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Clinical Pharmacokinetics Nov 2021Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex...
BACKGROUND
Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data.
OBJECTIVE
The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates.
METHODS
Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods.
RESULTS
The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods.
CONCLUSION
A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data.
Topics: Drug Elimination Routes; Humans; Infant, Newborn; Machine Learning; Metabolic Clearance Rate; Models, Biological; Vancomycin
PubMed: 34041714
DOI: 10.1007/s40262-021-01033-x -
Acta Tropica May 2021Pseudomonas aeruginosa (P. aeruginosa) is an important environmental, opportunistic and nosocomial pathogen with a significant threat to public health. The objectives of...
Pseudomonas aeruginosa (P. aeruginosa) is an important environmental, opportunistic and nosocomial pathogen with a significant threat to public health. The objectives of this study were to determine the in vitro antimicrobial susceptibility patterns of, and antibiotic drug combinations with synergistic effects against P. aeruginosa isolated from drinking water and hospitalized patients in Jordan. A total of 16 P. aeruginosa isolates were obtained from hospitalized patients and 15 were isolated from bottled drinking water were used in the study. Bacterial isolation and identification was performed using routine microbiological methods and confirmed using PCR technique targeting the 16S rDNA gene. The antimicrobial susceptibility patterns were determined by measuring the minimum inhibitory concentration (MIC) using the 2-fold microdilution method. Synergy interaction between various antimicrobials was determined using the checkerboard method and fractional inhibitory concentration index (FICI). The majority of water isolates were sensitive to gentamicin (93.3%), ticarcillin (86.7%) and ciprofloxacin, levofloxacin, amikacin, colistin, piperacillin, azlocillin, aztreonam, ceftazidime and imipenem (100% each). All water isolates (100%) were resistant to amoxicillin, oxytetracycline and doxycycline (93.3% and 86.7, respectively). For the clinical isolates, all (100%) were sensitive to ceftazidime, 81.3% were sensitive to aztreonam, while 62.5% were sensitive to ciprofloxacin, levofloxacin, gentamicin, amikacin, colistin, piperacillin, ticracillin, azlocillin, and imipenem. All clinical isolates (100%) were resistant to oxytetracycline, doxycycline and amoxicillin. Analysis of the checkerboard synergy assay of multi-drug resistant isolates (n=26) showed significant synergism (P ≤ 0.05) when ciprofloxacin or gentamicin were included in the combination. There were no significant differences in synergistic activity between ciprofloxacin and levofloxacin when combined with other antimicrobial agents of the beta-lactams or aminoglycosides classes. There were no significant differences in the synergistic activities between beta lactams - aminoglycoside and beta lactams - fluoroquinolone combinations. Results of this study indicate an alarming widespread presence of multidrug-resistant P. aeruginosa associated with chronic suppurative infections in hospitalized patients and apparently clean drinking water in Jordan. Treatment of clinical suppurative lesions must be based on culture and in vitro susceptibility testing using potent antimicrobial combinations to avoid emergence of resistant strains and to improve the clinical outcome of treated patients.
Topics: Anti-Bacterial Agents; Drinking Water; Drug Resistance, Bacterial; Drug Resistance, Multiple; Drug Synergism; Hospitalization; Humans; Jordan; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 33582141
DOI: 10.1016/j.actatropica.2021.105859 -
The Journal of Antimicrobial... Feb 2021Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming...
OBJECTIVES
Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming practical and ethical hurdles. This proof-of-concept study aimed to assess the population pharmacokinetics of azlocillin in neonates using real-world data, to make subsequent dose recommendations and to test these in neonates with early-onset sepsis (EOS).
METHODS
This prospective, open-label, investigator-initiated study of azlocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of azlocillin was developed, using an empirical dosing regimen combined with opportunistic samples resulting from waste material. Second, a Phase II clinical trial (ClinicalTrials.gov: NCT03932123) of this newly developed model-based dosing regimen of azlocillin was conducted to assure optimized target attainment [free drug concentration above MIC during 70% of the dosing interval ('70% fT>MIC')] and to investigate the tolerance and safety in neonates.
RESULTS
A one-compartment model with first-order elimination, using 167 azlocillin concentrations from 95 neonates (31.7-41.6 weeks postmenstrual age), incorporating current weight and renal maturation, fitted the data best. For the second step, 45 neonates (30.3-41.3 weeks postmenstrual age) were subsequently included to investigate target attainment, tolerance and safety of the pharmacokinetic-pharmacodynamic model-based dose regimen (100 mg/kg q8h). Forty-three (95.6%) neonates reached their pharmacokinetic target and only two neonates experienced adverse events (feeding intolerance and abnormal liver function), possibly related to azlocillin.
