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1.
Nature ; 579(7798): 260-264, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32132711

RESUMO

The production of pore-forming toxins that disrupt the plasma membrane of host cells is a common virulence strategy for bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA)1-3. It is unclear, however, whether host species possess innate immune mechanisms that can neutralize pore-forming toxins during infection. We previously showed that the autophagy protein ATG16L1 is necessary for protection against MRSA strains encoding α-toxin4-a pore-forming toxin that binds the metalloprotease ADAM10 on the surface of a broad range of target cells and tissues2,5,6. Autophagy typically involves the targeting of cytosolic material to the lysosome for degradation. Here we demonstrate that ATG16L1 and other ATG proteins mediate protection against α-toxin through the release of ADAM10 on exosomes-extracellular vesicles of endosomal origin. Bacterial DNA and CpG DNA induce the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protect host cells in vitro by serving as scavengers that can bind multiple toxins, and improve the survival of mice infected with MRSA in vivo. These findings indicate that ATG proteins mediate a previously unknown form of defence in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Toxinas Bacterianas/metabolismo , Exossomos/metabolismo , Células A549 , Proteína ADAM10/metabolismo , Animais , Toxinas Bacterianas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , DNA Bacteriano/farmacologia , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Feminino , Células HEK293 , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Staphylococcus aureus Resistente à Meticilina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções Estafilocócicas/mortalidade
2.
Artigo em Inglês | MEDLINE | ID: mdl-32178604

RESUMO

From 1 January to 31 December 2018, thirty-six institutions around Australia participated in the Australian Staphylococcus aureus Sepsis Outcome Programme (ASSOP). The aim of ASSOP 2018 was to determine the proportion of Staphylococcus aureus bacteraemia (SAB) isolates in Australia that are antimicrobial resistant, with particular emphasis on susceptibility to methicillin, and to characterise the molecular epidemiology of the methicillin-resistant isolates. A total of 2,673 S. aureus bacteraemia episodes were reported, of which 78.9% were community-onset. A total of 17.4% of S. aureus isolates were methicillin resistant. The 30-day all-cause mortality associated with methicillin-resistant SAB was 17.1% which was not significantly higher than the 13.6% mortality associated with methicillin-susceptible SAB (p = 0.1). With the exception of the ß-lactams and erythromycin, antimicrobial resistance in methicillin-susceptible S. aureus was rare. However in addition to the ß-lactams approximately 42% of methicillin-resistant S. aureus (MRSA) were resistant to erythromycin, 36% to ciprofloxacin and approximately 13% resistant to co-trimoxazole, tetracycline and gentamicin. When applying the EUCAST breakpoints teicoplanin resistance was detected in two S. aureus isolates. Resistance was not detected for vancomycin and linezolid. Resistance to non-beta-lactam antimicrobials was largely attributable to two healthcare-associated MRSA clones: ST22-IV [2B] (EMRSA-15) and ST239-III [3A] (Aus-2/3 EMRSA). The ST22-IV [2B] (EMRSA-15) clone is the predominant healthcare-associated clone in Australia. Seventy-eight percent of methicillin-resistant SAB episodes in 2018 were due to community-associated clones. Although polyclonal, approximately 76.3% of community-associated clones were characterised as ST93-IV [2B] (Queensland CA-MRSA), ST5-IV [2B], ST45-VT [5C2&5], ST1-IV [2B], ST30-IV [2B], ST78-IV [2B] and ST97-IV [2B]. Community-associated MRSA, in particular the ST45-VT [5C2&5] clone, has acquired multiple antimicrobial resistance determinants including ciprofloxacin, erythromycin, clindamycin, gentamicin and tetracycline. The ST45-VT [5C2&5] clone accounted for 11.7% of CA-MRSA. As CA-MRSA is well established in the Australian community, it is important that antimicrobial resistance patterns in community- and healthcare-associated SAB are monitored, as this information will guide therapeutic practices in treating S. aureus sepsis.


