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1.
PLoS One ; 15(8): e0238195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845920

RESUMO

Nosocomial infections caused by extensively drug-resistant (XDR) or Pan-Drug resistant (PDR) Acinetobacter (A.) baumannii have recently increased dramatically creating a medical challenge as therapeutic options became very limited. The aim of our study was to investigate the antibiotic-resistance profiles and evaluate the various combinations of ciprofloxacin (CIP) or levofloxacin (LEV) with antimicrobial agents and non-antimicrobial agents to combat antimicrobial resistance of XDR A. baumannii. A total of 100 (6.25%) A. baumannii clinical isolates were recovered from 1600 clinical specimens collected from hospitalized patients of two major university hospitals in Upper Egypt. Antimicrobial susceptibility tests were carried out according to CLSI guidelines. Antimicrobial susceptibility testing of the respective isolates showed a high percentage of bacterial resistance to 19 antimicrobial agents ranging from 76 to99%. However, a lower percentage of resistance was observed for only colistin (5%) and doxycycline (57%). The isolates were categorized as PDR (2; 2%), XDR (68; 68%), and multi-drug resistant (MDR) (30; 30%). Genotypic analysis using ERIC-PCR on 2 PDR and 32 selected XDR isolates showed that they were not clonal. Combinations of CIP or LEV with antibiotics (including, ampicillin, ceftriaxone, amikacin, or doxycycline) were tested on these A. baumannii non-clonal isolates using standard protocols where fractional inhibitory concentrations (-FICs) were calculated. Results of the respective combinations showed synergism in 23.5%, 17.65%, 32.35%, 17.65% and 26.47%, 8.28%, 14.71%, 26.47%, of the tested isolates, respectively. CIP or LEV combinations with either chlorpromazine (CPZ) 200 µg/ml, propranolol (PR) in two concentrations, 0.5 mg/ml and 1.0 mg/ml or diclofenac (DIC) 4 mg/ml were carried out and the MIC decrease factor (MDF) of each isolate was calculated and results showed synergism in 44%, 50%, 100%, 100% and 94%, 85%, 100%, 100%, of the tested isolates, respectively. In conclusion, combinations of CIP or LEV with CPZ, PR, or DIC showed synergism in most of the selected PDR and XDR A. baumannii clinical isolates. However, these combinations have to be re-evaluated in vivo using appropriate animal models infected by XDR- or PDR- A. baumannii.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Clorpromazina/farmacologia , Diclofenaco/farmacologia , Fluoroquinolonas/farmacologia , Propranolol/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/genética , Acinetobacter baumannii/isolamento & purificação , Ciprofloxacino/farmacologia , Infecção Hospitalar/microbiologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Egito , Humanos , Levofloxacino/farmacologia
2.
Medicine (Baltimore) ; 99(28): e21128, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664140

RESUMO

RATIONALE: Fulminant macrolide-resistant Mycoplasma pneumoniae pneumonia (MPP) has seldom been reported, and cases of MPP usually show rapid improvement after fluoroquinolones or tetracyclines addition. The purpose of this case report is to highlight the importance of proper selection of antibiotics for treatment of severe MPP and increase awareness concerning the emergence of fluoroquinolone-resistant MPP. PATIENT CONCERNS: A case of severe life-threatening pneumonia in a 26-year-old man with high fever and cough was non-responsive to azithromycin and fluoroquinolones. DIAGNOSES: The patient was diagnosed with MPP based on the test results of bronchoalveolar lavage using real-time quantitative PCR method. INTERVENTIONS: Tigecycline was given to the patient after azithromycin and fluoroquinolones failed. OUTCOMES: The patients fever subsided within the first day of tigecycline therapy. He showed rapid symptom resolution and improvement in lung infiltration after 4 days of tigecycline therapy. LESSONS: The case suggests that fulminant MPP should be timely treated with proper antibiotics, and the possible emergence of fluoroquinolone-resistant MPP should be of concern.


Assuntos
Azitromicina/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Mycoplasma pneumoniae/efeitos dos fármacos , Pneumonia por Mycoplasma/tratamento farmacológico , Tigeciclina/uso terapêutico , Doença Aguda , Adulto , Antibacterianos/uso terapêutico , Brochothrix , Humanos , Masculino , Mycoplasma pneumoniae/isolamento & purificação , Pneumonia por Mycoplasma/diagnóstico , Pneumonia por Mycoplasma/microbiologia , Tomografia Computadorizada por Raios X
3.
BMC Infect Dis ; 20(1): 390, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32487030

