Should empirical combination or mono antibiotic therapy be used in adult ICU patients with severe sepsis and septic shock ? Fredrik Sjövall MD PhD

Combination or mono antibiotic therapy? A previous healthy 39 year old woman is admitted to the intensive care unit for hypotension, anuria and altered mentation despite 3 litres of intravenous lactated ringers infusion.  She is febrile and found to have gram negative bacteremia from unknown source.  Her lactate is 4.3 mmol/L with a mean arterial pressure of 63 mmHg whilst on norepinephrine and vasopressin infusions. Her urine output is low and she has just been intubated due to respiratory failure.

Combination or mono antibiotic therapy? A 39 year old woman with neutropenia is admitted to the intensive care unit for hypotension, anuria and altered mentation despite 3 litres of intravenous lactated ringers infusion.  She is febrile and found to have gram negative bacteremia from unknown source.  Her lactate is 4.3 mmol/L with a mean arterial pressure of 63 mmHg whilst on norepinephrine and vasopressin infusions.  Her urine output is low and she has just been intubated due to respiratory failure.

Theoretical advantages of combination antibiotic therapy Broader empirical coverage Synergistic effect – more effective killing of the causative organism Decreased risk of developement of resistance

Recommendations from Surviving Sepsis Campaign - 2016 6. We suggest empiric combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at the most likely bacterial pathogen(s) for the initial management of septic shock (weak recommendation, low quality of evidence). 7. We suggest that combination therapy not be routinely used for ongoing treatment of most other serious infections, including bacteremia and sepsis without shock (weak recommendation, low quality of evidence). 8. We recommend against combination therapy for the routine treatment of neutropenic sepsis/bacteremia (strong recommendation, moderate quality of evidence). 9. If combination therapy is initially used for septic shock, we recommend de-escalation with discontinuation of combination therapy within the first few days in response to clinical improvement and/or evidence of infection resolution. This applies to both targeted (for culture-positive infections) and empiric (for culture-negative infections) combination therapy (BPS). Rhodes A, et al: Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. March 2017, Volume 43, Issue 3, pp 304–377

IDSA - Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer – Febrile patients with neutropenia High-risk patients require IV empirical antibiotic therapy; monotherapy with an antipseudomonal b-lactam agent, such as cefepime, a carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended (A-I). Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the initial regimen for management of complications (eg, hypotension and pneumonia) or if antimicrobial resistance is suspected or proven (B-III). Freifeld et al CID 2011:52 (15 February)

Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO) We recommend initial treatment with meropenem or with imipenem/cilastatin or with piperacillin/ tazobactam (AIII). A combination treatment with an aminoglycoside may be considered in neutropenic patients with septic shock and severe sepsis (BIII). Penack et al. Ann Hematol (2014) 93:1083–1095

Research Question Is empirical combination antibiotic therapy superior to single antibiotic therapy in adult ICU patients with severe sepsis or septic shock?

Methods A systematic review with meta-analysis and trial sequential analysis of RCTs Only patient important outcomes Cochrane Collaboration Recommendations PRISMA protocol (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) Prepublished in PROSPERO (International Prospective Register of Systematic Reviews)

Search string PubMed EMBASE Cochrane Library (sepsis OR septicemia OR septic shock OR critically ill OR intensive care OR severe) AND (antibiotic* OR lactam OR quinolone OR cephalo* OR carbapen* OR aminoglyc*) AND (combination OR duplicate OR mono*)

Trial selection 2640 records identified 152 full-text articles screened 13 trials included

Study characteristics 13 trials with 2633 adult ICU patients 9 Europe 1 Europe + Africa 3 North America 5 single center 8 multi center 5 surgical 8 mixed

Type of antibiotics Combination Mono 7 β-lactam + aminoglycoside 3 β-lactam + quinolone 1 β-lactam + aminoglycoside or quinolone 1 β-lactam + vancomycin 1 Clindamycin + aminoglycoside β-lactam = 11 Carbapenems = 8 2nd, 3rd or 4th generation cephalosporines = 3 quinolones = 2

Risk of bias No trial had ”low risk of bias” Lack of adequate blinding - all trials were open label Only 4 trials with adequate random sequence generation 9 trials twith potential financial bias due to sponsoring

Results - All-cause mortality at longest follow-up Ten trials, comprising 2267 (86%) patients

TSA – all-cause mortality at longest follow-up

Secondary infections ICU length of stay

Subgroup analyses

Conclusions No difference in mortality or other patient-important outcome measures between the use of empirical combination vs. mono antibiotic therapy in adult ICU patients with severe sepsis or septic shock. The quantity and quality of data was low, with no firm evidence for benefit or harm of combination therapy.

All cause mortality - 44 trials - 5577 patients Same β-lactam (13 studies n=1431): RR 0.97 (95% CI 0.73 – 1.30) Different β-lactams: RR 0.85 ( 95% CI 0.71 – 1.01) (towards mono) Nephrotoxicity: RR 0.30 (95% CI 0.23 – 0.39) (favouring mono) Cochrane Database of Systematic Reviews 2014, Issue 1.

No difference in all cause mortality (RR 0. 87, 95% CI 0. 75 to 1 No difference in all cause mortality (RR 0.87, 95% CI 0.75 to 1.02, towards mono) Trials comparing the same beta-lactam in both trial arms (RR 0.74, 95% CI 0.53 to 1.06) Trials comparing different beta-lactams (usually a broad-spectrum betalactam compared with a narrower-spectrum beta-lactam combined with an aminoglycoside) (RR 0.91, 95%CI 0.77 to 1.09) Adverse events were more frequent with combination therapy (numbers needed to harm 4; 95% CI 4 to 5). Cochrane Database of Systematic Reviews 2013, Issue 6.

Mortality < 15%: OR 1.53 (1.16 – 2.03) Death / Clinical Failure – 50 articles - 62 data subsets – 8504 patients Overall: OR 0.865 (0.71 – 1.03) Mortality < 15%: OR 1.53 (1.16 – 2.03) Mortality 15-25%: OR 1.05 (0.81 – 1.34) Mortality > 25%: OR 0.54 (0.45 – 0.66) 95% CI Kumar et al. Crit Care Med 2010 Vol. 38, No 8

Subgroup analyses

Retrospective - 4662 patients - Propensity-matched analysis Kumar, et al Crit Care Med 2010, Vol 38, No 9

Ingen skillnad dock med carbapenemer Anand Kumar, MD; Ryan Zarychanski, MD; Bruce Light, MD et al Crit Care Med 2010, Vol 38, No 9

Conclusions As long as the causative pathogen is covered with mono empirical therapy. Additional agents will not give any additonal benefits There doesn’t seem to be any difference between non- neutropenic and neutropenic patients in this regard.