Despite efforts towards the management and prevention of Tuberculosis (TB) having shown some success, Multidrug-Resistant Tuberculosis (MDR-TB) may potentially compromise these endeavours. MDR-TB has the potential to become the most dominant form of TB in low- and middle-income countries (LMICs). The impact of environmental health factors on the optimization of health of MDR-TB infected individuals, as well as on the prevention of transmission to household contacts, is not well documented. Current Sustainable Development Goals (SDGs) aim to achieve inclusivity, sustainability and resilience, not only through economic and social changes, but also through environmental targets in order to achieve optimal health and well-being for all. However, without appropriate acknowledgment of the environment's influence on outcomes during TB treatment, these targets are potentially unattainable. Establishing the recommendations of environmental health risk factors for individuals living at home with MDR-TB will have important policy implications as well as assist in decision making for those affected with MDR-TB in LMICs, such as South Africa. This systematic review, therefore, sought to identify the environmental health factors in LMICs that affect treatment outcomes for individuals living at home with MDR-TB, to optimize their health during completion of their treatment regimen and prevent transmission to household contacts. Part A outlines the current literature available for such a topic as well as methodology used within the systematic search and analysis of included articles. Prominent environmental health exposure variables of interest that have previously been identified as having a significant role in TB transmission or influencing the well-being of infected individuals, were identified within the literature. These included air pollution, nutrition, migration, urbanization, smoking, alcohol, other substance use and housing. Outcomes of interest included optimization of health and prevention of MDR-TB transmission to household contacts. The article (part B) represents the results from the systematic search as well as the application to current policy recommendations. After screening and reviewing the full text of potential articles for inclusion (N = 87), only thirteen articles were eligible for inclusion into the final sample. All included studies were primary observational studies, examining the relationship between MDRTB and the pre-defined exposures and outcomes in populations ≥13 years of age. Environmental risk factors for household transmission of MDR-TB potentially included malnutrition but showed no significant relationship with overcrowding. There was disagreement as to whether smoking was as a significant predictor of mortality but findings did indicate that smoking did have a negative impact on sputum culture conversion among patients receiving treatment. Other substance use was found to have a significant role in the default of treatment. The use of alcohol was associated with poor treatment outcomes, default of treatment and lack of sputum culture conversion. In terms of household conditions, an association was found between substandard housing conditions and treatment default. Formal housing was associated with a decline in treatment default but a residential address change was associated with defaulting treatment. The results of the review presented contradictory results regarding the risk of mortality and underweight/overweight BMI estimates. The review potentially highlighted vulnerable population groups including gender groups, children and HIV positive individuals. Therefore, this systematic review highlighted the potential relationship between environmental risk factors and optimising the health of individuals on treatment for MDR-TB, as well as the role that promoting environmental health may play in preventing the transmission to household contacts. In conclusion, environmental risk factors should be incorporated into local health system strategies and global policy. This includes WHO targets in TB prevention efforts, as well as in action areas for the attainment of relevant SDGs (e.g. SDG 3 and SDG 5), to address the burden of MDR-TB and decrease MDR-TB transmission in LMICs, effectively and sustainably.

