-
Nature Reviews. Microbiology Jul 2023Streptococcus pyogenes (Group A Streptococcus; GAS) is exquisitely adapted to the human host, resulting in asymptomatic infection, pharyngitis, pyoderma, scarlet fever... (Review)
Review
Streptococcus pyogenes (Group A Streptococcus; GAS) is exquisitely adapted to the human host, resulting in asymptomatic infection, pharyngitis, pyoderma, scarlet fever or invasive diseases, with potential for triggering post-infection immune sequelae. GAS deploys a range of virulence determinants to allow colonization, dissemination within the host and transmission, disrupting both innate and adaptive immune responses to infection. Fluctuating global GAS epidemiology is characterized by the emergence of new GAS clones, often associated with the acquisition of new virulence or antimicrobial determinants that are better adapted to the infection niche or averting host immunity. The recent identification of clinical GAS isolates with reduced penicillin sensitivity and increasing macrolide resistance threatens both frontline and penicillin-adjunctive antibiotic treatment. The World Health Organization (WHO) has developed a GAS research and technology road map and has outlined preferred vaccine characteristics, stimulating renewed interest in the development of safe and effective GAS vaccines.
Topics: Humans; Anti-Bacterial Agents; Macrolides; Drug Resistance, Bacterial; Streptococcal Infections; Streptococcus pyogenes; Penicillins
PubMed: 36894668
DOI: 10.1038/s41579-023-00865-7 -
Trends in Biochemical Sciences Sep 2018Macrolide antibiotics inhibit protein synthesis by targeting the bacterial ribosome. They bind at the nascent peptide exit tunnel and partially occlude it. Thus,... (Review)
Review
Macrolide antibiotics inhibit protein synthesis by targeting the bacterial ribosome. They bind at the nascent peptide exit tunnel and partially occlude it. Thus, macrolides have been viewed as 'tunnel plugs' that stop the synthesis of every protein. More recent evidence, however, demonstrates that macrolides selectively inhibit the translation of a subset of cellular proteins, and that their action crucially depends on the nascent protein sequence and on the antibiotic structure. Therefore, macrolides emerge as modulators of translation rather than as global inhibitors of protein synthesis. The context-specific action of macrolides is the basis for regulating the expression of resistance genes. Understanding the details of the mechanism of macrolide action may inform rational design of new drugs and unveil important principles of translation regulation.
Topics: Anti-Bacterial Agents; Macrolides; Protein Biosynthesis
PubMed: 30054232
DOI: 10.1016/j.tibs.2018.06.011 -
Emerging Infectious Diseases Jul 2020A high prevalence rate of macrolide-resistant Mycoplasma pneumoniae (MRMP) has been reported in Asia. We performed a systematic review and meta-analysis to investigate... (Meta-Analysis)
Meta-Analysis
A high prevalence rate of macrolide-resistant Mycoplasma pneumoniae (MRMP) has been reported in Asia. We performed a systematic review and meta-analysis to investigate the effect of macrolide resistance on the manifestations and clinical judgment during M. pneumoniae infections. We found no difference in clinical severity between MRMP and macrolide-sensitive Mycoplasma pneumoniae (MSMP) infections. However, in the pooled data, patients infected with MRMP had a longer febrile period (1.71 days), length of hospital stay (1.61 day), antibiotic drug courses (2.93 days), and defervescence time after macrolide treatment (2.04 days) compared with patients infected with MSMP. The risk of fever lasting for >48 hours after macrolide treatment was also significantly increased (OR 21.24), and an increased proportion of patients was changed to second-line treatment (OR 4.42). Our findings indicate diagnostic and therapeutic challenges after the emergence of MRMP. More precise diagnostic tools and clearly defined treatment should be appraised in the future.