Assuntos
Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Sepse , Infecções Estafilocócicas , Staphylococcus aureus , Antibacterianos/farmacologia , Austrália/epidemiologia , Bacteriemia , Infecção Hospitalar/tratamento farmacológico , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Resistência a Meticilina , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Epidemiologia Molecular , Sepse/tratamento farmacológico , Sepse/etiologia , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos
3.
R I Med J (2013) ; 103(2): 18-20, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32122094

RESUMO

Hospital antibiograms, because they are typically derived from samples obtained from hospitalized patients, may overestimate the prevalence of methicillin resistance in S. aureus in individuals presenting to the hospital for surgery. Because hospital antibiograms are commonly used to justify empiric perioperative prophylactic antibiotic selection prior to surgery, this may lead to unnecessary treatment with broad-spectrum antibiotics such as vancomycin. In a single-institution study, we observed that in our hospital antibiogram the proportion of S. aureus that are methicillin-resistant (MRSA) was significantly higher (45%) than isolates in preoperative nasal cultures obtained at the same hospital in outpatients prior to their lower extremity joint replacement surgery (13%): mean difference 0.32, [95% CI 0.25, 0.39], p <0.0001. These data suggest that hospital antibiograms may overstate the true prevalence of MRSA in those at risk for MRSA surgical site infections who present from the outpatient setting.


Assuntos
Antibacterianos/farmacologia , Portador Sadio/microbiologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Cavidade Nasal/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus/isolamento & purificação , Adulto , Antibacterianos/uso terapêutico , Portador Sadio/epidemiologia , Feminino , Humanos , Masculino , Resistência a Meticilina , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Período Pré-Operatório , Prevalência , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/classificação , Staphylococcus aureus/efeitos dos fármacos
4.
Med Lav ; 111(1): 54-62, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32096773

RESUMO

BACKGROUND: The nasal carriage rate of Staphylococcus aureus in healthcare workers (HCWs) is higher than the general population. Their hands serve as vectors for transmitting S.aureus colonized in the nose to patients. OBJECTIVES: To determine the rate of nasal S.aureus carriage and methicillin resistance in HCWs and to evaluate the relationship between carriage and personal risk factors and hand hygiene behaviors. METHODS: The questionnaire included questions about sociodemographic characteristics, occupational and personal risk factors for S.aureus carriage, the "Hand Hygiene Belief Scale (HHBS)," and "Hand Hygiene Practices Inventory (HHPI)". Nasal culture was taken from all participants. Presence of S.aureus, methicillin and mupirocin resistance were investigated in samples. RESULTS: The study was carried out with 269 HCWs. The prevalence of S.aureus carriage was 20.1% (n:54). Among 54 S.aureus carriers, only one person had MRSA (0.37%). All S.aureus isolates were susceptible to mupirocin. S.aureus carriage was found to be significantly lower in the smoker group (p:0.015) and in the personnel wearing gloves during the procedures of each patient (p:0.002). S.aureus culture positivity was found to decrease significantly with increasing handwashing frequency (p:0.003). The mean HHPI score was higher in women (p:0.001). The mean HHPI score was lower in the group with nasal carriers than in non-carriers (p:0.176). CONCLUSION: The knowledge of hand hygiene practices, high frequency of handwashing, and wearing different gloves during the procedure of each patient decrease S.aureus nasal carriage in HCWs. In addition mupirocin is still effective in nasal S.aureus carriers.


Assuntos
Portador Sadio , Higiene das Mãos , Pessoal de Saúde , Staphylococcus aureus Resistente à Meticilina , Feminino , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Nariz , Staphylococcus aureus/isolamento & purificação
5.
JAMA ; 323(6): 527-537, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32044943

RESUMO

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the ß-lactam was administered for 7 days. Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.


Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Daptomicina/uso terapêutico , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/uso terapêutico , beta-Lactamas/uso terapêutico , Adulto , Idoso , Antibacterianos/efeitos adversos , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Cefazolina/uso terapêutico , Cloxacilina/uso terapêutico , Quimioterapia Combinada , Endocardite Bacteriana/tratamento farmacológico , Feminino , Floxacilina/uso terapêutico , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Falha de Tratamento , beta-Lactamas/efeitos adversos
6.
J Photochem Photobiol B ; 204: 111782, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32062389

RESUMO

BACKGROUND: Ultraviolet (UV) fluorescent lamp (FL) was applied in mainstream riboflavin photochemical method (RPM) to inactivate pathogens in blood components. Low UV irradiance emitted by UV-FL resulted in more time to achieve effective inactivation. MATERIALS AND METHODS: A novel light emitting diode (LED) UV illumination with adjustable irradiance was developed by us. Two strains of drug-resistant bacteria (DRB), pan-drug resistant Acinetobacter baumannii (PDRAB) and methicillin-resistant Staphylococcus aureus (MRSA) were cultured and used for evaluating the inactivation effectiveness of RPM using UV-LED or UV-FL against DRB in plasma or platelets. Three plasma factors and four platelet parameters were measured after treatments. RESULTS: There was a linear relationship between UV-LED irradiance and electric current, the minimum UV irradiance was 24 mW/cm2, and the maximum was 258 mW/cm2. At the same UV dose of 15 J/cm2, inactivation effectiveness of UV-LED with 258 mW/cm2 against PDRAB in plasma or platelets were comparable to that of UV-FL with 16 mW/cm2, both above 98%. UV-FL treatment required 10-15 min, but UV-LED only required 1-2 min. However, MRSA showed a resistance to UV-LED (inactivation effectiveness was around 40%) compared with UV-FL (inactivation effectiveness was above 98%). The retention of fibrinogen, factor V, factor VII in plasma and platelet counts in platelets with UV-LED treatment were significantly higher than UV-FL at the same UV dose. CONCLUSION: The treatment of RPM using UV-LED with high UV irradiance was able to dramatically shorten inactivation time against PDRAB in plasma or platelets and improve retention of blood components compared with UV-FL.


Assuntos
Proteínas Sanguíneas/metabolismo , Riboflavina/química , Raios Ultravioleta , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/efeitos da radiação , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Plaquetas/efeitos da radiação , Farmacorresistência Bacteriana/efeitos dos fármacos , Fator V/metabolismo , Fibrinogênio/metabolismo , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos da radiação , Contagem de Plaquetas , Riboflavina/farmacologia
7.
Zhonghua Shao Shang Za Zhi ; 36(1): 24-31, 2020 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-32023714