RESUMO

BACKGROUND: Fluoroquinolones are broad-spectrum antibiotics that are recommended, and increasingly important, for the treatment of multidrug-resistant tuberculosis (MDR-TB). Resistance to fluoroquinolones is caused by mutations in the Quinolone Resistance Determining Region (QRDR) of gyrA and gyrB genes of Mycobacterium tuberculosis. In this study, we characterized the phenotypic and genotypic resistance to fluoroquinolones for the first time in northeast Iran. METHODS: A total of 123 Mycobacterium tuberculosis isolates, including 111 clinical and 12 collected multidrug-resistant isolates were studied. Also, 19 WHO quality control strains were included in the study. The phenotypic susceptibility was determined by the proportion method on Löwenstein-Jensen medium. The molecular cause of resistance to the fluoroquinolone drugs ofloxacin and levofloxacin was investigated by sequencing of the QRDR region of the gyrA and gyrB genes. RESULTS: Among 123 isolates, six (4.8%) were fluoroquinolone-resistant according to phenotypic methods, and genotypically three of them had a mutation at codon 94 of the gyrA gene (Asp→ Gly) which was earlier reported to cause resistance. All three remaining phenotypically resistant isolates had a nucleotide change in codon 95. No mutations were found in the gyrB gene. Five of the 19 WHO quality control strains, were phenotypically fluoroquinolone-resistant, four of them were genotypically resistant with mutations at codon 90, 91 of the gyrA gene and one resistant strain had no detected mutation. CONCLUSIONS: Mutation at codon 94 of the gyrA gene, was the main cause of fluoroquinolone resistance among M. tuberculosis isolates in our region. In 3/6 fluoroquinolone-resistant isolates, no mutations were found in either gyrA or gyrB. Therefore, it can be concluded that various other factors may lead to fluoroquinolone resistance, such as active efflux pumps, decreased cell wall permeability, and drug inactivation.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Códon , Farmacorresistência Bacteriana/genética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/genética , Feminino , Genótipo , Humanos , Irã (Geográfico) , Levofloxacino/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/isolamento & purificação , Ofloxacino/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
4.
PLoS One ; 15(6): e0220350, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544163

RESUMO

Mycoplasma hyopneumoniae is the major pathogenic microorganism causing enzootic pneumonia in pigs. With increasing resistance of M. hyopneumoniae to conventional antibiotics, treatment is becoming complicated. Herein, we investigated the mutant selection window (MSW) of doxycycline, tylosin, danofloxacin, tiamulin, and valnemulin for treating the M. hyopneumoniae type strain (ATCC 25934) to determine the likelihood of promoting resistance with continued use of these antibiotics. Minimum inhibitory concentration (MIC) values against M. hyopneumoniae were determined for each antimicrobial agent based on microdilution broth and agar dilution methods (bacterial numbers ranged from 105 colony-forming units (CFU)/mL to 109 CFU/mL). The minimal concentration inhibiting colony formation by 99% (MIC99) and the mutant prevention concentration (MPC) were determined by the agar dilution method with three inoculum sizes. Antimicrobial killing was determined based on MIC99 and MPC values for all five agents. MIC values ranged from 0.001 to 0.25 µg/mL based on the microdilution broth method, and from 0.008 to 1.0 µg/mL based on the agar dilution method. MPC values ranged from 0.0016 to 10.24 µg/mL. MPC/MIC99 values were ordered tylosin > doxycycline > danofloxacin > tiamulin > valnemulin. MPC achieved better bactericidal action than MIC99. Based on pharmacodynamic analyses, danofloxacin, tylosin, and doxycycline are more likely to select resistant mutants than tiamulin and valnemulin.


Assuntos
Antibacterianos/farmacologia , Viabilidade Microbiana/efeitos dos fármacos , Mutação , Mycoplasma hyopneumoniae/efeitos dos fármacos , Mycoplasma hyopneumoniae/genética , Diterpenos/farmacologia , Doxiciclina/farmacologia , Fluoroquinolonas/farmacologia , Cinética , Testes de Sensibilidade Microbiana , Mycoplasma hyopneumoniae/fisiologia , Tilosina/farmacologia
5.
PLoS One ; 15(6): e0234211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497083

RESUMO

Fluoroquinolone resistance in Salmonella Typhimurium is becoming a major concern. Hence, an intervention to limit the growth in resistance is inevitable. One way to combat this challenge is through combination therapy. The combination of antibiotics with phytochemicals has become an ideal means of preventing antimicrobial resistance. Recently, in an in vitro study, the combination of methyl gallate (MG) with marbofloxacin (MAR) has shown to prevent Salmonella Typhimurium invasion. It is also worth to study the effects of plant extracts on the pharmacokinetics of antibiotics. Hence, the objective of this study was to determine the effect of MG on the pharmacokinetics of MAR and pharmacokinetics/pharmacodynamics integration of MG and MAR. The micro-broth dilution method was used to obtain the minimum inhibitory concentration (MIC), and fractional inhibitory concentration (FIC) of MAR and MG. Whereas, the pharmacokinetic was conducted in rats by administering either MAR alone or combined with MG through oral and/or intravenous routes. The results indicated that the MIC of MAR and MG against standard strain Salmonella Typhimurium (ATCC 14028) was 0.031 and 500 µg/mL, respectively. The FICindex of the combination of MAR and MG was 0.5. For orally administered drugs, the Cmax and AUC24h of MAR were 1.04 and 0.78 µg/mL and 5.98 and 6.11 h.µg/mL when MAR was given alone and in combination with MG, respectively. The intravenous administration of MAR showed a half-life of 3.8 and 3.9 h; a clearance rate of 1.1 and 0.73 L/h/kg and a volume of distribution of 5.98 and 4.13 L/kg for MAR alone and in combination with MG, respectively. The AUC24/MIC for MAR alone and in combination with MG was 192.8 and 381.9 h, respectively. In conclusion, MG has shown to increase the antimicrobial activity of MAR in vitro and ex vivo experiments without affecting the pharmacokinetics of MAR in rats.


