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Gebreegziabher EA, Ouattara M, Bountogo M, Coulibaly B, Boudo V, Ouedraogo T, Lebas E, Hu H, O'Brien KS, Hsiang MS, Glidden DV, Arnold BF, Lietman TM, Sié A, Oldenburg CE. The role of Seasonal Malaria Chemoprevention in the effect of Azithromycin on Child Mortality: A Secondary Analysis of the CHAT Cluster Randomized Clinical Trial. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.04.30.25326740. [PMID: 40343013 PMCID: PMC12060949 DOI: 10.1101/2025.04.30.25326740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 05/11/2025]
Abstract
Objective Mass treatment with azithromycin (AZ) and administration of seasonal malaria chemoprevention (SMC) are both effective in reducing mortality among children under 5. However, it is not clear whether the benefit of AZ for mortality varies in the presence of routine SMC administration. The objective of this study was to examine whether the effect of mass AZ distribution on all-cause mortality among children less than 5 years of age varies with SMC administration season or SMC coverage. Methods This was a secondary analysis of the Community Health with Azithromycin Trial (CHAT), a cluster randomized placebo-controlled trial of 341 communities in the Nouna District of Burkina Faso. Communities randomized to intervention received treatment with twice yearly mass AZ while control communities receive placebo. All communities received SMC as standard-of-care. SMC administration and coverage data were provided from National Malaria Control Program. SMC administration season was defined as the period during and immediately following SMC (July-December) versus the months of no SMC (January-June). SMC coverage was assessed as proportion of the population covered and by whether it was below or above a threshold of 80%. We used Poisson regression models with person-time at risk used as an offset and robust standard error to analyze mortality rates by treatment group and SMC subgroups and assessed interaction on both the multiplicative and additive scales. Results Mortality was higher in SMC seasons for both arms, with a mortality rate of 10.3 per 1,000 person-years (95% CI: 9.0 to 11.6) in SMC seasons and 7.9 (95% CI: 6.9 to 9.0) in non-SMC seasons. Compared to placebo, the mortality rate in AZ clusters was 0.77 (95% CI: 0.60 to 0.98) during SMC season, while it was 0.89 (95% CI: 0.68 to 1.15) during the non-SMC seasons. The effect of AZ compared to placebo in clusters with <80% SMC coverage was 0.73 95%CI (0.56 to 0.96) and in clusters with ≥80% SMC coverage, it was 1.0 95%CI (0.59 to 1.69). The interaction between AZ and SMC season or coverage was not statistically significant on the additive or multiplicative scales. Conclusion While our findings did not reach statistical significance, they raise the question of whether prioritizing MDA AZ during high transmission periods or in regions with low SMC coverage could be beneficial. Further research is needed to determine if targeting these periods or areas could lead to greater reductions in child mortality. Trial Registration ClinicalTrials.gov Identifier: NCT03676764.
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Affiliation(s)
- Elisabeth A Gebreegziabher
- Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco
| | | | | | | | - Valentin Boudo
- Centre de Recherche en Sante de Nouna, Nouna, Burkina Faso
| | | | - Elodie Lebas
- Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA
| | - Huiyu Hu
- Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA
| | - Kieran S O'Brien
- Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco
- Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA
| | - Michelle S Hsiang
- Department of Epidemiology and Biostatistics, University of California, San Francisco
- Malaria Elimination Initiative, Institute for Global Health Sciences, University of California San Francisco, San Francisco, CA, USA
- Division of Pediatric Infectious Diseases, Department of Pediatrics, San Francisco, CA, USA
| | - David V Glidden
- Department of Epidemiology and Biostatistics, University of California, San Francisco
| | - Benjamin F Arnold
- Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA
- Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA
| | - Thomas M Lietman
- Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA
- Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA
| | - Ali Sié
- Centre de Recherche en Sante de Nouna, Nouna, Burkina Faso
| | - Catherine E Oldenburg
- Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco
- Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA
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Szajewska H, Scott KP, de Meij T, Forslund-Startceva SK, Knight R, Koren O, Little P, Johnston BC, Łukasik J, Suez J, Tancredi DJ, Sanders ME. Antibiotic-perturbed microbiota and the role of probiotics. Nat Rev Gastroenterol Hepatol 2025; 22:155-172. [PMID: 39663462 DOI: 10.1038/s41575-024-01023-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 12/13/2024]
Abstract
The disruptive effect of antibiotics on the composition and function of the human microbiota is well established. However, the hypothesis that probiotics can help restore the antibiotic-disrupted microbiota has been advanced, with little consideration of the strength of evidence supporting it. Some clinical data suggest that probiotics can reduce antibiotic-related side effects, including Clostridioides difficile-associated diarrhoea, but there are no data that causally link these clinical effects to microbiota protection or recovery. Substantial challenges hinder attempts to address this hypothesis, including the absence of consensus on the composition of a 'normal' microbiota, non-standardized and evolving microbiome measurement methods, and substantial inter-individual microbiota variation. In this Review, we explore these complexities. First, we review the known benefits and risks of antibiotics, the effect of antibiotics on the human microbiota, the resilience and adaptability of the microbiota, and how microbiota restoration might be defined and measured. Subsequently, we explore the evidence for the efficacy of probiotics in preventing disruption or aiding microbiota recovery post-antibiotic treatment. Finally, we offer insights into the current state of research and suggest directions for future research.
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Affiliation(s)
- Hania Szajewska
- Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
| | - Karen P Scott
- Rowett Institute, University of Aberdeen, Aberdeen, UK
| | - Tim de Meij
- Department of Paediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands
| | - Sofia K Forslund-Startceva
- Experimental and Clinical Research Center, a joint cooperation of Max Delbruck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Max Delbruck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Rob Knight
- Department of Pediatrics, University of California San Diego, San Diego, CA, USA
- Department of Computer Science & Engineering, University of California San Diego, San Diego, CA, USA
- Shu Chien - Gene Lay Department of Bioengineering, University of California San Diego, San Diego, CA, USA
- Halıcıoğlu Data Science Institute, University of California San Diego, San Diego, CA, USA
- Center for Microbiome Innovation, University of California San Diego, San Diego, CA, USA
| | - Omry Koren
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
| | - Paul Little
- Primary Care Research Centre, University of Southampton, Southampton, UK
| | - Bradley C Johnston
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA
- Department of Epidemiology and Biostatistics, School of Public Health, Texas A&M University, College Station, TX, USA
| | - Jan Łukasik
- Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
| | - Jotham Suez
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Daniel J Tancredi
- Department of Pediatrics, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Mary Ellen Sanders
- International Scientific Association for Probiotics and Prebiotics, Consulting Scientific Advisor, Centennial, CO, USA.
