Journal of Antimicrobial Chemotherapy (1999) 43, 645-649
© 1999 The British Society for Antimicrobial Chemotherapy
Anti-pneumococcal activity of gatifloxacin compared with other quinolone and non-quinolone agents
a Departments of Pathology, Hershey Medical Center, 500 University Drive, Hershey, PA 17033; b Case Western Reserve University, Cleveland, OH 44106, USA
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Abstract |
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An agar dilution MIC method was used to test the activity of gatifloxacin, a new broad-spectrum fluoroquinolone, compared with ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, amoxycillin, cefuroxime, ceftriaxone and clarithromycin against 71 penicillin-susceptible, 81 penicillin-intermediate and 55 penicillin-resistant pneumococci. Quinolone activity was unaffected by penicillin susceptibility, with MIC 50/MIC 90s (mg/L) of 0.25/0.5 for gatifloxacin; 1/2 for ciprofloxacin; 1/2 for levofloxacin; 0.25/0.5 for sparfloxacin; 0.125/0.25 for trovafloxacin. ß-Lactam and clarithromycin MICs rose with those of penicillin G; MIC 50/MIC 90 values (mg/L) for penicillin-susceptible, -intermediate and -resistant strains were: 0.03/0.06, 0.25/1, 2/4 for penicillin G; 0.03/0.03, 0.125/1, 2/4 for amoxycillin; 0.03/0.125, 0.5/4, 8/16 for cefuroxime; 0.03/0.03, 0.25/0.5, 2/4 for ceftriaxone; 0.03/0.06, 0.03/>64, 1/>64 for clarithromycin. Time-kill testing of four penicillin-susceptible, four -intermediate and four -resistant strains showed that levofloxacin at the MIC, gatifloxacin and sparfloxacin at 2 x MIC, and trovafloxacin and ciprofloxacin at 4 x MIC, were bactericidal (99.9% killing) for all strains after 12 h and 24 h. By contrast, amoxycillin, cefuroxime and ceftriaxone showed bactericidal activity after 24 h against all strains at 4, 8 and 4 x MIC, respectively. Against ten organisms with clarithromycin MICs of 0.03-4.0 mg/L, clarithromycin was bactericidal against seven strains at 8 x MIC after 24 h. Quinolones showed more rapid killing at lower concentrations and earlier time periods than did ß-lactams and clarithromycin.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The incidence of pneumococci resistant to penicillin G and other ß-lactam and non-ß-lactam compounds has increased worldwide at an alarming rate. Major foci of infection currently include South Africa, Spain, central and eastern Europe and parts of Asia. 1 ,2 ,3 ,4 In the USA a recent survey has shown an increase in resistance to penicillin from <5% before 1989 (including <0.02% of isolates with MICs
2.0 mg/L) to 6.6% in
1991-1992 (with 1.3% of isolates with MICs 2.0 mg/L).
5 In another more recent survey,
6 23.6% (360) of 1527 clinically significant
pneumococcal isolates were not susceptible to penicillin. It is also important to note the high
rates of isolation of penicillin-intermediate and -resistant pneumococci (approximately
30%) in middle ear fluids from patients with refractory otitis media, compared with other
isolation sites.
7 There is an urgent need of oral compounds for outpatient treatment of respiratory tract infections caused by penicillin-intermediate and -resistant pneumococci. 2 ,3 ,4 8 Available quinolones such as ciprofloxacin and ofloxacin yield moderate in-vitro activity against pneumococci, with MICs clustering around the breakpoints. 4 ,9 ,10 ,11 Gatifloxacin (AM-1155, CG 5501) is a new broad-spectrum 8-methoxyquinolone which shares with sparfloxacin and grepafloxacin a methyl piperazinyl side-chain at position 7 and a cyclopropyl substituent at position 1. 12 ,13 ,14 ,15 ,16 ,17 Preliminary MIC studies with small numbers of strains have shown that gatifloxacin has good activity against penicillin-susceptible and -resistant pneumococci. 12 ,13 ,14 ,15 ,16 ,17
This study expands studies of the anti-pneumococcal activity of gatifloxacin by comparing its activity with that of four other quinolones, three ß-lactams and clarithromycin against 207 penicillin-susceptible, intermediate resistant and -resistant pneumococci. Drugs were chosen to represent a range of oral quinolone and non-quinolone agents, and one parenteral agent, which might be indicated for empirical treatment of community-acquired respiratory tract infections. The activity of the above compounds against 12 penicillin-susceptible and -resistant pneumococci was also investigated by broth MIC and time- kill methodology.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Bacteria
For agar dilution MICs, the pneumococci comprised 71 penicillin-susceptible (MIC 
0.06
mg/L), 81 penicillin-intermediate (MIC 0.125-1.0 mg/L) and 55 penicillin- resistant (MIC
2.0-16.0 mg/L) strains. All susceptible, and some intermediate and resistant strains, were recent
USA
isolates. The remainder of the intermediate and resistant strains were isolated in South Africa,
Spain, France, central and eastern Europe and Korea. For time-kill studies, four
penicillin-susceptible, four -intermediate and four -resistant strains were tested.
