Распространение резистентной грамотрицательной микрофлоры приводит к ограничению выбора антибактериальных препаратов (АБП), увеличению продолжительности лечения и росту летальности. При отсутствии новых АБП, активных в отношении полирезистентных штаммов, важно получение максимального эффекта от уже имеющихся АБП, что может быть достигнуто с помощью оптимизации их фармакологических параметров. Помимо этого, необходимо расширять экспериментальные и клинические исследования, способствующие изучению условий формирования резистентности микробов в процессе лечения антибиотиками, детализировать влияние других факторов, позволяющих преодолевать этот процесс, и оптимизировать антибактериальную терапию. Ключевые слова: резистентность, полирезистентные штаммы, выбор антибиотика, преодоление резистентности.
________________________________________________
The spread of resistant gram-negative microflora leads to a limited selection of antimicrobial drugs, an increase in the duration of treatment and increased mortality. In the absence of new antibacterial agents active against polyresistant strains, it is important to obtain maximum benefit from existing antibacterial agents that can be achieved by optimizing their pharmacological parameters. In addition, the need to expand the experimental and clinical studies to facilitate the study of the conditions of the development of resistance of microbes in the course of treatment with antibiotics, detailing the impact of other factors allows to overcome this process and optimize antibiotic therapy. Key words: resistance, multiresistant strains, the choice of antibiotic, overcoming resistance.
1. Ho J, Tambyah PA, Paterson DL. Multiresistant Gramnegative infections: a global perspective. Curr Opin Infect Dis 2010; 23: 546–53.
2. Qureshi ZA, Paterson DL, Peleg AY et al. Clinical characteristics of bacteraemia caused by extendedspectrum blactamaseproducing Enterobacteriaceae in the era of CTXMtype and KPCtype
b-lactamases. Clin Microbiol Infect 2012; 18: 887–93.
3. Gudiol C, Calatayud L, GarciaVidal C et al. Bacteraemia due to extendedspectrumbetalactamaseproducing Escherichia coli (ESBLEC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome. J Antimicrob Chemother 2010; 65: 333–41.
4. Tam VH, Rogers CA, Chang KT et al. Impact of multidrugresistant Pseudomonas aeruginosa bacteremia on patient outcomes. Antimicrob Agents Chemother 2010; 54: 3717–22.
5. Mauldin PD, Salgado CD, Hansen IS et al. Attributable hospital cost and length of stay associated with health careassociated infections caused by antibioticresistantgramnegative bacteria. Antimicrob Agents Chemother 2010; 54: 109–15.
6. Tamma PD, Cosgrove SE. Antimicrobial stewardship. Infect Dis Clin North Am 2011; 25: 245–60.
7. Nowak MA, Nelson RE, Breidenbach JL et al. Clinical and economic outcomes of a prospective antimicrobial stewardship program. Am J Health Syst Pharm 2012; 69: 1500–8.
8. Абакумов М.М., Багдасарова Е.А., Багненко С.Ф. и др. Стратегия и тактика применения антимикробных средств в лечебных учреждениях России. Российские национальные рекомендации. Под ред. В.С.Савельева, Б.Р.Гельфанда, С.В.Яковлева.
М.: Компания Боргес, 2012.
9. Slain D, Sarwari AR, Petros KO et al. Impact of a Multimodal Antimicrobial Stewardship Program on Pseudomonas aeruginosa Susceptibility and Antimicrobial Use in the ICU Setting. Crit Care Res Pract 2011: 416426.
10. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26: 1–10.
11. Drusano GL. Pharmacokinetics and pharmacodynamics of antimicrobials. Clin Infect Dis 2007; 45: S89–95.
12. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987; 155: 93–9.
13. Forrest A, Nix DE, Ballow CH et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993; 37: 1073–81.
14. Fenton C, Keating GM, Curran MP. Daptomycin. Drugs 2004; 64: 445–55.
15. Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broadspectrum cephalosporins. Diagn Microbiol Infect Dis 1995; 22: 89–96.
16. Hatano K, Wakai Y, Watanabe Y, Mine Y. Simulation of human plasma levels of betalactams in mice by multiple dosing and the relationship between the therapeutic efficacy and pharmacodynamic parameters. Chemotherapy1994; 40: 1–7.
17. Negri MC, Morosini MI, Loza E, Baquero F. In vitro selective antibiotic concentrations of betalactams for penicillinresistant Streptococcus pneumoniae populations. Antimicrob Agents Chemother 1994; 38: 122–5.
