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

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 % 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 % of patients. (Janes, et al. and Detry, et al.)

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

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 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 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

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.)

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).

Antibiotics in Complicated Diverticulitis  Ampicillin 2 g IV q 6 hours plus gentamicin g IV q 8 hours plus metronidazole 500 mg IV q 8 hours  Imipenem/cilastin 500 mg IV q 6 hours  Piperacillin-tazobactam 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 g IV q 8 hours plus metronidazole 500 mg IV q 8 hours  Imipenem/cilastin 500 mg IV q 6 hours  Piperacillin-tazobactam 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.

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).

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.

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!

References  Krobot K, et al. Eur J Clin Microbiol Infect Dis 2004 Sep;23(9):  Papi C, et al. Aliment Pharmacol Ther 9:  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 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:  Janes S, et al. Br J Surg 2005; 92:  Detry R, et al. Int J Colorectal Dis 1992; 7:  Kellum JM, et al. Clin Ther 1992; 14:  Solomkin JS, et al. Clin Infect Dis; 37(8):  Goldstein EJ, et al: In vitro activity of moxifloxacin against 923 anaerobes isolated from human intra-abdominal infections. Antimicrob Agents Chemother 50. (1):  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  Krobot K, et al. Eur J Clin Microbiol Infect Dis 2004 Sep;23(9):  Papi C, et al. Aliment Pharmacol Ther 9:  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 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:  Janes S, et al. Br J Surg 2005; 92:  Detry R, et al. Int J Colorectal Dis 1992; 7:  Kellum JM, et al. Clin Ther 1992; 14:  Solomkin JS, et al. Clin Infect Dis; 37(8):  Goldstein EJ, et al: In vitro activity of moxifloxacin against 923 anaerobes isolated from human intra-abdominal infections. Antimicrob Agents Chemother 50. (1):  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