Antimicrobial Resistance with Streptococcus Pneumoniae in the United States

Streptococcus pneumoniae S. pneumoniae

are considered susceptible. Prior to the early 1990s in the U.S., the vast majority of clinical isolates of S. pneumoniae remained susceptible to penicillin. Despite the emergence of high rates of penicillin resistant S. pneumoniae (PRSP) in many other parts of the world, this problem remained uncommon in the U.S. A national surveillance program conducted by the Centers of Disease Control and Prevention (CDC) between 1979 and 1987, which involved 35 sentinel institutions across the country revealed annual national rates of resistance of 2 to 7% and importantly when resistance was observed, it was invariably only of the intermediate level. 2 A 15-center U.S. surveillance study in 1989 coordinated by the University of Texas Health Science Center in San Antonio and the University of Massachusetts Medical Center revealed an overall prevalence of 3.8% resistance among 847 isolates of S. pneumoniae, with only two organisms being high-level penicillin resistant. 3 By 1990-1991, however, the overall resistance rate had jumped to 17.6% with the recognition for the first time of appreciable numbers of high-level penicillin resistant strains. 4 During the past 7 years in the U.S., several more national surveillance studies have revealed an extraordinary increase in the prevalence of PRSP. [5][6][7] The most recent published study, which characterized 1601 isolates from 34 geographically diverse medical centers, conducted between November, 1997 and April, 1998, revealed an overall rate of penicillin resistance of 29.5%, with approximately 40% of nonsusceptible strains being high-level penicillin resistant. 8 In other words, roughly one decade after the problem first became manifest in the U.S., nearly one third of pneumococcal isolates are now nonsusceptible to penicillin. Few organisms have changed more rapidly with respect to antibiotic resistance than has the pneumococcus in the U.S.

Question: What is the mechanism of penicillin resistance with S. pneumoniae?
The mechanism of penicillin resistance with S. pneumoniae is alterations of the targets of penicillin action, penicillin binding proteins (PBPs). Six high molecular weight binding proteins have been identified in S. pneumoniae 1a, 1b, 2a, 2b, 2x, and 3. 9-14 Alterations in 1a, 2x, and 2b are most responsible for elevated penicillin MICs. The actual degree of change in PBPs correlates with the magnitude of penicillin MIC increase.
Alterations in PBPs result from a mosaic of changes in the chromosome of S. pneumoniae. 15 There is convincing evidence that at least some strains of PRSP originally developed resistance through interspecies transfer of transforming DNA derived from species of viridans streptococci. [16][17][18] As a group, viridans streptococci, especially S. mitis, is typically characterized by rates of penicillin resistance equivalent to, if not higher, than what is currently seen in the U.S. with S. pneumoniae. 19 Question: What is the percentage of strains of S. pneumoniae that are likely to develop penicillin resistance in the U.S. in the future and what is the degree of penicillin resistance that is likely to evolve?
Regarding this question, there is much to be learned from the experience of other countries and other parts of the world. Although insufficient information exists upon which to make precise estimates, in general, it appears that in other developed parts of the world where PRSP have existed for a much longer period of time and reached much higher prevalences than in the U.S. (e.g., parts of Spain and France), a plateauing effect seems to occur when aggregate rates of resistance reach 50 to 60%. [20][21][22] At this point, among all PRSP, perhaps half of isolates will express high-level penicillin resistance.
Regarding the degree of penicillin resistance likely to be reached among PRSP, currently in the U.S. among high-level resistant strains in large national surveillance studies, typically approximately two thirds of isolates have MICs of 2 g/mL with the vast majority of remaining resistant strains having MICs of 4 g/mL. 8 MICs of 8 are uncommon (< 1%) and organisms with MICs of Ն 16 g/mL almost unheard of in the U.S. 8 Pneumococcal isolates with MICs of 16 and 32 have been recognized in other parts of the world, but even in hot beds of PRSP, such strains remain uncommon. 23,24 There are two possible reasons for this. As noted previously, penicillin resistance with S. pneumoniae is a result of alterations in PBPs. It could be that because PBPs are actually enzymes necessary for cell wall biosynthesis, changes in PBPs sufficient to yield organisms with MICs of a magnitude of 16 to 32 g/mL are likely to be lethal mutations. A second, and not mutually exclusive possibility, is that clonal spread as has previously occurred with lower level PRSP, simply has not yet occurred with truly high-level resistant strains and as a result they occur infrequently.
