La vancomycine n’est plus le traitement de référence des infections à S. aureus Jean-François Timsit INSERM U 823 Université Joseph Fourier Réanimation médicale polyvalente Grenoble

Vanco…has been….? Depuis toujours la vanco est inférieure aux beta-lactamines anti-staphylococcique dans le traitement des SAMS Depuis toujours la vancomycine diffuse mal Il existe une augmentation des CMI à la vancomycine ses dernières années Il existe des molécules qui se compare favorablement à la vancomycine en terme d’efficacité L’augmentation des posologies de vanco n’est pas associée à une augmentation d’efficacité…. Mais à une augmentation de la toxicité…

Vanco…has been….? Depuis toujours la vanco est inférieure aux beta-lactamines anti-staphylococcique dans le traitement des SAMS Depuis toujours la vancomycine diffuse mal Il existe une augmentation des CMI à la vancomycine ses dernières années Il existe des molécules qui se compare favorablement à la vancomycine en terme d’efficacité L’augmentation des posologies de vanco n’est pas associée à une augmentation d’efficacité…. Mais à une augmentation de la toxicité…

Antibiotiques lentement bactéricides temps dépendant Time-kill curves (MIC X 4) Bactericidal titer (log10 cfu/ml) 10 endocardites 2 bacteriemies persistantes à 7 et 16 jours Vitesse de bactéricidies in vitro: diminution de 1.4 vs 2.8 log10 à 24 heures: p<0.001 P<0.001 hours Small PM et al – AAC 1990; 34:1227

Moindre efficacité de la vancomycine dans les infections à SASM 63 patients recevant un traitement efficace > 48 h par vanco (n = 31 ; 17 SASM ; 20 SARM) ou cloxacilline (22 SASM) Mortalité liée à l’infection (%) SARM* (11/22) SASM* (14/41) Vancomycine (8/17) Cloxacilline (0/10) SASM infection 50 34 47 10 20 30 40 60 Gonzalez C et al. Clin Infect Dis 1999; 29: 1171-1177.

Bactériémie récidivante à S. aureus:Facteurs de risque Pas de récidive Rechute OR AOR (n = 271) (n = 23) Présence de corps étranger* 56 (21 %) 19 (83 %) 18,2 16,9 [6,0-60] Vancomycine* 145 (53 %) 19 (82 %) 4,1 3,5 [1,2-12,7] Hémodialyse* 75 (27 %) 14 (61 %) 4,1 1,6 Diabètes 63 (23 %) 7 (30 %) 1,4 - SARM 85 (31 %) 7 (30 %) 1,0 - Infection métastatique 79 (29 %) 6 (26 %) 0,9 - *Interaction significative entre les 3 variables Fowler et al, JID 1999; 179: 1157-61

Vanco…has been….? Depuis toujours la vancomycine diffuse mal Depuis toujours la vanco est inférieure aux beta-lactamines anti-staphylococcique dans le traitement des SAMS Depuis toujours la vancomycine diffuse mal Il existe une augmentation des CMI à la vancomycine ses dernières années Il existe des molécules qui se compare favorablement à la vancomycine en terme d’efficacité L’augmentation des posologies de vanco n’est pas associée à une augmentation d’efficacité…. Mais à une augmentation de la toxicité…

Diffusion tissulaire des glycopeptides Organe Vancomycine1-6 Téicoplanine7-9 Osseux ≤ 15 % ≤ 60 % LCR ≤ 20 % ≤ 10 % ELF ≤ 20 % - Muscle ~ 30 % ~ 40 % 1. Graziani 1988; 2. Matzke 1986; 3. Albanese 2000; 4. Georges 1997; 5. Lamer 1993; 6. Daschner 1987; 7. Wilson 2000; 8. Stahl 1987; 9. Frank 1997;

Quel objectif de concentration?? Log 10 cfu/ml S aureus ATCC 25923 CMI=CMB=2 mg/l temps Modèle de méningite expérimentale à S. aureus Nagl et al – AAC 1999; 43:1932

Toujours actif sur la bactérie, quelque soit le site ? Pour être actif il faut [C] tissulaire = 4 X CMI et ce pour un temps de contact prolongé. Nagl M. AAC 1999 ; 43 : 1932-4 Mauvaise diffusion tissulaire : [C]plasm/ [C]tis = 6-10 C tissulaire à 6 heures < 4 CMI

Vancomycine et poumon Lamer et al. AAC. 1993.

Objectif de concentration au site infecté Diapo Pr Michel Wolff

 Biofilm  Glycopeptides Activité bactéricide temps-dépendante sur les staphylocoques et les streptocoques Efficacité maximale si concentrations maintenues en permanence au dessus de la CMB de la bactérie. Bactéricidie lente (24 heures) < Péni M sur les SASM Diffusion mediocre  Activité sur la paroi   Biofilm 

Vanco…has been….? Depuis toujours la vanco est inférieure aux beta-lactamines anti-staphylococcique dans le traitement des SAMS Depuis toujours la vancomycine diffuse mal Il existe une augmentation des CMI à la vancomycine ses dernières années Il existe des molécules qui se compare favorablement à la vancomycine en terme d’efficacité L’augmentation des posologies de vanco n’est pas associée à une augmentation d’efficacité…. Mais à une augmentation de la toxicité…

