Background Fluoroquinolones are now recommended for the treatmentof respiratory tract infections due to Streptococcus pneumoniae,particularly when the isolates are resistant to ß-lactamantibiotics. Although pneumococci with reduced susceptibilityto fluoroquinolones have been identified, their prevalence hasnot been determined in a defined population.
Methods We performed susceptibility testing on 7551 isolatesof S. pneumoniae obtained from surveillance in Canada in 1988and from 1993 to 1998. Pneumococci with reduced susceptibilityto fluoroquinolones (defined as a minimal inhibitory concentrationof ciprofloxacin of at least 4 µg per milliliter) werefurther characterized. We also examined antibiotic prescriptionsdispensed in Canadian retail pharmacies.
Results Between 1988 and 1997, fluoroquinolone prescriptionsincreased from 0.8 to 5.5 per 100 persons per year. The prevalenceof pneumococci with reduced susceptibility to fluoroquinolonesincreased from 0 percent in 1993 to 1.7 percent in 1997 and1998 (P=0.01). Among adults, the prevalence increased from 1.5percent in 1993 and 1994 combined to 2.9 percent in 1997 and1998 combined. The prevalence was higher in isolates from olderpatients (2.6 percent among those 65 years of age or older vs.1.0 percent among those 15 to 64 years of age, P<0.001) andamong those from Ontario (1.5 percent, vs. 0.4 percent amongthose from the rest of Canada; P< 0.001). Fluoroquinoloneuse was greatest among the elderly and in Ontario. The 75 isolates(17 serotypes) of pneumococci with reduced susceptibility tofluoroquinolones were submitted by 40 laboratories in eightprovinces. Reduced susceptibility to fluoroquinolones was associatedwith resistance to penicillin.
Conclusions The prevalence of pneumococci with reduced susceptibilityto fluoroquinolones is increasing in Canada, probably as a resultof selective pressure from the increased use of fluoroquinolones.
Streptococcus pneumoniae is the most common bacterial causeof community-acquired pneumonia, meningitis, otitis media, andsinusitis. The emergence of resistance to antimicrobial agentscommonly used for the treatment of pneumococcal disease hasled to changes in recommended regimens of antimicrobial treatment.1,2,3,4,5The earlier fluoroquinolones, including norfloxacin, ciprofloxacin,and ofloxacin, have borderline activity against pneumococciat the recommended dosages and therefore are not recommendedfor the treatment of pneumococcal infections.6 However, withthe increase in the use of ciprofloxacin and the introductionof newer fluoroquinolones such as levofloxacin, grepafloxacin,and trovafloxacin that have greater in vitro activity againstS. pneumoniae, these agents are now being recommended for thetreatment of pneumococcal infections, including community-acquiredpneumonia, acute bacterial exacerbations of chronic bronchitis,and sinusitis.7,8,9
Although there is increasing evidence that antimicrobial resistanceis directly related to increased use, some question the needfor concern about the fluoroquinolones, since after 15 yearsof clinical use, there have been only occasional reports ofpneumococci with reduced susceptibility.4,10,11,12,13 However,the development of reduced susceptibility to fluoroquinolonesrequires sequential mutations, and one might thus expect a substantialdelay between the introduction of fluoroquinolones and the appearanceof clinically significant reductions in susceptibility.14,15,16,17To determine whether the susceptibility of pneumococci to fluoroquinoloneshas changed in Canada, we systematically examined pneumococcalisolates collected by the Canadian Bacterial Surveillance Networkbetween 1988 and 1998.
Methods
Members of the Canadian Bacterial Surveillance Network, whichconsists of private laboratories and community and university-affiliatedhospitals in all 10 provinces in Canada, were asked to collectthe first 20 consecutive clinical isolates and then all sterile-siteisolates of S. pneumoniae in 1988 and from October 1993 throughSeptember 1998. The date of collection, the source of the specimen,and the patient's age and sex were recorded on a standardizedform. Duplicate isolates from the same patient were excluded.