Bakgrund Antibiotikaresistens är rangeras idag som ett av de största hoten mot folkhälsan. Bärare av multiresistenta bakterier är ofta dåligt införstådda i vad det innebär att vara bärare vilket leder till ett minskat välbefinnande. Sjuksköterskor har en central roll i att informera patienter om deras hälsotillstånd och ska säkerställa att informationen är förstådd. Syfte Att undersöka sjuksköterskors upplevelse av att informera patienter som bär på multiresistenta bakterier om deras bärarskap. Metod Kvalitativ intervjustudie med induktiv ansats. Semistrukturerade intervjuer genomfördes med sju sjuksköterskor på ett sjukhus i Mellansverige. Data analyserades med kvalitativ innehållsanalys. Resultat Analysen resulterade i fyra kategorier: arbetsmiljö, sjuksköterskans roll, patientens förutsättningar och okunskap. Informanterna upplevde att det var otydliga rutiner kring vilken information som skulle ges till patienterna. Informanterna antog att patienter redan var införstådda i sitt bärarskap när de ankom avdelningen. Patientens tillstånd och språk var faktorer som påverkade informationsgivandet. Det fanns en okunskap hos patienter och anhöriga som ofta ledde till en rädsla och onödig förstorning av bärarskapet. Kunskapsbrister existerade även hos vårdutbildade och kunde leda till att patienter blev felbehandlade. Slutsats Informanterna upplevde att det förekom otydliga rutiner kring vilken information som skulle ges till bärare av MRB om deras bärarskap. Förförståelse om att patienten redan var införstådd i sitt bärarskap samt patientens förutsättning att kunna motta information påverkade givandet av information. Att ge korrekt information till patienten och säkerställa sig om att informationen är förstådd är viktiga faktorer som leder till minskat lidande hos patienten samt minskad spridning av MRB i samhället. / Background Antimicrobial resistance is an increasingly serious threat to public health. Carriers of multidrug-resistant bacteria are often poorly understood in what it implies to be a carrier. This can lead to a reduced sense of wellbeing. Nurses have a central role in informing patients about their health condition and also in ensuring that the information is apprehended. Aim To investigate nurses’ experience of informing patients who carry multidrug-resistant bacteria about their colonisation. Method Qualitative interview study. Semi structured interviews were conducted with 7 nurses at a university hospital in central Sweden. The interviews were analyzed using content analysis. Result The analyze resulted in four categories: work environment, role of the nurse, patients’ conditions and lack of knowledge. The informants experienced uncertain routines concerning what information they should distribute to the patients about multidrug-resistant bacteria. The informants often assumed that the patients were well informed and understood  about colonisation of multidrug-resistant bacteria prior to the hospital stay. The patients’ condition and language could affect the distributed information. The informants recognized a lack of knowledge in patients and relatives that could lead to fear and exaggeration of the colonisation. Lack of knowledge was also seen among health care professionals and could lead to patients being mistreated at the hospital. Conclusion The informants experienced uncertain guidelines about what information to give carriers of multidrug-resistant bacteria. The patients’ condition and the preunderstanding that the patient already was well informed about being a carrier were two factors affecting the distribution of information. It is essential that nurses distribute adequate information and ensure that patients understand their condition in order to reduce the patient suffering and the spreading of multidrug-resistant bacteria in the society.

A surgimento de bactérias multirresistentes é uma ameaça global. Essas bactérias têm sido associadas com infecções hospitalares, no entanto, diversos casos de infecções multirresistentes adquiridas na comunidade vêm sendo relatadas, o que acendo um alerta quanto a propagação destes micro-organismos para além do ambiente hospitalar. Em todo o mundo o consumo indiscriminado de antibióticos tem aumentado significativamente, sendo este o principal fator para o surgimento e propagação de novas formas de resistência. Outro fator preocupante é a velocidade com que estas novas formas de resistência cruzam fronteiras internacionais se disseminando facilmente em todo o mundo. Este fato tem preocupado líderes mundiais, os quais consideram o aparecimento de \"superbactérias\" um