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Respiratory Medicine Oct 2014Macrolide antibiotics have anti-inflammatory and immunomodulatory properties in addition to antibacterial activity. Until recently, only a small number of studies... (Review)
Review
Macrolide antibiotics have anti-inflammatory and immunomodulatory properties in addition to antibacterial activity. Until recently, only a small number of studies evaluating macrolides in patients with non-cystic fibrosis (CF) bronchiectasis had been published. These were open-label, uncontrolled, short-duration studies that included small numbers of patients. However, these studies suggested that macrolides can reduce exacerbation frequency, reduce sputum volume, and improve lung function in patients with non-CF bronchiectasis. Three recently published randomised, double-blind, placebo-controlled studies showed that macrolides (azithromycin or erythromycin) taken for between 6 and 12 months led to significant reductions in exacerbation rate and reduced the decline in lung function. In all studies, macrolides were generally well tolerated. The advantages of macrolide maintenance therapy need to be balanced against the risks, which include emergence of bacterial resistance, cardiotoxicity and ototoxicity. In addition, a key need is the consistent definition of endpoints for studies in non-CF bronchiectasis, particularly the definition of exacerbation, to allow systematic data analysis. Existing studies on the use of low-dose macrolides in non-CF bronchiectasis are encouraging, but further studies are needed to define the optimal agent, dose, duration for treatment, and the patients likely to benefit and long-term safety.
Topics: Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Erythromycin; Evidence-Based Medicine; Female; Forced Expiratory Volume; Humans; Macrolides; Male; Middle Aged; Randomized Controlled Trials as Topic; Respiration; Treatment Outcome
PubMed: 25301290
DOI: 10.1016/j.rmed.2014.09.005 -
Rheumatology International Dec 2022Colchicine is increasingly used as the number of potential indications expands. However, it also has a narrow therapeutic index that is associated with bothersome to...
Colchicine is increasingly used as the number of potential indications expands. However, it also has a narrow therapeutic index that is associated with bothersome to severe side effects. When concomitantly use with medications inhibiting its metabolism, higher plasma levels will result and increase likelihood of colchicine toxicity. We conducted a cohort study using electronic health records comparing encounters with colchicine plus a macrolide and colchicine with an antibiotic non-macrolide. We assessed the relationship between the two groups using adjusted multivariate logistic regression models and the risk of rhabdomyolysis, pancytopenia, muscular weakness, heart failure, acute hepatic failure and death. 12670 patients on colchicine plus an antibiotic non-macrolide were compared to 2199 patients exposed to colchicine plus a macrolide. Patients exposed to colchicine and a macrolide were majority men (n = 1329, 60.4%) and white (n = 1485, 67.5%) in their late sixties (mean age in years 68.4, SD 15.6). Heart failure was more frequent in the colchicine plus a macrolide cohort (n = 402, 18.3%) vs the colchicine non-macrolide one (n = 1153, 9.1%) (p < 0.0001) and also had a higher mortality rate [(85 (3.87%) vs 289 (2.28%), p < 0.0001 macrolides vs non-macrolides cohorts, respectively]. When the sample was limited to individuals exposed to either clarithromycin or erythromycin and colchicine, the adjusted OR for acute hepatic failure was 2.47 (95% CI 1.04-5.91) and 2.06 for death (95% CI 1.07-3.97). There is a significant increase in the risk of hepatic failure and mortality when colchicine is concomitantly administered with a macrolide. Colchicine should not be used concomitantly with these antibiotics or should be temporarily discontinued to avoid toxic levels of colchicine.
Topics: Anti-Bacterial Agents; Clarithromycin; Cohort Studies; Colchicine; Erythromycin; Humans; Macrolides; Male
PubMed: 36104598
DOI: 10.1007/s00296-022-05201-5 -
Respiration; International Review of... 2011The available evidence for long-term, low-dose treatment with 14- and 15-membered ring macrolides in non-cystic fibrosis (CF) bronchiectasis, COPD, chronic sinusitis,... (Review)
Review
The available evidence for long-term, low-dose treatment with 14- and 15-membered ring macrolides in non-cystic fibrosis (CF) bronchiectasis, COPD, chronic sinusitis, and asthma is reviewed with special attention to possible adverse effects and the emergence of resistance during long-term macrolide treatment. Macrolide maintenance therapy has been proven to be of benefit in diffuse panbronchiolitis and CF, presumably due to an anti-inflammatory mechanism of action in addition to its direct antimicrobial effect. Solid evidence to justify this treatment regimen for non-CF bronchiectasis, asthma, or sinusitis is still lacking, although a beneficial effect of long-term macrolide therapy has been found in small clinical trials on these subjects. Data from randomized trials of long-term macrolide treatment in COPD are conflicting. A sufficiently long duration of treatment and the careful selection of patients appears to be crucial. Aside from its beneficial effects, possible side effects of macrolide treatment should be taken into account, the most important of these being gastrointestinal upset and cardiac arrhythmias. Development of macrolide resistance among respiratory pathogens is very common during long-term macrolide treatment. Whether this finding is clinically significant is a matter of debate.
Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Arrhythmias, Cardiac; Bacterial Infections; Chronic Disease; Drug Administration Schedule; Drug Dosage Calculations; Drug Resistance, Bacterial; Gastrointestinal Diseases; Humans; Long-Term Care; Macrolides; Patient Selection; Randomized Controlled Trials as Topic; Respiratory Tract Diseases; Time
PubMed: 20733282
DOI: 10.1159/000320320 -
Respiratory Medicine May 2013Long-term treatment with macrolides has recently been shown to reduce COPD exacerbations in doses lower than bactericidal doses. This article aims to critically review... (Review)
Review
Long-term treatment with macrolides has recently been shown to reduce COPD exacerbations in doses lower than bactericidal doses. This article aims to critically review the international literature relating to the long-term effectiveness and safety of macrolides and to estimate the budget impact of preventing exacerbations with azithromycin in Belgium. Controlled clinical studies focusing on the prevention of COPD exacerbations with long-term macrolide treatment were identified in PubMed, EMBASE, Controlled Trials Registry of the Cochrane Library, and Social Science and Citation Index. The budget impact of preventing exacerbations with azithromycin in Belgium over a one-year period was calculated as the difference between the additional expenditure of annual treatment with azithromycin and the savings in hospital expenditure arising from fewer COPD exacerbations in patients with GOLD stages II-IV. Prevalence and resource use data were derived from the literature and unit cost data from Belgian sources. The literature review suggests that long-term treatment of COPD patients with azithromycin, erythromycin or clarithromycin is effective and safe, and reduces exacerbations and related hospitalizations. However, uncertainty remains about the specific patient population that is most likely to benefit from long-term macrolide treatment, the optimal dose and duration of macrolide treatment, and the potential impact of long-term macrolide treatment on resistance. The budget impact analysis demonstrated that annual hospital savings of €950 million resulting from fewer exacerbations outweighed additional expenditure on azithromycin of €595 million, implying that the prevention of COPD exacerbations with azithromycin is a cost saving strategy in Belgium.
Topics: Anti-Bacterial Agents; Azithromycin; Belgium; Clarithromycin; Drug Costs; Erythromycin; Health Care Costs; Humans; Macrolides; Pulmonary Disease, Chronic Obstructive; Treatment Outcome
PubMed: 23352223
DOI: 10.1016/j.rmed.2012.12.019 -
Journal of Natural Products Apr 2017A carefully timed coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded eight new 16-membered-ring macrolides, berkeleylactones A-H (1, 4,...
A carefully timed coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded eight new 16-membered-ring macrolides, berkeleylactones A-H (1, 4, 6-9, 12, 13), as well as the known antibiotic macrolide A26771B (5), patulin, and citrinin. There was no evidence of the production of the berkeleylactones or A26771B (5) by either fungus when grown as axenic cultures. The structures were deduced from analyses of spectral data, and the absolute configurations of compounds 1 and 9 were determined by single-crystal X-ray crystallography. Berkeleylactone A (1) exhibited the most potent antimicrobial activity of the macrolide series, with low micromolar activity (MIC = 1-2 μg/mL) against four MRSA strains, as well as Bacillus anthracis, Streptococcus pyogenes, Candida albicans, and Candida glabrata. Mode of action studies have shown that, unlike other macrolide antibiotics, berkeleylactone A (1) does not inhibit protein synthesis nor target the ribosome, which suggests a novel mode of action for its antibiotic activity.