Question: What does penicillin resistance with S. pneumoniae mean with respect to the activity of other ␤-lactams against this organism?
All ␤-lactam antimicrobial agents utilize at least to some extent as their targets the same PBPs in S. pneumoniae that are necessary for manifesting the antibacterial effect of penicillin. As a result, PRSP in all cases, have elevated MICs to all other ␤lactams. The actual magnitude of increase in MICs is strikingly consistent among different ␤-lactams. For example, in Table 1 are listed the MICs ob-tained with seven different ␤-lactams versus S. pneumoniae sorted according to penicillin resistance category. As can be seen, with all of the agents in this  table, MICs obtained with intermediate resistant  strains are consistently 8-to 16-fold higher than  those obtained with penicillin-susceptible strains. Another fourfold increase in MICs is observed as organisms become high-level penicillin resistant. The relative change in MICs is constant irrespective of the ␤-lactam. What differs is the intrinsic activity of various ␤-lactams for S. pneumoniae in the first place. Agents such as cefotaxime and ceftriaxone are significantly more active than agents such as cefazolin and cefaclor, and as a result their MICs are lower, not only for penicillin-susceptible strains, but also for penicillin-intermediate and penicillinresistant strains.
An even more conspicuous way of depicting this relationship is to compare MICs obtained with penicillin and other beta-lactam antimicrobial agents on a strain-by-strain basis (Fig. 1). 25 The absolutely linear relationship between the activity of penicillin and cefuroxime depicted in Figure 1 was also observed when penicillin MICs were compared to those obtained with amoxicillin, amoxicillinclavulanate, cefaclor, loracarbef, cefprozil, cefixime, cefpodoxime, and ceftriaxone. 25 In other words, there exists near complete cross-resistance among beta-lactams with respect to their activity versus S. pneumoniae.

Question: What is the clinical relevance of penicillin resistance with Streptococcus pneumoniae?
A comprehensive and insightful review of this question has recently been published by Kaplan and Mason. 26 This is an issue that has prompted lively debate and as is usually the case, one for which there exists limited data upon which to make definitive judgments. Finally, it is an important question, insofar as one of the principle ramifications of defining S. pneumoniae as being intermediate or resistant to penicillin is to encourage use of alternative expensive, often broad-spectrum or otherwise problematic antimicrobial agents. For example, in patients with systemic pneumococcal infections, characterization of an isolate as intermediate or resistant to penicillin, mitigates for the use of vancomycin as an alternative agent. In localized, nonlife-threatening infections of the respiratory tract, consideration may be given to use of less traditional agents such as oral, early generation fluoroquinolones, for example, ciprofloxacin or even more commonly, levofloxacin.
The current breakpoints that define penicillin activity versus Streptococcus pneumoniae, that is, Յ 0.06 g/mL (S), 0.12-1 (I), and Ն 2 (R) are without question relevant to patients with meningitis. 27 Specifically, patients infected with resistant strains of S. pneumoniae will usually fail therapy when treated with penicillin. Infections caused by intermediate strains may be associated with failure or more commonly relapse during therapy. A likely explanation for the latter outcome is that as meningeal inflammation diminishes during the first few days of therapy, penetration of penicillin into the subarachnoid space is also compromised, such that if there remain any viable organisms, drug levels fall below the threshold necessary to inhibit and kill pneumococci with moderately elevated penicillin MICs. Strains with intermediate levels of penicillin resistance were originally referred to as "relatively resistant." 1 This is an appropriate term, at least with regard to pneumococcal infections of the leptomeninges.
The penicillin MIC breakpoints listed above have been promulgated by the National Committee for Clinical Laboratory Standards (NCCLS) for pneumococcal susceptibility tests for many years. 28 The NCCLS is a consensus organization that defines susceptibility test methods and results interpretive criteria that are used in clinical microbiology laboratories when performing in vitro susceptibility tests.