The isolates were transported on chocolate-agar slants or swabsto a central laboratory. On receipt, the isolates were confirmedto be S. pneumoniae by standard methods. After storage at –70°C,the isolates were thawed and subcultured on blood agar twicebefore susceptibility testing was undertaken. In vitro susceptibilitytesting was performed by broth microdilution according to theguidelines of the National Committee for Clinical LaboratoryStandards.18 To determine the minimal inhibitory concentration(MIC) for each isolate, the following concentrations of antimicrobialagents (in micrograms per milliliter) were tested, with theuse of doubling dilutions: penicillin G, 0.03 to 8; ciprofloxacin,0.06 to 64; gatifloxacin, 0.06 to 32; grepafloxacin, 0.06 to32; levofloxacin, 0.06 to 64; sparfloxacin, 0.06 to 64; trovafloxacin,0.06 to 32; moxifloxacin, 0.03 to 32; gemifloxacin, 0.03 to32; erythromycin, 0.12 to 16; clindamycin, 0.25 to 16; tetracycline,1 to 32; trimethoprim–sulfamethoxazole, 0.25 to 128 (trimethoprimcomponent); and chloramphenicol, 2 to 16. The antimicrobialagents were supplied by their manufacturers.
Pneumococci with reduced susceptibility to fluoroquinoloneswere defined as those for which the MIC of ciprofloxacin wasat least 4 µg per milliliter. This degree of resistanceis associated with mutations in the fluoroquinolone-resistance–determiningregions of genes encoding DNA topoisomerase IV (parC) and DNAgyrase A (gyrA).14,16,17 Moreover, this MIC is above the usualpeak serum concentration of ciprofloxacin. The isolates wereclassified as susceptible to penicillin (MIC, 0.06 µgper milliliter), of intermediate susceptibility to penicillin(MIC, >0.06 to <2.0 µg per milliliter), or resistantto penicillin (MIC, 2.0 µg per milliliter). The interpretivestandards for MICs of the National Committee for Clinical LaboratoryStandards were also used to classify pneumococcal isolates assusceptible, of intermediate susceptibility, or resistant tothe other antimicrobials tested.18 Because of the relativelysmall numbers of isolates in 1993 and 1998, in some places wereport combined data for 1993 and 1994 and for 1997 and 1998.
All isolates with MICs of ciprofloxacin of at least 4 µgper milliliter were serotyped by the National Reference Centerfor Streptococcus (Edmonton, Alta.) with the use of type-specificantiserum.19 The genomic DNA of two groups of 12 and 14 randomlychosen isolates with MICs of ciprofloxacin of 1 µg permilliliter and 2 µg per milliliter, respectively, as wellas all isolates with MICs of ciprofloxacin of at least 4 µgper milliliter, were examined by pulsed-field gel electrophoresisafter digestion with SmaI in order to clarify clonal relationships.20,21These isolates were further characterized by polymerase-chain-reactionand restriction-fragment–length polymorphism analysiswith HinfI for the most commonly recognized mutations in parCand gyrA associated with resistance to fluoroquinolones thathave previously been described in Staphylococcus aureus andEscherichia coli.22,23
Differences in group proportions were assessed with the chi-squaretest or Fisher's exact test. The Wilcoxon rank-sum test or single-factoranalysis of variance was used for comparison of means. Multivariatelogistic-regression modeling with SAS software (version 6.12,SAS Institute, Cary, N.C.) was used to test the associationsin isolates of pneumococci between reduced susceptibility tofluoroquinolones and other characteristics of the isolates.Variables in the logistic-regression modeling included thoseassociated with resistance in univariate analysis (P<0.10).