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Getanda P, Jagne I, Bognini JD, Camara B, Sanyang B, Darboe S, Sambou E, Barry M, Kassibo K, Cham A, Mendy H, Singateh BKJ, Ndure E, Rouamba T, Bojang A, Bottomley C, Howden BP, D’Alessandro U, Tinto H, Roca A. Impact of Intrapartum Azithromycin on the Carriage and Antibiotic Resistance of Escherichia coli and Klebsiella pneumoniae in Mothers and Their Newborns: A Substudy of a Randomized, Double-Blind Trial Conducted in The Gambia and Burkina Faso. Clin Infect Dis 2024; 79:1338-1345. [PMID: 38752311 PMCID: PMC11650870 DOI: 10.1093/cid/ciae280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND Limited data exist on the effects of intrapartum azithromycin on the prevalence of carriage and antibiotic resistance of Enterobacterales. METHODS We conducted a randomized trial in The Gambia and Burkina Faso where women received intrapartum azithromycin (2 g) or placebo. We determined the impact of treatment on the prevalence of carriage and antibiotic resistance of Escherichia coli and Klebsiella pneumoniae by analyzing rectal swabs (RS), nasopharyngeal swabs (NPS), breast milk, and rectovaginal swabs (RVS). Bacteria were isolated microbiologically; antibiotic susceptibility was confirmed with an E-test. Prevalence ratios (PRs) with 95% confidence intervals (CIs) were used for comparison between arms. RESULTS In infants, E. coli carriage in RS was lower in the intervention than in the placebo arm at day 6 (63.0% vs 75.2%; PR, 0.84; 95% CI, .75-.95) and day 28 (52.7% vs 70.4%; 0.75; 0.64-0.87) post-intervention. Prevalence of azithromycin-resistant E. coli was higher in the azithromycin arm at day 6 (13.4% vs 3.6%; 3.75; 1.83-7.69) and day 28 (16.4% vs 9.6%; 1.71; 1.05-2.79). For K. pneumoniae, carriage in RS was higher in the intervention than in the placebo arm at day 6 (49.6% vs 37.2%, 1.33; 1.08-1.64) and day 28 (53.6% vs 32.9%, 1.63; 1.31-2.03). Prevalence of azithromycin-resistant K. pneumoniae was higher in the azithromycin arm at day 28 (7.3% vs 2.1%; 3.49; 1.30-9.37). No differences were observed for other sample types. CONCLUSIONS Intrapartum azithromycin decreased E. coli carriage but increased both K. pneumoniae carriage and azithromycin resistance in both bacteria. These data need to be considered together with efficacy results to balance the potential short- and long-term impact of the intervention. Clinical Trials Registration. www.clinicaltrials.gov: NCT03199547.
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Affiliation(s)
- Pauline Getanda
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Isatou Jagne
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Joel D Bognini
- Clinical Research Unit of Nanoro, Institut de Recherche en Sciences de la Santé, Nanoro, Burkina Faso
| | - Bully Camara
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Bakary Sanyang
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Saffiatou Darboe
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Ellen Sambou
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Momodou Barry
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Kady Kassibo
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Aminata Cham
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Harriet Mendy
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Bintou K J Singateh
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Ebrahim Ndure
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Toussaint Rouamba
- Clinical Research Unit of Nanoro, Institut de Recherche en Sciences de la Santé, Nanoro, Burkina Faso
| | - Abdoulie Bojang
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Christian Bottomley
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Benjamin P Howden
- Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Umberto D’Alessandro
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
| | - Halidou Tinto
- Clinical Research Unit of Nanoro, Institut de Recherche en Sciences de la Santé, Nanoro, Burkina Faso
| | - Anna Roca
- Disease Control and Elimination Theme, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine (MRCG @ LSHTM), Banjul, The Gambia
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Sansone NMS, Boschiero MN, Marson FAL. Efficacy of Ivermectin, Chloroquine/Hydroxychloroquine, and Azithromycin in Managing COVID-19: A Systematic Review of Phase III Clinical Trials. Biomedicines 2024; 12:2206. [PMID: 39457519 PMCID: PMC11505156 DOI: 10.3390/biomedicines12102206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/18/2024] [Accepted: 09/21/2024] [Indexed: 10/28/2024] Open
Abstract
Background: During the coronavirus disease (COVID)-19 pandemic several drugs were used to manage the patients mainly those with a severe phenotype. Potential drugs were used off-label and major concerns arose from their applicability to managing the health crisis highlighting the importance of clinical trials. In this context, we described the mechanisms of the three repurposed drugs [Ivermectin-antiparasitic drug, Chloroquine/Hydroxychloroquine-antimalarial drugs, and Azithromycin-antimicrobial drug]; and, based on this description, the study evaluated the clinical efficacy of those drugs published in clinical trials. The use of these drugs reflects the period of uncertainty that marked the beginning of the COVID-19 pandemic, which made them a possible treatment for COVID-19. Methods: In our review, we evaluated phase III randomized controlled clinical trials (RCTs) that analyzed the efficacy of these drugs published from the COVID-19 pandemic onset to 2023. We included eight RCTs published for Ivermectin, 11 RCTs for Chloroquine/Hydroxychloroquine, and three RCTs for Azithromycin. The research question (PICOT) accounted for P-hospitalized patients with confirmed or suspected COVID-19; I-use of oral or intravenous Ivermectin OR Chloroquine/Hydroxychloroquine OR Azithromycin; C-placebo or no placebo (standard of care); O-mortality OR hospitalization OR viral clearance OR need for mechanical ventilation OR clinical improvement; and T-phase III RCTs. Results: While studying these drugs' respective mechanisms of action, the reasons for which they were thought to be useful became apparent and are as follows: Ivermectin binds to insulin-like growth factor and prevents nuclear transportation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), therefore preventing cell entrance, induces