Topics: Anti-Bacterial Agents; Asia; Child; Community-Acquired Infections; Drug Resistance, Bacterial; Humans; Macrolides; Mycoplasma pneumoniae; Pneumonia, Mycoplasma
PubMed: 32568052
DOI: 10.3201/eid2607.200017 -
Veterinary Research Nov 2022Streptococcus suis is a zoonotic agent that causes sepsis and meningitis in pigs and humans. S. suis infections are responsible for large economic losses in pig... (Review)
Review
Streptococcus suis is a zoonotic agent that causes sepsis and meningitis in pigs and humans. S. suis infections are responsible for large economic losses in pig production. The lack of effective vaccines to prevent the disease has promoted the extensive use of antibiotics worldwide. This has been followed by the emergence of resistance against different classes of antibiotics. The rates of resistance to tetracyclines, lincosamides, and macrolides are extremely high, and resistance has spread worldwide. The genetic origin of S. suis resistance is multiple and includes the production of target-modifying and antibiotic-inactivating enzymes and mutations in antibiotic targets. S. suis genomes contain traits of horizontal gene transfer. Many mobile genetic elements carry a variety of genes that confer resistance to antibiotics as well as genes for autonomous DNA transfer and, thus, S. suis can rapidly acquire multiresistance. In addition, S. suis forms microcolonies on host tissues, which are associations of microorganisms that generate tolerance to antibiotics through a variety of mechanisms and favor the exchange of genetic material. Thus, alternatives to currently used antibiotics are highly demanded. A deep understanding of the mechanisms by which S. suis becomes resistant or tolerant to antibiotics may help to develop novel molecules or combinations of antimicrobials to fight these infections. Meanwhile, phage therapy and vaccination are promising alternative strategies, which could alleviate disease pressure and, thereby, antibiotic use.
Topics: Humans; Swine; Animals; Streptococcus suis; Streptococcal Infections; Anti-Bacterial Agents; Macrolides; Swine Diseases
PubMed: 36371221
DOI: 10.1186/s13567-022-01111-3 -
Pulmonary Pharmacology & Therapeutics Dec 2021Macrolide antibiotics are well known for their antibacterial properties, but extensive research in the context of inflammatory lung disease has revealed that they also... (Review)
Review
Macrolide antibiotics are well known for their antibacterial properties, but extensive research in the context of inflammatory lung disease has revealed that they also have powerful immunomodulatory properties. It has been demonstrated that these drugs are therapeutically beneficial in various lung diseases, with evidence they significantly reduce exacerbations in patients with COPD, asthma, bronchiectasis and cystic fibrosis. The efficacy demonstrated in patients infected with macrolide tolerant organisms such as Pseudomonas aeruginosa supports the concept that their efficacy is at least partly related to immunomodulatory rather than antibacterial effects. Inconsistent data and an incomplete understanding of their mechanisms of action hampers the use of macrolide antibiotics as immunomodulatory therapies. Macrolides recently demonstrated no clinically relevant immunomodulatory effects in the context of COVID-19 infection. This review provides an overview of macrolide antibiotics and discusses their immunomodulatory effects and mechanisms of action in the context of inflammatory lung disease.
Topics: Anti-Bacterial Agents; COVID-19; Cystic Fibrosis; Humans; Immunomodulation; Macrolides; SARS-CoV-2
PubMed: 34740749
DOI: 10.1016/j.pupt.2021.102095 -
JAMA Network Open Jul 2022The proportion of macrolide-resistant Mycoplasma pneumoniae (MRMP) infections has changed, and it differs according to geographical region. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The proportion of macrolide-resistant Mycoplasma pneumoniae (MRMP) infections has changed, and it differs according to geographical region.
OBJECTIVE
To analyze the global patterns, including the temporal trends, regional variations, and variant types, in the proportion of MRMP infections in this systematic review and meta-anaysis.
DATA SOURCES
PubMed, Cochrane Library, and Embase databases were searched for observational studies from inception to September 10, 2021.
STUDY SELECTION
Observational studies reporting the proportion of MRMP infections were screened independently by 2 authors. The presence of MRMP infection was defined as any case of M pneumoniae infection positive for any variants associated with macrolide resistance identified using respiratory samples.
DATA EXTRACTION AND SYNTHESIS
Data were extracted independently and in duplicate by 2 reviewers. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was used. Random-effects meta-analyses were used to estimate the proportion of MRMP infections.
MAIN OUTCOMES AND MEASURES
The global patterns in the proportion of MRMP infections were estimated, and the temporal trends and variant types of MRMP infection with regional differences were investigated.
