Pharmacogenomics and adverse effects of anti-infective drugs in children.

Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti-infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti-infective drugs. However, data from paediatric-based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti-infective drugs recommended for gene-guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children.

New Palladium(II) Complexes Containing Methyl Gallate and Octyl Gallate: Effect against Mycobacterium tuberculosis and Campylobacter jejuni.

This work describes the preparation, characterization and antimicrobial activity of four palladium(II) complexes, namely, [Pd(meg)(1,10-phen)] 1, [Pd(meg)(PPh3)2] 2, [Pd(og)(1,10-phen)] 3 and [Pd(og)(PPh3)2] 4, where meg = methyl gallate, og = octyl gallate, 1,10-phen = 1,10-phenanthroline and PPh3 = triphenylphosphine. As to the chemical structures, spectral and physicochemical studies of 1-4 indicated that methyl or octyl gallate coordinates a palladium(II) ion through two oxygen atoms upon deprotonation. A chelating bidentate phenanthroline or two triphenylphosphine molecules complete the coordination sphere of palladium(II) ion, depending on the complex. The metal complexes were tested against the Mycobacterium tuberculosis H37Rv strain and 2 exhibited high activity (MIC = 3.28 µg/mL). As to the tests with Campylobacter jejuni, complex 1 showed a significant effect in reducing bacterial population (greater than 7 log CFU) in planktonic forms, as well as in the biomass intensity (IBF: 0.87) when compared to peracetic acid (IBF: 1.11) at a concentration of 400 µg/mL. The effect provided by these complexes has specificity according to the target microorganism and represent a promising alternative for the control of microorganisms of public health importance.

Application of machine learning in the therapeutic drug monitoring and individual drug therapy / 中国药房

Machine learning has been applied in the medical field due to its powerful data analysis and exploration capabilities. In recent years， more and more studies have applied it to therapeutic drug monitoring and individual drug therapy of immunosuppressants， anti-infective drugs， antiepileptic drugs， etc. Compared with the traditional population pharmacokinetic modeling methods， the constructed models based on machine learning can predict blood drug concentration and drug dose more accurately， improve the level of clinical precision drug use and reduce the occurrence of adverse drug reactions. Based on this， this article reviews the application of machine learning in therapeutic drug monitoring and individual drug therapy， with a view to providing theoretical basis and technical support for clinical precise drug use.

Antimicrobial use-related drug therapy problems and associated factors among patients in the medical ward of Wachemo University Nigist Eleni Mohammed Memorial Comprehensive Specialized Hospital, Southwest Ethiopia.

Objective: This study assessed the antimicrobial use-related drug therapy problems (DTPs) among patients admitted to the medical ward of Wachemo University Nigist Eleni Mohammed Memorial Comprehensive Specialized Hospital (WCUNEMMCSH), Southwest Ethiopia. Methods: A hospital-based prospective observational study design was used to assess antimicrobial use-related DTPs among patients admitted to the medical ward of WCUNEMMCSH from June to August 2021. Data were collected using a structured data abstraction format. Results: In all, 128 patients admitted to the medical ward were enrolled. Among the study participants, at least one form of antimicrobial DTP occurred in 98 (76.6%) of them. The most prevalent DTPs were unnecessary drug treatment in 42 (32.8%), the need for additional drug treatment in 36 (28.1%), and non-adherence in 30 (23.4%) of the patients. There were a total of 288 antimicrobial drug orders. Ceftriaxone 120 (41.7%) and azithromycin 69 (24.0%) were the most commonly prescribed antimicrobial drugs. In multivariate logistic analysis, the length of hospital stay (adjusted odds ratio (AOR) = 2.97, 95% confidence interval (CI): 1.06-8.32; p = 0.04) and the number of diagnosed diseases (AOR = 3.10, 95% CI: 1.12-8.15, p = 0.02) were predictors of antimicrobial use-related DTPs. Conclusion: Antimicrobial use-related DTPs are common among patients admitted to the medical ward of WCUNEMMCSH. Health professionals should work together to reduce the high prevalence of DTPs among medical ward admitted patients in this hospital.

