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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.

16th European Congress of Clinical Microbiology and Infectious Diseases

Nice, France / April 1-4, 2006

Methicillin-resistant Staphylococcus aureus (MRSA) is among the most important pathogens acquired in the hospital environment today, giving rise to severe, hospital-based infections including complicated skin and soft-tissue infections, nosocomial pneumonia and catheter-related infections. As discussed by Dr. Gary French, Professor of Microbiology, Kings College, London, UK, and Dr. Kamal Itani, Professor of Surgery, Boston University, Massachusetts, in the absence of stringent infection control strategies, MRSA can be readily transferred from patient to patient. Controlling transmission is difficult, even under ideal conditions, because frequent ward and hospital transfers constantly reintroduce resistant organisms. Prevalence rates vary widely from country to country and even from hospital to hospital. Nonetheless, they continue to climb, and rates in the US, southern Europe, Ireland and the UK are high, at least compared to Scandinavian countries, where MSRA rates are among the lowest in the world.

MRSA prevalence rates in Canada range between 5% and 20% and are typically higher in major metropolitan areas, although not necessarily higher in major teaching hospitals. Reasons for the rise in methicillin-resistant organisms are likely legion and complex but some evidence suggests that overuse of the fluoroquinolones contributes to the development of MRSA.

Vancomycin-resistant Enterococcus (VRE) represents another important hospital-acquired infection, ranking next to MRSA as a major clinical challenge in infectious disease control, and many suspect that widespread use of the third-generation cephalosporins selects out Enterococci that become resistant to vancomycin.

Gram-negative bacteria can, in turn, procure resistance more readily than gram-positive bacteria and they are more promiscuous, as noted by Dr. Timothy Walsh, Reader in Medical Microbiology, University of Bristol, UK. Therefore, it is not surprising that multi-treatment resistance has steadily increased among gram-negative bacteria in the past 10 years, especially among Acinetobacter sp., dubbed the new “superbug,” as resistance to carbapenems is growing and mortality due to these infections is high. Increasing proportions of Pseudomonas aeruginosa and the extended-spectrum beta-lactamase (ESBL)-producing organisms, among them the Enterobacter species (E. coli) and Klebsiella pneumoniae, are also acquiring resistance to multiple antibiotics.

“Perhaps due to the ease of international travel, gram-negative antimicrobial resistance must be considered a global issue,” Dr. Walsh cautioned. “Resistance is also likely to escalate and this highlights the critical need for new and innovative molecules to combat gram-negative resistance.” Factors that contribute to antibiotic resistance and spread in hospitals are predictable and include the greater severity of illness among hospitalized patients, newer devices and procedures now in use and ineffective infection control and isolation practices.

However, it is indisputable that increased use of antimicrobial prophylaxis, polyantimicrobial therapy and high antimicrobial use in the intensive care unit are driving the rise in antibiotic resistance seen in hospitals around the world. It thus follows that judicious use of antibiotics can help curtail development of resistance, as once resistance appears, it will decline slowly, if at all. As emphasized by Dr. Mark Wilcox, Professor of Medical Microbiology, University of Leeds, UK, physicians should show a decided preference for the use of a single antibiotic over combination therapy, as there is no evidence that two antibiotics are better than one, even in the most critical of infections, and some evidence exists that clinical failure is more common with combination therapy, at least in studies comparing different beta-lactams, he noted. “Inadequate initial antimicrobial therapy is also associated with a worse outcome,” Dr. Wilcox observed, with all studies showing that mortality essentially doubles if the initial antimicrobial choice is incorrect.

Several studies have also demonstrated that cycling of antimicrobials did not result in a significant change in the acquisition of resistant gram-negative organisms, “so we should mix antibiotics; the more choices we have, the better, because we reduce the selective pressure for resistance that rotation can cause,” Dr. Wilcox told delegates.

Dr. David Jay Weber, Professor of Medicine, Pediatrics and Epidemiology, University of North Carolina, Chapel Hill, reminded physicians that good hand hygiene, preferably with waterless products, surveillance and contact precautions—including the use of gloves when entering the hospital room, gowns when coming in close contact with patients or the environment and environmental disinfection—can all help improve infection control and lessen the likelihood that hospital-based pathogens will be spread to other patients.

