains a leading cause of death, underscoring the urgent need for a new vaccine. Progress in vaccine development is hampered by incomplete understanding of how <em>Mycobacterium tuberculosis</em> causes infection and disease, and of protective immunity following natural infection and vaccination. Addressing these gaps requires biological samples from tuberculosis cases and contacts or healthy controls as well as from protected and unprotected vaccinated individuals. Numerous observational studies and clinical trials on tuberculosis are conducted each year, collecting and storing diverse samples—including blood derivatives, urine, sputum, saliva, and even radiographic images—from participants. In this Personal View, we suggest that pooling samples from these studies could enable the scientific community to address important and understudied research questions at an unprecedented scale. This approach could generate new insights into fundamental disease mechanisms and the requirements for an effective vaccine. We propose linking existing biorepositories from tuberculosis studies worldwide to facilitate large-scale studies and accelerate breakthroughs in tuberculosis vaccine development.</div></div>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":"7 2","pages":"Article 101279"},"PeriodicalIF":20.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145835024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.lanmic.2025.101277
Victoria T Chu MD MPH , Natasha Spottiswoode MD DPhil , Ryan Ward BS , Deborah S Yokoe MD , Lynn Ramirez-Avila MD , Maira S Phelps BS , Abigail Glascock PhD , Emily D Crawford PhD , Jack Kamm PhD , Samantha Hao MD , Lucy Li PhD , David Dynerman PhD , Eric Waltari PhD , Saba Nafees PhD , Katrina L Kalantar PhD , Saharai Caldera BS , Sharline Madera MD , Estella Sanchez Guerrero PhD , Daniel Ivashin BS , Paula Hayakawa Serpa MD , Charles R Langelier MD PhD
Advances in genomic technologies have revolutionised practices for hospital infection prevention and control programmes. In this Personal View, we describe a genomic epidemiology service called the Rapid Response (RR) programme at University of California, San Francisco, a large academic medical centre. In collaboration with the hospital infection-prevention team, the RR programme uses whole-genome sequencing and metagenomic next-generation sequencing for outbreak investigations, special interest analyses of emerging pathogens, and surveillance of high-priority microbes. Over 7 years (2017–24), the RR programme conducted a diversity of outbreak investigations and other analyses; most investigations ruled out transmission, and the rapid turnaround of genomic results averted further resource-intensive work. Longitudinal surveillance enabled early detection of changing incidence trends and guided timely infection-prevention responses. Our experiences with the RR programme build upon growing evidence that genomic epidemiology programmes enhance hospital infection prevention and control, augment priority pathogen surveillance, and improve patient safety.
{"title":"Implementation and outcomes of a rapid response genomic hospital epidemiology programme at an academic medical centre over 7 years","authors":"Victoria T Chu MD MPH , Natasha Spottiswoode MD DPhil , Ryan Ward BS , Deborah S Yokoe MD , Lynn Ramirez-Avila MD , Maira S Phelps BS , Abigail Glascock PhD , Emily D Crawford PhD , Jack Kamm PhD , Samantha Hao MD , Lucy Li PhD , David Dynerman PhD , Eric Waltari PhD , Saba Nafees PhD , Katrina L Kalantar PhD , Saharai Caldera BS , Sharline Madera MD , Estella Sanchez Guerrero PhD , Daniel Ivashin BS , Paula Hayakawa Serpa MD , Charles R Langelier MD PhD","doi":"10.1016/j.lanmic.2025.101277","DOIUrl":"10.1016/j.lanmic.2025.101277","url":null,"abstract":"<div><div>Advances in genomic technologies have revolutionised practices for hospital infection prevention and control programmes. In this Personal View, we describe a