Β-lactam antibiotics in Ukraine: market and consumption analysis in 2013–2018

Стратегія боротьби проти розвитку антибіотикорезистентності – глобальний виклик для наукової спільноти задля життя і здоров’я населення. Аналіз взаємозв’язку між рівнями споживання антимікробних препаратів та розвитком антибіотикорезистентності – один з інструментів стримування останньої. Збільшення споживання антимікробних препаратів знижує можливості лікування інфекційних захворювань. Антимікробні препарати групи β-лактамів, за даними звітів Європейської мережі нагляду за споживанням антимікробних засобів, є одними з найбільш споживаних серед інших груп антибіотиків у Європі. В Україні рівень споживання β-лактамів значно нижчий середньоєвропейського. Такі дані вимагають детальної оцінки рівня споживання β-лактамних антимікробних препаратів, за окремими МНН, аналізу балансу їх застосування. Метою роботи є аналіз ринку та споживання АМП групи β-лактамів в Україні за 2013-2018 роки за допомогою ATC/DDD-методології, а також порівняння отриманих об’ємів споживання з аналогічними результатами в Європейському Союзі. Результати. Загальна кількість АМП групи β-лактамів представлених на ринку України у 2018 році становить 343 торгових найменування (ТН), з них – 92 пропозиції вітчизняних і 251 – іноземних фірм-виробників, що свідчить про високу насиченість українського фармацевтичного ринку імпортними препаратами В Україні у 2017 році пеніцилінів спожито у 4,48 разу менше ніж у середньому по ЄС, а цефалоспоринів та карбапенемів майже стільки ж. Найбільше було спожито препаратів МНН з групи пеніцилінів – Амоксициліну та Амоксициліну з інгібіторами β-лактамаз, а лідерами за об’ємами споживання серед цефалоспоринів є лікарські засоби за МНН Цефтріаксону і Цефуроксиму. Висновки. Антимікробні препарати групи β-лактамів добре вивчені та широко використовуються у медичній практиці, в асортименті представлені на ринку України (343 ТН), але тільки менше третини з них (92 ТН) – вітчизняного виробництва, що свідчить про високу насиченість українського фармацевтичного ринку імпортними препаратами. Об’єм споживання антимікробних препаратів групи βлактамів в Україні майже в 4,5 рази менший, ніж у країнах ЄС. Найбільш споживаними є препарати Амоксициліну – групи пеніцилінів широкого спектру дії та серед цефалоспоринів – препарати Цефтріаксону та Цефуроксиму Ключові слова: фармацевтичний ринок; β-лактамні антибіотики; споживання лікарських засобів; ATC/DDD-методологія


Introduction
After the discovery of penicillin in 1928 by a Scottish scientist and Nobel laureate, Alexander Fleming, antibiotics have come a long way to development [1].
More than 100 different types of antimicrobials (AMIs) have been invented to date. It has also been established that AMIs are active against different types of pathogens of infectious diseases, but there are "supermicroorganisms" with resistance to drugs, which creates new challenges for researchers.

Formulation of the problem in a general way, the relevance of the theme and its connection with important scientific and practical issues
Strategy against antibiotic resistance (ABR) is a global challenge for the scientific community for life and health of the population. Over the past decades around the world there has been a sharp increase in infections caused by pathogens with multiple ABR [2,3].

Analysis of recent studies and publications in which a solution of the problem are described and to which the author refers
The authors of the ABR study note the importance of a systematic view of current knowledge about the use of AMI and the prevention of infectious diseases [2][3][4][5]. Among publications, an important place is meta-analysis that allows us to rely on a number of relevant sources about the relationship between AMI consumption and the development of ABR [4].
A study of the consumption of β-lactam antibiotics in Ukraine was conducted by prof. Iakovlievа L. V. and assistant Matyashova N. O., but their work was published in 2010-2013, which requires updating data in order to identify new trends in the use of these drug groups.

The field of research considering the general problem, which is described in the article
Increased resistance to antibiotic drugs may be due to reasons such as inappropriate and uncontrolled use of antibiotics (affordability through sale without prescription); the use of antibiotics with a wide spectrum of action in the case of the effectiveness of agents with a narrower spectrum; non-compliance by patients with certain conditions of admission and inappropriate prophylactic use; uncontrolled and unregulated use in veterinary and rural (agrarian) farming; the absence of new groups of antibacterial agents. An analysis of the relationship between AMI consumption levels and the development of ABR is one of the tools to curb the latter. Increasing AMI consumption can not only provide greater stability at the level of individual strains of pathogens to antibiotics, which creates problems for their further use [4,5].

Formulation of goals (tasks) of article
The aim of this work is to analyze the market and consumption of AMI of the β-lactam group in Ukraine for 2013-2018, using the ATC / DDD methodology, identify trends in their use, and compare the obtained consumption volumes with similar results in the European Union.

Presentation of the main research material (methods and objects) with the justification of the results
Data on the consumption of the investigational drugs are determined using the ATC / DDD methodology recommended by the WHO. The DDDs per 1000 inhabitants per day (DID) were used to calculate the consumption of antibacterial agents of the study group. The calculations were carried out according to the analytical system of the pharmaceutical market research "Pharmstandard" of "Morion" company.

