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1.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445137

RESUMO

Disrupted glutamate clearance in the synaptic cleft leads to synaptic dysfunction and neurological diseases. Decreased glutamate removal from the synaptic cleft is known to cause excitotoxicity. Data on the physiological effects of increased glutamate clearance are contradictory. This study investigated the consequences of ceftriaxone (CTX), an enhancer of glutamate transporter 1 expression, treatment on long-term synaptic potentiation (LTP) in the hippocampus of young rats. In this study, 5-day administration of CTX (200 mg/kg) significantly weakened LTP in CA3-CA1 synapses. As shown by electrophysiological recordings, LTP attenuation was associated with weakening of N-Methyl-D-aspartate receptor (NMDAR)-dependent signaling in synapses. However, PCR analysis did not show downregulation of NMDAR subunits or changes in the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. We assume that extracellular burst stimulation activates fewer synapses in CTX-treated animals because increased glutamate reuptake results in reduced spillover, and neighboring synapses do not participate in neurotransmission. Attenuation of LTP was not accompanied by noticeable behavioral changes in the CTX group, with no behavioral abnormalities observed in the open field test or Morris water maze test. Thus, our experiments show that increased glutamate clearance can impair long-term synaptic plasticity and that this phenomenon can be considered a potential side effect of CTX treatment.


Assuntos
Ceftriaxona/farmacologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo
2.
Euro Surveill ; 26(31)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34355690

RESUMO

We monitored antimicrobial susceptibility developments of Neisseria gonorrhoeae in Germany from January 2014 to May 2021. The proportion of isolates with azithromycin minimum inhibitory concentrations above the epidemiological cut-off increased substantially, from 1.3% in 2014 to 12.2% in 2020. Preliminary data from 2021 showed a further rise (January to May: 20.7%). Therefore, azithromycin as part of the recommended dual therapy in Germany for non-adherent patients is challenged. Antimicrobial susceptibility testing in clinical practice is crucial and continuous susceptibility surveillance indispensable.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Azitromicina/farmacologia , Ceftriaxona/farmacologia , Farmacorresistência Bacteriana , Alemanha/epidemiologia , Gonorreia/tratamento farmacológico , Gonorreia/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/genética
3.
J Forensic Leg Med ; 81: 102207, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34214895

RESUMO

The determination of the post-mortem interval (PMI) is one of the main tasks of forensic entomology, where growth and stages of development of arthropods are used for PMI determination. It is well acknowledged that maggot development is significantly influenced by temperature. Attention has also been paid to the microbial populations of the cadaver, because toxic substances contained in the substrate can influence the microorganisms and affect arthropods growth and development. However, little is known about the influence of antibiotics taken during lifetime of a person on insect development after that persons death. The aim of this study was to test the hypothesis that the antibiotics ceftriaxone and levofloxacin cause inhibition of growth and delay of pupation of the blow fly Calliphora vomitoria, which would then lead to an incorrect determination of the post-mortem interval in forensic cases. It was found that maggot development was delayed by levofloxacin mixed in minced pork, where a mixture of both antibiotics increased this effect. The maggot growth in the samples with ceftriaxone was not delayed. Pupation was delayed in treatments with a mixture of both antibiotics. The mortality was reduced by separate or combined application of ceftriaxone and levofloxacin, which we attribute to a bactericidal effect of the antibiotics on maggot pathogens. Depending on the concentration of the antibiotics, an underestimation of the post-mortem interval between 24 and 48 h could be suspected. We conclude that antibiotics need to be considered if instar stages are to be used to determine the PMI and that some antibiotics may improve the breeding conditions of maggots.


Assuntos
Antibacterianos/farmacologia , Calliphoridae/crescimento & desenvolvimento , Ceftriaxona/farmacologia , Larva/efeitos dos fármacos , Levofloxacino/farmacologia , Animais , Entomologia Forense , Mudanças Depois da Morte
4.
Expert Opin Drug Metab Toxicol ; 17(9): 1039-1048, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34225556

