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Objective: To determine the risk factors associated with therapeutic failure of vancomycin in hospitalized adult patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. Design: Case-control study. Setting: Conducted in a high complexity hospital in Cali, Colombia. Participants: Adult hospitalized from January 1, 2015, to December 31, 2021, with MRSA infections with confirmed microbiological isolation. Methods: Cases were patients with therapeutic failure of vancomycin (mortality, poor clinical improvement, change of antibiotic used, early relapse, or persistence of positive blood cultures) and control patients were those who did not present failure. Significant variables from the bivariate analysis were included in a multiple analysis with an asymmetric logistic regression model. Results: A total of 105 patients were included in the study, 28 in the treatment group and 77 in the control group. The median age was 49 years and 59 (56%) of participants were men. The following variables: age (OR 1.034; 95% CI 1.007-1.061, p=0.011), osteomyelitis/ septic arthritis (OR 6.035; 95% CI 2.282-15.956, p=0.000) and minimum inhibitory concentration (MIC) (OR 5.971; 95% CI 1.321-26.979, p=0.020) were found to be independent risk factors associated with therapeutic failure of vancomycin. Vancomycin trough levels were not different between cases and controls (OR 0.976; 95% CI 0.911-1.044, p=0.478). Conclusions: When a multiple analysis was performed to control for confounding factors, only 3 variables were found to be significant and were considered risk factors for therapeutic failure of vancomycin in adult patients with MRSA infection: age, MIC, and osteomyelitis/ septic arthritis.

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Patients with cutaneous leishmaniasis (CL) present an exacerbated inflammatory response associated with tissue damage and ulcer development. In recent years, higher rates of failure to pentavalent antimoniate therapy have been observed, yet the underlying reason remains poorly understood. We hypothesize that the eicosanoid PGE2 favours the establishment of infection by L. braziliensis, which contributes to therapeutic failure. The aim of the present study was to investigate the influence of PGE2 on the survival of L. braziliensis in macrophages and rates of therapeutic failure in CL patients. PGE2, an eicosanoid derived from the metabolism of arachidonic acid by the COX-2 enzyme, plays several roles in immune response. We found that increased PGE2 decreases the microbicidal function of macrophages and is associated with disease severity and therapeutic failure. Additionally, the neutralization of COX-2 by NS398, a selective NSAID, increases the ability of macrophages to kill L. braziliensis and protects against the pathological inflammatory response. Our data suggest that NS398 may serve as an adjunct treatment for CL patients.

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BACKGROUND: Kawasaki disease is a systemic vasculitis that affects small and medium-sized vessels, primarily the coronary arteries. First-line treatment includes intravenous immunoglobulin (IVIG) and acetylsalicylic acid; however, 20% do not respond adequately despite treatment. We describe a case treated with etanercept after initial IVIG failure, showing a good response. CASE REPORT: A 5-year-old female was diagnosed with classic Kawasaki disease. Echocardiography and angiotomography revealed giant and fusiform aneurysms in the coronary arteries. A first dose of IVIG therapy was administered without improvement; after the second dose, the fever persisted, so etanercept was administered, and the fever subsided. There were no new lesions in medium-caliber vessels and the previously identified coronary lesions did not progress. CONCLUSIONS: The use of etanercept in Kawasaki disease has demonstrated a clinically favorable response. Controlled clinical trials of this drug are needed to establish it as a formal therapy in cases of initial IVIG failure.

