1. Antibiotic treatment choices for SBP Treviso 8 Giugno 2009 P. Angeli Dept. of Clinical and Experimental Medicine University of Padova

2. Empirical antibiotic therapy must be initiated immediately after the diagnosis of the infection is made. Several antibiotics can be used for the initial therapy of SBP: cefotaxime or other third-generation cephalosporins, or amoxicillin-clavulanic acid or quinolones. The optimal cost- effective dosage has only been investigated for cefotaxime. For this antibiotic, a minimum dose of 2 g/12 hr i.v. should be administered in patients with normal renal function. In addition a minimum duration of 5 days of cefotaxime therapy is recommended. A. Rimola, et al. J. Hepatol. 2000 ; 32 : 142-153. Infections in cirrhosis Treatment of spontaneous bacterial peritonitis (SBP)

3. In 1990s cefotaxime or other third generation cephalosporins were investigated more extensively in the treatment of SBP on the basis of two factors: Gram negative aerobic bacteria from the family of Enterobacteriaceae were the most common causative microrganisms. A favourable pharmacokinetic property (i.e antibiotic concentration in the ascitic fluid > MIC 90 for causative microrganisms. Treatment of spontaneous bacterial peritonitis Infections in cirrhosis A. Rimola, et al. J. Hepatol. 2000 ; 32 : 142-153.

4. P < 0.001 Prevalence of multiresistance to cefotaxime or amoxicillin/clavulanic acid in 224 patients with cirrhosis and bacterial infections Infections in cirrhosis (%) J.G. Acevedo et. al. 2009 EASL Meeting P < 0.001P < 0.05P = N.S.

5. Main multiresistant bacteria isolated in 224 patients with cirrhosis and bacterial infections Infections in cirrhosis (number of cases) P < 0.001 J.G. Acevedo et. al. 2009 EASL Meeting

6. Risk factors for SBP due to extended-spectrum β-lactamase- producing Escherichia Coli and Klebsiella species (ESBL-EK) Infections in cirrhosis Risk factorESBL-EK (n=26) Non ESBl-EK (n=78) OR (95% CI) Hospital stay  2 weeks 13 (50%)3 (4%)35.11 (4.57 to 269.72) Previous history of SBP 19 (73%)23 (30%)12.91 (2.88 to 57.96) Prior use of antibiotics within 30 days 21 (81%)13 (17%)15.13 (4.44 to 51.52) ICU care5 (19%)7 (9%)2.53 (0.70 to 9.12) Presentation of septic shock 11 (42%)22 (28%)2.21 (0.78 to 6.31) Kyoung-Ho Song et al. BMC Infect. Dis. 2009 ; 9 : 41 (Epub ahead of print)

7. P < 0.001 Resolution of bacterial infections with cefotaxime or amoxicillin/clavulanic acid in 224 patients with cirrhosis and bacterial infections Infections in cirrhosis (%) J.G. Acevedo et. al. 2009 EASL Meeting P < 0.001 P < 0.005P = 0.05

8. Mortality rate of spontaneous bacterial peritonitis and bacteremia by types of bacteria Infections in cirrhosis B. Campillo et al. Clin. Infect. Dis. 2002 ; 35 : 1-10. (%) P < 0.001

9. Infections in cirrhosis Resistances to antibiotic therapy in in 169 inpatients with cirrhosis and bacterial infections Preliminary unpublished data of an Italian multicenter study

10. Thirty day-mortality rate of spontaneous bacterial peritonitis by types of bacteria Infections in cirrhosis Kyoung-Ho Song et al. BMC Infect. Dis. 2009 ; 9 : 41 (Epub ahead of print) 5 P < 0.05 15days201025 SBP due to non ESBL-EK SBP due to ESBL-EK

11. A. Umgelter, et al. Infection 2009 ; (Epub ahead of print) Mortality in cirrhotic patients with ascites and SBP who failed to respond to the common first line therapies Infections in cirrhosis (%)(%) P < 0.001

12. Thirty day mortality in cirrhotic patients with SBP according to the efficacy of initial antibiotic therapy Infections in cirrhosis (%)(%) Kyoung-Ho Song et al. BMC Infect. Dis. 2009 ; 9 : 41 (Epub ahead of print) P < 0.001

