Background: The aim of surgical antibiotic prophylaxis (SAP) is to prevent surgical site infection (SSI) by administering an appropriate antimicrobial agent perioperatively. However, SAP may be associated with adverse effects and incurs added costs. The primary objective of this prospective study is to establish whether clinicians are adhering to existing perioperative antibiotic prophylaxis guidelines in terms of indication, dosage and timing of SAP. Secondary objectives are to determine the proportion of patients receiving inappropriate antibiotics; and to evaluate correct practice concerning re-dosing and duration of SAP. Methods: A cross-sectional prospective audit of the anaesthetic records and prescription charts of surgical patients was conducted at Groote Schuur Hospital, a tertiary level teaching hospital in Cape Town, South Africa, over a period of one week. Data were collected by anaesthetists – blinded to the study objectives – and the investigators; then captured on Excel spread sheets and compared to existing SAP guidelines. Descriptive statistics and binary logistic regression were used for analysis. Results: Of the 192 patients consented, 180 questionnaires were completed for data analysis. The median age of participants was 44.5 years (IQR: 31.5-58), with a preponderance of females (58.7%). SAP was administered in 149 cases (82.8%) and withheld in 31 (17.2%). This was appropriate in 91.9% (137/149) and 77.4% (24/31) respectively. Twelve patients (6.7%) received inappropriate antibiotics and in seven (3.9%) it was inappropriately withheld. Of the 156 patients who should have received SAP, choice of drug was correct in 121 (77.6%), dosage in 110 (70.5%) and timing in 87 (55.8%). Absolute compliance was achieved in 44.4% (80/180). Errors were mostly related to timing, re-dosing and duration of SAP. Conclusion: Anaesthetists and surgeons at Groote Schuur Hospital demonstrate variable adherence to surgical antibiotic prophylaxis guidelines. Interventions aimed at improving compliance are warranted.

Objective: To determine whether echocardiography affects the decisions to use beta blockers or to recommend bacterial endocarditis prophylaxis in patients suspected of having mitral valve prolapse (MVP). Design: Retrospective review of echocardiograms and clinical records. Setting: Military tertiary care hospital. Patients: 127 patients with clinically suspected MVP (105) or incidentally discovered MVP (22). Main results: Beta blockers were used more often in patients with suspected MVP and positive echocardiograms (45%) than in patients with normal echocardiograms (13%, p<0.001). Bacterial endocarditis prophylaxis was recommended more often in patients with suspected MVP and positive echocardiograms (65%) than in patients with normal echocardiograms (11%, p<0.001). Presence or absence of a murmur did not influence the decision to recommend bacterial endocarditis prophylaxis. Patients in whom MVP was incidentally discovered were unlikely to receive either beta blockers or the recommendation for bacterial endocarditis prophylaxis. Conclusions: The results of echocardiography affect the decisions to use beta blockers or to recommend bacterial endocarditis prophylaxis in patients with suspected MVP.

Objective: Serious morbidity and mortality following snakebite injuries are common in tropical regions of the world. Although antivenom administration is clinically effective, it carries an important risk of early anaphylactic reactions, ranging from relatively benign nausea, vomiting, and urticaria to life-threatening angioedema, bronchospasm and hypotension. Currently, no adequately powered study has demonstrated significant benefit from the use of any prophylactic drug. A high rate of anaphylactic reactions observed during a trial of three different antivenoms in Ecuador prompted adoption of premedication with intravenous (IV) hydrocortisone and diphenhydramine together with dilution and slower administration of antivenom. Design: In a rural mission hospital in Eastern Ecuador, 53 consecutive snakebite victims received a new antivenom regimen in 2004-2006, comprising prophylactic drugs and IV infusion of diluted antivenom over 60 min. They were compared to an historical control cohort of 76 patients treated in 1997-2002 without prophylactic drugs and with IV "push" injection of undiluted antivenom over 10 min. All these patients had incoagulable blood on admission and all were treated with Brazilian Instituto Butantan polyspecific antivenom. Results: Baseline characteristics of the historical control and premedicated groups were broadly similar. In the historical group, early reaction rates were as follows: 51% of patients had no reaction; 35% had mild reactions; 6% moderate; and 6% severe. In the premedicated/slow IV group, 98% of patients had no reaction; 0 mild; 0 moderate; and 2% severe. The difference in reaction rates was statistically significant (p < 0.001). Conclusions: Premedication with intravenous hydrocortisone and diphenhydramine together with dilution of antivenom and its administration by IV infusion over 60 min appeared to reduce both the frequency and severity of anaphylactic reactions. A randomized blinded controlled trial is needed to confirm these encouraging preliminary findings.

