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Gestione della Sepsi in Medicina Interna: la terapia antibiotica

Alessandro Russo

Department of Public Health and Infectious Diseases

“Sapienza” University of Rome

a.russo@uniroma1.it

A continuum of severity describing the host systemic inflammatory response

SEPSIS

700,000 cases

Crude mortality

NEJM 2002;347:966-7.

Bed-side decision

Timing of prescription

Spectrum of causative pathogens

Recognition of risk factors for MDR pathogens

PK/PD considerations

Monotherapy/combination therapy

Effect of timing on survival

Crit Care Med 2006;34:1589-96

Time from hypotension onset (hours)

Frac

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f to

tal p

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nts

Appropriate Antibiotic Treatment in Severe Sepsis and Septic Shock: Timing Is Everything.

7

GRAM – (47.9%):

• E. Coli

• Klebsiella spp

• Pseudomonas spp

GRAM + (38%)

• S. aureus

• Streptococchi

• Enterococchi

• CONS

FUNGI (8.6%)

• Candida spp

• Aspergillus spp

Others (4.4%)

• Anaerobes

• Mycobacteriumtubercolosis

Etiology of sepsis

Crit Care Med. 2006;34:1589-96.

Risk Factors

MDR/Health-care associated pathogens Fungemia

• broad spectrum antibiotics within 90 d• hospitalization >5 d• local high antibiotic resistance rates• residence in LTCF• chronic dialysis within 30 d• home wound care• family member with MDR infection• mechanical ventilation ≥5 d• immunosuppression• structural lung disease• IV drug use• COPD• Influenza

• broad-spectrum antibiotics• central venous catheter• parenteral nutrition• renal replacement therapy in

ICU• neutropenia• hematologic malignancy• implantable prosthetic devices• Immunosuppression• chemotherapy• diabetes

Choice of antibiotic therapy

STEP 1: The best drug

STEP 2: Alone or in combination?

STEP 3: Optimal dosage

STEP 4: De-escalate and stop therapy

Effect of inappropriate antibiotics on survival in patient with septic shock

Chest 2009;136:1237-48

Appropriate (n=4579)

Inappropriate (n=1136)

OR (95% CI)

Survived 52 10.3 9.45 (7.74 – 11.54)

P value

Immuno-suppressed*

15 19.8 < 0.05

COPD 13.6 14.1 < 0.05

Dialysis 7.3 10.7 < 0.05

All numbers expressed as % unless otherwise specified* Immunosuppression = chemotherapy or chronic steroids (>10mg prednisone daily)

0

5

10

15

20

25

30

35

Possible sources of infection

Lung Intra- Genito- SSTI Bloodstreamabdominal urinary

Crit Care Med. 2006;34:1589-96.

Positivity of blood cultures in different clinical syndromes

Endocarditis and bloodstream infections 85% - 95%

Bacteremic pneumonia 5% - 30%

Ascending Pyelonefritis 30% - 50%

Ematogenous osteomyelitis 30% - 50%

Bacterial Meningitis Variable

Intra-abdominal abscesses Variable

FUO Variable

Crit Care Med. 2006;34:1589-96.

Not the least expensive drug

BUT

The best drug

KNOW YOUR “MICROBIOLOGICAL” REALITY

• Paziente di 69 anni, diabetica, ipertesa, BPCO, BMI 31. Seimesi prima polipectomia per neoplasia del colon destro,controlli successivi negativi.

• Due mesi prima ricovero per riacutizzazione di BPCO,trattata con ciprofloxacina e cortisone.

• Ricovero complicato da infezione da Clostridium difficile,trattata con vancomicina 125 mg ogni 6 ore per 14 giorni.

• Da 10 giorni presenta diarrea con progressiva dispnea. Nofebbre.

• Accesso in Pronto Soccorso

• Paziente sofferente e fortemente dispnoica; diarreaprofusa. Riscontro di leucocitosi neutrofila (WBC:19000) ed insufficienza renale acuta (cretininemia2.2 mg/dl)

• Al Torace riduzione dei rumori respiratori in campomedio-basale destro, addome trattabile ma dolentein tutti i quadranti.

• All’EGA presenza di insufficienza respiratoria acutacon acidosi metabolica. Trasferimento in reparto diMedicina Interna.

• RX Torace: presenza di versamento pleurico destro;tossina Clostridium difficile: positiva, ribotipo 027.

• Iniziata terapia con vancomicina 250 mg ogni 6 h epiperacillina/tazobactam ev.

• In III giornata di ricovero la paziente diventa febbrile;viene eseguita toracentesi che mostra la presenza diempiema pleurico.

• Viene eseguita TC Torace che mostra la presenza diinfiltrati multipli bilateralmente.

• In VI giornata positivizzazione emocolture perCandida albicans ed instaurata terapia confluconazolo.

• Dalla Microbiologia informano che la coltura delliquido pleurico mostra la crescita di Candidaalbicans.

• Progressivo aggravamento delle condizionicliniche, peggioramento del quadro respiratorio.Necessità di NIV e comparsa di shock settico.

• Paziente continua ad essere febbrile con emocolturepersistentemente positive per Candida.

• In XI giornata viene eseguito EcocardiogrammaTranstoracico che mostra la presenza di immagine di nonchiara interpretazione, compatibile con vegetazioneendocarditica su valvola tricuspide.

• Viene associata terapia con amfotericina B liposomiale +micafungina.

• Exitus della paziente in XII giornata di ricovero.

