meropenem 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

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

New Delhi metallo-β-lactamase-1 (NDM-1) poses a threat to public health due to its capability to hydrolyze nearly all β-lactam antibiotics, leaving limited treatment options for NDM-1 positive pathogens. Regrettably, there are presently no effective NDM-1 inhibitors in clinical use. This compels us to seek new compounds to combat multi-drug resistant bacterial infections (MDR). In our study, Zndm19 was identified as a new NDM-1 inhibitor through virtual screening and an NDM-1 enzyme activity inhibition assay. Subsequently, we employed the checkerboard method, time-killing assay, and combined disk test to investigate the synergistic bactericidal efficacy of Zndm19 in combination with meropenem (MEM). Meanwhile, molecular docking and site-directed mutagenesis were conducted to uncover the crucial amino acid residues engaged in Zndm19 binding. Finally, we established a mice peritonitis infection model to assess the synergistic effect of Zndm19 and MEM in vivo. Our findings demonstrated that 16 µg/mL of Zndm19 inhibited NDM-1 activity without affecting NDM-1 expression, restoring the bactericidal activity of MEM against NDM-1-positive Escherichia coli in vitro. Furthermore, MET-67, ASP-124, HIS-189, and HIS-250 amino acid residues constituted the active site of Zndm19 in NDM-1. Importantly, this combination therapy exhibited synergistic anti-infection activity in the mice peritonitis infection model, leading to an approximate 60% increase in survival rates and reduction of tissue bacterial load, effectively combating bacterial infection in vivo. In summary, our research validates that the synthetic novel NDM-1 inhibitor Zndm19 holds promise as a drug to treat drug-resistant bacterial infections, especially those harboring NDM-1.

Topics: Amino Acids; Animals; Disease Models, Animal; Isatin; Meropenem; Mice; Molecular Docking Simulation

Heteroresistance is a poorly understood mechanism of resistance which refers to a phenomenon where there are different subpopulations of seemingly isogenic bacteria which exhibit a range of susceptibilities to a particular antibiotic. In the current study, we identified a multidrug-resistant, carbapenemase-positive K. pneumoniae strain SWMUF35 which was classified as susceptible to amikacin and resistant to meropenem by clinical diagnostics yet harbored different subpopulations of phenotypically resistant cells, and has the ability to form biofilm. Population analysis profile (PAP) indicated that SWMUF35 showed heteroresistance towards amikacin and meropenem which was considered as co-heteroresistant K. pneumoniae strain. In vitro experiments such as dual PAP, dual Times-killing assays and checkerboard assay showed that antibiotic combination therapy (amikacin combined with meropenem) can effectively combat SWMUF35. Importantly, using an in vivo mouse model of peritonitis, we found that amikacin or meropenem monotherapy was unable to rescue mice infected with SWMUF35. Antibiotic combination therapy could be a rational strategy to use clinically approved antibiotics when monotherapy would fail. Furthermore, our data warn that antibiotic susceptibility testing results may be unreliable due to undetected heteroresistance which can lead to treatment failure and the detection of this phenotype is a prerequisite for a proper choice of antibiotic to support a successful treatment outcome.

Topics: Amikacin; Animals; Anti-Bacterial Agents; Carbapenems; Disease Models, Animal; Klebsiella pneumoniae; Meropenem; Mice; Microbial Sensitivity Tests; Treatment Failure

To compare the efficacy of topical meropenem and cefepime treatments with respect to moxifloxacin as new treatment options in an experimental Pseudomonas keratitis model.. Twenty-four rabbits in which keratitis are induced using Pseudomonas aeruginosa were divided into four groups according to treatment options. A solution of 50 mg/mL meropenem was prepared and topically applied to the first group, 50 mg/mL cefepime solution to the second group, topical 0.5% moxifloxacin drop to the third group, and topical isotonic (0.9% saline) solution to the fourth (control) group. The eyes were examined before and after treatment to score the clinical severity. After the subjects were sacrificed, their corneas were excised. To determine the efficacy of treatments, clinical score, bacterial load, and histopathological and immunohistochemical findings were evaluated.. When the three treatment groups were compared, there was a significant difference in the colony-forming unit (CFU) value, polymorph-nuclear leukocyte (PMNL) infiltration, and matrix metalloproteinase (MMP)-9 immunoreactivity (P=0.022, P=0.038, and P=0.037, respectively). The CFU values, PMNL infiltration scores and MMP-9 immunoreactivity were significantly lower in the meropenem and moxifloxacin groups compared with the cefepime group (P<0.05 for all). There was no significant difference between the meropenem and moxifloxacin groups in respect of the CFU values, PMNL infiltration, and MMP-9 immunoreactivity (P=0.842, P=0.784, and P=0.699, respectively).. The results of our study indicate that topical meropenem is at least as effective as topical moxifloxacin in the treatment of Pseudomonas keratitis. The meropenem and moxifloxacin are safer and suitable in the limited corneal invasion than cefepime. Thus, topical meropenem may be an alternative drug in the treatment of this condition. Clinical studies are needed to be conducted to assess this possibility more accurately.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Cefepime; Colony Count, Microbial; Disease Models, Animal; Eye Infections, Bacterial; Fluoroquinolones; Keratitis; Meropenem; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits

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

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

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

As Bacillus anthracis spores pose a proven bio-terror risk, the treatment focus has shifted from exposed populations to anthrax patients and the need for effective antibiotic treatment protocols increases. The CDC recommends carbapenems and Linezolid (oxazolidinone), for the treatment of anthrax, particularly for the late, meningeal stages of the disease. Previously we demonstrated that treatment with Meropenem or Linezolid, either as a single treatment or in combination with Ciprofloxacin, fails to protect rabbits from anthrax-meningitis. In addition, we showed that the failure of Meropenem was due to slow BBB penetration rather than low antibacterial activity. Herein, we tested the effect of increasing the dose of the antibiotic on treatment efficacy. We found that for full protection (88% cure rate) the dose should be increased four-fold from 40 mg/kg to 150 mg/kg. In addition, B. anthracis is a genetically stable bacterium and naturally occurring multidrug resistant B. anthracis strains have not been reported. In this manuscript, we report the efficacy of classical β-lactams as a single treatment or in combination with β-lactamase inhibitors in treating anthrax meningitis. We demonstrate that Ampicillin based treatment of anthrax meningitis is largely efficient (66%). The high efficacy (88-100%) of Augmentin (Amoxicillin and Clavulonic acid) and Unasyn (Ampicillin and Sulbactam) makes them a favorable choice due to reports of β-lactam resistant B. anthracis strains. Tazocin (Piperacillin and Tazobactam) proved inefficient compared to the highly efficient Augmentin and Unasyn.

Topics: Amoxicillin-Potassium Clavulanate Combination; Ampicillin; Animals; Anthrax; Anti-Bacterial Agents; Bacillus anthracis; Bacteria; beta-Lactamase Inhibitors; beta-Lactams; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Rabbits; Sulbactam

Increasing multidrug resistance has led to renewed interest in phage-based therapy. A combination of the bacteriophages and antibiotics presents a promising approach enhancing the phage therapy effectiveness. First, phage candidates for therapy should be deeply characterized. Here we characterize the bacteriophage vB_AbaP_AGC01 that poses antibacterial activity against clinical Acinetobacter baumannii strains. Moreover, besides genomic and phenotypic analysis our study aims to analyze phage-antibiotic combination effectiveness with the use of ex vivo and in vivo models. The phage AGC01 efficiently adsorbs to A. baumannii cells and possesses a bacteriolytic lifecycle resulting in high production of progeny phages (317 ± 20 PFU × cell

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacteriolysis; Bacteriophages; Ciprofloxacin; Combined Modality Therapy; Disease Models, Animal; Genome, Viral; Hot Temperature; Humans; Lepidoptera; Meropenem; Phage Therapy; Phenotype; Species Specificity; Whole Genome Sequencing

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

The widespread prevalence of metallo-β-lactamase (MβL)-mediated pathogens has seriously caused a loss of efficacy of carbapenem antibacterials, the last resort for the treatment of severe infectious diseases. The development of effective MβL inhibitors is an ideal alternative to restore the efficacy of carbapenems. Here we report that Ru complexes can irreversibly inhibit clinically relevant B1 subclass MβLs (NDM-1, IMP-1 and VIM-2) and potentiate meropenem efficacy against MβL-expressing bacteria in vitro and in a mice infection model. The Cys208 residue at the Zn(ii)-binding site and Met67 residue at the β-hairpin loop of an enzyme active pocket are critical for Ru complexes to inhibit NDM-1, which was verified by enzyme kinetics, thermodynamics, NDM-1-C208A mutation and MALDI-TOF-MS analysis. This study will undoubtedly aid efforts to develop metal-based MβL inhibitors in combination with carbapenems to deal with the clinical crisis of carbapenem-resistant E. coli harboring MβLs.