pesadelo, o que pode vir a ser em um futuro próximo uma catástrofe mundial. Diante desse quadro preocupante, a necessidade de desenvolvimento de novos agentes antimicrobianos para combater essas infecções se torna iminente. Neste contexto, os compostos nitrofurânicos tem se destacado por sua atividade contra bactérias com caráter de multirresistência. Por isto, este trabalho teve como objetivo o desenvolvimento de novos compostos nitrofurânicos, tendo como composto-protótipo a nifuroxazida. O processo de desenvolvimento das estruturas análogas a nifuroxazida foi realizado a partir do planejamento da série de compostos 5-nitro-2-furfurilidênicos, com base nos parâmetros estabelecidos por Lipinski para obtenção de compostos com características farmacocinéticas e farmacodinâmicas que favorecem a biodisponibilidade, com vistas a administração por via oral. Os ensaios de avaliação da atividade antimicrobiana dos compostos foram realizados com base no método de teste de sensibilidade a agentes antimicrobianos por diluição para bactérias de crescimento aeróbio, norma M07-A9, e como base no método de padrões de crescimento para teste de suscetibilidade a antimicrobianos, vigésimo terceiro suplemento informativo, M100-S23, aprovados pelo Clinical and Laboratory Standards Institute. Os resultados de avaliação da atividade antimicrobiana indicam que o composto mais ativo c24, 6-amino-N\'-((5-nitrofurano-2-il)metileno)-2-naftohidrazida, teve atividade significativa frente a todas cepas, sendo superior a nifuroxazida, NF; nitrofurantoína, NTF; oxacilina, OXA; e vancomicina, VAN; [ (Staphylococcus aureus ATCC 29213, c24 - IC90 = 0.31 µM ± 0.06; NF - IC90 = 2.39 µM ± 0.08; NTF - IC90 = 5.26 µM ± 0.39; OXA - IC90 = 1.14 µM ± 0.18; VAN - IC90 = 0.31 µM ± 0.06); (Staphylococcus aureus resistente à oxacilina, c24 - IC90 = 0.52 µM ± 0.26; NF - IC90 = 5.37 µM ± 0.67; NTF - IC90 = 8.20 µM ± 1.66; OXA - IC90 = s. a.; VAN - IC90 = 0.50 µM ± 0.20); (Staphylococcus aureus cepa heterogênea com resistência intermediária à vancomicina, hVISA-FCFHV36, c24 - IC90 = 0.82 µM ± 0.07; NF - IC90 = 7.22 µM ± 0.29; NTF - IC90 = 13.14 µM ± 0.94; OXA - IC90 = s. a.; VAN - IC90 = 0.88 µM ± 0.05); (Staphylococcus epidermidis com perfil de resistência a linezolida, c24 - IC90 = 0.74 µM ± 0.02; NF - IC90 = 4.36 µM ± 0.54; NTF - IC90 = 8.46 µM ± 0.60; OXA - IC90 = 12.66 µM ± 0.36; VAN - IC90 = 1.40 µM ± 0.28); e (Enterococcus faecalis resistente à vancomicina fenótipo vanA, c24 - IC90 = 0.72 µM ± 0.02; NF - IC90 = 5.09 µM ± 0.08; NTF - IC90 = 9.28 µM ± 0.32; OXA - IC90 = 12.26 µM ± 0.72, VAN - IC90 = s. a.) ]. Entre as propriedades de maior influência na atividade do composto c24 estão ClogP e PSA. / The emergence of multidrug-resistant bacteria is a global threat. These bacteria have been associated with nosocomial infections, however, many cases of community-acquired multidrug resistant infections have been reported which light a warning about the spread of these microorganisms other than the hospital environment. Worldwide the indiscriminate use of antibiotics has increased significantly, which is the main factor for the emergence and spread of new forms of resistance. Another factor of concern is the speed with which these new forms of resistance cross international boundaries easily spreading worldwide. This has worried world leaders, who consider the emergence of \"superbugs\" a nightmare, which might be in the near future a global catastrophe. Faced with this alarming situation, the need for development of new antimicrobial agents to combat such infections becomes imminent. In this context, nitrofuran compounds has been noted for its activity against bacteria with multidrug resistance character. Therefore, this study aimed to develop new nitrofuran compounds, with the composite prototype to nifuroxazida. The process of developing similar structures nifuroxazida was performed using the designed series of substituted 5-nitro-2-furfurilidênicos, based on parameters set by Lipinski to obtain compounds with pharmacokinetic and pharmacodynamic properties that promote the bioavailability in order administration orally. The evaluation of the antimicrobial activity tests of the compounds were carried out based on the method of the antimicrobial susceptibility testing by dilution for bacterial aerobic growth, M07-A9 standard, and based on the method of growth standards for antimicrobial susceptibility testing , twenty-third informational supplement M100-S23, approved by the Clinical and Laboratory Standards Institute. The results of evaluation of the antimicrobial