Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Analysis of the Russian Database of Spontaneous Reports.

(1) Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are extremely severe cutaneous adverse drug reactions which are relatively rare in routine clinical practice. An analysis of a national pharmacovigilance database may be the most effective method of obtaining information on SJS and TEN. (2) Methods: Design-a retrospective descriptive pharmacoepidemiologic study of spontaneous reports (SRs) with data on SJS and TEN retrieved from the Russian National Pharmacovigilance database for the period from 1 April 2019 to 31 December 2023. Descriptive statistics was used to assess the demographic data of patients and the structure of suspected drugs. (3) Results: A total of 170 SRs on SJS and TEN were identified, of which 32.9% were SJS and 67.1%-TEN. In total, 30% were pediatric SRs, 21.2%-SRs of the elderly. There were 12 lethal cases, and all cases were TEN. The leading culprit drugs were anti-infectives for systemic use and nervous system agents. The top 10 involved drugs are as follows: lamotrigine (23.5%), ibuprofen (12.9%), ceftriaxone (8.8%), amoxicillin and amoxicillin with beta-lactam inhibitors (8.8%), paracetamol (7.6%), carbamazepine (5.9%), azithromycin (4.1%), valproic acid (4.1%), omeprazole (3.5%), and levetiracetam (3.5%). (4) Conclusions: Our study was the first study in Russia aimed at the assessment of the structure of the drugs involved in SJS and TEN on the national level.

An Antimicrobial Copper-Plastic Composite Coating: Characterization and In Situ Study in a Hospital Environment.

A method has been proposed for creating an operationally durable copper coating with antimicrobial properties for the buttons of electrical switches based on the gas dynamic spray deposition of copper on acrylonitrile butadiene styrene (ABS) plastic. It is shown that during the coating process, a polymer film is formed on top of the copper layer. Comparative in situ studies of microbial contamination have shown that the copper-coated buttons have a significant antimicrobial effect compared to standard buttons. Analysis of swabs over a 22-week study in a hospital environment showed that the frequency of contamination for a copper-coated button with various microorganisms was 2.7 times lower than that of a control button. The presented results allow us to consider the developed copper coating for plastic switches an effective alternative method in the fight against healthcare-associated infections.

Drug-Induced Anaphylaxis: National Database Analysis.

(1) Background: National health system databases represent an important source of information about the epidemiology of adverse drug reactions including drug-induced allergy and anaphylaxis. Analysis of such databases may enhance the knowledge of healthcare professionals regarding the problem of drug-induced anaphylaxis. (2) Methods: A retrospective descriptive analysis was carried out of spontaneous reports (SRs) with data on drug-induced anaphylaxis (SRsAs) extracted from the Russian National Pharmacovigilance database (analyzed period 2 April 2019-21 June 2023). The percentage of SRsAs among SRs of drug-induced allergy (SRsDIAs) was calculated, as well as of pediatric, elderly, and fatal SrsAs. Drugs involved in anaphylaxis were assessed among total SRsAs, pediatric, and elderly SRsAs, and among fatal SRsAs. Demographic parameters of patients were assessed. (3) Results: SRsAs were reported in 8.3% of SRsDIAs (2304/27,727), the mean age of patients was 48.2 ± 15.8 years, and females accounted for 53.2% of cases. The main causative groups of drugs were antibacterials (ABs) for systemic use (44.6%), local anesthetics (20.0%), and cyclooxygenase (COX) inhibitors (10.1%). Fatal SRsAs were reported in 9.5% (218/2304) of cases, the mean age of patients was 48.0 ± 16.7 years, and females accounted for 56.4% of cases. Pediatric SRsAs accounted for 3.9% of pediatric SRsDIAs and 5.8% of all SRsAs, with a mean age of 11.8 ± 4.5 years, and females acccounted for 51.9% of cases. Elderly SRsAs accounted for 2% of elderly SRsDIAs and 2.8% of all SRsAs, and the mean age was 73.0 ± 5.3 years, and females accounted for 43.5% of cases. ABs caused 40% of SRsAs in the elderly, 42.9% in children, and 50% of fatal SRsAs. (4) Conclusions: Our study revealed a relatively high proportion of anaphylaxis among SRs of drug-induced allergy. ABs were the most prevalent causative agents, especially in fatal SRsAs.

Pharmacokinetics of Antibacterial Agents in the Elderly: The Body of Evidence.

Infections are important factors contributing to the morbidity and mortality among elderly patients. High rates of consumption of antimicrobial agents by the elderly may result in increased risk of toxic reactions, deteriorating functions of various organs and systems and leading to the prolongation of hospital stay, admission to the intensive care unit, disability, and lethal outcome. Both safety and efficacy of antibiotics are determined by the values of their plasma concentrations, widely affected by physiologic and pathologic age-related changes specific for the elderly population. Drug absorption, distribution, metabolism, and excretion are altered in different extents depending on functional and morphological changes in the cardiovascular system, gastrointestinal tract, liver, and kidneys. Water and fat content, skeletal muscle mass, nutritional status, use of concomitant drugs are other determinants of pharmacokinetics changes observed in the elderly. The choice of a proper dosing regimen is essential to provide effective and safe antibiotic therapy in terms of attainment of certain pharmacodynamic targets. The objective of this review is to perform a structure of evidence on the age-related changes contributing to the alteration of pharmacokinetic parameters in the elderly.

