Comparison of antimicrobial in vitro activities against Streptococcus pneumoniae independent of MIC susceptibility breakpoints using MIC frequency distribution curves, scattergrams and linear regression analyses

Robert J. Fass,* and Jean Barnishan

Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Comparing in vitro activities of antimicrobial agents against Streptococcus pneumoniae using per cent susceptible to recommended MIC breakpoints is not optimal. In this study, MICs of penicillin G, ampicillin/sulbactam, ceftriaxone, cefuroxime, erythromycin, tetracycline, trimethoprim/sulfamethoxazole, ciprofloxacin, levofloxacin, trovafloxacin and moxifloxacin were determined for 646 strains. Drug activities were compared using MIC frequency distribution curves, scattergrams and linear regression analyses of MICs (log2). MIC frequency distributions did not always correspond to recommended breakpoints for distinguishing susceptible, intermediate and resistant strains. Penicillin G, ampicillin/sulbactam and ceftriaxone had similar activities and were each c. 1–1.5 dilution steps more active than cefuroxime. For all ß-lactam drug pairs, there was a high correlation of MICs with regression line slopes (a '1) and coefficients of determination (R2 = 0.90–0.97). Although ß-lactam-resistant strains were more likely to be resistant to erythromycin, tetracycline and/or trimethoprim/sulfamethoxazole than were ß-lactam-susceptible strains, MIC correlations were relatively poor (R2 = 0.14–0.46), as they were when the non-ß-lactam drugs were compared with each other (R2 = 0.10–0.25). Trovafloxacin and moxifloxacin were each c. 2.5 dilution steps more active than ciprofloxacin and levofloxacin. There was no correlation of quinolone MICs with MICs of any other drug class (R2 0.02). Among the quinolones, however, there was a high correlation of MICs with a '1 and R2 = 0.81–0.92. With the quinolone drug pairs, lines of best fit were second-order polynomial equations, consistent with a dissociation of low level resistance mechanisms. In summary, ß-lactam and quinolone MICs were predictable within drug classes and testing multiple derivatives within each class is probably not necessary. Although there was some relationship between ß-lactam, erythromycin, tetracycline and trimethoprim/sulfamethoxazole MICs, predictability of MICs between drug classes was poor. There was no relationship between quinolone MICs and MICs of any of the other drugs tested.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Streptococcus pneumoniae is an important respiratory pathogen that causes potentially lethal pneumonia, bacteraemia and meningitis. In the past, penicillin G was highly active (MICs <= 0.03 mg/L) against all strains and was considered to be the treatment of choice for these infections. The first clinical isolate with reduced susceptibility (MIC 0.6 mg/L) to penicillin G was reported in 1967.1 By 1977, resistant strains had been described from multiple geographical areas. In two Johannesburg hospitals, strains with MICs 0.12–4 mg/L were relatively prevalent; many of those strains were also resistant to other ß-lactams, erythromycin, clindamycin, tetracycline and chloramphenicol, but not to vancomycin.2

In 1988, the American Academy of Pediatrics recommended that the newer cephalosporins (cefotaxime, ceftriaxone and cefuroxime) be used in preference to ampicillin and chloramphenicol for the initial empirical treatment of childhood meningitis.3 The recommendation was based on pharmacodynamic advantages and favourable clinical trials with the new cephalosporins, rather than on considerations of emerging resistance.

By the 1990s, however, resistance of S. pneumoniae to commonly used antimicrobials had become prevalent in North America and Europe.4–8 As a result, there has been great interest in comparing the in vitro activities of antimicrobials to facilitate the choice of empirical therapy, particularly for community-acquired respiratory tract infections. A standardized test with recommended breakpoints9,10 is used and the percentage of strains that are susceptible to the various antimicrobials are compared. This has been problematic for three reasons. First, breakpoints for ß-lactams and S. pneumoniae have historically been oriented to include the treatment of meningitis, whereas breakpoints for other classes of drugs have been oriented to treating blood and other non-central nervous system infections. Secondly, breakpoints for some drugs occur close to where MICs are naturally clustered and a one dilution step difference in a breakpoint can make a large difference in the percentage of strains considered to be susceptible. It is unlikely that one would observe a therapeutic difference when treating infections caused by strains with identical resistance mechanisms that happen to straddle either side of a breakpoint. Thirdly, laboratories can perform susceptibility tests for a limited number of drugs. It would be desirable if the results of testing one or two drugs in a class could reliably predict the susceptibilities to other drugs in the same class.

