Suspected poor-quality medicines in Kenya: a retrospective descriptive study of medicine quality-related complaints reports in Kenya's pharmacovigilance database.

Poor-quality, substandard and falsified, medicines pose a significant public health threat, particularly in low-middle-income countries. A retrospective study was performed on Kenya's Pharmacovigilance Electronic Reporting System (2014-2021) to characterize medicine quality-related complaints and identify associations using disproportionality analysis. A total of 2767 individual case safety reports were identified, categorized into medicines with quality defects (52.1%), suspected therapeutic failure (41.6%), and suspected adverse drug reactions (6.3%). Predominantly reported were antineoplastic agents (28.6%), antivirals (11.7%), and antibacterial agents (10.8%) potentially linked to non-adherence to good manufacturing practices, inappropriate usage and supply chain degradation. Notably, analgesics (8.2%), and medical devices (3.5%) notified had quality defects, predominantly from government health facilities (60.0%). Antineoplastic agents (20.2%) and antivirals (3.7%) were frequently reported from suspected therapeutic failures and suspected adverse drug reactions, respectively, across both private for-profit facilities (26.5%) and not-for-profit facilities (5.4%). Underreporting occurred in unlicensed health facilities (8.1%), due to unawareness and reporting challenges. Pharmacists (46.1%), and pharmaceutical technicians (11.7%) predominantly reported quality defects, while medical doctors (28.0%) reported suspected therapeutic failures. Orally administered generic medicines (76.9%) were commonly reported, with tablets (5.8%) identified as potential sources of suspected adverse drug reactions, while quality defects were notified from oral solutions, suspensions, and syrups (7.0%) and medical devices (3.9%). The COVID-19 pandemic correlated with reduced reporting possibly due to prioritization of health surveillance. This study provides valuable evidence to supporting the use of medicine quality-related complaints for proactive, targeted regulatory control of high-risk medicines on the market. This approach can be strengthened by employing standardized terminology to prioritize monitoring of commonly reported suspected poor-quality medicines for risk-based sampling and testing within the supply chain.

Predictive and Prognostic 18F-Fluorocholine PET/CT Radiomics Nomogram in Patients with Castration-Resistant Prostate Cancer with Bone Metastases Treated with 223Ra.

PURPOSE: We aimed to develop a nomogram able to predict treatment failure, skeletal events, and overall survival (OS) in patients with castration-resistant prostate cancer with bone metastases (CRPC-BM) treated with Radium-223 dichloride (223Ra). PATIENTS AND METHODS: Patients from the Castilla-La Mancha Spanish region were prospectively included in the ChoPET-Rad multicenter study from January 2015 to December 2022. Patients underwent baseline, interim, and end-of-treatment bone scintigraphy (BS) and 18F-Fluorocholine PET/CT (FCH PET/CT) scans, obtaining multiple imaging radiomics as well as clinical and biochemical variables during follow-up and studying their association with the previously defined end-points. Survival analysis was performed using the Kaplan-Meier method and Cox regression. Multivariate logistic and Cox regression models were calculated, and these models were depicted by means of nomograms. RESULTS: Median progression-free survival (PFS) and OS were 4 and 14 months (mo), respectively. The variables that showed independent and significant association with therapeutic failure were baseline alkaline phosphatase (AP) levels (p = 0.022) and the characteristics of BM on the CT portion of PET/CT (p = 0.017). In the case of OS, the significant variables were therapeutic failure (p = 0.038), the number of lines received after 223Ra (p < 0.001), average SUVmax (p = 0.002), bone marrow infiltration in FCH PET/CT (p = 0.006), and interim FCH PET/CT response (p = 0.048). Final nomograms included these variables, showing good discrimination among the 100 patients included in our study. In the study of skeletal events, only OS showed a significant association in the multivariate analysis, resulting in an inconsistent nomogram design. CONCLUSIONS: FCH PET/CT appears to be a good tool for evaluating patients eligible for treatment with 223Ra, as well as for their follow-up. Thus, findings derived from it, such as the morphological characteristics of BM in the CT, bone marrow infiltration, or the response to 223Ra in the interim study, have proven to be solid and useful variables in the creation of nomograms for predicting therapeutic failure and OS.