An ultra sensitive and rapid SERS detection method based on vortex aggregation enhancement effect for anti-infective drug residues detection in water.

The environmental pollution and human health risks caused by anti-infective residual drugs in the environment have attracted much attention. More convenient and effective detection methods to achieve the rapid and high sensitivity detection for such pollutants are required. In this work, a novel surface-enhanced Raman scattering (SERS) strategy based on vortex aggregation of AgNPs was proposed for the detection of anti-infective drugs in environmental water. The method enhanced the Raman signal of the targets by 2-7.4 times. The mechanism of aggregation enhancement effect under the low-frequency oscillation procedure which significantly enhanced the SERS signal of targets molecular on the aggregated AgNPs was revealed by UV-vis and ICP-MS methods. Three drugs of cefazolin sodium, pefloxacin, and chloroquine phosphate were determined. The detect limits were 3.97 × 10-9 mol/L, 2.42 × 10-10 mol/L, and 7.34 × 10-9 mol/L for cefazolin sodium, pefloxacin, and chloroquine phosphate, respectively. The quantitative relationships were obtained in a wide linear range of 4-5 orders as well as good accuracy and stability with the recoveries of 84.0%-97.1% and the relative standard deviations (RSDs) less than 4.6% for spiked in actual water samples. This method also had excellent repeatability and stability, which have potential application for rapid detection of trace pollutants in water environment.

Multitargeted anti-infective drugs: resilience to resistance in the antimicrobial resistance era.

The standard drug discovery paradigm of single molecule - single biological target - single biological effect is perhaps particularly unsuitable for anti-infective drug discovery. This is due to the rapid evolution of resistance likely to be observed with single target drugs. Multitargeted anti-infective drugs are likely to be superior due to their lower susceptibility to target-related resistance mechanisms. Strathclyde minor groove binders are a class of compounds which have been developed by adopting the multitargeted anti-infective drugs paradigm, and their effectiveness against a wide range of pathogenic organisms is discussed. The renaming of this class to Strathclyde nucleic acid binders is also presented due to their likely targets including both DNA and RNA.

Rebound of cyst number following discontinuation of guanabenz treatment for latent toxoplasmosis.

Toxoplasma gondii is a protozoan parasite that causes opportunistic infection in immunocompromised individuals. The parasite forms latent tissue cysts that are refractory to current treatments and give rise to life-threatening reactivated infection following immune suppression. Previously, we showed that guanabenz sharply reduces brain cyst count in BALB/c mice harboring latent toxoplasmosis; however, whether cyst count would change once drug treatment stopped was not addressed. In the present study, we observed a rebound in brain cysts following the discontinuation of guanabenz or a guanabenz-pyrimethamine combination therapy. The re-expansion of brain cysts was not accompanied by symptoms of acute toxoplasmosis. We also tested whether the rebound in cyst counts could be ameliorated by administering pyrimethamine during or after guanabenz treatment.

Reasons for antimicrobial treatment failures and predictive value of in-vitro susceptibility testing in veterinary practice: An overview.

The choice of the most suitable antimicrobial agent for the treatment of an animal suffering from a bacterial infection is a complex issue. The results of bacteriological diagnostics and the in-vitro antimicrobial susceptibility testing (AST) provide guidance of potentially suitable antimicrobials. However, harmonized AST methods, veterinary-specific interpretive criteria and quality control ranges, which are essential to conduct AST in-vitro and to evaluate the corresponding results lege artis, are not available for all antimicrobial compounds, bacterial pathogens, animal species and sites of infection of veterinary relevance. Moreover, the clinical benefit of an antimicrobial agent (defined as its in vivo efficacy) is not exclusively dependent on the in-vitro susceptibility of the target pathogen. Apart from the right choice of an antibacterial drug with suitable pharmacokinetic properties and an appropriate pharmaceutical formulation, the success of treatment depends substantially on its adequate use. Even if this is ensured and in-vitro susceptibility confirmed, an insufficient improvement of clinical signs might be caused by biofilm-forming bacteria, persisters, or specific physicochemical conditions at the site of infection, such as pH value, oxygen partial pressure and perfusion rate. This review summarizes relevant aspects that have an impact on the predictive value of in-vitro AST and points out factors, potentially leading to an ineffective outcome of antibacterial treatment in veterinary practice. Knowing the reasons of inadequate beneficial effects can help to understand possible discrepancies between in-vitro susceptibility and in vivo efficacy and aid in undertaking strategies for an avoidance of treatment failures.