In this study, MICs of penicillin G, ampicillin/sulbactam, ceftriaxone, cefuroxime, erythromycin, tetracycline, trimethoprim/sulfamethoxazole, ciprofloxacin, levofloxacin, trovafloxacin and moxifloxacin were determined for 646 strains of S. pneumoniae. In vitro activities were compared and cross-susceptibility and cross-resistance were described using frequency distribution curves, scattergrams and linear regression analyses. We believe that such information provides a perspective on the relative activities of anti-pneumococcal drugs that is not always apparent from a tabulation of percentage susceptible based on MIC breakpoints. It also provides support for selective class testing and reporting of ß-lactam and quinolone class susceptibilities for anti-pneumococcal derivatives that have sufficient intrinsic activity to be appropriate as therapeutic agents.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Organisms

The organisms studied were 646 isolates of S. pneumoniae; 535 were isolated from the blood of adults in central Ohio and 111 were clinical isolates collected from multiple sources to provide a population of isolates relatively resistant to ß-lactams, quinolones or both. The population tested did not represent the ecology of strains from a specific population or geographical area. Duplicate isolates from individual patients were excluded.

Antimicrobial agents

Ampicillin/sulbactam and trovafloxacin were obtained from Pfizer Inc., Groton, CT, USA; ciprofloxacin and moxifloxacin from Bayer Corp., West Haven, CT, USA; levofloxacin from Ortho-McNeil Pharmaceutical, Raritan, NJ, USA; penicillin G, erythromycin and cefuroxime from Eli Lilly and Co., Indianapolis, IN, USA; ceftriaxone and trimethoprim/sulfamethoxazole from Roche Pharmaceuticals, Nutley, NJ, USA; and tetracycline from Lederle Standard Products, Philadelphia, PA, USA.

Laboratory standard powders were diluted in accordance with manufacturers' recommendations and were then dispensed into microdilution plates in log2 dilution steps from 0.06 to 8 mg/L (0.06 to 16 mg/L for quinolones) using a Quick Spense II dispensing machine (Dynatech Laboratories, Inc., Chantilly, VA, USA). Plates were stored at –70°C until used.

Susceptibility tests

MICs were determined by a standardized microdilution method9 in 0.1 mL volumes of cation-adjusted Mueller– Hinton broth with 5% lysed horse blood. Microdilution plates were inoculated with disposable inoculators (Dynatech) so that the final inoculum was c. 5 x 105 cfu/mL. Incubation was in air for c. 20 h. Recommended control strains were used. MIC breakpoints for defining S. pneumoniae susceptibility that are currently recommended by the NCCLS,10 drug manufacturers or both are shown in the TableGo.


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Table. MIC interpretive standards for S. pneumoniaea
 
Frequency distribution curves, scattergrams and regression analyses

MICs were entered into a Macintosh 7500/100 computer using File Maker Pro software. MICs were converted to log2 values and then exported to Cricket Graph III. MIC frequency distribution curves and scattergrams were drawn. Regression lines of best fit were calculated using the formula y = ax + b, where x is the MIC (log2) of one drug, a was the slope, b was the y-axis intercept and y is the MIC (log2) of the comparative drug. For comparing the quinolones, a second order polynomial equation (y = ax2 + bx + c) provided more accurate lines of best fit. R2, the coefficient of determination, indicates the proportion of the total variance in y that can be explained by the variance in x. For example, if R2 = 0.85, 85% of the total variance in the MIC of drug y is determined by the MIC of drug x.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Figure 1Go shows the MIC frequency distribution curves for the 11 study drugs against the 646 isolates of S. pneumoniae. The MICs for all 11 study drugs had bimodal distributions, with the larger portion of strains being relatively susceptible, a minority of strains being relatively resistant and a few intermediate.



