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Frontiers in Cellular and Infection... 2023is an important pathogen causing upper and lower respiratory tract infections in children and other age groups. Macrolides are the recommended treatments of choice for...
is an important pathogen causing upper and lower respiratory tract infections in children and other age groups. Macrolides are the recommended treatments of choice for infections. However, macrolide resistance in is increasing worldwide, which complicates the treatment strategies. The mechanisms of macrolide resistance have been extensively studied focusing on the mutations in and ribosomal proteins. Since the secondary treatment choice for pediatric patients is very limited, we decided to look for potential new treatment strategies in macrolide drugs and investigate possible new mechanisms of resistance. We performed an selection of mutants resistant to five macrolides (erythromycin, roxithromycin, azithromycin, josamycin, and midecamycin) by inducing the parent strain M129 with increasing concentrations of the drugs. The evolving cultures in every passage were tested for their antimicrobial susceptibilities to eight drugs and mutations known to be associated with macrolide resistance by PCR and sequencing. The final selected mutants were also analyzed by whole-genome sequencing. Results showed that roxithromycin is the drug that most easily induces resistance (at 0.25 mg/L, with two passages, 23 days), while with midecamycin it is most difficult (at 5.12 mg/L, with seven passages, 87 days). Point mutations C2617A/T, A2063G, or A2064C in domain V of were detected in mutants resistant to the 14- and 15-membered macrolides, while A2067G/C was selected for the 16-membered macrolides. Single amino acid changes (G72R, G72V) in ribosomal protein L4 emerged during the induction by midecamycin. Genome sequencing identified sequence variations in , , , , and in one of the () genes in the mutants. Mutants induced by the 14- or 15-membered macrolides were resistant to all macrolides, while those induced by the 16-membered macrolides (midecamycin and josamycin) remained susceptible to the 14- and 15-membered macrolides. In summary, these data demonstrated that midecamycin is less potent in inducing resistance than other macrolides, and the induced resistance is restrained to the 16-membered macrolides, suggesting a potential benefit of using midecamycin as a first treatment choice if the strain is susceptible.
Topics: Humans; Child; Anti-Bacterial Agents; Mycoplasma pneumoniae; Macrolides; Roxithromycin; Josamycin; RNA, Ribosomal, 23S; Microbial Sensitivity Tests; Drug Resistance, Bacterial; Pneumonia, Mycoplasma
PubMed: 37284499
DOI: 10.3389/fcimb.2023.1186017 -
Clinical Infectious Diseases : An... Jun 2021The Infectious Diseases Society of America recommends either a fluoroquinolone or a macrolide as a first-line antibiotic treatment for Legionella pneumonia, but it is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The Infectious Diseases Society of America recommends either a fluoroquinolone or a macrolide as a first-line antibiotic treatment for Legionella pneumonia, but it is unclear which antibiotic leads to optimal clinical outcomes. We compared the effectiveness of fluoroquinolone versus macrolide monotherapy in Legionella pneumonia using a systematic review and meta-analysis.
METHODS
We conducted a systematic search of literature in PubMed, Cochrane, Scopus, and Web of Science from inception to 1 June 2019. Randomized controlled trials and observational studies comparing macrolide with fluoroquinolone monotherapy using clinical outcomes in patients with Legionella pneumonia were included. Twenty-one publications out of an initial 2073 unique records met the selection criteria. Following PRISMA guidelines, 2 reviewers participated in data extraction. The primary outcome was mortality. Secondary outcomes included clinical cure, time to apyrexia, length of hospital stay (LOS), and the occurrence of complications. The review and meta-analysis was registered with PROSPERO (CRD42019132901).
RESULTS
Twenty-one publications with 3525 patients met inclusion criteria. The mean age of the population was 60.9 years and 67.2% were men. The mortality rate for patients treated with fluoroquinolones was 6.9% (104/1512) compared with 7.4% (133/1790) among those treated with macrolides. The pooled odds ratio assessing risk of mortality for patients treated with fluoroquinolones versus macrolides was 0.94 (95% confidence interval, .71-1.25, I2 = 0%, P = .661). Clinical cure, time to apyrexia, LOS, and the occurrence of complications did not differ for patients treated with fluoroquinolones versus macrolides.
CONCLUSIONS
We found no difference in the effectiveness of fluoroquinolones versus macrolides in reducing mortality among patients with Legionella pneumonia.
