Влияние фармакологического профиля антимикробного препарата на эффективность терапии инфекций мочевыводящих путей

Духанин А.С. Влияние фармакологического профиля антимикробного препарата на эффективность терапии инфекций мочевыводящих путей. Consilium Medicum. 2019; 21 (7): 69–74. DOI: 10.26442/20751753.2019.7.190509

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Dukhanin A.S. Effect of antibacterial agent PK/PD index on efficacy of lower urinary tract infection therapy. Consilium Medicum. 2019; 21 (7): 69–74. DOI: 10.26442/20751753.2019.7.190509

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Аннотация

Индивидуальный фармакологический профиль антимикробного препарата (АМП) определяется его фармакокинетическими/фармакодинамическими свойствами и обозначается как PK/PD-профиль. На основании расчетных показателей PK/PD-индекса выделены различные типы антимикробной активности: концентрация-зависимые и время-зависимые АМП. Фторхинолоны относятся к антимикробным средствам с концентрация-зависимым эффектом, для которых важна пиковая концентрация действующего вещества для достижения бактерицидного эффекта. Наряду с ми-нимальной ингибирующей концентрацией для оценки микробиологической эффективности ципрофлоксацина важен показатель минимальной концентрации, предотвращающей мутации, который отражает наличие «окна селекции мутации». Основным препятствием на пути повышения биодоступности и формирования максимальных плазменных концентраций ципрофлоксацина является «узкое окно всасывания». Оригинальная пролонгированная лекарственная форма ципрофлоксацина 1000 мг для однократного приема в день (Цифран® ОД 1000 мг) основана на ФДД-тех-нологии: флотирования, диспергирования и диффундирования. За счет создаваемых более высоких значений максимальной плазменной концентрации АМП таблетированная форма пролонгированного высвобождения позволяет преодолевать «окно селекции мутации» основных уропатогенов. Доказанное снижение частоты терапевтических неудач при использовании схемы дозирования ципрофлоксацина 1000 мг 1 раз в сутки обусловлено возможностью замедлить скорость мутационного процесса и препятствовать селекционному отбору резистентных штаммов уропатогенов на фоне антимикробной терапии, а также повышением приверженности терапии.

Ключевые слова: фармакокинетика, фармакодинамика, антимикробная резистентность, фторхинолоны, ципрофлоксацин, лекарственная форма, эффективность терапии, терапевтические неудачи.

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The individual pharmacological profile of an antimicrobial drug (AMP) is determined by its pharmacokinetic/pharmacodynamic properties and is referred to as the PK/PD profile. Based on the estimated PK/PD index, various types of antimicrobial activity were identified: concentration-dependent and time-dependent AMP. Fluoroquinolones are antimicrobial agents with a concentration-dependent effect, for which the peak concentration of the active substance is important to achieve a bactericidal effect. Along with the minimum inhibitory concentration, for assessing the microbiological efficacy of ciprofloxacin, an indicator of the mi-nimum concentration preventing mutations, which reflects the presence of the “mutation selection window”, is important. The main obstacle to increasing bio-availability and the formation of maximum plasma concentrations of ciprofloxacin is a “narrow absorption window”. The original prolonged dosage form of ciprof-loxacin 1000 mg for a single dose per day (Cifran® OD 1000 mg) is based on FDD technology: flotation, dispersion and diffusion. Due to the higher Cmax values created, the tablet form of the sustained release allows overcoming the “window of selection mutation” of the main uropathogens. The proven reduction in the frequency of therapeutic failures when using the ciprofloxacin 1000 mg dosing regimen 1 time per day is due to the possibility of slowing down the mutation rate and preventing the selection of resistant strains of uropathogens against the background of antimicrobial therapy, as well as increasing adherence to therapy.

Key words: pharmacokinetics, pharmacodynamics, antimicrobial resistance, fluoroquinolones, ciprofloxacin, dosage form, therapeutic efficacy, therapeutic failure.

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Список литературы

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________________________________________________

