The thesis deals with the evaluation of the impact of preoperative application of gentamicin on vestibular compensations of patient after vestibular schwannoma surgery. The trial involved 32 patients with diagnosed vestibular schwannoma and hospitalized with the indicated for neurosurgical resection at the University Hospital Motol. Ototoxic gentamicin was transtympanically applied to ten of these patients two months before their surgery. After the surgery the patients underwent a rehabilitation program based on the visual biofeedback using the Homebalance system. To evaluate the vestibular compensation the subjective visual vertical measurement and the Dynamic Gait Index standardized walking test were used. In total, each patient performed three examinations: before the surgery, after the surgery and before the end of hospitalization. Statistical analysis of the measured data showed the statistically significant increase tilt of subjective visual vertical and the decrease in the overall score of Dynamic Gait Index after surgery. Reduction in the subjective visual vertical tilt and the overall score of Dynamic Gait Index after rehabilitation has not been proven to be statistically significant. Any statistically significant difference was found between the group of patients treated by gentamicin and...

Les pneumopathies acquises sous ventilation mécanique (PAVM) sont responsables d'une mortalité élevée. La nébulisation d'antibiotiques permet d'améliorer l'efficacité de leur traitement. Pour autant, aucune donnée pharmacocinétique portant sur la colistine et la gentamicine ne permet de recommander un schéma posologique particulier.Nous avons comparé les propriétés pharmacocinétiques plasmatique et intra-pulmonaire de la colistine (administrée sous forme de prodrogue, le colistiméthate sodique ou CMS) et de la gentamicine selon le mode d'administration (nébulisation ou perfusion intraveineuse) chez des patients de réanimation présentant une PAVM.Les concentrations intra-pulmonaires de colistine et de gentamicine étaient, respectivement, de 10 à 40 et 50 à 70 fois supérieures, après nébulisation, à celles retrouvées après administration d'une même dose par voie intraveineuse. La nébulisation permettrait également de limiter le risque de toxicité systémique avec une biodisponibilité inférieure à 10%.En assurant de fortes concentrations intra-pulmonaires et un faible passage systémique, la nébulisation de CMS et de gentamicine pourrait être une bonne alternative à leur administration intraveineuse dans le traitement des PAVM. / Ventilator-associated pneumonia (VAP) is associated with high mortality. Nebulization of antibiotics improves outcome of patient with VAP. However, pharmacokinetic data concerning colistin and gentamicin allowing for optimal dosing regimen recommendation are lacking.We compared systemic and pulmonary concentrations of colistin (administered as an inactive prodrug, colistin methanesulfonate or CMS) and gentamicin according to the route of administration (nebulization and intravenous infusion) in critically ill patients with VAP.Intra-pulmonary concentrations of colistin and gentamicin were 10 to 40-fold and 50 to 70-fold much higher after nebulization than after the same dose by intravenous route, respectively. Nebulization has also the theoretical potential advantage to improve patients' safety in relation to the colistin biodisponibility lower than 10%.With high intra-pulmonary concentrations and very low systemic absorption, CMS and gentamicin nebulization may be good alternatives to intravenous infusion for VAP treatment.