RESUMO

Objective: To analyze the distribution and drug resistance of pathogens isolated from patients with catheter-related bloodstream infection (CRBSI) in burn intensive care unit (BICU). Methods: From January 2011 to December 2018, among 2 264 patients who were peripherally inserted central venous catheter at the BICU of the First Affiliated Hospital of Army Medical University (the third Military Medical University), hereinafter referred to as the author's unit, 159 patients were diagnosed CRBSI, including 131 males and 28 females, aged 43 (1, 79) years. The pathogens primarily isolated from peripheral venous blood and central venous catheter blood/anterior central venous catheter specimen of patients with CRBSI were retrospectively analyzed. API bacteria identification kits and automatic microorganism identification instrument were used to identify pathogens. Broth micro-dilution method or Kirby-Bauer paper disk diffusion method was used to detect the drug resistance of the pathogens to 5 antifungal drugs including fluconazole and itraconazole, etc., and 37 antibacterial drugs including tigecycline and imipenem, etc. Modified Hodge test was used to further identify imipenem- and meropenem-resistant Klebsiella pneumonia. D test was used to detect erythromycin-induced clindamycin resistant Staphylococcus aureus. The WHONET 5.6 software was applied to analyze the annual incidence of CRBSI, mortality of patients with CRBSI, incidence of CRBSI cases, distribution of infection site, and duration of catheterization, detection of Gram-negative and Gram-positive bacteria, fungi, methicillin-resistant Staphylococcus aureus (MRSA), and methicillin-sensitive Staphylococcus aureus (MSSA), and drug resistance of fungi and major Gram-negative and Gram-positive bacteria to the commonly used antibiotics in clinic. Results: (1) The incidence of CRBSI was 7.0% (159/2 264) during the eight years, which was slightly higher in 2014 and 2017 with 13.6% (30/221) and 11.1% (24/217) respectively. The mortality rate of patients with CRBSI was 7.5% (12/159). (2) The incidence of CRBSI cases was 14.9% (338/2 264); the main infection site was femoral vein, totally 271 cases (80.2%), and the duration of catheterization of this site was 9 (2, 25) d. (3) During the eight years, totally 543 strains of pathogens were isolated, including 353 (65.0%) strains of Gram-negative bacteria, 140 (25.8%) strains of Gram-positive bacteria, and 50 (9.2%) strains of fungi. The top three isolated pathogens with isolation rate from high to low were Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa, accounting for 23.2% (126/543), 17.1% (93/543), and 15.7% (85/543), respectively. Fungi were mainly Candida parapsilosis. Among the Staphylococcus aureus, the detection rate of MRSA was 98.9% (92/93), and that of MSSA was 1.1% (1/93). (4) Except for the low drug resistance rates to polymyxin B, minocycline, and tigecycline, the drug resistance rates of Acinetobacter baumannii to the other antibiotics were considerably high (80.1%-100.0%). Pseudomonas aeruginosa was not resistant to polymyxin B but highly resistant to netilmicin (88.7%) and piperacillin (92.6%), with resistance rates to the other antibiotics from 34.5% to 62.7%. Klebsiella pneumoniae was not resistant to tigecycline and lowly resistant to imipenem and meropenem (28.9%, 9 imipenem- and meropenem-resistant strains were further confirmed by modified Hodge test), with resistance rates to the other antibiotics from 40.9% to 95.2%. The resistance rates of MRSA to most antibiotics were higher than those of MSSA. MRSA was not resistant to linezolid, vancomycin, teicoplanin, sulfamethoxazole, or tigecycline. The resistance rates of MRSA to clindamycin and erythromycin were 7.9% and 62.0%, respectively, and those to the other antibiotics were higher than 91.5%. Except for the complete resistance to penicillin G and tetracycline, MSSA was not resistant to the other antibiotics. Thirty-three strains of Staphylococcus aureus showed resistance to erythromycin-induced clindamycin. Fungi was not resistant to amphotericin B, with drug resistance rates to voriconazole, itraconazole, ketoconazole, and fluconazole from 4.2% to 6.2%. Conclusions: The incidence of CRBSI and mortality of patients with CRBSI are high in BICU of the author's unit, and the main infection site is femoral vein. There are various types of pathogens in patients with CRBSI, and most of them are Gram-negative. The top three isolated pathogens are Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa, accompanying with grim drug resistance phenomenon.


Assuntos
Bacteriemia , Staphylococcus aureus Resistente à Meticilina , Adolescente , Adulto , Idoso , Antibacterianos , Criança , Pré-Escolar , Resistência a Medicamentos , Farmacorresistência Bacteriana , Feminino , Humanos , Lactente , Unidades de Terapia Intensiva , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
10.
J Photochem Photobiol B ; 203: 111774, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31931386

RESUMO

Zeolitic imidazole framework (ZIF) is an emerging class of metal organic frameworks exhibiting unique features such as crystalline nature with tunable pore size, large surface area and biocompatible nature. Exceptional thermal and chemical stabilities of ZIF-L make it a suitable candidate for biomedical applications. The present study has focused on the single step fabrication of catechin encapsulated ZIF-L and evaluation of its antibiofilm efficiency, larvicidal activity and dye degradation ability. The as- prepared CA@ZIF-L nanocomposite was characterized by spectroscopic and microscopic techniques. The results revealed that the CA@ZIF-L showed significant toxicity against mosquito larvae in a dose dependent manner with the IC50 63.43±1.25 µg/mL. CA@ZIF-L showed dose dependent reduction of biofilm formation in both ATCC and clinical MRSA strains. In addition, CA@ZIF-L exhibited excellent photocatalytic activity with around 92% degradation of methylene blue under direct sunlight. Overall, the present work highlights the possibility of employing the multifunctional CA@ZIF-L nanocomposite as a suitable material for biomedical and photocatalytic applications.