[Clinical pharmacokinetics of anti-infective drugs in extracorporeal membrane oxygenation]. / Klinische Pharmakokinetik der Antiinfektiva bei extrakorporaler Membranoxygenierung.

Extracorporeal membrane oxygenation (ECMO) is becoming more and more clinically important. The extracorporeal circuit for membrane oxygenation consists of a pump, a membrane oxygenator and large volume tubing. The ECMO device forms an additional compartment, which can absorb drugs with high lipophilia and protein binding. Thus, ECMO affects the volume of distribution and the clearance. As a consequence, the pharmacokinetic-pharmacodynamic (pk-pd) target parameters cannot be achieved. The selection of an appropriate substance and the mode of application, combined with therapeutic drug monitoring (TDM), can significantly improve the therapeutic outcome of critically ill patients.

Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform.

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion-toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 ( TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.

Half blind superiority tests for clinical trials of anti-infective drugs.

This paper introduces a test of superiority of new anti-infective drug B over comparator drug A based on a randomized clinical trial. This test can be used to demonstrate assay (trial) sensitivity for noninferiority trials and rigorously tailor drug choice for individual patients. Our approach uses specialized baseline covariates XA ,XB , which should predict the benefits of drug A and drug B, respectively. Using a response surface model for the treatment effect, we test for superiority at the (XA ,XB ) point that is most likely to show superiority. We identify this point based on estimates from a novel half-blind pseudo likelihood, where we augment a blinded likelihood (mixed over the treatment indicator) with likelihoods for the overall success rates for drug A and drug B (mixed over XA ,XB ). The augmentation results in much better estimates than those based on the mixed blinded likelihood alone but, interestingly, the estimates almost behave as if they were based on fully blinded data. We also develop an analogous univariate method using XA for settings where XB has little variation. Permutation methods are used for testing. If the "half-blind" test rejects, pointwise confidence interval can be used to identify patients who would benefit from drug B. We compare the new tests to other methods with an example and via simulations.

Development of a High-Throughput Biochemical Assay to Screen for Inhibitors of Aerobactin Synthetase IucA.

Acquiring sufficient quantities of iron to support survival is often a critical limitation for pathogenic bacteria. To meet this demand, bacteria have evolved unique strategies to scavenge iron and circumvent the nutritional immunity exerted by their hosts. One common strategy, which is often a key virulence factor for bacterial pathogens, involves the synthesis, secretion, and reuptake of iron chelators known as siderophores. In vitro and in vivo studies have demonstrated that the siderophore aerobactin is critical for virulence in the hypervirulent pathotype of Klebsiella pneumoniae (hvKP). Given the high rate of multidrug resistance in K. pneumoniae, and in light of the ever-increasing demand for novel Gram-negative therapeutic targets, we identified aerobactin production as a promising antivirulence target in hvKP. Herein, we describe the development of a high-throughput biochemical assay for identifying inhibitors of the aerobactin synthetase IucA. The assay was employed to screen ~110,000 compounds across several commercially available small-molecule libraries. IucA inhibitors with activity at micromolar concentrations were identified in our screening campaigns and confirmed using secondary orthogonal assays. However, the most potent compounds also exhibited some properties commonly observed with promiscuous/nonspecific inhibitors, including incubation time and target enzyme concentration dependence, as well as the potential to antagonize unrelated enzymes.

[Drug administration to pediatric patients: Evaluation of the nurses' preparation habits in pediatric units]. / Préparation et administration des médicaments dans les services de pédiatrie. Évaluation des pratiques des soignants.

