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Frontiers in Cellular and Infection... 2023With the widespread use of macrolide antibiotics in China, common pathogens causing children's infections, such as , (including , ), , , and , have shown varying... (Review)
Review
With the widespread use of macrolide antibiotics in China, common pathogens causing children's infections, such as , (including , ), , , and , have shown varying degrees of drug resistance. In order to provide such problem and related evidence for rational use of antibiotics in clinic, we reviewed the drug resistance of common bacteria to macrolides in children recent 20 years.
Topics: Drug Resistance, Bacterial; Macrolides; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Humans; Child; China
PubMed: 37637457
DOI: 10.3389/fcimb.2023.1181633 -
Scientific Reports Feb 2024Knowing about the antibiotic resistance, serotypes, and virulence-associated genes of Group B Streptococcus for epidemiological and vaccine development is very...
Knowing about the antibiotic resistance, serotypes, and virulence-associated genes of Group B Streptococcus for epidemiological and vaccine development is very important. We have determined antimicrobial susceptibility patterns, serotype, and virulence profiles. The antibiotic susceptibility was assessed for a total of 421 Streptococcus agalactiae strains, isolated from pregnant women and neonates. Then, 89 erythromycin and/or clindamycin-resistant strains (82 isolates obtained from pregnant women and seven isolates derived from neonates) were assessed in detail. PCR techniques were used to identify the studied strains, perform serotyping, and assess genes encoding selected virulence factors. Phenotypic and genotypic methods determined the mechanisms of resistance. All tested strains were sensitive to penicillin and levofloxacin. The constitutive MLS mechanism (78.2%), inducible MLS mechanism (14.9%), and M phenotype (6.9%) were identified in the macrolide-resistant strains. It was found that macrolide resistance is strongly associated with the presence of the ermB gene and serotype V. FbsA, fbsB, fbsC, scpB, and lmb formed the most recurring pattern of genes among the nine surface proteins whose genes were analysed. A minority (7.9%) of the GBS isolates exhibited resistance to lincosamides and macrolides, or either, including those that comprised the hypervirulent clone ST-17. The representative antibiotic resistance pattern consisted of erythromycin, clindamycin, and tetracycline resistance (71.9%). An increase in the fraction of strains resistant to macrolides and lincosamides indicates the need for monitoring both the susceptibility of these strains and the presence of the ST-17 clone.
Topics: Infant, Newborn; Female; Humans; Pregnancy; Anti-Bacterial Agents; Macrolides; Streptococcus agalactiae; Clindamycin; Pregnant Women; Poland; Streptococcal Infections; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Lincosamides; Erythromycin
PubMed: 38366099
DOI: 10.1038/s41598-024-54521-y -
Antimicrobial Agents and Chemotherapy Nov 2023Rifampicin is recommended for the treatment of complex pulmonary disease alongside azithromycin and ethambutol. We evaluated the azithromycin-ethambutol backbone with...
Rifampicin is recommended for the treatment of complex pulmonary disease alongside azithromycin and ethambutol. We evaluated the azithromycin-ethambutol backbone with and without rifampicin in an intracellular hollow fiber model and performed RNA sequencing to study the differences in adaptation. In an hollow fiber experiment, we simulated epithelial lining fluid pharmacokinetic profiles of the recommended 3-drug (rifampicin, ethambutol, and azithromycin) or a 2-drug (ethambutol and azithromycin) treatment. THP-1 cells infected with ATCC700898 were exposed to these regimens for 21 days. We determined intra- and extra-cellular bacterial load- and THP-1 cell densities on days 0, 3, 7, 14, and 21, alongside RNA sequencing. The emergence of macrolide resistance was studied by inoculating intra- and extra-cellular fractions of azithromycin-containing Middlebrook 7H10 agar plates. Complete pharmacokinetic profiles were determined at days 0 and 21. Both therapies maintained stasis of both intra- and extra-cellular bacterial populations for 3 days, whilst regrowth coinciding with the emergence of a macrolide-resistant subpopulation was seen after 7 days. THP-1 cell density remained static. Similar transcriptional profiles were observed for both therapies that were minimally influenced by exposure duration. Transcriptional response was slightly larger during 2-drug treatment. Rifampicin did not add to the antimycobacterial effect to the 2-drug therapy or suppression of emergence resistance. RNA transcription was not greatly altered by the addition of rifampicin, which may be due to strong transcriptional influence of azithromycin and host cells. This questions the role of rifampicin in the currently recommended therapy. These findings should be confirmed in clinical trials.