activity indicate that the compound more active c24, 6-amino-N\'-((5-nitrofuran-2-yl) methylene)-2-naftohidrazida had significant activity against all strains, exceeding nifuroxazida, NF; nitrofurantoin, NTF; oxacillin, OXA; and vancomycin, VAN; [(Staphylococcus aureus ATCC 29213, c24 - IC90 = 0:31 uM ± 12:06; NF - IC90 = 2.39 uM ± 12:08; NTF - IC90 = 5.26 uM ± 12:39; OXA - IC90 = 1.14 uM ± 00:18; VAN - IC90 = 0:31 uM ± 12:06); (Staphylococcus aureus resistant to methicillin, c24 - IC90 = 0:52 uM ± 00:26; NF - IC90 = 5:37 uM ± 0.67; NTF - IC90 = 8.20 uM ± 1.66; OXA - IC90 = s to .; VAN - IC90 = 0:50 uM ± 00:20.); (Staphylococcus aureus heterogeneous strain with intermediate resistance to vancomycin, hVISA-FCFHV36, c24 - IC90 = 0.82 uM ± 00:07; NF - IC90 = 7.22 uM ± 00:29; NTF - IC90 = 13:14 uM ± 0.94; OXA - IC90 = sa; VAN - IC90 = 0.88 ± 0.05 uM); (Staphylococcus epidermidis with linezolid resistance profile, c24 - IC90 = 0.74 uM ± 12:02; NF - IC90 = 4:36 uM ± 00:54; NTF - IC90 = 8:46 uM ± 0.60; OXA - IC90 = 12.66 uM ± 12:36; VAN - IC90 = uM 1:40 ± 0:28); and (Enterococcus faecalis Vancomycin-resistant vanA phenotype, c24 - IC90 = 0.72 uM ± 00:02; NF - IC90 = 9.5 uM ± 12:08; NTF - IC90 = 9.28 uM ± 00:32; OXA - IC90 = 12.26 uM ± 0.72, VAN - IC90 = sa)]. Among the most influential properties in the activity of the compound c24 are ClogP and PSA

A surgimento de bactérias multirresistentes é uma ameaça global. Essas bactérias têm sido associadas com infecções hospitalares, no entanto, diversos casos de infecções multirresistentes adquiridas na comunidade vêm sendo relatadas, o que acendo um alerta quanto a propagação destes micro-organismos para além do ambiente hospitalar. Em todo o mundo o consumo indiscriminado de antibióticos tem aumentado significativamente, sendo este o principal fator para o surgimento e propagação de novas formas de resistência. Outro fator preocupante é a velocidade com que estas novas formas de resistência cruzam fronteiras internacionais se disseminando facilmente em todo o mundo. Este fato tem preocupado líderes mundiais, os quais consideram o aparecimento de \"superbactérias\" um pesadelo, o que pode vir a ser em um futuro próximo uma catástrofe mundial. Diante desse quadro preocupante, a necessidade de desenvolvimento de novos agentes antimicrobianos para combater essas infecções se torna iminente. Neste contexto, os compostos nitrofurânicos tem se destacado por sua atividade contra bactérias com caráter de multirresistência. Por isto, este trabalho teve como objetivo o desenvolvimento de novos compostos nitrofurânicos, tendo como composto-protótipo a nifuroxazida. O processo de desenvolvimento das estruturas análogas a nifuroxazida foi realizado a partir do planejamento da série de compostos 5-nitro-2-furfurilidênicos, com base nos parâmetros estabelecidos por Lipinski para obtenção de compostos com características farmacocinéticas e farmacodinâmicas que favorecem a biodisponibilidade, com vistas a administração por via oral. Os ensaios de avaliação da atividade antimicrobiana dos compostos foram realizados com base no método de teste de sensibilidade a agentes antimicrobianos por diluição para bactérias de crescimento aeróbio, norma M07-A9, e como base no método de padrões de crescimento para teste de suscetibilidade a antimicrobianos, vigésimo terceiro suplemento informativo, M100-S23, aprovados pelo Clinical and Laboratory Standards Institute. Os resultados de avaliação da atividade antimicrobiana indicam que o composto mais ativo c24, 6-amino-N\'-((5-nitrofurano-2-il)metileno)-2-naftohidrazida, teve atividade significativa frente a todas cepas, sendo superior a nifuroxazida, NF; nitrofurantoína, NTF; oxacilina, OXA; e vancomicina, VAN; [ (Staphylococcus aureus ATCC 29213, c24 - IC90 = 0.31 µM ± 0.06; NF - IC90 = 2.39 µM ± 0.08; NTF - IC90 = 5.26 µM ± 0.39; OXA - IC90 = 1.14 µM ± 0.18; VAN - IC90 = 0.31 µM ± 0.06); (Staphylococcus aureus resistente à oxacilina, c24 - IC90 = 0.52 µM ± 0.26; NF - IC90 = 5.37 µM ± 0.67; NTF - IC90 = 8.20 µM ± 1.66; OXA - IC90 = s. a.; VAN - IC90 = 0.50 µM ± 0.20); (Staphylococcus aureus cepa heterogênea com resistência intermediária à vancomicina, hVISA-FCFHV36, c24 - IC90 = 0.82 µM ± 0.07; NF - IC90 = 7.22 µM ± 0.29; NTF - IC90 = 13.14 µM ± 0.94; OXA - IC90 = s. a.; VAN - IC90 = 0.88 µM ± 0.05); (Staphylococcus epidermidis com perfil de resistência a linezolida, c24 - IC90 = 0.74 µM ± 0.02; NF - IC90 = 4.36 µM ± 0.54; NTF - IC90 = 8.46 µM ± 0.60; OXA - IC90 = 12.66 µM ± 0.36; VAN - IC90 = 1.40 µM ± 0.28); e (Enterococcus faecalis resistente à vancomicina