slides and discussion

girardis.massimo@unimo.it

COSTRUIAMO INSIEME LA TERAPIA EMPIRICO-RAGIONATA PER IL PAZIENTE CRITICO

Stratificazione del rischio(vista da un intensivista)

REPORT PETALO INFEZIONI 2018: 114 Polyvalent ICUs: 37926 Adult patients

Infected at ICU admission: 10417 (27,9)

Pneumonia 4010 (38,5)

sCAP/HAP 2678/1332 (66,6/33,4)

Peritonitis – no post surgery 1108 (10,6)

UTI 923 (8,9)

Tracheobronchitis 693 (6,7)

Peritonitis –post surgery 686 (6,6)

Biliary Tract infections 501 (4,8)

Skin Soft Tissue infections 440 (4,2)

Multisite 1042 (10,0)

Infected during ICU stay: 2382 (4,8)

Pneumonia 1235 (36,5)

Tracheobronchitis (VA) 795 (23,5)

CR-BSI 493 (13,1)

BSI 444 (11,2)

Peritonitis post-surgery 130 (3,8)

Skin-Surgical site 123 (3,5)

Multisite 760 (22,5)

Empiric Antibiotic Therapy in Critically ill Patients

i. Timeii. Moleculeiii.Dose

Clin Infect Dis. 2017 Nov 22. [Epub ahead of print]

A. DISTINGUISHING SEPSIS FROM NON-INFECTIOUS SYNDROMES: The Surviving SepsisCampaign Guidelines do not differentiate between patients with suspected sepsis and suspectedseptic shock (one-size-fits-all recommendations). Reasonable to use antibiotic in suspected septicshock. Caution to use antibiotics in suspected sepsis, gain time, because many are notsepsis….overuse of antibiotics

B. TIME TO INITIATION OF EMPIRIC ANTIBIOTIC THERAPY: antimicrobials as soon as possible topatients with severe infections. But aggressive fixed time period may lead to an increased use ofbroad-spectrum antibiotics to uninfected patients with syndromes that look like infections.

C. BLOOD CULTURES AND IV ACCESS CATHETERS : Not clear specification on blood cultures inpatients with catheters, the removal strategy and the management of implanted catheters

D. COMBINATION AND MULTIDRUG THERAPY: Confusing terms for combination, empiric,targeted, multidrug strategy. Many indications are not based on evidences (particularly incombination therapy)

E. PROCALCITONIN: The guidelines indicate that procalcitonin “can be used”. Our interpretation isthat RCTS demonstrate that procalcitonin guidance for duration of antibiotic therapy is feasible andsafe in critically ill patients with infections

F. PK/PD-PROPHYLAXIS-ANTIBIOTIC THERAPY DURATION

Less vs More 3 Hours Less vs More 1 Hours

In patients with severe sepsis and septic shock,

administration of antibiotics within 3 hours of ED

triage or within 1 hour of recognition of severe

sepsis/septic shock did not confer mortality

benefit. These results suggest that currently

recommended specific timing metrics in

international guidelines are not supported by the

currently available evidence.

STRATIFICATION

TIME

CONCLUSIONS

More rapid completion of a 3-hour

bundle of sepsis care and rapid

administration of antibiotics, but not

rapid completion of an initial bolus of

intravenous fluids, were associated

with lower risk-adjusted in-hospital

mortality

• 49,331 patients at 149 hospitals,

• Patients had a sepsis protocol initiated within 6

hours after arrival in ED in a 3-hour bundle of care

for patients with sepsis (i.e., blood cultures, broad-

spectrum antibiotic agents, and lactate

measurement) completed

• 40,696 (82.5%) had the 3-hour bundle

• median time to completion of the 3-hour bundle

1.30 hours (IQR 0.65 to 2.35),

• median time to the administration of antibiotics

was 0.95 hours (IQR 0.35 to 1.95)

STRATIFICATION

TIME

STRATIFICATION

TIME

@ Study/Dbase: IMPACT-HAP (US 4 University Hospitals)

@ Population: 413 ICU patients with pneumonia pre-after implementation (2006-2007)

@ 303/413 (73%) at risk for MDR

@ 174/303 (57%) no compliant guidelines

STRATIFICATION

TIME

STRATIFICATION

TIME

@ multicenter prospective, 1170 adults hospitalized with CAP, 115 with invasive respiratory or vasopressor support (IRVS)

@ association PCT at hospital presentation with the IRVS within 72 h

CHEST 2016; 150(4):819-828

STRATIFICATION

MOLECULE Mirror, mirror on the wall which is the fairest

risk factor (or score) of them all ?

