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1.
J Antimicrob Chemother ; 79(3): 589-594, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38297994

RESUMO

OBJECTIVES: Amoxycillin/clavulanic acid is the most common antimicrobial cause of drug-induced liver injury in adults. It is a less common cause of severe drug-related hepatotoxicity in children despite its frequent use. We studied the incidence, characteristics and predictive factors for amoxycillin/clavulanic acid hepatoxicity in children. DESIGN: Retrospective cohort study of children who received oral or intravenous amoxycillin/clavulanic acid at a quaternary children's hospital over a 5-year period. Children were included if they had liver function tests (LFTs) determined at baseline, during and within 3 months after the treatment course. Causality was assessed using the Naranjo criteria for adverse drug reactions and Roussel Uclaf Causality Assessment Method. RESULTS: Of 3271 children prescribed amoxycillin/clavulanic acid, 374 were included. Forty-nine (13%) had LFT abnormalities related to amoxycillin/clavulanic acid. Fourteen (3.6%) fulfilled Common Terminology Criteria for Adverse Events (CTCAE) grade 2 criteria with clinically significant hepatotoxicity. Age <2 years, sepsis, post-gastrointestinal surgical indications, prolonged treatment course of >7 days and higher cumulative amoxycillin (>10 g) and clavulanic acid dose (>1 g) were predictive of hepatotoxicity. The median time to resolution of LFT abnormalities was 4 weeks (range 3-7). CONCLUSIONS: The incidence of amoxycillin/clavulanic acid related LFT abnormalities (CTCAE Grade 2 or above) in children was 3.6%. A prolonged treatment course >7 days, high cumulative amoxycillin (10 g) and clavulanic acid (>1 g) doses, those aged <2 years, and patients with sepsis or post-gastrointestinal surgery were predictive of a higher likelihood of abnormal LFTs. LFT monitoring should be considered in children receiving ≥7 days of treatment, particularly in those with other predisposing factors.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Sepse , Adulto , Criança , Humanos , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Ácidos Clavulânicos/efeitos adversos , Incidência , Estudos Retrospectivos , Quimioterapia Combinada , Austrália/epidemiologia , Amoxicilina/farmacologia , Ácido Clavulânico/efeitos adversos , Sepse/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hospitais
2.
ACS Appl Bio Mater ; 5(8): 3826-3840, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35819369

RESUMO

Antimicrobial resistance (AMR) is one of the major threats to modern healthcare. Many types of bacteria have developed resistance to multiple antibiotic treatments, while additional antibiotics have not been recently brought to market. One approach to counter AMR based on the beta-lactamase enzyme has been to use cotreatments of an antibiotic and an inhibitor, to enhance the antibiotic action. Here, we aimed to enhance this technique by developing nanocarriers of two cationic beta-lactam class antibiotics, amoxicillin, and ticarcillin, combined with a beta-lactamase inhibitor, clavulanic acid, which can potentially overcome this type of AMR. We demonstrate for the first time that beta-lactamase inhibitor-loaded nanocarriers in cotreatments with either free or nanocarrier-loaded beta-lactam antibiotics can enhance their effectiveness further than when used alone. We use surface-functionalized shellac-/Poloxamer 407-stabilized antibiotic nanocarriers on Pseudomonas aeruginosa, which is susceptible to ticarcillin but is resistant to amoxicillin. We show an amplification of the antibiotic effect of amoxicillin and ticarcillin loaded in shellac nanoparticles, both alone and as a cotreatment with free or nanocarrier-loaded clavulanic acid. We also report a significant increase in the antimicrobial effects of clavulanic acid loaded in such nanocarriers as a cotreatment. We explain the increased antimicrobial activity of the cationically functionalized antibiotic-loaded nanoparticles with electrostatic attraction to the bacterial cell wall, which delivers higher local antibiotic and inhibitor concentrations. The effect is due to the accumulation of the clavulanic acid-loaded nanocarriers on the bacterial cell walls that allows a higher proportion of the inhibitor to engage with the produced intracellular beta-lactamases. These nanocarriers were also found to have a very low cytotoxic effect against human keratinocytes, which shows great potential for overcoming enzyme-based AMR.


Assuntos
Antibacterianos , Ticarcilina , Amoxicilina/farmacologia , Antibacterianos/farmacologia , Bactérias , Ácido Clavulânico/farmacologia , Ácidos Clavulânicos/farmacologia , Farmacorresistência Bacteriana , Humanos , Ticarcilina/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/farmacologia
3.
Diagn Microbiol Infect Dis ; 100(2): 115343, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33652305

