Ингаляционные антибактериальные препараты: современные возможности применения при инфекциях дыхательных путей

Необходимость поиска путей повышения эффективности антибактериальной терапии обусловлена драматической эскалацией резистентности к антибактериальным препаратам (АБП), при этом темпы роста сопротивляемости микроорганизмов АБП опережают динамику разработки новых лекарственных средств. Согласно имеющимся данным, путь введения АБП может коррелировать с явлением развития резистентности к АБП. В статье рассмотрены актуальные данные о существующих ингаляционных АБП, позволяющие оценить их эффективность и безопасность. При терапии пациентов с инфекционными заболеваниями дыхательных путей альтернативой системному применению АБП может послужить ингаляционное введение ряда АБП, активность которых зависит от концентрации.

1. Zimlichman Е., Henderson D., Tamir О. et al. Health care-associated infections. a meta-analysis of costs and financial impact on the US health care system. JAMA Intern. Med. 2013; 173 (22): 2039–2046. DOI: 10.1001/jamainternmed.2013.9763.

2. Spellberg B., Blaser M., Guidos R.J. et al. Combating antimicrobial resistance: policy recommendations to save lives. Clin. Infect. Dis. 2011; 52 (Suppl. 5): S397–428. DOI: 10.1093/cid/cir153.

3. Aslam B., Wang W., Arshad M.I. et al. Antibiotic resistance: a rundown of a global crisis. Infect. Drug Resist. 2018; 11: 1645–1658. DOI: 10.2147/IDR.S173867.

4. Singer A.C., Shaw H., Rhodes V., Hart A. Review of antimicrobial resistance in the environment and its relevance to environmental regulators. Front. Microbiol. 2016; 7: 1728. DOI: 10.3389/fmicb.2016.01728.

5. Castro-Sánchez E., Moore L.S.P., Husson F., Holmes A.H. What are the factors driving antimicrobial resistance? Perspectives from a public event in London, England. BMC Infect. Dis. 2016; 16: 465. DOI: 10.1186/s12879-016-1810-x.

6. Chokshi A., Sifri Z., Cennimo D., Horng H. Global contributors to antibiotic resistance. J. Glob. Infect. Dis. 2019; 11 (1): 36–42. DOI: 10.4103/jgid.jgid_110_18.

7. Li J., Xie S., Ahmed S. et al. Antimicrobial activity and resistance: influencing factors. Front. Pharmacol. 2017; 8: 364. DOI: 10.3389/fphar.2017.00364.

8. Allcock S., Young E.H., Holmes M. et al. Antimicrobial resistance in human populations: challenges and opportunities. Glob. Health Epidemiol. Genom. 2017; 2: e4. DOI: 10.1017/gheg.2017.4.

9. Langdon A., Crook N., Dantas G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med. 2016; 8: 39. DOI: 10.1186/s13073-016-0294-z.

10. Becattini S., Taur Y., Pamer E.G. Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol. Med. 2016; 22 (6): 458–478. DOI: 10.1016/j.molmed.2016.04.003.

11. Teo S.M., Mok D., Pham K. et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe. 2015; 17 (5): 704–715. DOI: 10.1016/j.chom.2015.03.008.

12. Cuthbertson L., Rogers G.B., Walker A.W. et al. Respiratory microbiota resistance and resilience to pulmonary exacerbation and subsequent antimicrobial intervention. ISME J. 2016; 10: 1081–1091. DOI: 10.1038/ismej.2015.198.

13. Deshmukh H.S., Liu Y., Menkiti O.R. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 2014; 20: 524–530. DOI: 10.1038/nm.3542.

14. Ichinohe T., Pang I.K., Kumamoto Y. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl. Acad. Sci. USA. 2011; 108 (13): 5354–5359. DOI: 10.1073/pnas.1019378108.

15. Clarke T.B. Early innate immunity to bacterial infection in the lung is regulated systemically by the commensal microbiota via nod-like receptor ligands. Infect. Immun. 2014; 82 (11): 4596–4606. DOI: 10.1128/IAI.02212-14.