S aureus dont la résistance est homogène à la methicilline… Smith TL et al – N eng J Med 1999; 340:493 SARM sensible aux gp SARM VISA : épaississement paroi

High MICs and failure MRSA BSI Vancomycin > 24h Survival > 24h There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective cohort study was conducted among patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and May 2007. The inclusion criteria were as follows: at least 18 years old, nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administration. Failure was defined as 30-day mortality, bacteremia >10 days on vancomycin therapy, or a recurrence of MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART) analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART analysis was >1.5 mg/liter. The 66 patients with vancomycin MICs of >1.5 mg/liter had a 2.4-fold increase in failure compared to patients with MICs of <1.0 mg/liter (36.4% and 15.4%, respectively; P 0.049). In the Poisson regression, a vancomycin MIC of >1.5 mg/liter was independently associated with failure (adjusted risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P 0.01). These data strongly suggest that patients with MRSA bloodstream infections with vancomycin MICs of >1.5 mg/liter respond poorly to vancomycin. Alternative anti-MRSA therapies should be considered for these patients. Loidise et al - AAC, Sept. 2008, p. 3315–3320

High MICs and mortality 414 septicémies traitée par vancomycine Background. Vancomycin treatment failure in methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is not uncommon, even when MRSA is susceptible to vancomycin. The aim of our study was to evaluate whether vancomycin minimum inhibitory concentration has any influence on the mortality associated with MRSA bacteremia. Methods. A total of 414 episodes of MRSA bacteremia were prospectively followed-up from 1991 through 2005. MIC of vancomycin for the first isolate was determined by E-test. Clinical variables recorded were age, comorbidity, prior administration of vancomycin, use of corticosteroids, prognosis of underlying disease, source of bacteremia, the need for mechanical ventilation, shock, and mortality. A “treatment group” variable was created and defined as follows: (1) receipt of empirical vancomycin and an isolate with a vancomycin MIC of 1 mg/mL (38 episodes), (2) receipt of empirical vancomycin and an isolate with a vancomycin MIC of 1.5 mg/mL (90 episodes), (3) receipt of empirical vancomycin and an isolate with a vancomycin MIC of 2 mg/mL (40 episodes), and (4) receipt of inappropriate empirical therapy (246 episodes). Univariate and multivariate analyses were performed. Results. Episodes caused by strains with a vancomycin MIC of 2 mg/mL were independently associated with a lower risk of shock (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.15–0.75). Multivariate analysis selected receipt of empirical vancomycin and an isolate with a vancomycin MIC of 2 mg/mL (OR, 6.39; 95% CI, 1.68– 24.3), receipt of inappropriate empirical therapy (OR, 3.62; 95% CI, 1.20–10.9), increasing age (OR, 1.02; 95% CI, 1.00–1.04), use of corticosteroids (OR, 1.85; 95% CI, 1.04–3.29), an ultimately (OR, 10.2; 95% CI, 2.85–36.8) or rapidly (OR, 1.81; 95% CI, 1.06–3.10) fatal underlying disease, high-risk (OR, 3.60; 95% CI, 1.89–6.88) and intermediate-risk (OR, 2.18; 95% CI, 1.17–4.04) sources of bacteremia, and shock (OR, 7.38; 95% CI, 4.11–13.3) as the best predictors of mortality. Conclusions. Mortality associated with MRSA bacteremia was significantly higher when the empirical antibiotic was inappropriate and when vancomycin was empirically used for treatment of infection with strains with a high vancomycin MIC (11 mg/mL). (*) Information about Vancomycin concentration are lacking Loidise et al - CID. 2008

Les CMI à la Vanco montent… Robert J et al. JAC 2006;57:506-10 (Pitié-Salpêtrière)

Evolution du niveau de sensibilité à la vancomycine et à la teicoplanine (CMI par E-test) SARM gentamicine-résistant (n=1075) 172 253 40 104 62 52 87 78 69 84 74 (Number of strains) vancomycine teicoplanine J. Robert JAC 2006

Evolution du niveau de sensibilité à la vancomycine et à la teicoplanine (CMI par E-test) SARM gentamicine-sensible (n=370) (Number of strains) 49 43 43 36 45 147 vancomycine teicoplanine J. Robert JAC 2006

Vanco…has been….? Depuis toujours la vanco est inférieure aux beta-lactamines anti-staphylococcique dans le traitement des SAMS Depuis toujours la vancomycine diffuse mal Il existe une augmentation des CMI à la vancomycine ses dernières années Il existe des molécules qui se compare favorablement à la vancomycine en terme d’efficacité L’augmentation des posologies de vanco n’est pas associée à une augmentation d’efficacité…. Mais à une augmentation de la toxicité…

Caractéristiques pharmacocinétiques du linézolide (1) Concentrations à l’état d’équilibre dans différents milieux biologiques (administration répétée chez un nombre limité de sujets volontaires) Rapport/plasma Salive 1,2/1,0 Sueur 0,55/1,0 Liquide de revêtement épithélial (poumon) 4,5/1,0 Cellules alvéolaires (poumon) 0,15/1,0 LCR 0,7/1,0 1) RCP ZYVOXID®. Dictionnaire Vidal 2004.

