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1.
J Assoc Physicians India ; 68(3): 59-63, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32138486

RESUMO

Introduction: Doxycycline acts against a broad range of gram-positive, gramnegative and 'atypical' bacteria as well as some protozoan pathogens such as malaria. In this era of increasing multidrug-resistance, recycling of old antimicrobials should be considered and need more focus in this domain of research. We, therefore, aimed to assess the antimicrobial susceptibility patterns of commonly isolated pathogens against doxycycline, azithromycin, cefuroxime, and amoxicillin from common clinical specimens by using laboratory-based diagnostic data from western India. Materials and Methods: The non-interventional retrospective study was conducted on secondary data extracted from multi-center diagnostic laboratory based in Mumbai, India. Susceptibility data of bacteria isolated from blood, urine, pus, and sputum were used in the study and culture positive samples were segregated. Antimicrobial susceptibility status of doxycycline was checked and compared with azithromycin, cefuroxime, and amoxicillin. Chi-square tests of significance were carried out to assess significant differences in susceptibility patterns. Association between variables was considered statistically significant if the p-value was <0.05. Results: Percentage susceptibility of collective bacterial isolates was found to be highest for doxycycline in all four specimens (93.1%). Individual percentage susceptibility was observed to be highest for sputum isolates (97.5%) followed by blood (93.8%), pus (92.7%) and urine (70.0%). The activity of doxycycline was found to be 93.5% for the samples resistant to azithromycin. Doxycycline also showed good susceptibility for the isolates resistant to amoxicillin and cefuroxime which was 75.9% and 64.8%, respectively. Conclusion: Several bacterial isolates from all four sources were found to be susceptible to Doxycycline. It has an important role in the form of a better alternative of major antimicrobial agents like azithromycin, cefuroxime, and amoxicillin against gram-positive cocci. Doxycycline appeared to show better activity against isolates which were resistant to other three antimicrobials.


Assuntos
Antibacterianos/farmacologia , Amoxicilina/farmacologia , Azitromicina/farmacologia , Cefuroxima/farmacologia , Doxiciclina/farmacologia , Índia , Testes de Sensibilidade Microbiana , Estudos Retrospectivos
3.
BMC Infect Dis ; 19(1): 1040, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822275

RESUMO

BACKGROUND: European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) antimicrobial resistance (AMR) data are used to inform gonorrhoea treatment guidelines; therefore the data need to be robust and representative. We assessed the extent to which Euro-GASP reflects national measures of the AMR situation for Neisseria gonorrhoeae across the European Union/European Economic Area (EU/EEA). METHODS: We compared data from Euro-GASP with published national gonococcal AMR data from 15 countries for azithromycin, cefixime and ciprofloxacin for the period 2009 to 2013 and performed Poisson regression to identify differences (p < 0.05) between the proportions of resistant isolates. The 2014 Euro-GASP AMR data for each country (n = 19) were weighted to account for differences in the distribution of patient characteristics between Euro-GASP and EU/EEA epidemiological gonorrhoea surveillance data. Data were compared to determine whether estimates of resistance levels differed with regards to the 5% threshold used to assess the clinical utility of first-line gonorrhoea treatments. We assessed the quality of decentralised testing by comparing AMR data for isolates tested both centrally and in the participating laboratories, and by evaluating external quality assessment (EQA) performance. RESULTS: There was no significant difference for azithromycin, cefixime and ciprofloxacin resistance when Euro-GASP country data were compared with data from national reports. Weighting slightly altered the Euro-GASP AMR estimates (by between - 4.7 and 4.7% from the unweighted estimates). Weighting resulted in greater changes in estimates of resistance to azithromycin (from - 9.5 to 2.7%) and ciprofloxacin (from - 14.8 to 17.9%) in countries with low isolate numbers and low completeness of reporting (n = 3). Weighting caused AMR levels to fall below or above the 5% threshold for cefixime or azithromycin, respectively in only two countries. Susceptibility category data submitted from the decentralised Euro-GASP laboratories were concordant with the Euro-GASP data (> 90%). EQA performance was also good; < 5% of the minimum inhibitory concentration (MIC) results differed by > 4-fold from the modal MIC of the EQA isolate. CONCLUSIONS: The overall prevalence of AMR reported by Euro-GASP reflects closely the AMR situation for N. gonorrhoeae in the EU/EEA. Euro-GASP data can be used to provide robust AMR estimates to inform the European guideline for the management of gonorrhoea.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Neisseria gonorrhoeae/efeitos dos fármacos , Antibacterianos/uso terapêutico , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Cefixima/farmacologia , Cefixima/uso terapêutico , Ciprofloxacino/farmacologia , Ciprofloxacino/uso terapêutico , União Europeia , Gonorreia/diagnóstico , Gonorreia/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/isolamento & purificação
4.
PLoS Negl Trop Dis ; 13(11): e0007868, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31730615