Population PK/PD modelling of meropenem in preterm newborns based on therapeutic drug monitoring data.

Background: Preterm neonates rarely participate in clinical trials, this leads to lack of adequate information on pharmacokinetics for most drugs in this population. Meropenem is used in neonates to treat severe infections, and absence of evidence-based rationale for optimal dosing could result in mismanagement. Aim: The objective of the study was to determine the population pharmacokinetic (PK) parameters of meropenem in preterm infants from therapeutic drug monitoring (TDM) data in real clinical settings and to evaluate pharmacodynamics (PD) indices as well as covariates affecting pharmacokinetics. Materials and methods: Demographic, clinical and TDM data of 66 preterm newborns were included in PK/PD analysis. The NPAG program from the Pmetrics was used for modelling based on peak-trough TDM strategy and one-compartment PK model. Totally, 132 samples were assayed by high-performance liquid chromatography. Meropenem empirical dosage regimens (40-120 mg/kg/day) were administered by 1-3-h IV infusion 2-3 times a day. Regression analysis was used to evaluate covariates (gestation age (GA), postnatal age (PNA), postconceptual age (PCA), body weight (BW), creatinine clearance, etc.) influenced on PK parameters. Results: The mean ± SD (median) values for constant rate of elimination (Kel) and volume of distribution (V) of meropenem were estimated as 0.31 ± 0.13 (0.3) 1/h and 1.2 ± 0.4 (1.2) L with interindividual variability (CV) of 42 and 33%, respectively. The median values for total clearance (CL) and elimination half-life (T1/2) were calculated as 0.22 L/h/kg and 2.33 h with CV = 38.0 and 30.9%. Results of the predictive performance demonstrated that the population model by itself gives poor prediction, while the individualized Bayesian posterior models give much improved quality of prediction. The univariate regression analysis revealed that creatinine clearance, BW and PCA influenced significantly T1/2, meropenem V was mostly correlated with BW and PCA. But not all observed PK variability can be explained by these regression models. Conclusion: A model-based approach in conjunction with TDM data could help to personalize meropenem dosage regimen. The estimated population PK model can be used as Bayesian prior information to estimate individual PK parameter values in the preterm newborns and to obtain predictions of desired PK/PD target once the patient's TDM concentration(s) becomes available.

Developmental Pharmacokinetics of Antibiotics Used in Neonatal ICU: Focus on Preterm Infants.

Neonatal Infections are among the most common reasons for admission to the intensive care unit. Neonatal sepsis (NS) significantly contributes to mortality rates. Empiric antibiotic therapy of NS recommended by current international guidelines includes benzylpenicillin, ampicillin/amoxicillin, and aminoglycosides (gentamicin). The rise of antibacterial resistance precipitates the growth of the use of antibiotics of the Watch (second, third, and fourth generations of cephalosporines, carbapenems, macrolides, glycopeptides, rifamycins, fluoroquinolones) and Reserve groups (fifth generation of cephalosporines, oxazolidinones, lipoglycopeptides, fosfomycin), which are associated with a less clinical experience and higher risks of toxic reactions. A proper dosing regimen is essential for effective and safe antibiotic therapy, but its choice in neonates is complicated with high variability in the maturation of organ systems affecting drug absorption, distribution, metabolism, and excretion. Changes in antibiotic pharmacokinetic parameters result in altered efficacy and safety. Population pharmacokinetics can help to prognosis outcomes of antibiotic therapy, but it should be considered that the neonatal population is heterogeneous, and this heterogeneity is mainly determined by gestational and postnatal age. Preterm neonates are common in clinical practice, and due to the different physiology compared to the full terms, constitute a specific neonatal subpopulation. The objective of this review is to summarize the evidence about the developmental changes (specific for preterm and full-term infants, separately) of pharmacokinetic parameters of antibiotics used in neonatal intensive care units.

Gene Polymorphism of Biotransformation Enzymes and Ciprofloxacin Pharmacokinetics in Pediatric Patients with Cystic Fibrosis.