LINEZOLIDE dans les pneumonies nosocomiales Modèle de pneumonie hématogène à souche GISA, le linézolide comparé à la vanco a permis de réduire significativement les comptes bactériens et d’augmenter la survie Bacteriostatique

Linezolid vs Vancomycine Cumul 2 études Méta-Analyse rétrospective de 2 études d’équivalences. Essais prospectifs, randomisés, contrôlés vs placebo. Double aveugle, analyse en intention de traiter (ITT). - Linézolide 600 mg/12 h ± Aztréonam 1-2 g/8 h pdt 7-21 j - Vancomycine 1 g/12 h ± Aztréonam 1-2 g/8 h pdt 7-21 j Sélection des patients avec VAP Kollef M et al, ICM 2004, 30:388-394

Linezolid vs Vancomycine Cumul 2 études Rétrospectif Ventilator Associated Pneumonia p = 0,02 p = 0,07 p = 0,06 p = 0,001 Kollef. ICM. 2004.

Linezolid vs Vancomycine Cumul 2 études Rétrospectif Kollef et al. ICM. 2004.

Linezolid vs Vancomycine Cumul 2 études Rétrospectif Kollef et al. ICM. 2004.

Linezolid vs Vancomycine Cumul 2 études Rétrospectif Ventilator Associated Pneumonia p = 0,15 p = 0,07 p = 0,19 p = 0,02 Kollef. ICM. 2004.

Linezolid vs Vancomycine Cumul 2 études Rétrospectif Kollef et al. ICM. 2004.

LNZ vs comparator: a meta-analysis Linezolid has been approved for the treatment of patients with infections caused by Gram-positive cocci that are resistant to traditionally used antibiotics, including glycopeptides. This oxazolidinone antibiotic has been reported to have excellent pharmacokinetics and eff ectiveness. We did a meta-analysis of randomised controlled trials (RCTs) to clarify whether linezolid is superior to glycopeptides or β-lactams for the treatment of Gram-positive infections. 12 RCTs, involving 6093 patients, were included. Overall, with respect to treatment success, linezolid was more eff ective than glycopeptides or β-lactams (odds ratio [OR] 1·41 [95% CI 1·11–1·81]). Mortality was similar between the groups (OR 0·97 [0·79–1·19]). Linezolid was more eff ective than comparators in patients with skin and soft-tissue infections (OR 1·67 [1·31–2·12]) and bacteraemia (OR 2·07 [1·13–3·78]). However, there was no diff erence in treatment success for patients with pneumonia (OR 1·03 [0·75–1·42]). Treatment with linezolid was not associated with more adverse eff ects in general (OR 1·40 [0·95–2·06]); however, thrombocytopenia was recorded more commonly in patients receiving linezolid (OR 11·72 [3·66–37·57]). Although linezolid is more eff ective than its comparators for the empirical treatment of selected patients, several points, such as the use of less potent antistaphylococcal β-lactams, the same all-cause mortality, and the higher probability of thrombocytopenia, should be taken into account and may limit the use of linezolid to specifi c patient populations or infections that are diffi cult to treat with other antibiotics. Falagas et al - Lancet Infect Dis 2008; 8: 53–66

Daptomycine Lipopeptides Activité sur SARM, SERM, GISA, PRSp et VRE Bactéricidie concentration-dépendante (Cmax et ASC) Forte fixation protéique 1 inj. /24h = 4mg/kg en 30 mn Non compatible avec les sol. glucosées Élimination rénale / adaptation si ins rénale? (fin d’EER, AUC, CPK++)

Daptomycine:bactericidie 1.6- 2 heures Ceftobiprole: 8 heures Activities of Ceftobiprole, Linezolid, Vancomycin, and Daptomycin against Community-Associated and Hospital-Associated Methicillin-Resistant Staphylococcus aureus Leonard et al AAC Aug. 2008, p. 2974–2976 HA MRSA 100 CA-MRSA and 100 clinical HAMRSA strains Patients at the Detroit Medical Center We evaluated the activity of ceftobiprole against 100 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and 100 hospital-associated MRSA (HA-MRSA) isolates. Eight isolates were evaluated by time-kill studies for kill rate and potential for synergy with tobramycin. Ceftobiprole MIC50 and MIC90 values were 1 and 2 g/ml, respectively, against CA-MRSA and HA-MRSA. In time-kill analysis, ceftobiprole was bactericidal at all concentrations tested. Comment figure: In the time-kill analysis, ceftobiprole was bactericidal and killed to detection limits (2 log10 CFU/ml) by 24 h. Kill rates (T99.9) were as follows: daptomycin (1.6 h) had a kill rate greater than that of daptomycin plus serum (2.2 h), which was greater than that of ceftobiprole (8 h), which was equal to that of vancomycin (8.6 h), which was greater than that of linezolid (did not reach 99.9% kill) (P 0.001) against CA-MRSA; and daptomycin (1.6 h) had a kill rate greater than that of daptomycin plus serum (2.1 h), which was greater than that of vancomycin (8.6 h), which was greater than that of ceftobiprole (11.8 h), which was greater than that of linezolid (did not reach 99.9% kill) (P 0.001) for HA-MRSA. Results are shown in Fig. 1. When ceftobiprole was combined with tobramycin, all isolates displayed indifference at 24 h. Ceftobiprole alone was bactericidal at both 1 and 0.5 the MIC. Although there was a trend toward slower killing at 0.5 MIC, there was no difference in bactericidal rates between ceftobiprole at 4 MIC, at 1 MIC (T99.9 8.6 h), or at 0.5 MIC (T99.9 14.2 h) (P 0.172). CA MRSA Daptomycine:bactericidie 1.6- 2 heures Ceftobiprole: 8 heures Vanco 8 heures Linezolide>24 heures