IMS HEALTH, Canada, provided an estimate of the total numberof antibiotic prescriptions dispensed in Canadian retail pharmaciesbased on a representative sample of 2000 pharmacies stratifiedaccording to type, size, and province. A representative sampleof 652 office-based physicians stratified according to provinceand specialty was used to provide total estimated fluoroquinoloneuse according to age group. Demographic information based onnational census data for the country and provinces was obtainedfrom Statistics Canada.
Results
Between 1988 and 1998, members of the Canadian Bacterial SurveillanceNetwork submitted 7551 isolates of S. pneumoniae to the surveillanceprogram. The number of participating centers was 15 in 1988,24 in 1993, and from 42 to 141 between 1994 and 1998. Nineteenprivate laboratories serving physicians' offices and nursinghomes submitted 1303 isolates (17 percent of the total), and162 laboratories in hospitals (with a median of 360 beds perhospital and a range of 36 to 837) submitted the remaining 6248(83 percent of the total). The median number of isolates submittedper center was 21 (range, 1 to 760).
Of the isolates, 2630 (35 percent) were from blood or othersterile sites (2411 from blood, 101 from cerebrospinal fluid,and 118 from other sterile fluids), 2769 (37 percent) were fromthe respiratory tract (1910 from sputum, 337 from bronchoscopicspecimens, 246 from nasal or sinus specimens, 238 from pharyngealspecimens, and 38 from other respiratory tract specimens), and2073 (27 percent) were from other sites (1482 from eye swabs,522 from ear swabs, and 69 from other sites). The source of79 isolates (1.0 percent) was not specified.
The patient's age was requested on surveillance forms in allyears except 1988. The patient's age was provided for 6335 of7551 isolates (84 percent); among these, 2311 specimens werefrom children under 15 years of age (36 percent), 2060 werefrom adolescents and adults 15 to 64 years of age (33 percent),and 1964 were from adults 65 years of age or older (31 percent).
Overall, 684 isolates (9.1 percent) were not susceptible topenicillin (resistant or of intermediate susceptibility). Theprevalence of isolates that were not susceptible to penicillinincreased from 2.4 percent (4 of 166) in 1988 to 13.9 percent(256 of 1844) in 1997 and 1998 combined. Over the same period,the rate of resistance to macrolides increased from 1.2 percent(2 of 166) to 6.7 percent (124 of 1844), resistance to trimethoprim–sulfamethoxazoleincreased from 1.8 percent (3 of 163) to 11.6 percent (207 of1791), and resistance to tetracycline increased from 2.4 percent(4 of 166) to 6.9 percent (128 of 1844).
The overall prevalence of pneumococci with reduced susceptibilityto fluoroquinolones was 1.0 percent (75 of 7551). The prevalenceincreased from 0 percent (0 of 327) in 1988 and 1993 to 1.7percent (32 of 1844) in 1997 and 1998 (P=0.01). No pneumococciwith reduced susceptibility to fluoroquinolones were obtainedfrom children. Among adults, the prevalence increased from 1.5percent (24 of 1566) in 1993 and 1994 combined to 2.9 percent(29 of 1016) in 1997 and 1998 combined. The greatest changewas seen among people 15 to 64 years of age, in whom the percentageof pneumococcal isolates with reduced susceptibility to fluoroquinolonesincreased from 0.5 percent (4 of 833) in 1993 and 1994 to 2.0percent (10 of 492) in 1997 and 1998 (Figure 1). The prevalenceof pneumococci with reduced susceptibility to fluoroquinoloneswas higher in isolates from elderly patients (2.6 percent [51of 1964] in those 65 years of age or older, as compared with1.0 percent [20 of 2060] in those 15 to 64 years of age; P<0.001)and in those from Ontario (1.5 percent [60 of 4090], vs. 0.4percent [15 of 3461] among those from the rest of Canada; P<0.001).These findings were consistent in all years for which data wereavailable.
Figure 1. Fluoroquinolone Prescriptions per Capita (Curve) and Frequency of Pneumococci with Reduced Susceptibility to Fluoroquinolones in Canada According to the Patient's Age (Bars).
