Chapter 128. Pneumococcal Infections (Part 6) Pneumococcal Infections: Treatment Antibiotic Susceptibility β-Lactam antibiotics, the cornerstone of therapy for serious pneumococcal infection, bind covalently to the active site and thereby block the action of enzymes (endo-, trans-, and carboxypeptidases) needed for cell-wall synthesis. Because these enzymes were identified by their reaction with radiolabeled penicillin, they are called penicillin-binding proteins. Until the late 1970s, virtually all clinical isolates of S. pneumoniae were susceptible to penicillin (i.e., were inhibited in vitro by concentrations of <0.06 µg/mL). Since then, an increasing number of isolates have shown some degree of resistance to penicillin. Resistance results when spontaneous mutation or acquisition of new genetic material alters penicillin-binding proteins in a manner that reduces their affinity for penicillin, thereby necessitating a higher concentration of penicillin for their saturation. The genetic information that renders pneumococci resistant to penicillin is acquired from oral streptococci and is transmitted along with genes that convey resistance to other antibiotics as well. Selection of antibiotic-resistant strains worldwide—especially in countries where antibiotics are available without prescription and in loci of high antibiotic use, such as day-care centers—greatly contributes to the prevalence of multidrug resistance. At present, ~20% of pneumococcal isolates in the United States exhibit intermediate resistance to penicillin [minimal inhibitory concentration (MIC) 0.1– 1.0 μg/mL], and 15% are resistant (MIC ≥2.0 μg/mL; Fig. 128-3). The rate of resistance is lower in countries that, by tradition, are conservative in their antibiotic use (e.g., Holland and Germany) and higher in countries where usage is more liberal (e.g., France). In Hong Kong and Korea, resistance rates approach 80%. These definitions of resistance, however, were based on drug levels achievable in CSF during treatment of meningitis, whereas levels reached in the bloodstream, lungs, and sinuses are actually much higher. Thus the MIC needs to be interpreted in light of the infection being treated. Pneumonia caused by a penicillin-resistant strain is likely to respond to conventional doses of β-lactam antibiotics, whereas meningitis may not. The recently revised definition of amoxicillin resistance (susceptible, MIC ≤2 µg/mL; intermediately resistant, MIC = 4 μg/mL; and resistant, MIC ≥8 μg/mL) is based on susceptibility to serum levels, with the assumption that no physician would knowingly treat meningitis with this oral medication. Pneumonia due to a pneumococcal strain with intermediate amoxicillin resistance is still likely to respond to treatment with this drug, whereas that due to a resistant strain may not. On the assumption that antibiotic concentrations in middle-ear fluid or sinus cavities approach those in serum, similar inferences can be made about the treatment of otitis or sinusitis. Figure 128-3 The e-strip method currently used by m ost laboratories to determine the susceptibility of S. pneumoniae to antibiotics. After the plate is streaked with a suspension of pneumococci, a strip impregnated with graded concentrations of the antibiotic under study (penicillin in the example shown) i s placed on the surface, and the plate is incubated overnight at 37°C. The organism on the left is inhibited by a penicillin concentration of 0.016 µg/mL and is fully susceptible to this drug. The organism on the right is inhibited only by a penicillin con centration of 0.25 µg/mL and is intermediately resistant to this agent. Penicillin-susceptible pneumococci are susceptible to all commonly used cephalosporins. Penicillin-intermediate strains tend to be resistant to all first- and many second-generation cephalosporins (of which cefuroxime retains the best efficacy), but most are susceptible to certain third-generation cephalosporins, including cefotaxime, ceftriaxone, cefepime, and the oral cefpodoxime. One-half of highly penicillin-resistant pneumococci are also resistant to cefotaxime, ceftriaxone, and cefepime, and nearly all are resistant to cefpodoxime. Just as in the case of penicillin, susceptibility to cefotaxime and ceftriaxone is defined on the basis of achievable CSF levels. Thus pneumonia caused by intermediately resistant strains (MIC = 2 µg/mL) still responds well to usual doses of these drugs, and pneumonia due to a resistant organism (MIC ≥4 µg/mL) is likely to respond. Meningitis due to intermediately resistant strains may not respond, and meningitis due to a resistant strain is likely not to respond to treatment with cefotaxime or ceftriaxone. About one-quarter of all pneumococcal isolates in the United States are resistant to erythromycin and the newer macrolides, including azithromycin and clarithromycin, with much higher rates of resistance among penicillin-resistant strains. This resistance will certainly affect empirical therapy for bronchitis, sinusitis, and pneumonia. In the United States, the majority of macrolide-resistant pneumococci bear the so-called M phenotype (erythromycin MIC = 1–8 µg/mL) and are susceptible to clindamycin. In this case, resistance is mediated by an efflux pump mechanism; to some extent, M-type resistance can be overcome by clinically achievable levels of macrolides. In Europe, most macrolide resistance is due to a mutation in ermB, which confers high-level resistance not only to macrolides but also to clindamycin; >90% of pneumococcal isolates in the United States are susceptible to clindamycin. Rates of doxycycline resistance are similar to those observed for macrolides. One-third of pneumococcal isolates are resistant to trimethoprim-sulfamethoxazole. The newer fluoroquinolones remain effective against pneumococci; the rate of resistance is generally <2–3% in the United States but is higher elsewhere and may be much higher in closed environments where these drugs are heavily prescribed, such as nursing homes and assisted- living facilities. Ketolides (such as telithromycin) appear to be uniformly effective against pneumococci, as does vancomycin. . Chapter 128. Pneumococcal Infections (Part 6) Pneumococcal Infections: Treatment Antibiotic Susceptibility β-Lactam antibiotics, the cornerstone of therapy for serious pneumococcal. >90% of pneumococcal isolates in the United States are susceptible to clindamycin. Rates of doxycycline resistance are similar to those observed for macrolides. One-third of pneumococcal. [minimal inhibitory concentration (MIC) 0.1– 1.0 μg/mL], and 15% are resistant (MIC ≥2.0 μg/mL; Fig. 128- 3). The rate of resistance is lower in countries that, by tradition, are conservative in their