48th ICAAC - C1-141 Antimicrobial Activity of Daptomycin and Comparators Tested Against S. aureus from 20 USA Hospitals in 2005-2008: Evaluation of Potency Trends H. S. SADER, T. R. FRITSCHE, P. R. RHOMBERG, R. N. JONES; C1-141 Antimicrobial Activity of Daptomycin and Comparators Tested Against S. aureus from 20 USA Hospitals in 2005-2008: Evaluation of Potency Trends H. S. SADER, T. R. FRITSCHE, P. R. RHOMBERG, R. N. JONES; JMI Lab., North Liberty, IA. Background: Daptomycin (DAP) is a lipopeptide with potent bactericidal activity against Gram-positive pathogens, approved by USA-FDA for treatment of skin and soft tissue infection in 2003. We evaluated DAP potency trends in a 4-year period (2005-2008) following USA-FDA release for clinical use. Methods:Consecutive, unique patient strains of clinical significance were collected in 20 USA hospitals and susceptibility (S) tested in a central reference laboratory against DAP and various comparators by CLSI broth microdilution methods. Mueller-Hinton broth was supplemented to 50 mg/L of calcium when testing DAP. Results: Among 11,243 strains tested, 53.7% were resistant (R) to oxacillin (OXA). OXA R increased from 51.8% in 2005 to 58.8% in 2008. R to other antimicrobials included: erythromycin (65.8%), levofloxacin (43.9%), clindamycin (24.8%) and trimethoprim-sulfamethoxazole (2.0%); these R remained stable over the study period. The highest DAP MIC observed was 2 μg/ml (3 strains). No significant variation in DAP potency was noted against OXA-R or OXA-S S. aureus (SA) (Table). Linezolid (LZD; MIC50/90, 1/2 μg/ml, >99.9% S) and vancomycin (VAN; MIC50/90, 1/1 μg/ml, >99.9% S) were also very active, but four-fold less potent than DAP (MIC50/90, 0.25/0.5 μg/ml). Year (no. tested) % inhibited at DAP MIC (μg/ml) of: No. of DAP non-S strains ≤0.12 0.25 0.5 1 2 MRSA 2005 (1731) 1.7 66.9 29.3 0.06 2006 (1885) 3.2 78.4 16.1 0.3 0.05 2007 (1721) 3.7 80.9 12.9 0.4 0.0 2008 (701) 1.1 75.8 22.3 All years (6038) 2.7 73.1 23.7 0.6 0.1 3 All MSSA (5205) 6.5 78.1 15.2 0.2 Conclusions: DAP was highly active against SA and its activity remained stable across the 4-year period evaluated (2005-2008) using reference methods. Decrease in DAP potency (ìMIC creepî) has not been observed since USA-FDA approval and widespread clinical use. R to OXA increased during the same period but did not adversely influence DAP activity. R to LZD, VAN and DAP remain uncommon among SA isolated in USA hospitals.

Daptomycine et poumon Pertel et al – CID2008;46:1142–1151 Clinical Infectious Diseases 2008;46:1142–1151 © 2008 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2008/4608-0003$15.00DOI: 10.1086/533441MAJOR ARTICLE Effects of Prior Effective Therapy on the Efficacy of Daptomycin and Ceftriaxone for the Treatment of Community-Acquired Pneumonia Peter E. Pertel,1 Patricia Bernardo,1 Charles Fogarty,3 Peter Matthews,4 Rebeca Northland,5 Mark Benvenuto,1 Grace M. Thorne,1 Steven A. Luperchio,1 Robert D. Arbeit,2 and Jeff Alder1 1Cubist Pharmaceuticals, Lexington, and 2Paratek Pharmaceuticals, Boston, Massachusetts; 3Spartanburg Medical Center, Spartanburg, South Carolina; 4Middelburg Hospital, Middelburg, South Africa; and 5Hospital de Carabineros, Santiago, Chile Objective.  We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP). Methods.  Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5–14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points. Results.  After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, −12.4% to −0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, −13.8% to −3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, −6.1% to 11.5%). Conclusions.  Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment.

Dapto 6mg/kg..Doses plus élevées? Traitement de référence ? 2006; 355: 653-65 Fowler VG et al "Daptomycin is not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis" Essai ouvert Dapto 6mg/kg..Doses plus élevées? Traitement de référence ? Dosage ? Effets indésirables