RESUMO

Minimal inhibitory concentrations (MICs) of ticarcillin/clavulanic acid (TLc), ceftolozane/tazobactam (C/T), and aztreonam (AT) were determined for 6 SPM-1-producing Pseudomonas aeruginosa (PSA) using Etest® strips and the synergistic effect of such antimicrobials against was evaluated by gradient diffusion strip crossing (GDSC) test. The fraction inhibitory concentration indexes (FICI) were calculated and showed a synergistic (n = 3) and additive (n = 2) effects of TLc + AT against SPM-1 producers, while TLc + C/T combination caused no effect. Average MIC reduction of TLc and AT by GDSC was 3-fold and 2-fold dilutions, respectively. Thus, TLc + AT might be a candidate as a combination therapy to treat SPM-1-producing PSA infections.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , beta-Lactamases/metabolismo , Aztreonam/administração & dosagem , Aztreonam/farmacologia , Cefalosporinas/farmacologia , Ácidos Clavulânicos/administração & dosagem , Ácidos Clavulânicos/farmacologia , Sinergismo Farmacológico , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Tazobactam/farmacologia , Ticarcilina/administração & dosagem , Ticarcilina/farmacologia , beta-Lactamases/genética
4.
Medicine (Baltimore) ; 99(8): e19250, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080131

RESUMO

Stenotrophomonas maltophilia (S. maltophilia) is an important nosocomial bacterial pathogen. However, the clinical features of children with S. maltophilia infection, the predisposing factors, and the antibiotic susceptibility of the bacteria have not been fully evaluated.In this study, the data of children with S. maltophilia infection from the West China Second University Hospital of Sichuan University (Chengdu, China) between July 2010 and October 2017 were collected and analyzed. The clinical features of enrolled children, the predisposing factors, and the antibiotic susceptibility were reported.In total, infection of S. maltophilia was identified in 128 patients. Most of these patients were under 1 year old (67.2%) and were mainly diagnosed as pneumonia (69%). A large proportion had underlying diseases (45.3%), received immunosuppressive therapy (53.1%), had undergone invasive operations (41.4%), had a history of carbapenem antibiotics use within 7 days before culture acquisition (54.7%), history of intensive care unit (ICU) hospitalization within previous 30 days (34.4%), and other risk factors. In particular, invasive operation (95% confidence interval [CI]: 1.125-14.324, P = .032), especially mechanical ventilation (95% CI: 1.277-20.469, P = .021), and ICU admission (95% CI: 1.743-22.956, P = .005) were independent risk factors for the children to develop severe S. maltophilia infection. As for antibiotic susceptibility, trimethoprim sulfamethoxazole (TMP-SMX), piperacillin tazobactam, ticarcillin clavulanate, and ceftazidime exhibited strong antibacterial activities against S. maltophilia, the susceptibility rates were 97.5%, 86.7%, 92.9%, and 81.5%, respectively.We report the clinical features of children with S. maltophilia infection, the predisposing factors and the antibiotic susceptibility. TMP-SMX can continue to be the first choice for the treatment of S. maltophilia infection. Piperacillin tazobactam, ticarcillin clavulanate, and the third generation cephalosporins can be used as alternative drugs.


Assuntos
Infecções por Bactérias Gram-Negativas/epidemiologia , Stenotrophomonas maltophilia , Distribuição por Idade , Antibacterianos/uso terapêutico , Carbapenêmicos/uso terapêutico , Ceftazidima/uso terapêutico , Pré-Escolar , China/epidemiologia , Ácidos Clavulânicos/uso terapêutico , Comorbidade , Feminino , Infecções por Bactérias Gram-Negativas/diagnóstico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Humanos , Imunossupressores/uso terapêutico , Lactente , Unidades de Terapia Intensiva Pediátrica , Tempo de Internação/estatística & dados numéricos , Masculino , Combinação Piperacilina e Tazobactam/uso terapêutico , Respiração Artificial/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Ticarcilina/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
5.
Med Mal Infect ; 50(3): 305-307, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32014291

RESUMO

OBJECTIVE: To compare the minimum inhibitory concentrations (MIC) of the ceftazidime-avibactam (CZA) combination versus ceftazidime alone (TZ) for Stenotrophomonas maltophilia. PATIENTS AND METHODS: MIC comparison was performed by E-tests. We assumed that CZA was more effective in vitro than TZ alone when CZA led to a category change from "Resistant" with TZ alone to "Susceptible" or "Intermediate" with CZA, or if the MIC of CZA was at least 4-fold lower than the MIC of TZ for TZ-susceptible isolates. RESULTS: For the 54 clinical isolates included in the study, CZA showed better results in terms of the proportion of susceptible isolates (66.7% vs. 38.9%, P<0.01), MIC50 (2µg/mL vs. 12µg/mL, P<0.05), and MIC distribution. According to our definition, CZA was also more effective in vitro than TZ alone for 50% of the isolates. CONCLUSION: Using CZA for empirical treatments in severe or polymicrobial infections with S. maltophilia seems appropriate.


