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.

47th Interscience Conference on Antimicrobial Agents and Chemotherapy

Chicago, Illinois / September 17-20, 2007

Since the late 1990s, Enterobacteriaceae—mostly Escherichia coli—that produce novel extended-spectrum beta-lactamases (ESBL) were identified as a cause of community-acquired urinary tract infections and secondarily, bloodstream infections. Out of some 10 different ESBL types, these new EBSLs, CTX-M-producing E. coli, are currently causing a pandemic of multiresistant E. coli for which treatment options are limited, especially for serious infections. A Canadian study was therefore designed to determine the in vitro activity of carbapenems, along with tigecycline and a variety of other antibiotics, against multiresistant CTX-M-producing E. coli isolated from clinical specimens.

As presented by Dr. Johann Pitout, Associate Professor of Pathology and Microbiology, University of Calgary, Alberta, Calgary Laboratory Services researchers collected 181 ESBL-producing E. coli between April 2002 and June 2006. Another 21 control strains were also included in the study. Minimum inhibitory concentrations (MIC50 and MIC90) were determined for ertapenem, meropenem, ciprofloxacin, gentamicin, tobramycin, amikacin, trimethoprim-sulfamethoxazole, piperacillin/tazobactam and tigecycline. The Vitek Legacy, Vitek 2 Compact and custom-made microdilution panels were used to determine the percentage resistance to the different antimicrobial agents.

Researchers also carried out pulsed field gel electrophoresis on the CTX-M-producing isolates in order to ensure that CTX-M-14- and CTX-M-15-producing E. coli did not belong to the same cluster. Results of these tests indicated that these two types of ESBL-producing E. coli were not related to each other. In vitro susceptibility results of the 181 ESBL-producing E. coli, along with 10 of the control isolates, showed resistance levels among CTX-M-producing E. coli were high for piperacillin/tazobactam, amikacin, ciprofloxacin, gentamicin, tobramycin and trimethoprim-sulfamethoxazole, “underlining the multiresistant nature of the isolates included in the study,” study authors pointed out. In contrast, carbapenems, including ertapenem, demonstrated significantly improved in vitro activity against all ESBL-producing E. coli. “The MIC50 and the MIC90 levels of these drugs were very low,” they emphasized, “and this study supports the notion that these agents are the first choice of therapy for serious infections caused by ESBL-producing E. coli.”

Further commenting on this key finding, Dr. Pitout noted that a separate study also presented here during the scientific sessions helped identify patients who are most likely to develop a community-acquired infection due to ESBL-producing E. coli. In the prospective, population-based surveillance study of Calgary Health Region residents, the team identified 248 community-onset infections, 78% of which were classified as community-acquired and 22% of them being healthcare-associated. The risk of developing an infection caused by ESBL-producing E. coli increased with advancing age, female gender and the presence of comorbid medical conditions.

Importantly, too, foreign travel (excluding the US) was associated with a “significantly increased risk” among community-acquired cases, where more than half of those with ESBL-producing E. coli infections had travelled overseas in the preceding year. Of particular note, travel to Southeast Asia was associated with infections caused by CTX-M-14 organisms, while travel to Europe and the Indian subcontinent was associated with infections caused by CTX-M-15-producing E. coli. “For patients with risk factors for these types of infection, you have to consider using the carbapenems, including ertapenem,” Dr. Pitout offered.

Additional results from susceptibility testing on community-acquired ESBL-producing isolates found that tigecycline also had low MIC50 and MIC90 to the ESBL-producing isolates, indicating that it may be considered as an alternative in the treatment of ESBL-producing E. coli as well.

As a final observation, the Calgary team described findings from susceptibility testing for piperacillin/tazobactam using the Vitek technology as “worrisome.” “Vitek failed to detect resistance among 70 out of 156 CTX-M-producing strains,” they observed, “and we recommend that laboratories using Vitek should use an alternative susceptibility method for piperacillin/tazobactam before reporting this agent on ESBL-producing E. coli, especially if high numbers of CTX-Ms are prevalent.”