Topics: Amino Acid Sequence; Animals; Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases; Binding Sites; Carbapenems; Coordination Complexes; Disease Models, Animal; Drug Development; Drug Resistance, Microbial; Escherichia coli; Infections; Meropenem; Mice; Microbial Sensitivity Tests; Prospective Studies; Protein Binding; Protein Conformation; Ruthenium; Structure-Activity Relationship; Zinc

Escherichia coli is the most common cause of Gram-negative prosthetic joint infections (PJIs) and ciprofloxacin is the first-line antibiofilm antibiotic. Due to the emergence of fluoroquinolone resistance, management of E. coli PJIs has become challenging and is associated with high treatment failure rates. We evaluated the efficacy of a newly isolated bacteriophage ɸWL-3 as a therapeutic agent in combination with ciprofloxacin, fosfomycin, gentamicin, meropenem or ceftriaxone against biofilm of a ciprofloxacin/ceftriaxone-resistant E. coli strain and the ATCC 25922 reference strain. ɸWL-3 was first characterised in terms of virion morphology, absorption rate, burst size and killing kinetics against both E. coli strains. The tested antibiotics presented high inhibitory concentrations (ranging from 16 to >1024 μg/mL) when tested alone against biofilms. Co-administration of ɸWL-3 with antibiotics improved the antibiotic efficacy against biofilm, especially after staggered exposure, reducing the minimum biofilm bactericidal concentration (MBBC) up to 512 times. The in vivo antimicrobial activity of ɸWL-3/fosfomycin combination against both E. coli strains was assessed in a Galleria mellonella invertebrate infection model. Treatment of infected larvae after lethal doses of E. coli resulted in enhanced survival rates when combinatorial therapy with ɸWL-3/fosfomycin was applied on E. coli ATCC 25922-infected larvae compared with monotherapy, but not for EC1-infected larvae, which we speculated could be due to higher release of endotoxins in a shorter period in EC1-infected larvae exposed to ɸWL-3. Our study provides new insights into the use of bacteriophages and antibiotics in the treatment of biofilm-associated infections caused by antibiotic-resistant bacteria.

Topics: Animals; Anti-Bacterial Agents; Bacteriophages; Biofilms; Ceftriaxone; Ciprofloxacin; Combined Modality Therapy; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Fluoroquinolones; Fosfomycin; Gentamicins; Meropenem; Microbial Sensitivity Tests; Moths; Phage Therapy; Prosthesis-Related Infections

The antibiotics cefepime and meropenem are recommended for the treatment of neutropenia. However, cefepime has been found to be associated with both peripheral and central adverse events such as renal impairment and seizures, respectively. Previous studies showed that cefepime exacerbated convulsions in corneal kindled mouse models of epilepsy. However, its involvement in chemotherapy-induced side effects is unknown.. In this study, we examined the convulsive potential of cefepime (500 mg/kg) and meropenem (500 mg/kg) in pentylenetetrazol (PTZ)-kindled mice using an electroconvulsive shock test with low-intensity stimulus currents. Then, the effects of 5-fluorouracil (5-FU, 200 and 400 mg/kg, i.p.) treatment, a model of chemotherapy-induced side effects, were investigated in the PTZ-kindled mouse model.. In fully PTZ-kindled mice, intravenous administration of cefepime (500 mg/kg) or meropenem (500 mg/kg) did not elicit any convulsions in the electroconvulsive shock test with low-intensity stimulus currents. In the PTZ-kindled mice treated with 5-FU (200 mg/kg), intravenous administration of cefepime (500 mg/kg) exacerbated the convulsions that occurred within 1 min in the electroconvulsive shock test, and the mice subsequently developed convulsive status epilepticus. However, intravenous administration of meropenem (500 mg/kg) did not produce such effects.. These findings suggest that the combination of 5-FU and cefepime exacerbates early-onset convulsive seizures and elicits delayed-onset convulsive status epilepticus. Additionally, 5-FU treatment increases the risk of induction of neurotoxic side effects by cefepime.

Topics: Animals; Anti-Bacterial Agents; Cefepime; Convulsants; Disease Models, Animal; Fluorouracil; Kindling, Neurologic; Male; Meropenem; Mice; Mice, Inbred ICR; Pentylenetetrazole; Seizures

The emergence, prevalence, and rapid spread of New Delhi metallo-β-lactamases (NDMs) in Gram-negative pathogens threaten our traditional regimen to treat bacterial infectious diseases. Discovery of novel NDMs inhibitors offers an alternative approach to restore the carbapenems activity. However, thus far, no clinical inhibitor of NDMs has been approved. In this study, the potential of peptides and analogues as carbapenems adjuvant in NDMs-positive pathogens was investigated. Herein, we successfully found that peptidomimetic 4 (PEP4) is a potential inhibitor of NDM enzymes. PEP4 displayed significant synergistic activity with Meropenem against NDM-expression Gram-negative bacteria

Topics: Animals; beta-Lactamase Inhibitors; beta-Lactamases; Disease Models, Animal; Drug Repositioning; Drug Synergism; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Meropenem; Mice; Molecular Structure; Peptidomimetics

Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem.. Prospective randomized animal study.. Animal Research, University of Barcelona, Spain.. Thirty female pigs.. The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance.. We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004).. Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.

Topics: Administration, Inhalation; Administration, Intravenous; Amikacin; Animals; Anti-Bacterial Agents; Bacterial Load; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Lung; Meropenem; Nebulizers and Vaporizers; Pneumonia; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Random Allocation; Swine; Trachea

Drug resistance traits are rapidly disseminated across bacteria by horizontal gene transfer, especially through plasmids. Plasmid curing agents that are active both in vitro and in vivo will resensitize Multi Drug Resistant (MDR) bacteria to antimicrobial agents. Pectin capped platinum nanoparticles (PtNPs) at sub MIC (20 µM) concentration was effective, in causing loss of Extended Spectrum Beta Lactamase (ESBL) harboring plasmid as evidenced by, absence of plasmid in agarose gel and by a concomitant (16-64 fold) drop in MIC for cell wall inhibitors ceftriaxone and meropenem, in carbapenem resistant Escherichia coli (CREC). Interestingly, the plasmid cured strain exhibited small colony morphology and displayed slower growth both in vitro and in vivo. Complementation of cured strain with plasmid from the wild type strain restored resistance towards meropenem and ceftriaxone. Relative to wild type, plasmid cured strain displayed 50% reduction in biofilm formation. Plasmid curing also occurred in vivo in infected zebrafish with curing efficiency of 17% for nanoparticle + meropenem treatment. PtNPs + meropenem reduced bioburden of CREC in infected zebrafish by 2.4 log CFU. Mechanistic studies revealed that nanoparticle interacted with cell surface and perturbed inner membrane integrity. PtNPs did not induce ROS, yet it caused plasmid DNA cleavage, as evidenced by gyrase inhibition assay. Our study for the first time reveals that PtNPs as plasmid curing agent can resensitize MDR bacteria to selective antimicrobial agents in vivo.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Ceftriaxone; Cell Membrane; Disease Models, Animal; DNA Cleavage; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Gene Transfer, Horizontal; Humans; Meropenem; Metal Nanoparticles; Microbial Sensitivity Tests; Plasmids; Platinum; Zebrafish

The recently approved combination of meropenem and vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Disease Models, Animal; Drug Combinations; Escherichia coli; Humans; Klebsiella pneumoniae; Meropenem; Mice; Microbial Sensitivity Tests; Pyelonephritis; Urinary Tract Infections

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

Efficacies of ceftazidime-avibactam (4:1 w/w) and ceftazidime were tested against ceftazidime-susceptible (bla

Topics: Abdominal Abscess; Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Ceftazidime; Disease Models, Animal; Drug Combinations; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Rats; Thienamycins

Treatment of anthrax is challenging, especially during the advanced stages of the disease. Recently, the Centers for Disease Control and Prevention (CDC) updated its recommendations for postexposure prophylaxis and treatment of exposed populations (before and after symptom onset). These recommendations distinguished, for the first time, between systemic disease with and without meningitis, a common and serious complication of anthrax. The CDC considers all systemic cases meningeal unless positively proven otherwise. The treatment of patients suffering from systemic anthrax with suspected or confirmed meningitis includes the combination of three antibiotics, i.e., a fluoroquinolone (levofloxacin or ciprofloxacin), a β-lactam (meropenem or imipenem), and a protein synthesis inhibitor (linezolid or clindamycin). In addition, treatment with an antitoxin (anti-protective antigen antibodies) and dexamethasone should be applied. Since the efficacy of most of these treatments has not been demonstrated, especially in animal meningitis models, we developed an anthrax meningitis model in rabbits and tested several of these recommendations. We demonstrated that, in this model, ciprofloxacin, linezolid, and meropenem were ineffective as single treatments, while clindamycin was highly effective. Furthermore, combined treatments of ciprofloxacin and linezolid or ciprofloxacin and dexamethasone failed in treating rabbits with meningitis. We demonstrated that dexamethasone actually hindered blood-brain barrier penetration by antibiotics, reducing the effectiveness of antibiotic treatment of anthrax meningitis in this rabbit model.

Topics: Animals; Anthrax; Anti-Bacterial Agents; Antitoxins; Bacillus anthracis; Central Nervous System; Ciprofloxacin; Clindamycin; Dexamethasone; Disease Models, Animal; Drug Combinations; Imipenem; Levofloxacin; Linezolid; Meningitis, Bacterial; Meropenem; Rabbits; Treatment Failure

The use of antibiotics is mandatory in patients during extracorporeal membrane oxygenation (ECMO) support. Clinical studies have shown high variability in the antibiotic concentrations, as well as sequestration of them by the ECMO circuit, suggesting that the doses and/or interval administration used during ECMO may not be adequate. Thus, a fast response sensor to estimate antibiotic concentrations in this setting would contribute to improve dose adjustments. The biosensor PenP has been shown to have a dynamic range, sensitivity and specificity useful for pharmacokinetic (PK) tests in healthy subjects. However, the use of this biosensor in the context of a complex critical condition, such as ECMO during acute respiratory distress syndrome (ARDS), has not been tested.. To describe, by using PenP Biosensor, the pharmacokinetic of meropenem in a 24-h animal ARDS/ECMO model.. The PK of meropenem was evaluated in a swine model before and during ECMO.. The PK parameters such as maximum concentration (Cmax), elimination rate constant (Ke), and cleareance (Cl), were not significantly altered during ECMO support.. (a) ECMO does not affect the PK of meropenem, at least during the first 24 h; and (b) PenP has the potential to become an effective tool for making medical decisions associated with the dose model of antibiotics in a critical patient context.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; beta-Lactamases; Biosensing Techniques; Disease Models, Animal; Extracorporeal Membrane Oxygenation; Half-Life; Meropenem; Respiratory Distress Syndrome; ROC Curve; Swine; Thienamycins

