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49 th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 12–15, San Francisco, CA. USA.

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* E-mail address: cgdelamaria@yahoo.es

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  1. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 12–15, San Francisco, CA. USA. POSTER ID: B-056DAPTOMYCIN (DAP) IN THE TREATMENT (Tx) OF EXPERIMENTAL ENDOCARDITIS (EE) DUE TO METHICILLIN-RESISTANT (MRSE) AND REDUCED SUSCEPTIBILITY TO GLYCOPEPTIDES (GISE) Staphylococcus epidermidis . C. García de la Mària*, Y. Armero, A. Del Río, A. Moreno, D. Soy, M. Almela, S. Ninot, C. Falces , CA. Mestres, C. Cervera, JM. Gatell, MT. Jiménez De Anta, F. Marco, JM. Miró and the Hospital Clinic Endocarditis Study Group. Hospital Clínic - IDIBAPS. University of Barcelona. Barcelona, Spain *E-mail address: cgdelamaria@yahoo.es

  2. ABSTRACT Background:DAP is a lipopeptide antibiotic with potent activity against Gram-positive cocci. We evaluated the activity of DAP in the Tx of MRSE or GISE aortic EE in rabbits. Methods: 48 h after formation of catheter-induced aortic valve vegetations, 1.5 x 109 cfu/mL of MRSE [MRSE-375] or GISE [NRS6] was injected intravenously. 48 h post-infection the animals were treated for 2 days with either DAP [6 mg/kg iv qd] or vancomycin (VAN) at the standard dose; SD-VAN [15 mg/kg/12h iv]. For the MRSE-375 strain, a higher VAN dose (HD-VAN [30 mg/kg/6h iv]) was administered to achieve an AUC/MIC > 350. Antibiotics were administered with a computer-controlled infusion pump system simulating human serum kinetics. Results: DAP and VAN MIC/MBCs were 0.5/1 and 2/4 mg/L for MRSE-375 and 2/4 and 8/16 mg/L for NRS6 respectively. Peak/trough levels for DAP, SD-VAN, and HD-VAN were 86/15 mg/L, 46/6 mg/L, and 50/15 mg/L, respectively. For the MRSE-375 strain, Tx with DAP sterilized significantly more vegetations than SD-VAN (aP = 0.02) and tended to be more effective than SD-VAN or HD-VAN in reducing the density of bacteria in valve vegetations. Tx with HD-VAN showed better activity against SD-VAN (bP = 0.35). For the NRS6 strain, DAP was more effective than SD-VAN in reducing the density of bacteria in valve vegetations (cP = 0.02). Treatment group Sterile vegetation, no./total, no. (%) Median (IQR)(log10 CFU/g of veg) MRSE EE – Control 0/15 (0) 7.4 (6–8.3) DAP 9/15 (60)a, 0 (0–4.1) SD-VAN 3/16 (19)a,b 2 (2–2) HD-VAN 5/15 (33)b 2 (0–2.8) GISE EE –Control 0/16 (0) 8.4 (7.9–8.9) DAP 1/17 (6) 3.7 (2–6)c SD-VAN 0/15 (0) 7.1 (5.2–8.5)c Conclusions: After 2 days of Tx, DAP showed significatively better activity than VAN in the treatment of EE due to MRSE or GISE.

  3. BACKGROUND • Daptomycin is a cyclic lipopeptide antibiotic with activity against S. epidermidis and other CoNS, (including MRSE and GISE).It is approved by the Food and Drug Administration for the treatment of complicated skin and skin structure infections as well as bacteremia and right-sided IE caused by S. aureus. Daptomycin has demonstrated efficacy in the treatment of CoNS bacteremia and is a potential therapeutic option for IE caused by S. epidermidis. • CoNS are a common cause of nosocomial bloodstream infections, cardiac device infections, and prosthetic valve endocarditis (PVE) and an emerging cause of native valve endocarditis (NVE). Moreover, as many as 41% of NVE cases are caused by methicillin-resistant strains. At this moment, there is little published information regarding the in vivoactivity of daptomycin against these pathogens. • Antimicrobial treatment of MRSE NVE is based upon the administration of a glycopeptide agent, such as vancomycin, while gentamicin and rifampin are typically added to vancomycin for the management of PVE. Unfortunately, resistance to rifampin and gentamicin among MRSE, as well as the growing prevalence of glycopeptide-intermediate S. epidermidis (GISE), limits our therapeutic options and warrants investigation of alternative agents.

