Graduation date: 1995

Förekomsten av bakterier med olika typer av resistensmekanismer ökar globalt. De varianter som på engelska benämns ”Extended spectrum β-lactamases” (ESBL) är en heterogen grupp β- laktamaser som genom hydrolys inaktiverar β-laktamantibiotika och därigenom ger resistens mot bland annat β -laktamantibiotika som penicilliner och cefalosporiner. Resistensbestämning på kliniska laboratorier utförs huvudsakligen med lappdiffusion eller Minimum Inhibiting Concentration (MIC)-bestämning med gradienttester. Infektioner orsakade av ESBL-producerande organismer kan behandlas med β-laktamantibiotika kombinerat med en β-laktamasinhibitor. I Europa rekommenderas resistensbestämning med bestämd koncentration β-laktamasinhibitor, men produkter på marknaden saknas. Syftet med projektet var att utvärdera olika typer av gradienttester med amoxicillin- klavulansyra från två leverantörer (Etest och MIC Test Strip, MTS) och undersöka hur klavulansyra påverkar resistensbestämningen, samt att se hur resultat från lappdiffusion korrelerar med resultat från ovan nämnda tester. Lappdiffusion och MIC- bestämning med gradienttester med antingen bestämt förhållande av amoxicillin-klavulansyra (2:1) (Etest och MTS) eller bestämd koncentration klavulansyra (2mg/L) (MTS) utfördes med Escherichia coli (både med ESBL-positiva och ESBL-negativa stammar) samt med Proteus mirabilis. ESBL-detektion med cefpodoxim och cefpodoxim-klavulansyra utfördes parallellt. För P. mirabilis korrelerade lappdiffusionsresultat mycket bra med resultat från samtliga gradienttester. För E. coli korrelerade lappdiffusionsresultat mycket bra med MIC-värden vid användning av Etest 2:1 medan MTS 2:1 gav högre MIC-värden än referensdistributionen och resulterade i sämre korrelation. MIC-bestämning med MTS 2 mg/L resulterade i högre MIC-värden. Den nuvarande zonbrytpunkten behöver justeras för att korrelera med tolkningen från amoxicillin-klavulansyra med bestämd koncentration av klavulansyra 2 mg/L, framförallt för ESBL- producerande E. coli.

This thesis describes a novel "Tablet-in-a-Bottle" oral suspension formulation. Ingredients with unstable physical or chemical characteristics can be placed in a core tablet, and then dry compression coated with an outer layer which provides separation from other components. The new suspension formulation comprises fast disintegrating clavulanic acid (KCA) tablets with a powder mixture containing amoxicillin. Hardness, friability, flow properties and weight uniformity of tablets for three different formulations were investigated and were all improved in a third formulation. Stability tests under different humidities were conducted. Amoxicillin and clavulanic acid in the new formulations showed the same stabilities when compared with the marketed product Augmentin��. Preliminary pharmacokinetics and bioavailability of one new formulation were evaluated by comparing in vitro release rates and in vivo urinary excretion rates. In vitro dissolution studies were carried out according to the USP XXIII paddle method. The new formulation showed faster release rates during the first hour when stirring speed was 25 rpm. However, when 75 rpm stirring speed was applied, the dissolution profiles for the new formulation and the reference marketed product were identical. A randomized two-way crossover bioequivalence study was designed to evaluate the bioavailabilities. Cmax, Tmax and AUC[subscript o--->t] of amoxicillin were within ��20% of the reference pharmacokinetic values. However, Cmax and Tmax of clavulanate were not within ��20%. Bioeqivalence between this new suspension formulation and the marketed product (Augmentin��) were evaluated using a two one-sided t-test. There is not sufficient statistical support with this test to conclude that the two products are bioequivalent. However, this is most likely due to small sample size and high intersubject variation and statistical support for bioequivalence is expected in a larger study group. / Graduation date: 1998

OBJECTIVES: Penicillin allergies are the most commonly reported drug allergy. However, recent research has supported the concept that reported penicillin allergy does not equal true allergy. False penicillin allergies and associated alternative antibiotic use can result in inferior clinical outcomes. Determination of true versus self-reported allergy can be determined through skin testing to penicillin and oral challenge to amoxicillin. Penicillin allergy evaluations improve antibiotic utilization but penicillin skin testing (PST) requires more resources than oral amoxicillin challenge alone. Because amoxicillin challenge without preceding PST may be safe in low-risk patients, we assessed a risk stratification tool for outpatient penicillin allergy evaluations that stratify low-risk patients to receive amoxicillin challenge without prior skin testing. METHODS: The patient population was identified using the Massachusetts General Hospital Allergy Associates clinic schedule in EPIC from the beginning of January 2017 through the end of July 2018. Patients were classified into one of