apoptosis, and osmotic cell death and disrupts viral replication. Chloroquine/Hydroxychloroquine blocks the movement of SARS-CoV-2 from early endosomes to lysosomes inside the cell, also, this drug blocks the binding between SARS-CoV-2 and Angiotensin-Converting Enzyme (ACE)-2 inhibiting the interaction between the virus spike proteins and the cell membrane and this drug can also inhibit SARS-CoV-2 viral replication causing, ultimately, the reduction in viral infection as well as the potential to progression for a higher severity phenotype culminating with a higher chance of death. Azithromycin exerts a down-regulating effect on the inflammatory cascade, attenuating the excessive production of cytokines and inducing phagocytic activity, and acts interfering with the viral replication cycle. Ivermectin, when compared to standard care or placebo, did not reduce the disease severity, need for mechanical ventilation, need for intensive care unit, or in-hospital mortality. Only one study demonstrated that Ivermectin may improve viral clearance compared to placebo. Individuals who received Chloroquine/Hydroxychloroquine did not present a lower incidence of death, improved clinical status, or higher chance of respiratory deterioration compared to those who received usual care or placebo. Also, some studies demonstrated that Chloroquine/Hydroxychloroquine resulted in worse outcomes and side-effects included severe ones. Adding Azithromycin to a standard of care did not result in clinical improvement in hospitalized COVID-19 participants. In brief, COVID-19 was one of the deadliest pandemics in modern human history. Due to the potential health catastrophe caused by SARS-CoV-2, a global effort was made to evaluate treatments for COVID-19 to attenuate its impact on the human species. Unfortunately, several countries prematurely justified the emergency use of drugs that showed only in vitro effects against SARS-CoV-2, with a dearth of evidence supporting efficacy in humans. In this context, we reviewed the mechanisms of several drugs proposed to treat COVID-19, including Ivermectin, Chloroquine/Hydroxychloroquine, and Azithromycin, as well as the phase III clinical trials that evaluated the efficacy of these drugs for treating patients with this respiratory disease. Conclusions: As the main finding, although Ivermectin, Chloroquine/Hydroxychloroquine, and Azithromycin might have mechanistic effects against SARS-CoV-2 infection, most phase III clinical trials observed no treatment benefit in patients with COVID-19, underscoring the need for robust phase III clinical trials.
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Affiliation(s)
- Nathália Mariana Santos Sansone
- Laboratory of Molecular Biology and Genetics, Laboratory of Clinical and Molecular Microbiology, LunGuardian Research Group—Epidemiology of Respiratory and Infectious Diseases, São Francisco University, Bragança Paulista 12916-900, SP, Brazil; (N.M.S.S.); (M.N.B.)
| | - Matheus Negri Boschiero
- Laboratory of Molecular Biology and Genetics, Laboratory of Clinical and Molecular Microbiology, LunGuardian Research Group—Epidemiology of Respiratory and Infectious Diseases, São Francisco University, Bragança Paulista 12916-900, SP, Brazil; (N.M.S.S.); (M.N.B.)
- São Paulo Hospital, Federal University of São Paulo, São Paulo 04023-062, SP, Brazil
| | - Fernando Augusto Lima Marson
- Laboratory of Molecular Biology and Genetics, Laboratory of Clinical and Molecular Microbiology, LunGuardian Research Group—Epidemiology of Respiratory and Infectious Diseases, São Francisco University, Bragança Paulista 12916-900, SP, Brazil; (N.M.S.S.); (M.N.B.)
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Paulet E, Contreras V, Galhaut M, Rosenkrands I, Holland M, Burton M, Dietrich J, Gallouet AS, Bosquet N, Relouzat F, Langlois S, Follmann F, Le Grand R, Labetoulle M, Rousseau A. Multimodal mucosal and systemic immune characterization of a non-human primate trachoma model highlights the critical role of local immunity during acute phase disease. PLoS Negl Trop Dis 2024; 18:e0012388. [PMID: 39093884 PMCID: PMC11333008 DOI: 10.1371/journal.pntd.0012388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 08/19/2024] [Accepted: 07/19/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Trachoma is a leading cause of infection-related blindness worldwide. This disease is caused by recurrent Chlamydia trachomatis (Ct) infections of the conjunctiva and develops in two phases: i) active (acute trachoma, characterized by follicular conjunctivitis), then long-term: ii) scarring (chronic trachoma, characterized by conjunctival fibrosis, corneal opacification and eyelid malposition). Scarring trachoma is driven by the number and severity of reinfections. The immune system plays a pivotal role in trachoma including exacerbation of the disease. Hence the immune system may also be key to developing a trachoma vaccine. Therefore, we characterized clinical and local immune response kinetics in a non-human primate model of acute conjunctival Ct infection and disease. METHODOLOGY/PRINCIPAL FINDINGS The conjunctiva of non-human primate (NHP, Cynomolgus monkeys-Macaca fascicularis-) were inoculated with Ct (B/Tunis-864 strain, B serovar). Clinical ocular monitoring was performed using a standardized photographic grading system, and local immune responses were assessed using multi-parameter flow cytometry of conjunctival cells, tear fluid cytokines, immunoglobulins, and Ct quantification. Clinical findings were similar to those observed during acute trachoma in humans, with the development of typical follicular conjunctivitis from the 4th week post-exposure to the 11th week. Immunologic analysis indicated an early phase influx of T cells in the conjunctiva and elevated interleukins 4, 8, and 5, followed by a late phase monocytic influx accompanied with a decrease in other immune cells, and tear fluid cytokines returning to initial levels. CONCLUSION/SIGNIFICANCE Our NHP model accurately reproduces the clinical signs of acute trachoma, allowing for an accurate assessment of the local immune responses in infected eyes. A progressive immune response occurred for weeks after exposure to Ct, which subsided into a persistent innate immune response. An understanding of these local responses is the first step towards using the model to assess new vaccine and therapeutic strategies for disease prevention.
