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.

PRIORITY PRESS - 19th European Congress of Clinical Microbiology (ECCMID)

Helsinki, Finland / May 16-19, 2009

The emergence of resistant microorganisms worldwide represents a major challenge for the medical community that calls for a concerted effort by all involved to rein in inappropriate antimicrobial use. According to Dr. Roman Kozlov, Director, Institute of Antimicrobial Chemotherapy, Smolensk State Medical Academy, Russian Federation, “Antimicrobial resistance is the greatest threat to a nation’s security in the opinion of many, and a potential post-antibiotic era is threatening present and future medical advances in the treatment of infectious diseases.” Speakers here concurred that the solution will not be forthcoming from new drug development in the foreseeable future. “Everyone who is involved in prescribing antibiotics needs to become involved in antimicrobial stewardship,” Dr. Kozlov added.

Evaluating Appropriate Antibiotic Use

The two cornerstones of antimicrobial stewardship are prospective audit of antimicrobial use and formulary restriction. For example, at the Amphia Hospital in The Netherlands—where antimicrobial use is already very low—prevalence surveys of nosocomial infections have been carried out since 1990 and documentation of antimicrobial use since 2001. In determining the appropriateness of antimicrobial use, data were analyzed from six separate prevalence surveys involving 4105 patients, 938 of whom were on antimicrobial therapy. Using a scoring system developed to determine whether therapy was appropriate, researchers determined that 351 patients (37.4%) were treated inappropriately: 13% unjustifiably, 15% incorrectly and in 10%, the antibiotic was correctly chosen but incorrectly used.

By multivariate analyses, “Use of the quinolones was the only statistically significant factor associated with inappropriate use,” observed Dr. Jan Kluytmans, Professor of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, “and when patients in orthopedic surgery, urology or neurology were treated with quinolones, more than 75% of the time such therapy was inappropriate.”

The same hospital then targeted quinolone use using a variety of interventions including, critically, education of hospital prescribers. Not only did each successive intervention result in a significant reduction in quinolone use in the hospital, “but we saw a reduction in Escherichia coli resistance as well, and I think this is a strong indication that our goals can be achieved, especially with the quinolones,” Dr. Kluytmans concluded.

Decreasing Antibiotic Resistance

Other practical strategies that infectious disease experts may advocate in their role of “antimicrobial watchdog” is to ensure that the fewest number of agents are used as initial therapy. As noted by Dr. Lance Peterson, Professor of Pathology and Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, replacing two or three antimicrobials with one broad-spectrum agent exposes bacteria to one-third to one-half less antibiotic, thereby decreasing selection pressure for resistance. “We also must re-evaluate the initial treatment when culture results are available and no later than the third day of treatment,” he added, “and treat for the shortest effective time to obtain a successful outcome.”

Dr. Peterson also reminded delegates that the literature does not support the use of combination therapy, with no benefit vs. monotherapy reported in either sepsis, endocarditis or neutropenia. “There is a need to consider novel antibiotic prescribing programs to reduce progression of antimicrobial resistance,” he concluded, “and to consider new agents in a ‘care bundle’ for practical implementation of an antimicrobial stewardship program.”

A Canadian Surveillance Program

In vitro studies indicate that the new glycylcycline antibacterial tigecycline is highly active against virtually every species, including resistant species, with the exception of Pseudomonas aeruginosa.

The Tigecycline Evaluation Surveillance Trial (T.E.S.T.) was carried out in Canada between 2004 and 2008, during which 2578 isolates were collected from 25 participating sites. Results showed that the agent’s MIC₉₀ of 1 mg/L was comparable to imipemen’s MIC₉₀ of 0.5 mg/L and was four- to 64-fold better than the ß-lactam/ß-lactam inhibitor combinations and levofloxacin against all Enterobacteriaceae tested. “Tigecycline also demonstrated excellent in vitro activity against extended-spectrum-ß-lactamase (ESBL) and non-ESBL-producing E. coli, Klebsiella oxytoca and K. pneumoniae with MIC₉₀ of 1 mg/L,” investigators added. “Potent activity” was also seen against Staphylococcus aureus and S. pneumoniae regardless of the phenotype tested.

