colistin and Disease-Models--Animal

The most effective way to control severity and mortality rate of the novel coronavirus disease (COVID-19) is through sensitive diagnostic approaches and an appropriate treatment protocol. We aimed to identify the effect of adding corticosteroid and Tocilizumab to a standard treatment protocol in treating COVID-19 patients with chronic disease through hematological and lab biomarkers.. This study was performed retrospectively on 68 COVID-19 patients with chronic disease who were treated by different therapeutic protocols. The patients were categorized into four groups: control group represented the patients' lab results at admission before treatment protocols were applied; group 1 included patients treated with anticoagulants, Hydroxychloroquine, and antibiotics; group 2 comprised patients treated with Dexamethasone; and group 3 included patients treated with Dexamethasone and Tocilizumab.. The study paves the way into the effectiveness of combining Dexamethasone with Tocilizumab in treatment COVID-19 patients with chronic diseases.. La forma más eficaz de controlar la gravedad y la tasa de mortalidad de la enfermedad del nuevo coronavirus (COVID-19) es mediante enfoques de diagnóstico sensibles y un protocolo de tratamiento adecuado. Nuestro objetivo fue identificar el efecto de agregar corticosteroides y tocilizumab a un protocolo de tratamiento estándar en el tratamiento de pacientes con COVID-19 con enfermedad crónica a través de biomarcadores hematológicos y de laboratorio.. Este estudio se realizó de forma retrospectiva en 68 pacientes COVID-19 con enfermedad crónica que fueron tratados por diferentes protocolos terapéuticos. Los pacientes se clasificaron en cuatro grupos: el grupo de control representaba los resultados de laboratorio de los pacientes en el momento de la admisión antes de que se aplicaran los protocolos de tratamiento; el grupo 1 incluyó a pacientes tratados con anticoagulantes, hidroxicloroquina y antibióticos; el grupo 2 estaba compuesto por pacientes tratados con dexametasona; y el grupo 3 incluyó a pacientes tratados con dexametasona y tocilizumab.. El estudio allana el camino hacia la eficacia de la combinación de dexametasona con tocilizumab en el tratamiento de pacientes con COVID-19 con enfermedades crónicas.. The Child-Mother Index constitutes a potential useful risk factor indicator for statistical analyses on data after birth. The value of the Child-Mother Index based on the estimated fetal weight before birth deserves evaluation.. Six ceria supports synthesized by various synthesis methodologies were used to deposit cobalt oxide. The catalysts were thoroughly characterized, and their catalytic activity for complete methane oxidation was studied. The supports synthesized by direct calcination and precipitation with ammonia exhibited the best textural and structural properties as well as the highest degree of oxidation. The remaining supports presented poorer textural properties to be employed as catalytic supports. The cobalt deposited over the first two supports presented a good dispersion at the external surface, which induced a significant redox effect that increased the number of Co. Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents’ genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent’s weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child’s mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child’s own weight. For older children and adolescents, this may not be the case, and the individual’s own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.. The development of an efficient photocatalyst for C2 product formation from CO. Оценка антиастенического эффекта последовательной терапии левокарнитином (ЛК) и ацетилкарнитином (АЛК) пациентов с артериальной гипертензией и/или ишемической болезнью сердца (ИБС) с астеническим синдромом (АС).. В открытое сравнительное исследование были включены 120 пациентов в возрасте 54—67 лет с артериальной гипертензией и/или ИБС с АС. Пациенты 1-й группы (. У больных 1-й группы отмечено статистически значимое уменьшение различных проявлений АС. Отличия носили достоверный характер по сравнению как с исходным уровнем, так и со 2-й группой. Установлено эндотелийпротективное действие ЛК и АЛК.. Полученные результаты свидетельствуют, что у таких коморбидных пациентов использование ЛК и АЛК уменьшает выраженность проявлений АС, а установленные эндотелиотропные свойства препаратов позволяют рекомендовать их в составе комплексной персонифицированной терапии пациентов с сердечно-сосудистыми заболеваниями.. Naproxen sodium 440 mg/diphenhydramine 50 mg combination demonstrated improvement in sleep maintenance (WASO) vs. naproxen sodium 550 mg and higher efficiency in average daily pain reduction compared with the comparison groups. The treatment was well tolerated There were no serious or unexpected adverse events reported in the study.. Сравнительный анализ эффективности и безопасности новой комбинации напроксена натрия и дифенгидрамина у пациентов с неспецифическим болевым синдромом в пояснично-крестцовом отделе спины (M54.5 «Боль внизу спины») и нарушением сна (G47.0 «Нарушения засыпания и поддержания сна [бессонница]»).. Проведено проспективное многоцентровое рандомизированное открытое сравнительное в параллельных группах клиническое исследование. Пациенты были рандомизированы в 3 группы. Больные 1-й группы получали напроксен натрия (440 мг) и дифенгидрамин (50 мг), 2-й — напроксен натрия (550 мг), 3-й — парацетамол (1000 мг) и дифенгидрамин (50 мг). Исследуемые препараты пациенты принимали однократно перед сном в течение 3 дней. Все пациенты также принимали 275 мг (1 таблетка) напроксена натрия в качестве препарата фоновой терапии. Первичным критерием эффективности было общее время бодрствования после наступления сна (WASO), измеряемое методом актиграфии. Также использовались критерии оценки продолжительности и качества сна и выраженности боли.. Анализ эффективности проведен для ITT популяции (. Применение комбинации напроксена натрия (440 мг) и дифенгидрамина (50 мг) характеризовалось более выраженным поддержанием сна по сравнению с напроксеном натрия 550 мг и более высокой эффективностью в отношении снижения интенсивности боли по сравнению со 2-й и 3-й группами. Отмечена хорошая переносимость препарата, серьезных нежелательных явлений зарегистрировано не было.

Topics: Acetaminophen; Acetylcarnitine; Acetylcholinesterase; Acids; Acinetobacter baumannii; Acinetobacter Infections; Adaptation, Psychological; Adolescent; Adsorption; Adult; Aged; Alcohol Drinking; Alzheimer Disease; Amikacin; Ammonia; Anaerobiosis; Animals; Anorexia; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Anxiety; Aptamers, Nucleotide; Asthenia; Attention Deficit Disorder with Hyperactivity; Bacterial Proteins; Beryllium; beta-Lactamases; Biofuels; Biomass; Biosensing Techniques; Bismuth; Blister; Body Mass Index; Body Surface Area; Boronic Acids; Brain; Breast Neoplasms; Butyrylcholinesterase; Cannabis; Carbapenems; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Carboxylic Acids; Carcinoma, Hepatocellular; Cardiovascular Diseases; Carnitine; Case-Control Studies; Catalysis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Child; China; Cholinesterase Inhibitors; Clarithromycin; Clostridioides; Clostridioides difficile; Clostridium Infections; Cohort Studies; Colistin; Colitis; Colon; Coloring Agents; Coronary Artery Bypass; Creatinine; Crystalloid Solutions; Cytokines; Depression; Dextran Sulfate; Dextrans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dietary Supplements; Diphenhydramine; Disease Models, Animal; Disease Outbreaks; Double-Blind Method; Doxorubicin; Drosophila; Drug Tapering; Dysbiosis; Electrons; Escherichia coli; Extracellular Vesicles; Fatigue; Female; Fermentation; gamma-Cyclodextrins; Gastrointestinal Microbiome; Glucose; Graft Survival; Graft vs Host Disease; Head and Neck Neoplasms; Heart Arrest, Induced; Hematopoietic Stem Cell Transplantation; High-Intensity Interval Training; Hippocampus; Humans; Hydrogen-Ion Concentration; Hypertension; Incidence; Interferon-gamma; Italy; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Lactoferrin; Larva; Length of Stay; Lignin; Liver; Liver Neoplasms; Liver Transplantation; Living Donors; Low Back Pain; Lung; Lung Volume Measurements; Macrophages; Male; Melphalan; Men; Mendelian Randomization Analysis; Meropenem; Methane; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mitochondrial Proteins; Molecular Docking Simulation; Molecular Structure; Mothers; Motivation; Mycoplasma; Mycoplasma hominis; Mycoplasma Infections; NAD; Nanocomposites; Nanoparticles; Nanotubes, Carbon; Naproxen; Neovascularization, Pathologic; Neurons; Nitrates; Nucleolin; Opuntia; Paratyphoid Fever; Phenotype; Phosphatidylinositol 3-Kinases; Phytochemicals; Plant Extracts; Pregnancy; Prevalence; Prospective Studies; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Resveratrol; Retrospective Studies; Rifampin; Risk Factors; RNA, Messenger; Selenium; Sleep; Social Behavior; Soil; Soil Pollutants; Squamous Cell Carcinoma of Head and Neck; Staphylococcus aureus; Structure-Activity Relationship; Suicidal Ideation; Suicide; Superoxide Dismutase-1; Surveys and Questionnaires; Swimming; Syndrome; Tannins; Temperature; Transforming Growth Factor beta; Transplantation Conditioning; Treatment Outcome; Triple Negative Breast Neoplasms; Troponin T; Tumor Microenvironment; United Kingdom; Ureaplasma; Ureaplasma urealyticum; Urinary Tract Infections; Viscum; Waste Disposal Facilities; Wastewater; Water; Water Pollutants, Chemical; Wolfiporia; Young Adult

Colistin is an old antibiotic, which is abandoned decades ago because of high nephrotoxicity rates. However, it is reintroduced to clinical medicine due to lack of newly discovered antibiotics and is still widely used for the treatment of resistant gram-negative infections. Discovering mechanisms to reduce nephrotoxicity risk is of significant importance since exposed patients may have many other factors that alter kidney functions. Several agents were evaluated in animal models of colistin nephrotoxicity as a means to prevent kidney injury. Considerable heterogeneity exists in terms of reporting colistin dosing and experimental designs. This issue leads clinicians to face difficulties in designing studies and sometimes may lead to report dosing strategies inadequately. Here, we present a review according to animal models of colistin nephrotoxicity using data gathered from previous experiments to draw attention on possible complexities that researchers may encounter.

Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Dose-Response Relationship, Drug; Kidney; Rats; Rats, Sprague-Dawley; Rats, Wistar; Risk Factors; Toxicity Tests

Polymyxin B and colistin (polymyxin E) are bactericidal pentacationic lipopeptides that act specifically on Gram-negative bacteria, first by disrupting their outermost permeability barrier, the outer membrane (OM), and then damaging the cytoplasmic membrane. The discovery of both polymyxin B and colistin was published independently by three laboratories as early as in 1947. They were subsequently used in intravenous therapy. Unfortunately, they also exhibit significant and dose-limiting nephrotoxicity. Therefore, polymyxins were reserved as agents of last-line defense. The emergence of extremely multiresistant strains has now forced clinicians to reinstate polymyxins in the therapy of severe infections. However, the current dosage regimens lead to insufficient drug concentrations in serum and clinicians have been advised to use larger doses, which further increases the risk of nephrotoxicity. Very recently, the interest in developing better tolerated and more effective polymyxins has grown. This review focuses on describing four development programs that have yielded novel derivatives that are more effective than the old polymyxins in animal infection models. Compounds from three programs are superior to the old polymyxins in the rodent lung infection model with Acinetobacter baumannii and/or Pseudomonas aeruginosa. One of them is also more effective than polymyxin B in A. baumannii mouse thigh infection. The fourth program includes compounds that are approximately tenfold more effective in Escherichia coli murine pyelonephritis than polymyxin B.

Topics: Animals; Colistin; Communicable Diseases; Disease Models, Animal; Humans; Polymyxin B; Polymyxins; Treatment Outcome

Topics: Aminoglycosides; Anaerobiosis; Animals; Anti-Bacterial Agents; Bacteria; Chloramphenicol; Clindamycin; Colistin; Disease Models, Animal; Erythromycin; Fusidic Acid; Humans; Lactams; Lincomycin; Microbial Sensitivity Tests; Nitrofurans; Nitroimidazoles; Polymyxins; Rifamycins; Sulfamethoxazole; Tetracyclines; Trimethoprim; Vancomycin

Topics: Animals; Antibodies, Bacterial; Antineoplastic Agents; Arthritis, Infectious; Bone Diseases; Burns; Carbenicillin; Carrier State; Colistin; Cross Infection; Cystic Fibrosis; Disease Models, Animal; Drug Therapy, Combination; Gentamicins; Humans; Immunologic Deficiency Syndromes; Leukemia; Lung Diseases; Pneumonia; Polymyxins; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Therapy; Skin Diseases, Infectious; Surgical Wound Infection; Transplantation, Homologous

The most effective way to control severity and mortality rate of the novel coronavirus disease (COVID-19) is through sensitive diagnostic approaches and an appropriate treatment protocol. We aimed to identify the effect of adding corticosteroid and Tocilizumab to a standard treatment protocol in treating COVID-19 patients with chronic disease through hematological and lab biomarkers.. This study was performed retrospectively on 68 COVID-19 patients with chronic disease who were treated by different therapeutic protocols. The patients were categorized into four groups: control group represented the patients' lab results at admission before treatment protocols were applied; group 1 included patients treated with anticoagulants, Hydroxychloroquine, and antibiotics; group 2 comprised patients treated with Dexamethasone; and group 3 included patients treated with Dexamethasone and Tocilizumab.. The study paves the way into the effectiveness of combining Dexamethasone with Tocilizumab in treatment COVID-19 patients with chronic diseases.. La forma más eficaz de controlar la gravedad y la tasa de mortalidad de la enfermedad del nuevo coronavirus (COVID-19) es mediante enfoques de diagnóstico sensibles y un protocolo de tratamiento adecuado. Nuestro objetivo fue identificar el efecto de agregar corticosteroides y tocilizumab a un protocolo de tratamiento estándar en el tratamiento de pacientes con COVID-19 con enfermedad crónica a través de biomarcadores hematológicos y de laboratorio.. Este estudio se realizó de forma retrospectiva en 68 pacientes COVID-19 con enfermedad crónica que fueron tratados por diferentes protocolos terapéuticos. Los pacientes se clasificaron en cuatro grupos: el grupo de control representaba los resultados de laboratorio de los pacientes en el momento de la admisión antes de que se aplicaran los protocolos de tratamiento; el grupo 1 incluyó a pacientes tratados con anticoagulantes, hidroxicloroquina y antibióticos; el grupo 2 estaba compuesto por pacientes tratados con dexametasona; y el grupo 3 incluyó a pacientes tratados con dexametasona y tocilizumab.. El estudio allana el camino hacia la eficacia de la combinación de dexametasona con tocilizumab en el tratamiento de pacientes con COVID-19 con enfermedades crónicas.. The Child-Mother Index constitutes a potential useful risk factor indicator for statistical analyses on data after birth. The value of the Child-Mother Index based on the estimated fetal weight before birth deserves evaluation.. Six ceria supports synthesized by various synthesis methodologies were used to deposit cobalt oxide. The catalysts were thoroughly characterized, and their catalytic activity for complete methane oxidation was studied. The supports synthesized by direct calcination and precipitation with ammonia exhibited the best textural and structural properties as well as the highest degree of oxidation. The remaining supports presented poorer textural properties to be employed as catalytic supports. The cobalt deposited over the first two supports presented a good dispersion at the external surface, which induced a significant redox effect that increased the number of Co. Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents’ genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent’s weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child’s mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child’s own weight. For older children and adolescents, this may not be the case, and the individual’s own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.. The development of an efficient photocatalyst for C2 product formation from CO. Оценка антиастенического эффекта последовательной терапии левокарнитином (ЛК) и ацетилкарнитином (АЛК) пациентов с артериальной гипертензией и/или ишемической болезнью сердца (ИБС) с астеническим синдромом (АС).. В открытое сравнительное исследование были включены 120 пациентов в возрасте 54—67 лет с артериальной гипертензией и/или ИБС с АС. Пациенты 1-й группы (. У больных 1-й группы отмечено статистически значимое уменьшение различных проявлений АС. Отличия носили достоверный характер по сравнению как с исходным уровнем, так и со 2-й группой. Установлено эндотелийпротективное действие ЛК и АЛК.. Полученные результаты свидетельствуют, что у таких коморбидных пациентов использование ЛК и АЛК уменьшает выраженность проявлений АС, а установленные эндотелиотропные свойства препаратов позволяют рекомендовать их в составе комплексной персонифицированной терапии пациентов с сердечно-сосудистыми заболеваниями.. Naproxen sodium 440 mg/diphenhydramine 50 mg combination demonstrated improvement in sleep maintenance (WASO) vs. naproxen sodium 550 mg and higher efficiency in average daily pain reduction compared with the comparison groups. The treatment was well tolerated There were no serious or unexpected adverse events reported in the study.. Сравнительный анализ эффективности и безопасности новой комбинации напроксена натрия и дифенгидрамина у пациентов с неспецифическим болевым синдромом в пояснично-крестцовом отделе спины (M54.5 «Боль внизу спины») и нарушением сна (G47.0 «Нарушения засыпания и поддержания сна [бессонница]»).. Проведено проспективное многоцентровое рандомизированное открытое сравнительное в параллельных группах клиническое исследование. Пациенты были рандомизированы в 3 группы. Больные 1-й группы получали напроксен натрия (440 мг) и дифенгидрамин (50 мг), 2-й — напроксен натрия (550 мг), 3-й — парацетамол (1000 мг) и дифенгидрамин (50 мг). Исследуемые препараты пациенты принимали однократно перед сном в течение 3 дней. Все пациенты также принимали 275 мг (1 таблетка) напроксена натрия в качестве препарата фоновой терапии. Первичным критерием эффективности было общее время бодрствования после наступления сна (WASO), измеряемое методом актиграфии. Также использовались критерии оценки продолжительности и качества сна и выраженности боли.. Анализ эффективности проведен для ITT популяции (. Применение комбинации напроксена натрия (440 мг) и дифенгидрамина (50 мг) характеризовалось более выраженным поддержанием сна по сравнению с напроксеном натрия 550 мг и более высокой эффективностью в отношении снижения интенсивности боли по сравнению со 2-й и 3-й группами. Отмечена хорошая переносимость препарата, серьезных нежелательных явлений зарегистрировано не было.