16. Khosravi A., Yanez A., Price J. et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe. 2014; 15 (3): 374–381. DOI: 10.1016/j.chom.2014.02.006.

17. Gauguet S., D'Ortona S., Ahnger-Pier K. et al. Intestinal microbiota of mice influences resistance to Staphylococcus aureus pneumonia. Infect. Immun. 2015; 83 (10): 4003–4014. DOI: 10.1128/IAI.00037-15.

18. Schuijt T.J., Lankelma J.M., Scicluna B.P. et al. The gut microbiota plays a protective role in the host defense against pneumococcal pneumonia. Gut. 2016; 65 (4): 575–583. DOI: 10.1136/gutjnl-2015-309728.

19. Brown R.L., Sequeira R.P., Clarke T.B. The microbiota protects against respiratory infection via GM-CSF signaling. Nat. Commun. 2017; 8: 1512. DOI: 10.1038/s41467-017-01803-x.

20. Zhang L., Huang Y., Zhou Y. et al. Antibiotic administration routes significantly influence the levels of antibiotic resistance in gut microbiota. Antimicrob. Agents Chemother. 2013; 57 (8): 3659–3666. DOI: 10.1128/AAC.00670-13.

21. Wenzler E., Fraidenburg D.R., Scardina T., Danziger L.H. Inhaled antibiotics for gram-negative respiratory infections. Clin. Microbiol. Rev. 2016; 29 (3): 581–632. DOI: 10.1128/CMR.00101-15.

22. Rodvold K.A., George J.M., Yoo L. Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents. Clin. Pharmacokinet. 2011; 50 (10): 637–664. DOI: 10.2165/11594090-000000000-00000.

23. Sylvester J.T., Shimoda L.A., Aaronson P.I., Ward J.P.T. Hypoxic pulmonary vasoconstriction. Physiol. Rev. 2012; 92 (1): 367–520. DOI: 10.1152/physrev.00041.2010.

24. McWilliam S.J., Antoine D.J., Smyth R.L., Pirmohamed M. Aminoglycoside-induced nephrotoxicity in children. Pediatr. Nephrol. 2017; 32: 2015–2025. DOI: 10.1007/s00467-016-3533-z.

25. Heta S., Robo I. The side effects of the most commonly used group of antibiotics in periodontal treatments. Med. Sci. (Basel). 2018; 6 (1): 6. DOI: 10.3390/medsci6010006.

26. Ma T.K.W., Chow K.M., Choy A.S.M. et al. Clinical manifestation of macrolide antibiotic toxicity in CKD and dialysis patients. Clin. Kidney. J. 2014; 7 (6): 507–512. DOI: 10.1093/ckj/sfu098.

27. Francis J.K., Higgins E. Permanent peripheral neuropathy: a case report on a rare but serious debilitating side-effect of fluoroquinolone administration. J. Investig. Med. High Impact Case Rep. 2014; 2 (3): 2324709614545225. DOI: 10.1177/2324709614545225.

28. Michalak K., Sobolewska-Włodarczyk A., Włodarczyk M. et al. Treatment of the fluoroquinolone-associated disability: the pathobiochemical implications. Oxid. Med. Cell. Longev. 2017; 2017: 8023935. DOI: 10.1155/2017/8023935.

29. Telfer S.J. Fluoroquinolone antibiotics and type 2 diabetes mellitus. Med. Hypotheses. 2014; 83 (3): 263–269. DOI: 10.1016/j.mehy.2014.05.013.

30. Wiest D.B., Cochran J.B., Tecklenburg F.W. Chloramphenicol toxicity revisited: a 12-year-old patient with a brain abscess. J. Pediatr. Pharmacol. Ther. 2012; 17 (2): 182–188. DOI: 10.5863/1551-6776-17.2.182.