  4. AIM OF THE STUDY The aim of this study was to evaluate the activity of daptomycin (6 mg/kg 24h iv) in the treatment of experimental MRSE or GISE aortic endocarditis using a human-like pharmacokinetic model.

  5. MATERIALS & METHODS (I) 1. IN VITRO STUDIES 1.1. Microorganisms Two clinical isolates of MRSE were selected for the study. MRSE-375 was isolated from a patient with endocarditis at Hospital Clínic University in Barcelona. NRS6, a GISE strain, was obtained through the Network of Antimicrobial Resistance in S. aureus (NARSA) program supported under NIAID/NIH Contract #HHSN272200700055C. Daptomycin and vancomycin MICs/MBCs were 0.5/1 and 2/4 mcg/mL for MRSE-375 strain and 2/4 and 8/16 for NRS6 strain, respectively (determined by using the micro-dilution method).

  6. MATERIALS & METHODS (II) 1.2. Population analysis profile (PAP) studies. The recovered bacteria were retested to measure daptomycin and vancomycin MICs for comparison to pretreatment MIC values. In addition, daptomycin and vancomycin population analysis studies (PAPs) were done. 2. IN VIVO STUDIES 2.1. Antibiotics (daptomycin 6 mg/kg 24h iv, vancomycin at standard dose [15 mg/Kg/12h iv] and vancomycin at high dose [30 mg/Kg/6h iv]) were administered using a computer-controlled infusion pump system designed to reproduce human serum pharmacokinetics in rabbits by intravenous infusion.

  7. MATERIALS & METHODS (III) 2.2. Establishment of endocarditis according to the model described by Garrison and Freedman and installation of the infusion pump system. 3. ANALYSIS OF ENDOCARDIAL VEGETATIONS. The results were expressed as the number of log10 CFUs per gram of vegetation. The result was assigned a value of 2 if there was no growth on the quantitative plates but of there was growth in the qualitative culture (the rest of the homogenate in tryptic soy broth). The result was assigned a value of zero, and the vegetation was considered sterile if there was no growth from the initial quantitative culture or from the homogenates cultured for a week.

  8. MATERIALS & METHODS (IV) • 4. TREATMENT GROUPS • - DAPTOMYCIN (simulating 6 mg/Kg/24h iv) • - SD-VANCOMYCIN (simulating 15 mg/Kg/12h iv) • HD-VANCOMYCIN (simulating 15 mg/Kg/6h iv)* • *(only for MRSE-375 strain, in order to achieve a • Vancomycin AUC/MIC>400.) • 5. STATISTICAL ANALYSIS • Fisher’s exact test was used to compare the rate of sterile vegetations and analyze whether there were differences between the different treatment groups. The Mann-Whitney nonparametric test was used to compare the median log10 cfu/g tissue values between the different treatment groups.

  9. EXPERIMENTAL ENDOCARDITIS MODEL Day Induction of nonbacterial thrombotic endocarditis of the aortic valve (the polyethylene catheter was left in place). 0 2 Intravenous MRSE or GISE challenge (1,5 x 109 cfu/mL). After 48h, blood cultures were taken from all the animals, antibiotic treatment was started using the infusion pump system and control animals were sacrificed. 4 5 6 Antibiotic treatment was maintained for 48 hours. Animals were sacrificed after six half-lives after antibiotic treatment (22 hours for daptomycin and 8 hours for vancomycin). 7 Aortic valve vegetations were quantitatively and qualitatively cultured in Tryptic Soy Broth.