two evaluation methods based on allergy history, using the MGH Allergy Associates Outpatient Penicillin Allergy Pathway. Patients deemed low-risk were evaluated with direct 2-step oral amoxicillin challenge. Intermediate-risk patients were evaluated with PST and subsequent oral amoxicillin challenge. Skin testing (ST) was performed using epi-cutaneous prick tests with a major and minor determinate of penicillin, histamine (positive) and saline (negative) controls, followed by intradermal injections of the same reagents. ST was followed by one oral dose of 500mg amoxicillin. Direct oral challenge involved doses of 50mg of amoxicillin in the first step or 500mg of amoxicillin in the second step. These patients’ charts were retrospectively reviewed for information regarding the initial antibiotic allergic reaction, type of allergy testing administered, and outcomes of the outpatient allergy testing. Analysis was performed to assess and significant differences in patient characteristics, safety, and outcomes in patients given preceding skin testing or direct oral amoxicillin challenge. RESULTS: Overall, 509 eligible patients were reviewed. Four hundred twenty-six patients underwent PST with subsequent oral amoxicillin challenge. The remaining 83 patients received direct, two-step oral amoxicillin challenge. Across both groups, 43 adverse drug reactions (ADRs) were observed, 26 of which were considered hypersensitivity reactions (HSRs). The proportion of patients in each testing group that experienced ADRs was near equal, 8.5% of the skin tested group and 8.4% of the direct challenge group. One patient in each group had an HSR requiring treatment with epinephrine. Using multivariate logarithmic analysis to evaluate potential predictors for ADRs and HSRs, female sex was the only variable associated with significant increased odds for an ADR. There were no significant findings for increased odds for HSRs, including evaluation method with direct drug challenge. The proportion of patients considered to have a true penicillin allergy was similar in the two groups. DISCUSSION: PST is a vitally important aspect of antibiotic stewardship, especially when conducted before antibiotic treatment is required. Though the standard procedure is skin testing with penicillin, followed by oral amoxicillin challenge, direct oral challenges can be considered for appropriately selected low-risk patients presenting for penicillin allergy evaluation. PST is nonetheless advisable for patients with higher risk allergy histories, pregnant patients, and patients with tenuous cardiac or pulmonary status.

This thesis is compromised of two distinct formulation sections, which are described below: New compression-coated tablet formulations were developed for amoxicillin/clavulanate. Amoxicillin in an outer coat was separated from clavulanic acid in a core tablet by inactive ingredients in a middle coat. A chewable compression-coated tablet formulation with 50% stearic acid in the middle coat showed high clavulanic acid stability in comparison to the marketed traditional tablet formulation. Stearic acid acted as a hydrophobic barrier that prevents passage of moisture through the outer coats into the core and it helped in the bonding of the outer coats to the core because it softens upon compression. The bioavailability of clavulanic acid, however, was reduced which was attributed to the effect of stearic acid. Stearic acid was removed from the formulation of swallow tablets and replaced with Avicel��, consequently, the outer coat did not adhere tightly to the core and tended to cap off, which resulted in low stability of clavulanic acid. In bioavailability studies of the swallow tablets, the two formulations were equivalent to the marketed formulation for amoxicillin, but not for clavulanic acid, which is most likely due to the small sample size studied and high intersubject variation. Nisin, an antimicrobial protein, was evaluated for ability to emulsify oil-in-water using conductivity measurements. In comparison to Tween�� 80 and ��-casein, nisin showed substantial emulsifying activity. The emulsifying activity was found to be highly concentration- and pH-dependent. Nisin was found to form a gel-like structure at the oil water interface which retarded release of the drug sulfasalazine. Interfacial tension kinetics exhibited by nisin at an oil-water interface were monitored with DuNoy tensiometry. Interfacial pressure kinetics were interpreted with reference to a simple model that allows for a protein to be adsorbed in structurally dissimilar states. The model suggested that nisin's tendency to adapt a more unfolded structure at the oil-water interface increases with decreasing concentration. The effects of nisin on drug release from oil-in-water emulsions, and on erythrocytes were evaluated as well. It was found that nisin retards drug release in emulsions and lyses red blood cells. / Graduation date: 1999

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1991. / Vita. Abstract. Includes bibliographical references (leaves 44-51). Also available via the Internet.