RESUMO

Introduction: Usage of ceftriaxone-based therapy to treat Methicillin-Susceptible Staphylococcus aureus (MSSA) infections is a controversial issue, from in vitro to clinical studies.Area covered: We conducted a literature review using PubMed of articles with ceftriaxone pharmacokinetics parameters and built a probability of target attainment (PTA) based on PK values from stable conditions (non-critically-ill patients) with goals of fT>55%, fT>75%, and fT>100%. Ceftriaxone's minimal inhibitory concentration from 31 MSSA strains (0.25-64 mg/L) was used to build the cumulative fraction response (CFR). The isolates were clinically relevant from blood, bronchoalveolar lavage, and soft tissue biopsy.Expert opinion: The results from controversies about using ceftriaxone for MSSA infections have been commonly addressed in the literature. However, variables such as (i) pharmacokinetic profile, (ii) pharmacodynamic target, (iii) site of infection, and (iv) MIC distributions may influence divergences. From this pharmacokinetics-pharmacodynamics perspective, ceftriaxone may be a reasonable option for MSSA infections when the MIC50 and MIC90 were 4 mg/L and 8 mg/L. CFR analysis demonstrated that ceftriaxone 1 g q24 h could be used if bacteriostasis is the aim (fT>55%), while 1 g q12h should be used for bactericidal effects (fT>75% or fT>100%). These dosing regimens should be considered in other clinical trials.


Assuntos
Antibacterianos/administração & dosagem , Ceftriaxona/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Ceftriaxona/farmacocinética , Ceftriaxona/farmacologia , Esquema de Medicação , Farmacorresistência Bacteriana , Humanos , Meticilina/farmacologia , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/isolamento & purificação
5.
Emerg Infect Dis ; 27(8): 2127-2134, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34287121

RESUMO

We performed a spatial and mixed ecologic study of community-onset Enterobacteriaceae isolates collected from a public healthcare system in Cook County, Illinois, USA. Individual-level data were collected from the electronic medical record and census tract-level data from the US Census Bureau. Associations between individual- and population-level characteristics and presence of ceftriaxone resistance were determined by logistic regression analysis. Spatial analysis confirmed nonrandom distribution of ceftriaxone resistance across census tracts, which was associated with higher percentages of Hispanic, foreign-born, and uninsured residents. Individual-level analysis showed that ceftriaxone resistance was associated with male sex, an age range of 35-85 years, race or ethnicity other than non-Hispanic Black, inpatient encounter, and percentage of foreign-born residents in the census tract of isolate provenance. Our findings suggest that the likelihood of community-onset ceftriaxone resistance in Enterobacteriaceae is influenced by geographic and population-level variables. The development of effective mitigation strategies might depend on better accounting for these factors.


Assuntos
Ceftriaxona , Enterobacteriaceae , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ceftriaxona/farmacologia , Hispano-Americanos , Humanos , Illinois/epidemiologia , Masculino , Pessoa de Meia-Idade
6.
Biomed Pharmacother ; 138: 111094, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311521

RESUMO

Currently, several studies propose that the dominant intestinal bacteria are core flora. Besides keeping the homeostasis of the intestinal environment, the intestinal microflora also plays a role in body metabolism, production of some vitamins, and control of barrier function. The study aimed to investigate the jejunum microbiota in diabetic rats as well as it's the relationship with Ceftriaxone sodium-mediated gut dysbiosis, diabetic parameters, and intestinal permeability. Thirty-two Wistar rats (Male) were enrolled and divided into four groups (A, B, C, and D; N = 8). Subsequently, T2DM was induced in C and D groups by HFD/STZ model and then gut dysbiosis in B and D groups via intragastric administration of Ceftriaxone sodium for two weeks. The food-water intake, body weight, fasting blood glucose, plasma insulin, HOMA-IR, intestinal permeability, and jejunum microbiota and it's histology were investigated. In this study, T2DM was associated with a significant decrease in the richness and diversity of jejunum microbiota, elevation in the intestinal permeability, and higher abundance of some opportunistic pathogens. Ceftriaxone sodium-induced gut dysbiosis declined food-water intake, damagedthe villi of jejunum tissue, increased intestinal permeability, and affected the diversity of jejunum microbiota. In diabetic rats, Ceftriaxone sodium-mediated gut dysbiosis also declined the abundance of someSCFAs bacteria and raised the abundant of some opportunistic bacteria such as Staphylococcus_sciuri. Interestingly, we found that several bacteria were negatively correlated with HOMA-IR, fasting blood glucose, body weight, and intestinal permeability. Overall, the study highlighted the jejunum microflora alterations in HFD/STZ diabetic rats and assessed the effect of Ceftriaxone sodium-induced gut dysbiosis on diabetic parameters, jejunum microbiota and histology, and intestinal permeability, which are of potential for further studies.