Topics: Animals; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Disease Models, Animal; Drug Combinations; Drug Synergism; Meropenem; Microbial Sensitivity Tests; Moths; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Piperacillin

The bacterium Burkholderia ubonensis is commonly co-isolated from environmental specimens harbouring the melioidosis pathogen, Burkholderia pseudomallei. B. ubonensis has been reported in northern Australia and Thailand but not North America, suggesting similar geographic distribution to B. pseudomallei. Unlike most other Burkholderia cepacia complex (Bcc) species, B. ubonensis is considered non-pathogenic, although its virulence potential has not been tested. Antibiotic resistance in B. ubonensis, particularly towards drugs used to treat the most severe B. pseudomallei infections, has also been poorly characterised. This study examined the population biology of B. ubonensis, and includes the first reported isolates from the Caribbean. Phylogenomic analysis of 264 B. ubonensis genomes identified distinct clades that corresponded with geographic origin, similar to B. pseudomallei. A small proportion (4%) of strains lacked the 920kb chromosome III replicon, with discordance of presence/absence amongst genetically highly related strains, demonstrating that the third chromosome of B. ubonensis, like other Bcc species, probably encodes for a nonessential pC3 megaplasmid. Multilocus sequence typing using the B. pseudomallei scheme revealed that one-third of strains lack the "housekeeping" narK locus. In comparison, all strains could be genotyped using the Bcc scheme. Several strains possessed high-level meropenem resistance (≥32 μg/mL), a concern due to potential transmission of this phenotype to B. pseudomallei. In silico analysis uncovered a high degree of heterogeneity among the lipopolysaccharide O-antigen cluster loci, with at least 35 different variants identified. Finally, we show that Asian B. ubonensis isolate RF23-BP41 is avirulent in the BALB/c mouse model via a subcutaneous route of infection. Our results provide several new insights into the biology of this understudied species.

Topics: Animals; Anti-Bacterial Agents; Australia; Burkholderia; Burkholderia Infections; Disease Models, Animal; Environmental Microbiology; Genetic Variation; Genotype; Meropenem; Mice, Inbred BALB C; Multilocus Sequence Typing; O Antigens; Papua New Guinea; Phylogeography; Puerto Rico; Thailand; Thienamycins; Virulence

Novel drug discovery against non-tuberculous mycobacteria is beset with a large number of challenges including the existence of myriad innate drug resistance mechanisms as well as a lack of suitable animal models, which hinders effective translation. In order to identify molecules acting via novel mechanisms of action, we screened the Library of Pharmacologically Active Compounds against non-tuberculous mycobacteria to identify such compounds.. Whole-cell growth inhibition assays were used to screen and identify novel inhibitors. The hit compounds were tested for cytotoxicity against Vero cells to determine the selectivity index, and time-kill kinetics were determined against Mycobacterium fortuitum. The compound's ability to synergize with amikacin, ceftriaxone, ceftazidime and meropenem was determined using fractional inhibitory concentration indexes followed by its ability to decimate mycobacterial infections ex vivo. Finally, the in vivo potential was determined in a neutropenic murine model mimicking mycobacterial infection.. We have identified diphenyleneiodonium chloride (DPIC), an NADPH/NADH oxidase inhibitor, as possessing potent antimicrobial activity against non-tuberculous mycobacteria. DPIC exhibited concentration-dependent bactericidal activity against M. fortuitum and synergized with amikacin, ceftriaxone, ceftazidime and meropenem. When tested in a murine neutropenic M. fortuitum infection model, DPIC caused a significant reduction in bacterial load in kidney and spleen. The reduction in bacterial count is comparable to amikacin at a 100-fold lower concentration.. DPIC exhibits all properties to be repositioned as a novel anti-mycobacterial therapy and possesses a potentially new mechanism of action. Thus, it can be projected as a potential new therapeutic against ever-increasing non-tuberculous mycobacterial infections.

Topics: Amikacin; Animals; Anti-Bacterial Agents; Bacterial Load; Chlorocebus aethiops; Disease Models, Animal; Drug Discovery; Kinetics; Meropenem; Mice; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Neutropenia; Nontuberculous Mycobacteria; Onium Compounds; Small Molecule Libraries; Thienamycins; Vero Cells

Emerging multidrug-resistant bacteria are a challenge for modern medicine, but how these pathogens are so successful is not fully understood. Robust antibacterial vaccines have prevented and reduced resistance suggesting a pivotal role for immunity in deterring antibiotic resistance. Here, we show the increased prevalence of Klebsiella pneumoniae lipopolysaccharide O2 serotype strains in all major drug resistance groups correlating with a paucity of anti-O2 antibodies in human B cell repertoires. We identify human monoclonal antibodies to O-antigens that are highly protective in mouse models of infection, even against heavily encapsulated strains. These antibodies, including a rare anti-O2 specific antibody, synergistically protect against drug-resistant strains in adjunctive therapy with meropenem, a standard-of-care antibiotic, confirming the importance of immune assistance in antibiotic therapy. These findings support an antibody-based immunotherapeutic strategy even for highly resistant K. pneumoniae infections, and underscore the effect humoral immunity has on evolving drug resistance.

Topics: Animals; Anti-Bacterial Agents; Antibodies, Bacterial; Antibodies, Monoclonal; Cell Line; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Humans; Immunity, Humoral; Immunologic Factors; Immunotherapy; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; O Antigens; Serogroup; Survival Rate; Thienamycins

High-dose meropenem (MEPM; 6 g/day) has been approved as a treatment for purulent meningitis; however, little is known regarding its in vivo efficacy in refractory lower respiratory tract infections. The purpose of this study was to evaluate the efficacy of MEPM at 6 g/day in a murine model of severe pneumonia caused by MEPM-resistant Pseudomonas aeruginosa Experimental pneumonia induced by MEPM-resistant P. aeruginosa was treated with normal-dose MEPM (150 mg/kg of body weight, simulating a 3-g/day regimen in humans) or high-dose MEPM (500 mg/kg, simulating a 6-g/day regimen in humans). Mice treated with high-dose MEPM showed significantly restored survival relative to that of untreated mice and tended to show a survival rate higher than that of mice treated with normal-dose MEPM. The viable bacterial counts (of two clinical isolates) in the lungs decreased significantly in mice treated with high-dose MEPM from those for untreated mice (P < 0.001) or mice treated with normal-dose MEPM (P, <0.01 and <0.05). The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was also significantly lower in mice treated with high-dose MEPM than in untreated mice. The free MEPM concentration in the epithelial lining fluid (ELF) exceeded 16 μg/ml for 85 min in mice treated with high-dose MEPM, but not for mice treated with normal-dose MEPM. Our results demonstrate that high-dose MEPM (6 g/day) might provide better protection against pneumonia caused by MEPM-resistant strains of P. aeruginosa than the dose normally administered (less than 3 g/day).

Topics: Animals; Anti-Bacterial Agents; Biological Availability; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Administration Schedule; Female; Humans; Lung; Meropenem; Microbial Sensitivity Tests; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Mucosa; Survival Analysis; Thienamycins; Treatment Outcome

Mycobacterium tuberculosis remains a global health threat largely due to the lengthy duration of curative antibiotic treatment, contributing to medical nonadherence and the emergence of drug resistance. This prolonged therapy is likely due to the presence of M. tuberculosis persisters, which exhibit antibiotic tolerance. Inorganic polyphosphate [poly(P)] is a key regulatory molecule in the M. tuberculosis stringent response mediating antibiotic tolerance. The polyphosphate kinase PPK1 is responsible for poly(P) synthesis in M. tuberculosis, while the exopolyphosphatases PPX1 and PPX2 and the GTP synthase PPK2 are responsible for poly(P) hydrolysis. In the present study, we show by liquid chromatography-tandem mass spectrometry that poly(P)-accumulating M. tuberculosis mutant strains deficient in ppx1 or ppk2 had significantly lower intracellular levels of glycerol-3-phosphate (G3P) and 1-deoxy-xylulose-5-phosphate. Real-time PCR revealed decreased expression of genes in the G3P synthesis pathway in each mutant. The ppx1-deficient mutant also showed a significant accumulation of metabolites in the tricarboxylic acid cycle, as well as altered arginine and NADH metabolism. Each poly(P)-accumulating strain showed defective biofilm formation, while deficiency of ppk2 was associated with increased sensitivity to plumbagin and meropenem and deficiency of ppx1 led to enhanced susceptibility to clofazimine. A DNA vaccine expressing ppx1 and ppk2, together with two other members of the M. tuberculosis stringent response, M. tuberculosis rel and sigE, did not show protective activity against aerosol challenge with M. tuberculosis, but vaccine-induced immunity enhanced the killing activity of isoniazid in a murine model of chronic tuberculosis. In summary, poly(P)-regulating factors of the M. tuberculosis stringent response play an important role in M. tuberculosis metabolism, biofilm formation, and antibiotic sensitivity in vivo.

