Gestione della Sepsi in Medicina Interna: la terapia antibiotica

Dimensione: px

Iniziare la visualizzazioe della pagina:

Download "Gestione della Sepsi in Medicina Interna: la terapia antibiotica"

Giuliano Gigli
5 anni fa
Visualizzazioni

1 1

2 Gestione della Sepsi in Medicina Interna: la terapia antibiotica Alessandro Russo Department of Public Health and Infectious Diseases Sapienza University of Rome

3 A continuum of severity describing the host systemic inflammatory response

4 Crude mortality SEPSIS 700,000 cases NEJM 2002;347:966-7.

5 Bed-side decision Timing of prescription Spectrum of causative pathogens Recognition of risk factors for MDR pathogens Monotherapy/combination therapy PK/PD considerations

6 Fraction of total patients Effect of timing on survival Time from hypotension onset (hours) Crit Care Med 2006;34:

7 Appropriate Antibiotic Treatment in Severe Sepsis and Septic Shock: Timing Is Everything. 7

8 Etiology of sepsis GRAM + (38%) S. aureus Streptococchi Enterococchi CONS FUNGI (8.6%) Candida spp Aspergillus spp Others (4.4%) Anaerobes Mycobacterium tubercolosis GRAM (47.9%): E. Coli Klebsiella spp Pseudomonas spp Crit Care Med. 2006;34:

9 Risk Factors MDR/Health-care associated pathogens 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 Fungemia broad-spectrum antibiotics central venous catheter parenteral nutrition renal replacement therapy in ICU neutropenia hematologic malignancy implantable prosthetic devices Immunosuppression chemotherapy diabetes

10 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

11 Effect of inappropriate antibiotics on survival in patient with septic shock Appropriate (n=4579) Inappropriate (n=1136) OR (95% CI) Survived ( ) Immunosuppressed* P value < 0.05 COPD < 0.05 Dialysis < 0.05 All numbers expressed as % unless otherwise specified * Immunosuppression = chemotherapy or chronic steroids (>10mg prednisone daily) Chest 2009;136:

Possible sources of 35 infection 30 25 20 15 10 5 0 Lung Intra-

12 Possible sources of 35 infection Lung Intra- Genito- SSTI Bloodstream abdominal urinary Crit Care Med. 2006;34:

13 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 Intra-abdominal abscesses FUO Variable Variable Variable Crit Care Med. 2006;34:

14 Not the least expensive drug BUT The best drug KNOW YOUR MICROBIOLOGICAL REALITY

15 Paziente di 69 anni, diabetica, ipertesa, BPCO, BMI 31. Sei mesi 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. No febbre. Accesso in Pronto Soccorso

16 Paziente sofferente e fortemente dispnoica; diarrea profusa. Riscontro di leucocitosi neutrofila (WBC: 19000) ed insufficienza renale acuta (cretininemia 2.2 mg/dl) Al Torace riduzione dei rumori respiratori in campo medio-basale destro, addome trattabile ma dolente in tutti i quadranti. All EGA presenza di insufficienza respiratoria acuta con acidosi metabolica. Trasferimento in reparto di Medicina Interna.

17 RX Torace: presenza di versamento pleurico destro; tossina Clostridium difficile: positiva, ribotipo 027. Iniziata terapia con vancomicina 250 mg ogni 6 h e piperacillina/tazobactam ev. In III giornata di ricovero la paziente diventa febbrile; viene eseguita toracentesi che mostra la presenza di empiema pleurico. Viene eseguita TC Torace che mostra la presenza di infiltrati multipli bilateralmente.

18 In VI giornata positivizzazione emocolture per Candida albicans ed instaurata terapia con fluconazolo. Dalla Microbiologia informano che la coltura del liquido pleurico mostra la crescita di Candida albicans. Progressivo aggravamento delle condizioni cliniche, peggioramento del quadro respiratorio. Necessità di NIV e comparsa di shock settico.

19 Paziente continua ad essere febbrile con emocolture persistentemente positive per Candida. In XI giornata viene eseguito Ecocardiogramma Transtoracico che mostra la presenza di immagine di non chiara interpretazione, compatibile con vegetazione endocarditica su valvola tricuspide. Viene associata terapia con amfotericina B liposomiale + micafungina. Exitus della paziente in XII giornata di ricovero.

