MRSA ventilatorassociated pneumonia Jean Chastre, M.D. www.reamedpitie.com
Conflicts of interest Consulting or lecture fees: Medimmune/Astrazeneca, Bayer, Pfizer, Arsanis, Cubist/Merck, Basilea, Aridis, Astellas, Cubist/Merck,
Methicillin-resistant Staphylococcus aureus WTA = wall teichoic acid PVL = Panton-Valentine leukocidin CHIP = chemotaxis inhibitory protein Foster TJ. JCI 2004;114:1693.
o The proportion of MRSA isolates is decreasing in 8 European countries, including the UK, Germany, Luxembourg, Belgium, France, Ireland, Portugal and Italy. o However, it remains above 20% in 11 (37%) and above 10% in 19 (63%). o The EU/EEA populationweighted mean is 17,4%. http://ecdc.europa.eu/en/publications/ Publications/1111_SUR_AMR_data.pdf.pdf 4
Prevalence of VAT/VAP caused by MRSA Martin-Loeches Lancet Respir Med. 2015;3:859-68.
Mortality Rates According to Aetiological Pathogens Found in 224 HAP and 465 VAP Episodes Rello J, et al. Eur Repir J 2011;37:1332 9 80 Mortality, % 60 40 20 58.3 57.3 37.6 33.9 30.8 n= 0 102 82 117 189 78 HAP, hospital-acquired pneumonia; MRSA, methicillin-resistant Stapylococcus aureus, MSSA, methicillinsusceptible S. aureus; VAP, ventilator-acquired pneumonia 6
VAP: impact of organisms on clinical resolution and medical resources utilization MSSA with appropriate AB Rx. H. influenzae with appropriate AB Rx. susceptible P aeruginosa MRSA with appropriate AB Rx. P. aeruginosa with initial IAT. Vidaur L., et al. Chest. 2008;133(3):625-32 P. aeruginosa MRSA P. aeruginosa MRSA 7
Management of Adults With HAP/VAP: 2016 Clinical Practice Guidelines by IDSA and ATS Kalil AC, et al. Clinical Infect Dis 2016;63(5):e61 111 VAP-Initial empiric antibiotics Gram positive: We suggest including an agent active against MRSA for the empiric treatment of suspected VAP ONLY in patients with any of the following: a risk factor for antimicrobial resistance, patients being treated in units where >10% 20% of S. aureus isolates are methicillin resistant, and patients in units where the prevalence of MRSA is not known (weak recommendation, very low-quality evidence). If no treatment for MRSA is required, coverage for MSSA should be provided.
Antimicrobial Agents for the Treatment of MRSA Infections Vancomycin/teicoplanin Trimethoprim-SMS /rifampicin/fosfomycin Linezolid/tedizolid Daptomycin (excluding pneumonia) Ceftaroline/ceftobiprole Telavancin Tigecycline Dalbavancin/oritavancin Tedizolid, Telavancin and Dalbavacin / Oritavancin are not approved by ANVISA in Brazil. 9
Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of MRSA Infections Liu C, et al. CID 2011;52(3):e18-e55 IV vancomycin 15 20 mg/kg/dose every 8 12 h, not to exceed 2 g per dose, is recommended in patients with normal renal function (B-III) In seriously ill patients, a loading dose of 25 30 mg/kg may be considered For serious infections, vancomycin trough conc. of 15 20 ug/ml are recommended (B-II) 10
Intrinsic Limitations of Vancomycin for Treating MRSA Infections 1. Relatively slow bacterial killing 2. Poor tissue penetration, particularly in the lung 3. Potential for toxicity 4. Decreased susceptibility to glycopeptides and emergence of strains with intermediate-level vancomycin resistance MRSA, methicillin-resistant Staphylococcus aureus; VAP, ventilator-associated pneumonia 11
Evaluation of vancomycin MIC creep in MRSA infections: a systematic review and meta-analysis Pooled proportion of MRSA with vancomycin MIC 2 mg/l Diaz R, et al. Clin Microbiol Infect. 2017, Ahead of Print 22