Assuntos
Compostos Azabicíclicos/farmacologia , Ceftazidima/farmacologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Stenotrophomonas maltophilia/efeitos dos fármacos , Ácidos Clavulânicos/farmacologia , Fibrose Cística/complicações , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana , Estudos Multicêntricos como Assunto , Ticarcilina/farmacologia
6.
Vet Microbiol ; 241: 108553, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31928700

RESUMO

The objectives of this work were to evaluate ß-lactamase-mediated ß-lactam resistance in Campylobacter coli and Campylobacter jejuni isolates obtained from broiler chickens, expression of the blaOXA-61 gene in relation to ß-lactamase production, and the possible association between blaOXA-61 gene expression and the action of inhibitors when combined with ß-lactams. All strains were tested by disk diffusion and nitrocefin methods to assess antibiotic susceptibility and ß-lactamase production, respectively. PCR and qPCR amplification were performed to evaluate qualitative and quantitative blaOXA-61 expression. Campylobacter spp. showed a high level of resistance to the most of antimicrobials tested. C. coli strains were ampicillin resistant and blaOXA-61 positive, and 59 out of 60 isolates were positive in the nitrocefin test. Twenty C. jejuni isolates were positive for blaOXA-61 and the nitrocefin test, although two isolates were ampicillin sensitive. Amoxicillin/clavulanic acid and ticarcillin/clavulanic acid do not seem to be active against C. coli, as 73.3 %, and 88.3 % of isolates were resistant to amoxicillin/clavulanic acid and ticarcillin/clavulanic acid, respectively. C. jejuni was not susceptible to amoxicillin/clavulanic acid, with 90 % of the strains showing resistance, whereas ticarcillin associated with clavulanic acid was significantly more efficient than ticarcillin alone (P < 0.01), with 90 % of the strains found to be susceptible. An association between blaOXA-61 expression and amoxicillin/clavulanic acid and ticarcillin/clavulanic acid resistance (P = 0.0001) was seen in C. coli, as well as in C. jejuni for ampicillin/sulbactam (P = 0.0001). Our results suggest that the clavulanic acid only shows an inhibitory effect on C. jejuni when combined with ticarcillin and that the inhibitors action is lower if the blaOXA-61 gene is highly expressed.


Assuntos
Antibacterianos/farmacologia , Campylobacter coli/efeitos dos fármacos , Campylobacter jejuni/efeitos dos fármacos , Resistência beta-Lactâmica , Inibidores de beta-Lactamases/farmacologia , Algoritmos , Resistência a Ampicilina , Animais , Campylobacter coli/genética , Campylobacter coli/isolamento & purificação , Campylobacter jejuni/genética , Campylobacter jejuni/isolamento & purificação , Galinhas , Ácidos Clavulânicos/farmacologia , Cloaca/microbiologia , Expressão Gênica , RNA Bacteriano/química , RNA Bacteriano/isolamento & purificação , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Ticarcilina/farmacologia , beta-Lactamases/genética , beta-Lactamases/metabolismo
7.
Surg Infect (Larchmt) ; 21(3): 284-292, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31770083

RESUMO

Background: Empirical antibiotherapy (EA) should target all bacteria in post-operative peritonitis (PP). Nevertheless, recent studies failed to prove a link between adequacy of EA and prognosis of PP. We sought to confirm this loss of association between adequate EA and prognosis and to analyze the evolution of patients' characteristics and antimicrobial strategies. Methods: This is was retrospective study. Patients with a positive fungal culture were excluded. The cohort was divided into two time periods. Data of survivors and non-survivors were compared within each time period. Differences between the two periods were assessed. A multivariable analysis searched for parameters associated with a higher hospital mortality rate. Results: Two hundred fifty-one patients were included, with 92 patients in the first period (P1) and 152 patients in the second period (P2). Inadequate EA was associated with a worse outcome only in P1. The multivariable analysis in the whole cohort showed that inadequate EA was associated with a higher mortality rate. When the differences noticed between the two periods were entered in the model (presence of resistant gram-positive cocci and EA comprising glycopeptides), inadequate EA was no longer associated with worse outcome. In P1, the most severe patients had more resistant bacteria, hence, had a higher rate of inadequate EA. This artifact disappeared in P2, during which broader antibiotherapies with triple EA were more often prescribed for the most severe patients. Conclusion: This study showed that the link between inadequate EA and outcome of patients with PP was at least partly artifactual in older studies.


