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SUPPLEMENT ARTICLE Antimicrobial Drug Use and Resistance among Respiratory Pathogens in the Community Donald E. Low Department of Microbiology, Mount Sinai Hospital, and the University Health Network, University of Toronto, Toronto There is substantial evidence that the overuse of antibiotics is a major cause for the emergence of resistance in respiratory pathogens in the community. However, it is also recognized that the mechanisms of resistance, the cost of resistance to the fitness of the organism, and the ability of the resistant strain to disseminate are all important contributors to this problem. Therefore, when developing strategies to control and/or prevent the emergence of resistance, health care professionals must take each of these factors into consideration. As we enter a new era in the use of fluoroquinolones for the treatment of respiratory tract infections, we have an opportunity to apply such lessons learned in the past to minimize or prevent the development of resistance to this class of antimicrobial drugs in the future. Numerous reviews in the medical literature, reports by national and international organizations, conferences, and papers commissioned by governments have addressed the crisis of antimicrobial drug resistance [1–3]. Most agree that this is a direct result of inappropriate antimicrobial drug use, including overuse and misuse [4–8]. However, the magnitude of this effect and the time frame in which it occurs also depend on the mechanism of resistance, the cost of resistance to the fitness of the organism, and the ability of the resistant organism to disseminate. EMERGENCE OF RESISTANCE Resistance can be either inherent or acquired. Inherent resistance is resistance that results from the normal genetic, structural, or physiological state of the microorganism. Acquired resistance develops when the organism has been able to either (1) undergo spontaneous Financial support: Canadian Bacterial Diseases Network, University of Calgary, Calgary, Alberta, Canada. Reprints or correspondence: Dr. Donald E. Low, Dept. of Microbiology, Mount Sinai Hospital, 600 University Ave., Rm. 1487, Toronto, Ontario, Canada M5G 1X5 ([email protected]). Clinical Infectious Diseases 2001; 33(Suppl 3):S206–13 2001 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2001/3306S3-0017$03.00 S206 • CID 2001:33 (Suppl 3) • Low mutation that has resulted in a resistant phenotype or (2) acquire resistance genes by horizontal transfer. The frequency with which spontaneous mutations result in a resistant phenotype depends on the spontaneous mutation rate, the number of mutations required in a gene and the number of genes involved [9]. Among Mycobacterium tuberculosis, resistance to streptomycin results from a change in 1 nucleotide of the gene that encodes ribosomal protein S12 [10]. Horizontal gene transfer allows organisms to share complex and elegant resistance mechanisms that may have evolved eons ago [11]. However, no matter how an organism becomes resistant, the use of antibiotics is what creates for these bacteria a selective environment that allows them to become the dominant flora. COST OF RESISTANCE If one of the solutions for the prevention and control of resistance is to curtail the overuse of antimicrobial drugs, then for such an approach to be successful, the acquisition of a resistant trait by an organism must be associated with a deleterious cost to the organism’s fitness. The effect of chromosomal mutations usually is negative, occasionally is neutral, but rarely is positive [12]. Schrag and Perrot [13] showed that spontaneous chromosomal mutations that resulted in a streptomy- cin-resistant rpsL mutant of Escherichia coli had a growth disadvantage relative to the parental stain. A number of investigators have presented evidence that, in the absence of selection for the genes that they are carrying, plasmids impose a cost on the fitness of their host bacteria [14, 15]. However, Chiew et al. [16] monitored streptomycin resistance in Enterobacteriaceae in their hospital in 1991, ∼20 years after the cessation of the use of this agent. They found that up to 20% of isolates were resistant to streptomycin. Four years after the prohibition of the use of tetracycline as a food additive to promote growth in pigs, there was no significant reduction in the percentage of pigs that harbored tetracycline-resistant E. coli [17]. These examples, in which antibiotic use has been curtailed or discontinued yet resistance has not significantly decreased, suggest that, at least for some antibiotics, the cost of resistance is low and/or there is some other selective factor associated with the resistant trait [14, 18–20]. MINIMIZING THE COST OF RESISTANCE Mechanisms by which the cost of resistance to the fitness of the bacteria can be minimized or eliminated include gene variation, which allows the bacteria to adapt and/or control expression of the resistance trait in the absence of antibiotic selective pressure. Because most newly arising mutations are neutral or deleterious, it has been argued that the mutation rate has evolved to be as low as possible. However, not all mutations are deleterious. Mutations may be beneficial for the microorganism that has found itself in a new environment (e.g., exposure to antibiotics) or host. Under such