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1.
J Glob Antimicrob Resist ; 18: 37-44, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31154007

RESUMO

BACKGROUND: Extensively drug-resistant (XDR) Pseudomonas aeruginosa (P. aeruginosa) and particularly P. aeruginosa high-risk clones, are of growing concern because treatment options are limited. For years, colistin monotherapy has been the only available treatment, but is well known that is not an optimal treatment. A combination of colistin with another antibiotic could be a possible therapeutic option. OBJECTIVES: This study aimed to investigate effective antibiotic combinations against 20 XDR P. aeruginosa isolates obtained in a Spanish multicentre study (2015). METHODS: Forty-five checkerboards with six antipseudomonal antibiotics (amikacin, aztreonam, ceftazidime, meropenem, colistin, and ceftolozane/tazobactam) were performed to determine whether combinations were synergic or additive by fractional inhibitory concentration indices. On average, 15 different regimens were evaluated in duplicate against the three most prevalent high-risk clones (ST175, ST235, ST111) by time-kill analyses over 24h. The combination showing synergism in the three high-risk clones was validated in all studied XDR isolates. RESULTS: In time-kill curves, the untreated control failed, as did each study regimen when administered alone. Two combinations were synergistic in the three high-risk clones that were initially studied: amikacin plus ceftazidime and colistin plus meropenem, with the second being the most effective combination. The efficacy of colistin plus meropenem was then tested in all 20 isolates. A synergistic bacterial density reduction for the duration of the study occurred in 80% of the entire XDR collection. CONCLUSIONS: These data suggest that colistin plus meropenem may be a useful combination for the treatment of infections due to XDR P. aeruginosa, including high-risk clones, which warrants evaluation in a clinical trial.

2.
Artigo em Inglês | MEDLINE | ID: mdl-29530842

RESUMO

The aim of this study was to investigate the efficacy of ceftolozane-tazobactam in combination with meropenem against an extensively drug-resistant (XDR) Pseudomonas aeruginosa high-risk clone, sequence type 175, isolated in a Spanish university hospital. A 14-day hollow-fiber infection model was used to simulate clinical exposure of the two drug regimens alone and in combination, and serial samples were collected to determine drug concentrations and CFU counts. The untreated control failed, as did each study regimen when administered alone. However, when ceftolozane-tazobactam was administered in combination with meropenem, there was a >4-log10 CFU/ml bacterial density reduction and suppression of resistance for the duration of the study. These data suggest that ceftolozane-tazobactam plus meropenem may be a useful combination for treating XDR P. aeruginosa.

4.
Microb Drug Resist ; 24(2): 113-119, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28650275

RESUMO

This study describes the molecular characterization of an NDM-7 carbapenemase-producing Escherichia coli strain Ec188, recovered from a rectal swab of a male patient who had travelled to Pakistan before his hospitalization at the Hospital del Mar in Barcelona, Spain. The Ec188 isolate, assigned to a new multilocus sequence type ST679, was resistant to all beta-lactams, aminoglycosides (gentamicin, tobramycin, and with reduced susceptibility to amikacin), and ciprofloxacin. The blaNDM-7 gene was located on a 50 kb IncX4 plasmid (pEc188-NDM7), both in the original and transconjugant strains. In addition, blaCTX-M-15 was located on a 150 kb IncFIA plasmid and blaCMY-2 on a 95 kb undetermined plasmid type, only in the wild-type strain. The immediate genetic surroundings of blaNDM-7 included the bleo, trpf, and dsbC genes, and it was flanked by the insertion sequences IS26 and ISAba125, which appeared interrupted by IS5. The res and parA genes were found in the same orientation downstream of the IS26 element. To our knowledge, this is the first report of an NDM-7-carbapenemase carried on an IncX4 plasmid, as well as the first E. coli strain belonging to ST679 harboring an NDM ß-lactamase, possibly associated with previous travel to Pakistan. In addition, this study highlights the dissemination of NDM variants accompanied by IncX-type plasmids.


Assuntos
Proteínas de Escherichia coli/genética , Escherichia coli/genética , Genes Bacterianos , Plasmídeos/metabolismo , beta-Lactamases/genética , Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Ciprofloxacino/farmacologia , Farmacorresistência Bacteriana Múltipla , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/metabolismo , Expressão Gênica , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Paquistão , Plasmídeos/química , Espanha , Viagem , beta-Lactamases/metabolismo , beta-Lactamas/farmacologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-28874376