The current NCCLS breakpoints for penicillin are, however, not predictive of outcome in patients with bronchopulmonary infections such as acute ex- acerbation of chronic bronchitis (AECB) and community-acquired pneumonia. There exists data from several studies that clearly indicate that current penicillin MIC breakpoints are overly conservative with respect to pneumococcal bronchopulmonary infections. [29][30][31] Specifically, they over predict failure. Stated another way, many patients respond to therapy with penicillin despite infection due to organisms with elevated MICs. Clearly, the NCCLS needs to revise the breakpoints to be applied to penicillin susceptibility tests on isolates of S. pneumoniae from patients with lower respiratory tract infections. What should the penicillin breakpoints be? Patients infected with organisms with MICs of Յ 2 g/mL will generally respond to therapy when treated with moderate but typical dosages of penicillin (i.e., 6-12 million units of intravenous penicillin per day in 4-6 divided doses). Therefore, reasonable breakpoints for defining penicillin resistance with isolates of S. pneumoniae from patients with lower respiratory tract infections would be: Յ 2 g/mL (S), Ն 4 g/mL (R), with no intermediate category or perhaps Յ 1 g/mL (S), 2 g/mL (I), and Ն 4 g/mL (R). Would these breakpoints be valid in patients with bacteremic pneumococcal infections of the lung or in patients with seeding of the pleural space? In the first case, existing data suggests that these breakpoints would be applicable even to patients with bacteremia. With respect to pneumococcal pleural empyema, there exists no data upon which to answer the question.

Question: What are current rates of resistance to other beta-lactam antimicrobials versus S. pneumoniae in the U.S. and what is the clinical relevance of this resistance in patients with pneumococcal infections?
As was the case with penicillin, the answer to both of these questions rests largely with the breakpoints that are used to define resistance in the first place. Current NCCLS interpretive criteria for 10 beta-lactam antimicrobial agents are listed in Table  2. In addition, rates of resistance based on these breakpoints are listed. The resistance rates listed in  Table 2 are predicated on a large collection of clinically significant isolates of S. pneumoniae (n = 1601) obtained from out-patients, most of whom had bronchitis or pneumonia, and were seen in 34 U.S. medical centers during the winter of 1997-1998. 8 This represents the most recent systematic, nationwide surveillance study conducted in the U.S. with data published in the peer-reviewed literature.
It is immediately apparent from Table 2 that there exist major inconsistencies between percentages of isolates of S. pneumoniae classified as nonsusceptible to different beta-lactams based on current NCCLS MIC breakpoints. Many of these differences are illogical. For example, rates of penicillin resistance (I + R) are roughly 30%, whereas only 4 to 5% of isolates would be considered immediate or resistant to amoxicillin and amoxicillin clavulanate; approximately 15% of isolates would be defined as being nonsusceptible to the parenteral cephalosporins, cefotaxime and ceftriaxone, while resistance rates (I + R) to marginally active oral cephalosporins such as cefaclor, loracarbef, and cefprozil exist at similar levels of 26.9, 24.7, and 19.4%, respectively.
Do in vitro susceptibility tests with beta-lactams other than penicillin, adequately predict outcome in patients with pneumococcal lower respiratory tract infections, when such tests are predicated on current NCCLS MIC interpretive criteria? There exists far less objective information upon which to base an answer to this important question, than was the case with penicillin. 32 My own view is that the MIC breakpoints for all of the oral agents in Table 2, except cefpodoxime and cefdinir, are too high and as a result will overestimate favorable therapeutic responses in patients with pneumococcal bronchopulmonary infections even when treated with aggressive dosages of these agents. In other words, too many isolates will be called susceptible, precisely the mistake one would most like to avoid. The cefpodoxime and cef-dinir breakpoints appear to be appropriate. Conversely, the cefotaxime and ceftriaxone breakpoints are too conservative and will have the opposite effect of grossly underestimating therapeutic efficacy when patients with pneumococcal infections of the lower respiratory tract are treated with these agents administered parenterally, even at modest dosages. 33 As noted above, this is precisely the same problem that attends current penicillin MIC interpretive criteria. As was the case, however, with penicillin, current cefotaxime and ceftriaxone breakpoints appear to be applicable to patients with pneumococcal infections of the central nervous system. 34,35 Obviously the foregoing discussion underscores the central importance of MIC interpretive criteria when defining rates of resistance and in predicting therapeutic outcome based on in vitro susceptibility tests. Unfortunately, all of the MIC breakpoints listed in Table 2 for oral cephalosporins have only recently been adopted by the NCCLS and so as a result are likely to remain unchanged for the foreseeable future. 28 Also, the issue of pneumococcal breakpoints for the parenteral beta-lactams, penicillin, cefotaxime and ceftriaxone, has recently been specifically addressed by the NCCLS, and a decision made to retain existing breakpoints.