Topics: Anti-Bacterial Agents; Community-Acquired Infections; Fluoroquinolones; Humans; Legionella; Macrolides; Male; Middle Aged; Pneumonia
PubMed: 32296816
DOI: 10.1093/cid/ciaa441 -
The Cochrane Database of Systematic... Jan 2021Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterised by persistent respiratory symptoms and airflow limitation. Acute... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterised by persistent respiratory symptoms and airflow limitation. Acute exacerbations punctuate the natural history of COPD and are associated with increased morbidity and mortality and disease progression. Chronic airflow limitation is caused by a combination of small airways (bronchitis) and parenchymal destruction (emphysema), which can impact day-to-day activities and overall quality of life. In carefully selected patients with COPD, long-term, prophylactic use of antibiotics may reduce bacterial load, inflammation of the airways, and the frequency of exacerbations.
OBJECTIVES
To assess effects of different prophylactic antibiotics on exacerbations, quality of life, and serious adverse events in people with COPD in three separate network meta-analyses (NMAs), and to provide rankings of identified antibiotics.
SEARCH METHODS
To identify eligible randomised controlled trials (RCTs), we searched the Cochrane Airways Group Specialised Register of trials and clinical trials registries. We conducted the most recent search on 22 January 2020.
SELECTION CRITERIA
We included RCTs with a parallel design of at least 12 weeks' duration evaluating long-term administration of antibiotics prophylactically compared with other antibiotics, or placebo, for patients with COPD.
DATA COLLECTION AND ANALYSIS
This Cochrane Review collected and updated pair-wise data from two previous Cochrane Reviews. Searches were updated and additional studies included. We conducted three separate network meta-analyses (NMAs) within a Bayesian framework to assess three outcomes: exacerbations, quality of life, and serious adverse events. For quality of life, we collected data from St George's Respiratory Questionnaire (SGRQ). Using previously validated methods, we selected the simplest model that could adequately fit the data for every analysis. We used threshold analysis to indicate which results were robust to potential biases, taking into account each study's contributions to the overall results and network structure. Probability ranking was performed for each antibiotic class for exacerbations, quality of life, and serious adverse events.
MAIN RESULTS
Characteristics of studies and participants Eight trials were conducted at multiple sites that included hospital clinics or academic health centres. Seven were single-centre trials conducted in hospital clinics. Two trials did not report settings. Trials durations ranged from 12 to 52 weeks. Most participants had moderate to severe disease. Mean age ranged from 64 years to 73 years, and more males were recruited (51% to 100%). Forced expiratory volume in one second (FEV₁) ranged from 0.935 to 1.36 L. Most participants had previous exacerbations. Data from 12 studies were included in the NMAs (3405 participants; 16 treatment arms including placebo). Prophylactic antibiotics evaluated were macrolides (azithromycin and erythromycin), tetracyclines (doxycyclines), quinolones (moxifloxacin) and macrolides plus tetracyclines (roxithromycin plus doxycycline). Risk of bias and threshold analysis Most studies were at low risk across domains, except detection bias, for which only seven studies were judged at low risk. In the threshold analysis for exacerbations, all comparisons in which one antibiotic was compared with another were robust to sampling variation, especially macrolide comparisons. Comparisons of classes with placebo were sensitive to potential bias, especially macrolide versus placebo, therefore, any bias in the comparison was likely to favour the active class, so any adjustment would bring the estimated relative effect closer to the null value, thus quinolone may become the best class to prevent exacerbations. Exacerbations Nine studies were included (2732 participants) in this NMA (exacerbations analysed as time to first exacerbation or people with one or more exacerbations). Macrolides and quinolones reduced exacerbations. Macrolides had a greater effect in reducing exacerbations compared with placebo (macrolides: hazard ratio (HR) 0.67, 95% credible interval (CrI) 0.60 to 0.75; quinolones: HR 0.89, 95% CrI 0.75 to 1.04), resulting in 127 fewer people per 1000 experiencing exacerbations on macrolides. The difference in exacerbations between tetracyclines and placebo was uncertain (HR 1.29, 95% CrI 0.66 to 2.41). Macrolides ranked first (95% CrI first to second), with quinolones ranked second (95% CrI second to third). Tetracyclines ranked fourth, which was lower than placebo (ranked third). Contributing studies were considered as low risk of bias in a threshold analysis. Quality of life (SGRQ) Seven studies were included (2237 participants) in this NMA. SGRQ scores improved with macrolide treatment compared with placebo (fixed effect-fixed class effect: mean difference (MD) -2.30, 95% CrI -3.61 to -0.99), but the mean difference did not reach the minimally clinical important difference (MCID) of 4 points. Tetracyclines and quinolones did not improve quality of life any more than placebo, and we did not detect a difference between antibiotic classes. Serious adverse events Nine studies were included (3180 participants) in the NMA. Macrolides reduced the odds of a serious adverse event compared with placebo (fixed effect-fixed class effect: odds ratio (OR) 0.76, 95% CrI 0.62 to 0.93). There was probably little to no difference in the effect of quinolone compared with placebo or tetracycline plus macrolide compared with placebo. There was probably little to no difference in serious adverse events between quinolones or tetracycline plus macrolide. With macrolide treatment 49 fewer people per 1000 experienced a serious adverse event compared with those given placebo. Macrolides ranked first, followed by quinolones. Tetracycline did not rank better than placebo. Drug resistance Ten studies reported drug resistance. Results were not combined due to variation in outcome measures. All studies concluded that prophylactic antibiotic administration was associated with the development of antimicrobial resistance.
