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The prevalence of fluoroquinolone resistance among clinically significant respiratory tract isolates of Streptococcus pneumoniae in the United States and Canada—1997 results from the SENTRY Antimicrobial Surveillance Program
The Prevalence of Fluoroquinolone Resistance Among Clinically Significant Respiratory Tract Isolates of Streptococcus pneumoniae in the United States and Canada—1997 Results from the SENTRY Antimicrobial Surveillance Program Gary V. Doern, Michael A. Pfaller, Meridith E. Erwin, Angela B. Brueggemann, and Ronald N. Jones
As part of the SENTRY antimicrobial resistance surveillance program, a total of 1100 clinically significant respiratory tract isolates of Streptococcus pneumoniae were tested for susceptibility to six fluoroquinolone antimicrobial agents: ciprofloxacin, levofloxacin, gatifloxacin, grepafloxacin, sparfloxacin, and trovafloxacin. Isolates were obtained during the 5-month period, February to June, 1997 from 27 United States medical center laboratories and seven laboratories in Canadian health care institutions. All testing was performed in a single center. Of 1100 test strains, 3 (0.3%), all from different U.S. centers, were fluoroquinolone resistant. Among the remaining 1097
fluoroquinolone-susceptible isolates, the rank order of activity among the six agents tested in this study was grepafloxacin (modal MIC 5 0.25 mg/mL) 5 trovafloxacin (modal MIC 5 0.25 mg/mL) 5 sparfloxacin (0.25 mg/mL) . gatifloxacin (0.5 mg/mL) . levofloxacin (1 mg/mL) 5 ciprofloxacin (1 mg/mL). Fluoroquinolone resistance is currently uncommon among respiratory tract isolates of S. pneumoniae in North America, but there exist clear differences between the in vitro activities of different fluoroquinolones for this organism. © 1998 Elsevier Science Inc.
Antimicrobial resistance has emerged as a significant problem with clinical isolates of Streptococcus pneumoniae in North America. Current rates of penicillin resistance are 43.8% in the United States and 30.2% in Canada (Doern et al. 1998). Because of the mechanism of penicillin resistance, i.e., altered penicillin binding proteins (PBPs), the antipneumococcal activ-
ity of other b-lactam antimicrobials such as amoxicillin/clavulanate and the cephalosporins has also diminished dramatically (Doern et al. 1998). Resistance has also emerged with non-b-lactam agents. Currently in the U.S., among clinical isolates of S. pneumoniae, overall rates of resistance to the macrolides, tetracycline, chloramphenicol, trimethoprim/ sulfamethoxazole (TMP/SMX) and clindamycin exists at levels of approximately 13%, 10%, 5%, 23%, and 3%, respectively (Doern et al. 1998). In view of the scope and magnitude of the problem of antimicrobial resistance with S. pneumoniae, consideration is now being given to the use of nontraditional regimens in the management of pneumo-
From the Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa. Address reprint requests to Dr. Gary V. Doern, Department of Pathology, C606 GH, University of Iowa College of Medicine, Iowa City, IA 52242. Received 01 June 1998; revised and accepted 01 July 1998.
DIAGN MICROBIOL INFECT DIS 1998;32:313–316 © 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0732-8893/98/$19.00 PII S0732-8893(98)00081-9
Doern et al.
