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1.
Arch Microbiol ; 206(4): 154, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38478112

RESUMO

Although the trans-translation system is a promising target for antcibiotic development, its antibacterial mechanism in Klebsiella pneumoniae (KP) is unclear. Considering that tmRNA was the core component of trans-translation, this study firstly investigated phenotypic changes caused by various environmental stresses in KP lacking trans-translation activities (tmRNA-deleted), and then aimed to evaluate antibacterial activities of the trans-translation-targeting antibiotic combination (tobramycin/ciprofloxacin) in clinical KP isolates based on inhibition activities of aminoglycosides against trans-translation. We found that the tmRNA-deleted strain P4325/ΔssrA was significantly more susceptible than the wild-type KP strain P4325 under environments with hypertonicity (0.5 and 1 M NaCl), hydrogen peroxide (40 mM), and UV irradiation. No significant differences in biofilm formation and survivals under human serum were observed between P4325/ΔssrA and P4325. tmRNA deletion caused twofold lower MIC values for aminoglycosides. As for the membrane permeability, tmRNA deletion increased ethidium bromide (EtBr) uptake of KP in the presence or absence of verapamil and carbonyl cyanide-m-chlorophenylhydrazone (CCCP), decreased EtBr uptake in presence of reserpine in P4325/ΔssrA, and reduced EtBr efflux in P4325/ΔssrA in the presence of CCCP. The time-kill curve and in vitro experiments revealed significant bactericidal activities of the tmRNA-targeting aminoglycoside-based antibiotic combination (tobramycin/ciprofloxacin). Thus, the corresponding tmRNA-targeting antibiotic combinations (aminoglycoside-based) might be effective and promising treatment options against multi-drug resistant KP.


Assuntos
Ciprofloxacina , Klebsiella pneumoniae , Humanos , Ciprofloxacina/farmacologia , Klebsiella pneumoniae/genética , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Antibacterianos/farmacologia , Aminoglicosídeos/farmacologia , Tobramicina/farmacologia , Testes de Sensibilidade Microbiana
2.
BMC Microbiol ; 24(1): 72, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443813

RESUMO

BACKGROUND: The intrinsic concentration of RpoS, the second most abundant sigma factor, varies widely across the E. coli species. Bacterial isolates that express high levels of RpoS display high resistance to environmental stresses, such as temperature, pH and osmolarity shifts, but are less nutritional competent, making them less capable of utilising alternative nutrient sources. The role of RpoS in antibiotic resistance and persistence in standard laboratory domesticated strains has been examined in several studies, most demonstrating a positive role for RpoS. RESULTS: Using disk diffusion assays we examined bacterial resistance to 15 different antibiotics, including ß -lactams (penicillins, monobactams, carbapenems and cephalosporins), aminoglycosides, quinolones and anti-folates, in a representative collection of 328 E. coli natural isolates displaying a continuum of different levels of RpoS. There was an overall trend that isolates with higher levels of RpoS were slightly more resistant to these antibiotics. In addition, the effect of RpoS on bacterial tolerance and persistence to 3 different antibiotics - ampicillin, ciprofloxacin and kanamycin was evaluated through time-kill curves. Again, there was a small beneficial effect of RpoS on tolerance and persistence to these antibiotics, but this difference was not statistically significant. Finally, a K-12 strain expressing high levels of RpoS was compared with its isogenic RpoS-null counterpart, and no significant effect of RpoS was found. CONCLUSION: Based on a representative collection of the species E. coli, RpoS was found to have a very small impact on antibiotic resistance, tolerance, or persistence.


Assuntos
Antibacterianos , Escherichia coli , Escherichia coli/genética , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Canamicina , Aminoglicosídeos
3.
Exp Dermatol ; 33(3): e15042, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38459626

RESUMO

In the context of rare genetic diseases caused by nonsense mutations, the concept of induced stop codon readthrough (SCR) represents an attractive avenue in the ongoing search for improved treatment options. Epidermolysis bullosa (EB)-exemplary for this group of diseases-describes a diverse group of rare, blistering genodermatoses. Characterized by extreme skin fragility upon minor mechanical trauma, the most severe forms often result from nonsense mutations that lead to premature translation termination and loss of function of essential proteins at the dermo-epidermal junction. Since no curative interventions are currently available, medical care is mainly limited to alleviating symptoms and preventing complications. Complementary to attempts of gene, cell and protein therapy in EB, SCR represents a promising medical alternative. While gentamicin has already been examined in several clinical trials involving EB, other potent SCR inducers, such as ataluren, may also show promise in treating the hitherto non-curative disease. In addition to the extensively studied aminoglycosides and their derivatives, several other substance classes-non-aminoglycoside antibiotics and non-aminoglycoside compounds-are currently under investigation. The extensive data gathered in numerous in vitro experiments and the perspectives they reveal in the clinical setting will be discussed in this review.