Topics: Anti-Bacterial Agents; Coculture Techniques; Macrolides; Microbial Sensitivity Tests; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Penicillium; Streptococcus pneumoniae; Streptococcus pyogenes
PubMed: 28326781
DOI: 10.1021/acs.jnatprod.7b00133 -
Clinical Microbiology and Infection :... Dec 2022Pseudomonas aeruginosa colonizes the cystic fibrosis (CF) airways causing chronic bacterial lung infections. CF patients are routinely treated with macrolides, however,...
OBJECTIVES
Pseudomonas aeruginosa colonizes the cystic fibrosis (CF) airways causing chronic bacterial lung infections. CF patients are routinely treated with macrolides, however, P. aeruginosa is considered insusceptible as consequence of inadequate susceptibility testing leaving resistance mechanism completely overlooked. Here, we investigated a new mechanism of macrolide resistance caused by ribosomal protein mutations.
METHODS
Investigating a longitudinal collection of 529 isolates from CF patients and analysing 5758 protein sequences from different sources, mutations in P. aeruginosa's ribosomal proteins connected to macrolide resistance were identified. Using a modified susceptibility testing protocol, isolates harbouring a mutated uL4 ribosomal protein were tested for resistance against macrolide antibiotics and macrolide-induced quorum sensing modulation. Proteome and ribosome profiling were applied to assess the impact of the mutations on the bacterial physiology.
RESULTS
Five uL4 mutations were identified in isolates from different CF patients. Most mapped to the conserved loop region of uL4 and resulted in increased macrolide tolerance (>10-fold relative to wt strains). Greater concentrations (>10-fold) of macrolide antibiotic were needed to inhibit the growth, reduce swimming motility, and induce redox sensitivity of the uL4 mutants. 16 proteins involved in ribosome adaptation displayed altered expression possibly to compensate for the uL4 mutations, which changed the ribosome stoichiometry without negatively affecting bacterial physiology.
CONCLUSIONS
Macrolide antibiotics should, therefore, be considered as active antimicrobial agents against P. aeruginosa and resistance development should be contemplated when patients are treated with prolonged courses of macrolides. Importantly, improved macrolide susceptibility testing is necessary for the detection of resistant bacteria.
Topics: Humans; Anti-Bacterial Agents; Cystic Fibrosis; Drug Resistance, Bacterial; Macrolides; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Ribosomal Proteins; Viral Envelope Proteins
PubMed: 35988850
DOI: 10.1016/j.cmi.2022.08.003 -
Journal of Global Antimicrobial... Mar 2021The aim of this study was to investigate the biological characteristics and effect of antibiotic treatment for different Mycoplasma pneumoniae isolates co-infecting the...
OBJECTIVES
The aim of this study was to investigate the biological characteristics and effect of antibiotic treatment for different Mycoplasma pneumoniae isolates co-infecting the same patient.
METHODS
Two throat swab specimens from a single patient, on the day of admission (Sp01) and discharge (Sp13), were liquid cultured and subcultured on agar medium to obtain M. pneumoniae monoclones. The 23S rRNA gene of 50 monoclones from specimens Sp01 and Sp13 were analysed. Real-time PCR assay was used for detection of mutations and genotyping. Two typical monoclones were isolated for antimicrobial susceptibility testing.
RESULTS
Genotype 1 monoclones accounted for 70.8% (34/48) in Sp01 and 95.7% (44/46) in Sp13. All genotype 1 monoclones were of the 4-5-7-2 multilocus variable-number tandem-repeat analysis (MLVA) type, while all genotype 2 monoclones were 3-5-6-2 MLVA type. The genotype 1 monoclone, which harboured the A2063G mutation in 23S rRNA gene, was resistant to erythromycin and azithromycin in vitro, whilst genotype 2, which did not carry the mutation, was susceptible to macrolides. The proportion of macrolide-resistant M. pneumoniae monoclones in the specimen cultures collected rose from 70.8% to 95.7% at the time of discharge.