genomic epidemiology service called the Rapid Response (RR) programme at University of California, San Francisco, a large academic medical centre. In collaboration with the hospital infection-prevention team, the RR programme uses whole-genome sequencing and metagenomic next-generation sequencing for outbreak investigations, special interest analyses of emerging pathogens, and surveillance of high-priority microbes. Over 7 years (2017–24), the RR programme conducted a diversity of outbreak investigations and other analyses; most investigations ruled out transmission, and the rapid turnaround of genomic results averted further resource-intensive work. Longitudinal surveillance enabled early detection of changing incidence trends and guided timely infection-prevention responses. Our experiences with the RR programme build upon growing evidence that genomic epidemiology programmes enhance hospital infection prevention and control, augment priority pathogen surveillance, and improve patient safety.</div></div>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":"7 2","pages":"Article 101277"},"PeriodicalIF":20.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145946565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.lanmic.2025.101273
Johanna Rhodes PhD , Sui Ting Hui MRes , Sarah Dellière MD , Richard C Summerbell PhD , James A Scott PhD , Amtoj Kaur MSc , Richard C Barton PhD , Rodrigo Leitao MSc , Samuel Hemmings MSc , Rebeca Goiriz MD , Jonathan Lambourne PhD , Rhys A Farrer PhD , Silke Schelenz PhD , Prof Roderick J Hay DM , Prof Andrew M Borman PhD , Prof Anuradha Chowdhary MD , Alireza Abdolrasouli PhD , Prof Matthew C Fisher PhD
Background
Trichophyton species cause the greatest burden of dermatophytosis worldwide, with the Trichophyton mentagrophytes species complex being particularly associated with the emergence of new aggressive infections. One emerging species, Trichophyton indotineae is notable for its clinical resistance to terbinafine antifungal treatment and rapid global spread. In this study we aim to characterise the epidemiology of this emerging pathogen using genomics.
Methods
In this retrospective genomic epidemiology study, to better understand the epidemiology of this disease, we sourced isolates collected from patients with severe cases of dermatophytosis (identified either by internal transcribed spacer sequencing or phenotypic characterisation) in the UK, Ireland, France, Canada, and India for the period 2014–23, including the T indotineae type strain from Japan. We used whole-genome sequencing to confirm 90 isolates were T indotineae, and antifungal susceptibility testing to assess susceptibility to terbinafine.
Findings
103 cases of severe dermatophytosis caused by Trichophyton species collected between 2018 and 2023 in the UK, France, Canada, Ireland, and India were included in this study. Susceptibility testing indicated that 63 (70%) of 90 T indotineae isolates were resistant to terbinafine (minimum inhibitory concentration [MIC] ≥0·5 mg/L). Pairwise genetic distances showed very high identity with only 147 (range 1–414) single-nucleotide polymorphisms (SNPs) separating isolates that were nested within a monophyletic phylogeny, supporting a single evolutionary origin of T indotineae. Genome-wide analyses identified multiple non-synonymous SNPs in SQLE (ERG1), the squalene epoxidase target of terbinafine, that were associated with terbinafine in vitro resistance of 0·5 mg/L or higher. However, six isolates exhibited high MIC values without SQLE mutations, suggesting the presence of alternative resistance mechanisms.
Interpretation
That no clear geographical clustering of isolates was observed confirms the rapid transcontinental spread of T indotineae from its likely centre of diversity in Asia. Our findings highlight the importance of better genomic surveillance to understand and manage this severe and rapidly emerging terbinafine-resistant dermatophyte.