Topics: Humans; Rifampin; Mycobacterium avium; Anti-Bacterial Agents; Ethambutol; Azithromycin; Macrolides; Drug Resistance, Bacterial; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Lung Diseases
PubMed: 37877693
DOI: 10.1128/aac.00874-23 -
Revue Medicale Suisse Apr 2024
Topics: Humans; Macrolides; Anti-Bacterial Agents; Community-Acquired Infections; Pneumonia
PubMed: 38568069
DOI: 10.53738/REVMED.2024.20.868.727 -
Scientific Reports Nov 2023The prevalence of Mycobacterium avium complex-pulmonary disease (MAC-PD) has become a growing concern worldwide, and current treatments involving macrolides...
The prevalence of Mycobacterium avium complex-pulmonary disease (MAC-PD) has become a growing concern worldwide, and current treatments involving macrolides (clarithromycin [CLR] or azithromycin), ethambutol, and rifampicin have limited success, highlighting the need for better therapeutic strategies. Recently, oxazolidinone drugs have been identified as novel anti-tuberculosis drugs effective against drug-resistant M. tuberculosis. However, the effects of these drugs against MAC are still controversial due to limited data. Here, we first evaluated the intracellular anti-MAC activities of two oxazolidinone drugs, linezolid (LZD) and delpazolid (DZD), against 10 macrolide-susceptible MAC strains and one macrolide-resistant M. avium strain in murine bone marrow-derived macrophages (BMDMs) and found that both drugs demonstrated similar potential. The synergistic efficacies with CLR were then determined in a chronic progressive MAC-PD murine model by initiating a 4-week treatment at 8 weeks post-infection. Upon assessment of bacterial burdens and inflamed lesions, oxazolidinone drugs exhibited no anti-MAC effect, and there was no significant difference in the synergistic effect of CLR between LZD and DZD. These findings suggest that oxazolidinone drugs inhibit intracellular bacterial growth, even against macrolide-resistant MAC, but their clinical application requires further consideration.
Topics: Humans; Mice; Animals; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Oxazolidinones; Anti-Bacterial Agents; Antitubercular Agents; Clarithromycin; Macrolides; Lung Diseases
PubMed: 37996500
DOI: 10.1038/s41598-023-48001-y -
Unlocking the path to efficient eradication: Embracing potassium-competitive acid blockers (P-CABs).Saudi Journal of Gastroenterology :... 2023
Topics: Humans; Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Potassium; Proton Pump Inhibitors; Treatment Outcome
PubMed: 37706422
DOI: 10.4103/sjg.sjg_297_23 -
Microbial Genomics Sep 2023() is a leading vaccine-preventable cause of childhood invasive disease. Nigeria has the second highest pneumococcal disease burden globally, with an estimated...
() is a leading vaccine-preventable cause of childhood invasive disease. Nigeria has the second highest pneumococcal disease burden globally, with an estimated ~49 000 child deaths caused by pneumococcal infections each year. Ten-valent pneumococcal conjugate vaccine (GSK; PCV10) was introduced in December 2014 in a phased approach. However, few studies have characterized the disease-causing pneumococci from Nigeria. This study assessed the prevalence of serotypes, antibiotic susceptibility and genomic lineages using whole genome sequencing and identified lineages that could potentially escape PCV10 (GSK). We also investigated the potential differences in pneumococcal lineage features between children with and without sickle cell disease. A collection of 192 disease-causing pneumococcal isolates was obtained from Kano (=189) and Abuja (=3) states, Nigeria, between 1 January 2014 and 31 May 2018. The majority (99 %, 190/192) of specimens were recovered from children aged 5 years or under. Among them, 37 children had confirmed or traits of sickle cell disease. Our findings identified 25 serotypes expressed by 43 Global Pneumococcal Sequence Clusters (GPSCs) and 85 sequence types (STs). The most common serotypes were 14 (18 %, =35), 6B (16 %, =31), 1 (9 %, =17), 5 (9 %, =17) and 6A (9 %, =17); all except serotype 6A are included in PCV10 (GSK). PCV10 (SII; PNEUMOSIL) and PCV13 formulations include serotypes 6A and 19A which would increase the overall coverage from 67 % by PCV10 (GSK) to 78 and 82 %, respectively. The pneumococcal lineages were a mix of globally spreading and unique local lineages. Following the use of PCV10 (GSK), GPSC5 expressing serotype 6A, GPSC10 (19A), GPSC26 (12F and 46) and GPSC627 (9L) are non-vaccine type lineages that could persist and potentially expand under vaccine-selective pressure. Approximately half (52 %, 99/192) of the pneumococcal isolates were resistant to the first-line antibiotic penicillin and 44 % (85/192) were multidrug-resistant. Erythromycin resistance was very low (2 %, 3/192). There was no significant difference in clinical manifestation, serotype prevalence or antibiotic resistance between children with and without traits of or confirmed sickle cell disease. In summary, our findings show that a high percentage of the pneumococcal disease were caused by the serotypes that are covered by currently available vaccines. Given the low prevalence of resistance, macrolide antibiotics, such as erythromycin, should be considered as an option to treat pneumococcal disease in Nigeria. However, appropriate use of macrolide antibiotics should be vigilantly monitored to prevent the potential increase in macrolide resistance.