18. Drlica K. The mutant selection window and antimicrobial resistance. J Antimicrob Chemother 2003; 52: 11–7.
19. Hawkey PM, Jones AM. The changing epidemiology of resistance.
J Antimicrob Chemother 2009; 64 (Suppl. 1): i3–10.
20. Welte T, Pletz MW. Antimicrobial treatment of nosocomial meticillinresistant Staphylococcus aureus (MRSA) pneumonia: current and future options. Int J Antimicrob Agents 2010; 36: 391–400.
21. Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillinresistant Staphylococcus aureus. Clin Infect Dis 2011; 52: 1156–63.
22. Eagle H. The multiple mechanisms of penicillin resistance. J Bacteriol 1954; 68: 610–6.
23. Arias CA, Murray BE. Antibioticresistant bugs in the 21st century – A clinical superchallenge. N Engl J Med 2009; 360: 439–43.
24. Rossi F, Baquero F, Hsueh PR et al. In vitro susceptibilities of aerobic and facultatively anaerobic Gramnegative bacilli isolated from patients with intra abdominal infections worldwide: 2004 results from SMART Study. J Antimicrob Chemother 2006; 58: 205–10.
25. Dowzicky MJ, Park CH. Update on antimicrobial susceptibility rates among gramnegative and grampositive organisms in the United States: results from the Tigecycline Evaluation and Surveillance Trial (TEST) 2005 to 2007. Clin Ther 2008; 30: 2040–50.
26. Mouton JW, den Hollander JG. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob Agents Chemother 1994; 38: 931–6.
27. Mouton JW, Punt N, Vinks AA. Concentrationeffect relationship of ceftazidime explains why the time above the MIC is 40 percent for a static effect in vivo. Antimicrob Agents Chemother 2007; 51: 3449–51.
28. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillintazobactam for Pseudomonas aeruginosa infection: clinical implications of an extendedinfusion dosing strategy. Clin Infect Dis 2007; 44: 357–63.
29. Scaglione F, Paraboni L. Pharmacokinetics/pharmacodynamics of antibacterials in the Intensive Care Unit: setting appropriate dosing regimens. Int J Antimicrob Agents 2008; 32: 294–301.
30. Adembri C, Novelli A. Pharmacokinetic and pharmacodynamic parameters of antimicrobials: potential for providing dosing regimens that are less vulnerable to resistance. Clin Pharmacokinet 2009; 48: 517–28.
31. McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents 2008; 31: 345–51.
32. Sinnollareddy MG, Roberts MS, Lipman J, Roberts JA. bLactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: a structured review. Clin Exp Pharmacol Physiol 2012; 39: 489–96.
33. AbdulAziz MH, Dulhunty JM, Bellomo R et al. Continuous betalactam infusion in critically ill patients: the clinical evidence. Ann Intensive Care 2012; 2: 37.
34. Bhat SV, Peleg AY, Lodise TP et al. Failure of current cefepime breakpoints to predict clinical outcomes of bacteremia caused by gramnegative organisms. Antimicrob Agents Chemother 2007; 51: 4390–5.
35. Tam VH, Gamez EA, Weston JS et al. Outcomes of bacteremia due to Pseudomonas aeruginosa with reduced susceptibility to piperacillintazobactam: implications on the appropriateness of the resistance breakpoint. Clin Infect Dis 2008; 46: 862–7.
36. Alou L, Aguilar L, Sevillano D et al. Is there a pharmacodynamic need for the use of continuous versus intermittent infusion with ceftazidime against Pseudomonas aeruginosa? An in vitro pharmacodynamic model. J Antimicrob Chemother 2005; 55: 209–13.
37. Gerber AU, Craig WA, Brugger HP et al. Impact of dosing intervals on activity of gentamicin and ticarcillin against Pseudomonas aeruginosa in granulocytopenic mice. J Infect Dis 1983; 147: 910–7.
38. Lau WK, Mercer D, Itani KM et al. Randomized, openlabel, comparative study of piperacillintazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intraabdominal infection. Antimicrob Agents Chemother 2006; 50: 3556–61.
39. Roberts JA, Webb S, Paterson D et al. A systematic review on clinical benefits of continuous administration of betalactam antibiotics. Crit Care Med 2009; 37: 2071–8.
40. Kasiakou SK, Sermaides GJ, Michalopoulos A et al. Continuous versus intermittent intravenous administration of antibiotics: a metaanalysis of randomised controlled trials. Lancet Infect Dis 2005; 5: 581–9.