There can be no question that pneumococci have changed dramatically with respect to diminished activity of beta-lactams during the past decade in the U.S. What these changes actually mean in terms of therapy efficacy when the beta-lactams are used to treat pneumococcal lower respiratory tract infections remains to be determined.

Question: Is resistance to nonbeta-lactam antimicrobial agents a problem with S. pneumoniae in the United States?
Yes. Currently in the U.S., the following approximate overall resistance rates exist with S. pneu-  8 An interesting connection exists between penicillin resistance and resistance to all of the nonbetalactam agents listed above. Specifically, in all cases, highest resistance rates with the nonbeta-lactam agents are observed among isolates of S. pneumoniae that are penicillin resistant, lower rates are noted with isolates that are penicillin intermediate and the lowest resistance rates occur with penicillin susceptible strains ( Table 3). 8 This association is not explained mechanistically because both genotypically and phenotypically, resistance to nonbeta-lactam agents is completely distinct from penicillin resistance in S. pneumoniae. The explanation for this association rests with the clonal spread that has occurred with antibiotic resistant S. pneumoniae in the U.S. This phenomena is described below in the section concerning the epidemiology of pneumococcal antimicrobial resistance.
Vancomycin has remained uniformly active versus S. pneumoniae in the U.S. and world-wide. Resistance has not been described. Of concern, however, are the recent descriptions of clinical isolates of S. pneumoniae that were found to be vancomycin tolerant, that is, the concentration of vancomycin necessary to kill these isolates was 16-to 32-fold higher than the inhibitory concentration. 36 In one case of meningitis, a tolerant strain was associated with recrudescence of disease in a patient treated with vancomycin. 37

Question: Are all of the macrolides comparable in terms of their activity for S. pneumoniae and what does macrolide resistance mean clinically?
Clarithromycin is consistently twice as active as erythromycin (i.e., MICs are one doubling dilution lower), which in turn, is twice as active as azithromycin. 8 The fact that percentages of strains resistant to these three agents are generally found to be the same is merely a reflection of the different breakpoints that are recommended by the NCCLS for use in interpreting macrolide MICs with S. pneumoniae. The azithromycin breakpoints are higher than the erythromycin and clarithromycin breakpoints. 28 Are these differences meaningful in terms of efficacy? Maybe. Although definitive comparative data are lacking, it appears that clarithromycin is a more effective agent than azithromycin, at least in the management of serious pneumococcal respiratory tract infections. This would not be surprising insofar as azithromycin is not only fourfold less active than clarithromycin versus S. pneumoniae, it has inferior pharmacokinetics, that is, approximate peak serum levels of 0.2-0.3 g/mL with azithromycin in comparison to 2.5-3 g/mL with clarithromycin when both agents are administered in typical dosages.
