In Vitro Activity of the New Quinolone Lomefloxacin against Mycobacterium tuberculosis 1 ,2
CLAUDIO PIERSIMONI, VALERIA MORBIDUCCI, STEFANO BORNIGIA, GIUSEPPINA DE SIO, and GIORGIO SCALISE
Introduction
Despite recent advances in chemotherapy and a steady improvement in health conditions, tuberculosis in Italy still represents a common disease in the community, and it has been gaining increasing clinical relevance in immunocompromised patients, especially those with human immunodeficiency virus (HIV) infection (1-3). Current chemotherapy is usually highly effective against Mycobacterium tuberculosis; however, there is an increasing need for alternative drugs because resistance may ensue and standard drugs have considerable toxicity, which may lead to the withdrawal of one or more of them. Some of the new fluorinated quinolones have proved to have good activity against mycobacteria, including M. tuberculosis and nontuberculous mycobacteria (4). The activity of the new quinolones seems to be independent of resistance to other antimycobacterial agents. Moreover, these compounds appear to readily penetrate the human macrophages. This property is important for the treatment of intracellular pathogens such as M tuberculosis (5). Previous in vitro studies have shown that ciprofloxacin and ofloxacin are the most active drugs against M tuberculosis (6, 7). Recently, a new quinolone, sparfloxacin, was revealed to possess a broad spectrum of antimycobacterial activity with in vitro efficacy against M tuberculosis better than those of ofloxacin and ciprofloxacin (8). Lomefloxacin (SC-47111; NY-198) is a new difluoroquinolone antibacterial agent that has the additional advantage of possessing a relatively long elimination half-life (7 to 8 h) (9).
In this report we determined the minimal inhibitory concentration (MIC) values of lomefloxacin in comparison with those of ofloxacin and ciprofloxacin against clinical isolates of M tuber-
SUMMARY Minimal inhibitory concentrations (MIC) of ciprofloxacin, ofloxacin and lomefloxacln were determined for 90 Mycobacterium tuberculosis strains Isolated from both AIDS and other patients. Eleven (12.2%) of these strains showed in vitro resistance to one or more tirst-line antituberculosis drugs. Susceptibility tests were done in 7H12 broth by the radiometric method. The MIC range tor clprofloxacln was 0.125 to 4.0 j.lg/ml; for otloxacin, 0.25 to 4.0; and tor lomefloxacln 0.5 to 4.0 j.lg/ml. On the basis of our data, we believe that the tollowing MIC, when determined In 7H12 broth radiometrically, should be used as break points to classify the strain as susceptible: clprofloxacln and ofloxacln, 1 Il9/ml or less; lomefloxacin, 2 j.lg/ml or less. Lomefloxacln on a once-dally basis deserves further evaluation as a potential supplementary drug tor the treatment of tuberculosis. AM REV RESPIR DIS 1992; 146:1445-1447
culosis recovered from both AIDS and other patients. Methods Bacterial Strains Ninety clinical isolates of M tuberculosis, 11 (12.2"70) of which showed in vitro resistance to one or more standard antituberculosis drugs, were included in this study. The resistant isolates included seven single-drug-resistant strains (six to isoniazid and one to streptomycin), two double-drug-resistant strains (one to isoniazid plus rifampicin and the other to streptomycin plus rifampicin), and two multidrug-resistant strains. All the strains were primarily isolated on LOwenstein Jensen (L-J) medium or by Bactee culture system and identified by standard procedures and specific DNA probe (GenProbe Inc., San Diego, CA). An inoculum was prepared by seeding a 7Hl2B medium vial (Becton Dickinson, Towson, MD) with a fresh bacterial suspension made by scraping single colonies from L-J slants and homogenizing them by shaking in sterile distilled water with 2-mmdiameter glass beads. The bacterial suspension was adjusted to the optical density of a No. I McFarland standard. The vial was incubated until growth in it reached a radiometric growth index (GI) of 400to 500by daily reading in the BactecTB-460instrument (Becton Dickinson). This culture was used as an inoculum for a set of vials used to determine MIC values by the radiometric method.