RESULTS
This study included 153 studies from 150 articles (27 408 samples in 26 countries) in the meta-analysis. The global patterns in the proportion of MRMP infections showed an increasing trend with regional differences. The proportion of MRMP infections was highest in the Western Pacific regions (53.4%; 95% CI, 47.4%-60.3%), followed by the South East Asian region (9.8%; 95% CI, 0.8%-100%), the region of the Americas (8.4%; 95% CI, 6.1%-11.6%), and the European region (5.1%; 95% CI, 3.3%-8.0%). The most commonly identified variant of MRMP infection was A2063G (96.8%; 95% CI, 95.8%-97.7%), followed by A2064G (4.8%; 95% CI, 3.5%-6.7%). The proportion of MRMP infections was the highest in studies including only children (37.0%; 95% CI, 29.8%-46.1%), followed by those including only adults (15.9%; 95% CI, 6.4%-39.7%) and those including both children and adults (16.7%; 95% CI, 10.1%-27.6%).
CONCLUSIONS AND RELEVANCE
This study provides global trends in the proportion of MRMP infections and suggests that strategies to prevent the spread of MRMP infection and to treat MRMP infections are needed to decrease disease burden.
Topics: Adult; Anti-Bacterial Agents; Child; Drug Resistance, Bacterial; Humans; Macrolides; Microbial Sensitivity Tests; Pneumonia, Mycoplasma; United States
PubMed: 35816304
DOI: 10.1001/jamanetworkopen.2022.20949 -
Nature Nov 2021Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease. Despite this...
Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease. Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species. Antibiotic classes exhibited distinct inhibition spectra, including generation dependence for quinolones and phylogeny independence for β-lactams. Macrolides and tetracyclines, both prototypic bacteriostatic protein synthesis inhibitors, inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal and human gut microbiomes. To mitigate this collateral damage of macrolides and tetracyclines, we screened for drugs that specifically antagonized the antibiotic activity against abundant Bacteroides species but not against relevant pathogens. Such antidotes selectively protected Bacteroides species from erythromycin treatment in human-stool-derived communities and gnotobiotic mice. These findings illluminate the activity spectra of antibiotics in commensal bacteria and suggest strategies to circumvent their adverse effects on the gut microbiota.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacteria, Anaerobic; Bacteroides; Clostridioides difficile; Dicumarol; Erythromycin; Feces; Female; Gastrointestinal Microbiome; Germ-Free Life; Humans; Macrolides; Male; Mice; Microbiota; Symbiosis; Tetracyclines
PubMed: 34646011
DOI: 10.1038/s41586-021-03986-2 -
BMC Infectious Diseases Sep 2021Mycoplasma pneumoniae is a common pathogen that causes community-acquired pneumonia in school-age children. Macrolides are considered a first-line treatment for M.... (Meta-Analysis)
Meta-Analysis
Efficacy of tetracyclines and fluoroquinolones for the treatment of macrolide-refractory Mycoplasma pneumoniae pneumonia in children: a systematic review and meta-analysis.
BACKGROUND
Mycoplasma pneumoniae is a common pathogen that causes community-acquired pneumonia in school-age children. Macrolides are considered a first-line treatment for M. pneumoniae infection in children, but macrolide-refractory M. pneumoniae (MRMP) strains have become more common. In this study, we assessed the efficacy of tetracyclines and fluoroquinolones in MRMP treatment in children through a systematic review and meta-analysis.
METHODS
Two reviewers individually searched 10 electronic databases (Medline/Pubmed, Embase, the Cochrane Library, and core Korean, Chinese, and Japanese journals) for papers published from January 1, 1990 to March 8, 2018. The following data for each treatment group were extracted from the selected studies: intervention (tetracyclines and fluoroquinolones/comparator), patient characteristics (age and sex), and outcomes (fever duration, hospital stay length, treatment success rate, and defervescence rates 24, 48, and 72 h after starting treatment).
RESULTS
Eight studies involving 537 participants were included. Fever duration and hospital stay length were shorter in the tetracycline group than in the macrolide group (weighted mean difference [WMD] = - 1.45, 95% confidence interval [CI]: - 2.55 to - 0.36, P = 0.009; and WMD = - 3.33, 95% CI: - 4.32 to - 2.35, P < 0.00001, respectively). The therapeutic efficacy was significantly higher in the tetracycline group than in the macrolide group (odds ratio [OR]: 8.80, 95% CI: 3.12-24.82). With regard to defervescence rate, patients in the tetracycline group showed significant improvement compared to those in the macrolide group (defervescence rate after 24 h, OR: 5.34, 95% CI: 1.81-15.75; after 48 h, OR 18.37, 95% CI: 8.87-38.03; and after 72 h, OR: 40.77, 95% CI: 6.15-270.12). There were no differences in fever improvement within 24 h in patients in the fluoroquinolone group compared to those in the macrolide group (OR: 1.11, 95% CI: 0.25-5.00), although the defervescence rate was higher after 48 h in the fluoroquinolone group (OR: 2.78, 95% CI: 1.41-5.51).