No isolates with reduced susceptibility were identified for persons who were younger than 15 years. Solid bars indicate an age of 15 to 64 years, and open bars an age of 65 years or older. Data on per capita fluoroquinolone prescriptions were obtained from 1988 through 1997, and data on the frequency of pneumococci with decreased susceptibility to fluoroquinolones in each age group were obtained in 1988 and in 1993 through 1998. No isolates with reduced susceptibility were identified in 1988 or 1993.
Overall, the number of fluoroquinolone prescriptions increasedfrom 0.8 to 5.5 per 100 persons per year between 1988 and 1997(Figure 1). Per capita fluoroquinolone use was greatest amongthe elderly and in Ontario. Between 1993 and 1997 the numberof fluoroquinolone prescriptions ranged from 13 to 18 per 100persons per year among people 65 or older. In the province ofOntario, there was an increase from less than 1 per 100 in 1988to 6.8 per 100 in 1997. In addition to the increase in the prevalenceof pneumococci with reduced susceptibility to fluoroquinolones,the degree of reduction in susceptibility to fluoroquinolonesalso changed. From 1994 to 1998, there was a statistically significantincrease in the proportion of isolates with an MIC of ciprofloxacinof at least 32 µg per milliliter (P=0.04).
The 75 pneumococcal isolates with reduced susceptibility tofluoroquinolones were obtained from 40 different laboratories(38 hospital-based and 2 private) located in eight provinces.Seventeen different serotypes were identified among 73 isolatessuccessfully serotyped. The most frequent serotypes were 11A(nine isolates); 23F (eight isolates); 9V (seven isolates);6A, 6B, and 9N (six isolates each); 22F (five isolates); and14 (four isolates). With the exception of two serotype 3 isolateswith the same electrophoretic pattern identified from the samelaboratory in the same year, serotyping and pulsed-field gelelectrophoresis revealed no clustering of pneumococci with reducedsusceptibility to fluoroquinolones. The 10 isolates with MICsof ciprofloxacin of at least 32 µg per milliliter were3 isolates of serotype 11A (2 clonally related according toelectrophoresis), 2 of serotype 19F (clonally distinct accordingto electrophoresis), and 1 each of serotypes 6A, 6B, 9V, 18A,and 19A.
The increases in the MIC of ciprofloxacin were paralleled byincreases in the MICs of the other fluoroquinolones. In general,the newer fluoroquinolones had MICs that were lower than thatof ciprofloxacin by a factor of at least four, with gemifloxacinhaving the greatest in vitro activity against S. pneumoniae(Table 1). Mutations in the fluoroquinolone-resistance–determiningregion of the parC and gyrA genes encoding subunits of topoisomeraseIV and DNA gyrase A have been found in isolates with decreasedsusceptibility to fluoroquinolones.22 After HinfI restriction-fragment–lengthpolymorphism analysis, 12 randomly chosen isolates with MICsof ciprofloxacin of no more than 1 µg per milliliter didnot have evidence of mutations at the key Asp80–Ser81(gyrA) or Asp78–Ser79 (parC) loci. In contrast, 5 of 14isolates associated with MICs of ciprofloxacin of 2 µgper milliliter (36 percent), 21 of 41 with MICs of 4 µgper milliliter (51 percent), 11 of 13 with MICs of 8 µgper milliliter (85 percent), and 21 of 21 with MICs of at least16 µg per milliliter (100 percent) (P<0.001) were foundto have these mutations. The proportion of isolates with mutationsdemonstrable by HinfI restriction-fragment–length polymorphismanalysis in both parC and gyrA also increased with increasingMICs of ciprofloxacin. Twelve of 21 isolates associated withMICs of at least 16 µg per milliliter (57 percent) hadthese mutations in both parC and gyrA, as compared with 2 of13 for which the MIC was 8 µg per milliliter (15 percent)and 1 of 41 for which the MIC was 4 µg per milliliter(2 percent) (P<0.001).