Results and their discussion
Today, the group of β-lactam AMI includes a number of drugs, most of which are well-studied and have long existed on world markets.
β-lactam antibiotics are bactericidal agents that interrupt the formation of a bacterial cell wall as a result of covalent binding to etheric penicillin-binding proteins (PBPs), enzymes involved in the final stages of crosslinking peptidoglycan, a bacterial wall component in gram-negative and gram-positive bacteria. Each bacterial species has its own distinct set of PBPs, which can range from three to eight enzymes to one species. The death of microbial cells can occur as a result of inhibition of one or more of these PBPs [7].
Penicillin G (Benzylpenicillin) was the first βlactam to be used in the clinic, most often for the treatment of streptococcal infections, to which it exhibited high activity. Another natural penicillin-Phenoxymethylpenicillin is used therapeutically and prophylactically for the mild and moderate severity of infections caused by susceptible Streptococcus spp., including use in children [8]. Among the penicillinase-resistant penicillins, clinical significance has Methicillin, Oxacillin, Cloxacillin and Nafcillin, and the latter is proposed as β-lactate for skin infections caused by methicillinsusceptible Staphylococcus aureus.
All these drugs were used primarily for the treatment of patients with Staphylococcus aureus before the onset of methicillin resistant S. aureus (MRSA) strains in 1979-1980 [9].
Penicillins with improved activity relative to gram-negative pathogens included bioavailable Ampicillin and Amoxicillin, both of which were marketed in the 1970s. These AMIs were initially used to treat infections caused by Enterobacteriaceae and did not effectively suppress the growth of Pseudomonas aeruginosa. Carbenicillin was the first anti-pseudomonal penicillin, but did not have resistance to hydrolysis by β-lactamase and was less potent than Piperacillin or Ticarcillin. The latter preparations were considered as potent penicillins of a wide range of effects, which counteract penicillinsensitive staphylococci, intestinal bacteria, anaerobes and P. aeruginosa. Since the late 1980s, they have been widely used to treat intra-infectious diseases, especially in combination with a β-lactamase inhibitor [11].
The increase in β-lactamase levels limited the therapeutic use of penicillins as monotherapy. Ampicillin, Amoxicillin, Piperacillin, and Tricacillin are continued in combination with a β-lactamase inhibitor [10]. However, Ampicillin, Amoxicillin, Benzylpenicillin, and Phenoxymethylpenicillin are still active as monotherapy for Group A streptococci and Treponema pallidum, which do not produce β-lactamase [12].
In the 1950's, the discovery of natural penicillinresistant Cephalosporin C indicated the pathway for the development of new cephalosporins for the treatment of infections, mainly caused by pathogens producing penicillinase (S. aureus). At that time dozens of cephalosporins were introduced into clinical practice either as parenteral or as oral agents [13]. The molecules showed antibacterial activity not only against staphylococci, but also against Streptococcus pneumoniae and non-β-lactamaseproducing bacteria.
Cefazolin is often used for the prevention of surgery and the treatment of abdominal infections [14] and is effective as empirical therapy in 80 % of Japanese children at the first infection of the upper urinary tract [15].
The total amount of AMI of the group β-lactams presented in the market of Ukraine in 2018 is 343 trade names (TNs), of which 92 are domestic and 251 foreign manufacturers, which indicates the high saturation of the Ukrainian pharmaceutical market with imported drugs (Table 1).
For comparison, in 2011 in the domestic market, 13 INN of penicillin group with 118 TNs were presented (26 Ukrainian and 92 imported) [16].  Data on the consumption of AMI β-lactams by the European Union (EU) in 2017 were taken from the reports of the European Surveillance of Antimicrobial Consumption Network (ESAC-Net) [18].
In Ukraine, in 2017 penicillins consumed at 4.48 and 3.7 times less than the EU average and Italy (the country with the highest consumption), and ceph alosporins and carbapenems are almost the same. Comparison with the Netherlands (the country with the lowest levels of consumption) suggests practically the same level of consumption of AMI of the βlactam group and 51.3 times higher consumption of the subgroup of cephalosporins and carbapenems (Fig. 1).

Fig. 1. Consumption of AMI β-lactams group in 2017 in DID
The consumption of AMI of β-lactam group in the period from 2013 to 2018 in Ukraine has increased (Tabl. 2); although in 2015 there was a decrease in consumption.
The most commonly used drugs were INNs from the penicillin group -Amoxicillin and Amoxicillin with inhibitors of β-lactamase. This choice of physicians is due to the wide range of amoxicillin used as a monotherapy for infectious diseases caused by streptococci and the activity of combinations of amoxicillin with β-lactamase inhibitors to all coccidian pathogens producing βlactamase. In Ukraine, these combinations (see tab. 2) are used as first-line drugs that stimulate the development of ABR and should only be used as second-line drugs [19].
The leaders in terms of consumption among cephalosporins are INN Ceftriaxone (III generation) and Cefuroxime (II generation). The choice of these drugs is due to their pharmacological properties. Cefuroxime has a wider range of antimicrobial effects than I generation drugs and is widely used for monotherapy not only in Ukraine but also in Europe as a cheap generic drug. Ceftriaxone is widely used in connection with its pharmacokinetic properties, because it is sufficient to administer once a day, which characterizes its high compliance [19]. Table 2 Consumption of AMI of β-lactam group from 2013 to 2018 in Ukraine

Conclusions from the conducted research and prospects for further development of this field
1. Antimicrobial preparations of the β-lactam group are well-studied and widely used in medical practice.
2. Preparations of the β-lactam group are widely represented in the Ukrainian market (343 TNs), but only less than a third of them (92 TNs) of domestic production, indicating a high saturation of the Ukrainian pharmaceutical market with imported drugs.
3. The volume of consumption of AMI of the βlactam group (penicillins) in Ukraine is almost 4.5 times lower than in the EU, which may indicate unbalanced use of different groups of AMI in terms of DDDs per 1000 inhabitants per day (DID). 4. Consumption in general of all β-lactam groups from 2013 to 2018 has increased, although years of decline in consumption (2015) have been noted.
5. The most consumed during the study period are drugs Amoxicillin -a group of broad-spectrum penicillins and among cephalosporins preparations Ceftriaxone and Cefuroxime.