Targets of Resistance

Most antimicrobial compounds currently under development are designed to target resistant gram-positive infections, as noted by Dr. Jean Carlet, Department Chair, Service de réanimation polyvalente, Fondation Hôpital Saint-Joseph, Paris, France. However, a wide array of in vitro and several pivotal in vivo studies presented here during the scientific sessions indicate that tigecycline, a first-in-class glycylcycline, has excellent activity against a wide range of gram-positive and gram-negative organisms, including MDR pathogens and atypicals.

As reported by researchers affiliated with International Health Management Associates, Schaumburg, Illinois, in vitro results showed that tigecycline may be used to treat a wide range of serious nosocomial infections. A summary of the glycylcycline’s performance follows:

• Inhibited 96% of all study strains of Enterobacteriaceae.

• At an MIC90 of 1 mcg/mL, it was equivalent to imipenem and cefepime against all Enterobacteriaceae and eight- to 64-fold lower than other comparator antimicrobials.

• Potent in vitro activity against many different resistant phenotypes of Enterobacteriaceae.

• Inhibited 99% of all ESBL-producing E. coli, 90% of K. pneumoniae and 92% of K. oxytoca.

• Had the lowest MIC90 against A. baumannii among the broad-spectrum antimicrobials tested.

• Inhibited the growth of 99% of all S. aureus at an activity level comparable to linezolid and vancomycin.

• Comparable activity against MRSA as linezolid and vancomycin and greater activity than levofloxacin, imipenem and the beta-lactams.

• Potent in vitro activity against VRE, inhibiting 100% of strains at MIC90 £0.25 mcg/mL.

• Significantly lower MIC90 against vancomycin-resistant E. faecium than linezolid.

• Had the lowest MIC90 of all study agents against all strains of Acinetobacter (eight- to 64-fold lower than imipenem, levofloxacin and cefepime).

• Inhibited >97% of all MDR Acinetobacter strains.

• Remained highly active against most tetracycline- resistant isolates.

• Minimal activity against Proteus sp. and P. aeruginosa.

Complicated Infections

The promising results achieved on in vitro testing may translate well in the setting of complicated intra-abdominal or complicated skin and skin structure infections, where tigecycline may be used as monotherapy. As presented by Dr. Evelyn Ellis-Grosse, Collegeville, Pennsylvania, the glycylcycline and active comparator data were pooled from four phase III studies in complicated skin and skin structure infections or in complicated intra-abdominal infections. In complicated skin infections, patients received either tigecycline intravenously (i.v.) at a loading dose of 100 mg, then 50 mg every 12 hours or vancomycin/aztreonam i.v. at a dose of 1 g/2 g every 12 hours, up to 14 days. In intra-abdominal infections, patients received the same dose of tigecycline or imipenem/cilastatin i.v. at a dose of 200 mg to 500 mg, based on body weight and calculated creatinine clearance, every six hours for up to 14 days.

Among patients with skin infections, clinical cure rates at the test of cure assessment in all clinically evaluable patients were 86.5% in the monotherapy group vs. 88.6% in the combination cohort. In clinically evaluable patients with baseline bacteremia, clinical cure rates were 82.6% and 87.5% for the monotherapy and combination cohorts, respectively. In intra-abdominal infections, clinical cure rates at time of cure assessment were 86.1% and 86.3%, respectively. In microbiologically evaluable patients with baseline bacteremia, clinical cure rates were similar, at 82.5% in the tigecycline arm and 80% in the imipenem/cilastatin cohort.

Nausea and vomiting were more frequent with monotherapy compared with the combination therapy but other adverse events, along with discontinuation rates, were comparable between the two groups in the skin infection studies. “No strains developed tigecycline resistance on therapy,” investigators added, “and results support the hypothesis that tigecycline may play an important role in the empiric treatment of these hospitalized patients with bacteremia.”

Reporting on the European experience in the treatment of complicated intra-abdominal infections, Dr. R. Maroko, Collegeville, corroborated results from the pooled analysis of the four studies. “Nearly all intra-abdominal infections are caused by multiple micro-organisms that comprise the intestinal flora: aerobes and facultative and obligate anerobes, with Enterobacteriaceae [e.g. Escherichia coli, K. pneumoniae], Enterococci and Bacteroides fragillis being isolated most frequently,” he observed, “and inappropriate antimicrobial therapy may delay clinical resolution and increase hospital stay and risk of mortality.”

