Alternatives a Vancomicina

Transcription

1 Alternatives a Vancomicina Juan M Pericàs Servei de Malalties Infeccioses Hospital Clínic de Barcelona IDIBAPS-UB SESSIÓ SCMIMC 21/05/15

2 OBJECTIUS 1. Exposar l evidència (fonamentalment clínica) que recolça l ús d antibiòtics alternatius a vancomicina en les infeccions per SASM, SARM i CoNS. 2. Posar el focus en l eficàcia que han demostrat front a soques amb CMI de vancomicina 1.5 µg/ml. 3. Extrapolar conclusions a partir BSI/IE. 4. Fonamentar les recomanacions sobre dosificació i ús en combinació. 5. Fer esment dels mecanismes de resistència més comuns i les taxes aproximades que s han descrit.

3 Quins problemes planteja l ús de vancomicina en el tractament de les infeccions estafilocòciques? - Pobra activitat bactericida - Escassa difussió a les vegetacions - CMI (AUC/MIC PD target) - Soques hvisa - Tolerància Alta taxa de fracassos

4 Antimicrobial Agents Against Staphylococcal Infections Old drugs TMP-SMX Fusidic acid Fosfomycin Marketed drugs Quinupristin/dalfopristin Linezolid Tigecycline Daptomycin Recently approved drugs Telavancin Dalbavancin Oritavancin Ceftaroline Ceftobiprole Tedizolid Investigational drugs Teixobactim, Iclaprim, Ivernimicin, lysostaphin, new quinolones and other antibiotics.

5 Therapy for Endocarditis Due to Methicillin- Susceptible Staphylococcus aureus (MSSA) or Coagulase Negative Staphylococci (MS-CoNS) in the Absence of Prosthetic Material Baddour L et al. Circulation. 2005; Habib G et al. Eur Heart J, Antibiotic Dosage and Route Duration Nafcillin/Cloxacillin ± Gentamicin Cefazolin ± Gentamicin Vancomycin* Daptomycin (RS-IE) 2 g/4 h IV + 1 mg/kg/8 h IV/IM 2 g/8 h IV + 1 mg/kg/8 h IV/IM 30 mg/kg/24 h IV (in 2 doses) 6 mg/kg/24 h IV 4-6 wk 3-5 days 4-6 wk 3-5 days 4-6 wk 4-6 wk CNS: Coagulase-Negative Staphylococci; IV: intravenously; IM: intramuscularly. * Adjust dosage to achieve 1-h serum concentration of µg/ml and trough concentration of µg/ml;

6 Therapy for Endocarditis Caused by Methicillin- Resistant Staphylococcus aureus (MRSA) Baddour L et al. Circulation. 2005; Habib G et al. Eur Heart J, 2009 Regimen Dosage and route Duration (weeks)* Vancomycin ± Rifampin ± Gentamicin Daptomycin Linezolid Fosfomycin + Imipenem Other drugs 30 mg/kg/24 h. IV (in 2 doses)* mg/8 h. PO/IV + 3 mg/kg/24h. IV/IM (in 2-3 doses) 6 mg/kg 24 h. IV 600 mg/12 h. PO/IV 2 g/6h IV + 1 g/6h IV * Adjust dosage to achieve trough concentration of µg/ml.

7 Efficacy of daptomycin at 6 mg/kg for SAB/IE Fowler VG et al. N Engl J Med 2006;355: Patients, % Clinical success* in S. aureus-infected patients: mitt population MSSA and MRSA Bacteremia/IE? 31.8 MSSA (n=144) Difference in success rates: 4.0% 95% CI: 20.3, 12.3 MRSA (n=89) Difference in success rates: 12.6%, 95% CI: 7.4, 32.6 Daptomycin Comparator What is the best empiric therapy against Daptomycin (A-I) Nafcillin/Cloxacillin + Vancomycin (B-III) 33/74 Gudiol F et 34/70 al. Enferm Infecc Microbiol 20/45 Clin /44 *Clinical success at the visit 6 weeks after the end of therapy. Failure defined as clinical failure, microbiological failure, death, failure to obtain blood culture, receipt of potentially effective non-study antibiotics or premature discontinuation of the study medication

8 Daptomycin vs. Vancomycin in the treatment of Experimental Endocarditis due to MRSA with a vancomycin MIC of 2 µg/ml Marco F et al. Antimicrob Agents Chemother. 2008; 52: Treatment groups - Control - Vancomycin-RD - Vancomycin-HD No. sterile vegetations/ No. total (%) 0/20 (0) 7/20 (35)* 9/18 (50%) Median (IQR) log 10 cfu/g veg 9 (8.6; 9.3) 2 (0; 5.6) & 1 (0; 2) - Daptomycin 13/18 (72)* Vancomycin-RD (recommended dose) simulating 1 g q 12 h i.v.; vancomycin-hd (high dose; [AUC/MIC>350]) simulating 1 g q 6 h i.v.; Daptomycin, simulating 6 mg/kg q 24 h i.v. 0 (0; 1.5) & * p=0.02; & p=0.02