The investigations in this dissertation have been 'conducted to investigate the formulation and analysis of a paediatric amoxycillin suppository. The oral administration of antibiotics to young children can at times be roblematic. Compliance is sometimes poor because of a sore throat, nausea, vomiting, a high fever or a dislike for the taste or smell of the medicine:- In-such cases the rectal administration of an antibiotic could provide an alternative route of administration that avoids some of the problems that affect oral administration. Difficulties associated with rectal administration are bioavailability, local irritation, acceptability to patients and rejection of the dosage form. Few data, however, are available on the usefulness in children of suppositories in general, and antibiotic suppositories in particular. The areas of investigation have included the formulation of an amoxycillin suppository in various fatty bases, the quantitation of amoxycillin in both aqueous solution and human serum, assessment of stability of amoxycillin in stored aqueous and biological samples, in vitro drug release testing of suppositories, and bioavailability and pharmacokinetics following administration to human subjects of capsule, suppository, oral suspension and rectal suspension dosage forms. Suppositories containing 250 mg amoxycillin were prepared in theobroma oil and in the semisynthetic bases Witepso[ W35, Suppocire A32, Novata BD and Novata 299. The in vitro release characteristics of amoxycillin from these lipophilic suppository formulations were investigated using the USP rotating basket method. The dissolution of a drug from a solid dosage unit is an important parameter affecting drug bioavialability. High Performance Liquid Chromatography (HPLC) was used as the main analytical technique. An original HPLC method for analysis of amoxycillin in aqueous solution, using ultraviolet detection at 230 nm was develcfped. The validated method was a~plied to the determination of the stability of aqueous amoxycillin solutions, and was utilized to determine the amount of drug released during dissolution testing. Differential scanning calorimetry (DSC) is a technique commonly used in preformulation studies. Dissolution testing was used in conjunction with DSC to select a suppository base suitable for formulation with amoxycillin trihydrate. An HPLC method for analysis of amoxycillin in human serum using UV detection at 230 nm is presented. The method involves a solid phase extraction procedure followed by chromatography on a reversed phase column. The limit of sensitivity of 0.3 ILg/mL in serum is sufficiently sensitive to monitor serum concentrations of amoxycillin in humans after the administration of a single 250 mg oral dose. Pharmacokinetic parameters were calculated from data obtained following the administration of a capsule and oral suspension. These parameters were consistent with previously published results. Following administration of a lipophilic suppository and a rectal suspension, to human volunteers, it was concluded that amoxycillin trihydrate is not readily absorbed from the rectum. Further investigations into the modification of the suppository dosage form with absorption enhancers to improve rectal absorption of amoxycillin, as well as elucidation of the mechanism of absorption of the drug, could assist in improving this formulation so that it is suitable for paediatric use.