The main objective of these two studies was to demonstrate non-inferiority of tigecycline compared with imipenem/cilastatin in hospitalized patients with complicated intra-abdominal infections. Study protocols were the same as those detailed in the pooled analysis of the four studies. In the modified, intent-to-treat population, investigators reported that on the last day of therapy, cure was achieved in 91.4% of those receiving monotherapy and in 90.2% of the combination group. Some 7.8% of the former group were classified as failures, as were 9% of the comparator group, and a minority in each treatment arm was considered indeterminate. The incidence of nausea and vomiting were slightly higher in the former group but incidence rates were still low. “This large, pooled, multi-country analysis demonstrated that tigecycline is a safe and well-tolerated option for the treatment of hospital patients with complicated intra-abdominal infections and is non-inferior to the comparator imipenem/cilastatin,” investigators concluded.

A similar conclusion was reached by researchers involved in the European trials observing tigecycline and vancomycin/aztreonam in the treatment of complicated skin and skin structure infections. “The primary efficacy time point was test-of-cure visit 12 to 92 days after the last dose,” investigators under lead author Dr. Nathalie Dartois, Paris, noted. Cure was defined as resolution of signs and symptoms such that no further antibiotic therapy was required. Based on the modified intent-to-treat population, cure was achieved in 84.1% of the monotherapy group vs. 88.2% of the combination group. Equal percentages of patients failed therapy (9% in each treatment arm) and roughly equal numbers of patients at approximately 2% were classified as indeterminate in both arms.

Nausea was significantly more frequent in the glycylcycline arm at 17% vs. 3.2% in the comparator arm, but otherwise, the adverse-event profile was minimal in both arms and relatively comparable. Researchers noted that treatment interruptions and discontinuations, largely associated with nausea and vomiting, were infrequent in the monotherapy program and that overall, discontinuations among patients receiving the glycylcycline have been comparable to rates in the comparator arms. “This analysis demonstrated that the clinical efficacy of 50 mg of tigecycline, as a single agent infused every 12 hours [after an initial loading dose of 100 mg], is non-inferior to the combination antibiotic regimen of 1g/2g vancomycin/aztreonam infused every 12 hours in the treatment of hospitalized patients with complicated skin and skin structure infections,” investigators concluded.

Questions and Answers

The following question-and-answer section is based on an interview with Dr. Daryl Hoban, Professor of Medical Microbiology and Infectious Disease, University of Manitoba and Clinical Microbiologist, Diagnostic Services of Manitoba, Health Sciences Centre, Winnipeg. Q: As reported by the group from Ireland [Oza et al. Abstract 1011], there are suggestions that MRSA infections are associated with a higher mortality risk than MSSA [methicillin-susceptible S. aureus] infections. Do MRSA organisms differ from MSSA organisms in any way that might explain this?

A: MRSA are typically not more virulent than MSSA, so no, MRSA typically do not possess extra virulence factors than MSSA. What happens, though, is that patients in hospital acquire MRSA and then it usually takes longer to treat them; they require high-powered therapy and invariably stay in hospital longer. Unfortunately, the longer you stay in hospital, the greater the likelihood of increased morbidity and mortality, so length of hospital stay is a huge risk factor for poor outcomes and increased likelihood of acquiring MRSA. Patients who are admitted to hospital are also more at risk for adverse events—they are usually older and sicker—and they have probably been on antibiotics previously. So when you come into hospital, you are being set up for hospital-acquired pathogens and unfortunately, that usually means resistant pathogens.

Q: What agents do we currently use to treat MRSA infections and how active are they?

A: The main agents for MRSA infections are invariably parenteral agents, so you are using linezolid, daptomycin, vancomycin and related compounds. Actually, you can take vancomycin orally but these are all agents we do not want to use very often: they are expensive; some of them are problematic to administer; and there are also some adverse events, so we only use them when we really have a problem with patients in hospital. From a public health perspective, we need to keep our MRSA rates as low as possible, so we do not have to switch to these more powerful agents.

Q: How do you perceive tigecycline as another option for the treatment of complicated intra-abdominal and skin/skin structure infections?

A: My opinion is that we have so few new antibiotics coming to the market now, either in oral or i.v. formulations, that are both safe and effective that we should welcome any new treatment that comes along. It is not going to be inexpensive and it may not be used first-line, but it is nice to see that we will have an alternative. One advantage to having tigecycline for these infections is that it can be used as monotherapy. Typically, when patients come into hospital, they usually go on combination therapy, usually with expensive carbapenems and expensive beta-lactams, which affects body flora and which select for resistance. So if we can get away with using a compound as monotherapy, either empirically or as directed therapy later on, all the better.