RESUMO

BACKGROUND: With the rise in fluoroquinolone-resistant Salmonella Typhi and the recent emergence of ceftriaxone resistance, azithromycin is one of the last oral drugs available against typhoid for which resistance is uncommon. Its increasing use, specifically in light of the ongoing outbreak of extensively drug-resistant (XDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, cotrimoxazole, streptomycin, fluoroquinolones and third-generation cephalosporins) in Pakistan, places selective pressure for the emergence and spread of azithromycin-resistant isolates. However, little is known about azithromycin resistance in Salmonella, and no molecular data are available on its mechanism. METHODS AND FINDINGS: We conducted typhoid surveillance in the two largest pediatric hospitals of Bangladesh from 2009-2016. All typhoidal Salmonella strains were screened for azithromycin resistance using disc diffusion and resistance was confirmed using E-tests. In total, we identified 1,082 Salmonella Typhi and Paratyphi A strains; among these, 13 strains (12 Typhi, 1 Paratyphi A) were azithromycin-resistant (MIC range: 32-64 µg/ml) with the first case observed in 2013. We sequenced the resistant strains, but no molecular basis of macrolide resistance was identified by the currently available antimicrobial resistance prediction tools. A whole genome SNP tree, made using RAxML, showed that the 12 Typhi resistant strains clustered together within the 4.3.1.1 sub-clade (H58 lineage 1). We found a non-synonymous single-point mutation exclusively in these 12 strains in the gene encoding AcrB, an efflux pump that removes small molecules from bacterial cells. The mutation changed the conserved amino acid arginine (R) at position 717 to a glutamine (Q). To test the role of R717Q present in azithromycin-resistant strains, we cloned acrB from azithromycin-resistant and sensitive strains, expressed them in E. coli, Typhi and Paratyphi A strains and tested their azithromycin susceptibility. Expression of AcrB-R717Q in E. coli and Typhi strains increased the minimum inhibitory concentration (MIC) for azithromycin by 11- and 3-fold respectively. The azithromycin-resistant Paratyphi A strain also contained a mutation at R717 (R717L), whose introduction in E. coli and Paratyphi A strains increased MIC by 7- and 3-fold respectively, confirming the role of R717 mutations in conferring azithromycin resistance. CONCLUSIONS: This report confirms 12 azithromycin-resistant Salmonella Typhi strains and one Paratyphi A strain. The molecular basis of this resistance is one mutation in the AcrB protein at position 717. This is the first report demonstrating the impact of this non-synonymous mutation in conferring macrolide resistance in a clinical setting. With increasing azithromycin use, strains with R717 mutations may spread and be acquired by XDR strains. An azithromycin-resistant XDR strain would shift enteric fever treatment from outpatient departments, where patients are currently treated with oral azithromycin, to inpatient departments to be treated with injectable antibiotics like carbapenems, thereby further burdening already struggling health systems in endemic regions. Moreover, with the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against widespread mortality from typhoid. In addition to rolling out the WHO prequalified typhoid conjugate vaccine in endemic areas to decrease the risk of pan-resistant Salmonella Typhi strains, it is also imperative to implement antimicrobial stewardship and water sanitation and hygiene intervention to decrease the overall burden of enteric fever.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Farmacorresistência Bacteriana , Salmonella paratyphi A/efeitos dos fármacos , Salmonella typhi/efeitos dos fármacos , Febre Tifoide/microbiologia , Proteínas de Bactérias , Bangladesh , DNA Bacteriano/química , DNA Bacteriano/genética , Genótipo , Hospitais Pediátricos , Humanos , Proteínas de Membrana Transportadoras , Testes de Sensibilidade Microbiana , Polimorfismo de Nucleotídeo Único , Salmonella paratyphi A/classificação , Salmonella paratyphi A/genética , Salmonella paratyphi A/isolamento & purificação , Salmonella typhi/classificação , Salmonella typhi/genética , Salmonella typhi/isolamento & purificação , Sequenciamento Completo do Genoma
5.
Emerg Microbes Infect ; 8(1): 1546-1549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31661379