CONCLUSIONS
Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.
Topics: Anti-Bacterial Agents; Azlocillin; Humans; Infant, Newborn; Microbial Sensitivity Tests; Prospective Studies; Sepsis
PubMed: 33188385
DOI: 10.1093/jac/dkaa468 -
Infection Control and Hospital... Dec 2020To investigate the touch-contact antimicrobial efficacy of novel cold spray surface coatings composed of copper and silver metals, regard to their rate of microbial...
OBJECTIVE
To investigate the touch-contact antimicrobial efficacy of novel cold spray surface coatings composed of copper and silver metals, regard to their rate of microbial elimination.
DESIGN
Antimicrobial time-kill assay.
SETTING
Laboratory-based study.
METHODS
An adapted time-kill assay was conducted to characterize the antimicrobial efficacy of the developed coatings. A simulated touch-contact pathogenic exposure to Gram-positive Staphylococcus aureus (ATCC 25923), Gram-negative Pseudomonas aeruginosa (ATCC 27853), and the yeast Candida albicans (ATCC 10231), as well as corresponding resistant strains of gentamicin-methicillin-resistant S. aureus (ATCC 33592), azlocillin-carbenicillin-resistant P. aeruginosa (DSM 46316), and a fluconazole-resistant C. albicans strain was undertaken. Linear regression modeling was used to deduce microbial reduction rates.
RESULTS
A >7 log reduction in microbial colony forming units was achieved within minutes on surfaces with cold spray coatings compared to a single log bacterial reduction on copper metal sheets within a 3 hour contact period. Copper-coated 3-dimensional (3D) printed acrylonitrile butadiene styrene (ABS) achieved complete microbial elimination against all tested pathogens within a 15 minute exposure period. Similarly, a copper-on-copper coating achieved microbial elimination within 10 minutes and within 5 minutes with the addition of silver powder as a 5 wt% coating constituent.
CONCLUSIONS
In response to the global need for alternative solutions for infection control and prevention, these effective antimicrobial surface coatings were proposed. A longitudinal study is the next step toward technology integration.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Humans; Laboratories; Longitudinal Studies; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests
PubMed: 32811579
DOI: 10.1017/ice.2020.335 -
Scientific Reports Mar 2020Lyme disease is one of most common vector-borne diseases, reporting more than 300,000 cases annually in the United States. Treating Lyme disease during its initial...
Lyme disease is one of most common vector-borne diseases, reporting more than 300,000 cases annually in the United States. Treating Lyme disease during its initial stages with traditional tetracycline antibiotics is effective. However, 10-20% of patients treated with antibiotic therapy still shows prolonged symptoms of fatigue, musculoskeletal pain, and perceived cognitive impairment. When these symptoms persists for more than 6 months to years after completing conventional antibiotics treatment are called post-treatment Lyme disease syndrome (PTLDS). Though the exact reason for the prolongation of post treatment symptoms are not known, the growing evidence from recent studies suggests it might be due to the existence of drug-tolerant persisters. In order to identify effective drug molecules that kill drug-tolerant borrelia we have tested two antibiotics, azlocillin and cefotaxime that were identified by us earlier. The in vitro efficacy studies of azlocillin and cefotaxime on drug-tolerant persisters were done by semisolid plating method. The results obtained were compared with one of the currently prescribed antibiotic doxycycline. We found that azlocillin completely kills late log phase and 7-10 days old stationary phase B. burgdorferi. Our results also demonstrate that azlocillin and cefotaxime can effectively kill in vitro doxycycline-tolerant B. burgdorferi. Moreover, the combination drug treatment of azlocillin and cefotaxime effectively killed doxycycline-tolerant B. burgdorferi. Furthermore, when tested in vivo, azlocillin has shown good efficacy against B. burgdorferi in mice model. These seminal findings strongly suggests that azlocillin can be effective in treating B. burgdorferi sensu stricto JLB31 infection and furthermore in depth research is necessary to evaluate its potential use for Lyme disease therapy.
Topics: Animals; Anti-Bacterial Agents; Azlocillin; Borrelia burgdorferi; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Female; Humans; Lyme Disease; Mice, Inbred C3H
PubMed: 32123189
DOI: 10.1038/s41598-020-59600-4 -
Analytica Chimica Acta Mar 2020The uncontrolled usage of veterinary antibiotics has led to their widespread pollution in waterways and milk products. Potential impact of antibiotic residues on the...