Predictive potential of serum and cerebrospinal fluid biomarkers for disease activity in treated multiple sclerosis patients.

BACKGROUND: Our objective was to explore various biomarkers for predicting suboptimal responses to disease-modifying treatments (DMTs) in patients with MS (pwMS). METHODS: We conducted a longitudinal, bicentric study with pwMS stratified based on their DMTs responses. Treatment failure (TF) was defined as the onset of a second relapse, presence of two or more T2 new lesions, or disability progression independent of relapse during the follow-up period. We evaluated intrathecal synthesis (ITS) of IgG and IgM using OCB, linear indices, and Reibergrams. Free kappa light chains ITS was assessed using the linear index (FKLCi). NfL and GFAP in serum and CSF, and CHI3L1 in CSF were quantified. Quantitative variables were dichotomized based on the third quartile. Predictive efficacy was assessed through bivariate and multivariate analyses, adjusting for age, sex, EDSS, acute inflammatory activity (AI) -defined as the onset of a relapse or gadolinium-enhancing lesions within a 90-day window of lumbar puncture-, treatment modality, study center, and time from disease onset to treatment initiation. In case of collinearity, multiple models were generated or confounding variables were excluded if collinearity existed between them and the biomarker. The same methodology was used to investigate the predictive potential of various combinations of two biomarkers, based on whether any of them tested positive or exceeded the third quartile. RESULTS: A total of 137 pwMS were included. FKLCi showed no differences based on AI, no correlation with EDSS and was significantly higher in pwMS with TF (p = 0.008). FKLCi>130 was associated with TF in bivariate analysis (Log-Rank p = 0.004). Due to collinearity between age and EDSS, two different models were generated with each of them and the rest of the confounding variables, in which FKLCi>130 showed a Hazard Ratio (HR) of 2.69 (CI: 1.35-5.4) and 2.67 (CI: 1.32-5.4), respectively. The combination of either FKLC or sNfL exceeding the third quartile was also significant in bivariate (Log-Rank p = 0.04) and multivariate (HR=3.1 (CI: 1.5-6.5)) analyses. However, when analyzed independently, sNfL did not show significance, and FKLCi mirrored the pattern obtained in the previous model (HR: 3.04; CI: 1.51-6.1). Treatment with highefficacy DMTs emerged as a protective factor in all models. DISCUSSION: Our analysis and the fact that FKLCi is independent of EDSS and AI suggest that it might be a valuable parameter for discriminating aggressive phenotypes. We propose implementing high-efficacy drugs in pwMS with elevated FKLCi.

HIV diagnosis in Equatorial Guinea. Keys to reduce the diagnostic and therapeutic delay.

BACKGROUND: In Equatorial Guinea, only 54 % of people living with HIV know their HIV status. There are no confirmatory or molecular diagnostic techniques for early diagnosis or monitoring of infection in the country. Rapid diagnostic tests can induce false-positive diagnoses if used as a confirmatory technique. Our study aimed to identify the challenges of early HIV diagnosis in Equatorial Guinea by analyzing the rate of false positive diagnoses, diagnostic and therapeutic delays, and treatment failures among those on antiretroviral therapy. METHODS: From 2019-2022, dried blood from 341 children, adolescents and adults diagnosed in Equatorial Guinea as HIV-positive by rapid diagnostic testing, and from 54 HIV-exposed infants were collected in Bata and sent to Madrid to confirm HIV-infection by molecular (Xpert HIV-1Qual, Cepheid) and/or serological confirmatory assays (Geenius-HIV-1/2, BioRad). HIV diagnostic delay (CD4 <350cells/mm3), advanced disease at diagnosis (CD4 <200cells/mm3) and antiretroviral treatment delay and failure (viraemia >1,000RNA-HIV-1-copies/ml) were also studied after viral quantification (XpertVL HIV-1, Cepheid). RESULTS: False-positive diagnoses were identified in 5 % of analysed samples. HIV infection was confirmed in 90.5 % of previously diagnosed patients in Equatorial Guinea and 3.7 % of HIV-exposed children undiagnosed in the field. Two-thirds of each new HIV patient had delayed diagnosis, and one-third had advanced disease. Treatment delay occurred in 28.3 % of patients, being around four times more likely in adolescents/adults than children. More than half (56 %) of 232 treated patients presented treatment failure, being significantly higher in children/adolescents than in adults (82.9 %/90 % vs. 45.6 %, p < 0.001). CONCLUSION: We identified some challenges of early HIV diagnosis in Equatorial Guinea, revealing a high rate of false positive diagnoses, diagnostic/treatment delays, and treatment failures that need to be addressed. The implementation of more accurate rapid diagnostic techniques and confirmatory tests, along with improving access to care, treatment, awareness, and screening, would contribute to controlling the spread of HIV in the country.

