Considerations for antibiotic therapy Christoph K. Naber Interventional Cardiology Heartcenter - Elisabeth Hospital Essen
Infective Endocarditis There will never be a cure for this malignant disease! Sir William Osler Gulstonian Lectures - 1885
Endocarditis: Mortality 1885 Osler Osler Triad 1949 Christie: Penicillin 1956 Vancomycin 1961 Kay: Surgery 1960-62 Ampicillin Methicillin Oxacillin 1988 Erbel: TEE 1994 Durack Duke Criteria 100 75 50 25 0 30 % Hunter 1951 26 % Hasbun 2003 27 % Wallace 2002 35 % Cabell 2002 17 % Hoen 2002
Effective Antibiotic Therapy Effective antibiotic therapy Ineffective antibiotic therapy
Effective Antibiotic Therapy 1. Targeted therapy 2. Appropriate concentration at site of infection 3. Appropriate timing of administration of antiobiotics 4. Bactericidal antibiotics & combination therapy? 5. Ambulatory therapy possible?
Culturnegative Endocarditis Author Year Incidene % Tunkel 1933 87 218/2345 9 Lamas 1975 00 63/516 12 Hogewik 1984 88 12/99 12 Rognon 1983 93 12/124 10 Sandre 1985 93 14/135 10 Werner 1984-96 100/487 20 Hoen Block 1990 91 1996-1998 88/620 189/704 14 27
Culturenegative Endocarditis Author, Year Abraham, 1984 n 20 Previous antibiotics 16 Fastidious bacteria n.g. Noninfectious n.g. Pesanti, 1979 52 32 3 4 Hoen, 1995 88 42 15 n.g. Lamas, 2003 63 21 31 n.g. Werner, 2003 116 45 3 16 All 339 156(46%) 52(15%) 20(6%)
Embolic Risk n=207 Steckelberg et al. Ann Int Med 1991 8
Effective Antibiotic Therapy 1. Targeted therapy 2. Appropriate concentration at site of infection - i.v. versus p.o.? - renal function? 3. Appropriate timing of administration of antiobiotics 4. Bactericidal antibiotics & combination therapy? 5. Ambulatory therapy possible?
Endocarditis = Biofilm Infection
Endocarditis = Biofilm Infection antibiotic agents antibodies biofilm free floating planctonic bacteria phagozyte device surface peri-device tissue Modified from Trampuz et al. 2003
Effective Antibiotic Therapy 1. Targeted therapy 2. Appropriate concentration at site of infection - i.v. versus p.o.? - renal function? 3. Appropriate timing of administration of antiobiotics 4. Bactericidal antibiotics & combination therapy? 5. Ambulatory therapy possible?
Concentration Effective Antibiotic Therapy Betalactams (Time over MIC) Aminoglycosides (Peak Concentration) Quinolones (area under the curve) MIC Time Time Time Aministration: 6 times / day once daily 1-2 times / day
Effective Antibiotic Therapy 1. Targeted therapy 2. Appropriate concentration at site of infection - i.v. versus p.o.? - renal function? 3. Appropriate timing of administration of antiobiotics 4. Bactericidal antibiotics & combination therapy? 5. Ambulatory therapy possible?
Effective Antibiotic Therapy 1. Targeted therapy 2. Appropriate concentration at site of infection - i.v. versus p.o.? - renal function? 3. Appropriate timing of administration of antiobiotics 4. Bactericidal antibiotics & combination therapy? 5. Ambulatory therapy possible?
IE Stages of Disease
OPAT Andrews MM, von Reyn CF. Patient selection criteria and management guidelines for outpatient parenteral antibiotic therapy for native valve infective endocarditis. Clin Infect Dis 2001;33:203 209. Monteiro CA, Cobbs CG. Outpatient management of infective endocarditis. Curr Infect Dis Rep 2001;3:319 327. Huminer D, Bishara J, Pitlik S. Home intravenous antibiotic therapy for patients with infective endocarditis. Eur J Clin Microbiol Infect Dis 1999;18:330 334.