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Figure 1. MIC frequency distribution curves for 646 isolates of S. pneumoniae. Trimethoprim/sulfamethoxazole in a 1:19 ratio is expressed as the trimethoprim concentration. Key: top panel: —–, penicillin G; – – –, ampicillin/sulbactam; •••••••, ceftriaxone; - — -, cefuroxime. Middle panel: —–, trimethoprim/sulfamethoxazole; – – –, erythromycin; •••••••, tetracycline. Bottom panel: —–, ciprofloxacin; – – –, levofloxacin; •••••••, trovafloxacin; - — -, moxifloxacin.

 
Scattergrams and regression analyses comparing MICs of ceftriaxone, erythromycin, tetracycline, trimethoprim/ sulfamethoxazole, ciprofloxacin and trovafloxacin with MICs of penicillin G are shown in Figure 2Go. The ceftriaxone–penicillin G comparison was representative of results for all ß-lactam drug pairs; activities were nearly identical (except cefuroxime was c. 1–1.5 dilution steps less active than the other ß-lactams) with a {approx}1 and R2 = 0.90–0.97.



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Figure 2. Scattergrams comparing the MICs of ceftriaxone, erythromycin, tetracycline, trimethoprim/sulfamethoxazole (TMP/SMZ), ciprofloxacin and trovafloxacin with MICs of penicillin G for 646 isolates of S. pneumoniae. Solid lines indicate the lines of best fit. Dashed lines indicates lines of identity.

 
Although penicillin G-resistant strains were more likely to be resistant to erythromycin, tetracycline and trimethoprim/sulfamethoxazole than were penicillin G-susceptible strains, predictability of MICs for these drugs based on penicillin G MICs (R2 = 0.14, 0.39 and 0.46, respectively), or MICs of any ß-lactam, was poor. The correlation of all MIC drug pairs for erythromycin, tetracycline and trimethoprim/sulfamethoxazole MICs was also poor (R2 = 0.10–0.25).

There was no correlation of ß-lactam and quinolone MICs (R2 <= 0.01). Indeed, there was no correlation of quinolone MICs with MICs of any other drug class (R2 <= 0.02).

Scattergrams and regression analyses comparing MICs for selected quinolone drug pairs are shown in Figure 3Go. Second-order polynomial equations, rather than firstorder equations, provided the lines of best fit. Ciprofloxacin and levofloxacin MICs were nearly identical, as were trovafloxacin and moxifloxacin MICs. Trovafloxacin and moxifloxacin were c. 2.5 dilution steps more active than ciprofloxacin and levofloxacin. There was a high correlation of quinolone MICs for all drug pairs (including those not illustrated) with a {approx}1 and R2 = 0.81–0.92.



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Figure 3. Scattergrams comparing the MICs of selected quinolone drug pairs for 646 isolates of S. pneumoniae. Solid lines indicate the lines of best fit. Dashed lines indicates lines of identity.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Pneumococcal resistance became a growing problem in the USA, Canada and Europe in the early 1990s and was widespread by the end of the decade.4–8 By 1997–1998, most reports indicated c. 10–22% intermediate resistance and c. 6–14% resistance to penicillin G. Penicillin resistance was associated with resistance to other ß-lactams, macrolides, clindamycin, tetracycline, trimethoprim/sulfamethoxazole and chloramphenicol. Quinolone, rifampicin, vancomycin, quinupristin/dalfopristin and linezolid resistance were rare or not observed. When there were a small percentage of resistant strains to some of those drugs, there was usually no apparent cross-resistance with penicillin G or other ß-lactams.

In all of the above studies,4–8 S. pneumoniae was divided into three categories of penicillin G susceptibility, with MIC for susceptible <=0.06 mg/L, for intermediate 0.12–1 mg/L and for resistant >=2 mg/L.10 These breakpoints were first proposed in 19782 to describe the patterns of penicillin resistance among isolates from two hospitals in Johannesburg. Patients with meningitis caused by strains resistant to 0.1–0.5 mg/L tended to have poor therapeutic responses. MIC breakpoints for cephalosporins have always been higher, based on higher achievable serum and CSF concentrations: susceptible <=0.5 mg/L, intermediate 1 mg/L and resistant >=2 mg/L.10