Assuntos
Fluoroquinolonas/farmacologia , Fluoroquinolonas/farmacocinética , Ácido Gálico/análogos & derivados , Salmonella typhimurium/efeitos dos fármacos , Animais , Interações Medicamentosas , Ácido Gálico/farmacocinética , Ácido Gálico/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Ratos , Ratos Sprague-Dawley
6.
Artigo em Inglês | MEDLINE | ID: mdl-32365881

RESUMO

Fluoroquinolones (FQs) are antibiotics commonly used in clinical practice, although nowadays they are becoming ineffective due to the emergence of several mechanisms of resistance in most bacteria. The complexation of FQs with divalent metal ions and phenanthroline (phen) is a possible approach to circumvent antimicrobial resistance, since it forms very stable complexes known as metalloantibiotics. This work is aimed at determining the antimicrobial activity of metalloantibiotics of Cu(II)FQphen against a panel of multidrug­resistant (MDR) clinical isolates and to clarify their mechanism of action. Minimum inhibitory concentrations (MICs) were determined against MDR isolates of Escherichia coli, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). Metalloantibiotics showed improved antimicrobial activity against several clinical isolates, especially MRSA. Synergistic activity was evaluated in combination with ciprofloxacin and ampicillin by the disk diffusion and checkerboard methods. Synergistic and additive effects were shown against MRSA isolates. The mechanism of action was studied though enzymatic assays and atomic force microscopy (AFM) experiments. The results indicate a similar mechanism of action for FQs and metalloantibiotics. In summary, metalloantibiotics seem to be an effective alternative to pure FQs against MRSA. The results obtained in this work open the way to the screening of metalloantibiotics against other Gram­positive bacteria.


Assuntos
Fluoroquinolonas , Metais , Staphylococcus aureus Resistente à Meticilina , Antibacterianos , Fluoroquinolonas/farmacologia , Meticilina , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico
7.
BMC Infect Dis ; 20(1): 314, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345231

RESUMO

BACKGROUND: Mycoplasma genitalium is an emerging sexually transmitted infection, with increasing rates of resistance to fluroquinolones and macrolides, the recommended treatments. Despite this, M. genitalium is not part of routine screening for Sexually Transmitted Infections (STIs) in many countries and the prevalence of infection and patterns of disease remain to be determined in many populations. Such data is of particular importance in light of the reported rise in antibiotic resistance in M. genitalium isolates. METHODS: Urine and urethral swab samples were collected from the primary public sexual health clinic in Singapore and tested for C. trachomatis (CT) or N. gonorrhoeae (NG) infection and for the presence of M. genitalium. Antibiotic resistance in M. genitalium strains detected was determined by screening for genomic mutations associated with macrolide and fluroquinolone resistance. RESULTS: We report the results of a study into M. genitalium prevalence at the national sexual health clinic in Singapore. M. genitalium was heavily associated with CT infection (8.1% of cases), but present in only of 2.4% in CT negative cases and not independently linked to NG infection. Furthermore, we found high rates of resistance mutations to both macrolides (25%) and fluoroquinolones (37.5%) with a majority of resistant strains being dual-resistant. Resistance mutations were only found in strains from patients with CT co-infection. CONCLUSIONS: Our results support targeted screening of CT positive patients for M. genitalium as a cost-effective strategy to reduce the incidence of M. genitalium in the absence of comprehensive routine screening. The high rate of dual resistance also highlights the need to ensure the availability of alternative antibiotics for the treatment of multi-drug resistant M. genitalium isolates.


