Tuberculosis in renal transplant patients: The experience of a single center in Medellín-Colombia, 2005-2013

Introduction: Tuberculosis is a common opportunistic infection in renal transplant patients. Objective: To obtain a clinical and laboratory description of transplant patients diagnosed with tuberculosis and their response to treatment during a period ranging from 2005 to 2013 at the Pablo Tobón Uribe Hospital. Methods: Retrospective and descriptive study. Results: In 641 renal transplants, tuberculosis was confirmed in 12 cases. Of these, 25% had a history of acute rejection, and 50% had creatinine levels greater than 1.5 mg/dl prior to infection. The disease typically presented as pulmonary (50%) and disseminated (33.3%). The first phase of treatment consisted of 3 months of HZRE (isoniazid, pyrazinamide, rifampicin and ethambutol) in 75% of the cases and HZME (isoniazid, pyrazinamide, moxifloxacin and ethambutol) in 25% of the cases. During the second phase of the treatment, 75% of the cases received isoniazid and rifampicin, and 25% of the cases received isoniazid and ethambutol. The length of treatment varied between 6 and 18 months. In 41.7% of patients, hepatotoxicity was associated with the beginning of anti-tuberculosis therapy. During a year-long follow-up, renal function remained stable, and the mortality rate was 16.7%. Conclusion: Tuberculosis in the renal transplant population studied caused diverse nonspecific symptoms. Pulmonary and disseminated tuberculosis were the most frequent forms and required prolonged treatment. Antituberculosis medications had a high toxicity and mortality. This infection must be considered when patients present with a febrile syndrome of unknown origin, especially during the first year after renal transplant.

Implication des biofilms dans la rhinosinusite chronique et l’évaluation des traitements avec un modèle in vitro

Introduction : La chronicité de la rhinosinusite, sa résistance aux antibiotiques, et ses exacerbations aiguës laissent croire que les biofilms sont impliqués dans la rhinosinusite chronique. Objectifs : Nous avons évalué la capacité des bactéries Pseudomonas aeruginosa, staphylocoques à coagulase négative et Staphylococcus aureus à former des biofilms par un essai in vitro, et si cette capacité de formation a un lien avec l’évolution de la maladie. Nous avons évalué in vitro l’effet de la moxifloxacine, un antibiotique utilisé dans le traitement de la rhinosinusite chronique sur des biofilms matures de Staphylococcus aureus. Méthodes : Trent et une souches bactériennes ont été isolées de 19 patients atteints de rhinosinusite chronique et qui ont subit au moins une chirurgie endoscopique des sinus. L’évolution de la maladie a été notée comme "bonne" ou "mauvaise" selon l’évaluation du clinicien. La production de biofilm a été évaluée grâce à la coloration au crystal violet. Nous avons évalué la viabilité du biofilm après traitement avec la moxifloxacine. Ces résultats ont été confirmés en microscopie confocale à balayage laser et par la coloration au LIVE/DEAD BacLight. Résultat et Conclusion : Vingt deux des 31 souches ont produit un biofilm. La production d’un biofilm plus importante chez Pseudomonas aeruginosa et Staphylococcus aureus était associée à une mauvaise évolution. Ceci suggère un rôle du biofilm dans la pathogenèse de la rhinosinusite chronique. Le traitement avec la moxifloxacine, à une concentration de 1000X la concentration minimale inhibitrice réduit le nombre des bactéries viables de 2 à 2.5 log. Ces concentrations (100 µg/ml - 200 µg/ml) sont faciles à atteindre dans des solutions topiques. Les résultats de notre étude suggèrent que l’utilisation de concentrations supérieure à la concentration minimale inhibitrice sous forme topique peut ouvrir des voies de recherche sur de nouveaux traitements qui peuvent être bénéfiques pour les patients atteints de forme sévère de rhinosinusite chronique surtout après une chirurgie endoscopique des sinus.