While it is appropriate to use ceftriaxone or cefotaxime rather than penicillin G to treat pneumococcal meningitis based on pharmacokinetic differences, the perception that susceptibility testing needs to be performed with multiple ß-lactams and that there is a population of penicillinresistant, ceftriaxone-susceptible strains of S. pneumoniae is unfortunate. Pneumococci develop resistance to penicillin G by mutations of the structural genes for the penicillin-binding proteins (PBPs). These altered PBPs have a reduced affinity for penicillin G and all ß-lactam antibiotics. The more PBPs that are altered, the more resistant the individual strain.11 This study and others12,13 have shown that, while ß-lactams may vary in potency, there is a strong linear relationship of MICs, with a {approx}1 and R2 usually >0.90 for all drug pairs studied. Among commonly used ß-lactams, the most active derivatives have been penicillin G, ampicillin, ceftriaxone and cefotaxime. Cefuroxime and ceftazidime were less active than those drugs, and most oral drugs were also considerably less active.

Clinically, ß-lactams such as penicillin G, cefotaxime and ceftriaxone have been equally effective in treating pneumococcal bacteraemia and pneumonia caused by S. pneumoniae strains with MICs <= 2 mg/L.14 The outcome of treating infections caused by strains with MICs >= 4 mg/L was suboptimal with the cephalosporins as well as with penicillin G. In a prospective study of 504 adults with pneumococcal pneumonia,15 neither penicillin G MICs 0.12–4 mg/L nor ceftriaxone or cefotaxime MICs 1–4 mg/L were associated with increased mortality when compared with infections caused by more susceptible strains. Perhaps adopting uniform breakpoints for penicillin G, ampicillin, ceftriaxone and cefotaxime would facilitate drug selection for the treatment of respiratory tract infections. Special consideration could be given to patients with meningitis as is done with other classes of drugs. Using less active ß-lactams would not be appropriate for treating any life-threatening pneumococcal infection.

ß-Lactam-resistant strains of S. pneumoniae often carry resistance traits for other unrelated antibacterial agents, most frequently erythromycin, clindamycin, tetracycline, trimethoprim/sulfamethoxazole and chloramphenicol.4–8 While this generalization is true, the mechanisms of resistance are different and, for individual isolates, we have shown that knowing the MIC of one drug is not reliable for predicting the MIC of any drugs in a different class.

In all of the above surveillance studies of S. pneumoniae resistance,4–8 quinolone resistance was infrequent. Quinolone resistance is mediated through chromosomal point mutations in gyrA and gyrB, which encode subunits of DNA gyrase, mutations in parC and parE, which encode subunits of DNA topoisomerase IV, or overexpression of pmrA, which encodes an efflux pump. High levels of resistance occur through the accumulation of mutations. In a study of 70 clinical isolates with ciprofloxacin MICs >= 4 mg/L and 28 with ciprofloxacin MICs <= 2 mg/L,16 low-level resistance (MICs 4–8 mg/L) was either due to a mutation in parC, active efflux or both, while high-level resistance (MICs >= 16 mg/L) was due to mutations in both parC and gryA. Regardless of the mutations identified, the order of activity of the various quinolones tested was conserved: gemifloxacin, clinafloxacin, sitafloxacin > moxifloxacin, trovafloxacin, grepafloxacin, gatifloxacin > sparfloxacin > ciprofloxacin, levofloxacin.7,8,16–19 The activities of the newer, more potent derivatives were, however, sometimes less impacted by certain mutations to resistance. For example, clinafloxacin and gemifloxacin MICs were less impacted by parC and gyrA mutations and dual or additional mutations were required for high-level resistance. In addition to enhanced potency, it has been speculated that this dissociation of MICs compared with older derivatives may result in fewer problems with the emergence of resistance.18–20

Previous studies21,22 have found a high degree of cross-susceptibility and cross-resistance among the quinolones for a variety of species. In this study, the two newer 7-azabicyclo-6-fluoroquinolone (trovafloxacin and moxifloxacin) derivatives were more potent than the older 7-piperazinyl-6-fluoroquinolones (ciprofloxacin and levofloxacin), but organisms relatively susceptible to one quinolone were relatively susceptible to all quinolones, and organisms relatively resistant to one were relatively resistant to all. It is of interest that there was some dissociation of quinolone MICs, as illustrated by the second-order lines of best fit, which was most pronounced between the new and the old drugs. The dissociation was only apparent, however, for organisms with low-level quinolone resistance (ciprofloxacin MICs 2–4 mg/L).