INTRODUCCIÓN: La enfermedad de Kawasaki es una vasculitis sistémica que afecta los vasos de pequeño y mediano calibre con predominio de las arterias coronarias. El tratamiento de primera línea incluye inmunoglobulina intravenosa (IGIV) y ácido acetilsalicílico; a pesar del tratamiento, el 20% de los pacientes no responden adecuadamente. Se presenta un caso tratado con etanercept debido a la falla inicial a IGIV, con buena respuesta. CASO CLÍNICO: Se trata de una paciente de 5 años de edad, a quien se diagnosticó con enfermedad de Kawasaki clásica. En ecocardiografía y angiotomografía se evidenciaron aneurismas gigantes y fusiformes en las coronarias. Se administró una primera dosis con IGIV, sin mejoría; después de la segunda dosis, la paciente persistió con fiebre, por lo que se administró etanercept, tras lo cual esta cesó. No aparecieron nuevas lesiones en vasos de mediano calibre y las lesiones coronarias previas no progresaron. CONCLUSIONES: Con el uso de etanercept se presentó una respuesta favorable clínicamente en la enfermedad de Kawasaki. Se requieren ensayos clínicos controlados con este fármaco para establecerlo como terapia formal en los casos de falla inicial a IGIV.

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Abstract Background: Kawasaki disease is a systemic vasculitis that affects small and medium-sized vessels, primarily the coronary arteries. First-line treatment includes intravenous immunoglobulin (IVIG) and acetylsalicylic acid; however, 20% do not respond adequately despite treatment. We describe a case treated with etanercept after initial IVIG failure, showing a good response. Case report: A 5-year-old female was diagnosed with classic Kawasaki disease. Echocardiography and angiotomography revealed giant and fusiform aneurysms in the coronary arteries. A first dose of IVIG therapy was administered without improvement; after the second dose, the fever persisted, so etanercept was administered, and the fever subsided. There were no new lesions in medium-caliber vessels and the previously identified coronary lesions did not progress. Conclusions: The use of etanercept in Kawasaki disease has demonstrated a clinically favorable response. Controlled clinical trials of this drug are needed to establish it as a formal therapy in cases of initial IVIG failure.

Resumen Introducción: La enfermedad de Kawasaki es una vasculitis sistémica que afecta los vasos de pequeño y mediano calibre con predominio de las arterias coronarias. El tratamiento de primera línea incluye inmunoglobulina intravenosa (IGIV) y ácido acetilsalicílico; a pesar del tratamiento, el 20% de los pacientes no responden adecuadamente. Se presenta un caso tratado con etanercept debido a la falla inicial a IGIV, con buena respuesta. Caso clínico: Se trata de una paciente de 5 años de edad, a quien se diagnosticó con enfermedad de Kawasaki clásica. En ecocardiografía y angiotomografía se evidenciaron aneurismas gigantes y fusiformes en las coronarias. Se administró una primera dosis con IGIV, sin mejoría; después de la segunda dosis, la paciente persistió con fiebre, por lo que se administró etanercept, tras lo cual esta cesó. No aparecieron nuevas lesiones en vasos de mediano calibre y las lesiones coronarias previas no progresaron. Conclusiones: Con el uso de etanercept se presentó una respuesta favorable clínicamente en la enfermedad de Kawasaki. Se requieren ensayos clínicos controlados con este fármaco para establecerlo como terapia formal en los casos de falla inicial a IGIV.

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Background: Intra-abdominal infection (IAI) results in prolonged in-hospital length-of-stay, critical care unit requirements, and multiple surgical procedures. Several antimicrobial agents are available for treatment of IAI. In Colombia, there are no data on the comparative effectiveness of the different regimens used. Patients and Methods: A multicenter retrospective cohort study was completed in four third-level hospitals by comparing treatment effectiveness of five different antibiotic protocols (ampicillin-sulbactam, clindamycin-amikacin, piperacillin-tazobactam, amikacin-metronidazole, and cefuroxime-metronidazole) in patients with a diagnosis of IAI. Analysis was based on a composed outcome of therapeutic failure (change of antibiotic because of no clinical improvement, requirement of surgical re-intervention, post-operative infection, change of antibiotic because of antimicrobial resistance, and in-hospital mortality). Association of each antibiotic protocol to therapeutic failure was assessed through logistic regression analysis. Results: Five hundred ninety-three individuals were included. Two hundred twenty-nine were prescribed ampicillin-sulbactam; 170, clindamycin-amikacin; 77, amikacin-metronidazole; 83, piperacillin-tazobactam; and 34, cefuroxime-metronidazole. Therapeutic failure rate was 22%. Multivariable analysis showed none of the evaluated antibiotic protocols had an association with the primary outcome. Variables having an association for higher risk were age >70 years old (odds ratio [OR], 2.08; 95% confidence interval [CI], 1.04-4.18); complicated IAI (OR, 3.36; 95% CI, 1.4-8.07); and World Society of Emergency Surgery (WSES) Sepsis Severity Score (OR, 1.31; 95% CI, 1.18-1.45). Adequate source control (OR, 0.16; 95% CI, 0.05-0.45) and hospitalization at Health Center 2 (OR, 0.30; 95% CI, 0.14-0.63) were identified as protective factors. Conclusions: There are no differences between the rate of therapeutic failure among the different antibiotic protocols evaluated. This outcome depends heavily on risk factors related to disease severity when surgical intervention occurs.

