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1.
Pathog Dis ; 79(6)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34143186

RESUMO

Bacterial infection may have a pathophysiological role in refractory Detrusor Overactivity (DO). The aim of this study was to observe any impact of antibiotic therapy upon bacterial colonization of urothelial cells, and to determine whether a relationship existed between colonization and symptom severity. Mid-stream urine samples were collected as part of a clinical trial of antibiotics in women with refractory DO. Wright stained urothelial cells were categorized according to the degree of bacterial colonization as; 'clear' (free of bacteria), or as associated with bacteria that were 'adjacent' to the cell or 'intracellular' at low or high density. The average percentages were compared with routine microbiology cultures, over the 26 week trial, and with patient clinical outcome measures of DO severity. In patients receiving placebo, 'high-density intracellular bacteria' significantly increased during urinary tract infection (P = 0.0008). In antibiotic patients, 'clear' cells were more prevalent. Amoxicillin & Clavulanic Acid significantly decreased bacterial colonization within urothelial cells, suggesting that these antibiotics possess the greatest intracellular efficacy. 'High-density intracellular bacteria' positively correlated with symptom severity, measured by leakage on pad test (P = 0.014), leaks per day (P = 0.004), and voids per day (P = 0.005). Thus, by decreasing high density intracellular bacteria, antibiotic treatment may improve the refractory DO condition.


Assuntos
Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Ácido Clavulânico/administração & dosagem , Cistite/tratamento farmacológico , Bexiga Inativa/tratamento farmacológico , Urotélio/microbiologia , Técnicas Bacteriológicas , Cistite/microbiologia , Feminino , Humanos , Microscopia Confocal , Índice de Gravidade de Doença , Resultado do Tratamento , Infecções Urinárias/tratamento farmacológico , Urina/microbiologia , Urotélio/citologia
2.
AAPS J ; 23(3): 65, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33948771

RESUMO

To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CLR) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CLR post-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CLR was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CLint,OAT1,3,invivo) and its ontogeny. CLint,OAT1,3,invivo ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CLR predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months-15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within ±50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CLint,OAT1,3,invivo that yields accurate CLR predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters.


Assuntos
Rim/metabolismo , Modelos Biológicos , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Eliminação Renal/fisiologia , Adolescente , Amoxicilina/administração & dosagem , Amoxicilina/farmacocinética , Variação Biológica da População , Cefazolina/administração & dosagem , Cefazolina/farmacocinética , Criança , Pré-Escolar , Ácido Clavulânico/administração & dosagem , Ácido Clavulânico/farmacocinética , Interações Medicamentosas , Taxa de Filtração Glomerular/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Piperacilina/administração & dosagem , Piperacilina/farmacocinética
3.
JAMA Netw Open ; 4(3): e212713, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33755168

RESUMO

Importance: Acute bacterial sinusitis is common, but currently recommended antibiotic treatment provides minimal benefit. Objective: To confirm the previous finding that high-dose amoxicillin plus clavulanate (with double the amount of amoxicillin) may be superior to standard-dose amoxicillin plus clavulanate in adults. Design, Setting, and Participants: This double-blind, comparative-effectiveness randomized clinical trial was conducted from February 26, 2018, through May 10, 2020, at the academic primary care internal medicine and pediatrics practice of Albany Medical Center, located in Cohoes, New York. Participants included adults aged 18 years or older who were prescribed amoxicillin plus clavulanate for acute bacterial sinusitis diagnosed in accordance with the Infectious Diseases Society of America guidelines. Interventions: Amoxicillin 875 mg with clavulanate 125 mg plus either placebo (standard dose) or amoxicillin 875 mg (high dose) twice a day for 7 days. Main Outcomes and Measures: The primary efficacy outcome was a global rating of "a lot better" or "no symptoms" at the end of 3 days of treatment using a Global Rating of Improvement scale, with outcomes ranging from 1 (a lot worse) to 6 (no symptoms). The primary adverse effect outcome was severe diarrhea at 3 or 10 days after the start of treatment. Results: At an unplanned interim analysis prompted by COVID-19 restrictions, 157 of a projected 240 participants had been enrolled (mean age, 48.5 [range, 18.7-84.0] years; 117 women [74.5%]), with 79 randomized to the standard dose and 78 to the high dose; 9 and 12, respectively, withdrew or were lost to follow-up before the assessment of the primary outcome. At day 3, 31 of 70 participants (44.3%) in the standard-dose group reported a global rating of "a lot better" or "no symptoms," as did 24 of 66 (36.4%) in the high-dose group, for a difference of -7.9% (95% CI, -24.4% to 8.5%; P = .35). The study was, therefore, stopped for futility. Diarrhea was common in both groups by day 3, with any diarrhea reported in 29 of 71 participants (40.8%) receiving the standard dose and 28 of 65 (43.1%) receiving the high dose and severe diarrhea reported in 5 of 71 (7.0%) and 5 of 65 (7.7%), respectively. Conclusions and Relevance: The results of this randomized clinical trial suggest that adults treated for clinically diagnosed acute sinusitis did not appear to benefit from taking high-dose compared with standard-dose amoxicillin plus clavulanate. Trial Registration: ClinicalTrials.gov Identifier: NCT03431337.