RESUMO

The growing multidrug-resistant Neisseria gonorrhoeae is a serious global threat to gonococcal therapy. During 2017-2018, we identified a rare multidrug-resistant (ceftriaxone and azithromycin) strain (GC250) and four strains (GC185, GC195, GC196 and GC249) with both resistance to ceftriaxone and decreased susceptibility to azithromycin. All strains belonged to NG-STAR ST1143, including the mosaic penA-60.001, which is closely related to ceftriaxone resistance. The characterization of antimicrobial resistance (AMR) determinants and phylogenetic analysis showed these five strains were closely related to internationally spreading ceftriaxone-resistant N. gonorrhoeae FC428, but with higher azithromycin MIC. Findings here demonstrated that this clone not only initiated clonal expansion in China, but acquired azithromycin resistance.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Ceftriaxona/farmacologia , Farmacorresistência Bacteriana Múltipla , Gonorreia/microbiologia , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/isolamento & purificação , China , Feminino , Heterossexualidade , Humanos , Masculino , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/classificação , Neisseria gonorrhoeae/genética , Filogenia
6.
Nat Commun ; 10(1): 4280, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537784

RESUMO

Bloodstream infections by Salmonella enterica serovar Typhimurium constitute a major health burden in sub-Saharan Africa (SSA). These invasive non-typhoidal (iNTS) infections are dominated by isolates of the antibiotic resistance-associated sequence type (ST) 313. Here, we report emergence of ST313 sublineage II.1 in the Democratic Republic of the Congo. Sublineage II.1 exhibits extensive drug resistance, involving a combination of multidrug resistance, extended spectrum ß-lactamase production and azithromycin resistance. ST313 lineage II.1 isolates harbour an IncHI2 plasmid we name pSTm-ST313-II.1, with one isolate also exhibiting decreased ciprofloxacin susceptibility. Whole genome sequencing reveals that ST313 II.1 isolates have accumulated genetic signatures potentially associated with altered pathogenicity and host adaptation, related to changes observed in biofilm formation and metabolic capacity. Sublineage II.1 emerged at the beginning of the 21st century and is involved in on-going outbreaks. Our data provide evidence of further evolution within the ST313 clade associated with iNTS in SSA.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Adaptação Fisiológica/genética , Animais , Azitromicina/farmacologia , Biofilmes/crescimento & desenvolvimento , Linhagem Celular , Ciprofloxacino/farmacologia , República Democrática do Congo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Plasmídeos/genética , Salmonella typhimurium/isolamento & purificação , Células THP-1 , Sequenciamento Completo do Genoma
7.
BMC Infect Dis ; 19(1): 827, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547805

RESUMO

BACKGROUND: The worldwide expansion of macrolide-resistant Mycoplasma genitalium (MG) in cases of genital infections has led to an increased recurrence rate of these infections after first-line azithromycin treatment. By detecting the presence of azithromycin-resistant MG, the patient's antibiotic treatment can be targeted and the spread of resistance prevented. With this aim in mind, macrolide-resistance detection kits are helpful tools for the physician. METHODS: Azithromycin resistance mutations in MG are targeted using a four-color multiplex real-time RT-PCR assay. Tested targets include plasmid DNA (as positive controls) as well as macrolide-sensitive and macrolide-resistant genomic DNA from characterized cell lines and clinical samples. RESULTS: The analytical data presented here were generated from plasmid DNA and genomic RNA/DNA and include adaptation to an internal control, specificity between targets, specificity vs non-MG species, limit of detection (LoD) and interference studies (co-infection and endogenous substances). The clinical data were based on the application of the assay to clinical samples characterized by sequencing. CONCLUSIONS: A new NAAT (nucleic acid amplification test) prototype has been developed in collaboration with the Diagenode s.a. company, this prototype targets MG and azithromycin-resistance mutations in that pathogen.