Assuntos
Códon sem Sentido , Epidermólise Bolhosa , Humanos , Códon de Terminação , Gentamicinas/farmacologia , Gentamicinas/uso terapêutico , Aminoglicosídeos/farmacologia , Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Epidermólise Bolhosa/genética , Epidermólise Bolhosa/terapia
6.
Sci Rep ; 14(1): 4163, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378700

RESUMO

Resistance against aminoglycosides is widespread in bacteria. This study aimed to identify genes that are important for growth of E. coli during aminoglycoside exposure, since such genes may be targeted to re-sensitize resistant E. coli to treatment. We constructed three transposon mutant libraries each containing > 230.000 mutants in E. coli MG1655 strains harboring streptomycin (aph(3″)-Ib/aph(6)-Id), gentamicin (aac(3)-IV), or neomycin (aph(3″)-Ia) resistance gene(s). Transposon Directed Insertion-site Sequencing (TraDIS), a combination of transposon mutagenesis and high-throughput sequencing, identified 56 genes which were deemed important for growth during streptomycin, 39 during gentamicin and 32 during neomycin exposure. Most of these fitness-genes were membrane-located (n = 55) and involved in either cell division, ATP-synthesis or stress response in the streptomycin and gentamicin exposed libraries, and enterobacterial common antigen biosynthesis or magnesium sensing/transport in the neomycin exposed library. For validation, eight selected fitness-genes/gene-clusters were deleted (minCDE, hflCK, clsA and cpxR associated with streptomycin and gentamicin resistance, and phoPQ, wecA, lpp and pal associated with neomycin resistance), and all mutants were shown to be growth attenuated upon exposure to the corresponding antibiotics. In summary, we identified genes that are advantageous in aminoglycoside-resistant E. coli during antibiotic stress. In addition, we increased the understanding of how aminoglycoside-resistant E. coli respond to antibiotic exposure.


Assuntos
Aminoglicosídeos , Antibacterianos , Antibacterianos/farmacologia , Aminoglicosídeos/farmacologia , Escherichia coli/genética , Farmacorresistência Bacteriana/genética , Testes de Sensibilidade Microbiana , Estreptomicina/farmacologia , Gentamicinas/farmacologia , Neomicina/farmacologia
7.
Comput Biol Med ; 171: 108094, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38335823

RESUMO

Pseudomonas aeruginosa, a resilient gram-negative bacterium, poses a persistent threat as a leading cause of nosocomial infections, particularly in resource-constrained regions. Despite existing treatment and control measures, the bacterium continues to challenge healthcare systems, especially in developing nations. This paper introduces a fractional-order model to elucidate the dynamic behavior of nosocomial infections caused by P. aeruginosa and to compare the efficacy of carbapenems and aminoglycosides in treatment. The model's existence and uniqueness are established, and both global and local stability are confirmed. The effective reproduction number is computed, revealing an epidemic potential with a value of 1.02 in Northern Cyprus. Utilizing real-life data from a university hospital and employing numerical simulations, our results indicate that patients exhibit higher sensitivity and lower resistance to aminoglycoside treatment compared to carbapenems. Aminoglycosides consistently outperform carbapenems across key metrics, including the reduction of susceptible population, infection numbers, treatment efficacy, total infected population, hospital occupancy, and effective reproduction number. The fractional-order approach emerges as a suitable and insightful tool for studying the transmission dynamics of the disease and assessing treatment effectiveness. This research provides a robust foundation for refining treatment strategies against P. aeruginosa infections, contributing valuable insights for healthcare practitioners and policymakers alike.