Topics: Humans; Child; Streptococcus pneumoniae; Nigeria; Anti-Bacterial Agents; Drug Resistance, Bacterial; Macrolides; Pneumococcal Infections; Erythromycin; Anemia, Sickle Cell; Protein Synthesis Inhibitors
PubMed: 37712828
DOI: 10.1099/mgen.0.001094 -
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 -
The Journal of Biological Chemistry Jun 2024Antimicrobial resistance poses a serious threat to human health worldwide and its incidence continues to increase owing to the overuse of antibiotics and other factors....
Antimicrobial resistance poses a serious threat to human health worldwide and its incidence continues to increase owing to the overuse of antibiotics and other factors. Macrolide antibiotics such as erythromycin (EM) have immunomodulatory effects in addition to their antibacterial activity. Long-term, low-dose administration of macrolides has shown clinical benefits in treating non-infectious inflammatory respiratory diseases. However, this practice may also increase the emergence of drug-resistant bacteria. In this study, we synthesized a series of EM derivatives, and screened them for two criteria: (i) lack of antibacterial activity and (ii) ability to suppress tumor necrosis factor-α (TNF-α) production in THP-1 cells stimulated with lipopolysaccharide. Among the 37 synthesized derivatives, we identified a novel 12-membered ring macrolide EM982 that lacked antibacterial activity against Staphylococcus aureus and suppressed the production of TNF-α and other cytokines. The effects of EM982 on Toll-like receptor 4 (TLR4) signaling were analyzed using a reporter assay and Western blotting. The reporter assay showed that EM982 suppressed the activation of transcription factors, NF-κB and/or activator protein 1 (AP-1), in HEK293 cells expressing human TLR4. Western blotting showed that EM982 inhibited the phosphorylation of both IκB kinase (IKK) β and IκBα, which function upstream of NF-κB, whereas it did not affect the phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and c-Jun N-terminal kinase, which act upstream of AP-1. These results suggest that EM982 suppresses cytokine production by inhibiting phosphorylation of IKKβ and IκBα, resulting in the inactivation of NF-κB.
Topics: Humans; I-kappa B Kinase; Phosphorylation; NF-KappaB Inhibitor alpha; Cytokines; Erythromycin; THP-1 Cells; Tumor Necrosis Factor-alpha; Anti-Bacterial Agents; Macrolides; NF-kappa B; Signal Transduction; Staphylococcus aureus; Toll-Like Receptor 4
PubMed: 38762177
DOI: 10.1016/j.jbc.2024.107384 -
Frontiers in Cellular and Infection... 2023This study aimed to investigate sudapyridine (WX-081) antibacterial activity against and its effect on bacterial growth and host survival using a zebrafish model of...
OBJECTIVE
This study aimed to investigate sudapyridine (WX-081) antibacterial activity against and its effect on bacterial growth and host survival using a zebrafish model of infection.
METHODS
WX-081 antibacterial activity was assessed based on growth inhibition of standard strain ATCC19977 and 36 clinical isolates. Maximum tolerated concentrations (MTCs) of WX-081, bedaquiline, and azithromycin and inhibition of growth were assessed after fluorescently labelled bacilli and drugs were injected into zebrafish. Bacterial counts were analysed using one-way ANOVA and fluorescence intensities of zebrafish tissues were analysed and expressed as the mean ± SE. Moreover, Kaplan-Meier survival analysis was conducted to assess intergroup differences in survival of -infected zebrafish treated with different drug concentrations using a log-rank test, with a p value <0.05 indicating a difference was statistically significant.
RESULTS
Drug sensitivity testing of standard strain ATCC19977 and 36 clinical isolates revealed MICs ranging from 0.12-0.96 µg/mL and MIC and MIC values of 0.48 µg/mL and 0.96 µg/mL, respectively. Fluorescence intensities of -infected zebrafish tissues was lower after treatment with the WX-081 MTC (62.5 µg/mL) than after treatment with the azithromycin MTC (62.5 µg/mL) and the bedaquiline MTC (15.6 µg/mL). When the concentration of WX-081 increased from 1.95µg/mL to 1/8 MTC(7.81µg/mL), the survival rate of zebrafish at 4-9 dpf decreased from 90.00% to 81.67%.
CONCLUSION
WX-081 effectively inhibited growth and and prolonged survival of -infected zebrafish, thus indicating that WX-081 holds promise as a clinical treatment for infection.
Topics: Animals; Azithromycin; Mycobacterium abscessus; Zebrafish; Anti-Bacterial Agents
PubMed: 37662015
DOI: 10.3389/fcimb.2023.1217975