Made available in DSpace on 2014-12-02T11:16:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-11-19Bitstream added on 2014-12-02T11:21:08Z : No. of bitstreams: 1 000739611_20150901.pdf: 184242 bytes, checksum: f2983c9fe2f0e1828f684d9a828fa734 (MD5) Bitstreams deleted on 2015-09-01T11:42:31Z: 000739611_20150901.pdf,. Added 1 bitstream(s) on 2015-09-01T11:43:05Z : No. of bitstreams: 1 000739611.pdf: 2181513 bytes, checksum: 43fa21f5dbb88909e854a9b0310a0e69 (MD5) / O uso da amoxicilina durante a primeira infância tem sido relacionado ao desenvolvimento de defeitos de esmalte denominados Hipomineralização Molar-Incisivo (HMI). Ademais, há relatos de possível potencialização dos efeitos do fluoreto no esmalte pela amoxicilina. Objetivo: A proposta do presente estudo foi avaliar o efeito da amoxicilina, e da associação amoxicilina com fluoreto no desenvolvimento do esmalte dentário de ratos. Metodologia: O experimento foi dividido em três capítulos. Capítulo 1 - Quinze ratas prenhas (Rattus norvegicus, albinus, Holtzman) foram aleatoriamente distribuídas em três grupos que receberam, a cada 24 h, dose intragástrica de amoxicilina 100 mg/kg/dia (grupo GA100), amoxicilina 500 mg/kg/dia (grupo GA500) ou soro fisiológico (grupo GS), a partir do 130 dia de prenhez. Após o nascimento, doze filhotes de cada grupo receberam o mesmo tratamento das respectivas mães durante os períodos de 7 dias (n=6) e 12 dias (n=6) de vida. Após a eutanásia, as cabeças dos ratos foram removidas, fixadas e processadas para inclusão em parafina. Os cortes frontais da cabeça exibindo os primeiros molares superiores foram em parte corados com H&E e em parte submetidos à reação imuno-histoquímica para detecção de amelogenina e metaloproteinases da matriz-20 (MMP-20). Os cortes corados com H&E foram utilizados para análise morfológica e mensuração da espessura da camada de esmalte. A imunoexpressão para amelogenina e MMP-20 foram avaliados por análise semiquantitativa (H-score). Os dados foram analisados estatisticamente pelo teste Tukey com nível de significância de 5%. Capítulo 2 - Quinze ratas prenhas (Rattus norvegicus, albinus, Holtzman) foram aleatoriamente distribuídas em três grupos, que receberam, amoxicilina 100 mg/kg/dia (grupo GA100), amoxicilina 500 mg/kg/dia (grupo GA500) ou soro fisiológico (grupo GS), conforme descrito no capítulo 1. Após o na... / Background: Amoxicillin use in early childhood has been associated with molarincisor hypomineralization. Moreover, it has been supposed an association between amoxicillin and fluoride on enamel defects. Aim. This study aimed to evaluate in vivo the effect of amoxicillin and amoxicillin associated with fluoride on the enamel development of rat tooth. Materials and Methods: The research was divided into three studies. Chapter 1 – Fifteen pregnant Holtzman rats (Rattus norvegicus albinus) were divided randomly into three groups to receive saline (SG), 100 mg/kg/day amoxicillin (A100G), or 500 mg/kg/day amoxicillin (A500G), intragastrically, from days 13 to 22 of pregnancy. Twelve offsprings per group got the same dose until day 12. After 7 and 12 days, the specimens were fixed and embedded in paraffin. In the HEstained sections, the thickness of enamel matrix of upper molar germs was evaluated. Moreover, detection of amelogenin on day 7 and matrix metalloproteinase 20 (MMP - 20) on day 12 by immunohistochemistry were carried out. Chapter 2 - Fifteen rats (Rattus norvegicus, Albinus,Holtzman) were randomly divided into three groups to receive saline (SG), 100 mg/kg/day amoxicillin (A100G), or 500 mg/kg/day amoxicillin (A500G), as described in Chapter 1. Ten offspring per group received the same dose until day 40. The animals were euthanized on day 40. A total of 60 upper incisors and 60 upper first molars from 30 animals were dissected. Calcium (Ca) determination was performed by the compleximetric titration method and phosphorus (Pi) determination by colorimetric analysis using a spectrophotometer at 680 nm. A total of 30 lower first molars from 15 animals were analyzed under X-ray microtomography (XMT). Chapter 3 - Forty rats were, randomly, divided into four groups exposed to fluoride in water (100 ppm (mg F/L) or intragastric administration of amoxicillin (500 mg /kg body weight), according to the...