AUTHORS' CONCLUSIONS
This NMA evaluated the safety and efficacy of different antibiotics used prophylactically for COPD patients. Compared to placebo, prolonged administration of macrolides (ranked first) appeared beneficial in prolonging the time to next exacerbation, improving quality of life, and reducing serious adverse events. No clear benefits were associated with use of quinolones or tetracyclines. In addition, antibiotic resistance was a concern and could not be thoroughly assessed in this review. Given the trade-off between effectiveness, safety, and risk of antibiotic resistance, prophylactic administration of antibiotics may be best reserved for selected patients, such as those experiencing frequent exacerbations. However, none of the eligible studies excluded patients with previously isolated non-tuberculous mycobacteria, which would contraindicate prophylactic administration of antibiotics, due to the risk of developing resistant non-tuberculous mycobacteria.
Topics: Adult; Aged; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacterial Load; Bayes Theorem; Bias; Disease Progression; Female; Forced Expiratory Volume; Humans; Macrolides; Male; Middle Aged; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Randomized Controlled Trials as Topic; Tetracyclines; Treatment Outcome
PubMed: 33448349
DOI: 10.1002/14651858.CD013198.pub2 -
American Journal of Obstetrics &... Jul 2023Various prophylactic antibiotic regimens are used in the management of preterm premature rupture of membranes. We investigated the efficacy and safety of these regimens... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Various prophylactic antibiotic regimens are used in the management of preterm premature rupture of membranes. We investigated the efficacy and safety of these regimens in terms of maternal and neonatal outcomes.
DATA SOURCES
We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 20, 2021.
STUDY ELIGIBILITY CRITERIA
We included randomized controlled trials involving pregnant women with preterm premature rupture of membranes before 37 weeks of gestation and a comparison of ≥2 of the following 10 antibiotic regimens: control/placebo, erythromycin, clindamycin, clindamycin plus gentamicin, penicillins, cephalosporins, co-amoxiclav, co-amoxiclav plus erythromycin, aminopenicillins plus macrolides, and cephalosporins plus macrolides.
METHODS
Two investigators independently extracted published data and assessed the risk of bias with a standard procedure following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Network meta-analysis was conducted using the random-effects model.
RESULTS
A total of 23 studies that recruited a total of 7671 pregnant women were included. Only penicillins (odds ratio, 0.46; 95% confidence interval, 0.27-0.77) had significantly superior effectiveness for maternal chorioamnionitis. Clindamycin plus gentamicin reduced the risk of clinical chorioamnionitis, with borderline significance (odds ratio, 0.16; 95% confidence interval, 0.03-1.00). By contrast, clindamycin alone increased the risk of maternal infection. For cesarean delivery, no significant differences were noted among these regimens.
CONCLUSION
Penicillins remain the recommended antibiotic regimen for reducing maternal clinical chorioamnionitis. The alternative regimen includes clindamycin plus gentamicin. Clindamycin should not be used alone.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Clindamycin; Chorioamnionitis; Amoxicillin-Potassium Clavulanate Combination; Network Meta-Analysis; Anti-Bacterial Agents; Premature Birth; Erythromycin; Macrolides; Gentamicins; Cephalosporins
PubMed: 37094635
DOI: 10.1016/j.ajogmf.2023.100978 -
Respiratory Investigation Mar 2024The evidence for macrolide therapy in adult asthma is not properly established and remains controversial. We conducted a systematic review and meta-analysis to examine... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The evidence for macrolide therapy in adult asthma is not properly established and remains controversial. We conducted a systematic review and meta-analysis to examine the efficacy and safety of macrolide therapy for adult asthma.