Cellular and Molecular Determinants of Biologic Drugs Resistance and Therapeutic Failure in Inflammatory Bowel Disease.

The advent of biologic drugs has revolutionized the treatment of Inflammatory Bowel Disease, increasing rates of response and mucosal healing in comparison to conventional therapies by allowing the treatment of corticosteroid-refractory cases and reducing corticosteroid-related side effects. However, biologic therapies (anti-TNFα inhibitors, anti-α4ß7 integrin and anti-IL12/23) are still burdened by rates of response that hover around 40% (in biologic-naïve patients) or lower (for biologic-experienced patients). Moreover, knowledge of the mechanisms underlying drug resistance or loss of response is still scarce. Several cellular and molecular determinants are implied in therapeutic failure; genetic predispositions, in the form of single nucleotide polymorphisms in the sequence of cytokines or Human Leukocyte Antigen, or an altered expression of cytokines and other molecules involved in the inflammation cascade, play the most important role. Accessory mechanisms include gut microbiota dysregulation. In this narrative review of the current and most recent literature, we shed light on the mentioned determinants of therapeutic failure in order to pave the way for a more personalized approach that could help avoid unnecessary treatments and toxicities.

Candent issues in pneumonia. Reflections from the Fifth Annual Meeting of Spanish Experts 2023.

Pneumonia is a multifaceted illness with a wide range of clinical manifestations, degree of severity and multiple potential causing microorganisms. Despite the intensive research of recent decades, community-acquired pneumonia remains the third-highest cause of mortality in developed countries and the first due to infections; and hospital-acquired pneumonia is the main cause of death from nosocomial infection in critically ill patients. Guidelines for management of this disease are available world wide, but there are questions which generate controversy, and the latest advances make it difficult to stay them up to date. A multidisciplinary approach can overcome these limitations and can also aid to improve clinical results. Spanish medical societies involved in diagnosis and treatment of pneumonia have made a collaborative effort to actualize and integrate last expertise about this infection. The aim of this paper is to reflect this knowledge, communicated in Fifth Pneumonia Day in Spain. It reviews the most important questions about this disorder, such as microbiological diagnosis, advances in antibiotic and sequential therapy, management of beta-lactam allergic patient, preventive measures, management of unusual or multi-resistant microorganisms and adjuvant or advanced therapies in Intensive Care Unit.

Risk factors for therapeutic failure in adults with methicillin-resistant Staphylococcus aureus (MRSA) infection treated with vancomycin in a high-complexity hospital in Cali, Colombia.

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.

Ten Issues for Updating in Community-Acquired Pneumonia: An Expert Review.

Community-acquired pneumonia represents the third-highest cause of mortality in industrialized countries and the first due to infection. Although guidelines for the approach to this infection model are widely implemented in international health schemes, information continually emerges that generates controversy or requires updating its management. This paper reviews the most important issues in the approach to this process, such as an aetiologic update using new molecular platforms or imaging techniques, including the diagnostic stewardship in different clinical settings. It also reviews both the Intensive Care Unit admission criteria and those of clinical stability to discharge. An update in antibiotic, in oxygen, or steroidal therapy is presented. It also analyzes the management out-of-hospital in CAP requiring hospitalization, the main factors for readmission, and an approach to therapeutic failure or rescue. Finally, the main strategies for prevention and vaccination in both immunocompetent and immunocompromised hosts are reviewed.