{"title":"Emerging terbinafine-resistant Trichophyton indotineae between 2018 and 2023: a multinational genomic epidemiology study","authors":"Johanna Rhodes PhD , Sui Ting Hui MRes , Sarah Dellière MD , Richard C Summerbell PhD , James A Scott PhD , Amtoj Kaur MSc , Richard C Barton PhD , Rodrigo Leitao MSc , Samuel Hemmings MSc , Rebeca Goiriz MD , Jonathan Lambourne PhD , Rhys A Farrer PhD , Silke Schelenz PhD , Prof Roderick J Hay DM , Prof Andrew M Borman PhD , Prof Anuradha Chowdhary MD , Alireza Abdolrasouli PhD , Prof Matthew C Fisher PhD","doi":"10.1016/j.lanmic.2025.101273","DOIUrl":"10.1016/j.lanmic.2025.101273","url":null,"abstract":"<div><h3>Background</h3><div><em>Trichophyton</em> species cause the greatest burden of dermatophytosis worldwide, with the <em>Trichophyton mentagrophytes</em> species complex being particularly associated with the emergence of new aggressive infections. One emerging species, <em>Trichophyton indotineae</em> is notable for its clinical resistance to terbinafine antifungal treatment and rapid global spread. In this study we aim to characterise the epidemiology of this emerging pathogen using genomics.</div></div><div><h3>Methods</h3><div>In this retrospective genomic epidemiology study, to better understand the epidemiology of this disease, we sourced isolates collected from patients with severe cases of dermatophytosis (identified either by internal transcribed spacer sequencing or phenotypic characterisation) in the UK, Ireland, France, Canada, and India for the period 2014–23, including the <em>T indotineae</em> type strain from Japan. We used whole-genome sequencing to confirm 90 isolates were <em>T indotineae</em>, and antifungal susceptibility testing to assess susceptibility to terbinafine.</div></div><div><h3>Findings</h3><div>103 cases of severe dermatophytosis caused by <em>Trichophyton</em> species collected between 2018 and 2023 in the UK, France, Canada, Ireland, and India were included in this study. Susceptibility testing indicated that 63 (70%) of 90 <em>T indotineae</em> isolates were resistant to terbinafine (minimum inhibitory concentration [MIC] ≥0·5 mg/L). Pairwise genetic distances showed very high identity with only 147 (range 1–414) single-nucleotide polymorphisms (SNPs) separating isolates that were nested within a monophyletic phylogeny, supporting a single evolutionary origin of <em>T indotineae</em>. Genome-wide analyses identified multiple non-synonymous SNPs in <em>SQLE</em> (<em>ERG1</em>), the squalene epoxidase target of terbinafine, that were associated with terbinafine in vitro resistance of 0·5 mg/L or higher. However, six isolates exhibited high MIC values without <em>SQLE</em> mutations, suggesting the presence of alternative resistance mechanisms.</div></div><div><h3>Interpretation</h3><div>That no clear geographical clustering of isolates was observed confirms the rapid transcontinental spread of <em>T indotineae</em> from its likely centre of diversity in Asia. Our findings highlight the importance of better genomic surveillance to understand and manage this severe and rapidly emerging terbinafine-resistant dermatophyte.</div></div><div><h3>Funding</h3><div>None.</div></div>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":"7 2","pages":"Article 101273"},"PeriodicalIF":20.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1016/j.lanmic.2025.101245
Jean Claude Dejon Agobé, Oumou Maïga-Ascofaré, Ayôla Akim Adegnika, Christoph Pfaffendorf, Joseph Marfo Boaheng, Jean Ronald Edoa, Isaac Darko Agyiri, Romeo Bayode Adegbite, Esi Yacoba Bart-Plange, Ebenezer Ahenkan, Dorothea Ekoka Mbassi, Francisca Naana Sarpong, Esther Placca, Dominic Kwabena Kanin, Portia Bakari, Wibke Loag, Jenny Kettenbeil, Sanjeev Krishna, Bertrand Lell, Selidji Todagbe Agnandji, John Humphrey Amuasi, Rella Zoleko-Manego, Ghyslain Mombo-Ngoma, Peter Gottfried Kremsner, Sebastian G Wicha, Michael Ramharter, Johannes Mischlinger