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The western Amazon basin is an important endemic area for malaria by P. vivax. In recent years, several reports showed the treatment failure with chloroquine, which can be related to resistance. The assessment of chloroquine resistance requires the evaluation of drug exposure, and when possible, the estimation of the pharmacokinetic parameters. However, there is no data on the pharmacokinetics of chloroquine in this endemic area. Moreover, the influence of the early reappearance of parasites in blood on the exposure to the drug was low exploited in the literature. The present study described the pharmacokinetic parameters of chloroquine in whole blood of adult patients with P. vivax malaria from the western Brazilian Amazon basin and compared the area under the curve (AUC) with the parasitological outcome at day 28. A total of 19 patients with parasite recurrence within 28 days and 20 patients with no recurrence were included in the study. Chloroquine was measured by high-performance liquid chromatography (HPLC). The pharmacokinetic parameters were estimated by non-compartmental modeling. The maximum concentration ranged from 1285 to 2030 ng/mL. The terminal half-life varied from 5.3 to 12.8 days. The volume of distribution from 1090 to 2340 L/kg, and the area under the curve to the last measurable concentration from 247 to 432 ng/mL.h. The pharmacokinetic parameters were similar in both groups, which suggests the lack of influence of early reappearance of parasites on chloroquine pharmacokinetics.

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BACKGROUND: Psoriasis is a chronic disease that seriously impacts quality of life. There are known genetic and environmental factors that influence its onset and progression. Even though there is no cure for it, there are a variety of treatments available today to control its symptoms, although many of them fail to do so substantially. OBJECTIVE: To identify the association of multiple sociodemographic, clinical, and pharmacological factors with therapeutic failure. METHODS: Observational, descriptive, cross-sectional, retrospective, and analytical study of therapeutic failure in patients with moderate or severe psoriasis between 2020 and 2021 was performed. RESULTS: In total 1051 patients with moderate or severe psoriasis were evaluated. Gender (ORa: 0.579 CI 95%: 0.382-0.878), type of therapy (biologic or non-biologic; ORa: 1.939 CI 95%: 1.242-3.027), age (ORa: 1.018 CI 95%: 1.003-1.034), days of treatment (ORa: 1 CI 95%: 0.999-1) and DLQI (ORa: 1.212 CI 95%: 1.172-1.253) are significantly associated with therapeutic failure. CONCLUSION: Being male and receiving biologic therapy are associated with a higher incidence of therapeutic failure in the treatment of moderate or severe psoriasis. The increase in DLQI increase in the probability of failure, and mayor age or days of treatment decrease in the probability of failure.