Ten Issues to Update in Nosocomial or Hospital-Acquired Pneumonia: An Expert Review.

Nosocomial pneumonia, or hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) are important health problems worldwide, with both being associated with substantial morbidity and mortality. HAP is currently the main cause of death from nosocomial infection in critically ill patients. Although guidelines for the approach to this infection model are widely implemented in international health systems and clinical teams, information continually emerges that generates debate or requires updating in its management. This scientific manuscript, written by a multidisciplinary team of specialists, reviews the most important issues in the approach to this important infectious respiratory syndrome, and it updates various topics, such as a renewed etiological perspective for updating the use of new molecular platforms or imaging techniques, including the microbiological diagnostic stewardship in different clinical settings and using appropriate rapid techniques on invasive respiratory specimens. It also reviews both Intensive Care Unit admission criteria and those of clinical stability to discharge, as well as those of therapeutic failure and rescue treatment options. An update on antibiotic therapy in the context of bacterial multiresistance, in aerosol inhaled treatment options, oxygen therapy, or ventilatory support, is presented. It also analyzes the out-of-hospital management of nosocomial pneumonia requiring complete antibiotic therapy externally on an outpatient basis, as well as the main factors for readmission and an approach to management in the emergency department. Finally, the main strategies for prevention and prophylactic measures, many of them still controversial, on fragile and vulnerable hosts are reviewed.

Immunoglobulin-resistant Kawasaki disease.

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.

Prostaglandin E2 contributes to L. braziliensis survival and therapeutic failure in cutaneous leishmaniasis.

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.

Immunoglobulin-resistant Kawasaki disease / Enfermedad de Kawasaki refractaria a tratamiento con inmunoglobulina

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.

Sociodemographic and clinical characteristics associated with multiple biologic failure in psoriasis: A 2015-2022 prospective cohort analysis of the CorEvitas psoriasis registry.

BACKGROUND: Psoriasis patients with poor therapeutic response to multiple biologic agents are not well-characterized. OBJECTIVE: To describe the characteristics associated with development of multiple biologic failure (MBF) versus good clinical response (GR) to the first biologic. METHODS: This prospective cohort analysis evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for ≥24 months. Multivariable logistic regression identified sociodemographic, clinical, and patient-reported outcomes that differed between MBF (discontinued ≥2 biologics of different classes, each used for ≥90 days, due to inadequate efficacy) and GR (continued use of first biologic for ≥2 years) patients. RESULTS: One thousand thirty-nine patients were analyzed (490 GR [47.2%], 65 MBF [6.3%]). Female sex, shorter psoriasis duration, earlier year of biologic initiation, prior nonbiologic systemic therapy use, history of hyperlipidemia, and Medicaid insurance were significantly associated with MBF, though the latter 2 variables exhibited wider confidence intervals, indicating a lower level of support. The first-to-second biologic sequence most observed with MBF was Tumor necrosis factor-α inhibitor to IL-17 inhibitor use. LIMITATIONS: Biologic adherence between visits was not evaluated. CONCLUSION: Approximately 6% of psoriasis patients met MBF criteria. The results identify characteristics associated with MBF that may distinguish patients warranting more frequent follow-up.

Biological parameters determining the effectiveness of monitoring of HIV / AIDS infected patients in Morocco.