circumstances, mutations may play an important role in adaptive evolution [21, 22]. Schrag and Perrot [13] created streptomycin-resistant E. coli that were found to have a growth disadvantage of ⭓14% per generation relative to the growth of the wild-type strain. However, after 180 generations of evolution occurred in the absence of exposure to antibiotics, they found that the cost of resistance was substantially reduced. Schrag et al. [23] were further able to demonstrate that the second-site mutations that compensated for the streptomycin-resistant mutations in E. coli created a genetic background in which streptomycin-susceptible alleles had a selective disadvantage of 4%–30% per generation relative to the adapted resistant strains. In addition, it appears that these compensatory mutations have been fixed in long-term, streptomycin-resistant laboratory strains of E. coli, which may account for the persistence of streptomycin resistance in populations maintained in the absence of the antibiotic. Sniegowski et al. [24] reported an increase in hypermutable strains in populations of E. coli that were undergoing longterm adaptation to a new environment. LeClerc et al. [25] reported that the incidence of mutators among isolates of pathogenic E. coli and Salmonella enteritidis was high (11%). They found defects in the methyl-directed mismatch repair system in all mutator phenotypes described. Of 9 independently derived hypermutable strains, 7 contained a defective mutS allele. LeClerc and colleagues speculated that because these mutant alleles increase the mutation rate and enhance recombination among diverse species, this might help explain the rapid emergence of antibiotic resistance and of virulence genes. In addition to mutator alleles, a variety of other mechanisms of genetic variation have been identified, including recombination, gene conversion, translocation, and inversion [26]. Down-regulation of the expression of a resistance function can reduce the cost of resistance in an antibiotic-free environment. There are many resistance genes that are quiescent and that are only induced in the presence of the antibiotic for which they encode resistance. Many gram-negative species respond to the presence of b-lactam antibiotics by inducing the synthesis of a chromosomal AmpC b-lactamase [27]. The biosynthetic machinery that is required to protect the cell wall target of Enterococcus faecium and Enterococcus faecalis from vancomycin is found on a transposable element that incorporates 5 genes that are necessary to confer high-level, inducible glycopeptide resistance. Two of these gene products, VanR and VanS, are required for the vancomycin-induced resistance response. Therefore, if a glycopeptide is not sensed in the environment, transcription of these genes ceases, thereby minimizing the cost to the fitness of the organism. If there is a minimal cost to the fitness of the organism as a result of its being resistant, then it may take considerable time until there is a reduction or elimination of the resistant bacteria once the antibiotic selective pressure is removed. DISSEMINATION For a resistant organism to emerge, it must possess characteristics that allow it to (1) effectively multiply within and disseminate from its hosts and (2) translocate to and colonize new hosts. Many factors, or combinations of factors, contribute to the transmissibility of resistant bacteria. Human demographics and behavior play a critical role. For example, the increase in the number of families in which both parents are working has resulted in an increase in the number of children who attend day care facilities and are exposed to other children who may be carrying resistant organisms [28, 29]. International and national travel allows for rapid and widespread dissemination of bacteria. Isolates of Streptococcus pneumoniae serotype 23F, which has high levels of resistance to penicillin and which was found initially in Spain, were isolated from children who attended a day care center in Cleveland [30]. In Iceland, almost all of the multiresistant pneumococci that suddenly appeared in clinical specimens from 1989 through 1992 belonged to serotype 6B, which was indistinguishable from a subgroup of Antimicrobial Drug Use and Resistance • CID 2001:33 (Suppl 3) • S207 Figure 1. Association between annual human consumption of macrolides (in tons) and frequency of macrolide resistance among group A streptococci in Japan [39, 41, 42]. multiresistant pneumococci of serotype 6B that was present with high incidence in Spain [31]. The use of antimicrobial drugs to which an organism is resistant facilitates an increase in both the number and the transmission of that organism. Brook and Gober [32] studied the effect of prophylaxis with amoxicillin or sulfisoxazole in children and found that the rate of recovery of oropharyngeal b-lactamase–producing bacteria increased only after administration of amoxicillin, increasing from 20% to 100%. Three to 5 months after amoxicillin prophylaxis was discontinued, the rate of carriage returned to baseline levels. Numerous studies have identified prior antibiotic use to be the most significant risk factor for carriage and transmission of penicillin-resistant S. pneumoniae [33–36]. INAPPROPRIATE USE OF ANTIBIOTICS AND RESISTANCE Overuse. Overuse of antibiotics includes unnecessary antibiotic