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Affiliation(s)
- Elodie Paulet
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Vanessa Contreras
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Mathilde Galhaut
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Ida Rosenkrands
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Martin Holland
- Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Matthew Burton
- International Centre for Eye Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Jes Dietrich
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Anne-Sophie Gallouet
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Nathalie Bosquet
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Francis Relouzat
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Sébastien Langlois
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Frank Follmann
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Roger Le Grand
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Marc Labetoulle
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
- Service d’Ophtalmologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
- Service d’Ophtalmologie, Hôpital National de la Vision des 15-20, IHU Foresight, Paris, France
| | - Antoine Rousseau
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
- Service d’Ophtalmologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
- Service d’Ophtalmologie, Hôpital National de la Vision des 15-20, IHU Foresight, Paris, France
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John CC, Namazzi R, Schneider JG. Azithromycin for Prevention of Mortality in African Children: More Data, More Questions. JAMA 2024; 331:475-476. [PMID: 38349381 DOI: 10.1001/jama.2023.27329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/15/2024]
Affiliation(s)
| | - Ruth Namazzi
- Makerere University College of Health Sciences, Kampala, Uganda
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Fishbein SRS, Mahmud B, Dantas G. Antibiotic perturbations to the gut microbiome. Nat Rev Microbiol 2023; 21:772-788. [PMID: 37491458 DOI: 10.1038/s41579-023-00933-y] [Citation(s) in RCA: 127] [Impact Index Per Article: 63.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2023] [Indexed: 07/27/2023]
Abstract
Antibiotic-mediated perturbation of the gut microbiome is associated with numerous infectious and autoimmune diseases of the gastrointestinal tract. Yet, as the gut microbiome is a complex ecological network of microorganisms, the effects of antibiotics can be highly variable. With the advent of multi-omic approaches for systems-level profiling of microbial communities, we are beginning to identify microbiome-intrinsic and microbiome-extrinsic factors that affect microbiome dynamics during antibiotic exposure and subsequent recovery. In this Review, we discuss factors that influence restructuring of the gut microbiome on antibiotic exposure. We present an overview of the currently complex picture of treatment-induced changes to the microbial community and highlight essential considerations for future investigations of antibiotic-specific outcomes. Finally, we provide a synopsis of available strategies to minimize antibiotic-induced damage or to restore the pretreatment architectures of the gut microbial community.
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Affiliation(s)
- Skye R S Fishbein
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Bejan Mahmud
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Gautam Dantas
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
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Pheeha SM, Tamuzi JL, Chale-Matsau B, Manda S, Nyasulu PS. A Scoping Review Evaluating the Current State of Gut Microbiota Research in Africa. Microorganisms 2023; 11:2118. [PMID: 37630678 PMCID: PMC10458939 DOI: 10.3390/microorganisms11082118] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 08/15/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The gut microbiota has emerged as a key human health and disease determinant. However, there is a significant knowledge gap regarding the composition, diversity, and function of the gut microbiota, specifically in the African population. This scoping review aims to examine the existing literature on gut microbiota research conducted in Africa, providing an overview of the current knowledge and identifying research gaps. A comprehensive search strategy was employed to identify relevant studies. Databases including MEDLINE (PubMed), African Index Medicus (AIM), CINAHL (EBSCOhost), Science Citation index (Web of Science), Embase (Ovid), Scopus (Elsevier), WHO International Clinical Trials Registry Platform (ICTRP), and Google Scholar were searched for relevant articles. Studies investigating the gut microbiota in African populations of all age groups were included. The initial screening included a total of 2136 articles, of which 154 were included in this scoping review. The current scoping review revealed a limited number of studies investigating diseases of public health significance in relation to the gut microbiota. Among these studies, HIV (14.3%), colorectal cancer (5.2%), and diabetes mellitus (3.9%) received the most attention. The top five countries that contributed to gut microbiota research were South Africa (16.2%), Malawi (10.4%), Egypt (9.7%), Kenya (7.1%), and Nigeria (6.5%). The high number (n = 66) of studies that did not study any specific disease in relation to the gut microbiota remains a gap that needs to be filled. This scoping review brings attention to the prevalent utilization of observational study types (38.3%) in the studies analysed and emphasizes the importance of conducting more experimental studies. Furthermore, the findings reflect the need for more disease-focused, comprehensive, and population-specific gut microbiota studies across diverse African regions and ethnic groups to better understand the factors shaping gut microbiota composition and its implications for health and disease. Such knowledge has the potential to inform targeted interventions and personalized approaches for improving health outcomes in African populations.
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Affiliation(s)
- Sara M. Pheeha
- Division of Epidemiology and Biostatistics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7500, South Africa; (S.M.P.)
- Department of Chemical Pathology, Faculty of Medicine and Health Sciences, Sefako Makgatho Health Sciences University, Pretoria 0208, South Africa
- National Health Laboratory Service, Dr George Mukhari Academic Hospital, Pretoria 0208, South Africa
| | - Jacques L. Tamuzi
- Division of Epidemiology and Biostatistics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7500, South Africa; (S.M.P.)
| | - Bettina Chale-Matsau
- Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria 0028, South Africa
- National Health Laboratory Service, Steve Biko Academic Hospital, Pretoria 0002, South Africa
| | - Samuel Manda
- Department of Statistics, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria 0028, South Africa
| | - Peter S. Nyasulu
- Division of Epidemiology and Biostatistics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7500, South Africa; (S.M.P.)
- Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
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9
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Vallet N, Salmona M, Malet-Villemagne J, Bredel M, Bondeelle L, Tournier S, Mercier-Delarue S, Cassonnet S, Ingram B, Peffault de Latour R, Bergeron A, Socié G, Le Goff J, Lepage P, Michonneau D. Circulating T cell profiles associate with enterotype signatures underlying hematological malignancy relapses. Cell Host Microbe 2023; 31:1386-1403.e6. [PMID: 37463582 DOI: 10.1016/j.chom.2023.06.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 07/20/2023]
Abstract
Early administration of azithromycin after allogeneic hematopoietic stem cell transplantation was shown to increase the relapse of hematological malignancies. To determine the impact of azithromycin on the post-transplant gut ecosystem and its influence on relapse, we characterized overtime gut bacteriome, virome, and metabolome of 55 patients treated with azithromycin or a placebo. We describe four enterotypes and the network of associated bacteriophage species and metabolic pathways. One enterotype associates with sustained remission. One taxon from Bacteroides specifically associates with relapse, while two from Bacteroides and Prevotella correlate with complete remission. These taxa are associated with lipid, pentose, and branched-chain amino acid metabolic pathways and several bacteriophage species. Enterotypes and taxa associate with exhausted T cells and the functional status of circulating immune cells. These results illustrate how an antibiotic influences a complex network of gut bacteria, viruses, and metabolites and may promote cancer relapse through modifications of immune cells.