1. Asín-Prieto E, Rodríguez-Gascón A, Isla A. Applications of the pharmacokinetic/pharmacodynamic (PK/PD) analysis of antimicrobial agents. J Infect Chemother 2015; 21 (5): 319–29.
2. Dukhanin AS, Patrashev DV, Ogurtsov SI. Intracellular ph in thymocytes at the early stages of apoptosis and necrosis. Bull Exp Biol Med 1999; 128 (4): 991–3.
3. Sergeev PV, Galenko-Yaroshevskii PA, Khankoeva AI, Dukhanin AS. A study of the mechanism of action of befol on Ca2+ metabolism in cardiomyocytes using a fura-2 fluorescent probe. Bull Exp Biol Med 1996; 121 (3): 265–7.
4. Onufrak NJ, Forrest A, Gonzalez D. Pharmacokinetic and Pharmacodynamic Principles of Anti-Infective Dosing. Clin Ther 2016; 38(9): 1930–47.
5. Strachunsky L.S., Belousov Yu.B., Kozlov S.N. Practical Guide to Anti-infective Chemotherapy. http:// www.antibiotic.ru/ab/ (in Russian).
6. Kapoor G, Saigal S, Elongavan A. Action and resistance mechanisms of antibiotics: A guide for clinicians. J Anaesthesiol Clin Pharmacol 2017; 33 (3): 300–5.
7. Owens RC, Shorr AF. Rational dosing of antimicrobial agents: Pharmacokinetic and pharmacodynamic strategies. Am J Health Syst Pharm 2009; 66 (Suppl. 4): S23–S30.
8. MacDougall C, Chambers HF. Aminoglycosides. In: Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th Ed., edited by Brunton LL, Hilal-Dandan R, Knollmann BC, NewYork, McGraw-Hill Education, 2017; p. 1039–48.
9. Sab A, Tomas A, Tomić N et al. Pharmacokinetic/pharmacodynamic based dosing of ciprofloxacin in complicated urinary tract infections. Bangladesh J Pharmacol 2015; 10: 621–6.
10. Szałek E, Tomczak H, Kamińska A et al. The PK/PD index for ciprofloxacin in critically ill patients. Anestezjologia i Ratownictwo 2010; 4: 409–13.
11. Eyler RF, Shvets K. Clinical Pharmacology of Antibiotics. Clin J Am Soc Nephrol 2019. DOI: 10.2215/CJN.08140718
12. Levison ME, Levison JH. Pharmacokinetics and Pharmacodynamics of Antibacterial Agents. Infect Dis Clin North Am 2009; 23 (4):791–vii.
13. Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. Pharm Ther 2015; 40 (4): 277–83.
14. Blair JMA, Webber MA, Baylay AJ et al. Molecular mechanisms of antibiotic resistance. Nature Rev Microbiol 2015; 13 (1): 42–51.
15. Drlica K. The mutant selection window and antimicrobial resistance. J Antimicrob Chemother 2003; 52: 11–7.
16. Aldred KJ, Kerns RJ, Osheroff N. Mechanism of Quinolone Action and Resistance. Biochemistry 2014; 53 (10): 1565––74.
17. Blondeau JM, Zhao X, Hansen G, Drlica K. Mutant Prevention Concentrations of Fluoroquinolones for Clinical Isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 2001; 45 (2): 433–8.
18. Drlica K. The mutant selection window and antimicrobial resistance. J Antimicrob Chemother 2003; 52: 11–7.
19. Barber A, Norton J, Spivak A, Mulvey M. Urinary tract infections: Current and emerging management strategies. Clin Infect Dis 2013; 57: 719–24.
20. VanScoy BD, McCauley J, Ellis-Grosse EJ et al. Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an In Vitro Infection Model. Antimicrob Agents Chemother 2015; 59 (12): 7170–7.
21. Novelli A, Rosi E. Pharmacological properties of oral antibiotics for the treatment of uncomplicated urinary tract infections. J Chemother 2017; 29 (Supp1.): 10–8.
22. Dalhoff A, Schubert S, Venteb A. Pharmacodynamics of Finafloxacin, Ciprofloxacin, and Levofloxacin in Serum and Urine against TEM- and SHV-Type Extended-Spectrum-b-Lactamase-Producing Enterobacteriaceae Isolates from Patients with Urinary Tract Infections. Antimicrob Agents Chemother 2017; 61 (5): e02446–16.
23. Davis SS. Formulation strategies for absorption windows. Drug Discov Today 2005; 10 (4): 249–57.
24. Arza RA, Gonugunta CS, Veerareddy PR. Formulation and evaluation of swellable and floating gastroretentive ciprofloxacin hydrochloride tablets. AAPS Pharm Sci Tech 2009; 10 (1): 220–6.
25. Harder S, Fuhr U, Beermann D, Staib AH. Ciprofloxacin absorption in different regions of the human gastrointestinal tract. Investigations with the hf-capsule. Br J Clin Pharmacol 1990; 30 (1): 35–9.
26. Lopes CM, Bettencourt C, Rossi A et al. Overview on gastroretentive drug delivery systems for improving drug bioavailability. Int J Pharmaceut 2016; 510: 144–58.
27. Fourcroy JL, Berner B, Chiang YK et al. Efficacy and safety of a novel once-daily extended-release ciprofloxacin tablet formulation for treatment of uncomplicated urinary tract infection in women. Antimicrob Agents Chemother 2005; 49 (10): 4137–43.
28. Hickerson AD, Carson CC. The treatment of urinary tract infections and use of ciprofloxacin extended release. Expert Opin Investig Drugs 2006; 15 (5): 519–32.
29. Mirone V, Fusco F, Taglialatela D et al. Efficacy and safety of ciprofloxacin XR 1000 mg once daily versus ciprofloxacin 500 mg twice daily in the treatment of complicated urinary tract infections. J Chemother 2009; 21 (6): 651–60.
30. Iremashvili VV. New in the treatment of urinary tract infections: sustained release ciprofloxacin. RMJ 2008; 16 (5): 312–5 (in Russian).
31. Talan DA et al. Once daily, extended release ciprofloxacin for complicated urinary tract infections and acute uncomplicated pyelonephritis. J Urol 2004; 171 (2 Pt 1): 734–9.
32. Rasko DA, Sperandio V. Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov 2010; 9 (2): 117–28.
33. Cantas L, Shah SQA, Cavaco LM et al. A brief multi-disciplinary review on antimicrobial resistance in medicine and its linkage to the global environmental microbiota. Front Microbiol 2013; 4: 1–14.
34. Bjarnsholt T, Ciofu O, Molin S et al. Applying insights from biofilm biology to drug development – can a new approach be developed. Nature Rev Drug Discovery 2013; 12: 791–808.

Авторы

А.С. Духанин

ФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия
das03@rambler.ru

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Aleksandr S. Dukhanin

Pirogov Russian National Research Medical University, Moscow, Russia
das03@rambler.ru

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