A infecção bacteriana é a principal complicação que um procedimento de artroplastia de quadril ou joelho pode apresentar. Mesmo após a incorporação de antibiótico (gentamicina) ao cimento ósseo, as taxas de infecções após este procedimento cirúrgico continuam gerando sérios prejuízos para o hospital e para o paciente. As principais bactérias envolvidas nas infecções relacionadas aos implantes ortopédicos são Pseudomonas aeruginosa, Staphylococcus aureus e Staphylococcus epidermidis. O objetivo deste trabalho foi avaliar a aderência e formação de biofilme de S. aureus, S. epidermidis e P. aeruginosa sobre o cimento ósseo polimetilmetacrilato (PMMA) com e sem antibiótico (gentamicina), de procedência nacional e internacional, por meio de microscópio eletrônico de varredura (MEV) e por cultura. Também, estimar quantitativamente as células viáveis recuperadas dos biofilmes formados. Foram produzidos discos de polimetilmetacrilato de 10,0 mm de diâmetro e 3,0 mm de espessura. Foram utilizadas cepas Pseudomonas aeruginosa - ATCC 27853, Staphylococcus epidermidis - ATCC 12228 e Staphylococcus aureus - ATCC 25932. Para este estudo foram utilizados corpos-de-prova de cimento ósseo de procedência nacional (BAUMER, CMM e BIOMECANICA) e internacional (BIOMET com gentamicina, BIOMET sem gentamicina e SIMPLEX). Biofilmes foram produzidos in vitro a partir da inoculação da suspensão bacteriana (\'10 POT.8\' unidades formadoras de colônia/mL) em Tryptic Soy Broth e incubados nos períodos de tempo de 1, 6, 24, 48, e 72 horas. Após os períodos de incubação os corpos-de-prova foram removidos do meio de cultura, lavados, sonicados e do sobrenadante realizadas diluições seriadas (\'10 POT.-1\' a \'10 POT.-5\'). A seguir, os corpos-de-prova foram preparados para observação por MEV. Os resultados de MEV mostraram bacilos e cocos aderidos e agrupados formando biofilme. Para P. aeruginosa: as contagens das células viáveis em média (UFC/mL) foram de 2,8 \'+ OU -\' 1,7 x \'10 POT.6\' (BAUMER), 1,7 \'+ OU -\' 0,9 x \'10 POT.6\' (BIOMECANICA), 1,7 \'+ OU -\' 0,7 x \'10 POT.6\' (CMM), 1,6 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMET sem gentamicina), 6,0 \'+ OU -\' 5,5 x \'10 POT.4\' (BIOMET com gentamicina) e 1,9 \'+ OU -\' 0,9 x \'10 POT.6\' (SIMPLEX); para S. epidermidis: 1,3 \'+ OU -\' 0,1 x \'10 POT.6\' (BAUMER), 1,5 \'+ OU -\' 0,2 x \'10 POT.6\' (BIOMECANICA), 2,3 \'+ OU -\' 1,7 x \'10 POT.6\' (CMM), 1,5 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMET sem gentamicina), 1,5 \'+ OU -\' 0,2 x \'10 POT.6\' (BIOMET com gentamicina) e 1,2 \'+ OU -\' 0,1 x \'10 POT.6\' (SIMPLEX); para S. aureus: 1,7 \'+ OU -\' 0,8 x \'10 POT.6\' (BAUMER), 1,6 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMECANICA), 1,4 \'+ OU -\' 0,6 x \'10 POT.6\' (CMM), 1,1 \'+ OU -\' 0,5 x \'10 POT.6\' (BIOMET sem gentamicina), 3,0 \'+ OU -\' 6,0 x \'10 POT.5\' (BIOMET com gentamicina) e 1,3 \'+ OU -\' 0,6 x \'10 POT.6\' (SIMPLEX), respectivamente. Os dados obtidos mostraram que o cimento ósseo de polimetilmetacrilato com e sem gentamicina não evitaram a aderência da Pseudomonas aeruginosa, Staphylococcus epidermidis e Staphylococcus aureus e formação de biofilme, como demonstrado pela MEV. Em conclusão, isto é um fator de risco para infecções. / The bacterial infection is the main complication of a procedure for hip or knee arthroplasty can present. Even after the addition of antibiotic (gentamicin) in the bone cement, the rates of infection after the surgical procedure continue causing serious damage to the hospital and the patient. The main bacteria involved in infections related to orthopedic implants are Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis. The objective of this study was to evaluate the adhesion and biolfilm formation of the S. aureus, S. epidermidis and P. aeruginosa on the bone cement polymethylmethacrylate (PMMA) with and without antibiotic (gentamicin) from national and international origin, by