Resistance among Streptococcus pneumoniae: Implications for Drug Selection

Peter C. Appelbaum () 0 0 Departments of Pathology and Clinical Microbiology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine , Hershey Streptococcus pneumoniae is an important pathogen in many community-acquired respiratory infections in the United States and a leading cause of morbidity and mortality worldwide. Unfortunately, S. pneumoniae is becoming increasingly resistant to a variety of antibiotics. Results of recent surveillance studies in the United States show that the prevalence of penicillin-nonsusceptible S. pneumoniae ranges from 25% to 150%, and rates of macrolide resistance among pneumococci are reported to be as high as 31%. A high prevalence of resistance to other antimicrobial classes is found among penicillin-resistant strains. Newer quinolones (e.g., gatifloxacin, gemifloxacin, and moxifloxacin) that have better antipneumococcal activity in vitro are the most active agents and therefore are attractive options for treatment of adults with community-acquired respiratory infections. Efforts should be made to prevent pneumococcal infections in high-risk patients through vaccination. - EPIDEMIOLOGY OF DRUG-RESISTANT S. PNEUMONIAE The worldwide spread of resistant pneumococci is thought to be related to the spread of a few highly resistant clones, such as serotypes 6B, 19F, and 23F [7, 8]. Population-based active surveillance surveys capture data from as many laboratories as possible within a given community; however, these findings may be more representative of the communities studied than of the world. Penicillin resistance among S. pneumoniae. The current National Committee for Clinical Laboratory Standards (NCCLS) [9] interpretive MIC breakpoints for penicillin are 0.06 mg/mL (susceptible), 0.121.0 mg/mL (intermediate), and 2.0 mg/mL (resistant). Isolates classified as either intermediately resistant or resistant are considered to be nonsusceptible. Breakpoints for amoxicillin, with or without clavulanate, are 2.0 mg/mL (susceptible), 4.0 mg/mL (intermediate), and 8.0 mg/mL (resistant). Breakpoints for individual oral cephalosporins are not identical, and some cephalosporins (e.g., cefixime) do not have specific NCCLS breakpoints. For cefdinir and cefpodoxime, the breakpoints are 0.5 mg/mL (susceptible), 1.0 mg/mL (intermediate), and 2.0 mg/mL (resistant). For cefaclor and cefuroxime axetil, the breakpoints are higher: !1.0 mg/mL (susceptible), 2.0 mg/mL (intermediate), and 4.0 mg/mL (resistant). The breakpoints for cefprozil and loracarbef are 2.0 mg/mL (susceptible), 4.0 mg/mL (intermediate), and 8.0 mg/mL (resistant). After the report of a resistant pneumococcal isolate in Australia [1], reports of penicillin-resistant pneumococci were sporadic until the late 1970s, when numerous isolates resistant to penicillin (MICs, 14 mg/mL) were identified in South Africa [2, 10]. Many of these strains were resistant to b-lactams, macrolides, tetracycline, chloramphenicol, and clindamycin [11]. In the late 1980s, the prevalence of penicillin-nonsusceptible S. pneumoniae in the United States was 4.0% [12], but, in less than a single decade, it increased to 25% [13, 14]. Of interest was the increase in intermediate-level penicillin resistance, from 3.8% during 19871988 [12] to 18% in 1994 [14]. Results of recent surveillance studies in the United States show that the prevalence of penicillin-nonsusceptible S. pneumoniae ranges from 25% to 150%, and intermediate-level resistance ranges from 11% to 28% (table 2) [1519]. In some parts of the world, rates of resistance are even higher (table 1). Resistance of S. pneumoniae to other antimicrobials. As the use of nonpenicillin antimicrobials has increased, so has the development of resistance to these agents among pneumococci. However, rates of pneumococcal resistance to the quinolones are relatively low (typically !0.5%) [16, 18, 19]. Recent data from the Canadian Bacterial Surveillance Network show that the prevalence of pneumococcal isolates with ciprofloxacin MICs of 4 mg/mL may be on the rise (the rate was 0% in 1993 and 1.7% in 1997), coincident with increased use of ciprofloxacin to treat adults in Canada [20]. In addition, increasing resistance to quinolones has been documented in Hong Kong and in Barcelona, Spain [21, 22]. Older quinolones (e.g., ciprofloxacin and ofloxacin) that have MICs of 1.04.0 mg/mL are considered to have poor in vitro activity against pneumococci. Levofloxacin (the l-isomer of ofloxacin) has better activity, and the newer quinolones (e.g., gatifloxacin, gemifloxacin, and moxifloxacin) have much better in vitro activity, with lower MICs and better pharmacodynamics for activity against S. pneumoniae; they can be effective in treatment of community-acquired pneumococcal respiratory tract infections, such as acute bacterial sinusitis, acute exacerbations of chronic bronchitis, and pneumonia [2325]. Resistance of S. pneumoniae to the macrolides and azalides (e.g., clarithromycin, erythromycin, and azithromycin) has been increasing since the late 1980s. In the United States, 0.2% of S. pneumoniae were resistant to macrolides in 1988 [12]. This increased to 6.4% in 1992, 10.6% in 1995, 13.9% in 1996, and 20.4% in 1999 [26, 27]. In recent US surveillance studies, rates of macrolide resistance among the pneumococci have been reported to be as high as 31% (table 3) [14, 16, 18, 28]. There also have been recent reports of clinical failure of macrolide treatment for infections caused by S. pneumoniae [29, 30]. Penicillin-resistant pneumococci also are resistant to trimethoprim-sulfamethoxazole (20%35.9%) and tetracycline (8%16.6%) [14, 17]. Resistance to vancomycin, both in vitro and in vivo, has been described in pneumococcal strains. How Geographic area North America Canada United States Latin America Brazil Colombia Argentina Prevalence of nonsusceptibility,a % of isolates NOTE. Data are from the SENTRY Antimicrobial Surveillance Program and the Alexander Project (adapted from [5], with permission; additional data from [3]). a Either intermediate-level (MIC, 0.121 mg/mL) or high-level (MIC, 2.0 mg/mL) resistance. ever, it is doubtful that these findings are clinically relevant (table 3) [3133]. Most strains of S. pneumoniae still are highly susceptible to rifampin, although this drug is not commonly used in the United States to treat pneumococcal infections. Multidrug resistance. Pneumococci resistant to 3 separate classes of antibiotics are considered to be multiply resistant. The reasons that pneumococci develop simultaneous resistance to several antimicrobial classes are not clear, but some resistance determinants are carried together on the same transposon. Multiply resistant pneumococci that are resistant to penicillin, tetracycline, erythromycin, clindamycin, trimethoprimsulfamethoxazole, and chloramphenicol were first described in South Africa [34]. Today, isolation of multiply resistant pneumococci from both adults and children has b (...truncated)