RESUMO

This study assessed the molecular epidemiology, resistance mechanisms, and susceptibility profiles of a collection of 150 extensively drug-resistant (XDR) Pseudomonas aeruginosa clinical isolates obtained from a 2015 Spanish multicenter study, with a particular focus on resistome analysis in relation to ceftolozane-tazobactam susceptibility. Broth microdilution MICs revealed that nearly all (>95%) of the isolates were nonsusceptible to piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem, and ciprofloxacin. Most of them were also resistant to tobramycin (77%), whereas nonsusceptibility rates were lower for ceftolozane-tazobactam (31%), amikacin (7%), and colistin (2%). Pulsed-field gel electrophoresis-multilocus sequence typing (PFGE-MLST) analysis revealed that nearly all of the isolates belonged to previously described high-risk clones. Sequence type 175 (ST175) was detected in all 9 participating hospitals and accounted for 68% (n = 101) of the XDR isolates, distantly followed by ST244 (n = 16), ST253 (n = 12), ST235 (n = 8), and ST111 (n = 2), which were detected only in 1 to 2 hospitals. Through phenotypic and molecular methods, the presence of horizontally acquired carbapenemases was detected in 21% of the isolates, mostly VIM (17%) and GES enzymes (4%). At least two representative isolates from each clone and hospital (n = 44) were fully sequenced on an Illumina MiSeq. Classical mutational mechanisms, such as those leading to the overexpression of the ß-lactamase AmpC or efflux pumps, OprD inactivation, and/or quinolone resistance-determining regions (QRDR) mutations, were confirmed in most isolates and correlated well with the resistance phenotypes in the absence of horizontally acquired determinants. Ceftolozane-tazobactam resistance was not detected in carbapenemase-negative isolates, in agreement with sequencing data showing the absence of ampC mutations. The unique set of mutations responsible for the XDR phenotype of ST175 clone documented 7 years earlier were found to be conserved, denoting the long-term persistence of this specific XDR lineage in Spanish hospitals. Finally, other potentially relevant mutations were evidenced, including those in penicillin-binding protein 3 (PBP3), which is involved in ß-lactam (including ceftolozane-tazobactam) resistance, and FusA1, which is linked to aminoglycoside resistance.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Aminoglicosídeos/farmacologia , Proteínas de Bactérias/genética , Cefalosporinas/farmacologia , Fluoroquinolonas/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Epidemiologia Molecular , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Polimixinas/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Espanha/epidemiologia , Tazobactam , Resistência beta-Lactâmica/genética , beta-Lactamases/genética
6.
BMC Infect Dis ; 17(1): 11, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28056821

RESUMO

BACKGROUND: Colistin has a narrow therapeutic window with nephrotoxicity being the major dose-limiting adverse effect. Currently, the optimal doses and therapeutic plasma levels are unknown. METHODS: Prospective observational cohort study, including patients infected by colistin-susceptible P. aeruginosa treated with intravenous colistimethate sodium (CMS). Clinical data and colistin plasma levels at steady-state (Css) were recorded. The primary and secondary end points were clinical cure and 30-day all-cause mortality. RESULTS: Ninety-one patients were included. Clinical cure was observed in 72 (79%) patients. The mean (SD) Css was 1.49 (1.4) mg/L and 2.42 (1.5) mg/L (p = 0.01) in patients who achieved clinical cure and those who not, respectively. Independent risk factors for clinical failure were male sex (OR 5.88; 95% CI 1.09-31.63), APACHE II score (OR 1.15; 95% CI 1.03-1.27) and nephrotoxicity at the EOT (OR 9.13; 95% CI 95% 2.06-40.5). The 30-day mortality rate was 30.8%. Risk factors for 30-day mortality included the APACHE II score (OR 1.98; 95% CI 1-1.20), the McCabe score (OR 2.49; 95% CI 1.14-5.43) and the presence of nephrotoxicity at the end of treatment (EOT) (OR 3.8; 95% CI 1.26-11.47). CONCLUSION: In this series of patients with infections caused by XDR P. aeruginosa infections, Css is not observed to be related to clinical outcome.


Assuntos
Antibacterianos/sangue , Colistina/sangue , Farmacorresistência Bacteriana Múltipla , Infecções por Pseudomonas/sangue , Pseudomonas aeruginosa , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Disponibilidade Biológica , Colistina/administração & dosagem , Colistina/efeitos adversos , Colistina/análogos & derivados , Colistina/farmacocinética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Feminino , Humanos , Nefropatias/sangue , Nefropatias/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
7.
Int J Antimicrob Agents ; 48(6): 725-727, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28128096