means scanning electron microscope (SEM) and by culture. Also, quantitatively estimate the viable cells recovered from biofilms formed. Discs of cement were produced from 10.0 mm in diameter and 3.0 mm thick. Strains used were Pseudomonas aeruginosa - ATCC 27853, Staphylococcus epidermidis - ATCC 12228 e Staphylococcus aureus - ATCC 25932. For this study we used coupons cement of national origin (Baumer, CMM and biomechanics) and international (BIOMET with gentamicin, BIOMET without gentamicin and SIMPLEX). Biofilms were produced in vitro from the inoculation of bacterial suspension (108 Colony-Forming Units/mL) in Tryptic Soy Broth and incubated for the time periods of 1, 6, 24, 48 and 72 hours. After the incubation periods of the coupons they were removed from the medium culture, washed, sonicated and serial dilutions of supernatant taken (\'10 POT.-1\' a \'10 POT.-5\'). Next, the coupons were prepared for observation by SEM. The results of SEM showed adherent cocci bacilli, and adhered to each other form a biofilm. For P. aeruginosa: the couting of viable cells on average (CFU/mL) were 2,8 \'+ OU -\' 1,7 x \'10 POT.6\' (BAUMER), 1,7 \'+ OU -\' 0,9 x \'10 POT.6\' (BIOMECANICA), 1,7 \'+ OU -\' 0,7 x \'10 POT.6\' (CMM), 1,6 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMET sem gentamicina), 6,0 \'+ OU -\' 5,5 x \'10 POT.4\' (BIOMET com gentamicina) e 1,9 \'+ OU -\' 0,9 x \'10 POT.6\' (SIMPLEX); para S. epidermidis: 1,3 \'+ OU -\' 0,1 x \'10 POT.6\' (BAUMER), 1,5 \'+ OU -\' 0,2 x \'10 POT.6\' (BIOMECANICA), 2,3 \'+ OU -\' 1,7 x \'10 POT.6\' (CMM), 1,5 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMET sem gentamicina), 1,5 \'+ OU -\' 0,2 x \'10 POT.6\' (BIOMET com gentamicina) e 1,2 \'+ OU -\' 0,1 x \'10 POT.6\' (SIMPLEX); para S. aureus: 1,7 \'+ OU -\' 0,8 x \'10 POT.6\' (BAUMER), 1,6 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMECANICA), 1,4 \'+ OU -\' 0,6 x \'10 POT.6\' (CMM), 1,1 \'+ OU -\' 0,5 x \'10 POT.6\' (BIOMET sem gentamicina), 3,0 \'+ OU -\' 6,0 x \'10 POT.5\' (BIOMET com gentamicina) e 1,3 \'+ OU -\' 0,6 x \'10 POT.6\' (SIMPLEX), respectively. The data showed that of polymethylmethacrylate bone cement with and without gentamicin did not prevent the adhesion of Pseudomonas aeruginosa, Staphylococcus epidermidis and Staphylococcus aureus and formation of biofilms, as demonstrated by SEM. In conclusion, this is risk factor for infections.

<p>Patients with idiopathic anal fistula (n=85) were compared with 215 control subjects, matched for age and sex, through a 180-item questionnaire. Obesity, smoking, constipation and bowel symptoms associated with IBS were more common in the patients.</p><p>Endoanal ultrasound (EUS) and magnetic resonance imaging (MRI) were compared in the preoperative evaluation of anal fistula in 23 patients. For classifying the primary tract, EUS and surgical findings agreed in 14 cases, and MRI and surgery for 11: for identifying an internal opening, the corresponding figures were 17 and 10.</p><p>Healing and sphincter function were studied in 42 patients operated with fistula excision and closure of the internal opening. Twenty-three patients healed primarily and another 10 after one re-operation, whereas nine required further surgery until healed. Anal resting pressure was reduced after three and 12 months, and squeeze pressure after 12 months.</p><p>Eighty-three patients were randomised to surgery with or without application of gentamicin-collagen underneath the flap: 26/42 of patients randomised to gentamicin-collagen healed primarily compared with 21/41 of patients randomised to surgery only (n.s).</p><p>Micro perfusion in the flap was studied by laser Doppler flowmetry during surgery in 16 patients. No correlation was seen between change in blood flow during surgery and non-healing/recurrence of the fistula.</p><p>In conclusion, obesity, functional bowel symptoms and possibly smoking are more common in patients with idiopathic anal fistula than in the general population. Endoanal ultrasound is a useful tool in the preoperative evaluation of anal fistula. Advancement flap repair has a reasonably high primary recurrence rate and healing is not significantly improved by local application of gentamicin-collagen: impaired intraoperative blood perfusion of the flap is an unlikely reason for non-healing. A decrease in continence occurs also after this kind of surgery, probably due to an impaired internal anal sphincter function.</p>

