Of global concern has been the increasing prevalence of antibiotic resistance among CAP pathogens. Bacteria may become resistant to an antibiotic because of a change in target site, production of antibiotic- modifying or antibiotic-inactivating enzymes, decreased penetration of the agent into the bacteria, or presence of an efflux pump. The overuse of antibiotics in humans and agriculture are 2 factors contributing to the rise in antibiotic resistance. This rise in resistance has resulted in significant changes in the management of CAP over the past decade. For example, the emergence of H. influenzae and Moraxella catarrhalis capable of producing ^-lactamase (an inactivating enzyme) has limited the use of older £-lactam antibiotics such as penicillin and amoxicillin.

Over the past decade, concern has focused on the emergence of penicillin-resistant S. pneumoniae (PRSP). The susceptibility of S. pneumoniae is currently defined by the Clinical and Laboratory Standards Institute (CLSI) (formerly the National Committee for Clinical Laboratory Standards) as follows: penicillin-susceptible, minimum inhibitory concentration (MIC) less than 0.06 pg/mL; intermediate susceptibility, MIC 0.12 to 1 pg/mL; and penicillin-resistant, MIC greater than 2 pg/mL. PRSP was first described in the 1960s and remained relatively uncommon in North America until the 1990s. Penicillin resistance in this organism is due to a gene mutation resulting in a change in the penicillin-binding proteins, enzymes in the bacterial cell membrane which are responsible for synthesis of the bacterial cell wall and which are the target sites for penicillin. Selective pressure from the overuse of penicillin and other £-lactam antibiotics is thought to have been the major contributor to the emergence of PRSP. The prevalence of PRSP in Canada was 2.5% in 1988. More recently, the prevalence of PRSP (intermediate susceptibility and resistant) ranged from 21.2% to 24% among respiratory isolates of S. pneumoniae collected between 1997 and 2003. Of particular importance has been the rise in resistant 5. pneumoniae isolates, from 2.4% in 1999 to 13.8% in 2002. In addition, the proportion of multidrug- resistant (MDR) 5. pneumoniae increased from 2.7% in 1997 to 8.8% in 2002. Strains of 5. pneumoniae resistant to antibiotics such as macrolides and fluoroquinolones have been reported globally.
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The prevalence of macrolide resistance in Canada is increasing, although its clinical impact remains to be determined. Reports of macrolide treatment failure have been published, although the number of cases remains low (because of low volume of macrolide use). The mechanism for macrolide resistance is an efflux pump (due to the mefA gene) or ribosomal methylation (due to the ermB gene) blocking the binding of macrolides to the ribosomal target site in S. pneumoniae. In North America, the mechanism of resistance is evenly divided between efflux and ribosomal methylation.

The impact of increased fluoroquinolone consumption and the emergence of fluoroquinolone-resistant S. pneumoniae in Canada have been described by Chen and others. The annual number of fluoroquinolone prescriptions increased from 0.8 to 5.5 per 100 persons between 1988 and 1997, while the prevalence of S. pneumoniae with reduced susceptibility to fluoroquinolones increased from 0% in 1993 to 1.7% in 1997/98. Not surprisingly, treatment failure in patients with CAP receiving respiratory fluoroquinolones (e.g., levofloxacin), caused by fluoroquinolone-resistant S. pneumoniae, has since been reported. The mechanism of this resistance is related to changes in S. pneumoniae DNA gyrase and topoisomerase (fluoroquinolone target sites) caused by gene mutations or by the presence of an efflux pump. These reports highlight the selective pressure of increasing use of fluoroquinolones and the selection of antibiotic resistance in S. pneumoniae. In an update on CAP management, Mandell and others expressed concern about the overuse of fluoroquinolones and the potential loss of this drug class as a treatment for pneumonia.
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