Assuntos
Infecção Hospitalar , Infecções por Pseudomonas , Humanos , Pseudomonas aeruginosa , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Chipre , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Aminoglicosídeos , Testes de Sensibilidade Microbiana
8.
J Hazard Mater ; 468: 133811, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38382341

RESUMO

Chlorine and its derivatives, such as sodium hypochlorite (NaClO) and chlorine dioxide, are frequently employed as disinfectants throughout the pork supply chain in China. Nevertheless, the extensive use of NaClO has the potential to cause the creation of 'chlorine-tolerant bacteria' and accelerate the evolution of antibiotic resistance. This study evaluated the efficacy of NaClO disinfection by examining alterations in the microbiome and resistome of a pork wholesale market (PWM), and bacteria isolation and analysis were performed to validate the findings. As expected, the taxonomic compositions of bacteria was significantly different before and after disinfection. Notably, Salmonella enterica (S. enterica), Salmonella bongori (S. bongori), Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), and Pseudomonas aeruginosa (P. aeruginosa) were observed on all surfaces, indicating that the application of NaClO disinfection treatment in PWM environments for pathogenic bacteria is limited. Correlations were identified between antibiotic resistance genes (ARGs) associated with aminoglycosides (aph(3'')-I, aph(6')-I), quinolone (qnrB, abaQ), polymyxin (arnA, mcr-4) and disinfectant resistance genes (emrA/BD, mdtA/B/C/E/F). Furthermore, correlations were found between risk Rank I ARGs associated with aminoglycoside (aph(3')-I), tetracycline (tetH), beta_lactam (TEM-171), and disinfectant resistance genes (mdtB/C/E/F, emrA, acrB, qacG). Importantly, we found that Acinetobacter and Salmonella were the main hosts of disinfectant resistance genes. The resistance mechanisms of the ARGs identified in PWM were dominated by antibiotic deactivation (38.7%), antibiotic efflux (27.2%), and antibiotic target protection (14.4%). The proportion of genes encoding efflux pumps in the PWM resistome increased after disinfection. Microbial cultures demonstrated that the traits of microbial contamination and antibiotic resistane were consistent with those observed by metagenomic sequencing. This study highlights the possibility of cross-resistance between NaClO disinfectants and antibiotics, which should not be ignored.


Assuntos
Desinfetantes , Carne de Porco , Carne Vermelha , Suínos , Animais , Antibacterianos/farmacologia , Desinfecção , Hipoclorito de Sódio , Escherichia coli , Cloro/farmacologia , Desinfetantes/farmacologia , Bactérias/genética , Aminoglicosídeos , Halogênios
9.
ACS Chem Biol ; 19(3): 687-695, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38407057

RESUMO

Natural nucleosides are nonfluorescent and do not have intrinsic labels that can be readily utilized for analyzing nucleic acid structure and recognition. In this regard, researchers typically use the so-called "one-label, one-technique" approach to study nucleic acids. However, we envisioned that a responsive dual-app nucleoside system that harnesses the power of two complementing biophysical techniques namely, fluorescence and 19F NMR, will allow the investigation of nucleic acid conformations more comprehensively than before. We recently introduced a nucleoside analogue by tagging trifluoromethyl-benzofuran at the C5 position of 2'-deoxyuridine, which serves as an excellent fluorescent and 19F NMR probe to study G-quadruplex and i-motif structures. Taking forward, here, we report the development of a ribonucleotide version of the dual-app probe to monitor antibiotics-induced conformational changes in RNA. The ribonucleotide analog is derived by conjugating trifluoromethyl-benzofuran at the C5 position of uridine (TFBF-UTP). The analog is efficiently incorporated by T7 RNA polymerase to produce functionalized RNA transcripts. Detailed photophysical and 19F NMR of the nucleoside and nucleotide incorporated into RNA oligonucleotides revealed that the analog is structurally minimally invasive and can be used for probing RNA conformations by fluorescence and 19F NMR techniques. Using the probe, we monitored and estimated aminoglycoside antibiotics binding to the bacterial ribosomal decoding site RNA (A-site, a very important RNA target). While 2-aminopurine, a famous fluorescent nucleic acid probe, fails to detect structurally similar aminoglycoside antibiotics binding to the A-site, our probe reports the binding of different aminoglycosides to the A-site. Taken together, our results demonstrate that TFBF-UTP is a very useful addition to the nucleic acid analysis toolbox and could be used to devise discovery platforms to identify new RNA binders of therapeutic potential.


