Teeba Jihad, Xiaoyuan S Chi, Zhiqing He, Kwok Lee, Elie Needle, Jakob Loschko, Jessica Goymer, Helen Wang, Helene Boigard, Camille Robertson, Jennifer Obregon, Kasey Wilson, Isis Kanevsky, Paul Liberator, Yury V Matsuka, Mark R Walter, Kathrin U Jansen, Xinzhen Yang, Philip R Dormitzer, Kena A Swanson, Nicholas J Buchkovich
A human cytomegalovirus vaccine to prevent congenital disease is a public health priority. We previously demonstrated that vaccine-elicited rhesus CMV (RhCMV) neutralizing titers and T cell responses comparable to natural infection failed to protect from RhCMV infection after experimental oral challenge. Consequently, we established a natural transmission model in which newborn rhesus macaques are co-housed with their RhCMV-positive mothers and immunized five times between 0 and 24 months with gB, pentamer, pp65 and in one group vIL-10. While no significant differences were observed in infection rate between the vaccine and placebo groups at forty weeks after birth, partial protection was observed at week 52 (83.3% infection in placebo, 42.1-50% in vaccine recipients). Within 14 weeks of juvenile macaques transfer to group-housing, all shed RhCMV. These results suggest that the neonatal RhCMV natural transmission model may recapitulate observations in humans immunized with recombinant gB and can be a useful tool for evaluating CMV vaccine candidates.
{"title":"Establishment of a Neonatal Natural Transmission Model for CMV Vaccine Development","authors":"Teeba Jihad, Xiaoyuan S Chi, Zhiqing He, Kwok Lee, Elie Needle, Jakob Loschko, Jessica Goymer, Helen Wang, Helene Boigard, Camille Robertson, Jennifer Obregon, Kasey Wilson, Isis Kanevsky, Paul Liberator, Yury V Matsuka, Mark R Walter, Kathrin U Jansen, Xinzhen Yang, Philip R Dormitzer, Kena A Swanson, Nicholas J Buchkovich","doi":"10.1093/infdis/jiag170","DOIUrl":"https://doi.org/10.1093/infdis/jiag170","url":null,"abstract":"A human cytomegalovirus vaccine to prevent congenital disease is a public health priority. We previously demonstrated that vaccine-elicited rhesus CMV (RhCMV) neutralizing titers and T cell responses comparable to natural infection failed to protect from RhCMV infection after experimental oral challenge. Consequently, we established a natural transmission model in which newborn rhesus macaques are co-housed with their RhCMV-positive mothers and immunized five times between 0 and 24 months with gB, pentamer, pp65 and in one group vIL-10. While no significant differences were observed in infection rate between the vaccine and placebo groups at forty weeks after birth, partial protection was observed at week 52 (83.3% infection in placebo, 42.1-50% in vaccine recipients). Within 14 weeks of juvenile macaques transfer to group-housing, all shed RhCMV. These results suggest that the neonatal RhCMV natural transmission model may recapitulate observations in humans immunized with recombinant gB and can be a useful tool for evaluating CMV vaccine candidates.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lindley A Barbee,Shengruo Zhang,Matthew R Golden,Christine M Khosropour,Olusegun O Soge,Lisa E Manhart
BACKGROUNDLittle is known about Mycoplasma genitalium's (MG) natural history in the throat and the rectum. Methods: Men who have sex with men (MSM) enrolled in a longitudinal cohort study on the natural history of extragenital gonorrhea and chlamydia. Men self-collected pharyngeal and rectal specimens weekly and completed electronic symptom and sexual behavior diaries for 48 weeks. Prevalent infections were detected on the first week of testing; incident infections were ≥2 consecutive weeks of positive specimens after a negative test. We calculated duration using Kaplan-Meier analysis.RESULTSOf 140 enrolled MSM, 112 participated and 108 submitted samples on week one. Ten (9.3%) had prevalent rectal MG; there were fifteen incident rectal MG infections (incidence 19.8 per 100 person years (py), 95% CI:11.5-34.1 per 100 py). Rectal MG had a median duration of 42 weeks (95% CI: 7.3 weeks - undefined); most infections (60%) were entirely asymptomatic. Four (3.7%) participants had prevalent pharyngeal infections. Fourteen incident pharyngeal infections arose (incidence 17.5 per 100 person years, 95% CI: 9.9-30.8 per 100 py). Pharyngeal MG had a median duration of 12 weeks (95% CI: 6.3 weeks - undefined); symptoms were rare (6%).CONCLUSIONSRectal and pharyngeal MG was common in this cohort. Half of the rectal MG infections persisted for nearly a year; many remained positive on week 48 suggesting persistence beyond one year. Pharyngeal infection persisted three months. The absence of symptoms or other morbidity in most infections suggests testing for MG at these sites would have uncertain individual benefit.