Topics: Acid Anhydride Hydrolases; Animals; Antitubercular Agents; Biofilms; Citric Acid Cycle; Clofazimine; Disease Models, Animal; Drug Resistance, Bacterial; Gene Expression; Glycerophosphates; Isoenzymes; Isoniazid; Meropenem; Mice; Mycobacterium tuberculosis; Naphthoquinones; Phosphotransferases (Phosphate Group Acceptor); Polyphosphates; Thienamycins; Tuberculosis Vaccines; Tuberculosis, Multidrug-Resistant; Vaccines, DNA; Xylose

Meropenem plus levofloxacin treatment was shown to be a promising combination in our in vitro hollow fiber infection model. We strove to validate this finding in a murine Pseudomonas pneumonia model.. A dose-ranging study with meropenem and levofloxacin alone and in combination against Pseudomonas aeruginosa was performed in a granulocytopenic murine pneumonia model. Meropenem and levofloxacin were administered to partially humanize their pharmacokinetic profiles in mouse serum. Total and resistant bacterial populations were estimated after 24 hours of therapy. Pharmacokinetic profiling of both drugs was performed in plasma and epithelial lining fluid, using a population model.. Meropenem and levofloxacin penetrations into epithelial lining fluid were 39.3% and 64.3%, respectively. Both monotherapies demonstrated good exposure responses. An innovative combination-therapy analytic approach demonstrated that the combination was statistically significantly synergistic (α = 2.475), as was shown in the hollow fiber infection model. Bacterial resistant to levofloxacin and meropenem was seen in the control arm. Levofloxacin monotherapy selected for resistance to itself. No resistant subpopulations were observed in any combination therapy arm.. The combination of meropenem plus levofloxacin was synergistic, producing good bacterial kill and resistance suppression. Given the track record of safety of each agent, this combination may be worthy of clinical trial.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Levofloxacin; Meropenem; Mice; Microbial Sensitivity Tests; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Pseudomonas aeruginosa is an opportunistic bacterial pathogen capable of causing a wide range of disease manifestations, including severe bacterial pneumonia. Recently, clinics have reported a rise in nosocomial infections with multidrug resistant (MDR) species, including MDR strains of P. aeruginosa. In order to quickly evaluate the efficacy of new therapeutics for MDR infections, highly reproducible and validated animal models need to be developed for pre-clinical testing. Here, we describe the characterization of two murine models to study MDR P. aeruginosa respiratory disease. We evaluated and compared these models using a non-invasive intratracheal instillation method and established the 50% lethal dose, course of infection, biometric parameters of disease and degree of pneumonia development for each model. Further, we tested meropenem as a proof-of-concept therapeutic and report efficacy data that suggests that the leukopenic model could serve a robust pre-clinical model to test novel therapeutics.

Topics: Animals; Anti-Bacterial Agents; Biometry; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Female; Lethal Dose 50; Meropenem; Mice, Inbred BALB C; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Treatment Outcome

Multidrug-resistant Acinetobacter baumannii becomes an increasing challenge due to the overuse of antibiotics. Combination therapies are considered as effective options to overcome this matter. The present study was to investigate the synergistic activity of meropenem combined with other antibiotics in vitro and in vivo. Checkerboard assay and time-kill assay were performed to study the combination effects in vitro. For the animal model, a murine sepsis model injected with inoculums intraperitoneally was used. Susceptibility test showed that all the twelve strains in this study were resistant to most of the antibiotics except rifampicin. In combination, meropenem plus rifampicin exhibited synergistic activity against six of twelve strains. In the sepsis model, meropenem monotherapy had no therapeutic effect in this model while it can enhance the activity of rifampicin in both survival rate and bacterial clearance from blood. Moreover, combination therapy significantly reduced plasma IL-6 levels compared with rifampicin monotherapy. Pharmacokinetic analysis of rifampicin was also performed in this study. These data above showed that there was synergistic activity between meropenem and rifampicin against multidrug-resistant Acinetobacter baumannii both in vitro and for experimental model of sepsis. It suggested that combining meropenem with rifampicin may be appropriate in treating multidrug-resistant Acinetobacter baumannii infections.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Male; Meropenem; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Rifampin; Sepsis; Thienamycins; Treatment Outcome

The inoculum effect is a laboratory phenomenon in which the minimal inhibitory concentration (MIC) of an antibiotic is increased when a large number of organisms are exposed. Due to the emergence of extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-Kpn) infections, the inoculum effect of ESBL-Kpn on β-lactams was studied in vitro and in vivo using an experimental model of pneumonia. The in vitro inoculum effect of 45 clinical ESBL-Kpn isolates on β-lactams was evaluated at standard (10(5) CFU/mL) and high (10(7) CFU/mL) organism concentrations. The MIC50 of piperacillin-tazobactam, cefotaxime and cefepime was increased eight-fold or more and that of meropenem was increased two-fold. The in vivo inoculum effect was evaluated in an ESBL-Kpn pneumonia mouse model treated with bacteriostatic effect-adjusted doses of piperacillin-tazobactam (1000 mg/kg four times daily, %T>MIC; 32.60%) or meropenem (100 mg/kg twice daily, %T>MIC; 28.65%) at low/standard (10(4) CFU/mouse) and high (10(6) CFU/mouse) inocula. In mice administered a low inoculum, no mice died after treatment with piperacillin-tazobactam or meropenem, whereas all the control mice died. In contrast, in the high inoculum model, all mice in the piperacillin-tazobactam-treated group died, whereas all meropenem-treated mice survived and had a decreased bacterial load in the lungs and no invasion into the blood. In conclusion, meropenem was more resistant to the inoculum effect of ESBL-Kpn than piperacillin-tazobactam both in vitro and in vivo. In the management of severe pneumonia caused by ESBL-Kpn, carbapenems may be the drugs of choice to achieve a successful outcome.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Disease Models, Animal; Klebsiella Infections; Klebsiella pneumoniae; Lung; Male; Meropenem; Mice, Inbred BALB C; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Survival Analysis; Thienamycins

Beta-lactams, in combination with beta-lactamase inhibitors, are reported to have activity against Mycobacterium tuberculosis bacteria growing in broth, as well as inside the human macrophage. We tested representative beta-lactams belonging to 3 different classes for activity against replicating M. tuberculosis in broth and nonreplicating M. tuberculosis under hypoxia, as well as against streptomycin-starved M. tuberculosis strain 18b (ss18b) in the presence or absence of clavulanate. Most of the combinations showed bactericidal activity against replicating M. tuberculosis, with up to 200-fold improvement in potency in the presence of clavulanate. None of the combinations, including those containing meropenem, imipenem, and faropenem, killed M. tuberculosis under hypoxia. However, faropenem- and meropenem-containing combinations killed strain ss18b moderately. We tested the bactericidal activities of meropenem-clavulanate and amoxicillin-clavulanate combinations in the acute and chronic aerosol infection models of tuberculosis in BALB/c mice. Based on pharmacokinetic/pharmacodynamic indexes reported for beta-lactams against other bacterial pathogens, a cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) of 20 to 40% was achieved in mice using a suitable dosing regimen. Both combinations showed marginal reduction in lung CFU compared to the late controls in the acute model, whereas both were inactive in the chronic model.

Topics: Amoxicillin-Potassium Clavulanate Combination; Animals; Anti-Bacterial Agents; beta-Lactams; Clavulanic Acid; Disease Models, Animal; Drug Therapy, Combination; Female; Humans; Meropenem; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Streptomycin; Thienamycins; Treatment Outcome; Tuberculosis, Pulmonary

Pseudomonas aeruginosa pneumonia remains a difficult therapeutic problem. Optimal doses and modes of administration of single agents often do not result in acceptable outcomes. Further, emergence of resistance occurs frequently in this setting with single-agent chemotherapy. The purpose of these experiments was to evaluate combination chemotherapy with meropenem plus tobramycin for P. aeruginosa in a murine pneumonia model. Neutropenia was induced by cyclophosphamide. Pharmacokinetics of meropenem and tobramycin were determined using a population pharmacokinetic approach. Both drugs were given at 4-h intervals. Meropenem was administered as total daily doses of 30 to 600 mg/kg of body weight, while tobramycin doses ranged from 50 to 400 mg/kg. Combination therapy evaluated all combinations of 50, 100, and 150 mg/kg/day of tobramycin doses with 60 or 300 mg/kg/day of meropenem. Total and drug-resistant organisms were enumerated. Meropenem alone had a near-maximal effect at 60 mg/kg/day (3.18 log10 [CFU/g] kill from stasis). The time > MIC in epithelial lining fluid (ELF) at this dose was 35.25% of 24 h. For tobramycin alone, the near-maximal effect was at 150 mg/kg/day and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) in ELF was 240.3. Resistance suppression occurred at an ELF AUC/MIC ratio of 110.6. For combination therapy, the near-maximal effect was reached at 60 mg/kg/day and 50 mg/kg/day of meropenem and tobramycin, which produced a 35.25% time > MIC in ELF and an ELF AUC/MIC ratio of 80.1. The interaction was additive. All combination regimens suppressed resistance. Combination therapy produced additive drug interaction and suppressed all resistance amplification. It is likely that optimal therapy for Pseudomonas aeruginosa pneumonia will involve a combination of agents.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Female; Humans; Lung; Meropenem; Mice; Microbial Sensitivity Tests; Models, Theoretical; Pneumonia, Bacterial; Pseudomonas aeruginosa; Thienamycins; Tobramycin; Treatment Outcome

The purpose of this study was to investigate the relationship between efficacy and percentage of time above the MIC (%T>MIC) in the cerebrospinal fluid (CSF) for different dosing regimens of meropenem against an experimental lethal meningitis model in guinea pigs with type b β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (Hib BLNAR). Guinea pigs were intrathecally inoculated with 10(8) CFU/head of Hib BLNAR 8 h before the start of therapy. A single dose of 20, 40, or 80 mg/kg meropenem or multiple doses of 40 mg/kg meropenem were subcutaneously administered. Numbers of bacteria in CSF were counted 8 h after the start of therapy. Meropenem concentration in serum and CSF were determined in infected guinea pigs receiving a single dose of 40 mg/kg. In the single-dose regimen, 40 and 80 mg/kg meropenem significantly reduced the number of bacteria in CSF compared with the control, but 20 mg/kg meropenem did not. The %T>MIC for an 8-h period of 20, 40, and 80 mg/kg meropenem were 41, 52, and 62, respectively. Two and four doses of 40 mg/kg meropenem, for both of which %T>MIC was calculated as 100, had similar efficacy and were significantly superior to a single-dose of 40 mg/kg. In conclusion, meropenem had high efficacy when %T>MIC in the CSF was increased because of the high dose level and shortening of the dosing interval in a guinea pig meningitis model caused by Hib BLNAR, suggesting that high and frequent doses of meropenem are useful for treatment of meningitis with Hib BLNAR.