9 Activity of Cloxacillin (CLO) plus Vancomycin (VAN) against MRSA-277 EE Castañeda X et al. ICAAC 2012 Strain Sterile Median(IQR) veg/total (%) Log 10 CFU/g veg Control VAN (1 g/6h) DAP (6mg/Kg/d) CLO+VAN 0/15(0) 8/16 (50) a,b 13/18 (72) b,c 13/15 (87) a,c 9 ( ) 1 (0-2.2) d 0 (0-1.5) 0 (0-0) d a p=0.05, b p=0.29, c p=0.6 d p=0.09

10 Vancomycin MICs 1 µg/ml: Outcomes against MRSAB improved with Daptomycin in 2 cohort studies Patients with MRSA BSI with higher vancomycin MICs (>1 µg/ml) and failing on vancomycin have a higher probability of survival at 60 days when treated with daptomycin: p= Outcomes with vancomycin MIC >1 µg/ml in patients with MRSAB 2 Factor 1. Moore CL et al. Clin Infect Dis 2011;54:51 2. Murray KP et al. Clin Infect Dis 2013;56:1562 Daptomycin (N=85) Vancomycin (N=85) P-value Clinical failure, n 17 (20.0) 41 (48.2) <0.001 Mortality at 30 days, n 3 (3.5) 11 (12.9) Persistent bacteraemia, n 16 (18.8) 36 (42.4) Duration of bacteraemia, days 3 (2 5) 5 (3 8) Length of stay, days 11 (8 18) 12 (8 17) Duration of treatment, days 10 (8 17) 9 (6 16) Recurrence of MRSAB within 30 days, n (%) 0 (0) 3 (4.1) 0.104

11 Daptomycin vs. Vancomycin as Initial Therapy for MSSA and MRSA Infections Jobson et al. Clin Ther 2011 VAN=108 (73 MRSA) DAP= 57 (46 MRSA) Only 23% had BSI

12 Strain Activity of Cloxacillin (CLO) plus Vancomycin (VAN) against MSSA-678 EE Castañeda X et al. ICAAC 2012 Sterile Median (IQR) veg/total (%) Log 10 CFU/g veg Control CLO (2 g/4h) VAN (1.25 g/8h) DAP (6 mg/kg/d) 0/15(0) 9/15 (60) a,b 10/14 (71) c 13/13 (100) a,c,d 9 (8-9.2) 0 (0-2) 0 (1-1.5) 0 (0-0) CLO+VAN a p=0.02; b p=0.7; c p=0.09; d p= /14 (71) b,d 0 (0-1.5)

13 Com podem millorar l activitat de daptomicina? Sembla que augmentant la dosi de daptomicina no n hi ha prou a l EI. - Cmax/MIC - AUC/MIC mg/kg/d - Dosis encara més altes (12 mg/kg/d)? Combinar daptomicina amb altres atb* - Per tractar d assolir una acció sinèrgica amb activitat bactericida - Per evitar el desenvolupament de resistències - Per disminuir les dosis de cada atb * Gentamicina, rifampicina, fosfomicina, b-lactàmics,

14 Efficacy of daptomycin for SAB/IE at 6 mg/kg/d Fowler VG et al. N Engl J Med 2006;355: Success rates at 6-week TOC by final diagnosis*: mitt population Success rate (%) Uncomplicated bacteraemia Complicated bacteraemia 43.8 Right-sided IE Daptomycin Comparator MRSA IE 0/5 0/ /32 16/29 26/60 23/61 8/19 7/16 1/9 2/ Left-sided IE *Final diagnoses as follows: 26% uncomplicated bacteraemia; 51% complicated bacteraemia, 15% right-sided IE, 8% left-sided IE; Limited data in left-sided IE preclude determination of efficacy.

15 Reasons for Microbiological Failure in Patients with SAB/IE Treated with Daptomycin at 6 mg/kg Fowler VG et al. N Engl J Med 2006;355: patients (16%) had microbiological failure. - Complications of endocarditis, 7 cases - Intravascular infections, 6 cases - Osteomyelitis or septic arthritis, 4 cases - Undrained abscesses, 2 cases Daptomycin MIC increased on therapy from 0.25 (5 isolates) or 0.5 (1) to 2.0 (5) and 4.0 (1) µg/ml.