314 coccal infections. One such class of agents is the fluoroquinolones. Ciprofloxacin and ofloxacin, two fluoroquinolones that have been available for human use in North America for several years, have generally not been used extensively in the management of infections caused by S. pneumoniae. Minimum inhibitory concentrations of these agents versus typical isolates are relatively high (MIC90 values of 1–2 mg/ mL) (Ballow et al. 1997; Brueggemann et al. 1997; Jones et al. 1994), and at least with ciprofloxacin, mutation to resistance while on therapy is well described (Perez-Trallero et al. 1990). Newer fluoroquinolones with either equivalent in vitro activity and a more favorable pharmacokinetic/pharmacodynamic profile (e.g., levofloxacin) or with both greater potency for S. pneumoniae as well as more desirable pharmacologic characteristics (e.g., sparfloxacin, gatifloxacin, grepafloxacin and trovafloxacin) have been introduced recently or are in advanced stages of development. The question arises what are the rates of fluoroquinolone resistance with current clinical isolates of S. pneumoniae in North America. Only two published studies have examined this issue systematically in the U.S. (Ballow et al. 1997; Brueggemann et al. 1997). The first, performed in 1994 –95, characterized 404 isolates of S. pneumoniae obtained from patients with various infections in 30 different U.S. medical centers (Brueggemann et al. 1997). Two isolates (0.5%) with apparent high-level fluoroquinolone resistance were detected. The second was an investigation that examined 2,542 clinical isolates of S. pneumoniae from 187 U.S. health care centers collected during the last 6 months of 1996 (Ballow et al. 1997). Using sparfloxacin as an indicator, eight fluoroquinoloneresistant strains (0.3%) were detected. There have been no published studies documenting nationwide rates of fluoroquinolone resistance with S. pneumoniae in Canada.
In an attempt to provide a more current data base, 1100 clinical isolates of S. pneumoniae recovered from patients with respiratory tract infections between February and June of 1997 were characterized. These patients had been seen in 27 different U.S. medical centers (n 5 890 isolates) and in seven different Canadian health care institutions (n 5 210 isolates) as part of the multinational SENTRY antimicrobial resistance surveillance program. Isolates were forwarded to the University of Iowa College of Medicine (Iowa City, IA) for species characterization and antimicrobial susceptibility testing. A detailed description of this study including rates of resistance to various non-fluoroquinolone antimicrobials has published elsewhere (Doern et al. 1998). Minimum inhibitory concentrations of ciprofloxacin, levofloxacin, gatifloxacin, grepafloxacin, sparfloxacin, and trovafloxacin were determined with all isolates using a microdilution method in MuellerHinton broth supplemented with 3% lysed horse blood according to the recommendations of the National Committee for Clinical Laboratory Standards (NCCLS) (5). Microdilution trays were incubated for 20 to 24 h at 35°C in ambient air before determining MIC values. The final inoculum concentration was approximately 5 3 105 CFU/mL. A strain of S. pneumoniae (ATCC 49619) served as a control. Table 1 lists the MICs obtained with the S. pneumoniae isolates examined in this study. There existed a clear rank order of in vitro activity among the fluoroquinolones tested in this investigation; grepafloxacin 5 trovafloxacin 5 sparfloxacin . gatifloxacin . levofloxacin 5 ciprofloxacin. In this collection of 1100 isolates of S. pneumoniae, 3 (0.3%) had conspicuously higher MICs compared with those obtained with the remainder of the organism collection. These strains are highlighted in Table 1 and generally had MICs 8- to 32-fold higher than the modal MIC values obtained with the other isolates. These
TABLE 1 Fluoroquinolone MIC Frequency Distributions Obtained with 1,100 Isolates of S. pneumoniae Collected in the U.S. and Canada During the First 6 Months of 1997 Antimicrobial Agent
0.03
0.06
0.12
0.25
0.5
1
2
4
8
16
32
Geometric mean MICa
Ciprofloxacin Levofloxacin Gatifloxacin Sparfloxacin Grepafloxacinc Trovafloxacin
—b — — — 1 8
— — 5 — 26 36
— — 60 116b 377 158
13 — 247 619 589 709
82 68 769 352 44 185
557 625 12 10 0 1
443 398 4 0 0 0
2 6 0 0 2 2
0 0 3 2 1 1
1 1 0 1 0 0
2 2 0 0 0 0
1.2 1.3 0.4 0.3 0.2 0.2
a
Number of Isolates with an MIC (mg/mL) of:
The geometric mean MICs were calculated based on the MICs of the apparently susceptible isolates, i.e., the MICs of the three presumed resistant strains were deleted from these calculations. The three strains highlighted in the ciprofloxacin row were the same three strains highlighted in the levofloxacin, gatifloxacin, sparfloxacin, and trovafloxacin rows. b Indicates that this concentration was not tested. c Grepafloxacin was tested against 1040 of the 1100 isolates.
