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MEDICAL FRONTIERS - 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/46th Annual Meeting of the Infectious Diseases Society of America (IDSA)

Washington, DC / October 25-28, 2008

In the hospital, the community and now the intensive care unit (ICU), nonfermenting gram-negative bacteria such as Pseudomonas spp and Acinetobacter spp (Acinetobacter baumannii), are frequently implicated as causes of serious infections. These organisms are increasingly becoming resistant to multiple antimicrobial agents, a pattern that is prevalent worldwide.

The costs of gram-negative resistance are high. Compared with sensitive strains of gram-negative rods, resistant strains are associated with increased hospital costs; increased utilization of antibiotics; greater antibiotic costs; more hospital mortality; a longer length of overall stay; and increased ICU stay. Evidence suggests that clinical outcomes are worse and hospital costs are greater with extended-spectrum beta-lactamase (ESBL)-producing organisms, resistant ESBL-producing organisms and inappropriate initial antibiotic selection.

The proliferation of ESBL-producing multidrug-resistant Enterobacteriaceae, the increasing prevalence of Acinetobacter spp as a pathogen and the emergence of resistant P. aeruginosa require the promotion of proper antibiotic use, antibiotic stewardship and methods to overcome antimicrobial resistance.

SMART Program Tracks Gram-negative Susceptibilities

Multiple analyses from SMART (Study for Monitoring Antimicrobial Resistance Trends), which monitors global trends in the activity of various antimicrobial drugs against gram-negative bacteria from intra-abdominal infections, were reported here during the scientific sessions. SMART was conducted in multiple countries in 2007 and monitored the activity of ertapenem, imipenem, amikacin, cefepime, cefotaxime, ceftazidime, ciprofloxacin, levofloxacin, ampicillin/sulbactam and piperacillin/tazobactam. “Levels of resistance can vary dramatically geographically. It is therefore increasingly important to monitor susceptibility trends in various regions of the world over time to detect, define, track and communicate those trends so that effective therapeutic measures can be determined and customized to meet local needs,” explained Aaron Johnson, International Health Management Associates (IHMA), Schaumburg, Illinois.

The ESBL-positive rates for E. coli, K. pneumoniae and Klebsiella oxytoca increased dramatically from 2003 to 2007, especially in Asia/Pacific and Latin America. At the same time, susceptibilities of these three species declined dramatically to many of the drugs. “Ertapenem and imipenem remain remarkably effective in vitro vs. ESBL-positive strains, inhibiting 93.6% and 97.2%, respectively, of all isolates. All other study drugs inhibited less than 84% of these strains; the percentage susceptible to ciprofloxacin and levofloxacin were both less than 30%,” according to IHMA investigators.

Therapeutic options in regions of extremely high incidences of ESBL-positive strains are being diminished, with the exception of the carbapenems such as ertapenem and imipenem, they concluded. “For effective drug therapy, ertapenem should definitely be on the formulary and be prescribed for any of the ESBL-producing pathogens because of the success rate it is showing in vitro,” confirmed Mr. Johnson.

According to IHMA clinical microbiologist Dr. Jack Johnson, “With the high rate of ESBL-producing strains, we do not have a whole lot of choices. In countries with high rates of ESBL producers, you almost have to use a carbapenem. It is pretty disturbing as far as what we will have left to use against these organisms. You are eliminating cephalosporins and penicillins because they are not effective anymore [against ESBL-producing strains].”

High ESBL Rates in Asia/Pacific Rim, Latin America

The overall ESBL rates in the Asia/Pacific region for E. coli and Klebsiella spp. are 42% and 36%, respectively. This high proportion of ESBL-producing Enterobacteriaceae is reflected in the low susceptibility to all of the drugs studied except ertapenem and imipenem. “Based on the strains that we received, K. oxytoca was producing ESBL 100% of the time in India,” reported Mr. Johnson. “The ESBL-positive rates observed in India and China are especially alarming, given the concomitant high levels of resistance observed to several other drugs in ESBL-positive strains.” The ESBL rates for E. coli were 78.8% and 54.7% in India and China, respectively.

In Asia, of the antimicrobials tested, ertapenem and imipenem were the most active, inhibiting more than 90% of all species except Pseudomonas aeruginosa, which was less than 90% susceptible to all of the study drugs, and K. pneumoniae, which was more than 90% susceptible only to imipenem. Ampicillin/sulbactam had been recommended as monotherapy for mild to moderate intra-abdominal infections in Asia as recently as 2007, but it now appears to have poor in vitro activity against community-isolated pathogens, inhibiting only 34.5% of Enterobacteriaceae, they noted. “Empiric therapy of intra-abdominal infections in Asia should be adjusted to reflect these exceptionally high ESBL and resistance rates,” remarked Mr. Johnson.

