-
The New England Journal of Medicine Nov 2020Mass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Mass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear.
METHODS
We investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants' gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months.
RESULTS
Over the entire 48-month period, the mean (±SD) coverage was 86.6±12% in the villages that received placebo and 83.2±16.4% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of nonmacrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa.
CONCLUSIONS
Among villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02047981.).
Topics: Anti-Bacterial Agents; Azithromycin; Child Mortality; Child, Preschool; Drug Resistance, Bacterial; Female; Gastrointestinal Microbiome; Humans; Infant; Macrolides; Male; Mass Drug Administration; Metagenome; Niger; Sequence Analysis, DNA
PubMed: 33176084
DOI: 10.1056/NEJMoa2002606 -
PloS One 2019The environment receives antibiotics through a combination of direct application (e.g., aquaculture and fruit production), as well as indirect release through...
The environment receives antibiotics through a combination of direct application (e.g., aquaculture and fruit production), as well as indirect release through pharmaceutical manufacturing, sewage and animal manure. Antibiotic concentrations in many sewage-impacted rivers are thought to be sufficient to select for antibiotic resistance genes. Yet, because antibiotics are nearly always found associated with antibiotic-resistant faecal bacteria in wastewater, it is difficult to distinguish the selective role of effluent antibiotics within a 'sea' of gut-derived resistance genes. Here we examine the potential for macrolide and fluoroquinolone prescribing in England to select for resistance in the River Thames catchment, England. We show that 64% and 74% of the length of the modelled catchment is chronically exposed to putative resistance-selecting concentrations (PNEC) of macrolides and fluoroquinolones, respectively. Under current macrolide usage, 115 km of the modelled River Thames catchment (8% of total length) exceeds the PNEC by 5-fold. Similarly, under current fluoroquinolone usage, 223 km of the modelled River Thames catchment (16% of total length) exceeds the PNEC by 5-fold. Our results reveal that if reduced prescribing was the sole mitigating measure, that macrolide and fluoroquinolone prescribing would need to decline by 77% and 85%, respectively, to limit resistance selection in the catchment. Significant reductions in antibiotic prescribing are feasible, but innovation in sewage-treatment will be necessary for achieving substantially-reduced antibiotic loads and inactivation of DNA-pollution from resistant bacteria. Greater confidence is needed in current risk-based targets for antibiotics, particularly in mixtures, to better inform environmental risk assessments and mitigation.
Topics: Anti-Bacterial Agents; Databases, Factual; Drug Prescriptions; Drug Resistance, Microbial; England; Fluoroquinolones; Macrolides; Rivers; Seasons; Sewage
PubMed: 31483803
DOI: 10.1371/journal.pone.0221568 -
Pharmacogenetics and Genomics Apr 2017
Topics: Anti-Bacterial Agents; Azithromycin; Bacteria; Clarithromycin; Erythromycin; Humans; Macrolides; Pharmacogenetics; Signal Transduction
PubMed: 28146011
DOI: 10.1097/FPC.0000000000000270 -
Microbiology Spectrum Aug 2023Long-term low-dose macrolide therapy is now widely used in the treatment of chronic respiratory diseases for its immune-modulating effects, although the antimicrobial...
Long-term low-dose macrolide therapy is now widely used in the treatment of chronic respiratory diseases for its immune-modulating effects, although the antimicrobial properties of macrolides can also have collateral impacts on the gut microbiome. We investigated whether such treatment altered intestinal commensal microbiology and whether any such changes affected systemic immune and metabolic regulation. In healthy adults exposed to 4 weeks of low-dose erythromycin or azithromycin, as used clinically, we observed consistent shifts in gut microbiome composition, with a reduction in microbial capacity related to carbohydrate metabolism and short-chain fatty acid biosynthesis. These changes were accompanied by alterations in systemic biomarkers relating to immune (interleukin 5 [IL-5], IL-10, monocyte chemoattractant protein 1 [MCP-1]) and metabolic (serotonin [5-HT], C-peptide) homeostasis. Transplantation of erythromycin-exposed murine microbiota into germ-free mice demonstrated that changes in metabolic homeostasis and gastrointestinal motility, but not systemic immune regulation, resulted from changes in intestinal microbiology caused by macrolide treatment. Our findings highlight the potential for long-term low-dose macrolide therapy to influence host physiology via alteration of the gut microbiome. Long-term macrolide therapy is widely used in chronic respiratory diseases although its antibacterial activity can also affect the gut microbiota, a key regulator of host physiology. Macrolide-associated studies on the gut microbiota have been limited to short antibiotic courses and have not examined its consequences for host immune and metabolic regulation. This study revealed that long-term macrolides depleted keystone bacteria and impacted host regulation, mediated directly by macrolide activity or indirectly by alterations to the gut microbiota. Understanding these macrolide-associated mechanisms will contribute to identifying the risk of long-term exposure and highlights the importance of targeted therapy for maintenance of the gut microbiota.