Assuntos
Azitromicina/farmacologia , Farmacorresistência Bacteriana/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Mutação , Mycoplasma genitalium/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Antibacterianos/farmacologia , Humanos , Infecções por Mycoplasma/tratamento farmacológico , Infecções por Mycoplasma/microbiologia , Especificidade por Substrato
8.
Microb Pathog ; 135: 103658, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31398531

RESUMO

The increasing resistance of Pseudomonas aeruginosa towards antimicrobial agents has been a major cause for the escalation of untreatable diabetic foot ulcer cases around the globe. This demands research towards alternative natural products that inhibit biofilm formation by P. aeruginosa. The study focuses on enhancing as well as understanding the anti-biofilm property of lutein from Chlorella pyrenoidosa against MTCC strain of P. aeruginosa PAO1. C. pyrenoidosa was subjected to nutrient starvation (N-, S- and P-) and their growth, biomass, chlorophyll pigments and total carotenoids were estimated. Lutein extracted from nutrient starved C. pyrenoidosa were quantified using High Performance Liquid Chromatography (HPLC) and also used for quantification of biofilm formation, cell surface hydrophobicity (CSH), extracellular polymeric substances (EPS) and pyocyanin degradation. The results showed 20 µg/mL concentration of lutein showed maximum inhibition and degradation of biofilm formation, pyocyanin production, Cell Surface Hydrophobicity Extracellular Polymeric Substances, when compared to other concentrations. Azithromycin was used as a standard drug to compare the efficiency of lutein as a potential antibiofilm compound. Docking studies confirmed the interaction of lutein with the four proteins - LasI, LasR, RhlI and RhlR, involved in the quorum sensing mechanism during biofilm formation. Among them, RhlI protein was found to strongly interact and LasI exhibiting the least interaction with lutein. Gene expression analyses of las and rhl genes in P. aeruginosa PAO1 revealed a significant down regulation of both the genes in the cultures treated with different concentrations of lutein. Therefore, it can be understood that lutein is an effective antibiofilm agent and can be used in combination with generic drugs that are used for treating diseases such as diabetic foot ulcers, which are ineffective due to high biofilm forming capability of P. aeruginosa and other bacterial species.


Assuntos
Biofilmes/efeitos dos fármacos , Chlorella/metabolismo , Luteína/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Azitromicina/farmacologia , Proteínas de Bactérias/genética , Biofilmes/crescimento & desenvolvimento , Biomassa , Carotenoides , Parede Celular/efeitos dos fármacos , Clorofila , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Ligases/genética , Luteína/química , Microalgas , Simulação de Acoplamento Molecular , Pseudomonas aeruginosa/genética , Piocianina/metabolismo , Percepção de Quorum/genética , Transativadores/genética , Fatores de Transcrição/genética
9.
Int J Nanomedicine ; 14: 5957-5976, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440052

RESUMO

Background: Efficient localized cervicovaginal antibacterial therapy, enabling the delivery of antibiotic to the site of action at lower doses while escaping systemic drug effects and reducing the risk of developing microbial resistance, is attracting considerable attention. Liposomes have been shown to allow sustained drug release into vaginal mucosa and improve delivery of antibiotics to bacterial cells and biofilms. Azithromycin (AZI), a potent broad-spectrum macrolide antibiotic, has not yet been investigated for localized therapy of cervicovaginal infections, although it is administered orally for the treatment of sexually transmitted diseases. Encapsulation of AZI in liposomes could improve its solubility, antibacterial activity, and allow the prolonged drug release in the cervicovaginal tissue, while avoiding systemic side effects. Purpose: The objective of this study was to develop AZI-liposomes and explore their potentials for treating cervicovaginal infections. Methods: AZI-liposomes that differed in bilayer elasticity/rigidity and surface charge were prepared and evaluated under simulated cervicovaginal conditions to yield optimized liposomes, which were assessed for antibacterial activity against several planktonic and biofilm-forming Escherichia coli strains and intracellular Chlamydia trachomatis, ex vivo AZI vaginal deposition/penetration, and in vitro cytotoxicity toward cervical cells. Results: Negatively charged liposomes with rigid bilayers (CL-3), propylene glycol liposomes (PGL-2) and deformable propylene glycol liposomes (DPGL-2) were efficient against planktonic E. coli ATCC 700928 and K-12. CL-3 was superior for preventing the formation of E. coli ATCC 700928 and K-12 biofilms, with IC50 values (concentrations that inhibit biofilm viability by 50%) up to 8-fold lower than those of the control (free AZI). DPGL-2 was the most promising for eradication of already formed E. coli biofilms and for treating C. trachomatis infections. All AZI-liposomes were biocompatible with cervical cells and improved localization of the drug inside vaginal tissue compared with the control. Conclusion: The performed studies confirm the potentials of AZI-liposomes for localized cervicovaginal therapy.