Six of the nine Latin American countries had ESBL-positive rates of E. coli in excess of 25% and seven of the nine had ESBL-positive rates of K. pneumoniae of 40% or greater.

Emergence of CTX-M-Type ESBLs

In another presentation, Dr. Robert A. Weinstein, Stroger (Cook County) Hospital, Chicago, Illinois, cited a recent paper in which cefotaxime-hydrolyzing (CTX-M)-type ESBLs have emerged as the predominant ESBL type isolated from patients in the University Health System of San Antonio, Texas (Lewis et al. Antimicrob Agents Chemother 2007;51(11):4015-21). This ESBL type is “spreading from E. coli to other species,” Dr. Weinstein told delegates, and are probably moving to other cities.

He mentioned the appearance and rapid dissemination of beta lactamases, such as CTX-M, broad-spectrum oxacillinases and KPC serine carbapenemases, among Enterobacteriae that are complicating the treatment of gram-negative infections in many US hospitals (Castanheira et al. Microb Drug Resist 2008;14(3):211-6). For example, in 2007, CTX-M-encoding genes were detected in almost 40% of ESBL-positive isolates and were observed in 80% of hospitals that participated in the MYSTIC Program 2007. Genes encoding OXA-23 and -24 were detected in 30% of carbapenem-resistant Acinetobacter spp strains.

Dr. Weinstein also pointed out the identification of carbapenem-resistant E. coli isolates harbouring K. pneumoniae carbapenemase (KPC)-2 or KPC-3 enzymes in patients residing in long-term care facilities; CTX-M-type beta lactamases were also documented in three isolates (Clin Infect Dis 2008;46:e127-e130).

Findings From the Hospital Setting

In the UK, resistance or decreased susceptibility to carbapenems (particularly ertapenem) in Enterobacter cloacae is an emerging problem, stated Prof. Michel Doumith, Antibiotic Resistance Monitoring and Reference Laboratory Centre for Infections, Health Protection Agency, London, UK. In investigating mechanisms of resistance among 20 ertapenem-resistant E. cloacae isolates from 18 hospitals, isolates typed by PFGE revealed great diversity; only one single site pair of related isolates was identified. The resistance is co-mediated by ESBLs, depressed AmpC or, very rarely, KPC carbapenemase together with a loss or greatly diminished expression of OmpC and/or OmpF porins. He concluded that “ertapenem-resistant E. cloacae isolates comprise diverse strains and not national clones.”

Multi-drug-resistant P. aeruginosa infections may impart a negative impact on clinical and economic outcomes, including higher mortality and longer length of stay. The overuse of group 2 carbapenems may contribute to P. aeruginosa resistance, noted Prof. Priscilla Oliveira, Hospital das Clínicas, São Paulo, Brazil, and colleagues. She found that in her hospital, increased use of ertapenem along with restricted use of imipenem has had a positive impact on P. aeruginosa susceptibility to imipenem.

She reported that ertapenem is a group 1 carbapenem “with good activity against ESBL-producing Enterobacteriaceae, but with minimal P. aeruginosa activity, a characteristic that is thought to spare P. aeruginosa from resistance.” In her 200-bed hospital, the impact on the susceptibility of P. aeruginosa to imipenem was measured after a program to restrict the use of group 2 carbapenems and mandate use of ertapenem in treating ESBL-producing Enterobacteriaceae infections.

After one year, the defined daily doses of imipenem declined from 58.4 to 23.8 per 1000 patient-days. During the 12 months prior to ertapenem introduction, 20 P. aeruginosa strains were isolated as causative pathogens, four of which were resistant to imipenem. Over the 12 months following ertapenem introduction, none of the 18 P. aeruginosa strains isolated were resistant to imipenem (although the trend in the reduced number of resistant isolates was not significant).

At Rush University Medical Center, Chicago, a significant increase in ertapenem use did not change the percentage of P. aeruginosa strains susceptible to imipenem, according to Dr. Christopher W. Crank, Infectious Diseases Clinical Pharmacy Specialist, Rush University. He examined carbapenem utilization and susceptibility rates from 2000 to 2007 at his institution. The change in utilization of carbapenems and imipenem and meropenem susceptibility for P. aeruginosa were compared from 2000 to 2003 (period 1) and 2004 to 2007 (period 2). Ertapenem was added to the Rush University Medical Center formulary in 2003, he noted.