• Età avanzata

• Diabete mellito tipo 2

• Recidiva infezione da Clostridium difficile

• CDI severa

• Precedente intervento chirurgico sull’intestino

• Precedente terapia antibiotica

• Precedente terapia steroidea

• Candida score all’ingresso =1

• Fluconazolo Vs echinocandine

Caratteristiche della paziente

C. difficile is the most common pathogen causing health care–associated infections

Magill SS et al, N Engl J Med 2014;370:1198-208

PatogensHCA-

infections(N=504)

Pneumonia(N=110)

Surgical-site

infections(N=110)

GI-infections

(N=86)

UTIs(N=65)

BSI(N=50)

C. difficile 61 (12,1%) 0 0 61 (70,9%) 0 0

S. aureus 54 (10,7%) 18 (16,4%) 17 (15,5%) 1 (1,2%) 2 (3,1%) 7 (14%)

K. pneumoniae

50 (9,9%) 13 (11,8%) 15 (13,6%) 1 (1,2%)15

(23,1%)4 (8%)

Candida spp 32 (6,3%) 4 (3,6%) 3 (2,7%) 3 (3,5%) 3 (4,6%) 11 (22%)

MECHANISM OF MICROBIAL TRANSLOCATION

Metcalfe D, et al. Clinical Science (2012) 123, 627-634

INTESTINAL BACTERIAL OVERGROWTH

• Hypomobility – delayed transit time

• Portal HTN

• Oxidative stress

ENHANCED INTESTINAL PERMEABILITY

• Mucosal hypoxia

• Inflammation

• ATP depletion

IMPAIRED IMMUNITY

• Chemiotaxis

• Migration

• Phagocytic function

18% of CDI

• 140 patients (65 ± 22.98 years of age; 52% male)• 100 patients had negative results and 40 positive results for CDI, 10 patients were infected bythe 027 ribotype• CDI was significantly associated with Candida colonization (83% CDI positive vs 66% CDInegative)• Candida albicans was the species more often implicated• All except 1 of the ten 027 ribotype–infected patients were colonized by the yeast (7 were C.albicans)

Clin Infect Dis. 2014

Warren CA et al. Antimicrob Agents Chemother. 2013 Feb;57(2):689-96.

Choice of antibiotic therapy

STEP 1: The best drug

STEP 2: Alone or in combination?

STEP 3: Optimal dosage

STEP 4: De-escalate and stop therapy

Combination therapy vs. monotherapy for septic shock

Crit Care Med 2010;38:1773-85

Mortality rate *

Monotherapy (n=1223)

Combination Rx (n=1223)

HR (95% CI)

28-Day, % 36.3 29 0.77 (0.67 – 0.88)

ICU, % 35.7 28.8 0.75 (0.63 – 0.88)

Hospital, % 47.8 37.4 0.69 (0.59 – 0.81)

* Propensity score adjusted

# deaths

All Gram + , % 39.9 30.7 0.73 (0.58 – 0.92)

All Gram - , % 34.5 28.2 0.79 (0.67 – 0.94)

Importance of source control and in vitro actvity

Clin Infect Dis 2012; 54:1739-46

Lower mortality rate in enderly pts with community onset pneumonia on treatment with aspirin

Falcone M, Russo A, Farcomeni A, Taliani G, Venditti M & Violi F J Am Heart Assoc 2015;4:e001595

Macrolide versus nonmacrolide therapy and mortality in critically illpatients with community-acquired pneumonia (n = 9 studies)

Sligl W at al Crit Care Med 2014

Combination antibiotic therapy with macrolides improves survival in intubated patients

with community-acquired pneumonia

Martin-Loeches I et al, Intensive Care Med. 2009

Aspirin plus macrolides improves survival of patients with community-onset pneumonia presenting with septic shock

Falcone M, Russo A, Bertazzoni G, Violi F & Venditti M Intensive Care Medicine 2015

Choice of antibiotic therapy

STEP 1: The best drug

STEP 2: Alone or in combination?

STEP 3: Optimal dosage

STEP 4: De-escalate and stop therapy

Implications of septic shock in antibiotic PK

Chest 2011; 139: 1210-1220

Obesity

Tempo-dipendenti

Concentrazione-dipendenti

PK/PD

Tempo

CONCENTRAZIONE

Cmin (valle)

Cmax (picco)

Cmax:MIC

AminoglicosidiFluorochinoloniLinezolidDaptomicinaTigecyclinaEchinocandine

PenicillineCefalosporineCarbapenemMacrolidiVancomicinaClindamicina

AUC:MIC

AUC, area under the concentration–time curve; PAE, post-antibiotic effect..

Rybak MJ. Am J Med. 2006;119:S37-S44.

PAE

MIC

AUC

T > MIC

0

Concentration

Time (hours)

Renal clearance

Hepatic metabolism

Drug interactions

Impaired clearance

Toxicity?

Accelerated clearance

Loss of efficacy?

MIC

Implications of septic shock in antibiotic PK

Clin Infect Dis 2013; 57:1568-76

Clinical features of patientswith augmented daptomycin

clearance

Clin Infect Dis 2013; 57:1568-76

Clin Infect Dis 2013; 57:1568-76

Probability of target attainment (PTA) and toxicity inpatients with severe sepsis or septic shock at Monte

Carlo simulation

49Clin Infect Dis 2013; 57:1568-76

Choice of antibiotic therapy

STEP 1: The best drug

STEP 2: Alone or in combination?

STEP 3: Optimal dosage

STEP 4: De-escalate and stop therapy

Procalcitonin in septic shock

Muller and Trampuz. Int J Antimicrob Agents 2007; 30 Suppl 1: S16-23

How to manage septic shock?

• Cover most frequent pathogens

• Measure the risk for MDR

• Avoid induction/selection of antibiotic resistance

• Reduce the systemic inflammatory response toinfection

• Reduce complications (i.e. cardiovascular)

• Therapeutic drug monitoring

• Early switch to oral therapy

• Decide the optimal duration of antibiotic therapy