CONCLUSION
Tetracyclines may shorten fever duration and hospital stay length in patients with MRMP infection. Fluoroquinolones may achieve defervescence within 48 h in patients with MRMP infection. However, these results should be carefully interpreted as only a small number of studies were included, and they were heterogeneous.
Topics: Anti-Bacterial Agents; Child; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Macrolides; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Tetracyclines
PubMed: 34563128
DOI: 10.1186/s12879-021-06508-7 -
European Respiratory Review : An... Jun 2023Bronchiectasis is a common progressive respiratory disease with recognisable radiological abnormalities and a clinical syndrome of cough, sputum production and recurrent...
Bronchiectasis is a common progressive respiratory disease with recognisable radiological abnormalities and a clinical syndrome of cough, sputum production and recurrent respiratory infections. Inflammatory cell infiltration into the lung, in particular neutrophils, is central to the pathophysiology of bronchiectasis. Herein we explore the roles and relationships between infection, inflammation and mucociliary clearance dysfunction in the establishment and progression of bronchiectasis. Microbial and host-mediated damage are important processes underpinning bronchiectasis and the relative contribution of proteases, cytokines and inflammatory mediators to the propagation of inflammation is presented. We also discuss the emerging concept of inflammatory endotypes, defined by the presence of neutrophilic and eosinophilic inflammation, and explore the role of inflammation as a treatable trait. Current treatment for bronchiectasis focuses on treatment of underlying causes, enhancing mucociliary clearance, controlling infection and preventing and treating complications. Data on airway clearance approaches exercise and mucoactive drugs, pharmacotherapy with macrolides to decrease exacerbations and the usefulness of inhaled antibiotics and bronchodilators are discussed, finishing with a look to the future where new therapies targeting host-mediated immune dysfunction hold promise.
Topics: Humans; Adult; Bronchiectasis; Inflammation; Cough; Anti-Bacterial Agents; Macrolides
PubMed: 37286220
DOI: 10.1183/16000617.0015-2023 -
International Journal of Molecular... Jul 2023Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of... (Review)
Review
The Global Burden of Community-Acquired Pneumonia in Adults, Encompassing Invasive Pneumococcal Disease and the Prevalence of Its Associated Cardiovascular Events, with a Focus on Pneumolysin and Macrolide Antibiotics in Pathogenesis and Therapy.
Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of infection-related mortality globally. Confronting the ongoing threat posed by (the pneumococcus), the most common bacterial cause of CAP, particularly to the non-immune elderly, remains challenging due to the propensity of the elderly to develop invasive pneumococcal disease (IPD), together with the predilection of the pathogen for the heart. The resultant development of often fatal cardiovascular events (CVEs), particularly during the first seven days of acute infection, is now recognized as a relatively common complication of IPD. The current review represents an update on the prevalence and types of CVEs associated with acute bacterial CAP, particularly IPD. In addition, it is focused on recent insights into the involvement of the pneumococcal pore-forming toxin, pneumolysin (Ply), in subverting host immune defenses, particularly the protective functions of the alveolar macrophage during early-stage disease. This, in turn, enables extra-pulmonary dissemination of the pathogen, leading to cardiac invasion, cardiotoxicity and myocardial dysfunction. The review concludes with an overview of the current status of macrolide antibiotics in the treatment of bacterial CAP in general, as well as severe pneumococcal CAP, including a consideration of the mechanisms by which these agents inhibit the production of Ply by macrolide-resistant strains of the pathogen.
Topics: Adult; Humans; Aged; Pneumonia, Pneumococcal; Prevalence; Pneumococcal Infections; Streptococcus pneumoniae; Anti-Bacterial Agents; Macrolides; Community-Acquired Infections; Cardiovascular Diseases
PubMed: 37446214
DOI: 10.3390/ijms241311038