Assuntos
Antibacterianos/farmacologia , Bactérias/crescimento & desenvolvimento , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal , Jejuno/microbiologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Ceftriaxona/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Disbiose , Microbioma Gastrointestinal/efeitos dos fármacos , Absorção Intestinal , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Permeabilidade , Ratos Wistar , Estreptozocina
7.
J Pak Med Assoc ; 71(6): 1639-1643, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34111088

RESUMO

OBJECTIVE: To see the efficacy of rapid colour test for the sensitivity of ceftriaxone against clinical isolates of salmonella typhi. METHODS: The cross-sectional validation study was conducted at the Department of Microbiology, Pakistan Navy Ship Shifa Hospital, Karachi, from Nov 2018 to April 2019, and comprised clinical isolates of salmonella typhi that were obtained from five different hospitals in Karachi and Hyderabad. The isolates were tested using the rapid colour test. All the isolates were also tested using the conventional disc diffusion method and minimum inhibitory concentrations on the Vitek-2 version 8.01. RESULTS: Of the 97 isolates, 83(85.5%) were ceftriaxone-resistant and 14(14.4%) were ceftriaxone-sensitive. Sensitivity and specificity of the rapid colour test were 100% when compared with the results of the other methods. All the results were readable within 2 hours on the colour test. CONCLUSIONS: The colour test was found to be a rapid, accurate and inexpensive tool to screen for ceftriaxone resistance in typhoid-endemic areas.


Assuntos
Preparações Farmacêuticas , Febre Tifoide , Antibacterianos/farmacologia , Ceftriaxona/farmacologia , Estudos Transversais , Humanos , Testes de Sensibilidade Microbiana , Paquistão , Salmonella typhi , Febre Tifoide/diagnóstico , Febre Tifoide/tratamento farmacológico , Febre Tifoide/epidemiologia
9.
ACS Biomater Sci Eng ; 7(7): 3242-3255, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34189904

RESUMO

Advances in liposomal formulation carrying multiple neuroprotective drugs, such as ceftriaxone (CEF), FK506, and nilotinib, can point toward an approach to obviating the difficulties in Parkinson's disease (PD) treatment. We prepared functionalized liposomes decorated with glutathione (GSH) to penetrate the blood-brain barrier (BBB) and cardiolipin (CL) to link up apoptotic neurons. Further, the effect of CEF-FK506-nilotinib-GSH-CL-liposomes on a PD model established by SH-SY5Y cells with 1-methyl-4-phenylpyridinium-induced neurotoxicity was investigated. An increment of the mole percentage of dihexadecyl phosphate and CL increased the particle size and the absolute value of ζ potential, improved the entrapment efficiency of CEF, FK506, and nilotinib, and reduced the drug-releasing rate. The toxicity studies revealed that CEF, FK506, and nilotinib-encapsulated liposomes could enhance the survival of SH-SY5Y cells. Western blot and immunofluorescence revealed that incorporation of CL in a lipid bilayer ameliorated the docking of CEF-FK506-nilotinib-GSH-CL-liposomes at α-synuclein (α-syn), indicating a better targeting capability of the liposomes to degenerated neurons. Treatment with CEF-FK506-nilotinib-GSH-CL-liposomes reduced the expression of Bax and α-syn and promoted the expression of Bcl-2, tyrosine hydroxylase, and the dopamine transporter. GSH- and CL-conjugated liposomes showed combined activity of targeting the BBB and α-syn and augmented the efficiency of the three drugs in rescuing dopaminergic neurons for neurodegenerative therapy.


Assuntos
Dopamina , Lipossomos , Ceftriaxona/farmacologia , Neurônios Dopaminérgicos , Glutationa , Pirimidinas , Tacrolimo
10.
Ann Clin Microbiol Antimicrob ; 20(1): 26, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879172