Note strains of S. pneumoniae had been isolated from sputa obtained from elderly patients in three distinct areas of the U.S. (Wilmington, DE; Rochester, NY; Omaha, NE). Molecular characterization of these strains using PCR and then amplicon sequence analysis (Gootz et al. 1996; Pan et al. 1996) revealed all three to harbor a par C mutation resulting in a phenylalanine substitution at the serine79 residue of the C subunit of topoisomerase IV and a gyr A mutation resulting in a phenylalanine substitution at the serine83 residue of the A subunit of DNA gyrase. Based on the distinctly higher MICs of these three strains together with the fact that all three had mutations in both the par C and gyr A genes that are associated with fluoroquinolone resistance, we presume these isolates to be resistant. The question, of course, is whether these isolates of S. pneumoniae fail therapy if treated with standard dosages of the six fluoroquinolones examined in this study. One approach to answering this question is to compare the MICs of individual fluoroquinolones versus these strains to the 24-h serum AUCs obtained with the same agents. A 24-h serum AUC/ MIC ratio of approximately 100 is thought to be predictive of a favorable outcome when patients are treated with fluoroquinolones (Craig 1998). Based on this assumption, none of the six fluoroquinolones examined in this study would be likely to effectively treat infections attributable to organisms such as the three we identified with uniformly higher MICs. In other words, all three isolates seem to be clinically
315 resistant and there was complete cross resistance between the six study drugs. In conclusion, the results of this study confirm previous observations regarding the relative activity of ciprofloxacin, levofloxacin, grepafloxacin, gatifloxacin, sparfloxacin, and trovafloxacin versus S. pneumoniae (Brueggemann et al. 1997; Eliopoulos et al. 1993; Jones et al. 1998a, 1998b; Plouffe et al. 1996; Wakebe et al. 1994). Secondly, accepting the difficulty in defining what precisely constitutes fluoroquinolone resistance with S. pneumoniae, current rates of high-level resistance seem to exist at very low levels in North America; 3 of 890 isolates (0.3%) were resistant in the U.S.; no resistant strains were noted among 210 isolates in Canada. In light of the roughly equivalent rates of resistance reported in two recent surveillance studies (Ballow et al. 1997; Brueggemann et al. 1997), it seems that quinolone resistance is not increasing in prevalence in North America. However, with respect to the potential for the further emergence of resistance, these observations also serve as an important baseline on which to assess the effect of more extensive use of fluoroquinolones in the future to treat pneumococcal infections.
The authors thank Ms. Kay Meyer for her excellent secretarial assistance. The study was supported by a grant from BristolMyers Squibb and Company.
REFERENCES Ballow CH, Jones RN, Johnson DM, Deinhart JA, Schentag JJ, the SPAR Study Group (1997) Comparative in vitro assessment of sparfloxacin activity and spectrum using results from over 14,000 pathogens isolated at 190 medical centers in the USA. Diagn Microbiol Infect Dis 29: 173–186. Brueggemann AB, Kugler KC, Doern GV (1997) In vitro activity of BAY 12-8039, a novel 8-methoxyquinolone, compared to activities of six fluoroquinolones against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrob Agents Chemother 41: 594–1597. Craig WA (1997) Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–12. Doern GV, Pfaller MA, Kugler K, Freeman J, Jones RN (1998) Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY Antimicrobial Surveillance Program. Clin Infect Dis (Accepted for publication) Eliopoulos GM, Klimm K, Eliopoulos CT, Ferraro MJ, Moellering Jr RC (1993) In vitro activity of CP-99,219, a new fluoroquinolone, against clinical isolates of Gram-