Antimicrobial Agents The drugs in powder form were provided by the following suppliers: ciprofloxacin, Bayer
Pharmaceuticals, Leverkusen, Germany; ofloxacin, Daiichi Pharmaceuticals, Tokyo, Japan; lomefloxacin, Schiapparelli-Searle Pharmaceuticals, Turin, Italy. Stock solutions of the drug were prepared in distilled water to a concentration 40 times the highest desired concentration and sterilized through a filter unit that had a pore size of 0.22 11m. Serial doubling dilutions of the stock solutions were made in sterile distilled water. Aliquots of each concentration were stored at - 70° C.
MIC Determination by the Radiometric Method The susceptibility testing was done by radiometric method according to the technique developed by Heifets and colleagues (10). We employed Bactec 7Hl2B Middlebrook TB medium containing "C-Iabeled palmitic acid as a source of carbon. Growth was measured as a function of the ability of the bacteria to catabolize the substrate, with subsequent release of "carbon dioxide into the atmosphere above the medium in the sealed vial (11). The growth, in terms of the amount
(Received in originalform December 23, 1991 and in revised form May 26, 1992) 1 From the Department of Clinical Microbiology, General Hospital "Umberto IO-Torrette," Ancona, Italy, and the Institute ofInfectious Disease, University of Ancona, Ancona, Italy. 2 Correspondence and requests for reprints should be addressed to Claudio Piersimoni, M.D., Department of Clinical Microbiology, General Hospital "Umberto IO-Torrette," via Conca, 60020, Torrette di Ancona, Italy.
1445
1446
PIERSIMONI, MORBIDUCCI, BORNIGIA, DE SIO, AND SCALISE
of carbon dioxide liberated, was expressed as a numerical OI value ranging from 1 to 999. When O.1-ml of working solutions were injected into standard 4.0-ml 7H12 broth vials, the final concentrations in a twofold dilution scale were: ofloxacin, ciprofloxacin, and lomefloxacin, 0.062 to 8.0 ug/ml, A set of vials was inoculated from a 7H12B culture when its daily radiometric OI value reached 400 to 500. Two drug-free vials were inoculated as controls, one in the same way as the test vials and the other with a 1:100 dilution of the inoculum (1:100 control). The initial concentration of bacteria, when 0.1 ml of the bacterial suspension was injected into a 4-ml vial, was usually from 104 to lOS cfu/ml in the test vials and 102 to 103 cfu/ml in the 1:100 control (12, 13). The vials were incubated at 37° C, and the OI value was recorded daily in the Bactec TB460 instrument until a daily OI value of 30 or greater was found in the 1:100control vial (usually after 6 to 7 days of cultivation). The MIC was defined as the concentration in the presence of which the daily OI increase and the final reading were lower than in the 1:100 control. This was an indication that the concentration inhibited more than 990/0 of the bacterial population (14, 15).
TABLE 1 MINIMAL INHIBITORY CONCENTRATIONS OF OFLOXACIN FOR 90 MYCOBACTERIUM TUBERCULOSIS STRAINS No. of Strains Susceptible strains Resistant strains
MIC (/Jglm/)
0.12
79 11
0.25
0.5
1.0
35 3
41 5
3
2.0
4.0
Range
50%
90%
2
0.25-1.0 0.25-4.0
0.27 0.37
0.35 0.92
Range
50%
90%
0.125-1.0 0.25-4.0
0.23 0.25
0.27 0.52
Range
50%
90%
0.5-2.0 1.0-4.0
0.96 1.0
1.02 1.1
TABLE 2 MINIMAL INHIBITING CONCENTRATIONS OF CIPROFLOXACIN FOR 90 MYCOBACTERIUM TUBERCULOSIS STRAINS No. of Strains Susceptible strains Resistant strains
79 11
MIC (/Jglm/)
0.12
0.25
0.5
4
58 7
16 1
1.0
2.0
4.0
TABLE 3 MINIMAL INHIBITORY CONCENTRATIONS OF LOMEFLOXACIN FOR 90 MYCOBACTERIUM TUBERCULOSIS STRAINS No. of Strains Susceptible strains Resistant strains
MIC (/Jglm/)
0.12
0.25
79 11
0.5
1.0
2.0
3
65 9
11 1
4.0
Results