Topics: Animals; Mice; Gastrointestinal Microbiome; Macrolides; Anti-Bacterial Agents; Erythromycin; Respiratory Tract Diseases
PubMed: 37347185
DOI: 10.1128/spectrum.00831-23 -
Accounts of Chemical Research Apr 2021Continued, rapid development of antimicrobial resistance has become worldwide health crisis and a burden on the global economy. Decisive and comprehensive action is...
Continued, rapid development of antimicrobial resistance has become worldwide health crisis and a burden on the global economy. Decisive and comprehensive action is required to slow down the spread of antibiotic resistance, including increased investment in antibiotic discovery, sustainable policies that provide returns on investment for newly launched antibiotics, and public education to reduce the overusage of antibiotics, especially in livestock and agriculture. Without significant changes in the current antibiotic pipeline, we are in danger of entering a post-antibiotic era.In this Account, we summarize our recent efforts to develop next-generation streptogramin and lankacidin antibiotics that overcome bacterial resistance by means of modular chemical synthesis. First, we describe our highly modular, scalable route to four natural group A streptogramins antibiotics in 6-8 steps from seven simple chemical building blocks. We next describe the application of this route to the synthesis of a novel library of streptogramin antibiotics informed by in vitro and in vivo biological evaluation and high-resolution cryo-electron microscopy. One lead compound showed excellent inhibitory activity in vitro and in vivo against a longstanding streptogramin-resistance mechanism, virginiamycin acetyltransferase. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.Second, we recount our modular approaches toward lankacidin antibiotics. Lankacidins are a group of polyketide natural products with activity against several strains of Gram-positive bacteria but have not been deployed as therapeutics due to their chemical instability. We describe a route to several diastereomers of 2,18--lankacidinol B in a linear sequence of ≤8 steps from simple building blocks, resulting in a revision of the C4 stereochemistry. We next detail our modular synthesis of several diastereoisomers of -lankacidinol that resulted in the structural reassignment of this natural product. These structural revisions raise interesting questions about the biosynthetic origin of lankacidins, all of which possessed uniform stereochemistry prior to these findings. Finally, we summarize the ability of several - and -lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro, providing important insights into structure-function relationships for the class.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Escherichia coli; Gram-Negative Bacteria; Gram-Positive Bacteria; Macrolides; Microbial Sensitivity Tests; Molecular Conformation; Molecular Dynamics Simulation; Ribosomes; Streptogramins; Virginiamycin
PubMed: 33792282
DOI: 10.1021/acs.accounts.0c00894 -
Microbiology Spectrum Aug 2023We present two independent cases of recurrent multidrug-resistant Campylobacter jejuni infection in immunocompromised hosts and the clinical challenges encountered due...
We present two independent cases of recurrent multidrug-resistant Campylobacter jejuni infection in immunocompromised hosts and the clinical challenges encountered due to the development of high-level carbapenem resistance. The mechanisms associated with this unusual resistance for were characterized. Initial macrolide and carbapenem-susceptible strains acquired resistance to erythromycin (MIC > 256mg/L), ertapenem (MIC > 32mg/L), and meropenem (MIC > 32mg/L) during treatment. Carbapenem-resistant isolates developed an in-frame insertion resulting in an extra Asp residue in the major outer membrane protein PorA, within the extracellular loop L3 that connects β-strands 5 and 6 and forms a constriction zone involved in Ca binding. The isolates presenting the highest MIC to ertapenem exhibited an extra nonsynonymous mutation (G167A|Gly56Asp) at PorA's extracellular loop L1. Carbapenem susceptibility patterns suggest drug impermeability, related to either insertion and/or single nucleotide polymorphism (SNP) within A. Similar molecular events occurring in two independent cases support the association of these mechanisms with carbapenem resistance in Campylobacter spp.