CONCLUSION
This is the first report on the isolation of macrolide-resistant and -susceptible strains of M. pneumoniae from the same patient. After treatment, the proportion of macrolide-resistant M. pneumoniae increased, but the patient still carried viable macrolide-susceptible strains, meaning that the macrolide-susceptible strains did not disappear completely.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Macrolides; Microbial Sensitivity Tests; Mycoplasma pneumoniae; Pneumonia, Mycoplasma
PubMed: 33460841
DOI: 10.1016/j.jgar.2020.12.019 -
Clinical Microbiology and Infection :... 2001Since their discovery, the macrolide antimicrobials have proved clinically valuable for the treatment of respiratory tract infections, offering coverage against a broad... (Comparative Study)
Comparative Study Review
Since their discovery, the macrolide antimicrobials have proved clinically valuable for the treatment of respiratory tract infections, offering coverage against a broad spectrum of pathogens and excellent tolerability. However, the global increase in macrolide resistance among respiratory pathogens, particularly Streptococcus pneumoniae, threatens their future usefulness. The ketolides, of which telithromycin is the first to reach clinical development, represent a new generation of antimicrobials that have been developed with a view to overcoming the problem of macrolide resistance. Telithromycin is structurally derived from macrolides, and possesses several distinguishing features that are important for its improved microbiological profile. The L-cladinose at position C3 of the miacrolactone ring has been replaced with a keto function. This modification enables telithromycin to bind to its target without tripping the inducible resistance to macrolide-lincosamide-streptograminB (MLS(B)) drugs that many groups of pathogens exhibit. The C6 position has been modified by the addition of a methoxy group. This helps prevent hemiketalization of the C6 position with the 3- and 9-keto groups, thereby conferring excellent acid stability, particularly at gastric pH values. Telithromycin is differentiated from other ketolide compounds by the addition of a large aromatic N-substituted carbamate extension from positions C11/C12. This carbamate extension improves binding of the drug to its target, the 50S ribosomal subunit, as demonstrated in in vitro experiments. Telithromycin binds to wild-type ribosomes with 10-fold greater affinity than erythromycin A and 6-fold greater affinity than clarithromycin; its affinity for MLS(B)-resistant ribosomes is > 20 times that of both macrolides. The increased ribosomal affinity of telithromycin correlates with its superior potency against Gram-positive cocci both in vitro and in vivo, and is one of the factors determining the drug's activity against MLS(B)-resistant respiratory pathogens.
Topics: Anti-Bacterial Agents; Base Sequence; Humans; Ketolides; Macrolides; Molecular Sequence Data; Ribosomes; Structure-Activity Relationship
PubMed: 11523556
DOI: No ID Found -
Journal of Clinical Microbiology Sep 2021Clonal multidrug resistance recently emerged in Rhodococcus equi, complicating the therapeutic management of this difficult-to-treat animal- and human-pathogenic...
Clonal multidrug resistance recently emerged in Rhodococcus equi, complicating the therapeutic management of this difficult-to-treat animal- and human-pathogenic actinomycete. The currently spreading multidrug-resistant (MDR) "2287" clone arose in equine farms upon acquisition, and coselection by mass macrolide-rifampin therapy, of the pRErm46 plasmid carrying the (46) macrolide-lincosamide-streptogramin resistance determinant, and of an mutation. Here, we screened a collection of susceptible and macrolide-resistant strains from equine clinical cases using a panel of 15 antimicrobials against rapidly growing mycobacteria (RGM) and nocardiae and other aerobic actinomycetes (NAA). R. equi isolates-including MDR ones-were generally susceptible to linezolid, minocycline, tigecycline, amikacin, and tobramycin according to Staphylococcus aureus interpretive criteria, plus imipenem, cefoxitin, and ceftriaxone based on Clinical and Laboratory Standards Institute (CLSI) guidelines for RGM/NAA. Susceptibility to ciprofloxacin and moxifloxacin was borderline according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. Molecular analyses linked pRErm46 to significantly increased MICs for trimethoprim-sulfamethoxazole and doxycycline, in addition to clarithromycin, within the RGM/NAA panel, and to streptomycin, spectinomycin, and tetracycline resistance. pRErm46 variants with spontaneous deletions in the class 1 integron (C1I) region, observed in ≈30% of (46)-positive isolates, indicated that the newly identified resistances were attributable to the C1I's sulfonamide () and aminoglycoside () resistance cassettes and adjacent (33) determinant. Most MDR isolates carried the mutation of the 2287 clone, while different mutations (S531L, S531Y) detected in two cases suggest the emergence of novel MDR strains.
Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Bacterial; Horses; Humans; Macrolides; Microbial Sensitivity Tests; Rhodococcus; Rhodococcus equi
PubMed: 34319806
DOI: 10.1128/JCM.01149-21 -
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