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.

Association of Medical Microbiology and Infectious Disease (AMMI) Canada—Canadian Association for Clinical Microbiology and Infectious Diseases (CACMID) 2006 Annual Conference

Victoria, British Columbia / March 15-19, 2006

Understanding the scope of antibiotic resistance is central to finding potential solutions both preventive and curative. According to Dr. Coleman Rotstein, Professor of Medicine, Director, Division of Infectious Diseases, McMaster University and Chief, Infectious Disease Service, Hamilton Health Sciences, Henderson Site, Ontario, “There is in an increasing prevalence of nosocomial- and community-acquired strains of methicillin-resistant Staphylococcus aureus [MRSA],” particularly in skin infections.

In general, nosocomial infections are associated with increased incidence of mortality and morbidity, longer hospital stay and higher overall health care costs. Common pathogens are increasingly resistant to conventional antibiotic therapies. For instance, recent shifts in the epidemiological profile of MRSA have made it an increasingly problematic pathogen in the hospital setting and beyond (McDonald LC. Clin Infect Dis 2006;42(Suppl 2):S65-S71). Many gram-positive bacteria, gram-negative bacteria and anaerobic bacteria have developed resistance to the more commonly used agents such as ß-lactams (penicillin and cephalosporins), fluoroquinolones and macrolides (Zhanel et al. Expert Rev Anti Infect Ther 2006;4(1):9-25). Dr. Rotstein highlighted these problems, citing a study that found “infectious complications after coronary artery bypass graft surgery are the number one reason for hospital readmission.”

The Epidemiology of Nosocomial Infections

As part of the ongoing Canadian Intensive Care Unit (CAN-ICU) Surveillance Study, ICU facilities across Canada are collaborating to assess the prevalence of antibiotic-resistant pathogens, as well as the effectiveness of specific antimicrobial agents.

“The CAN-ICU study has shown that there are tremendous differences between centres,” reported Dr. George Zhanel, Professor, Department of Microbiology/Infectious Diseases, University of Manitoba and Coordinator, Antimicrobial Resistance Program, Health Sciences Centre, Winnipeg. As Dr. Zhanel emphasized, “You have got to know what is going on in your particular hospital.”

Dr. Donald E. Low, Professor, University of Toronto and Medical Director, Ontario Public Health Laboratories Branch, Ontario and colleagues assessed the activity of tigecycline, a new glycylcycline with documented activity against many resistant gram-positive and gram-negative pathogens found in ICUs. The study utilized data from 20 ICU sites located in tertiary medical care centres, soliciting up to 250 pathogen isolates per centre (one pathogen per cultured site per patient). The isolates that were deemed clinically significant were collected from respiratory tract, blood/sterile sites, urinary tract and wound/intravenous (i.v.) sites; excluded from the study were anaerobic organisms, fungi and yeasts.

To assess tigecycline activity, pathogens were classified as either susceptible (S), intermediate (I) or resistant (R) to tigecycline using the following breakpoints (µg/mL): S. aureus and MRSA £0.5 (S); Enterococcus spp. £0.25 (S); Enterobacteriaceae £2.0 (S), 4.0 (I) and ³8.0 (R). The Enterobacteriaceae breakpoints were used for Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter spp.

The study tested the effects of the glycylcycline and its comparators on 3368 isolates. The isolates were subcultured onto appropriate media and then minimum inhibitory concentration (MIC) testing was conducted. After culturing, the in vitro activities of tigecycline, piperacillin/tazobactam, cefazolin, ceftriaxone, cefepime, gentamicin, ciprofloxacin, levoflaxacin, meropenem and vancomycin were determined by microbroth dilution. Susceptibility testing was then performed using guidelines established by the Clinical and Laboratory Standards Institute (2006). The most common ICU pathogens displayed the following susceptibility to tigecycline treatment: S. aureus: 100% (n=571); Escherichia coli: 100% (n=453); P. aeruginosa: 2.1% (n=352); Enterococcus spp.: 100% (n=208); Klebsiella pneumoniae: 95.4% (n=183); MRSA: 100% (n=154); S. maltophilia: 69.1% (n=88); and Acinetobacter spp.: 91.7% (n=24).

Researchers concluded that tigecycline is very active against MRSA, Enterococcus spp. (including vancomycin-resistant Enterococcus spp., or VRE) and Enterobacteriaceae, including extended-spectrum ß-lactamase producers. In particular, the study found that the glycylcycline displays activity against S. maltophilia (69.1% susceptibility) and Acinetobacter spp (91.7% susceptibility), but is not as effective against P. aeruoginosa (2.1% susceptibility). They further concluded that based upon the susceptibility profile of a wide range of pathogens, as well as its activity in comparison to other antibiotic therapies, the novel antibiotic appears to be a promising agent against many pathogens isolated from ICUs.

“In addition, tigecycline was shown to be effective in treatment of patients with resistant gram-negative bacteria, such as E. coli and Klebsiella,” concluded Dr. Low.

Addressing Problem Pathogens

As the CAN-ICU findings demonstrated, despite their differences, there are also similarities among ICU sites. “The number one pathogen in every single centre is S. aureus,” Dr. Zhanel told delegates. In the CAN-ICU study, S. aureus (methicillin-sensitive Staphylococcus aureus, MSSA) accounted for 17.0% of the total isolates (n=571). When coupled with the incidence of MRSA, S. aureus accounted for over 20% of all ICU isolates.

Among ICU patients, the study findings indicated that the most common infection site was the respiratory tract (n=1,844, 54.8%), followed by blood/sterile sites (n=556, 16.5%), wound/i.v. sites (n=476, 14.1%) and the urinary tract (n=492, 14.6%).

These findings are consistent with presentations made by Dr. Rotstein, who discussed the most common complicated skin and soft tissue infections in North America and Europe. Studies have found that both these regions experience the same pathogens. The most common was S. aureus, accounting for around 40% of infections, followed by P. aeruginosa, Enterococcus spp., E. coli, Enterobacter spp. and ß-hemolytic streptococci.

Investigators have found that ICU pathogens exhibit approximately a 10% resistance to piperacillin/tazobactam and meropenem. The CAN-ICU study also showed that isolates from ICUs across Canada demonstrate about a 20% resistance to third-generation cephalosporins, fluoroquinolones and gentamicin. These findings underscore the need for additional tools to combat these problem pathogens.

Options Old and New

Dr. Low also described the trends of microbial resistance in nosocomial infections. He identified the most problematic pathogens as Enterobacteriaceae, P. aeruginosa, Acinetobacter spp., MRSA, VRE and Bacteroides spp. Some of the therapies Dr. Low discussed combine the use of old and new antimicrobial agents in the treatment of multidrug-resistant organisms. Polymyxins, such as colistin, are an example of more conventional therapies that are being used to combat problem pathogens. Polymyxins target the bacterial cell membrane, and in patients are primarily excreted through renal clearance. Colistin in particular is known to be active against Acinetobacter spp., P. aeruginosa and Enterobacteriaceae. Adverse effects of colistin therapy include nephrotoxicity and neurotoxicity.

According to Dr. Low, new agents, such as ertapenem and tigecycline, have less associated toxicity. A member of the carbapenem class, ertapenem has demonstrated excellent clinical efficacy for approved indications and does not have a known potential for treatment interactions. It allows for once-daily dosing and has a low toxicity profile. However, it is not indicated for the treatment of P. aeruginosa. Tigecycline may be recommended as a single agent therapy for indications such as skin and intra-abdominal infections, pneumonia and resistant organisms. The therapy was developed as a broad-spectrum antibiotic, and has been shown to have limited side effects in phase III data.