16 Daptomycin-Resistance and Cell Surface Electrostatic Repulsion in DNS S. aureus Resposta a estrés de l envolta celular: yycfg i vrasr Metabolisme de fosfolípids: cls, pgsa, mprf Síntesi d àcids teicoics: dltabcd Síntesi d ARN: rpob, rpoc DAP/ Cationic antimicrobial peptides (CAMPs) DAP/CAMPs 1. Augment de la càrrega positiva de la membrana cel lular 2. Canvis en la fluïdesa de membrana 3. Engruiximent Mutations in MprF identified in daptomycin-ns de la paret S. aureus cel lular. Ernst et al., PLoS Pathog 2009; 5:e

17 Daptomycin and β-lactams (Nafcillin) Dhand A et al. Clin Infect Dis. 2011;53: DAP + NAF as salvage regimen 7 cases with persistent MRSA bacteremia (7-22 days) DAP used as 2 nd line agent in all Only one case with DAP nonsusceptibility Bacteremia cleared with nafcillin (NAF) Why? Increased daptomycin membrane binding with addition of NAF. Nafcillin led to a reduction in the net positive surface charge. DAP (green) binding with & without NAF (yellow)

18 β-lactams Increase the Antibacterial Activity of Daptomycin against Clinical MRSA Strains and Prevent Selection of Daptomycin-Resistance Mehta S et al. AAC. 2012, 56(12):6192. Oxacillin Imipenem AMC Ceftriaxone and ceftaroline too!!!

19 Daptomycin plus Fosfomycin is Synergistic against Methicillin-susceptible (MSSA) and Methicillin-resistant Staphylococcus aureus (MRSA) Strains Miró JM et al. Antimicrob Agents Chemother. 2012; 56: Two patients with complicated MRSA NV IE and one patient with MSSA PVE were succesfully treated with the combination of daptomycin plus fosfomycin. MSSA (N=6) MRSA (N=6)

20 The Combination of Daptomycin plus Fosfomycin has Synergistic, Potent, and Rapid Bactericidal Activity against MRSA in a Rabbit Model of EE Miró JM et al. 53 rd ECCMID, Barcelona 2014 MIC MRSA STRAIN=2 µg/ml

21 Daptomycin plus Fosfomycin or Rifampin and Fosfomycin and Imipenem against MRSA in the Experimental FBI Model Garrigós et al, AAC 2013

22 Evaluation of the efficacy and safety of Daptomycin Fosfomycin for the treatment of MRSA BSI in Spain PI 12/ Dr. Miquel Pujol (H. Bellvitge) Multicenter, Randomized (1:1) Open-label Clinical Trial MRSA BSI (N=240) Daptomycin (DAP) 10 mg/kg/d DAP (10 mg/kg/d) + Fosfomycin (2 g/6h) Recruitment: ; 12 weeks of F/U. Drugs adjusted to renal failure Susceptible to study drugs End points: TOC 12 weeks after finishing Rx, Toxicity, Resistance and Mortality.

23 Daptomycin plus Cloxacillin against MRSA in the Experimental FBI Model Garrigós et al, AAC 2012 The combination modestly enhanced the activity of DAP and prevented the emergence of resistance

24 Daptomycin plus Cloxacillin is as effective as Cloxacillin plus Rifampin in vivo against MSSA in the FBI Model El Haj et al, AAC 2015

25 Addition of Gentamicin or Rifampin Does Not Enhance the Effectiveness of Daptomycin in Treatment of MRSA Experimental Endocarditis with a Vancomycin MIC of 2 µg/ml Miró JM et al. Antimicrob Agents Chemother. 2009; 53:

26 Outcomes of Daptomycin alone or with Concomitant Beta-Lactams for SAB in Patients with mild or Moderate Renal Impairment Moise et al, AAC 2012 NO DIFFERENCES WERE FOUND REGARDING OUTCOMES BETWEEN MSSA AND MRSA 80 patients (70% MRSA) Prior vancomycin failure= 27.5% 66 received concomitant atb 30 BL 17 RIF 12 FQ 9 VAN 8 GEN 3 CLIN 2 LIN 2 S/T 1 TYG

27 The combination of Daptomycin plus TMP/SMX is Synergistic and Rapidly Bactericidal against Daptomycin-Nonsusceptible (DNS) MRSA in an In Vitro Model of Endocarditis Steed ME et al, AAC 2010 SA-684 strain Klaevs KC et al. AAC N=28 cases Addition of TMP/SMX to DAP for clinical failure Microbiological eradication in 24 cases (86%) Bacteremia cleared in 2.5 days (median) DAP+TMP/SMX Time