Assuntos
Antibacterianos/uso terapêutico , Procedimentos Cirúrgicos do Sistema Digestório , Mortalidade Hospitalar , Peritonite/tratamento farmacológico , Infecção da Ferida Cirúrgica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoglicosídeos/uso terapêutico , Fístula Anastomótica , Líquido Ascítico/microbiologia , Ácidos Clavulânicos/uso terapêutico , Estudos de Coortes , Técnicas de Cultura , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Farmacorresistência Bacteriana Múltipla , Feminino , Fluoroquinolonas/uso terapêutico , Humanos , Imipenem/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Análise Multivariada , Peritonite/microbiologia , Combinação Piperacilina e Tazobactam/uso terapêutico , Complicações Pós-Operatórias , Prognóstico , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/microbiologia , Ticarcilina/uso terapêutico , Resultado do Tratamento , Vancomicina/uso terapêutico
8.
Thorax ; 74(8): 740-748, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31203197

RESUMO

BACKGROUND: While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown. AIM: To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years. METHODS: Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years. RESULTS: Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event. CONCLUSION: In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/complicações , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/epidemiologia , Pseudomonas aeruginosa , Aspergilose Pulmonar/epidemiologia , Antibacterianos/administração & dosagem , Lavagem Broncoalveolar , Ceftazidima/uso terapêutico , Pré-Escolar , Ciprofloxacina/uso terapêutico , Ácidos Clavulânicos/uso terapêutico , Estudos Transversais , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Prevalência , Aspergilose Pulmonar/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Fatores de Risco , Ticarcilina/uso terapêutico , Tobramicina/uso terapêutico
9.
Int J Antimicrob Agents ; 54(2): 261-264, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30904466

RESUMO

There are very limited data on ticarcillin-clavulanate elimination by haemofiltration. We measured in vitro ticarcillin-clavulanate adsorption to polyacrylonitrile (PAN) filters and the sieving coefficient using a well-described bench model of haemofiltration. The dose of ticarcillin-clavulanate was 60/2 mg or 180/3 mg, and 0 or 12 g albumin was added to the 1 L of circulating blood-crystalloid mixture to produce four different experimental conditions. The experiment was repeated four times under each condition. Median (interquartile range [IQR] ) ticarcillin adsorption varied from 28 (27-30) mg to 85 (78-90) mg. Adsorption was increased when the dose of ticarcillin was higher (P<0.001), but was not affected by the addition of albumin. Median (IQR) adsorption of clavulanate ranged from 0.67 (0.55-0.75) mg to 1.8 (0.33-3.5) mg and was neither dose dependent (P = 0.505) nor significantly affected by the addition of albumin. Median (IQR) ticarcillin sieving coefficient ranged from 0.73 (0.67-0.75) to 0.99 (0.97-1.03). It was significantly higher with a higher dose of ticarcillin (P = 0.021) and without addition of albumin (P = 0.015). Median (IQR) clavulanate sieving coefficient ranged from 1.03 (1.00-2.24) to 2.0 (1.98-2.47). Clavulanate sieving coefficient was not significantly affected by dose or the addition of albumin. These data indicate that significant adsorption of both ticarcillin and clavulanate occurs in vitro; however, this requires confirmation by clinical pharmacokinetic studies. The sieving coefficient data may help guide appropriate dosing of critically ill patients receiving haemofiltration until more extensive clinical pharmacokinetic data are available.


Assuntos
Adsorção , Antibacterianos/farmacocinética , Hemofiltração/métodos , Inibidores de beta-Lactamases/farmacocinética , Resinas Acrílicas/química , Antibacterianos/sangue , Ácidos Clavulânicos/sangue , Ácidos Clavulânicos/farmacocinética , Humanos , Técnicas In Vitro , Ticarcilina/sangue , Ticarcilina/farmacocinética , Inibidores de beta-Lactamases/sangue
10.
Br J Clin Pharmacol ; 85(5): 1021-1027, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30710387

RESUMO

Ticarcillin-clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants <30 weeks gestational age, pharmacokinetic data to guide ticarcillin-clavulanate dosing are lacking. We enrolled 15 premature infants <30 weeks gestational age, determined pharmacokinetic parameters, and performed dosing simulations to determine optimal dosing for ticarcillin-clavulanate. The infants had a median (range) postnatal age (PNA) of 18 days (6-44 days) and gestational age of 25 weeks (23-28 weeks). Clearance was lower in infants with a PNA <14 days (0.050 L/kg/h [range 0.043-0.075]) compared with a PNA ≥14-45 days (0.078 L/kg/h [0.047-0.100]), consistent with maturation of renal function. Dosing simulations determined that ticarcillin 75 mg/kg q12h (PNA <14 days) or q8h (PNA ≥ 14-45 days) achieved the target exposure for organisms with a minimum inhibitory concentration ≤16 µ/mL in >90% of simulated infants. For highly resistant organisms (minimum inhibitory concentration 32 µg/mL), increased dosing frequency or extended infusion are necessary.