31. Dhand R. The rationale and evidence for use of inhaled antibiotics to control Pseudomonas aeruginosa infection in non-cystic fibrosis bronchiectasis. J. Aerosol. Med. Pulm. Drug Deliv. 2018; 31 (3): 121–138. DOI: 10.1089/jamp.2017.1415.

32. Carcas A.J., Garcia-Satue J.L., Zapater P., Frias-Iniesta J. Tobramycin penetration into epithelial lining fluid of patients with pneumonia. Clin. Pharmacol. Ther. 1999; 65 (3): 245–250. DOI: 10.1016/S0009-9236(99)70103-7.

33. Lu Q., Girardi C., Zhang M. et al. Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa. Intens. Care Med. 2010; 36: 1147–1155. DOI: 10.1007/s00134-010-1879-4.

34. Elborn J.S., Flume P.A., Cohen F. et al. Safety and efficacy of prolonged levofloxacin inhalation solution (APT-1026) treatment for cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. J. Cyst. Fibros. 2016; 15 (5): 634–640. DOI: 10.1016/j.jcf.2016.01.005.

35. Elborn J.S., Geller D.E., Conrad D. et al. A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients. J. Cyst. Fibros. 2015; 14 (4): 507–514. DOI: 10.1016/j.jcf.2014.12.013.

36. Cipolla D., Blanchard J., Gonda I. Development of liposomal ciprofloxacin to treat lung infections. Pharmaceutics. 2016; 8 (1): 6. DOI: 10.3390/pharmaceutics8010006.

37. Wilson R., Welte T., Polverino E. et al. Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study. Eur. Respir. J. 2013; 41 (5): 1107–1115. DOI: 10.1183/09031936.00071312.

38. De Soyza A., Aksamit T., Bandel T.J. et al. Efficacy and tolerability of ciprofloxacin dry powder for inhalation (ciprofloxacin DPI) in bronchiectasis (non-CF etiology): results from the phase III RESPIRE 1 study. Chest. 2016; 150 (4, Suppl.): 1315A. DOI: 10.1016/j.chest.2016.08.1446.

39. Haworth C.S., Bilton D., Chalmers J.D. et al. Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials. Lancet Respir. Med. 2019; 7 (3): 213–226. DOI: 10.1016/S2213-2600(18)30427-2.

40. Hansen C., Skov M. Evidence for the efficacy of aztreonam for inhalation solution in the management of Pseudomonas aeruginosa in patients with cystic fibrosis. Ther. Adv. Respir. Dis. 2015; 9 (1): 16–21. DOI: 10.1177/1753465814561624.

41. Barker A.F., O'Donnell A.E., Flume P. et al. Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials. Lancet Respir. Med. 2014; 2 (9): 738–749. DOI: 10.1016/S2213-2600(14)70165-1.

42. Murray M.P., Govan J.R.W., Doherty C.J. et al. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am. J. Respir. Crit. Care Med. 2011; 183 (4): 491–499. DOI: 10.1164/rccm.201005-0756OC.

43. Niederman M.S., Chastre J., Corkery K. et al. BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia. Intensive Care Med. 2012; 38: 263–271. DOI: 10.1007/s00134-011-2420-0.

44. Barker A.F., Couch L., Fiel S.B. et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am. J. Respir. Crit. Care Med. 2000; 162 (2, Pt 1): 481–485. DOI: 10.1164/ajrccm.162.2.9910086.

45. Drobnic M.E., Suñé P., Montoro J.B. et al Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. Ann. Pharmacother. 2005; 39 (1): 39–44. DOI: 10.1345/aph.1E099.

46. Vendrell M., Muñoz G., de Gracia J. Evidence of inhaled tobramycin in non-cystic fibrosis bronchiectasis. Open Respir. Med. J. 2015; 9: 30–36. DOI: 10.2174/1874306401509010030.

47. Schuster A., Haliburn C., Döring G. et al. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax. 2013; 68 (4): 344–350. DOI: 10.1136/thoraxjnl-2012-202059.