Topics: Animals; Anti-Bacterial Agents; beta-Lactam Resistance; Ceftriaxone; Disease Models, Animal; Guinea Pigs; Haemophilus influenzae type b; Male; Meningitis, Haemophilus; Meropenem; Microbial Sensitivity Tests; Thienamycins

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

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; beta-Lactam Resistance; Carbapenems; Colony Count, Microbial; Disease Models, Animal; Doripenem; Humans; Imipenem; Lung; Meropenem; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Thienamycins; Treatment Outcome

Biapenem (BIPM) has high bactericidal activity against Pseudomonas aeruginosa and similar activity in vitro as meropenem (MEPM). We used a murine model to examine the efficacy of biapenem against ventilator-associated pneumonia (VAP) caused by P. aeruginosa. Mice were treated by intraperitoneal injection with 100 mg/kg BIPM or MEPM every 12 h beginning 12 h after inoculation with P. aeruginosa. Survival was evaluated for 7 days, and 24 h after infection, lung histopathology was analyzed and the number of viable bacteria in the lungs and blood was counted. In addition, the pharmacokinetics of BIPM and MEPM were analyzed after the initial treatment. BIPM and MEPM significantly prolonged survival compared to control (P < 0.05). The lungs of mice treated with BIPM or MEPM had significantly fewer viable bacteria (3.54 ± 0.28 vs. 3.77 ± 0.14 log(10) CFU/ml) than in the lungs of control mice (6.65 ± 0.57 log(10) CFU/ml) (P < 0.05). Furthermore, viable bacteria were not detected in the blood of mice treated with BIPM or MEPM (control 2.85 ± 0.85 log(10) CFU/ml) (P < 0.05). Histopathological examination of lung specimens indicated that BIPM and MEPM prevent the progression of lung inflammation, including alveolar neutrophil infiltration and hemorrhage. The % time above MIC for BIPM and MEPM was 15.4% and 18.3% in plasma and 19.8% and 19.8% in lungs, respectively. These results show that BIPM and MEPM significantly prolongs survival and reduces the number of viable bacteria in a murine model of VAP caused by P. aeruginosa. Therefore, BIPM might be a potent and effective treatment for VAP caused by this bacterium.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Case-Control Studies; Colony Count, Microbial; Disease Models, Animal; Histocytochemistry; Lung; Male; Meropenem; Mice; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Specific Pathogen-Free Organisms; Statistics, Nonparametric; Thienamycins

The US Public Health Emergency Medical Countermeasures Enterprise convened subject matter experts at the 2010 HHS Burkholderia Workshop to develop consensus recommendations for postexposure prophylaxis against and treatment for Burkholderia pseudomallei and B. mallei infections, which cause melioidosis and glanders, respectively. Drugs recommended by consensus of the participants are ceftazidime or meropenem for initial intensive therapy, and trimethoprim/sulfamethoxazole or amoxicillin/clavulanic acid for eradication therapy. For postexposure prophylaxis, recommended drugs are trimethoprim/sulfamethoxazole or co-amoxiclav. To improve the timely diagnosis of melioidosis and glanders, further development and wide distribution of rapid diagnostic assays were also recommended. Standardized animal models and B. pseudomallei strains are needed for further development of therapeutic options. Training for laboratory technicians and physicians would facilitate better diagnosis and treatment options.

Topics: Amoxicillin-Potassium Clavulanate Combination; Animals; Anti-Bacterial Agents; Burkholderia mallei; Burkholderia pseudomallei; Ceftazidime; Disease Models, Animal; Disease Susceptibility; Glanders; Humans; Melioidosis; Meropenem; Post-Exposure Prophylaxis; Risk Factors; Thienamycins; Trimethoprim, Sulfamethoxazole Drug Combination

We evaluated the efficacy of NXL104, a novel β-lactamase inhibitor, in combination with ceftazidime (CAZ) in two murine infection models (septicemia and thigh infection). We chose two KPC-producing Klebsiella pneumoniae strains (VA-361 and VA-406) showing MICs of CAZ of ≥256 μg/ml. Septicemia was induced by the intraperitoneal injection of KPC-producing K. pneumoniae followed 30 min later by a single subcutaneous treatment with CAZ alone or CAZ-NXL104 in ratios of 2:1, 4:1, 8:1, and 16:1. In this model, the median effective doses for 50% (ED(50)) of the animals for CAZ alone versus VA-361 and VA-406 were 1,578 and 709 mg/kg of body weight, respectively. When combined with NXL104 at 2:1, 4:1, 8:1, and 16:1 ratios, the CAZ ED(50)s for VA-361 and VA-406 were reduced to 8.1 and 3.5 mg/kg, 15.1 and 3.8 mg/kg, 16.9 and 7.2 mg/kg, and 29.5 and 12.1 mg/kg, respectively. For thigh infection, neutropenia was induced by the intraperitoneal injection of cyclophosphamide at days -4 and -1 preinfection. Infection was established by the intramuscular injection of KPC-producing K. pneumoniae into the right thigh. Mice were treated 1.5 h postinfection with either CAZ alone or CAZ-NXL104 at constant ratios of 4:1. When thighs were removed at 24 h postinfection, a >2-log CFU reduction was observed for mice treated with CAZ-NXL104 at doses of ≥128:32 mg/kg. In contrast, CAZ doses of ≥1,024 mg/kg were unable to reduce the numbers of CFU. Despite resistance to CAZ and possessing a complex β-lactamase background, NXL104 combined with CAZ proved to be very effective in murine models of infection due to contemporary highly resistant KPC-producing K. pneumoniae isolates.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Disease Models, Animal; Female; Klebsiella Infections; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests; Sepsis

Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log(10) CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log(10) CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log(10) CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; beta-Lactamases; Carbapenems; Cytokines; Disease Models, Animal; Doripenem; Female; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Lung; Meropenem; Mice; Mice, Inbred C3H; Microbial Sensitivity Tests; Pneumonia, Bacterial; Thienamycins; Treatment Outcome

Given their popularity and favorable safety profile, it is no wonder that there has been considerable interest in developing strategies to most effectively use beta-lactam therapy. Dating back to the first days of penicillin, it was noted that there was an observed benefit to prolonging the infusion time or dosing more frequently. Since that time, considerable research has been performed to help understand and justify these dosing strategies. This article discusses the pharmacology behind these dosing strategies and presents some of the contemporary literature describing the perceived and observed clinical benefits.

Topics: Adult; Animals; Anti-Bacterial Agents; beta-Lactams; Child; Computer Simulation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Infusions, Intravenous; Kidney; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Thienamycins; Time Factors

New antibiotics that are active against multidrug-resistant (MDR) Acinetobacter baumannii are urgently needed. BAL30072, a siderophore monosulfactam antibiotic that rapidly penetrates the outer membrane of A. baumannii and has potent activity against most isolates, including those harbouring AmpC β-lactamases and metallo- (class B) or OXA- (class D) carbapenemases, is being developed to meet that need.. We assessed the in vitro activity of BAL30072, meropenem and the combination of BAL30072 and meropenem (2:1 and 1:1 ratios) by MIC and time-kill studies. Proof-of-principle in vivo efficacy was determined using a rat soft-tissue infection model. Five diverse strains with defined phenotypic and genetic profiles were tested (AB307-0294, AB8407, AB1697, AB3340 and AB0057).. In microdilution assays, combining BAL30072 with meropenem lowered meropenem MICs 2-8-fold. In time-kill studies, the BAL30072 and meropenem combinations resulted in bactericidal concentrations 2-8-fold lower than those of meropenem or BAL30072 alone. In the rat model, BAL30072 was active against four of five strains (AB307-0294, AB8407, AB1697 and AB3340), including meropenem-susceptible and -non-susceptible strains. AB0057 was the only strain resistant to BAL30072 in vivo and in vitro (MIC >64 mg/L). Meropenem was active in vivo against two of the five strains tested (AB307-0294 and AB3340). Both BAL30072 and BAL30072 with meropenem were equally effective in vivo.. These data support the continued evaluation of BAL30072 for use in the treatment of infections caused by MDR A. baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Interactions; Meropenem; Microbial Sensitivity Tests; Monobactams; Rats; Rodent Diseases; Siderophores; Thiazoles; Thienamycins; Treatment Outcome

There are few options for prophylaxis after exposure to Bacillus anthracis, especially in children and women of childbearing potential. Faropenem is a beta-lactam in the penem subclass that is being developed as an oral prodrug, faropenem medoxomil, for the treatment of respiratory tract infections. Faropenem was shown to have in vitro activity against B. anthracis strains that variably express the bla1 beta-lactamase (MIC range,

Topics: Animals; Anthrax; Anti-Bacterial Agents; Bacillus anthracis; beta-Lactamases; beta-Lactams; Blood Proteins; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inhalation Exposure; Mice; Mice, Inbred BALB C; Models, Biological

