Resistance Trends

Surveillance studies conducted in the U.S. over the last decade have revealed significant levels of in vitro resistance to beta-lactams among all major respiratory pathogens. Approximately 30% of S. pneumoniae isolates are nonsuscep-tible to penicillin, and a similar proportion of H. influenzae isolates produce beta-lactamase, which mediates resistance to ampicillin (Principen, Apothecon),  (e.g., Amoxil drug, GlaxoSmithKline), and certain cephalosporins.

With S. pneumoniae, resistance to macrolides currently affects approximately 30% of isolates collected in the U.S. Modification of the drug target site and active efflux of the drug from the cell are the two main mechanisms of pneumococcal macrolide resistance. The most common form of target-site modification results from the presence of the erm(B) gene, which encodes an enzyme that methylates bacterial ribosomal RNA, whereas macrolide efflux from bacteria is mediated by the product of the mef(A) gene.

Historically, the mef(A) genotype has been associated with low-to-moderate levels of macrolide resistance, characterized by minimum inhibitory concentration (MIC) ranges of 1 to 16 mcg/ml); erm (B)-mediated resistance has been associated with higher-level resistance (MIC ranges of 64 mcg/ml or greater). However, results from the PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the US) surveillance study have demonstrated an increase in macrolide MICs among mef(A)-positive S. pneumoniae isolates (range, from 1 to more than 256 mcg/ml). These results suggest that mef(A)-positive pneumococcal strains can no longer necessarily be regarded as displaying low-level resistance to macrolides.

Data collected over four years of the PROTEKT US study (from 2000-2001 to 2003-2004) have confirmed that in the U.S., the mef(A)-mediated mechanism of macrolide resistance predominates among S. pneumoniae clinical isolates. However, the prevalence of mef(A) in macrolide-resistant isolates decreased from 68.8°% in 2000-2001 to 62.3°% in 2003-2004, whereas a concomitant increase in the proportions of isolates positive for both erm(B) and mef(A) occurred (from 9.7% in 2000-2001 to 18.4% in 2003-2004).

Of note, almost all S. pneumoniae isolates with this dual mechanism of resistance were shown to be multidrug-resistant and displayed high-level resistance to a range, including penicillin, canadian amoxicillin, tetracycline, (Pfizer), and trimethoprim-sulfamethoxazole (Bactrim, Women First).

Factors Contributing to the Development of Resistance, Carriage, and Spread

The inappropriate use of antibiotics, for example, in treating viral upper RTIs, has been identified as a major contributor to the development and spread of antibiotic resistance among respiratory pathogens. Analyses of data from national and international surveillance studies have indicated a link between increased macrolide consumption and increased rates of pneumococcal resistance to this class of antibiotics.

The use of broad-spectrum drugs (i.e., agents with activity extending beyond the common respiratory pathogens) may also increase the risk of resistance in nonrespiratory gram-negative bacteria, such as normal gastrointestinal flora. For example, the increased use of the fluoroquinolones has been associated with the emergence of resistance among gram-negative bacilli in the gastrointestinal flora, including clinically important pathogens such as Pseudomonas aeruginosa, Enterobacter agglomerans, and Escherichia coli.22,23

Differences in the pharmacokinetic and pharmacodynamic properties of antibiotics may also influence the development of resistance in bacterial pathogens. Antibiotics, such as the macrolides, with a bacteriostatic mode of activity, have a greater potential to select for resistance than agents with bactericidal activity, such as penicillins, fluoroquinolones, and ketolides. The half-life of a drug can also contribute to the selection of resistance: agents with long elimination half-lives result in prolonged exposure of bacteria to sub-inhibitory concentrations of the drug, compared with agents with shorter half-lives.

A study conducted by Kastner and Guggenbichler in 2001 compared the promotion of resistance in the oral flora of children treated with one of two macrolide antibiotics (azithro-mycin and clarithromycin), with half-lives of 60 to 70 hours and three to seven hours, respectively. Six weeks after treatment, only 33% of the patients receiving clarithromycin (e.g., Biaxin, Abbott) had macrolide-resistant isolates, compared with 87% of the patients receiving (Zithromax canadian, Pfizer).

Adequate drug concentrations at the site of infection are also important to prevent the development of resistant strains. Azithromycin achieves low concentrations in lung epithelium-lining fluid, compared with other macrolides. This not only limits its clinical utility in terms of current macrolide resistance rates; it also has important implications for the further selection of resistance.

Various patient-related risk factors are also associated with an increased risk of carriage and spread of antibiotic-resistant bacterial strains. Patients identified as being particularly at risk include the young (younger than five years of age), the elderly (older than 65 years of age), those with coexisting illness or underlying disease, and patients with immunodeficiency or human immunodeficiency virus (HIV) infection. Clonal dissemination of drug-resistant strains of bacteria may occur in children attending day care centers or in family members of a child attending day care. Among adults, rates of carriage of drug-resistant strains are highest among those who are institutionalized in hospitals, jails, and nursing homes.
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Prior antibiotic use (i.e., within the three months preceding treatment) has been identified as an important predictor of infection with drug-resistant bacterial strains. A Canadian analysis of data from 3,339 patients with invasive pneumo-coccal infections demonstrated that the single most important risk factor for resistance to beta-lactams, macrolides, fluoro-quinolones, or trimethoprim-sulfamethoxazole was the previous use of an agent from the same class. Of note, in addition to being a major risk factor for infection with macrolide-resist-ant S. pneumoniae, prior azithromycin therapy was also associated with an increased risk of infection with strains resistant to penicillin or trimethoprim-sulfamethoxazole. The results also demonstrated that infection with fluoroquinolone-resist-ant pneumococci was associated with residing in a nursing home and in acquiring pneumococcal infection in a hospital.