Assuntos
Benzofuranos , Aplicativos Móveis , RNA Ribossômico , Antibacterianos/farmacologia , Nucleotídeos , Nucleosídeos/química , RNA Bacteriano , Uridina Trifosfato , Corantes Fluorescentes/química , RNA/metabolismo , Aminoglicosídeos/metabolismo , Conformação de Ácido Nucleico
10.
Sci Rep ; 14(1): 1900, 2024 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-38253756

RESUMO

Bacterial resistance to antimicrobials is fast becoming a big challenge as resistance to multiple drugs is rising rapidly. The emergence of resistant Staphylococcus aureus worldwide is life-threatening in both humans and animals and yet little is known about the burden of antimicrobial resistance (AMR) in developing countries including Uganda. Therefore, the aims of this study were to determine the prevalence of antimicrobial resistant S. aureus among humans and animals as well as assess the perceptions and practices of farmers in Kamuli and Isingiro districts in Uganda regarding AMR of S. aureus. A cross-sectional study was conducted between July and September 2020 in 147 randomly selected cattle-keeping households in Isingiro and Kamuli districts. A structured questionnaire uploaded in the Kobo-collect online data collection tool was used to assess farmers' perceptions and practices pertaining to AMR in each of the selected households. Nasal swabs (n = 147) were collected from both cattle and humans (farmers). Bacterial isolation and confirmation was done using Gram-staining and biochemical tests. This was followed by antimicrobial susceptibility testing (AST) using the Kirby Bauer disc diffusion method. Only 14/147 (9.5%) cattle samples and 45/147(30.6%) human samples tested positive for S. aureus. All cattle S. aureus isolates were resistant to Nitroimidazoles while 92.9% were resistant to Penicillins. None of the isolates were resistant to Fluoroquinolones and Aminoglycosides. All the 14 isolates exhibited AMR to at least one of the assessed antibiotics and 92.9% (13/14) showed evidence of multidrug resistance (MDR). Likewise, S. aureus human isolates showed high levels of resistance to Nitroimidazoles (100%) and Penicillins (93.3%), with none of the isolates having resistance to Aminoglycosides, and only one exhibiting resistance to Fluoroquinolones (2.2%). All the 45 human isolates exhibited AMR to at least one antibiotic while 93% (42/45) had MDR. Most farmers had good perceptions of AMR, with a significantly higher proportion of respondents from Isingiro than Kamuli showing a better understanding of AMR. Antibiotic prophylaxis was reported to be the least practiced measure of diseases and parasites control (17.0%), with more farmers in Isingiro (33.3%) undertaking it than those in Kamuli (1.3%) (p < 0.001). Penicillins and Nitroimidazoles were reported to be the most used antibiotics among cattle and humans. This study provides evidence of occurrence of S. aureus resistance to antimicrobials commonly used in both humans and livestock in Isingiro and Kamuli districts. Farmers had good perceptions regarding AMR as well as good antimicrobial use practices which can form a basis for mitigation of AMR.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Nitroimidazóis , Infecções Estafilocócicas , Humanos , Bovinos , Animais , Staphylococcus aureus , Uganda/epidemiologia , Estudos Transversais , Agricultura , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/veterinária , Antibacterianos/farmacologia , Penicilinas , Aminoglicosídeos , Fluoroquinolonas
11.
Int J Antimicrob Agents ; 63(2): 107089, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38218322

RESUMO

OBJECTIVES: Aminoglycoside resistance in bacteria is typically conferred by specific drug-modifying enzymes. Infrequently, such resistance is achieved through 16S ribosomal RNA methyltransferases, such as NpmA and KamB encoded by Escherichia coli and Streptoalloteichus tenebrarius, respectively. These enzymes are not widespread and have not been described in Nocardia species to date. METHODS: We report the genomic mining of 18 Nocardia wallacei isolates that were found to be specifically and substantially resistant to amikacin. RESULTS: We identified a gene coding for a protein with very distant homology to NpmA and KamB. However, 3-D modeling revealed that the tertiary structure of these three proteins was highly similar. Cloning and expressing this gene in two susceptible bacteria Nocardia asteroides, and Mycobacterium smegmatis (another Actinobacterium) led to high-level, pan-aminoglycoside resistance in both cases. We named this gene warA (Wallacei Amikacin Resistance A). CONCLUSIONS: This is the first description and experimental characterization of a gene of this family in Nocardia, and the first demonstration that such activity could lead to pan-aminoglycoside resistance in Mycobacteria as well. The discovery of this novel gene has important biotechnology and clinical implications.