(1) Background: Ciprofloxacin (CPF) is widely used for the treatment of cystic fibrosis, including pediatric patients, but its pharmacokinetics is poorly studied in this population. Optimal CPF dosing in pediatric patients may be affected by gene polymorphism of the enzymes involved in its biotransformation. (2) Materials and Methods: a two-center prospective non-randomized study of CPF pharmacokinetics with sequential enrollment of patients (n-33, mean age 9.03 years, male-33.36%), over a period from 2016 to 2021. All patients received tablets of the original CPF drug Cyprobay® at a dose of 16.5 mg/kg to 28.80 mg/kg. Blood sampling schedule: 0 (before taking the drug), 1.5 h; 3.0 h; 4.5 h; 6.0 h; 7.5 h after the first dosing. CPF serum concentrations were analyzed by high performance liquid chromatography mass spectrometry. The genotype of biotransformation enzymes was studied using total DNA isolated from whole blood leukocytes by the standard method. (4) Results: a possible relationship between the CA genotype of the CYP2C9 gene (c.1075A > C), the GG genotype of the CYP2D6*4 gene (1846G > A), the AG genotype of the GSTP1 gene (c.313A > G), the GCLC* genotype 7/7 and the CPF concentration in plasma (increased value of the area under the concentration−time curve) was established. Conclusions: Gene polymorphism of biotransformation enzymes may affect ciprofloxacin pharmacokinetics in children.

Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia.

BACKGROUND: A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clinical trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim analysis of this phase 3 trial. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial at 25 hospitals and polyclinics in Moscow, Russia. We included participants aged at least 18 years, with negative SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrolment, and no other vaccinations in the 30 days before enrolment. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. Investigators, participants, and all study staff were masked to group assignment. The vaccine was administered (0·5 mL/dose) intramuscularly in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S. The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. All analyses excluded participants with protocol violations: the primary outcome was assessed in participants who had received two doses of vaccine or placebo, serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The trial is registered at ClinicalTrials.gov (NCT04530396). FINDINGS: Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome analysis. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6-95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered associated with vaccination, with confirmation from the independent data monitoring committee. Four deaths were reported during the study (three [<0·1%] of 16 427 participants in the vaccine group and one [<0·1%] of 5435 participants in the placebo group), none of which were considered related to the vaccine. INTERPRETATION: This interim analysis of the phase 3 trial of Gam-COVID-Vac showed 91·6% efficacy against COVID-19 and was well tolerated in a large cohort. FUNDING: Moscow City Health Department, Russian Direct Investment Fund, and Sberbank.

Detecting medication errors associated with the use of beta-lactams in the Russian Pharmacovigilance database.

BACKGROUND: Comprehensive analysis of all available data in spontaneous reports (SRs) can reveal previously unidentified medication errors (MEs). METHODS: To detect MEs, we performed a retrospective analysis of SRs submitted to the Russian pharmacovigilance database in the period from January 01, 2012, to August 01, 2014. This study evaluated SRs of cases where beta-lactam antibiotics were the suspected drug. RESULTS: A total of 3608 SRs were analyzed. MEswere detected in 1043 reports (28.9% of all cases). The total number of detected errors was 1214. Reporters themselves indicated MEs in 29 SRs. A term denoting an ME was selected in the "Adverse Reactions" section in 18 of these SRs, whereas in the other 11 reports information on the ME was found only in the "Case narrative" section. MEs were associated with wrong indications in 32.5% of the cases; 61.0% of these cases were viral infections. Various dosing regimen violations constituted 29.7% of MEs. A contraindicated drug was administered in 17.3% of all detected MEs, most commonly to a patient with a history of allergy to the suspected drug or severe hypersensitivity reactions to other drugs of the same group. CONCLUSION: Automatic identification of MEs in the pharmacovigilance database is sometimes precluded by the absence of a code for the respective episode in the "Adverse Reactions" section, even when the error was detected by the reporter. The most frequent types of MEs associated with the use of beta-lactams in Russia are the leading risk factors of growing bacterial resistance.

Comparative genome analysis of global and Russian strains of community-acquired methicillin-resistant Staphylococcus aureus ST22, a 'Gaza clone'.

In this study, we identified the relationship between the genetic lineage of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) sequence type 22 (ST22) from Russia and other regions. Sixty ST22 isolates from Russia were characterised through whole-genome sequencing. To evaluate the phylogenetic relationship of Russian isolates with the global ST22 population, we analysed 1283 genomes obtained from NCBI's GenBank. The phylogenetic tree of the ST22 global population consisted of three main clusters (A, B and C). The first (cluster A) was represented by EMRSA-15 isolates, the second (cluster B) by heterogeneous isolates from different regions harbouring different sets of virulence genes, and the third (cluster C) by isolates from the Middle East previously recognised as 'Gaza clone' and similar isolates from Russia. Presence of the toxic shock syndrome toxin (tsst) and elastin-binding protein S (ebpS) genes as well as the hypothetical proteins NCTC13616_00051 and NCTC13616_00047 were the most useful factors in discriminating ST22 lineages. Although the CA-MRSA 'Gaza clone' was mainly recovered from carriers, its widespread occurrence is a cause for concern. Differentiation of the 'Gaza clone' from other MRSA lineages is necessary for planning infection control measures.