Table 1. In Vitro Activity of Selected Fluoroquinolones against 75 Pneumococcal Isolates with MICs of Ciprofloxacin of 4 µg per Milliliter Collected in Canada from 1994 through 1998.
According to univariate analysis, pneumococci with reduced susceptibilityto fluoroquinolones were significantly more likely to be isolatedfrom older patients, from respiratory tract specimens, frompatients in the province of Ontario, and during the later yearsof surveillance (Table 2). Pneumococci with reduced susceptibilityto fluoroquinolones were also significantly more likely to beresistant to penicillin (relative risk, 5.0; 95 percent confidenceinterval, 2.5 to 10), trimethoprim–sulfamethoxazole (relativerisk, 3.9; 95 percent confidence interval, 2.2 to 7.0), andtetracycline (relative risk, 2.7; 95 percent confidence interval,1.2 to 5.8). According to multivariate analysis, pneumococciwith reduced susceptibility to fluoroquinolones were significantlymore likely to be isolated from older patients, from respiratorytract specimens, from patients in Ontario, and during the lateryears of surveillance, and were also more likely to be resistantto penicillin (Table 3). Secondary analysis using only the 3278isolates from laboratories that submitted isolates in all fouryears between 1994 and 1997 yielded the same associations asthe primary analysis (data not shown).
Table 3. Multivariate Analysis of Factors Associated with Reduced Susceptibility to Fluoroquinolones in Isolates of Streptococcus pneumoniae.
Discussion
This study provides evidence that the increase in the use offluoroquinolones in Canada is associated with an increase inthe frequency and degree of reduced susceptibility to fluoroquinolonesamong pneumococci, especially among penicillin-resistant S.pneumoniae. Previous studies have shown strong associationsbetween the use of antimicrobial agents in the community andthe emergence of antimicrobial resistance in a number of organisms.24,25,26,27,28,29Our study demonstrates that the prevalence of pneumococci withreduced susceptibility to fluoroquinolones not only increasedover time but also was associated with the age group (persons65 or older) and geographic location (Ontario) with the highestper capita use of fluoroquinolones.
Pneumococci with reduced susceptibility to fluoroquinoloneswere reported by 40 of the participating laboratories. Serotypingand pulsed-field gel electrophoresis demonstrated that the pneumococciwith reduced susceptibility to fluoroquinolones were of multipleclones and serotypes, suggesting that new resistance is developingin multiple indigenous strains. Together, these results furthersupport the hypothesis that selective pressure applied to manystrains simultaneously is the important determinant of the emergenceof resistance. However, the increased prevalence of pneumococciwith reduced susceptibility to fluoroquinolones might also resultfrom clonal dissemination.30 The dramatic increase in S. pneumoniaethat are not susceptible to penicillin in Iceland, resultingfrom the spread of a serotype 6B clone, and the well-documentedinternational dissemination of a multiresistant serotype 23Fclone, serve as reminders of the efficiency with which a fit,resistant pneumococcal strain can spread.31,32,33,34,35
Penicillin resistance is a marker for resistance to other antimicrobialagents, including trimethoprim–sulfamethoxazole, erythromycin,and tetracycline.1,3,4,5,36,37 However, there are conflictingreports about the relation between penicillin resistance andreduced susceptibility to fluoroquinolones in S. pneumoniae.4,38,39,40,41Our results suggest that the relation exists but may be difficultto detect, because ß-lactam use is highest among children,whereas fluoroquinolones are used mainly by adults. This associationis of particular concern, since the current and future fluoroquinoloneswith enhanced activity against S. pneumoniae will be targetedfor use against infections due to penicillin-resistant S. pneumoniae.8,9
As with penicillin resistance, there can be both regional andtemporal variation in the prevalence of pneumococci with reducedsusceptibility to fluoroquinolones.42,43,44,45,46 Participationin the Canadian Bacterial Surveillance Network is voluntary,and the participation of specific centers varies from year toyear. Therefore, these data cannot be used to examine detailedregional differences, and the Canadian population is not fullyrepresented. However, the consistency of identified associationsin the secondary analysis and the fact that the rates of penicillinresistance in this system are very similar to those reportedby other Canadian surveillance systems support the data presented.10Nonetheless, these data need to be confirmed in studies of surveillancedata from other geographic areas, and ongoing surveillance isrequired to assess the evolution of pneumococci with reducedsusceptibility to fluoroquinolones in Canada and in other countries.