RESUMO

Nephrotoxicity limits the effective use of colistin for the treatment of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections. We previously defined a steady-state colistin plasma concentration (Css) of 2.42 mg/L that predicted nephrotoxicity at end of treatment (EOT). The objective of this study was to validate this breakpoint in a prospective cohort. This was a multicentre, prospective, observational study conducted at three hospitals with a cohort of patients treated for MDR-GNB infection with colistin methanesulfonate from September 2011 until January 2015. Nephrotoxicity was evaluated at Day 7 and at EOT using the RIFLE criteria. Css values were measured and analysed using HPLC. Taking the previously defined breakpoint for colistin concentration as a criterion, patients were divided into two groups (Css, ≤2.42 mg/L vs. >2.42 mg/L). Sixty-four patients were included. Seven patients (10.9%) had a Css > 2.42 mg/L and were compared with the remaining patients. Bivariate analysis showed that patients with a Css > 2.42 mg/L were older and had a significantly higher incidence of nephrotoxicity at Day 7 and EOT. Although not statistically significant, nephrotoxicity occurred earlier in these patients (6.2 days vs. 9.2 days in patients with lower Css; P = 0.091). Multivariate analysis of nephrotoxicity showed that Css > 2.42 mg/L was the only predictive factor. Nephrotoxicity was more frequent and occurred earlier in patients with colistin plasma concentrations higher than the previously defined breakpoint (2.42 mg/L). Colistin therapeutic drug monitoring should be routinely considered to avoid reaching this toxicity threshold and potential clinical consequences.


Assuntos
Lesão Renal Aguda , Antibacterianos/efeitos adversos , Antibacterianos/análise , Colistina/análogos & derivados , Plasma/química , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Colistina/administração & dosagem , Colistina/efeitos adversos , Colistina/análise , Monitoramento de Medicamentos , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
8.
BMC Infect Dis ; 13: 380, 2013 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-23957376

RESUMO

BACKGROUND: Data regarding the most efficacious and least toxic schedules for the use of colistin are scarce. The aim of this study was to determine the incidence and the potential risk factors of colistin-associated nephrotoxicity including colistin plasma levels. METHODS: A prospective observational cohort study was conducted for over one year in patients receiving intravenous colistin methanesulfonate sodium (CMS). Blood samples for colistin plasma levels were collected immediately before (Cmin) and 30 minutes after CMS infusion (Cmax). Renal function was assessed at baseline, on day 7 and at the end of treatment (EOT). Severity of acute kidney injury (AKI) was defined by the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria. RESULTS: One hundred and two patients met the inclusion criteria. AKI related to CMS treatment on day 7 and at the end of treatment (EOT) was observed in 26 (25.5%) and 50 (49.0%) patients, respectively. At day 7, Cmin (OR, 4.63 [2.33-9.20]; P < 0.001) was the only independent predictor of AKI. At EOT, the Charlson score (OR 1.26 [1.01-1.57]; P = 0.036), Cmin (OR 2.14 [1.33-3.42]; P = 0.002), and concomitant treatment with ≥ 2 nephrotoxic drugs (OR 2.61 [1.0-6.8]; P = 0.049) were independent risk factors for AKI. When Cmin was evaluated as a categorical variable, the breakpoints that better predicted AKI were 3.33 mg/L (P < 0.001) on day 7 and 2.42 mg/L (P < 0.001) at EOT. CONCLUSIONS: When using the RIFLE criteria, colistin-related nephrotoxicity is observed in a high percentage of patients. Cmin levels are predictive of AKI. Patients who receive intravenous colistin should be closely monitored and Cmin might be a new useful tool to predict AKI.


Assuntos
Antibacterianos/sangue , Colistina/sangue , Nefropatias/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/toxicidade , Colistina/toxicidade , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Nefropatias/sangue , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Espanha/epidemiologia
11.
Crit Care ; 12(1): R10, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18237375

RESUMO

BACKGROUND: An outbreak of severe nosocomial Burkholderia cepacia infections in patients admitted to intensive care unit (ICU), including investigation of the reservoir, is described. METHODS: Over a period of 18 days, isolates of Burkholderia cepacia were recovered from different biological samples from five patients who were admitted to a multidisciplinary 18-bed intensive care unit. Isolation of B. cepacia was associated with bacteraemia in three cases, lower respiratory tract infection in one and urinary tract infection in one. Contact isolation measures were instituted; new samples from the index patients and adjacent patients were collected; and samples of antiseptics, eau de Cologne and moisturizing body milk available in treatment carts at that time were collected and cultured. RESULTS: B. cepacia was isolated from three samples of the moisturizing body milk that had been applied to the patients. Three new hermetically closed units, from three different batches, were sent for culture; two of these were positive as well. All strains recovered from environmental and biological samples were identified as belonging to the same clone by pulsed-field gel electrophoresis. The cream was withdrawn from all hospitalization units and no new cases of B. cepacia infection developed. CONCLUSION: Moisturizing body milk is a potential source of infection. In severely ill patients, the presence of bacteria in cosmetic products, even within accepted limits, may lead to severe life-threatening infections.


Assuntos
Infecções por Burkholderia/epidemiologia , Burkholderia cepacia/isolamento & purificação , Infecção Hospitalar/epidemiologia , Surtos de Doenças , Reservatórios de Doenças/microbiologia , Emolientes/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Infecções por Burkholderia/transmissão , Burkholderia cepacia/patogenicidade , Infecção Hospitalar/transmissão , Eletroforese em Gel de Campo Pulsado , Humanos , Unidades de Terapia Intensiva , Espanha/epidemiologia
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