1. Choice of Antibiotics in Diverticulitis Jeff Poynter University of Michigan Medical School Jeff Poynter University of Michigan Medical School

2. The Problem: Uncomplicated Diverticulitis  Uncomplicated diverticulitis represents a localized infection, primarily by Gram- negative rods and anaerobes, mostly E. coli and B. fragilis. (Ambrosetti P, et al.)  Conservative (medical) treatment of acute uncomplicated diverticulitis is successful in 70-100% of patients. (Janes, et al. and Detry, et al.)  Uncomplicated diverticulitis represents a localized infection, primarily by Gram- negative rods and anaerobes, mostly E. coli and B. fragilis. (Ambrosetti P, et al.)  Conservative (medical) treatment of acute uncomplicated diverticulitis is successful in 70-100% of patients. (Janes, et al. and Detry, et al.)

3. Some Common Choices of Antibiotics: Dual-Agent Coverage  Quinolone with metronidazole (Ciprofloxacin, 500 mg PO BID plus metronidazole, 500 mg PO BID)  Ciprofloxacin 400 mg IV q 12 hours plus metronidazole 500 mg PO/IV q 6-8 hours  Levofloxacin 500 mg IV daily plus metronidazole 500 mg PO/IV q 6-8 hours  Choices made in part with regard to history of drug allergies  Quinolone with metronidazole (Ciprofloxacin, 500 mg PO BID plus metronidazole, 500 mg PO BID)  Ciprofloxacin 400 mg IV q 12 hours plus metronidazole 500 mg PO/IV q 6-8 hours  Levofloxacin 500 mg IV daily plus metronidazole 500 mg PO/IV q 6-8 hours  Choices made in part with regard to history of drug allergies

4. Some Common Choices of Antibiotics: Single-Agent Therapy  Amoxicillin-clavulanate 875/125 mg PO BID  Ampicillin-sulbactam 3 g IV q 6 hours  Piperacillin-tazobactam 3.375 or 4.5 g IV q 6 hours  Ticarcillin-clavulanate 3.1 g IV q 4 hours  Imipenem 500 mg IV q 6 hours  Meropenem 1 g IV q 8 hours  Amoxicillin-clavulanate 875/125 mg PO BID  Ampicillin-sulbactam 3 g IV q 6 hours  Piperacillin-tazobactam 3.375 or 4.5 g IV q 6 hours  Ticarcillin-clavulanate 3.1 g IV q 4 hours  Imipenem 500 mg IV q 6 hours  Meropenem 1 g IV q 8 hours

5. Single- versus Dual-Antibiotic Therapy  Single and multiple antibiotic regimens are equally effective as long as both Gram-negative rods and anaerobes are covered adequately. (Kellum, et al.)

6. The Problem: Complicated Diverticulitis  Complications include obstruction, abscess formation, fistula formation or perforation.  Requires IV antibiotics plus surgery (usually Hartmann operation).  Complications include obstruction, abscess formation, fistula formation or perforation.  Requires IV antibiotics plus surgery (usually Hartmann operation).

7. Antibiotics in Complicated Diverticulitis  Ampicillin 2 g IV q 6 hours plus gentamicin 1.5-2.0 g IV q 8 hours plus metronidazole 500 mg IV q 8 hours  Imipenem/cilastin 500 mg IV q 6 hours  Piperacillin-tazobactam 3.375 mg IV q 6 hours  Moxifloxacin  Tigecycline, a new drug, has recently been approved for the treatment of intra-abdominal infections; it has not been shown to be superior to the traditional regimens.  Lots of choices- the goal is to cover GNRs and anaerobes and proceed to definitive surgery. No single regimen has been shown to be definitely superior to the others.  Ampicillin 2 g IV q 6 hours plus gentamicin 1.5-2.0 g IV q 8 hours plus metronidazole 500 mg IV q 8 hours  Imipenem/cilastin 500 mg IV q 6 hours  Piperacillin-tazobactam 3.375 mg IV q 6 hours  Moxifloxacin  Tigecycline, a new drug, has recently been approved for the treatment of intra-abdominal infections; it has not been shown to be superior to the traditional regimens.  Lots of choices- the goal is to cover GNRs and anaerobes and proceed to definitive surgery. No single regimen has been shown to be definitely superior to the others.

8. Krobot K, et al  425 patients who required surgery for community-acquired secondary peritonitis, including patients with complicated diverticulitis.  13% of patients did not receive appropriate antibiotics, defined as not covering all bacteria later isolated or not empirically covering typical aerobic and anaerobic organisms in the absence of culture results.  26% of appropriately treated patients and 30% of inappropriately treated patients had colonic sources of infection.  Resolution of infection with initial or step-down therapy after primary surgery was significantly less likely to occur (53% vs. 79%).  Failure of resolution of infection due to inadequate choice of antibiotics resulted in six-day prolongation of stay in hospital (20 versus 14 days total).  425 patients who required surgery for community-acquired secondary peritonitis, including patients with complicated diverticulitis.  13% of patients did not receive appropriate antibiotics, defined as not covering all bacteria later isolated or not empirically covering typical aerobic and anaerobic organisms in the absence of culture results.  26% of appropriately treated patients and 30% of inappropriately treated patients had colonic sources of infection.  Resolution of infection with initial or step-down therapy after primary surgery was significantly less likely to occur (53% vs. 79%).  Failure of resolution of infection due to inadequate choice of antibiotics resulted in six-day prolongation of stay in hospital (20 versus 14 days total).