28 What would be the antibiotic combinations to treat Daptomycin-Non Susceptible (DNS) SAB/IE? Daptomycin + Beta-lactams* Daptomycin + Trimethoprim-Sulfamethoxazole** Daptomycin + Fosfomycin Fosfomycin + Imipenem Other antibiotic combinations*** * Ceftaroline, cloxacillin/nafcillin. *** Trimethoprim-Sulfamethoxazole + Clindamycin; Linezolid + Carbapenems. ** Steed ME et al. AAC. 2010; 54: ; Claeys KC et al. AAC :

29 Fosfomycin Combined with Imipenem in the Treatment of Experimental Endocarditis due to MRSA García de la Màría C et al. 43rd ICAAC. Chicago Abs. B-1091 Treatment groups Survival rate (%) Sterile vegetations Mean ± SD log 10 cfu/g veg Control 15/15 (100) a 0/15 (0) 9 ± 0.5 Fosfomycin (FOS) Imipenem 12/16 (75) 14/16 (88) 0/12 (0) 1/14 (7) 8.5 ± 0.7 b 5.6 ± 2 Vancomycin FOS + Imipenem 16/16 (100) 15/16 (94) 5/16 (31)* 11/15 (73)* a Control animals were sacrificed 18 h. after the i.v. MRSA challenge. b Five out of the 12 isolated strains (42%) developed resistance to fosfomycin. c None of the 10 isolated strains had resistance to fosfomycin. 4.4 ± 2.6* 2.1 ± 0.2 c * *p<0.05

30 70% N = 16 cases (12 with IE) Patients with VAN or DAP microbiological failure Microbiological eradication in all cases (100%) Bacteremia cleared in <3 days Clin Infect Dis Oct 15;59(8): doi: /cid/ciu580. Epub 2014 Jul 21

31 Therapy for Prosthetic Valve Endocarditis Caused by Methicillin-Resistant CoNS Baddour L et al. Circulation. 2005; Habib G et al. Eur Heart J Regimen Dosage and route Duration (weeks)* Vancomycin + Rifampin (PVE) + Gentamicin (PVE) 30 mg/kg/24 h. IV (in 2 doses)* mg/8 h. PO/IV + 3 mg/kg/24h. IV/IM (in 2-3 doses) Alternatives - Daptomycin - Linezolid - Other 6 mg/kg 24 h. IV 600 mg/12 h. PO/IV 6 6 * Adjust vancomycin to achieve trough concentration of µg/ml

32 Influence of Methicillin Susceptibility and Vancomycin MIC on the Outcome of 85 Episodes of Coagulase- Negative Staphylococci (CoNS) IE Garcia de la Maria C et al. PLoS One Cloxacillin N=38 Van MIC 1.5 mg/l N=27 Van MIC 2.0 mg/l N=20 S. epidermidis strains PV/MCP IE Surgery Mortality* 66% 71% 74% 21% 74% 63% 59% 44% 85% 65% 60% 55% *P = 0.022

33 Daptomycin in the Treatment of Experimental Endocarditis due to Methicillin-Resistant Staphylococcus epidermidis (MRSE) Garcia-de-la-Maria C et al. Antimicrob Agents Chemother. 2010, 54: Treatment groups Control Vancomycin-SD (1 g q12h iv) Vancomycin-HD (1 g q6h iv) Daptomycin-SD (6 mg/kg q24h iv) Daptomycin-HD (10 mg/kg q24h iv) # Sterile veg./ # total (%) 0/15 (0) 3/16 (19) & 5/15 (33)* 9/15 (60) & 11/15 (73%)* Median (IQR) log10 cfu/g veg 7.4 (6; 8.3) 2 (2; 2) 2 (0; 3) 0 (0; 4) 0 (0; 1) & P=0.02 * P=0.03. Vancomycin and Daptomycin MIC/MBCs were 2/4 and 0.5/1 mg/l, respectively.