Topics: Acetaminophen; Acetylcarnitine; Acetylcholinesterase; Acids; Acinetobacter baumannii; Acinetobacter Infections; Adaptation, Psychological; Adolescent; Adsorption; Adult; Aged; Alcohol Drinking; Alzheimer Disease; Amikacin; Ammonia; Anaerobiosis; Animals; Anorexia; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Anxiety; Aptamers, Nucleotide; Asthenia; Attention Deficit Disorder with Hyperactivity; Bacterial Proteins; Beryllium; beta-Lactamases; Biofuels; Biomass; Biosensing Techniques; Bismuth; Blister; Body Mass Index; Body Surface Area; Boronic Acids; Brain; Breast Neoplasms; Butyrylcholinesterase; Cannabis; Carbapenems; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Carboxylic Acids; Carcinoma, Hepatocellular; Cardiovascular Diseases; Carnitine; Case-Control Studies; Catalysis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Child; China; Cholinesterase Inhibitors; Clarithromycin; Clostridioides; Clostridioides difficile; Clostridium Infections; Cohort Studies; Colistin; Colitis; Colon; Coloring Agents; Coronary Artery Bypass; Creatinine; Crystalloid Solutions; Cytokines; Depression; Dextran Sulfate; Dextrans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dietary Supplements; Diphenhydramine; Disease Models, Animal; Disease Outbreaks; Double-Blind Method; Doxorubicin; Drosophila; Drug Tapering; Dysbiosis; Electrons; Escherichia coli; Extracellular Vesicles; Fatigue; Female; Fermentation; gamma-Cyclodextrins; Gastrointestinal Microbiome; Glucose; Graft Survival; Graft vs Host Disease; Head and Neck Neoplasms; Heart Arrest, Induced; Hematopoietic Stem Cell Transplantation; High-Intensity Interval Training; Hippocampus; Humans; Hydrogen-Ion Concentration; Hypertension; Incidence; Interferon-gamma; Italy; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Lactoferrin; Larva; Length of Stay; Lignin; Liver; Liver Neoplasms; Liver Transplantation; Living Donors; Low Back Pain; Lung; Lung Volume Measurements; Macrophages; Male; Melphalan; Men; Mendelian Randomization Analysis; Meropenem; Methane; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mitochondrial Proteins; Molecular Docking Simulation; Molecular Structure; Mothers; Motivation; Mycoplasma; Mycoplasma hominis; Mycoplasma Infections; NAD; Nanocomposites; Nanoparticles; Nanotubes, Carbon; Naproxen; Neovascularization, Pathologic; Neurons; Nitrates; Nucleolin; Opuntia; Paratyphoid Fever; Phenotype; Phosphatidylinositol 3-Kinases; Phytochemicals; Plant Extracts; Pregnancy; Prevalence; Prospective Studies; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Resveratrol; Retrospective Studies; Rifampin; Risk Factors; RNA, Messenger; Selenium; Sleep; Social Behavior; Soil; Soil Pollutants; Squamous Cell Carcinoma of Head and Neck; Staphylococcus aureus; Structure-Activity Relationship; Suicidal Ideation; Suicide; Superoxide Dismutase-1; Surveys and Questionnaires; Swimming; Syndrome; Tannins; Temperature; Transforming Growth Factor beta; Transplantation Conditioning; Treatment Outcome; Triple Negative Breast Neoplasms; Troponin T; Tumor Microenvironment; United Kingdom; Ureaplasma; Ureaplasma urealyticum; Urinary Tract Infections; Viscum; Waste Disposal Facilities; Wastewater; Water; Water Pollutants, Chemical; Wolfiporia; Young Adult

Due to its high transmissibility, Klebsiella pneumoniae is one of the leading causes of nosocomial infections. Here, we studied the biological cost of colistin resistance, an antibiotic of last resort, in this opportunistic pathogen using a murine model of gut colonization and transmission. Colistin resistance in K. pneumoniae is commonly the result of the inactivation of the small regulatory protein MgrB. Without a functional MgrB, the two-component system PhoPQ is constitutively active, leading to an increase in lipid A modifications and subsequent colistin resistance. Using an isogenic

Topics: Animals; Bacterial Proteins; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Klebsiella Infections; Klebsiella pneumoniae; Mice

Alternative treatments are needed against NDM-1-producing Escherichia coli. Colistin (COL) and fosfomycin (FOS) often remain active in vitro but selection of resistant mutants is frequent if used separately. We determined whether the combination of colistin and fosfomycin may be useful to treat infections with NDM-1-producing E. coli with varying levels of resistance.. Isogenic derivatives of E. coli CFT073 with blaNDM-1 and variable levels of resistance to colistin and fosfomycin (CFT073-NDM1, CFT073-NDM1-COL and CFT073-NDM1-FOS, respectively) were used. The combination (colistin + fosfomycin) was tested in vitro and in a fatal peritonitis murine model. Mortality and bacterial loads were determined and resistant mutants detected.. Colistin MICs were 0.5, 16 and 0.5 mg/L and fosfomycin MICs were 1, 1 and 32 mg/L against CFT073-NDM1, CFT073-NDM1-COL and CFT073-NDM1-FOS, respectively. In time-kill curves, combining colistin with fosfomycin was synergistic and bactericidal against CFT073-NDM1 and CFT073-NDM1-FOS, with concentrations of 4× MIC (for both drugs), but not against CFT073-NDM1-COL (concentrations of colistin = 0.5× MIC), due to regrowth with fosfomycin-resistant mutants. Mice died less and bacterial counts were lower in spleen with the combination compared with monotherapy against all strains; the combination prevented selection of resistant mutants except for CFT073-NDM1-COL where fosfomycin-resistant mutants were found in all mice.. Combining colistin and fosfomycin was beneficial in vitro and in vivo against NDM-1-producing E. coli, even with strains less susceptible to colistin and fosfomycin. However, the combination failed to prevent the emergence of fosfomycin-resistant mutants against colistin-resistant strains. Combining colistin and fosfomycin constitutes an alternative for treatment of NDM-1 E. coli, except against colistin-resistant strains.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Colistin; Disease Models, Animal; Drug Synergism; Escherichia coli; Fosfomycin; Mice; Microbial Sensitivity Tests; Peritonitis

Colistin is a potent antibiotic which is mainly preferred in the treatment of multidrug-resistant (MDR) gram-negative bacilli. However, due to the increased risk of acute kidney injury following its use, the clinical application is limited. This nephrotoxicity is known to be induced by oxidative stress and related inflammation. In this study on rats, potent antioxidants Dexpanthenol (DEX) and Ascorbic acid (Vit C) have been administered in combination with Colistin to find out whether they would weaken Colistin's nephrotoxic effects.. Inflammation biomarkers were studied with enzyme-linked immunosorbent assay (ELISA) kits, and oxidative stress biomarkers were studied with different photometric methods in blood and tissue samples taken after treatment with DEX and Vit C in rats with colistin nephrotoxicity. In addition, inflammation and necrosis in the kidney tissues were examined pathologically.. It has been observed in the serum and tissue samples that DEX and Vit C decrease oxidative stress and inflammation biomarkers, therefore acting as nephroprotective agents.. These compounds have been found to ameliorate the nephrotoxic effects of Colistin, which were demonstrated in the rats treated with Colistin, as well as the combinations.

Topics: Acute Kidney Injury; Animals; Ascorbic Acid; Colistin; Disease Models, Animal; Inflammation; Injections, Intraperitoneal; Male; Neuroprotective Agents; Oxidative Stress; Pantothenic Acid; Rats; Rats, Sprague-Dawley

Colistin is an antibiotic of last resort, but has poor efficacy and resistance is a growing problem. Whilst it is well established that colistin disrupts the bacterial outer membrane (OM) by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in. Antibiotics are life-saving medicines, but many bacteria now have the ability to resist their effects. For some infections, all frontline antibiotics are now ineffective. To treat infections caused by these highly resistant bacteria, clinicians must use so-called ‘antibiotics of last resort’. These antibiotics include a drug called colistin, which is moderately effective, but often fails to eradicate the infection. One of the challenges to making colistin more effective is that its mechanism is poorly understood. Bacteria have two layers of protection against the outside world: an outer cell membrane and an inner cell membrane. To kill them, colistin must punch holes in both. First, it disrupts the outer membrane by interacting with molecules called lipopolysaccharides. But how it disrupts the inner membrane was unclear. Bacteria have evolved several different mechanisms that make them resistant to the effects of colistin. Sabnis et al. reasoned that understanding how these mechanisms protected bacteria could reveal how the antibiotic works to damage the inner cell membrane. Sabnis et al. examined the effects of colistin on

Topics: Animals; Anti-Bacterial Agents; Cell Membrane; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Escherichia coli; Escherichia coli Proteins; Female; Humans; Lipopolysaccharides; Membrane Fluidity; Mice, Inbred C57BL; Microbial Viability; Peptides, Cyclic; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections

The increasing emergence and dissemination of multidrug resistant (MDR) bacterial pathogens accelerate the desires for new antibiotics. Natural products dominate the preferred chemical scaffolds for the discovery of antibacterial agents. Here, the potential of natural flavonoids from plants against MDR bacteria, is demonstrated. Structure-activity relationship analysis shows the prenylation modulates the activity of flavonoids and obtains two compounds, α-mangostin (AMG) and isobavachalcone (IBC). AMG and IBC not only display rapid bactericidal activity against Gram-positive bacteria, but also restore the susceptibility of colistin against Gram-negative pathogens. Mechanistic studies generally show such compounds bind to the phospholipids of bacterial membrane, and result in the dissipation of proton motive force and metabolic perturbations, through distinctive modes of action. The efficacy of AMG and IBC in four models associated with infection or contamination, is demonstrated. These results suggest that natural products of plants may be a promising and underappreciated reservoir to circumvent the existing antibiotic resistance.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Female; Flavonoids; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Plant Extracts

Although in vitro data suggest that tigecycline is active against Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp), experimental and clinical data are limited. We studied the effect of tigecycline alone or in combination for experimental infections by KPC-Kp. A total of 540 male C57BL/6 mice were infected with three genetically diverse KPC-Kp isolates susceptible to tigecycline with meropenem minimum inhibitory concentrations (MICs) of 4, 16 and 256 μg/mL, respectively. Mice were randomly treated with water for injection, tigecycline, meropenem and colistin alone, and double or triple combinations of tigecycline, colistin and meropenem. Mouse survival was recorded for 14 days. In separate experiments, mice were sacrificed 6 h and 24 h after bacterial challenge for quantitative culture of tissues and serological analysis. Time-kill curves were performed. Tigecycline, colistin and meropenem concentrations were measured in tissues and serum by high-performance liquid chromatography (HPLC). Survival was significantly prolonged when mice were treated with tigecycline alone and tigecycline-containing regimens compared with control mice and mice treated with tigecycline-sparing regimens. Tigecycline-sparing regimens were active only against the isolate with a meropenem MIC of 4 μg/mL. Mortality was associated with progression to multiple organ failure. Tigecycline and tigecycline-containing regimens achieved a rapid decrease of bacterial loads both in tissues and in vitro. Tigecycline concentrations in tissues were negatively correlated with tissue bacterial load. Tigecycline alone or in combination with meropenem and/or colistin achieves effective treatment of experimental KPC-Kp infections irrespective of the meropenem MIC.

Topics: Animals; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Colistin; Disease Models, Animal; Drug Combinations; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Mice; Tigecycline

To determine the possible adverse effects and safe dose range of intravitreal colistin, an antibiotic, after its intravitreal application.. Twenty eyes of 20 adult male and female New Zealand white rabbits were selected. Various concentrations of colistin were prepared. In each rabbit, 0.1 mL of colistin solution or saline solution was injected intravitreally into the right eye. Electroretinographic recordings were taken before and 2 weeks after injection. Histopathological examination was made using a light microscope following enucleation and fixation procedures. In histopathologic cross-sections, the differences between drug-injected eyes and control eyes were evaluated.. Electroretinographic examination showed a decrease of 30% as a significant value in the a and b wave amplitudes of the rabbits that injected 400 µg/0.1 ml and higher concentrations. Histological examination revealed histiocytic infiltration, histiocytic vacuoles, inflammation, and retinal degeneration in rabbit eyes given 400 µg/0.1 ml, 800 µg/0.1 ml, and 1.6 mg/0.1 ml concentrations of colistin.. Based on our findings, the safe concentration of colistin is 0.2 mg/0.1 ml. Administration of 0.4 mg/0.1 ml was associated with cataract development, electrophysiological depression, and pathological changes in retinal layers.

Topics: Animals; Anti-Bacterial Agents; Cataract; Colistin; Disease Models, Animal; Electroretinography; Endophthalmitis; Female; Humans; Intravitreal Injections; Male; Rabbits; Retina; Toxicity Tests, Acute

The widespread emergence of antibiotic resistance, including multidrug resistance in Gram-negative (G-) bacterial pathogens, poses a critical challenge to the current antimicrobial armamentarium. Antibody-drug conjugates (ADCs), primarily used in anticancer therapy, offer a promising treatment alternative due to their ability to deliver a therapeutic molecule while simultaneously activating the host immune response. The Cloudbreak platform is being used to develop ADCs to treat infectious diseases, composed of a therapeutic targeting moiety (TM) attached via a noncleavable linker to an effector moiety (EM) to treat infectious diseases. In this proof-of-concept study, 21 novel dimeric peptidic molecules (TMs) were evaluated for activity against a screening panel of G- pathogens. The activities of the TMs were not impacted by existing drug resistance. Potent TMs were conjugated to the Fc fragment of human IgG1 (EM), resulting in 4 novel ADCs. These ADCs were evaluated for immunoprophylactic efficacy in a neutropenic mouse model of deep thigh infection. In colistin-sensitive infections, 3 of the 4 ADCs offered protection similar to that of therapeutically dosed colistin, while CTC-171 offered enhanced protection. The efficacy of these ADCs was unchanged in colistin-resistant infections. Together, these results indicate that the ADCs used here are capable of potent binding to G- pathogens regardless of lipopolysaccharide (LPS) modifications that otherwise lead to antibiotic resistance and support further exploration of ADCs in the treatment of infections caused by drug-resistant G- bacteria.

Topics: Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Lipopolysaccharides; Mice

Limited therapeutic options exist for treating severe infections caused by multidrug-resistant (MDR) and extensively drug-resistant Gram-negative bacteria (GNB). In this study, the activity of colistin (COL) as monotherapy and in combination with other antibiotics against Acinetobacter baumannii in vitro was investigated. In addition, the efficacy of intravenous colistimethate sodium (CMS) was evaluated in a murine model of urinary tract infection (UTI) induced by MDR Escherichia coli.. Minimum inhibitory concentration (MIC), Monte Carlo simulation, fractional inhibitory concentration index (FICI), time-kill study and erythrocyte lysis assay were applied to evaluate the effect and cytotoxicity of COL, meropenem, imipenem, doripenem (DOR) and sulbactam alone and in combination. For the in vivo experiment, determination of the bacterial burden and histopathological examination were performed to evaluate the efficacy of CMS against UTI.. Of 106 A. baumannii isolates, 104 (98.1%) were susceptible to COL. In the chequerboard assay, COL + DOR showed the highest rate of synergism (60%). No antagonism or cytotoxicity was observed. All COL-based combinations were able to inhibit or slow bacterial re-growth in a time-kill assay. In an in vivo activity study, intravenous CMS reduced not only the bacterial load but also inflammation and maintained structural integrity of infected bladders and kidneys.. The effectiveness of COL alone in vitro and in vivo suggested that intravenous CMS will be an effective and available therapeutic strategy for UTI due to MDR-GNB. In-depth in vitro tests demonstrated that COL + DOR could be an attractive option, especially when the COL MIC is ≥1 μg/mL.

Topics: Acinetobacter baumannii; Administration, Intravenous; Animals; Anti-Bacterial Agents; Biofilms; Colistin; Disease Models, Animal; Doripenem; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Female; Humans; Imipenem; Meropenem; Mice; Microbial Sensitivity Tests; Monte Carlo Method; Sulbactam; Treatment Outcome; Urinary Tract Infections

The rapid emergence and dissemination of multidrug-resistant (MDR) bacterial pathogens pose a serious threat to global healthcare. One particular concern is the carbapenem-resistant Enterobacteriaceae (CRE), a group of Gram-negative bacteria that have evolved resistance to all or nearly all available antibiotics. Coupled with the fact of barren antibiotic development pipeline nowadays, a critical approach is to revitalize existing antibiotics using antibiotic adjuvants. We found a short linear antibacterial peptide (SLAP)-S25 carrying four non-natural amino acids of 2,4-diaminobutanoic acid (Dab), which solely showed weak antibacterial activity but boosted the efficacy of antibiotics covering all major classes, including cefepime, colistin, ofloxacin, rifampicin, tetracycline and vancomycin, against MDR Gram-negative pathogens. Mechanistic studies showed that SLAP-S25 triggers membrane damage by binding to both lipopolysaccharide (LPS) in the outer membrane and phosphatidylglycerol (PG) in bacterial cytoplasmic membrane, to potentiate antibiotic efficacy through collaborative strategies. Lastly, SLAP-S25 effectively enhanced the activity of colistin against MDR Escherichia coli-associated infections in three animal models. Our findings provide a potential therapeutic option using existing antibiotics in combination with broad-spectrum antibiotic adjuvants, to address the prevalent infections caused by MDR Gram-negative pathogens worldwide.

