Retrospective Analysis of the Safety of Antibacterial Medicinal Products for Elderly Patients with Community-Acquired Lower Respiratory Tract Infections

Cephalosporins are the empirical antibiotic therapy (ABT) of choice for patients with community-acquired pneumonia (CAP). When treated with antibiotics, elderly patients, especially those with comorbidities, are at higher risk of developing adverse drug reactions (ADRs).The aim of the study was to analyse data on the safety and efficacy of initial empirical ABT with cephalosporins in elderly patients over 75 years old with CAP admitted to multidisciplinary hospitals in Moscow.Materials and methods. The retrospective study included 305 medical records of patients with CAP admitted to three multidisciplinary hospitals in Moscow in 2017–2019 and prescribed initial mono- and/or combination ABT including a cephalosporin. Initial ABT was considered effective if the body temperature normalised within 48–72 h from the start of treatment. It was considered safe if there were no ADRs during hospital stay.Results. Mostly, patients were prescribed ceftriaxone monotherapy or ceftriaxone and azithromycin combination therapy. These ABT regimens were effective in 69.07% and 78.10% of the cases, respectively. Patients with severe CAP needed their initial ABT adjusted significantly more often than those with non-severe CAP. The initial ABT was changed for a number of reasons, including ineffectiveness, ADRs, abscesses formed as a complication of CAP, sputum culture results enabling causal ABT, secondary hospital-acquired infections, and exacerbated chronic infections. All patients had comorbidities, and the most prevalent were arterial hypertension (83.9%), coronary heart disease (45.6%), chronic heart failure (44.9%), cerebrovascular disease (40.9%), atrial fibrillation (26.9%), diabetes mellitus (21.3%), and chronic obstructive pulmonary disease (19.0%). Initial ABT was significantly more often considered ineffective in patients with chronic heart failure and cerebrovascular disease. The most common causative agent of CAP in the study population was Streptococcus pneumoniae (31.9%). In 16% of patients, the authors identified ADRs associated with the antibiotics used as initial therapy. The most common were diarrhoea, anaemia, leucopenia, and hepatopathy. Ceftriaxone was associated with ADRs in 11% of patients.Conclusions. The study results suggest that initial mono- and/or combination ABT including a cephalosporin is effective and relatively safe; therefore, this treatment option is expedient for elderly patients with CAP. For this population, the safety of ABT may be improved through the wider use of existing markers of ADRs and the identification of new ones

Evaluation of the Efficacy and Safety of Initial Empirical Antibiotic Therapy for Community-Acquired Pneumonia in Middle-Aged People

β-lactam antibiotics, including cephalosporins, are the drugs of choice for empirical antibiotic therapy (ABT) in patients with community-acquired pneumonia. Unreasonable and irrational use of antibiotics leads to an increased risk of adverse reactions, contributes to the growth of antibiotic resistance.The aim of the study was to analyse data on the efficacy and safety of initial empirical ABT using cephalosporins for community-acquired pneumonia in middle-aged patients of multidisciplinary hospitals in Moscow.Materials and methods: the authors analysed 177 archived medical records of the patients admitted to three multidisciplinary hospitals (I.V. Davydovsky City Clinical Hospital, City Clinical Hospital 52 and City Clinical Hospital 4) in Moscow from 2017 to 2019 and prescribed mono- and/or combination therapy including a cephalosporin antibiotic as a starting therapy for community-acquired pneumonia. The initial ABT was considered effective if a patient’s body temperature normalised within 48–72 h following initiation of treatment and safe if no adverse reactions developed during the period of inpatient treatment.Results: the combination of ceftriaxone and azithromycin was the most frequently prescribed ABT regimen; its effectiveness was 71.9%. Ceftriaxone monotherapy was the second in frequency of prescription; its effectiveness amounted to 77.2%. The third regimen included cefotaxime and azithromycin and was effective in 70% of cases. The patients who needed a change in initial ABT had a significantly higher incidence of developing severe community-acquired pneumonia and complications. The study results indicate that the structure of comorbidity did not affect the effectiveness of initial empirical ABT. Streptococcus pneumoniae was found to be the most common causative agent of community-acquired pneumonia in the studied population (44.8% of cases). Only 13% of the patients faced adverse reactions associated with the use of antibiotics as part of the initial empirical ABT; the most common were leukopenia and diarrhoea.Сonclusions: the results of the study indicate the feasibility of mono- and/or combination ABT including a cephalosporin antibiotic as a starting empirical therapy for community-acquired pneumonia due to its effectiveness and favourable safety profile