Assuntos
Mycobacterium , Nocardia , Aminoglicosídeos/metabolismo , Amicacina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Nocardia/genética , Nocardia/metabolismo , Escherichia coli/genética , Mycobacterium/genética , Mycobacterium/metabolismo , RNA Ribossômico 16S/genética , Farmacorresistência Bacteriana/genética
12.
Int J Mol Sci ; 25(1)2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38203824

RESUMO

The role of marine environments in the global spread of antibiotic resistance still remains poorly understood, leaving gaps in the One Health-based research framework. Antibiotic resistance genes (ARGs) encoding resistance to five major antibiotic classes, including sulfonamides (sul1, sul2), tetracyclines (tetA, tetB), ß-lactams (blaCTX-M, blaTEMblaVIM), macrolides (ermB, mphA), aminoglycosides (aac3-2), and integrase gene (intl1) were quantified by RT-qPCR, and their distribution was investigated in relation to environmental parameters and the total bacterial community in bottom layer and surface waters of the central Adriatic (Mediterranean), over a 68 km line from the wastewater-impacted estuary to coastal and pristine open sea. Seasonal changes (higher in winter) were observed for antibiotic resistance frequency and the relative abundances of ARGs, which were generally higher in eutrophic coastal areas. In particular, intl1, followed by blaTEM and blaVIM, were strongly associated with anthropogenic influence and Gammaproteobacteria as their predominant carriers. Water column stratification and geographic location had a significant influence on ARGs distribution in the oligotrophic zone, where the bacterial community exhibited a seasonal shift from Gammaproteobacteria in winter to Marine group II in summer.


Assuntos
Antibacterianos , Gammaproteobacteria , Antibacterianos/farmacologia , Sulfanilamida , Aminoglicosídeos , Archaea , Resistência Microbiana a Medicamentos/genética
13.
Antimicrob Agents Chemother ; 68(2): e0139323, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38169309

RESUMO

Aminoglycosides are important treatment options for serious lung infections, but modeling analyses to quantify their human lung epithelial lining fluid (ELF) penetration are lacking. We estimated the extent and rate of penetration for five aminoglycosides via population pharmacokinetics from eight published studies. The area under the curve in ELF vs plasma ranged from 50% to 100% and equilibration half-lives from 0.61 to 5.80 h, indicating extensive system hysteresis. Aminoglycoside ELF peak concentrations were blunted, but overall exposures were moderately high.


Assuntos
Aminoglicosídeos , Antibacterianos , Humanos , Antibacterianos/farmacocinética , Pulmão , Amicacina
14.
Clin Infect Dis ; 78(Supplement_1): S15-S28, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38294108

RESUMO

BACKGROUND: Francisella tularensis, the causative agent of tularemia, is endemic throughout the Northern Hemisphere and requires as few as 10 organisms to cause disease, making this potential bioterrorism agent one of the most infectious bacterial pathogens known. Aminoglycosides, tetracyclines, and, more recently, fluoroquinolones are used for treatment of tularemia; however, data on the relative effectiveness of these and other antimicrobial classes are limited. METHODS: Nine databases, including Medline, Global Health, and Embase, were systematically searched for articles containing terms related to tularemia. Articles with case-level data on tularemia diagnosis, antimicrobial treatment, and patient outcome were included. Patient demographics, clinical findings, antimicrobial administration, and outcome (eg, intubation, fatality) were abstracted using a standardized form. RESULTS: Of the 8878 publications identified and screened, 410 articles describing 870 cases from 1993 to 2023 met inclusion criteria. Cases were reported from 35 countries; more than half were from the United States, Turkey, or Spain. The most common clinical forms were ulceroglandular, oropharyngeal, glandular, and pneumonic disease. Among patients treated with aminoglycosides (n = 452 [52%]), fluoroquinolones (n = 339 [39%]), or tetracyclines (n = 419 [48%]), the fatality rate was 0.7%, 0.9%, and 1.2%, respectively. Patients with pneumonic disease who received ciprofloxacin had no fatalities and the lowest rates of thoracentesis/pleural effusion drainage and intubation compared to those who received aminoglycosides and tetracyclines. CONCLUSIONS: Aminoglycosides, fluoroquinolones, and tetracyclines are effective antimicrobials for treatment of tularemia, regardless of clinical manifestation. For pneumonic disease specifically, ciprofloxacin may have slight advantages compared to other antimicrobials.