Assuntos
Antibacterianos/farmacologia , Infecções por Chlamydia/diagnóstico , Chlamydia trachomatis/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Infecções por Mycoplasma/diagnóstico , Mycoplasma genitalium/efeitos dos fármacos , Instituições de Assistência Ambulatorial , Antibacterianos/uso terapêutico , Infecções por Chlamydia/complicações , Infecções por Chlamydia/tratamento farmacológico , Chlamydia trachomatis/genética , Chlamydia trachomatis/isolamento & purificação , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Farmacorresistência Bacteriana Múltipla/genética , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Humanos , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Infecções por Mycoplasma/complicações , Infecções por Mycoplasma/tratamento farmacológico , Infecções por Mycoplasma/epidemiologia , Mycoplasma genitalium/genética , Mycoplasma genitalium/isolamento & purificação , Prevalência , RNA Ribossômico 23S/química , RNA Ribossômico 23S/genética , RNA Ribossômico 23S/metabolismo , Análise de Sequência de DNA , Singapura/epidemiologia , Uretra/microbiologia
8.
Klin Lab Diagn ; 65(5): 308-315, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32298548

RESUMO

Salmonella is one of the leading bacterial pathogens of acute diarrhea as well as foodborne outbreaks. Salmonellosis can occur as gastroenteritis with the development of complications and generalization of infection, also the extra intestinal diseases that require antibiotic therapy are often registered. Currently, the effectiveness of many antibiotics is reduced due to the development of resistance in Salmonella. National Salmonella surveillance systems monitor Salmonella resistance to «critically important for medicine¼ antibiotics (extended-spectrum cephalosporins and fluoroquinolones), as well as multidrug resistance. Quinoloneresistant Salmonella is considered as a high-priority resitant pathogen by the World Health Organization. The article describes the current situation on salmonellosis in the world. Foreign and Russian current data about the leading Salmonella serotypes in different regions of the world are presented. The prevalence of clinically significant resistance depending of the Salmonella serotypes in countries with state monitoring systems is shown. The authors described the leading molecular resistance mechanisms (chromosomal and plasmid mediated) and showed their prevalence in different Salmonella serotypes. The article gives the information about Salmonella successful international multidrug resistant clones with specific resistance phenotypes and genotypes. The authors describe the molecular methods for detection of resistance mechanisms, and show the necessity and significance of antimicrobial susceptibility monitoring in the epidemiological Salmonella surveillance.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Salmonella/efeitos dos fármacos , Cefalosporinas/farmacologia , Fluoroquinolonas/farmacologia , Testes de Sensibilidade Microbiana
9.
Int J Infect Dis ; 96: 68-72, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32339719

RESUMO

BACKGROUND: Whole-genome sequencing (WGS) has been proposed to be a powerful tool to predict drug resistance for antitubercular drugs. However, the feasibility of WGS in predicting final treatment outcomes for multidrug-resistant tuberculosis (MDR-TB) patients remains unclear PATIENTS AND METHODS: In this prospective observational study conducted from January 2014 to September 2016, MDR-TB patients were enrolled consecutively. Genotypic drug sensitivity testing was performed via WGS using culture isolates. Patients were followed for two years to determine the treatment outcomes. Multivariate analysis was used to identify the association between information provided by WGS and the final treatment outcomes RESULTS: A total of 123 patients with MDR-TB were included in this study. The overall favorable treatment outcome rate was 60.2%. Multivariate analysis showed that independent risk factors associated with unfavorable treatment outcome including high-level moxifloxacin phenotypic resistance (OR, 4.362; 95%CI, 1.364-13.950; p=0.013), cycloserine phenotypic resistance (OR, 7.457; 95%CI, 1.644-33.819; p=0.009), mutations causing high-level fluoroquinolones resistance (OR, 3.947; 95%CI, 1.195-13.034; p=0.024), and ethA mutation (OR, 3.817; 95% CI, 1.154-12.823; p=0.028). WGS costs for each patient are ¥450 ($63), and the average turnaround time was one week CONCLUSIONS: In summary, WGS showed promising feasibility in predicting treatment outcomes for MDR-TB patients within a clinically relevant time frame.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Sequenciamento Completo do Genoma , Adulto , Antituberculosos/farmacologia , Farmacorresistência Bacteriana/genética , Feminino , Fluoroquinolonas/farmacologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina/farmacologia , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Estudos Prospectivos , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/economia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Sequenciamento Completo do Genoma/economia
10.
Xenobiotica ; 50(10): 1149-1157, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32283993

RESUMO

WCK 771 (INN: levonadifloxacin) is a novel antibacterial agent belonging to benzoquinolizine subclass of fluoroquinolones which is under clinical development as a parenteral formulation and its prodrug WCK 2349 (INN: alalevonadifloxacin) as an oral option. Both the drugs have been approved recently in India based on phase III trial completed for ABSSSI.In vitro CYP inhibition potential of levonadifloxacin and its sulfate metabolite (WCK 2146) were assessed in this study. The inhibitory effects of levonadifloxacin and its sulfate metabolite were assessed for seven key human liver CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 using human liver microsome (HLM) employing validated LC-MS/MS method.The results showed that levonadifloxacin and its metabolite did not inhibit enzyme activity of any of the key CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) even at supra therapeutic concentrations (12-24X, Clinical Cmax: 25-35µg/mL).These in vitro CYP inhibition studies of levonadifloxacin and its sulfate metabolite indicate lack of potential for pharmacokinetic drug interactions of levonadifloxacin when co-administered with drugs which are substrate of these isoforms. Therefore, further clinical studies evaluating CYP mediated drug-drug interactions are not warranted for levonadifloxacin and alalevonadifloxacin.