For ofloxacin, the range of the brothdetermined MIC was from 0.25 to 1.0 ug/rnl for standard drug-susceptible strains and from 0.25 to 4.0 ug/ml for standard drug-resistant strains. Only three (3.3010) of the 90 tested strains were inhibited by the highest concentrations of 2.0 and 4.0 ug/ml, respectively. The MIC so and MIC 90 of ofloxacin were, respectively, 0.27/0.35 ug/ml for standard drug-susceptible strains and 0.37/0.92 for standard drug-resistant strains (table 1). In the same manner, the brothdetermined MIC of ciprofloxacin were within the same range, and slightly lower than those of ofloxacin; the highest MIC, 4 ug/ml, was found for one strain only. The MIC so and MIC 90 of ciprofloxacin were, respectively, 0.23/0.27 ug/ml for standard drug-susceptible strains and 0.25/0.52 ug/rnl for standard drug-resistant strains (table 2). For lomefloxacin, the range of the broth-determined MIC was from 0.5 to 4.0 ug/ml, The MIC so and MIC 90 of lomefloxacin were,respectively, 0.96/1.02 ug/ml for standard drug-susceptible strains and 1.0/1.1 ug/ml for standard drug-resistant strains (table 3). Except for one strain, no differences in MIC values were recorded between the M tuberculosis isolates susceptible to the first-choice antituberculosis drugs and
the M tuberculosis strains resistant to one or more of these drugs. Discussion
Recent studies from Chen and colleagues (16) suggest the MIC of 1.0 ug/ml and 2.0 ug/ml be used as break points to classify an M tuberculosis strain as susceptible to ciprofloxacin and ofloxacin, respectively. On the basis of our data, we propose the MIC of 1.0 ug/rnl as a susceptible break point for both ciprofloxacin and ofloxacin. We also suggest 2.0 ug/ml as a susceptible break point for lomefloxacin. It should be emphasized that these MIC are below the peak concentrations of the drugs in human serum, that is, 10.7 ug/rnl for ofloxacin (17), 2.9 ug/rnl for ciprofloxacin (18), and 4.9 ug/rnl for lomefloxacin (9). These peak concentrations wereattained after singleoral doses of 600, 1,000, and 400 mg, respectively. Moreover, our results showed that the MIC of these three quinolones werewithin a narrow range for most of the M tuberculosis tested strains. It is also important to stress that our results correlate well with other reports (16). Previous studies, however, investigated only M. tuberculosis strains fully susceptible to the antituberculosis drugs.
In addition, inasmuch as no significant differencesin susceptibilityto ciprofloxacin, ofloxacin, and lomefloxacin were noted between the M. tuberculosis isolates susceptible to first-choice antituberculosis drugs and M tuberculosis strains resistant to one or more of these drugs, weconclude that there is not a true cross-resistance betweenthese quinolones and standard antituberculosis drugs. The discovery of the new quinolones has broadened the range of therapeutic tools used against mycobacterial infections. Although none of these quinolones have been approved for use against M. tuberculosis, combination therapy will probably be recommended for fluoroquinolones as for other antimycobacterial drugs. In this regard, the results of our study suggest that lomefloxacin, because of its pharmacokinetic property (long serum elimination half-life), should merit further evaluation as a potential supplementary drug for the treatment of tuberculosis. In conclusion, lomefloxacin, administered orally once daily, should provide serum levels effective against most M tuberculosis clinical isolates. References 1. Chaisson RE, Slutkin G. Tuberculosis and hu-
SUSCEPTIBILITY OF M. TUBERCULOSIS TO LOMEFLOXACIN
man immunodeficiency virus infection. J Infect Dis 1989; 159:96-100. 2. Barnes PF, Bloch AB, Davidson PT, Snider DE Jr. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991; 324:1644-50. 3. Antonucci G, Armignacco 0, Girardi E. Association between tuberculosis and HIV infection: a multicentre program study. G Malatt Infett Parassit 1991; 43:48-51. 4. Furet YX, Pechere I'C. Newly documented antimicrobial activity of quinolones. Eur J Clin Microbiol Infect Dis 1991; 10:249-54. 5. Leysen DC, Haemers A, Pattyn SR. Mycobacteria and the new quinolones. Antimicrob Agents Chernother 1989; 33:1-5. 6. Young LS, Berlin OGW, Inderlied CB. Activity of ciprofloxacin and other fluorinated quinolones against mycobacteria. Am J Med 1987; 82(suppl 4A):23-6. 7. Van Caekenberghe D. Comparative in-vitro activities of ten fluoroquinolones and fusidic acid against Mycobacterium spp. J Antimicrob Chemother 1990; 26:381-6.