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Affiliation(s)
- Nicolas Vallet
- Université de Paris Cité, INSERM U976, 75010 Paris, France
| | - Maud Salmona
- Université de Paris Cité, INSERM U976, 75010 Paris, France; Virology Department, AP-HP, Saint-Louis Hospital, 75010 Paris, France
| | - Jeanne Malet-Villemagne
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Domaine de Vilvert, 78350 Jouy-en-Josas, France
| | - Maxime Bredel
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Domaine de Vilvert, 78350 Jouy-en-Josas, France
| | - Louise Bondeelle
- Pneumology Unit, AP-HP, Saint-Louis Hospital, 75010 Paris, France
| | - Simon Tournier
- Core Facilities, Saint-Louis Research Institute, Université de Paris Cité, UAR 2030/US 53, 75010 Paris, France
| | | | - Stéphane Cassonnet
- Service de Biostatistique et Information Médicale, AP-HP, Saint-Louis Hospital, 75010 Paris, France
| | | | - Régis Peffault de Latour
- Hematology Transplantation, AP-HP, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75010 Paris, France; Cryostem Consortium, 13382 Marseille, France
| | - Anne Bergeron
- Pneumology Department, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Gérard Socié
- Université de Paris Cité, INSERM U976, 75010 Paris, France; Hematology Transplantation, AP-HP, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75010 Paris, France
| | - Jérome Le Goff
- Université de Paris Cité, INSERM U976, 75010 Paris, France; Virology Department, AP-HP, Saint-Louis Hospital, 75010 Paris, France
| | - Patricia Lepage
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Domaine de Vilvert, 78350 Jouy-en-Josas, France
| | - David Michonneau
- Université de Paris Cité, INSERM U976, 75010 Paris, France; Hematology Transplantation, AP-HP, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75010 Paris, France.
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10
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Luchen CC, Chibuye M, Spijker R, Simuyandi M, Chisenga C, Bosomprah S, Chilengi R, Schultsz C, Mende DR, Harris VC. Impact of antibiotics on gut microbiome composition and resistome in the first years of life in low- to middle-income countries: A systematic review. PLoS Med 2023; 20:e1004235. [PMID: 37368871 PMCID: PMC10298773 DOI: 10.1371/journal.pmed.1004235] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 04/13/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Inappropriate antimicrobial usage is a key driver of antimicrobial resistance (AMR). Low- and middle-income countries (LMICs) are disproportionately burdened by AMR and young children are especially vulnerable to infections with AMR-bearing pathogens. The impact of antibiotics on the microbiome, selection, persistence, and horizontal spread of AMR genes is insufficiently characterized and understood in children in LMICs. This systematic review aims to collate and evaluate the available literature describing the impact of antibiotics on the infant gut microbiome and resistome in LMICs. METHODS AND FINDINGS In this systematic review, we searched the online databases MEDLINE (1946 to 28 January 2023), EMBASE (1947 to 28 January 2023), SCOPUS (1945 to 29 January 2023), WHO Global Index Medicus (searched up to 29 January 2023), and SciELO (searched up to 29 January 2023). A total of 4,369 articles were retrieved across the databases. Duplicates were removed resulting in 2,748 unique articles. Screening by title and abstract excluded 2,666 articles, 92 articles were assessed based on the full text, and 10 studies met the eligibility criteria that included human studies conducted in LMICs among children below the age of 2 that reported gut microbiome composition and/or resistome composition (AMR genes) following antibiotic usage. The included studies were all randomized control trials (RCTs) and were assessed for risk of bias using the Cochrane risk-of-bias for randomized studies tool. Overall, antibiotics reduced gut microbiome diversity and increased antibiotic-specific resistance gene abundance in antibiotic treatment groups as compared to the placebo. The most widely tested antibiotic was azithromycin that decreased the diversity of the gut microbiome and significantly increased macrolide resistance as early as 5 days posttreatment. A major limitation of this study was paucity of available studies that cover this subject area. Specifically, the range of antibiotics assessed did not include the most commonly used antibiotics in LMIC populations. CONCLUSION In this study, we observed that antibiotics significantly reduce the diversity and alter the composition of the infant gut microbiome in LMICs, while concomitantly selecting for resistance genes whose persistence can last for months following treatment. Considerable heterogeneity in study methodology, timing and duration of sampling, and sequencing methodology in currently available research limit insights into antibiotic impacts on the microbiome and resistome in children in LMICs. More research is urgently needed to fill this gap in order to better understand whether antibiotic-driven reductions in microbiome diversity and selection of AMR genes place LMIC children at risk for adverse health outcomes, including infections with AMR-bearing pathogens.