Assuntos
Biofilmes/efeitos dos fármacos , Catequina/química , Estruturas Metalorgânicas/química , Nanocompostos/toxicidade , Zeolitas/química , Animais , Catálise , Culicidae/efeitos dos fármacos , Culicidae/crescimento & desenvolvimento , Imidazóis/química , Larva/efeitos dos fármacos , Luz , Staphylococcus aureus Resistente à Meticilina/fisiologia , Azul de Metileno/química , Nanocompostos/química , Tamanho da Partícula , Fotólise/efeitos da radiação
11.
J Photochem Photobiol B ; 203: 111776, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31931388

RESUMO

Due to the emergence of antibiotic resistance, antimicrobial photodynamic therapy (aPDT) has recently been demonstrated as a promising alternative to antibiotics to treat wound infections caused by multidrug-resistant (MDR) pathogens. This study aimed to evaluate the bacterial killing efficiency of aPDT mediated by methylene blue (MB) loaded thermosensitive hydrogels against methicillin-resistant Staphylococcus aureus (MRSA). Box-Behnken Design method was employed to investigate the impacts of the polymer compositions, Poloxamer 407, Poloxamer 188 and Carbopol 934P, on the gelation temperature (Tsol-gel) and release rate of MB. The viscosity and in vitro bacterial killing efficiency of three selected formulations with Tsol-gel ranged 25-34 °C and MB release in 2 h (the incubation time used for aPDT experiment) ≥ 70%, were assessed. The viscosity was found to increase with increasing P407 content and increasing total gel concentration. In the in vitro aPDT experiment, all tested MB-hydrogels demonstrated >2.5 log10 colony forming unit (CFU) reduction against three clinical relevant MRSA strains. Interestingly, the bacterial reduction increased with decreasing amount of gel added (reduced MB concentration). This was possibly attributed to the increased viscosity at higher gel concentration reducing the diffusion rate of released MB towards bacterial cells leading to reduced aPDT efficiency. In summary, aPDT with the thermosensitive MB hydrogel formulations is a promising treatment strategy for wound infections.


Assuntos
Anti-Infecciosos/química , Hidrogéis/química , Azul de Metileno/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Luz , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Azul de Metileno/metabolismo , Azul de Metileno/farmacologia , Reologia , Temperatura Ambiente , Viscosidade
12.
World J Microbiol Biotechnol ; 36(2): 22, 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31955251

RESUMO

Staphylococcus aureus strains resistant to the last line antibiotic, vancomycin, have been of clinical concern. These include heterogeneous vancomycin-intermediate S. aureus (hVISA) and VISA. The hVISA phenotype cannot be detected by routine laboratory methods. Characterization of hVISA/VISA by new technologies is necessary to differentiate them rapidly from the vancomycin-susceptible isolates (VSSA). In this study, we developed a model for discrimination of hVISA from VSSA by using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy combined with multivariate data analysis, displaying a phenotypic signature of the bacteria. ATR-FTIR spectra were acquired from a total of 59 clinical methicillin-resistant S. aureus (MRSA) isolates comprising 28 hVISA and 31 VSSA strains. Principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) were used to analyze 351 spectra of 39 isolates and develop a discrimination model for identifying hVISA and VSSA. The classification model, which was used for blind testing of 90 spectra from each of 10 hVISA, and 10 VSSA isolates, provided 100% sensitivity and specificity. The modeling revealed that the major discrimination between hVISA and VSSA phenotypes involved bands related to cell wall content (1087 and 1057 cm-1). This study showed that ATR-FTIR technique may be an alternative method for rapid detection of low-level vancomycin-resistant S. aureus.