Esquema secuencial con moxifloxacina de primera línea en el tratamiento del helicobacter pylori: estudio piloto

INTRODUCCIÓN: El éxito de erradicación del H. pylori con las terapias convencionales ha disminuido a niveles inaceptables. Se buscan óptimos esquemas terapéuticos con excelentes tasas de erradicación. OBJETIVO: Cuantificar los desenlaces clínicos evaluados como efectividad, adherencia y seguridad, de una terapia secuencial de primera línea con Esomeprazol, Moxifloxacina, Amoxicilina y Tinidazol para la erradicación individual del H. pylori. METODOLOGÍA: Estudio prospectivo no controlado, piloto, abierto, único centro. Consecutivamente se incluirán adultos con prueba microbiológica positiva para H. pylori y síntomas dispépticos. Los pacientes recibirán un régimen de tratamiento de 10 días que consistirá los 5 primeros días de (Esomeprazol 40 mg, bd; Amoxicilina 1 g, bd). Del día 6 a 10 (Esomeprazol 40 mg, bd ; Tinidazol 500 mg, bd y Moxifloxacina 500 mg, bd). Se realizará una prueba de antígeno en materia fecal, para evaluar la efectividad terapéutica al menos a las 4 semanas de finalizar el tratamiento. RESULTADOS: 38 de 42 pacientes completaron el estudio. La tasa de erradicación fue de 87% (Intervalo de Confianza (IC) 95% (75,5 – 98,5%) en análisis por protocolo (PP), y 79% (IC) 95% (65 – 93%) en análisis por intención de tratar (ITT). La adherencia al tratamiento fue del 95% (40 pacientes), de los pacientes que ingresaron al estudio 48% presentaron al menos un efecto secundario menor principalmente diarrea y nauseas. CONCLUSIONES: Diez días de terapia secuencial basada en moxifloxacina proporciona tasas de erradicación óptimas, con una buena adherencia y efectos secundarios leves y transitorios.

Pneumonias

Pneumonia is an infectious disease with great morbidity and mortality worldwide. According to the current guidelines recommendations the authors reviewed the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). In this paper will be presented data about etiology, clinics and diagnostic tools. © Copyright Moreira Jr. Editora.

In Vitro and In Vivo Activities of Ruthenium(II) Phosphine/Diimine/Picolinate Complexes (SCAR) against Mycobacterium tuberculosis

Rifampicin, discovered more than 50 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class form part of a 6-month regimen that is ineffective against MDR and XDR TB, and incompatible with many antiretroviral drugs. Investments in R&D strategies have increased substantially in the last decades. However, the number of new drugs approved by drug regulatory agencies worldwide does not increase correspondingly. Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. In this study, promising results inspired us to seek a better understanding of the biological activity of these complexes. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated absence of mutagenicity. © 2013 Pavan et al.

Treatment failure in pneumonia: Impact of antibiotic treatment and cost analysis

The aim of this study was to investigate treatment failure (TF) in hospitalised community-acquired pneumonia (CAP) patients with regard to initial antibiotic treatment and economic impact. CAP patients were included in two open, prospective multicentre studies assessing the direct costs for in-patient treatment. Patients received treatment either with moxifloxacin (MFX) or a nonstandardised antibiotic therapy. Any change in antibiotic therapy after >72 h of treatment to a broadened antibiotic spectrum was considered as TF. Overall, 1,236 patients (mean ± SD age 69.6 ± 16.8 yrs, 691 (55.9%) male) were included. TF occurred in 197 (15.9%) subjects and led to longer hospital stay (15.4 ± 7.3 days versus 9.8 ± 4.2 days; p < 0.001) and increased median treatment costs (€2,206 versus €1,284; p<0.001). 596 (48.2%) patients received MFX and witnessed less TF (10.9% versus 20.6%; p < 0.001). After controlling for confounders in multivariate analysis, adjusted risk of TF was clearly reduced in MFX as compared with β-lactam monotherapy (adjusted OR for MFX 0.43, 95% CI 0.27-0.68) and was more comparable with a β-lactam plus macrolide combination (BLM) (OR 0.68, 95% CI 0.38-1.21). In hospitalised CAP, TF is frequent and leads to prolonged hospital stay and increased treatment costs. Initial treatment with MFX or BLM is a possible strategy to prevent TF, and may thus reduce treatment costs.