20 Caratteristiche della paziente 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

21 C. difficile is the most common pathogen causing health care associated infections Patogens HCAinfections (N=504) Pneumonia (N=110) Surgicalsite infections (N=110) GIinfections (N=86) UTIs (N=65) C. difficile 61 (12,1%) (70,9%) 0 0 BSI (N=50) 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%) Magill SS et al, N Engl J Med 2014;370:

MECHANISM OF MICROBIAL TRANSLOCATION INTESTINAL

time Portal HTN Oxidative stress ENHANCED INTESTINAL

depletion IMPAIRED IMMUNITY Chemiotaxis Migration

23 MECHANISM OF MICROBIAL TRANSLOCATION 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 Metcalfe D, et al. Clinical Science (2012) 123,

24 18% of CDI

26 140 patients (65 ± years of age; 52% male) 100 patients had negative results and 40 positive results for CDI, 10 patients were infected by the 027 ribotype CDI was significantly associated with Candida colonization (83% CDI positive vs 66% CDI negative) 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

28 Warren CA et al. Antimicrob Agents Chemother Feb;57(2):

30 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

31 Combination therapy vs. monotherapy for septic shock Monotherapy (n=1223) Mortality rate * Combination Rx (n=1223) HR (95% CI) 28-Day, % ( ) ICU, % ( ) Hospital, % ( ) # deaths All Gram +, % ( ) All Gram -, % ( ) * Propensity score adjusted Crit Care Med 2010;38:

33 Importance of source control and in vitro actvity

34 Clin Infect Dis 2012; 54:

36 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

37 Macrolide versus nonmacrolide therapy and mortality in critically ill patients with community-acquired pneumonia (n = 9 studies) Sligl W at al Crit Care Med 2014

38 Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia Martin-Loeches I et al, Intensive Care Med. 2009

39 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

40 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

41 Implications of septic shock in antibiotic PK Obesity Chest 2011; 139:

CONCENTRAZIONE PK/PD C max (picco) C max :MIC Aminoglicosidi

Concentrazionedipendenti AUC AUC:MIC Penicilline Cefalosporine

T > MIC PAE C min (valle) Tempo AUC, area under the concentration

42 CONCENTRAZIONE PK/PD C max (picco) C max :MIC Aminoglicosidi Fluorochinoloni Linezolid Daptomicina Tigecyclina Echinocandine Concentrazionedipendenti AUC AUC:MIC Penicilline Cefalosporine Carbapenem Macrolidi Vancomicina Clindamicina Tempodipendenti MIC T > MIC PAE C min (valle) Tempo AUC, area under the concentration time curve; PAE, post-antibiotic effect.. Rybak MJ. Am J Med. 2006;119:S37-S44.

44 Implications of septic shock in antibiotic PK Concentration Renal clearance Impaired clearance Toxicity? Hepatic metabolism 0 Time (hours) MIC Accelerated clearance Loss of efficacy? Drug interactions

46 Clin Infect Dis 2013; 57:

47 Clinical features of patients with augmented daptomycin clearance Clin Infect Dis 2013; 57:

48 Clin Infect Dis 2013; 57:

49 Probability of target attainment (PTA) and toxicity in patients with severe sepsis or septic shock at Monte Carlo simulation Clin Infect Dis 2013; 57:

50 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

52 Procalcitonin in septic shock Muller and Trampuz. Int J Antimicrob Agents 2007; 30 Suppl 1: S16-23

55 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 to infection Reduce complications (i.e. cardiovascular) Therapeutic drug monitoring Early switch to oral therapy Decide the optimal duration of antibiotic therapy

Documenti analoghi

Le associazioni sinergiche vale la pena impegnare il microbiologo? Enrico Tagliaferri U.O. Malattie Infettive, Pisa

Le associazioni sinergiche vale la pena impegnare il microbiologo? Enrico Tagliaferri U.O. Malattie Infettive, Pisa Terapia degli MDR Terapia di associazione Spesso off label per via di somministrazione