The aim of this study was to compare doripenem with imipenem and meropenem in an experimental rabbit model of Pseudomonas aeruginosa pneumonia and then to compare different doripenem doses and methods of intravenous administration.. Using a rabbit experimental model of pneumonia, efficacy was assessed following 2 days of treatment by colony counts of different tissues (lung, spleen and blood culture).. Mean pulmonary bacterial loads were 3.17 ± 0.53, 3.42 ± 0.61 and 2.75 ± 0.59 log(10) cfu/g for imipenem, doripenem (0.5 g three times daily) and meropenem, respectively, compared with 7.57 ± 0.99 cfu/g for control animals. At a higher dose (1 g three times daily), doripenem showed significantly better efficacy (2.70 ± 0.65 log(10) cfu/g) than the standard regimen of doripenem. Sterilization of spleen cultures was achieved with standard regimens of imipenem (1 g three times daily) and a higher dose of doripenem.. In this model of P. aeruginosa pneumonia, doripenem had an efficacy equivalent to that of meropenem and imipenem at a high dose of 1 g three times a day and lower efficacy at a standard dose (0.5 g three times daily) than the other two agents in terms of bacteria cultivated from spleens. Doripenem is a new drug that offers new therapeutic options, especially for difficult-to-treat infections such as pneumonia due to non-fermenting Gram-negative bacteria.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Blood; Carbapenems; Disease Models, Animal; Doripenem; Female; Imipenem; Infusions, Intravenous; Lung; Meropenem; Plasma; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Spleen; Thienamycins; Treatment Outcome

Nonmammalian model systems of infection such as Galleria mellonella (caterpillars of the greater wax moth) have significant logistical and ethical advantages over mammalian models. In this study, we utilize G. mellonella caterpillars to study host-pathogen interactions with the gram-negative organism Acinetobacter baumannii and determine the utility of this infection model to study antibacterial efficacy. After infecting G. mellonella caterpillars with a reference A. baumannii strain, we observed that the rate of G. mellonella killing was dependent on the infection inoculum and the incubation temperature postinfection, with greater killing at 37 degrees C than at 30 degrees C (P = 0.01). A. baumannii strains caused greater killing than the less-pathogenic species Acinetobacter baylyi and Acinetobacter lwoffii (P < 0.001). Community-acquired A. baumannii caused greater killing than a reference hospital-acquired strain (P < 0.01). Reduced levels of production of the quorum-sensing molecule 3-hydroxy-C(12)-homoserine lactone caused no change in A. baumannii virulence against G. mellonella. Treatment of a lethal A. baumannii infection with antibiotics that had in vitro activity against the infecting A. baumannii strain significantly prolonged the survival of G. mellonella caterpillars compared with treatment with antibiotics to which the bacteria were resistant. G. mellonella is a relatively simple, nonmammalian model system that can be used to facilitate the in vivo study of host-pathogen interactions in A. baumannii and the efficacy of antibacterial agents.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Disease Models, Animal; Host-Pathogen Interactions; Moths; Quorum Sensing; Virulence

The clinical course in acute necrotizing pancreatitis is mainly influenced by bacterial infection of pancreatic and peripancreatic necrosis. The effect of two antibiotic treatments for early prophylaxis was studied in the taurocholate model of necrotizing pancreatitis in the rat.. Sixty male Sprague-Dawley rats were divided into three pancreatitis groups (15 animals each) and a sham-operated group (15 animals, control group). Pancreatitis was induced by intraductal infusion of 3% taurocholate under sterile conditions. Animals were placed on one of two different antibiotic regimens (15 mg/kg ertapenem or 20 mg/kg meropenem, one shot) after the induction of pancreatitis or received no antibiotics (control). All animals were sacrificed after 24 h to study pancreatic and extrapancreatic infection.. Early antibiotic prophylaxis with either erapenam or meropenem significantly decreased pancreatic infection from 12/15 (control group) to 4/15 (ertapenem antibiotic group) and 3/15 (meropenem antibiotic group) (P < 0.05).. In our animal model of necrotizing pancreatitis, early antibiotic prophylaxis with ertapenem and meropenem reduced bacterial infection of the pancreas. The efficacy of early antibiotic prophylaxis with ertapenem in the clinical setting should be subject to further research.

Topics: Animals; Antibiotic Prophylaxis; Bacterial Infections; beta-Lactams; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Ertapenem; Male; Meropenem; Pancreatitis, Acute Necrotizing; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Risk Factors; Sensitivity and Specificity; Severity of Illness Index; Thienamycins

Meropenem is a broad-spectrum carbapenem antibiotic that is highly active against the pathogens causing meningitis. The aims of this study was to determine the efficacies of meropenem alone and combined with rifampin against two Streptococcus pneumoniae strains with different susceptibility to beta-lactams using the guinea pig meningitis model and compare them with the standard ceftriaxone plus vancomycin therapy. All treatments except rifampin were bactericidal from 6 h. The addition of rifampin did not improve the activity of meropenem alone. Our results provide good evidence of the efficacy of meropenem in the treatment of penicillin- and cephalosporin-susceptible and -resistant pneumococcal meningitis similar to that of ceftriaxone plus vancomycin, suggesting that meropenem might be a good option in the management of this infection.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Guinea Pigs; Humans; Meningitis, Pneumococcal; Meropenem; Microbial Viability; Rifampin; Streptococcus pneumoniae; Thienamycins; Time Factors; Treatment Outcome; Vancomycin

A pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategy to simulate in vivo bactericidal effects for three carbapenem antibiotics, doripenem (DRPM), meropenem (MEPM)/cilastatin (CS), and imipenem (IPM)/CS, against a Pseudomonas aeruginosa (P. aeruginosa) strain is proposed. The PD model we have already developed to explain in vitro time-kill profiles was modified to incorporate the growth rate, bactericidal activities, and PK profiles in murine lung infection models. Plasma concentration data and bacterial time-kill data for each antibiotic consist of six and eight time points, respectively, at one dose regimen (four or five mouse/point). In vivo time-kill curves could be well simulated for each antibiotic by the PK/PD model. Simulated bacterial counts at 24 h and PK/PD indices derived from total drug concentrations (time above the minimum inhibitory concentration (MIC) (T > MIC), C(max)/MIC, and AUC/MIC) for various dose regimens were examined for MEPM/CS and IPM/CS. Simulated bacterial counts correlated only with T > MIC (correlation coefficient: 0.951 for MEPM/CS, 0.982 for IPM/CS) and T > MIC values to achieve a bacteriostatic effect and a 2-log killing effect for both antibiotics were estimated to be approximately 15 and 20%, respectively, which are similar to previously reported results. These findings suggested that the proposed PK/PD model is a good tool for predicting in vivo bactericidal effects.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Carbapenems; Cilastatin; Disease Models, Animal; Doripenem; Female; Imipenem; Meropenem; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Models, Biological; Thienamycins

Meropenem is a carbapenem antibiotic that is highly active against the pathogens causing meningitis. Results with meropenem in the experimental rabbit model of penumococcal meningitis have been controversial, and the possible role of renal dehydropeptidase I in meropenem efficacy has been suggested. The aim of this study was to determine the efficacy of meropenem in two meningitis models and the possible influence of the animal model over results. Two strains of Streptococcus pneumoniae with different susceptibility to beta-lactams have been used in a guinea pig model and the classical rabbit meningitis model. Meropenem was bactericidal at 6 h in the guinea pig model against both strains with a reduction of >4 log ufc/ml. In the rabbit model it was bactericidal at 6 h against the susceptible strain, but against the resistant 3/8 therapeutical failures were recorded at 6 h, being bactericidal at 24 h. In conclusion, meropenem has shown bactericidal activity in both experimental models. This work emphasises the importance of an adequate election of the animal model for the appropriate development of studies of antimicrobial efficacy. We believe that guinea pig should be considered the best choice among laboratory animal species when assessing meropenem efficacy.

Topics: Animals; Cephalosporin Resistance; Cephalosporins; Disease Models, Animal; Guinea Pigs; Meningitis, Bacterial; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae; Thienamycins

The purpose of this study was to examine the in vivo efficacies of meropenem and ertapenem against extended-spectrum-beta-lactamase (ESBL)-producing isolates with a wide range of MICs. Human-simulated dosing regimens in mice were designed to approximate the free drug percent time above the MIC (fT>MIC) observed for humans following meropenem at 1 g every 8 h and ertapenem at 1 g every 24 h. An in vivo neutropenic mouse thigh infection model was used to examine the bactericidal effects against 31 clinical ESBL Escherichia coli and Klebsiella pneumoniae isolates and 2 non-ESBL isolates included for comparison at a standard 10(5) inoculum. Three isolates were examined at a high 10(7) inoculum as well. Meropenem displayed greater in vitro potency, with a median MIC (range) (microg/ml) of 0.125 (0.03 to 32), than did ertapenem, with 0.5 (0.012 to 128). Seven of the 31 ESBL isolates were removed from the efficacy analysis due to their inability to establish infection in the mouse model. When MICs wereMIC>or=23%) and meropenem (fT>MIC>or=75%). Ertapenem showed bacterial regrowth for seven of eight isolates, with MICs of>or=2 microg/ml (fT>MICMIC=30 to 65%). At a 10(7) inoculum, both agents eradicated bacteria due to adequate exposures (fT>MIC=20 to 45%). Due to low MICs, no difference in bacterial kill was noted for the majority of ESBL isolates tested. However, for isolates with raised ertapenem MICs of>or=2 microg/ml, meropenem displayed sustained efficacy due to its greater in vitro potency and higher resultant fT>MIC.