International Collaboration on Endocarditis ~1700 prospective infective endocarditis cases from 16 countries 21% S. aureus 32% Coagulase-negative staphylococci 11% S. bovis Viridans streptococci Enterococcus spp 18% 7% 11% Other pathogens/ culture negative CK Naber et al. EHJ Suppl. 2006
Francioli P, Ruch W, Stamboulian D. Clin Infect Dis 1995;21:1406 1410. Francioli P, Etienne J, Hoigne R, Thys JP, Gerber A. JAMA 1992;267:264 267. Sexton DJ, Tenenbaum MJ, Wilson WR, Steckelberg JM, Tice AD, Gilbert D, Dismukes W, Drew RH, Durack DT. Clin Infect Dis 1998;27:1470 1474. 09.09.2010 19
Fragen? 09.09.2010 20
Gentamicin in S. aureus IE? Ann Intern Med. 1982 Oct;97(4):496-503. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: A prospective study. Korzeniowski O, Sande MA. Single (nafcillin for 6 weeks) and combined (nafcillin for 6 weeks plus gentamicin for 2 weeks) drug regimens were compared in two separate multicenter prospective randomized trials. 48 parenteral drug addicts and 30 nonaddicts with clinically and bacteriologically documented Staphylococcus aureus endocarditis were studied. In the addicts, combined therapy effected a more rapid mean clinical response (defervescence and normalization of leukocyte count) and a reduced duration of bacteremia in patients with right-sided endocarditis. In the nonaddicts, combined therapy effected more rapid clearance of bacteremia, but was associated with a higher incidence of azotemia. The addition of gentamicin did not alter morbidity or mortality in either group.
Gentamicin in Sepsis 64 Studies 7586 Patients Studies comparing same beta-lactam all-cause fatality RR 1.01 (95% CI 0.75-1.35) clinical failure RR 1.11 (95% CI 0.95-1.29) Nephrotoxicity RR 0.30 (95% CI 0.23-0.39) for monotherapy Paul M. et al.: Cochrane Database Syst Rev. 2006 23
Aminoglycosides and Endocarditis Death Clinical Cure Falagas et al. JAC 57 (4): 639. (2006) 24
Isolates (%) Vancomycin Tolerance 100 80 Tolerant 60 40 40 20 20 10 14 15 0 1 2 4 8 16 MBC:MIC Ratio (n=105) 74% of hvisa isolates are tolerant to vancomycin MRSA=methicillin-resistant Staphylococcus aureus; MBC:MIC=minimum bactericidal concentration:minimum inhibitory concentration; hvisa=heteroresistant vancomycin-intermediate S. aureus. Jones. Clin Infect Dis 2006;42:S13 24
Vancomycin treatment success, % Vancomycin treatment success, % Vancomycin MIC in MRSA infections 100 80 60 40 20 0 55,6 P=0.01 9,5 n=9 n=21 Sakoulas 2004 1 Vancomycin MIC 0.5 µg/ml 1.0 2.0 µg/ml 100 80 60 Vancomycin MIC 0.5 µg/ml 1.0 µg/ml 2.0 µg/ml 52 77 71 100 80 60 40 20 0 P=0.02 85 62 n=40 n=39 Hidayat 2006 2 Vancomycin MIC 1.0 µg/ml 2.0 µg/ml 40 20 29 8 n=21 n=17 n=25 0 Moise-Broder 2004 3 * Moise 2007 4 * *P-value not reported Success measured as eradication at end of treatment 21 n=13 n=7 n=14 1. Sakoulas G et. al. J Clin Microbiol 2004;42:2398 2402 2. Hidayat L et al. Arch Intern Med 2006;166:2138 2144 3. Moise-Broder P et al. Clin Infect Dis 2004;38:1700 1705 4. Moise P et al. Antimicrob Agents Chemother 2007;51:2582 2586
Proportion patients, % Antibiotic treatment of MSSA bacteraemia b-lactams versus vancomycin for the treatment of MSSA bacteraemia 1 100 90 80 70 60 50 40 30 20 10 0 P<0.05 Vancomycin (n=133) 84 62 20 b-lactam (n=110) 12 4 6 Cure Relapse Death 1. Fowler V, et al. Clin Infect Dis 1998;27:478 486
Phase III S. aureus bacteraemia and infective endocarditis study Blood culture + S. aureus Study design and conduct 2 Work-up includes TEE within 5 days Daptomycin 6 mg/kg i.v. q24h Comparator Vancomycin 1 g i.v. q12h + gentamicin 1 mg/kg i.v. q8h 4 days SSP 2 g i.v. q4h + gentamicin 1 mg/kg i.v. q8h 4 days End of therapy (EOT) Outcome 6 weeks Test of cure (TOC) Outcome Primary endpoint SSP = Semisynthetic penicillin (nafcillin, oxacillin or flucloxacillin) TEE = transesophogeal echocardiography Fowler VG, et al. NEJM 2006;355:653 665
Success Rate (%) Daptomycin in SAB and Right Sided Endocarditis Daptomycin 70 Vancomycin* + gentamicin 60 50 44.4 44.6 46.7 Semisynthetic penicillin + gentamicin 40 30 32.6 20 10 0 20/45 14/43 33/74 28/60 MRSA MSSA.Fowler VG, et al. NEJM 2006;355:653 665
Summary 1. Identify the causative microorganism 2. Use bactericidal antibiotics in an appropriate concentration as i.v. infusion 3. Treat patients generally in the hospital, even eligible candidates should be treated at least two weeks before submitted to your OPAT program 4. Cooperate with an ID specialist and/or a clinical microbiologist 5. Refer to the guidelines!