Daptomycin vs vancomycin ° gentamicin – bacteremia MRSA a,b:Success rate Analyse de sous groupe du papier de Fowler Objectives: In a prospective, randomized trial, daptomycin was non-inferior to standard therapy for Staphylococcus aureus bacteraemia and right-sided endocarditis. Since rates of infection due to methicillin-resistant S. aureus (MRSA) infection are increasing and treatment outcomes for bacteraemia caused by MRSA are generally worse than those observed with methicillin-susceptible S. aureus bacteraemia, clinical characteristics and treatment results in the trial’s pre-specified subset of patients with MRSA were analysed. Methods: Clinical characteristics and outcomes of patients receiving daptomycin were compared with those receiving vancomycin plus low-dose gentamicin. Success was defined as clinical improvement with clearance of bacteraemia among patients who completed adequate therapy, received no potentially effective non-study antibiotics and had negative blood cultures 6 weeks after end of therapy. Results: Twenty of the 45 (44.4%) daptomycin patients and 14 of the 43 (32.6%) vancomycin/gentamicin patients were successfully treated (difference 11.9%; confidence interval 28.3 to 32.1). Success rates for daptomycin versus vancomycin/gentamicin were 45% versus 27% in complicated bacteraemia, 60% versus 45% in uncomplicated bacteraemia and 50% versus 50% in right-sided MRSA endocarditis. Cure rates in patients with septic emboli and in patients who received pre-enrolment vancomycin were similar between treatment groups. However, in both treatment groups, success rates were lower in the elderly (75 years). Persisting or relapsing bacteraemia occurred in 27% of daptomycin and 21% of vancomycin/gentamicin patients; among these patients, MICs of 2 mg/L occurred in five daptomycin and four vancomycin/gentamicin patients. The clinical course of several patients may have been influenced by lack of surgical intervention. Conclusions: Daptomycin was an effective alternative to vancomycin/gentamicin for MRSA bacteraemia or right-sided endocarditis. Taux de vanco med 14.7 mg/l Rehm SJ et al – JAC 2008 doi:10.1093/jac/dkn372

Dérivé de la vancomycine Efficacité in vitro > vancomycine Mars 07 Dérivé de la vancomycine Efficacité in vitro > vancomycine Bactéricide sur CG+ Actif sur : SARM, VISA, VRSA VRE (sauf Van A) Posologie 10 mg/kg x 1/24 h Développement en cours : - infect. « compliquées » peau et tissus mou - PAVM - bactériémies

K-530 Telavancin for Treatment of Hospital-Acquired Pneumonia (HAP) Caused by MRSA and MSSA: The ATTAIN Studies E. RUBINSTEIN1, G. R. COREY 2, M. E. STRYJEWSKI 2,3, J. L. VINCENT 4, J. Y. FAGON 5, M. H. KOLLEF 6, M. M. KITT 7, H. D. FRIEDLAND 7, On Behalf Of The Attain Study Group; 1Univ. of Manitoba, Winnipeg, Canada, 2DCRI, Durham, NC, 3CEMIC, Buenos Aires, Argentina, 4HÙpital Erasme, Brussels, Belgium, 5HÙpital EuropÈen Georges Pompidou, Paris, France, 6Washington Univ., St. Louis, MO, 7Theravance, Inc., South San Francisco, CA Baseline pathogen Pooled clinical cure rates at TOCa TLV % (n/N) VAN % (n/N) Difference, % (95% CI)b Single Gram+d 85 (139/164) 76 (125/165) 8.9 (0.3, 17.5) MRSA 82 (72/88) 74 (86/116) 7.9 (-3.5, 19.3) MSSA 88 (51/58) 75 (27/36) 12.2 (-4.2, 28.8)c S. pneumoniae 93 (13/14) 92 (11/12) 1.2 (-22.7, 26.3)c apatients with mixed Gram+/Gram- infection are not included; btwo-sided confidence interval (CI); c CI uses Agresti-Caffo adjustment; dincludes infections with Enterococcus spp 85 % 76 % K-530 Telavancin for Treatment of Hospital-Acquired Pneumonia (HAP) Caused by MRSA and MSSA: The ATTAIN Studies E. RUBINSTEIN1, G. R. COREY 2, M. E. STRYJEWSKI 2,3, J. L. VINCENT 4, J. Y. FAGON 5, M. H. KOLLEF 6, M. M. KITT 7, H. D. FRIEDLAND 7, On Behalf Of The Attain Study Group; 1Univ. of Manitoba, Winnipeg, Canada, 2DCRI, Durham, NC, 3CEMIC, Buenos Aires, Argentina, 4HÙpital Erasme, Brussels, Belgium, 5HÙpital EuropÈen Georges Pompidou, Paris, France, 6Washington Univ., St. Louis, MO, 7Theravance, Inc., South San Francisco, CA. Background: Vancomycin (VAN) is the standard-of-care for the treatment of methicillin-resistant S. aureus (MRSA) pneumonia but is felt to be less effective for infections with methicillin-susceptible (MSSA) strains. Telavancin (TLV) is an investigational, bactericidal lipoglycopeptide with potent activity against Gram-positive pathogens in vitro. We compared the efficacy of TLV and VAN for treatment of HAP caused by Gram-positive bacteria. Methods: ATTAIN 1 and 2 were randomized, methodologically identical, double-blind, phase 3, clinical studies. Patients (≥18 years of age) with HAP suspected or documented to be due to Gram-positive pathogens were randomized to receive TLV 10 mg/kg IV q 24 h or VAN 1 g IV q 12 h for 7-21 days. Respiratory and blood specimens were to be obtained at baseline. Test-of-cure (TOC) visit was conducted 7-14 days after end of study treatment. The microbiologically evaluable (ME) population consisted of clinically evaluable patients (met pre-specified criteria for evaluability) with Gram-positive pathogen isolated at baseline. Results: Baseline pathogen Pooled clinical cure rates at TOCa TLV % (n/N) VAN % (n/N) Difference, % (95% CI)b Single Gram+d 85 (139/164) 76 (125/165) 8.9 (0.3, 17.5) MRSA 82 (72/88) 74 (86/116) 7.9 (-3.5, 19.3) MSSA 88 (51/58) 75 (27/36) 12.2 (-4.2, 28.8)c S. pneumoniae 93 (13/14) 92 (11/12) 1.2 (-22.7, 26.3)c apatients with mixed Gram+/Gram- infection are not included; btwo-sided confidence interval (CI); c CI uses Agresti-Caffo adjustment; dincludes infections with Enterococcus spp. Conclusions: TLV achieved numerically higher clinical cure rates in patients with HAP caused by MRSA and MSSA. These results suggest that the methicillin resistance status of S. aureus may be less important when treating with TLV compared with VAN. 48th ICAAC Oct 2008