fenótipo vanA, c24 - IC90 = 0.72 µM ± 0.02; NF - IC90 = 5.09 µM ± 0.08; NTF - IC90 = 9.28 µM ± 0.32; OXA - IC90 = 12.26 µM ± 0.72, VAN - IC90 = s. a.) ]. Entre as propriedades de maior influência na atividade do composto c24 estão ClogP e PSA. / The emergence of multidrug-resistant bacteria is a global threat. These bacteria have been associated with nosocomial infections, however, many cases of community-acquired multidrug resistant infections have been reported which light a warning about the spread of these microorganisms other than the hospital environment. Worldwide the indiscriminate use of antibiotics has increased significantly, which is the main factor for the emergence and spread of new forms of resistance. Another factor of concern is the speed with which these new forms of resistance cross international boundaries easily spreading worldwide. This has worried world leaders, who consider the emergence of \"superbugs\" a nightmare, which might be in the near future a global catastrophe. Faced with this alarming situation, the need for development of new antimicrobial agents to combat such infections becomes imminent. In this context, nitrofuran compounds has been noted for its activity against bacteria with multidrug resistance character. Therefore, this study aimed to develop new nitrofuran compounds, with the composite prototype to nifuroxazida. The process of developing similar structures nifuroxazida was performed using the designed series of substituted 5-nitro-2-furfurilidênicos, based on parameters set by Lipinski to obtain compounds with pharmacokinetic and pharmacodynamic properties that promote the bioavailability in order administration orally. The evaluation of the antimicrobial activity tests of the compounds were carried out based on the method of the antimicrobial susceptibility testing by dilution for bacterial aerobic growth, M07-A9 standard, and based on the method of growth standards for antimicrobial susceptibility testing , twenty-third informational supplement M100-S23, approved by the Clinical and Laboratory Standards Institute. The results of evaluation of the antimicrobial activity indicate that the compound more active c24, 6-amino-N\'-((5-nitrofuran-2-yl) methylene)-2-naftohidrazida had significant activity against all strains, exceeding nifuroxazida, NF; nitrofurantoin, NTF; oxacillin, OXA; and vancomycin, VAN; [(Staphylococcus aureus ATCC 29213, c24 - IC90 = 0:31 uM ± 12:06; NF - IC90 = 2.39 uM ± 12:08; NTF - IC90 = 5.26 uM ± 12:39; OXA - IC90 = 1.14 uM ± 00:18; VAN - IC90 = 0:31 uM ± 12:06); (Staphylococcus aureus resistant to methicillin, c24 - IC90 = 0:52 uM ± 00:26; NF - IC90 = 5:37 uM ± 0.67; NTF - IC90 = 8.20 uM ± 1.66; OXA - IC90 = s to .; VAN - IC90 = 0:50 uM ± 00:20.); (Staphylococcus aureus heterogeneous strain with intermediate resistance to vancomycin, hVISA-FCFHV36, c24 - IC90 = 0.82 uM ± 00:07; NF - IC90 = 7.22 uM ± 00:29; NTF - IC90 = 13:14 uM ± 0.94; OXA - IC90 = sa; VAN - IC90 = 0.88 ± 0.05 uM); (Staphylococcus epidermidis with linezolid resistance profile, c24 - IC90 = 0.74 uM ± 12:02; NF - IC90 = 4:36 uM ± 00:54; NTF - IC90 = 8:46 uM ± 0.60; OXA - IC90 = 12.66 uM ± 12:36; VAN - IC90 = uM 1:40 ± 0:28); and (Enterococcus faecalis Vancomycin-resistant vanA phenotype, c24 - IC90 = 0.72 uM ± 00:02; NF - IC90 = 9.5 uM ± 12:08; NTF - IC90 = 9.28 uM ± 00:32; OXA - IC90 = 12.26 uM ± 0.72, VAN - IC90 = sa)]. Among the most influential properties in the activity of the compound c24 are ClogP and PSA

BACKGROUND: Multi drug resistant Tuberculosis (MDR-TB) is a serious public health concern in many parts of the world. As per the WHO- 2010 global report on Surveillance and response 3.6% of all incident TB cases globally are multidrug resistant. In this regard, there is an increasing demand for timely, reliable and comprehensive drug susceptibility testing (DST) as MDR-TB surveillance is being geared up. The intent of this analysis is to determine whether there is a need to continue routine confirmatory DST testing at CDC in addition to just sending the isolates for genotyping. Analysis is done by measuring the discordance between the results of laboratory DST at CDC and the local labs drug type, drug testing concentrations, and study sites. METHODS: The data for this analysis was provided by the Tuberculosis Trials Consortium (TBTC), CDC. Data for this analysis was collected over nearly two decades (1993-2011), gathered from 7 clinical trials. Discordance between the local and CDC lab DST results was measured using Kappa statistic. Sensitivity and specificity analysis was done by taking