Topics: A549 Cells; Animals; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Chlorocebus aethiops; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Escherichia coli; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Phosphatidylglycerols; Vero Cells

Industry screens of large chemical libraries have traditionally relied on rich media to ensure rapid bacterial growth in high-throughput testing. We used eukaryotic, nutrient-limited growth media in a compound screen that unmasked a previously unknown hyperactivity of the old antibiotic, rifabutin (RBT), against highly resistant Acinetobacter baumannii. In nutrient-limited, but not rich, media, RBT was 200-fold more potent than rifampin. RBT was also substantially more effective in vivo. The mechanism of enhanced efficacy was a Trojan horse-like import of RBT, but not rifampin, through fhuE, only in nutrient-limited conditions. These results are of fundamental importance to efforts to discover antibacterial agents.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Proteins; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Gene Deletion; Gene Expression Regulation, Bacterial; High-Throughput Screening Assays; Male; Mice; Mice, Inbred C3H; Microbial Sensitivity Tests; Nutrients; Receptors, Cell Surface; Rifabutin; Rifampin

Peptide antibiotics are an abundant and synthetically tractable source of molecular diversity, but they are often cationic and can be cytotoxic, nephrotoxic and/or ototoxic, which has limited their clinical development. Here we report structure-guided optimization of an amphipathic peptide, arenicin-3, originally isolated from the marine lugworm Arenicola marina. The peptide induces bacterial membrane permeability and ATP release, with serial passaging resulting in a mutation in mlaC, a phospholipid transport gene. Structure-based design led to AA139, an antibiotic with broad-spectrum in vitro activity against multidrug-resistant and extensively drug-resistant bacteria, including ESBL, carbapenem- and colistin-resistant clinical isolates. The antibiotic induces a 3-4 log reduction in bacterial burden in mouse models of peritonitis, pneumonia and urinary tract infection. Cytotoxicity and haemolysis of the progenitor peptide is ameliorated with AA139, and the 'no observable adverse effect level' (NOAEL) dose in mice is ~10-fold greater than the dose generally required for efficacy in the infection models.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Carbapenems; Cell Membrane Permeability; Colistin; Disease Models, Animal; Drug Discovery; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Helminth Proteins; Humans; Male; Mice; Microbial Sensitivity Tests; Peritonitis; Pneumonia; Urinary Tract Infections

Topics: Animals; Bacterial Proteins; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Drugs, Generic; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Osteomyelitis; Rabbits; Therapeutic Equivalency

Topics: Animals; Anti-Bacterial Agents; Bacterial Outer Membrane; Cell Membrane Permeability; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Female; Humans; Melatonin; Mice; Microbial Sensitivity Tests; Plasmids

Recently, paradoxical combinations of colistin with anti-Gram-positive bacterial agents were introduced as a treatment alternative for multidrug-resistant Acinetobacter baumannii (MDRAB) infection. We assessed the therapeutic efficacy of the colistin-linezolid combination regimen in vitro and in a murine model of Acinetobacter baumannii pneumonia. A multidrug-resistant clinical strain (MDRAB31) and an extensively drug-resistant clinical strain (XDRAB78) were used in this study. The survival rates of mice and bacterial counts in lung tissue were used to assess the effects of colistin-linezolid combination. The survival rates of colistin-linezolid combination groups significantly increased compared with colistin groups for MDRAB31 (72% versus 32%, P = 0.03) and for XDRAB78 (92% versus 68%, P = 0.031). The colistin-linezolid combination groups significantly reduced the bacterial counts in lung tissue compared with colistin groups for MDRAB31 and for XDRAB78 (P < 0.05). The colistin-linezolid combination had a bactericidal and synergistic effect compared with colistin alone in time-kill assay and in murine model of pneumonia. Our data demonstrated the synergistic effect of colistin-linezolid combination regimen as a treatment alternative for the severe pulmonary infection caused by MDRAB and XDRAB.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Antitubercular Agents; Colistin; Disease Models, Animal; Drug Synergism; Extensively Drug-Resistant Tuberculosis; Female; Linezolid; Lung; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Pneumonia, Bacterial; Time Factors; Tuberculosis, Multidrug-Resistant

Unfortunately, the options for treating multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections are extremely limited. Recently, fosfomycin and minocycline were newly introduced as a treatment option for MDR A. baumannii infection. Therefore, we investigated the efficacy of the combination of colistin with fosfomycin and minocycline, respectively, as therapeutic options in MDR A. baumannii pneumonia. We examined a carbapenem-resistant A. baumannii isolated from clinical specimens at Severance Hospital, Seoul, Korea. The effect of colistin with fosfomycin, and colistin with minocycline on the bacterial counts in lung tissue was investigated in a mouse model of pneumonia caused by MDR A. baumannii. In vivo, colistin with fosfomycin or minocycline significantly (p < 0.05) reduced the bacterial load in the lungs compared with the controls at 24 and 48 h. In the combination groups, the bacterial loads differed significantly (p < 0.05) from that with the more active antimicrobial alone. Moreover, the combination regimens of colistin with fosfomycin and colistin with minocycline showed bactericidal and synergistic effects compared with the more active antimicrobial alone at 24 and 48 h. This study demonstrated the synergistic effects of combination regimens of colistin with fosfomycin and minocycline, respectively, as therapeutic options in pneumonia caused by MDR A. baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Female; Fosfomycin; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Minocycline; Pneumonia; Tigecycline

Pulmonary surfactant spreads rapidly over the airway epithelium, a property that could be harnessed to transport drugs into the lungs. For efficient drug delivery, an interaction between pulmonary surfactant and the drug to be administered is likely needed. On the other hand, the interaction should not compromise the activity of surfactant or the drug once delivered in vivo. The antibiotics gentamicin (an aminoglycoside) and polymyxin E represent drugs that could benefit from being delivered directly to the lung, thereby increasing local concentrations and reducing systemic side effects. Our aim was to study how the animal-derived surfactant poractant alfa (Curosurf. In vitro antimicrobial assays and a neonatal near-term rabbit model were used to evaluate the combinations of antibiotics and surfactant against Pseudomonas aeruginosa.. The bactericidal activity of polymyxin E, but not of gentamicin, against P. aeruginosa was partly reduced in vitro in the presence of poractant alfa. In contrast, in the rabbit model of P. aeruginosa pneumonia, polymyxin E administrated together with surfactant was superior in lowering the bacterial load in the lungs compared to polymyxin E alone, without affecting plethysmographically recorded lung compliance.. The results suggest that polymyxin E interacts with poractant alfa, which reduces the antibacterial effect in vitro. However, when polymyxin E mixed with surfactant is used in the in vivo pneumonia model, increased bactericidal effect was observed. This may be due to a more efficient spreading mediated by interactions between polymyxin E and surfactant. These results warrant further studies of surfactant preparations for drug delivery against lung infections.

Topics: Animals; Anti-Bacterial Agents; Biological Products; Colistin; Disease Models, Animal; Drug Carriers; Gentamicins; Phospholipids; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Pulmonary Surfactants; Rabbits

The emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes.. To comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose-response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs).. Combinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs.. The synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Female; Genotyping Techniques; Mice, Inbred ICR; Microbial Sensitivity Tests; Treatment Outcome

The emergence of Acinetobacter baumannii with resistance to colistin (ABRC) led to the investigation of daptomycin as an adjunctive to colistin for these isolates. In this study, one ABRC carbapenemase-producing bloodstream isolate was examined. Minimum inhibitory concentrations (MICs) were >512, >512 and 8 µg/mL for imipenem, daptomycin and colistin, respectively. First, a 'humanised' model of the pharmacokinetics of daptomycin and colistin was developed in 18 male C57BL/6 mice. Then, 112 mice were infected by intraperitoneal injection of the ABRC isolate and were randomly assigned into four groups of once-daily treatment for 7 days: group A, controls treated with saline; group B, treated with 20 mg/kg colistin; group C, treated with 50 mg/kg daptomycin; and group D, treated with both agents. Survival was recorded for 7 days in ten mice per group. The remaining mice were sacrificed at regular time intervals following bacterial challenge and the bacterial outgrowth in the liver, lung and right kidney was determined. Mean serum concentrations of daptomycin at 15, 30 and 60 min post-dose were 121.8, 110.3 and 100.4 µg/mL, respectively. The respective concentrations of colistin were 13.9, 9.1 and 7.5 µg/mL. The 7-day mortality in groups A, B, C and D was 100%, 50%, 100% and 0%, respectively. Tissue outgrowth of the right kidney was significantly decreased in group D compared with group B after 72 h. Daptomycin used in combination with colistin leads to prolonged survival in an experimental infection by ABRC. Failure of colistin alone is probably related to rebound of tissue outgrowth.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Daptomycin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Imipenem; Male; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests

Acinetobacter baumannii is a critical nosocomial pathogen. A. baumannii infections have become a grave challenge due to their ability to develop resistance to different antimicrobial agents. The current study aimed to evaluate the potential synergism and bactericidal activity of a combination of colistin and cotrimoxazole against carbapenem-resistant A. baumannii (CRAB) in a Galleria mellonella model.. Four clinical A. baumannii isolates were biochemically and molecularly identified. Their antimicrobial susceptibility levels were established and the molecular characterization of the carbapenemase-encoding genes was performed. The synergism and bactericidal effect of the colistin/cotrimoxazole combination was assessed using the checkerboard assay and time-kill experiments. An in vivo evaluation of the activity of the combination was performed using the Galleria mellonella model.. A fractional inhibitory concentration index (FICI) of ≤0.5 was found for all strains, indicating that the colistin/cotrimoxazole combination exhibited powerful synergistic activity. The combination displayed both synergistic and bactericidal activity at sub-breakpoint concentrations for all strains. Cotrimoxazole monotherapy showed the least protective activity in the G. mellonella model. The survival rate ranged from 66.7-79.2 % at 24 h and was 29.2-60.4 % at 96 h for the tested isolates. Colistin monotherapy performed better than cotrimoxazole monotherapy; the G. mellonella survival rate ranged from 77.1-97.9 %, at 24 h and from 64.5-72. % at 96 h. The colistin/cotrimoxazole combination improved G. mellonella's survival rate at 96 h remarkably in comparison to colistin or cotrimoxazole monotherapy.. Finally, the combination of colistin and cotrimoxazole appears to be a promising therapeutic option for the management of CRAB-associated infections. It is essential to assess the clinical application and the dose-response relationships of combinations such as colistin plus cotrimoxazole.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Lepidoptera; Microbial Sensitivity Tests; Trimethoprim, Sulfamethoxazole Drug Combination

Colistin resistance in

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Proteins; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Humans; Lipid A; Microbial Sensitivity Tests; Moths; Transcription Factors

The use of colistin in the treatment of multidrug-resistant Gram-negative bacterial infections is restricted due to nephrotoxicity. We investigated the effects of aged black garlic extract (ABGE) on colistin-induced kidney injury in rats. Rats were assigned to four groups. Normal saline was intraperitoneally and intragastrically injected for control group. ABGE was intragastrically injected for garlic group. Ten mg/kg of colistin was intraperitoneally injected for 6 consecutive days for colistin group. One percent of ABGE was done 30 min prior to colistin injection for treatment group. Rats were sacrificed on the next day after last colistin injection. Colistin injection increased the serum levels of blood urea nitrogen and creatinine; however, ABGE prevented deterioration of these serum levels. ABGE also alleviated tubular damage, including vacuolation and necrosis. TUNEL-positive cells were observed less frequently for the ABGE-treated groups. CD68 positive cells were significantly decreased by pretreatment with ABGE. Levels of oxidative stress biomarkers such as 8-hydroxydeoxyguanosine and malondialdehyde were lower in the ABGE-treated groups. Levels of NF-κB, inducible NO synthase, COX-2, and TGF-β1 were lower in rats that had been treated with ABGE injection. Renal levels of IL-1β and TNF-α were increased by colistin administration whereas renal SOD, catalase, and GSH levels were restored by ABGE administration. These results suggest that ABGE, which has antioxidant and anti-inflammatory properties, might be a potential therapeutic agent to prevent renal toxicity of colistin.

Topics: Acute Kidney Injury; Animals; Antioxidants; Colistin; Disease Models, Animal; Garlic; Gram-Negative Bacterial Infections; Humans; Kidney; Male; Oxidative Stress; Plant Extracts; Rats; Rats, Sprague-Dawley; Treatment Outcome; Water

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Female; Glycopeptides; Mice; Mice, Inbred C3H; Microbial Sensitivity Tests; Pneumonia; Survival Rate; Teicoplanin; Vancomycin

Treatment of infections caused by A. baumannii is becoming a challenge due to the ability to develop multidrug-resistance, virulence, and high mortality. We described the colistin resistance and virulence genes present in sixA. baumannii clinical isolates using WGS, expression by qPCR, and virulence in the Galleria mellonella model. The colistin-resistant isolates were assigned as ST233 and the colistin-susceptible isolates as ST236 and ST407. The colistin-resistant isolates contained mutations within PmrA/PmrB, and the pmrA showed up-regulation in all of them. Only one colistin-resistant isolate indicating virulence in G. mellonella. This particular isolate belonged to a different clone, and it was the only isolate that presented non-synonymous mutations in pmrB. Colistinresistance in A. baumannii isolates seems to be caused by up-regulation of pmrA gene. Only one isolate appeared to be virulent in the G. mellonella model. This finding indicating low virulence in isolates belonging to emerging clones circulating in our hospital.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Proteins; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Genome, Bacterial; Humans; Microbial Sensitivity Tests; Moths; Mutation; Transcription Factors; Virulence

In a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross-resistance to host defence peptides (HDPs).. KPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MIC = 4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICs = 1 mg/L) and fosfomycin (MIC = 32 mg/L). Time-kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin + fosfomycin.. In vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (P < 0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (P = 0.025). Tigecycline reduced the efficacy of colistin (P = 0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37.. In this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo.

Topics: Animals; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Colistin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Osteomyelitis; Rabbits

Topics: Animals; Anti-Bacterial Agents; Arthritis; Carbapenem-Resistant Enterobacteriaceae; Colistin; Debridement; Disease Models, Animal; Female; Injections, Intra-Articular; Injections, Intramuscular; Klebsiella Infections; Klebsiella pneumoniae; Prosthesis-Related Infections; Rabbits; Treatment Outcome

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections represent a major therapeutic problem and combination therapy may be the chemotherapeutic option.. Bioluminescent CRPA was developed through sequential subcultures in subinhibitory concentrations of meropenem from an engineered strain of bioluminescent PA Xen5. Then CRPA was injected intraperitoneally to establish an intraperitoneal murine infection model. Treatments of colistin alone or combined with rifampicin or meropenem were started 1 h after infection. In vivo bioluminescence imaging was applied dynamically at 0 h, and 2 and 5 h after treatment. Ex vivo bacterial counts from liver, kidney, spleen, lung and blood samples were also determined 5 h after treatment.. In vivo imaging showed that both low- and high-dose colistin combined with rifampicin resulted in a significant decrease in bioluminescence signals compared with monotherapy of colistin or rifampicin alone, whereas colistin and meropenem combination therapy did not show a greater bactericidal effect compared with monotherapy. Ex vivo bacterial count results also confirmed that combination of both low- and high-dose colistin with rifampicin resulted in significantly reduced colony counts from five kinds of tissue samples. However, only combination of high-dose colistin + meropenem resulted in reduced colony counts merely in lung and blood samples.. Compared with single drugs, colistin and rifampicin combination therapy could exert synergistic effects, which might provide a better alternative when treating CRPA infections in clinical practice. Combination of colistin and meropenem should be considered with caution because it barely shows any synergism in the present in vivo model.

Topics: Animal Structures; Animals; Anti-Bacterial Agents; Bacterial Load; beta-Lactam Resistance; Colistin; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Intraabdominal Infections; Luminescent Measurements; Meropenem; Mice, Inbred BALB C; Pseudomonas aeruginosa; Pseudomonas Infections; Rifampin; Staining and Labeling; Treatment Outcome

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Klebsiella pneumoniae; Lung; Mice; Microbial Sensitivity Tests; Respiratory Tract Infections

Colistin (polymyxin E) is an important constituent of the polymyxin class of cationic polypeptide antibiotics. Intrarenal oxidative stress can contribute to colistin-induced nephrotoxicity. Nicotinamide adenine dinucleotide 3-phosphate oxidases (Noxs) are important sources of reactive oxygen species. Among the various types of Noxs, Nox4 is predominantly expressed in the kidney.. We investigated the role of Nox4 and benefit of Nox4 inhibition in colistin-induced acute kidney injury using in vivo and in vitro models.. Human proximal tubular epithelial (HK-2) cells were treated with colistin with or without NOX4 knockdown, or GKT137831 (most specific Nox1/4 inhibitor). Effects of Nox4 inhibition on colistin-induced acute kidney injury model in Sprague-Dawley rats were examined.. Nox4 expression in HK-2 cells significantly increased following colistin exposure. SB4315432 (transforming growth factor-β1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells. Knockdown of NOX4 transcription reduced reactive oxygen species production, lowered the levels of pro-inflammatory markers (notably mitogen-activated protein kinases) implicated in colistin-induced nephrotoxicity and attenuated apoptosis by altering Bax and caspase 3/7 activity. Pretreatment with GKT137831 replicated these effects mediated by downregulation of mitogen-activated protein kinase activities. In a rat colistin-induced acute kidney injury model, administration of GKT137831 resulted in attenuated colistin-induced acute kidney injury as indicated by attenuated impairment of glomerulus function, preserved renal structures, reduced expression of 8-hydroxyguanosine and fewer apoptotic cells.. Collectively, these findings identify Nox4 as a key source of reactive oxygen species responsible for kidney injury in colistin-induced nephrotoxicity and highlight a novel potential way to treat drug-related nephrotoxicity.

Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Cell Line; Colistin; Disease Models, Animal; Epithelial Cells; Humans; Models, Biological; NADPH Oxidase 4; Oxidative Stress; Rats, Sprague-Dawley; Transforming Growth Factor beta

Antibiotic resistance is a growing crisis and a grave threat to human health. It is projected that antibiotic-resistant infections will lead to 10 million annual deaths worldwide by the year 2050. Among the most significant threats are carbapenem-resistant

Topics: Animals; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Enterobacteriaceae; Klebsiella Infections; Klebsiella pneumoniae; Mice; Polymyxins

β-lactam-β-lactamase inhibitors (BLIs) have previously demonstrated antimicrobial activity against Acinetobacter baumannii (AB). Colistin retains the highest susceptibility rate against A. baumannii, and has demonstrated synergy with other antimicrobials, including β-lactam-BLIs. Therefore, we assessed the potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) A. baumannii isolates in neutropenic thigh and lung infection models. In vitro, colistin and tazobactam MICs were 1 and 16 µg/mL against AB 25-49 (CS) and 1 and 128 µg/mL against AB 5075 (MDR) respectively. In the lung model, tazobactam alone and in combination with colistin achieved a 1-log reduction in CFU, while colistin alone was not active against AB 25-49. No activity was observed against AB 5075. In the thigh model, tazobactam with and without colistin was bacteriostatic against AB 25-49 but did not demonstrate any activity against AB 5075. Avibactam and colistin alone and in combination were not active against either isolate. No synergy was observed; however, we found tazobactam activity against A. baumannii. This activity was not observed for the non-β-lactam-BLI, avibactam. This suggests that binding to penicillin-binding proteins of the β-lactam molecule is required for tazobactam activity against A. baumannii. These data point to an added role of β-lactam-BLIs beyond their primary purpose of β-lactamase inhibition in the treatment of MDR A. baumannii infections by enhancing the activity of peptide antibiotics, a property that is not shared by the novel non-β-lactam-BLIs. Future studies are needed to define tazobactam and colistin activity in an A. baumannii infection model.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Female; Humans; Lung; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Penicillanic Acid; Tazobactam; Thigh

To investigate the molecular mechanisms of colistimethate sodium-induced nephrotoxicity and the protective effect of N-acetylcysteine (NAC) against nephrotoxicity.. Twenty-eight Wistar rats were divided into four groups comprised of control, colistin, NAC, and colistin-NAC co-treatment, respectively. Serum creatinine and urine N-acetyl-β-d-glucosaminidase (NAG) levels were measured at different time intervals. Histological changes, apoptosis, total oxidant and antioxidant status, and the expression levels of endothelial nitric oxide synthase (eNOS), superoxide dismutase 2 (SOD2), and matrix metalloproteinase 3 (MMP3) were evaluated in renal tissue.. In the colistin group, post-treatment creatinine levels were higher than pretreatment levels (p = .001). There was a significant increase in urine NAG level following colistin treatment on day 10, compared to the baseline value and the first day of treatment (p = .001 and .0001, respectively). Urine NAG levels were higher in the colistin group on the 10th day of treatment than in the other groups (p < .01). Colistin treatment increased the apoptosis index and renal histological damage score (RHDS) significantly and these changes were reversed in NAC co-treatment (RHSD and apoptosis index were 45 and 0 for sterile saline group, 29 and 2 for NAC group, 122 and 7 for colistin group, and 66 and 2 for colistin + NAC group). We observed no difference between groups regarding total antioxidant and total oxidant status in the kidneys. The expression levels of eNOS, SOD2, and MMP3 decreased significantly in the kidneys of colistin-treated rats; these changes were reversed in the kidneys of NAC co-treated rats.. N-acetylcysteine prevented colistin-induced nephrotoxicity through activation of expression levels of SOD2, eNOS, and MMP3.