Patients with idiopathic anal fistula (n=85) were compared with 215 control subjects, matched for age and sex, through a 180-item questionnaire. Obesity, smoking, constipation and bowel symptoms associated with IBS were more common in the patients. Endoanal ultrasound (EUS) and magnetic resonance imaging (MRI) were compared in the preoperative evaluation of anal fistula in 23 patients. For classifying the primary tract, EUS and surgical findings agreed in 14 cases, and MRI and surgery for 11: for identifying an internal opening, the corresponding figures were 17 and 10. Healing and sphincter function were studied in 42 patients operated with fistula excision and closure of the internal opening. Twenty-three patients healed primarily and another 10 after one re-operation, whereas nine required further surgery until healed. Anal resting pressure was reduced after three and 12 months, and squeeze pressure after 12 months. Eighty-three patients were randomised to surgery with or without application of gentamicin-collagen underneath the flap: 26/42 of patients randomised to gentamicin-collagen healed primarily compared with 21/41 of patients randomised to surgery only (n.s). Micro perfusion in the flap was studied by laser Doppler flowmetry during surgery in 16 patients. No correlation was seen between change in blood flow during surgery and non-healing/recurrence of the fistula. In conclusion, obesity, functional bowel symptoms and possibly smoking are more common in patients with idiopathic anal fistula than in the general population. Endoanal ultrasound is a useful tool in the preoperative evaluation of anal fistula. Advancement flap repair has a reasonably high primary recurrence rate and healing is not significantly improved by local application of gentamicin-collagen: impaired intraoperative blood perfusion of the flap is an unlikely reason for non-healing. A decrease in continence occurs also after this kind of surgery, probably due to an impaired internal anal sphincter function.

Antibiotics are among the most commonly prescribed drugs. Although the majority of these drugs were developed several decades ago, optimal dosage (dose, dosing interval and treatment duration) have still not been well defined. This thesis focuses on the development and evaluation of pharmacometric models that can be used as tools in the establishment of improved dosing strategies for novel and already clinically available antibacterial drugs. Infectious diseases are common causes of death in preterm and term newborn infants. A population pharmacokinetic (PK) model for gentamicin was developed based on data from a prospective study. Body-weight and age (gestational and post-natal age) were found to be major factors contributing to variability in gentamicin clearance and therefore important patient characteristics to consider for improved dosing regimens. A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model was also developed, to characterize in vitro bacterial growth and killing kinetics following exposure to six antibacterial drugs, representing a broad selection of mechanisms of action and PK as well as PD characteristics. The model performed well in describing a wide range of static and dynamic drug exposures and was easily applied to other bacterial strains and antibiotics. It is, therefore, likely to find application in early drug development programs. Dosing of antibiotics is usually based on summary