{"title":"The Natural History of Mycoplasma genitalium at the Pharynx and Rectum in a Cohort of Men who have Sex with Men: Prevalence, Incidence, Duration and Symptomatology.","authors":"Lindley A Barbee,Shengruo Zhang,Matthew R Golden,Christine M Khosropour,Olusegun O Soge,Lisa E Manhart","doi":"10.1093/infdis/jiag173","DOIUrl":"https://doi.org/10.1093/infdis/jiag173","url":null,"abstract":"BACKGROUNDLittle is known about Mycoplasma genitalium's (MG) natural history in the throat and the rectum. Methods: Men who have sex with men (MSM) enrolled in a longitudinal cohort study on the natural history of extragenital gonorrhea and chlamydia. Men self-collected pharyngeal and rectal specimens weekly and completed electronic symptom and sexual behavior diaries for 48 weeks. Prevalent infections were detected on the first week of testing; incident infections were ≥2 consecutive weeks of positive specimens after a negative test. We calculated duration using Kaplan-Meier analysis.RESULTSOf 140 enrolled MSM, 112 participated and 108 submitted samples on week one. Ten (9.3%) had prevalent rectal MG; there were fifteen incident rectal MG infections (incidence 19.8 per 100 person years (py), 95% CI:11.5-34.1 per 100 py). Rectal MG had a median duration of 42 weeks (95% CI: 7.3 weeks - undefined); most infections (60%) were entirely asymptomatic. Four (3.7%) participants had prevalent pharyngeal infections. Fourteen incident pharyngeal infections arose (incidence 17.5 per 100 person years, 95% CI: 9.9-30.8 per 100 py). Pharyngeal MG had a median duration of 12 weeks (95% CI: 6.3 weeks - undefined); symptoms were rare (6%).CONCLUSIONSRectal and pharyngeal MG was common in this cohort. Half of the rectal MG infections persisted for nearly a year; many remained positive on week 48 suggesting persistence beyond one year. Pharyngeal infection persisted three months. The absence of symptoms or other morbidity in most infections suggests testing for MG at these sites would have uncertain individual benefit.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gregory C Gray,Cody J Warren,Richard J Webby,Andrew S Bowman
{"title":"Why We Must Vaccinate US Dairy Cattle Against HPAI H5N1.","authors":"Gregory C Gray,Cody J Warren,Richard J Webby,Andrew S Bowman","doi":"10.1093/infdis/jiag183","DOIUrl":"https://doi.org/10.1093/infdis/jiag183","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Monika Mani,Steven J Clipman,Justin R Bailey,Richard K Sterling,Mark S Sulkowski,Mark Anderson,Ana Olivo,Giulia Belluccini,Gavin Cloherty,Ruy M Ribeiro,Chloe L Thio,Ashwin Balagopal
BACKGROUNDThe high error rate of the hepatitis B virus (HBV) polymerase leads to a genetically diverse quasispecies in individuals with chronic hepatitis B (CHB). Data regarding the propagation of these variants in individual hepatocytes may provide insight into viral replication and diversity of covalently closed circular DNA (cccDNA), which is the template for HBV replication.METHODSWe developed sequencing protocols to characterize HBV diversity between and within hepatocytes using RNA extracted from individually isolated hepatocytes. We sequenced HBV in >200 hepatocytes in four liver biopsies from people with HIV/HBV (HB1, HB2, HB3, HB6).RESULTSWe found that two biopsies (HB1 and HB6) showed HBV diversity between hepatocytes that met an experimentally identified threshold. Specifically, in HB1, HBV sequences from 86 individual cells were from two different haplotypes of genotype D: 70.2% of cells with haplotype a, 5.8% with haplotype b, and 24% with both haplotypes in the same cell. Furthermore, within single hepatocytes, up to three different HBV sequences were present per cell, including some cells with both genotypes A and D. HB6, who received years of lamivudine monotherapy, had evidence of drug-resistance (DR) mutations distributed among hepatocytes and demonstrated up to three different sequences, including wild-type and drug-resistant sequences, in the same hepatocyte. Modeling of infected hepatocytes did not reveal evidence of local HBV spread based on spatial proximity.CONCLUSIONSTaken together, our findings demonstrate that individual hepatocytes may harbor multiple, transcriptionally active HBV cccDNA molecules, which likely arose from distinct infection events.
