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 piperacillintazobactam, 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
Outcome measure
Subgroups
n
Relative risk
(95% CI)
All-cause mortality
Surgical ICUs
271
0.79 (0.48-1.31)
Mixed ICUs
1996
1.13 (0.96-1.33)
APACHE II ≥ 20
1324
1.05 (0.87-1.26)
APACHE II < 20
278
1.33 (0.81-2.18)
Trial conducted ≥ 2000
1867
1.12 (0.95-1.32)
Trial conducted < 2000
400
0.88 (0.55-1.39)
GI focus
98
0.86 (0.31-2.37)
Not GI focus
1556
1.09 (0.89-1.34)
308
0.75 (0.46-1.23)
Mixed ICUs
904
0.99 (0.63-1.56)
APACHE II ≥ 20
176
0.55 (0.11-2.69)
APACHE II < 20
175
0.88 (0.29-2.72)
Trials conducted ≥ 2000 724
0.96 (0.76-1.22)
Trials conducted < 2000 558
0.89 (0.55-1.43)
GI focus
186
1.05 (0.5-2.23)
Not GI focus
418
0.73 (0.37-1.42)
Secondary infections Surgical ICUs
Test-of-interaction
(p-value)
0.19
0.38
0.32
0.46
0.49
0.63
0.78
0.47
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 1.02,
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.
• Death / Clinical Failure – 50 articles - 62 data subsets – 8504 patients
• Overall: OR 0.865
95% CI
(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)
Kumar et al. Crit Care Med 2010 Vol. 38, No 8
Subgroup analyses
Outcome measure
Subgroups
n
Relative risk
(95% CI)
All-cause mortality
Surgical ICUs
271
0.79 (0.48-1.31)
Mixed ICUs
1996
1.13 (0.96-1.33)
APACHE II ≥ 20
1324
1.05 (0.87-1.26)
APACHE II < 20
278
1.33 (0.81-2.18)
Trial conducted ≥ 2000
1867
1.12 (0.95-1.32)
Trial conducted < 2000
400
0.88 (0.55-1.39)
GI focus
98
0.86 (0.31-2.37)
Not GI focus
1556
1.09 (0.89-1.34)
308
0.75 (0.46-1.23)
Mixed ICUs
904
0.99 (0.63-1.56)
APACHE II ≥ 20
176
0.55 (0.11-2.69)
APACHE II < 20
175
0.88 (0.29-2.72)
Trials conducted ≥ 2000 724
0.96 (0.76-1.22)
Trials conducted < 2000 558
0.89 (0.55-1.43)
GI focus
186
1.05 (0.5-2.23)
Not GI focus
418
0.73 (0.37-1.42)
Secondary infections Surgical ICUs
Test-of-interaction
(p-value)
0.19
0.38
0.32
0.46
0.49
0.63
0.78
0.47
• Retrospective
- 4662 patients
- Propensity-matched analysis
Kumar, et al Crit Care Med 2010, Vol 38, No 9
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 nonneutropenic and neutropenic patients in this regard.