Antimicrobials and MIC testing
Gatifloxacin powder was obtained from Bristol-Myers Pharmaceutical Research Institute (Wallingford, CT, USA) and other antimicrobials were obtained from their respective manufacturers. Two hundred and seven strains were tested by agar dilution methodology as described previously, 3 ,4 on Mueller-Hinton agar (BBL Microbiology Systems, Cockeysville, MD, USA) supplemented with 5% sheep blood. Broth dilution MICs for 12 strains were determined according to NCCLS recommendations 18 with cation-adjusted Mueller-Hinton broth with 5% lysed defibrinated horse blood. Standard quality control strains, including Streptococcus pneumoniae ATCC 49619, were included in each run of agar and broth dilution MICs. All strains used in this study have been subcultured many times and therefore do not require CO 2 for growth. All incubations were therefore in ambient air.
Time- kill testing
For time-kill studies, glass tubes containing 5 mL cation-adjusted Mueller-Hinton broth (Difco Laboratories, Detroit, MI, USA) plus 5% lysed horse blood with doubling antibiotic concentrations were inoculated with 5 x 105 to 5 x 106 cfu/mL and incubated at 35°C in a shaking water bath. Antibiotic concentrations were chosen to comprise three doubling dilutions above and three dilutions below the agar dilution MIC. Growth controls with inoculum but no antibiotic were included with each experiment. 19 ,20
Lysed horse blood was prepared as described previously. 19 ,20 The bacterial inoculum was prepared by diluting a 16 h broth culture (medium as above) in the same medium. Dilutions required to obtain the correct inoculum (5 x 105 -5 x 106 cfu/mL) were determined by prior viability studies with each strain.
To inoculate each tube of serially diluted antibiotic, 50 µL of diluted inoculum was delivered by pipette beneath the surface of the broth. Tubes were then vortexed and plated for viable counts within 10 min. The original inoculum was determined by using the untreated growth control. Only tubes containing an initial inoculum within the range of 5 x 105-5 x 106 cfu/mL were acceptable. 19 ,20
Viable counts of antibiotic-containing suspensions were determined according to standard methodology, by plating ten-fold dilutions of 0.1 mL aliquots from each tube in sterile Mueller- Hinton broth on to plates of trypticase soy agar with 5% sheep blood (BBL Microbiology Systems). Recovery plates were incubated for up to 72 h. Colony counts were performed on plates yielding 30- 300 colonies. The lower limit of sensitivity of colony counts was 300 cfu/mL. All incubation was in ambient air without CO 2.
Time-kill assays were analysed by determining the number of strains which yielded a change in
log
10 cfu/mL of -1, -2 and -3 at 0, 4, 6, 12 and 24 h, compared
with counts at time 0 h. Antimicrobials were considered bactericidal at the lowest concentration
that reduced the original inoculum by 3 log
10 cfu/mL (99.9%) at each of the time periods, and bacteriostatic if the
inoculum was reduced by 0-3 log
10 cfu/mL. With the sensitivity threshold and inocula used in these studies, no
problems were encountered in delineating 99.9% killing, when present. The problem of
bacterial carryover was addressed as described previously.
19
,20 For clarithromycin time- kill testing, only strains with
MICs 4.0 mg/L were tested. Time-kill experiments were performed in duplicate and
arithmetic means of results taken. In all cases, results of repeat testing were practically identical.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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MICs are presented in Table I. Quinolone MICs were independent of those of penicillin G, while those of ß-lactams (amoxycillin, cefuroxime and ceftriaxone) and clarithromycin rose with those of penicillin G. Trovafloxacin had the lowest quinolone MICs, followed by gatifloxacin, sparfloxacin, levofloxacin and ciprofloxacin.