Topics: Humans; Macrolides; Carbapenems; Campylobacter jejuni; Ertapenem; Drug Resistance, Bacterial; Anti-Bacterial Agents; Campylobacter Infections; Microbial Sensitivity Tests
PubMed: 37358443
DOI: 10.1128/spectrum.01070-23 -
Malaria Journal Nov 2016Malaria, a parasite vector-borne disease, is one of the most significant health threats in tropical regions, despite the availability of individual chemoprophylaxis.... (Review)
Review
Malaria, a parasite vector-borne disease, is one of the most significant health threats in tropical regions, despite the availability of individual chemoprophylaxis. Malaria chemoprophylaxis and chemotherapy remain a major area of research, and new drug molecules are constantly being developed before drug-resistant parasites strains emerge. The use of anti-malarial drugs is challenged by contra-indications, the level of resistance of Plasmodium falciparum in endemic areas, clinical tolerance and financial cost. New therapeutic approaches are currently needed to fight against this disease. Some antibiotics that have shown potential effects on malaria parasite have been recently studied in vitro or in vivo intensively. Two families, tetracyclines and macrolides and their derivatives have been particularly studied in recent years. However, other less well-known have been tested or are being used for malaria treatment. Some of these belong to older families, such as quinolones, co-trimoxazole or fusidic acid, while others are new drug molecules such as tigecycline. These emerging antibiotics could be used to prevent malaria in the future. In this review, the authors overview the use of antibiotics for malaria treatment.
Topics: Anti-Bacterial Agents; Antimalarials; Drug Repositioning; Humans; Macrolides; Malaria, Falciparum; Plasmodium falciparum; Tetracyclines
PubMed: 27846898
DOI: 10.1186/s12936-016-1613-y -
Antimicrobial Agents and Chemotherapy Mar 2023In Streptococcus pneumoniae (), the 5.4 to 5.5 kb Macrolide Genetic Assembly (Mega) encodes an efflux pump (Mef[E]) and a ribosomal protection protein (Mel) conferring...
In Streptococcus pneumoniae (), the 5.4 to 5.5 kb Macrolide Genetic Assembly (Mega) encodes an efflux pump (Mef[E]) and a ribosomal protection protein (Mel) conferring antibiotic resistance to commonly used macrolides in clinical isolates. We found the macrolide-inducible Mega operon provides heteroresistance (more than 8-fold range in MICs) to 14- and 15-membered ring macrolides. Heteroresistance is commonly missed during traditional clinical resistance screens but is highly concerning as resistant subpopulations can persist despite treatment. strains containing the Mega element were screened via Etesting and population analysis profiling (PAP). All Mega-containing strains screened displayed heteroresistance by PAP. The heteroresistance phenotype was linked to the mRNA expression of the (E)/ operon of the Mega element. Macrolide induction uniformly increased Mega operon mRNA expression across the population, and heteroresistance was eliminated. A deletion of the 5' regulatory region of the Mega operon results in a mutant deficient in induction as well as in heteroresistance. The (E) leader peptide sequence of the 5' regulatory region was required for induction and heteroresistance. Treatment with a noninducing 16-membered ring macrolide antibiotic did not induce the (E)/ operon or eliminate the heteroresistance phenotype. Thus, inducibility of the Mega element by 14- and 15-membered macrolides and heteroresistance are linked in The stochastic variation in (E)/ expression in a population containing Mega provides the basis for heteroresistance.
Topics: Anti-Bacterial Agents; Streptococcus pneumoniae; Macrolides; Drug Resistance, Bacterial; Ribosomal Proteins; RNA, Messenger; Microbial Sensitivity Tests; Bacterial Proteins
PubMed: 36847556
DOI: 10.1128/aac.01319-22 -
Frontiers in Cellular and Infection... 2023(MG) is one of the most warning emerging sexually transmitted pathogens also due to its ability in developing resistance to antibiotics. MG causes different conditions...
