Combination vs Monotherapy for Gram Negative Septic Shock

Combination vs Monotherapy for Gram Negative Septic Shock Critical Care Canada Forum November 8, 2018 Michael Klompas MD, MPH, FIDSA, FSHEA Professor, Harvard Medical School Hospital Epidemiologist, Brigham and Women s Hospital

Disclosures o Grant funding o U.S. Centers for Disease Control and Prevention o Massachusetts Department of Public Health

Crit Care Med 2017;45:486-552

Reasons offered for combo therapy 1. Increase probability the initial empiric regimen includes an active agent 2. Achieve a faster decrease in bacterial bioburden 3. Leverage synergy between agents to enhance therapeutic effectiveness 4. Decrease likelihood of resistance emerging

The use of multiple antibiotics with specific intent of covering known or suspected pathogens with more than one antibiotic to accelerate pathogen clearance rather than to broaden antimicrobial coverage Crit Care Med 2017;45:486-552

In Septic Shock, Time Matters Crit Care Med 2006;34:1589-1596

but does the number of antibiotics matter? 1. Is it the bacteria or the inflammatory cascade that kills the patient? 2. If it s the inflammatory cascade, will more antibiotics arrest the cascade faster? 3. If it s the bacteria, will more antibiotics lead to faster pathogen clearance? Crit Care Med 2017;45:1930-1932

Randomized Trials of Combination vs Monotherapy for Sepsis No difference! J Infection 2017;74:331-344

Randomized Trials of Combination vs Monotherapy for VAP Odds Ratio for Death with Combo Therapy 1.05 95% CI (0.78-1.42) No difference! Crit Care Med 2008;36:108-117

Combination vs Monotherapy for Pseudomonas Bacteremia No difference! Clin Infect Dis 2013;57:217-220

Concerns with combo therapy 1. Increased risk of drug toxicity 2. Increased risk of selecting for drug resistant pathogens 3. Increased risk of Clostridium difficile

Short Course Adjunctive Gent for Empirical Therapy of Sepsis & Septic Shock Prospective comparison of 648 patients in 2 Dutch hospitals: one hospital recommended empiric adjunctive gent for sepsis for up to 3 days, the other did not Renal Failure or Dead on d.14 Persistent Shock or Death Dead by Day 14 0.75 1.0 1.5 Better with Gent Worse with Gent Odds Ratios Clinical Infect Dis 2017;64:1731-1736

Crit Care Med 2017;45:486-552

Meta-Analysis of 50 Trials of Combo vs Monotherapy Control arm death/failure <15% (N=2,780) Control arm death/failure 15-25% (N=3,432) Control arm death/failure >25% (N=2,292) 0.5 1.0 2.0 Odds Ratio for Death or Clinical Failure with Combo Therapy Limitations: 1. Conflated multiple clinical outcomes: death, infection death, & clinical failure 2. Conflated multiple infection types 3. Conflated observational (N=38) and randomized trials (N=12) 4. Most studies very old (2/3 published before 2000) Crit Care Med 2010;38:1651-1654

A Closer Look Observational study of β-lactam + macrolide vs β-lactam or macrolide monotherapy for pneumococcal pneumonia β-lactam + macrolide 31/198 died (15.7%) β-lactam alone 27/251 died (10.8%) Not GNR sepsis, no risk adjustment, combo harmful! Retrospective study of cancer patients with Klebsiella infections treated in MD Anderson between 1972-1981. Cephalothin + aminoglycoside 21% clinical failure Cephalothin alone 54% clinical failure No risk adjustment, no relation to current treatments! Observational study of patients with community acquired pneumonia and septic shock from 33 hospitals in Spain. Monotherapy Amox-clavulanic acid (33%) Combotherapy Cephalosporin + FQ/Macrolide (78%) Inadequate risk adjustment, very different treatments per arm!

Randomized Controlled Trials Study Included All Randomized Patients? Used Death as the Outcome? Kljucar 1990 D Antonio 1992 Klatersky 1973 Fainstein 1983 Heyland 2008

Updated Meta-Analysis (Include All Patients, Use Death as Outcome) Klatersky 1973 Fainstein 1983 Kljucar 1990 D Antonio 1992 Heyland 2008 Odds Ratio for Death 1.14 (95% CI 0.60-2.19) No Difference!

o Retrospective, multicenter cohort study (28 hospitals, 3 countries) o Canada, USA, Saudi Arabia o 4,662 patients with culture positive bacterial septic shock o Monotherapy: o Combo therapy: any single, appropriate agent N=2888 (63%) two appropriate agents; second agent counted if continued 1 day; (<1 day okay if patient died in <24h) N=1714 (37%) o Primary outcome: 28-day mortality Crit Care Med 2010;38:1773-1785

% Surviving Combo Therapy Monotherapy Days Crit Care Med 2010;38:1773-1785

Hours Substantial Differences between Mono & Combo Patients o Monotherapy more common (63% vs 37%) 4 Mono Combo o Monotherapy patients much sicker: 3.5 o Older 3 o More organ failure 2.5 o o More time in hospital before onset of septic shock More time until first appropriate antibiotic 2 o More nosocomial infections 1.5 o o More cirrhosis, diabetes, and renal insufficiency More Staph aureus 1 0.5 o Propensity-matching to try to adjust for differences o Able to match 2446/4662 patients (52%) 0 Time to First Antibiotic (median hours) Crit Care Med 2010;38:1773-1785

28-day Mortality Outcomes 50% 40% Mono Combo Risk adjustment substantially diminished the difference in mortality rates between the combo and mono groups. 30% 20% High concern then that the residual difference is due to residual confounding. 10% 0% Unadjusted Propensity Adjusted Crit Care Med 2010;38:1773-1785

We Need Randomized Controlled Trial Data! o 600 patients with severe sepsis or septic shock randomized to meropenem alone versus meropenem + moxifloxacin o 29% severe sepsis o 71% septic shock JAMA 2012;307:2390-2399

28-day Mortality RCT of Mono vs Combo Rx for Sepsis 600 patients randomized to meropenem alone vs meropenem + moxifloxacin 50% 40% Mono Combo Mortality rates higher with combo therapy for septic shock! 30% 20% 10% 0% Sepsis Septic Shock JAMA 2012;307:2390-2399

% of Patients Study-Related Adverse Events 600 patients randomized to meropenem alone vs meropenem + moxifloxacin 10.0% 7.5% Mono Combo Adverse events more common with combo therapy 5.0% 2.5% 0.0% Adverse Events JAMA 2012;307:2390-2399

Summary o Both studies cited by Surviving Sepsis Campaign suggesting a benefit in septic shock are at high risk of bias o Meta-analysis & meta-regression included many observational studies with substantial differences between groups; unadjusted o RCTs used small subgroups and clinical failure as outcome in multiple instances rather than mortality o Retrospective cohort at high risk for residual confounding o RCT of combo vs monotherapy for severe sepsis reported higher mortality in patients with septic shock o Bottom Line: No evidence for sustained combination therapy in septic shock. Tailor to monotherapy as soon as susceptibilities available

Thank You! mklompas@bwh.harvard.edu