41. Tamma PD, Putcha N, Suh YD et al. Does prolonged blactam infusions improve clinical outcomes compared to intermittent infusions? A metaanalysis and systematic review of randomized, controlled trials. BMC Infect Dis 2011; 11: 181.
42. Yost RJ, Cappelletty DM. RECEIPT Study group. The Retrospective Cohort of Extended Infusion PiperacillinTazobactam (RECEIPT) study: amulticenter study. Pharmacotherapy 2011; 31: 767–75.
43. Patel GW, Patel N, Lat A et al. Outcomes of extended infusion piperacillin/tazobactam for documented Gramnegative infections. Diagn Microbiol Infect Dis 2009; 64: 236–40.
44. Xamplas RC, Itokazu GS, Glowacki RC et al. Implementation of an extendedinfusion piperacillintazobactam program at an urban teaching hospital. Am J Health Syst Pharm 2010; 67: 622–8.
45. Nichols KR, Knoderer CA, Cox EG, Kays MB. Systemwide implementation of the use of an extendedinfusion piperacillin/tazobactam dosing strategy: feasibility of utilization from a children’s hospital perspective. Clin Ther 2012; 34: 1459–65.
46. Nordmann P, Picazo JJ, Mutters R et al. Comparative activity of carbapenem testing: the COMPACT study. J Antimicrob Chemother 2011; 66: 1070–8.
47. Bratu S, Landman D, Haag R et al. Rapid spread of carbapenemresistant Klebsiella pneumoniae in New York City: a new threat to our antibiotic armamentarium. Arch Intern Med 2005; 165: 1430–5.
48. Mena A, Plasencia V, Garcia L et al. Characterization of a large outbreak by CTXM1producing Klebsiella pneumoniae and mechanisms leading to in vivo carbapenem resistance development. J Clin Microbiol 2006; 44: 2831–7.
49. Hidron AI, Edwards JR, Patel J et al. Annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007. Infect Control Hosp Epidemiol 2008; 29: 996–1011.
50. Rhomberg PR, Jones RN. Summary trends for the Meropenem Yearly Susceptibility Test Information Collection Program: a 10year experience in the United States (1999–2008). Diagn Microbiol Infect Dis 2009; 65: 414–26.
51. Craig WA. The pharmacology of meropenem, a new carbapenem antibiotic. Clin Infect Dis 1997; 24: S266–75.
52. Ong CT, Tessier PR, Li C et al. Comparative in vivo efficacy of meropenem, imipenem, and cefepime against Pseudomonas aeruginosa expressing MexAMexBOprM efflux pumps. Diagn Microbiol Infect Dis 2007; 57: 153–61.
53. Roberts JA, Kirkpatrick CM, Roberts MS et al. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother 2009; 64: 142–50.
54. Lorente L, Lorenzo L, Martin MM et al. Meropenem by continuous versus intermittent infusion in ventilatorassociated pneumonia due to gramnegative bacilli. Ann Pharmacother 2006; 40: 219–23.
55. Krueger WA, Bulitta J, KinzigSchippers M et al. Evaluation by montecarlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers. Antimicrob Agents Chemother 2005; 49: 1881–9.
56. Mattoes HM, Kuti JL, Drusano GL, Nicolau DP. Optimizing antimicrobial pharmacodynamics: dosage strategies for meropenem. ClinTher 2004; 26: 1187–98.
57. Kotapati S, Nicolau DP, Nightingale CH, Kuti JL. Clinical and economic benefits of a meropenem dosage strategy based on pharmacodynamic concepts. Am J Health Syst Pharm 2004; 61: 1264–70.
58. Kuti JL, Florea NR, Nightingale CH, Nicolau DP. Pharmacodynamics of meropenem and imipenem against Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Pharmacotherapy 2004; 24: 8–15.
59. Ariano RE, Nyhlacen A, Donnelly JP et al. Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia. Ann Pharmacother 2005; 39: 32–8.
60. Arnold HM, McKinnon PS, Augustin KM et al. Assessment of an alternative meropenem dosing strategy compared with imipenem–cilastatin or traditional meropenem dosing after cefepime failure or intolerance in adults with neutropenic fever. Pharmacotherapy 2009; 29: 914–23.
61. Patel GW, Duquaine SM, McKinnon PS. Clinical outcomes and cost minimization with an alternative dosing regimen for meropenem in a community hospital. Pharmacotherapy 2007; 27: 1637–43.
62. Li C, Kuti JL, Nightingale CH, Nicolau DP. Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patients. J Clin Pharmacol 2006; 46: 1171–8.