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Affiliation(s)
- Charlie C. Luchen
- Amsterdam UMC, location University of Amsterdam, Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
- Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
- Amsterdam Institute of Infection and Immunity, Infectious Diseases, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Mwelwa Chibuye
- Amsterdam UMC, location University of Amsterdam, Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
- Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
- Amsterdam Institute of Infection and Immunity, Infectious Diseases, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Rene Spijker
- Amsterdam UMC, location University of Amsterdam, Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
| | - Michelo Simuyandi
- Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
| | - Caroline Chisenga
- Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
| | - Samuel Bosomprah
- Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
- Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana
| | - Roma Chilengi
- Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
- Zambia National Public Health Institute, Ministry of Health, Lusaka, Zambia
- Republic of Zambia State House, Lusaka, Zambia
| | - Constance Schultsz
- Amsterdam UMC, location University of Amsterdam, Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
- Amsterdam Institute of Infection and Immunity, Infectious Diseases, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology, Amsterdam, the Netherlands
| | - Daniel R. Mende
- Amsterdam Institute of Infection and Immunity, Infectious Diseases, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology, Amsterdam, the Netherlands
| | - Vanessa C. Harris
- Amsterdam UMC, location University of Amsterdam, Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
- Amsterdam Institute of Infection and Immunity, Infectious Diseases, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Amsterdam UMC, location University of Amsterdam, Department of Internal Medicine, Division of Infectious Diseases, Amsterdam, the Netherlands
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11
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Sinhorelli BS, Oliveira SD. Antimicrobial Prophylaxis in Dentistry: Survey among Dental Surgeons in Porto Alegre, Brazil, and the Metropolitan Region. Am J Trop Med Hyg 2023; 108:1071-1077. [PMID: 36940669 PMCID: PMC10160882 DOI: 10.4269/ajtmh.22-0580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 12/19/2022] [Indexed: 03/23/2023] Open
Abstract
The irrational use of antimicrobial drugs has become a serious epidemiological problem due to the development of bacterial resistance, causing consequences for global health. In dentistry, antibiotics are the second most common pharmacological class prescribed. Thus, we evaluated the use of antimicrobial prophylaxis by dentists in Porto Alegre, Brazil, and the metropolitan region using an online questionnaire. Dentists were asked to complete an anonymous questionnaire concerning antimicrobial prescription. The questionnaire was prepared on the Microsoft Forms platform and shared with dentists through social media and was available for a period of 40 days. The questionnaire was answered by 82 dentists, and 85.3% of them reported prescribing antibiotic prophylaxis (AP). Many different protocols were observed, but the majority of dentists prescribe amoxicillin (2 g) 1 hour before a procedure. The greatest diversity was found in the prescriptions for post-procedure prophylaxis, but most professionals prescribe 500 mg of antibiotics every 8 hours for 7 days. An overwhelming 91.5% of participants think that guidelines for prescribing antibiotics in dentistry are necessary, and 62.2% believe that the use of AP can have some impact on bacterial resistance. There is a wide range of different prescriptions for antimicrobials, suggesting a need for better aligned guidelines and education of professionals on the proper use of antimicrobials and its consequences on bacterial resistance to antibiotics.
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Affiliation(s)
- Bethina S. Sinhorelli
- Laboratório de Imunologia e Microbiologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
- Programa de Pós-graduação em Odontologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
| | - Sílvia D. Oliveira
- Laboratório de Imunologia e Microbiologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
- Programa de Pós-graduação em Odontologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
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12
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Kaur R, Kaur R, Varghese A, Garg N, Arora S. Antibiotics in Paediatrics: A Boon or a Bane? ANTI-INFECTIVE AGENTS 2023; 21. [DOI: 10.2174/2211352520666220822145139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 04/29/2022] [Accepted: 05/11/2022] [Indexed: 01/05/2025]
Abstract
Antibiotics play an essential role in antimicrobial therapy. Among all the medications
in children, the most commonly prescribed therapy is antibiotics and is currently the indispensable
means to cure transmissible diseases. Several categories of antibiotics have been introduced into
clinical practice to treat microbial infections. Reducing the unnecessary use of antibiotics is a
global need and priority. This article aims to provide better knowledge and understanding of the
impact of the early use of antibiotics. This article highlights the proper use of antibiotics in children,
detailing how early and inappropriate use of antibiotics affect the gut microbiome during
normal body development and consequently affect the metabolism due to diabetes mellitus, obesity,
and recurrence of infections, such as UTI. Several new antibiotics in their development stage,
newly marketed antibiotics, and some recalled and withdrawn from the market are also briefly
discussed in this article. This study will help future researchers in exploring the latest information
about antibiotics used in paediatrics.
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Affiliation(s)
- Rajwinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Rupinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Ashlin Varghese
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Nidhi Garg
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Sandeep Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
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13
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Kahn R, Eyal N, Sow SO, Lipsitch M. Mass drug administration of azithromycin: an analysis. Clin Microbiol Infect 2023; 29:326-331. [PMID: 36309328 DOI: 10.1016/j.cmi.2022.10.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 10/13/2022] [Accepted: 10/16/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND WHO recommends mass drug administration (MDA) of the antibiotic azithromycin for children aged 1-11 months in areas with high rates of infant and child mortality. Notwithstanding the substantial potential benefits of lowering childhood mortality, MDA raises understandable concerns about exacerbating antibiotic resistance. OBJECTIVES In this study, we aimed to evaluate the use of MDA using both quantitative and ethical considerations. SOURCES We performed a series of literature searches between July 2019 and June 2022. CONTENT We first compared MDA with other uses of antibiotics using the standard metric of 'number needed to treat', and five additional criteria: (1) other widely accepted uses of anti-infectives (2) absolute use (i.e. total number), of antibiotics, (3) risk-benefit trade-off, (4) availability of short-term alternatives, and (5) the precedent for implementing similar interventions. We found that MDA falls well within a justifiable range when compared with widely accepted uses of antibiotics in terms of the number needed to treat. The other five criteria we considered provided further support for the use of MDA to prevent childhood mortality. IMPLICATIONS Although better data on antibiotic use and resistance are needed, efforts to reduce antibiotic use and resistance should not start with halting MDA of azithromycin in the areas with the highest rates of childhood mortality. Improving data to inform this decision is critical. However, on the basis of the best evidence available, we believe that concerns regarding resistance should not thwart MDA; instead, MDA should be accompanied by robust plans to monitor its efficacy and changes in resistance levels. Similar considerations could be included in a framework for evaluating the benefits of antibiotics against the risk of resistance in other contexts.
