Abstract
By using current NCCLS broth microdilution methods, we found that gatifloxacin inhibited 90% of the isolates of the Mycobacterium fortuitum group at ≤0.12 μg/ml and 90% of the Mycobacterium chelonae isolates at ≤4 μg/ml. Gatifloxacin was generally fourfold more active than ciprofloxacin. We recommend that both gatifloxacin and ciprofloxacin be tested routinely against rapidly growing mycobacteria.
The fluoroquinolones have become increasingly important in the treatment of infections due to mycobacteria. Previous studies involving a wide variety of clinical bacterial isolates and the new 8-methoxy quinolone, gatifloxacin, have shown that gatifloxacin is more active than ciprofloxacin against untreated strains (1, 5) and that its activity (MIC) is less affected overall by mutations responsible for increasing quinolone resistance. Thus, we undertook a comparative study of the in vitro susceptibilities of the rapidly growing mycobacteria (RGM) to gatifloxacin and ciprofloxacin.
(A portion of this study was presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill., 16 to 19 December 2001.)
We tested ciprofloxacin and gatifloxacin against 124 random clinical isolates of RGM. Isolates included Mycobacterium abscessus (24 isolates), M. chelonae (32 isolates), the M. fortuitum group (39 isolates, including 20 isolates of M. fortuitum, 7 isolates of M. peregrinum, 3 isolates of M. mageritense, 4 isolates of sorbitol-positive M. fortuitum third biovariant, and 5 isolates of sorbitol-negative M. fortuitum third biovariant), M. smegmatis group (3 isolates of M. wolinskyi and 2 isolates each of M. smegmatis sensu stricto and M. goodii) (2), M. immunogenum (2 isolates) (16), and M. mucogenicum (20 isolates). Susceptibilities were determined only once for each isolate.
The American Type Culture Collection (ATCC) strains of RGM studied included M. fortuitum ATCC 6841T, M. peregrinum ATCC 14467T, M. peregrinum ATCC 700686, M. abscessus ATCC 19977T, M. chelonae ATCC 35752T, M. smegmatis sensu stricto ATCC 19420T, M. wolinskyi ATCC 700010T, M. goodii ATCC 700504T, sorbitol-positive M. fortuitum third biovariant ATCC 49403, and sorbitol-negative M. fortuitum third biovariant ATCC 49404.
RGM were identified by using conventional methods, including drug susceptibility patterns (15), carbohydrate utilization tests, and PCR restriction enzyme analysis of a 439-bp sequence (Telenti fragment) of the 65-kDa hsp gene (8, 10).
MICs were determined by use of the NCCLS-approved broth microdilution technique (6, 7). MICs of gatifloxacin were 0.12 to 32 μg/ml, while those of ciprofloxacin were 0.12 to 16 μg/ml (one lot number of panels used contained concentrations of ciprofloxacin of ≤0.25 to 16 μg/ml). The MIC breakpoints indicating susceptibility, moderate susceptibility (intermediate), and resistance to gatifloxacin were ≤2, 4, and ≥8 μg/ml, and those for ciprofloxacin were ≤1, 2, and ≥4 μg/ml (the NCCLS breakpoints for Enterobacteriaceae and Staphylococcus species) (6). Gatifloxacin breakpoints for RGM have not yet been addressed by the NCCLS (7).
For quality control tests, Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922 were used. Acceptable MIC ranges for S. aureus ATCC 29213 are 0.03 to 0.12 and 0.12 to 0.5 μg/ml for gatifloxacin and ciprofloxacin, respectively. Acceptable MIC ranges for E. coli ATCC 25922 are 0.008 to 0.03 and 0.004 to 0.016 μg/ml for gatifloxacin and ciprofloxacin, respectively (6).
Results for the major species (groups) of pathogenic RGM are shown in Tables 1 and 2. Generally, the MICs of gatifloxacin for all of the RGM except M. abscessus were 1 to 4 dilutions lower than those of ciprofloxacin.
TABLE 1.
Comparison of ranges, MIC50s, MIC90s, and percentages of gatifloxacin- and ciprofloxacin-susceptible mycobacteria
| Species and drug | No. of isolates testedb | MIC (μg/ml)a
|
% Suscep- tible | ||
|---|---|---|---|---|---|
| Range | 50% | 90% | |||
| M. abscessus | 24 | ||||
| Gatifloxacin | 2->32 | 16 | >32 | 10 | |
| Ciprofloxacin | 8->16 | 16 | >16 | 0 | |
| M. chelonae | 32 | ||||
| Gatifloxacin | ≤0.12-8 | 1 | 4 | 96 | |
| Ciprofloxacin | 0.25->16 | 4 | >16 | 8 | |
| M. fortuitum group | 39 | ||||
| Gatifloxacin | ≤0.12-0.5 | ≤0.12 | ≤0.12 | 100 | |
| Ciprofloxacin | ≤0.12-2 | 0.25 | 1 | 100 | |
| M. mucogenicum | 20 | ||||
| Gatifloxacin | ≤0.12-0.5 | ≤0.25 | ≤0.25 | 100 | |
| Ciprofloxacin | ≤0.25-1 | 0.5 | 0.5 | 100 | |
TABLE 2.