Topics: Animals; beta-Lactamases; beta-Lactams; Disease Models, Animal; Ertapenem; Escherichia coli; Escherichia coli Infections; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Mice; Microbial Sensitivity Tests; Thienamycins

We studied the mechanisms and dynamics of the development of resistance to ceftazidime (CAZ) alone or combined with tobramycin (TOB) or ciprofloxacin (CIP) in vitro and in vivo (using a mouse model of lung infection with human antibiotic regimens). Pseudomonas aeruginosa strain PAO1 and its hypermutable derivative PAODeltamutS were used, and the results were compared with those previously obtained with CIP, TOB, and CIP plus TOB (CIP-TOB) under the same conditions. An important (200-fold) amplification of the number of resistant mutant cells was documented for PAODeltamutS-infected mice that were under CAZ treatment compared to the number for mice that received placebo, whereas the median number of resistant mutant cells was below the detection limits for mice infected by PAO1. These results were intermediate between the high amplification with CIP (50,000-fold) and the low amplification with TOB (10-fold). All CAZ-resistant single mutant cells selected in vitro or in vivo hyperproduced AmpC. On the other hand, the three combinations studied were found to be highly effective in the prevention of in vivo resistance development in mice infected with PAODeltamutS, although the highest therapeutic efficacy (in terms of mortality and total bacterial load reduction) compared to those of the individual regimens was obtained with CIP-TOB and the lowest was with CAZ-CIP. Nevertheless, mutant cells that were resistant to the three combinations tested were readily selected in vitro for PAODeltamutS (mutation rates from 1.2 x 10(-9) to 5.8 x 10(-11)) but not for PAO1, highlighting the potential risk for antimicrobial resistance development associated with the presence of hypermutable strains, even when combined therapy was used. All five independent CAZ-TOB-resistant PAODeltamutS double mutants studied presented the same resistance mechanism (AmpC hyperproduction plus an aminoglycoside resistance mechanism not related to MexXY), whereas four different combinations of resistance mechanisms were documented for the five CAZ-CIP-resistant double mutants.

Topics: Animals; Anti-Bacterial Agents; Ceftazidime; Ciprofloxacin; Disease Models, Animal; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Female; Humans; In Vitro Techniques; Lung; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

This study compared the in-vitro properties and in-vivo effects of Escherichia coli filaments, spheroplasts and normal cells in a murine thigh infection model. E. coli was exposed to ceftazidime, meropenem or saline to obtain filaments, spheroplasts or normal bacilli, which were then injected into neutropenic mice. After 24 h, morphology, CFUs, local and circulating endotoxin levels, cytokine levels and mortality were recorded, and correlations between bacterial and host parameters of infection were investigated. Filaments and spheroplasts contained more endotoxin/CFU than controls. Histological studies showed that morphologically altered bacteria changed into rod-shaped cells in the absence of antibiotics. Bacterial spread to the liver was significantly higher in mice challenged with rod-shaped cells, compared with antibiotic-exposed bacteria (p 0.007). Muscle endotoxin levels correlated significantly with circulating interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha, and both pro-inflammatory cytokines were correlated significantly (p 0.011). Despite a tendency toward higher local and systemic concentrations of endotoxin in the filament group, inflammatory responses and survival did not differ between groups. It was concluded that morphologically altered bacteria contain more endotoxin and can regain a rod shape after withdrawal of antibiotics, while non-antibiotic-exposed bacteria show greater spread to the liver. There was a clear intra-individual relationship between local endotoxin, systemic endotoxin, TNF-alpha and IL-6 production, but these parameters did not differ among groups.

Topics: Animals; Animals, Outbred Strains; Anti-Bacterial Agents; Ceftazidime; Cyclophosphamide; Cytoskeleton; Disease Models, Animal; Endotoxins; Escherichia coli; Escherichia coli Infections; Female; Interleukin-6; Liver; Meropenem; Mice; Muscles; Muscular Diseases; Neutropenia; Spheroplasts; Thienamycins; Thigh; Tumor Necrosis Factor-alpha

With the widespread emergence of antimicrobial resistance, combination regimens of ceftriaxone and vancomycin (C+V) or ceftriaxone and rifampin (C+R) are recommended for empirical treatment of pneumococcal meningitis. To evaluate the therapeutic efficacy of meropenem (M), we compared various treatment regimens in a rabbit model of meningitis caused by penicillin-resistant Streptococcus pneumoniae (PRSP). Therapeutic efficacy was also evaluated by the final bacterial concentration in the cerebrospinal fluid (CSF) at 24 hr. Each group consisted of six rabbits. C+V cleared the CSF at 10 hr, but regrowth was noted in 3 rabbits at 24 hr. Meropenem monotherapy resulted in sterilization at 10 hr, but regrowth was observed in all 6 rabbits at 24 hr. M+V also resulted in sterilization at 10 hr, but regrowth was observed in 2 rabbits at 24 hr. M+V was superior to the meropenem monotherapy at 24 hr (reduction of 4.8 vs. 1.8 log10 cfu/mL, respectively; p=0.003). The therapeutic efficacy of M+V was comparable to that of C+V (reduction of 4.8 vs. 4.0 log10 cfu/mL, respectively; p=0.054). The meropenem monotherapy may not be a suitable choice for PRSP meningitis, while combination of meropenem and vancomycin could be a possible alternative in the treatment of PRSP meningitis.

Topics: Animals; Anti-Bacterial Agents; Cerebrospinal Fluid; Disease Models, Animal; Drug Resistance, Microbial; Humans; Male; Meningitis, Pneumococcal; Meropenem; Penicillins; Rabbits; Streptococcus pneumoniae; Thienamycins; Time Factors

The aim of the present study was to investigate the potential synergy between meropenem and levofloxacin in vitro and in experimental meningitis and to determine the effect of meropenem on levofloxacin-induced resistance in vitro. Meropenem increased the efficacy of levofloxacin against the penicillin-resistant pneumococcal strain KR4 in time-killing assays in vitro and acted synergistically against a second penicillin-resistant strain WB4. In the checkerboard, only an additive effect (FIC indices: 1.0) was observed for both strains. In cycling experiments in vitro, levofloxacin alone led to a 64-fold increase in the MIC for both strains after 12 cycles. Addition of meropenem in sub-MIC concentrations (0.25 x MIC) completely inhibited the selection of levofloxacin-resistant mutants in WB4 after 12 cycles. In KR4, the addition of meropenem led to just a twofold increase in the MIC for levofloxacin after 12 cycles. Mutations detected in the genes encoding for topoisomerase IV (parC) and gyrase (gyrA) confirmed the levofloxacin-induced resistance in both strains. Addition of meropenem was able to completely suppress levofloxacin-induced mutations in WB4 and led to only one mutation in parE in KR4. In experimental meningitis, meropenem, given in two doses (2 x 125 mg/kg), produced a good bactericidal activity (-0.45 Deltalog10 cfu/ml.h) comparable to one dose (1 x 10 mg/kg) of levofloxacin (-0.44 Deltalog10 cfu/ml.h) against the penicillin-resistant strain WB4. Meropenem combined with levofloxacin acted synergistically (-0.93 Deltalog10 cfu/ml.h), sterilizing the CSF of all rabbits.

Topics: Animals; Disease Models, Animal; DNA, Bacterial; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Female; Levofloxacin; Male; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Ofloxacin; Penicillin Resistance; Polymerase Chain Reaction; Rabbits; Reference Values; Sensitivity and Specificity; Streptococcus pneumoniae; Thienamycins

Efficacy of panipenem/betamipron (PAPM/BP) against experimental pneumonia caused by penicillin-resistant Streptococcus pneumoniae (PRSP: MIC of benzylpenicillin, > or = 1.56 micrograms/ml) in mice was compared with those of imipenem/cilastatin (IPM/CS), meropenem (MEPM), cefozopran (CZOP), ceftriaxone (CTRX), ampicillin (ABPC), and vancomycin (VCM). The infection was induced by inoculating a PRSP clinical isolate, 9601 (serotype 6) or 10,693 (serotype 19), into ddY male mice intranasally. Drugs were administered subcutaneously at doses of 0.4, 2, and 10 mg/kg, 18, 26, 42, and 50 hours post-infection. Viable cell counts in the lungs were determined 66 hours post-infection. PAPM/BP showed the greatest efficacy against the infections among tested drugs. MICs of PAPM against PRSP 9601 and 10,693 were both 0.125 microgram/ml, which were superior to those of IPM (0.25 and 0.5 microgram/ml, respectively), MEPM (0.5 and 1 microgram/ml, respectively), CZOP (2 and 1 microgram/ml, respectively), CTRX (both 1 microgram/ml), ABPC (both 4 micrograms/ml), and VCM (0.5 and 0.25 microgram/ml, respectively). These results suggest that the potent in vivo activity of PAPM/BP reflects the potent in vitro activity of PAPM. MICs of PAPM, IPM, MEPM, and CZOP against clinical isolates, penicillin-susceptible S. pneumoniae (PSSP: MIC of benzylpenicillin, < or = 0.05 microgram/ml), penicillin-intermediate S. pneumoniae (PISP: MIC of benzylpenicillin, 0.1-0.78 microgram/ml), and PRSP, were tested by an agar dilution method. MIC90s of the drugs against the PSSP, PISP, and PRSP were as follows: PAPM, 0.012, 0.05, and 0.39 microgram/ml; IPM, < or = 0.006, 0.1, and 0.78 microgram/ml; MEPM, 0.05, 0.39, and 1.56 micrograms/ml; and CZOP, 0.2, 0.78, and 6.25 micrograms/ml, respectively. Thus, PAPM showed the most potent activity among tested drugs against clinical isolates of PISP and PRSP.

Topics: Ampicillin; Animals; beta-Alanine; Cefozopran; Ceftriaxone; Cephalosporins; Cilastatin; Cilastatin, Imipenem Drug Combination; Disease Models, Animal; Drug Combinations; Drug Resistance; Imipenem; Male; Meropenem; Mice; Mice, Inbred Strains; Penicillin Resistance; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Thienamycins; Vancomycin

In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 microg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (-0.48+/-0.14 deltalog10 cfu/ml h) and slightly superior to ceftriaxone (-0.34+/-0.23 deltalog10 cfu/ml x h) and vancomycin (-0.39+/-0.19 deltalog10 cfu/ml x h). Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (-0.55+/-0.19 deltalog10 cfu/ml x h), only an insignificant gain was observed by the addition of vancomycin to meropenem (-0.55+/-0.28 deltalog10 cfu/ml x h).