endpoints such as the PK/PD indices. Predictions based on the PKPD model showed that the commonly used PK/PD indices were well identified for all investigated drugs, supporting that models based on in vitro data can be predictive of antibacterial effects observed in vivo. However, the PK/PD indices were sensitive to the study conditions and were not always consistent between patient populations. The PK/PD indices may therefore extrapolate poorly across sub-populations. A semi-mechanistic modeling approach, utilizing the type of models described here, may thus have higher predictive value in a dose optimization tailored to specific patient populations.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

A infecção bacteriana é a principal complicação que um procedimento de artroplastia de quadril ou joelho pode apresentar. Mesmo após a incorporação de antibiótico (gentamicina) ao cimento ósseo, as taxas de infecções após este procedimento cirúrgico continuam gerando sérios prejuízos para o hospital e para o paciente. As principais bactérias envolvidas nas infecções relacionadas aos implantes ortopédicos são Pseudomonas aeruginosa, Staphylococcus aureus e Staphylococcus epidermidis. O objetivo deste trabalho foi avaliar a aderência e formação de biofilme de S. aureus, S. epidermidis e P. aeruginosa sobre o cimento ósseo polimetilmetacrilato (PMMA) com e sem antibiótico (gentamicina), de procedência nacional e internacional, por meio de microscópio eletrônico de varredura (MEV) e por cultura. Também, estimar quantitativamente as células viáveis recuperadas dos biofilmes formados. Foram produzidos discos de polimetilmetacrilato de 10,0 mm de diâmetro e 3,0 mm de espessura. Foram utilizadas cepas Pseudomonas aeruginosa - ATCC 27853, Staphylococcus epidermidis - ATCC 12228 e Staphylococcus aureus - ATCC 25932. Para este estudo foram utilizados corpos-de-prova de cimento ósseo de procedência nacional (BAUMER, CMM e BIOMECANICA) e internacional (BIOMET com gentamicina, BIOMET sem gentamicina e SIMPLEX). Biofilmes foram produzidos in vitro a partir da inoculação da suspensão bacteriana (\'10 POT.8\' unidades formadoras de colônia/mL) em Tryptic Soy Broth e incubados nos períodos de tempo de 1, 6, 24, 48, e 72 horas. Após os períodos de incubação os corpos-de-prova foram removidos do meio de cultura, lavados, sonicados e do sobrenadante realizadas diluições seriadas (\'10 POT.-1\' a \'10 POT.-5\'). A seguir, os corpos-de-prova foram preparados para observação por MEV. Os resultados de MEV mostraram bacilos e cocos aderidos e agrupados formando biofilme. Para P. aeruginosa: as contagens das células viáveis em média (UFC/mL) foram de 2,8 \'+ OU -\' 1,7 x \'10 POT.6\' (BAUMER), 1,7 \'+ OU -\' 0,9 x \'10 POT.6\' (BIOMECANICA), 1,7 \'+ OU -\' 0,7 x \'10 POT.6\' (CMM), 1,6 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMET sem gentamicina), 6,0 \'+ OU -\' 5,5 x \'10 POT.4\' (BIOMET com gentamicina) e 1,9 \'+ OU -\' 0,9 x \'10 POT.6\' (SIMPLEX); para S. epidermidis: 1,3 \'+ OU -\' 0,1 x \'10 POT.6\' (BAUMER), 1,5 \'+ OU -\' 0,2 x \'10 POT.6\' (BIOMECANICA), 2,3 \'+ OU -\' 1,7 x \'10 POT.6\' (CMM), 1,5 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMET sem gentamicina), 1,5 \'+ OU -\' 0,2 x \'10 POT.6\' (BIOMET com gentamicina) e 1,2 \'+ OU -\' 0,1 x \'10 POT.6\' (SIMPLEX); para S. aureus: 1,7 \'+ OU -\' 0,8 x \'10 POT.6\' (BAUMER), 1,6 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMECANICA), 1,4 \'+ OU -\' 0,6 x \'10 POT.6\' (CMM), 1,1 \'+ OU -\' 0,5 x \'10 POT.6\' (BIOMET sem gentamicina), 3,0 \'+ OU -\' 6,0 x \'10 POT.5\' (BIOMET com gentamicina) e 1,3 \'+ OU -\' 0,6 x \'10 POT.6\' (SIMPLEX), respectivamente. Os dados obtidos mostraram que o cimento ósseo de polimetilmetacrilato com e sem gentamicina não evitaram a aderência da Pseudomonas aeruginosa, Staphylococcus epidermidis e Staphylococcus aureus e formação de biofilme, como demonstrado pela MEV. Em conclusão, isto é um fator de