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 - 20th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

Vienna, Austria / April 10-13, 2010

Infections caused by both gram-negative and -positive bacteria represent a major disease burden worldwide. In the case of pneumococcal infections, the estimated incidence of invasive disease is 15 to 20 cases per 100,000 population and mortality ranges from 7% to 28% for respiratory infection. Evidence that resistance to traditional agents used to treat these infections has been emerging. For example, the Canadian Bacterial Surveillance Network reported an increase in b-lactam-resistant strains of Streptococcus pneumoniae from 0.9% in 1993 to 8.3% in 2009. For macrolides, increase has been more significant—from 1.9% in 1993 to 22.4% in 2007.

Treating MRSA Infections

In S. pneumoniae respiratory infections, the development of fluoroquinolones such as levofloxacin and, more recently, moxifloxacin has been important. These agents are potent and extremely useful when used appropriately and surveillance suggests that resistance currently remains low and stable, despite widespread use. However, overuse is associated with increased incidence of Clostridium difficile and methicillin-resistant Staphylococcus aureus (MRSA) infections. Consequently, many institutions now have antimicrobial stewardship programs in place to ensure that antibiotics are used in such a way as to slow the emergence of resistance (and to prevent patients from being exposed to unnecessary treatments and reduce costs). “MRSA is a significant contributor to all types of pneumonia, from 9% for community-acquired pneumonia to almost 15% for ventilator-acquired pneumonia,” remarked Dr. Emilio Bouza, Gregorio Marañón University General Hospital, Madrid, Spain. Moreover, mortality in these cases is high, especially in cases of inappropriate treatment. In particular, a delay in initiating therapy may have detrimental effects on outcome. In cases of nosocomial pneumonia, most guidelines recommend empirical therapy with vancomycin or linezolid. “Vancomycin remains a standard of care and is widely used,” confirmed Dr. Bouza, “but the results are often far from ideal.” Bacterial killing is slow, penetration into the alveolar lining fluid is poor, and there is concern about increasing minimum inhibitory concentrations (MICs) in isolates, the so-called vancomycin MIC creep. In the case of linezolid, there have been relatively few reports of loss of susceptibility.

Skin and Soft-tissue Infections and the Threat of Community-acquired MRSA

Skin and soft-tissue infections (SSTIs) are generally classed as either complicated or uncomplicated. For uncomplicated infections, surgical incision and drainage is usually sufficient, while complicated infections usually also require antibiotic therapy for successful resolution. According to Dr. Matteo Bassetti, San Martino Teaching Hospital, Genoa, Italy, “It is important to define the type of MRSA because when we discuss treatment approaches, this will have a bearing.” Thus, health care-associated (HA)-MRSA, in which the patient generally has a history of prior hospital procedures, is differentiated from community-acquired (CA)-MRSA, which is thought to be endemic in the US. It differs from HA-MRSA in the age of the patients (CA-MRSA usually affects younger patients) and the site of infection (CA-MRSA mainly involves the skin). CA-MRSA is usually virulent, an observation linked to the expression of panton-valentine leukocidin (PVL). This cytotoxin is associated with necrotic lesions in skin infections. “It is interesting to note that linezolid and clindamycin decrease PVL production, oxacillin increases PVL, while vancomycin has no effect; this is important information for treatment decisions,” Dr. Bassetti told delegates.

As in respiratory infections, the two most widely used agents for MRSA SSTIs are linezolid and vancomycin, while other options include daptomycin and tigecycline. In hospitalized patients, vancomycin is the first choice for treating MRSA while linezolid, daptomycin and tigecycline should be administered to patients who are unresponsive to or intolerant of vancomycin (Breen JO. Am Fam Physician 2010;81(7):893-9). In one study comparing linezolid and vancomycin, no difference was found in clinical and microbiological cure (Itani et al. Am J Surg 2010 Mar 12. Epub ahead of print). “What was interesting, though,” observed Dr. Bassetti, “was the duration of intravenous [i.v.] therapy [5.6 days for linezolid vs. 10.4 days for vancomycin], which was lower among patients treated with linezolid because you can switch from i.v. to oral therapy.”

Cost-Effectiveness

The shorter duration of i.v. therapy with linezolid shortens hospital stays and facilitates out-of-hospital patient management. A switch from i.v. to oral therapy is only possible if a good oral agent is available, as is the case for linezolid. “This reduction in the duration of i.v. therapy opens up the possibility of reducing the number of days in hospital,” explained Dr. Andrew Seaton, Gartnavel General Hospital, Glasgow, UK. This can represent considerable savings as one of the main cost drivers in these patients is hospital stay. Indeed, in one Canadian study, hospitalization accounted for 81% of total cost compared to only 4% for antimicrobial therapy (Goetghebeur et al. Can J Infect Dis Med Microbiol 2007;18(1):27-34).

In some cases oral therapy may not be possible, either because an appropriate oral agent is not available or due to repeated vomiting or other conditions. In these situations, another possibility discussed by Dr. Seaton was outpatient parenteral antibiotic therapy (OPAT). This modality can ensure good compliance but it requires an infrastructure and the i.v. access has the inherent risk of a line infection. “OPAT is also more costly than a tablet, so we transfer some of the hospital savings into the community,” Dr. Seaton noted.

Broad Antibacterial Activity

Besides being active against many species such as Enterococcus spp., Streptococcus spp. and Klebsiella spp., tigecycline is also active against Staphylococcus spp. (including both methicillin-susceptible SA and MRSA). “Given this broad spectrum of activity, it is well suited to treat mixed infections,” stated Dr. Bassetti.

A further benefit is that it is stable against mechanisms of tetracycline resistance through increased binding affinity to tetracycline-resistant ribosomes and inhibition of efflux determinants, as discussed by Dr. David Farrell, JMI Laboratories, North Liberty, Iowa. As part of the European SENTRY Antimicrobial Surveillance Program, 24 medical centres from 11 European countries forwarded over 5500 isolates for susceptibility testing. Most Enterococcus spp. (96.4%) and all b-hemolytic streptococci were susceptible (MIC =0.25 mg/mL). Activity was also good against species such as extended-spectrum b-lactamase-producing Enterobacteriaceae.

Summary

Antibacterial resistance is a continuous threat in many settings. Gram-negative bacteria have developed resistance to some of the most widely used antibiotics. For tigecycline, the emergence of resistance has so far been limited. In the treatment of respiratory infections, fluoroquinolones have retained activity against their target bacteria but the emergence of MRSA and C. difficile is associated with misuse. For MRSA infections themselves, linezolid and vancomycin are widely used, although there are some indications of emerging resistance to vancomycin.