The glycylcycline also demonstrated a very low MIC₉₀ (0.5 mg/L) against Haemophilus influenzae and was unaffected by the presence of ß-lactamase. Importantly, given the presence of vancomycin-resistant enterococci (VRE) in many parts of the world, it also had the lowest MIC₉₀ value of all the comparator agents against vancomycin-sensitive and vancomycin-resistant Enterococcus faecium and E. faecalis.

Commenting on the T.E.S.T. data, Jack Johnson, International Health Management Associates (IHMA) of Schaumburg, Illinois, where all the in vitro test results were carried out, noted that the most significant finding was the drug’s activity against methicillin-resistant S. aureus (MRSA) organisms. While MRSA rates are not high in Canada, he suggested that “if it happens, then a drug like tigecycline provides a real option.” This would also be the case in the event of carbapenem-resistant Acinetobacter activity.

Concurrent Evidence from European Surveillance

Further data generated by the IHMA group from selected clinical isolates from 320 centres in Europe showed that tigecycline’s MIC₉₀ of 1 mg/L against all Enterobacteriaceae tested was equivalent to imipenem and eight- to 64-fold better than ß-lactam/ß-lactam inhibitor combinations and levofloxacin. Perhaps not surprisingly, its activity against European clinical isolates coincided closely with that seen in the Canadian T.E.S.T. program; activity was again unaffected by methicillin-resistant phenotype, penicillin resistance in S. pneumoniae or the presence of ß-lactamase in H. influenzae.

“The in vitro activity of this drug looks very good against a lot of resistant pathogens and while it should be emphasized this is in vitro, not in vivo data, it does suggest that tigecycline is a promising compound in the treatment of serious infections caused by the most commonly encountered community and nosocomial pathogens,” Robert Badal, IHMA, told delegates.

Outbreaks of Clostridium difficile have occurred in Canada and while usually responsive to traditional agents, this is not always the case. Using 258 European isolates, tigecycline was compared to agents often used to treat C. difficile including clindamycin, meropenem, metronidazole, penicillin and piperacillin/tazobactam. Results showed that it had the lowest MIC₉₀ of the five agents tested (0.06/0.25 mg/dL), suggesting that if traditional agents such as metronidazole fail, physicians would have another option.

From in vitro to Real-world Experience

Recently, tigecycline was approved for the treatment of community-acquired pneumonia (CAP) based partly on its excellent in vitro activity against pathogens normally involved in CAP. In an assessment of its worldwide activity against community-acquired respiratory tract infections, over 9200 clinical isolates were tested between 2006 and 2008.

As reported by Douglas Biedenbach, JMI Laboratories, North Liberty, Iowa, and colleagues, 100% of both methicillin-susceptible and MRSA isolates proved susceptible to the agent, virtually all isolates at an MIC90 of <u><</u>0.25 mg/L. All S. aureus isolates tested in the same worldwide assessment were also susceptible to the agent at established breakpoints of <u><</u>0.5 mg/L. Researchers stressed that in vitro activity does not necessarily translate into clinical activity. Consequently, evidence supporting the clinical efficacy of tigecycline is paramount.

A pooled analysis of eight phase III clinical trials involving patients with secondary bacteremia from complicated intra-abdominal infections, complicated skin and skin structure infections and CAP showed that 76.6% who were treated with tigecycline achieved a clinical cure rate compared with 77.1% of comparator controls. Gastrointestinal side effects were more common with tigecycline and cough and phlebitis were more common in the comparator arm.

“Regardless of the primary site of disease or the infecting pathogen, tigecycline’s clinical efficacy was similar to comparators and without a demonstrable difference in failure rates across susceptible MICs as defined by the FDA,” investigators concluded.