Assuntos
Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Alanina , Antibacterianos/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Fluoroquinolonas/metabolismo , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Microssomos Hepáticos/metabolismo
11.
PLoS One ; 15(4): e0230423, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32236115

RESUMO

Campylobacter jejuni is one of the most prevalent causes of bacterial gastroenteritis worldwide, and it is largely associated with consumption of contaminated poultry. Current Campylobacter control measures at the poultry production level remain insufficient, and hence there is the need for alternative control strategies. We evaluated the potential of the monoterpene (-)-α-pinene for control of C. jejuni in poultry. The antibacterial and resistance-modulatory activities of (-)-α-pinene were also determined against 57 C. jejuni strains. In addition, the anti-quorum-sensing activity of (-)-α-pinene against C. jejuni NCTC 11168 was determined for three subinhibitory concentrations (125, 62.5, 31.25 mg/L) over three incubation times using an autoinducer-2 bioassay based on Vibrio harveyi BB170 bioluminescence measurements. The effects of a subinhibitory concentration of (-)-α-pinene (250 mg/L) on survival of C. jejuni, and in combination with enrofloxacin on fluoroquinolone resistance development in C. jejuni, were determined in a broiler chicken model, by addition of (-)-α-pinene to the broiler water supply. The reduction of C. jejuni numbers by (-)-α-pinene was further determined in broiler chickens that were colonized with either fluoroquinolone-susceptible or -resistant strains, by direct gavage treatment. We observed weak in vitro antimicrobial activity for (-)-α-pinene alone (MIC >500 mg/L), but strong potentiating effects on antibiotics erythromycin and ciprofloxacin against different Campylobacter strains (>512 fold change). After 24 h of treatment of C. jejuni with (-)-α-pinene, its quorum-sensing signaling was reduced by >80% compared to the untreated control. When given in the drinking water, (-)-α-pinene did not show any significant inhibitory effects on the level of C. jejuni in the colonized chickens, and did not reduce fluoroquinolone resistance development in combination with enrofloxacin. Conversely, when (-)-α-pinene was administered by direct gavage, it significantly reduced the number of fluoroquinolone susceptible C. jejuni in the colonized broiler chickens. These results demonstrate that (-)-α-pinene modulates quorum-sensing in Campylobacter, potentiates antibiotics against different Campylobacter strains, and reduces Campylobacter colonization in broiler chickens.


Assuntos
Antibacterianos/farmacologia , Monoterpenos Bicíclicos/farmacologia , Campylobacter jejuni/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Monoterpenos Bicíclicos/uso terapêutico , Infecções por Campylobacter/patologia , Infecções por Campylobacter/prevenção & controle , Campylobacter jejuni/fisiologia , Ceco/microbiologia , Galinhas , Ciprofloxacino/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Eritromicina/farmacologia , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Testes de Sensibilidade Microbiana , Doenças das Aves Domésticas/patologia , Doenças das Aves Domésticas/prevenção & controle
12.
PLoS Comput Biol ; 16(3): e1007608, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32119670

RESUMO

The evolution of antimicrobial resistance (AMR) poses a persistent threat to global public health. Sequencing efforts have already yielded genome sequences for thousands of resistant microbial isolates and require robust computational tools to systematically elucidate the genetic basis for AMR. Here, we present a generalizable machine learning workflow for identifying genetic features driving AMR based on constructing reference strain-agnostic pan-genomes and training random subspace ensembles (RSEs). This workflow was applied to the resistance profiles of 14 antimicrobials across three urgent threat pathogens encompassing 288 Staphylococcus aureus, 456 Pseudomonas aeruginosa, and 1588 Escherichia coli genomes. We find that feature selection by RSE detects known AMR associations more reliably than common statistical tests and previous ensemble approaches, identifying a total of 45 known AMR-conferring genes and alleles across the three organisms, as well as 25 candidate associations backed by domain-level annotations. Furthermore, we find that results from the RSE approach are consistent with existing understanding of fluoroquinolone (FQ) resistance due to mutations in the main drug targets, gyrA and parC, in all three organisms, and suggest the mutational landscape of those genes with respect to FQ resistance is simple. As larger datasets become available, we expect this approach to more reliably predict AMR determinants for a wider range of microbial pathogens.