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Abstract Background: Undernutrition is frequent among children living with HIV in developing countries. An interaction between malnutrition and HIV pediatric infection remains incompletely characterized in Colombia. Methodology: Retrospective longitudinal study, descriptive in nature, in 28 patients with a diagnosis of HIV infection, less than 18 years of age and receiving anti retroviral therapy. Variables were retrieved from clinical records at start of antiretroviral therapy and after 12 months. Statistical analysis was exploratory. Results: 4 out of 28 patients were stunted (14,3%; 95%CI: 1,3 - 27,2), 2 out of 7 patients were wasted (28,6%; 95%CI: 0 - 62), 5 out of 17 patients were underweight (27,8%; 95%CI: 7,1 - 48,5) and 4 out of 28 patients had thinness (29,6%; 95%CI: 12,4 - 46,8). No clinically relevant anthropometric change was detected during follow-up. Anemia prevalence was 52% and 82% of patients had some degree of dyslipidemia. Both viral load (p=0,001) and CD4 count (p=0,01), significantly increased and the proportion of patients with therapeutic failure remained invariable during follow-up. Conclusion: Malnutrition is frequent and its prevalence might have decreased. HIV program improved medical control of the disease, with stable therapeutic failure rates that were comparable with previous reports. Nonetheless, anemia and dyslipidemia remain to be a paramount therapeutic challenge.

Resumen Introducción: La desnutrición es frecuente en niños con VIH en países en desarrollo. En Colombia, la interacción entre la desnutrición y la infección pediátrica por VIH se encuentra insuficientemente caracterizada. Metodología: Estudio longitudinal retrospectivo de carácter descriptivo, en 28 pacientes con diagnóstico de infección por VIH, edad menor a 18 años y con terapia antirretroviral en curso. Se extrajeron variables mediante revisión de historias clínicas en el momento de inicio de la terapia antirretroviral y 12 meses después. El análisis estadístico fue exploratorio. Resultados: 4 de 28 pacientes sufrían retraso del crecimiento (14,3%; IC95%: 1,3 - 27,2), 2 de 7 pacientes sufrían emaciación (28,6%; IC95%: 0 - 62), 5 de 17 pacientes sufrían insuficiencia ponderal (27,8%; IC95%: 7,1 - 48,5) y 4 de 28 pacientes se encontraban en delgadez (29,6%; IC95%: 12,4 - 46,8). No hubo cambios antropométricos clínicamente relevantes con el seguimiento. La prevalencia de anemia fue del 52% y 82% de los pacientes tenían algún grado de dislipidemia. Tanto la carga viral (p=0,001) como el conteo de CD4 (p=0,01), mejoraron significativamente y la proporción de pacientes con fallo terapéutico no cambió durante el seguimiento. Conclusión: La desnutrición es frecuente y su prevalencia podría haber disminuido. El programa de VIH mejoró el control médico de la enfermedad, con tasas de fallo terapéutico estables y comparables con reportes previos. No obstante, la anemia y la dislipidemia continúan siendo un gran reto terapéutico.

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BACKGROUND: Ocular toxoplasmosis is an infection caused by Toxoplasma gondii. In South America, the clinical course of ocular toxoplasmosis is more severe than in Europe and North America because virulent strains of the parasite are present. Ocular toxoplasmosis is the leading cause of posterior uveitis and retinochoroiditis in Colombia, requiring timely and appropriate treatment. However, there is no standardized therapy protocol based on economic studies for the country. PURPOSE: To compare the cost-effectiveness of four first-line treatment regimens for active ocular toxoplasmosis in immunocompetent adults in Colombia, using the number of averted therapeutic failures as the outcome. METHODS: We performed an economic and cost-effectiveness analysis to compare four first-line treatment regimens for ocular toxoplasmosis from the perspective of a third-party payer (Colombian General System of Social Security in Health). A decision analysis tree was used over a 24-week time horizon, considering only direct costs. Additionally, we performed a discrete sensitivity analysis and a probabilistic sensitivity analysis with 10,000 iterations in the Monte Carlo simulation. RESULTS: For the base case, trimethoprim/sulfamethoxazole showed 86% effectiveness at a cost of <57 United States Dollars, resulting in the most cost-effective first-line alternative. When performing the probabilistic sensitivity analysis and maintaining the willingness to pay 466.00 United States Dollars, the trimethoprim/sulfamethoxazole regimen remained the most cost-effective alternative. CONCLUSION: Ocular toxoplasmosis is a public health issue in Latin America. Despite severe visual consequences for affected patients, there are no standardized treatment guidelines in countries such as Colombia. Our evidence supports the use of trimethoprim/sulfamethoxazole as first-line treatment in Colombia because of its availability and optimal cost-effectiveness performance; it reduces recurrences and complications, while averting therapeutic failure. Furthermore, our evidence can be generalized to other Latin American countries with similar frequencies and severities of Toxoplasma gondii ocular infection and health systems similar to the Colombian system.