Pseudomonas aeruginosa Susceptibility

Concerns that increasing use of ertapenem might compromise Pseudomonas aeruginosa susceptibility to imipenem had been countered by results from separate studies presented at ICAAC 2006, where investigators showed increasing use of ertapenem actually increased the susceptibility of P. aeruginosa to imipenem. (Ertapenem has limited activity against P. aeruginosa, necessitating preservation of antipseudomonals that are active against it, such as imipenem.) The same findings were reiterated again this year.

As pointed out by Dr. Debra Goff, Clinical Associate Professor of Pharmacy, Ohio State University, Columbus, ertapenem, which has in vitro activity against gram-positive and gram-negative aerobes and anaerobes, was added to the medical centre’s formulary in May 2003. “Our purpose was to monitor ertapenem’s effect on imipenem susceptibility to P. aeruginosa from 2003 to 2006,” investigators stated, “and other antipseudomonals on the formulary—piperacillin/tazobactam, cefepime and tobramycin—were also examined.” Investigators used the defined daily dose (DDD)/1000 patient-days as a method to track antipseudomonal use in their hospital year to year. DDD data are easily available from pharmacy records and equalize daily doses of antibiotics given in different quantities.

Susceptibility to the various antipseudomonals tested were determined by microdilution MICs using MicroScan panels except for ertapenem, for which the Etest was used for all ESBL-producing E. coli. Results showed that 96% of ESBL Klebsiella pneumoniae and 100% of ESBL E. coli and K. oxytoca isolates tested were susceptible to ertapenem with an MIC of £2. P. aeruginosa susceptibility to imipenem, piperacillin/tazobactam, cefepime and tobramycin remained either the same or had improved over the intervening four years, even though total carbapenem use in their centre increased significantly between 2003 and 2006, with ertapenem use in particular increasing significantly at between 13% and 26% over the four years. “The addition of ertapenem [to the formulary] did not negatively affect the susceptibilities of the [tested antipseudomonals] to P. aeruginosa,” investigators concluded, a finding that Dr. Goff characterized as “very reassuring” in that the goal is to “preserve the antipseudomonal antibiotics, since there are no new classes of antipseudomonal antibiotics in the pipeline.”

Another study presented here confirmed that ertapenem is not associated with increased P. aeruginosa resistance to imipenem. As pointed out by lead author Dr. Yehuda Carmeli, Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Israel, imipenem and meropenem are both Group 2 carbapenems and are able to select resistant strains for P. aeruginosa. Ertapenem is a Group 1 carbapenem; because of its limited activity against P. aeruginosa, it has not been associated with an increased risk of P. aeruginosa resistance to imipenem, at least in vitro, as well as individual studies.

In the retrospective longitudinal study, researchers collected data on patients, antibiotic use and resistance patterns on nine medical wards between 2001 and 2005. A total of 139,185 patient admissions and 540,255 patient-days were included in the analysis. Over 541,000 antibiotic DDDs were prescribed, among them, 4637 DDDs of imipenem and meropenem and 2130 DDDs of ertapenem. Resistance data identified 779 P. aeruginosa isolates resistant to imipenem at an incidence rate of 5.6 cases/1000 patient-admissions.

According to multivariate analysis, the incidence of imipenem-resistant P. aeruginosa increased at a rate of 3.8% a year, which was significant (P<0.001). The same analysis also showed that the use of Group 2 carbapenems was “highly associated” with an increase in P. aeruginosa resistance to imipenem, and that for each 100 DDDs of the Group 2 carbapenem compounds given, there was a 20% increase in the incidence of imipenem-resistant P. aeruginosa. In fact, Group 2 carbapenem use was the only variable associated with an increase in the rate of imipenem-resistant P. aeruginosa, investigators noted. In contrast, ertapenem was not associated with a higher incidence of imipenem-resistant P. aeruginosa. “When carbapenems are indicated for the treatment of resistant organisms and P. aeruginosa is not present, then ertapenem is preferable,” Dr. Carmeli suggested.