/ Azienda Ospedaliera S. Camillo Forlanini Unità Operativa di Gastroenterologia Moscow June 2006 Cosimo Prantera
ANTIBIOTICS AND BACTERIAL SPECIES Metronidazole Bacteroides - Clostridia Ciprofloxacin Escherichia coli METRONIDAZOLE: active against protozoa and most Gram-negative and Gram-positive anaerobic bacteria. It is working also by suppressing cellular immunity CIPROFLOXACINE:: quinolone derivative with selective action against E Coli and aerobic Enterobacteria
THE THREE MAIN SITUATIONS FOR ANTIBIOTIC USE IN CD: a) perianal Crohn s disease b) acute flares c) maintenance
TREATMENT of FISTULAE in PERIANAL CD : Metronidazole Bernstein (1980) 21 Metronidazole 20 mg /Kg / d Complete healing 48% Advanced healing 24% Jakobovits (1984) 8 Metronidazole 1-1.5 gr / d Complete healing 50% Metronidazole
TREATMENT OF FISTULAE IN CD: METRONIDAZOLE AND CIPROFLOXACINE Reference Antibiotic Response Turunen Ciprofloxacine 20% healed (1993) 1000-1500 mg/d perianal lesions for > than 2 years 50% had recurrences successfully treated with 3-months courses of therapy. Solomon Ciprofloxacine healed, 21% (1993) 1000-1500 mg/d improved, 64% + Metronidazole 500-1500 mg/d 70 60 50 40 30 20 10 0 n=14 n=10 Turunen 1993 Solomon 1993 healed improved
Perianal Crohn s disease Treatment of fistulae: antibiotics plus Aza Response rates of treatment at week 20 in 49 patients %of patients with response 90 80 70 60 50 40 30 20 10 0 no response complete response response without AZA with AZA Dejaco C (2003)
THE THREE MAIN SITUATIONS FOR ANTIBIOTIC USE IN CD: a) perianal Crohn s disease b) acute flares c) maintenance
Antibiotic trials as primary therapy in acute flares Author (year) Patients (n ) Antibiotic Period (wks) control Remission active control Ursing (1982) 78 Metronidazole 800 mg/d 16 sulfasalazine no difference from sulfasalazine Sutherland (1991) 99 Metronidazole 10 or 20 mg/kg 16 placebo 27% 25% 36% Colombel (1999) 40 Ciprofloxacin 500 mg bid 6 mesalamine 56% 55% Arnold (2002) 47 Ciprofloxacin 500 mg bid 26 placebo P <0.001 Prantera (1996) 41 Ciprofloxacin 500 mg bid + metronidazole 500 mg bid 12 Methylprednisol 0.7-1 mg/kg 45.5% 63% Greenbloom (1998) 72 Ciprofloxacin 500 mg bid + metronidazole 250 mg tid 10 ---- 68% ---- Leiper (2000) Clarithromycin 250 mg bid 4 ---- 48%
In patients with active Crohn s disease the addition of ciprofloxacin and metronidazole to budesonide may improve outcome when the colon is involved percent remission 60 50 40 30 20 10 Overall n=130 Small Bowel n= 97 Small Bowel & Colon n= 33 0 2 wks 8 wks 2 wks 8 wks 2 wks 8 wks budesonide/placebo budesonide/antibiotics
LABORATORY TESTS AND ANTIBIOTIC TREATMENT IN CROHN S DISEASE TEST VALUE before treatment after treatment CRP 27 ± 36 9 ± 11 (Colombel,1999 -Ciprofloxacine) Ferritin 113 ± 13.4 37.1 ± 33.1 Serum Iron 38 ± 25.8 61 ± 37.6 ESR 40.8 ± 24.2 21.7 ± 13.4 Seromucoids 166 ± 71.9 120 ± 27.4 (Prantera,1996-Metronidazole + Ciprofloxacine)
Different commensal bacterial species selectively initiate intestinal inflammation with distinct anatomic distribution in Interleukin 10 deficient mice Enterococcus faecalis E.coli causes distal colon and is the cause of duodenum involvement; cecum involvement It causes obstruction Kim S et al. (2005) Metronidazole is effective in the inflammation of the colon. Vancomycin-Imipemen treat ileal and colonic locations. Ciprofloxacin is most effective in the treatment of caecal inflammation. Hoentjen F et al. (2003)