Cytomegalovirus (CMV) is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as, reduced overall patient and allograft survival. Risk factors for CMV disease are often interrelated, and include CMV D+/R-serostatus, acute rejection, female gender, age, use of high-close mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specific CD4+ and CD8+ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-). However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease-ranged from 16% to 47% of CMV D+/R- liver transplant recipients. Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being performed comparing the efficacy and safety of maribavir, a novel benzimidazole riboside, and oral ganciclovir as prophylaxis against primary CMV disease in liver transplant recipients. The treatment of CMV disease consists mainly of intravenous (IV) ganciclovir, and if feasible, a reduction in the degree of immunosuppression. A recent controlled clinical trial demonstrated that valganciclovir is as effective and safe as IV ganciclovir for the treatment of CMV disease in solid organ (including liver) transplant recipients. In this article, the author reviews the current state and the future perspectives of prevention and treatment of CMV disease after,liver transplantation.

Invasive fungal infections (IFIs) are associated with considerable morbidity and mortality among high-risk individuals. Outcomes for IFI historically have been suboptimal and associated with a high mortality rate, hence global prophylaxis strategies have been applied to at-risk populations. Among certain populations, fluconazole prophylaxis has reduced systemic and superficial infections caused by Candida species. Newer azoles are currently being evaluated as prophylaxis and have the potential to provide protection against mould pathogens that are more troublesome to treat once they occur. Global prophylaxis strategies have the shortcoming of subjecting patients to therapy that ultimately will not need it. Targeted prophylaxis has the advantage of treating only patients at highest risk using some parameter of greater host susceptibility. Prophylaxis strategies are most suitable in patients at the highest risk for IFI. For patient groups whose risk is somewhat lower or when suspicion of IFI occurs in patients receiving prophylaxis, empirical antifungal therapy is often employed following a predefined period of fever. Again this approach subjects many non-infected patients to unnecessary and toxic therapy. A more refined approach such as presumptive or pre-emptive therapy whereby treatment is only initiated upon positive identification of a surrogate marker of infection in combination with clinical and radiological signs will subject fewer patients to toxic and expensive treatments.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13110号 / 論医博第2128号 / 新制||医||1022(附属図書館) / (主査)教授 髙折 晃史, 教授 佐藤 俊哉, 教授 川上 浩司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction :La prévalence de l’obésité, parmi les patients hospitalisés, est en augmentation. Les patients obèses présentent un risque accru de développer des infections nosocomiales par rapport aux individus non-obèses. Parmi les antibiotiques, la classe des β-lactames est la plus utilisée à l’hôpital tant en prophylaxie chirurgicale que pour le traitement des infections. Les recommandations de doses en vigueur sont basées sur des études pharmacocinétiques (PK) effectuées chez des patients non-obèses. Cependant, les patients obèses présentent des altérations physiologiques qui pourraient théoriquement être à l’origine de modifications des paramètres PK de ces antibiotiques. L’utilisation de doses standards d’antibiotiques pourrait avoir comme conséquence des concentrations sériques inadéquates chez ces patients; elles peuvent, dès lors, conduire à des échecs thérapeutiques et/ou favoriser l’émergence de souches résistantes. Objectifs: Ce travail de thèse a pour but d’approfondir les connaissances sur la PK des β-lactames chez les patients obèses présentant des scores de sévérité clinique différents. Patients et Méthodes: Quatre études PK ont été réalisées chez les patients obèses :1) une étude prospective de patients obèses, et non-obèses, ayant reçu de la céfazoline (CFZ) en prophylaxie de chirurgie digestive, 2) une étude préliminaire, prospective incluant uniquement des patients obèses traités pour des infections non sévères par l’un des 4 β-lactames à large spectre (pipéracilline-tazobactam (TZP), ceftazidime/céfépime (CEF), et méropénem (MEM)), 3) une étude prospective, avec groupe contrôle de patients non-obèses, étudiant la PK du TZP donné en traitement d’infections non sévères et 4) une étude rétrospective cas-témoin