In vivo studies on antibiotic combination for the treatment of carbapenem-resistant Gram-negative bacteria: a systematic review and meta-analysis protocol

ObjectiveThere is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae and provide an unbiased overview of existing knowledge. The results of the study can help prioritising future research on the most promising therapies against CR bacteria.Methods and analysisThis protocol was formulated using the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) Checklist. Publications will be collected from PubMed, Scopus, Embase and Web of Science. Quality checklists adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies and SYRCLE's risk of bias tool will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by I2 test. Subgroup meta-analysis will be performed when possible to assess the impact of the studies on efficacy of the treatments. Funnel plotting will be used to evaluate the risk of publication bias.DisseminationThis systematic review and meta-analysis is part of a wider research collaboration project, the COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric population: EvideNCE and common practice (COHERENCE) study that includes also the analyses of in vitro and human studies. Data will be presented at international conferences and the results will be published in peer-reviewed journals.PROSPERO registration numberCRD42019128104(available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128104)

Murine Model for Measuring Effects of Humanized-Dosing of Antibiotics on the Gut Microbiome.

There is a current need for enhancing our insight in the effects of antimicrobial treatment on the composition of human microbiota. Also, the spontaneous restoration of the microbiota after antimicrobial treatment requires better understanding. This is best addressed in well-defined animal models. We here present a model in which immune-competent or neutropenic mice were administered piperacillin-tazobactam (TZP) according to human treatment schedules. Before, during and after the TZP treatment, fecal specimens were longitudinally collected at established intervals over several weeks. Gut microbial taxonomic distribution and abundance were assessed through culture and molecular means during all periods. Non-targeted metabolomics analyses of stool samples using Quadrupole Time of Flight mass spectrometry (QTOF MS) were also applied to determine if a metabolic fingerprint correlated with antibiotic use, immune status, and microbial abundance. TZP treatment led to a 5-10-fold decrease in bacterial fecal viability counts which were not fully restored during post-antibiotic follow up. Two distinct, relatively uniform and reproducible restoration scenarios of microbiota changes were seen in post TZP-treatment mice. Post-antibiotic flora could consist of predominantly Firmicutes or, alternatively, a more diverse mix of taxa. In general, the pre-treatment microbial communities were not fully restored within the screening periods applied. A new species, closely related t

Characterization of Pharmacokinetics and Nephrotoxicity of Polymyxin B

Objective: Increasing prevalence of multidrug resistant Gram-negative infections has led to renewed interest in the use of systemic polymyxin B. However, the pharmacological properties of polymyxin B are still poorly understood. The objective of this study was to characterize the pharmacokinetics, renal disposition and nephrotoxicity of systemic polymyxin B. Methods: Pharmacokinetic parameters of the different polymyxin B components following intravenous administration in rats were derived and compared. Renal recovery and kidney concentration of polymyxin B were evaluated. In addition, the pharmacokinetics of polymyxin B was estimated in renal insufficiency and compared to those observed in normal renal function. Finally, the nephrotoxicity potential was evaluated in vitro and in vivo; the impact of dosing frequency on the onset of nephrotoxicity was examined. Results: The pharmacokinetic parameters of the major components did not appear to be significantly different. Prolonged residence of polymyxin B in kidneys was observed. Less than 1% of the dose was recovered unchanged in urine. The pharmacokinetics of polymyxin B was not significantly altered by renal insufficiency. Polymyxin B was toxic to renal cells in vitro. In vivo, polymyxin Binduced nephrotoxicity manifested as elevation in serum creatinine and acute tubular necrosis. The onset of nephrotoxicity was dose-dependent; more frequent dosing appeared to be associated with earlier onset of nephrotoxicity. Conclusion: Polymyxin B components have similar pharmacokinetics. Mechanism(s) other than renal excretion could be involved in polymyxin B elimination, and dosing adjustment in renal insufficiency may not be necessary. Polymyxin B preferentially persists in kidneys, which suggests a selective uptake process in renal cells. Polymyxin B induced nephrotoxicity, which could be attributed to drug accumulation in kidneys and appeared to be dependent on the dose as well as the dosing frequency.Pharmacological and Pharmaceutical Sciences, Department o

Breast Cancer: Conventional Diagnosis and Treatment Modalities and Recent Patents and Technologies

Breast cancer is the most prevalent cancer among women worldwide. However, increased survival is due to the dramatic advances in the screening methods, early diagnosis, and breakthroughs in treatments. Over the course of the last decade, many acquisitions have taken place in this critical field of research in the pharmaceutical industry. Advances in molecular biology and pharmacology aided in better understanding of breast cancer, enabling the design of smarter therapeutics able to target cancer and respond to its microenvironment efficiently. Patents and research papers investigating diagnosis and treatment strategies for breast cancer using novel technologies have been surveyed for the past 15 years. Various nanocarriers have been introduced to improve the therapeutic efficacy of anticancer drugs, including liposomes, polymeric micelles, quantum dots, nanoparticles, and dendrimers. This review provides an overview of breast cancer, conventional therapy, novel technologies in the management of breast cancer, and rational approaches for targeting breast cancer. Highlights Breast cancer is the most common cancer in women worldwide. However, survival rates vary widely, optimistically heading toward a positive trend. Increased survival is due to the drastic shift in the screening methods, early diagnosis, and breakthroughs in treatments. Different strategies of breast cancer classification and staging have evolved over the years. Intrinsic (molecular) subtyping is essential in clinical trials and well understanding of the disease. Many novel technologies are being developed to detect distant metastases and recurrent disease as well as to assess response to breast cancer management. Intensive research efforts are actively ongoing to take novel breast cancer therapeutics to potential clinical application. Most of the recent research papers and patents discuss one of the following strategies: the development of new drug entities that specifically target the breast tumor cells; tailor designing a novel carrier system that can multitask and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a therapeutic drug moiety with a targeting moiety, diagnostic moiety or pharmacokinetics altering moiety; or the use of innovative nontraditional approaches such as genetic engineering, stem cells, or vaccinations

