-
European Journal of Internal Medicine Mar 2016A large body of evidences suggested that macrolide therapy could improve the survival of patients with various infections. While in the same time, macrolides are known... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A large body of evidences suggested that macrolide therapy could improve the survival of patients with various infections. While in the same time, macrolides are known to increase fatal arrhythmogenic risks and cause cardiac death. To assess the risks and benefits of macrolide therapy, we systematically reviewed all studies of macrolide use, cardiac death and mortality among patients with various infections.
METHODS
We searched Pubmed, Embase and Cochrane library and reviewed reference lists from 1980 through April 2015. Studies were included if they compared macrolides to other antibiotics in adults with various infections. The outcome measures were the overall mortality and the risk of cardiac death.
RESULTS
Overall, macrolide use was associated with a statistically significant mortality reduction compared with nonmacrolide use (OR: 0.65, 95% CI: 0.46-0.92). There was no difference in the risk of cardiac death between macrolide and nonmacrolide regimes (OR: 1.43, 95% CI: 0.86-2.40). In subgroup analyses, macrolide use was found to be associated with the decreased risk of mortality in a population of older individuals (age>48 years, OR: 0.69; 95% CI: 0.66-0.72). While in a general population of young and middle-aged adults, the use of macrolide-based regimens could not decrease the risk of death from any cause (age<48 years, OR: 0.42; 95% CI: 0.02-11.01). As for cardiac death, macrolide use was found to be associated with increased risk of cardiac death in a population of older individuals (age>48 years, OR: 1.99; 95% CI: 1.53-2.59).
CONCLUSION
Despite the potential cardiotoxic effects, there is a net benefit associated with macrolide use in older patients with various infections and macrolide use except roxithromycin was found to be associated with increased risk of cardiac death in a population of adults aged > 48 years.
Topics: Anti-Bacterial Agents; Arrhythmias, Cardiac; Bacterial Infections; Case-Control Studies; Death; Humans; Macrolides; Mortality; Protective Factors; Risk Factors
PubMed: 26412674
DOI: 10.1016/j.ejim.2015.09.009 -
Revista Espanola de Quimioterapia :... Jun 2023Mycoplasma pneumoniae is a bacterium that lacks a cell wall. It produces infections all It produces infections world-wide, in epidemic outbreaks every 4-7 years, or... (Review)
Review
Mycoplasma pneumoniae is a bacterium that lacks a cell wall. It produces infections all It produces infections world-wide, in epidemic outbreaks every 4-7 years, or endemically. Its clinical manifestations occur mostly in the respiratory tract and it is a common cause of atypical pneumonia. The treatment is with macrolides, tetracyclines or fluoroquinolones. Since 2000, an increase in resistance to macrolides has been detected worldwide, being more frequent in Asia. In Europe the frequency of resistance ranges between 1% and 25%, depending on the country. Molecular techniques and serology techniques provides very high sensitivity in diagnostic confirmation, being very useful for detecting and controlling M. pneumoniae outbreaks. The detection of resistance to macrolides requires a sequencing technique.
Topics: Humans; Mycoplasma pneumoniae; Macrolides; Drug Resistance, Bacterial; Pneumonia, Mycoplasma; Anti-Bacterial Agents; Europe
PubMed: 36966384
DOI: 10.37201/req/118.2022 -
American Journal of Respiratory and... Oct 2019
Topics: Anti-Bacterial Agents; Azithromycin; Double-Blind Method; Hospitalization; Humans; Macrolides; Patient Readmission; Pulmonary Disease, Chronic Obstructive
PubMed: 31188635
DOI: 10.1164/rccm.201905-0957ED -
International Journal of Molecular... May 2023Various chronic inflammatory airway diseases can be treated with low-dose, long-term (LDLT) macrolide therapy. LDLT macrolides can be one of the therapeutic options for... (Review)
Review
Various chronic inflammatory airway diseases can be treated with low-dose, long-term (LDLT) macrolide therapy. LDLT macrolides can be one of the therapeutic options for chronic rhinosinusitis (CRS) due to their immunomodulatory and anti-inflammatory actions. Currently, various immunomodulatory mechanisms of the LDLT macrolide treatment have been reported, as well as their antimicrobial properties. Several mechanisms have already been identified in CRS, including reduced cytokines such as interleukin (IL)-8, IL-6, IL-1β, tumor necrosis factor-α, transforming growth factor-β, inhibition of neutrophil recruitment, decreased mucus secretion, and increased mucociliary transport. Although some evidence of effectiveness for CRS has been published, the efficacy of this therapy has been inconsistent across clinical studies. LDLT macrolides are generally believed to act on the non-type 2 inflammatory endotype of CRS. However, the effectiveness of LDLT macrolide treatment in CRS is still controversial. Here, we reviewed the immunological mechanisms related to CRS in LDLT macrolide therapy and the treatment effects according to the clinical situation of CRS.