The uncontrolled usage of veterinary antibiotics has led to their widespread pollution in waterways and milk products. Potential impact of antibiotic residues on the environment and human health such as increased antibiotic resistance of microorganisms and triggering allergic reactions in humans have been reported. In this work, we developed a highly selective and sensitive voltammetric aptasensor for on-step, sensitive and low cost detection of azlocillin antibiotic, one of the broad spectrum β-lactam antibiotics. The successful selection of DNA aptamers against azlocillin was accomplished using systemic evolution of ligands by exponential enrichment (SELEX) method. Fluorescence-binding assays showed dissociation constant of 55 nM for one of the selected aptamers (Az9). This aptamer was used to construct a competitive voltammetric aptasensor for azlocillin. A limit of detection of 1.2 pg/mL as well as remarkable selectivity against potential interfering agents, including amoxicillin, were achieved. This signal-off competitive sensor takes 30-50 min to complete the quantification of the target antibiotic. The sensor was challenged by detecting the target directly in complex environments such as tap and waste water where good recovery percentages were achieved.
Topics: Anti-Bacterial Agents; Aptamers, Nucleotide; Azlocillin; Base Sequence; Biosensing Techniques; DNA; Drinking Water; Electrochemical Techniques; Limit of Detection; Wastewater; Water Pollutants, Chemical
PubMed: 32029106
DOI: 10.1016/j.aca.2019.12.023 -
EBioMedicine Apr 2019Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a...
BACKGROUND
Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time- and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment.
METHODS
In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with >1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions.
FINDINGS
We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line.
INTERPRETATION
Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.
Topics: Cell Line, Tumor; Cell Survival; Drug Discovery; Drug Repositioning; Gene Expression Profiling; Genes, Reporter; Genome, Human; Genomics; Humans; Male; Metabolic Networks and Pathways; Metabolomics; Piperidines; Prostatic Neoplasms; Proteome; Proteomics
PubMed: 30905848
DOI: 10.1016/j.ebiom.2019.03.009 -
Journal of Pharmaceutical and... Feb 2019This work proposes a new method for the in vitro evaluation of the effect of UV irradiation on the production of free radicals and other reactive species during the...
This work proposes a new method for the in vitro evaluation of the effect of UV irradiation on the production of free radicals and other reactive species during the photodecomposition of drugs. The method was based on the UV irradiation of antibiotics molecules to generate excited states that undergo to homolytic bond cleavages. These reactive species can be detected by their ability to oxidize the luminol, producing the electronically excited aminophtalate, which decays to the ground state releasing electromagnetic radiation in the visible zone of the spectrum. This method was applied to penicillin G, nafcillin, azlocillin and neomycin dissolved in water. It was found that the intensity of the luminol chemiluminescence emission (CL) was proportional to the concentration and dependent on the molecular structure of these drugs. Under the optimized conditions, it was found that penicillin and azlocillin were the most susceptible to photodegradation, while neomycin sulfate was the less affected by the UV light. It was observed that the addition to the antibiotics dissolutions of a hydro-alcoholic extract of petals of calyxes of Roselle reduced the CL intensity, indicating that the extract was able to scavenge the free radicals in the irradiated drugs. This result suggest that its addition to the antibiotics can help in the protection against the radicals formed during the exposition to solar light of patients treated with topic similar antibiotics.
Topics: Administration, Topical; Anti-Bacterial Agents; Azlocillin; Dermatitis, Phototoxic; Flowers; Free Radical Scavengers; Free Radicals; Hibiscus; Luminescent Agents; Luminescent Measurements; Luminol; Neomycin; Oxidation-Reduction; Penicillins; Plant Extracts; Sunlight; Ultraviolet Rays
PubMed: 30471635
DOI: 10.1016/j.jpba.2018.11.004 -
IET Nanobiotechnology Dec 2017In recent years, the problems associated with bacterial resistance to antibiotics caused nanodrugs to be considered as a new way for infectious diseases treatment. The...
In recent years, the problems associated with bacterial resistance to antibiotics caused nanodrugs to be considered as a new way for infectious diseases treatment. The main purpose of this study was to develop a new agent against a very difficult bacterium to treat, based on azlocillin antibiotic and silver nanoparticles (AgNPs). Azlocillin was conjugated with AgNPs by chemical methods and its antimicrobial activity was studied against . using well diffusion agar method. Then, minimum inhibitory concentration and minimum bactericidal concentration of the new conjugate was specified with macro-dilution method. The animal study showed the considerable enhanced antibacterial effect of azlocillin in conjugation with AgNPs against . in comparison with azlocillin alone, AgNPs alone and azlocillin in combination with AgNPs.
Topics: Animals; Anti-Bacterial Agents; Azlocillin; Female; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Silver; Spectroscopy, Fourier Transform Infrared
PubMed: 29155393
DOI: 10.1049/iet-nbt.2017.0009