Assuntos
Francisella tularensis , Tularemia , Humanos , Tularemia/diagnóstico , Tularemia/tratamento farmacológico , Tularemia/epidemiologia , Antibacterianos/uso terapêutico , Ciprofloxacina/uso terapêutico , Aminoglicosídeos/uso terapêutico , Tetraciclinas/uso terapêutico
15.
Clin Infect Dis ; 78(Supplement_1): S29-S37, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38294115

RESUMO

BACKGROUND: Tularemia, a potentially fatal zoonosis caused by Francisella tularensis, has been reported from nearly all US states. Information on relative effectiveness of various antimicrobials for treatment of tularemia is limited, particularly for newer classes such as fluoroquinolones. METHODS: Data on clinical manifestations, antimicrobial treatment, and illness outcome of patients with tularemia are provided voluntarily through case report forms to the US Centers for Disease Control and Prevention by state and local health departments. We summarized available demographic and clinical information submitted during 2006-2021 and evaluated survival according to antimicrobial treatment. We grouped administered antimicrobials into those considered effective for treatment of tularemia (aminoglycosides, fluoroquinolones, and tetracyclines) and those with limited efficacy. Logistic regression models with a bias-reduced estimation method were used to evaluate associations between antimicrobial treatment and survival. RESULTS: Case report forms were available for 1163 US patients with tularemia. Francisella tularensis was cultured from a clinical specimen (eg, blood, pleural fluid) in approximately half of patients (592; 50.9%). Nearly three-quarters (853; 73.3%) of patients were treated with a high-efficacy antimicrobial. A total of 27 patients (2.3%) died. After controlling for positive culture as a proxy for illness severity, use of aminoglycosides, fluoroquinolones, and tetracyclines was independently associated with increased odds of survival. CONCLUSIONS: Most US patients with tularemia received high-efficacy antimicrobials; their use was associated with improved odds of survival regardless of antimicrobial class. Our findings provide supportive evidence that fluoroquinolones are an effective option for treatment of tularemia.


Assuntos
Anti-Infecciosos , Francisella tularensis , Tularemia , Humanos , Tularemia/tratamento farmacológico , Tularemia/epidemiologia , Tularemia/prevenção & controle , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Fluoroquinolonas/uso terapêutico , Aminoglicosídeos/uso terapêutico , Tetraciclinas/uso terapêutico
16.
Clin Infect Dis ; 78(Supplement_1): S55-S63, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38294117

RESUMO

BACKGROUND: Neuroinvasive infection with Francisella tularensis, the causative agent of tularemia, is rare. Establishing clinical suspicion is challenging if risk factors or clinical features classically associated with tularemia are absent. Tularemia is treatable with antibiotics; however, there are limited data to inform management of potentially fatal neuroinvasive infection. METHODS: We collected epidemiologic and clinical data on 2 recent US cases of neuroinvasive F. tularensis infection, and performed a literature review of cases of neuroinvasive F. tularensis infection published after 1950. RESULTS: One patient presented with focal neurologic deficits and brain lesions; broad-range molecular testing on resected brain tissue detected F. tularensis. The other patient presented with meningeal signs; tularemia was suspected based on animal exposure, and F. tularensis grew in cerebrospinal fluid (CSF) culture. Both patients received combination antibiotic therapy and recovered from infection. Among 16 published cases, tularemia was clinically suspected in 4 cases. CSF often displayed lymphocytic pleocytosis. Among cases with available data, CSF culture was positive in 13 of 16 cases, and F. tularensis antibodies were detected in 11 of 11 cases. Treatment typically included an aminoglycoside combined with either a tetracycline or a fluoroquinolone. Outcomes were generally favorable. CONCLUSIONS: Clinicians should consider neuroinvasive F. tularensis infection in patients with meningitis and signs suggestive of tularemia or compatible exposures, lymphocyte-predominant CSF, unrevealing standard microbiologic workup, or lack of response to empiric bacterial meningitis treatment. Molecular testing, culture, and serologic testing can reveal the diagnosis. Favorable outcomes can be achieved with directed antibiotic treatment.