positive bacteria. Antimicrob Agents Chemother 37:366– 370. Gootz TD, Zaniewski R, Haskell S, Schmieder B, Tankovic J, Girard D, Courvalin P, Polzer RJ (1996) Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyprase and topoisomerase IV mutants of Streptococcus pneumoniae selected in vitro. Antimicrob Agents Chemother 40:2691–2697. Jones RN, Hoban DJ, The North American Ofloxacin Study Group (1994) North American (United States and Canada) comparative susceptibility of two fluoroquinolones: Ofloxacin and ciprofloxacin. A 53-medical center sample of spectra of activity. Diagn Microbiol Infect Dis 18:49–56. Jones RN, Ballow CH, Schentag JJ, Johnson DM, Deinhart JA, the SPAR Study Group (1998a) In vitro evaluation of sparfloxacin activity and spectrum Against 24,940 pathogens isolated in the United States and Canada, the final analysis. Diagn Microbiol Infect Dis 30:1–21. Jones RN, Johnson DM, Erwin ME, Beach ML, Biedenbach DJ, Pfaller MA, the Quality Control Study Group (1998b) Comparative antimicrobial activity of gatifloxacin tested against Streptococcus spp. including quality
316
control guidelines and Etest method validation. Diagn Microbiol Infect Dis (accepted for publication). National Committee for Clinical Laboratory Standards (1997) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. Approved standard M7–A4. National Committee for Clinical Laboratory Standards, Wayne, PA. Pan X-S, Ambler J, Mehtar S, Fisher LM (1996) Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother 40:2321–2326. Perez-Trallero E, Garcia-Arenzana JM, Jimenez JA, Peris A (1990) Therapeutic failure and selection of resistance to quinolones in a case of pneumococcal pneumonia
Doern et al.
treated with ciprofloxacin. Eur J Clin Microbiol Infect Dis 9:905–906. Plouffe JF, the Franklin County Pneumonia Study Group (1996) Levofloxacin in vitro activity against bacteremic isolates of S. pneumoniae. Diagn Microbiol Infect Dis 25: 43–45. Trautmann M, Ruhnke M, Borner K, Wagner J, Koeppe P (1996) Pharmacokinetics of sparfloxacin and serum bactericidal activity against pneumococci. Antimicrob Agents Chemother 40:776–779. Wakebe H, Imada T, Yoneda H, Mukai F, Ohguro K, Ohmori K, Tamaoka H, Yabuuchi Y (1994) Evaluation of OPC-17116 against important pathogens that cause respiratory tract infections. Antimicrob Agents Chemother 38:2340–2345.
As part of the SENTRY antimicrobial resistance surveillance program, a total of 1100 clinically significant respiratory tract isolates of Streptococcus pneumoniae were tested for susceptibility to six fluoroquinolone antimicrobial agents: ciprofloxacin, levofloxacin, gatifloxacin, grepafloxacin, sparfloxacin, and trovafloxacin. Isolates were obtained during the 5-month period, February to June, 1997 from 27 United States medical center laboratories and seven laboratories in Canadian health care institutions. All testing was performed in a single center. Of 1100 test strains, 3 (0.3%), all from different U.S. centers, were fluoroquinolone resistant. Among the remaining 1097
fluoroquinolone-susceptible isolates, the rank order of activity among the six agents tested in this study was grepafloxacin (modal MIC 5 0.25 mg/mL) 5 trovafloxacin (modal MIC 5 0.25 mg/mL) 5 sparfloxacin (0.25 mg/mL) . gatifloxacin (0.5 mg/mL) . levofloxacin (1 mg/mL) 5 ciprofloxacin (1 mg/mL). Fluoroquinolone resistance is currently uncommon among respiratory tract isolates of S. pneumoniae in North America, but there exist clear differences between the in vitro activities of different fluoroquinolones for this organism. © 1998 Elsevier Science Inc.