Further increases in both the prevalence and the degree of reducedsusceptibility to fluoroquinolones can be anticipated if fluoroquinoloneuse continues to increase. As the prevalence of penicillin-resistantpneumococci and multiresistant strains has increased, therehas been a growing impetus to use fluoroquinolones in children,who are major reservoirs of pneumococci. The potential roleof fluoroquinolones in pediatric infections has long been underconsideration.47 Studies approved by the Food and Drug Administrationare currently investigating the use of newer fluoroquinolonesin children (McCracken GH Jr: personal communication). Clinicalisolates associated with MICs of newer fluoroquinolones of atleast 8 µg per milliliter have already been described.13,48,49If the value of this important group of antimicrobial agentsis to be preserved, it is essential not only to control theirinappropriate use but also to learn which fluoroquinolones,and which doses and durations of therapy, will minimize theselection of resistant bacteria.50,51,52
Supported in part by a grant from the Canadian Bacterial DiseasesNetwork.
* The other members of the Canadian Bacterial Surveillance Networkare listed in the Appendix.
Source Information
From the Departments of Medicine (D.K.C., A.M., D.E.L.) and Laboratory Medicine and Pathobiology (A.M., J.C.A., D.E.L.), University of Toronto; and the Departments of Microbiology, Mount Sinai Hospital and Toronto Hospital (A.M., J.C.A., D.E.L.) — all in Toronto.
Address reprint requests to Dr. Low at the Department of Microbiology, Mount Sinai Hospital, 600 University Ave., Toronto, ON M5G 1X5, Canada, or at dlow{at}mtsinai.on.ca.
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Appendix
Other investigators of the Canadian Bacterial Surveillance Networkare as follows: C. Duncan, L. Trpeski, D. Libertucci, S. Pong-Porter,and D. Bast (Mount Sinai Hospital, Toronto); R. Davidson andK. Forward (Queen Elizabeth II Health Sciences Centre, Halifax,N.S.); L. Mandell (McMaster University, Hamilton, Ont.); A.Simor (Sunnybrook Health Science Centre, Toronto); D. Hobanand G. Zhanel (University of Manitoba, Winnipeg); M. Laverdiereand K. Weiss (Hôpital Maisonneuve-Rosemont, Universityof Montreal, Montreal); L. Abbott (Queen Elizabeth Hospital,Charlottetown, P.E.I.); J. Blondeau (St. Paul's Hospital andUniversity of Saskatchewan, Saskatoon); G. Murray (Centre HospitalierUniversitaire de Québec St. Sacrement, Sainte Foy); G.Randhawa (Kelowna General Hospital, Kelowna, B.C.); G. Hardingand S. Hoban (St. Boniface General Hospital, Winnipeg, Man.);D. Hinds (Richmond Hospital, Richmond, B.C.); C. Gaudreau (CampusSaint-Luc, Centre Hospitalier de l'Université de Montréal,Montreal); R. Roy (Vernon Jubilee Hospital, Vernon, B.C.); D.Groves (St. Joseph's Hospital, Hamilton, Ont.); M. Bergeron(Université Laval, Quebec, Que.); D. Gregson (St. Joseph'sHealth Centre, London, Ont.); P. Jessamine and B. Toye (OttawaCivic Hospital and Ottawa General Hospital, Ottawa, Ont.); P.Kibsey (Victoria General Hospital, Victoria, B.C.); R. Rennie,University of Alberta Hospitals, Edmonton); P. Turgeon (HôpitalSaint-Luc and Université de Montréal, Montreal);P. Leighton (Dr. Everett Chalmers Hospital, Fredericton, N.B.);L. Thibault (Dr. Georges L. Dumont Hospital, Moncton, N.B.);M. Kuhn (Moncton Hospital, Moncton, N.B.); R. Lewis (Cape BretonRegional Hospital, Sydney, N.S.); P. Jutras (Centre HospitalierRégional de Rimouski, Rimouski, Que.); D. Church (CalgaryLaboratory Services, Calgary, Alta.); J. Nigrin, E. Blondel-Hill,and J. Galbraith (Dynacare Kasper Medical Laboratories, Edmonton,Alta.); M. Lovgren (National Centre for Streptococcus, Edmonton,Alta.); and J.M. Hutchinson (Health Sciences Centre, St. John's,Newf.).