Comparison of susceptibilities of RGM to gatifloxacin and ciprofloxacin at specified MICs
| Species and drug | No. of isolates testeda | No. (cumulative %) of isolates susceptible at an MIC (μg/ml) of:
|
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.12b | ≤0.25a | 0.5 | 1 | 2 | 4 | 8 | 16 | >16 | 32 | >32 | ||
| M. abscessus | 24 | |||||||||||
| Gatifloxacin | 1 (4) | 2 (13) | 2 (21) | 4 (38) | 6 (63) | 6 (88) | 3 (100) | |||||
| Ciprofloxacin | 3 (12) | 1 (15) | 3 (27) | 3 (38) | 16 (100) | |||||||
| M. chelonae | 32 | |||||||||||
| Gatifloxacin | 1 (3) | 2 (9) | 10 (41) | 12 (78) | 6 (97) | 1 (100) | ||||||
| Ciprofloxacin | 1 (3) | 1 (6) | 17 (59) | 6 (78) | 3 (88) | 4 (100) | ||||||
| M. fortuitum group | 39 | |||||||||||
| Gatifloxacin | 38 (97) | 1 (100) | ||||||||||
| Ciprofloxacin | 13 (33) | 11 (62) | 8 (82) | 4 (92) | 3 (100) | |||||||
| M. mucogenicum | 20 | |||||||||||
| Gatifloxacin | 8 (40) | 10 (90) | 2 (100) | |||||||||
| Ciprofloxacin | 1 (5) | 7 (40) | 11 (95) | 1 (100) | ||||||||
A total of 115 isolates were tested.
The two lowest MICs reflect different lot numbers of panels used.
For the M. fortuitum group, 39 of 39 (100%) of the isolates were susceptible to gatifloxacin at MICs of ≤0.5 μg/ml, whereas only 32 of 39 (82%) were susceptible to ciprofloxacin at ≤0.5 μg/ml (Table 2).
Of the M. chelonae isolates, 31 of 32 (97%) were susceptible or intermediate to gatifloxacin at an MIC of ≤4 μg/ml, compared to 1 of 32 (6%) to ciprofloxacin at 2 μg/ml and 17 of 32 (59%) to ciprofloxacin at 4 μg/ml.
Of the 24 isolates of M. abscessus tested against gatifloxacin, only 21% were intermediate or susceptible, while 12% of the same isolates tested against ciprofloxacin were such.
The gatifloxacin MICs for all seven isolates of the three members of the M. smegmatis group (M. smegmatis sensu stricto [3], M. wolinskyi [2], and M. goodii [2]) were ≤0.12 μg/ml (data not shown). The MICs required for 50% inhibition (MIC50s) of M. smegmatis sensu stricto, M. goodii, and M. wolinskyi were 1, ≤0.12, and 1 μg/ml, respectively (data not shown).
The ciprofloxacin and gatifloxacin MIC test results for 10 mycobacterial ATCC isolates are shown in Table 3. Quality control results were within the acceptable ranges defined by the NCCLS (6, 7).
TABLE 3.
MICs of gatifloxacin and ciprofloxacin for RGM reference strains
| Strain | MIC (μg/ml)
|
|
|---|---|---|
| Gatifloxacin | Ciprofloxacin | |
| M. fortuitum group | ||
| M. fortuitum ATCC 6841T | ≤0.12 | ≤0.12 |
| M. peregrinum ATCC 14467T | ≤0.12 | ≤0.12 |
| M. peregrinum ATCC 700686a | ≤0.12 | 0.25 |
| M. fortuitum third biovariant | ||
| ATCC 49403 (sorbitol positive) | ≤0.12 | 0.25 |
| ATCC 49404 (sorbitol negative) | ≤0.12 | 0.5 |
| M. abscessus ATCC 19977T | 4 | >16 |
| M. chelonae ATCC 35752T | ≤0.12 | 0.25 |
| M. smegmatis sensu stricto ATCC 19420T | ≤0.12 | 0.5 |
| M. wolinskyi ATCC 700010 | ≤0.12 | 0.5 |
| M. goodii ATCC 700504 | ≤0.12 | ≤0.12 |
NCCLS-recommended MIC control strain.
The only oral drugs currently available for M. chelonae that inhibit >90% isolates at clinically active levels are the macrolides (clarithromycin or azithromycin) (3, 12) and linezolid (4, 13). Clarithromycin is the drug of choice for disease caused by M. chelonae, but monotherapy has a significant risk for mutational resistance (estimated to be 10 to 15%) in the setting of disseminated cutaneous disease in immunosuppressed individuals (9, 14). Linezolid use is limited by its high cost and concerns for long-term hematologic toxicity (4, 13). On the basis of the present results, gatifloxacin is the third oral agent to inhibit >90% of M. chelonae isolates at clinically achievable levels.
Currently there are no clinical data available for results of treatment with gatifloxacin for infections caused by RGM.
The NCCLS has recommended that the fluoroquinolone ciprofloxacin be tested against the RGM (7) but clearly has not predicted gatifloxacin activity against M. chelonae. We recommend that both gatifloxacin and ciprofloxacin be routinely tested against the RGM at the concentrations in broth previously noted.
Since the gatifloxacin MICs for the M. fortuitum group isolates are lower than those of ciprofloxacin, these isolates may be less likely to develop clinical resistance to gatifloxacin following a single mutational event. As this resistance is a problem with M. fortuitum and the earlier fluoroquinolones, the use of monotherapy with the M. fortuitum group is precluded (11).
Acknowledgments
We thank both Bristol-Myers Squibb for its support of this research and Joanne Woodring for preparing the manuscript.
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