prescribing practices in clinical medicine and the use of antibiotics to prevent disease and to promote animal growth in agriculture. Much of the efforts to control resistance, some of which have been successful, have been aimed at reducing the overuse of antibiotics. However, establishing a precise quantitative relationship between the frequency of resistance to a defined antibiotic and the volume of drug use has proved to be difficult because of the paucity of longitudinal studies that have recorded resistance and drug use patterns [37]. Despite this lack of data, it seems reasonable to assume that such a relationship exists because it is biologically plausible, because there has been consistent evidence of the association in several studies, and because the sequence of events over time supports such a notion [38]. In Japan, the use of macrolides increased sharply after 1970, S208 • CID 2001:33 (Suppl 3) • Low and ∼165–170 tons of macrolides were used annually in 1974, 1976, and 1977 [39]. Associated with this increase in use was a rapid increase in macrolide resistance among group A streptococci (figure 1) [40, 41]. In 1972, 12% of group A streptococci were resistant to macrolides. By 1974, this percentage had increased to 60%. During the late 1970s and 1980s, the use of macrolides gradually decreased to 65–85 tons annually. Associated with this decrease in use was a marked reduction in macrolide resistance (to !1%) [39, 40]. Although the great majority of resistant isolates in the 1970s were M type 12 strains, macrolide resistance among these strains had decreased from 86% to 13% by the 1980s [42]. In Finland, the use of erythromycin increased from 1.1 defined daily doses per 1000 inhabitants per day in 1979 to 3.2 defined daily doses per 1000 inhabitants per day in 1988 [43]. The frequency of erythromycin resistance among group A streptococci was 4% in 1988, 7% in 1989, and 24% in 1990. Resistance was represented by several different serotypes. As a result of this frequency of resistance, there were nationwide recommendations for the reduction in erythromycin use for respiratory and skin infections in outpatients. These recommendations resulted in a 50% reduction in the number of macrolide prescriptions, followed by an ∼50% decrease in resistance to macrolides among group A streptococci (figure 2) [44]. Toward the end of the study period, there was a gradual increase in the use of the newer macrolides, such as azithromycin and roxithromycin. However, there have been no further data presented as to the impact of these agents on macrolide resistance. In Canada, there has been a significant reduction in the use of outpatient antibiotics (from 25.4 million prescriptions in 1995 to 22.6 million prescriptions in 1999; IMS HEALTH). Amoxicillin was the antimicrobial drug for which the reduction in use was greatest. Associated with that reduction was a re- Figure 2. Association between macrolide consumption and frequency of macrolide resistance among group A streptococci in Finland. Consumption is expressed in terms of defined daily doses per 1000 inhabitants per day. Adapted from Seppala et al. [44]. duction in the prevalence of b-lactamase–producing Haemophilus influenzae, whereas the prevalence of b-lactamase–producing Moraxella catarrhalis remained at 190% (figure 3) [45]. A possible explanation may be related to the cost of resistance. H. influenzae is unusually permeable to the aminopenicillins; therefore, for a b-lactamase–producing isolate to be protected against the action of an amoxicillin, it must produce large amounts of b-lactamase to inactivate all the antibiotic [53]. This is accomplished by the presence of 2 strong, overlapping b-lactamase promoters and, in some cases, by having multiple copies of the b-lactamase plasmid [54, 55]. In M. catarrhalis, the b-lactamase genes are present as single copies on the chromosome and sometimes have deletions in their promoters [56, 57]. This is reflected by the increased susceptibility of b-lactamase–producing M. catarrhalis to aminopenicillins, compared with the susceptibility of b-lactamase–producing H. influenzae to aminopenicillins [46, 47, 56]. Therefore, as a result of the smaller amounts of enzyme produced, b-lactamase– producing M. catarrhalis may be more fit then its H. influenzae counterpart in the absence of the selective pressure of aminopenicillins. Misuse. Misuse of antibiotics includes inappropriate dose, duration, and/or frequency of administration. Bacterial exposure to low and/or prolonged concentrations of an antibiotic may have a role in the selection of resistance [6, 58, 59]. This may occur by killing the susceptible normal flora and allowing preexisting resistant organisms to survive or by increasing the likelihood for subsequent colonization of the host with resistant bacteria. Another mechanism involves selecting for isolates that have developed antibiotic resistance de novo by spontaneous chromosomal mutations [9]. For example, drug-resistant tuberculosis is produced by the selection of resistant strains in patients who have failure to complete chemotherapy with the correct combination of drugs. M. tuberculosis becomes drug resistant through random, spontaneous genetic mutations. The proportion of naturally occurring resistance has been established for several of the primary antituberculosis drugs: for rifampin, 