BACKGROUND
(MG) is one of the most warning emerging sexually transmitted pathogens also due to its ability in developing resistance to antibiotics. MG causes different conditions ranging from asymptomatic infections to acute mucous inflammation. Resistance-guided therapy has demonstrated the best cure rates and macrolide resistance testing is recommended in many international guidelines. However, diagnostic and resistance testing can only be based on molecular methods, and the gap between genotypic resistance and microbiological clearance has not been fully evaluated yet. This study aims at finding mutations associated with MG antibiotic resistance and investigating the relationship with microbiological clearance amongst MSM.
METHODS
From 2017 to 2021, genital (urine) and extragenital (pharyngeal and anorectal swabs) biological specimens were provided by men-who-have-sex-with-men (MSM) attending the STI clinic of the Infectious Disease Unit at the Verona University Hospital, Verona, Italy. A total of 1040 MSM were evaluated and 107 samples from 96 subjects resulted positive for MG. Among the MG-positive samples, all those available for further analysis (n=47) were considered for detection of mutations known to be associated with macrolide and quinolone resistance. 23S rRNA, and genes were analyzed by Sanger sequencing and Allplex™ MG and AziR Assay (Seegene).
RESULTS
A total of 96/1040 (9.2%) subjects tested positive for MG in at least one anatomical site. MG was detected in 107 specimens: 33 urine samples, 72 rectal swabs and 2 pharyngeal swabs. Among them, 47 samples from 42 MSM were available for investigating the presence of mutations associated with macrolide and quinolone resistance: 30/47 (63.8%) showed mutations in 23S rRNA while 10/47 (21.3%) in or genes. All patients with positive Test of Cure (ToC) after first-line treatment with azithromycin (n=15) were infected with 23S rRNA-mutated MG strains. All patients undergoing second-line moxifloxacin treatment (n=13) resulted negative at ToC, even those carrying MG strains with mutations in gene (n=6).
CONCLUSION
Our observations confirm that mutations in 23S rRNA gene are associated with azithromycin treatment failure and that mutations in gene alone are not always associated with phenotypic resistance to moxifloxacin. This reinforces the importance of macrolide resistance testing to guide the treatment and reduce antibiotic pressure on MG strains.
Topics: Male; Humans; Anti-Bacterial Agents; Moxifloxacin; Azithromycin; Mycoplasma genitalium; Homosexuality, Male; Fluoroquinolones; RNA, Ribosomal, 23S; Macrolides; Drug Resistance, Bacterial; Sexual and Gender Minorities; Mutation; Sexually Transmitted Diseases; Genitalia; Prevalence
PubMed: 37065200
DOI: 10.3389/fcimb.2023.1155451 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2015Macrolide antibiotics, such as azithromycin and erythromycin, are in widespread use for the treatment of bacterial infections. Macrolides are taken up and excreted...
Macrolide antibiotics, such as azithromycin and erythromycin, are in widespread use for the treatment of bacterial infections. Macrolides are taken up and excreted mainly by bile. Additionally, they have been implicated in biliary system diseases and to modify the excretion of other drugs through bile. Despite mounting evidence for the interplay between macrolide antibiotics and bile acids, the molecular details of this interaction remain unknown. Herein, we show by NMR measurements that macrolides directly bind to bile acid micelles. The topology of this interaction has been determined by solvent paramagnetic relaxation enhancements (solvent PREs). The macrolides were found to be bound close to the surface of the micelle. Increasing hydrophobicity of both the macrolide and the bile acid strengthen this interaction. Both bile acid and macrolide molecules show similar solvent PREs across their whole structures, indicating that there are no preferred orientations of them in the bile micelle aggregates. The binding to bile aggregates does not impede macrolide antibiotics from targeting bacteria. In fact, the toxicity of azithromycin towards enterotoxic E. coli (ETEC) is even slightly increased in the presence of bile, as was shown by effective concentration (EC50 ) values.
Topics: Anti-Bacterial Agents; Bile Acids and Salts; Macrolides; Molecular Structure
PubMed: 25655041
DOI: 10.1002/chem.201406413