RESUMO

BACKGROUND: Antimicrobial-resistant strains of Streptococcus pneumoniae have become one of the greatest challenges to global public health today and inappropriate use of antibiotics and high level of antibiotic use is probably the main factor driving the emergence of resistance worldwide. The aim of this study is, therefore, to assess the antimicrobial resistance profiles and multidrug resistance patterns of S. pneumoniae isolates from patients suspected of pneumococcal infections in Ethiopia. METHODS: A hospital-based prospective study was conducted from January 2018 to December 2019 at Addis Ababa city and Amhara National Region State Referral Hospitals. Antimicrobial resistance tests were performed from isolates of S. pneumoniae that were collected from pediatric and adult patients. Samples (cerebrospinal fluid, blood, sputum, eye discharge, ear discharge, and pleural and peritoneal fluids) from all collection sites were initially cultured on 5% sheep blood agar plates and incubated overnight at 37 °C in a 5% CO2 atmosphere. Streptococcus pneumoniae was identified and confirmed by typical colony morphology, alpha-hemolysis, Gram staining, optochin susceptibility, and bile solubility test. Drug resistance testing was performed using the E-test method according to recommendations of the Clinical and Laboratory Standards Institute. RESULTS: Of the 57 isolates, 17.5% were fully resistant to penicillin. The corresponding value for both cefotaxime and ceftriaxone was 1.8%. Resistance rates to erythromycin, clindamycin, tetracycline, chloramphenicol and trimethoprim-sulfamethoxazole were 59.6%, 17.5%, 38.6%, 17.5 and 24.6%, respectively. Multidrug resistance (MDR) was seen in 33.3% isolates. The most common pattern was co-resistance to penicillin, erythromycin, clindamycin, and tetracycline. CONCLUSIONS: Most S. pneumoniae isolates were susceptible to ceftriaxone and cefotaxime. Penicillin has been used as a drug of choice for treating S. pneumoniae infection. However, antimicrobial resistance including multidrug resistance was observed to several commonly used antibiotics including penicillin. Hence, it is important to periodically monitor the antimicrobial resistance patterns to select empirical treatments for better management of pneumococcal infection.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Infecções Pneumocócicas/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Cefotaxima/farmacologia , Ceftriaxona/farmacologia , Cloranfenicol/farmacologia , Clindamicina/farmacologia , Eritromicina/farmacologia , Etiópia/epidemiologia , Feminino , Hospitais , Humanos , Masculino , Testes de Sensibilidade Microbiana , Penicilinas/farmacologia , Estudos Prospectivos , Tetraciclina/farmacologia , Combinação Trimetoprima e Sulfametoxazol/farmacologia
11.
J Antimicrob Chemother ; 76(7): 1769-1775, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-33930160

RESUMO

OBJECTIVES: To investigate the spread of ceftriaxone-resistant Neisseria gonorrhoeae lineages similar to strains H041 (2009) and FC428 (2015), we characterized 55 strains collected in 2013 from hospitals across Japan. METHODS: Susceptibility testing and whole-genome sequencing. RESULTS: Susceptibility rates were 58% for cefixime and 98% for ceftriaxone. The 55 strains were whole-genome sequenced and classified into nine MLST-STs. MLST-ST1901 was the most prevalent (n = 19) followed by MLST-ST7363 (n = 12) and MLST-ST7359 (n = 11). The most prevalent penA [encoding penicillin binding protein 2 (PBP2)] mosaic types, based on the N. gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) scheme, were 10.001 (n = 20) followed by 34.001 (n = 13). The H041 and FC428 strains were not detected; however, a single ceftriaxone-resistant strain (TUM15748) with a MIC of 0.5 mg/L ceftriaxone was identified. The TUM15748 strain belonged to MLST-ST7359 and N. gonorrhoeae multiantigen sequence typing-ST6771, and had a novel PBP2 (PBP2TUM15748, penA type 169.001). The amino acid sequence of PBP2TUM15748 showed partial similarity to that of PBP2 from N. gonorrhoeae GU140106 and commensal Neisseria perflava and Neisseria cinerea. Natural transformation and recombination experiments using full-length TUM15748 penA showed that the ceftriaxone MICs of transformants increased 16-fold or more compared with the parental ceftriaxone-susceptible recipient strain (NG9807, belonging to MLST-ST7363). No ceftriaxone-resistant MLST-ST7359 strains have previously been reported. CONCLUSIONS: We showed here that a ceftriaxone-susceptible lineage acquired a mutant PBP2 mosaic type, integrating partial PBP2 sequences from commensal Neisseria species, resulting in the emergence of ceftriaxone-resistant strains.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ceftriaxona/farmacologia , Gonorreia/tratamento farmacológico , Gonorreia/epidemiologia , Humanos , Japão/epidemiologia , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Neisseria , Neisseria gonorrhoeae/genética
12.
PLoS One ; 16(3): e0248177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33690674