1/108; for ioniazid and streptomycin, 1/10 6 ; and for ethambutol, 1/10 4. The probability of ioniazid and rifampin resistance occurring in the same organism is 1/10 8 ⫻ 1/10 6 (or 1/1014). Because the total number of bacilli in an infected person, even in a person with advanced cavitary disease, does not approach this value (1014), spontaneous evolution of drug-resistant tuberculosis occurs infrequently. Therefore, to prevent the emergence of resistance, physicians must ensure that effective regimens for the treatment of tuberculosis contain multiple drugs to which the organisms are susceptible. When ⭓2 drugs are used simultaneously, each drug helps prevent the emergence of tubercle bacilli that are resistant to the other drugs. This approach to the prevention of the emergence of M. tuberculosis resistance could be applied to strategies for the prevention of resistance to fluoroquinolones. However, 1 drug (the fluoroquinolone) that is able to bind to and inhibit each of its 2 targets is used, rather than 2 drugs, each of which has a different target. The fluoroquinolones are potent antibacterial agents that have DNA gyrase and DNA topoisomerase IV as their intracellular targets. The key step in quinolone action is trapping of gyrase or topoisomerase IV on DNA as ternary drug-enzyme-DNA complexes [60]. The complexes block replication fork movement, inhibiting DNA synthesis. Inhibition of DNA synthesis correlates well with inhibition of growth as measured by MIC. Depending on the fluoroquinolone and the organism, 1 of these will be the primary target—that is, the target for which the fluoroquinolone has greater affinity—and the other will be the secondary target. For example, in Neisseria gonorrhoeae, the primary target for ciprofloxacin is DNA gyrase and the secondary target is topoisomerase IV. If an inadequate dose of ciprofloxacin is used, then concentrations of ciprofloxacin that only allow inhibition of the primary target may be achieved (figure 4, solid line). The likelihood of a preexisting Antimicrobial Drug Use and Resistance • CID 2001:33 (Suppl 3) • S209 Figure 3. Frequency of b-lactamase–positive Haemophilus influenzae and Moraxella catarrhalis in Canada. Dark bars denote H. influenzae, and light bars denote M. catarrhalis. Data were adapted both from previous publications [46, 47, 48–52] and from the Canadian Bacterial Surveillance Network (Mount Sinai Hospital, Toronto). spontaneous mutation in the quinolone-resistance–determining region (QRDR) of the GyrA subunit of the DNA gyrase that results in resistance is in the order of 1/10 8 . However, if a dose of ciprofloxacin is used that provides concentrations that allow for binding to both DNA gyrase and topoisomerase IV (figure 4, broken line), then the likelihood of preexisting spontaneous mutations occurring in both targets is in the order of 1/10 8 ⫻ 1/10 8 (or 1016). The Centers for Disease Control and Prevention in Atlanta have recommended the use of singledose, oral therapy with 500 mg of ciprofloxacin for the treatment of uncomplicated gonorrhea due to N. gonorrhoeae [61]. However, in some countries, gonococcal infections have been treated with a single, orally administered dose of 250 mg of ciprofloxacin. The failure of gonococcal infections to respond to treatment with 250 mg of ciprofloxacin has been well documented [62]. The continued use of inadequate doses of fluoroquinolones for the treatment of N. gonorrhoeae may account for the continuing de novo emergence of resistant strains [63]. The emergence of resistance of S. pneumoniae to antimicrobial drugs that are used to treat respiratory pathogens has led to changes in recommended antimicrobial drug treatment regimens [64, 65]. Fluoroquinolones, such as levofloxacin, moxifloxacin, and gatifloxacin, are now recommended as therapeutic options when patients with pneumonia are at risk for infection due to multidrug-resistant pneumococci. Of concern is the potential for the emergence of S. pneumoniae that is resistant to the fluoroquinolone class as a whole [66]. For example, the treatment of acute exacerbations of chronic bronchitis (AECB) with 500 mg of ciprofloxacin given twice daily may not achieve adequate bactericidal concentrations at the site of colonization or infection, thereby creating a selective environment that favors those strains of S. pneumoniae with preexisting mutations in the primary target and an elevated MIC S210 • CID 2001:33 (Suppl 3) • Low (figure 4, solid line). Specific rates of eradication of S. pneumoniae in patients with AECB have been variable, ranging from 63% to 90% [67, 68]. Clinical trials of the treatment of patients with AECB have reported strains of fluoroquinolone-resistant S. pneumoniae for which selection occurred during fluoroquinolone therapy [68, 69]. Emergence of resistance of S. pneumoniae to fluoroquinolones has already been described in Canada, Spain, Hong Kong, and Ireland. In Canada, Chen et al. [70] found that the prevalence of ciprofloxacin-resistant pneumococci (MIC, ⭓4 mg/ mL) increased from 0% in 1993 to 1.7% in 1997–1998 (P p .01; figure 5). In adults, the prevalence increased from 0% in 1993 to 3.7% in 1998. This was associated with an increase in the consumption of fluoroquinolones. Overall, the number of fluoroquinolone prescriptions increased from 0.8 to 5.5 per 100 persons per year from 1988 through 1997 [70]. In