In hospitals, the nursing staff is often confronted with the problem of the preparation and administration of drugs for their pediatric patients because of the lack of indication, pediatric dosage, and appropriate galenic form. The goal of this study was to give an overview of the nurses' preparation habits in pediatric units and highlight their daily problems. This single-center prospective study was conducted through an observation of the nursing staff during the drug preparation process in medicine, surgery and intensive care units. We included 91 patients (55 boys and 36 girls), with an average age of 6.3 years (youngest child, 10 days old; oldest child, 18 years old). We observed a mean 2.16 drug preparations per patient [1-5]. We collected 197 observation reports regarding 66 injectable drugs and 131 oral drugs (71 liquid forms and 60 solid forms). The majority of these reports concerned central nervous system drugs (63/197), metabolism and digestive system drugs (50/197), and anti-infective drugs (46/197). The study highlights the nurses' difficulties: modification of the solid galenic forms, lack of knowledge on oral liquid form preservation or reconstitution methods, withdrawal of small volumes, and vague and noncompliant labeling. This study led to the creation of a specific working group for pediatrics. This multidisciplinary team meets on a regular basis to work toward improving the current habits to both simplify and secure drug administration to hospitalized children.

Analysis of off-label use of anti-infective drugs in children / 中国小儿急救医学

Off-label use or unlicensed use of anti-infective drugs is most commonly in children both in the outpatient and inpatient settings. Off-label anti-infective drug use is due to dosage,frequency,patient age,indication,route of administration,or contraindications. Off-label use of drugs does not necessarily mean unsafe use. Off-label drug use should be based on high-quality evidence;use within the context of a formal research proposal and exceptional use.

Antibiotic Effects of Loperamide: Homology of Human Targets of Loperamide with Targets in Acanthamoeba spp.

BACKGROUND: Loperamide is an anti-diarrheal drug prescribed for non-infectious diarrhea. The drug is an opioid receptor agonist, blocker of voltage-dependent calcium channel (Cav) and calmodulin (CaM) inhibitor on human cells. Loperamide has been reported to exert anti-amoebic effects against pathogenic strains of Acanthamoeba castellanii. OBJECTIVES: The precise mode of antibiotic action, cellular target homology with human counterparts and the pattern of cell death induced by loperamide in Acanthamoeba castellanii remain to be established. Additionally, we attempt to establish the presence a primitive Cav in Acanthamoeba castellanii. METHODS: Bioinformatics, 3D structural modelling, ligand binding predictions and apoptotic/ amoebicidal assays were used in this study to answer the above queries. Amino acid sequences and structural models were compared between human and A. castellanii proteins that are involved in the regulation of calcium (Ca+2) homeostasis. RESULTS: Our results show that A. castellanii expresses similar, to near identical types of primitive calcium channels Cav Ac and CaM that are well known targets of loperamide in humans. The growth assays showed anti-amoebic effects of loperamide at different doses, both alone and in combinations with other Ca+2- CaM inhibitors. The synergistic actions of loperamide with haloperidol showed to be more amoebicidal than when either of them used alone. Imaging with Annexin V, Acridine orange and Propidium iodide showed apoptosis in A. castellanii at a dose of 100 µg/ml and necrosis at higher doses of 250 µg/ml. CONCLUSION: Though, Acanthamoeba does not express a homolog of the human mu-opioid receptor, but does shows evidence of the homologs for other known human targets of loperamide that are involved in Ca+2 uptake and Ca+2 signal transduction pathways. This suggests optimization of similar drug interactions with these targets may be useful in developing new approaches to control the growth of this parasite and possibly the diseases caused by it.