Telavancin for Hospital-Acquired Pneumonia Caused by S Telavancin for Hospital-Acquired Pneumonia Caused by S. aureus: Efficacy Analysis According to the In Vitro Susceptibility to Vancomycin G. R. COREY1,2, E. RUBINSTEIN 3, T. LALANI 2,1, M. H. KOLLEF 4, A. F. SHORR 5, F. GENTER 6, S. L. BARRIERE 6, H. D. FRIEDLAND 6, On Behalf Of The Attain Study Group; Pooled clinical cure rates (ME patients) at TOC, % (n/N ) VAN MIC μg/mL ≤0.5 a ≥1 b Treatment group TLV VAN S. aureus 89% (33/37) 79% (22/28) 87% (74/85)c 74% (78/105) MRSA 92% (11/12) 86% (12/14) 86% (50/58) 75% (66/88) MSSA 88% (22/25) 71% (10/14) 89% (24/27) 71% (12/17) aAll MICs are 0.5 μg/mL, except for 1 TLV patient with MIC ≤ 0.25 μg/mL. bAll MICs are 1 μg/mL, except for 2 TLV patients with MIC = 2 μg/mL. c p<0.05 vs VAN 87 % 74 % K-528 Telavancin for Hospital-Acquired Pneumonia Caused by S. aureus: Efficacy Analysis According to the In Vitro Susceptibility to Vancomycin G. R. COREY1,2, E. RUBINSTEIN 3, T. LALANI 2,1, M. H. KOLLEF 4, A. F. SHORR 5, F. GENTER 6, S. L. BARRIERE 6, H. D. FRIEDLAND 6, On Behalf Of The Attain Study Group; 1DCRI, Durham, NC, 2Duke Univ. Med. Ctr., Durham, NC, 3Univ. of Manitoba, Winnipeg, Canada, 4Washington Univ., St. Louis, MO, 5Georgetown Univ., Washington, DC, 6Theravance, Inc., South San Francisco, CA. Background: Telavancin (TLV) is an investigational lipoglycopeptide that is rapidly bactericidal against Gram-positive pathogens including methicillin-susceptible and -resistant S. aureus (MSSA, MRSA). The clinical cure rates of patients treated for monomicrobial S. aureus hospital-acquired pneumonia (HAP) with TLV or vancomycin (VAN) in the ATTAIN study were analyzed by the minimum inhibitory concentration (MIC) of VAN against the respective baseline isolates. Methods: ATTAIN 1 and 2 were methodologically identical, randomized, double-blind, multinational, phase 3 clinical studies. Patients aged ≥ 18 years with HAP caused by suspected or confirmed Gram-positive pathogens were randomized to receive TLV 10 mg/kg IV q 24 h or VAN 1 g IV q 12 h for 7-21 days. Test-of-cure visit was scheduled 7-14 days after end of study treatment. Microbiologically evaluable (ME) patients were those who met pre-specified criteria for evaluability and from whom a Gram-positive pathogen was recovered at baseline. MICs were determined by broth microdilution (CLSI). Results: TLV clinical cure rate was numerically higher than VAN for all subgroups and statistically significantly higher for patients infected with S. aureus with a VAN MIC ≥1 μg/mL (Table). Pooled clinical cure rates (ME patients) at TOC, % (n/N ) VAN MIC μg/mL ≤0.5 a ≥1 b Treatment group TLV VAN S. aureus 89% (33/37) 79% (22/28) 87% (74/85)c 74% (78/105) MRSA 92% (11/12) 86% (12/14) 86% (50/58) 75% (66/88) MSSA 88% (22/25) 71% (10/14) 89% (24/27) 71% (12/17) aAll MICs are 0.5 μg/mL, except for 1 TLV patient with MIC ≤ 0.25 μg/mL. bAll MICs are 1 μg/mL, except for 2 TLV patients with MIC = 2 μg/mL. c p<0.05 vs VAN Conclusions: TLV appears more effective than vancomycin for the treatment of HAP due to S. aureus with VAN MIC ≥ 1 μg/mL. p<0.05 vs VAN 48th ICAAC Oct 2008

Vanco…has been….? Depuis toujours la vanco est inférieure aux beta-lactamines anti-staphylococcique dans le traitement des SAMS Depuis toujours la vancomycine diffuse mal Il existe une augmentation des CMI à la vancomycine ses dernières années Il existe des molécules qui se compare favorablement à la vancomycine en terme d’efficacité L’augmentation des posologies de vanco n’est pas associée à une augmentation d’efficacité…. Mais à une augmentation de la toxicité…