With respect to the issue of efficacy as it relates to macrolide resistance with S. pneumoniae, much as was the case with beta-lactam agents, there exist many unanswered questions. There are two mechanisms of macrolide resistance with S. pneumoniae, mefEencoded efflux and ermAM-mediated ribosomal alterations. 38,39 Efflux mutants have macrolide MICs of 1-32 g/mL and account for approximately 75% of macrolide resistant strains of S. pneumoniae in the U.S. 8,40 The remaining one-quarter macrolideresistant isolates have altered ribosomes and express high levels of macrolide resistance (MICs, Ն 64 g/ mL). 8,40 There is a great deal of circumstantial evidence that suggests that efflux mutants will respond to therapy when treated with clarithromycin, the macrolide with the greatest in vitro potency for S. pneumoniae and the most favorable pharmacokinetic profile. If this is so, then clinical rates of resistance with this agent in patients with pneumococcal bronchopulmonary infections would exist at levels of 4 to 6%, rather than the 20% resistance rates that are derived from MICs interpreted according to NCCLS breakpoints. The lower value is certainly more consistent with the consistently high efficacy rates that have remained relatively unchanged during the past decade according to published clinical studies that have assessed clarithromycin therapy in patients with bronchitis and pneumonia. [41][42][43][44] How does the clinician respond to this dichotomy between laboratory definitions of macrolide activity and predictions of efficacy in patients with pneumococcal infections of the lower respiratory tract. One approach is to use in vitro susceptibility test results obtained with clindamycin as a basis for making therapeutic decisions, at least with clarithromycin. Pneumococcal isolates with efflux as their mechanism of macrolide resistance are uniformly susceptible to clindamycin; ermAM-positive strains with altered ribosomes as their mechanism of macrolide resistance are uniformly resistant to clindamycin. 8 If it is believed that only the latter strains will fail therapy when treated with clarithromycin, then the clindamycin in vitro result can be used as a surrogate means of estimating clarithromycin efficacy. Clindamycin is readily tested in the laboratory; indeed, many clinical microbiology laboratories already routinely test this antimicrobial against clinical isolates of S. pneumoniae.

Question: Are the fluoroquinolones useful agents for treating lower respiratory tract infections caused by S. pneumoniae?
Among the fluoroquinolones, three agents are relevant to this discussion: levofloxacin, gatifloxacin, and moxifloxacin. Levofloxacin was introduced in January of 1997, moxifloxacin in December of 1999, and gatifloxacin in January of 2000. With respect to in vitro activity against S. pneumoniae, moxifloxacin is consistently twofold more active than gatifloxacin, which in turn, is consistently four times more active than levofloxacin. [45][46][47] Because all three agents have similar pharmacokinetic profiles, it follows that among these agents, gatifloxacin and moxifloxacin are the most appropriate choices for treating pneumococcal infections such as acute exacerbation of chronic bronchitis and pneumonia. Other fluoroquinolones such as ciprofloxacin and ofloxacin should not be used to treat pneumococcal infections because of marginal activity and limiting pharmacokinetics. Sparfloxacin, grepafloxacin and trovafloxacin, all introduced into the U.S. market during 1998 and all characterized by extensive potency for Gram-positive bacteria including S. pneumoniae, were in all cases, limited by their side-effect profiles. As a result, they have either been withdrawn from the U.S. market or are no longer currently being actively marketed.
The desirability of moxifloxacin and gatifloxacin over levofloxacin as choices for treating bronchopulmonary infections caused by S. pneumoniae in underscored by the apparent relationship between levofloxacin usage and the emergence of fluoroquinolone resistance with this organism. When the in vitro activity of levofloxacin versus S. pneumoniae is assessed in the context of its pharmacokinetic properties, it can be inferred that this agent rests squarely on the fence in terms of being an effective modality for treating pneumococcal infections. Indeed, the fact that most patients receiving this drug for management of infections caused by S. pneumoniae are elderly and as a result, have some degree of renal dysfunction, may explain why levofloxacin has in the past often proven to be effective. 48 Levofloxacin is excreted primarily by the kidneys and any degree of renal dysfunction leads to drug accumulation. As a result, in patients actually receiving this compound, pharmacodynamic indices are greater than would be predicted based on pharmacokinetics derived from studies conducted in young healthy volunteers, that is, the setting in which such data are usually accumulated. 48 Notwithstanding this concern, however, levofloxacin must be considered to be an agent that is just barely active enough for treating pneumococcal infections. The more important issue may be resistance.