Topics: Animals; Ceftriaxone; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Penicillin Resistance; Rabbits; Streptococcus pneumoniae; Thienamycins; Vancomycin

NEW IN VITRO MODELS: Numerous posters at the ICAAC were devoted to in vitro models simulating plasma kinetics, including many concerning new molecules, especially fluoroquinolones. Gatifloxacine, for example, has been found to be very active against Gram positive and intracellular germs. The performance of clinafloxacine against Gram negatives was also announced. Moxifloxacine was studied with a novel dynamic in vitro model against penicillin-resistant Streptococcus pneumoniae. In this model, the bactericidal effect was very rapid and complete, with no regrowth. ADVANCES IN THE PRECLINICAL PHASE: There was much discussion concerning in vitro models and experimental infections which are being used to further accelerate preclinical investigations of new compounds.

Topics: Animals; Anti-Infective Agents; Aza Compounds; Disease Models, Animal; Drug Resistance, Microbial; Fluoroquinolones; Humans; In Vitro Techniques; Meropenem; Moxifloxacin; Quinolines; Quinolones; Thienamycins

Three female Yucatan micropigs were included and received a single dose of amikacin (15 mg/kg) by short infusion (30 min) combined either with a single dose of cefepime or cefpirome (30 mg/kg/12 h) or meropenem (7 mg/kg/8 h). The beta-lactams were administered either by intravenous intermittent injection or by continuous infusion. The mean elimination half-life and clearance value of amikacin were 1.88 h and 2.15 ml/min.kg-1 respectively. These pharmacokinetic parameters were similar to those obtained in man (t1/2 = 2,42 h et Cl = 1,61 ml/min kg-1). Furthermore, they were not affected by coadministration of cefepime, cefpirome and to meropenem. While resistant to cefepime, cefpirome and amikacin, Klebsiella pneumoniae producing ESBL was susceptible to combination of these cephalosporins with amikacin in an in vitro/ex vivo micropig model. For the six dosage regimens used in this study, the killing activities were similar and resulted in at least 4 log decrease at 6 h after drug exposure. For antimicrobial combination consisting of bolus dosing of amikacin plus continuous infusion of cefepime or cefpirome, the 12 h serum bactericidal titers (SBTs) were 1:8 for cefepime and 1:2 for cefpirome dosage regimen. When each drug administered intermittently, the 12 h SBTs were 1:4 for cefepime and 1:2 for cefpirome. The 8 h SBTs for dosing schedule containing meropenem combined with amikacin were 1:4 and 1:16 after 30 min short infusion and continuous infusion respectively. In conclusion, our study showed that the micropig model is a reliable model for pharmacokinetic investigation of amikacin. It was concluded that beta-lactam antibiotics tested with amikacin may be coadministered by using the standard recommended dosing regimen of amikacin. Continuous infusion of beta-lactams combined with once dosing of amikacin seems to be as or more effective than intermittent injection of each drug.

Topics: Amikacin; Animals; Anti-Bacterial Agents; Cefepime; Cefpirome; Cephalosporins; Disease Models, Animal; Drug Therapy, Combination; Female; Humans; In Vitro Techniques; Klebsiella pneumoniae; Meropenem; Perfusion; Serum Bactericidal Test; Swine; Thienamycins

Meropenem is a new carbapenem antibiotic of with an antibacterian spectrum similar to that of imipenem, but from which it may mainly be differentiated by the possibility of its administration at high doses and it has no demonstrated proconvulsive effect, properties which make it applicable in the treatment of bacterial meningitis. The clinical and experimental experience in the treatment of bacterial meningitis with this antibiotic is herein reviewed. It has been observed that the efficacy and safety of meropenem in meningitis caused by N. meningitidis, H. influenzae and pneumococci sensitive to penicillin may be similar to that of cefotaxime or ceftriaxone in both the pediatric and adult population. There are very few reports on the treatment of meningitis caused by pneumococci resistant to penicillin. However, given that the activity of meropenem on these pneumococci is similar to that of cefotaxime and that the doses administered are much lower, it does not appear to be recommendable in the treatment of this indication, although it should be tested in all meningeal strain to these characteristics isolated. It may currently be considered that the main indication of meropenem in the infections of the central nervous system is in nosocomial meningitis by multiresistant gram negative bacilli such as those of the Klebsiella-Serratia-Enterobacter and Acinetobacter sp. group. Therefore a limited, albeit favorable, report on the clinical experience with meropenem is herein presented. Meropenem may also be useful in the treatment of meningitis by Pseudomonas aeruginosa in which other treatments have failed.

Topics: Adult; Animals; Blood-Brain Barrier; Child; Cross Infection; Disease Models, Animal; Humans; Meningitis, Bacterial; Meropenem; Rabbits; Thienamycins

Infected, neutropenic animals are used as experimental models to evaluate the relative efficacies of antimicrobial agents and host-pathogen-antibiotic interactions. In the past, these models used death as the study end point. Because of the concern about use of death as an end point, we evaluated the accuracy with which various signs of infection predicted mortality in a neutropenic guinea pig model of treated and untreated Pseudomonas aeruginosa sepsis. The potential surrogate markers studied included ruffled fur, respiratory distress, diarrhea, hunched posture, lethargy, abnormal neurologic movements (twitching, paralysis of a limb), inappetence for > 48 h, the inability to ambulate, and the inability of a supine animal to stand. In addition, we evaluated whether percentage of weight loss or change in daily food and water consumption were predictive of mortality. Animals were inspected for these signs at least every 4 h during the day and every 8 h in the evening. In treated and untreated animals, 100% of subjects that were unable to ambulate or to rise from the supine position died (positive predictive value for death was 100% for either sign). Guinea pigs that could not rise from a supine position expired between 1 and 8 h after this sign was observed. Those that could not ambulate died between 4 and 40 h after that sign was observed. In treated and untreated animals, none of the survivors manifested either sign of disease (100% specificity for each sign). However, 59% of untreated and 69% of treated animals that were ambulatory were found dead at the next observation period, underscoring the rapidity with which this infection progresses to death when it enters its final stage. No other signs of infection distinguished animals that survived or died. Thus, the inability of neutropenic, infected guinea pigs to rise from a supine position and the inability to ambulate were the only signs that accurately predicted death and, therefore, are the only signs that can be used as surrogates for death in this experimental model of P. aeruginosa sepsis.

Topics: Animals; Anti-Bacterial Agents; Biomarkers; Ceftazidime; Cephalosporins; Diarrhea; Disease Models, Animal; Female; Guinea Pigs; Imipenem; Meropenem; Movement Disorders; Neutropenia; Predictive Value of Tests; Pseudomonas Infections; Regression Analysis; Respiration; Thienamycins; Time Factors; Tobramycin; Weight Loss

The miniature pig exhibits physiological and anatomical similarities to man. In addition, its reduced size and its docility make it appropriate for laboratory use. Curiously, this model remains seldom used in experimental pharmacokinetics. We present here in a chronic model of catheterized micropig allowing long term investigations of antiinfective agents. We work with Yucatan adult female micropigs weighing between 20 and 40kg. A catheter (60 cm x 2 mm) is placed in the external jugular vein under general anaesthesia and exits in the midline dorsal neck. The catheter is flushed every two days with heparinized saline to retain its potency. At the time of kinetic studies, the antiinfective agent is injected in an ear vein. Blood samples are obtained using the jugular catheter. The mean time of viability of the device is 13 weeks (SD: 10 weeks). Thrombosis was the main cause of arrest of the model. In conclusion, this chronic model of catheterized micropig is suitable for long term pharmacokinetic and pharmacodynamic investigations of antiinfective agents.

Topics: Adult; Animals; Antibiotics, Antitubercular; Antifungal Agents; Catheterization, Peripheral; Cefepime; Cefpirome; Ceftriaxone; Cephalosporins; Disease Models, Animal; Female; Humans; Injections, Intravenous; Meropenem; Swine; Thienamycins

Acute respiratory infection with penicillin-insensitive Streptococcus pneumoniae (MIC and MBC, 1 and 2 micrograms/ml, respectively) was established in guinea pigs. Intratracheal instillation of 0.5 ml of an overnight culture of S. pneumoniae concentrated 25 times (approximately 3 x 10(9) CFU) induced a bacteremic and fatal pneumonia in > 85% of untreated animals within 46 h, with a mean +/- standard deviation bacterial count of 8.83 +/- 1.11 log10 CFU in lung homogenates. This model was used to evaluate the efficacies of two doses each of amoxicillin, cefotaxime, and meropenem given 1 h after bacterial inoculation. The antibiotics were given at 8-h intervals for up to a total of four injections. The dose of 50 mg of any antibiotic per kg of body weight gave 66.6% survival, compared with 5.05% survival for untreated control animals (P < 0.001). A dose of 200 mg/kg gave a survival rate of 77.8% for meropenem and 83.3% for amoxicillin and cefotaxime, while survival for untreated controls was 11.1% (P < 0.001). Although antibiotic treatment decreased mortality compared with that in untreated controls, the antibiotics contributed to a high early (less than 9 h after bacterial inoculation) mortality, being 53.5% compared with only 6.06% for the untreated controls (P < 0.001). Quantitative cultures of the lungs of animals that died during the 46-h observation period or that were killed after this time showed a significant reduction in the numbers of organisms among treated animals compared with numbers among the control animals (P < 0.001). The described model is an appropriate system for evaluating antibiotic efficacy in invasive pulmonary infection caused by penicillin-insensitive S. pneumoniae.

Topics: Amoxicillin; Animals; Cefotaxime; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Female; Guinea Pigs; Lung; Meropenem; Penicillin Resistance; Penicillins; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Thienamycins

The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 microgram/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Cefpirome; Ceftriaxone; Cephalosporins; Disease Models, Animal; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Fluoroquinolones; Male; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Penicillin Resistance; Quinolones; Rabbits; Rifampin; Thienamycins; Vancomycin