Features of Toxic Nephropathy Development during Antibiotic Therapy

Antibacterials can have nephrotoxic effects because medicinal products of this class are primarily excreted by the kidneys. The aim of the study was to analyse literature data on the mechanisms, risk factors and specific features of toxic nephropathy development during antibiotic therapy. The article considers mechanisms of development of acute interstitial nephritis, acute tubular necrosis, crystal deposits in the tubules, proximal or distal tubulopathy with electrolyte abnormalities during the use of antibiotics. Nephrotoxicity was shown to be most often associated with the use of aminoglycosides, beta-lactams, and vancomycin. The authors analysed the dependence of nephrotoxicity on antibacterial agent lipophilicity and drug-drug interactions. The main risk factors for developing nephropathy are older age; male sex; black race; hypovolemia; arterial hypotension; angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs or their combinations; and individual genetic characteristics. Nephrotoxicity is associated with genetic characteristics of the systems responsible for metabolism and excretion of antibacterial products: cytochrome P450 isoenzymes, P-glycoprotein, multidrug resistance protein (MRP), multidrug and toxin extrusion (MATE), breast cancer resistance protein (BCRP), and organic anion transporters. Severe generalised infections change pharmacokinetic parameters of antibacterial products. This should be taken into account when prescribing the hydrophilic antibiotics that are excreted by tubular secretion and reabsorbed in the renal tubules. The study demonstrated the effectiveness of the method comprising a combination of dose adjustment based on therapeutic drug monitoring results and renal function monitoring for improving the safety of antibiotic therapy

Особенности развития токсической нефропатии при проведении антибиотикотерапии

Antibacterials can have nephrotoxic effects because medicinal products of this class are primarily excreted by the kidneys. The aim of the study was to analyse literature data on the mechanisms, risk factors and specific features of toxic nephropathy development during antibiotic therapy. The article considers mechanisms of development of acute interstitial nephritis, acute tubular necrosis, crystal deposits in the tubules, proximal or distal tubulopathy with electrolyte abnormalities during the use of antibiotics. Nephrotoxicity was shown to be most often associated with the use of aminoglycosides, beta-lactams, and vancomycin. The authors analysed the dependence of nephrotoxicity on antibacterial agent lipophilicity and drug-drug interactions. The main risk factors for developing nephropathy are older age; male sex; black race; hypovolemia; arterial hypotension; angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs or their combinations; and individual genetic characteristics. Nephrotoxicity is associated with genetic characteristics of the systems responsible for metabolism and excretion of antibacterial products: cytochrome P450 isoenzymes, P-glycoprotein, multidrug resistance protein (MRP), multidrug and toxin extrusion (MATE), breast cancer resistance protein (BCRP), and organic anion transporters. Severe generalised infections change pharmacokinetic parameters of antibacterial products. This should be taken into account when prescribing the hydrophilic antibiotics that are excreted by tubular secretion and reabsorbed in the renal tubules. The study demonstrated the effectiveness of the method comprising a combination of dose adjustment based on therapeutic drug monitoring results and renal function monitoring for improving the safety of antibiotic therapy.Антибактериальные препараты могут оказывать нефротоксическое действие, поскольку препараты этой группы преимущественно элиминируются почками. Цель работы — анализ данных литературы о механизмах, факторах риска и особенностях развития токсической нефропатии при проведении антибиотикотерапии. Рассмотрены механизмы развития острого интерстициального нефрита, острого некроза канальцев, отложения кристаллов внутри канальцев, проксимальной или дистальной тубулопатии с аномалиями расходования электролитов на фоне применения антибиотиков. Показано, что нефротоксичность наиболее часто ассоциирована с применением аминогликозидных, бета-лактамных антибактериальных средств, ванкомицина. Проанализирована зависимость нефротоксичности от липофильности антибактериальных препаратов и межлекарственного взаимодействия. Определено, что основными факторами риска развития нефропатии являются пожилой возраст, мужской пол, негроидная раса, гиповолемия, артериальная гипотензия, прием ингибиторов ангиотензинпревращающего фермента, блокаторов рецепторов ангиотензина II, нестероидных противовоспалительных препаратов или их комбинации, индивидуальные генетические особенности. Отмечена связь нефротоксичности и генетических особенностей систем метаболизма и выведения антибактериальных средств: изоферментов цитохрома P450, Р-гликопротеина, белков семейства множественной лекарственной резистентности MRP (multidrug resistance-associated protein) и MATE (multidrug and toxin extrusion protein), белка резистентности рака молочной железы BCRP (breast cancer resistance protein). Тяжелая генерализованная инфекция изменяет фармакокинетические параметры антибактериальных лекарственных средств, что следует учитывать при назначении гидрофильных антибиотиков, которые выводятся путем канальцевой секреции и реабсорбируются в почечных канальцах. Показано, что коррекция дозирования антибактериальных лекарственных препаратов на основе результатов терапевтического лекарственного мониторинга в совокупности с контролем функции почек является эффективным методом повышения безопасности антибиотикотерапии

Major Aspects of Detection and Monitoring of Adverse Reactions Associated with Cephalosporin Antibiotic Treatment

