Antibacterials Recent data on linezolid and daptomycin Patricia Muñoz, MD. Ph.D. (pmunoz@micro.hggm.es) Hospital General Universitario Gregorio Marañón Universidad Complutense de Madrid. 1 GESITRA
Reasons to attend this talk 1. Vancomycin is worse than Beta-lactam drugs against Staphylococcus infections. 2. The Vanco- creep phenomena is out of discussion in many centers and the Vanco MIC elevation is not easy to detect. 3. Vancomycin treatment of staphylococcal infections with MIC 1.5 mg/l associated to a worse prognosis
Reasons to attend this talk 4. Penetration of Vancomycin in lining epithelial fluid in the lung is poor. 5. Increasing doses increases toxicity but not necessarily results. 6. Combination of Vancomycin with other drugs does not increase efficacy in VAP 7. So we need to know linezolid and daptomycin Finally, I would really appreciate if you stay, thanks
Review of last year literature
1. Linezolid Index
Linezolid. General characteristics New class of antibiotics (oxazolidinones) First approved in 2000 Unique mechanisms of action High tissue penetration Bioavailability ~ 100% Used mainly in SSTI, VAP, MDR infections, others Safe drug (short periods) Myelosuppression, lactic acidosis, serotonin syndrome, peripheral/optic neuropathy Adjust dose if <65 kg or renal impairment?? Eur J Clin Pharmacol 2014; 70(1):23-8.
Spectrum of activity Gram positives (including Listeria spp, Corynebacterium spp, C. difficile, VRE) Anaerobes (B. fragilis, Fusobacterium sp., Porphyromonas, Prevotella sp., Peptostreptococcus sp. A few Gram negatives (P. multocida, Fusobacterium, Moraxella catarrhalis, Legionella, Bordetella, E. meningoseptica, Capnocytophaga) Nocardia sp., Mycobacterium, Actinomyces J Antimicrob Chemother 2014; 69: 1582 1588
Estudio de pfizer Linezolid en neumonía
Multicentric, retrospective, observational Adults with MRSA VAP: vanco vs line 188 patients (101 linezolid and 87 vancomycin) Linezolid Vancomycin p APACHE II 21± 11 19 ± 9 0.041 Clinical success 85% 69% 0.009 After adjusting for confounding factors, linezolidpts were 24% more likely to experience clinical success (P = 0.018) (NNT=6) Peyrani P Critical Care 2014, 18:R118
Peyrani et al. Critical Care 2014, 18:R118
Kalil AC, et al. BMJ Open 2013;3:e003912
Meta-analysis of MRSA hospital-acquired pneumonia treatment Wunderink RG, et al. BMJ 2014;348:g1469 *Includes some methicillin-sensitive cases
Bassetti M. Clin Microbiol Infect 2014
30 day all cause mortality Balli et al. Antimicrobial Agents and Chemotherapy 2014;58(2):734 739
Infection related (A) and inhospital mortality (B) Balli et al. Antimicrobial Agents and Chemotherapy 2014;58(2):734 739
****P <0.05 vs. C (8 hours after infection) and VAN (8 hours after infection) Linezolid modulates proinflammatory cytokines during methicillin-resistant Staphylococcus aureus induced pneumonia IL-1β, interleukin 1β Four groups of mice were studied: sham-treated (noninfected, nontreated) mice (Sham), untreated (control) mice (C), linezolid-treated mice (LZD), and vancomycin-treated mice (VAN). Boxes represent median (interquartile range). Data are representative of 3 independent experiments (6 mice/group) Jacqueline C, et al. J Infect Dis. 2014;210(5):814-23
Neutrophil-mediated inflammation is decreased in linezolid-treated animals ***P <0.01 vs. all other groups Simple interactive object extraction analysis of Ly6Gstained paraffin sections of mouse lungs 8 hours after infection. Four groups of mice were studied: Sham mice, control mice, linezolid-treated mice, and vancomycin-treated mice. Boxes represent median (IQR). Data are representative of 2 independent experiments. Six fields per specimen (2 animals/group)were analyzed Jacqueline C,, et al. JID. 2010 Aug;65(8):1749-52.