Assuntos
Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Vancomicina/farmacologia , Análise dos Mínimos Quadrados , Testes de Sensibilidade Microbiana , Fenótipo , Análise de Componente Principal , Espectroscopia de Infravermelho com Transformada de Fourier , Resistência a Vancomicina
13.
BMC Infect Dis ; 20(1): 24, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31914949

RESUMO

BACKGROUND: Despite recent improvement in management, infective endocarditis (IE) continues to be associated with considerable risk of morbidity and mortality. Early identification of predictors of inpatient mortality is key in improving patient outcomes in IE. The aim of our study was to evaluate the role of serum troponin levels measurements as a marker of increased mortality. METHODS: A case-control study included adult patients with IE admitted to a tertiary care hospital in east Tennessee between December 2012 and July 2017. Cases were defined as patients with definitive IE who died in-hospital; controls were patients who did not die in hospital. First patient admission was included only. Data collected included the patients' demographic and baseline clinical information, microbiological data, injection drug use status, elevated serum troponins levels. RESULTS: Two hundred eighty three patients with definitive IE were included; median (IQR) age was 41 (30-57) years, and 153 (54%) patients were men. One-hundred sixty-four (58%) were injection drug users. The most frequent IE type was: 167 (59%) right-sided, 86 (30%) left-sided, 24 (9%) both left and right-sided, and 10 (4%) device related. The most commonly isolated organism was Staphylococcus aureus (n = 141), and 64% were methicillin-resistant. Two-hundred twelve (75%) patients had a troponin level obtained, and 57 (27%) had an elevated troponin value. Thirty-six (13%) patients died in-hospital; in-hospital mortality was associated elevated troponin values (adjusted odds ratio [adjOR], 7.3; 95%CI, 3.3-15.9), and methicillin-resistant S. aureus IE (adjOR 2.6; 95%CI, 1.2-5.8). Forty-four (16%) patients received IE valve surgery, and none of these patients died in the hospital. CONCLUSION: Inpatient mortality was higher in patients with IE and elevated cardiac troponin levels compared to patients with normal levels.


Assuntos
Endocardite/diagnóstico , Endocardite/mortalidade , Mortalidade Hospitalar , Troponina/sangue , Adulto , Idoso , Estudos de Casos e Controles , Usuários de Drogas/estatística & dados numéricos , Endocardite/microbiologia , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/microbiologia , Endocardite Bacteriana/mortalidade , Feminino , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Abuso de Substâncias por Via Intravenosa/diagnóstico , Abuso de Substâncias por Via Intravenosa/microbiologia , Abuso de Substâncias por Via Intravenosa/mortalidade , Tennessee/epidemiologia , Estados Unidos/epidemiologia
14.
Eur J Med Chem ; 188: 112022, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901744

RESUMO

Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 µg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25-1 µg/mL vs. 1-64 µg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6-155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.


Assuntos
Antibacterianos/farmacologia , Quinolonas/farmacologia , Tiadiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , DNA Girase/metabolismo , Desenho de Drogas , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Feminino , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/toxicidade , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/toxicidade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/toxicidade
15.
BMC Infect Dis ; 20(1): 6, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900118

RESUMO

BACKGROUND: An efficient surface cleaning strategy would first target cleaning to surfaces that make large contributions to the risk of infections. METHODS: In this study, we used data from the literature about methicillin-resistant Staphylococcus aureus (MRSA) and developed an ordinary differential equations based mathematical model to quantify the impact of contact heterogeneity on MRSA transmission in a hypothetical 6-bed intensive care unit (ICU). The susceptible patients are divided into two types, these who are cared by the same nurse as the MRSA infected patient (Type 1) and these who are not (Type 2). RESULTS: The results showed that the mean MRSA concentration on three kinds of susceptible patient nearby surfaces was significantly linearly associated with the hand-touch frequency (p < 0.05). The noncompliance of daily cleaning on patient nearby high-touch surfaces (HTSs) had the most impact on MRSA transmission. If the HTSs were not cleaned, the MRSA exposure to Type 1 and 2 susceptible patients would increase 118.4% (standard deviation (SD): 33.0%) and 115.4% (SD: 30.5%) respectively. The communal surfaces (CSs) had the least impact, if CSs were not cleaned, the MRSA exposure to Type 1 susceptible patient would only increase 1.7% (SD: 1.3). The impact of clinical equipment (CE) differed largely for two types of susceptible patients. If the CE was not cleaned, the exposure to Type 1 patients would only increase 8.4% (SD: 3.0%), while for Type 2 patients, it can increase 70.4% (SD: 25.4%). CONCLUSIONS: This study provided a framework to study the pathogen concentration dynamics on environmental surfaces and quantitatively showed the importance of cleaning patient nearby HTSs on controlling the nosocomial infection transmission via contact route.


