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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 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
tio
n o
f to
tal p
atie
nts
Appropriate Antibiotic Treatment in Severe Sepsis and Septic Shock: Timing Is Everything.
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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