Assuntos
Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacocinética , Ácidos Clavulânicos/administração & dosagem , Ácidos Clavulânicos/farmacocinética , Simulação por Computador , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Modelos Biológicos , Estudos Prospectivos , Infecções Estafilocócicas/microbiologia , Staphylococcus/fisiologia , Ticarcilina/administração & dosagem , Ticarcilina/farmacocinética , Inibidores de beta-Lactamases/administração & dosagem
11.
Appl Environ Microbiol ; 84(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30194098

RESUMO

The oppA2 gene encodes an oligopeptide-binding protein similar to the periplasmic substrate-binding proteins of the ABC transport systems. However, oppA2 is an orphan gene, not included in an ABC operon. This gene is located in the clavulanic acid (CA) gene cluster of Streptomyces clavuligerus and is essential for CA production. A transcriptomic study of the oppA2-null mutant S. clavuligerus ΔoppA2::aac showed changes in the expression levels of 233 genes from those in the parental strain. These include genes for ABC transport systems, secreted proteins, peptidases, and proteases. Expression of the clavulanic acid, clavam, and cephamycin C biosynthesis gene clusters was not significantly affected in the oppA2 deletion mutant. The genes for holomycin biosynthesis were upregulated 2-fold on average, and the level of upregulation increased to 43-fold in a double mutant lacking oppA2 and the pSCL4 plasmid. Strains in which oppA2 was mutated secreted into the culture the compound N-acetylglycyl-clavaminic acid (AGCA), a putative intermediate of CA biosynthesis. A culture broth containing AGCA, or AGCA purified by liquid chromatography-mass spectrometry (LC-MS), was added to the cultures of various non-CA-producing mutants. Mutants blocked in the early steps of the pathway restored CA production, whereas mutants altered in late steps did not, establishing that AGCA is a late intermediate of the biosynthetic pathway, which is released from the cells when the oligopeptide-binding protein OppA2 is not available.IMPORTANCE The oppa2 gene encodes an oligopeptide permease essential for the production of clavulanic acid. A transcriptomic analysis of S. clavuligerus ΔoppA2::aac in comparison to the parental strain S. clavuligerus ATCC 27064 is reported. The lack of OppA2 results in different expression of 233 genes, including genes for proteases and genes for transport systems. The expression of the clavulanic acid genes in the oppA2 mutant is not significantly affected, but the genes for holomycin biosynthesis are strongly upregulated, in agreement with the higher holomycin production by this strain. The oppA2-mutant is known to release N-acetylglycyl-clavaminic acid to the broth. Cosynthesis assays using non-clavulanic acid-producing mutants showed that the addition of pure N-acetylglycyl-clavaminic acid to mutants in which clavulanic acid formation was blocked resulted in the recovery of clavulanic acid production, but only in mutants blocked in the early steps of the pathway. This suggests that N-acetylglycyl-clavaminic acid is a previously unknown late intermediate of the clavulanic acid pathway.


Assuntos
Proteínas de Bactérias/genética , Ácido Clavulânico/biossíntese , Proteínas de Membrana Transportadoras/genética , Deleção de Sequência , Streptomyces/enzimologia , Streptomyces/metabolismo , Transcrição Gênica , Proteínas de Bactérias/metabolismo , Ácido Clavulânico/química , Ácidos Clavulânicos/metabolismo , Regulação Bacteriana da Expressão Gênica , Proteínas de Membrana Transportadoras/metabolismo , Família Multigênica , Óperon , Streptomyces/genética
12.
Electron. j. biotechnol ; 32: 41-46, Mar. 2018. tab, ilus, graf
Artigo em Inglês | LILACS | ID: biblio-1022633

RESUMO

Background: In view of the current low efficacy of bacterial infection treatment the common trend towards searching for antibiotic systems exhibiting synergistic action is well justified. Among carbapenem analogues a particularly interesting option is provided by combinations of clavulanic acid with meropenem, which have proven to be especially effective. Results: Determination of the minimal inhibitory concentration (MIC) along with the method based on flow cytometry constitutes an important tool in the identification of bacterial sensitivity to active substances. Within this study the inhibitory effect of doripenem, clavulanic acid and the doripenem-clavulanate acid system was analyzed in relation to such bacteria as Salmonella enteritidis, Salmonella typhimurium, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Clostridium butyricum and Clostridium pasteurianum, Acinetobacter baumannii, Enterobacter aerogenes. The lowest MIC, amounting to 0.03 µg/mL, was observed for the doripenem-clavulanate acid system in the case of E. coli ATCC 25922. In turn, the lowest MIC for doripenem applied alone was recorded for K. pneumoniae ATCC 31488, for which it was 0.1 µg/mL. The strain which proved to be most resistant both to doripenem and the doripenem-clavulanate acid system, was A. baumannii, with MIC of 32 µg/mL (clinical isolate) and 16 µg/mL (reference strain). Cytometric analysis for P. aeruginosa ATCC 27853 and S. aureus ATCC 25923 showed changes in cells following exposure to limiting concentrations of the active substance. Conclusions: Analysis of MIC supplies important information concerning microbial sensitivity to active substances, mainly in terms of limiting concentrations causing mortality or vitality of the tested species, which is essential when selecting appropriate antibiotic therapy.