the CDC DST lab results as the gold standard. Discordance levels were calculated by local sites and baseline drug resistance for each antibiotic in each study was measured. RESULTS: Average Kappa values for inter rater agreement for all the studies was 0.6444 whereas the overall level of discordance across all studies is 7.786%. Drug resistance at baseline was highest for Isoniazid and Streptomycin (except Study 23 and 22). CONCLUSION: Though the current results show few DST result discordances between local and CDC labs, it is better to continue to send isolates to the centralized lab (CDC) in view of the worldwide threat of drug resistant TB epidemic, the recommendations of the current literature and the benefits of reliable confirmatory testing services and availability of other molecular diagnostic methods.

This thesis presents results from three studies conducted in a veterinary teaching hospital (VTH). Study 1 retrospectively examined a collection of enterococci from clinical infections. Five recurring strains of Enterococcus faecium, and one strain of Enterococcus faecalis were identified using pulsed-field gel electrophoresis (PFGE) as causing clinical infections. Study 2 examined the gastrointestinal tract enterococci as a source of enteroccocal infections in dogs. Enterococcal catheter-associated bacteriuria (CA-bacteriuria) rate was 8%. In 3 of 4 sets of bacteriuria and rectal isolates, CA-bacteriuria isolates were indistinguishable from rectal isolates suggesting that the patient’s fecal enterococci represented the infection source. In all 3 sets of wound and rectal isolates, fecal carriage of the infection isolate was observed. Study 3 examined the prevalence of bacterial species and the overall CA-bacteriuria rate. CA-bacteriuria rate was 24%, with Enterococcus spp., E. coli, Staphylococcus spp., Streptococcus spp. and Enterobacter spp., as the most prevalent bacteria in listed order. / PetTrust

Les infections nosocomiales à bactéries multi-résistantes sont en constante augmentation en réanimation. Elles ont des conséquences individuelles et collectives majeures. La mortalité en réanimation et les prolongations des durées de séjour sont les deux principales conséquences individuelles connues à ce jour. Plusieurs facteurs confondants rendent l'interprétation des études difficiles, dont l'état sous jacent du patient, la virulence de la bactérie et l'adéquation thérapeutique. Mesurer la part de chacun de ces facteurs et préciser leur responsabilité respective est indispensable pour mobiliser les différents acteurs et améliorer le pronostic des patients en réanimation. Dans cette thèse nous avons souhaité approcher la réponse quant aux conséquences individuelles. A partir d'une base de données incluant des patients de réanimation, nous avons utilisé les méthodes statistiques les plus récentes et avons tenté de prendre en compte les différents facteurs confondants , pour répondre à trois questions précises que sont : la mortalité liée à une espèce bactérienne donnée, les facteurs associés à la mortalité des patients présentant un sepsis sévère ou choc septique en réanimation et les conséquences liées à l'isolement des patients infectés ou colonisés avec une bactérie multi-résistante. Nous montrons que (1) par l'intermédiaire d'une prolongation de la durée de séjour en réanimation, l'infection à Clostridium difficile augmente la pression de colonisation, sans pour autant avoir d'impact direct sur le décès. (2) que le pronostic des sepsis sévères et des chocs septiques dépend de l'adéquation de l'antibiothérapie et que les bactéries résistantes sont plus souvent traitées de manière inadéquate. (3) que l'isolement contact est associé non seulement à une augmentation attendue du risque de pneumonie nosocomiale a germe multi-résistants mais aussi à une augmentation du risque d'erreurs thérapeutiques et d'événements indésirables non infectieux. Cet impact délétère suggéré par des études en dehors de la réanimation doit être pris en compte lors de la mise en place des précautions contact en réanimation. / Nosocomial infections with multidrug-resistant bacteria are increasing in ICU. They have major individual and collective consequences. Mortality in the ICU and prolongation of length of stay are the two main individual consequences known to date. Several confounding factors make it difficult to interpret studies, including the patient's underlying condition, the virulence of bacteria and the adequacy of therapy. It is essential to measure the share of each of these factors and to clarify their respective responsibilities