Assuntos
Azitromicina/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Colo do Útero/microbiologia , Vagina/microbiologia , Animais , Antibacterianos/farmacologia , Azitromicina/farmacologia , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Materiais Biocompatíveis/farmacologia , Biofilmes/efeitos dos fármacos , Chlamydia trachomatis/efeitos dos fármacos , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Lipossomos , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Plâncton/efeitos dos fármacos , Suínos
11.
MMWR Morb Mortal Wkly Rep ; 68(33): 713-717, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31437141

RESUMO

In September 2018, CDC identified Salmonella enterica serotype Newport (Newport) infections that were multidrug resistant (MDR), with decreased susceptibility to azithromycin, a recommended oral treatment agent. Until 2017, decreased susceptibility to azithromycin had occurred in fewer than 0.5% of Salmonella isolates from U.S. residents. This report summarizes the investigation of a multistate MDR Salmonella outbreak conducted by CDC, state and local health departments, and the U.S. Department of Agriculture's Food Safety and Inspection Service. During June 2018-March 2019, 255 cases of infection with the outbreak strain were identified in 32 states; 43% of patients (89 of 206 with information on travel) reported recent travel to Mexico. Infections were linked to consumption of soft cheese obtained in Mexico and beef obtained in the United States. Consumers should avoid eating soft cheese that could be made from unpasteurized milk, regardless of the source of the cheese. When preparing beef, a food thermometer should be used to ensure that appropriate cooking temperatures are reached. When antibiotic treatment is needed for a patient, clinicians should choose antibiotics based on susceptibility testing wherever possible.


Assuntos
Azitromicina/farmacologia , Surtos de Doenças , Farmacorresistência Bacteriana Múltipla , Intoxicação Alimentar por Salmonella/epidemiologia , Salmonella/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Queijo/microbiologia , Criança , Pré-Escolar , Feminino , Microbiologia de Alimentos , Humanos , Lactente , Masculino , México , Pessoa de Meia-Idade , Carne Vermelha/microbiologia , Salmonella/genética , Intoxicação Alimentar por Salmonella/tratamento farmacológico , Doença Relacionada a Viagens , Estados Unidos/epidemiologia , Adulto Jovem
12.
J Colloid Interface Sci ; 555: 595-606, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404843

RESUMO

HYPOTHESIS: The widespread resistance of bacteria to traditional antibiotic treatments has expedited the search for novel therapies against these pathogens. The hypothesis of this work is that two distinctively different polymeric delivery systems, specifically D-α-tocopherol polyethylene glycol 1000 succinate (TPGS)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles and octenyl succinic anhydride-modified low molecular weight hyaluronic acid (OSA-HA) nanogels may be used to substantially improve the properties of azithromycin, allowing its use for effective treatment of Pseudomonas aeruginosa biofilm infections. EXPERIMENTS: Azithromycin was encapsulated in both delivery systems and the physicochemical properties of the loaded delivery systems, including size, surface charge and drug loading were evaluated. Additionally, particle interaction with a mucin layer, penetration into a bacterial biofilm, prevention of biofilm formation and eradication of pre-formed biofilms, the influence on production of virulence factors and bacterial motility as well as cytotoxicity towards hepatocytes and lung epithelial cells were compared head-to-head. FINDINGS: The TPGS-PLGA nanoparticles noticeably improved the antimicrobial activity and the biofilm prevention activity of azithromycin whereas the OSA-HA nanogels showed reduced mucin interactions together with improved reduction of pre-formed biofilms and maintained the low eukaryotic cell cytotoxicity of azithromycin.


Assuntos
Azitromicina/farmacologia , Biofilmes/efeitos dos fármacos , Ácido Hialurônico/farmacologia , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Azitromicina/química , Ácido Hialurônico/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Propriedades de Superfície
13.
Future Microbiol ; 14: 749-755, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31271060