Assuntos
Biologia Computacional/métodos , Farmacorresistência Bacteriana/genética , Genoma Bacteriano/genética , Antibacterianos/farmacologia , Anti-Infecciosos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/genética , Fluoroquinolonas/farmacologia , Humanos , Aprendizado de Máquina , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/genética , Staphylococcus aureus/genética , Sequenciamento Completo do Genoma/métodos
13.
J Infect Public Health ; 13(4): 472-479, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32139293

RESUMO

BACKGROUND: The present work is an extension of ongoing efforts toward the development and identification of new molecules as monotherapy displaying anti-inflammatory and anti-infective activities and a wide-range of gastrointestinal selectivity. A series of novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and evaluated for their in-vitro and in-vivo anti-inflammatory activities. Synthesized trisubstituted thiazole compounds were also evaluated for their potential antibacterial activity against clinical pathogens causing infectious disease. MATERIAL AND METHOD: The structures of synthesized compounds were characterized by FTIR, 1H NMR, Mass spectroscopic techniques and evaluated for their in-vitro and in-vivo anti-inflammatory effects using the human red blood cell (HRBC) membrane stabilization method and a carrageenan-induced rat paw oedema model, respectively, Diclofenac sodium and Ibuprofen were used as standard drugs. The synthesized compounds AR-17atoAR-27a screened for their in-vitro antibacterial activity against the gram-positive bacteria Staphylococcus aureus (ATCC25923) and Enterococcus faecalis (ATCC29212) and the gram-negative bacteria Escherichia coli (ATCC8739) and Pseudomonas aeruginosa (ATCC9027) using ciprofloxacin and cefdinir as standard drugs. RESULT: Compounds AR-17a and AR-27a elicited maximum anti-inflammatory activity, providing 59% and 61% protection at 20mg/kg, respectively, in the inflamed paw model. Among the tested compounds, AR-17a (6.25), (54) and AR-27a (1.56), (52) had the least minimum inhibitory concentration values and the highest zone of inhibition, indicating their marked antibacterial activities. The lowest conc. were observed at 1.56, 6.25µg/mL for inhibition of bacteria by most of the compounds. CONCLUSION: Novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and characterized successfully. The preliminary screening revealed that these compounds possess promising anti-inflammatory and antibacterial activities. In addition, the objective of the study was achieved with few of the promising structures like AR-17a to AR-27a, which are prove to be potential monotherapy candidates for the treatment of chronic inflammatory diseases and bacterial infections.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Anti-Inflamatórios/síntese química , Edema/tratamento farmacológico , Feminino , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química
15.
BMC Infect Dis ; 20(1): 94, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005138

RESUMO

BACKGROUND: Enterobacter cloacae complex (ECC) is one of the most common extended-spectrum ß-lactamase and carbapenemase-producing pathogen that threatens millions of the elderly and vulnerable sick persons. The objective of this study was to perform the molecular characteristics of the carbapenem-resistant E. cloacae complex (CREC) emerged in Heilongjiang Province of China. METHODS: Six CREC strains were isolated from the patients with infectious diseases. The identities of ECC isolates were confirmed by sequencing the polymerase chain reaction (PCR) products of 16S rRNA gene. The characterization of the CREC isolates were analyzed by sequencing PCR products of the carbapenemase, ampC and fluoroquinolone resistance genes and performing multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and whole genome sequencing. RESULTS: All 6 isolates harbored multiple resistance genes. Of them, 5 carried metallo-ß-lactamases and one was blaKPC-2-positive. The levofloxacin and ciprofloxacin-resistant strains had substitutions of gyrA83, gyrA87, and parC80 in the quinolone-resistance determining regions. The MLST analyses revealed that 6 isolates belonged to five sequence types (ST520, ST528, ST1119, ST1120, and ST93) while the PFGE patterns of the isolates fallen into four clusters. The strain ST1120 was found to carry two separated plasmids that encode blaNDM-1 and blaIMP-4. CONCLUSIONS: Our study, for the first time, identified a CREC strain that co-produces blaNDM-1 and blaIMP-4 in the Northeast China. Our finding emphasizes an urgent need for more intensive surveillance and precaution measures to prevent the CERC spread.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Farmacorresistência Bacteriana/genética , Enterobacter cloacae/efeitos dos fármacos , Enterobacter cloacae/genética , beta-Lactamases/genética , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Técnicas de Tipagem Bacteriana , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , China , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterobacter cloacae/classificação , Enterobacter cloacae/isolamento & purificação , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Fluoroquinolonas/farmacologia , Humanos , Tipagem de Sequências Multilocus , RNA Ribossômico 16S
16.
Appl Environ Microbiol ; 86(8)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32033955