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High levels of pro-inflammatory cytokines in cutaneous leishmaniasis patients are associated with tissue damage and ulcer development. We found higher levels of TNF and IL-1ß in peripheral blood mononuclear cell supernatants in response to soluble Leishmania antigen in individuals with a longer duration of disease. In addition, Leishmania braziliensis-infected patients with a longer disease progression before treatment presented a shorter time to cure after treatment onset. No associations were found between the levels of the pro-inflammatory cytokines IL-6, TNF and IL-1-ß and patients' response to pentavalent antimony treatment. Our data suggest that while the Leishmania antigen-specific pro-inflammatory cytokines investigated may lead to ulcer development, they do not influence therapeutic failure in cutaneous leishmaniasis patients.

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Trypanosoma cruzi uses various mechanisms of infection to access humans. Since 1967, food contaminated with metacyclic trypomastigotes has triggered several outbreaks of acute infection of Chagas disease by oral transmission. Follow-up studies to assess the effectiveness of anti-parasitic treatment of oral outbreaks are rather scarce. Here, we report a 10-year laboratory follow-up using parasitological, serological, and molecular tests of 106 individuals infected in 2007 of the largest known outbreak of orally transmitted Chagas disease, which occurred in Caracas city, Venezuela. Before treatment (2007), specific IgA, IgM and IgG, were found in 71% (75/106), 90% (95/106) and 100% (106/106), respectively, in addition to 21% (9/43) parasitemia, Complement Mediated Lysis (CML) in 98% (104/106) and 79% (34/43) parasitic DNA for PCR. Blood culture detected parasitemia up to 18 months post-treatment in 6% (6/106) of the patients. In 2017, the original number of cases in the follow-up decreased by 46% and due to the country's economic situation, not all the trials could be carried out in the entire population. During follow-up, IgA and IgM disappeared promptly, with IgM persisting in 19% (20/104) of the patients three years after treatment. The anti-T. cruzi IgG remained positive 10 years later in 41% (20/49) of the individuals evaluated. CML remained positive seven years later in 79% (65/82) of the cases. PCR positive cases decreased after treatment but progressively recovered, being positive in 69% (32/46) of the individuals evaluated in 2017. The group of children (under 18 years of age) showed the highest PCR positivity with 76% (26/34) of the cases, but their parasitic load tended to diminish, while in adults the parasitic load regained their initial values. The simultaneous evaluation of serological tests and PCR of the patients allowed us to separate patients among responders and non-responders to the anti-parasitic treatment, and this information prompted us to apply a second anti-parasitic treatment in the group of non-responders. In this population not subjected to the like lihood of re-infection, adult patients were more likely to be non-responders when compared to children. These results suggest that rigorous laboratory follow-up with T. cruzi infectious biomarkers is essential to detect cases of parasite persistence.

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We aimed to characterize the genetic constitution of natural T. cruzi populations involved in an Oral Chagas Disease (OCD) outbreak at a rural school of the community of Chichiriviche de la Costa, Venezuela, which affected patients did not respond to the etiological treatment. Peripheral blood samples and/or hemocultures were obtained from twenty-nine OCD patients at time of diagnosis or along nine years of Post-treatment (Tx) follow-up. The IgG serology, T. cruzi discrete typing units (DTU), satellite DNA-qPCR parasitic loads, and minicircle signatures were determined at Pre-Tx and after Tx. The serological titles and parasitic loads changed after treatment, with a significant decrease of IgG titers (Spearman's r value= -0.961) and median parasite loads from 2.869 [IQR = 2.113 to 3.720] to 0.105 [IQR = -1.147 to 1.761] log10 par eq. /mL at Pre-Tx and Post-Tx, respectively, suggesting infection evolution from acute to chronic phase, without seroconversion or parasitological eradication, which was indicative of treatment failure. All patients were infected with T. cruzi DTU I populations. At Pre-Tx their median Jaccard genetic distances were 0.775 [IQR = 0.708 to 0.882], decreasing in genetic variability towards the end of follow-up (Mann-Whitney U test p= 0.0031). Interestingly, no Post-Tx minicircle signature was identical to its Pre-Tx counterpart population in a same patient, revealing selection of parasite subpopulations between the primary infection and Post-Tx. The parasitic populations isolated from hemocultures showed a lower number of bands in the minicircle signatures with respect to the signatures obtained directly from the patients' blood samples, demonstrating a process of parasitic selection and reduction of the population variability that initially infected the patients. Decrease of parasitic loads after treatment as well as Pre- and Post-Tx intra-TcI diversity might be a consequence of both, natural evolution of the acute infection to the chronic phase and persistence of refractory populations due to Tx selection.