RISK FACTORS and SCORESfor DIFFICULT MICRO-ORGANISMS

CAPPES pathogens: P. aeruginosa, ESBL

producing Enterobacteriaceae, MRSA,

Webb BJ et al (2015) Predicting risk of drug- resistant organisms in pneumonia: moving beyond the HCAP model. Respir Med 109:1–10

Torres A et al (2019) Challenges in severe community-acquired pneumonia: a point-of-view review. Intensive Care Med 45:159–171

Prina E et al (2015) Risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia. Ann Am Thorac Soc 12:153–60.

Cilloniz C et al (2019) Multidrug Resistant Gram-Negative Bacteria in Community-Acquired Pneumonia. Critical Care 23:79

STRATIFICATION

MOLECULE Mirror, mirror on the wall which is the fairest

risk factor (or score) of them all ?

RISK FACTORS and SCORESfor DIFFICULT MICRO-ORGANISMS

CAPPES pathogens: P. aeruginosa, ESBL

producing Enterobacteriaceae, MRSA,

STRATIFICATION

MOLECULE Mirror, mirror on the wall which is the fairest

risk factor (or score) of them all ?

RISK FACTORS and SCORESfor DIFFICULT MICRO-ORGANISMS

HAP/VAPP. aeruginosa, ESBL producing

Enterobacteriaceae, CR MRSA, Acinetobacter

When MRSA

a) Risk factorsb) units where >10%–20% of S. aureus isolates

are methicillin resistant.c) patients in units where the prevalence of

MRSA is not Knownd) Shock or need VM (in HAP)

When 2 Abx Anti-Pseudo

a) Risk factorb) units >10% of gram-negative isolates are

resistant to an agent considered for monotherapy,

c) local antimicrobial susceptibility rates are not available

STRATIFICATION

MOLECULE Mirror, mirror on the wall which is the fairest

risk factor (or score) of them all ?

RISK FACTORS and SCORESfor DIFFICULT MICRO-ORGANISMS

HAP/VAPP. aeruginosa, ESBL producing

Enterobacteriaceae, CR MRSA, Acinetobacter

vs

STRATIFICATION

MOLECULE Mirror, mirror on the wall which is the fairest

risk factor (or score) of them all ?

RISK FACTORS and SCORESfor DIFFICULT MICRO-ORGANISMS

CRE

ADULTICU PATIENTS

STRATIFICATION

MOLECULE

@ Several studies have demonstrated that, providing some conditions, ETA can be routinely performed to reliably predict the microorganisms of VAP.

@ However, the literature is inconsistent, and a confirmation study with a robust methodology and focusing on the patient’s prognosis is still lacking to definitively conclude and recommend the widespread use of routine surveillance of tracheobronchial flora.

@ The growing challenge of broad-spectrum antibiotics sparing combined with the development of microbial rapid identification tools might open the way to the revival of this strategy.

SURVEILLANCE SAMPLES

Kabak E et al BMC Infect Dis 2019;19:756

Detection of S. aureus in the ETA preceded S.

aureus VAP by approximately 4 days, while

Gram-negative organisms were first detected 2.5

days prior to Gram-negative VAP

We found that approximately 30% with heavy S.

aureus or Gram-negative colonization progressed

to VAP with a corresponding pathogen and only

15% lightly colonized with S. aureus progressed to

VAP, and no patient with Gram-negative light

colonization did so

STRATIFICATION

MOLECULE

@ 240 patients admitted to 3 ICUs in US mechanically ventilated for > 2 days

@ 125 patients with pathogenic bacteria from ETAs

@ 85 patients with VAP

SURVEILLANCE SAMPLES

STRATIFICATION

DOSEJA Roberts Lancet Infect Dis 2014;498:509.

UNDER DOSINGGENERAL ISSUES

STRATIFICATION

DOSEUNDER DOSINGLOCAL ISSUES

PNEUMONIA

PERITONITIS

Lodise et al. Antimicrob Agent

Chemother 2011;55:1606-1610.