RESUMO

BACKGROUND: Gut colonization by ESBL-producing Enterobacteriaceae (ESBL-PE) is widespread and is promoted by antibiotic exposure. Higher fecal abundance of ESBL-PE promotes the dissemination of the bacteria in the environment and is associated with increased risk of infection. Ceftriaxone and temocillin are commonly used antibiotics with a different activity on gut flora. Their impact on fecal abundance of ESBL-producing Enterobacteriaceae has not been studied. The objective of this study was to compare the propensity of ceftriaxone and temocillin to modify the abundance of ESBL-producing Escherichia coli in feces of colonized mice. METHODS: Mice received broad-spectrum antibiotics in order to disrupt their normal gut flora. A CTX-M-type ESBL-producing E. coli clinical isolate was then administered orally, leading to durable colonization. Thirty days later, mice received either temocillin or ceftriaxone with drinking water at a concentration simulating human intestinal exposure. Third-generation-cephalosporin resistant (3GCR) E. coli were enumerated in feces on selective medium before, 2 days and 10 days after the end of antibiotic exposure. The experiment was performed with two E. coli isolates with different temocillin minimum inhibitory concentrations. RESULTS: Exposure to ceftriaxone induced an increase in the fecal abundance of 3GCR E. coli. In contrast, temocillin had no effect or transiently decreased the number of 3GCR E. coli. Results obtained with the two strains were similar. CONCLUSION: Contrary to ceftriaxone, temocillin does not promote expansion of ESBL-producing E. coli in feces of colonized mice. Thus temocillin may be a therapeutic of choice when a temocillin-susceptible strain infection is suspected or proven to prevent the expansion of ESBL-PE in a previously colonized patient.


Assuntos
Ceftriaxona/farmacologia , Escherichia coli/efeitos dos fármacos , Penicilinas/farmacologia , Animais , Antibacterianos/farmacologia , Ceftriaxona/metabolismo , Modelos Animais de Doenças , Enterobacteriaceae/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Fezes/química , Fezes/microbiologia , Feminino , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Penicilinas/metabolismo , beta-Lactamases/farmacologia
13.
J Antimicrob Chemother ; 76(7): 1759-1768, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-33739419

RESUMO

BACKGROUND: Emerging resistance to cephalosporins in Neisseria gonorrhoeae (Ng) is a major public health threat, since these are considered antibiotics of last resort. Continuous surveillance is needed to monitor the circulation of resistant strains and those with reduced susceptibility. OBJECTIVES: For the purpose of epidemiological surveillance, genomic population analysis was performed on Ng isolates from Amsterdam with a focus on isolates with reduced susceptibility to ceftriaxone. METHODS: WGS data were obtained from 318 isolates from Amsterdam, the Netherlands between 2014 and 2019. Isolates were typed according to MLST, Ng Multi-Antigen Sequence Typing (NG-MAST) and Ng Sequence Typing for Antimicrobial Resistance (NG-STAR) schemes and additional resistance markers were identified. Phylogenetic trees were created to identify genetic clusters and to compare Dutch and non-Dutch MLST7827 isolates. RESULTS: MLST7363 and MLST1901 were the predominant strains having reduced susceptibility to ceftriaxone during 2014-16; MLST7827 emerged and dominated during 2017-19. NG-STAR38 and NG-MAST2318/10386 were predominant among MLST7827 isolates. MLST7827 reduced susceptibility isolates carried a non-mosaic 13.001 penA allele with an A501V mutation and porB1b G120K/A121D mutations, which were lacking in susceptible MLST7827 isolates. Phylogenetic analysis of all publicly available MLST7827 isolates showed strong genetic clustering of Dutch and other European MLST7827 isolates. CONCLUSIONS: MLST7827 isolates with reduced ceftriaxone susceptibility have emerged during recent years in Amsterdam. Co-occurrence of penA A501V and porB1b G120K/A121D mutations was strongly associated with reduced susceptibility to ceftriaxone. Genetic clustering of Dutch and other European MLST7827 isolates indicates extensive circulation of this strain in Europe. Close monitoring of the spread of this strain having an alarming susceptibility profile is needed.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Ceftriaxona/farmacologia , Cefalosporinas/farmacologia , Células Clonais , Farmacorresistência Bacteriana/genética , Europa (Continente) , Genômica , Gonorreia/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Neisseria gonorrhoeae/genética , Países Baixos/epidemiologia , Filogenia
14.
J Antimicrob Chemother ; 76(5): 1221-1228, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33564854