{"title":"Single-cell hepatitis B sequencing reveals distinct viral infection events consistent with superinfection.","authors":"Monika Mani,Steven J Clipman,Justin R Bailey,Richard K Sterling,Mark S Sulkowski,Mark Anderson,Ana Olivo,Giulia Belluccini,Gavin Cloherty,Ruy M Ribeiro,Chloe L Thio,Ashwin Balagopal","doi":"10.1093/infdis/jiag181","DOIUrl":"https://doi.org/10.1093/infdis/jiag181","url":null,"abstract":"BACKGROUNDThe high error rate of the hepatitis B virus (HBV) polymerase leads to a genetically diverse quasispecies in individuals with chronic hepatitis B (CHB). Data regarding the propagation of these variants in individual hepatocytes may provide insight into viral replication and diversity of covalently closed circular DNA (cccDNA), which is the template for HBV replication.METHODSWe developed sequencing protocols to characterize HBV diversity between and within hepatocytes using RNA extracted from individually isolated hepatocytes. We sequenced HBV in >200 hepatocytes in four liver biopsies from people with HIV/HBV (HB1, HB2, HB3, HB6).RESULTSWe found that two biopsies (HB1 and HB6) showed HBV diversity between hepatocytes that met an experimentally identified threshold. Specifically, in HB1, HBV sequences from 86 individual cells were from two different haplotypes of genotype D: 70.2% of cells with haplotype a, 5.8% with haplotype b, and 24% with both haplotypes in the same cell. Furthermore, within single hepatocytes, up to three different HBV sequences were present per cell, including some cells with both genotypes A and D. HB6, who received years of lamivudine monotherapy, had evidence of drug-resistance (DR) mutations distributed among hepatocytes and demonstrated up to three different sequences, including wild-type and drug-resistant sequences, in the same hepatocyte. Modeling of infected hepatocytes did not reveal evidence of local HBV spread based on spatial proximity.CONCLUSIONSTaken together, our findings demonstrate that individual hepatocytes may harbor multiple, transcriptionally active HBV cccDNA molecules, which likely arose from distinct infection events.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDAzole therapy is currently not used against Candida auris infections. Although fluconazole resistance is prevalent, 10-45% of isolates among clades remain non-resistant (MICs ≤32 mg/L). We evaluated fluconazole pharmacokinetics/pharmacodynamics (PK/PD) against these isolates using a Galleria mellonella model.METHODSNine C. auris isolates representing five clades and MICs 1-128 mg/L were studied, and four Candida albicans isolates were included for model validation. Larvae were infected with lethal inocula and treated for four days with human-equivalent fluconazole doses. Efficacy endpoints were 24-hour change in fungal burden and 7-day survival. Free-drug 24-hour area under the concentration-time curve divided by the MIC (fAUC0-24/MIC) targets were derived using a sigmoidal Emax model, and Monte Carlo simulations estimated probability of target attainment (PTA).RESULTSFor C. albicans, the fAUC0-24/Clinical and Laboratory Standards Institute (CLSI) MIC corresponding to EI50 for 24-hour fungal burden reduction was 35.5, consistent with murine models. EI90 survival targets were 76.5 (CLSI) and 68.9 (European Committee on Antimicrobial Susceptibility Testing, EUCAST), supporting the clinical breakpoints and validating the model. For C. auris, EI90 targets for survival were 93.2 (CLSI) and 63.2 (EUCAST) and PTA >95% were found for isolates with MICs up to 2, 4, and 8 mg/L with fluconazole doses of 400, 800, and 1,200 mg/day, respectively.CONCLUSIONSFluconazole demonstrated similar in vivo activity against C. auris and C. albicans. Putative WT isolates with MICs ≤8 mg/L may be treatable with 1,200 mg/day. Clinical studies are needed to verify the efficacy of fluconazole against C. auris.