évaluant la PK de 4 β-lactames à large spectre (TZP, CEF, ou MEM) donnés pour le traitement d’infections sévères aux soins intensifs. Les taux sériques de ces antibiotiques ont été mesurés par chromatographie liquide et corrélés à plusieurs paramètres démographiques, biologiques et hémodynamiques. Résultats: Etude sur CFZ :Soixante-trois patients ont participé à l’étude: parmi ceux-ci, 43 avaient un index de masse corporelle (IMC) ≥ 35 kg/m2, et 22 un poids total ≥ 120 kg. Sur l’ensemble des patients, les concentrations sériques de CFZ étaient adéquates chez 100% des patients à 180 minutes (T180) et chez 64% (40/63) à 240 minutes (T240) après le début de l’infusion de CFZ. Il n’y avait pas de différence significative entre le pourcentage des patients avec des taux sériques adéquats à T240, quel que soit le paramètre utilisé pour la comparaison (IMC ≥ 35 kg/m2 versus IMC < 35 kg/m2, ou poids total ≥ 120 kg versus poids total < 120 kg). Etude préliminaire sur TZP, CEF et MEM: Cinquante-six patients obèses ont été inclus dans l’étude ;14 ont reçu du MEM, 31 du TZP et 11 du CEF. Parmi ces patients, les concentrations sériques adéquates pour traiter une infection à P. aeruginosa ont été atteintes chez 93% des patients traités par MEM, 68% des patients traités par TZP, et 73% des patients traités par CEF. Le volume de distribution (VD) et la clearance totale (CL) des β-lactames étaient augmentés par rapport à des valeurs rapportées dans la littérature chez les patients non-obèses. En effet, plus de 25% des patients présentaient une clearance en créatinine (CrCl) mesurée supérieure à 150 ml/minute, ce facteur étant identifié comme facteur de risque de concentrations sériques insuffisantes. Etude sur TZP: Trente-deux patients (14 non-obèses et 18 obèses) ont été inclus dans l’étude et ont reçu les doses standards de TZP. Une augmentation du VD (25.4 ± 5.6L vs. 21.0 ± 3.9 L, p= 0.018) et de la CL (18.1 ± 4.7 vs. 13.5 ± 40.1, p= 0.007) a été observé chez les patients obèses par rapport aux non-obèses conduisant à des concentrations statistiquement inférieures de TZP libre par rapport aux patients non-obèses. De même, malgré des valeurs de créatinine sérique semblables (0.8 ± 0.3 versus 0.9 ± 0.3 mg/dl, p=0.26), la CrCl mesurée sur des urines de 24h, était significativement plus élévée chez les obèses par rapport aux non-obèses (128 ± 58 vs. 79 ± 26 ml/min, p=0.006). Etude rétrospective cas-témoin sur TZP, CEF, et MEM aux soins intensifs: Quarante-neuf patients obèses et 59 patients non-obèses ont été inclus. Soixante-huit monitoring thérapeutiques ont été effectués chez les patients obèses et comparés à 68 monitoring thérapeutiques effectués chez les patients non-obèses. Après administration des doses standards des β-lactames, 1/3 des patients obèses avait des concentrations sériques insuffisantes pour traiter des infections à P. aeruginosa, et 1/4 de ces patients avait des concentrations sériques excessives, potentiellement toxiques. Par contre, aucune différence statistiquement significative n’a été observée entre les concentrations sériques des β-lactames des patients obèses et non-obèses. Conclusions :Lors de la prophylaxie chirurgicale, l’administration des doses standards de CFZ a montré des concentrations sériques insuffisantes pour assurer une couverture prophylactique adéquate en cas d’intervention chirugicale d’une durée supérieure à 180 minutes. Ni le poids total, ni l’IMC n’a pu identifier les patients qui nécessiteront une dose plus élevée de CFZ. De même, les doses standards des β-lactames à large spectre se sont avérées insuffisantes dans le traitement des infections non sévères et sévères dues à P. aeruginosa chez les patients obèses. En cas d’infections peu sévères, les concentrations sériques, chez ces patients, étaient significativement moindres que chez les patients non-obèses ;ceci étant lié à une augmentation du VD et de la CL des β-lactames. Un facteur de risque majeur retrouvé était une CrCl augmentée chez les patients obèses. Chez les patients avec infections sévères, la PK des β-lactames n’était par contre pas significativement différente entre les patients obèses et non-obèses. Ceci probablement à cause des perturbations déjà importantes de la PK des β-lactames liées à la séverité du sepsis. En conclusion, ces études identifient des perturbations de la PK des β-lactames chez les patients obèses. Parmi celles-ci, l’augmentation de la clearance rénale est un élement déterminant dans l’inadéquation des concentrations sériques. La situation est plus complexe chez les patients obèses aux soins intensifs où d’autres facteurs peuvent encore s’associer et perturber la PK des β-lactames. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