Assuntos
Amoxicilina , Ácido Clavulânico , Sinusite , Doença Aguda , Amoxicilina/administração & dosagem , Amoxicilina/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Ácido Clavulânico/administração & dosagem , Ácido Clavulânico/efeitos adversos , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sinusite/diagnóstico , Sinusite/tratamento farmacológico , Resultado do Tratamento , Inibidores de beta-Lactamases/administração & dosagem , Inibidores de beta-Lactamases/efeitos adversos
4.
Ann Afr Med ; 19(2): 103-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32499466

RESUMO

Background: Postcesarean wound infection is a leading cause of prolonged hospital stay. Considerable debates still exist regarding choice of antibiotics, dose, and duration of use. Objectives: The objective is to compare the efficacy of 2 doses of amoxicillin-clavulanic acid versus a 7 days combination of amoxicillin-clavulanic acid and metronidazole as prophylactic antibiotics following cesarean section (CS). Methodology: It was a randomized controlled trial that was conducted among 160 women undergoing CS at Aminu Kano Teaching Hospital. Women were randomized into two groups. Group I (study group) received 2 doses of 1.2 g amoxicillin-clavulanic acid. Group II (control group) received a 7 days course of amoxicillin-clavulanic acid and metronidazole. The data obtained were analyzed using SPSS version 17. Categorical (qualitative) variables were analyzed using Chi-square test and Fisher's exact test as appropriate while continuous (quantitative) variables were analyzed using independent sample t-test. P < 0.05 was considered statistically significant. Results: There was no statistically significant association in the occurrence of fever (12.8% vs. 15.8%, P = 0.6), wound infection (6.4% vs. 10.5%, P = 0.36), endometritis (7.7% vs. 11.8%, P = 0.38), UTI (6.4% vs. 5.3%, P = 1.00), mean duration of hospital stay (129.7 vs. 134.2 h, P = 0.48), and neonatal outcomes between the two groups. There was statistically significant difference in the mean cost of antibiotics (₦2883/US$9.5 vs. ₦7040/US$23.1, P < 0.001) and maternal side effects (10.3% vs. 26.3%, P < 0.001) between the study and the control groups, respectively. Conclusion: This study found no statistically significant difference in infectious morbidity, duration of hospital stay, and neonatal outcomes when two doses of amoxicillin-clavulanic acid was compared with a 7 days course of prophylactic antibiotic following CS. The use of two doses of amoxicillin-clavulanic acid has the advantages of reduced cost and some maternal side effects. The two doses were cheaper with minimal side effects.


RésuméContexte: L'infection des plaies post-césariennes est l'une des principales causes d'hospitalisation prolongée. Des débats considérables existent toujours concernant le choix antibiotiques, dose et durée d'utilisation. Objectifs: L'objectif est de comparer l'efficacité de 2 doses d'acide amoxicilline-clavulanique par rapport à 7 jours association d'acide amoxicilline-clavulanique et de métronidazole comme antibiotiques prophylactiques après une césarienne (CS). Méthodologie: c'était un essai contrôlé randomisé mené auprès de 160 femmes subissant une CS à l'hôpital universitaire Aminu Kano. Les femmes ont été randomisées en deux groupes. Le groupe I (groupe d'étude) a reçu 2 doses d'acide amoxicilline-clavulanique de 1,2 g. Le groupe II (groupe témoin) a reçu 7 jours de l'acide amoxicilline-clavulanique et du métronidazole. Les données obtenues ont été analysées à l'aide de SPSS version 17. Catégorie (qualitative) les variables ont été analysées à l'aide du test du chi carré et du test exact de Fisher, selon le cas, tandis que les variables continues (quantitatives) ont été analysées en utilisant un test t pour échantillon indépendant. P <0,05 était considéré comme statistiquement significatif. Résultats: Il n'y avait pas d'association statistiquement significative en cas de fièvre (12,8% vs 15,8%, P = 0,6), infection des plaies (6,4% vs 10,5%, P = 0,36), endométrite (7,7% vs 11,8%, P = 0,38), IVU (6,4% contre 5,3%, P = 1,00), durée moyenne de séjour à l'hôpital (129,7 contre 134,2 h, P = 0,48) et résultats néonatals entre les deux groupes. Il y avait une différence statistiquement significative dans le coût moyen des antibiotiques (83 2883 / US $ 9,5 contre ₦ 7040 / US $ 23,1, P <0,001) et côté maternel effets (10,3% contre 26,3%, P <0,001) entre l'étude et les groupes témoins, respectivement. Conclusion: Cette étude n'a trouvé aucune statistique différence significative dans la morbidité infectieuse, la durée du séjour à l'hôpital et les résultats néonatals lorsque deux doses d'amoxicilline-clavulanique l'acide a été comparé à un traitement antibiotique prophylactique de 7 jours après la CS. L'utilisation de deux doses d'acide amoxicilline-clavulanique a avantages du coût réduit et de certains effets secondaires maternels. Les deux doses étaient moins chères avec des effets secondaires minimes.