to mobilize the different actors and improve the prognosis of patients in intensive care. In this thesis, and drawing upon a database including ICU patients, we used the latest statistical methods and tried to take into account the various confounding factors to evaluate the individual consequences of multidrug-resistant bacteria in ICU. We sought to address three specific questions: mortality linked to specific bacterial species, factors associated with mortality in patients with severe sepsis or septic shock in intensive care unit, and the consequences of the isolation of patients infected or colonized with multidrug-resistant bacteria. We demonstrated that (1) because they are associated with a longer stay in intensive care unit, Clostridium difficile infections increase the pressure of colonization although they have no direct consequence on mortality; (2) the prognosis of sever sepsis or septic shock depends on the adequacy of the antibiotic therapy and that resistant bacteria are often inadequately treated; and (3) that isolation is not only associated with an expected increase in the risk of nosocomial pneumonia with multi-drug resistant pathogens strains but also with an increase in non-infectious adverse events.

Magister Pharmaceuticae - MPharm / Tuberculosis and HIV are arguably South Africa’s largest and most important health issues. With drug-resistant strains of tuberculosis on the increase and little research on new drugs, there is an urgent need for research around the drugs presently available to ensure their optimal use and to minimise their sometimes serious and significant side effects. Treatment of drug-resistant tuberculosis is expensive and lengthy, and is complicated by a limited choice of drugs with lower efficacies and higher toxicities. Treatment is further complicated in patients with HIV due to several factors including drug interactions. While some authors suggest that HIV and malabsorption might be associated with poor clinical outcomes, other researchers have found no link. Patients may benefit from Therapeutic Drug Monitoring in order to ensure that their doses of antituberculosis drugs are reaching the required minimum effective concentrations, without attaining toxic levels in the plasma which may cause unpleasant side effects. There is little research concerning drug levels in HIV patients with TB in South Africa, let alone in patients with drug-resistant forms of tuberculosis, and there are no studies in this country that use Liquid Chromatography-Mass Spectrometry to investigate the plasma levels of pyrazinamide in patients with MDR-TB. This study aimed to investigate whether or not there is a difference in the pharmacokinetics of PZA in MDR-TB patients with HIV, and those without HIV infection. It also aimed to establish whether LC-MS could be used to study the levels of pyrazinamide in the plasma of patients with multidrug-resistant tuberculosis with and without concurrent HIV infection. The plasma levels of pyrazinamide in 32 MDR-TB patients (23 HIV negative and 9 HIV positive), were successfully 2 analysed using LC-MS, and the pharmacokinetics of PZA in these 2 populations was described. It was established that the Tmax of pyrazinamide was significantly higher in HIV-negative patients than in HIV-positive patients. Although there was a difference between the Ka in the two populations, this difference did not quite reach statistical significance. There were no statistically significant differences between HIV-negative and HIV-positive patients with regards to the other pharmacokinetic parameters investigated. Our findings established that there was little evidence to suggest that there is a difference between the pharmacokinetics of the antimycobacterial drug pyrazinamide in HIV-positive patients and that in HIV-negative patients. We were also able to successfully develop and validate an assay for the analysis of PZA in plasma using LC-MS, and this finding could be very valuable for further studies. Although our study failed to prove this, the possibility still exists that HIV-positive patients could exhibit altered kinetics of antiTB drugs and this has not been fully investigated in South Africa. The clinical impact of low plasma levels of antimycobacterial drugs is still largely unexplored and further research with larger sample sizes should be done in order to establish which factors may contribute to low plasma levels of anti-tuberculosis drugs in MDR-TB patients, and whether or not these low levels are increasing the risk of treatment failure or other poor clinical outcomes.