Antimicrobial resistance has emerged as a significant problem with clinical isolates of Streptococcus pneumoniae in North America. Current rates of penicillin resistance are 43.8% in the United States and 30.2% in Canada (Doern et al. 1998). Because of the mechanism of penicillin resistance, i.e., altered penicillin binding proteins (PBPs), the antipneumococcal activ-
ity of other b-lactam antimicrobials such as amoxicillin/clavulanate and the cephalosporins has also diminished dramatically (Doern et al. 1998). Resistance has also emerged with non-b-lactam agents. Currently in the U.S., among clinical isolates of S. pneumoniae, overall rates of resistance to the macrolides, tetracycline, chloramphenicol, trimethoprim/ sulfamethoxazole (TMP/SMX) and clindamycin exists at levels of approximately 13%, 10%, 5%, 23%, and 3%, respectively (Doern et al. 1998). In view of the scope and magnitude of the problem of antimicrobial resistance with S. pneumoniae, consideration is now being given to the use of nontraditional regimens in the management of pneumo-
From the Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa. Address reprint requests to Dr. Gary V. Doern, Department of Pathology, C606 GH, University of Iowa College of Medicine, Iowa City, IA 52242. Received 01 June 1998; revised and accepted 01 July 1998.
DIAGN MICROBIOL INFECT DIS 1998;32:313–316 © 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0732-8893/98/$19.00 PII S0732-8893(98)00081-9
Doern et al.
314 coccal infections. One such class of agents is the fluoroquinolones. Ciprofloxacin and ofloxacin, two fluoroquinolones that have been available for human use in North America for several years, have generally not been used extensively in the management of infections caused by S. pneumoniae. Minimum inhibitory concentrations of these agents versus typical isolates are relatively high (MIC90 values of 1–2 mg/ mL) (Ballow et al. 1997; Brueggemann et al. 1997; Jones et al. 1994), and at least with ciprofloxacin, mutation to resistance while on therapy is well described (Perez-Trallero et al. 1990). Newer fluoroquinolones with either equivalent in vitro activity and a more favorable pharmacokinetic/pharmacodynamic profile (e.g., levofloxacin) or with both greater potency for S. pneumoniae as well as more desirable pharmacologic characteristics (e.g., sparfloxacin, gatifloxacin, grepafloxacin and trovafloxacin) have been introduced recently or are in advanced stages of development. The question arises what are the rates of fluoroquinolone resistance with current clinical isolates of S. pneumoniae in North America. Only two published studies have examined this issue systematically in the U.S. (Ballow et al. 1997; Brueggemann et al. 1997). The first, performed in 1994 –95, characterized 404 isolates of S. pneumoniae obtained from patients with various infections in 30 different U.S. medical centers (Brueggemann et al. 1997). Two isolates (0.5%) with apparent high-level fluoroquinolone resistance were detected. The second was an investigation that examined 2,542 clinical isolates of S. pneumoniae from 187 U.S. health care centers collected during the last 6 months of 1996 (Ballow et al. 1997). Using sparfloxacin as an indicator, eight fluoroquinoloneresistant strains (0.3%) were detected. There have been no published studies documenting nationwide rates of fluoroquinolone resistance with S. pneumoniae in Canada.
In an attempt to provide a more current data base, 1100 clinical isolates of S. pneumoniae recovered from patients with respiratory tract infections between February and June of 1997 were characterized. These patients had been seen in 27 different U.S. medical centers (n 5 890 isolates) and in seven different Canadian health care institutions (n 5 210 isolates) as part of the multinational SENTRY antimicrobial resistance surveillance program. Isolates were forwarded to the University of Iowa College of Medicine (Iowa City, IA) for species characterization and antimicrobial susceptibility testing. A detailed description of this study including rates of resistance to various non-fluoroquinolone antimicrobials has published elsewhere (Doern et al. 1998). Minimum inhibitory concentrations of ciprofloxacin, levofloxacin, gatifloxacin, grepafloxacin, sparfloxacin, and trovafloxacin were determined with all isolates using a microdilution method in MuellerHinton broth supplemented with 3% lysed horse blood according to the recommendations of the National Committee for Clinical Laboratory Standards (NCCLS) (5). Microdilution trays were incubated for 20 to 24 h at 35°C in ambient