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Microbroth MICs for the 12 individual strains examined by time-kill were all the same as those seen by inspection of time-kill results with 11 strains and within one dilution with one strain. Microbroth and time-kill MICs for individual strains were also within one dilution of those obtained by agar dilution testing. Time-kill results (Table II) showed that levofloxacin at the MIC, gatifloxacin and sparfloxacin at 2 x MIC and trovafloxacin and ciprofloxacin at 4 x MIC, were bactericidal (99.9% killing) for all strains after 12 h and 24 h. By contrast, amoxycillin, cefuroxime and ceftriaxone showed bactericidal activity after 24 h against all strains at 4, 8 and 4 x MIC, respectively. Against ten organisms with clarithromycin MICs of 0.03 - 4.0 mg/L, clarithromycin was bactericidal against seven strains at 8 x MIC. Quinolones showed more rapid killing at lower concentrations and earlier time periods than did ß-lactams and clarithromycin. In some strains, regrowth occurred at the MIC after 24 h: this effect disappeared at 2- 4 x MIC.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Gatifloxacin is a new 6-fluoro-8-methoxy quinolone with a wide spectrum of activity against aerobic and anaerobic bacteria. In a recent study, Wise and co-workers 16 have reported that gatifloxacin inhibited 90% of Enterobacteriaceae at
0.5 mg/L, exceptions being Enterobacter (MIC
90 2 mg/L) and Serratia spp. (MIC
90 4 mg/L). MIC
90s for Pseudomonas aeruginosa, Stenotrophomonas maltophilia
and Acinetobacter spp. were 16, 4 and 1 mg/L, respectively. Haemophilus
influenzae and Moraxella catarrhalis strains were all inhibited by gatifloxacin at
0.125 mg/L. Gatifloxacin was active against staphylococci (MIC
90 2 mg/L), including methicillin-resistant strains (MIC
90 4 mg/L), which were generally ciprofloxacin resistant. Enterococcus faecalis was generally two to four times more susceptible to gatifloxacin or trovafloxacin than to
ciprofloxacin. Gatifloxacin was very active against Bacteroides fragilis (MIC
90 0.25 mg/L), chlamydia (MIC 0.125 mg/L) and Mycobacterium
tuberculosis(MIC 0.5 mg/L). Bauernfeind
17 reported MICs similar to those of Wise and colleagues;
16 additionally, gatifloxacin MICs were found to be
comparable to those of moxifloxacin (Bay 12-8039) and clinafloxacin.
Several workers have reported that gatifloxacin is very active against a small number of
pneumococcal strains tested, with MIC
50s of 0.125 - 0.39 mg/L and MIC
90s of 0.2 - 0.5 mg/L.
12
,13
,15
,16
,17
Our findings of MIC
50 and MIC
90 values of 0.25 and 0.5 mg/L respectively, with a larger number of strains confirm
the earlier reports. Time-kill studies, which have not been reported previously, showed that at
0.5 mg/L gatifloxacin was bactericidal after 12 h against all pneumococcal strains tested.
Lower MICs of amoxycillin and ceftriaxone against penicillin-intermediate and -resistant pneumococci, and raised clarithromycin MICs in the latter two groups, have been described before. 4 ,21 Kill kinetics of other quinolones tested, including slightly more rapid killing by levofloxacin compared with other quinolones, have been described previously. 22 ,23
Nakashima and co-workers 14 have reported gatifloxacin C max values (mg/L) in healthy human volunteers of 0.873, 1.71, 3.35 and 5.41 after single oral doses of 100, 200, 400 and 600 mg, respectively. AUC values (mg·h/L) after the four doses were 7.0, 14.5, 32.4 and 53.5, respectively. Serum concentrations reached a peak between 1 and 2 h. With the above pharmacokinetic data taken into consideration together with the MIC and time-kill results obtained in our study, gatifloxacin shows promise in treatment of infections caused by penicillin-susceptible and -resistant pneumococci. Clinical studies will be necessary to validate these in-vitro findings.
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Acknowledgments |
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This study was supported by a grant from Bristol-Myers Squibb Laboratories, Wallingford, CT, USA.
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Notes |
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* Corresponding author: Tel +1-717-531-5113; Fax +1-717-531-7953; E-mail: pappelbaum{at}psghs.edu
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References |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Received 29 May 1998; returned 22 September 1998; revised 26 October 1998; accepted 30 January 1999
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