Assuntos
Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Antibioticoprofilaxia/métodos , Infecções Bacterianas/prevenção & controle , Cesárea/efeitos adversos , Ácido Clavulânico/administração & dosagem , Metronidazol/administração & dosagem , Infecção Puerperal/prevenção & controle , Adulto , Antibioticoprofilaxia/efeitos adversos , Infecções Bacterianas/tratamento farmacológico , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hospitais de Ensino , Humanos , Nigéria , Gravidez , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecção da Ferida Cirúrgica/prevenção & controle , Resultado do Tratamento
5.
Drug Des Devel Ther ; 14: 103-109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021095

RESUMO

RATIONALE: Previously, we have been able to outpace bacterial mutation by replacing increasingly ineffective antibiotics with new agents. However, with the discovery of new antibiotics diminishing, optimising the administration of existing broad-spectrum antibiotics such as co-amoxiclav has become a necessity. METHODS: A stability indicating HPLC method was developed and validated in compliance with International Council for Harmonisation (ICH) guidelines. Stability of co-amoxiclav at clinical concentration was evaluated at three temperatures (4°C, ambient (23-25°C) and 37°C) in three diluents (water for injection (WFI), 0.9% w/v NaCl and Ringer's solution). To establish whether there were significant differences at the level of both diluent and temperature, results were analysed using analysis of covariance (ANCOVA) to assess differences between the attained slopes of regression. RESULTS: Data obtained indicated co-amoxiclav stability superior to that previously proposed making it suitable for extended infusion therapy. The degradation of amoxicillin appeared to follow a linear trend, with the rate of degradation elevated at higher temperatures, demonstrated by the magnitude of the regression slopes in these conditions. Analysis of regression slopes via ANCOVA demonstrated that diluent and temperature both significantly affected co-amoxiclav stability. Amoxicillin retained 90% of its initial concentration for 7.8 to 10 hrs when stored at 4°C, 5.9 to 8.8 hrs at ambient and 3.5 to 4.5 hrs when incubated at 37°C. CONCLUSION: Co-amoxiclav is suitable for administration via prolonged infusion. Findings from this study aid in ameliorating current dosing regimens to optimise antibiotic efficacy. Other valuable applications conferred from these findings include the ability to pre-prepare solutions for use in bolus administration, minimising preparation time and workload.


Assuntos
Amoxicilina/análise , Antibacterianos/análise , Ácido Clavulânico/análise , Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Ácido Clavulânico/administração & dosagem , Estabilidade de Medicamentos , Quimioterapia Combinada , Temperatura
7.
Br J Clin Pharmacol ; 85(12): 2856-2863, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31486528

RESUMO

AIMS: The goal of the current study was to assess the risk for major congenital malformations following first-trimester exposure to amoxicillin, or amoxicillin and clavulanic acid (ACA). METHODS: A population-based retrospective cohort study was conducted, by linking 4 computerized databases: maternal and infant hospitalization records, drug dispensing database of Clalit Health Services in Israel and data concerning pregnancy terminations. Multivariate negative-binomial regression was used to assess the risk for major malformations following first-trimester exposure, adjusted for mother's age, ethnicity (Bedouin vs Jewish), parity, diabetes mellitus, lack of perinatal care, and the year of birth. RESULTS: The study included 101 615 pregnancies, of which 6919 (6.8%) were exposed to amoxicillin: 1045 (1.0%) to amoxicillin only and 6041 (5.9%) to ACA. No significant association was found, in the univariate and multivariate analyses, between first-trimester exposure to amoxicillin or ACA and major malformations in general (crude relative risk, 1.05 95% confidence interval 0.95-1.16; adjusted relative risk 1.09, 95% confidence interval 0.98-1.20), or for major malformations according to organ systems. No dose-response relationship was found between exposure in terms of the defined daily dose and major malformations. CONCLUSION: Exposure to amoxicillin and ACA during the first trimester of pregnancy was not associated with an increased risk of major congenital malformations.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Amoxicilina/efeitos adversos , Antibacterianos/efeitos adversos , Ácido Clavulânico/efeitos adversos , Anormalidades Induzidas por Medicamentos/etiologia , Adulto , Amoxicilina/administração & dosagem , Amoxicilina/uso terapêutico , Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Ácido Clavulânico/administração & dosagem , Ácido Clavulânico/uso terapêutico , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Recém-Nascido , Análise Multivariada , Gravidez , Primeiro Trimestre da Gravidez , Estudos Retrospectivos , Fatores de Risco
8.
Drug Dev Res ; 80(8): 1110-1119, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31482584

RESUMO

We investigated whether clavulanic acid could improve learning and memory, in rats underwent bilateral occlusion of common carotid artery (2VO). Seventy male Wistar rats were subjected to 2VO, with a 1-week interval between right and left artery occlusions. After 2VO, animals received clavulanic acid (10, 20, 40 mg/kg, intraperitoneally), from day 8 to 20. Spatial memory was assessed in the Morris water maze, 1 week after the induction of 2VO (day 15). The mRNA expression levels of bcl-2, bcl2-associated x protein (bax), caspase-3, inducible nitric oxide synthase (iNOS), and amyloid beta precursor protein (APP) were measured in the neocortex and hippocampus. Clavulanic acid significantly decreased the escape latency and swimming time in the training trial days. As well, it increased time and distance percentage in the target quadrant, while it decreased such factors in the opposite quadrant in the final trial day, compared to 2VO + normal saline animals. Real time-PCR data showed a significant higher mRNA expression of bax, caspase 3, and iNOS in the hippocampus and neocortex of 2VO animal compared to nonoccluded rats. APP increased in the neocortex but not hippocampus. Compared with 2VO animals, clavulanic acid significantly down-regulated the expression of iNOS, caspase 3, and APP, accompanied by diminishing the bax/bcl2 ratio. Our results reveal a potential therapeutic use of clavulanic acid for cognitive dysfunction associated with cerebral hypoperfusion in vascular dementia and Alzheimer disease.


