Antibiotika zur Behandlung von Infektionen durch Methicillin-resistente Staphylococcus aureus (MRSA)^[*]

Zusammenfassung

In den vergangenen 50 Jahren haben sich die Methicillin-resistenten S. aureus-Stämme (MRSA) weltweit verbreitet. Nach wie vor ist Vancomycin das überwiegend empfohlene Antibiotikum zur Behandlung entsprechender Infektionen. Teicoplanin stellt eine Alternative mit längerer Halbwertzeit dar. Telavancin ist ein neueres Vancomycin-Derivat, das in klinischen Studien etwa gleich wirksam wie Vancomycin war. Bei Patienten mit Niereninsuffizienz sollte es nicht angewandt werden. Nephrotoxische Wirkungen der Glykopeptide schränken ihre therapeutische Verwendbarkeit ein. Das Oxazolidinon Linezolid ist dem Vancomycin therapeutisch gleichwertig bis überlegen. Bei einer Therapie mit dieser Substanz sind Blutbildkontrollen notwendig, neurotoxische Wirkungen wurden vor allem bei längerer Behandlungsdauer beobachtet. Beachtet werden müssen die Interaktionen mit serotoninerg wirksamen Arzneistoffen. Neue Möglichkeiten eröffnen sich mit Ceftarolin, dem ersten MRSA-wirksamen β-Laktamantibiotikum. Kontrollierte Studien bei pulmonalen MRSA-Infektionen liegen allerdings nicht vor. Daptomycin, ein Lipopeptid, und Tigecyclin, ein Glycylcyclin, zeigen in vitro ebenfalls Aktivität gegen MRSA, kommen aber zur Behandlung pulmonaler MRSA-Infektionen ebenfalls nicht in Betracht. Am Beispiel dieser Antibiotika wird deutlich, dass der Nachweis einer in vitro-Aktivität zwar von Bedeutung ist, dass aber die für eine Therapieentscheidung notwendigen Erkenntnisse nur aus doppelblind-randomisierten klinischen Studien abgeleitet werden können.

Abstract

Over the last 50 years methicillin-resistant S. aureus (MRSA) spread globally. Vancomycin is still the most recommended antibiotic for MRSA-infections. Teicoplanin is an alternative glycopeptide with longer elimination half-life. Telavancin is a more recently developed derivative of vancomycin with similar clinical efficacy as vancomycin. It is not recommended for treatment of patients with renal insufficiency. Nephrotoxicity limits the therapeutic use of glycopeptide antibiotics. The oxazolidinone linezolid exhibits similar to superior therapeutic efficacy. Hematologic controls are necessary during treatment with this antibacterial agent. Neurotoxic effects have been observed mainly in patients who received prolonged linezolid treatment. Attention must be paid to possible interactions with concomitantly given drugs acting on the serotonergic system. New therapeutic options arise with ceftaroline, the first β-lactam antibiotic with activity against MRSA. However, controlled clinical trials with pulmonary MRSA infections have not been conducted with ceftaroline. Daptomycin, a lipopeptide, and tigecycline, a glycylcyclin are active in vitro against MRSA as well, but are also not indicated in pulmonary MRSA infections. These antibiotics show in an exemplary manner that antibacterial activity in vitro is an important prerequisite, but relevant data for a therapeutic decision should be derived from randomized controlled clinical double-blind trials.

^* Professor Hartmut Lode zum 75. Geburtstag gewidmet.