RESUMO

Aim: Antibiotic resistance in Mycobacterium abscessus renders treatment poorly effective. Despite erm(41)-gene-mediated macrolide resistance, treatment with azithromycin or clarithromycin is recommended. It is contested whether macrolides differ in erm(41) induction. We determine whether this is the case. Methods: M. abscessus CIP104536 was used. Minimum inhibitory concentrations of clarithromycin and azithromycin were determined. Time-kill kinetics of M. abscessus exposed to azithromycin or clarithromycin were performed and RNA was isolated at predetermined intervals for erm(41) quantification. Results: Minimum inhibitory concentrations increased >30-fold. Time-kill kinetics showed a temporary bacteriostatic effect, abrogated by induced resistance. Erm(41) expression was increased following exposure to either macrolide for 7 days. Conclusion: Both macrolides induce resistance similarly, and this should not be an argument in choosing either macrolide for therapy.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Claritromicina/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Mycobacterium abscessus/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Perfilação da Expressão Gênica , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , RNA Bacteriano/análise , RNA Mensageiro/análise
14.
Artigo em Inglês | MEDLINE | ID: mdl-31334131

RESUMO

Synthetic peptidomimetics may be designed to mimic functions of antimicrobial peptides, including potentiation of antibiotics, yet possessing improved pharmacological properties. Pairwise screening of 42 synthetic peptidomimetics combined with the antibiotics azithromycin and rifampicin in multidrug-resistant (MDR) Escherichia coli ST131 and Klebsiella pneumoniae ST258 led to identification of two subclasses of α-peptide/ß-peptoid hybrids that display synergy with azithromycin and rifampicin (fractional inhibitory concentration indexes of 0.03-0.38). Further screening of the best three peptidomimetics in combination with a panel of 21 additional antibiotics led to identification of peptidomimetics that potentiated ticarcillin/clavulanate and erythromycin against E. coli, and clindamycin against K. pneumoniae. The study of six peptidomimetics was extended to Pseudomonas aeruginosa, confirming synergy with antibiotics for five of them. The most promising compound, H-(Lys-ßNPhe)8-NH2, exerted only a minor effect on the viability of mammalian cells (EC50 ≥ 124-210 µM), and thus exhibited the highest selectivity toward bacteria. This compound also synergized with rifampicin and azithromycin at sub-micromolar concentrations (0.25-0.5 µM), thereby inducing susceptibility to these antibiotics at clinically relevant concentrations in clinical MDR isolates. This peptidomimetic lead and its analogs constitute promising candidates for efficient repurposing of rifampicin and azithromycin against Gram-negative pathogens.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Peptidomiméticos/farmacologia , Rifampina/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Contagem de Colônia Microbiana , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Células Hep G2 , Humanos , Klebsiella pneumoniae , Camundongos , Testes de Sensibilidade Microbiana , Células NIH 3T3 , Pseudomonas aeruginosa/efeitos dos fármacos
15.
J Antibiot (Tokyo) ; 72(10): 759-768, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31300721

RESUMO

The pandemic influenza 2009 (A(H1N1)pdm09) virus currently causes seasonal and annual epidemic outbreaks. The widespread use of anti-influenza drugs such as neuraminidase and matrix protein 2 (M2) channel inhibitors has resulted in the emergence of drug-resistant influenza viruses. In this study, we aimed to determine the anti-influenza A(H1N1)pdm09 virus activity of azithromycin, a re-positioned macrolide antibiotic with potential as a new anti-influenza candidate, and to elucidate its underlying mechanisms of action. We performed in vitro and in vivo studies to address this. Our in vitro approaches indicated that progeny virus replication was remarkably inhibited by treating viruses with azithromycin before infection; however, azithromycin administration after infection did not affect this process. We next investigated the steps inhibited by azithromycin during virus invasion. Azithromycin did not affect attachment of viruses onto the cell surface, but blocked internalization into host cells during the early phase of infection. We further demonstrated that azithromycin targeted newly budded progeny virus from the host cells and inactivated their endocytic activity. This unique inhibitory mechanism has not been observed for other anti-influenza drugs, indicating the potential activity of azithromycin before and after influenza virus infection. Considering these in vitro observations, we administered azithromycin intranasally to mice infected with A(H1N1)pdm09 virus. Single intranasal azithromycin treatment successfully reduced viral load in the lungs and relieved hypothermia, which was induced by infection. Our findings indicate the possibility that azithromycin could be an effective macrolide for the treatment of human influenza.