risco para infecções. / The bacterial infection is the main complication of a procedure for hip or knee arthroplasty can present. Even after the addition of antibiotic (gentamicin) in the bone cement, the rates of infection after the surgical procedure continue causing serious damage to the hospital and the patient. The main bacteria involved in infections related to orthopedic implants are Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis. The objective of this study was to evaluate the adhesion and biolfilm formation of the S. aureus, S. epidermidis and P. aeruginosa on the bone cement polymethylmethacrylate (PMMA) with and without antibiotic (gentamicin) from national and international origin, by means scanning electron microscope (SEM) and by culture. Also, quantitatively estimate the viable cells recovered from biofilms formed. Discs of cement were produced from 10.0 mm in diameter and 3.0 mm thick. Strains used were Pseudomonas aeruginosa - ATCC 27853, Staphylococcus epidermidis - ATCC 12228 e Staphylococcus aureus - ATCC 25932. For this study we used coupons cement of national origin (Baumer, CMM and biomechanics) and international (BIOMET with gentamicin, BIOMET without gentamicin and SIMPLEX). Biofilms were produced in vitro from the inoculation of bacterial suspension (108 Colony-Forming Units/mL) in Tryptic Soy Broth and incubated for the time periods of 1, 6, 24, 48 and 72 hours. After the incubation periods of the coupons they were removed from the medium culture, washed, sonicated and serial dilutions of supernatant taken (\'10 POT.-1\' a \'10 POT.-5\'). Next, the coupons were prepared for observation by SEM. The results of SEM showed adherent cocci bacilli, and adhered to each other form a biofilm. For P. aeruginosa: the couting of viable cells on average (CFU/mL) were 2,8 \'+ OU -\' 1,7 x \'10 POT.6\' (BAUMER), 1,7 \'+ OU -\' 0,9 x \'10 POT.6\' (BIOMECANICA), 1,7 \'+ OU -\' 0,7 x \'10 POT.6\' (CMM), 1,6 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMET sem gentamicina), 6,0 \'+ OU -\' 5,5 x \'10 POT.4\' (BIOMET com gentamicina) e 1,9 \'+ OU -\' 0,9 x \'10 POT.6\' (SIMPLEX); para S. epidermidis: 1,3 \'+ OU -\' 0,1 x \'10 POT.6\' (BAUMER), 1,5 \'+ OU -\' 0,2 x \'10 POT.6\' (BIOMECANICA), 2,3 \'+ OU -\' 1,7 x \'10 POT.6\' (CMM), 1,5 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMET sem gentamicina), 1,5 \'+ OU -\' 0,2 x \'10 POT.6\' (BIOMET com gentamicina) e 1,2 \'+ OU -\' 0,1 x \'10 POT.6\' (SIMPLEX); para S. aureus: 1,7 \'+ OU -\' 0,8 x \'10 POT.6\' (BAUMER), 1,6 \'+ OU -\' 0,7 x \'10 POT.6\' (BIOMECANICA), 1,4 \'+ OU -\' 0,6 x \'10 POT.6\' (CMM), 1,1 \'+ OU -\' 0,5 x \'10 POT.6\' (BIOMET sem gentamicina), 3,0 \'+ OU -\' 6,0 x \'10 POT.5\' (BIOMET com gentamicina) e 1,3 \'+ OU -\' 0,6 x \'10 POT.6\' (SIMPLEX), respectively. The data showed that of polymethylmethacrylate bone cement with and without gentamicin did not prevent the adhesion of Pseudomonas aeruginosa, Staphylococcus epidermidis and Staphylococcus aureus and formation of biofilms, as demonstrated by SEM. In conclusion, this is risk factor for infections.

L’ostéomyélite chronique est une infection chronique du tissu osseux et de la moelle. C’est une infection grave du fait de sa localisation au sein d’un tissu profond, de la complexité de sa prise en charge thérapeutique et de la mise en jeu du pronostic fonctionnel. L’incidence de l’ostéomyélite chronique est accrue sur certains terrains (drépanocytose, diabète, et polyarthrite rhumatoïde entre autres). Son traitement classique repose sur un curettage chirurgical associé à une antibiothérapie par voie générale durant au moins 6 semaines. Ce traitement est marqué le plus souvent par des échecs du fait de la difficulté de faire parvenir des antibiotiques à doses efficaces et de manière prolongée ou continue au niveau de l'os infecté.<p>\ / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

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