Fluoroquinolone resistance has, until recently, remained distinctly uncommon among isolates of S. pneumoniae from patients in North America. Recent evidence from Canada, however, suggests that fluoroquinolone resistance with S. pneumoniae is beginning to emerge as a problem in that country. 49 One possible explanation for this is that marginally active fluoroquinolones such as ciprofloxacin and ofloxacin have been used extensively in Canada during the 1990s for the management of out-patient respiratory tract infections, and that the recent emergence of resistance is related to the selective pressure that results from the use of these agents. 49 In distinction to what has happened in Canada, fluoroquinolone resistance has not yet emerged as a problem in the United States, perhaps because ciprofloxacin and ofloxacin have not been used extensively to treat bronchitis and communityacquired pneumonia in this country. 6,8,45,47 In January of 1997, levofloxacin was introduced into the US and Canadian markets and since that time has become very popular as an agent for treating outpatient respiratory tract infections in adults. As noted above, levofloxacin is roughly comparable to ciprofloxacin in terms of its potency for S. pneumoniae. Will continued usage of levofloxacin in the United States eventually lead to the emergence of fluoroquinolone resistance among pneumococci in this country, much as has already happened in Canada because of ciprofloxacin and ofoxacin usage? Obviously, only time will tell; however, when high-level resistance arises due to mutations in both topoisomerase IV and DNA gyrase (i.e., the enzyme targets of fluoroquinolone action), as a result of selection by a marginally-active agent such as levofloxacin, such strains express cross-resistance to all existing agents in this class, including the more potent compounds, moxifloxacin and gatifloxacin. 45 In view of the foregoing, assuming comparable sideeffect profiles and equivalent cost, it would be hard to justify using levofloxacin as opposed to moxifloxacin or gatifloxacin to treat a lower respiratory tract infection known or suspected to be due to S. pneumoniae.
The larger question, namely, when should fluoroquinolones be used in the first place is obviously influenced by rates of resistance to other more traditional agents such as beta-lactams, macrolides, tetracyclines and TMP-SMX, together with what resistance to these agents actually means from a clinical perspective.

Question: Are there newer antimicrobials in development that might be of value in managing pneumococcal infections?
Three antimicrobial agents or classes of agents deserve consideration in answering this question. Quinupristin/dalfopristin is a recently introduced parenteral streptogramin antimicrobial that is uniformly active against S. pneumoniae. 50,51 Linezolid, an oxazolidinone antimicrobial, has also recently been introduced along in its development, and is likewise, uniformly active against the pneumococcus. 52,53 Linezolid is available for administration intravenously and per os. Finally there are two investigational agents in the ketolide family, ABT-773 and HMR-3647, that appear promising. [54][55][56][57][58] Both are in the process of being developed; resistance has not been recognized with S. pneumoniae. On a weight basis, ABT-773 appears to be approximately twice as active as HMR-3647 for this organism.
The actual role these agents will play in the management of pneumococcal infections depends, to large extent, upon what happens to resistance rates with the antimicrobial agents discussed above.
Question: What is the epidemiology of antimicrobial resistance with S. pneumoniae in the U.S.?
Highest rates of resistance are observed among isolates from patients with acute otitis media and maxillary sinusitis; lowest rates with isolates from blood cultures and normally sterile body fluids representative of systemic infections. 8 Rates of resistance with isolates from patients with lower respiratory tract infections due to S. pneumoniae generally fall somewhere in between. 8 Not surprisingly therefore, when sorted according to patient age, highest resistance rates are typically observed at the ex-tremes of age, that is, very young children and the elderly.
Interestingly, there exist variations in antimicrobial resistance rates based on geographic area of the country. Highest resistance rates are found in the Southwestern U.S., lowest rates in the Northeast. 8 There are no obvious explanations for these differences.
The vast majority of antibiotic resistant strains of S. pneumoniae are restricted to one of five capsular serotypes, 6B, 9V, 14, 19F, and 23F. [57][58][59][60][61] An explanation for this serotype association with resistance is not readily apparent. Lower numbered serotypes (e.g., 1, 3, 4, and 5), which are most frequently found to cause systemic life-threatening pneumococcal infections are typically uniformly susceptible to both beta-lactam and nonbeta-lactam antimicrobial agents. The increasing prevalence of disease due to serotype 6B, 9V, 14, 19F, and 23F strains is probably the result of such strains being more commonly antibiotic resistant. In this respect, antibiotic resistance functions as a virulence determinant.