Prior Vancomycin Use Predicts High MICs No prior vancomycin Prior vancomycin Percent of Isolates 80 74 70 63 60 50 40 35 30 20 11 10 0 16 2 0,5 1 2 Vancomycin MIC (mcg/ml) Moise et al, JAC 2008;61:85 90 P = 0.002 Logistic Regression Analysis of Risk Factors Associated with Vancomycin MIC 1.5 mcg/ml Variable Vancomycin last 30 days ICU-acquired bacteremia AOR (95% CI) 9.4 (1.1-80.7) 5.3 (1.4-20.4) Lodise et al, JAC 2008;62:1138-41 P value 0.04 0.02 13
Vancomycin Exposure in 123 Patients With MRSA Bloodstream Infections: How Much Is Enough? Lodise TP et al. Clin Infect Dis. 2014;59:666-75 Failure was defined as 30-day mortality, bacteremia was 7 days, or recurrence 14
Using PK-PD Data to Optimize Vancomycin Therapy Target: AUIC/MIC >300 Peak Antibiotic (C) 24h AUC Antibiotic (C) 24h AUC MIC=0.5 µg/ml MIC 1.5 µg/ml Time (h) Time (h) Adapted from: Drusano GL, Clin Infect Dis. 2007;45:753 760 McKinnon PS & Davis SL. Eur J Clin Microbiol Infect Dis. 2004;23:271 288 15
Vancomycin-Associated Nephrotoxicity in 1,430 Critically Ill Patients: A Retrospective Multivariate Regression Analysis Precision Of Predicting Nephrotoxicity And Incremental Risk Increase Of Different Threshold Values For Highest Measured Vancomycin Serum Concentrations Threshold Level (mg/l) Nephrotoxicity (%) Relative Risk Sensitivity Specificity Increase a Youden Index Positive Predictive Value Negative Predictive Value 10 21.7% 1 0.043 0.043 0.217 1 15 23.2% 1.069 0.936 0.178 0.115 0.232 0.914 20 26.2% 1.207 0.84 0.372 0.212 0.262 0.898 25 33.1% 1.525 0.747 0.600 0.346 0.331 0.899 30 41.5% 1.912 0.603 0.774 0.377 0.415 0.880 > 30 47.9% 2.207 0.303 0.912 0.216 0.478 0.831 a Relative to first threshold level (10 mg/l). Hanrahan TP, et al. Crit Care Med 2014;42(12):2527 36. 16
Vancomycin-Associated Nephrotoxicity in 1,430 Critically Ill Patients: A Retrospective Multivariate Regression Analysis Hanrahan TP, et al. Crit Care Med 2014;42(12):2527 36. The prevalence of new onset nephrotoxicity was reported using RIFLE criteria. Concomitant vasoactive therapy (OR=1.63; p <0.001), median serum vancomycin (OR=1.11; p <0.001), and duration of therapy (OR=1.041; p 0.001) were positive predictors of nephrotoxicity. Intermittent infusion was associated with significantly greater risk of nephrotoxicity than continuous infusion (OR=8.2; p 0.001). 17
Is it possible to increase vancomycin efficacy by combining it with a second agent? 18
Effect of vancomycin plus rifampicin in the treatment of 83 episodes of nosocomial MRSA pneumonia Jung YJ et al. Crit Care Med 2010;38:175 80 P = 0.047 P = 0.079 P = 0.15 P = 0.042
Combination of Vancomycin and Flucloxacillin Therapy for MRSA BSI: A Pilot Multicenter Randomized Controlled Trial Davis JS, et al. Clin Infect Dis. 2016;62(2):173-80 20
Linezolid/Tedizolid: Mechanism of Action Oxazolidinones exert antibacterial activity by binding to the 50S subunit of the bacterial ribosome, resulting in inhibition of protein synthesis Oxazolidinone binding site Peptidyl Transferase center Decoding region 50S subunit A P E Amino acid mrna Tedizolid is only approved for ABSSSI by FDA/EMA. 30S subunit Figure adapted from Locke et al. (2010)
Tedizolid Exposure in ELF and Alveolar Macrophage Cells (AM) are Above MIC 90 for Entire Dosing Period Tedizolid ELF & AM Concentrations (200 mg QD Day 3) Concentration (µg/ml) ELF: epithelial lining fluid AM: alveolar macrophage Penetration Ratio ELF AM Tedizolid 1 41.2 20.0 Linezolid 2 5.2 0.2 TZD ELF TZD AM MRSA MIC 90 SP MIC 90 Time (hours) Tedizolid is only approved for ABSSSI by FDA/EMA. Compared with linezolid, ELF penetration is 8x and AM penetration is 100x higher for tedizolid than linezolid Housman ST, et al. AAC 2012;56(5):2627 2634. Conte JE, et al. AAC 2002;46(5):1475 1480. MRSA: methicillin-resistant S. aureus SP: Streptococcus pneumoniae 22