RESUMO

In a structured survey of all major chicken-meat producers in Australia, we investigated the antimicrobial resistance (AMR) and genomic characteristics of Campylobacter jejuni (n = 108) and C. coli (n = 96) from cecal samples of chickens at slaughter (n = 200). The majority of the C. jejuni (63%) and C. coli (86.5%) samples were susceptible to all antimicrobials. Fluoroquinolone resistance was detected among both C. jejuni (14.8%) and C. coli (5.2%), although this only included three sequence types (STs) and one ST, respectively. Multidrug resistance among strains of C. jejuni (0.9%) and C. coli (4.1%) was rare, and fluoroquinolone resistance, when present, was never accompanied by resistance to any other agent. Comparative genome analysis demonstrated that Australian isolates were found dispersed on different branches/clusters within the international collection. The major fluoroquinolone-resistant STs of C. jejuni (ST7323, ST2083, and ST2343) and C. coli (ST860) present in Australian chickens were similar to those of international isolates and have been reported previously in humans and animals overseas. The detection of a subpopulation of Campylobacter isolates exclusively resistant to fluoroquinolone was unexpected since most critically important antimicrobials such as fluoroquinolones are excluded from use in Australian livestock. A number of factors, including the low level of resistance to other antimicrobials, the absence of fluoroquinolone use, the adoption of measures for preventing spread of contagion between flocks, and particularly the genomic identities of isolates, all point to humans, pest species, or wild birds as being the most plausible source of organisms. This study also demonstrates the need for vigilance in the form of surveillance for AMR based on robust sampling to manage AMR risks in the food chain.IMPORTANCE Campylobacter is one of the most common causes of gastroenteritis in humans, with infections frequently resulting from exposure to undercooked poultry products. Although human illness is typically self-limiting, a minority of cases do require antimicrobial therapy. Ensuring that Campylobacter originating from meat chickens does not acquire resistance to fluoroquinolones is therefore a valuable outcome for public health. Australia has never legalized the use of fluoroquinolones in commercial chickens and until now fluoroquinolone-resistant Campylobacter has not been detected in the Australian poultry. This structured survey of meat chickens derived from all major Australian producers describes the unexpected emergence of fluoroquinolone resistance in Campylobacter jejuni and C. coli Genetic characterization suggests that these isolates may have evolved outside the Australian poultry sector and were introduced into poultry by humans, pest species, or wild birds. The findings dramatically underline the critical role of biosecurity in the overall fight against antimicrobial resistance.


Assuntos
Antibacterianos/farmacologia , Infecções por Campylobacter/veterinária , Campylobacter coli/efeitos dos fármacos , Campylobacter jejuni/efeitos dos fármacos , Farmacorresistência Bacteriana , Fluoroquinolonas/farmacologia , Doenças das Aves Domésticas/epidemiologia , Animais , Austrália/epidemiologia , Infecções por Campylobacter/epidemiologia , Infecções por Campylobacter/microbiologia , Campylobacter coli/fisiologia , Campylobacter jejuni/fisiologia , Galinhas , Testes de Sensibilidade Microbiana , Doenças das Aves Domésticas/microbiologia
17.
Sci Rep ; 10(1): 1917, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024860

RESUMO

The Lesotho guidelines for the management of drug-resistant tuberculosis (TB) recommend initiation of patients diagnosed with rifampicin resistant (RR)-TB on a standardized drug resistant regimen while awaiting confirmation of rifampicin resistant TB (RR-TB) and complete drug susceptibility test results. Review of diagnostic records between 2014 and 2016 identified 518 patients with RR-TB. Only 314 (60.6%) patients could be linked to treatment records at the Lesotho MDR hospital. The median delay in treatment initiation from the availability of Xpert MTB/RIF assay result was 12 days (IQR 7-19). Only 32% (101) of patients had a documented first-line drug resistant test. MDR-TB was detected in 56.4% of patients while 33.7% of patients had rifampicin mono-resistance. Only 7.4% of patients assessed for second-line resistance had a positive result (resistance to fluoroquinolone). Treatment success was 69.8%, death rate was 28.8%, loss to follow up was 1.0%, and 0.4% failed treatment. Death was associated with positive or unavailable sputum smear at the end of first month of treatment (Fisher exact p < 0.001) and older age (p = 0.007). Urgent attention needs to be given to link patients with RR-TB to care worldwide. The association of death rate with positive sputum smear at the end of the first month of treatment should trigger early individualization of treatment.


Assuntos
Antibióticos Antituberculose/farmacologia , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Pulmonar/diagnóstico , Adolescente , Adulto , Antibióticos Antituberculose/normas , Antibióticos Antituberculose/uso terapêutico , Farmacorresistência Bacteriana , Feminino , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Seguimentos , Humanos , Lesoto/epidemiologia , Masculino , Testes de Sensibilidade Microbiana/normas , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Rifampina/uso terapêutico , Escarro/microbiologia , Tempo para o Tratamento/normas , Tempo para o Tratamento/estatística & dados numéricos , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/mortalidade , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/mortalidade , Adulto Jovem
18.
Int J Infect Dis ; 92: 241-246, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978580