9. Schechter S, et al  Survey of 373 Fellows of the American Society of Colon and Rectal Surgeons surveyed regarding diagnosis and treatment of acute uncomplicated diverticulitis  Half of responders chose a single-drug regimen: second- generation cephalosporin (27%) or ampicillin/sulbactam (16%).  Single-therapy oral antibiotics at discharge were ciprofloxacin (18%), amoxicillin/clavulanate (14%), metronidazole (7%) and doxycycline (6%).  Combinations chosen were ciprofloxacin/metronidazole (28%) and TMP-SMX/metronidazole (6%). 21% chose various other antibiotics.  Survey of 373 Fellows of the American Society of Colon and Rectal Surgeons surveyed regarding diagnosis and treatment of acute uncomplicated diverticulitis  Half of responders chose a single-drug regimen: second- generation cephalosporin (27%) or ampicillin/sulbactam (16%).  Single-therapy oral antibiotics at discharge were ciprofloxacin (18%), amoxicillin/clavulanate (14%), metronidazole (7%) and doxycycline (6%).  Combinations chosen were ciprofloxacin/metronidazole (28%) and TMP-SMX/metronidazole (6%). 21% chose various other antibiotics.

10. Summary  Antibiotic coverage must cover both Gram-negative rods and anaerobes, or infections will persist longer and prolong length of stay in hospital.  Single or multiple antibiotic regimens are equally effective as long as coverage is adequate- this equivalency amongst choices is probably why there aren’t any recent studies attempting to identify superior drugs!  Top choices by ASCRS Fellows include: ciprofloxacin plus metronidazole, ciprofloxacin alone and amoxicillin/clavulanate.  The dominant consideration regarding choice of antibiotics is coverage of GNRs and anaerobes!  Antibiotic coverage must cover both Gram-negative rods and anaerobes, or infections will persist longer and prolong length of stay in hospital.  Single or multiple antibiotic regimens are equally effective as long as coverage is adequate- this equivalency amongst choices is probably why there aren’t any recent studies attempting to identify superior drugs!  Top choices by ASCRS Fellows include: ciprofloxacin plus metronidazole, ciprofloxacin alone and amoxicillin/clavulanate.  The dominant consideration regarding choice of antibiotics is coverage of GNRs and anaerobes!

11. References  Krobot K, et al. Eur J Clin Microbiol Infect Dis 2004 Sep;23(9):682-7.  Papi C, et al. Aliment Pharmacol Ther 9:33-39.  Schechter S, et al. Dis Colon Rectum 1999; 42:470.  Up-to-Date, “Diverticulitis”.  Imbembo, AL, Bailey, RW. Diverticular disease of the colon. In: Textbook of Surgery, 14th ed, Sabiston, DC Jr (Ed), Churchill Livingstone 1992. p.910.  Rafferty, J, Shellito, P, Hyman, NH, Buie, WD. Practice parameters for sigmoid diverticulitis. Dis Colon Rectum 2006; 49:939.  Ambrosetti P, et al. Dis Colon Rectum 2000; 43:1363-7.  Janes S, et al. Br J Surg 2005; 92:133-42.  Detry R, et al. Int J Colorectal Dis 1992; 7:38-42.  Kellum JM, et al. Clin Ther 1992; 14:376-84.  Solomkin JS, et al. Clin Infect Dis; 37(8): 997-1005.  Goldstein EJ, et al: In vitro activity of moxifloxacin against 923 anaerobes isolated from human intra-abdominal infections. Antimicrob Agents Chemother 50. (1): 148-155.2006.  Olivia ME, et al: A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections. BMC Infect Dis 5. 88.2005.  Krobot K, et al. Eur J Clin Microbiol Infect Dis 2004 Sep;23(9):682-7.  Papi C, et al. Aliment Pharmacol Ther 9:33-39.  Schechter S, et al. Dis Colon Rectum 1999; 42:470.  Up-to-Date, “Diverticulitis”.  Imbembo, AL, Bailey, RW. Diverticular disease of the colon. In: Textbook of Surgery, 14th ed, Sabiston, DC Jr (Ed), Churchill Livingstone 1992. p.910.  Rafferty, J, Shellito, P, Hyman, NH, Buie, WD. Practice parameters for sigmoid diverticulitis. Dis Colon Rectum 2006; 49:939.  Ambrosetti P, et al. Dis Colon Rectum 2000; 43:1363-7.  Janes S, et al. Br J Surg 2005; 92:133-42.  Detry R, et al. Int J Colorectal Dis 1992; 7:38-42.  Kellum JM, et al. Clin Ther 1992; 14:376-84.  Solomkin JS, et al. Clin Infect Dis; 37(8): 997-1005.  Goldstein EJ, et al: In vitro activity of moxifloxacin against 923 anaerobes isolated from human intra-abdominal infections. Antimicrob Agents Chemother 50. (1): 148-155.2006.  Olivia ME, et al: A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections. BMC Infect Dis 5. 88.2005.