Assuntos
Bactérias/efeitos dos fármacos , Ácidos Clavulânicos/farmacologia , Doripenem/farmacologia , Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Salmonella/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Clostridium/efeitos dos fármacos , Interações Medicamentosas , Citometria de Fluxo , Klebsiella pneumoniae/efeitos dos fármacos
13.
Artigo em Inglês | MEDLINE | ID: mdl-28607010

RESUMO

A novel algorithm designed for the screening of carbapenemase-producing Enterobacteriaceae (CPE), based on faropenem and temocillin disks, was compared to that of the Committee of the Antibiogram of the French Society of Microbiology (CA-SFM), which is based on ticarcillin-clavulanate, imipenem, and temocillin disks. The two algorithms presented comparable negative predictive values (98.6% versus 97.5%) for CPE screening among carbapenem-nonsusceptible Enterobacteriaceae However, since 46.2% (n = 49) of the CPE were correctly identified as OXA-48-like producers by the faropenem/temocillin-based algorithm, it significantly decreased the number of complementary tests needed (42.2% versus 62.6% with the CA-SFM algorithm).


Assuntos
Algoritmos , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Enterobacteriáceas Resistentes a Carbapenêmicos/enzimologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão/métodos , Imipenem/farmacologia , Penicilinas/farmacologia , beta-Lactamases/metabolismo , beta-Lactamas/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacteriáceas Resistentes a Carbapenêmicos/metabolismo , Ácidos Clavulânicos/farmacologia , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Humanos , Ticarcilina/farmacologia
14.
Int J Infect Dis ; 58: 18-21, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28257816

RESUMO

OBJECTIVES: The aim of this study was to evaluate the in vitro effects and clinical efficacies of trimethoprim-sulfamethoxazole (SXT) combined with other antimicrobial agents against Stenotrophomonas maltophilia. METHODS: In vitro analysis was conducted on 89 S. maltophilia strains isolated from blood and the respiratory tract between June 2012 and October 2014. Levofloxacin (LVX), ticarcillin-clavulanic acid (TIM), and minocycline (MIN) were selected for an examination of their effects when individually combined with SXT by the checkerboard method. In addition, 29 S. maltophilia bacteremia cases were reviewed and the clinical efficacies of SXT-based combination therapies were analyzed. RESULTS: SXT+LVX showed synergy in 21, no interactions in 61, and antagonism in 7. SXT+TIM showed synergy in 71, and no interactions in 18. SXT+MIN showed synergy in 10, and no interactions in 79. The review of clinical data indicated that a combination of SXT+fluoroquinolone was not associated with improved prognosis compared with monotherapy. CONCLUSIONS: The in vitro data indicated that SXT+TIM had beneficial microbiological effects and was not antagonistic. Our in vitro and clinical data analyses do not support the routine use of SXT+fluoroquinolone combination therapy for S. maltophilia infection.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Neoplasias/complicações , Stenotrophomonas maltophilia , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Idoso , Bacteriemia/tratamento farmacológico , Ácidos Clavulânicos , Quimioterapia Combinada , Feminino , Fluoroquinolonas/uso terapêutico , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Levofloxacino/uso terapêutico , Masculino , Pessoa de Meia-Idade , Minociclina/uso terapêutico , Neoplasias/tratamento farmacológico , Stenotrophomonas maltophilia/isolamento & purificação , Ticarcilina , Resultado do Tratamento
15.
BMC Infect Dis ; 17(1): 78, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28095794

RESUMO

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) are difficult to identify among carbapenem non-susceptible Enterobacteriaceae (NSE). We designed phenotypic strategies giving priority to high sensitivity for screening putative CPE before further testing. METHODS: Presence of carbapenemase-encoding genes in ertapenem NSE (MIC > 0.5 mg/l) consecutively isolated in 80 French laboratories between November 2011 and April 2012 was determined by the Check-MDR-CT103 array method. Using the Mueller-Hinton (MH) disk diffusion method, clinical diameter breakpoints of carbapenems other than ertapenem, piperazicillin+tazobactam, ticarcillin+clavulanate and cefepime as well as diameter cut-offs for these antibiotics and temocillin were evaluated alone or combined to determine their performances (sensitivity, specificity, positive and negative likelihood ratios) for identifying putative CPE among these ertapenem-NSE isolates. To increase the screening specificity, these antibiotics were also tested on cloxacillin-containing MH when carbapenem NSE isolates belonged to species producing chromosomal cephalosporinase (AmpC) but Escherichia coli. RESULTS: Out of the 349 ertapenem NSE, 52 (14.9%) were CPE, including 39 producing OXA-48 group carbapenemase, eight KPC and five MBL. A screening strategy based on the following diameter cut offs, ticarcillin+clavulanate <15 mm, temocillin <15 mm, meropenem or imipenem <22 mm, and cefepime <26 mm, showed 100% sensitivity and 68.1% specificity with the better likelihood ratios combination. The specificity increased when a diameter cut-off <32 mm for imipenem (76.1%) or meropenem (78.8%) further tested on cloxacillin-containing MH was added to the previous strategy for AmpC-producing isolates. CONCLUSION: The proposed strategies that allowed for increasing the likelihood of CPE among ertapenem-NSE isolates should be considered as a surrogate for carbapenemase production before further CPE confirmatory testing.