We conclude that ß-lactam and quinolone MICs for S. pneumoniae are highly predictable within each drug class. There are differences in potency between drugs within each class, but strains relatively susceptible to one drug are relatively susceptible to all and strains relatively resistant to one drug are relatively resistant to all. The results of testing one or two drugs in a class could reliably predict the susceptibilities to other drugs in the same class. Modifying currently recommended breakpoints would be helpful to accomplishing this. It is important to emphasize, however, that not all ß-lactams or quinolones are interchangeable therapeutically, because of appreciable differences in activity and/or pharmacokinetics. For example, ß-lactams with reduced activity against all strains of S. pneumoniae, such as ceftizoxime,23 ceftazidime12 and most oral cephalosporins,13 which were deliberately excluded from this study, should not be used for the treatment of serious pneumococcal infections.

While we did not find evidence of dissociation of ß-lactam MICs against S. pneumoniae, we did find evidence of dissociation of quinolone MICs. This was apparent only at low levels of resistance and had a minimal impact on the linear relationship of the MICs of the quinolones tested.

The relationship of MICs for S. pneumoniae for drugs in different classes was quite different from the relationships within the ß-lactam and quinolone classes. Although there was evidence of cross-susceptibility and cross-resistance between classes (excluding the quinolones), MIC correlations were poor and one could not reliably predict susceptibilities of individual strains among drug classes.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Joseph F. Plouffe, The Ohio State University, Mario Marcon, Columbus Children's Hospital, Ronald N. Jones, University of Iowa, Peter C. Appelbaum, Hershey Medical Center, C. Douglas Webb, Pfizer, Inc. and Barbara G. Painter, Bayer Corp. kindly provided some of the strains that were studied. This work was supported by a grant from Pfizer, Inc., New York, NY.


    Notes
 
* Corresponding author. University Hospitals Clinics, 456 West 10 Avenue, Columbus, OH 43210, USA. Tel: +1-614-293-8732; Fax: +1-614-293-5240; E-mail: fass.1{at}osu.edu Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
1 . Hansman, D. & Bullen, M. M. (1967). A resistant pneumococcus. Lancet ii, 264–5.

2 . Jacobs M. R., Koornhof, H. J., Robins-Browne, R. M., Stevenson, C. M., Vermaak, Z. A., Freiman, I. et al. (1978). Emergence of multiply resistant pneumococci. New England Journal of Medicine 299, 735–40.[Abstract]

3 . American Academy of Pediatrics Committee on Infectious Diseases. (1988). Treatment of bacterial meningitis. Pediatrics 81, 904–7.[ISI][Medline]

4 . Doern, G. V., Brueggemann, A. B., Huynh, H., Wingert, E. & Rhomberg, P. (1999). Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997–98. Emerging Infectious Diseases 5, 757–65.[ISI][Medline]

5 . Thornsberry, C., Jones, M. E., Hickey, M. L., Mauriz, Y., Kahn, J. & Sahm, D. F. (1999). Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated in the United States, 1997–1998. Journal of Antimicrobial Chemotherapy 44, 749–59.[Abstract/Free Full Text]

6 . Whitney, C. G., Farley, M. M., Hadler, J., Harrison, L. H., Lexau, C., Reingold, A. et al. (2000). Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. New England Journal of Medicine 343, 1917–24.[Abstract/Free Full Text]

7 . Chen, D. K., McGeer, A., de Azavedo, J. C. & Low, D. E. for the Canadian Bacterial Surveillance Network. (1999). Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. New England Journal of Medicine 341, 233–9.[Abstract/Free Full Text]

8 . Schmitz, F.-J., Verhoef, J., Fluit, A. C. & the SENTRY Participants Group. (1999). Comparative activity of 27 antimicrobial compounds against 698 Streptococcus pneumoniae isolates originating from 20 European University Hospitals. European Journal of Clinical Microbiology and Infectious Diseases 18, 450–3.[ISI][Medline]

9 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Fourth Edition: Approved Standard M7-A4. NCCLS, Villanova, PA.