addition to the increase in the prevalence of pneumococci with reduced susceptibility to fluoroquinolones, the degree of resistance has also increased (figure 5). From 1994 through 1998, there was a statistically significant increase in the proportion of isolates with an MIC of ciprofloxacin of ⭓32 mg/mL (P p .04). Linares et al. [71] found an increase in the proportion of ciprofloxacinresistant pneumococci in Spain (from 0.9% in 1991–1992 to 3% in 1997–1998). Both groups of investigators found that the resistant strains were more likely to be isolated from the sputum of older patients, which suggests a possible source and reservoir for fluoroquinolone-resistant pneumococci. Ho et al. [72] examined the susceptibilities of 181 pneumococcal isolates from 4 regional laboratories in Hong Kong and found that 12% of Figure 4. The consequence of DNA gyrase and DNA topoisomerase IV mutations on fluoroquinolone activity. The dark bars and light bars denote the 2 topoisomerase enzymes (topoisomerase IV or DNA gyrase, respectively) that are the intracellular targets for the fluoroquinolones. The height of the bars indicates the amount of fluoroquinolone required to bind to and inhibit enzyme function and have an antibacterial effect. The solid lines and broken lines denote the concentration that the fluoroquinolone is able to achieve as a result of either the dosage or activity of the agent. Figure 5. The increasing prevalence and MICs of Streptococcus pneumoniae that is not susceptible to ciprofloxacin (MIC, ⭓4 mg/mL) in Canada. All MIC units are in micrograms per milliliter. Adapted from Chen et al. [70]. stains had MICs of ciprofloxacin of ⭓4 mg/mL. In Northern Ireland ciprofloxacin resistance was linked to penicillin resistance. Eighteen (42.9%) of 42 penicillin-resistant pneumococci were resistant to ciprofloxacin [73]. The prevalence of fluoroquinolone-resistant pneumococci may increase dramatically as they are increasingly used for lower respiratory tract infections. In pneumococcal pneumonia, the total number of bacteria may be as high as 1010 to 1012 [74]. Therefore, if an agent is used that only achieves levels that result in binding to 1 of the 2 targets, then the likelihood of selecting for an isolate with a preexisting mutation in the QRDR of the primary target is 1/10 8 [75]. Weiss et al. [76] described an outbreak of S. pneumoniae serotype 23F that caused lower respiratory infection among patients in a chronic respiratory disease ward. The isolate in the first cluster of infections had an elevated MIC of ciprofloxacin of 4 mg/mL as the result of a parC mutation in topoisomerase IV. In the second cluster of cases, the MIC had increased to 16 mg/mL as the result of an additional mutation in gryA. Two patients in the first cluster (both with AECB) and 3 patients in the second cluster (1 with hospital-acquired pneumonia and 2 with AECB) had treatment failure with 500 mg of ciprofloxacin given twice daily. Davidson et al. [77] described 2 patients with community-acquired pneumonia due to S. pneumoniae that were treated as outpatients with levofloxacin. Both patients had treatment failure in association with the selection of resistance to levofloxacin as the result of parC and gyrA mutations during therapy. A possible strategy to curtail or prevent the emergence of fluoroquinolone resistance in S. pneumoniae is the use of fluoroquinolones with the lowest MICs and, therefore, with the greatest affinity for the topoisomerase target enzymes (figure 4, broken line) [78]. By the use of such agents that bind to both targets at therapeutic drug levels, the likelihood of selecting a strain with a mutation in both target sites while therapy is administered would be 1/10 8 ⫻ 1/10 8 (or 1016) [79]. Evidence that such a strategy may be effective is provided by the experience with the fluoroquinolones and the treatment of infections due to H. influenzae and M. catarrhalis. Despite the widespread use of ciprofloxacin for the treatment of lower respiratory tract infections, including AECB, during the past 10 years, reports of resistant isolates are rare [80–83]. For both organisms, the MIC90 of ciprofloxacin is !0.06 mg/mL [84]. The area under the curve (AUC) for ciprofloxacin is ∼20–30 (mg 7 mg 7 mL⫺1) when an oral dose of 500 mg is used [85]. Therefore, the AUC/MIC ratio when treating infections due to H. influenzae and M. catarrhalis would be 1300, a value well above the ratio of 125 that is predictive of clinical cures and microbiological eradication when treating infections due to gram-negative pathogens [86, 87]. Similarly with the new fluoroquinolones, such as moxifloxacin, the AUC/MIC ratio for susceptible S. pneumoniae is ∼180 and the peak/MIC ratio is 20, ratios that are well above the peak/MIC ratio that is predictive of microbiological eradication and favorable clinical outcomes [88–90]. CONCLUSION Although the data are compelling for the association between resistance and the volume of antimicrobials consumed, there are numerous other factors that must be taken into account if we are to devise appropriate strategies to control or prevent the emergence of antimicrobial resistance in the outpatient setting. We are entering a new era with the recent approval of several new fluoroquinolones for the treatment of respiratory pathogens, including S. pneumoniae, and the prospect of several additional candidates in the near future. If we are to preserve this class of antimicrobial drugs, it is incumbent upon us to not only avoid overusing these agents by prescribing them for trivial infections, but also to learn how to use them appropriately so as to minimize the emergence of resistance [91]. References 1. Bell D. Controversies in the prevention and control of antimicrobial drug resistance. Emerg Infect Dis 1998; 4:473–4. 