63. Lomaestro BM, Drusano GL. Pharmacodynamic evaluation of extending the administration time of meropenem using a Monte Carlo simulation. Antimicrob Agents Chemother 2005; 49: 461–3.
64. Jaruratanasirikul S, Sriwiriyajan S, Punyo J. Comparison of the pharmacodynamics of meropenem in patients with ventilatorassociated pneumonia following administration by 3hour infusion or bolus injection. Antimicrob Agents Chemother 2005; 49: 1337–9.
65. Keam SJ. Doripenem: a review of its use in the treatment of bacterial infections. Drugs 2008; 68: 2021–57.
66. Mandell L. Doripenem: a new carbapenem in the treatment of nosocomial infection. Clin Infect Dis 2009; 49: S1–3.
67. Queenan AM, Shang W, Flamm R, Bush K. Hydrolysis and inhibition profiles of betalactamases from molecular classes A to D with doripenem, imipenem, and meropenem. Antimicrob Agents Chemother 2010; 54: 565–9.
68. Psathas PA, Kuzmission A, Ikeda K, Yasuo S. Stability of doripenem in vitro in representative infusion solutions and infusion bags. Clin Ther 2008; 30: 2075–87.
69. Bhavnani SM, Hammel JP, Cirincione BB et al. Use of pharmacokineticpharmacodynamic target attainment analyses to support phase 2 and 3 dosing strategies for doripenem. Antimicrob Agents Chemother 2005; 49: 3944–7.
70. Ikawa K, Morikawa N, Ikeda K et al. Pharmacodynamic assessment of doripenem in peritoneal fluid against Gramnegative organisms: use of population pharmacokinetic modeling and Monte Carlo simulation. Diagn Microbiol Infect Dis 2008; 62: 292–7.
71. Samtani MN, Flamm R, Kaniga K, Nandy P. Pharmacokineticpharmacodynamicmodelguided doripenem dosing in critically ill patients. Antimicrob Agents Chemother 2010; 54: 2360–4.
72. Van Wart SA, Andes DR, Ambrose PG, Bhavnani SM. Pharmacokinetic–pharmacodynamic modeling to support doripenem dose regimen optimization for critically ill patients. Diagn Microbiol Infect Dis 2009; 63: 409–14.
73. Chastre J, Wunderink R, Prokocimer P et al. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilatorassociated pneumonia: a multicenter, randomized study. Crit Care Med 2008; 36: 1089–96.
74. Eagle H, Fleischman R, Musselman AD. Effect of schedule of administration on the therapeutic efficacy of penicillin; importance of the aggregate time penicillin remains at effectively bactericidal levels. Am J Med 1950; 9: 280–99.
75. Mouton JW, Ambrose PG, Canton R et al. Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective. Drug Resist Updat 2011; 14: 107–17.
76. Firsov AA, Gilbert D, Greer K et al. Comparative pharmacodynamics and antimutant potentials of doripenem and imipenem with ciprofloxacinresistant Pseudomonas aeruginosa in an in vitro model. Antimicrob Agents Chemother 2012; 56: 1223–8.
77. Tam VH, Schilling AN, Neshat S et al. Optimization of meropenem minimum concentration/MIC ratio to suppress in vitro resistance of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005; 49: 4920–7.
78. Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005; 44: 1009–34.
79. Roberts DM, Roberts JA, Roberts MS et al. Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study. Crit Care Med 2012; 40: 1523–8.
80. Patel N, Cardone K, Grabe DW et al. Use of pharmacokinetic and pharmacodynamic principles to determine optimal administration of daptomycin in patients receiving standardized thriceweekly hemodialysis. Antimicrob Agents Chemother 2011; 55: 1677–83.
81. Koomanachai P, Bulik CC, Kuti JL, Nicolau DP. Pharmacodynamic modeling of intravenous antibiotics against gramnegative bacteria collected in the United States. Clin Ther 2010; 32: 766–79.
82. Conte JE, Golden JA, Kelley MG, Zurlinden E. Intrapulmonary pharmacokinetics and pharmacodynamics of meropenem. Int J Antimicrob Agents 2005; 26: 449–56.
83. Chandorkar G, Huntington JA, Gotfried MH et al. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects. J Antimicrob Chemother 2005; 67: 2463–9.
84. Zeitlinger MA, Derendorf H, Mouton JW et al. Protein binding: do we ever learn? Antimicrob Agents Chemother 2011; 55: 3067–74.
85. Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother 2012; 56: 2795–805.
Авторы
В.Б.Белобородов
ГБОУ ДПО Российская медицинская академия последипломного образования Минздрава России, Москва