METHODS
We searched randomized controlled trials from MEDLINE via the PubMed, CENTRAL, and Ichushi Web databases. The primary outcome was asthma exacerbation. The secondary outcomes were serious adverse events (including mortality), asthma-related quality of life (symptom scales, Asthma Control Questionnaire, and Asthma Quality of Life Questionnaire), rescue medication (puffs/day), respiratory function (morning peak expiratory flow, evening peak flow, and forced expiratory volume in 1 s), bronchial hyperresponsiveness, and minimum oral corticosteroid dose. Of the 805 studies, we selected seven studies for the meta-analysis, which was conducted using a random-effects model.
SYSTEMATIC REVIEW REGISTRATION
University Hospital Medical Information Network Clinical Trials Registry (UMIN000050824).
RESULTS
No significant difference between macrolide and placebo for asthma exacerbations was observed (risk ratio 0.71, 95 % confidence interval [CI] 0.46-1.09; p = 0.12). Macrolide therapy for adult asthma showed a significant improvement in rescue medication with short-acting beta-agonists (mean difference -0.41, 95 % CI -0.78 to -0.04; p = 0.03). Macrolide therapy did not show more serious adverse events (odd ratio 0.61, 95 % CI 0.34-1.10; p = 0.10) than those with placebo. The other secondary outcomes were not significantly different between the macrolide and placebo groups.
CONCLUSIONS
Macrolide therapy for adult asthma may be more effective than placebo and could be a treatment option.
Topics: Adult; Humans; Macrolides; Quality of Life; Disease Progression; Asthma; Anti-Bacterial Agents; Adrenal Cortex Hormones
PubMed: 38211545
DOI: 10.1016/j.resinv.2023.12.015 -
British Journal of Pharmacology Sep 2017Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a... (Review)
Review
Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a macrocyclic lactone of different ring sizes, to which one or more deoxy-sugar or amino sugar residues are attached. Macrolides act as antibiotics by binding to bacterial 50S ribosomal subunit and interfering with protein synthesis. The high affinity of macrolides for bacterial ribosomes, together with the highly conserved structure of ribosomes across virtually all of the bacterial species, is consistent with their broad-spectrum activity. Since the discovery of the progenitor macrolide, erythromycin, in 1950, many derivatives have been synthesised, leading to compounds with better bioavailability and acid stability and improved pharmacokinetics. These efforts led to the second generation of macrolides, including well-known members such as azithromycin and clarithromycin. Subsequently, in order to address increasing antibiotic resistance, a third generation of macrolides displaying improved activity against many macrolide resistant strains was developed. However, these improvements were accompanied with serious side effects, leading to disappointment and causing many researchers to stop working on macrolide derivatives, assuming that this procedure had reached the end. In contrast, a recent published breakthrough introduced a new chemical platform for synthesis and discovery of a wide range of diverse macrolide antibiotics. This chemical synthesis revolution, in combination with reduction in the side effects, namely, 'Ketek effects', has led to a macrolide renaissance, increasing the hope for novel and safe therapeutic agents to combat serious human infectious diseases.
Topics: Anti-Bacterial Agents; Bacteria; Communicable Diseases; Humans; Macrolides
PubMed: 28664582
DOI: 10.1111/bph.13936 -
Toxins May 2021Macrolides are a diverse class of hydrophobic compounds characterized by a macrocyclic lactone ring and distinguished by variable side chains/groups. Some of the most... (Review)
Review
Macrolides are a diverse class of hydrophobic compounds characterized by a macrocyclic lactone ring and distinguished by variable side chains/groups. Some of the most well characterized macrolides are toxins produced by marine bacteria, sea sponges, and other species. Many marine macrolide toxins act as biomimetic molecules to natural actin-binding proteins, affecting actin polymerization, while other toxins act on different cytoskeletal components. The disruption of natural cytoskeletal processes affects cell motility and cytokinesis, and can result in cellular death. While many macrolides are toxic in nature, others have been shown to display therapeutic properties. Indeed, some of the most well known antibiotic compounds, including erythromycin, are macrolides. In addition to antibiotic properties, macrolides have been shown to display antiviral, antiparasitic, antifungal, and immunosuppressive actions. Here, we review each functional class of macrolides for their common structures, mechanisms of action, pharmacology, and human cellular targets.