RESUMO

OBJECTIVES: Novel antimicrobials for treatment of gonorrhoea are imperative. The first-in-class spiropyrimidinetrione zoliflodacin is promising and currently in an international Phase 3 randomized controlled clinical trial (RCT) for treatment of uncomplicated gonorrhoea. We evaluated the in vitro activity of and the genetic conservation of the target (GyrB) and other potential zoliflodacin resistance determinants among 1209 consecutive clinical Neisseria gonorrhoeae isolates obtained from 25 EU/European Economic Area (EEA) countries in 2018 and compared the activity of zoliflodacin with that of therapeutic antimicrobials currently used. METHODS: MICs of zoliflodacin, ceftriaxone, cefixime, azithromycin and ciprofloxacin were determined using an agar dilution technique for zoliflodacin or using MIC gradient strip tests or an agar dilution technique for the other antimicrobials. Genome sequences were available for 96.1% of isolates. RESULTS: Zoliflodacin modal MIC, MIC50, MIC90 and MIC range were 0.125, 0.125, 0.125 and ≤0.004-0.5 mg/L, respectively. The resistance was 49.9%, 6.7%, 1.6% and 0.2% to ciprofloxacin, azithromycin, cefixime and ceftriaxone, respectively. Zoliflodacin did not show any cross-resistance to other tested antimicrobials. GyrB was highly conserved and no zoliflodacin gyrB resistance mutations were found. No fluoroquinolone target GyrA or ParC resistance mutations or mutations causing overexpression of the MtrCDE efflux pump substantially affected the MICs of zoliflodacin. CONCLUSIONS: The in vitro susceptibility to zoliflodacin was high and the zoliflodacin target GyrB was conserved among EU/EEA gonococcal isolates in 2018. This study supports further clinical development of zoliflodacin. However, additional zoliflodacin data regarding particularly the treatment of pharyngeal gonorrhoea, pharmacokinetics/pharmacodynamics and resistance selection, including suppression, would be valuable.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Azitromicina/farmacologia , Barbitúricos , Ceftriaxona/farmacologia , Ciprofloxacina/farmacologia , Farmacorresistência Bacteriana , Europa (Continente) , Gonorreia/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/genética , Compostos de Espiro
15.
PLoS Pathog ; 17(2): e1009251, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33524048

RESUMO

Biofilm formation protects bacteria from antibiotics. Very little is known about the response of biofilm-dwelling bacteria to antibiotics at the single cell level. Here, we developed a cell-tracking approach to investigate how antibiotics affect structure and dynamics of colonies formed by the human pathogen Neisseria gonorrhoeae. Antibiotics targeting different cellular functions enlarge the cell volumes and modulate within-colony motility. Focusing on azithromycin and ceftriaxone, we identify changes in type 4 pilus (T4P) mediated cell-to-cell attraction as the molecular mechanism for different effects on motility. By using strongly attractive mutant strains, we reveal that the survivability under ceftriaxone treatment depends on motility. Combining our results, we find that sequential treatment with azithromycin and ceftriaxone is synergistic. Taken together, we demonstrate that antibiotics modulate T4P-mediated attractions and hence cell motility and colony fluidity.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Ceftriaxona/farmacologia , Neisseria gonorrhoeae/efeitos dos fármacos , Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Sinergismo Farmacológico , Fímbrias Bacterianas/efeitos dos fármacos , Fímbrias Bacterianas/fisiologia , Movimento/efeitos dos fármacos
16.
J Antimicrob Chemother ; 76(6): 1523-1531, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33569588