Assuntos
Algoritmos , Proteínas de Bactérias/análise , Carbapenêmicos/metabolismo , Farmacorresistência Bacteriana , Enterobacteriaceae/metabolismo , beta-Lactamases/análise , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Carbapenêmicos/farmacologia , Cefepima , Cefalosporinas/farmacologia , Ácidos Clavulânicos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Enterobacteriaceae/fisiologia , Ertapenem , Humanos , Imipenem/metabolismo , Imipenem/farmacologia , Meropeném , Testes de Sensibilidade Microbiana , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Penicilinas/farmacologia , Tazobactam , Tienamicinas/metabolismo , Tienamicinas/farmacologia , Ticarcilina/farmacologia , beta-Lactamases/metabolismo , beta-Lactamas/metabolismo , beta-Lactamas/farmacologia
16.
Transplant Proc ; 48(5): 1411-3, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27496417

RESUMO

BACKGROUND: Blood infections with multidrug-resistant Gram-negative carbapenem-resistant bacilli are particularly dangerous and challenging to treat in organ transplant recipients. Resistance to carbapenems may be acquired, for example, in Enterobacteriaceae, Pseudomonas, or Acinetobacter spp. or innate, for example, in Stenotrophomonas maltophilia. The purpose of this study was to analyze blood infections caused by S maltophilia in organ transplant recipients and to compare drug susceptibility of these bacteria and the same species isolated from the blood of other inpatients. METHODS: A total of 26 S maltophilia strains isolated from blood samples of 26 patients (including 14 liver or kidney transplant recipients) hospitalized during 2011 to 2014 were evaluated in this study. Antibiotic susceptibility was determined via E-test and disk diffusion methods. RESULTS: Stenotrophomonas maltophilia strains isolated from blood exhibited sensitivity to trimethoprim/sulfamethoxazole (100%), levofloxacin (96.2%), ciprofloxacin (92.3%), ticarcillin/clavulanic acid (80.8%), and ceftazidime (53.9%). CONCLUSIONS: Because appropriate antibiotic therapy in the case of S maltophilia differs from the standard empirical therapy administered in the case of most other Gram-negative bacilli, early identification of this pathogen is of particular significance. The use of antibiotics to which this pathogen is sensitive eliminates the infection and helps avoid graft loss.


Assuntos
Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Testes de Sensibilidade Microbiana , Transplante de Órgãos/efeitos adversos , Antibacterianos/uso terapêutico , Ceftazidima/uso terapêutico , Ciprofloxacina/uso terapêutico , Ácidos Clavulânicos/uso terapêutico , Farmacorresistência Bacteriana , Hospitais de Ensino , Humanos , Levofloxacino/uso terapêutico , Stenotrophomonas maltophilia , Ticarcilina/uso terapêutico , Transplantados/estatística & dados numéricos , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
17.
Pediatr Emerg Care ; 32(3): 154-6, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26928094

RESUMO

The treatment of acute hematogenous osteomyelitis has evolved in recent years to a shorter parenteral treatment with an early switch to the oral route. Current publications recommend a 2- to 4-day parenteral treatment before the oral switch. We retrospectively analyzed a series of 45 children aged 1 to 11 years and treated in our department for acute osteomyelitis without severity criterion. Nineteen of 45 patients were treated by an exclusive ambulatory oral treatment by amoxicillin and clavulanic acid. Twenty six of 45 patients had a 2- to 4-day parenteral treatment before the oral switch. The minimum follow-up was 6 months. The primary endpoint was a clinical, radiographic, and biologic healing, 6 months after the beginning of the treatment. The secondary endpoints evaluated were the length of hospitalization, the total duration of treatment, and the type of antibiotic used. On the primary endpoint, we did not find any significant difference between the 2 treatments (P = 0.38). On the duration of treatment, we found a significant difference (P = 0.049) in favor of oral treatment. The ambulatory oral treatment by amoxicillin and clavulanic acid seems to be a valid alternative to the classical parenteral then oral sequence in the treatment of acute hematogenous osteomyelitis in children without severity criterion.