Vancomycine: AUIC et SARM: infections respiratoires Cut off: AUIC24   Guérison clinique Eradication   345 866 Moise PA et al. Am J Health Syst Pharm 2000 Melange sams et samr Diagnostic de pneumonie essentiellement clinique…

La relation PK – efficacité n’est pas évidente Analyse rétrospective de 102 pneumonies nosocomiales à SARM diagnostiquée par LBA quantitatif Objective: The goal of this investigation was to determine whether vancomycin pharmacokinetic indexes (eg, serum trough concentrations or area under the concentration curve [AUC] values) were associated with mortality for patients with health-care–associated pneumonia (HCAP) attributed to methicillin-resistant Staphylococcus aureus (MRSA). Design: A retrospective, single-center, observational cohort study. Setting: Barnes-Jewish Hospital, a 1,200-bed urban teaching facility. Patients: Adult patients requiring hospitalization who were identified as having HCAP attributed to MRSA by BAL semi-quantitative cultures. Interventions: Retrospective data collection from automated hospital, microbiology, and pharmacy databases. Measurements and main results: One hundred two patients with MRSA HCAP were identified over a 6.5-year period. Thirty-two patients (31.4%) died during their hospitalization. The mean ( SD) vancomycin trough concentrations (13.6 5.9 vs 13.9 6.7 g/mL, respectively; p 0.866) and AUC values (351 143 vs 354 109 g/h/mL, respectively; p 0.941) did not differ between survivors and nonsurvivors. The stratification of the vancomycin trough concentrations and AUC values yielded no relationship with hospital mortality. Conclusions: We found no evidence that greater vancomycin trough concentrations or AUC values correlated with hospital outcome. Based on these results, aggressive dosing strategies for vancomycin (eg, trough concentrations of > 15 g/mL) may not offer any advantage over traditional dose targets (range, 5 to 15 g/mL). (CHEST 2006; 130:947–955) Meghan N. Jeffres et al - Chest 2006;130;947-955

La relation PK – efficacité n’est pas évidente Objective: The goal of this investigation was to determine whether vancomycin pharmacokinetic indexes (eg, serum trough concentrations or area under the concentration curve [AUC] values) were associated with mortality for patients with health-care–associated pneumonia (HCAP) attributed to methicillin-resistant Staphylococcus aureus (MRSA). Design: A retrospective, single-center, observational cohort study. Setting: Barnes-Jewish Hospital, a 1,200-bed urban teaching facility. Patients: Adult patients requiring hospitalization who were identified as having HCAP attributed to MRSA by BAL semi-quantitative cultures. Interventions: Retrospective data collection from automated hospital, microbiology, and pharmacy databases. Measurements and main results: One hundred two patients with MRSA HCAP were identified over a 6.5-year period. Thirty-two patients (31.4%) died during their hospitalization. The mean ( SD) vancomycin trough concentrations (13.6 5.9 vs 13.9 6.7 g/mL, respectively; p 0.866) and AUC values (351 143 vs 354 109 g/h/mL, respectively; p 0.941) did not differ between survivors and nonsurvivors. The stratification of the vancomycin trough concentrations and AUC values yielded no relationship with hospital mortality. Conclusions: We found no evidence that greater vancomycin trough concentrations or AUC values correlated with hospital outcome. Based on these results, aggressive dosing strategies for vancomycin (eg, trough concentrations of > 15 g/mL) may not offer any advantage over traditional dose targets (range, 5 to 15 g/mL). (CHEST 2006; 130:947–955) Meghan N. Jeffres et al - Chest 2006;130;947-955

Vanco…has been….? Mais à une augmentation de la toxicité… Depuis toujours la vanco est inférieure aux beta-lactamines anti-staphylococcique dans le traitement des SAMS Depuis toujours la vancomycine diffuse mal Il existe une augmentation des CMI à la vancomycine ses dernières années Il existe des molécules qui se compare favorablement à la vancomycine en terme d’efficacité L’augmentation des posologies de vanco n’est pas associée à une augmentation d’efficacité…. Mais à une augmentation de la toxicité…

Dosages des glycopeptides+++ Grosse variabilité inter-individuelle neutropéniques: 1 g de vancomycine concentration au pic de 8.9 à 80 mg/l !!!(Van der Auwera; AAC 91; 35:451) Enfants neutropéniques: dose de vanco nécessaire pour TR entre 5 et 15 mg/l variable entre 40 et 100 mg/kg (Chang 1994) Taux de16-20 mg/l (V) à atteindre au résiduel Taux de 20- 30 mg/l en HPLC (T)