The field of guideline development has made considerable progress in the past twenty years, particularly after the introduction of GRADE in 2004. However, there are many shortcomings in current guideline development including failure to use GRADE, low quality systematic reviews, and excessive delays from the publication of practice changing evidence to new recommendations. The objective of this thesis is to describe the development of evidence-based recommendations, to document methodological issues that arose and describe how the research team addressed the questions, and to document how the ultimate guidelines contributed to optimization of treatment in clinical practice. The relevant guidelines address the issues of gastrointestinal bleeding prophylaxis and coronavirus disease 2019 (COVID-19). The thesis begins by presenting three methodological issues that arose during the planning and implementation of the guideline process and the initial process of how the research team addressed the challenges. The thesis subsequently presents a published paper that documents recommendations regarding gastrointestinal bleeding prophylaxis in critically ill patients. Then, this thesis presents a published systematic review and meta-analysis addressing efficacy and safety of corticosteroids in COVID-19 based on direct evidence from patients with COVID-19, and indirect evidence from acute respiratory distress syndrome, community-acquired pneumonia, severe acute respiratory syndrome, middle east respiratory syndrome and influenza. Further, the thesis includes a published paper describing recommendations regarding corticosteroids, convalescent plasma and antiviral drugs in COVID-19 on the basis of evidence available very early during the pandemic. This thesis ends by presenting how the methodological issues were ultimately addressed in the relevant guidelines, the importance of the guidelines themselves, and presents perspectives on future research and opportunities in guideline development. / Thesis / Candidate in Philosophy

It is estimated that 50,000 individuals become newly infected with human immunodeficiency virus (HIV) every year in the United States. HIV is a lentivirus that is primarily spread through sexual contact. If left untreated, this viral infection can lead to decreased CD4+ T cells, increased susceptibility to opportunistic infections, and eventually progression to acquired immunodeficiency syndrome (AIDS) and death. HIV viral loads can be decreased to undetectable levels with the use of combination antiretroviral therapy (cART). In 2012 the Food and Drug Administration approved cART therapy, Truvada (tenofovir/emtricitabine), for safe use as pre-exposure prophylaxis (PrEP). When detectable levels of drug are present in the blood stream of patients, there is up to a 92% relative risk reduction in HIV infection compared to placebo. The implementation of PrEP has the potential to decrease the incidence of new HIV infections in at-risk populations worldwide. Because PrEP treatment is relatively new (2012), there are many barriers to administration to patients. Increased risky sexual behavior, known as risk compensation, is one of the concerns providers cite as a reason against prescribing PrEP. Most publications on PrEP have described randomized controlled trials that focused on safety, efficacy, and to a lesser extent, risk compensation behaviors. Now that Truvada is widely available, researchers are starting to elucidate patients’ sexual habits while using PrEP in the outpatient settings. However, there is a need for more longitudinal research regarding the behaviors of individuals using PrEP, specifically to determine how often risk compensation occurs and under what conditions. This study will initiate a PrEP clinic at Boston Medical Center and run a 3 year, open-label randomized controlled trial of eligible men who have sex with men (MSM) patients, who either start PrEP immediately or are delayed by one year. It is hypothesized that condom usage will decrease among immediate PrEP participants compared to the delayed participants. The study aims to determine if risk compensation occurs in these patients by following condom usage, development of sexually transmitted infections, number of sexual partners, and number/type of sexual encounter. Secondary outcomes will include measurements of medication adherence and number of HIV-seroconverters. These data will be collected through surveys and laboratory testing. The resulting information will help medical professionals better understand the risks and benefits of PrEP and also how to implement it most effectively in the fight to reduce the worldwide HIV burden.