Topics: Humans; Macrolides; Anti-Bacterial Agents; Sinusitis; Treatment Outcome; Cytokines; Chronic Disease; Rhinitis
PubMed: 37298439
DOI: 10.3390/ijms24119489 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2020The nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis-decalin moiety and a narrow spectrum of... (Review)
Review
The nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis-decalin moiety and a narrow spectrum of activity. Most family members were identified almost four decades ago and were placed on the shelf due to the numbers of broad-spectrum compounds available at the time. However, in light of rising rates of antimicrobial resistance, there has been a renewed interest in the use of narrow-spectrum antimicrobials. Here, we review the history of this family of compounds, including synthetic approaches, and highlight the recently uncovered genetic basis for nargenicin production. Given the renewed pharmaceutical interest in these compounds, we also investigate structure-activity relationships among these molecules, with a view to the future development of members of this unusual antibiotic family.
Topics: Anti-Bacterial Agents; Bridged-Ring Compounds; Humans; Lactones; Macrolides; Naphthalenes; Structure-Activity Relationship
PubMed: 31667915
DOI: 10.1002/chem.201904053 -
Current Topics in Medicinal Chemistry 2017Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as... (Review)
Review
Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encouraging developmental potential. Anti-inflammatory hybrids were obtained by combining macrolides with corticosteroid and non-steroidal anti-inflammatory drugs. They were found active in in vivo animal models of locally induced inflammation, asthma, inflammatory bowel disease and rheumatoid arthritis and demonstrated improved safety over parent steroid drugs. Overall, macrolide hybrids possess significant potential to be developed as potent novel medicines in therapeutic areas of utmost pharmaceutical interest.
Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antimalarials; Bacteria; Drug Discovery; Humans; Inflammation; Macrolides; Malaria
PubMed: 27697049
DOI: 10.2174/1568026616666160927160036 -
MSphere Oct 2022Escherichia coli is intrinsically resistant to macrolides due to outer membrane impermeability, but may also acquire macrolide resistance genes by horizontal transfer....