T cell-mediated hypersensitivity to quinolones: mechanisms and cross-reactivity

BACKGROUND: Quinolones are widely used, broad spectrum antibiotics that can induce immediate- and delayed-type hypersensitivity reactions, presumably either IgE or T cell mediated, in about 2-3% of treated patients. OBJECTIVE: To better understand how T cells interact with quinolones, we analysed six patients with delayed hypersensitivity reactions to ciprofloxacin (CPFX), norfloxacin (NRFX) or moxifloxacin (MXFX). METHODS: We confirmed the involvement of T cells in vivo by patch test and in vitro by means of the lymphocyte proliferation test (LTT). The nature of the drug-T cell interaction as well as the cross-reactivity with other quinolones were investigated through the generation and analysis (flow cytometry and proliferation assays) of quinolone-specific T cell clones (TCC). RESULTS: The LTT confirmed the involvement of T cells because peripheral blood mononuclear cells (PBMC) mounted an enhanced in vitro proliferative response to CPFX and/or NRFX or MXFX in all patients. Patch tests were positive after 24 and 48 h in three out of the six patients. From two patients, CPFX- and MXFX-specific CD4(+)/CD8(+) T cell receptor (TCR) alphabeta(+) TCC were generated to investigate the nature of the drug-T cell interaction as well as the cross-reactivity with other quinolones. The use of eight different quinolones as antigens (Ag) revealed three patterns of cross-reactivity: clones exclusively reacting with the eliciting drug, clones with a limited cross-reactivity and clones showing a broad cross-reactivity. The TCC recognized quinolones directly without need of processing and without covalent association with the major histocompatability complex (MHC)-peptide complex, as glutaraldehyde-fixed Ag-presenting cells (APC) could present the drug and washing quinolone-pulsed APC removed the drug, abrogating the reactivity of quinolone-specific TCC. CONCLUSION: Our data show that T cells are involved in delayed immune reactions to quinolones and that cross-reactivity among the different quinolones is frequent.

New therapies for pneumococcal meningitis

The treatment of pneumococcal meningitis remains a major challenge, as reflected by the continued high morbidity and case fatality of the disease. The worldwide increase of penicillin-resistant pneumococci and more recently cephalosporin- and vancomycin-tolerant pneumococci has jeopardised the efficacy of standard treatments based on extended spectrum cephalosporins alone or in combination with vancomycin. This review provides a summary of newly developed antibiotics tested in the rabbit meningitis model. In particular, newer beta-lactam monotherapies (cefepime, meropenem, ertapenem), recently developed quinolones (garenoxacin, gemifloxacin, gatifloxacin, moxifloxacin) and a lipopeptide antibiotic (daptomycin) are discussed. A special emphasis is placed on the potential role of combination treatments with some of the new compounds, which are of interest based on the background of increasing resistance problems due to their often synergistic activity in the rabbit model of pneumococcal meningitis.

Fluoroquinolones in the Treatment of Meningitis

The continuous increase of resistant pathogens causing meningitis has limited the efficacy of standard therapeutic regimens. Due to their excellent activity in vitro and their good penetration into the cerebrospinal fluid (CSF), fluoroquinolones appear promising for the treatment of meningitis caused by gram-negative microorganisms, ie, Neisseria meningitidis and nosocomial gram-negative bacilli. The newer fluoroquinolones (moxifloxacin, gemifloxacin, gatifloxacin, and garenoxacin) have excellent activity against gram-positive microorganisms. Studies in animal models and limited clinical data indicate that they may play a future role in the treatment of pneumococcal meningitis. Analysis of pharmacodynamic parameters suggests that CSF concentrations that produce a C(peak)/minimal bactericidal concentration (MBC) ratio of at least 5 and concentrations above the MBC during the entire dosing interval are a prerequisite for maximal bactericidal activity in meningitis. Of interest, newer fluoroquinolones act synergistically with vancomycin and beta-lactam antibiotics (ceftriaxone, cefotaxime, meropenem) against penicillin-resistant pneumococci in experimental rabbit meningitis, potentially providing a new therapeutic strategy. Clinical trials are needed to further explore the usefulness of quinolones as single agents or in combination with other drugs in the therapy of pneumococcal meningitis.