THE THREE MAIN SITUATIONS FOR ANTIBIOTIC USE IN CD: a) perianal Crohn s disease b) acute flares c) maintenance
Controlled trials of antibiotic therapy in prevention of postoperative recurrence of Crohn s Author Year N pts Antibiotic Duration of treatment Endoscopic recurrence Rutgeerts 1995 60 Metronidazole 20 mg / kg Placebo 12 wks 52% 75% Rutgeerts 1999 71 Ornidazole 1g / day Placebo 52 wks 62% 94%
Ornidazole for prophylaxis of postoperative Crohn s Disease recurrence: a Randomized, Double-Blind, Placebo-Controlled Trial patients % 100 80 60 40 20 P=.0046 ornidazole placebo 80 patients : ornidazole 1 g/day or placebo within 1 week of resection and for 1 year. patients % 0 100 80 60 40 1 year 2 years 3 years clinical recurrence P=.037 P =.047 P. Rutgeerts, Gastroenterology 2005 20 0 3 months 12 months endoscopical recurrence
Long term use of antibiotics in the treatment of active Crohn's disease: experience with metronidazole and ciprofloxacin Patients N =160 Metronidazole ciprofloxacine Metronidazole Ciprofloxacine Lenght of treatment (wks) range 11.6 1-86 7.9 1-104 12.3 1-50 Complete remission (SI 2) 54.4% 61.4% 55.2% failures 29.4% 27.2% 31% Withdrawal due to side effects 21.8% 15.2% 17.2% Prantera et Al (1998)
SIDE EFFECTS metronidazole + ciprofloxacin 50/160 (31.2%) withdrawal because of side effects 35/160 (21.8%) 10 23 10 7 34 epigastric pain nausea/vomiting > transaminase paraesthesia skin reactions Prantera C et al, (1998)
83 patients mild-to-moderate CD disease 100 90 80 70 ITT Population 60 50 40 30 20 P=0.01 Rifaximin 800 mg Rifaximin 1600 mg Placebo three treatments for 12 weeks: Group A (rifaximin 800 mg o.d.) Group B (rifaximin 800 mg b.d.) Group C (placebo b.d.). C Prantera et al. (2006) 10 0 % Clinical Remission % Treatment failure % Clinical Response
Clinical remission, clinical response and treatment failure at 12 weeks in 43 CD patients with baseline elevated CRP % Patients with elevated CRP at baseline 100 90 80 P =0.03 P=0.004 P=0.002 P=0.01 70 60 50 40 30 20 10 0 75.0 62.5 50.0 43.8 25.0 21.4 18.8 21.4 0 % Clinical Remission % Treatment failure % Clinical Response Rifaximin 800 mg Rifaximin 1600 mg Placebo Prantera C et al, (2006)
Antimycobacterial Trials Author Drug(s) N Time month Remission Elliot et al 1982 Sulphadoxine+Pyrimethamin Rifampicin +Ethambutol 51 12 33% vs 41.6% Shaffer et al 1984 Rifabutin 27 12 13 withdrawals Basilisco 1989 Clofazimine 24 6 42% vs 50% Afdhal et al 1991 Rifampicin+ Ethambutol +INH 49 12 48% vs 25% Swift et al 1994 Rifampicin+ Ethambutol +INH 12 24 NS Prantera et al 1994 Ethambutol, clofazimine, dapsone, rifampicin 40 9 50% vs 22.2% no healing Australian study 2006 Rifabutin Clarithromycin Clofazimine 102-111 RCC- Plac 24 43%vs 26% relapsed
Relapse rates in Australian antimycobacterial trial 1 year treatment 2 years treatment 39% (26/67) 56% (31/55) 26% (11/42) 43% (12/28) Mycobacterium avium ssp paratuberculosis (MAP) p = 0.14 OR APT vs Placebo 2.22 (0.62-7.96) NOT SIGNIFICANT APT Placebo APT p = 0.14 Placebo
An alternative to long term use of antibiotic could well be the manipulation of bacterial flora
Probiotics Living bacteria that belong to the natural flora and are important to the health and well-being of the host Used succesfully in many indications: Clostridium difficile infection Traveller s diarrhea Rotavirus diarrhoea Pouchitis Doubts about their usefulness in: UC CD Probiotics employed in the clinical practice: Lactobacillus rhamnosus strain GG, Bifidobacteria, Streptococci, E Coli Nissle 1917, Saccharomyces Boulardii, VSL#3.