Ertapenem use increased significantly during period 2, with 8.47 defined daily doses per 1000 patient-days compared with 0.95 defined daily doses per 1000 patient-days during period 1 (P<0.0001). The total carbapenem use also increased during period 2 compared to period 1. The percentage of imipenem-susceptible P. aeruginosa isolates remained unchanged between the two time periods, but there was a significant decrease in the percentage of meropenem-susceptible isolates of P. aeruginosa from period 1 to period 2 (76.6% vs. 71.92%; P=0.0001). When blood isolates of P. aeruginosa were examined, a significant increase in the percentage of P. aeruginosa blood isolates susceptible to imipenem was noted (64.61% during period 1 vs. 77.7% during period 2; P=0.28), while susceptibility to meropenem remained unchanged.

“Ertapenem use does not appear to be driving imipenem resistance in P. aeruginosa at our institution but may have affected meropenem susceptibility,” Dr. Crank concluded. “The mechanism of this apparent differential effect is unclear.”

Use in the ICU

Ertapenem also appears to be a reliable therapeutic option in cases of ESBL epidemics in the ICU, causing no adverse change in P. aeruginosa sensitivity, stated Prof. Frédéric Gonzalez, Medical and Surgical Intensive Care Unit, Réanimation médico-chirurgicale, Bobigny, France. “ESBL resistance is an important reason for antimicrobial therapy failure in the ICU,” he said. “An association between an increased prevalence of ESBL and antimicrobial use, particularly third-generation cephalosporins and amoxicillin/clavulanate, has been demonstrated.”

The impact of using ertapenem instead of third-generation cephalosporins or amoxicillin/clavulanate on the rate of ESBL acquisition was examined in patients admitted to his ICU. In his study, the rates of ESBL acquisition were compared during two periods: from January to March 2006 during which 101 consecutive patients received amoxicillin/clavulanate or a third-generation cephalosporin for the treatment of community-acquired infections (period 1); and from January to March 2007 during which 93 consecutive patients received ertapenem as a first-line antibiotic (period 2).

The ESBL acquisition rate was 9.9% during period 1 and 0% during period 2 (P=0.002). There was no increase in the acquisition rate of isolates resistant to P. aeruginosa (4.3% during period 1 vs. 5.9% during period 2; P=0.4).

Choice of Appropriate Empiric Therapy Critical

Two key strategies to treatment success in patients with ESBL-producing Enterobacter bacteremia are screening for ESBL production in Enterobacter isolates and appropriate empiric antibiotic therapy, stated Dr. Catherine O’Neal, Research Fellow, Division of Infectious Diseases and Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee. In her case-controlled study of patients with bloodstream infections caused by Enterobacter spp, 32% were ESBL-positive. Almost half (46%) of the ESBL-producing isolates were resistant to three or more antibiotic classes. The highest rates of resistance were observed with ampicillin/sulbactam (>90%) and piperacillin/tazobactam (>60%) while the lowest rate of resistance occurred with imipenem (<5%).

The likelihood of treatment failure was increased nearly threefold with ESBL-producing isolates and nearly fourfold with inappropriate antibiotic therapy, reported Dr. O’Neal. “The odds of treatment failure… appear mitigated when adjusting for inappropriate empiric antibiotic therapy. The principal determinant of treatment failure appears to be inappropriate empiric antibiotic therapy and not simply the presence of an ESBL-producing bacteremia.” She added that screening for ESBL production in Enterobacter isolates might aid in preventing the spread of plasmid-mediated mechanisms of resistance within an institution.

Prior Antibiotic Use Not a Factor in P. aeruginosa Resistance

Prior antibiotic use was not the culprit in patients with high-level meropenem-resistant P. aeruginosa at Hartford Hospital, observed Dr. David P. Nicolau, Director, Center for Anti-infective Research and Development, Connecticut. In his case-controlled study, “our population of patients with high-level meropenem resistance had not received carbapenems at a significantly different rate than those with susceptible organisms or no infection at all; in fact, carbapenem administration was nearly zero.” Instead, meropenem-resistant P. aeruginosa acquisition was associated with admission frequency and Foley catheters, indicating that “rigorous adherence to infection control measures will be necessary to reduce the transmission of meropenem-resistant P. aeruginosa.”

Summary

The role of carbapenems in the treatment of gram-negative infections is evolving. As reported here during the scientific sessions, carbapenems continue to have utility in the treatment of ESBL-producing organisms. Recent data have demonstrated continued carbapenem susceptibility to P. aeruginosa in both the community and hospital settings.