Topics: Acetylcysteine; Acetylglucosaminidase; Acute Kidney Injury; Animals; Colistin; Creatinine; Disease Models, Animal; Free Radical Scavengers; Humans; Kidney; Male; Matrix Metalloproteinase 3; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase

Preventing bacterial contact with host cells can provide an additional approach to tackling MDR Acinetobacter baumannii. Recently, we identified AOA-2 as a potential blocker of A. baumannii outer membrane protein A without presenting bactericidal activity. Here, we aimed to study whether AOA-2 can increase the activity of colistin against colistin-resistant A. baumannii in vitro and in vivo.. Reference and clinical A. baumannii strains susceptible and resistant to colistin (CST-S and CST-R) were used. Microdilution and time-kill curve assays were performed to determine the synergy between AOA-2 and colistin. SDS-PAGE assays with CST-S and CST-R outer membrane proteins and MALDI-TOF-TOF (MS-MS/MS) analysis were performed to determine the AOA-2 and colistin synergy mechanism. In a murine peritoneal sepsis model, the therapeutic efficacy of AOA-2 (10 mg/kg/24 h) in combination with a sub-optimal dose of colistin (10 mg/kg/24 h) against CST-R was evaluated by determining the bacterial load in tissues and blood, and mouse survival.. We showed that AOA-2 increased the in vitro colistin susceptibility of reference and clinical CST-S and CST-R strains. This combination also enhanced their killing activity after 24 h of drug exposure. This synergy is mediated by the overexpression of Omp25. In vivo, the combination of AOA-2 with colistin significantly reduced the bacterial load in tissues and blood, and increased mouse survival, compared with colistin monotherapy.. We identified a novel class of antimicrobial agents that has proven to be effective in combination with colistin in an experimental model of severe infection by CST-R A. baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Colistin; Disease Models, Animal; Drug Synergism; Enzyme Inhibitors; Female; Mice, Inbred C57BL; Microbial Sensitivity Tests; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Treatment Outcome

Biofilm-residing bacteria embedded in an extracellular matrix are protected from diverse physicochemical insults. In addition to the general recalcitrance of biofilm bacteria, high bacterial loads in biofilm-associated infections significantly diminish the efficacy of antimicrobials due to a low per-cell antibiotic concentration. Accordingly, present antimicrobial treatment protocols that have been established to serve the eradication of acute infections fail to clear biofilm-associated chronic infections. In the present study, we applied automated confocal microscopy on

Topics: Animals; Anti-Bacterial Agents; Biofilms; Colistin; Colonic Neoplasms; Colony Count, Microbial; Disease Models, Animal; Drug Administration Schedule; Drug Dosage Calculations; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Treatment Outcome

Colistin-resistant Escherichia coli are isolated from pigs suffering from post-weaning diarrhea (PWD). This study was designed to develop an experimental model of PWD using mcr-1-carrying shiga toxin-producing E. coli (STEC) or enterotoxigenic E. coli (ETEC), for the future evaluation of control measures. Three groups of eight piglets, kept in high biosecurity units, were orally inoculated with mcr-1-positive STEC or ETEC, and one unchallenged group was used as a control. Clinical signs were recorded. Regularly-collected fecal samples and samples obtained from the digestive tract of animals sacrificed one month after inoculation were cultured in selective media and isolates were characterized. Blood samples were used to genotype the polymorphisms of the pigs' intestinal receptors for F4 and F18 E. coli adhesins. Diarrhea was more frequent and more fecal samples contained the inoculated strain in the group inoculated with the O149-F4 ETEC strain than with the O141-F18 or O139-F18 STEC strains. However, fewer positive samples were obtained from the two pigs with the F4 resistant genotype. The three inoculated strains could be re-isolated up to the end of the experiment. Excretion peaked on the first week after inoculation with the O149-F4 ETEC strain, and later for the other two. An mcr-1 gene transfer to other commensal isolates was observed only for O139-F18 STEC, while the loss of mcr-1 from the inoculated strain occurred in all groups. The O149-F4 ETEC challenge may be used to evaluate alternative solutions to combat PWD caused by colistin-resistant E. coli in pigs.

Topics: Animals; Antibodies, Bacterial; Colistin; Diarrhea; Disease Models, Animal; Drug Resistance, Bacterial; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Feces; Genotype; Swine; Swine Diseases; Weaning

Host defense peptides are preferably administered as topical therapeutic agents. We have investigated whether peptide A3-APO can enter the circulation when applied to the ear skin. Efficacy of peptide monotherapy as transdermal administration option was assessed in a systemic mouse Acinetobacter baumannii model. A3-APO reduced mortality and demonstrated a statistically significant reduction of blood bacterial counts, regardless whether it was administered prior or after bacterial challenge. The peptidic metabolite of A3-APO was efficacious when applied to the ear or tail.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Cutaneous; Amino Acid Sequence; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Arginine; Bacteremia; Bacterial Load; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Ear; Humans; Mice; Proline; Skin; Survival Analysis

Despite of proven LPS neutralizing activity, intravenous polymyxin use was waned due to experience of associated nephrotoxicity. But, increasing resistance to all available antibiotics has necessitated their resurgence and the prodrug of colistin sulfate (CS), known as colistin-methanesulfonate (CMS), is increasingly used as the only therapeutic option in many infections. Currently available CMS employ very different dose definitions and thus because of complex pharmacokinetics/pharmacodynamics information and short half-life, this drug use remains confusing. We aimed to expose CS in endotoxic shock models by micro-osmotic pump and evaluated its effectiveness.. We used micro-osmotic pumps to deliver either sterile saline or CS at different dosages ranging from 0.25mg/day to 7mg/day for consecutive 3days in LPS (8mg/kg body weight) induced endotoxic mice and observed their outcome twice daily for a week to determine the survival rate. Serum pro-inflammatory cytokine levels and apoptosis in renal tissues in these models were evaluated.. We showed endotoxic shock was reversed and all mice survived with a CS administration at a dosage of 2mg/day for 3 days, in comparison to survival rate with saline administration (p≤0.0001) in endotoxic models. CS infusion in shock models using micro-osmotic pump ameliorated rising of serum TNF-α, IL-12p70 and IL-6 levels. Nephrotoxicity was evident only with a higher dosage, but not with a lower dosage which was optimum to control endotoxic shock in models.. These results highlighted that an optimal dosage of CS effectively improved outcome in endotoxic shock models without causing nephrotoxicity when administered at a slow and sustained manner. And a higher CS dosage administration was nephrotoxic and fatal. Thus this study bought an opportunity to consider future investigations with CS administration in murine Gram-negative bacterial infections in a novel way.

Topics: Animals; Apoptosis; Colistin; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxins; Gram-Negative Bacterial Infections; Kidney; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Necrosis; Polymyxins; Shock, Septic; Survival Rate

Extremely drug-resistant (XDR) Acinetobacter baumannii is one of the most commonly encountered, highly resistant pathogens requiring novel therapeutic interventions.. We developed C8, a monoclonal antibody (mAb), by immunizing mice with sublethal inocula of a hypervirulent XDR clinical isolate.. C8 targets capsular carbohydrate on the bacterial surface, enhancing opsonophagocytosis. Treating with a single dose of C8 as low as 0.5 μg/mouse (0.0167 mg/kg) markedly improved survival in lethal bacteremic sepsis and aspiration pneumonia models of XDR A. baumannii infection. C8 was also synergistic with colistin, substantially improving survival compared to monotherapy. Treatment with C8 significantly reduced blood bacterial density, cytokine production (tumor necrosis factor α, interleukin [IL] 6, IL-1β, and IL-10), and sepsis biomarkers. Serial in vitro passaging of A. baumannii in the presence of C8 did not cause loss of mAb binding to the bacteria, but did result in emergence of less-virulent mutants that were more susceptible to macrophage uptake. Finally, we developed a highly humanized variant of C8 that retains opsonophagocytic activity in murine and human macrophages and rescued mice from lethal infection.. We describe a promising and novel mAb as therapy for lethal, XDR A. baumannii infections, and demonstrate that it synergistically improves outcomes in combination with antibiotics.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Antibodies, Monoclonal; Biomarkers; Colistin; Cytokines; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; HL-60 Cells; Humans; Macrophages; Male; Mice; Mice, Inbred C3H; Sepsis; Treatment Outcome

MCR-1 is a lipid A modifying enzyme that confers resistance to the antibiotic colistin. Here, we analyse the impact of MCR-1 expression on E. coli morphology, fitness, competitiveness, immune stimulation and virulence. Increased expression of mcr-1 results in decreased growth rate, cell viability, competitive ability and significant degradation in cell membrane and cytoplasmic structures, compared to expression of catalytically inactive MCR-1 (E246A) or MCR-1 soluble component. Lipopolysaccharide (LPS) extracted from mcr-1 strains induces lower production of IL-6 and TNF, when compared to control LPS. Compared to their parent strains, high-level colistin resistance mutants (HLCRMs) show reduced fitness (relative fitness is 0.41-0.78) and highly attenuated virulence in a Galleria mellonella infection model. Furthermore, HLCRMs are more susceptible to most antibiotics than their respective parent strains. Our results show that the bacterium is challenged to find a delicate equilibrium between expression of MCR-1-mediated colistin resistance and minimalizing toxicity and thus ensuring cell survival.

Topics: Animals; Anti-Bacterial Agents; Cell Membrane; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Humans; Larva; Microbial Sensitivity Tests; Moths

There is an urgent unmet medical need for new treatments for wound and burn infections caused by multidrug-resistant Gram-negative "superbugs," especially the problematic Pseudomonas aeruginosa. In this work, the incorporation of colistin, a potent lipopeptide into a self-healable hydrogel (via dynamic imine bond formation) following the chemical reaction between the amine groups present in glycol chitosan and an aldehyde-modified poly(ethylene glycol), is reported. The storage module (G') of the colistin-loaded hydrogel ranges from 1.3 to 5.3 kPa by varying the amount of the cross-linker and colistin loading providing different options for topical wound healing. The majority of the colistin is released from the hydrogel within 24 h and remains active as demonstrated by both antibacterial in vitro disk diffusion and time-kill assays. Moreover and pleasingly, the colistin-loaded hydrogel performs almost equally well as native colistin against both the colistin-sensitive and also colistin-resistant P. aeruginosa strain in the in vivo animal "burn" infection model despite exhibiting a slower killing profile in vitro. Based on this antibiotic performance along with the biodegradability of the product, it is believed the colistin-loaded hydrogel to be a potential localized wound-healing formulation to treat burn wounds against microbial infection.

Topics: Animals; Anti-Infective Agents; Burns; Colistin; Disease Models, Animal; Elastic Modulus; Hydrogel, Polyethylene Glycol Dimethacrylate; Mice; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Wound Infection

This is the first report to test the loading dosage of colistin against Pseudomonas aeruginosa, including MDRP. Using in vivo murine thigh infection model, in the loading dosage regimen (Day 1:50 mg/kg q12 h, Day 2-3: 25 mg/kg q12 h) group, 5 to 6 log10 CFU/ml reduction compared with control were observed for both strains of P. aeruginosa with colistin MIC 0.5 and 1 μg/mL at 72 h. But, similar reduction was observed for the strains with colistin MIC 0.5 μg/mL only in normal dosage regimen (Day 1-3: 25 mg/kg q12 h) group. For P. aeruginosa with colistin MIC 1 μg/mL, colistin loading dosage regimens showed greater antimicrobial activity than that of without loading dosage group (p < 0.05). These data suggest that the colistin loading regimen would be one of the useful options for P. aeruginosa with antimicrobial resistance infection treatment.

Topics: Animals; Anti-Infective Agents; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Mice; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thigh

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Load; Bacterial Proteins; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Lepidoptera; Lipid A; Lung; Membrane Proteins; Mice, Inbred C57BL; Polymyxins; Survival Analysis; Virulence

The increasing use of polymyxins

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Drug Synergism; Gram-Negative Bacteria; Pentamidine

With increasing antibiotic resistance, the selection of effective treatment of A. baumannii infections is particularly challenging.. This study assessed the activities of the combination of vancomycin and colistin combination in vitro and in vivo using a Galleria mellonella model against four colistin-susceptible or colistin-resistant A. baumannii strains.. In checkerboard assays, synergy was observed between vancomycin and colistin for all four strains tested (0.156 ≤ Fractional inhibitory concentration indices [FICI] ≤ 0.281). In time-kill assays, the combination showed continued bactericidal activity and synergy after 24 h for colistin-susceptible strains. For colistin-resistant strains, the combination resulted in bactericidal activity within 8 h, but sustained bacterial re-growth was then observed. Treatment of G. mellonella larvae infected with lethal doses of A. baumannii (except 19606R) resulted in significantly increased survival rates when vancomycin was given with colistin compared to colistin treatment alone (p < 0.05).. These findings suggest that regimens containing vancomycin may be useful for infections due to multidrug-resistant Acinetobacter baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Larva; Moths; Vancomycin

The Gram-negative bacillus Stenotrophomonas maltophilia (SM) is an emerging MDR opportunistic pathogen. Recent studies identify a potentially relevant activity of azithromycin against Gram-negative bacteria overlooked in standard bacteriological testing. We investigated azithromycin activity against SM in testing conditions incorporating mammalian tissue culture medium and host defence factors.. MIC testing, chequerboard assays, time-kill assays and fluorescence microscopy were performed for azithromycin, the cationic peptide antibiotic colistin and the human defence peptide cathelicidin LL-37 alone or in combination in cation-adjusted Mueller-Hinton broth or mammalian tissue culture media. Azithromycin sensitization of SM to host immune clearance was tested in a human neutrophil killing assay and a murine pneumonia model.. We observed potent bactericidal activity of azithromycin against SM in mammalian tissue culture medium absent in bacteriological medium. Colistin and LL-37 strongly potentiated azithromycin killing of SM by increasing drug entry. Additionally, azithromycin sensitized SM to neutrophil killing and increased SM clearance in the murine pneumonia model.. Despite lack of activity in standard MIC testing, azithromycin synergizes with cationic peptide antibiotics to kill SM in medium mimicking tissue fluid conditions. Azithromycin, alone or in combination with colistin, merits further exploration in therapy of drug-resistant SM infections.

Topics: Animals; Anti-Infective Agents; Antimicrobial Cationic Peptides; Azithromycin; Cathelicidins; Colistin; Disease Models, Animal; Drug Synergism; Gram-Negative Bacterial Infections; Humans; Mice; Microbial Sensitivity Tests; Neutrophils; Pneumonia, Bacterial; Stenotrophomonas maltophilia; Treatment Outcome

For antibiotics, extensive animal PKPD studies are often performed to evaluate the PK/PD driver for subsequent use when recommending dosing regimens. The aim of this work was to evaluate a PKPD model, developed based on in vitro time-kill data for colistin, in predicting the relationships between PK/PD indices and the bacterial killing previously observed in mice.. An in silico PKPD model for Pseudomonas aeruginosa exposed to colistin was previously developed based on static in vitro time-kill data. The model was here applied to perform an in silico replication of an in vivo study where the effect of colistin on P. aeruginosa was studied in the thigh infection model. Concentration-time profiles of unbound colistin were predicted and used as input to drive the bacterial killing in the PKPD model. The predicted bacterial count at 24 h was related to each of the PK/PD indices and the results were compared with reported observations in vivo.. The model was found to adequately predict in vivo results from mice; both in terms of which PK/PD index best correlates to effect (fAUC/MIC) as well as the magnitude needed for a 2 log kill. The fAUC/MIC needed to achieve a 2 log reduction in bacterial counts after 24 h was here predicted to be 9 compared with 31 previously reported in vivo.. This study provides further support that PKPD models based on longitudinal data can be a useful tool to make drug development more efficient within the infectious diseases area.

Topics: Animals; Anti-Bacterial Agents; Colistin; Computer Simulation; Disease Models, Animal; Mice; Microbial Sensitivity Tests; Microbial Viability; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60-80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Female; Humans; Klebsiella pneumoniae; Male; Mice; Mice, Inbred BALB C; Pneumonia; Polyethylene Glycols; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis; Skin

Enterotoxigenic Escherichia coli (ETEC: F4) associated with post-weaning diarrhea (PWD) in pigs has developed resistance against several antimicrobial families, leading to increased use of colistin sulfate (CS) for the treatment of this disease. The objective of this study was to determine the efficacy of oral CS treatment in experimental PWD due to ETEC: F4 challenge and determine the effect of this challenge on CS intestinal absorption. In this study, 96 pigs were divided into two trials based on CS dose (100 000 or 50 000 IU/kg). Fecal shedding of ETEC: F4, total E. coli, and CS-resistant E. coli, diarrhea scores, and weight changes were evaluated. Colistin sulfate plasma concentrations were determined by HPLC-MS/MS. Regardless of the dose, CS treatment resulted in a reduction of fecal ETEC: F4 and total E. coli shedding, and in diarrhea scores but only during the treatment period. However, CS treatment resulted in a slight increase in fecal shedding of CS resistant E. coli and did not prevent weight loss in challenged pigs. In addition, challenge with ETEC: F4 resulted in an increase of CS intestinal absorption. Our study is among the first to demonstrate that under controlled conditions, CS was effective in reducing fecal shedding of ETEC: F4 and total E. coli in experimental PWD. However, CS treatment was associated with a slight selection pressure on E. coli and did not prevent pig weight loss. Further studies are needed in field conditions, to better characterize CS therapeutic regimen efficacy and bacterial resistance dissemination.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Bacterial Shedding; Colistin; Disease Models, Animal; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Feces; Intestinal Absorption; Porcine Reproductive and Respiratory Syndrome; Swine

Persisters are small populations of quiescent bacterial cells that survive exposure to bactericidal antibiotics and are responsible for many persistent infections and posttreatment relapses. However, little is known about how to effectively kill persister bacteria. In the work presented here, we found that colistin, a membrane-active antibiotic, was highly active against Escherichia coli persisters at high concentrations (25 or 50 μg/ml). At a clinically relevant lower concentration (10 μg/ml), colistin alone had no apparent effect on E. coli persisters. In combination with other drugs, this concentration of colistin enhanced the antipersister activity of gentamicin and ofloxacin but not that of ampicillin, nitrofurans, and sulfa drugs in vitro The colistin enhancement effect was most likely due to increased uptake of the other antibiotics, as demonstrated by increased accumulation of fluorescence-labeled gentamicin. Interestingly, colistin significantly enhanced the activity of ofloxacin and nitrofurantoin but not that of gentamicin or sulfa drugs in the murine model of urinary tract infection. Our findings suggest that targeting bacterial membranes is a valuable approach to eradicating persisters and should have implications for more effective treatment of persistent bacterial infections.