Assuntos
Busca de Comunicante/métodos , Unidades de Terapia Intensiva , Staphylococcus aureus Resistente à Meticilina/fisiologia , Modelos Teóricos , Infecções Estafilocócicas/transmissão , Busca de Comunicante/estatística & dados numéricos , Infecção Hospitalar/transmissão , Detergentes/farmacologia , Desinfecção , Feminino , Higiene das Mãos/estatística & dados numéricos , Humanos , Controle de Infecções/métodos , Transmissão de Doença Infecciosa do Paciente para o Profissional/estatística & dados numéricos , Transmissão de Doença Infecciosa do Profissional para o Paciente/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Resistência a Meticilina/fisiologia , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Propriedades de Superfície
16.
AAPS PharmSciTech ; 21(2): 43, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897806

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) is considered a common colonizer of burn wound and accounts for high morbidity and mortality all across the globe. Systemic antibiotic therapy which is generally prescribed for these patients has a number of limitations. These include high drug dose, toxicity, and chances of development of drug resistance. However, local delivery of drug not only addresses these limitations but also provides better efficacy at the site of infection. In the present study, hydrogel preparations were developed for the topical delivery of moxifloxacin for the treatment of S. aureus-infected burn wound. Moxifloxacin was characterized by UV, FTIR, DSC, hot-stage microscopy, NMR, and HPLC and loaded into conventional and Boswellia-containing novel gels. Gels were characterized by visual examination, pH, UV spectroscopy, and release assays. In vivo studies showed that both gels were effective in eradicating the bacteria completely from the wound site when treatment was started during the early stage of infection. On the contrary, delayed treatment of planktonic and biofilm cells with novel gel showed better efficacy as compared with conventional gel in S. aureus-infected burn wound. Histopathological analysis also showed better skin healing efficacy of novel gel than conventional gel. Our results show that moxifloxacin can be efficiently used topically in the management of burn wound infections along with other antibacterial agents. Since biofilm-mediated infections are on the rise especially in chronic bacterial disease, therefore, a preparation containing antibiofilm agent-like Boswellia as one of the excipients would be more meaningful.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Anti-Infecciosos Locais/administração & dosagem , Anti-Infecciosos Locais/farmacologia , Biofilmes/efeitos dos fármacos , Queimaduras/complicações , Quitosana/química , Hidrogéis/química , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Infecção dos Ferimentos/tratamento farmacológico , Animais , Antibacterianos/química , Anti-Infecciosos Locais/química , Boswellia/química , Composição de Medicamentos , Géis , Staphylococcus aureus Resistente à Meticilina , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Moxifloxacina/administração & dosagem , Moxifloxacina/química , Moxifloxacina/uso terapêutico , Infecções Estafilocócicas/microbiologia , Infecção dos Ferimentos/microbiologia
17.
BMC Infect Dis ; 20(1): 74, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31973753

RESUMO

BACKGROUND: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC. METHODS: Steady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. RESULTS: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively. CONCLUSIONS: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.


Assuntos
Antibacterianos/farmacologia , Bacteriemia/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/farmacologia , Antibacterianos/farmacocinética , Bacteriemia/microbiologia , Brasil , Cefalosporinas/farmacocinética , Cefalosporinas/farmacologia , Daptomicina/farmacocinética , Daptomicina/farmacologia , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Estudos Retrospectivos , Infecções Estafilocócicas/microbiologia , Vancomicina/farmacocinética
18.
BMC Infect Dis ; 20(1): 82, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996170