Investigation of Pharmaceutical Care for Pediatric Severe Infection Treatment by Clinical Pharmacists / 中国药房

OBJECTIVE:To investigate the role of clinical pharmacists in pediatric severe infection treatment,and to provide reference for rational drug use in clinic. METHODS:Based on related typical cases,the breakthrough points of clinical pharmacists providing pharmaceutical care in pediatric severe infection treatment plan were introduced. RESULTS:Clinical pharmacists formu-lated multi-drug resistance pathogenic antibacterial plan according to the results of pathogenic microbiological examination,use pharmacokinetics/pharmacodynamics,excluded interference to pediatric anti-infection treatment from ADR,and guideline and eco-nomical factors of patients. CONCLUSIONS:Clinical pharmacists adopt professional knowledge of pharmacy to provide pharmaceu-tical care in pediatric severe infection treatment and play professional assisted role so as to guarantee safe,effective and economical treatment.

11(th) National Meeting of Organic Chemistry and 4(th) Meeting of Therapeutic Chemistry.

For the first time under the auspices of Sociedade Portuguesa de Química, the competences of two important fields of Chemistry are brought together into a single event, the 11st National Organic Chemistry Meeting and the the 4th National Medicinal Chemistry Meeting, to highlight complementarities and to promote new synergies. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.

Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression.

Patients with severe lung disease may develop hypercapnia, elevation of the levels of CO2 in the lungs and blood, which is associated with increased risk of death, often from infection. To identify compounds that ameliorate the adverse effects of hypercapnia, we performed a focused screen of 8832 compounds using a CO2-responsive luciferase reporter in Drosophila S2* cells. We found that evoxine, a plant alkaloid, counteracts the CO2-induced transcriptional suppression of antimicrobial peptides in S2* cells. Strikingly, evoxine also inhibits hypercapnic suppression of interleukin-6 and the chemokine CCL2 expression in human THP-1 macrophages. Evoxine's effects are selective, since it does not prevent hypercapnic inhibition of phagocytosis by THP-1 cells or CO2-induced activation of AMPK in rat ATII pulmonary epithelial cells. The results suggest that hypercapnia suppresses innate immune gene expression by definable pathways that are evolutionarily conserved and demonstrate for the first time that specific CO2 effects can be targeted pharmacologically.

Adverse drug reactions during 2014 in Shengli Oil Field Central Hospital:analysis of 540 cases / 中国基层医药

Objective To investigate the characteristics of adverse drug reaction( ADR) in Shengli Oil Field Central Hospital and promote clinical rational use of drug.Methods 540 ADR cases collected in our hospital during 2014 were analyzed statistically in terms of patients'age and gender,drug types and route of administration,clinical manifestation etc.Results The 540 ADR cases occurred in male/female ratio of 1.01:1;209 cases(38.7%) aged≥60 years;425 cases(78.7%) were induced via intravenous injection;69 cases(12.8%) were induced by oral drugs;the anti-infective drugs ranked the first in terms of ADR incidence;285 cases ( 35.14%) manifested as lesions of skin and its appendants;148 cases involved the basic drugs.Conclusion It is important to strengthen ADR monitoring in hospital and achieve rational and standard use of anti-infective drugs so as to avoid or reduce the occurrence of severe ADR.

Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug therapy in cancer patients with kidney dysfunction.

Patients with cancer have a high inherent risk of infectious complications. In addition, the incidence of acute and chronic kidney dysfunction rises in this population. Anti-infective drugs often require dosing modifications based on an estimate of kidney function, usually the glomerular filtration rate (GFR). However, there is still no preferential GFR formula to be used, and in acute kidney injury there is always a considerable time delay between true kidney function and estimated GFR. In most cases, the anti-infective therapy should start with an immediate and high loading dose. Pharmacokinetic as well as pharmacodynamic principles must be applied for further dose adjustment. Anti-infective drugs with time-dependent action should be given with the target of high trough concentrations (e.g., beta lactam antibiotics, penems, vancomycin, antiviral drugs). Anti-infective drugs with concentration-dependent action should be given with the target of high peak concentrations (e.g., aminoglycosides, daptomycin, colistin, quinolones). Our group created a pharmacokinetic database, called NEPharm, hat serves as a reference to obtain reliable dosing regimens of anti-infective drugs in kidney dysfunction as well as renal replacement therapy. To avoid the risk of either too low or too infrequent peak concentrations, we prefer the eliminated fraction rule for dose adjustment calculations.