Topics: Animals; Anti-Bacterial Agents; Cell Membrane; Colistin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Escherichia coli Infections; Escherichia coli K12; Female; Gentamicins; Mice, Inbred C3H; Microbial Sensitivity Tests; Urinary Tract Infections; Uropathogenic Escherichia coli

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Colistin; Daptomycin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Male; Mice, Inbred BALB C; Microbial Sensitivity Tests; Sepsis; Survival Analysis; Teicoplanin; Treatment Outcome

To study the protective, preventive effect of luteolin from colistin-induced nephrotoxicity.. Four different treatment options were tested on rats: colistin, luteolin, and a combination of colistin and luteolin, intraperitoneally as two doses a day, for seven days. Another group of rats were used as the control and treated with sterile saline. Serum creatinine levels were measured before and after treatment. Histological changes and colistin-induced apoptosis (Insitu BrdU-red DNA Fragmentation Assay Kit) of the renal tissues were examined after the scarification procedure.. In the Colistin Group, post-treatment creatinine levels were statistically higher than the pretreatment levels (p = .001). In the remaining groups, no significant changes were observed. Cells that undergo apoptosis were counted and it was shown that all groups except the colistin-treated group had a similar number of apoptotic cells, whereas the colistin-treated group had statistically higher number of apoptotic cells compared to other groups (p = .0001). Renal histological damage was also measured and the score of the colistin treated group was higher as compared to other groups.. The results obtained from this study demonstrated us that luteolin was capable of preventing colistin-induced nephrotoxicity and that this effect was significant at histopathological level.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Colistin; Creatinine; Disease Models, Animal; Kidney; Kidney Diseases; Luteolin; Male; Oxidative Stress; Rats; Rats, Wistar

Recent findings have identified Escherichia coli strains that are pan-β-lactam susceptible (PBL-S) but piperacillin-tazobactam resistant (TZP-R) in vitro We assessed the in vivo significance of this resistance profile in a neutropenic murine pneumonia model using humanized exposures of TZP with 18 clinical E. coli isolates, 8 TZP-S/PBL-S and 10 genotypically confirmed TZP-R/PBL-S. Despite phenotypically and genotypically defined resistance, TZP displayed efficacy against these isolates. Additional studies are required to define the clinical implications of these TZP-R/PBL-S strains.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Colistin; Culture Media; Disease Models, Animal; Drug Administration Schedule; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Humans; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Tobramycin; Treatment Outcome

Nephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-κB mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

Topics: Animals; Anti-Bacterial Agents; Blood Urea Nitrogen; Carotenoids; Colistin; Disease Models, Animal; Female; Heme Oxygenase-1; Kidney; Kidney Diseases; Lycopene; Membrane Proteins; Metabolic Networks and Pathways; Mice, Inbred Strains; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Protective Agents

Antimicrobial treatment of multidrug-resistant Acinetobacter baumannii (MDR-AB) infections continues to pose significant challenges. With limited options, clinicians have been pushed towards using unorthodox combinations of licensed antibiotics. Although daptomycin/colistin combination appears to be a promising treatment option based on in vitro data, further preclinical work is needed. In this study, the A. baumannii-Galleria mellonella system was employed to study the in vivo efficacy of this combination in order to determine whether it should be explored further for the treatment of MDR-AB infections. The antimicrobial activity of colistin alone and in combination with daptomycin was assessed versus an A. baumannii type strain (ATCC 19606) and a MDR-AB clinical strain (GN2231) isolated in Anhui, China. Synergy studies were performed using the microtitre plate chequerboard assay and time-kill methodology. The in vivo activity of daptomycin/colistin combination was assessed using a G. mellonella larvae model. The combination of daptomycin and colistin was bactericidal against both strains tested. In chequerboard assays, daptomycin was highly active against A. baumannii when combined with colistin [fractional inhibitory concentration index (FICI) of <0.5]. Treatment of G. mellonella larvae infected with lethal doses of A. baumannii resulted in significantly enhanced survival rates when daptomycin was given with colistin compared with colistin treatment alone (P<0.05). This work suggests that daptomycin/colistin combination is highly active against A. baumannii both in vitro and in a simple invertebrate model of infection.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Colistin; Daptomycin; Disease Models, Animal; Drug Therapy, Combination; Lepidoptera

Patients suffering from cystic fibrosis (CF) are commonly affected by chronic Pseudomonas aeruginosa biofilm infections. This is the main cause for the high disease severity. In this study, we demonstrate that P. aeruginosa is able to efficiently colonize murine solid tumors after intravenous injection and to form biofilms in this tissue. Biofilm formation was evident by electron microscopy. Such structures could not be observed with transposon mutants, which were defective in biofilm formation. Comparative transcriptional profiling of P. aeruginosa indicated physiological similarity of the bacteria in the murine tumor model and the CF lung. The efficacy of currently available antibiotics for treatment of P. aeruginosa-infected CF lungs, such as ciprofloxacin, colistin, and tobramycin, could be tested in the tumor model. We found that clinically recommended doses of these antibiotics were unable to eliminate wild-type P. aeruginosa PA14 while being effective against biofilm-defective mutants. However, colistin-tobramycin combination therapy significantly reduced the number of P. aeruginosa PA14 cells in tumors at lower concentrations. Hence, we present a versatile experimental system that is providing a platform to test approved and newly developed antibiofilm compounds.

Topics: Animals; Anti-Infective Agents; Biofilms; Cell Line, Tumor; Colistin; Cystic Fibrosis; Disease Models, Animal; Female; Lung Diseases; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Antibiotic resistance poses an increasingly grave threat to the public health. Of pressing concern, rapid spread of carbapenem-resistance among multidrug-resistant (MDR) Gram-negative rods (GNR) is associated with few treatment options and high mortality rates. Current antibiotic susceptibility testing guiding patient management is performed in a standardized manner, identifying minimum inhibitory concentrations (MIC) in bacteriologic media, but ignoring host immune factors. Lacking activity in standard MIC testing, azithromycin (AZM), the most commonly prescribed antibiotic in the U.S., is never recommended for MDR GNR infection. Here we report a potent bactericidal action of AZM against MDR carbapenem-resistant isolates of Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. This pharmaceutical activity is associated with enhanced AZM cell penetration in eukaryotic tissue culture media and striking multi-log-fold synergies with host cathelicidin antimicrobial peptide LL-37 or the last line antibiotic colistin. Finally, AZM monotherapy exerts clear therapeutic effects in murine models of MDR GNR infection. Our results suggest that AZM, currently ignored as a treatment option, could benefit patients with MDR GNR infections, especially in combination with colistin.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Azithromycin; Cathelicidins; Cell Membrane Permeability; Colistin; Culture Media; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Female; Gram-Negative Bacteria; Humans; Mice, Inbred C57BL; Microbial Sensitivity Tests

Acinetobacter nosocomialis has increasingly been reported as an opportunistic pathogen causing nosocomial infections. Although it is more susceptible to all antimicrobial agents than Acinetobacter baumannii, MDR clinical isolates have also been described. In addition, several studies have shown a high percentage of resistance to colistin. Therefore, in the present study we investigated the mechanism of resistance to colistin in this microorganism.. Colistin-resistant strains were selected from the original colistin-susceptible A. nosocomialis strain following multi-step mutant selection. Comparative genomic and proteomic analyses of both colistin-susceptible and colistin-resistant A. nosocomialis strains were performed. In addition, virulence was investigated using the Caenorhabditis elegans assay.. The colistin-resistant mutants selected showed a lower resistance profile for other types of antibacterial agents together with a significant decrease in virulence. The LT50 (i.e. time required to kill 50% of the nematodes) for the colistin-susceptible strain (WT) was 7 days compared with 9 days for the colistin-resistant strain (256) (P < 0.0001). In the genomic studies, several mutations were observed in the lpxD genes, leading to the loss of LPS in the colistin-resistant strains. The proteomic studies showed several up- and down-regulated proteins that may be involved in colistin resistance or in a decrease in the resistance profile for several antibiotics.. This study shows that the mechanism of resistance to colistin by A. nosocomialis is mainly associated with the loss of LPS due to mutations in the lpxD gene, although changes in the expression of some proteins cannot be ruled out. In addition, the acquisition of colistin resistance is related to a decrease in virulence.

Topics: Acinetobacter; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Proteins; Caenorhabditis elegans; Colistin; Disease Models, Animal; DNA Mutational Analysis; Drug Resistance, Bacterial; Genome, Bacterial; Lipopolysaccharides; Mutation; Proteome; Serial Passage; Virulence; Virulence Factors

Exacerbations associated with chronic lung infection with Pseudomonas aeruginosa are a major contributor to morbidity, mortality and premature death in cystic fibrosis. Such exacerbations are treated with antibiotics, which generally lead to an improvement in lung function and reduced sputum P. aeruginosa density. This potentially suggests a role for the latter in the pathogenesis of exacerbations. However, other data suggesting that changes in P. aeruginosa sputum culture status may not reliably predict an improvement in clinical status, and data indicating no significant changes in either total bacterial counts or in P. aeruginosa numbers in sputum samples collected prior to pulmonary exacerbation sheds doubt on this assumption. We used our recently developed lung segmental model of chronic Pseudomonas infection in sheep to investigate the lung microbiota changes associated with chronic P. aeruginosa lung infection and the impact of systemic therapy with colistimethate sodium (CMS).. We collected protected specimen brush (PSB) samples from sheep (n = 8) both prior to and 14 days after establishment of chronic local lung infection with P aeruginosa. Samples were taken from both directly infected lung segments (direct) and segments spatially remote to such sites (remote). Four sheep were treated with daily intravenous injections of CMS between days 7 and 14, and four were treated with a placebo. Necropsy examination at d14 confirmed the presence of chronic local lung infection and lung pathology in every direct lung segment. The predominant orders in lung microbiota communities before infection were Bacillales, Actinomycetales and Clostridiales. While lung microbiota samples were more likely to share similarities with other samples derived from the same lung, considerable within- and between-animal heterogeneity could be appreciated. Pseudomonadales joined the aforementioned list of predominant orders in lung microbiota communities after infection. Whilst treatment with CMS appeared to have little impact on microbial community composition after infection, or the change undergone by communities in reaching that state, when Gram negative organisms (excluding Pseudomonadales) were considered together as a group there was a significant decrease in their relative proportion that was only observed in the sheep treated with CMS. With only one exception the reduction was seen in both direct and remote lung segments. This reduction, coupled with generally increasing or stable levels of Pseudomonadales, meant that the proportion of the latter relative to total Gram negative bacteria increased in all bar one direct and one remote lung segment.. The proportional increase in Pseudomonadales relative to other Gram negative bacteria in the lungs of sheep treated with systemic CMS highlights the potential for such therapies to inadvertently select or create a niche for bacteria seeding from a persistent source of chronic infection.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Bronchoalveolar Lavage Fluid; Chronic Disease; Colistin; Disease Models, Animal; Female; Injections, Intravenous; Lung; Male; Microbiota; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Sheep, Domestic

This study compared the effect of monotherapy of colistin, tigecycline, and their combination in sepsis model of mice. OXA-48 producing Carbapenem-resistant Klebsiella pneumoniae (CRKP) strain was used in Balb/c mice. The mice were divided into competent and Methylprednisolone acetate (MPA)-treated groups. Each group was sub-divided into (1) colistin or (2) tigecycline monotherapy and (3) colistin/tigecycline combination therapy. After 3 hours of intraperitoneal bacterial inoculation, antimicrobials were administered, and mice were sacrificed at 24 and 48 hours Time-kill curve study demonstrated that colistin sulphate had early bactericidal activity following re-growth. In competent and MPA-treated groups of mice at 24 hours, bacterial counts in liver samples significantly lowered compared to control, however, there were no statistically differences between monotherapy and combination therapy subgroup. Bacterial count in lung samples of competent group was significantly lesser than control for all three antimicrobial subgroups at 24 hours Colistin plus tigecycline combination therapy was not superior against colistin or tigecycline monotherapy.

Topics: Animals; Anti-Bacterial Agents; Carbapenems; Colistin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Klebsiella pneumoniae; Methylprednisolone; Methylprednisolone Acetate; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Minocycline; Sepsis; Structure-Activity Relationship; Tigecycline

The aim of our study was to evaluate the in vitro activity of IB-367 and its bactericidal effect for Pseudomonas aeruginosa and Escherichia coli, associated to a synergic study to test the antibiotic combinations between the peptide and colistin or imipenem. Minimum inhibitory concentrations (MICs), the minimum bactericidal concentrations (MBCs), the synergy test and killing study were carried out to evaluate the IB-367 activity. In the in vivo model, a wound was incised through the panniculus carnosus of BALB/c mice, and then inoculated with 5 × 107 colony-forming units of P. aeruginosa and E. coli. For each strain, the study included an infected or not infected group that did not receive any treatment, and five contaminated groups treated with local IB- 367, intraperitoneal imipenem, intraperitoneal colistin, topical IB-367 local plus intraperitoneal imipenem or intraperitoneal colistin. All isolates were inhibited by IB-367 at concentrations of 4-64 mg/l. Killing by IB-367 was shown to be very rapid: its activity on all Gram-negative bacteria was completed within a 40 min exposure period at a concentration of 2 × MIC/l. Synergy was demonstrated when IB-367 was combined with colistin or imipenem. In in vivo studies, the groups treated with topical IB-367 and intraperitoneal colistin showed the best results in terms of bacterial load inhibition either for Pseudomonas or for E. coli. The good in vitro activity and in vivo efficacy, as well as, the synergic interactions with antibiotics suggest that IB-367 is a promising candidate for potential application in the treatment of wound Gram-negative infections.

Topics: Acinetobacter baumannii; Administration, Topical; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Colistin; Disease Models, Animal; Drug Therapy, Combination; Escherichia coli; Gram-Negative Bacterial Infections; Humans; Imipenem; Injections, Intraperitoneal; Klebsiella pneumoniae; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa

We assessed the activity of tigecycline (TGC) combined with colistin (COL) against carbapenem-resistant enterobacteria. Synergy occurred in vitro against the majority of isolates, with the exception of Serratia marcescens. In a simple animal model (Galleria mellonella), TGC-COL was superior (P < 0.01) in treating Escherichia coli, Klebsiella pneumoniae, and Enterobacter infections, including those with TGC-COL resistance. Clinical studies are needed to determine whether TGC-COL regimens may be a viable option.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Enterobacter; Enterobacteriaceae; Enterobacteriaceae Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Moths; Tigecycline

The purposes of this study were to establish a rabbit multidrug-resistant Pseudomonas aeruginosa (MDRP) keratitis model, and test the efficacy of levofloxacin, colistin methanesulfate (CL-M), colistin sulfate (CL-S) and polymyxin B (PL-B) against MDRP infection. In a rabbit eye, making a 2-mm circular corneal excision, and MDRP strain #601 or representative P. aeruginosa strain IID1210 were instilled into the corneal concavity. IID1210 was used to confirm this model developed P. aeruginosa keratitis. After MDRP keratitis developed, we treated the eyes with levofloxacin, CL-M, CL-S or PL-B eye drops. The infected eyes were evaluated by clinical score, histopathological examination and viable bacterial count (CFU). Rabbits developed MDRP keratitis reproducibly after instilled the bacteria into the corneal lesion. MDRP produced severe keratitis similarly with IID1210, as shown by slit lamp examination and clinical score. In MDRP keratitis models, clinical scores and viable bacterial counts were significantly lower in levofloxacin- and CL-M-treated groups compared with PBS-treated group, but the magnitudes of reduction were not remarkable. However, clinical scores were dramatically lowered in CL-S- and PL-B-treated groups compared with PBS-treated group. CL-S- and PL-B-treated group were kept corneal translucency and little influx of polymorphonuclear neutrophils in histopathological examination. In addition, both CL-S- and PL-B-treated groups were not detected viable bacteria in infected cornea. Using our MDRP keratitis model, we showed that topical levofloxacin and CL-M are not adequately effective, while CL-S and PL-B are efficacious in controlling MDRP keratitis. Especially, PL-B, which is commercially available eye drop, might be most effective against MDRP.

Topics: Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Keratitis; Levofloxacin; Male; Microbial Sensitivity Tests; Polymyxin B; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits

The antimicrobial treatment of Stenotrophomonas maltophilia infections is complicated by intrinsic multidrug resistance and a lack of reliable susceptibility data. We assessed the activity of colistin (COL), rifampicin (RIF) and tigecycline (TGC) alone and in combination using a range of in vitro susceptibility testing methodologies and a simple invertebrate model of S. maltophilia infection (Galleria mellonella). Synergy [fractional inhibitory concentration indices (FICIs) ≤0.5] between COL and either RIF or TGC was observed against 92 % and 88 % of 25 S. maltophilia isolates, respectively, despite resistance to one or another of the single agents alone. In time-kill assays, COL combined with either RIF or TGC was superior to single agents, but only the COL/RIF regimen was reliably bactericidal. The in vitro findings correlated with treatment outcomes in G. mellonella, with heightened survival observed for larvae treated with COL/RIF or COL/TGC compared with COL, RIF or TGC alone. COL combined with RIF was the most effective combination overall in both in vitro and in vivo (p < 0.05) assays. Given the difficulty in selecting appropriate therapy for S. maltophilia infections, regimens consisting of COL combined with RIF or TGC could be considered for clinical use.

Topics: Animals; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Gram-Negative Bacterial Infections; Lepidoptera; Microbial Viability; Minocycline; Rifampin; Stenotrophomonas maltophilia; Survival Analysis; Tigecycline; Treatment Outcome

The purpose of this study was to evaluate the ocular distribution of intravenously administered colistin in a rabbit uveitis model.. Colistin, a polypeptide antibiotic against the multidrug-resistant (MDR) Gram-negative organisms, was given intravenously to rabbits at 5 mg/kg of body weight starting 24 h after induction of uveitis by intravitreal endotoxin injection. Colistin concentrations were determined by high-performance liquid chromatography-mass spectrometry assay in the aqueous humor, vitreous humor, and plasma 0.5, 3, 6, and 24 h after administration of a single dose.. The maximum colistin concentrations (mean±standard deviation) were found 0.5 h after the end of the intravenous administration and were 9.48±2.0 μg/mL in plasma and 0.62±0.07 μg/mL in the aqueous humor of the inflamed eye. After 24 h, no drug was detectable in the aqueous of the inflamed eyes. Colistin was undetectable in the aqueous of contralateral normal eyes at all time points. Drug concentrations in all the vitreous samples from both inflamed and normal eyes were undetectable, except at the 3-h inflamed eye group, and a colistin concentration of 0.02±0.01 μg/mL was found. Plasma levels of colistin fell to 0.93±0.07 and 0.24±0.08 μg/mL, after 3 and 6 h, respectively, and were not detectable 24 h after the given dose.. In our model, colistin did not reach therapeutically relevant levels in the aqueous and in the vitreous humor of rabbit eyes. The findings suggest a limited role for intravenously administered colistin in the treatment of Gram-negative bacterial endophthalmitis.