Assuntos
Francisella tularensis , Meningite , Tularemia , Animais , Humanos , Tularemia/diagnóstico , Tularemia/tratamento farmacológico , Tularemia/microbiologia , Antibacterianos/uso terapêutico , Aminoglicosídeos/uso terapêutico
17.
Braz J Microbiol ; 55(1): 429-439, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38228936

RESUMO

INTRODUCTION: Aminoglycosides are vital antibiotics for treating Brucella infections, because they interfere with bacterial protein production and are often combined with other antibiotics. They are cost-effective, have fewer side effects, and can penetrate biofilms. The prevalence of brucellosis has increased in recent years, increasing the need for effective treatments. In addition, the emergence of multidrug-resistant Brucella strains has highlighted the need for an updated and comprehensive understanding of aminoglycoside resistance. This systematic review aimed to provide a comprehensive overview of the global prevalence of aminoglycoside resistance in B. melitensis and B. abortus. METHODS: A systematic search of online databases was conducted and eligible studies met certain criteria and were published in English. Quality assessment was performed using the JBI Checklist. A random-effects model was fitted to the data, and meta-regression, subgroup, and outlier/influential analyses were performed. The analysis was performed using R and the metafor package. RESULTS: The results of this systematic review and meta-analysis suggested that the average prevalence rates of streptomycin, gentamicin, and amikacin resistance were 0.027 (95% confidence interval [CI], 0.015-0.049), 0.023 (95% CI, 0.017-0.032), and 0.008 (95% CI, 0.002-0.039), respectively. The prevalence of streptomycin resistance was higher in the unidentified Brucella group than in the B. abortus and B. melitensis groups (0.234, 0.046, and 0.017, respectively; p < 0.02). The prevalence of gentamicin resistance increased over time (r = 0.064; 95% CI, 0.018 to 0.111; p = 0.007). The prevalence of resistance did not correlate with the quality score for any antibiotic. Funnel plots showed a potential asymmetry for streptomycin and gentamicin. These results suggest a low prevalence of antibiotic resistance in the studied populations. CONCLUSION: The prevalence of aminoglycoside resistance in B. melitensis and B. abortus was low. However, gentamicin resistance has increased in recent years. This review provides a comprehensive and updated understanding of aminoglycoside resistance in B. melitensis and B. abortus.


Assuntos
Brucella melitensis , Brucelose , Humanos , Brucella melitensis/genética , Brucella melitensis/metabolismo , Brucella abortus/genética , Brucella abortus/metabolismo , Aminoglicosídeos/farmacologia , Prevalência , Brucelose/epidemiologia , Brucelose/microbiologia , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Estreptomicina/metabolismo , Gentamicinas/farmacologia
18.
Pediatr Infect Dis J ; 43(4): 351-354, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38241650

RESUMO

INTRODUCTION: The persistent patency of the ductus arteriosus frequently occurs in premature neonates and can cause infective endocarditis (IE) or ductal endarteritis (DE) during sepsis. Even though neonatal IE and DE are believed to be a rare eventuality, their incidence has been increasing in the last decades due to the improved survival of even more preterm babies, favored by highly invasive procedures and therapies. In parallel, antimicrobial resistance is another rising problem in neonatal intensive care units, which frequently compels to treat infections with broad-spectrum or last generation antibiotics. CASE PRESENTATION: We report the case of a preterm neonate affected by patent ductus arteriosus-associated DE that followed an episode of sepsis caused by a high-level aminoglycoside-resistant enterococcus. The neonate was successfully treated with the synergistic combination of ampicillin and cefotaxime. DISCUSSION: IE and patent ductus arteriosus-associated DE are rising inside neonatal intensive care units and neonatologists should be aware of these conditions. Enterococcal IE and patent ductus arteriosus-associated DE sustained by high-level aminoglycoside-resistant strains can be successfully treated with the synergistic combination of ampicillin and cefotaxime even in preterm neonates.