RESUMO

OBJECTIVES: Gonococcal infection is one of the most reported sexually transmitted infections and antimicrobial resistance in Neisseria gonorrhoeae (NG) is challenging for the treatment of this infection. This observational study aimed to describe antimicrobial resistance of NG and epidemiological data from patients with gonococcal infection in eight regions of Spain, for updating the local therapeutic guidelines. METHODS: MICs of penicillin, cefixime, ceftriaxone, azithromycin, ciprofloxacin, fosfomycin and gentamicin were determined by Etest for all NG isolates recovered from 1 April 2018 to 30 September 2019 from 10 hospitals in Spain. Resistance determinants were identified using logistic regression analysis. Differences with a P value <0.05 were considered statistically significant. RESULTS: Antimicrobial susceptibility testing was performed for 2571 gonococci isolated from 2429 patients. 44.5% (945/2124) of patients were MSM. The resistance rate to extended-spectrum cephalosporins was low, with 0.2% (6/2561) of isolates resistant to ceftriaxone and 1.7% (44/2517) of isolates resistant to cefixime. The overall azithromycin resistance rate was 12.1% (310/2560), but differed greatly depending on the area. 56.2% (1366/2429) of the strains studied were ciprofloxacin resistant. MIC50 and MIC90 values of gentamicin and fosfomycin were 4 and 8 mg/L and 24 and 48 mg/L, respectively. CONCLUSIONS: Our study shows that NG susceptibility to extended-spectrum cephalosporins remains high in Spain. The azithromycin resistance rate questions the suitability of dual therapy. This study provides data of interest for updating the national treatment guidelines and highlights the need to develop and implement a national sentinel gonococcal antimicrobial susceptibility programme.


Assuntos
Gonorreia , Minorias Sexuais e de Gênero , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Azitromicina/farmacologia , Ceftriaxona/farmacologia , Ciprofloxacina/farmacologia , Farmacorresistência Bacteriana , Gonorreia/tratamento farmacológico , Gonorreia/epidemiologia , Homossexualidade Masculina , Humanos , Masculino , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae , Estudos Prospectivos , Espanha/epidemiologia
17.
Alcohol ; 92: 1-9, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33465464

RESUMO

Repeated cycles of chronic intermittent ethanol (CIE) exposure increase voluntary consumption of alcohol (ethanol) in mice. Previous reports from our laboratory show that CIE increases extracellular glutamate in the nucleus accumbens (NAc) and that manipulating accumbal glutamate concentrations will alter ethanol drinking, indicating that glutamate homeostasis plays a crucial role in ethanol drinking in this model. A number of studies have shown that ceftriaxone increases GLT-1 expression, the major glutamate transporter, and that treatment with this antibiotic reduces ethanol drinking. The present studies examined the effects of ceftriaxone on ethanol drinking and GLT-1 in a mouse model of ethanol dependence and relapse drinking. The results show that ceftriaxone did not influence drinking at any dose in either ethanol-dependent or non-dependent mice. Further, ceftriaxone did not increase GLT-1 expression in the accumbens core or shell, with the exception of the ethanol-dependent mice receiving the highest dose of ceftriaxone. Interestingly, ethanol-dependent mice treated with only vehicle displayed reduced expression of GLT-1 in the accumbens shell and of the presynaptic mGlu2 receptor in the accumbens core. The reduced expression of the major glutamate transporter (GLT-1), as well as a receptor that regulates glutamate release (mGlu2), may help explain, at least in part, increased glutamatergic transmission in this model of ethanol dependence and relapse drinking.


Assuntos
Consumo de Bebidas Alcoólicas , Animais , Ceftriaxona/farmacologia , Etanol , Transportador 2 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/metabolismo , Recidiva
18.
PLoS One ; 16(1): e0246068, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33507976

RESUMO

It is known that hippocampal epileptogenesis is accompanied by hyperexcitability, glutamate-related neuronal dysfunctions and consequently cognitive deficits. However, the neuroprotective role of astrocytic glutamate uptake through the Glutamate Transporter-1 (GLT-1) remains to be unknown in these processes. Therefore, to assess the effect of glutamate uptake, pharmacological upregulation of GLT-1 using ceftriaxone administration (200 mg/kg/day, i.p, 5 days) was utilized in Li-PIL animal models of temporal lobe epilepsy (TLE). Glutamate concentration and glutamine synthetase activity were analyzed using biochemical assays. In addition, GLT-1 gene expression was assessed by RT-qPCR. Finally, cognitive function was studied using Morris water maze (MWM) test and novel object recognition task (NORT). Our results demonstrated that the acute phase of epileptogenesis (first 72 hours after Status Epilepticus) was accompanied by an increase in the hippocampal glutamate and downregulation of GLT-1 mRNA expression compared to controls. Ceftriaxone administration in epileptic animals led to a reduction of glutamate along with elevation of the level of glutamine synthetase activity and GLT-1 expression in the acute phase. In the chronic phase of epileptogenesis (4 weeks after Status Epilepticus), glutamate levels and GLT-1 expression were decreased compared to controls. Ceftriaxone treatment increased the levels of GLT-1 expression. Furthermore, impaired learning and memory ability in the chronic phase of epileptogenesis was rescued by Ceftriaxone administration. This study shows that astrocytic glutamate uptake can profoundly impact the processes of hippocampal epileptogenesis through the reduction of glutamate-induced excitotoxicity and consequently rescuing of cognitive deficits caused by epilepsy.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Epilepsia do Lobo Temporal/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Ceftriaxona/farmacologia , Ceftriaxona/uso terapêutico , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Resultado do Tratamento
19.
Mol Biol Evol ; 38(4): 1249-1261, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33432328