13. Treatment of nosocomial spontaneous bacterial peritonitis: proposal for consensus (1) Infections in cirrhosis Nosocomial bacterial infections including SBP are frequently caused by multiresistant bacteria in patients with cirrhosis. Third generation cephalosporins or amoxicillin-clavulanic acid are uneffective in a high percent of these patients and should not be used longer as first line empiric antibiotic treatment. A more effective empirical antibiotic therapy in these patients should include a combination of antibiotics with a broader spectrum such as carbapenems and glycopeptides or lipopeptides. In order to establish the best empirical antibiotic treatment of nosocomial infections in patients with cirrhosis further large multicenter studies are needed. De-escalation of the initially broad antimicrobial regimen should be undertaken only once definitive culture results are available.

14. Factors in the selection of antibiotics for enpirical therapy Infections in cirrhosis Expected antimicrobial susceptibility of infecting bacteria Potential risk to induce/select resistant bacteria Overall safety of the agents Their penetration in the site of infection Detrimental interactions with other drugs Costs

15. Pharmacokinetics and pahrmacodynamics of carbapenemes in peritoneal fluid Infections in cirrhosis K. Ikawa, et al. J. Infect. Chemother. 2008 ; 14 : 330-332.

16. Pharmacokinetics of teicoplanin in patients udergoing continuous ambulatory peritoneal dialysis Infections in cirrhosis D. Stamadiatis, et al. Perit. Dial. Int. 2003 ; 23 : 127-131.

17. Pharmacokinetics of daptomycin in patients udergoing continuous ambulatory peritoneal dialysis Infections in cirrhosis D. Stamadiatis, et al. Perit. Dial. Int. 2003 ; 23 : 127-131.

18. Failure of antibiotic treatment of spontaneous bacterial peritonitis (SBP) P. Angeli, et al. Aliment. Pharmacol. Ther. 2006 ; 23 : 75-84. FAILUREI.V. CEFTAZIDIME (n°=55) Switch therapy with CIPROFLOXACIN (n°=61) P No positive response9.09%11.47%N.S. Adverse effects1.82%3.28%N.S. Recurrence of infection 1.82%3.28%N.S. Superinfections3.64%1.64%N.S. TOTAL16.36%19.67%N.S. Infections in cirrhosis

19. Mean cost of treatment per patient with spontaneous bacterial peritonitis P. Angeli, et al. Aliment. Pharmacol. Ther. 2006 ; 23 : 75-84. Infections in cirrhosis * = P < 0.001 * * * (€)(€)

20. Microrganisms E.Coli Pseudomonas sp. Klebsiella sp. EnterococciStaph aureus 463 7 277 ESBL-producers17- 4 Resistance34 (76 %)2 (66%) 4 (57%) 18 (66%)5 (71%) Quinolones291 3 164 Cephalosporins232 3 - - Carbapenems12 - 43 Meticillin- -5 Vancomicina 1- Preliminary unpublished data of an Italian multicenter study Main multiresistant bacteria isolated in 169 inpatients with cirrhosis and bacterial infections Infections in cirrhosis

21. P < 0.001 Resolution of bacterial infections with cefotaxime or amoxicillin/clavulanic acid in 224 patients with cirrhosis and bacterial infections Infections in cirrhosis (%) J.G. Acevedo et. al. 2009 EASL Meeting P < 0.001 P < 0.005P = 0.05

22. Geographic distribution of Escherichia Coli strains with a reduced susceptibility to ciprofloxacin in community-acquired UTI in Europe Infections in cirrhosis S. Cagnacci et al. J. Clin. Microb. 2008 ; 46 : 2605-2612.

23. Treatment of community-acquired spontaneous bacterial peritonitis (SBP): proposal for consensus (2) Infections in cirrhosis Up to now, third generation cephalosporins or amoxicillin-clavulanic acid can still be considered as the first-line empirical antibiotic therapy in patients with cirrhosis and community-acquired SBP. Quinolones may still be an alternative antibiotic choice in community- acquired SBP but only in patients who are not on prophylaxis with norfloxacin and only in countries with low prevalence of quinolone- resistance E. coli.