Topics: Animals; Anti-Bacterial Agents; Aqueous Humor; Colistin; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Eye; Injections, Intravenous; Microbial Sensitivity Tests; Rabbits; Tissue Distribution; Uveitis; Vitreous Body

This study evaluated the usefulness of plasma Cystatin C (pCysC) along with urinary neutrophil gelatinase-associated lipocalin (NGAL), γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate (AST) and alanine (ALT) aminotransferase to monitor colistin nephrotoxicity.. Male rats were given intramuscular (i.m.) injections of colistin in doses of 150,000 (G1), 300,000 (G2) and 450,000 IU/kg/day (G3) or normal saline (Control), every 12 h for 7 days. After the 14th injection, animals were placed in metabolic cages and urine samples were collected in the next 12 h. Thereafter, animals were euthanized, blood samples were collected and kidneys were removed for histological assessment.. Nephrotoxicity was completely dose-dependent according to pathologic findings. The major insults were acute tubular necrosis in the tubules of G3. No significant change in pCr was observed in all treated groups, but pCysC increased in the G3 compared to the control. In urinary markers, uNGAL level showed a dose dependant increase with significant change in the G2 and G3 groups compared to the control. However, there was no significant change in the AST, ALT, LDH or ALP activities but only GGT increased in the G3 compared to the control.. Based on colistin doses used in our experimental study on rat model, histopathologic assessment remains the most accurate way to diagnose colistin nephrotoxicity. pCysC appears to be more reliable than pCr, and uNGAL seems to be the most sensitive factor of colistin nephrotoxicity.

Topics: Acute-Phase Proteins; Alanine Transaminase; Alkaline Phosphatase; Animals; Anti-Bacterial Agents; Aspartic Acid; Colistin; Cystatin C; Disease Models, Animal; Dose-Response Relationship, Drug; gamma-Glutamyltransferase; Kidney Diseases; L-Lactate Dehydrogenase; Lipocalin-2; Lipocalins; Male; Proto-Oncogene Proteins; Rats; Rats, Wistar

This study evaluated the in vitro and in vivo performance of antibiotic-releasing porous polymethylmethacrylate (PMMA)-based space maintainers comprising a gelatin hydrogel porogen and a poly(dl-lactic-co-glycolic acid) (PLGA) particulate carrier for antibiotic delivery. Colistin was released in vitro from either gelatin or PLGA microparticle loaded PMMA constructs, with gelatin-loaded constructs releasing colistin over approximately 7 days and PLGA microparticle-loaded constructs releasing colistin for up to 8 weeks. Three formulations with either burst release or extended release at different doses were tested in a rabbit mandibular defect inoculated with Acinetobacter baumannii (2×10(7) colony forming units ml(-1)). In addition, one material control that released antibiotic but was not inoculated with A. baumannii was tested. A. baumannii was not detectable in any animal after 12 weeks on culture of the defect, saliva, or blood. Defects with high dose extended release implants had greater soft tissue healing compared with defects with burst release implants, with 8 of 10 animals showing healed mucosae compared with 2 of 10 respectively. Extended release of locally delivered colistin via a PLGA microparticle carrier improved soft tissue healing compared with implants with burst release of colistin from a gelatin carrier.

Topics: Acinetobacter; Animals; Anti-Bacterial Agents; Bacterial Infections; Blood Urea Nitrogen; Colistin; Creatinine; Disease Models, Animal; Humans; Kidney Function Tests; Male; Mandible; Microbial Sensitivity Tests; Mouth Mucosa; Polymethyl Methacrylate; Porosity; Prostheses and Implants; Rabbits

Colistin (polymixin E) is an antibiotic prescribed with resurging frequency for multidrug resistant gram negative bacterial infections. It is associated with nephrotoxicity in humans in up to 55% of cases. Little is known regarding genes involved in colistin nephrotoxicity. A murine model of colistin-mediated kidney injury was developed. C57/BL6 mice were administered saline or colistin at a dose of 16 mg/kg/day in 2 divided intraperitoneal doses and killed after either 3 or 15 days of colistin. After 15 days, mice exposed to colistin had elevated blood urea nitrogen (BUN), creatinine, and pathologic evidence of acute tubular necrosis and apoptosis. After 3 days, mice had neither BUN elevation nor substantial pathologic injury; however, urinary neutrophil gelatinase-associated lipocalin was elevated (P = 0.017). An Illumina gene expression array was performed on kidney RNA harvested 72 h after first colistin dose to identify differentially expressed genes early in drug treatment. Array data revealed 21 differentially expressed genes (false discovery rate < 0.1) between control and colistin-exposed mice, including LGALS3 and CCNB1. The gene signature was significantly enriched for genes involved in cell cycle proliferation. RT-PCR, immunoblot, and immunostaining validated the relevance of key genes and proteins. This murine model offers insights into the potential mechanism of colistin-mediated nephrotoxicity. Further studies will determine whether the identified genes play a causative or protective role in colistin-induced nephrotoxicity.

Topics: Animals; Body Weight; Cell Cycle Checkpoints; Cluster Analysis; Colistin; Disease Models, Animal; Galectin 3; Gene Expression Profiling; In Situ Nick-End Labeling; Kidney; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Necrosis; Proliferating Cell Nuclear Antigen; Reproducibility of Results

In recent years, multidrug-resistant Acinetobacter baumannii has been reported as an important nosocomial pathogen, and treatment options are limited. The aim of this study was to investigate the additional effect of sulbactam on monotherapy with colistin, tigecycline and imipenem in experimental sepsis with carbapenem-resistant A. baumannii in mice.. Sepsis was developed in 8- to 10-week-old BALB/c mice by an intraperitoneal injection of A. baumannii. Antibiotic was given intraperitoneally 2 h after bacterial inoculation. Each experimental group had 15 mice and was divided into 3 subgroups. Mice were sacrificed at 24, 48 or 72 h. Lung, liver, heart and spleen samples were cultured, and homogenates of lung and liver were used to detect the number of colony-forming units per gram. Bacterial clearance was compared in lung and liver at different time points.. Imipenem did not decrease the bacterial load, but the other antibiotics showed significant bactericidal activity compared with the control group, and the combination of imipenem with sulbactam decreased the bacterial load in lung and liver. However, the addition of sulbactam to colistin and tigecycline had no significant effect on bacterial counts. Only the addition of sulbactam to imipenem showed better bactericidal activity compared to imipenem alone.. These results suggested that combining sulbactam with tigeycline or colistin does not increase the efficiency of these antibiotics.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Load; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Imipenem; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Minocycline; Sepsis; Sulbactam; Tigecycline; Time Factors

Treatment of Acinetobacter baumannii infections is challenging owing to widespread multidrug resistance and the lack of novel agents. There is now considerable interest in the potential of unorthodox combination therapies such as colistin and glycopeptides (e.g. vancomycin and teicoplanin), since potent synergy can be demonstrated in vitro. A simple invertebrate model (Galleria mellonella) has been developed to assess the in vivo activity of antimicrobial therapies and was used to investigate the efficacy of colistin combined with the lipoglycopeptide telavancin in the treatment of A. baumannii infection. Galleria mellonella larvae were inoculated with 10⁵ CFU/larvae of A. baumannii type strain ATCC 19606 or the multidrug-resistant clinical isolate AB210. Infected caterpillars were treated with either telavancin (10 mg/kg), colistin (2.5 mg/kg) or a telavancin/colistin combination. Larvae were incubated at 37 °C for up to 96 h and were scored daily. Survival curves were plotted and analysed using the log-rank test. The telavancin/colistin combination was effective in the treatment of larvae infected with both strains but was superior to colistin monotherapy in the treatment of A. baumannii AB210 (P<0.001). The combination of telavancin and colistin was effective in a simple invertebrate model of A. baumannii infection. This is in agreement with a previous in vitro study and provides preliminary in vivo evidence that such a combination might be useful therapeutically.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Aminoglycosides; Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Therapy, Combination; Larva; Lepidoptera; Lipoglycopeptides; Survival Analysis; Treatment Outcome

Lipopolysaccharide (LPS) is a major contributing factor to endotoxic shock. Colistin specifically binds to LPS. However, it has the disadvantages that adverse reactions are common and it has a short half-life. To overcome these disadvantages, we prepared slow-releasing colistin microspheres and examined the efficacy of these colistin microspheres in a mouse model of endotoxin-induced sepsis. We prepared the colistin microspheres using poly-lactic-co-glycolic acid. For acute toxicity investigations, mice were overdosed with colistin sulfate or colistin microspheres. The group administered with colistin microspheres was associated with less acute toxicity and fewer nephrotoxic changes on histopathological examination compared to the group administered with colistin sulfate alone. For pharmacokinetic analysis, mice were subcutaneously administered with colistin microspheres or colistin sulfate alone. The plasma concentration of colistin was higher in the colistin microspheres group than in the colistin sulfate group at 12 and 24 h after administration. Moreover, mice were intraperitoneally injected with LPS and then immediately subcutaneously administered with blank microspheres, colistin microspheres or colistin sulfate alone. The levels of endotoxin in the sera and cytokine in the spleens were then measured. A significant reduction in the serum endotoxin level in the colistin microspheres group was observed at 24 h. The reduced endotoxin levels in the sera were correlated with the lower cytokine levels in the spleens of mice treated with colistin microspheres. Our results suggest that the use of colistin microspheres may help to maintain a higher colistin concentration in blood, reduce the levels of endotoxin and cytokines in endotoxin-induced sepsis, and lead to decreased toxicity.

Topics: Animals; Anti-Bacterial Agents; Colistin; Delayed-Action Preparations; Disease Models, Animal; Endotoxins; Injections, Subcutaneous; Kidney; Lipopolysaccharides; Male; Mice; Mice, Inbred C3H; Microspheres; Shock, Septic

The identification of the optimal agent for administration via the respiratory tract when treating pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB).. A murine model of acute CRAB pneumonia was established by intratracheal (i.t.) inoculation with 2.5 × 10⁷ colony-forming units (CFU) of A. baumannii strain Ab396 plus 10% porcine mucin. After 4h the infected BALB/c mice were treated intratracheally with 25μl of either 0.85% saline (control group), colistimethate sodium (CMS) (166 666 U/kg, CMS group), imipenem/cilastatin (30/30 mg/kg, imipenem group), or meropenem (20mg/kg, meropenem group), every 8h. The therapeutic efficacy of these agents was examined.. A. baumannii strain Ab396 was susceptible to CMS only. However, meropenem treatment did give a significantly superior survival rate (100%) compared to treatment with imipenem (50%), CMS (33%), or saline (0%) (p<0.001 vs. the control and CMS groups, p=0.006 vs. the imipenem group, by log-rank test). Furthermore, compared to the other groups, the meropenem group demonstrated significantly more favorable results in terms of tissue penetration of the antibiotic, bacterial clearance, normalization of the wet lung-to-body weight ratio, and down-regulation of pro-inflammatory cytokine levels in the lungs.. Administration of meropenem via the respiratory tract proved to have the best therapeutic efficacy among the antibiotics tested when treating advanced murine CRAB pneumonia.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Acute Disease; Animals; Anti-Bacterial Agents; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Colistin; Cytokines; Disease Models, Animal; Drug Combinations; Drug Resistance, Bacterial; Female; Imipenem; Meropenem; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pneumonia, Bacterial; Stem Cells; Thienamycins

New Delhi metallo-β-lactamase-1 (NDM-1)-producing Enterobacteriaceae have emerged as a global threat. The aim of this study was to assess the efficacies of colistin and tigecycline in an experimental model of pneumonia caused by NDM-1-producing Escherichia coli and Klebsiella pneumoniae. The susceptibilities of K. pneumoniae NDM, E. coli NDM and K. pneumoniae ATCC 29665 were determined using the broth microdilution technique. The pharmacokinetics of colistin and tigecycline in an experimental model of pneumonia were performed using immunocompetent C57BL/6 mice. Mice were treated with colistin (60 mg/kg/day) or tigecycline (10 mg/kg/day). Mortality, bacteraemia and lung bacterial concentrations were recorded. The strains were susceptible to colistin and tigecycline. The ratio of area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC) for colistin was 158.5 (all three strains) and that for tigecycline was 18.5 (K. pneumoniae NDM) and 37 (K. pneumoniae ATCC 29665 and E. coli NDM). In vivo, colistin decreased bacterial lung concentrations of K. pneumoniae NDM and K. pneumoniae ATCC 29665 by 1.16 log colony-forming units (CFU)/g and 2.23 logCFU/g, respectively, compared with controls (not significant). Tigecycline reduced K. pneumoniae NDM and K. pneumoniae ATCC 29665 load by 2.67 logCFU/g and 4.62 logCFU/g (P<0.05). Colistin and tigecycline decreased lung concentrations of E. coli NDM by 2.27 logCFU/g and 4.15 logCFU/g (P<0.05), respectively, compared with controls, and was more active than colistin (P<0.05). In conclusion, these results suggest that colistin is inappropriate for treating pneumonia due to NDM-1-producing K. pneumoniae and its efficacy was suboptimal against NDM-1-producing E. coli. A high tigecycline dose was efficacious for treating experimental pneumonia due to NDM-1-producing E. coli and K. pneumoniae.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Bacterial Load; Bacterial Proteins; beta-Lactamases; Colistin; Disease Models, Animal; Drug Evaluation, Preclinical; Enterobacteriaceae Infections; Escherichia coli; Female; Klebsiella pneumoniae; Lung; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Minocycline; Tigecycline

Many Pseudomonas aeruginosa isolates from the airways of patients with cystic fibrosis (CF) are sensitive to antibiotics in susceptibility testing, but eradication of the infection is difficult. The main reason is the biofilm formation in the airways of patients with CF. The pharmacokinetics (PKs) and pharmacodynamics (PDs) of antimicrobials can reliably be used to predict whether antimicrobial regimens will achieve the maximum bactericidal effect against infections. Unfortunately, however, most PK/PD studies of antimicrobials have been done on planktonic cells and very few PK/PD studies have been done on biofilms, partly due to the lack of suitable models in vivo. In the present study, a biofilm lung infection model was developed to provide an objective and quantitative evaluation of the PK/PD profile of antimicrobials. Killing curves were set up to detect the antimicrobial kinetics on planktonic and biofilm P. aeruginosa cells in vivo. Colistin showed concentration-dependent killing, while imipenem showed time-dependent killing on both planktonic and biofilm P. aeruginosa cells in vivo. The parameter best correlated to the elimination of bacteria in lung by colistin was the area under the curve (AUC) versus MIC (AUC/MIC) for planktonic cells or the AUC versus minimal biofilm inhibitory concentration (MBIC; AUC/MBIC) for biofilm cells. The best-correlated parameter for imipenem was the time that the drug concentration was above the MIC for planktonic cells (T(MIC)) or time that the drug concentration was above the MBIC (T(MBIC)) for biofilm cells. However, the AUC/MIC of imipenem showed a better correlation with the efficacy of imipenem for biofilm infections (R(2) = 0.89) than planktonic cell infections (R(2) = 0.38). The postantibiotic effect (PAE) of colistin and imipenem was shorter in biofilm infections than planktonic cell infections in this model.

Topics: Alginates; Animals; Anti-Bacterial Agents; Area Under Curve; Biofilms; Cells, Immobilized; Colistin; Disease Models, Animal; Female; Glucuronic Acid; Hexuronic Acids; Humans; Imipenem; Lung; Microbial Sensitivity Tests; Plankton; Pseudomonas aeruginosa; Pseudomonas Infections

Extremely drug-resistant (XDR; i.e. resistant to all antibiotics except colistin or tigecycline) Acinetobacter baumannii has emerged as one of the most common and highly antibiotic-resistant causes of infection. Diabetes is a risk factor for acquisition of and worse outcomes from A. baumannii infection. We sought to develop diabetic mouse models of A. baumannii bacteraemia and pneumonia and validate these models by comparing the efficacy of antibiotic treatment in these models with the established neutropenic mouse models.. Diabetic or neutropenic mice were infected via intravenous inoculation or inhalation in an aerosol chamber with an XDR A. baumannii. Treatment with colistin started 24 h after infection and continued daily for 7 days. Survival served as the primary endpoint while tissue bacterial burden and histopathological examination served as secondary endpoints.. Lethal infection was achieved for the neutropenic and diabetic mice when infected intravenously or via inhalation. Neutropenic mice were more susceptible to infection than diabetic mice in the pneumonia model and equally susceptible in the bacteraemia model. Both models of bacteraemia were sensitive enough to detect virulence differences among different clinical strains of A. baumannii. In the pneumonia model, colistin treatment was effective in improving survival, reducing lung bacterial burden and histologically resolving the infection compared with placebo only in diabetic mice.. We developed novel models of A. baumannii bacteraemia and pneumonia in diabetic mice. These models can be used to study mechanisms of infection, develop immunotherapeutic strategies and evaluate drug efficacies against highly lethal A. baumannii infections.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacteremia; Bacterial Load; Colistin; Diabetes Complications; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Histocytochemistry; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Pneumonia, Bacterial; Survival Analysis; Treatment Outcome

The β-barrel assembly machinery (BAM) complex plays a critical role in outer membrane protein (OMP) biogenesis. The outer membrane (OM) of Pseudomonas aeruginosa is centrally involved in mechanisms of antibiotic resistance. This study aimed to identify effects of a synthetic peptide based on conserved sequences in the putative BamA-binding region of BamD, focusing on antibiotic susceptibility and OMP characteristics in P. aeruginosa.. We synthesized a peptide FIRL (Phe-Ile-Arg-Leu-CONH(2)) with a sequence related to that of the BamD protein. We assessed antibiotic susceptibility of P. aeruginosa PAO1 using the chequerboard method and a time-kill assay. Changes in OMPs and in OM permeability were examined using SDS-PAGE, western blot analysis and nitrocefin assays. The combined effects of the peptide and antibiotics were investigated using a mouse pneumonia model.. Although the peptide alone exerted no antimicrobial effect, it reduced the MICs of colistin, levofloxacin, erythromycin, vancomycin and rifampicin for P. aeruginosa PAO1 by 4-fold or more. Time-kill tests revealed bacterial numbers were significantly reduced after 2 h of incubation with the peptide plus colistin or levofloxacin. Moreover, in the presence of the peptide, expression of OprM was reduced by a third, and OM permeability was increased. The combination of the peptide (2.08 mg/kg) and colistin (1.25 mg/kg) significantly reduced P. aeruginosa by more than 1 log cfu/mL in a mouse pneumonia model.. We show, for the first time, that a synthetic peptide based on homologous sequences of BamD can potentiate antibiotic susceptibility of P. aeruginosa.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Bacterial Outer Membrane Proteins; Blotting, Western; Colistin; Disease Models, Animal; Drug Therapy, Combination; Electrophoresis, Polyacrylamide Gel; Female; Levofloxacin; Lung; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Ofloxacin; Peptides; Pneumonia, Bacterial; Protein Binding; Pseudomonas aeruginosa; Pseudomonas Infections; Treatment Outcome

Squalamine is a steroid extracted from sharks with proven in vitro antibacterial activity. We assessed its efficacy in reducing the lung bacterial load and histological lesions when given via inhalation in a rat model of chronic Pseudomonas aeruginosa pneumonia.. Sprague-Dawley rats were inoculated by tracheal intubation with 150 μL of a solution containing 10(8) cfu/mL of agar bead-embedded P. aeruginosa strain PAO1. MICs of squalamine and colistin for this strain were 2-8 and 0.5-1 mg/L, respectively. Starting the day after infection, the animals were treated twice daily with aerosolized squalamine (3 mg), colistin (160 mg) or 0.9% saline for 6 days. The bacterial load and lung histological lesions were evaluated on the seventh day.. Aerosols of squalamine and colistin resulted in a significant reduction in median (IQR) pulmonary bacterial count compared with saline [10(3) (6 × 10(2)-2 × 10(3)), 10(3) (9 × 10(2)-6 × 10(3)) and 10(5) (9 × 10(4)-2 × 10(5)) cfu/lung, respectively; P < 0.001 for both treated groups versus saline]. The lung weight and the lung histological severity score were significantly lower in both treated groups.. In a model of chronic P. aeruginosa pneumonia, treatment twice daily with a squalamine aerosol for 6 days leads to a significant reduction in the pulmonary bacterial count and pneumonia lesions with an efficacy comparable to that of colistin.