Widespread use of cephalosporin antibiotics in clinical practice calls for greater attention to the risk of adverse drug reactions. Information on serious or unexpected adverse events reported during post-marketing experience is submitted to national and international pharmacovigilance databases. Analysis of these reports helps to identify new adverse drug reactions.The aim of the study was to analyse the safety profile of cephalosporin antibiotics based on spontaneous reports in the international VigiBase database.Materials and methods: the analysis of the adverse reaction profile of cephalosporin antibiotics was based on MedDRA system organ classes and included spontaneous reports submitted to VigiBase from the moment of its creation until August 2020.Results: the authors identified the most clinically significant adverse reactions for different cephalosporin generations. They compared and analysed information on adverse events in VigiBase and in patient information leaflets of medicinal products authorised in the Russian Federation. It was demonstrated that some serious events described in VigiBase spontaneous reports for V-generation cephalosporins are not included in the “Side effects” section of the patient information leaflets. According to VigiBase, the use of ceftaroline was associated with the development of generalised exfoliative dermatitis, Stevens–Johnson syndrome, tubulointerstitial nephritis, while the use of ceftolozane was associated with acute kidney injury, renal insufficiency, sepsis, pneumonia, and respiratory insufficiency.Conclusion: reporting of unexpected and serious adverse drug reactions to cephalosporin antibiotics is an important task of healthcare practitioners. Availability of information on class-specific and generation-specific serious adverse reactions will help predict and prevent their development

Topical Issues of Drug Safety, Possibilities of Improving of Pharmacovigilance

Since 2010, Russia has been developing new drug legislation, internal quality control and safety of medical organizations, and has developed algorithms for submitting Individual Case Safety Reports (ICSR) using an automated information system. On April 1, 2019, Russia launched an updated national database of ICSR, which uses the international ICH E2B data standard, which may increase the amount of reporting to the Uppsala monitoring center. This publication covers the key aspects of pharmacovigilance system development in the Russian Federation. The analysis of pharmacovigilance structure in the Russian Federation is carried  out, its main problems are designated. Presents methods to identify causal relationships between adverse reaction and drug, evaluation of its degree of validity (questionnaires, algorithms, and scale), as already recommended by the WHO, and the new modifi ed versions. The expediency of using a scale for determining the degree of reliability of a causal relationship «an undesirable reaction — drug interaction» when analyzing spontaneous reports of undesirable reactions that may be caused by drug interactions is noted. An effective method of detection and prevention of adverse reactions is presented — the Global Trigger Tool (GTT). The question of the need for motivation and training of medical personnel in the correct design of spontaneous messages, as well as methods of identifying the causal relationship between adverse reactions of drugs. The directions of optimization of pharmacovigilance system are proposed, including methods of more effective active surveillance in the identifi cation and prevention of adverse reactions

Combined Therapy of Arterial Hypertension. The Opinion of a Clinical Pharmacologist

Modern tactics of treatment of arterial hypertension (AH) involves the use of both monotherapy and combination therapy. Monotherapy is recommended primarily for low-risk patients with systolic blood pressure (BP)< 150 mm Hg. Monotherapy should also be preferred in very high risk patients with high normal BP and frail elderly patients. However, combination therapy is recommended for most hypertensive patients as initial therapy. Starting combination therapy is more effective in lowering BP than monotherapy. Even at low doses, it is usually more effective than maximum dose monotherapy. The most commonly prescribed combinations today contain a renin-angiotensin system blocker (angiotensin converting enzyme inhibitors or angiotensin II receptor blocker) with a calcium antagonist or diuretic. The combination of lisinopril with amlodipine not only proved its high efficiency in various international and Russian studies, but also turned out to be pharmacoeconomically more profitable. Fixed combinations of lisinopril and amlodipine are the optimal choice in the treatment of hypertensive patients, due to all the advantages of both components: higher efficacy and safety rates compared to monotherapy and better patient adherence to treatment

Interchangeability of glibenclamide-containing drugs

The article analyses the problem of interchangeability of glibenclamide-containing drugs that sometimes lack therapeutic equivalence even though their bioequivalence has been proven. The authors formulated the key factors affecting interchangeability of glibenclamide drugs and highlighted conditions that compromise interchangeability. Special attention was given to clinical pharmacology of glibenclamide and adverse reactions associated with sulfonylurea products. The article offers a summary of the main groups of glibenclamide drugs. It also substantiates the need for better coordination of production and clinical use of glibenclamide drugs which will help to ensure the comparability of generic and reference glibenclamide drugs in the long run

Pharmacogenetic testing in the treatment of type 2 diabetes with sulfonylurea drugs

The article analyses scientific literature on the use of pharmacogenetic testing to optimize sulfonylurea treatment of patients with type 2 diabetes. It describes characteristics of modern sulfonylurea drugs used in the treatment of type 2 diabetes, including their mode of action, and the frequency of associated hypoglycaemia events. The authors analysed the main pharmacokinetic parameters of sulfonylureas (bioavailability, protein binding, metabolites, elimination, etc.), and adverse reactions associated with these drugs. Based on integrated data on Cytochrome P450 isoenzymes role in sulfonylureas metabolism, and determination of the role played by polymorphism of the gene encoding this fragment, the authors demonstrated the usefulness of pharmacogenetic testing combined with phenotypic (losartan) testing in the treatment of patients with type 2 diabetes