48. Abdellatif S., Trifi A., Daly F. et al. Efficacy and toxicity of aerosolised colistin in ventilator-associated pneumonia: a prospective, randomised trial. Ann. Intens. Care. 2016; 6: 26. DOI: 10.1186/s13613-016-0127-7.

49. Kim Y.K., Lee J.H., Lee H.K. et al. Efficacy of nebulized colistin-based therapy without concurrent intravenous colistin for ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii. J. Thorac. Dis. 2017; 9 (3): 555–567. DOI: 10.21037/jtd.2017.02.61.

50. Yang J.W., Fan L.C., Lu H.W. et al. Efficacy and safety of long-term inhaled antibiotic for patients with noncystic fibrosis bronchiectasis: a meta-analysis. Clin. Respir. J. 2016; 10 (6): 731–739. DOI: 10.1111/crj.12278.

51. Laska I.F., Crichton M.L., Shoemark A., Chalmers J.D. The efficacy and safety of inhaled antibiotics for the treatment of bronchiectasis in adults: a systematic review and meta-analysis. Lancet Respir. Med. 2019; 7 (10): 855–869. DOI: 10.1016/S2213-2600(19)30185-7.

52. Marchese A., Debbia E.A., Tonoli E. et al. In vitro activity of thiamphenicol against multiresistant Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus in Italy. J. Chemotherapy. 2002; 14 (6): 554–561. DOI: 10.1179/joc.2002.14.6.554.

53. Nurbaeti S.N., Olivier J.C., Adier C. et al. Active mediated transport of chloramphenicol and thiamphenicol in a Calu-3 lung epithelial cell model. J. Pharm. Sci. 2018; 107 (4): 1178–1184. DOI: 10.1016/j.xphs.2017.11.021.

54. Blasi F., Page C., Rossolini G.M. et al. The effect of N-acetylcysteine on biofilms: Implications for the treatment of respiratory tract infections. Respir. Med. 2016; 117:190–197. DOI: 10.1016/j.rmed.2016.06.015.

55. Foreman A., Psaltis A.J., Tan L.W. et al. Characterization of bacterial and fungal biofilms in chronic rhinosinusitis. Am. J. Rhinol. Allergy. 2009; 23 (6): 556–561. DOI: 10.2500/ajra.2009.23.3413.

56. Serra A., Schito G.C., Nicoletti G. et al. A therapeutic approach in the treatment of infections of the upper airways: thiamphenicol glycinate acetylcysteinate in sequential treatment (systemic-inhalatory route). Int. J. Immunopathol. Pharmacol. 2007; 20 (3): 607–617. DOI: 10.1177/039463200702000319.

57. Macchi A., Ardito F., Marchese A. Efficacy of N-acetyl-cysteine in combination with thiamphenicol in sequential (intramuscular/aerosol) therapy of upper respiratory tract infections even when sustained by bacterial biofilms. J. Chemother. 2006; 18 (5): 507–513. DOI: 10.1179/joc.2006.18.5.507.

58. Macchi A., Castelnuovo P. Aerosol antibiotic therapy in children with chronic upper airway infections: a potential alternative to surgery. Int. J. Immunopathol. Pharmacol. 2009; 22 (2): 303–310. DOI: 10.1177/039463200902200207.

59. Mogayzel P.J. Jr, Naureckas E.T., Robinson K.A. et al. Cystic Fibrosis Foundation pulmonary guideline. Pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann. Am. Thorac. Soc. 2014; 11 (10): 1640–1650. DOI: 10.1513/AnnalsATS.201404-166OC.

60. Polverino E., Goeminne P.C., McDonnell M.J. et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur. Respir. J. 2017; 50 (3): 1700629. DOI: 10.1183/13993003.00629-2017.

61. Feeley T.W., Du Moulin G.C., Hedley-Whyte J. et al. Aerosol polymyxin and pneumonia in seriously ill patients. N. Engl. J. Med. 1975; 293: 471–475. DOI: 10.1056/NEJM197509042931003.