Therapeutisches Drug Monitoring von Reserveantibiotika

Kernaussagen

• Eine effektive Antiinfektivatherapie ist angesichts fehlender neuer Präparate und zunehmender Resistenzen dringend zu empfehlen.

• Die große Variabilität der pharmakokinetischen Parameter bei kritisch kranken Patienten erschwert die Dosisvorhersage.

• Dosisreduktionen sind nicht so häufig erforderlich wie empfohlen. Die Gefahr der Unterdosierung von Antiinfektiva bei septischen Patienten ist zumindest für Betalactam-Antibiotika zweifellos schwerwiegender und häufiger als die Toxizität bei Überdosierung.

• Die weitere Entwicklung und Implementierung des TDM scheint eine adäquate Methode zu sein, optimale Dosierungen von Antibiotika für den einzelnen kritisch kranken Patienten einzusetzen.

• Kombinationstherapien bei Carbapenemase produzierenden Bakterieninfektionen scheinen therapeutische Vorteile gegenüber Monotherapien zu haben.

• Kombinationen mit Carbapenem scheinen wirkungsvoller zu sein als solche ohne Carbapenem, zumindest bis zu einem Resistenzlevel von unter 8 µg/ml.

• Auch bei einem Resistenzlevel über 8 µg/ml scheint eine Kombinationstherapie mit Carbapenemen und Colistin, Fosfomycin, Aminoglykosiden und Tigecyclin vielversprechend. Dies sollte durch TDM abgesichert werden.

• Für definitive Empfehlungen müssen Ergebnisse kontrollierter randomisierter Studien abgewartet werden.