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Background: Mucosal leishmaniasis (ML), the most inflammatory form of tegumentary leishmaniasis, is predominantly caused by Leishmania braziliensis. The disease is characterized by the development of lesions, mainly in the nasal mucosa. An exacerbated inflammatory response has been associated with the presence of destructive and disfiguring lesions, with stages of severity ranging from small nodulations to the complete destruction of the nasal pyramid architecture. As Leishmania is an intracellular parasite, most immunological studies have emphasized the cell-mediated immune response, while relatively few studies aimed to investigate the role antibodies in protection against, or the pathology of ML. Methods: Patients with a confirmed diagnosis of ML were classified according to clinical staging criteria. Serum levels of Leishmania-specific IgG, IgG1 and IgG2 antibodies were determined by ELISA before and after treatment with antimony or antimony plus pentoxifylline. Results: Patients in stages IV and V produced higher concentrations of IgG and IgG1 antibodies when compared to those in stage I and II. Significant reductions were seen in the concentrations of IgG and IgG2 antibodies in most patients who responded well to treatment. Conclusions: Our data demonstrate an association between IgG antibody titers and the severity of mucosal disease. The observed reduction in antibody production after successful treatment in most patients preliminarily indicates that these tests can be used to aid in the assessment of therapeutic response.

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Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. METHODS: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. RESULTS: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. CONCLUSION: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.

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O uso de antimicrobianos para profilaxia antimicrobiana ocorre rotineiramente na clínica cirúrgica veterinária. Entretanto, há condições específicas para a sua indicação tanto para prevenir a ocorrência de infecção do sítio cirúrgico quanto para impedir a seleção de bactérias multirresistentes. O presente trabalho foi delineado para auxiliar médicos-veterinários na tomada de decisão em relação ao protocolo antimicrobiano aplicado em pacientes cirúrgicos, visando tanto o sucesso dos tratamentos quanto a redução na seleção e disseminação de bactérias multirresistentes no contexto de Saúde Única.

Antimicrobial prophylaxis is routinely applied in veterinary surgery. However, there are specific conditions for its use in order to prevent the occurrence of surgical site infection and the selection of multidrug-resistant bacteria. This review aimed to help veterinarians’ surgeons in rational decision-making to the antimicrobial protocol applied in surgical patients. Thus, it was analysed not only how to achieve the treatment success, but also how to reduce the selection and spread of multidrug-resistant bacteria in the context of One Health.