Assuntos
Arteriopatias Oclusivas/etiologia , Artéria Carótida Primitiva , Ácido Clavulânico/administração & dosagem , Demência Vascular/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Animais , Arteriopatias Oclusivas/complicações , Caspase 3/genética , Ácido Clavulânico/farmacologia , Demência Vascular/etiologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Neocórtex/efeitos dos fármacos , Neocórtex/metabolismo , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/genética , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos , Proteína X Associada a bcl-2/genética
9.
Lancet Respir Med ; 7(9): 791-801, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31427252

RESUMO

BACKGROUND: Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin-clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment. METHODS: In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1-18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin-clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin-clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2-8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed. FINDINGS: Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillin-clavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99%) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65%) children in the amoxicillin-clavulanate group, 41 (61%) in the azithromycin group, and 29 (43%) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95% CI 1·08-2·09, p=0·015; number-needed-to-treat [NNT] 5 [95% CI 3-20]) in the amoxicillin-clavulanate group and 1·41 (1·01-1·97, p=0·042; NNT 6 [3-79]) in the azithromycin group. Adverse events were recorded in 19 (30%) children in the amoxicillin-clavulanate group, 20 (30%) in the azithromycin group, and 14 (21%) in the placebo group, but no events were severe or life-threatening. INTERPRETATION: Amoxicillin-clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting. FUNDING: National Health and Medical Research Council (Australia), Cure Kids (New Zealand).


Assuntos
Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Bronquiectasia/tratamento farmacológico , Bronquiectasia/fisiopatologia , Ácido Clavulânico/uso terapêutico , Administração Oral , Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Austrália , Azitromicina/administração & dosagem , Criança , Pré-Escolar , Ácido Clavulânico/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Nova Zelândia , Resultado do Tratamento
10.
Behav Neurosci ; 133(2): 247-254, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30714803

RESUMO

Research using the cocaine self-administration and reinstatement animal model of relapse finds that the beta-lactam antibiotic, ceftriaxone, attenuates cocaine-primed reinstatement of cocaine seeking and upregulates two proteins that regulate glutamate release and reuptake (xCT and GLT-1, respectively) in the nucleus accumbens core (NAc). We tested three compounds with beta-lactam rings for their ability to attenuate cue-primed reinstatement and increase GLT-1 and xCT expression in the NAc and prefrontal cortex (PFC). Rats self-administered intravenous cocaine for 1 hr/day for 7 days then 6 hrs/day for 10 days. Cue-primed reinstatement tests began after 8-9 days of extinction training. Rats received oral vehicle, clavulanic acid (CA), amoxicillin (AMX), or CA + AMX (Augmentin; AUG) for 5 days prior to testing. Only AMX-treated rats demonstrated a reduction of cocaine-seeking that trended toward significance, warranting future investigation of a wider range of doses. In the NAc, GLT-1a expression was reduced in vehicle-treated rats relative to cocaine-naïve controls and was not restored by AMX or AUG. CA-treated rats reinstated more than vehicle-treated rats and exhibited GLT-1a and xCT expression intermediate between cocaine-naïve controls and vehicle-treated cocaine rats. In agreement with our previous work, cocaine did not decrease PFC GLT-1a expression. Cocaine reduced xCT expression in the PFC that was unchanged by any of the three compounds. These results indicate that AMX may be another beta-lactam that attenuates cocaine relapse. Furthermore, the upregulation of both GLT-1 and xCT in the NAc may be needed to attenuate cocaine seeking. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Ácido Clavulânico/administração & dosagem , Cocaína/administração & dosagem , Comportamento de Procura de Droga/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Inibidores de beta-Lactamases/administração & dosagem , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Sinais (Psicologia) , Transportador 2 de Aminoácido Excitatório/metabolismo , Extinção Psicológica/efeitos dos fármacos , Masculino , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos Sprague-Dawley
11.
PLoS One ; 13(10): e0205324, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356296

RESUMO

Culture-based detection of Campylobacter can be affected by competing flora, temperature, incubation time, and presence of blood. The presence of extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli in poultry has become one of the most common factors interfering with the detection of Campylobacter. In the present study, we evaluated potassium clavulanate (ESBL inhibitor) as a supplement in Bolton broth (C-Bolton broth) for enrichment and detection of Campylobacter. First, we determined growth kinetics of Campylobacter in the presence of different concentrations of ESBL E. coli in C-Bolton broth during enrichment. The effects of other factors such as incubation time, incubation temperature, and presence of blood on Campylobacter detection in C-Bolton broth were also investigated. The growth of Campylobacter co-cultured at a low concentration (2 and 4 log10 CFU/mL) of ESBL E. coli was similar to that of Campylobacter alone in C-Bolton broth, and Campylobacter co-cultured at a high concentration (6 and 8 log10 CFU/mL) of ESBL E. coli showed slower growth than the pure Campylobacter culture. The Campylobacter detection limit was 1 log10 CFU/mL when mixed with 2, 4, or 6 log10 CFU/mL of E. coli and 3 log10 CFU/mL when mixed with 8 log10 CFU/mL of E. coli after 48 h enrichment in the broth. Campylobacter detection from chicken feces and litter samples was not affected by incubation time, or presence of blood in the broth. A modified procedure of enrichment in C-Bolton broth at 37°C for 24 h without blood showed a significantly (P ≤ 0.05) higher detection rate and a lower false-negative rate than the ISO 10272-1:2006 method for Campylobacter detection from chicken feces and litter samples. In summary, the present study demonstrates the efficacy of Bolton broth supplemented with potassium clavulanate in the detection of Campylobacter mixed with ESBL E. coli, and an improved procedure to detect Campylobacter from chicken feces and litter samples.