RESUMO

OBJECTIVES: To compare the prevalence of levofloxacin (LFX) resistance and the population structure of Mycobacterium tuberculosis (MTB) with different mutations conferring LFX resistance between 2005 and 2015. METHODS: A total 542 MTB isolates were randomly selected from pulmonary tuberculosis (TB) patients in 2005 and 2015 and analyzed regarding minimum inhibitory concentrations (MICs) and quinolone resistance-determining regions (QRDR). RESULTS: One hundred and eleven of the 542 MTB isolates analyzed (20.5%) were resistant to LFX. There were 42 and 69 LFX-resistant isolates from 2005 and 2015, respectively, and MIC high-level LFX resistance was significantly higher in 2015 (40.6%, 28/69) than in 2005 (16.7%, 7/42) (p = 0.02). There were 87 (78.4%) mutations of these 111 LFX-resistant isolates. In addition, a significant difference in proportion was observed in the isolates with mutations in codon 90 of the gyrA gene between 2005 and 2015 (11.9% in 2005 versus 29.0% in 2015, p = 0.04). CONCLUSIONS: There was an alarming increase in prevalence of LFX-resistant TB in China between 2005 and 2015. This dynamic change is mostly attributed to the increase in high-level LFX resistance. Moreover, a significant difference was noted in the proportion of LFX-resistant isolates harboring specific mutations within the gyrA gene between 2005 and 2015.


Assuntos
Farmacorresistência Bacteriana , Levofloxacino/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose Pulmonar/tratamento farmacológico , Adulto , China/epidemiologia , DNA Girase/genética , Feminino , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Humanos , Levofloxacino/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/isolamento & purificação , Prevalência , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia
19.
PLoS One ; 15(1): e0227257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910242

RESUMO

PURPOSE: Multidrug-resistant Enterobacteriaceae in urinary tract infection (UTI) has spread worldwide; one cause is overuse of broad-spectrum antimicrobial agents such as fluoroquinolone antibacterials. To improve antimicrobial agent administration, this study aimed to calculate a probability prediction formula to predict the organism strain causing UTI in real time from dip-stick testing and flow cytometry. METHODOLOGY: We examined 372 outpatient spot urine samples with observed pyuria and bacteriuria using dip-stick testing and flow cytometry. We performed multiple logistic-regression analysis on the basis of 11 measurement items and BACT scattergram analysis with age and sex as explanatory variables and each strain as the response variable and calculated a probability prediction formula. RESULTS: The best prediction formula for discrimination of the bacilli group and cocci or polymicrobial group was a model with 5 explanatory variables that included percentage of scattergram dots in an angular area of 0-25° (P<0.001), sex (P<0.001), nitrite (P = 0.002), and ketones (P = 0.133). For a predicted cut-off value of Y = 0.395, sensitivity was 0.867 and specificity was 0.775 (cross-validation group: sensitivity = 0.840, specificity = 0.760). The best prediction formula for P. mirabilis and other bacilli was a model with percentage of scattergram dots in an angular area of 0-20° (P<0.001) and nitrite (P = 0.090). For a predicted cut-off value of Y = 0.064, sensitivity was 0.889 and specificity was 0.788 (cross-validation group: sensitivity = 1.000, specificity = 0.766). CONCLUSION: Simultaneous use of the calculated probability prediction formula with urinalysis results facilitates real-time prediction of organisms causing UTI, thus providing helpful information for empiric therapy.


Assuntos
Gestão de Antimicrobianos , Infecções por Enterobacteriaceae/microbiologia , Enterobacteriaceae/isolamento & purificação , Urinálise/métodos , Infecções Urinárias/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/fisiologia , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/urina , Estudos de Viabilidade , Feminino , Citometria de Fluxo , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Humanos , Modelos Logísticos , Masculino , Sensibilidade e Especificidade , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/urina
20.
PLoS One ; 15(1): e0227535, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999701

RESUMO

BACKGROUND: Campylobacter jejuni is the most common bacterial cause of human infectious intestinal disease. METHODS: We genome sequenced 601 human C. jejuni isolates, obtained from two large prospective studies of infectious intestinal disease (IID1 [isolates from 1993-1996; n = 293] and IID2 [isolates from 2008-2009; n = 93]), the INTEGRATE project [isolates from 2016-2017; n = 52] and the ENIGMA project [isolates from 2017; n = 163]. RESULTS: There was a significant increase in the prevalence of the T86I mutation conferring resistance to fluoroquinolone between each of the three later studies (IID2, INTEGRATE and ENIGMA) and IID1. Although the distribution of major multilocus sequence types (STs) was similar between the studies, there were changes in both the abundance of minority STs associated with the T86I mutation, and the abundance of clones within single STs associated with the T86I mutation. DISCUSSION: Four population-based studies of community diarrhoea over a 25 year period revealed an increase over time in the prevalence of the T86I amongst isolates of C. jejuni associated with human gastrointestinal disease in the UK. Although associated with many STs, much of the increase is due to the expansion of clones associated with the resistance mutation.


Assuntos
Campylobacter jejuni/efeitos dos fármacos , Campylobacter jejuni/genética , Farmacorresistência Bacteriana/genética , Fluoroquinolonas/farmacologia , Enteropatias/microbiologia , Mutação , Campylobacter jejuni/isolamento & purificação , Campylobacter jejuni/fisiologia , Criança , Genoma Bacteriano/genética , Humanos , Filogenia , Polimorfismo de Nucleotídeo Único , Prevalência , Reino Unido
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