Vancomycin-functionalized Eudragit-based nanofibers: Tunable drug release and wound healing efficacy

There is an unmet demand for local vancomycin (VAN) delivery scaffolds with site retention and tunable release properties for cutaneous and surgical wounds. Nanofibers as drug delivery/cell regeneration promoting scaffolds offer great promise in this respect. High loading of the polar VAN into polymeric structures with tunable release properties can be achieved by simultaneous chemical bonding and polymer blending. Electrospinnable vancomycin-functionalized Eudragit E100 with a relatively high drug content and antibacterial activity (E-VAN) was investigated for the development of antimicrobial nanofibers with modifiable hydrophilicity, degradability, mechanical and release properties by blending with selected Eudragit polymers. A platform of fast dissolving nanofibers of value in immediate release applications and nanofibers with a wide spectrum of biphasic release profiles with either fast or sustained drug release at low, high and physiological pH for at least 7 days was generated. A selected nanofiber formulation with a relatively small size, adequate hydrophilicity, structural stability, and biphasic release profile at pH 7.4 showed high antibacterial activity against Staphylococcus aureus and healing efficacy of Staphylococcus aureus-inoculated full thickness excision wounds in a rat model. The E-VAN-based Eudragit nanofibers developed offer potential as versatile antimicrobial delivery/cell regeneration scaffolds for local applications under diverse pH conditions

Prevalence, Resistance Mechanisms, and Susceptibility of Multidrug-Resistant Bloodstream Isolates of Pseudomonas aeruginosa▿

Pseudomonas aeruginosa is an important pathogen commonly implicated in nosocomial infections. The occurrence of multidrug-resistant (MDR) P. aeruginosa strains is increasing worldwide and limiting our therapeutic options. The MDR phenotype can be mediated by a variety of resistance mechanisms, and the corresponding relative biofitness is not well established. We examined the prevalence, resistance mechanisms, and susceptibility of MDR P. aeruginosa isolates (resistant to ≥3 classes of antipseudomonal agents [penicillins/cephalosporins, carbapenems, quinolones, and aminoglycosides]) obtained from a large, university-affiliated hospital. Among 235 nonrepeat bloodstream isolates screened between 2005 and 2007, 33 isolates (from 20 unique patients) were found to be MDR (crude prevalence rate, 14%). All isolates were resistant to carbapenems and quinolones, 91% were resistant to penicillins/cephalosporins, and 21% were resistant to the aminoglycosides. By using the first available isolate for each bacteremia episode (n = 18), 13 distinct clones were revealed by repetitive-element-based PCR. Western blotting revealed eight isolates (44%) to have MexB overexpression. Production of a carbapenemase (VIM-2) was found in one isolate, and mutations in gyrA (T83I) and parC (S87L) were commonly found. Growth rates of most MDR isolates were similar to that of the wild type, and two isolates (11%) were found to be hypermutable. All available isolates were susceptible to polymyxin B, and only one isolate was nonsusceptible to colistin (MIC, 3 mg/liter), but all isolates were nonsusceptible to doripenem (MIC, >2 mg/liter). Understanding and continuous monitoring of the prevalence and resistance mechanisms of MDR P. aeruginosa would enable us to formulate rational treatment strategies to combat nosocomial infections

In vivo studies on antibiotic combination for the treatment of carbapenem-resistant Gram-negative bacteria: a systematic review and meta-analysis protocol

Systematic review and meta-analysis protocol for in vivo studies describing combination treatments for Gram-negative MDR bacteri

Quantitative Impact of Neutrophils on Bacterial Clearance in a Murine Pneumonia Model▿

The rapid increase in the prevalence of antibiotic-resistant pathogens is a global problem that has challenged our ability to treat serious infections. Currently, clinical decisions on treatment are often based on in vitro susceptibility data. The role of the immune system in combating bacterial infections is unequivocal, but it is not well captured quantitatively. In this study, the impact of neutrophils on bacterial clearance was quantitatively assessed in a murine pneumonia model. In vitro time-growth studies were performed to determine the growth rate constants of Acinetobacter baumannii ATCC BAA 747 and Pseudomonas aeruginosa PAO1. The absolute neutrophil count in mice resulting from different cyclophosphamide preparatory regimens was determined. The dynamic change of bacterial (A. baumannii BAA 747) burden in mice with graded immunosuppression over 24 h was captured by a mathematical model. The fit to the data was satisfactory (r2 = 0.945). The best-fit maximal kill rate (Kk) of the bacterial population by neutrophils was 1.743 h−1, the number of neutrophils necessary for 50% maximal killing was 190.8/μl, and the maximal population size was 1.8 × 109 CFU/g, respectively. Using these model parameter estimates, the model predictions were subsequently validated by the bacterial burden change of P. aeruginosa PAO1 at 24 h. A simple mathematical model was proposed to quantify the contribution of neutrophils to bacterial clearance and predict the bacterial growth/suppression in animals. Our results provide a novel framework to link in vitro and in vivo information and may be used to improve clinical treatment of bacterial infections