The single most striking epidemiological aspect of antibiotic resistance with S. pneumoniae is the clonality that exists among pneumococci that are resistant to antimicrobial agents. Clonal spread of antibiotic resistant strains of S. pneumoniae has been shown to occur among family members, 62 within closed environments such as day-care centers, [63][64][65][66] within communities, 67,68 in specific geographic regions 69 and within countries. [70][71][72][73][74][75] For example, if molecular characterization of the chromosomal genes encoding for ribosomal RNA is used as the basis for establishing clonal relationships, currently in the U.S., it appears that more than 50% of pneumococcal isolates with penicillin MICs of Ն 2 g/mL are represented by one of only four strains of S. pneumoniae. 61 Greater than 75% of penicillinresistant isolates in this country are accounted for only seven pneumococcal clones, again using ribotype analysis as the basis for defining clonality. 61 It is likely that at least certain of these strains had their origin in foreign countries and were introduced into the U.S. during the early part of the decade of the 1990s. Intercontinental spread of antibioticresistant S. pneumoniae has clearly been documented to occur. [76][77][78][79] Among the seven most common clones in the U.S., four are resistant not only to penicillin, but at least two other nonbeta-lactam antimicrobial classes (i.e., they are multiresistant). the pneumococcus is transmitted between humans, the frequency with which children spend appreciable periods of time in close contact with other children in day-care settings, the mobility of the general population, and the fact that S. pneumoniae often exists as part of the oropharyngeal flora in asymptomatic individuals. Clearly, however, the single most important determinant in the emergence of antimicrobial resistance with this important respiratory tract pathogen is the selective pressure of oral antibiotic usage. Many studies have clearly demonstrated this association. [80][81][82][83][84][85][86][87][88] Interestingly, the selective pressure of certain oral agents appears to be greatest. These include amoxicillin, amoxicillin/ clavulanate, and azithromycin. 84,87,89 Of note, in view of the clonality that often exists among antibioticresistant strains of S. pneumoniae, combined with the fact that several of the most common clones are multiresistant, use of any number of antimicrobial agents can have the effect of causing resistance rates with other unrelated drugs to rise.

Question: What can be done to diminish the problem of antimicrobial resistance with S. pneumoniae?
This is arguably the most important question. More judicious use of antibiotics in the management of respiratory tract infections in the community is clearly the most important immediate step. 90 Greater care must be exercised by primary-care clinicians in deciding who is to receive antimicrobial agents in the first place, and then having made the decision to treat, choice of antibiotic is crucial. Use of most potent versus just potent enough antibiotics is encouraged. Educational initiatives related to this issue, directed at currently practicing clinicians as well as physicians in training will be essential. Education of the lay public as to the scope and magnitude of the antimicrobial resistance problem will be important also because a great deal of antibiotic usage in the community is driven by patient expectation. In addition, managed care dictates that blindly mitigate against use of the most appropriate antibiotic in favor of the cheaper alternatives must be addressed. Similarly, managed-care environments that do not provide primary-care clinicians with sufficient time to counsel patients regarding issues of antibiotic usage as they relate to antimicrobial resistance must be changed.
Prevention of pneumococcal infections from occurring in the first place can play an important role in reducing the problem of antimicrobial resistance with this pathogen. Immunoprophylaxis through more aggressive use of the 23-valent adult pneumococcal capsular polysaccharide vaccine must be emphasized. Similarly, broad administration of conjugate antigen pneumococcal polysac-charide vaccines when they become available in children should be encouraged. Implementation of better infection control practices in circumstances where the transmission of S. pneumoniae is facilitated should be pursued. Examples include day-care centers, nurseries, chronic care facilities, and nursing homes.
Finally, it will be essential in any effort to diminish rates of antimicrobial resistance with S. pneumoniae, that we continually remain vigilant in tracking the scope and magnitude of the problem with continued performance of objective, systematic, and longitudinal surveillance studies. The most effective solutions will come only from the most definitive data.

ACKNOWLEDGMENTS
The author appreciates the excellent secretarial assistance of Ms. Kay Meyer.