RESUMO

BACKGROUND: No-touch environmental disinfection using ultraviolet devices has been highlighted in the past several years to control the transmission of multidrug-resistant organisms (MDROs). However, its effectiveness in non-US healthcare settings is yet to be examined. This study aimed to evaluate the effectiveness of disinfection by portable pulsed xenon ultraviolet (PX-UV) devices in controlling transmission of MDROs in a non-US healthcare setting. METHODS: All patients admitted in the intensive care unit in a 629-bed tertiary referral hospital in Japan from August 2016 to February 2019 were enrolled. During the study period, PX-UV disinfection was added to manual terminal cleaning after every patient transfer/discharge. For microbiological evaluation, surfaces were selected for sampling by contact plates before/after manual cleaning and after PX-UV. After overnight incubation, colonies on the plates were counted. RESULTS: The incidence of newly acquired methicillin-resistant Staphylococcus aureus (MRSA) declined significantly (13.8 to 9.9 per 10,000 patient days, incidence rate ratio 0.71, p = 0.002), as well as that of newly acquired drug-resistant Acinetobacter (48.5 to 18.1, 0.37, p < 0.001). The percent reduction of the microbiological burden by manual cleaning was 81%, but a further 59% reduction was achieved by PX-UV. CONCLUSIONS: PX-UV is effective in further reducing the microbial burden and controlling MDROs in a non-US healthcare setting.


Assuntos
Acinetobacter baumannii/efeitos da radiação , Infecção Hospitalar/prevenção & controle , Desinfecção/métodos , Farmacorresistência Bacteriana Múltipla/efeitos da radiação , Staphylococcus aureus Resistente à Meticilina/efeitos da radiação , Estudos Controlados Antes e Depois , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Desinfecção/instrumentação , Humanos , Incidência , Unidades de Terapia Intensiva , Japão/epidemiologia , Centros de Atenção Terciária , Raios Ultravioleta , Xenônio
19.
Int J Antimicrob Agents ; 55(3): 105892, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31926284

RESUMO

Three homologous oxygenated elansolid-type of polyketide spanned macrolides were isolated from a heterotrophic marine bacterium, Bacillus amyloliquefaciens MTCC 12716, associated with an intertidal red alga Hypnea valentiae. The complete genome of the bacterium was sequenced and all detectable natural product gene clusters were analysed. The B. amyloliquefaciens MTCC 12716 genome features polyketide synthase (pks) systems of every known formally classified family, nonribosomal peptide synthetases and hybrid clusters. Comprehensive spectroscopic studies revealed the compounds to possess isobenzofuranyl benzoate and 1H-furopyrano[2,3-c]oxacyclononadecine-6-carboxylate moieties. The identified compounds displayed broad-spectrum bactericidal activity against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, and drug-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae with minimum inhibitory concentrations (MICs) of ≤1.0 µg/mL, whereas the standard antibiotics ampicillin and chloramphenicol were active only at concentrations of ≥6.25 µg/mL. The plausible mechanism of elansolid-type macrolide biosynthesis by trans-AT polyketide synthases through the pks starter unit para-hydroxybenzoic acid was hypothesised, and the structures were correlated with the gene organisation, with the predicted gene cluster comprising 16 genes (~81 kb in size). The best binding poses for each compound with the peptide deformylase (PDF) protein of S. aureus revealed docking scores (>11.30 kcal/mol) greater than actinonin (6.96 kcal/mol), a natural PDF inhibitor. The higher electronic values along with optimum lipophilic parameters support the potential anti-infective properties of the studied macrolides. These antibacterial elansolid-type of polyketide spanned macrolides in marine symbiotic B. amyloliquefaciens could be potential leads for biotechnological and pharmaceutical applications against emerging multidrug-resistant pathogens.


Assuntos
Anti-Infecciosos/farmacologia , Bacillus amyloliquefaciens/química , Macrolídeos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Anti-Infecciosos/isolamento & purificação , Bacillus amyloliquefaciens/genética , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Macrolídeos/química , Macrolídeos/isolamento & purificação , Oxigênio
20.
Nat Commun ; 11(1): 140, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919415

RESUMO

Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.


Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Proteínas de Bactérias/metabolismo , Macrolídeos/metabolismo , Staphylococcus aureus Resistente à Meticilina/enzimologia , Peptídeos/metabolismo , Sítios de Ligação/fisiologia , Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Farmacorresistência Bacteriana/genética , Farmacorresistência Bacteriana/fisiologia , Macrolídeos/farmacologia , Peptídeos/farmacologia , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína
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