Meta-analysis of MRSA hospital-acquired pneumonia treatment Wunderink RG, et al. BMJ 2014;348:g1469. *Includes some methicillin-sensitive cases 23
Vancomycin nephrotoxicity is higher than that of linezolid Patients with nephrotoxicity (%) (n=224) (n=224) *0.5 mg/ml increase in serum creatinine if normal at baseline, or 50% increase if abnormal at baseline GFR, glomerular filtration rate Adapted from: Wunderink R, et al. Clin Infect Dis 2012;54:621 629 24
Clinical outbreak of linezolid-resistant S. aureus in an ICU Resistance to linezolid: Mediated by the cfr gene Morales CID 2010;50:821 Reduction of linezolid use and infection control measures were associated with the termination of the outbreak. Sanchez Garcia JAMA 2010;303:2260 2264
Wild-type Cfr-methylated A B Tedizolid MIC values are not impacted by mobile cfr gene Linezolid Tedizolid Phosphate C A2503 A2503 D Steric clash A2503 A2503 Tedizolid is only approved for ABSSSI by FDA/EMA. Locke JB, et al. Antimicrob Agents Chemother. 2010;54:5337-43 41
Management of Adults With HAP/VAP: 2016 Clinical Practice Guidelines by IDSA and ATS Kalil AC, et al. Clinical Infect Dis 2016;63(5):e61 111 Antibiotics that Should Be Used for the Treatment for MRSA HAP/VAP: We recommend that MRSA HAP/VAP be treated with either vancomycin or linezolid rather than other antibiotics or antibiotic combinations (strong recommendation, moderate-quality evidence). Remarks: The choice between vancomycin and linezolid may be guided by patient-specific factors such as blood cell counts, concurrent prescriptions for serotonin-reuptake inhibitors, renal function, and cost. 27
Telavancin: A New and Worthwhile Therapeutic Option? Hegde SS, et al. Expert Rev Anti Infect Ther. 2014;12:1463-75
ATTAIN: Clinical cure rates in S. aureus HAP by vancomycin MIC Vancomycin MIC 0.5 a Telavancin Vanco. p value Rubinstein E, et al. CID 2011;52:31 40 Clinical cure rates at TOC, % (n/n) Vancomycin MIC 1 b Telavancin Vanco. p value S. aureus 89 (33/37) 79 (22/28) 0.31 87 (74/85) 74 (78/105) 0.03 MRSA 92 (11/12) 86 (12/14) 1.00 86 (50/58) 75 (66/88) 0.14 MSSA 88 (22/25) 71 (10/14) 0.23 89 (24/27) 71 (12/17) 0.23 a All MICs were 0.5 μg/ml, except for 1 telavancin patient with a vancomycin MIC 0.25 μg/ml b All MICs were 1 μg/ml, except for 2 telavancin patients with a vancomycin MIC=2 μg/ml
Potential Nephrotoxicity of Telavancin versus Vancomycin Polyzos KA, et al. PLoS One. 2012;7(8):e41870
Ceftaroline/ceftobiprole Ceftaroline Ceftobiprole 31
Penetration of Ceftaroline into the ELF of Healthy Adult Subjects Riccobene TA, et al. Antimicrob Agents Chemother. 2016;60:5849-57 32
A phase 3 randomized double-blind comparison of ceftobiprole vs. ceftazidime plus linezolid for the treatment of HAP Awad SS, et al. Clin Infect Dis. 2014;59:51-61 33
Take-home messages 1. MRSA infection prevalence is decreasing in the ICU (Do not forget MSSA when selecting initial treatment!). 2. Vancomycin still on the front line (TDM mandatory). 3. Linezolid (or tedilozid if ongoing studies confirm its efficacy in VAP) may (should) be preferred in case of pneumonia, particularly in case of renal dysfunction or concomitant use of nephrotoxic drugs. 4. Ceftobiprole/ceftaroline could be a good option in case of concomitant bloodstream infection.