34 Daptomycin for CoNS Endocarditis EU-CORE Dohmen P et al. 20th ECCMID, Vienna (Austria), 2010 Poster O 511 Success Failure Non -evaluable Proportion of patients, % S. epidermidis (n=44) Other CoNS (n=32) E. faecalis (n=18) E. faecium (n=4) Clinical success was defined as the sum of cured and improved patients

35 New Therapies for NVE & PVE Caused by Methicillin-Resistant CoNS Regimen Dosage and route Duration (weeks)* NVE Daptomycin* + Beta-Lactams or Fosfomycin PVE Daptomycin* + Rifampin (PVE) + Gentamicin (PVE) 10 mg/kg/24 h. IV + 2 g/4 h. IV + 2 g/6 h. IV (in 2-3 doses) 10 mg/kg/24 h. IV mg/8 h. PO/IV + 3 mg/kg/24h. IV/IM (in 2-3 doses) Alternatives - Ceftaroline - Linezolid - Other antibiotics* 600 mg/kg/8h IV 600 mg/12 h. PO/IV * Fosfomycin plus Imipenem; Telavancin, Dalbavancin; Oritavancin, Tedizolid and other active antibiotics against MRSE 6 6

36 Antimicrobial Agents Against Staphylococcal Infections Old drugs TMP-SMX Fusidic acid Fosfomycin Marketed drugs Quinupristin/dalfopristin Linezolid Tigecycline Daptomycin Recently approved drugs Telavancin Dalbavancin Oritavancin Ceftaroline Ceftobiprole Tedizolid Investigational drugs Teixobactim, Iclaprim, Ivernimicin, lysostaphin, new quinolones and other antibiotics.

37 Ceftaroline for Salvage Treatment of SAB Author, year N, types of strains Rates of success (%) Comments Vázquez JA, , 67% MRSA with ABSSSI, 21 with CABP Paladino JA, , 100% MRSA MIC VANCO >2 354 cases with an controls treated with VAN (SR: 44%, P=0,06) File TM Jr, , SAB? MIC? 82,6 FOCUS; Comparator: CRO Corey GR, , SAB? 85 CANVAS; Comparator VAN+AZTr cure rate of 79% Polenakovik, , 100% MRSA 66 Ho, , 100% MRSA 66 Liu, , MRSA 80 1 failure due to delayed removal of knee prosthesis Arshad, , MRSA, CMI >1 83 8% relapses Rybak, , MRSA differ. CMI 75 - Casapao, , 86% MRSA 88 -

38 Ceftaroline for Staph. IE Around 60 cases published as rescue Rx - 51 MRSA, 4 MSSA & 5 MRSE - 26 cases combined with DAP - 1 case combined with TMX/SFX - > 50% strains MIC over 1.5 µg/ml Blood cultures cleared before 3 days in the majority of cases. Cure rates at EOT 80% (No data ToC)

39 Metaanalysis of the efficacy of Linezolid vs. Glycopeptides or Betalactams for GPC infections Falagas et al, Lancet Infect Dis 2008

40 Tedizolid vs. Linezolid in Acute Bacterial SSSIs Shorr et al, AAC 2015

41 Tedizolid for MRSA IE in the Rabbit Model Chan et al, AAC 2015

42 Tygecicline alone or plus Rifampin in the FBI Exp. Model Garrigós et al, J Infect 2011 MIC vanco 2 µg/ml The only favourable property is that tyg prevented the development of RIF resistance

43 Once-Week Dalvabancin vs. Linezolid bid for the Treatment of Complicated SSSIs Jauregui et al, CID 2005 N=572 N=283 90% S. aureus (51% MRSA)

44 Once-Weekly Dalvabancin vs. Daily Conventional Therapy for Skin Infections Boucher et al, NEJM 2014

45 Single dose Oritavancin for the Treatment of Acute Bacterial Skin Infections Corey GR et al, NEJM 2014

46 Potential Role of Telavancin in Bacteremic Patients due to S. aureus Corey et al, CID 2015 Totes les soques amb MIC <1 µg/ml

47 Telavancin against Dapto-NS MRSA in the Rabbit Ao IE model Xiong et al, AAC 2012 MIC VAN=2 µg/ml MIC VAN= 4 µg/ml

48 CONCLUSIONS Daptomicina s ha de fer servir en dosis altes (10 mg/kg) i en combinació. Evitar l ús combinat de daptomicina i rifampicina durant les fases inicials de la bacterièmia. Hi ha diverses opcions en combinació per a evitar el desenvolupament de R a daptomicina. Tedizolid no aporta gran cosa quant a eficàcia i no evita sempre els mecanismes de resistència que afecten a linezolid. Ceftarolina és el fàrmac recentment comercial litzat amb major potencial en SAB i EI No ens oblidem de fosfomicina i cotrimoxazol!

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50 Teixobactin Ling et al, Science 2015

51 Combinations of Betalactams and Aminoglycosides with Plectasin are Synergistic against MRSA and MSSA Hu et al, PLoSone 2015 Decrease vanco MIC with combined tx MIC vanco in vivo strains?

52 Efficacy of NZ2114, a Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in EE due to MRSA Xiong et al, AAC 2011 MIC vanco 0.5 µg/ml