air before determining MIC values. The final inoculum concentration was approximately 5 3 105 CFU/mL. A strain of S. pneumoniae (ATCC 49619) served as a control. Table 1 lists the MICs obtained with the S. pneumoniae isolates examined in this study. There existed a clear rank order of in vitro activity among the fluoroquinolones tested in this investigation; grepafloxacin 5 trovafloxacin 5 sparfloxacin . gatifloxacin . levofloxacin 5 ciprofloxacin. In this collection of 1100 isolates of S. pneumoniae, 3 (0.3%) had conspicuously higher MICs compared with those obtained with the remainder of the organism collection. These strains are highlighted in Table 1 and generally had MICs 8- to 32-fold higher than the modal MIC values obtained with the other isolates. These
TABLE 1 Fluoroquinolone MIC Frequency Distributions Obtained with 1,100 Isolates of S. pneumoniae Collected in the U.S. and Canada During the First 6 Months of 1997 Antimicrobial Agent
0.03
0.06
0.12
0.25
0.5
1
2
4
8
16
32
Geometric mean MICa
Ciprofloxacin Levofloxacin Gatifloxacin Sparfloxacin Grepafloxacinc Trovafloxacin
—b — — — 1 8
— — 5 — 26 36
— — 60 116b 377 158
13 — 247 619 589 709
82 68 769 352 44 185
557 625 12 10 0 1
443 398 4 0 0 0
2 6 0 0 2 2
0 0 3 2 1 1
1 1 0 1 0 0
2 2 0 0 0 0
1.2 1.3 0.4 0.3 0.2 0.2
a
Number of Isolates with an MIC (mg/mL) of:
The geometric mean MICs were calculated based on the MICs of the apparently susceptible isolates, i.e., the MICs of the three presumed resistant strains were deleted from these calculations. The three strains highlighted in the ciprofloxacin row were the same three strains highlighted in the levofloxacin, gatifloxacin, sparfloxacin, and trovafloxacin rows. b Indicates that this concentration was not tested. c Grepafloxacin was tested against 1040 of the 1100 isolates.
Note strains of S. pneumoniae had been isolated from sputa obtained from elderly patients in three distinct areas of the U.S. (Wilmington, DE; Rochester, NY; Omaha, NE). Molecular characterization of these strains using PCR and then amplicon sequence analysis (Gootz et al. 1996; Pan et al. 1996) revealed all three to harbor a par C mutation resulting in a phenylalanine substitution at the serine79 residue of the C subunit of topoisomerase IV and a gyr A mutation resulting in a phenylalanine substitution at the serine83 residue of the A subunit of DNA gyrase. Based on the distinctly higher MICs of these three strains together with the fact that all three had mutations in both the par C and gyr A genes that are associated with fluoroquinolone resistance, we presume these isolates to be resistant. The question, of course, is whether these isolates of S. pneumoniae fail therapy if treated with standard dosages of the six fluoroquinolones examined in this study. One approach to answering this question is to compare the MICs of individual fluoroquinolones versus these strains to the 24-h serum AUCs obtained with the same agents. A 24-h serum AUC/ MIC ratio of approximately 100 is thought to be predictive of a favorable outcome when patients are treated with fluoroquinolones (Craig 1998). Based on this assumption, none of the six fluoroquinolones examined in this study would be likely to effectively treat infections attributable to organisms such as the three we identified with uniformly higher MICs. In other words, all three isolates seem to be clinically
315 resistant and there was complete cross resistance between the six study drugs. In conclusion, the results of this study confirm previous observations regarding the relative activity of ciprofloxacin, levofloxacin, grepafloxacin, gatifloxacin, sparfloxacin, and trovafloxacin versus S. pneumoniae (Brueggemann et al. 1997; Eliopoulos et al. 1993; Jones et al. 1998a, 1998b; Plouffe et al. 1996; Wakebe et al. 1994). Secondly, accepting the difficulty in defining what precisely constitutes fluoroquinolone resistance with S. pneumoniae, current rates of high-level resistance seem to exist at very low levels in North America; 3 of 890 isolates (0.3%) were resistant in the U.S.; no resistant strains were noted among 210 isolates in Canada. In light of the roughly equivalent rates of resistance reported in two recent surveillance studies (Ballow et al. 1997; Brueggemann et al. 1997), it seems that quinolone resistance is not increasing in prevalence in North America. However, with respect to the potential for the further emergence of resistance, these observations also serve as an important baseline on which to assess the effect of more extensive use of fluoroquinolones in the future to treat pneumococcal infections.