2. Smith R. Action on antimicrobial resistance: not easy, but Europe can do it. BMJ 1998; 317:764. 3. Wise R. Antimicrobial resistance: is a major threat to public health. BMJ 1998; 317:609–10. 4. Butler JC, Hofmann J, Cetron MS, Elliott JA, Facklam RR, Breiman RF. The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention’s Pneumococcal Sentinel Surveillance System. J Infect Dis 1996; 174:986–93. 5. Arason VA. Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children? Cross sectional prevalence study. BMJ 1996; 313:387–91. 6. Guillemot D, Carbon C, Balkau B, et al. Low dosage and long treatment duration of b-lactam: risk factors for the carriage of penicillin-resistant Streptococcus pneumoniae. JAMA 1998; 279:365–70. Antimicrobial Drug Use and Resistance • CID 2001:33 (Suppl 3) • S211 7. Guillemot D, Carbon C, Vauzelle-Kervroedan F, et al. Inappropriateness and variability of antibiotic prescription among French officebased physicians. J Clin Epidemiol 1998; 51:61–8. 8. Guillemot D, Maison P, Carbon C, et al. Trends in antimicrobial drug use in the community: France, 1981–1992. J Infect Dis 1998; 177:492–7. 9. Martinez JL, Baquero F. Mutation frequencies and antibiotic resistance. Antimicrob Agents Chemother 2000; 44:1771–7. 10. Davies J. Inactivation of antibiotics and the dissemination of resistance genes. Science 1994; 264:375–82. 11. Courvalin P. The Garrod Lecture: evasion of antibiotic action by bacteria. J Antimicrob Chemother 1996; 37:855–69. 12. Elena SF, Ekunwe L, Hajela N, Oden SA, Lenski RE. Distribution of fitness effects caused by random insertion mutations in Escherichia coli. Genetica 1998; 102–103(1–6):349–58. 13. Schrag SJ, Perrot V. Reducing antibiotic resistance. Nature 1996; 381: 120–1. 14. Lenski RE. The cost of antibiotic resistance: from the perspective of a bacterium [discussion]. Ciba Found Symp 1997; 207:131–40. 15. Bouma JE, Lenski RE. Evolution of bacteria/plasmid association. Nature 1988; 335:351–2. 16. Chiew YF, Yeo SF, Hall LM, Livermore DM. Can susceptibility to an antimicrobial be restored by halting its use? The case of streptomycin versus Enterobacteriaceae. J Antimicrob Chemother 1998; 41:247–51. 17. Smith HW. Persistence of tetracycline resistance in pig E. coli. Nature 1975; 258:628–30. 18. Levin BR, Lipsitch M, Perrot V, et al. The population genetics of antibiotic resistance. Clin Infect Dis 1997; 24(Suppl 1):S9–16. 19. Salyers AA, Amabile-Cuevas CF. Why are antibiotic resistance genes so resistant to elimination? Antimicrob Agents Chemother 1997; 41: 2321–5. 20. Spratt BG. Antibiotic resistance: counting the cost. Curr Biol 1996; 6: 1219–21. 21. Taddei F, Matic I, Godelle B, Radman M. To be a mutator, or how pathogenic and commensal bacteria can evolve rapidly. Trends Microbiol 1997; 5:427–8. 22. Moxon ER. Microbial genetics. the tinkerer’s evolving tool-box. Nature 1997; 387:659. 23. Schrag SJ, Perrot V, Levin BR. Adaptation to the fitness costs of antibiotic resistance in Escherichia coli. Proc R Soc Lond B Biol Sci 1997; 264:1287–91. 24. Sniegowski PD, Gerrish PJ, Lenski RE. Evolution of high mutation rates in experimental populations of E. coli. Nature 1997; 387:703–5. 25. LeClerc JE, Li B, Payne WL, Cebula TA. High mutation frequencies among Escherichia coli and Salmonella pathogens [see comments]. Science 1996; 274:1208–11. 26. Deitsch KW. Shared themes of antigenic variation and virulence in bacterial, protozoal, and fungal infections. Microbiol Mol Biol Rev 1997; 61:281–93. 27. Jacobs C. Life in the balance: cell walls and antibiotic resistance. Science 1997; 278:1731–2. 28. Radetsky MS, Istre GR, Johansen TL, et al. Multiply resistant pneumococcus causing meningitis: its epidemiology within a day-care centre. Lancet 1981; 2(8250):771–3. 29. Boken DJ, Chartrand SA, Goering RV, Kruger R, Harrison CJ. Colonization with penicillin-resistant Streptococcus pneumoniae in a childcare center. Pediatr Infect Dis J 1995; 14:879–84. 30. Munoz R, Coffey TJ, Daniels M, et al. Intercontinental spread of a multiresistant clone of serotype 23F Streptococcus pneumoniae. J Infect Dis 1991; 164:302–6. 31. Soares S, Kristinsson KG, Musser JM, Tomasz A. Evidence for the introduction of a multiresistant clone of serotype 6B Streptococcus pneumoniae from Spain to Iceland in the late 1980s. J Infect Dis 1993; 168: 158–63. 32. Brook I, Gober AE. Prophylaxis with amoxicillin or sulfamethoxazole for otitis media: effect on recovery of penicillin resistant bacteria from children. Clin Infect Dis 1996; 22:143–5. 33. Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, Molstad S212 • CID 2001:33 (Suppl 3) • Low 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. S, Gudmundsson S. Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children? Cross-sectional prevalence study. BMJ 1996; 313:387–91. Arnold KE, Leggiadro RJ, Breiman RF, et al. Risk factors for carriage of drug-resistant Streptococcus pneumoniae among children in Memphis, Tennessee [see comments]. J Pediatr 1996; 128:757–64. Reichler MR, Allphin AA, Breiman RF, et al. The spread of multiply resistant Streptococcus pneumoniae at a day care center in Ohio. J Infect Dis 1992; 166:1346–53. Dowell SF, Schwartz B. Resistant pneumococci: protecting patients through judicious use of antibiotics [see comments]. Am Fam Physician 1997; 55:1647–8. Austin DJ, Kristinsson KG, Anderson RM. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance [see comments]. Proc Natl Acad Sci USA 1999; 96:1152–6. Guillemot D. Antibiotic use in humans and bacterial resistance. Curr Opin Microbiol 1999; 2:494–8. Fujita K, Murono K, Yoshikawa M, Murai T. Decline of erythromycin resistance of group A streptococci in Japan. Pediatr Infect Dis J 1994;13: 1075–8. Bass JW, Weisse ME, Plymyer MR, Murphy S, Eberly BJ. Decline of erythromycin resistance of group A beta-hemolytic streptococci in Japan. Comparison with worldwide reports [see comments]. Arch Pediatr Adolesc Med 1994; 148:67–71. Mitsuhashi S, Inoue M, Saito K, Nakae M. Drug resistance in Streptococcus pyogenes strains isolated in Japan. In: Schlessinger D, ed. Microbiology. Washington, DC: American Society for Microbiology, 1982: 151–4. Fujii R. Present and future in antibiotic treatment in pediatric patients. Jpn Infect Immun Child 1990; 2:53–64. Seppala H, Nissinen A, Jarvinen H, et al. Resistance to erythromycin in group A streptococci. N Engl J Med 1992; 326:292–7. Seppala H, Klaukka T, Vuopio-Varkila J, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance [see comments]. N Engl J Med 1997; 337:441–6. Karlowsky JA, Verma G, Zhanel GG, Hoban DJ. Presence of ROB-1 beta-lactamase correlates with cefaclor resistance among recent isolates of Haemophilus influenzae. J Antimicrob Chemother 2000; 45:871–5. Doern GV, Jones RN, Pfaller MA, Kugler K. Haemophilus influenzae and Moraxella catarrhalis from patients with community-acquired respiratory tract infections: antimicrobial susceptibility patterns from the SENTRY antimicrobial Surveillance Program (United States and Canada, 1997). Antimicrob Agents Chemother 1999; 43:385–9. Zhanel GG, Karlowsky JA, Low DE, Hoban DJ. Antibiotic resistance in respiratory tract isolates of haemophilus influenzae and Moraxella catarrhalis collected from across Canada in 1997–1998. J Antimicrob Chemother 2000; 45:655–62. Davidson RJ, Canadian Bacterial Surveillance Network, Low DE. A cross Canada surveillance of antimicrobial resistance in respiratory rract pathogens. Can J Infect Dis 1999; 10:128–33. Bannatyne RM, Toma S, Cheung R, Hodge D. Antibiotic susceptibility of blood and cerebrospinal fluid isolates of Haemophilus influenzae. J Antimicrob Chemother 1985; 15:187–91. Tremblay LD, L’Ecuyer J, Provencher P, Bergeron MG. Susceptibility of Haemophilus influenzae to antimicrobial agents used in Canada. Canadian Study Group [see comments]. CMAJ 1990; 143:895–901. Scriver SR, Walmsley SL, Kau CL, et al. Determination of antimicrobial susceptibility of Canadian isolates of Haemophilus influenzae and characterization of their b-lactamases. Antimicrob Agents Chemother 1994; 38:1678–80. Scriver SR, Low DE, Simor AE, et al. Broth dilution testing of Haemophilus influenzae with haemophilus test medium versus lysed horse blood broth. J Clin Microbiol 1992; 30:2284–9. Medeiros AA, O’Brien TF. Ampicillin-resistant Haemophilus influenzae 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. type B possessing a TEM-type beta-lactamase but little permeability barrier to ampicillin. Lancet 1975; 1:716–9. Chen ST, Clowes RC. Nucleotide sequence comparisons of plasmids pHD131, pJB1, pFA3, and pFA7 and beta-lactamase expression in Escherichia coli, Haemophilus influenzae, and Neisseria gonorrhoeae. J Bacteriol 1987; 169:3124–30. De Graaff J, Elwell LP, Falkow S. Molecular nature of two beta-lactamase-specifying plasmids isolated from Haemophilus influenzae type b. J Bacteriol 1976; 126:439–46. Richter SS, Winokur PL, Brueggemann AB, et al. Molecular characterization of the beta-lactamases from clinical isolates of Moraxella (Branhamella) catarrhalis obtained from 24 U.S. medical centers during 1994–1995 and 1997–1998. Antimicrob Agents Chemother 2000; 44: 444–6. Wallace RJ Jr, Steingrube VA, Nash DR, et al. BRO beta-lactamases of Branhamella catarrhalis and Moraxella subgenus Moraxella, including evidence for chromosomal beta-lactamase transfer by conjugation in B. catarrhalis, M. nonliquefaciens, and M. lacunata. Antimicrob Agents Chemother 1989; 33:1845–54. Baquero F. Evolving resistance patterns of Streptococcus pneumoniae: a link with long-acting macrolide consumption? J Chemother 1999; 11(Suppl 1):35–43. Morita JY, Kahn E, Thompson T, et al. Impact of azithromycin on oropharyngeal carriage of group A Streptococcus and nasopharyngeal carriage of macrolide-resistant Streptococcus pneumoniae. Pediatr Infect Dis J 2000; 19:41–6. Drlica K. Mechanism of fluoroquinolone action. Curr Opin Microbiol 1999; 2:504–8. Knapp JS, Fox KK, Trees DL, Whittington WL. Fluoroquinolone resistance in Neisseria gonorrhoeae [published erratum appears in Emerg Infect Dis 1997; 3:584]. Emerg Infect Dis 1997; 3:33–9. Jephcott AE, Turner A. Ciprofloxacin resistance in gonococci [letter; comment]. Lancet 1990; 335(8682):165. Trees DL, Sandul AL, Peto-Mesola V, et al. Alterations within the quinolone resistance–determining regions of