Assuntos
Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Ácidos Clavulânicos/administração & dosagem , Osteomielite/tratamento farmacológico , Administração Oral , Assistência Ambulatorial , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Infusões Parenterais , Masculino , Estudos Retrospectivos , Resultado do Tratamento
18.
Can J Microbiol ; 62(3): 233-40, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26854365

RESUMO

We investigated a collection of Pseudomonas aeruginosa strains from hospitalised patients (n = 20) and various environmental sources (n = 214) for their genetic relatedness; virulence properties; antibiotic resistance; and interaction with intestinal (Caco-2), renal (A-498), and lung (Calu-3) cell lines. Using RAPD-PCR, we found high diversity among the strains irrespective of their sources, with only 6 common (C) types containing strains from both a clinical and environmental source. Environmental strains belonging to these C-types showed greater adhesion to A-498 cells than did clinical strains (17 ± 13 bacteria/cell versus 13 ± 11 bacteria/cell; p < 0.001), whereas clinical strains showed significantly greater adhesion to Calu-3 and Caco-2 cells than did environmental strains (p < 0.001 for both). The virulence genes and antibiotic resistance profiles of the strains were similar; however, the prevalence of environmental strains carrying both exoS and exoU was significantly (p < 0.0368) higher than clinical strains. While all strains were resistant to ticarcillin and ticarcillin-clavulanic acid, resistance against aztreonam, gentamicin, amikacin, piperacillin, and ceftazidime varied among environmental and clinical strains. These results suggest that environmental strains of P. aeruginosa carry virulence properties similar to clinical strains, including adhesion to various human cell lines, with some strains showing a higher adhesion to specific cell lines, indicating they may have a better ability to cause infection in those sites under predisposing conditions of the host.


Assuntos
Pseudomonas aeruginosa/genética , Antibacterianos/farmacologia , Células CACO-2 , Ácidos Clavulânicos/farmacologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Microbiologia Ambiental , Humanos , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Técnica de Amplificação ao Acaso de DNA Polimórfico , Ticarcilina/farmacologia , Virulência/efeitos dos fármacos
19.
Mater Sci Eng C Mater Biol Appl ; 49: 500-508, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25686977

RESUMO

A facile one-step approach is developed to synthesize highly stable (up to 6months) gold nanoparticles (GNPs) using Clavam, pharmaceutical form of amoxicillin which contains a mixture of amoxicillin and potassium salt of clavulanic acid, at room temperature (25-30°C). The clavam stabilized GNPs are characterized using various techniques including UV-Visible, FT-IR spectrophotometry and transmission electron microscopy (TEM). Tunable release of clavam from clavam stabilized GNPs is demonstrated using intracellular concentrations of glutathione (GSH). The process is monitored using an UV-Vis spectroscopy and the amount of clavam released in terms of amoxicillin concentration is quantitatively estimated using reverse phase high performance liquid chromatographic (RP-HPLC) technique. In vitro study reveals that the clavam released from GNPs' surface was found to show a significant enhancement in antibacterial activity against Escherichia coli and the cause of enhancement is addressed.


Assuntos
Anti-Infecciosos/administração & dosagem , Ácidos Clavulânicos/administração & dosagem , Ouro/química , Nanopartículas Metálicas , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Linhagem Celular Tumoral , Ácidos Clavulânicos/química , Ácidos Clavulânicos/farmacocinética , Humanos , Microscopia Eletrônica de Transmissão , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Clin Infect Dis ; 60(2): 203-7, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25301207

RESUMO

BACKGROUND: A series of cases of piperacillin-tazobactam (P/T)-associated neutropenia has been observed recently in children in our center. Because neutropenia was seldom observed in children treated with ticarcillin-clavulanic acid (T/C), we conducted a study to determine if there is an increased risk of neutropenia in children exposed to P/T in comparison with T/C. METHODS: Medical records of subjects aged <18 years who received at least 1 dose of P/T or T/C between 1 January 2008 and 30 June 2011 were reviewed. RESULTS: Two hundred ninety-nine episodes of treatment (65 P/T, 234 T/C) met inclusion criteria. Among those episodes, 213 had data allowing complete white blood cell count analysis and were included in the final analysis. Thirteen cases of neutropenia were observed during the study period. The average time to onset was 17.6 days and all patients were aged <13 years. Seven cases (10.8%) occurred in the P/T group and 6 (2.6%) in the T/C group (unadjusted odds ratio, 4.59; 95% confidence interval, 1.48-14.17). Although a statistically significant correlation was observed between age, treatment duration, and total dose and the development of neutropenia (r = -0.121, P = .037; r = 0.267, P < .001; r = 0.260, P < .001, respectively), this was not the case for sex, indications, neutrophil count at initiation, and concomitant drug treatments. CONCLUSIONS: Although our results need to be confirmed, they suggest that children receiving long courses of therapy (>2 weeks) with P/T may be at increased risk of neutropenia, compared with T/C.


Assuntos
Antibacterianos/efeitos adversos , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Ácido Penicilânico/análogos & derivados , Adolescente , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Ácidos Clavulânicos/efeitos adversos , Ácidos Clavulânicos/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Ácido Penicilânico/efeitos adversos , Ácido Penicilânico/uso terapêutico , Piperacilina/efeitos adversos , Piperacilina/uso terapêutico , Combinação Piperacilina e Tazobactam , Estudos Retrospectivos , Medição de Risco , Ticarcilina/efeitos adversos , Ticarcilina/uso terapêutico
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