<p><strong>Background: </strong>The emergence of Plasmodium falciparum strains with reduced susceptibility to the artemisinin component of artemisinin combination therapies poses a serious threat to the treatment and control of malaria in sub-Saharan Africa. Regimens consisting of combinations of three or more conventional antimalarials have been proposed as a new treatment paradigm to overcome the impending problem of drug-resistant malaria. It was the aim of the MultiMal study to assess the safety, tolerability, and efficacy of the two novel multidrug antimalarial combination therapies, artesunate-pyronaridine-atovaquone-proguanil (APAP) and artesunate-fosmidomycin-clindamycin (AFC), in comparison with standard artesunate-pyronaridine (AP).</p><p><strong>Methods: </strong>This open-label, randomised, controlled, clinical, phase 2 trial was done in Lambaréné, Gabon, and Kumasi, Ghana. Patients with uncomplicated malaria who had fever or a history of fever in the preceding 24 h and a parasitaemia in the range of 1000-100 000 per μL of blood were enrolled. Random permuted blocks of variable block sizes stratified by country were computed to generate a treatment allocation sequence. Recruitment was done across three age groups: children aged 6 months to 10 years, adolescents aged 11-17 years, and adults aged 18-65 years. Weight-adjusted oral, once-daily therapy was administered for 3 consecutive days for AP and APAP regimens dosed according to the recommendations of the manufacturer and twice daily for AFC (dose: artesunate 2 mg/kg, fosmidomycin 30 mg/kg, and clindamycin 10 mg/kg). Participants were followed up over a 42-day period. The primary endpoints of the trial, related to pharmacokinetic analyses, are being reported elsewhere; this Article reports the secondary endpoints-safety, tolerability, and efficacy of the treatment regimens (defined as adequate clinical and parasitological response [ACPR]) at days 28 and 42 after treatment initiation. ACPRs were calculated in the intention-to-treat and PCR-corrected per-protocol populations at these timepoints, whereas safety and tolerability outcomes were assessed continuously over the 42-day follow-up period in the safety population. This trial is registered with pactr.samrc.ac.za, PACTR202008909968293 and is complete.</p><p><strong>Findings: </strong>Recruitment and follow-up took place between Jan 5 and Nov 5, 2021. Of 309 screened individuals, 100 patients with uncomplicated malaria were recruited into this clinical trial: 20 semi-immune patients aged 18-65 years, 40 adolescents aged between 11 and 17 years, and finally 40 patients aged 6 months to 10 years. PCR-corrected ACPR in the per-protocol set was 100% (95% CI 80-100) for AP, 100% (90-100) for APAP, and 97% (86-100) for AFC for day 28, and 87·5% (62-98) for AP, 85·3% (69-95) for APAP, and 94·4% (81-99) for AFC on day 42. Uncorrected ACPR in the intention-to-treat set was 85% (95% CI 62-97%) for AP, 87·5% (73-96) for APAP, and 82·5% (67-93)
{"title":"Artesunate-pyronaridine-atovaquone-proguanil and artesunate-fosmidomycin-clindamycin compared with standard artesunate-pyronaridine for the treatment of uncomplicated malaria (MultiMal): a randomised, controlled, clinical, phase 2 trial in Gabon and Ghana.","authors":"Jean Claude Dejon Agobé, Oumou Maïga-Ascofaré, Ayôla Akim Adegnika, Christoph Pfaffendorf, Joseph Marfo Boaheng, Jean Ronald Edoa, Isaac Darko Agyiri, Romeo Bayode Adegbite, Esi Yacoba Bart-Plange, Ebenezer Ahenkan, Dorothea Ekoka Mbassi, Francisca Naana Sarpong, Esther Placca, Dominic Kwabena Kanin, Portia Bakari, Wibke Loag, Jenny Kettenbeil, Sanjeev Krishna, Bertrand Lell, Selidji Todagbe Agnandji, John Humphrey Amuasi, Rella Zoleko-Manego, Ghyslain Mombo-Ngoma, Peter Gottfried Kremsner, Sebastian G Wicha, Michael Ramharter, Johannes Mischlinger","doi":"10.1016/j.lanmic.2025.101245","DOIUrl":"https://doi.org/10.1016/j.lanmic.2025.101245","url":null,"abstract":"<p><strong>Background: </strong>The emergence of Plasmodium falciparum strains with reduced susceptibility to the artemisinin component of artemisinin combination therapies poses a serious threat to the treatment and control of malaria in sub-Saharan Africa. Regimens consisting of combinations of three or more conventional antimalarials have been proposed as a new treatment paradigm to overcome the impending problem of drug-resistant malaria. It was the aim of the MultiMal study to assess the safety, tolerability, and efficacy of the two novel multidrug antimalarial combination therapies, artesunate-pyronaridine-atovaquone-proguanil (APAP) and artesunate-fosmidomycin-clindamycin (AFC), in comparison with standard artesunate-pyronaridine (AP).