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A Hanseníase é uma doença infectocontagiosa de caráter crônico, evolução lenta, causada pelo Mycobacterium leprae (M. leprae). A transmissão ocorre por meio do trato respiratório, e para o desenvolvimento da doença existe a necessidade da susceptibilidade, além do contato íntimo e prolongado. Para fins terapêuticos a Organização Mundial da Saúde (OMS) traz uma classificação mais simples que é baseada no número de lesões cutâneas. Os casos com até cinco lesões são considerados paucibacilares e aqueles com mais de cinco lesões são multibacilares. Apesar da implantação da poliquimioterapia (PQT) pela OMS ter sido um importante avanço técnico na história do controle da doença, em 2019 ainda foram notificados 202.185 novos casos no mundo, sendo o Brasil o segundo em concentração de casos. Um indicador importante para o controle da hanseníase são as taxas de retratamento, definido como nova notificação de hanseníase em paciente que já tenha recebido tratamento anterior, suas causas incluem abandono, insuficiência terapêutica, falência terapêutica, alteração de esquema por erro diagnóstico e recidiva. Embora um grande número de casos de recidivas seja detectado no Brasil, apenas 8,4%, 13,3% e 1,9% dos casos podem ser explicados por mutações que sabidamente conferem resistência bacilar aos medicamentos utilizados na PQT: rifampicina (RFP), dapsona (DDS) e ofloxacina (OFLO), respectivamente. Além dos aspectos relacionados ao patógeno, a contribuição do hospedeiro para esse cenário, apesar de pouco estudada, deve ser de grande importância. No geral a resposta ao medicamento é variável entre indivíduos, ocasionando falta de eficácia farmacológica ou reação adversas, em partes esses eventos podem ser explicados pela farmacogenética. Conhecer fatores genéticos que interferem no metabolismo dos medicamentos pode contribuir para melhores resultados terapêuticos. Dentre os desafios para atingir a eliminação da hanseníase estão a ausência de novas ferramentas de diagnóstico e de entendimento das causas associadas a recidiva e à não adesão a PQT, uma vez que a resistência medicamentosa explica pouco da reativação da doença, deste modo, o presente estudo teve como finalidade constituir banco de dados em hanseníase para estudos de associação do tipo caso-controle sobre os fatores associados com a falha terapêutica da PQT convencional. Dos 240 prontuários avaliados, 119 foram classificados como casos de falência terapêutica ou recidiva e 121 como sucesso terapêutico, aqui denominados como controles, a maioria dos pacientes era do sexo masculino, branco e procedente do estado de São Paulo; Em relação à faixa etária de diagnóstico, 18% foram diagnosticados com idade entre 40 e 49 anos, enquanto nos controles 14% tiveram diagnóstico com idade inferior a 19 anos; quanto à forma clínica da doença, 59% dos casos e 47% dos controles foram classificados como virchoviano. Dentre os casos de falência terapêutica ou recidiva, a resistência molecular explicou apenas 5,8 % dos casos de retratamento. Esse dado reforça a urgência de estudos que esclareçam as causas da falha terapêutica em hanseníase, contribuindo assim para o estabelecimento de medidas que visem o alcance de melhores índices relacionados aos desfechos terapêuticos.(AU)

Leprosy is a chronic infectious disease with insidious evolution, caused by Mycobacterium leprae (M. leprae). Transmission occurs through the respiratory tract, and the onset of the disease depends on susceptibility, in addition to intimate and prolonged contact with untreated patients. For therapeutic purposes, the World Health Organization's (WHO) classification is based on the number of skin lesions. Cases with up to five lesions are considered paucibacillary and those with more than five lesion are multibacillary. Although the implementation of multidrugtherapy (MDT) by WHO was an important technical advance in the history of disease control. In 2019, 202,185 new cases were reported in the world, with Brazil the second in the highest number of cases. An important indicator for the control of leprosy is retreatment rate, defined as a new notification of leprosy in a patient who has already received previous treatment. Its causes include abandonment, therapeutic failure, , alteration of the regimen due to diagnostic error and relapse. Although a large number of cases of relapses are detected in Brazil, only 8.4%, 13.3% and 1.9% of cases can be explained by mutations that are known to confer bacillary resistance to drugs used in the MDT: rifampicin (RFP), dapsone (DDS) and ofloxacin (OFLO), respectively. In addition to aspects related to the pathogen, the host's contribution to this scenario, although little studied, is highly important. In general, the response to the drug treatment is variable between individuals, causing a lack of pharmacological efficacy or adverse reactions. , These events may be explained by pharmacogenetics. Knowing genetic factors that interfere with drug metabolism can contribute to better therapeutic results. Among the challenges to achieve leprosy elimination are the absence of new diagnostic tools and understanding of the causes associated with relapse and non-adherence to MDT, since drug resistance explains little about the reactivation of the disease. Thus, the present study aimed at constituting a leprosy database for case-control association studies on factors associated with conventional MDT therapeutic failure. Of the 240 medical records evaluated, 119 were classified as cases of therapeutic failure or relapse and 121 as therapeutic success, here referred to as controls. The majority of patients were male, white and from the state of São Paulo. Regarding the age of diagnosis, 18% were diagnosed between 40 and 49 years, while in controls, 14% were diagnosed under 19 years; as to the clinical form of the disease, 59% of the cases and 47% of the controls were classified as lepromatous. Among the cases of therapeutic failure or relapse, molecular resistance explained only 5.8% of retreatment cases. This data reinforces the urgency of studies that clarify the causes of therapeutic failure in leprosy, thus contributing to the establishment of measures aimed at achieving better therapeutic outcomes(AU).