RESUMO

The Neisseria gonorrhoeae multilocus sequence type (ST) 1901 is among the lineages most commonly associated with treatment failure. Here, we analyze a global collection of ST-1901 genomes to shed light on the emergence and spread of alleles associated with reduced susceptibility to extended-spectrum cephalosporins (ESCs). The genetic diversity of ST-1901 falls into a minor and a major clade, both of which were inferred to have originated in East Asia. The dispersal of the major clade from Asia happened in two separate waves expanding from ∼1987 and 1996, respectively. Both waves first reached North America, and from there spread to Europe and Oceania, with multiple secondary reintroductions to Asia. The ancestor of the second wave acquired the penA 34.001 allele, which significantly reduces susceptibility to ESCs. Our results suggest that the acquisition of this allele granted the second wave a fitness advantage at a time when ESCs became the key drug class used to treat gonorrhea. Following its establishment globally, the lineage has served as a reservoir for the repeated emergence of clones fully resistant to the ESC ceftriaxone, an essential drug for effective treatment of gonorrhea. We infer that the effective population sizes of both clades went into decline as treatment schemes shifted from fluoroquinolones via ESC monotherapy to dual therapy with ceftriaxone and azithromycin in Europe and the United States. Despite the inferred recent population size decline, the short evolutionary path from the penA 34.001 allele to alleles providing full ceftriaxone resistance is a cause of concern.


Assuntos
Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Farmacorresistência Bacteriana/genética , Gonorreia/microbiologia , Neisseria gonorrhoeae/genética , Antibacterianos/farmacologia , Ceftriaxona/farmacologia , Gonorreia/tratamento farmacológico , Humanos , Neisseria gonorrhoeae/efeitos dos fármacos , Filogeografia
20.
J Antimicrob Chemother ; 76(4): 936-939, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33406237

RESUMO

OBJECTIVES: Ceftriaxone is currently the last-remaining empirical antimicrobial therapy for treatment of gonorrhoea. However, the high-level ceftriaxone-resistant gonococcal FC428 clone has shown transmission in China in recent years. Therefore, the aim of this study was to analyse ceftriaxone resistance among a collection of recent clinical isolates, with a specific focus on prevalence of the FC428 clone. METHODS: A total of 70 consecutive gonococcal isolates were collected between May and October 2019 from a single hospital in Hangzhou, China, and analysed for antimicrobial susceptibility by the agar dilution method. STs were determined by PCR and sequences and isolates related to the FC428 clone were further characterized by WGS and phylogenetic analysis. RESULTS: Ceftriaxone resistance (MIC >0.125 mg/L) was observed in 21 (30%) isolates, while 14 (20%) isolates displayed a ceftriaxone MIC of 0.125 mg/L. Importantly, seven (10%) isolates were related to the gonococcal FC428 clone based on the presence of mosaic penA allele 60.001, displaying identical or closely related STs, and phylogenetic analysis after WGS. These seven isolates displayed high-level ceftriaxone resistance (MIC = 1 mg/L) and all associated gonorrhoea cases resulted in treatment failure because oral cephalosporins were initially prescribed. Subsequent re-treatment with a higher dose (2 g) of IV ceftriaxone appeared to be successful because all patients returning for test-of-cure became culture-negative. CONCLUSIONS: Here, we report a high percentage of the internationally spreading gonococcal FC428 clone among clinical isolates from a single hospital in Hangzhou, China. A high dose of ceftriaxone is currently the only recommended and effective therapy.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ceftriaxona/farmacologia , China/epidemiologia , Células Clonais , Farmacorresistência Bacteriana , Gonorreia/tratamento farmacológico , Gonorreia/epidemiologia , Hospitais , Humanos , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/genética , Filogenia
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