Background & objective: Human Immunodeficiency Virus (HIV) remains one of the world's most serious health challenges. The development of therapeutic regimens has significantly increased survival and reduced HIV-associated morbidities in HIV-infected individuals. However, some people living with HIV may not respond as expected, resulting in treatment failure. The objective of this study is to identify and characterize, by immunological (T-cell CD4) and virological (viral load) parameters, HIV infected patients with therapeutic failure in Morocco. Methods: Prospective cross-sectional studies were conducted over a 5-years period (between January 2015 and December 2019) at the referral center of Ibn Zohr Hospital, Marrakech, Morocco. A total, of 1088 HIV-infected patients diagnosed by the rapid test (Immunochromatography) in addition to Western Blot analysis, was recruited. All patients were under the antiretroviral therapy (ART) for at least six months and followed every six months. Sociodemographic, clinical, and biological data as well as information on patient adherence were collected. Results: Out of 1088 patients, 92.46% were under treatment based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) including 26.20% first line first intention and 66.26% first line second intention, and 7.54% of patients on a protease inhibitor (PI) therapy. Regarding the immunological and virological status, 76% of HIV-infected patients had a CD4 count > 200 cells/µl and 24% had a CD4 count < 200 cells / µl, while 69.5% had an undetectable viral load and 30.05% had a detectable viral load (including 11.86% with viral load < 1000 copies / ml and 18.20% viral load > 1000 copies / ml) (P-values < 0.05). Conclusion: In our study, we showed a therapeutic failure rate of 18.2% in HIV-infected patients under treatment in Marrakech region. These failures were mainly related to poor adherence and low CD4+ rates at the initiation of treatment. We concluded that immunological monitoring alone is insufficient to predict virological suppression and therapeutic success. Consequently, we recommend the HIV plasma viral load test be accessible as a routine exam.

Imipenem heteroresistance but not tolerance in Haemophilus influenzae during chronic lung infection associated with chronic obstructive pulmonary disease.

Antibiotic resistance is a major Public Health challenge worldwide. Mechanisms other than resistance are described as contributors to therapeutic failure. These include heteroresistance and tolerance, which escape the standardized procedures used for antibiotic treatment decision-making as they do not involve changes in minimal inhibitory concentration (MIC). Haemophilus influenzae causes chronic respiratory infection and is associated with exacerbations suffered by chronic obstructive pulmonary disease (COPD) patients. Although resistance to imipenem is rare in this bacterial species, heteroresistance has been reported, and antibiotic tolerance cannot be excluded. Moreover, development of antibiotic heteroresistance or tolerance during within-host H. influenzae pathoadaptive evolution is currently unknown. In this study, we assessed imipenem resistance, heteroresistance and tolerance in a previously sequenced longitudinal collection of H. influenzae COPD respiratory isolates. The use of Etest, disc diffusion, population analysis profiling, tolerance disc (TD)-test methods, and susceptibility breakpoint criteria when available, showed a significant proportion of imipenem heteroresistance with differences in terms of degree among strains, absence of imipenem tolerance, and no specific trends among serial and clonally related strains could be established. Analysis of allelic variation in the ftsI, acrA, acrB, and acrR genes rendered a panel of polymorphisms only found in heteroresistant strains, but gene expression and genome-wide analyses did not show clear genetic traits linked to heteroresistance. In summary, a significant proportion of imipenem heteroresistance was observed among H. influenzae strains isolated from COPD respiratory samples over time. These data should be useful for making more accurate clinical recommendations to COPD patients.

[Drug-resistant pulmonary tuberculosis at Maradi Regional Hospital Center, Niger (2014-2018)]. / Tuberculose pulmonaire résistante à la rifampicine au Centre Hospitalier régional de Maradi, Niger (2014-2018).