{"title":"Can fluconazole be used to treat non-resistant Candida (Candidozyma) auris infections? Preclinical PK/PD data from a Galleria mellonella infection model.","authors":"Vasiliki Kroustali,Spyros Pournaras,Joseph Meletiadis","doi":"10.1093/infdis/jiag182","DOIUrl":"https://doi.org/10.1093/infdis/jiag182","url":null,"abstract":"BACKGROUNDAzole therapy is currently not used against Candida auris infections. Although fluconazole resistance is prevalent, 10-45% of isolates among clades remain non-resistant (MICs ≤32 mg/L). We evaluated fluconazole pharmacokinetics/pharmacodynamics (PK/PD) against these isolates using a Galleria mellonella model.METHODSNine C. auris isolates representing five clades and MICs 1-128 mg/L were studied, and four Candida albicans isolates were included for model validation. Larvae were infected with lethal inocula and treated for four days with human-equivalent fluconazole doses. Efficacy endpoints were 24-hour change in fungal burden and 7-day survival. Free-drug 24-hour area under the concentration-time curve divided by the MIC (fAUC0-24/MIC) targets were derived using a sigmoidal Emax model, and Monte Carlo simulations estimated probability of target attainment (PTA).RESULTSFor C. albicans, the fAUC0-24/Clinical and Laboratory Standards Institute (CLSI) MIC corresponding to EI50 for 24-hour fungal burden reduction was 35.5, consistent with murine models. EI90 survival targets were 76.5 (CLSI) and 68.9 (European Committee on Antimicrobial Susceptibility Testing, EUCAST), supporting the clinical breakpoints and validating the model. For C. auris, EI90 targets for survival were 93.2 (CLSI) and 63.2 (EUCAST) and PTA >95% were found for isolates with MICs up to 2, 4, and 8 mg/L with fluconazole doses of 400, 800, and 1,200 mg/day, respectively.CONCLUSIONSFluconazole demonstrated similar in vivo activity against C. auris and C. albicans. Putative WT isolates with MICs ≤8 mg/L may be treatable with 1,200 mg/day. Clinical studies are needed to verify the efficacy of fluconazole against C. auris.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caroline M Weight, Gabriele Pollara, Modupeh Betts, Roberta Ragazzini, Elisa Ramos-Sevillano, Jesús Reiné, Matthew Whelan, José Afonso Guerra-Assunção, Michael Connor, Paola Bonfanti, Clare Jolly, Mahdad Noursadeghi, Daniela M Ferreira, Jeremy S Brown, Robert S Heyderman
Background Nasopharyngeal colonization by Streptococcus pneumoniae is characterized by bacterial adherence to epithelial cells, microinvasion, and innate immune activation. Previously, we have shown that two serotype 6B S pneumoniae mutant strains affecting bacterial metabolism (ΔproABC/pia and Δfhs/pia) colonize humans and mice, but in a murine disease model do not cause invasive infection. Methods Using an experimental human pneumococcal challenge model, ex vivo airway cells, and in vitro nasopharyngeal epithelium, we explore whether microinvasion and innate immune responses persist despite disease attenuation. Results We show that under serum stress, these biosynthesis gene mutations had a broad but different impact on pneumococcal virulence gene expression, oxidative stress regulation, and purine and carbohydrate metabolism genes. However, although these mutations did not attenuate microinvasion in human challenge and epithelial models, there was less transmigration of Detroit 562 nasopharyngeal epithelial cells by the mutants compared to wild-type. Cellular reorganization of primary human airway epithelium varied considerably between strains. Compared to wild-type, infection of Detroit 562 epithelial cells by the Δfhs/piaA strain, but not the ΔproABC/piaA strain, was less proinflammatory, induced less caspase 8 production, and was associated with increased pneumococcal hydrogen peroxide and reduced pneumolysin secretion. Conclusions These findings suggest that differences in microinvasion and epithelial responses were driven by the differential expression of multiple bacterial virulence and metabolic pathways. These data highlight the complex impact of single gene mutations on bacterial virulence and suggest that the virulence determinants of pneumococcal epithelial colonization, microinvasion, and innate immunity are not necessarily directly linked to disease.