8. Rastogi N, Goh KS. In vitro activity of the new fluorinated quinolone sparfloxacin (AT-4140) against Mycobacterium tuberculosiscompared with activities of ofloxacin and ciprofloxacin. Antimicrob Agents Chernother 1991; 35:1933-6. 9. Kavi J, Stone J, Andrews JM, Ashby JP, Wise R. Tissue penetration and pharmacokinetics of lomefloxacin following multiple doses. Eur J Clin Microbiol Infect Dis 1989; 8:168-170. 10. Heifets LB, Lindholm-Levy P, Iseman MD. Rifabutine: minimal inhibitory and bactericidal concentrations for M tuberculosis. Am Rev Respir Dis 1988; 137:719-21. 11. Middlebrook G, Reggiardo Z, Tigert W. Automatable radiometric detection of growth of Mycobacterium tuberculosis in selectivemedia. Am Rev Respir Dis 1977; 115:1066-69. 12. Heifets LB, Iseman MD, Cook JL, LindholmLevy PJ, Drupa I. Determination of in vitro susceptibility of M. tuberculosis to cephalosporins by radiometric and conventional methods. Antimicrob Agents Chernother 1985; 27:11-5. 13. Heifets LB, Iseman MD, Lindholm-Levy PJ. Ethambutol MICs and MBCs for M avium com-
1447 plex and M tuberculosis. Antimicrob Agents Chemother 1986; 30:927-32. 14. Snider DE, Good RC, Kilburn JO. Rapid susceptibility testing of Mycobacterium tuberculosis. Am Rev Respir Dis 1981; 123:402-6. 15. Tarrand 11, Groschel DHM. Evaluation ofthe BACTEC radiometric method for detection of 1% resistant population of Mycobacterium tuberculosis. J Clin Microbiol 1985; 21:941-6. 16. Chen C, Shih GF, Lindholm-Levy PJ, Heifets L. Minimal inhibitory concentrations of rifabutin, ciprofloxacin and ofloxacin against Mycobacterium tuberculosis isolated before treatment of patients in Taiwan. Am Rev Respir Dis 1989; 140: 987-9. 17. Wise R, Lister D, McNulty CAM, Griggs D, Andrews JM. The comparative pharmacokinetics of five quinolones. J Antimicrob Chemother 1986; 18(suppl D):71-8. 18. Fong IW, Ledbetter WH, Vandenbroucke AC, Simbul M, Raham V.Ciprofloxacin concentrations in bone and muscle after oral dosing. Antimicrob Agents Chemother 1986; 29:405-8.
CLAUDIO PIERSIMONI, VALERIA MORBIDUCCI, STEFANO BORNIGIA, GIUSEPPINA DE SIO, and GIORGIO SCALISE
Introduction
Despite recent advances in chemotherapy and a steady improvement in health conditions, tuberculosis in Italy still represents a common disease in the community, and it has been gaining increasing clinical relevance in immunocompromised patients, especially those with human immunodeficiency virus (HIV) infection (1-3). Current chemotherapy is usually highly effective against Mycobacterium tuberculosis; however, there is an increasing need for alternative drugs because resistance may ensue and standard drugs have considerable toxicity, which may lead to the withdrawal of one or more of them. Some of the new fluorinated quinolones have proved to have good activity against mycobacteria, including M. tuberculosis and nontuberculous mycobacteria (4). The activity of the new quinolones seems to be independent of resistance to other antimycobacterial agents. Moreover, these compounds appear to readily penetrate the human macrophages. This property is important for the treatment of intracellular pathogens such as M tuberculosis (5). Previous in vitro studies have shown that ciprofloxacin and ofloxacin are the most active drugs against M tuberculosis (6, 7). Recently, a new quinolone, sparfloxacin, was revealed to possess a broad spectrum of antimycobacterial activity with in vitro efficacy against M tuberculosis better than those of ofloxacin and ciprofloxacin (8). Lomefloxacin (SC-47111; NY-198) is a new difluoroquinolone antibacterial agent that has the additional advantage of possessing a relatively long elimination half-life (7 to 8 h) (9).