Topics: Animals; Anti-Bacterial Agents; Cytoskeleton; Humans; Hydrophobic and Hydrophilic Interactions; Macrolides; Marine Toxins
PubMed: 34065929
DOI: 10.3390/toxins13050347 -
Emerging Microbes & Infections Dec 2022The objective of this paper is to explore the characteristics of (MP) epidemics in Beijing, China. Patients with acute respiratory tract infection (ARTI) were enrolled...
The objective of this paper is to explore the characteristics of (MP) epidemics in Beijing, China. Patients with acute respiratory tract infection (ARTI) were enrolled from 35 sentinel hospitals in Beijing, 2015-2020. Their medical records were reviewed and respiratory specimens were collected for assay for nucleic acids of 24 respiratory pathogens, including MP. The genotypes of MP were analysed using a real-time PCR method. The domain V of 23s rRNA gene was sequenced to identify macrolide-resistant mutations. A total of 41,677 specimens of ARTI patients were included, with an MP positive rate of 6.16%. MP prevalence mainly occurred between August and January, and peaked in October. The increase in the MP detection rate was coincident with the elevation of the reported number of patients with pneumonia in the 35 sentinel hospitals. One or more respiratory pathogens were co-detected in 27.1% of the MP-positive patients. Type 1 MP remained predominant, and the macrolide-resistant rate of MP had exceeded over 90%. A2063G mutation accounted for 99.0% of macrolide-resistant MP infections. MP epidemic in Beijing mainly occurred between August and January with a remarkable high macrolide-resistant rate. MP is one of the important contributors to the pneumonia epidemic in autumn and winter in Beijing.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Epidemics; Epidemiologic Studies; Humans; Macrolides; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Respiratory Tract Infections
PubMed: 35582916
DOI: 10.1080/22221751.2022.2078228 -
Angewandte Chemie (International Ed. in... Jun 2016Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades... (Review)
Review
Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last-resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled "Combat drug resistance: no action today means no cure tomorrow" triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Drug Design; Drug Resistance, Multiple, Bacterial; Macrolides; Molecular Dynamics Simulation; Organophosphates; Oxazoles; Oxazolidinones; Structure-Activity Relationship
PubMed: 27000559
DOI: 10.1002/anie.201506818 -
Frontiers in Cellular and Infection... 2016is a common commensal and an opportunistic pathogen. Suspected pneumococcal upper respiratory infections and pneumonia are often treated with macrolide antibiotics.... (Review)
Review
is a common commensal and an opportunistic pathogen. Suspected pneumococcal upper respiratory infections and pneumonia are often treated with macrolide antibiotics. Macrolides are bacteriostatic antibiotics and inhibit protein synthesis by binding to the 50S ribosomal subunit. The widespread use of macrolides is associated with increased macrolide resistance in , and the treatment of pneumococcal infections with macrolides may be associated with clinical failures. In , macrolide resistance is due to ribosomal dimethylation by an enzyme encoded by (B), efflux by a two-component efflux pump encoded by (E)/((D)) and, less commonly, mutations of the ribosomal target site of macrolides. A wide array of genetic elements have emerged that facilitate macrolide resistance in ; for example (B) is found on Tn, while the (E)/ operon is carried on the 5.4- or 5.5-kb Mega element. The macrolide resistance determinants, (B) and (E)/, are also found on large composite Tn-like elements most notably Tn, Tn, and Tn. Introductions of 7-valent and 13-valent pneumococcal conjugate vaccines (PCV-7 and PCV-13) have decreased the incidence of macrolide-resistant invasive pneumococcal disease, but serotype replacement and emergence of macrolide resistance remain an important concern.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Combinations; Drug Resistance, Bacterial; Genes, Bacterial; Genotype; Humans; Macrolides; Membrane Proteins; Microbial Sensitivity Tests; Mutation; Pneumococcal Infections; Pneumococcal Vaccines; RNA, Ribosomal; Serotyping; Streptococcus pneumoniae; Vaccines, Conjugate
PubMed: 27709102
DOI: 10.3389/fcimb.2016.00098