The authors thank Ms. Kay Meyer for her excellent secretarial assistance. The study was supported by a grant from BristolMyers Squibb and Company.
REFERENCES Ballow CH, Jones RN, Johnson DM, Deinhart JA, Schentag JJ, the SPAR Study Group (1997) Comparative in vitro assessment of sparfloxacin activity and spectrum using results from over 14,000 pathogens isolated at 190 medical centers in the USA. Diagn Microbiol Infect Dis 29: 173–186. Brueggemann AB, Kugler KC, Doern GV (1997) In vitro activity of BAY 12-8039, a novel 8-methoxyquinolone, compared to activities of six fluoroquinolones against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrob Agents Chemother 41: 594–1597. Craig WA (1997) Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–12. Doern GV, Pfaller MA, Kugler K, Freeman J, Jones RN (1998) Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY Antimicrobial Surveillance Program. Clin Infect Dis (Accepted for publication) Eliopoulos GM, Klimm K, Eliopoulos CT, Ferraro MJ, Moellering Jr RC (1993) In vitro activity of CP-99,219, a new fluoroquinolone, against clinical isolates of Gram-
positive bacteria. Antimicrob Agents Chemother 37:366– 370. Gootz TD, Zaniewski R, Haskell S, Schmieder B, Tankovic J, Girard D, Courvalin P, Polzer RJ (1996) Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyprase and topoisomerase IV mutants of Streptococcus pneumoniae selected in vitro. Antimicrob Agents Chemother 40:2691–2697. Jones RN, Hoban DJ, The North American Ofloxacin Study Group (1994) North American (United States and Canada) comparative susceptibility of two fluoroquinolones: Ofloxacin and ciprofloxacin. A 53-medical center sample of spectra of activity. Diagn Microbiol Infect Dis 18:49–56. Jones RN, Ballow CH, Schentag JJ, Johnson DM, Deinhart JA, the SPAR Study Group (1998a) In vitro evaluation of sparfloxacin activity and spectrum Against 24,940 pathogens isolated in the United States and Canada, the final analysis. Diagn Microbiol Infect Dis 30:1–21. Jones RN, Johnson DM, Erwin ME, Beach ML, Biedenbach DJ, Pfaller MA, the Quality Control Study Group (1998b) Comparative antimicrobial activity of gatifloxacin tested against Streptococcus spp. including quality
316
control guidelines and Etest method validation. Diagn Microbiol Infect Dis (accepted for publication). National Committee for Clinical Laboratory Standards (1997) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. Approved standard M7–A4. National Committee for Clinical Laboratory Standards, Wayne, PA. Pan X-S, Ambler J, Mehtar S, Fisher LM (1996) Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother 40:2321–2326. Perez-Trallero E, Garcia-Arenzana JM, Jimenez JA, Peris A (1990) Therapeutic failure and selection of resistance to quinolones in a case of pneumococcal pneumonia
Doern et al.
treated with ciprofloxacin. Eur J Clin Microbiol Infect Dis 9:905–906. Plouffe JF, the Franklin County Pneumonia Study Group (1996) Levofloxacin in vitro activity against bacteremic isolates of S. pneumoniae. Diagn Microbiol Infect Dis 25: 43–45. Trautmann M, Ruhnke M, Borner K, Wagner J, Koeppe P (1996) Pharmacokinetics of sparfloxacin and serum bactericidal activity against pneumococci. Antimicrob Agents Chemother 40:776–779. Wakebe H, Imada T, Yoneda H, Mukai F, Ohguro K, Ohmori K, Tamaoka H, Yabuuchi Y (1994) Evaluation of OPC-17116 against important pathogens that cause respiratory tract infections. Antimicrob Agents Chemother 38:2340–2345.