Aim of study: To describe the clinical, therapeutic and evolutionary profile of patients followed for rifampicin-resistant pulmonary tuberculosis (RR-TB) at the Regional Hospital Centre (RHC) of Maradi (Niger) from 2014 to 2018. Methods: We conducted a retrospective and descriptive study based on the records of patients followed for Multidrug-resistant tuberculosis (MDR-TB) between January 1, 2014 and June 30, 2018 at the resistant tuberculosis management unit in Maradi (Niger). This unit is located within the RHC of Maradi and has a capacity of 20 beds in 4 wards. It receives patients with tuberculosis resistant to first-line anti-tuberculosis drugs. In this study, patients diagnosed with RR-TB by genotypic (GeneXpert MTB/RIF) or phenotypic (culture) testing were included. We excluded from this study: patients previously treated for more than 1 month with second-line anti-TB drugs; patients with resistance to second-line injectables (SLI) and/or fluoroquinolones (FQ); patients with an electrocardiogram QTc greater than 500 ms (the corrected QT (QTc) estimates the QT interval at a rate of 60 beats per second); cases of atypical mycobacteriosis detected by phenotypic testing.Patients were previously on 2RHZE/4RH prior to the discovery of resistance. The treatment protocol for resistant TB was as follows: 4KmMfxPtoCfzHZE/5MfxCfzZE (The second-line injectable was replaced by Lzd in case of initial or treatment-emergent deafness). HIV co-infected patients received, in addition to anti-tuberculosis drugs, antiretrovirals and cotrimoxazole in preventive doses. Results: A total of 80 patients were included in the present study (70 males and 10 females, mean age 34.4 years with extremes ranging from 18 to 71 years). Patients aged 18-35 years accounted for more than half. Patients with primary treatment failure were the most frequent type (36%) followed by patients with retreatment failure (24%) and patients with retreatment relapse (17%). It should be noted that 77 patients (96%) were previously treated for TB and only 3 patients (4%) were new cases. The majority of patients (70%) had a Body mass index of less than 18 kg/m2. 7.5% of patients were HIV positive, one was diabetic, 52% of the patients had grade 2 radiological lesions. Grade 1 deafness was noted at the beginning of treatment in 3%. A third of patients (36%) were primary treatment failures. The treatment protocol was as follows: 4KmMfxPtoCfzHZE/5MfxCfzZE. Only 1 patient had a positive culture at the end of the 4th month of treatment. Most of the patients had experienced adverse events, mainly digestive, with vomiting being the most common. The therapeutic success rate was 88%. We noted 10% of deaths, 1% of therapeutic failure and 1% of lost to follow-up.Six months after treatment, 48 patients (60%) were smear negative and 43 (54%) were culture negative. In 32 patients (40%), the smear was not performed and culture was not performed in 37. Conclusion: The short treatment regime gives satisfactory results in the absence of resistance to fluoroquinolones, with rare adverse effects. In Niger, further efforts should be made to minimize the delay in diagnosis which is responsible for most deaths during treatment. A centre could usefully be designated to organize "TB consiliums" allowing any practitioner to submit difficult cases of MDR-TB.

Effectiveness of Five Antibiotic Regimens for the Treatment of Intra-Abdominal Infection in Bogotá.

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.

Pharmacokinetics of chloroquine in patients with malaria by P. vivax from the Western Brazilian Amazon basin.

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.

Transcriptome Analysis of Intracellular Amastigotes of Clinical Leishmania infantum Lines from Therapeutic Failure Patients after Infection of Human Macrophages.

Leishmaniasis is considered to be one of the most neglected tropical diseases affecting humans and animals around the world. Due to the absence of an effective vaccine, current treatment is based on chemotherapy. However, the continuous appearance of drug resistance and therapeutic failure (TF) lead to an early obsolescence of treatments. Identification of the factors that contribute to TF and drug resistance in leishmaniasis will constitute a useful tool for establishing future strategies to control this disease. In this manuscript, we evaluated the transcriptomic changes in the intracellular amastigotes of the Leishmania infantum parasites isolated from patients with leishmaniasis and TF at 96 h post-infection of THP-1 cells. The adaptation of the parasites to their new environment leads to expression alterations in the genes involved mainly in the transport through cell membranes, energy and redox metabolism, and detoxification. Specifically, the gene that codes for the prostaglandin f2α synthase seems to be relevant in the pathogenicity and TF since it appears substantially upregulated in all the L. infantum lines. Overall, our results show that at the late infection timepoint, the transcriptome of the parasites undergoes significant changes that probably improve the survival of the Leishmania lines in the host cells, contributing to the TF phenotype as well as drug therapy evasion.