Topics: Administration, Inhalation; Animals; Anti-Bacterial Agents; Bacterial Load; Cholestanols; Chronic Disease; Colistin; Disease Models, Animal; Lung; Male; Microbial Sensitivity Tests; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Sprague-Dawley; Treatment Outcome

Due to increasing drug resistance, available antimicrobial options are limited in the treatment of Acinetobacter baumannii infections. Particularly in cases caused by extensively drug-resistant (XDR) A. baumannii, combination regimens must also be taken into consideration. In this study, the efficacies of tigecycline, colistin and tigecycline/colistin combination on bacterial counts in lung tissue were investigated in a rat pneumonia model. One A. baumannii strain resistant to all antimicrobial agents except tigecycline and colistin was selected for the study. In vivo studies revealed a >3 log reduction in bacterial counts in the tigecycline, colistin and combination groups at 24 h and 48 h compared with the control group. No significant differences were determined between colistin, tigecycline and combination groups (P>0.05). On the other hand, differences between treatment groups and the control group were statistically significant (P=0.01). A greater reduction in bacterial counts was observed at 48 h compared with 24 h in the tigecycline group than in the colistin group (P=0.038 and P=0.139, respectively); the most significant decrease between 24 h and 48 h was observed in the combination group (P=0.014). Despite detection of in vitro synergistic activity in this study, no statistically significant differences were found between colistin, tigecycline and combination treatments in terms of efficacy on bacterial counts in lung tissue. In the treatment of infections with a high mortality rate such as pneumonia caused by XDR A. baumannii, combining tigecycline with colistin during the first 48 h and continuing treatment with one of these agents seems a rational approach.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Load; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Lung; Minocycline; Pneumonia, Bacterial; Rats; Rats, Wistar; Tigecycline; Time Factors; Treatment Outcome

Acinetobacter baumannii (American Type Culture Collection strain 19606) acquires mutations in the pmrB gene during the in vitro development of resistance to colistin. The colistin-resistant strain has lower affinity for colistin, reduced in vivo fitness (competition index, .016), and decreased virulence, both in terms of mortality (0% lethal dose, 6.9 vs 4.9 log colony-forming units) and survival in a mouse model of peritoneal sepsis. These results may explain the low incidence and dissemination of colistin resistance in A. baumannii in clinical settings.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Proteins; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Female; Mice; Mice, Inbred C57BL; Mutation; Peritonitis; Sepsis; Survival Analysis; Transcription Factors; Virulence

An experimental study was performed to evaluate the interaction between s-thanatin and colistin both in vitro and in vivo, using two Pseudomonas aeruginosa strains with different patterns of susceptibilities. We evaluated whether selecting for colistin-resistant P. aeruginosa could be prevented in vitro by combining colistin with s-thanatin. The strains were serially exposed in broth to twofold stepwise increasing concentrations of colistin alone or in combination with a fixed concentration [0.25× minimum inhibitory concentration (MIC)] of s-thanatin. We also performed an in vitro synergy study. For in vivo studies, a mouse model of Pseudomonas sepsis has been used. Main outcome measures were lethality and quantitative blood cultures. Exposure to colistin alone gradually selected for Pseudomonas strains with an increased MIC. In vitro studies, s-thanatin showed a positive interaction with colistin, and was able to prevent its resistance. In vivo studies, s-thanatin combined with colistin exhibited the highest efficacy on all main outcome measurements. These results highlight the potential usefulness of this combination and provide a future therapeutic alternative in severe Pseudomonas infections.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Colistin; Disease Models, Animal; Drug Resistance, Microbial; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis

Wound infections caused by multidrug-resistant bacteria are a major issue in wound care. An occlusive dressing delivering an antimicrobial agent to the wound may be advantageous. The objective of this study was to evaluate an occlusive silk membrane loaded with colistin to establish an effective antimicrobial wound dressing against Gram-negative bacteria in vitro and in vivo.. ST-silk protein membranes (thickness, 100 μm; pore size, <100 nm) were loaded with log-scale colistin dilutions (0.027 to 270 mg/ml) and tested in a modified microbroth dilution assay against Pseudomonas aeruginosa (American Type Culture Collection 27853). A rat burn infection model was used to demonstrate the antimicrobial activity of ST-silk membranes loaded with 270 mg/ml colistin. Finally, a porcine wound infection model was used to study dose response (2.7, 27, and 270 mg/ml colistin loading concentration) in a time-dependent manner (0, 2, 4, and 6 days).. The in vitro study demonstrated a concentration-dependent antimicrobial effect against P. aeruginosa, with complete elimination at the highest loading concentrations (2.7, 27, and 270 mg/ml). All colistin membranes demonstrated lower colony-forming unit counts compared with the corresponding phosphate-buffered saline or carrier controls. The rat burn infection model demonstrated a colony-forming unit reduction of greater than 3 log-scales for the colistin-loaded ST-silk membranes after 3 days. On average, the wounds' colony-forming unit quantity remained at greater than 1000 during the entire follow-up of 6 days, apart from three wounds where complete bacterial clearance was observed.. This study demonstrates that occlusive ST-silk membranes loaded with an antimicrobial agent may be an effective dressing for infected wounds.

Topics: Animals; Anti-Bacterial Agents; Bandages; Burns; Coated Materials, Biocompatible; Colistin; Disease Models, Animal; Membranes, Artificial; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Sprague-Dawley; Silk; Stem Cells; Treatment Outcome; Wound Infection

Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic (PK)/pharmacodynamic (PD) index that best correlates with the efficacy of colistin remains undefined. The activity of colistin against three strains of Pseudomonas aeruginosa was studied in neutropenic mouse thigh and lung infection models. The PKs of unbound colistin were determined from single-dose PK studies together with extensive plasma protein binding analyses. Dose-fractionation studies were conducted over 24 h with a dose range of 5 to 160 mg/kg of body weight/day. The bacterial burden in the thigh or lung was measured at 24 h after the initiation of treatment. Relationships between antibacterial effect and measures of exposure to unbound (f) colistin (area under the concentration-time curve [fAUC/MIC], maximum concentration of drug in plasma [fC(max)]/MIC, and the time that the concentration in plasma is greater than the MIC [fT > MIC]) were examined by using an inhibitory sigmoid maximum-effect model. Nonlinearity in the PKs of colistin, including its plasma protein binding, was observed. The PK/PD index that correlated best with its efficacy was fAUC/MIC in both the thigh infection model (R(2) = 87%) and the lung infection model (R(2) = 89%). The fAUC/MIC targets required to achieve 1-log and 2-log kill against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, while the corresponding values were 12.2 to 16.7 and 36.9 to 45.9 in the lung infection model. The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Colistin; Disease Models, Animal; Female; Humans; Lung; Lung Diseases; Mice; Microbial Sensitivity Tests; Neutropenia; Pseudomonas aeruginosa; Pseudomonas Infections; Specific Pathogen-Free Organisms; Thigh

Emergence of multidrug-resistant strains in intensive care units has renewed interest in colistin, which often remains the only available antimicrobial agent active against resistant Pseudomonas aeruginosa. The aim of this study is to compare lung tissue deposition and antibacterial efficiency between nebulized and intravenous administration of colistin in piglets with pneumonia caused by P. aeruginosa.. In ventilated piglets, colistimethate was administered 24 h following bronchial inoculation of Pseudomonas aeruginosa (minimum inhibitory concentration of colistin = 2 microg ml(-1)) either by nebulization (8 mg kg(-1) every 12 h, n = 6) or by intravenous infusion (3.2 mg kg(-1) every 8 h, n = 6). All piglets were killed 49 h after inoculation. Colistin peak lung tissue concentrations and lung bacterial burden were assessed on multiple post mortem subpleural lung specimens.. Median colistin peak lung concentration following nebulization was 2.8 microg g(-1) (25-75% interquartile range = 0.8-13.7 microg g(-1)). Colistin was undetected in lung tissue following intravenous infusion. In the aerosol group, peak lung tissue concentrations were significantly greater in lung segments with mild pneumonia (median = 10.0 microg g(-1), 25-75% interquartile range = 1.8-16.1 microg g(-1)) than in lung segments with severe pneumonia (median = 1.2 microg g(-1), 25-75% interquartile range = 0.5-3.3 microg g(-1)) (p < 0.01). After 24 h of treatment, 67% of pulmonary segments had bacterial counts <10(2) cfu g(-1) following nebulization and 28% following intravenous administration (p < 0.001). In control animals, 12% of lung segments had bacterial counts <10(2) cfu g(-1) 49 h following bronchial inoculation.. Nebulized colistin provides rapid and efficient bacterial killing in ventilated piglets with inoculation pneumonia caused by Pseudomonas aeruginosa.

Topics: Administration, Inhalation; Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Injections, Intravenous; Nebulizers and Vaporizers; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Swine

To elucidate the pharmacokinetic/pharmacodynamic (PK/PD) index that predicts colistin efficacy against Acinetobacter baumannii in neutropenic murine thigh and lung infection models, and to determine the extent of the emergence of resistance in vivo to colistin.. PK/PD of colistin was studied in thigh and lung infection models against A. baumannii ATCC 19606 and two multidrug-resistant clinical isolates (two of the three strains were colistin heteroresistant). Dose fractionation studies were conducted over a daily dose range of 1-160 mg/kg colistin sulphate. Bacterial burden in tissues was measured at 24 h. Non-linear least squares regression analyses were employed to determine the PK/PD index (fAUC/MIC, fC(max)/MIC or fT(>MIC)) best correlating with the efficacy of colistin in each model. Real-time population analysis profiles were conducted for tissue samples to monitor the emergence of resistance.. The fAUC/MIC was the PK/PD index that correlated best with efficacy in both thigh (R(2) = 0.90) and lung (R(2) = 0.80) infection models. The fAUC/MIC targets required to achieve stasis and 1 log kill against the three strains were 1.89-7.41 and 6.98-13.6 in the thigh infection model, respectively, while the corresponding values were 1.57-6.52 and 8.18-42.1 in the lung infection model. Amplification of colistin-resistant subpopulations was revealed for all strains in both models after 24 h colistin treatment.. This study indicates the importance of achieving adequate time-averaged exposure to colistin and defined target fAUC/MIC values for various magnitudes of kill. Amplification of resistant subpopulations indicates the importance of investigating rational combinations with colistin. The results will facilitate efforts to optimize colistin use in humans.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Area Under Curve; Colistin; Colony Count, Microbial; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Female; Lung; Mice; Microbial Sensitivity Tests; Thigh

The designer antibacterial peptide A3-APO is efficacious in mouse models of Escherichia coli and Acinetobacter baumannii systemic infections. Here we compare the efficacy of the peptide with that of imipenem and colistin in A. baumannii wound infections after burn injury.. CD-1 mice were inflicted with burn wounds and different inocula of A. baumannii, isolated from an injured soldier, were placed into the wound sites. The antibiotics were given intramuscularly (im) one to five times. Available free peptide in the blood and the systemic toxicity of colistin and A3-APO were studied in healthy mice.. While toxicity of colistin was observed at 25 mg/kg bolus drug administration, the lowest toxic dose of A3-APO was 75 mg/kg. In the A. baumannii blast injury models, 5 mg/kg A3-APO improved survival and reduced bacterial counts in the blood as well as in the wounds and improved wound appearance significantly better than any other antibiotic treatment. The free peptide concentration in the blood did not reach 1 µg/mL.. Peptide A3-APO, with an intramuscular therapeutic index of 15, is more efficacious and less toxic than any existing burn injury infection therapy modality against multidrug-resistant Gram-negative pathogens. A3-APO administered by the im route probably binds to a biopolymer that promotes the peptide's biodistribution.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Burns; Colistin; Disease Models, Animal; Female; Humans; Imipenem; Injections, Intramuscular; Mice; Peptides; Plasma; Treatment Outcome; Wound Infection

Acinetobacter baumannii is an important cause of nosocomial infection with increasing carbapenem resistance. The aim of this study was to compare the efficacy of colistin+rifampicin and imipenem+rifampicin combinations with that of several other antibiotic regimens against carbapenem-resistant A. baumannii pneumonia using an immunosuppressed mouse model. Three different A. baumannii strains with diverse resistance mechanisms (OXA-51-, IMP-1- and VIM-2-type beta-lactamases) were used. Among the monotherapy regimens, only rifampicin significantly reduced the bacterial load in lungs 24 h after infection with the OXA-51-producing strain. Addition of rifampicin to either imipenem or colistin yielded synergistic results after 48 h. Rifampicin was bactericidal against the IMP-1-producing strain, and only the imipenem+rifampicin combination yielded synergistic effects. In contrast, rifampicin alone was not effective against the VIM-2-producing strain, but the imipenem+rifampicin combination was bacteriostatic even at 24 h post-infection. Tigecycline and amikacin were not effective against any of the three strains. Rifampicin-based combinations were effective against A. baumannii bacteraemia and improved survival regardless of the strain type. Contrary to the similar minimum inhibitory concentration results, the antibacterial effects of rifampicin were quite different according to the strains; a tailored antibiotic strategy must be considered in treatment. Addition of rifampicin to either imipenem or colistin would be effective.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Humans; Imipenem; Immunosuppression Therapy; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Pneumonia, Bacterial; Rifampin; Treatment Outcome

Osteomyelitis (OM) from multidrug-resistant (MDR) Acinetobacter has emerged in >30% of combat-related injuries in Iraq and Afghanistan. While most of these strains are sensitive to colistin, the drug is not available in bone void fillers for local high-dose delivery. To address this, we developed a mouse model with MDR strains isolated from wounded military personnel. In contrast to S. aureus OM, which is osteolytic and characterized by biofilm in necrotic bone, A. baumannii OM results in blastic lesions that do not contain apparent biofilm. We also found that mice mount a specific IgG response against three proteins (40, 47, and 56 kDa) regardless of the strain used, suggesting that these may be immuno-dominant antigens. PCR for the A. baumannii-specific parC gene confirmed a 100% infection rate with 75% of the MDR strains, and in vitro testing confirmed that all strains were sensitive to colistin. We also developed a real-time quantitative PCR (RTQ-PCR) assay that could detect as few as 10 copies of parC in a sample. To demonstrate the efficacy of colistin prophylaxis in this model, mice were treated with either parenteral colistin (0.2 mg colistinmethate i.m. for 7 days), local colistin (PMMA bead impregnated with 1.0 mg colistin sulfate), or an unloaded PMMA bead control. While the parenteral colistin failed to demonstrate any significant effects versus the placebo, the colistin PMMA bead significantly reduced the infection rate such that only 29.2% of the mice had detectable levels of parC at 19 days (p < 0.05 vs. i.m. colistin and placebo).

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Female; Fractures, Bone; Mice; Mice, Inbred C57BL; Osteomyelitis

: To study the efficacy of intratracheal colistin sulfate therapy in a murine model of acute pneumonia caused by a clinical CRAB strain, Ab396. Colistin therapy has currently achieved a favorable outcome in patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections, but parenteral colistin may have limited therapeutic efficacy for CRAB pneumonia.. : A controlled, in vivo experimental study.. : Research laboratory of a medical center.. : Female BALB/c mice.. : The minimal inhibitory concentrations of antibiotics were measured. Acute pneumonia was established by intratracheal inoculation with an inoculum size of 2.5 x 10 colony-forming units Ab396 plus 10% porcine mucin into the lungs of mice, verified by histopathological examinations, and then treated with or without antibiotics. Mice received intratracheal saline treatment as a control group, intraperitoneal administration (IP) imipenem/cilastatin plus sulbactam (IP IS group, 80/80 mg/kg and 40 mg/kg every 8 hrs, n = 30), IP colistin sulfate (IP CS group, 150,000 U/kg every 8 hrs, n = 30), and intratracheal colistin sulfate (intratracheal CS group, 75,000 U/kg every 8 hrs, n = 30) at 2 hrs after intratracheal inoculation of Ab396.. : The minimal inhibitory concentrations of colistin sulfate, imipenem/cilastatin, or sulbactam for Ab396 were 2 microg/mL, 128 microg/mL, or 32 microg/mL, respectively. Compared with the mice in the control, IP IS, and IP CS groups, those in intratracheal CS group had a significantly favorable outcome at 72 hrs after infection (survival rate = 0%, 10%, 0% and 100%, respectively; all p < .001, log-rank test). Furthermore, intratracheal therapy decreased significantly the bacterial loads in the lungs and normalized the wet lung/body weight ratios in mice with acute pneumonia.. : The intratracheal colistin sulfate therapy led to more favorable outcomes than therapies by IP colistin sulfate or imipenem/cilastatin plus sulbactam in mice with early CRAB pneumonia.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Female; Mice; Mice, Inbred BALB C; Pneumonia, Bacterial; Time Factors; Trachea

The pathogenesis of inflammatory bowel disease involves dysfunctional mucosal immune responses to commensal bacteria in genetically predisposed hosts. Interactions between host cells and bacteria are complicated, making it a challenge to assess their relative contribution to intestinal pathology. We developed a zebrafish model of enterocolitis to study these interactions.. Enterocolitis was induced by intrarectal administration of the hapten oxazolone in adult wild-type and myeloperoxidase-reporter transgenic zebrafish in the presence or absence of antibiotics. Intestinal inflammation was evaluated by histological and flow cytometry analyses and cytokine profiling with quantitative real-time polymerase chain reaction. Changes in the composition of the intestinal microbiota following antibiotic administration were assessed by 16SrRNA sequencing and bacterial load was quantified by culture on nonselective media (colony-forming units).. In zebrafish, the infiltrate and severity of oxazolone-induced enterocolitis are influenced by the composition of the microbiota. Inflammation is characterized by granulocyte influx; epithelial damage; goblet cell depletion; and increased expression of interleukin-1beta, tumor necrosis factor-alpha, and interleukin-10. Zebrafish given vancomycin had bacterial populations dominated by Fusobacteria and reduced enterocolitis scores, intestinal damage, and percentages of infiltrating neutrophils and eosinophils. In contrast, zebrafish given colistin sulphate had a predominance of proteobacteria and reduced eosinophil and lymphocyte infiltration, but enterocolitis scores were not reduced.. In zebrafish with oxazolone-induced enterocolitis, components of the intestinal microbiota affect the severity and composition of the intestinal infiltrate.