LGG in the recurrence prevention of Crohn s disease RANDOMISED PATIENTS N = 45 LGG N = 23 PLACEBO N= 22 DROPOUTS N = 2 PROTOCOL VIOLATION N = 3 PROTOCOL VIOLATION N = 2 DROPOUT N = 1 ENDOSCOPIC RECURRENCE AT 1 YEAR N = 9 CLINICAL RECURRENCE N = 3 CLINICAL RECURRENCE N = 2 ENDOSCOPIC RECURRENCE AT 1 YEAR N = 6 ENDOSCOPIC REMISSION AT 1 YEAR N = 6 ENDOSCOPIC REMISSION AT 1 YEAR N = 11 Prantera C et al, GUT 2002
Lactobacillus GG in the prevention of postoperative recurrence of Crohn s disease 45 pts with CD 90 surgery 80 70 60 23 pts LGG* 22 pts placebo * LGG: 6. 10 9 cfu bid 12 months % 50 40 30 20 10 0 Clin Rem EndoRem LGG Placebo Prantera C et al, Gut 2002
Lactobacillus GG for maintenance of remission in 75 children with Crohn s disease LGG 10 10 bid or Placebo until clinical relapse 12 patients ( 31%) on LGG relapsed 6 patients ( 17%) on placebo relapsed (p=0.18) 21% and 6% of children were withdrawn for non compliance. Conclusion: The addition of Lactobacillus GG to standard maintenance therapy does not prolong remission in children with Crohn s disease. Bousvaros et Al Inflamm Bowel Dis (2005)
Lactobacillus johnsonii (LA1) for prevention of postoperative recurrence in CD LA1 2x10 9 cfu or placebo given for 6 months to 98 patients operated for CD. At 6 months: Endoscopic recurrence grade 2 : 64% placebo vs 49% LA1 (OR 1.85-95% CI 0.80-4.30 ; p=0.15) Clinical recurrence : in 4 patients on LA1 (2 with endoscopic relapse) and in 3 on placebo (all with endoscopic relapse) Marteau P et al: GUT (2006) in press
CD is a complex entity. Diverse locations and different disease behaviours may well condition the response to probiotics. The course of CD follows different Phases. CD is a complex entity. Diverse locations and different disease behaviours may well condition the response to probiotics for example, colonic location seems to respond better to antibiotics and, consequently, might be more susceptible to flora manipulation. N The course of CD follows different phases; probiotics might be more effective in the early ones. N There are many species of probiotic. One type might be more effective than another because strain specific properties might influence the efficacy in different cases and situations. N The quantity of bacterial content may condition the effectiveness of the probiotic. Probiotics might be more effective in the early ones. There are many species of probiotic. One type might be more effective than another because strain specific properties might influence the efficacy in different cases and situations. The quantity of bacterial content may condition the effectiveness of the probiotic.
Conclusions Clinical practice and studies suggest that antibiotics can be useful in some forms and stages of CD, but their employment is burdened by side effects. The use of antibiotics which work locally appears to be interesting. In CD the results of probiotics appear discouraging. The optimal composition, dose and length of probiotic treatment in various IBD clinical settings should be evaluated by large, well-designed, controlled prospective trials.
Role of intestinal flora in Ulcerative Colitis and Crohn s disease pathogenesis Lesions occur in gut areas with high bacterial concentration Bacteria are the cause of animal and human intestinal diseases similar to IBD Efficacy of diversion of fecal stream Recurrent lesions on restoration of fecal stream Antibodies against bacterial components Lymphocytes from IBD patients react against fecal antigens E. E. Coli recovered from 65% of chronic lesions (resected ileum) and from 100% of early postoperative lesions E. E. Coli strains have adhesive ability and synthesis of a cytotoxin : allow to colonize intestinal epithelium, to damage intestinal cellsc
Bacteria behaviour in IBD (bad guys and good guys) Possibly aggressive species Bacteroides E Coli adherent Enterococcus faecalis Fusobacterium varium Pseudomonas Fluorescens Possibly protective species Lactobacillus Bifidobacterium E Coli (?)