</p><p><strong>Methods: </strong>This open-label, randomised, controlled, clinical, phase 2 trial was done in Lambaréné, Gabon, and Kumasi, Ghana. Patients with uncomplicated malaria who had fever or a history of fever in the preceding 24 h and a parasitaemia in the range of 1000-100 000 per μL of blood were enrolled. Random permuted blocks of variable block sizes stratified by country were computed to generate a treatment allocation sequence. Recruitment was done across three age groups: children aged 6 months to 10 years, adolescents aged 11-17 years, and adults aged 18-65 years. Weight-adjusted oral, once-daily therapy was administered for 3 consecutive days for AP and APAP regimens dosed according to the recommendations of the manufacturer and twice daily for AFC (dose: artesunate 2 mg/kg, fosmidomycin 30 mg/kg, and clindamycin 10 mg/kg). Participants were followed up over a 42-day period. The primary endpoints of the trial, related to pharmacokinetic analyses, are being reported elsewhere; this Article reports the secondary endpoints-safety, tolerability, and efficacy of the treatment regimens (defined as adequate clinical and parasitological response [ACPR]) at days 28 and 42 after treatment initiation. ACPRs were calculated in the intention-to-treat and PCR-corrected per-protocol populations at these timepoints, whereas safety and tolerability outcomes were assessed continuously over the 42-day follow-up period in the safety population. This trial is registered with pactr.samrc.ac.za, PACTR202008909968293 and is complete.</p><p><strong>Findings: </strong>Recruitment and follow-up took place between Jan 5 and Nov 5, 2021. Of 309 screened individuals, 100 patients with uncomplicated malaria were recruited into this clinical trial: 20 semi-immune patients aged 18-65 years, 40 adolescents aged between 11 and 17 years, and finally 40 patients aged 6 months to 10 years. PCR-corrected ACPR in the per-protocol set was 100% (95% CI 80-100) for AP, 100% (90-100) for APAP, and 97% (86-100) for AFC for day 28, and 87·5% (62-98) for AP, 85·3% (69-95) for APAP, and 94·4% (81-99) for AFC on day 42. Uncorrected ACPR in the intention-to-treat set was 85% (95% CI 62-97%) for AP, 87·5% (73-96) for APAP, and 82·5% (67-93)","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":" ","pages":"101245"},"PeriodicalIF":20.4,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-24DOI: 10.1016/j.lanmic.2025.101295
Md Zakiul Hassan, Susan Khader Ibrahim, Eli Harriss, Peter Horby, Piero Olliaro, Amanda Rojek
Nipah virus is a priority pathogen with high mortality and pandemic potential. Therapies for Nipah virus disease, such as monoclonal antibodies and antivirals, are under development and require clinical trials for evaluation. However, designing such trials is challenging due to the limited understanding of the clinical characteristics, pathogenesis, and current management of Nipah virus disease. In this Review, we gathered essential data from 59 studies reporting 717 Nipah virus disease cases, to inform trial design. Nearly all patients (618 [99%] of 624) had fever. Neurological symptoms included headache (419 [70%] of 601 patients), confusion (74 [65%] of 114), and altered consciousness (358 [62%] of 580); respiratory symptoms included cough (244 [45%] of 541) and difficulty in breathing (184 [58%] of 317). Imaging data revealed chest abnormalities (29 [80%] of 36) and brain involvement (40 [71%] of 56). Viral RNA was detectable early in illness across various sample types. The median case-fatality rate was 69% (IQR 31-88%), with 51 (26%) of 197 survivors presenting with persistent neurological deficits. Clinical management varied widely, with incomplete reporting limiting insights. Prospective observational studies are needed to generate actionable data on clinical case definitions, predictors of adverse outcomes, current standards of care, and standardised endpoints, to inform future trials.
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