Escherichia coli is intrinsically resistant to macrolides due to outer membrane impermeability, but may also acquire macrolide resistance genes by horizontal transfer. We evaluated the prevalence and types of acquired macrolide resistance determinants in pig clinical E. coli, and we assessed the ability of peptidomimetics to potentiate different macrolide subclasses against strains resistant to neomycin, a first-line antibiotic in the treatment of pig-enteric infections. The erythromycin MIC distribution was determined in 324 pig clinical E. coli isolates, and 62 neomycin-resistant isolates were further characterized by genome sequencing and MIC testing of azithromycin, spiramycin, tilmicosin, and tylosin. The impact on potency achieved by combining these macrolides with three selected peptidomimetic compounds was determined by checkerboard assays in six strains representing different genetic lineages and macrolide resistance gene profiles. Erythromycin MICs ranged from 16 to >1,024 μg/mL. Azithromycin showed the highest potency in wild-type strains (1 to 8 μg/mL), followed by erythromycin (16 to 128 μg/mL), tilmicosin (32 to 256 μg/mL), and spiramycin (128 to 256 μg/mL). Isolates with elevated MIC mainly carried (B), either alone or in combination with other acquired macrolide resistance genes, including (42), (C), (A), (B), and (G). All peptidomimetic-macrolide combinations exhibited synergy (fractional inhibitory concentration index [FICI] < 0.5) with a 4- to 32-fold decrease in the MICs of macrolides. Interestingly, the MICs of tilmicosin in wild-type strains were reduced to concentrations (4 to 16 μg/mL) that can be achieved in the pig intestinal tract after oral administration, indicating that peptidomimetics can potentially be employed for repurposing tilmicosin in the management of E. coli enteritis in pigs. Acquired macrolide resistance is poorly studied in Escherichia coli because of intrinsic resistance and limited antimicrobial activity in Gram-negative bacteria. This study reveals new information on the prevalence and distribution of macrolide resistance determinants in a comprehensive collection of porcine clinical E. coli from Denmark. Our results contribute to understanding the correlation between genotypic and phenotypic macrolide resistance in E. coli. From a clinical standpoint, our study provides an initial proof of concept that peptidomimetics can resensitize E. coli to macrolide concentrations that may be achieved in the pig intestinal tract after oral administration. The latter result has implications for animal health and potential applications in veterinary antimicrobial drug development in view of the high rates of antimicrobial-resistant E. coli isolated from enteric infections in pigs and the lack of viable alternatives for treating these infections.
Topics: Swine; Animals; Escherichia coli; Anti-Bacterial Agents; Azithromycin; Peptidomimetics; Macrolides; Tylosin; Drug Resistance, Bacterial; Spiramycin; Erythromycin; Escherichia coli Infections; Neomycin
PubMed: 36154672
DOI: 10.1128/msphere.00402-22 -
Current Topics in Medicinal Chemistry 2021Staphylococcus aureus (S. aureus), recognized as one of the deadliest pathogens responsible for nosocomial and community acquired infections, is highly contagious and... (Review)
Review
Staphylococcus aureus (S. aureus), recognized as one of the deadliest pathogens responsible for nosocomial and community acquired infections, is highly contagious and associated with significant morbidity and mortality. The increasing emergency and rapid spread of various forms of drug-resistant S. aureus have already posed a heavy burden on the world health system, but newfangled antibiotics are right now being created at a much slower pace than our developing requirement. Macrolides could inhibit protein synthesis by targeting the bacterial ribosome and are a class of basic and widely used antibacterial agents in clinical practice to control infections caused by various bacteria, including S. aureus. However, the emergence of bacterial resistance to macrolide antibiotics, particularly in Gram-positive bacteria such as macrolide-resistant S. aureus, has already become one of the significant obstacles for effective chemotherapy. Therefore, there is a critical need for the development of novel macrolide candidates. This review provides an overview of macrolide hybrids with potential activity against S. aureus, including drug-resistant forms developed in the recent decade, with special emphasis on the structure-activity relationships and mechanism of actions.
Topics: Anti-Bacterial Agents; Humans; Macrolides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 33272187
DOI: 10.2174/1568026620999201203213733 -
Chest Jul 2022Long-term macrolide therapy has been shown to provide benefit to those with a range of chronic respiratory conditions. However, concerns remain about the impact of...
BACKGROUND
Long-term macrolide therapy has been shown to provide benefit to those with a range of chronic respiratory conditions. However, concerns remain about the impact of macrolide exposure on the carriage and abundance of antibiotic resistance genes within the oropharynx. The potential for onward transmission of resistance from macrolide recipients to their close contacts also is poorly understood.
RESEARCH QUESTION
Does long-term macrolide use impact carriage of resistance within the oropharyngeal microbiota in people with chronic respiratory conditions and risk of onward transmission to their close contacts?
STUDY DESIGN AND METHODS
Oropharyngeal swabs were collected from 93 individuals with chronic respiratory conditions, 53 of whom were receiving long-term macrolide therapy. An oropharyngeal swab also was collected from a close cohabiting contact of each patient. Detection and abundance of 10 macrolide-associated resistance genes with the potential to disseminate via horizontal gene transfer were assessed by quantitative polymerase chain reaction analysis.