Assuntos
Campylobacter/isolamento & purificação , Galinhas/microbiologia , Ácido Clavulânico/administração & dosagem , Inibidores de beta-Lactamases/administração & dosagem , Animais , Campylobacter/efeitos dos fármacos , Campylobacter/crescimento & desenvolvimento , Meios de Cultura/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Fezes/microbiologia , Microbiologia de Alimentos , Carne/microbiologia , Aves Domésticas/microbiologia , beta-Lactamases/metabolismo
12.
J Pharm Pharmacol ; 70(7): 883-892, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29633270

RESUMO

OBJECTIVES: Bioequivalence (BE) criteria for amoxicillin-clavulanic acid (Co-amoxiclav) oral formulations are based on 90% confidence interval for both amoxicillin and clavulanic acid. The aim of this work is to explore the relevance of demonstrating BE of clavulanic acid in Co-amoxiclav oral formulations and also to assess the impact on safety and efficacy of product due to bioinequivalent clavulanic acid. METHODS AND KEY FINDINGS: The subtherapeutic levels of clavulanic acid would continue to exert their action against ß-lactamases due to postß-lactamase inhibitor effect. Additionally, only minute quantities are required to inhibit ß-lactamases. Majority of adverse effects associated with Co-amoxiclav are of less serious nature, therefore, risk due to suprabioavailable clavulanic acid was determined to be low. 'Very rapid clavulanic acid release' in in vitro dissolution test would ensure that clinically significant differences between test and reference formulations if any are detected in advance. As an additional risk mitigation strategy, WHO recommends qualitative and quantitative composition similarity between test and reference formulations to ensure excipients do not adversely impact bioavailability. CONCLUSIONS: Co-amoxiclav with non-bioequivalent clavulanic acid, but bioequivalent amoxicillin would still achieve its therapeutic objectives without exposing patients to unwanted adverse effects. Therefore, the current regulatory criterion of demonstrating BE of clavulanic acid appears conservative.


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Combinação Amoxicilina e Clavulanato de Potássio/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Ácido Clavulânico/farmacocinética , Administração Oral , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Antibacterianos/efeitos adversos , Ácido Clavulânico/administração & dosagem , Ácido Clavulânico/efeitos adversos , Humanos , Testes de Sensibilidade Microbiana , Equivalência Terapêutica , Inibidores de beta-Lactamases/administração & dosagem , Inibidores de beta-Lactamases/efeitos adversos , Inibidores de beta-Lactamases/farmacocinética
13.
Int J Tuberc Lung Dis ; 22(1): 34-39, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29297423

RESUMO

BACKGROUND: Extensively drug-resistant tuberculosis (XDR-TB), defined as TB caused by a Mycobacterium strain resistant to at least rifampicin, isoniazid, any fluoroquinolone and one of the injectable anti-tuberculosis drugs, remains a worldwide public health threat. Among repurposed drugs empirically used for XDR-TB cases, carbapenems have been studied in vitro and in animal models, with encouraging results. However, only short-term follow-up data from clinical studies are currently available. OBJECTIVES: To study the long-term follow-up of XDR-TB cases treated with a regimen containing meropenem-clavulanate (M/Clav). DESIGN: Retrospective observational case series study at a single hospital. METHODS: All hospitalised drug-resistant TB patients who received M/Clav as part of their treatment from 2009 to 2016 were included. Demographic and clinical data were extracted from medical records. RESULTS: Eighteen XDR-TB patients were included in the analysis. The successful outcome and mortality rates were respectively 83.3% and 11.1%. No relapses were observed in cured patients after a median follow-up of 4 years. No specific adverse events were attributed to treatment with M/Clav. CONCLUSION: The rate of sustained successful treatment outcome observed here is far higher than the 26% observed in the 2014 World Health Organization XDR-TB cohort, suggesting that carbapenems may be beneficial for the treatment of difficult-to-treat TB cases.