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Affiliation(s)
- Rebecca Kahn
- Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
| | - Nir Eyal
- Center for Population-Level Bioethics, Rutgers University, New Brunswick, NJ, USA; Department of Health Behavior, Society and Policy, Rutgers School of Public Health, Piscataway, NJ, USA; Department of Philosophy, Rutgers University, New Brunswick, NJ, USA
| | - Samba O Sow
- Centre pour le Développement des Vaccins (CVD-Mali), Ministère de La Santé, BP251, Bamako, Mali; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Marc Lipsitch
- Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA
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14
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Rovira P. Short-Term Impact of Oxytetracycline Administration on the Fecal Microbiome, Resistome and Virulome of Grazing Cattle. Antibiotics (Basel) 2023; 12:antibiotics12030470. [PMID: 36978337 PMCID: PMC10044027 DOI: 10.3390/antibiotics12030470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/14/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
Antimicrobial resistance (AMR) is an important public health concern around the world. Limited information exists about AMR in grasslands-based systems where antibiotics are seldom used in beef cattle. The present study investigated the impacts of oxytetracycline (OTC) on the microbiome, antibiotic resistance genes (ARGs), and virulence factor genes (VFGs) in grazing steers with no previous exposure to antibiotic treatments. Four steers were injected with a single dose of OTC (TREAT), and four steers were kept as control (CONT). The effects of OTC on fecal microbiome, ARGs, and VFGs were assessed for 14 days using 16S rRNA sequencing and shotgun metagenomics. Alpha and beta microbiome diversities were significantly affected by OTC. Following treatment, less than 8% of bacterial genera had differential abundance between CONT and TREAT samples. Seven ARGs conferring resistance to tetracycline (tet32, tet40, tet44, tetO, tetQ, tetW, and tetW/N/W) increased their abundance in the post-TREAT samples compared to CONT samples. In addition, OTC use was associated with the enrichment of macrolide and lincosamide ARGs (mel and lnuC, respectively). The use of OTC had no significant effect on VFGs. In conclusion, OTC induced short-term alterations of the fecal microbiome and enrichment of ARGs in the feces of grazing beef cattle.
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Affiliation(s)
- Pablo Rovira
- Instituto Nacional de Investigación Agropecuaria (INIA Uruguay), Treinta y Tres 33000, Uruguay
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15
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de Campos LJ, Seleem MA, Feng J, Pires de Oliveira KM, de Andrade Dos Santos JV, Hayer S, Clayton JB, Kathi S, Fisher DJ, Ouellette SP, Conda-Sheridan M. Design, Biological Evaluation, and Computer-Aided Analysis of Dihydrothiazepines as Selective Antichlamydial Agents. J Med Chem 2023; 66:2116-2142. [PMID: 36696579 PMCID: PMC10056257 DOI: 10.1021/acs.jmedchem.2c01894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Chlamydia trachomatis (CT) causes the most prevalent sexually transmitted bacterial disease in the United States. The lack of drug selectivity is one of the main challenges of the current antichlamydial pharmacotherapy. The metabolic needs of CT are controlled, among others, by cylindrical proteases and their chaperones (e.g., ClpX). It has been shown that dihydrothiazepines can disrupt CT-ClpXP. Based on this precedent, we synthesized a dihydrothiazepine library and characterized its antichlamydial activity using a modified semi-high-throughput screening assay. Then, we demonstrated their ability to inhibit ClpX ATPase activity in vitro, supporting ClpX as a target. Further, our lead compound displayed a promising selectivity profile against CT, acceptable cytotoxicity, no mutagenic potential, and good in vitro stability. A two-dimensional quantitative structure-activity relationship (2D QSAR) model was generated as a support tool in the identification of more potent antichlamydial molecules. This study suggests dihydrothiazepines are a promising starting point for the development of new and selective antichlamydial drugs.
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Affiliation(s)
- Luana Janaína de Campos
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Mohamed A Seleem
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Jiachen Feng
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Kelly Mari Pires de Oliveira
- Faculty of Biological and Environmental Science, Federal University of Grande Dourados, Dourados, MS 79804-970, Brazil
| | | | - Shivdeep Hayer
- Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska 68182, United States
| | - Jonathan B Clayton
- Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska 68182, United States
- Department of Food Science and Technology, University of Nebraska─Lincoln, Lincoln, Nebraska 68588, United States
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
- Nebraska Food for Health Center, University of Nebraska─Lincoln, Lincoln, Nebraska 68508, United States
| | - Sharvath Kathi
- School of Biological Sciences, Southern Illinois University, Carbondale, Illinois 62901, United States
| | - Derek J Fisher
- School of Biological Sciences, Southern Illinois University, Carbondale, Illinois 62901, United States
| | - Scot P Ouellette
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Martin Conda-Sheridan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
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16
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Adubra L, Alber D, Ashorn P, Ashorn U, Cheung YB, Cloutman-Green E, Diallo F, Ducker C, Elovainio R, Fan YM, Gates L, Gruffudd G, Haapaniemi T, Haidara F, Hallamaa L, Ihamuotila R, Klein N, Luoma J, Martell O, Sow S, Vehmasto T, LAKANA Trial Team. Testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1-11-month-old infants in Mali (LAKANA): study protocol for a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial. Trials 2023; 24:5. [PMID: 36597115 PMCID: PMC9809521 DOI: 10.1186/s13063-022-06966-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 11/28/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Mass drug administration (MDA) of azithromycin (AZI) has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. A large-scale cluster-randomized trial conducted in Malawi, Niger, and Tanzania suggested that the effect differs by country, may be stronger in infants, and may be concentrated within the first 3 months after treatment. Another study found no effect when azithromycin was given concomitantly with seasonal malaria chemoprevention (SMC). Given the observed heterogeneity and possible effect modification by other co-interventions, further trials are needed to determine the efficacy in additional settings and to determine the most effective treatment regimen. METHODS LAKANA stands for Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin. The LAKANA trial is designed to address the mortality and health impacts of 4 or 2 annual rounds of azithromycin MDA delivered to 1-11-month-old (29-364 days) infants, in a high-mortality and malaria holoendemic Malian setting where there is a national SMC program. Participating villages (clusters) are randomly allocated in a ratio of 3:2:4 to three groups: placebo (control):4-dose AZI:2-dose AZI. The primary outcome measured is mortality. Antimicrobial resistance (AMR) will be monitored closely before, during, and after the intervention and both among those receiving and those not receiving MDA with the study drugs. Other outcomes, from a subset of villages, comprise efficacy outcomes related to morbidity, growth and nutritional status, outcomes related to the mechanism of azithromycin activity through measures of malaria parasitemia and inflammation, safety outcomes (AMR, adverse and serious adverse events), and outcomes related to the implementation of the intervention documenting feasibility, acceptability, and economic aspects. The enrolment commenced in October 2020 and is planned to be completed by the end of 2022. The expected date of study completion is December 2024. DISCUSSION If LAKANA provides evidence in support of a positive mortality benefit resulting from azithromycin MDA, it will significantly contribute to the options for successfully promoting child survival in Mali, and elsewhere in sub-Saharan Africa. TRIAL REGISTRATION ClinicalTrials.gov NCT04424511. Registered on 11 June 2020.