  10. RESULTS (I):DaptomycinPharmacokinetics Human values* Dosage 6 mg/Kg K (h-1) 0.073 t1/2b (h) 9.5 AUC0-12(µg.h/mL) 1600 Serum levels (mg/mL) On-pump animal values (n=5) K (h-1) 0.194+0.01 t1/2b (h) 3.6+0.2 AUC0-12(µg.h/mL) 846 +132 On-pump human-like values (n=5) K (h-1) 0.09+0.015 t1/2b (h) 7.6 + 1.3 AUC0-12(µg.h/mL) 1148 + 206 Time (h) * Cubist data

  11. RESULTS (II):VancomycinPharmacokinetics Human values Dosage 1g iv* K (h-1) 0.15 t1/2b (h) 4.6 AUC0-5(µg.h/mL)358.6 Serum levels (mg/mL) On-pump animal values (n=5) K (h-1) 0.53+0.14 t1/2b (h) 1.3+0.4 AUC0-5(µg.h/mL) 101.5+16 On-pump human-like values (n=5) K (h-1) 0.18+0.03 t1/2b (h) 3.8+1.2 AUC0-5(µg.h/mL) 298.8 Time (h) *Blouin R et al. Antimicrob Agents Chemother. 1982, 21:575-580

  12. RESULTS (III): MRSE-375study. Treatment groups Control Daptomycin (6 mg/Kg/24h iv) SD-Vancomycin (15 mg/Kg/12h iv) HD-Vancomycin (15 mg/Kg/6h iv) #Survival/ # total (%) -/- 15/15 (100) 16/16 (100) 15/15 (100) Sterile vegetations/ # total (%) 0/15 (0) 9/15 (60)ab 3/16 (19)ac 5/15 (33)bc Median (IQR) log10 cfu/g veg 7.4 (6-8.3) 0 (0-4.1) 2 (2-2) 2 (0-2.8) ap= 0.02, bp= 0.14 cp= 0.35

  13. RESULTS (IV): NRS6study. Treatment groups Control Daptomycin (6 mg/Kg/24h iv) SD-Vancomycin (15 mg/Kg/12h iv) #Survival/ # total (%) -/- 17/17 (100) 15/15 (100) Sterile vegetations/ # total (%) 0/15 (0) 1/17 (6) 0/15 (0) Median (IQR) log10 cfu/g veg 8.4 (7.9-8.9)a 3.7 (2-6)b 7.1 (5.2-8.5)ab ap=0.06, bp=0.02

  14. CONCLUSIONS (I) • After two days of therapy, daptomycin (6 mg/Kg 24h iv) was significantly (p=0.02) more effective in sterilizing vegetations than vancomycin at standard dose (15 mg/Kg/12h iv) in the treatment of MRSE experimental endocarditis. • For the MRSE-375 strain, with a vancomycin MIC of 2 mcg/ml, daptomycin compared with HD-vancomycin sterilized more vegetations but the difference did not reach statistical significance (P = 0.14).We didn’t find differences between the two different dosage vancomycin regimens (p=0.34). • For the NRS6 strain, daptomycin was significantly (p= 0.02) more effective than vancomycin in reducing the density of bacteria in valve vegetations in the treatment of GISE endocarditis.

  15. CONCLUSIONS (II) • All isolates recovered from vegetations remained susceptible to the antibiotics used in the study arms. PAP studies did not reveal the development of heteroresistance to daptomycin or vancomycin. • The results of this study shows the good activity of daptomycin for the treatment of experimental IE caused by MRSE and GISE and provide support for the study of daptomycin as an alternative to vancomycin for the treatment of MRSE IE in humans.

  16. ACKNOWLEDGEMENTS • This study has been supported by: • Cubist Pharmaceuticals (Lexington, MA, USA) • FIS 05/0170 (Instituto de Salud Carlos III, Madrid) • Fundació Clínic, Barcelona. • Fundación Máximo Soriano, Barcelona. • REIPI (Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Madrid), Spanish Network for the Research in Infectious Diseases [REIPI RD06/0008])

  17. Members of the Hospital Clinic Endocarditis Study Group. Hospital Clínic-IDIBAPS. University of Barcelona, Barcelona (Spain) Infectious Diseases JM. Miró A. del Río C. Cervera A. Moreno JM. Gatell Cardiology JC. Paré C. Falces M. Azqueta M. Sitges Ll. Mont M. Heras Cardiac Surgery CA. Mestres R. Cartañá S. Ninot JL. Pomar Microbiology F. Marco M. Almela MT. Jiménez de Anta Pharmacy/ Toxicology D. Soy M. Brunet Pathology N. Pérez J. Ramírez T. Ribalta Experimental Endocarditis Lab. C. García de la María Y. Armero C. Malucelli Statistical Analysis E. de Lazzari

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