Efeito do substituinte “-F” nas propriedades electrónicas e estruturais de fluoroquinolonas

Este estudo incide sobre as características que a presença do ião flúor em moléculas concede. Mais concretamente em fluoroquinolonas, antibióticos que cada vez são mais utilizados. Fez-se uma analise de vários parâmetros para obtermos informação sobre a interação fármaco-receptor nas fluoroquinolonas. Sendo para isso utilizadas técnicas de caracterização química computacional para conseguirmos caracterizar eletronicamente e estruturalmente (3D) as fluoroquinolonas em complemento aos métodos semi-empíricos utilizados inicialmente. Como é sabido, a especificidade e a afinidade para o sitio alvo, é essencial para eficácia de um fármaco. As fluoroquinolonas sofreram um grande desenvolvimento desde a primeira quinolona sintetizada em 1958, sendo que desde ai foram sintetizadas inúmeros derivados da mesma. Este facto deve-se a serem facilmente manipuladas, derivando fármacos altamente potentes, espectro alargado, factores farmacocinéticos optimizados e efeitos adversos reduzidos. A grande alteração farmacológica para o aumento do interesse neste grupo, foi a substituição em C6 de um átomo de flúor em vez de um de hidrogénio. Para obtermos as informações sobre a influência do ião flúor sobre as propriedades estruturais e electrónicas das fluoroquinolonas, foi feita uma comparação entre a fluoroquinolona com flúor em C6 e com hidrogénio em C6. As quatro fluoroquinolonas presentes neste estudo foram: ciprofloxacina, moxiflocacina, sparfloxacina e pefloxacina. As informações foram obtidas por programas informáticos de mecânica quântica e molecular. Concluiu-se que a presença de substituinte flúor não modificava de forma significativa a geometria das moléculas mas sim a distribuição da carga no carbono vicinal e nos átomos em posição alfa, beta e gama relativamente a este. Esta modificação da distribuição electrónica pode condicionar a ligação do fármaco ao receptor, modificando a sua actividade farmacológica.

Novas estratégias para entender o sistema de influxo de antibióticos e a resistência antimicrobiana a nível molecular

As fluoroquinolonas são antibióticos que têm um largo espectro de ação contra bactérias, especialmente Gram-negativas. O seu mecanismo de ação assenta na inibição de enzimas responsáveis pela replicação do DNA. Porém, devido ao seu uso indevido, o surgimento de resistência bacteriana a estes antibióticos tem-se tornado um grave problema de saúde pública. Uma vez que os seus alvos de ação se situam no meio intracelular, a redução da permeabilidade da membrana externa de bactérias Gram-negativas constitui um dos mecanismos de resistência mais conhecidos. Esta redução é associada à baixa expressão ou mutações em porinas necessárias para permitir o seu transporte, mais concretamente, da OmpF. Estudos prévios demonstraram que a coordenação de fluoroquinolonas com iões metálicos divalentes e 1,10-fenantrolina (genericamente designados metaloantibióticos) são potenciais candidatos como alternativa às fluoroquinolonas convencionais. Estes metaloantibióticos exibem um efeito antimicrobiano comparável ou superior à fluoroquinolona na forma livre, mas parecem ter uma via de translocação diferente, independente de porinas. Estas diferenças no mecanismo de captura podem ser fundamentais para contornar a resistência bacteriana. De forma a compreender o papel dos lípidos no mecanismo de entrada dos metaloantibióticos, estudou-se a interação e localização dos metaloantibióticos da Ciprofloxacina (2ª geração), da Levofloxacina (3ª geração) e Moxifloxacina (4ª geração) com um modelo de membranas de Escherichia coli desprovido de porinas. Estes estudos foram realizados através de técnicas de espectroscopia de fluorescência, por medições em modo estacionário e resolvida no tempo. Os coeficientes de partição determinados demonstraram uma interação mais elevada dos metaloantibióticos relativamente às respetivas fluoroquinolonas na forma livre, um facto que está diretamente relacionado com as espécies existentes em solução a pH fisiológico. Os estudos de localização mostraram que estes metaloantibióticos devem estar inseridos na membrana bacteriana, confirmando a sua entrada independente de porinas. Este mecanismo de entrada, pela via hidrofóbica, é potenciado por interações eletrostáticas entre as espécies catiónicas de metaloantibiótico que existem a pH 7,4 e os grupos carregados negativamente dos fosfolípidos da membrana. Desta forma, os resultados obtidos neste estudo sugerem que a via de entrada dos metaloantibióticos e das respetivas fluoroquinolonas deve ser diferente. Os metaloantibióticos são candidatos adequados para a realização de mais testes laboratoriais e uma alternativa promissora para substituir as fluoroquinolonas convencionais, uma vez que parecem ultrapassar um dos principais mecanismos de resistência bacteriana a esta classe de antibióticos.