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Affiliation(s)
- Laura Adubra
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Dagmar Alber
- grid.83440.3b0000000121901201Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Per Ashorn
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland ,grid.412330.70000 0004 0628 2985Department of Paediatrics, Tampere University Hospital, Tampere, Finland
| | - Ulla Ashorn
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Yin Bun Cheung
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland ,grid.428397.30000 0004 0385 0924Program in Health Services and Systems Research and Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore
| | - Elaine Cloutman-Green
- grid.83440.3b0000000121901201Great Ormond Street Institute of Child Health, University College London, London, UK
| | | | | | - Riku Elovainio
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Yue-Mei Fan
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Lily Gates
- grid.83440.3b0000000121901201Great Ormond Street Institute of Child Health, University College London, London, UK
| | | | - Tiia Haapaniemi
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | | | - Lotta Hallamaa
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Rikhard Ihamuotila
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Nigel Klein
- grid.83440.3b0000000121901201Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Juho Luoma
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | | | - Samba Sow
- Center for Vaccine Development, Bamako, Mali
| | - Taru Vehmasto
- grid.502801.e0000 0001 2314 6254Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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17
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Alasmar A, Kong AC, So AD, DeCamp M. Ethical challenges in mass drug administration for reducing childhood mortality: a qualitative study. Infect Dis Poverty 2022; 11:99. [PMID: 36114588 PMCID: PMC9482260 DOI: 10.1186/s40249-022-01023-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/01/2022] [Indexed: 11/10/2022] Open
Abstract
Background Mass drug administration (MDA) of medications to entire at-risk communities or populations has shown promise in the control and elimination of global infectious diseases. MDA of the broad-spectrum antibiotic azithromycin has demonstrated the potential to reduce childhood mortality in children at risk of premature death in some global settings. However, MDA of antibiotics raises complex ethical challenges, including weighing near-term benefits against longer-term risks—particularly the development of antimicrobial resistance that could diminish antibiotic effectiveness for current or future generations. The aim of this study was to understand how key actors involved in MDA perceive the ethical challenges of MDA. Methods We conducted 35 semi-structured interviews from December 2020–February 2022 with investigators, funders, bioethicists, research ethics committee members, industry representatives, and others from both high-income countries (HICs) and low- and middle-income countries (LMICs). Interview participants were identified via one of seven MDA studies purposively chosen to represent diversity in terms of use of the antibiotic azithromycin; use of a primary mortality endpoint; and whether the study occurred in a high child mortality country. Data were analyzed using constructivist grounded theory methodology. Results The most frequently discussed ethical challenges related to meaningful community engagement, how to weigh risks and benefits, and the need to target MDA We developed a concept map of how participants considered ethical issues in MDA for child mortality; it emphasizes MDA’s place alongside other public health interventions, empowerment, and equity. Concerns over an ethical double standard in weighing risks and benefits emerged as a unifying theme, albeit one that participants interpreted in radically different ways. Some thought MDA for reducing child mortality was ethically obligatory; others suggested it was impermissible. Conclusions Ethical challenges raised by MDA of antibiotics for childhood mortality—which span socio-cultural issues, the environment, and effects on future generations—require consideration beyond traditional clinical trial review. The appropriate role of MDA also requires attention to concerns over ethical double standards and power dynamics in global health that affect how we view antibiotic use in HICs versus LMICs. Our findings suggest the need to develop additional, comprehensive guidance on managing ethical challenges in MDA. Graphical Abstract ![]()
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Valentino MS, Esposito C, Colosimo S, Caprio AM, Puzone S, Guarino S, Marzuillo P, Miraglia del Giudice E, Di Sessa A. Gut microbiota and COVID-19: An intriguing pediatric perspective. World J Clin Cases 2022; 10:8076-8087. [PMID: 36159525 PMCID: PMC9403663 DOI: 10.12998/wjcc.v10.i23.8076] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 06/14/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) involvement has been reported in approximately 50% of patients with coronavirus disease 2019 (COVID-19), which is due to the pathogenic role of inflammation and the intestinal function of the angiotensin-converting enzyme 2 and its receptor. Accumulating adult data has pointed out that gut dysbiosis might occur in these patients with a potential impact on the severity of the disease, however the role of gut microbiota in susceptibility and severity of COVID-19 disease in children is still poorly known. During the last decades, the crosstalk between gut and lung has been largely recognized resulting in the concept of "gut-lung axis" as a central player in modulating the development of several diseases. Both organs are involved in the common mucosal immune system (including bronchus-associated and gut-associated lymphoid tissues) and their homeostasis is crucial for human health. In this framework, it has been found that the role of GI dysbiosis is affecting the homeostasis of the gut-liver axis. Of note, a gut microbiome imbalance has been linked to COVID-19 severity in adult subjects, but it remains to be clarified. Based on the increased risk of inflammatory diseases in children with COVID-19, the potential correlation between gut microbiota dysfunction and COVID-19 needs to be studied in this population. We aimed to summarize the most recent evidence on this striking aspect of COVID-19 in childhood.
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Affiliation(s)
- Maria Sole Valentino
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Claudia Esposito
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Simone Colosimo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Angela Maria Caprio
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Simona Puzone
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Stefano Guarino
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Emanuele Miraglia del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Anna Di Sessa
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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19
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Azithromycin Has Been Flying Off the Shelves: The Italian Lesson Learnt from Improper Use of Antibiotics against COVID-19. Medicina (B Aires) 2022; 58:medicina58030363. [PMID: 35334539 PMCID: PMC8955327 DOI: 10.3390/medicina58030363] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/11/2022] [Accepted: 02/28/2022] [Indexed: 01/11/2023] Open
Abstract
The warning by the Italian Medicines Agency on the high shortage of azithromycin in the country in January 2022 represents a paradigmatic lesson learnt from improper use of antibiotics during COVID-19 pandemic.
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