In this report we determined the minimal inhibitory concentration (MIC) values of lomefloxacin in comparison with those of ofloxacin and ciprofloxacin against clinical isolates of M tuber-
SUMMARY Minimal inhibitory concentrations (MIC) of ciprofloxacin, ofloxacin and lomefloxacln were determined for 90 Mycobacterium tuberculosis strains Isolated from both AIDS and other patients. Eleven (12.2%) of these strains showed in vitro resistance to one or more tirst-line antituberculosis drugs. Susceptibility tests were done in 7H12 broth by the radiometric method. The MIC range tor clprofloxacln was 0.125 to 4.0 j.lg/ml; for otloxacin, 0.25 to 4.0; and tor lomefloxacln 0.5 to 4.0 j.lg/ml. On the basis of our data, we believe that the tollowing MIC, when determined In 7H12 broth radiometrically, should be used as break points to classify the strain as susceptible: clprofloxacln and ofloxacln, 1 Il9/ml or less; lomefloxacin, 2 j.lg/ml or less. Lomefloxacln on a once-dally basis deserves further evaluation as a potential supplementary drug tor the treatment of tuberculosis. AM REV RESPIR DIS 1992; 146:1445-1447
culosis recovered from both AIDS and other patients. Methods Bacterial Strains Ninety clinical isolates of M tuberculosis, 11 (12.2"70) of which showed in vitro resistance to one or more standard antituberculosis drugs, were included in this study. The resistant isolates included seven single-drug-resistant strains (six to isoniazid and one to streptomycin), two double-drug-resistant strains (one to isoniazid plus rifampicin and the other to streptomycin plus rifampicin), and two multidrug-resistant strains. All the strains were primarily isolated on LOwenstein Jensen (L-J) medium or by Bactee culture system and identified by standard procedures and specific DNA probe (GenProbe Inc., San Diego, CA). An inoculum was prepared by seeding a 7Hl2B medium vial (Becton Dickinson, Towson, MD) with a fresh bacterial suspension made by scraping single colonies from L-J slants and homogenizing them by shaking in sterile distilled water with 2-mmdiameter glass beads. The bacterial suspension was adjusted to the optical density of a No. I McFarland standard. The vial was incubated until growth in it reached a radiometric growth index (GI) of 400to 500by daily reading in the BactecTB-460instrument (Becton Dickinson). This culture was used as an inoculum for a set of vials used to determine MIC values by the radiometric method.
Antimicrobial Agents The drugs in powder form were provided by the following suppliers: ciprofloxacin, Bayer
Pharmaceuticals, Leverkusen, Germany; ofloxacin, Daiichi Pharmaceuticals, Tokyo, Japan; lomefloxacin, Schiapparelli-Searle Pharmaceuticals, Turin, Italy. Stock solutions of the drug were prepared in distilled water to a concentration 40 times the highest desired concentration and sterilized through a filter unit that had a pore size of 0.22 11m. Serial doubling dilutions of the stock solutions were made in sterile distilled water. Aliquots of each concentration were stored at - 70° C.
MIC Determination by the Radiometric Method The susceptibility testing was done by radiometric method according to the technique developed by Heifets and colleagues (10). We employed Bactec 7Hl2B Middlebrook TB medium containing "C-Iabeled palmitic acid as a source of carbon. Growth was measured as a function of the ability of the bacteria to catabolize the substrate, with subsequent release of "carbon dioxide into the atmosphere above the medium in the sealed vial (11). The growth, in terms of the amount
(Received in originalform December 23, 1991 and in revised form May 26, 1992) 1 From the Department of Clinical Microbiology, General Hospital "Umberto IO-Torrette," Ancona, Italy, and the Institute ofInfectious Disease, University of Ancona, Ancona, Italy. 2 Correspondence and requests for reprints should be addressed to Claudio Piersimoni, M.D., Department of Clinical Microbiology, General Hospital "Umberto IO-Torrette," via Conca, 60020, Torrette di Ancona, Italy.