Assuntos
Permeabilidade do Canal Arterial , Endarterite , Endocardite Bacteriana , Endocardite , Sepse , Recém-Nascido , Humanos , Permeabilidade do Canal Arterial/complicações , Permeabilidade do Canal Arterial/tratamento farmacológico , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/tratamento farmacológico , Antibacterianos/uso terapêutico , Ampicilina/uso terapêutico , Cefotaxima , Aminoglicosídeos
19.
Clin Infect Dis ; 78(2): 277-282, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-37797310

RESUMO

BACKGROUND: Recurrent Clostridioides difficile infection (rCDI) occurs frequently, and concomitant antibiotic (CA) during the initial episode for treatment of non-CDI is a major risk factor. We sought to address the comparative efficacy of fidaxomicin versus vancomycin in the setting of CA during the initial CDI episode. METHODS: We conducted a randomized, controlled, open-label trial at 2 hospitals in Ann Arbor, Michigan. We consecutively consented and enrolled hospitalized patients ≥18 years old with diarrhea, a positive test for C. difficile, and ≥1 qualifying CA. Complicated CDI, CDI treatment for >24 hours prior to enrollment, and planned long-term (>12 weeks) CA use were notable exclusions. Clinical cure was defined as resolution of diarrhea for 2 consecutive days maintained until 2 days after therapy, and rCDI as recurrent diarrhea with positive testing ≤30 days after initial treatment. Patients were randomized to fidaxomicin or vancomycin. RESULTS: Baseline characteristics were similar in the 2 groups of 144 patients. Rates of clinical cure (73% vs 62.9%, P = .195) and rCDI (3.3% vs 4.0%; P > .99) were similar for fidaxomicin and vancomycin in the intention-to-treat and per-protocol cohorts, respectively. Only 4 patients developed rCDI. CONCLUSIONS: In this study of patients with CDI receiving CA, a numerically higher proportion were cured with fidaxomicin versus vancomycin, but this result did not reach statistical significance. Overall recurrence was lower than anticipated in both arms compared with previous studies that did not extend duration of CDI treatment during CA. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov (NCT02692651).


Assuntos
Clostridioides difficile , Infecções por Clostridium , Humanos , Adolescente , Antibacterianos/uso terapêutico , Vancomicina/uso terapêutico , Fidaxomicina/uso terapêutico , Aminoglicosídeos/uso terapêutico , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/induzido quimicamente , Diarreia/tratamento farmacológico
20.
Ultrastruct Pathol ; 48(1): 29-41, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-37970647

RESUMO

Investigation the protective effect of transient receptor potential channel modulator 2-Aminoethoxydiphenyl Borate (2-APB) on aminoglycoside nephrotoxicity caused by reactive oxygen species, calcium-induced apoptosis and inflammation was aimed. Forty Wistar rats were divided (n=8) as follows: Control group; DMSO group; 2-APB group; Gentamicin group (injected 100 mg/kg gentamicin intramuscularly for 10 days); Gentamicin+ 2-APB group (injected 2 mg/kg 2-APB intraperitoneally, then after 30 minutes 100 mg/kg gentamicin was injected intramuscularly for 10 days). Blood samples were collected for biochemical analyses, kidney tissue samples were collected for light, electron microscopic and immunohistochemical investigations. In gentamicin group glomerular degeneration, tubular dilatation, vacuolization, desquamation of tubular cells and hyaline cast formation in luminal space and leukocyte infiltration were seen. Disorganization of microvilli of tubular cells, apical cytoplasmic blebbing, lipid accumulation, myelin figure like structure formation, increased lysosomes, mitochondrial swelling and disorganization of cristae structures, apoptotic changes and widening of intercellular space were found. TNF-α, IL-6 and caspase 3 expressions were increased. BUN and creatinine concentrations were increased. Increase in MDA levels and decrease in SOD activities were determined. Even though degeneration still continues in gentamicin+2-APB treatment group, severity and the area it occupied were decreased and the glomerular and tubule structures were generally preserved. TNF-α, IL-6, caspase 3 immunoreactivities and BUN, creatinine, MDA concentrations were reduced and SOD activities were increased markedly compared to gentamicin group. In conclusion, it has been considered that 2-APB can prevent gentamicin mediated nephrotoxicity with its anti-oxidant, anti-apoptotic and anti-inflammatory effects.


Assuntos
Nefropatias , Rim , Ratos , Animais , Caspase 3/metabolismo , Caspase 3/farmacologia , Aminoglicosídeos/efeitos adversos , Aminoglicosídeos/metabolismo , Ratos Wistar , Creatinina/metabolismo , Creatinina/farmacologia , Fator de Necrose Tumoral alfa , Interleucina-6 , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Antibacterianos/efeitos adversos , Antioxidantes/farmacologia , Gentamicinas/toxicidade , Gentamicinas/metabolismo , Superóxido Dismutase/metabolismo , Estresse Oxidativo
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