Assuntos
Antituberculosos/administração & dosagem , Ácido Clavulânico/administração & dosagem , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Meropeném/administração & dosagem , Adulto , Quimioterapia Combinada , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
14.
Eur J Pain ; 22(2): 282-294, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28984398

RESUMO

BACKGROUND: Following nerve injury, down-regulation of astroglial glutamate transporters (GluTs) with subsequent extracellular glutamate accumulation is a key factor contributing to hyperexcitability within the spinal dorsal horn. Some ß-lactam antibiotics can up-regulate GluTs, one of which, ceftriaxone, displays analgesic effects in rodent chronic pain models. METHODS: Here, the antinociceptive actions of another ß-lactam clavulanic acid, which possesses negligible antibiotic activity, were compared with ceftriaxone in rats with chronic constriction injury (CCI)-induced neuropathic pain. In addition, the protein expression of glutamate transporter-1 (GLT1), its splice variant GLT1b and glutamate-aspartate transporter (GLAST) was measured in the spinal cord of CCI rats. Finally, protein expression of the same GluTs was evaluated in cultured astrocytes obtained from rodents and humans. RESULTS: Repeated injection of ceftriaxone or clavulanic acid over 10 days alleviated CCI-induced mechanical hypersensitivity, whilst clavulanic acid was additionally able to affect the thermal hypersensitivity. In addition, clavulanic acid up-regulated expression of GLT1b within the spinal cord of CCI rats, whereas ceftriaxone failed to modulate expression of any GluTs in this model. However, both clavulanic acid and ceftriaxone up-regulated GLT1 expression in rat cortical and human spinal astrocyte cultures. Furthermore, clavulanic acid increased expression of GLT1b and GLAST in rat astrocytes in a dose-dependent manner. CONCLUSIONS: Thus, clavulanic acid up-regulates GluTs in cultured rodent- and human astroglia and alleviates CCI-induced hypersensitivity, most likely through up-regulation of GLT1b in spinal dorsal horn. SIGNIFICANCE: Chronic dosing of clavulanic acid alleviates neuropathic pain in rats and up-regulates glutamate transporters both in vitro and in vivo. Crucially, a similar up-regulation of glutamate transporters in human spinal astrocytes by clavulanic acid supports the development of novel ß-lactam-based analgesics, devoid of antibacterial activity, for the clinical treatment of chronic pain.


Assuntos
Analgésicos/uso terapêutico , Ceftriaxona/uso terapêutico , Ácido Clavulânico/uso terapêutico , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Neuralgia/tratamento farmacológico , Analgésicos/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Ceftriaxona/administração & dosagem , Células Cultivadas , Ácido Clavulânico/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Masculino , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Regulação para Cima/efeitos dos fármacos
15.
Cochrane Database Syst Rev ; 11: CD012137, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29190037

RESUMO

BACKGROUND: Infectious morbidities contribute to considerable maternal and perinatal morbidity and mortality, including women at no apparent increased risk of infection. To reduce the incidence of infections, antibiotics are often administered to women after uncomplicated childbirth, particularly in settings where women are at higher risk of puerperal infectious morbidities. OBJECTIVES: To assess whether routine administration of prophylactic antibiotics to women after normal (uncomplicated) vaginal birth, compared with placebo or no antibiotic prophylaxis, reduces postpartum maternal infectious morbidities and improves outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2017), LILACS, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (22 August 2017) and reference lists of retrieved studies. SELECTION CRITERIA: We planned to include randomised or quasi-randomised trials evaluating the use of prophylactic antibiotics versus placebo or no antibiotic prophylaxis. Trials using a cluster-randomised design would have been eligible for inclusion, but we found none.In future updates of this review, we will include studies published in abstract form only, provided sufficient information is available to assess risks of bias. We will consider excluded abstracts for inclusion once the full publication is available, or the authors provide more information.Trials using a cross-over design are not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors conducted independent assessment of trials for inclusion and risks of bias. They independently extracted data and checked them for accuracy, resolving differences in assessments by discussion. They evaluated methodological quality using standard Cochrane criteria and the GRADE approach.We present the summaries as risk ratios (RRs) and mean difference (MDs) using fixed- or random-effect models. For one primary outcome we found considerable heterogeneity and interaction. We explored further using subgroup analysis to investigate the effects of the randomisation unit. All review authors discussed and interpreted the results. MAIN RESULTS: One randomised controlled trial (RCT) and two quasi-RCTs contributed data on 1779 women who had uncomplicated vaginal births, comparing different antibiotic regimens with placebo or no treatment. The included trials took place in the 1960s (one trial) and 1990s (two trials). The trials were conducted in France, the USA and Brazil. Antibiotics administered included: oral sulphamethoxypyridazine or chloramphenicol for three to five days, and intravenous amoxicillin and clavulanic acid in a single dose one hour after birth. We rated most of the domains for risk of bias as high risk, with the exception of reporting bias and other potential bias.The quality of evidence ranged from low to very low, based on the GRADE quality assessment, given very serious design limitations of the included studies, few events and wide confidence intervals (CIs) of effect estimates.We found a decrease in the risk of endometritis (RR 0.28, 95% CI 0.09 to 0.83, two trials, 1364 women,very low quality). However, one trial reported zero events for this outcome and we rate the evidence as very low quality. There was little or no difference between groups for the risk of urinary tract infection (RR 0.25, 95% CI 0.05 to 1.19, two trials, 1706 women,low quality), wound infection after episiotomy (reported as wound dehiscence in the included trials) (RR 0.78, 95% CI 0.31 to 1.96, two trials, 1364 women, very low quality) and length of maternal hospital stay in days (MD -0.15, 95% CI -0.31 to 0.01, one trial, 1291 women, very low quality). Cost of care in US dollar equivalent was 2½ times higher in the control group compared to the group receiving antibiotics prophylaxis (USD 3600: USD 9000, one trial, 1291 women). There were few or no differences between treated and control groups for adverse effects of antibiotics (skin rash) reported in one woman in each of the two trials (RR 3.03, 95% CI 0.32 to 28.95, two trials, 1706 women, very low quality). The incidence of severe maternal infectious morbidity, antimicrobial resistance or women's satisfaction with care were not addressed by any of the included studies. AUTHORS' CONCLUSIONS: Routine administration of antibiotics may reduce the risk of endometritis after uncomplicated vaginal birth. The small number and nature of the trials limit the interpretation of the evidence for application in practice, particularly in settings where women may be at higher risk of developing endometritis. The use of antibiotics did not reduce the incidence of urinary tract infections, wound infection or the length of maternal hospital stay. Antibiotics are not a substitute for infection prevention and control measures around the time of childbirth and the postpartum period. The decision to routinely administer prophylactic antibiotics after normal vaginal births needs to be balanced by patient features, childbirth setting and provider experience, including considerations of the contribution of indiscriminate use of antibiotics to raising antimicrobial resistance. Well-designed and high-powered randomised controlled trials would help to evaluate the added value of routine antibiotic administration as a measure to prevent maternal infections after normal vaginal delivery.