Orientador: Rita de Cássia Loiola Cordeiro / Co-orientador: Paulo Sergio Cerri / Banca: Lourdes dos Santos-Pinto / Banca: Angela Cristina Cilense Zuanon / Banca: Soraya Leal / Banca: Victor Aranha-Chaves / Resumo: O uso da amoxicilina durante a primeira infância tem sido relacionado ao desenvolvimento de defeitos de esmalte denominados Hipomineralização Molar-Incisivo (HMI). Ademais, há relatos de possível potencialização dos efeitos do fluoreto no esmalte pela amoxicilina. Objetivo: A proposta do presente estudo foi avaliar o efeito da amoxicilina, e da associação amoxicilina com fluoreto no desenvolvimento do esmalte dentário de ratos. Metodologia: O experimento foi dividido em três capítulos. Capítulo 1 - Quinze ratas prenhas (Rattus norvegicus, albinus, Holtzman) foram aleatoriamente distribuídas em três grupos que receberam, a cada 24 h, dose intragástrica de amoxicilina 100 mg/kg/dia (grupo GA100), amoxicilina 500 mg/kg/dia (grupo GA500) ou soro fisiológico (grupo GS), a partir do 130 dia de prenhez. Após o nascimento, doze filhotes de cada grupo receberam o mesmo tratamento das respectivas mães durante os períodos de 7 dias (n=6) e 12 dias (n=6) de vida. Após a eutanásia, as cabeças dos ratos foram removidas, fixadas e processadas para inclusão em parafina. Os cortes frontais da cabeça exibindo os primeiros molares superiores foram em parte corados com H&E e em parte submetidos à reação imuno-histoquímica para detecção de amelogenina e metaloproteinases da matriz-20 (MMP-20). Os cortes corados com H&E foram utilizados para análise morfológica e mensuração da espessura da camada de esmalte. A imunoexpressão para amelogenina e MMP-20 foram avaliados por análise semiquantitativa (H-score). Os dados foram analisados estatisticamente pelo teste Tukey com nível de significância de 5%. Capítulo 2 - Quinze ratas prenhas (Rattus norvegicus, albinus, Holtzman) foram aleatoriamente distribuídas em três grupos, que receberam, amoxicilina 100 mg/kg/dia (grupo GA100), amoxicilina 500 mg/kg/dia (grupo GA500) ou soro fisiológico (grupo GS), conforme descrito no capítulo 1. Após o na... / Abstract: Background: Amoxicillin use in early childhood has been associated with molarincisor hypomineralization. Moreover, it has been supposed an association between amoxicillin and fluoride on enamel defects. Aim. This study aimed to evaluate in vivo the effect of amoxicillin and amoxicillin associated with fluoride on the enamel development of rat tooth. Materials and Methods: The research was divided into three studies. Chapter 1 - Fifteen pregnant Holtzman rats (Rattus norvegicus albinus) were divided randomly into three groups to receive saline (SG), 100 mg/kg/day amoxicillin (A100G), or 500 mg/kg/day amoxicillin (A500G), intragastrically, from days 13 to 22 of pregnancy. Twelve offsprings per group got the same dose until day 12. After 7 and 12 days, the specimens were fixed and embedded in paraffin. In the HEstained sections, the thickness of enamel matrix of upper molar germs was evaluated. Moreover, detection of amelogenin on day 7 and matrix metalloproteinase 20 (MMP - 20) on day 12 by immunohistochemistry were carried out. Chapter 2 - Fifteen rats (Rattus norvegicus, Albinus,Holtzman) were randomly divided into three groups to receive saline (SG), 100 mg/kg/day amoxicillin (A100G), or 500 mg/kg/day amoxicillin (A500G), as described in Chapter 1. Ten offspring per group received the same dose until day 40. The animals were euthanized on day 40. A total of 60 upper incisors and 60 upper first molars from 30 animals were dissected. Calcium (Ca) determination was performed by the compleximetric titration method and phosphorus (Pi) determination by colorimetric analysis using a spectrophotometer at 680 nm. A total of 30 lower first molars from 15 animals were analyzed under X-ray microtomography (XMT). Chapter 3 - Forty rats were, randomly, divided into four groups exposed to fluoride in water (100 ppm (mg F/L) or intragastric administration of amoxicillin (500 mg /kg body weight), according to the... / Doutor