Thesis (MSc. (Medical Sciences)) -- University of Limpopo, 2015 / Introduction: Multidrug-resistant tuberculosis (MDR-TB) caused by resistance to at least rifampicin (RIF) and isoniazid (INH) drugs is a growing public health concern in South Africa. The detection of MDR-TB still relies on culture despite advancement in molecular diagnostic technology. Currently MTBDRplus and GeneXpert are the only available assays used in rapid diagnosis of MDR-TB using chromosomal mutations in drug target regions. Some strains are missed by these assays due to their limitation in mutational detection profile. Novel Seegene Anyplex assays simultaneously detect TB and resistance to RIF and INH using fifteen and six mutational probes, respectively within 3 hours. Limpopo Province has limited information on the circulating strains of TB. Aim: To determine drug-resistant Mycobacterium tuberculosis (M. tuberculosis) mutations using Anyplex™ MTB/NTM/MDR-TB real time assay and characterise the drug-resistant strains. Methods: We prospectively collected 204 clinical samples at Modimolle MDR-TB unit and retrospectively used 104 culture isolates from MRC laboratory in Pretoria. The MTBDRplus assay was used to screen for M. tuberculosis and drug resistant mutations to RIF and INH drugs. Anyplex™ MTB/NTM/MDR-TB assay was used for rapid detection of M. tuberculosis and drug resistance to RIF and INH within 3 hours. The discordance between phenotypic and genotypic assays was resolved by sequencing and the Anyplex™ resistant profiles were spoligotyped. Diagnostic data was collected from NHLS and MRC databases and analysed using the Microsoft excel and Epi Info version 3.5. Descriptive statistics (percentages and frequencies) were used to explain proportions. Results: The Anyplex™ MTB/NTM assay detected M. tuberculosis in 69/111(62%) and 100/104 (96%) of clinical and culture samples respectively. The sensitivities, specificity, PPV and NPV obtained for both RIF and INH resistance by Anyplex™ MDR-TB assay were 67%, 59%, 67%, 55% and 15%, 100%, 100% and 17%, respectively. Anyplex™ MTB/NTM/MDR-TB resolved 23/45 (51%) of discordant vi samples. Sequencing of remaining discordant isolates revealed L511P, L533P and D516Y mutations within rpoB gene. A novel R385W mutation within katG was also detected. Spoligotyping of Anyplex™ MDR-TB resistant clinical isolates revealed Euro American clade with 20% followed by 15% Manu2, 5% East African Indian, 5% H37Rv, 5% atypical and 50% were orphans. Conclusion: The novel Anyplex™ MTB/NTM/MDR-TB assay is a rapid and valid technique for detecting M. tuberculosis and most common mutations conferring resistance to RIF and INH. However further investigations are required, as the assay has a lower sensitivity as compared to already endorsed techniques. / National Research Foundation (NRF) and University of Limpopo TB Grant

Philosophiae Doctor - PhD / Although TB is a curable communicable disease, poor adherence to TB treatment is a major barrier to TB control in South Africa as it increases the risks of morbidity, mortality and drug resistance at individual and community level. As a result, multi-drug-resistant TB (MDR-TB) has become a serious public health issue. Underpinning this study was the assumption that a client-centred approach to treatment of MDR-TB clients, with a hospital programme which adopts an integrated multidisciplinary approach that is client-centred and is not purely biomedically driven, would improve treatment outcomes of MDR-TB clients.