Topics: Adjuvants, Immunologic; Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Enterocolitis; Intestines; Oxazolone; Vancomycin; Zebrafish

The effect of colistin on bacterial eradication and survival was tested in experimental infection by multidrug-resistant Acinetobacter baumannii. The thigh infection model was applied in 86 neutropenic Wistar rats. Six rats were used for the induction of neutropenia and for the selection of the dose regimen of colistin; the remainder was equally divided into four groups: A, controls; B, rifampicin; C, colistin; and D, both agents. Therapy was administered 5 h after bacterial challenge; 5mg/kg of rifampicin was administered intravenously and 3mg/kg of colistin intramuscularly. Survival was recorded in 10 animals of each group. The remaining 10 rats per group were killed 4h after therapy; blood and tissue samples were sampled. Median survival of animals of groups A, B, C and D was 2.00, 2.50, 4.00 and 4.00 days, respectively (P=0.0048 between A and C and P=0.0012 between A and D. Mortality rates after 6 days of follow-up were 100, 100, 100 and 70%, respectively (P=0.018 between groups). Statistically significant decreases of bacteria were found in blood, liver, lung and spleen of group B compared with A; in lung of group C compared with A; and in blood and liver of group D compared with A. Colistin was effective in prolonging survival in an experimental thigh infection by multidrug-resistant A. baumannii in neutropenic rats. Its activity was enhanced after co-administration with rifampicin. These results mandate the application of colistin in the event of infections by multidrug-resistant pathogens and the need for its co-administration with rifampicin.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Blood; Colistin; Cyclophosphamide; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Injections, Intramuscular; Injections, Intravenous; Liver; Lung; Male; Rats; Rats, Wistar; Rifampin; Spleen; Survival Analysis; Survival Rate; Treatment Outcome

The in-vivo activity of colistin was evaluated in an experimental rabbit model of Acinetobacter baumannii endocarditis with a strain susceptible to colistin and intermediate to imipenem. Compared to a control group, colistin was effective (p < 0.05) in bacterial clearance from blood and in the sterilisation of blood cultures, but was not effective in clearing A. baumannii from vegetations. Thus, although colistin may be effective in treating bacteraemia caused by susceptible strains of A. baumannii, it may not be a suitable treatment for endocarditis, perhaps because of poor penetration into vegetations and a low C(max)/MIC ratio in tissue.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacteremia; Colistin; Colony Count, Microbial; Disease Models, Animal; Endocarditis, Bacterial; Heart Valves; Humans; Microbial Sensitivity Tests; Rabbits; Treatment Outcome

Successful therapy of carbapenem-resistant Acinetobacter baumannii strains has been reported with colistin, but recently we argued against its use as monotherapy because of the poor results obtained in a mouse pneumonia model. Our aim was to identify antibiotic combinations that were valid therapeutic alternatives in the same model.. We used two carbapenem-resistant A. baumannii strains (D and E; MICs of imipenem, 8 and 512 mg/L, respectively). MICs of tobramycin, rifampicin and colistin for both strains were 8, 8 and 0.5 mg/L, respectively.. In infections caused by strain D, lung bacterial counts (log(10) cfu/g, mean +/- s.d.) were: controls (10.86+/-0.25), imipenem (5.99+/-0.59, P < 0.05 versus controls), and colistin (10.43 +/- 1.09); imipenem + tobramycin was the most active combination (5.46+/-0.62, P < 0.05 versus controls). In infections caused by strain E, results were: controls (10.82+/-0.33), rifampicin (5.62+/-0.26, P < 0.05 versus controls), colistin (8.38+/-1.22, P < 0.05 versus controls), and imipenem (11.01+/-0.2); rifampicin + imipenem (3.79+/-0.99) and rifampicin + tobramycin (3.96+/-0.30) were the most active combinations (P < 0.05); results with rifampicin + colistin (5.59+/-1.17) were similar to those with rifampicin alone.. Our data indicate that imipenem can still be the best alternative for carbapenem-resistant A. baumannii infections with moderate levels of imipenem resistance, preferably combined with aminoglycosides. For strains highly resistant to imipenem, a combination of rifampicin with imipenem, tobramycin or colistin may be useful, if resistance to rifampicin is only moderate.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; beta-Lactams; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Humans; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Pneumonia, Bacterial; Rifampin; Tobramycin

An animal study was performed to investigate the efficacy of two glycopeptides and two cationic peptides in the prevention of lethality in a septic shock rat model. Adult Wistar rats were given an intraperitoneal injection of 2x10(10) CFU of Escherichia coli ATCC 25922, with the exception of an uninfected control group (C0). Animals were randomized to receive, immediately after bacterial challenge, intraperitoneally isotonic sodium chloride solution (control group C1), 3 mg/Kg teicoplanin (group 1), 7 mg/Kg vancomycin (group 2), 1 mg/Kg colistin (group 3), 1 mg/Kg buforin II (group 4), or 60 mg/Kg piperacillin (group C(PIP)). In addition, four groups (1a, 2a, 3a, and 4a) received the above mentioned drugs in combination with piperacillin. All compounds and combinations significantly reduced the lethality and the number of E. coli in abdominal fluid compared with C1 group, with the exception of the glycopeptides. Colistin and buforin II combined with piperacillin significantly decreased the lethality compared with piperacillin alone. Finally, colistin, buforin II, and teicoplanin significantly reduced plasma endotoxin concentration in comparison with piperacillin and saline treatment. Antimicrobial peptides and teicoplanin act as antiendotoxin agents and enhance the efficacy of piperacillin.

Topics: Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Injections, Intraperitoneal; Male; Penicillins; Piperacillin; Proteins; Random Allocation; Rats; Rats, Wistar; Shock, Septic; Teicoplanin; Vancomycin

The efficacy of cationic peptides combined with betalactams was investigated in a peritonitis rat model. Intraabdominal sepsis was induced in adult Wistar rats via cecal ligation and single puncture. The study included eight drug-treated groups: each of them received intravenous polymyxin-E (1 mg/kg), buforin II (1 mg/kg), imipenem (20 mg/kg), amoxicillin-clavulanate (50 mg/kg), polymyxin-E (1 mg/kg) plus imipenem (20 mg/kg), or amoxicillin-clavulanate (50 mg/kg), and buforin II (1 mg/kg) plus imipenem (20 mg/kg), or amoxicillin-clavulanate (50 mg/kg). The study included an untreated control group that received intravenous isotonic sodium chloride solution. All compounds significantly reduced the lethality and the number of bacteria in abdominal fluid compared with saline treatment. Among compounds, imipenem showed the highest antimicrobial activity, while buforin II produced the highest reduction in plasma endotoxin and TNF-alpha levels. Overall, buforin II and imipenem association were the most effective therapeutic approach. Data presented here suggest the potential advantages of combining antimicrobial agents and compounds able to neutralize the biological effect of the endotoxin.

Topics: Amoxicillin-Potassium Clavulanate Combination; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Colistin; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Endotoxins; Exudates and Transudates; Imipenem; Male; Peritonitis; Proteins; Rats; Rats, Wistar; Sepsis; Tumor Necrosis Factor-alpha

To assess the effect of selective decontamination of the digestive tract (SDD) on intestinal secretory immunoglobulin A (sIgA) concentrations in a model of intestinal bacterial overgrowth and bacterial translocation induced by an elemental diet in rats.. Laboratory study.. University hospital, Germany.. 45 specific pathogen free female Crl:CD(R) BR rats.. For 7 days, 3 groups of rats were fed orally with standard chow (n = 15), total parenteral nutrition solution (ORAL-TPN, n = 15), or ORAL-TPN plus tobramycin (20 mg/L) and polymyxin E (25 mg/L) (ORAL-TPN + SDD).. Bacterial translocation to mesenteric lymph nodes (MLN), numbers of gram negative enterobacteria and total aerobic bacteria in the caecum, and intestinal concentrations of sIgA.. The incidence of bacterial translocation was significantly increased in the group given ORAL-TPN (8/15, 53%) compared with the group given chow (1/15, 7%, p < 0.01). Supplementation of ORAL-TPN with SDD reduced translocation to 0/15. The ORAL-TPN group had a pronounced overgrowth of aerobic bacteria in the caecum, mainly by gram negative enterobacteria, which was prevented by the SDD. The concentrations of intestinal sIgA were significantly reduced in the ORAL-TPN group. SDD resulted in both the soluble and insoluble sIgA fractions in the gut being within the reference ranges.. SDD prevents gram negative caecal overgrowth and translocation to MLN in rodents fed on ORAL-TPN. The significantly reduced mucosal immunity caused by ORAL-TPN alone is restored by SDD, although one might have expected a further reduction in sIgA concentrations with lower microbial populations than in the ORAL-TPN group. Not only does SDD not seem to affect the mucosa associated immune system adversely, but also depressed mucosal immunity was restored.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Bacterial Translocation; Colistin; Culture Techniques; Digestive System; Disease Models, Animal; Female; Food, Formulated; Fungi; Gram-Negative Bacteria; Intestinal Mucosa; Parenteral Nutrition, Total; Probability; Rats; Rats, Inbred Strains; Tobramycin

To determine the influence of pretreatment with selective decontamination of the digestive tract (SDD) on systemic immunosuppression, and the relationship between bacteria/endotoxin translocation and abnormalities of immune function in thermally injured rats.. Animals were subjected to a 40% full-thickness scald injury, and divided into SDD-treated and control groups. The treatment group received SDD (polymyxin E, tobramycin, and 5-flucytosine) by gavage twice daily for 3 days before the experiment and continued for 5 days after thermal injury. The control group was given the same amount of water. The parameters reflecting cell-mediated immunity, including splenocyte proliferation in response to mitogens, interleukin 2 (IL-2) production, and lymphocyte subpopulation, were measured before injury and 1 and 5 days after burn, respectively.. Thermal injury resulted in marked reduction in splenocyte proliferative response to T-cell mitogens, IL-2 production, and T-helper/suppressor cells (CD4/CD8) ratio. Prophylactic treatment with SDD significantly decreased the incidences of bacterial translocation and endotoxemia, prevented suppressive mitogenic response and inadequate IL-2 production (p < 0.05-0.01) but did not affect the abnormal ratio of CD4 to CD8 T lymphocytes in blood (p > 0.05).. These results suggest that bacteria/endotoxin translocation from the gut appears to be involved in cell-mediated immune dysfunction as a consequence of thermal injury. Pretreatment with SDD might attenuate postburn immunosuppression by preventing translocation events.

Topics: Animals; Anti-Bacterial Agents; Bacterial Translocation; Burns; Cell Division; Cells, Cultured; Colistin; Digestive System; Disease Models, Animal; Endotoxins; Flucytosine; Immunity, Cellular; Immunosuppression Therapy; Interleukin-2; Intestines; Lymphocyte Subsets; Rats; Rats, Sprague-Dawley; Spleen; Tobramycin

The authors test antibiotic strategies aimed at either mitigating bacterial translocation from the gut or delivering antibiotics specifically concentrated by the pancreas for prevention of early secondary infection after acute necrotizing pancreatitis.. Infection currently is the principal cause of death after severe pancreatitis. The authors have shown that the risk of bacterial infection correlates directly with the degree of tissue injury in a rodent model of pancreatitis. Bacteria most likely arrive by translocation from the colon.. Severe acute necrotizing pancreatitis was induced in rats by a combination of low-dose controlled intraductal infusion of glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. At 6 hours, animals were randomly allocated to five treatment groups: controls, selective gut decontamination (oral antibiotics and cefotaxime), oral antibiotics alone, cefotaxime alone, or imipenem. At 96 hours, surviving animals were killed for quantitative bacterial study of the cecum, pancreas, and kidney.. The 96-hour mortality (35%) was unaffected by any treatment regimen. Cecal gram-negative bacteria were significantly reduced only by the oral antibiotics. Pancreatic infection was significantly reduced by full-gut decontamination and by imipenem, but not by oral antibiotics or by cefotaxime alone. Renal infection was reduced by both intravenous antibiotics.. Early pancreatic infection after acute necrotizing pancreatitis can be reduced with a full-gut decontamination regimen or with an antibiotic concentrated by the pancreas (imipenem) but not by unconcentrated antibiotics of similar spectrum (cefotaxime) or by oral antibiotics alone. These findings suggest that 1) both direct bacterial translocation from the gut and hematogenous seeding interplay in pancreatic infection while hematogenous seeding is dominant at extrapancreatic sites and 2) imipenem may be useful in clinical pancreatitis.

Topics: Acute Disease; Administration, Oral; Amphotericin B; Animals; Bacteria; Bacterial Infections; Bacterial Physiological Phenomena; Cecal Diseases; Cefotaxime; Colistin; Disease Models, Animal; Drug Therapy, Combination; Imipenem; Injections, Intravenous; Kidney Diseases; Male; Necrosis; Pancreas; Pancreatic Diseases; Pancreatitis; Rats; Rats, Sprague-Dawley; Survival Rate; Tobramycin

It is important to be aware of the potential ototoxicity of any drug, vehicle, or antiseptic that is used in the middle ear. Frequently used ear drops (Cortisporin otic suspension, Coly-Mycin S Otic, and VoSoL otic solution) were studied for their ototoxicity. Compound action potentials were measured before and at 1, 2, and 24 hours following drug application on the round window membranes of chinchillas. Each drug was applied for 10 minutes and then was removed by rinsing. The sound pressure in decibels sound pressure level that produced a compound action potential amplitude of 10 microV was defined as the threshold. The change in threshold was interpreted as hearing loss. On the basis of the short-term results at 24 hours following drug application, the ototoxicity of Coly-Mycin was calculated to be twice that of Cortisporin, and the ototoxicity of VoSoL four times that of Cortisporin.

Topics: Acetates; Acetic Acid; Action Potentials; Administration, Topical; Animals; Benzethonium; Chinchilla; Colistin; Disease Models, Animal; Drug Combinations; Hearing Loss, Sensorineural; Hydrocortisone; Neomycin; Otitis Media; Polymyxin B; Propylene Glycols

The cyclic decapeptide, polymyxin B (PMXB), was found to inhibit hypoglycemia in mice receiving exogenous insulin (Amir, S., and Shechter, Y. (1985) Eur. J. Pharmacol. 110, 283-285). In this study, we have extended this observation to rats. Insulin-dependent hypoglycemia in rats is efficiently blocked at a 12:1 molar ratio of PMXB to insulin. This effect is highly specific, as it could not be mimicked by a variety of antibiotics or positively charged substances. Chemical modifications of PMXB have revealed that the ring structure, rather than the tail structure, is important for anti-insulin-like activity. Colistin A, which differs from PMXB by one conservative amino acid substitution in the ring structure, is devoid of this activity. Polymyxin B does not interact with insulin, nor does it alter the rate of insulin absorption and/or degradation, or the ability of insulin to bind to target tissues. This peptide inhibits hypoglycemia by blocking insulin-dependent activation of the hexose transport mechanism, as deduced by in vitro studies. The effect of insulin in stimulating hexose uptake (and subsequent glucose metabolism) in both isolated muscle tissue and adipocytes is blocked with little or no effect on the basal activities of these processes. Colistin A has no significant inhibiting effect. Other insulin-dependent activities, such as inhibition of lipolysis in adipocytes or synthesis of DNA in muscle cells, are not inhibited. It is concluded that PMXB inhibits, in a highly specific manner, the action of insulin in stimulating hexose transport and subsequent glucose metabolism, both in vitro and in the whole animal model.

Topics: Animals; Blood Glucose; Colistin; Deoxyglucose; Disease Models, Animal; Hypoglycemia; Insulin; Kinetics; Lipolysis; Mice; Muscles; Polymyxin B; Polymyxins; Rats

Topics: Administration, Topical; Animals; Burns; Colistin; Cross Infection; Disease Models, Animal; Drug Resistance, Microbial; Ecthyma; Enterobacteriaceae; gamma-Globulins; Gentamicins; Humans; Pneumonia; Providencia; Pseudomonas; Pseudomonas Infections; Rats; Sepsis; Simplexvirus; Sulfonamides; Surgical Wound Infection; Thrombophlebitis; Time Factors

Topics: Animals; Carbenicillin; Colistin; Disease Models, Animal; Drug Therapy, Combination; Gentamicins; Male; Mice; Microbial Sensitivity Tests; Polymyxins; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Animals; Colistin; Corneal Ulcer; Disease Models, Animal; Drug Combinations; Gentamicins; Ophthalmic Solutions; Pseudomonas Infections; Rabbits; Sulfates; Wound Healing

Topics: Animals; Anti-Bacterial Agents; Colistin; Corynebacterium; Disease Models, Animal; Escherichia coli; Female; Mastitis; Mice; Penicillins; Polymyxins; Pregnancy; Pseudomonas aeruginosa; Staphylococcus; Streptococcus

A chronic infection with Shigella flexneri 2a has been established in mice for the evaluation of compounds for therapeutic potential. Evidence of infection is indicated by prolonged symptomless excretion in the feces and by positive isolation of organisms from different segments of the intestinal tract and from mesenteric lymph nodes. Serum antibody titer reaches a maximum after 9 days of infection and remains at a low level until 32 days postinfection. In this model, five drugs used in human shigellosis were evaluated for efficacy. Ampicillin was found to be the most active followed by oxytetracycline and kanamycin. Neomycin and colistin were the least active in this system.

Topics: Administration, Oral; Ampicillin; Animals; Antibodies; Colistin; Disease Models, Animal; Dysentery, Bacillary; Feces; Hemagglutination Tests; Intestines; Kanamycin; Lymph Nodes; Male; Mesentery; Mice; Neomycin; Oxytetracycline; Shigella

Topics: Animals; Anti-Infective Agents; Cephalosporins; Colistin; Cystitis; Disease Models, Animal; Gentamicins; Nalidixic Acid; Pyelonephritis; Rats; Sulfadiazine; Urinary Tract Infections