GyrA and ParC of Neisseria gonorrhoeae isolated in the Far East and the United States. Int J Antimicrob Agents 1999; 12:325–32. Bartlett JG, Breiman RF, Mandell LA, File TMJ. Community-acquired pneumonia in adults: guidelines for management. The Infectious Diseases Society of America. Clin Infect Dis 1998; 26:811–38. Thornsberry C, Ogilvie PT, Holley HP, Jr, Sahm DF. Survey of susceptibilities of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolates to 26 antimicrobial agents: a prospective U.S. study. Antimicrob Agents Chemother 1999; 43:2612–23. Legg JM, Bint AJ. Will pneumococci put quinolones in their place? J Antimicrob Chemother 1999; 44:425–7. Chodosh S, Schreurs A, Siami G, et al. Efficacy of oral ciprofloxacin vs. clarithromycin for treatment of acute bacterial exacerbations of chronic bronchitis. Clin Infect Dis 1998; 27:730–8. Anzueto A, Niederman MS, Tillotson GS. Etiology, susceptibility, and treatment of acute bacterial exacerbations of complicated chronic bronchitis in the primary care setting: ciprofloxacin 750 mg b.i.d. versus clarithromycin 500 mg b.i.d. Bronchitis Study Group. Clin Ther 1998; 20:885–900. Chodosh S, Schreurs A, Siami G, et al. Efficacy of oral ciprofloxacin vs. clarithromycin for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group. Clin Infect Dis 1998; 27:730–8. Chen D, McGeer A, de Azavedo JC, Low DE, The Canadian Bacterial Surveillance Network. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N Engl J Med 1999; 341:233–9. Linares J, De La Campa AG, Pallares R. Fluoroquinolone resistance in Streptococcus pneumoniae [letter]. N Engl J Med 1999; 341:1546–7. Ho PL, Que TL, Tsang DN, Ng TK, Chow KH, Seto WH. Emergence of fluoroquinolone resistance among multiply resistant strains of Streptococcus pneumoniae in Hong Kong. Antimicrob Agents Chemother 1999; 43:1310–3. 73. Goldsmith CE, Moore JE, Murphy PG, Ambler JE. Increased incidence of ciprofloxacin resistance in penicillin-resistant pneumococci in Northern Ireland [letter; comment]. J Antimicrob Chemother 1998; 41:420–1. 74. Frisch AW, Tripp JW, Barrett CD, Pidgeon BE. The specific polysaccharide content of pneumonic lungs. J Exp Med 1942; 76:505–10. 75. Pan XS, Ambler J, Mehtar S, Fisher LM. Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother 1996; 40:2321–6. 76. Weiss K, Restieri C, Gauthier R, et al. A nosocomial outbreak of fluoroquinolone-resistant Streptococcus pneumoniae. Clin Infect Dis (in press). 77. Davidson RJ, de Azavedo J, Bast DJ, et al. Levofloxacin treatment failure of pneumococcal pneumonia and development of resistance during therapy [abstract 2103]. In: Programs and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (Toronto). Washington, DC: American Society for Microbiology, 2000: 127. 78. Fournier B, Zhao X, Lu T, Drlica K, Hooper DC. Selective targeting of topoisomerase IV and DNA gyrase in Staphylococcus aureus: different patterns of quinolone- induced inhibition of DNA synthesis. Antimicrob Agents Chemother 2000; 44:2160–5. 79. Pan XS, Ambler J, Mehtar S, Fisher LM. Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother 1996; 40:2321–6. 80. DiPersio JR, Jones RN, Barrett T, Doern GV, Pfaller MA. Fluoroquinolone-resistant Moraxella catarrhalis in a patient with pneumonia: report from the SENTRY Antimicrobial Surveillance Program (1998). Diagn Microbiol Infect Dis 1998; 32:131–5. 81. Georgiou M, Munoz R, Roman F, et al. Ciprofloxacin-resistant Haemophilus influenzae strains possess mutations in analogous positions of GyrA and ParC. Antimicrob Agents Chemother 1996; 40:1741–4. 82. Vila J, Ruiz J, Sanchez F, et al. Increase in quinolone resistance in a Haemophilus influenzae strain isolated from a patient with recurrent respiratory infections treated with ofloxacin. Antimicrob Agents Chemother 1999; 43:161–2. 83. Cunliffe NA, Emmanuel FX, Thomson CJ. Lower respiratory tract infection due to ciprofloxacin resistant Moraxella catarrhalis [letter]. J Antimicrob Chemother 1995; 36:273–4. 84. Deshpande LM, Jones RN. Antimicrobial activity of advanced-spectrum fluoroquinolones tested against more than 2000 contemporary bacterial isolates of species causing community-acquired respiratory tract infections in the United States (1999). Diagn Microbiol Infect Dis 2000; 37:139–42. 85. Lacy MK, Lu W, Xu X, et al. Pharmacodynamic comparisons of levofloxacin, ciprofloxacin, and ampicillin against Streptococcus pneumoniae in an in vitro model of infection. Antimicrob Agents Chemother 1999; 43:672–7. 86. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993; 37:1073–81. 87. Lode H, Borner K, Koeppe P. Pharmacodynamics of fluoroquinolones. Clin Infect Dis 1998; 27:33–9. 88. Wise R, Andrews JM, Marshall G, Hartman G. Pharmacokinetics and inflammatory-fluid penetration of moxifloxacin following oral or intravenous administration. Antimicrob Agents Chemother 1999; 43: 1508–10. 89. Preston SL, Drusano GL, Berman AL, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials [see comments]. JAMA 1998; 279:125–9. 90. Weiss K, Laverdiere M, Restieri C. Comparative activity of trovafloxacin and Bay 12–8039 against 452 clinical isolates of Streptococcus pneumoniae. J Antimicrob Chemother 1998; 42:523–5. 91. Hooper DC. New uses for new and old quinolones and the challenge of resistance. Clin Infect Dis 2000; 30:243–54. Antimicrobial Drug Use and Resistance • CID 2001:33 (Suppl 3) • S213