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Morosini, M.-I., Loza, E., del Campo, R., Almaraz, F., Baquero, F., Canton, R.
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47: 2692-2695
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Dean, N. C.
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Waterer, G. W., Buckingham, S. C., Kessler, L. A., Quasney, M. W., Wunderink, R. G.
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Davies, T. A., Goldschmidt, R., Pfleger, S., Loeloff, M., Bush, K., Sahm, D. F., Evangelista, A.
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Jacobs, M. R., Felmingham, D., Appelbaum, P. C., Gruneberg, R. N., the Alexander Project Group,
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Chow, K. M., Szeto, C. C.
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Balsalobre, L., Ferrandiz, M. J., Linares, J., Tubau, F., de la Campa, A. G.
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47: 2072-2081
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Hsueh, P.-R., Teng, L.-J., Wu, T.-L., Yang, D., Huang, W.-K., Shyr, J.-M., Chuang, Y.-C., Wan, J.-H., Yan, J.-J., Lu, J.-J., Wu, J.-J., Ko, W.-C., Chang, F.-Y., Yang, Y.-C., Lau, Y.-J., Liu, Y.-C., Lee, C.-M., Leu, H.-S., Liu, C.-Y., Luh, K.-T.
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47: 2145-2151
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Karlowsky, J. A., Thornsberry, C., Critchley, I. A., Jones, M. E., Evangelista, A. T., Noel, G. J., Sahm, D. F.
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47: 1790-1797
[Abstract][Full Text]
Zhanel, G. G., Palatnick, L., Nichol, K. A., Bellyou, T., Low, D. E., Hoban, D. J.
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Cottagnoud, P., Pfister, M., Cottagnoud, M., Acosta, F., Tauber, M. G.
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47: 1943-1947
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Cha, R., Rybak, M. J.
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47: 1984-1987
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Chaitram, J. M., Jevitt, L. A., Lary, S., Tenover, F. C.
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Johnson, C. N., Benjamin, W. H. Jr., Moser, S. A., Hollingshead, S. K., Zheng, X., Crain, M. J., Nahm, M. H., Waites, K. B.
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Gonzales, R.
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Brown, R. B., Iannini, P., Gross, P., Kunkel, M.
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[Abstract][Full Text]
0.06 µg per milliliter), of intermediate susceptibility to penicillin (MIC, >0.06 to <2.0 µg per milliliter), or resistant to penicillin (MIC, 
2.0 µg per milliliter). The interpretive standards for MICs of the National Committee for Clinical Laboratory Standards were also used to classify pneumococcal isolates as susceptible, of intermediate susceptibility, or resistant to the other antimicrobials tested.18 Because of the relatively small numbers of isolates in 1993 and 1998, in some places we report combined data for 1993 and 1994 and for 1997 and 1998. 
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