Assuntos
Antivirais/farmacologia , Azitromicina/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Células A549 , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Antivirais/administração & dosagem , Azitromicina/administração & dosagem , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Humanos , Pulmão/virologia , Camundongos , Infecções por Orthomyxoviridae/tratamento farmacológico , Resultado do Tratamento , Carga Viral , Liberação de Vírus/efeitos dos fármacos
16.
EBioMedicine ; 46: 193-201, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31353294

RESUMO

BACKGROUND: Multidrug-resistant (MDR) Acinetobacter baumannii infections have high mortality rates and few treatment options. Synergistic drug combinations may improve clinical outcome and reduce further emergence of resistance in MDR pathogens. Here we show an unexpected potent synergy of two translation inhibitors against the pathogen: commonly prescribed macrolide antibiotic azithromycin (AZM), widely ignored as a treatment alternative for invasive Gram-negative pathogens, and minocycline, among the current standard-of-care agents used for A. baumannii. METHODS: Media-dependent activities of AZM and MIN were evaluated in minimum inhibitory concentration assays and kinetic killing curves, alone or in combination, both in standard bacteriologic media (cation-adjusted Mueller-Hinton Broth) and more physiologic tissue culture media (RPMI), with variations of bicarbonate as a physiologic buffer. Synergy was calculated by fractional inhibitory concentration index (FICI). Therapeutic benefit of combining AZM and MIN was tested in a murine model of A. baumannii pneumonia. AZM + MIN synergism was probed mechanistically by bacterial cytological profiling (BCP), a quantitative fluorescence microscopy technique that identifies disrupted bacterial cellular pathways on a single cell level, and real-time kinetic measurement of translation inhibition via quantitative luminescence. AZM + MIN synergism was further evaluated vs. other contemporary high priority MDR bacterial pathogens. FINDINGS: Although two translation inhibitors are not expected to synergize, each drug complemented kinetic deficiencies of the other, speeding the initiation and extending the duration of translation inhibition as verified by FICI, BCP and kinetic luminescence markers. In an MDR A. baumannii pneumonia model, AZM + MIN combination therapy decreased lung bacterial burden and enhanced survival rates. Synergy between AZM and MIN was also detected vs. MDR strains of Gram-negative Klebsiella pneumoniae and Pseudomonas aeruginosa, and the leading Gram-positive pathogen methicillin-resistant Staphylococcus aureus. INTERPRETATION: As both agents are FDA approved with excellent safety profiles, clinical investigation of AZM and MIN combination regimens may immediately be contemplated for optimal treatment of A. baumannii and other MDR bacterial infections in humans. FUND: National Institutes of Health U01 AI124326 (JP, GS, VN) and U54 HD090259 (GS, VN). IC was supported by the UCSD Research Training Program for Veterinarians T32 OD017863.


Assuntos
Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/mortalidade , Acinetobacter baumannii/genética , Animais , Azitromicina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Camundongos , Testes de Sensibilidade Microbiana , Biossíntese de Proteínas/efeitos dos fármacos
17.
Nat Commun ; 10(1): 3255, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332179

RESUMO

Syphilis is a sexually transmitted infection caused by Treponema pallidum subspecies pallidum and may lead to severe complications. Recent years have seen striking increases in syphilis in many countries. Previous analyses have suggested one lineage of syphilis, SS14, may have expanded recently, indicating emergence of a single pandemic azithromycin-resistant cluster. Here we use direct sequencing of T. pallidum combined with phylogenomic analyses to show that both SS14- and Nichols-lineages are simultaneously circulating in clinically relevant populations in multiple countries. We correlate the appearance of genotypic macrolide resistance with multiple independently evolved SS14 sub-lineages and show that genotypically resistant and sensitive sub-lineages are spreading contemporaneously. These findings inform our understanding of the current syphilis epidemic by demonstrating how macrolide resistance evolves in Treponema subspecies and provide a warning on broader issues of antimicrobial resistance.


Assuntos
Farmacorresistência Bacteriana/efeitos dos fármacos , Macrolídeos/farmacologia , Sífilis/tratamento farmacológico , Treponema pallidum/genética , Antibacterianos/farmacologia , Azitromicina/farmacologia , Farmacorresistência Bacteriana/genética , Genoma Bacteriano/genética , Genômica , Genótipo , Humanos , Epidemiologia Molecular , Pandemias/prevenção & controle , Filogenia , Análise de Sequência de DNA , Especificidade da Espécie , Sífilis/epidemiologia , Sífilis/microbiologia , Treponema pallidum/classificação , Treponema pallidum/fisiologia
18.
Respir Res ; 20(1): 129, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234850