Made available in DSpace on 2015-09-17T15:25:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-05. Added 1 bitstream(s) on 2015-09-17T15:49:25Z : No. of bitstreams: 1 000845518_20160402.pdf: 83963 bytes, checksum: b27fb8e88a318385605bd8bd1405bf1a (MD5) Bitstreams deleted on 2016-04-04T12:10:26Z: 000845518_20160402.pdf,. Added 1 bitstream(s) on 2016-04-04T12:11:06Z : No. of bitstreams: 1 000845518.pdf: 674514 bytes, checksum: 62da913b8ef513635c243ef06495c521 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Cimentos endodônticos associados à amoxicilina têm sido pesquisados como uma alternativa para obturação do canal radicular. Os objetivos do presente estudo foram: Avaliar a citocompatibilidade do AH Plus e do Sealapex associados com amoxicilina em quantidade de 10% do peso total dos cimentos (Capítulo 1) e avaliar o escoamento e o tempo de presa dos cimentos AH Plus e Sealapex associados à amoxicilina em diferentes concentrações e a atividade antibiofilme dos cimentos associados a uma maior concentração de amoxicilina que não altera as propriedades físicas de ambos os cimentos (Capítulo 2). No Capítulo 1 a citocompatibilidade dos materiais foi avaliada utilizando fibroblastos L929 expostos por 24 horas a diferentes diluições dos extratos dos cimentos puros e associados à amoxicilina. Os ensaios de brometo de 3-(4,5-dimetil-2-tiazolil )-2,5-difenil-2Htetrazólio (MTT) e vermelho neutro foram utilizados para avaliação da viabilidade celular e a fluorescência para actina e α-tubulina foram utilizadas para análise do citoesqueleto. Os dados foram analisados empregando a análise de variância a dois critérios e pós teste de Bonferroni, com nível de significância de 5%. Os resultados mostraram que a incorporação de amoxicilina na concentração de 10% do peso total dos cimentos não diminuiu a viabilidade dos fibroblastos e não causou alterações estruturais nos componentes do citoesqueleto estudados. Conclui-se que à amoxicilina poderia ser um agente antimicrobiano promissor para ser incorporada aos cimentos endodônticos. No Capítulo 2 o escoamento a o tempo de presa dos cimentos puros ou associados à amoxicilina em concentrações de 0,25 a 10% foram estudadas de acordo com a especificação no6876 da Organização Internacional de Padronização (ISO 2012). A avaliação antibiofilme dos cimentos puros e associados à amoxicilina 1% foi realizada por teste de contato...(Resumo completo clicar acesso eletrônico) / Sealers associatedwith amoxicillinhave been developed as an alternative to root canal filling. The objectives of this study were to evaluate the cytocompatibility of AH Plus and Sealapex associated with amoxicillin in concentration of 10% of the total weight of sealer (Chapter 1) and evaluate the flow and the setting time of AH Plus sealer and Sealapex associated with amoxicillin at different concentrations and the activity of sealers antibiofilm associated with higher concentrations of amoxicillin which does not alter the physical properties of both sealers (Chapter 2). In Chapter 1 cytocompatibility of the materials was assessed using the L929 fibroblasts exposed for 24 hours with different dilutions of the extracts of pure sealer and associated with amoxicillin. The testing of 3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium (MTT), and neutral red were used for evaluation of cell viability and fluorescence actin and α-tubulin were used for analysis of the cytoskeleton. Data were analyzed using analysis of variance and two criteria Bonferroni post test at 5% significance level. The results showed that incorporation of amoxicillin at a concentration of 10% by weight of the sealer did not decrease the viability of fibroblasts and did not cause structural changes in the cytoskeletal components studied. It is concluded that amoxicillin could be a promising antimicrobial agent to be incorporated in sealers. In chapter 2 the flow and setting time of the sealer pure or associated with amoxicillin from 0.25 to 10% concentrations were evaluated according to no 6876 specification of the International Organization for Standardization (ISO 2012). The antibiofilm evaluation of pure sealer and 1% associated with amoxicillin was performed by direct contact test with Enterococcus faecalis biofilm previously induced in bovine dentin for 14 days. Fresh sealer were in contact with the biofilm... (Complete abstract electronic access below)