10 . National Committee for Clinical Laboratory Standards. (1999). Performance Standards for Antimicrobial Susceptibility Testing: Ninth Informational Supplement M100-S9. NCCLS, Villanova, PA.

11 . Tomasz, A. (1997). Antibiotic resistance in Streptococcus pneumoniae. Clinical Infectious Diseases 24, Suppl. 1, S85–8.[ISI][Medline]

12 . Barry, A. L., Brown, S. D. & Novick, W. J. (1995). In vitro activities of cefotaxime, ceftriaxone, ceftazidime, cefpirome, and penicillin against Streptococcus pneumoniae isolates. Antimicrobial Agents and Chemotherapy 39, 2193–6.[Abstract]

13 . Brueggemann, A. B., Pfaller, M. A. & Doern, G. V. (2001). Use of penicillin MICs to predict in vitro activity of other antimicrobial agents against Streptococcus pneumoniae. Journal of Clinical Microbiology 39, 367–9.[Abstract/Free Full Text]

14 . Kaplan, S. L. & Mason, Jr, E. O. (1998). Management of infections due to antibiotic-resistant Streptococcus pneumoniae. Clinical Microbiology Review 11, 628–44.[ISI]

15 . Pallares, R., Liñares, J., Vadillo, M., Cabellos, C., Manresa, F., Viladrich, P. F. et al. (1995). Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. New England Journal of Medicine 333, 474–80.[Abstract/Free Full Text]

16 . Bast, D. J., Low, D. E., Duncan, C. L., Kilburn, L., Mandell, L. A., Davidson, R. J., et al. (2000). Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance. Antimicrobial Agents and Chemotherapy 44, 3049–54.[Abstract/Free Full Text]

17 . Jones, M. E., Sahm, D. F., Martin, N., Scheuring, S., Heisig, P., Thornsberry, C. et al. (2000). Prevalence of gyrA, gyrB, parC, and parE mutations in clinical isolates of Streptococcus pneumoniae with decreased susceptibilities to different fluoroquinolones and originating from worldwide surveillance studies during the 1997– 1998 respiratory season. Antimicrobial Agents and Chemotherapy 44, 462–6.[Abstract/Free Full Text]

18 . Jorgensen, J. H., Weigel, L. M., Ferraro, M. J., Swenson, J. M. & Tenover, F. C. (1999). Activities of newer fluoroquinolones against Streptococcus pneumoniae clinical isolates including those with mutations in the gyrA, parC, and parE loci. Antimicrobial Agents and Chemotherapy 43, 329–34.[Abstract/Free Full Text]

19 . Jorgensen, J. H., Weigel, L. M., Swenson, J. M., Whitney, C. G., Ferraro, M. J. & Tenover, F. C. (2000). Activities of clinafloxacin, gatifloxacin, gemifloxacin, and trovafloxacin against recent clinical isolates of levofloxacin-resistant Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 44, 2962–8.[Abstract/Free Full Text]

20 . Pan, X.-S. & Fisher, L. M. (1998). DNA gyrase and topoisomerase IV are dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 42, 2810–16.[Abstract/Free Full Text]

21 . Fass, R. J. (1994). Use of frequency distribution curves, scattergrams and regression analyses to compare in vitro activities and describe cross-susceptibility and cross-resistance among four quinolones. Journal of Chemotherapy 6, 368–76.[ISI][Medline]

22 . Fass, R. J. (1997). In vitro activity of Bay 12-8039, a new 8-methoxyquinolone. Antimicrobial Agents and Chemotherapy 41, 1818–24.[Abstract]

23 . Haas, D. W., Stratton, C. W., Griffin, J. P., Weeks, L. & Alls, S. C. (1995). Diminished activity of ceftizoxime in comparison to cefotaxime and ceftriaxone against Streptococcus pneumoniae. Clinical Infectious Diseases 20, 671–6.[ISI][Medline]

Received 27 March 2001; returned 10 August 2001; revised 19 August 2001; accepted 5 September 2001





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