Assuntos
Antibioticoprofilaxia , Parto Obstétrico , Endometrite/prevenção & controle , Infecção Puerperal/prevenção & controle , Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Cloranfenicol/administração & dosagem , Ácido Clavulânico/administração & dosagem , Endometrite/epidemiologia , Episiotomia/efeitos adversos , Feminino , Humanos , Ensaios Clínicos Controlados não Aleatórios como Assunto , Gravidez , Infecção Puerperal/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfametoxipiridazina/administração & dosagem , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Infecções Urinárias/epidemiologia , Infecções Urinárias/prevenção & controle
16.
Niger J Clin Pract ; 20(9): 1189-1194, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29072245

RESUMO

AIM: To compare the impact of antibiotics on health-related quality of life (QoL) outcomes following third molar surgery. MATERIALS AND METHODS: The study population consisted of 135 subjects that required surgical extraction of mandibular third molar under local anesthesia and met the inclusion criteria. The subjects were randomized into three study groups of 45 subjects each: Group A - extended amoxicillin/clavulanic acid (GlaxoSmithKline Beecham England), 1 gram pre-operatively and then 625 mg BD for 5 days Group B - prophylactic amoxicillin/clavulanic acid (GlaxoSmithKline Beecham England) 1 gram pre-operatively only, and Group C - prophylactic levofloxacin 1 gram pre-operatively only. Patients were assessed pre- and post-operatively on days 1, 3, 5, 7, and 14 using the United Kingdom oral health-related QoL (OHRQoL) questionnaire. RESULTS: This study showed that surgical removal of impacted teeth exerted a negative influence on patient's QoL across various physical, social, and psychological aspects of life. Comparing the three groups, Group A showed a slightly better QoL score; although, there was no statistically significant difference among them. Studies have shown better clinical recovery following administration of antibiotics after third molar surgery. CONCLUSION: There was a significant deterioration in OHRQoL in the immediate postoperative period, particularly postoperative days 1 and 3 following third molar surgery. QoL was also observed to be slightly better in Group A than Groups B and C, although this was not statistically significant.


Assuntos
Antibacterianos/administração & dosagem , Antibioticoprofilaxia , Dente Serotino/cirurgia , Qualidade de Vida , Infecção da Ferida Cirúrgica/prevenção & controle , Extração Dentária/efeitos adversos , Dente Impactado/cirurgia , Adulto , Amoxicilina/administração & dosagem , Amoxicilina/farmacologia , Antibacterianos/farmacologia , Antibioticoprofilaxia/psicologia , Ácido Clavulânico/administração & dosagem , Ácido Clavulânico/farmacologia , Feminino , Humanos , Levofloxacino/administração & dosagem , Levofloxacino/farmacologia , Masculino , Saúde Bucal , Cuidados Pós-Operatórios , Cuidados Pré-Operatórios , Inquéritos e Questionários , Extração Dentária/psicologia , Resultado do Tratamento , Adulto Jovem , Inibidores de beta-Lactamases/administração & dosagem , Inibidores de beta-Lactamases/farmacologia
17.
Neurosci Lett ; 657: 140-145, 2017 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-28826758

RESUMO

Studies from our laboratory showed that upregulation of glutamate transporter 1 (GLT-1) and cystine-glutamate exchanger (xCT) expression with ceftriaxone, ß-lactam antibiotic, in the brain was associated with attenuation of ethanol consumption. In this study, we tested clavulanic acid, which is another ß-lactam compound with negligible antimicrobial activity, on ethanol consumption and expression of GLT-1, xCT and glutamate aspartate transporter (GLAST) in male alcohol-preferring (P) rats. Clavulanic acid has the central ß-lactam pharmacophore that is critical for the upregulation of GLT-1 and xCT expression. We found that clavulanic acid, at 5mg/kg (i.p.) dose, significantly attenuated ethanol consumption and ethanol preference in P rats as compared to vehicle-treated group. This effect was associated with a significant increase in water intake in clavulanic acid treated group. Importantly, we found that clavulanic acid increased the expression of GLT-1 and xCT in nucleus accumbens. However, there was no effect of clavulanic acid on GLAST expression in the nucleus accumbens. Clavulanic acid treatment did not upregulate the expression of GLT-1, xCT and GLAST in prefrontal cortex. These findings revealed that clavulanic acid at 20-40 fold lower dose than ceftriaxone can attenuate ethanol consumption, in part through upregulation of GLT-1 and xCT expression in the nucleus accumbens. Thus, we suggest that clavulanic acid might be used as an alternative option to ceftriaxone to attenuate ethanol drinking behavior.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Sistemas de Transporte de Aminoácidos Acídicos/efeitos dos fármacos , Ácido Clavulânico/farmacologia , Transportador 1 de Aminoácido Excitatório/efeitos dos fármacos , Transportador 2 de Aminoácido Excitatório/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacologia , Animais , Ácido Clavulânico/administração & dosagem , Modelos Animais de Doenças , Masculino , Ratos , Inibidores de beta-Lactamases/administração & dosagem
18.
Ann Agric Environ Med ; 24(2): 307-311, 2017 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-28664714