1445
1446
PIERSIMONI, MORBIDUCCI, BORNIGIA, DE SIO, AND SCALISE
of carbon dioxide liberated, was expressed as a numerical OI value ranging from 1 to 999. When O.1-ml of working solutions were injected into standard 4.0-ml 7H12 broth vials, the final concentrations in a twofold dilution scale were: ofloxacin, ciprofloxacin, and lomefloxacin, 0.062 to 8.0 ug/ml, A set of vials was inoculated from a 7H12B culture when its daily radiometric OI value reached 400 to 500. Two drug-free vials were inoculated as controls, one in the same way as the test vials and the other with a 1:100 dilution of the inoculum (1:100 control). The initial concentration of bacteria, when 0.1 ml of the bacterial suspension was injected into a 4-ml vial, was usually from 104 to lOS cfu/ml in the test vials and 102 to 103 cfu/ml in the 1:100 control (12, 13). The vials were incubated at 37° C, and the OI value was recorded daily in the Bactec TB460 instrument until a daily OI value of 30 or greater was found in the 1:100control vial (usually after 6 to 7 days of cultivation). The MIC was defined as the concentration in the presence of which the daily OI increase and the final reading were lower than in the 1:100 control. This was an indication that the concentration inhibited more than 990/0 of the bacterial population (14, 15).
TABLE 1 MINIMAL INHIBITORY CONCENTRATIONS OF OFLOXACIN FOR 90 MYCOBACTERIUM TUBERCULOSIS STRAINS No. of Strains Susceptible strains Resistant strains
MIC (/Jglm/)
0.12
79 11
0.25
0.5
1.0
35 3
41 5
3
2.0
4.0
Range
50%
90%
2
0.25-1.0 0.25-4.0
0.27 0.37
0.35 0.92
Range
50%
90%
0.125-1.0 0.25-4.0
0.23 0.25
0.27 0.52
Range
50%
90%
0.5-2.0 1.0-4.0
0.96 1.0
1.02 1.1
TABLE 2 MINIMAL INHIBITING CONCENTRATIONS OF CIPROFLOXACIN FOR 90 MYCOBACTERIUM TUBERCULOSIS STRAINS No. of Strains Susceptible strains Resistant strains
79 11
MIC (/Jglm/)
0.12
0.25
0.5
4
58 7
16 1
1.0
2.0
4.0
TABLE 3 MINIMAL INHIBITORY CONCENTRATIONS OF LOMEFLOXACIN FOR 90 MYCOBACTERIUM TUBERCULOSIS STRAINS No. of Strains Susceptible strains Resistant strains
MIC (/Jglm/)
0.12
0.25
79 11
0.5
1.0
2.0
3
65 9
11 1
4.0
Results
For ofloxacin, the range of the brothdetermined MIC was from 0.25 to 1.0 ug/rnl for standard drug-susceptible strains and from 0.25 to 4.0 ug/ml for standard drug-resistant strains. Only three (3.3010) of the 90 tested strains were inhibited by the highest concentrations of 2.0 and 4.0 ug/ml, respectively. The MIC so and MIC 90 of ofloxacin were, respectively, 0.27/0.35 ug/ml for standard drug-susceptible strains and 0.37/0.92 for standard drug-resistant strains (table 1). In the same manner, the brothdetermined MIC of ciprofloxacin were within the same range, and slightly lower than those of ofloxacin; the highest MIC, 4 ug/ml, was found for one strain only. The MIC so and MIC 90 of ciprofloxacin were, respectively, 0.23/0.27 ug/ml for standard drug-susceptible strains and 0.25/0.52 ug/rnl for standard drug-resistant strains (table 2). For lomefloxacin, the range of the broth-determined MIC was from 0.5 to 4.0 ug/ml, The MIC so and MIC 90 of lomefloxacin were,respectively, 0.96/1.02 ug/ml for standard drug-susceptible strains and 1.0/1.1 ug/ml for standard drug-resistant strains (table 3). Except for one strain, no differences in MIC values were recorded between the M tuberculosis isolates susceptible to the first-choice antituberculosis drugs and
the M tuberculosis strains resistant to one or more of these drugs. Discussion
Recent studies from Chen and colleagues (16) suggest the MIC of 1.0 ug/ml and 2.0 ug/ml be used as break points to classify an M tuberculosis strain as susceptible to ciprofloxacin and ofloxacin, respectively. On the basis of our data, we propose the MIC of 1.0 ug/rnl as a susceptible break point for both ciprofloxacin and ofloxacin. We also suggest 2.0 ug/ml as a susceptible break point for lomefloxacin. It should be emphasized that these MIC are below the peak concentrations of the drugs in human serum, that is, 10.7 ug/rnl for ofloxacin (17), 2.9 ug/rnl for ciprofloxacin (18), and 4.9 ug/rnl for lomefloxacin (9). These peak concentrations wereattained after singleoral doses of 600, 1,000, and 400 mg, respectively. Moreover, our results showed that the MIC of these three quinolones werewithin a narrow range for most of the M tuberculosis tested strains. It is also important to stress that our results correlate well with other reports (16). Previous studies, however, investigated only M. tuberculosis strains fully susceptible to the antituberculosis drugs.