• Literatur

• 1 Moellering RC Jr. MRSA: the first half century. J Antimicrob Chemother 2012; 67: 4-11
• 2 Lode HM. Clinical impact of antibiotic-resistant Gram-positive pathogens. Clin Microbiol Infect 2009; 15: 212-217
• 3 Arias CA, Murray BE. Antibiotic-resistant bugs in the 21st century -- a clinical super-challenge. N Engl J Med 2009; 360: 439-443
• 4 Levine DP. Vancomycin: a history. Clin Infect Dis 2006; 42 : 5-12
• 5 Gastmeier P, Schröder C, Behnke M et al. Dramatic increase in vancomycin-resistant enterococci in Germany. J Antimicrob Chemother 2014; 69: 1660-1664
• 6 Lodise TP, Drusano GL, Butterfield JM et al. Penetration of vancomycin into epithelial lining fluid in healthy volunteers. Antimicrob Agents Chemother 2011; 55: 5507-5511
• 7 Svetitsky S, Leibovici L, Paul M. Comparative efficacy and safety of vancomycin versus teicoplanin: systematic review and meta-analysis. Antimicrob Agents Chemother 2009; 53: 4069-4079
• 8 Lodise TP, Lomaestro B, Graves J et al. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 2008; 52: 1330-1336
• 9 Stahlmann R, Lode H. Pharmakokinetik von Antibiotika bei kritisch kranken und übergewichtigen Patienten. Dtsch Med Wschr 2014; (im Druck)
• 10 Bosso JA, Nappi J, Rudisill C et al. Relationship between vancomycin trough concentrations and nephrotoxicity: a prospective multicenter trial. Antimicrob Agents Chemother 2011; 55: 5475-5479
• 11 Cataldo MA, Tacconelli E, Grilli E et al. Continuous versus intermittent infusion of vancomycin for the treatment of Gram-positive infections: systematic review and meta-analysis. J Antimicrob Chemother 2012; 67: 17-24
• 12 Schmelzer TM, Christmas AB, Norton HJ et al. Vancomycin intermittent dosing versus continuous infusion for treatment of ventilator-associated pneumonia in trauma patients. Am Surg 2013; 79: 1185-1190
• 13 Gotfried MH, Shaw JP, Benton BM et al. Intrapulmonary distribution of intravenous telavancin in healthy subjects and effect of pulmonary surfactant on in vitro activities of telavancin and other antibiotics. Antimicrob Agents Chemother 2008; 52: 92-97
• 14 Saravolatz LD, Stein GE, Johnson LB. Telavancin: a novel lipoglycopeptide. Clin Infect Dis 2009; 49: 1908-1914
• 15 Rubinstein E, Lalani T, Corey GR et al. Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens. Clin Infect Dis 2011; 52: 31-40
• 16 Corey GR, Kollef MH, Shorr AF et al. Telavancin for Hospital-acquired Pneumonia: Clinical Response and 28-Day Survival. Antimicrob Agents Chemother 2014; 58: 2030-2037
• 17 NN 2014, Vibativ, Zusammenfassung der Merkmale des Arzneimittels. www.ema-europa.eu
• 18 Long KS, Vester B. Resistance to linezolid caused by modifications at its binding site on the ribosome. Antimicrob Agents Chemother 2012; 56: 603-12
• 19 Morales G, Picazo JJ, Baos E et al. Resistance to linezolid is mediated by the cfr gene in the first report of an outbreak of linezolid-resistant Staphylococcus aureus. Clin Infect Dis 2010; 50: 821-825
• 20 Locke JB, Morales G, Hilgers M et al. Elevated linezolid resistance in clinical cfr-positive Staphylococcus aureus isolates is associated with co-occurring mutations in ribosomal protein L3. Antimicrob Agents Chemother 2010; 54: 5352-5355
• 21 Mendes RE, Hogan PA, Streit JM et al. Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) Program: report of linezolid activity over 9 years (2004–12). J Antimicrob Chemother 2014; 69: 1582-1588
• 22 Locke JB, Finn J, Hilgers M et al. Structure-activity relationships of diverse oxazolidinones for linezolid-resistant Staphylococcus aureus strains possessing the cfr methyltransferase gene or ribosomal mutations. Antimicrob Agents Chemother 2010; 54: 5337-5343
• 23 Moellering RC. Tedizolid: a novel oxazolidinone for Gram-positive infections. Clin Infect Dis 2014; 58 : 1-3
• 24 Clemett D, Markham A. Linezolid. Drugs 2000; 59: 815-827
• 25 Honeybourne D, Tobin C, Jevons G et al. Intrapulmonary penetration of linezolid. J Antimicrob Chemother 2003; 51: 1431-1434
• 26 Nukui Y, Hatakeyama S, Okamoto K et al. High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. J Antimicrob Chemother 2013; 68: 2128-2133
• 27 Wunderink RG, Niederman MS, Kollef MH et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 2012; 54: 621-629
• 28 Chastre J, Blasi F, Masterton RG et al. European perspective and update on the management of nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid. Clin Microbiol Infect 2014; 20 : 19-36
• 29 Pucci MJ, Bush K. Investigational antimicrobial agents of 2013. Clin Microbiol Rev 2013; 26: 792-821
• 30 File TM Jr, Wilcox MH, Stein GE. Summary of ceftaroline fosamil clinical trial studies and clinical safety. Clin Infect Dis 2012; 55 : 173-180
• 31 Poon H, Chang MH, Fung HB. Ceftaroline fosamil: a cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Ther 2012; 34: 743-765
• 32 File TM Jr, Low DE, Eckburg PB et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis 2010; 51: 1395-1405
• 33 Casapao AM, Davis SL, Barr VO et al. A Large Retrospective Evaluation of the Effectiveness and Safety of Ceftaroline Fosamil Therapy. Antimicrob Agents Chemother 2014; 58: 2541-2546
• 34 Lagacé-Wiens PR, Rubinstein E. Pharmacokinetic and pharmacodynamics evaluation of ceftobiprole medocaril for the treatment of hospital-acquired pneumonia. Expert Opin Drug Metab Toxicol 2013; 9: 789-799
• 35 Gonzalez-Ruiz A, Beiras-Fernandez A, Lehmkuhl H et al. Clinical experience with daptomycin in Europe: the first 2.5 years. . J Antimicrob Chemother 2011; 66: 912-919
• 36 Seaton RA, Gonzalez-Ramallo VJ, Prisco V et al. Daptomycin for outpatient parenteral antibiotic therapy: a European registry experience. Int J Antimicrob Agents 2013; 41: 468-472
• 37 Silverman JA, Mortin LI, Vanpraagh AD et al. Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact. J Infect Dis 2005; 191: 2149-2152
• 38 Falcone M, Russo A, Venditti M et al. Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis 2013; 57: 1568-1576
• 39 Frampton JE, Curran MP. Tigecycline. Drugs 2005; 65: 2623-2637
• 40 Livermore DM. Tigecycline: what is it, and where should it be used?. J Antimicrob Chemother 2005; 56: 611-614
• 41 Pharmacia, 2013. Fachinformation Tygacil^®
• 42 Rodvold KA, McConeghy KW. Methicillin-resistant Staphylococcus aureus therapy: past, present, and future. Clin Infect Dis 2014; 58 : 20-27