RESUMO

Introduction. Multi-resistant Acinetobacter baumannii isolated from patients has become one of the most hazardous pathogens in health care settings. The aim of the study was to analyze pneumonia caused by Acinetobacter baumannii in patients hospitalized because of exacerbation of chronic obstructive pulmonary diseases (COPD), who were admitted to the Pulmonology Ward of the Masovian Specialistic Hospital in Radom (MSS). The incidence and drug sensitivity of these non-fermenting rods were evaluated, and compliance with antimicrobial procedure with the algorithm of the guidelines in applicable recommendations, was estimated. This should result in determining the local patterns of resistance and verifying therapeutic procedures in accordance with the assumptions of hospital antibiotic policy. In addition, the study examined the effectiveness of empiric and targeted therapy according to the clinical condition of the patient, and the eradication of A. baumannii, in comparison with the aggravating factors of the patient. Materials and Method. The retrospective study included 90 patients with exacerbation of COPD whose etiological factor of infection was A. baumannii, hospitalized in the Department of Pulmonology (MSS) in 2012-2016. Results. Studies were conducted on 90 patients with COPD exacerbation from which A. baumannii was isolated. Co-infections with other bacterial species among 41 patients were additionally noted. The majority of A. baumannii strains showed a high resistance (90%) to fluoroquinolones, ceftazidime, piperacillin/tazobactam. For strains causing a co-infection, drug resistance was successively 44-56%, 44%, 44%. All of patients received empirical therapy. The most commonly used drug was amoxicillin with a clavulanic acid, often combined with fluoroquinolone. This type of therapy was effective among 10% of patients. The mortality in this group was determined at 29%. Among 79% of patients with COPD, a targeted therapy was performed which proved to be effective in 58% of treated cases by susceptibility testing. The highest efficacy was observer after the use of colistin and carbapenems. Conclusion. In the performed study, the infections caused by multi-resistant Acinetobacter baumannii, were observed in COPD, which should be taken into consideration in choosing empirical antibiotic therapy. Simultaneously, the local resistance patterns of multi-drug-resistant (MDR) Gram-negative strains co-infecting COPD should be considered in empirical treatment. Moreover, both additional clinical complication and co-infections contribute to a more severe course of diseases. In this study, the mortality percent exceeded 29%.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/fisiologia , Idoso , Idoso de 80 Anos ou mais , Amoxicilina/administração & dosagem , Ácido Clavulânico/administração & dosagem , Farmacorresistência Bacteriana , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/microbiologia , Quinolinas/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
19.
Artigo em Inglês | MEDLINE | ID: mdl-28438923

RESUMO

Amoxicillin-clavulanate (A/C) is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but the standard dosage of 90 mg amoxicillin/6.4 mg clavulanate/kg of body weight/day commonly causes diarrhea. We examined whether an A/C formulation containing lower concentrations of clavulanate would result in less diarrhea while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate middle-ear pathogens and to achieve clinical success. We conducted an open-label study in children with AOM who were 6 to 23 months of age. In phase 1, we treated 40 children with a reduced-clavulanate A/C formulation providing 90 mg amoxicillin/3.2 mg clavulanate/kg/day for 10 days. In phase 2, we treated 72 children with the same formulation at a dosage of 80 mg amoxicillin/2.85 mg clavulanate/kg/day for 10 days. We compared the rates of protocol-defined diarrhea (PDD), diaper dermatitis, and AOM clinical response in these children with rates we had reported in children who received the standard A/C regimen, and we obtained plasma levels of amoxicillin and clavulanate at various time points. Outcomes in phase 1 children and in children who had received the standard regimen did not differ significantly. Rates of PDD in children receiving phase 2 and standard regimens were 17% and 26%, respectively (P = 0.10). The corresponding rates of diaper dermatitis were 21% and 33% (P = 0.04) and of AOM treatment failure were 12% and 16% (P = 0.44). Symptomatic responses did not differ significantly between regimens; both gave clavulanate levels sufficient to inhibit ß-lactamase activity. In young children with AOM, clavulanate dosages lower than those currently used may be associated with fewer side effects without reducing clinical efficacy. (This study has been registered at ClinicalTrials.gov under registration no. NCT02630992.).


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Antibacterianos/uso terapêutico , Ácido Clavulânico/uso terapêutico , Otite Média/tratamento farmacológico , Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Ácido Clavulânico/administração & dosagem , Ácido Clavulânico/efeitos adversos , Dermatite/etiologia , Diarreia/induzido quimicamente , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
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