Adnan et al. Surg Infect 2012;13:1-9.

Empiric Antibiotic Therapy in Critically ill Patients

TENTATIVE PERSONAL CONCLUSIONS

STRATIFICATION

TIME @ Very early (within 1-3 hours) antibiotic therapy is indicated in

patients with septic shock or sepsis with multiple OD or very high values of sepsis biomarkers (PCT, CRP, PROAdm)

@ Antibiotic therapy may be delayed (hours) In ICU patients with suspected infection without OD , waiting for micro findings (Gram stain / fast microbiology) (caveat: immunosuppressed)

STRATIFICATION

MOLECULE @ Risk factors, type of patient, clinical conditions and local

epidemiology should be used in patients admitted to ICU with sepsis for antibiotic strategy

@ In ICU patients the results of surveillance cultures may significantly help for infection prediction and antibiotic therapy

STRATIFICATION

DOSE

@ In the first hours after ICU admission, patient with sepsis and septic shock is at high risk for antibiotic underdosing (general and local)

@ Specific strategies should be used for individualized antibiotic dosages in the different stages of septic patient in ICU

STRATIFICATION

TIME & MOLECULE VAP

STRATIFICATION

TIME & MOLECULE VAP

How to improve antibiotic therapy in critically ill patients ?

@ Specific antibiotic dosing approaches

@ Dosing nomograms for individual patients

@ Dosing software

@ Therapeutic drug monitoring

@ Dosing software with adaptive feedback

STRATIFICATION

DOSE

TAKE HOME PICTURE

Empiric Antibiotic Therapy: TIME

INFECTIONS & AMS is an issue in ICU ?

Empiric Antibiotic Therapy ?Clinical

SignsClinical history(Community-Nosocomial)

Source (s)infection

Micro-organisms epidemiologyOrgan dysfunction (s)

(liver –kidney)

PK/PD

RCTEBM

Manage ICUAbx resistances

INFECTIONS & AMS is an issue in ICU ?

Use of Lab & Micro-Lab ?

O Use of the (new) biomarkers in antibiotic / antifungal therapy (e.g. PCT & galactomannan & β-d-glucan)

O Use of the new technologies in micro-organisms identification (time and sensitivity)

ANTIBIOTIC THERAPY and MDR

What’s an early appropriate antibiotic therapy in

a patient with severe sepsis/septic shock by

nosocomial or health care associated infection

in South Europe?

Meropenem HD or Ceftolozane/Tazobactam

&

Ceftazidime/Avibactam or Colistin and Gentamycin

&

Linezolid or Vancomycin

&

Echinocandin (if risk factors)

For at least 48-72 hours

APPROPRIATE ANTIBIOTIC THERAPYESBL-producing Gram Negative

Pipera-Tazo or Meropenem ?

Resistance

E. Coli Hospital (n = 197)

E. Coli ICU (n= 10)

Kleb P Hospital (n = 71)

Kleb. Pn ICU.( n=10)

Pseudo A. Hospital (n =

43)

Pseudo A. ICU (n = 7)

Proteus M Hospital (n=

26)

Proteus M ICU ( n =0)

2015 Hospital and ICU: BACTEREMIA

Delta

PI/TA vs MER

12% n = 24

25% n= 18

9% n = 4

25% n = 6

Pipera/Tazo increases

the risk of

innapproriate antibiotic

by

52/337 = 15%

(NNT = 6)

compared to

carbapenems

INFECTIONS & AMS in ICU

ID in ICU ?

TAKE HOME PICTURE

STRATIFICATION

TIME

3 Urban ED

291 Adult patients: septic

shock

35% Pneumonia, 25% Urinary,

17% Intrabdominal, 8% SSI

• Prospective, 68 ICUs; β-lactam blood concentration

• 361 patients 69%/31% infection/prophylaxis; 67%/33%

bolus /continuous

O High variability

O 50% fT > MIC: • 80% of patients bolus• 93% of continuous

O In the 16% patients without50% fT > MIC reducedprobability of positive outcome (OR 0,68 CI 0,51-0,91)

End-dose interval

STRATIFICATION

DOSE