Infections à SARM traitées par vancomycine (95 patients, 77% pneumonies) Cible: Population TR > 15 mg/l & TR >= CMI x 4 CMI<2 CMI=2 p Succès 85% 62% 0.02 Néphrotoxicité 12% <0.05 Mortalité 10% 24% 0.16 High-Dose Vancomycin Therapy for Methicillin-Resistant Staphylococcus aureus Infections Efficacy and Toxicity Levita K. Hidayat, PharmD; Donald I. Hsu, PharmD; Ryan Quist, PhD; Kimberly A. Shriner, MD; Annie Wong-Beringer, PharmD Arch Intern Med. 2006;166:2138-2144. Background  Vancomycin hydrochloride treatment failure for infections caused by susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains with high minimum inhibitory concentration (MIC) has prompted recent guidelines to recommend a higher vancomycin target trough of 15 to 20 µg/mL. Methods  A prospective cohort study of adult patients infected with MRSA was performed to determine the distribution of vancomycin MIC and treatment outcomes with vancomycin doses targeting an unbound trough of at least 4 times the MIC. The microbiology laboratory computer records were used to identify all patients from whom MRSA was isolated from August 1, 2004, through June 30, 2005. Primary outcome measures were clinical response, mortality, and nephrotoxicity. Patients were placed into subgroups based on target trough attainment and high vs low vancomycin MIC ( 2 vs <2 µg/mL) for efficacy and high vs low trough ( 15 vs <15 µg/mL) for nephrotoxicity analyses. Results  Of the 95 patients in the study, 51 (54%) were infected with high-MIC strains and had pneumonia (77%) and/or bacteremia. An initial response rate of 74% was achieved if the target trough was attained irrespective of MIC. However, despite achieving the target trough, the high-MIC group had lower end-of-treatment responses (24/39 [62%] vs 34/40 [85%]; P = .02) and higher infection-related mortality (11/51 [24%] vs 4/44 [10%]; P=.16) compared with the low-MIC group. High MIC (P = .03) and Acute Physiology and Chronic Health Evaluation II score (P = .009) were independent predictors of poor response in multivariate analysis. Nephrotoxicity occurred only in the high-trough group (11/63 [12%]), significantly predicted by concomitant therapy with other nephrotoxic agents. Conclusions  High prevalence of clinical MRSA strains with elevated vancomycin MIC (2 µg/mL) requires aggressive empirical vancomycin dosing to achieve a trough greater than 15 µg/mL. Combination or alternative therapy should be considered for invasive infections caused by these strains. Hidayat et al.- Arch Intern Med. 2006;166:2138-2144

L’augmentation des posologies n’est pas sans conséquences ABSTRACT Objective: The goal of this investigation was to determine whether more aggressive vancomycin dosing is associated with greater risk for renal toxicity in patients with health care–associated pneumonia (HCAP) attributed to methicilllin-resistant Staphylococcus aureus (MRSA). Methods: This was a retrospective, single-center, observational cohort study. The following information was obtained for all study patients from automated hospital, microbiology, and pharmacy databases: age, sex, weight, serial serum creatinine (SCr), ageand sex-adjusted creatinine clearance (CrCl) during receipt of vancomycin, vancomycin serum trough concentrations, duration of vancomycin therapy, and Acute Physiology and Chronic Health Evaluation II scores. Renal toxicity was defined as either a 0.5-mg/dL increase from baseline in SCr or a ≥50% increase in SCr based on serial SCr measurements. Data for patients who met the definition of renal toxicity were compared with data for those who did not. Results: Ninety-four patients (mean [SD] age, 59.0 [15.6] years; 59 [62.8%] men; 73 (77.7%) white; mean baseline CrCl, 70.3 [23.0] mL/min) were identified as having MRSA HCAP. Forty (42.6%) patients developed renal toxicity. Patients who developed renal toxicity were significantly more likely than patients who did not develop renal toxicity to have greater mean vancomycin serum trough concentrations (20.8 [9.9] μg/mL vs 14.3 [6.7] μg/mL, respectively; P < 0.001), vancomycin serum trough concentrations ≥15 μg/mL (67.5% vs 40.7%; P = 0.01), and a prolonged duration (≥14 days) of vancomycin treatment (45.0% vs 20.4%; P = 0.011). Logistic regression analysis identified identified a maximum vancomycin serum trough concentration of ≥15 μg/mL as being independently associated with renal toxicity (adjusted odds ratio = 2.82; 95% CI, 1.02–7.74; P = 0.045). The overall mean change in CrCl for the study population was –13.5 (–16.0) mL/min (range, 0.0 to –62.6 mL/min). Patients with maximum measured vancomycin serum trough concentrations ≥15 μg/mL (n = 49) had significantly greater absolute changes in CrCl compared with patients with maximum measured vancomycin serum trough concentrations <15 μg/mL (n = 45) (–18.9 [–17.0] vs –7.6 [–12.5] mL/min, respectively; P < 0.001). Conclusions: The results suggest that aggressive vancomycin dosing and prolonged vancomycin administration may be associated with greater risk for renal toxicity in patients with MRSA HCAP. However, this retrospective study cannot establish causation, and a prospective, randomized, double-blind trial is needed. (Clin Ther. 2007;29:1107–1115) Copyright © 2007 Excerpta Medica, Inc. Key words: renal toxicity, Staphylococcus aureus, methicillin resistance, pneumonia. Renal toxicity was defined as either a 0.5-mg/dL increase from baseline in SCr or a ≥50% increase in SCr based on serial SCr measurements. Jeffres et al - Clin Ther. 2007;29:1107–1115

Molécule de référence qui n’a pas démérité Bactéricidie modeste Vanco: Molécule de référence qui n’a pas démérité Bactéricidie modeste Diffusion médiocre Tolérance moyenne Incontestable « problème » avec les CGP SARM +++ VRE Nouvelles molécules intéressantes, actives, encore mal connues a coté du LNZ Place de la dapto? Nouvelles molécules…. Combinaisons…