{"title":"Disease-Attenuated Pneumococcal Biosynthesis Gene Mutants Invade the Mucosal Epithelium and Induce Innate Immunity","authors":"Caroline M Weight, Gabriele Pollara, Modupeh Betts, Roberta Ragazzini, Elisa Ramos-Sevillano, Jesús Reiné, Matthew Whelan, José Afonso Guerra-Assunção, Michael Connor, Paola Bonfanti, Clare Jolly, Mahdad Noursadeghi, Daniela M Ferreira, Jeremy S Brown, Robert S Heyderman","doi":"10.1093/infdis/jiag124","DOIUrl":"https://doi.org/10.1093/infdis/jiag124","url":null,"abstract":"Background Nasopharyngeal colonization by Streptococcus pneumoniae is characterized by bacterial adherence to epithelial cells, microinvasion, and innate immune activation. Previously, we have shown that two serotype 6B S pneumoniae mutant strains affecting bacterial metabolism (ΔproABC/pia and Δfhs/pia) colonize humans and mice, but in a murine disease model do not cause invasive infection. Methods Using an experimental human pneumococcal challenge model, ex vivo airway cells, and in vitro nasopharyngeal epithelium, we explore whether microinvasion and innate immune responses persist despite disease attenuation. Results We show that under serum stress, these biosynthesis gene mutations had a broad but different impact on pneumococcal virulence gene expression, oxidative stress regulation, and purine and carbohydrate metabolism genes. However, although these mutations did not attenuate microinvasion in human challenge and epithelial models, there was less transmigration of Detroit 562 nasopharyngeal epithelial cells by the mutants compared to wild-type. Cellular reorganization of primary human airway epithelium varied considerably between strains. Compared to wild-type, infection of Detroit 562 epithelial cells by the Δfhs/piaA strain, but not the ΔproABC/piaA strain, was less proinflammatory, induced less caspase 8 production, and was associated with increased pneumococcal hydrogen peroxide and reduced pneumolysin secretion. Conclusions These findings suggest that differences in microinvasion and epithelial responses were driven by the differential expression of multiple bacterial virulence and metabolic pathways. These data highlight the complex impact of single gene mutations on bacterial virulence and suggest that the virulence determinants of pneumococcal epithelial colonization, microinvasion, and innate immunity are not necessarily directly linked to disease.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Letter to the Editor: \"Bridging the Immunity Gap: Balancing Infant Protection and Long-term Immunity in the Post-Pandemic Era \".","authors":"Pan Ma,Gang Tian","doi":"10.1093/infdis/jiag177","DOIUrl":"https://doi.org/10.1093/infdis/jiag177","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"271 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kingsley King-Gee Tam, Carl J E Suster, Winkie Fong, Tanya Golubchik, Varsha Sivalingam, Neisha Jeoffreys, Enoch Tay, Danny Ko, Michael C Wehrhahn, Andrew N Ginn, Jennifer Robson, Indya Gardner, Lito E Papanicolas, Karina Kennedy, Maryza Graham, Thomas Tran, David Speers, Louise Cooley, Rob W Baird, Ella M Meumann, Jaimee Harbidge, Stuart Campbell, Kerri Basile, Sharon C-A Chen, Vitali Sintchenko, Jen Kok, Rebecca J Rockett
Background The resurgence of Mycoplasma pneumoniae (MP), first reported in China in 2023 was attributed to waning post-pandemic immunity with notable increases in macrolide-resistant MP (MRMP) (>80%). In Australia, infections peaked in early 2024, particularly among children under 15. While MRMP remains low in Europe, North America, and Australia (<5%), limited routine testing and surveillance restricts understanding of resistance dynamics. As macrolides are first-line therapy in many health settings, MRMP surveillance is essential for guiding empirical treatment and stewardship. Methods