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O uso de antimicrobianos para profilaxia antimicrobiana ocorre rotineiramente na clínica cirúrgica veterinária. Entretanto, há condições específicas para a sua indicação tanto para prevenir a ocorrência de infecção do sítio cirúrgico quanto para impedir a seleção de bactérias multirresistentes. O presente trabalho foi delineado para auxiliar médicos-veterinários na tomada de decisão em relação ao protocolo antimicrobiano aplicado em pacientes cirúrgicos, visando tanto o sucesso dos tratamentos quanto a redução na seleção e disseminação de bactérias multirresistentes no contexto de Saúde Única.(AU)

Antimicrobial prophylaxis is routinely applied in veterinary surgery. However, there are specific conditions for its use in order to prevent the occurrence of surgical site infection and the selection of multidrug-resistant bacteria. This review aimed to help veterinarians surgeons in rational decision-making to the antimicrobial protocol applied in surgical patients. Thus, it was analysed not only how to achieve the treatment success, but also how to reduce the selection and spread of multidrug-resistant bacteria in the context of One Health.(AU)

Assuntos

RESUMO

Resumen La leishmaniasis tegumentaria en Bolivia es producida mayoritariamente por L. braziliensis. Las manifestaciones clínicas son ulceras, que pueden generar lesiones satélites próximas a la inicial. Las drogas de primera elección para el tratamiento son los antimoniales pentavalentes; aunque con una eficacia variable. La falta de respuesta a estas drogas, induce al empleo de otras, consideradas como de segunda elección. Sin embargo, en todos los casos existe la posibilidad de falla terapéutica. El presente caso muestra la remisión de las lesiones usando tratamiento combinado de pentamidina, miltefosina y paromomicina, en un paciente con antecedente de falta de respuesta a la monoterapia con Glucantime®. La remisión de la enfermedad alcanzada al final de la terapia, probablemente sea resultado de la acción lítica simultánea de las tres drogas utilizadas y a la restauración de la respuesta inmune del paciente. Hasta los 21 meses de control pos tratamiento, todas las lesiones se mantuvieron cicatrizadas y ausencia de otras nuevas.

Abstract The tegumentary leishmaniasis in Bolivia is mainly caused by L. braziliensis. The clinical manifestations are ulcerative lesions which can generate satellite lesions close to the initial one. The first choice drugs for treatment are pentavalent antimonials; although with variable effectiveness. Lack of response to these drugs leads to the use of other alternatives, considered as second-choice drugs. However, in all cases there is the possibility of therapeutic failure. The present case shows the remission of the lesions using a combined treatment of pentamidine, miltefosine and paromomycin, in a patient with a history of lack of response to monotherapy with Glucantime® The remission of the disease achieved at the end of combined therapy is probably the result of the simultaneous lytic action of the three drugs used and the restoration of the patient's immune response. Up to 21 months of post-treatment control, all the lesions remained healed and the absence of new ones.

RESUMO

BACKGROUND: Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis. OBJECTIVE AND RATIONALE: We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments. SEARCH METHODS: We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment. OUTCOMES: Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response. WIDER IMPLICATIONS: Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions.

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