RESUMO

BACKGROUND: Azithromycin (Azm) is a macrolide recognized for its disease-modifying effects and reduction in exacerbation of chronic airway diseases. It is not clear whether the beneficial effects of Azm are due to its anti-microbial activity or other pharmacological actions. We have shown that Azm affects the integrity of the bronchial epithelial barrier measured by increased transepithelial electrical resistance. To better understand these effects of Azm on bronchial epithelia we have investigated global changes in gene expression. METHODS: VA10 bronchial epithelial cells were treated with Azm and cultivated in air-liquid interface conditions for up to 22 days. RNA was isolated at days 4, 10 and 22 and analyzed using high-throughput RNA sequencing. qPCR and immunostaining were used to confirm key findings from bioinformatic analyses. Detailed assessment of cellular changes was done using microscopy, followed by characterization of the lipidomic profiles of the multivesicular bodies present. RESULTS: Bioinformatic analysis revealed that after 10 days of treatment genes encoding effectors of sterol and cholesterol metabolism were prominent. Interestingly, expression of genes associated with epidermal barrier differentiation, KRT1, CRNN, SPINK5 and DSG1, increased significantly at day 22. Together with immunostaining, these results suggest an epidermal differentiation pattern. We also found that Azm induced the formation of multivesicular and lamellar bodies in two different airway epithelial cell lines. Lipidomic analysis revealed that Azm was entrapped in multivesicular bodies linked to different types of lipids, most notably palmitate and stearate. Furthermore, targeted analysis of lipid species showed accumulation of phosphatidylcholines, as well as ceramide derivatives. CONCLUSIONS: Taken together, we demonstrate how Azm might confer its barrier enhancing effects, via activation of epidermal characteristics and changes to intracellular lipid dynamics. These effects of Azm could explain the unexpected clinical benefit observed during Azm-treatment of patients with various lung diseases affecting barrier function.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Corpos Multivesiculares/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem Celular , Epiderme/metabolismo , Humanos , Corpos Multivesiculares/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo
20.
Indian J Med Res ; 149(3): 404-411, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31249207

RESUMO

Background & objectives: : Azithromycin has been in use as an alternate treatment option for enteric fever even when the guidelines on the susceptibility testing were not available. There is lack of data on susceptibility and mechanisms of resistance of azithromycin in Salmonella Typhi and S. Paratyphi A. The aim of the present study was to determine the azithromycin susceptibility and resistance mechanisms in typhoidal salmonellae isolates archived in a tertiary care centre in north India for a period of 25 years. Methods: : Azithromycin susceptibility was determined in 602 isolates of S. Typhi (469) and S. Paratyphi A (133) available as archived collection isolated during 1993 to 2016, by disc diffusion and E-test method.PCR was done for ereA, ermA, ermB, ermC, mefA, mphA and msrA genes from plasmid and genomic DNA and sequencing was done to detect mutations in acrR, rplD and rplV genes. Results: : Azithromycin susceptibility was seen in 437/469 [93.2%; 95% confidence interval (CI), 90.5 to 95.1%] isolates of S. Typhi. Amongst 133 isolates of S. Paratyphi A studied, minimum inhibitory concentration (MIC) of ≤16 mg/l was found in 102 (76.7%; 95% CI, 68.8 to 83.0). MIC value ranged between 1.5 and 32 mg/l with an increasing trend in MIC50and MIC90with time. Mutations were found in acrR in one and rplV in two isolates of S. Typhi. No acquired mechanism for macrolide resistance was found. Interpretation & conclusions: : Azithromycin could be considered as a promising agent against typhoid fever on the basis of MIC distribution in India. However, due to emergence of resistance in some parts, there is a need for continuous surveillance of antimicrobial susceptibility and resistance mechanisms. There is also a need to determine the breakpoints for S. Paratyphi A.


Assuntos
Azitromicina/farmacologia , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana/genética , Febre Tifoide/tratamento farmacológico , Azitromicina/efeitos adversos , Proteínas de Bactérias/classificação , Humanos , Índia/epidemiologia , Mutação/genética , Salmonella enterica/efeitos dos fármacos , Salmonella enterica/genética , Salmonella enterica/patogenicidade , Salmonella paratyphi A/efeitos dos fármacos , Salmonella paratyphi A/genética , Salmonella paratyphi A/patogenicidade , Salmonella typhi/efeitos dos fármacos , Salmonella typhi/genética , Salmonella typhi/patogenicidade , Febre Tifoide/epidemiologia , Febre Tifoide/genética , Febre Tifoide/microbiologia
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