We applied a novel capture-based targeted metagenomic sequencing (tNGS) to PCR-positive MP specimens (n=356) from across Australia. This approach enabled whole-genome recovery and MRMP detection directly from clinical specimens, without culture. MRMP detections were benchmarked against RT-PCR and clinical data were analysed to assess associations between resistance and healthcare utilisation. Results This is the first genomics-informed national study of MP in Australia. We recovered 124 high-quality genomes, revealing a genetically diverse population with co-circulation of P1 Type 1 (69%) and Type 2 (31%). MRMP was identified in 13% of genomes, all belonging to clades prior to 2024 had only been reported in Asia (ST3 and ST14). MRMP cases were geographically widespread, suggesting importation and local transmission. Unlike reports from China, macrolide-susceptible clades (ST3, ST7, ST17 and ST20) predominated (87%) and were associated to significant lower healthcare utilisation compared to MRMP cases. Conclusion Our findings demonstrate the utility of tNGS for genomic epidemiology and highlight the need for MRMP surveillance. Although macrolides remain effective in Australia, emerging MRMP strains require close monitoring to inform treatment guidelines and antimicrobial stewardship.
{"title":"Genomic Surveillance Reveals Emergence and Spread of Macrolide-Resistant Mycoplasma pneumoniae in Australia During the 2023–2024 Epidemic","authors":"Kingsley King-Gee Tam, Carl J E Suster, Winkie Fong, Tanya Golubchik, Varsha Sivalingam, Neisha Jeoffreys, Enoch Tay, Danny Ko, Michael C Wehrhahn, Andrew N Ginn, Jennifer Robson, Indya Gardner, Lito E Papanicolas, Karina Kennedy, Maryza Graham, Thomas Tran, David Speers, Louise Cooley, Rob W Baird, Ella M Meumann, Jaimee Harbidge, Stuart Campbell, Kerri Basile, Sharon C-A Chen, Vitali Sintchenko, Jen Kok, Rebecca J Rockett","doi":"10.1093/infdis/jiag163","DOIUrl":"https://doi.org/10.1093/infdis/jiag163","url":null,"abstract":"Background The resurgence of Mycoplasma pneumoniae (MP), first reported in China in 2023 was attributed to waning post-pandemic immunity with notable increases in macrolide-resistant MP (MRMP) (&gt;80%). In Australia, infections peaked in early 2024, particularly among children under 15. While MRMP remains low in Europe, North America, and Australia (&lt;5%), limited routine testing and surveillance restricts understanding of resistance dynamics. As macrolides are first-line therapy in many health settings, MRMP surveillance is essential for guiding empirical treatment and stewardship. Methods We applied a novel capture-based targeted metagenomic sequencing (tNGS) to PCR-positive MP specimens (n=356) from across Australia. This approach enabled whole-genome recovery and MRMP detection directly from clinical specimens, without culture. MRMP detections were benchmarked against RT-PCR and clinical data were analysed to assess associations between resistance and healthcare utilisation. Results This is the first genomics-informed national study of MP in Australia. We recovered 124 high-quality genomes, revealing a genetically diverse population with co-circulation of P1 Type 1 (69%) and Type 2 (31%). MRMP was identified in 13% of genomes, all belonging to clades prior to 2024 had only been reported in Asia (ST3 and ST14). MRMP cases were geographically widespread, suggesting importation and local transmission. Unlike reports from China, macrolide-susceptible clades (ST3, ST7, ST17 and ST20) predominated (87%) and were associated to significant lower healthcare utilisation compared to MRMP cases. Conclusion Our findings demonstrate the utility of tNGS for genomic epidemiology and highlight the need for MRMP surveillance. Although macrolides remain effective in Australia, emerging MRMP strains require close monitoring to inform treatment guidelines and antimicrobial stewardship.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aditi Mukherjee,Sofia O P Blomqvist,David Helekal,Apabrita A Das,Samantha G Palace,Yonatan H Grad