Niederman et al. http://dx.doi.org/10.1016/j.clinthera.2014.06.029
Linezolid is cost-effective alternative vancomycin for MRSA-confirmed NP, largely attributable to the higher clinical response Infection and Drug Resistance 2014:7 273 280
Index 1. Linezolid 2. Daptomycin
Daptomycin Approved Europe 2006 Lipopeptide with new Moa (disruption of cell membrane function without lysis) Bactericidal against Gram positives IV use. Adjust dose in renal insufficiency Little resistance, but in vivo increase of MICs Canepari P et al. AAC 1990;34:1220 1226; Cotroneo N et al. AAC 2008;52:2223 2225 Fowler VG Jr et al. N Engl J Med 2006;355:653 665; Int J Antimicrob Agents. 2014;43(5):465-9.
Daptomycin Approved for S. aureus BSI when associated with right-sided endocarditis or complicated SSTIs Active against biofilm Not clear what dose to use. Approved doses 4 mg/kg for cssti and 6 mg/kg for S. aureus bacteraemia/rie Raised CPK levels (rhabdomyolysis), peripheral neuropathy, eosinophilic pneumonia Excellent option for OPAT!! Canepari P et al. AAC 1990;34:1220 1226; Cotroneo N et al. AAC 2008;52:2223 2225; Fowler VG Jr et al. N Engl J Med 2006;355:653 665
Required 11 mg/kg/d to achieve levels Use ideal weight-based doses in obese patients
Single-center, retrospective cohort 98 patients (63 received daptomycin concurrent with statin, and 51 with statin held) CPK elevation: 5% at 7d and 12% at 14 days Concurrent therapy: 2-fold risk (NS) Holding statin during daptomycin therapy may not be necessary, but then increase monitoring of CPK Ann Pharmacother. 2014 Mar;48(3):320-7
Retrospective cohort of 150 pts (100 V, 50 D) In patients with MRSA bacteremia, daptomycin efficacy was not affected by GFR level and was similar to vancomycin s efficacy Clinical Infectious Diseases 2014;58(11):1533 9
Persistent bacteraemia in 22/124 (18%) MRSA BSI episodes treated with daptomycin Significant increases in daptomycin MIC in subsequent isolates (39%) Higher mortality (32%) and microbiological failure (41%) Daptomycin MIC increase was associated with microbiological failure (OR 27) and therapeutic failure (OR 16) J Antimicrob Chemother 2014:568-71
Combination therapy 106 pts treated with daptomycin for S. aureus bacteremia and mild or moderate renal (CORE registry) Moise et al. Antimicrob Agents Chemother 2013;57:1192-1200
Daptomycin treatment efficacy might be enhanced with β-lactam combination therapy in primary endovascular and bone/joint infections. Moise et al. Antimicrob Agents Chemother 2013;57:1192-1200
Cerón, JAC 2014
Analysis of published Mortality experience (Dapto no indication for VRE BSI) 13 studies (532 pts dapto, 656 line) Daptomycin vs. linezolid Daptomycin was associated with higher mortality (OR: 1.59, 95% CI: 1.02 2.50, p = 0.04) A prospective randomized study is needed Chuang et al. BMC Infectious Diseases 2014, 14:687
Clinical success MRSA Wang SZ, Hu JT, Zhang C, et al. BMJ Open 2014;4:e004744
1:2 nested case-control study of adult patients with MRSA OAIs (40 vanco vs 20 Dapto) Daptomycin Vancomycin Duration 46 48 0.5 Clinical success at 3 months 75% 68% 0.8 At 6 months 70% 58% 0.5 Adverse events 5% 18% 0.2 Eur J Clin Microbiol Infect Dis. 2014 ;33(4):659-64
1288 pts identified. 3:1 analysis. Mean OPAT duration: 19 d Daptomycin N=119 Vancomycin N= 357 OPAT days 2518 6649 NS Antimicrobial adverse event/1000 OPAT days 3.2 7.7 0.02 Antimicrobial intervention rates/1000 OPAT days 5.6 27.1 < 0.001 Readmissions 5% 7% NS Daptomycin OPAT: 60% fewer antimicrobial adverse events and require 80% fewer antimicrobial interventions J Antimicrob Chemother. 2014 May;69(5):1407-15.
In summary Despite having being a number of years in the market, still very active research performed and still needed with these interesting drugs!! Thank you very much