RESULTS
Detection of resistance genes in macrolide recipients was comparable with that in nonrecipients. However, the normalized gene abundance of erm(B) was significantly higher in the macrolide recipient group (P = .045). Among the close contacts, no between-group differences in resistance gene detection or abundance were identified. Within-group analysis showed that the detection of erm(F) and mef in macrolide recipients, but not nonrecipients, was associated significantly with detection in close contacts (P = .003 and P = .004, respectively). However, between-group analysis showed that treatment group did not predict cocarriage between patients and their close contacts (P > .05 for each gene).
INTERPRETATION
Although levels of erm(B) were higher in those receiving long-term macrolide therapy and evidence of gene cocarriage with close contacts was found, no evidence was found that macrolide use increased the onward transmission risk to their close contacts. This study therefore addresses concerns that long-term macrolide therapy could promote the dissemination of transmissible macrolide resistance.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Macrolides; Oropharynx
PubMed: 35122749
DOI: 10.1016/j.chest.2022.01.045 -
Molecular Pharmaceutics Dec 2023Macrolides are widely used for the long-term treatment of infections and chronic inflammatory diseases. The pharmacokinetic features of macrolides include extensive...
Macrolide and Ketolide Antibiotics Inhibit the Cytotoxic Effect of Trastuzumab Emtansine in HER2-Positive Breast Cancer Cells: Implication of a Potential Drug-ADC Interaction in Cancer Chemotherapy.
Macrolides are widely used for the long-term treatment of infections and chronic inflammatory diseases. The pharmacokinetic features of macrolides include extensive tissue distribution because of favorable membrane permeability and accumulation within lysosomes. Trastuzumab emtansine (T-DM1), a HER2-targeting antibody-drug conjugate (ADC), is catabolized in the lysosomes, where Lys-SMCC-DM1, a potent cytotoxic agent, is processed by proteinase degradation and subsequently released from the lysosomes to the cytoplasm through the lysosomal membrane transporter SLC46A3, resulting in an antitumor effect. We recently demonstrated that erythromycin and clarithromycin inhibit SLC46A3 and attenuate the cytotoxicity of T-DM1; however, the effect of other macrolides and ketolides has not been determined. In this study, we evaluated the effect of macrolide and ketolide antibiotics on T-DM1 cytotoxicity in a human breast cancer cell line, KPL-4. Macrolides used in the clinic, such as roxithromycin, azithromycin, and josamycin, as well as solithromycin, a ketolide under clinical development, significantly attenuated T-DM1 cytotoxicity in addition to erythromycin and clarithromycin. Of these, azithromycin was the most potent inhibitor of T-DM1 efficacy. These antibiotics significantly inhibited the transport function of SLC46A3 in a concentration-dependent manner. Moreover, these compounds extensively accumulated in the lysosomes at the levels estimated to be 0.41-13.6 mM when cells were incubated with them at a 2 μM concentration. The immunofluorescence staining of trastuzumab revealed that azithromycin and solithromycin inhibit the degradation of T-DM1 in the lysosomes. These results suggest that the attenuation of T-DM1 cytotoxicity by macrolide and ketolide antibiotics involves their lysosomal accumulation and results in their greater lysosomal concentrations to inhibit the SLC46A3 function and T-DM1 degradation. This suggests a potential drug-ADC interaction during cancer chemotherapy.
Topics: Humans; Female; Ado-Trastuzumab Emtansine; Breast Neoplasms; Ketolides; Immunoconjugates; Azithromycin; Clarithromycin; Maytansine; Receptor, ErbB-2; Antibodies, Monoclonal, Humanized; Trastuzumab; Antineoplastic Agents; Lysosomes; Anti-Bacterial Agents
PubMed: 37971309
DOI: 10.1021/acs.molpharmaceut.3c00490