Made available in DSpace on 2014-12-17T14:03:43Z (GMT). No. of bitstreams: 1 GloriaRGM.pdf: 347705 bytes, checksum: f20a585acbdd2c228097c779694d18db (MD5) Previous issue date: 2003-06-27 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Leptospirosis is a worldwide zoonosis of considerable medical and economical importance that affects humans in both urban and rural contexts, as well as domestic animals and wild fauna. Leptospira interrogans is the causative agent and is transmitted to humans by indirect contact with contaminated soil or water. The clinical syndromes include sub clinical infection, self-limited anicteric febrile illness, and severe and potentially fatal illness, known as Weil?s syndrome. In developed countries, leptospirosis is related to occupational or recreational activities while in developing countries, outbreaks occur during floods. In those regions, traditional strategies to prevent the transmission are difficulties to be implemented because of costs and lack of community acceptance. In addition, no efficient vaccine is available for human use. Several studies have suggested that chemoprophylaxis with doxycycline pre and post-exposure may be effective to prevent leptospirosis. Leptospirosis has been reported in rural areas of the State of Rio Grande do Norte, Brazil since 1985 in rice farmers who present the anicteric illness. The disease cause great social and economics impact. The study was conducted in S?o Miguel where an epidemic of leptospirosis in rice farmers was reported. The main objective was to determine the efficacy of doxycycline in preventing Leptospira exposure. A taxa de soropreval?ncia de leptospirose na popula??o estudada antes e ap?s a colheita foi de 14,2% (n=22) e de 16.6% (n=27) respectivamente. Anti-Leptospira serology was determined for 61 subjects in two instances, pre and post-exposure to potential contaminated water. There was an increased risk of 29.0 per cent in acquiring infection for individuals that did not use doxycycline. In addition, an increased risk of 30.0 % observed in farmers who did not use protection when exposed to Leptospira. The adhesion to preventive chemoprophylaxis was 55.7%. Therefore doxycycline, under specific circunstances appears to be an effective alternative to protect against leptosprirosis infection. A large sample composed of individuals to adhere to preventive therapy is needed to define time, dosage and length of use of doxycycline in this area / A leptospirose ? uma zoonose de distribui??o mundial que afeta, acidentalmente, o homem tendo como reservat?rios animais dom?sticos e silvestres. O agente causal, a Leptospira interrogans, ? transmitido ao homem, principalmente, por contato indireto com ?gua ou solo contaminados com a urina de ratos. O espectro cl?nico inclui infec??o subcl?nica, doen?a febril anict?rica e doen?a severa potencialmente fatal conhecida como s?ndrome de Weil. Em pa?ses desenvolvidos ? descrita, quase sempre, associada ? atividade profissional ou recreativa, enquanto nas regi?es em desenvolvimento epidemias tamb?m s?o associadas a enchentes. Nestas ?reas, medidas tradicionais de preven??o da doen?a, como, melhoria das condi??es sanit?rias, prote??o individual e controle de roedores s?o dif?ceis de serem implementadas por problemas econ?micos e pela baixa aceita??o da comunidade. Por outro lado, at? o momento n?o h? uma vacina eficaz para uso em humanos, mas, a quimioprofilaxia com doxiciclina tem sido apontada na literatura como uma alternativa adequada pra preven??o pr? e p?s-exposi??o de indiv?duos sob risco por determinado per?odo de tempo. Epidemias de leptospirose t?m sido relatadas na ?rea rural do Rio Grande do Norte, Brasil desde 1985, atingindo lavradores de arroz que apresentam a forma anict?rica da doen?a. Tais epidemias causam forte impacto econ?mico-social na regi?o por incapacitarem agricultores durante a ?poca da colheita do arroz e aumentarem os gastos da sa?de. O objetivo deste estudo foi avaliar a efic?cia da doxiciclina na prote??o contra infec??o por Leptospira em agricultores de arroz do munic?pio de S?o Miguel/RN, cuja taxa de soropreval?ncia antes da interven??o foi de 14,2%(n=22). Avalia??o sorol?gica pr? e p?s-colheita realizada em 61 indiv?duos demonstraram uma taxa de soroconvers?o de 8,8% (n=34) nos que utilizaram a droga e de 11,1%(n=27) naqueles que n?o utilizaram. A an?lise estat?stica revelou um risco adicional de aquisi??o da infec??o de 29% entre os agricultores que n?o utilizaram a doxiciclina, al?m de um risco adicional de 30% de adquirir a infec??o naqueles indiv?duos que trabalharam descal?os. A taxa de ades?o a quimioprofilaxia foi de apenas 55,7%. A doxiciciclina pode ser uma medida efetiva na profilaxia pr?-exposi??o de lavradores de arroz, entretanto, uma amostra maior composta por indiv?duos que apresentem maior ader?ncia ? terapia ? necess?ria para uso efetivo deste antibi?tico como profilaxia da infec??o por Leptospira nessa regi?o