Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

44th Annual Meeting of the Infectious Diseases Society of America

Toronto, Ontario / October 12-15, 2006

Concerns that increasing use of ertapenem might compromise Pseudomonas aeruginosa susceptibility to imipenem can be laid to rest with two separate studies showing that the organism’s susceptibility to imipenem in fact increases following the introduction of ertapenem to the hospital formulary, researchers reported.

Dr. Ellie Goldstein, Clinical Professor of Medicine, University of California Medical School, Los Angeles, presented a retrospective study on the effect that the introduction of ertapenem had on antimicrobial utilization in their own hospital (St. John’s Health Center, Santa Monica), as well as its impact on in vivo activity of imipenem, levofloxacin, cefepime, gentamicin and piperacillin/tazobactam on aerobic Gram-negative rods. The Gram-negative organisms studied included Escherichia coli, Klebsiella species, Enterobacter species and P. aeruginosa. After approximately one year of adding ertapenem to the hospital formulary, an autosubstitution order was instigated, whereby ampicillin sulbactam was automatically replaced with ertapenem. At the same time, empirical cefepime was restricted after 72 hours of therapy to treatment of infections involving P. aeruginosa and cefotaxime use was encouraged, investigators noted. After 3.5 years of having ertapenem on the formulary, cefoxtin use declined from 28 to eight defined daily dosages (DDD) per 1000 patient-days and imipenem use declined from 35 to 23 DDD per 1000 patient-days, while levofloxacin use declined from 107 to 73 DDD per 1000 patient-days.

This was accompanied by an increase in ertapenem use to 63 DDD per 1000 patient-days and a corresponding decrease in ampicillin sulbactam, while piperacillin/tazobactam and aminogycoside use remained stable. Most importantly, the susceptibility of imipenem against P. aeruginosa increased from 61% at the beginning of the study to 87% at study end, as did susceptibility to cefepime from 60% to 95% and levofloxacin from 50% to 65%. There were either minor or no changes in P. aeruginosa susceptibility to tobramycin or piperacillin/tazobactam.

Against E. coli, P. mirabilis, Klebsiella species and Enterobacter cloacae, there was either no change or only minor changes in susceptibility to the various agents and all of these organisms remained 100% susceptible to ertapenem. “Ertapenem does not have activity against Pseudomonas so people worried that using a class I carbapenem like ertapenem would carry resistance to the class II carbapenems like imipenem or meropenem,” Dr. Goldstein commented. “But that did not happen at all. Not only was there not a bad effect, there was a good effect for us in our hospital when we added ertapenem and we are continuing to autosubstitute.”

Comparable Findings

A second study presented by Christopher Crank, PharmD, Clinical Pharmacist in Infectious Disease, Rush University Medical Center, Chicago, Illinois, experienced comparable findings. In this analysis, researchers evaluated the effect that increased ertapenem use had on imipenem susceptibility rates for P. aeruginosa between 2003 (when ertapenem was added to the formulary at the medical centre) and 2005. Susceptibility rates were determined from microbiology reports. Changes in the use of carbapenems in general as well as susceptibility of P. aeruginosa to imipenem in particular were evaluated across the study interval.

Results revealed that ertapenem use increased significantly from 22.5% of total carbapenem use in 2003 to 42.4% in 2005. In terms of DDD, imipenem use remained stable. Susceptibility rates of P. aeruginosa to imipenem increased from 65% in 2003 to 75% in 2005 for both blood isolates and total isolates. Susceptibility of P. aeruginosa to meropenem remained stable across the same time period at 71% in 2003 and 75% in 2005.

Dr. Crank noted, “Ertapenem is given once a day so patients like it because it is more convenient and it is cost-effective as well.” The carbapenems are considered one of the mainstays for the treatment of resistant Pseudomonas. “If we lose our carbapenems for Pseudomonas, then we are losing one of our best therapies,” he remarked.

This study reaffirms previous findings that increased use of ertapenem does not appear to be driving the development of carbapenem-resistant P. aeruginosa isolates, given the increase in ertapenem use was paralleled by a significant increase in P. aeruginosa isolates susceptible to imipenem.

PREVENT Study

The soon to be published PREVENT (Prospective Randomized Trial of Ertapenem vs. Cefotetan Following Elective Colorectal Surgery) study will provide detailed findings in a peer-reviewed journal.

When PREVENT was designed, cefotetan, a second-generation cephalosporin, was often used for prophylaxis against a wide range of aerobic, anerobic, Gram-positive and Gram-negative organisms, including E. coli, H. influenzae and the Klebsiella species. It was also active against many strains of Staphylococcus and Streptococcus, although not E. enterococcus. Approximately half of clinically significant strains of Enterobacter species as well as P. aeruginosa were similarly resistant.

A cost analysis of ertapenem 1 g administered prophylactically 30 minutes prior to surgery vs. cefotetan 2 g at the same point was presented here during the scientific sessions by Dr. Robin Turpin, West Point, Pennsylvania.

A total of 338 patients received prophylactic ertapenem compared with 334 who received cefotetan. The costs included in the analysis consisted of the cost of each treatment—$45 (US) for ertapenem and $28 for cefotetan—plus “room and board” at the hospital, which worked out to $580.26 a day.

The most common reason for prophylaxis failure in both arms was surgical site infection. In the ertapenem arm, 28% of patients had failure of prophylaxis for any reason compared with 42.8% for the cefotetan arm.

For responders as well as prophylaxis failures, the mean length of stay in the ertapenem arm was 7.6 days vs. 8.7 days in the cefotetan arm while the mean length of stay for those who failed prophylaxis was 10.3 days for ertapenem compared with a mean of 11.6 days for cefotetan. However, mean lengths of stay varied depending on the reason for prophylaxis failure; for example, the mean length of stay for organ/space surgical site infections was 18.8 days for ertapenem vs. 14.3 days for cefotetan; 10.8 days vs. 23.4 days for deep incisional surgical site infections; and 7.6 vs. 8.5 days for superficial surgical site infections. Failure due to anastomatic leaks was associated with a mean stay of 21 days for ertapenem recipients compared with 18.1 for cefotetan.

The mean cost for all patients treated with prophylactic ertapenem was $4454.97 compared with $5076.26 for cefotetan, for a cost difference of $621.29 per patient. Cefotetan had been one of the most commonly used therapies for prophylaxis when the study began five years ago, although it is no longer available. Investigators concluded that this cost-analysis supports the use of ertapenem as an effective—and cost-effective—antimicrobial in the setting of elective colorectal cancer surgery.

Based on the following presentations of interest during the scientific sessions:

Goldstein et al. “Effect on antimicrobial usage and the in vitro susceptibility on aerobic, Gram-negative rods after the introduction of ertapenem onto a hospital formulary.”

Crank et al. “Effect of ertapenem utilization on Pseudomonas aeruginosa susceptibility to imipenem.”

Wilson et al. “A cost analysis of prophylaxis of ertapenem versus cefotetan in elective colorectal surgery based on the PREVENT Study.”