• Literatur

• 1 European Centre for Disease Prevention and Control. Carbapenemase-producing bacteria in Europe: interim results from the European Survey on carbapenemase-producing Enterobacteriaceae (EuSCAPE) project. Stockholm: ECDC Technical Report 2013;
• 2 Siegmund-Schultze N. Acinetobacter auf dem Vormarsch. Dtsch Arztebl 2015; 112: 5-162
• 3 Canton R, Akova M, Carmeli Y et al. Rapid evolution and spread of carbapenemases among Enterobacteriaceae in Europe. Clin Microbiol Infect 2012; 18: 413-431
• 4 Gross AS. Best practice in therapeutic drug monitoring. Br J Clin Pharmacol 1998; 46: 95-99
• 5 Prescott Jr WA, Gentile AE, Nagel JL et al. Continuous-infusion antipseudomonal Beta-lactam therapy in patients with cystic fibrosis. Pharm Therapeutics 2011; 36: 723-763
• 6 Le Guellec C, Gaudet ML, Lamanetre S et al. Stability of rifampin in plasma: consequences for therapeutic monitoring and pharmacokinetic studies. Ther Drug Monit 1997; 19: 669-674
• 7 Roberts JA, Lipman J. Antibacterial dosing in intensive care pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet 2006; 45: 755-773
• 8 European Committee on Antimicrobial Susceptibility Testing (EUCAST). Clinical breakpoints. See information on Clinical breakpoint tables. Breakpoint table for bacteria. Im Internet: http://www.eucast.org/clinical_breakpoints/ [Stand 18.05.2015]
• 9 Hanberger H, Svensson E, Nilsson LE et al. Pharmacodynamic effects of meropenem on gram-negative bacteria. Eur J Clin Microbiol Infect Dis 1995; 14: 383-390
• 10 Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2004; 2: 289-300
• 11 Rybak MJ, Lomaestro BM, Rotschafer JC et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases. Pharmacists. Pharmacotherapy 2009; 29: 1275-1279
• 12 Nielsen EI, Cars O, Friberg LE. Pharmacokinetic/pharmacodynamics (PK/PD) indices of antibiotics predicted by a semimechanistic PKPD model: a step toward mode-based dose optimization. Antimicrob Agents Chemother 2011; 55: 4619-4630
• 13 Lodise TP, Patel N, Lomaestro BM et al. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis 2009; 15: 507-514
• 14 Turnidge J. Pharmacodynamics and dosing of aminoglycosides. Infect Dis Clin North Am 2003; 17: 503-528
• 15 Udy AA, Roberts JA, Lipman J. Implications of augmented renal clerance in critically ill patients. Nat Rev Nephrol 2011; 7: 539-543
• 16 Tröger U, Drust A, Martens-Lobenhoffer J et al. Decreased meropenem levels in intensive care patients with augmented renal clearance: benefit of therapeutic drug monitoring. Int J Antimicrob Agents 2012; 40: 370-372
• 17 Tanev ID, Tröger U, Lohmeier S et al. Einfluss des therapeutischen Drug-Monitorings (TDM) zur Steuerung der Meropenem-Therapie bei Intensivpatienten. EP/02/08. 13. Kongress der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin Innovation trifft Kompetenz 04.–06.12.2013, Leipzig, Abstractband S. 22
• 18 Plachouras D, Karvanen M, Friberg LE et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother 2009; 53: 3430-3436
• 19 Strunk AK, Schmidt JJ, Baroke E et al. Single- and multiple-dose pharmacokinetics and total removal of colistin in a patient with acute kidney injury undergoing extended daily dialysis. J Antimicrob Chemother 2014; 69: 2008-2010
• 20 Bode-Böger SM, Schopp B, Tröger U et al. Intravenous colistin in a patient with serious burns and borderline syndrome: the benefits of therpeutic drug monitoring. Int J Antimicrob Agents 2013; 42: 357-360
• 21 Tzouvelekis LS, Markogiannakis A, Psichogiou M et al. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an envolving crisis of global dimensions. Clin Microbiol Rev 2012; 25: 682-707
• 22 Frossard M, Joukhadar C, Erovic BM et al. Distribution and antimicrobial activity of fosfomycin in the intestinal fluid of human soft tissues. Antimicrob Agents Chemother 2000; 44: 2728-2732
• 23 Patel SS, Balfour JA, Bryson HM. Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections. Drugs 1997; 53: 637-656
• 24 Matzke GR, Aronoff GR, Atkinson AJ et al. Drug dosing consideration in patients with acute and chronic kidney disease – a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011; 80: 1122-1137
• 25 Udy AA, Roberts JA, DeWaele JJ et al. Whatʼs behind the failure of emerging antibiotics on the critically ill? Understanding the impact of altered pharmacokinetics and augmented renal clearance. Int J Antimicrob Agents 2012; 39: 455-457
• 26 Parker S, Lipman J, Koulenti D et al. What is the relevance of fosfomycin pharmacokinetics in the treatment of serious infections in critically ill patients? A systematic review.. Int J Antimicrob Agents 2013; 42: 289-293
• 27 Perdigao-Neto LV, Oliveira MS, Rizek CF et al. Susceptibility to fosfomycin of multiresistant gram-negative bacteria and performance of different susceptibility testing methods: preparing for clinical use. Antimicrob Agents Chemother 2014; 58: 1763-1767
• 28 Samonis G, Maraki S, Karageorgopoulos SE et al. Synergy of fosfomycin with carbapenems, colistin, netilmicin, and tigecycline against multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates. Eur J Clin Microbiol Infect Dis 2012; 31: 695-701
• 29 Pfizer AG. Fachinformation Tygacil. Stand Dez. 2014
• 30 Peleg AY, Adams J, Paterson DL. Tigecycline efflux as a mechanism for nonsusceptibility in Acinetobacter baumannii. Antimicrob Agents Chemother 2007; 51: 2065-2069
• 31 FDA. FDA Drug Safety Communication: Increased risk of death with TYGACIL compared to other antibiotics used to treat similar infections. 01.09.2010
• 32 Giamarellou H, Poulakou G. Pharmacokinetic and pharmacodynamic evluation of tigecycline. Expert Opin Drug Metab Toxicol 2011; 7: 1459-1470
• 33 Korth-Bradley JM, Baird-Bellaire SJ, Patat AA et al. Pharmacokinetics and safety of a single intravenous dose of the antibiotic tigecycline in patients with cirrhosis. J Clin Pharmacol 2011; 51: 93-101
• 34 Korth-Bradley JM, Troy SM, Matschke K et al. Tigecycline pharmacokinetics in subjects with various degrees of renal function. J Clin Pharmacol 2012; 52: 1379-1387
• 35 Eyler RF, Mueller BA. Antibiotic dosing in critically ill patients with acute kidney injury. Nat Rev Nephrol 2011; 7: 226-235
• 36 Binder L, Schwörer H, Hoppe S et al. Pharmacokinetics of meropenem in critically ill patients with severe infections. Ther Drug Monit 2013; 35: 63-70
• 37 Casu GS, Hites M, Jacobs F et al. Can changes in renal function predict variations in beta-lactam concentrations in septic patients?. Int J Antimicrob Agents 2013; 42: 422-428
• 38 Roberts JA, Lipman J, Blot S et al. Better outcomes through continuous infusion of time-dependent antibiotics to critically ill patients?. Curr Opin Crit Care 2008; 14: 390-396
• 39 De Waele JJ, Lipman J, Akova M et al. Risk factors for target non-attainment during empirical treatment with (-lactam antibiotics in critically ill patients. Intensive Care Med 2014; 40: 1340-1351
• 40 Roberts JA, Webb S, Paterson D et al. A systematic review on clinical benefits of continuous administration of beta-lactam antibiotics. Crit Care Med 2009; 37: 2071-2078
• 41 Lips M, Siller M, Strojil J et al. Pharmacokinetics of imipenem in critically ill patients during empirical treatment of nosocomial pneumonia: a comparison of 0.5-h and 3-h infusions. Int J Antimicrob Agents 2014; 44: 358-362
• 42 MacGowan A. Revisiting Beta-lactams – PK/PD improves dosing of old antibiotics. Curr Opin Pharmacol 2011; 11: 470-476
• 43 Shiu J, Wang E, Tejani AM et al. Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections. Cochrane Database Syst Rev 2013; 3: CD008481
• 44 Cantón R, Morosini MI. Emergence and spread of antibiotic resistance following exposure to antibiotics. FEMS Microbiol Rev 2011; 35: 977-991
• 45 Li X, Wang L, Zhang XJ et al. Evaluation of meropenem regimens suppressing emergence of resistance in Acinetobacter baumannii with human simulated exposure in an in vitro intravenous-infusion hollow-fiber infection model. Antimicrob Agents Chemother 2014; 58: 6773-6781
• 46 Daikos GL, Tsaousi S, Tzouvelekis LS et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 2014; 58: 2322-2328
• 47 Rafailidis PI, Falagas ME. Options for treating carbapenem-resistant Enterobacteriaceae. Curr Opin Infect Dis 2014; 27: 479-483
• 48 Tanev ID, Tröger U, Smid J et al. Drug monitoring gesteuerte hochdosierte Antibiotikatherapie zur Behandlung einer schweren Pneumonie mit multiresistenten Acinetobacter baumanii P/02/09. 11. Kongress der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin. Fortschritt und Verantwortung. 30.11.–03.12.2011, Leipzig, Abstractband S. 42
• 49 Norrby SR. Neurotoxicity of carbapenem antibiotics: consequences for their use in bacterial meningitis. J Antimicrob Chem 2000; 45: 5-7
• 50 Tanaka A, Takechi K, Watanabe S et al. Comparison of the prevalence of convulsions associated with the use of cefepime and meropenem. Int J Clin Pharm 2013; 35: 683-687