BACKGROUNDThe emergence of multi-drug-resistant Neisseria gonorrhoeae has created an urgent need for new therapeutic options. Zoliflodacin and gepotidacin, two first-in-class topoisomerase inhibitors, are oral antibiotics recently approved by FDA for gonorrhea treatment. Resistance to zoliflodacin can occur through gyrBD429N, but this mutation's impact on fitness and on resistance to other topoisomerase targeting drugs have been unclear. The aim of this study was to investigate the in vitro fitness and antibiotic resistance implications of gyrBD429N in ciprofloxacin-resistant N. gonorrhoeae strains.METHODSWe introduced the gyrBD429N substitution into 9 clinical strains via transformation. Antimicrobial susceptibility testing was performed for zoliflodacin, gepotidacin, and ciprofloxacin using standard MIC assays. In vitro relative fitness of parent and resistant mutant strains was assessed by pairwise competition experiments.RESULTSgyrB D429N conferred cross-resistance to gepotidacin in 3 clinical strains, and its fitness effect varied by strain background. In particular, parCD86N appeared to potentiate gyrBD429N cross-resistance to gepotidacin, a drug for which resistance has previously only been seen in the presence of both parCD86N and gyrAA92T mutations.CONCLUSIONGenetic background modulated the phenotypic effects of a zoliflodacin-resistance determinant on fitness and cross-resistance to gepotidacin. These findings inform strategies for introducing the new topoisomerase inhibitors into clinical use and for surveillance of resistance.
{"title":"Genetic background modulates zoliflodacin and gepotidacin cross-resistance and fitness in Neisseria gonorrhoeae.","authors":"Aditi Mukherjee,Sofia O P Blomqvist,David Helekal,Apabrita A Das,Samantha G Palace,Yonatan H Grad","doi":"10.1093/infdis/jiag174","DOIUrl":"https://doi.org/10.1093/infdis/jiag174","url":null,"abstract":"BACKGROUNDThe emergence of multi-drug-resistant Neisseria gonorrhoeae has created an urgent need for new therapeutic options. Zoliflodacin and gepotidacin, two first-in-class topoisomerase inhibitors, are oral antibiotics recently approved by FDA for gonorrhea treatment. Resistance to zoliflodacin can occur through gyrBD429N, but this mutation's impact on fitness and on resistance to other topoisomerase targeting drugs have been unclear. The aim of this study was to investigate the in vitro fitness and antibiotic resistance implications of gyrBD429N in ciprofloxacin-resistant N. gonorrhoeae strains.METHODSWe introduced the gyrBD429N substitution into 9 clinical strains via transformation. Antimicrobial susceptibility testing was performed for zoliflodacin, gepotidacin, and ciprofloxacin using standard MIC assays. In vitro relative fitness of parent and resistant mutant strains was assessed by pairwise competition experiments.RESULTSgyrB D429N conferred cross-resistance to gepotidacin in 3 clinical strains, and its fitness effect varied by strain background. In particular, parCD86N appeared to potentiate gyrBD429N cross-resistance to gepotidacin, a drug for which resistance has previously only been seen in the presence of both parCD86N and gyrAA92T mutations.CONCLUSIONGenetic background modulated the phenotypic effects of a zoliflodacin-resistance determinant on fitness and cross-resistance to gepotidacin. These findings inform strategies for introducing the new topoisomerase inhibitors into clinical use and for surveillance of resistance.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"49 3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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