In addition, inasmuch as no significant differencesin susceptibilityto ciprofloxacin, ofloxacin, and lomefloxacin were noted between the M. tuberculosis isolates susceptible to first-choice antituberculosis drugs and M tuberculosis strains resistant to one or more of these drugs, weconclude that there is not a true cross-resistance betweenthese quinolones and standard antituberculosis drugs. The discovery of the new quinolones has broadened the range of therapeutic tools used against mycobacterial infections. Although none of these quinolones have been approved for use against M. tuberculosis, combination therapy will probably be recommended for fluoroquinolones as for other antimycobacterial drugs. In this regard, the results of our study suggest that lomefloxacin, because of its pharmacokinetic property (long serum elimination half-life), should merit further evaluation as a potential supplementary drug for the treatment of tuberculosis. In conclusion, lomefloxacin, administered orally once daily, should provide serum levels effective against most M tuberculosis clinical isolates. References 1. Chaisson RE, Slutkin G. Tuberculosis and hu-
SUSCEPTIBILITY OF M. TUBERCULOSIS TO LOMEFLOXACIN
man immunodeficiency virus infection. J Infect Dis 1989; 159:96-100. 2. Barnes PF, Bloch AB, Davidson PT, Snider DE Jr. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991; 324:1644-50. 3. Antonucci G, Armignacco 0, Girardi E. Association between tuberculosis and HIV infection: a multicentre program study. G Malatt Infett Parassit 1991; 43:48-51. 4. Furet YX, Pechere I'C. Newly documented antimicrobial activity of quinolones. Eur J Clin Microbiol Infect Dis 1991; 10:249-54. 5. Leysen DC, Haemers A, Pattyn SR. Mycobacteria and the new quinolones. Antimicrob Agents Chernother 1989; 33:1-5. 6. Young LS, Berlin OGW, Inderlied CB. Activity of ciprofloxacin and other fluorinated quinolones against mycobacteria. Am J Med 1987; 82(suppl 4A):23-6. 7. Van Caekenberghe D. Comparative in-vitro activities of ten fluoroquinolones and fusidic acid against Mycobacterium spp. J Antimicrob Chemother 1990; 26:381-6.
8. Rastogi N, Goh KS. In vitro activity of the new fluorinated quinolone sparfloxacin (AT-4140) against Mycobacterium tuberculosiscompared with activities of ofloxacin and ciprofloxacin. Antimicrob Agents Chernother 1991; 35:1933-6. 9. Kavi J, Stone J, Andrews JM, Ashby JP, Wise R. Tissue penetration and pharmacokinetics of lomefloxacin following multiple doses. Eur J Clin Microbiol Infect Dis 1989; 8:168-170. 10. Heifets LB, Lindholm-Levy P, Iseman MD. Rifabutine: minimal inhibitory and bactericidal concentrations for M tuberculosis. Am Rev Respir Dis 1988; 137:719-21. 11. Middlebrook G, Reggiardo Z, Tigert W. Automatable radiometric detection of growth of Mycobacterium tuberculosis in selectivemedia. Am Rev Respir Dis 1977; 115:1066-69. 12. Heifets LB, Iseman MD, Cook JL, LindholmLevy PJ, Drupa I. Determination of in vitro susceptibility of M. tuberculosis to cephalosporins by radiometric and conventional methods. Antimicrob Agents Chernother 1985; 27:11-5. 13. Heifets LB, Iseman MD, Lindholm-Levy PJ. Ethambutol MICs and MBCs for M avium com-
1447 plex and M tuberculosis. Antimicrob Agents Chemother 1986; 30:927-32. 14. Snider DE, Good RC, Kilburn JO. Rapid susceptibility testing of Mycobacterium tuberculosis. Am Rev Respir Dis 1981; 123:402-6. 15. Tarrand 11, Groschel DHM. Evaluation ofthe BACTEC radiometric method for detection of 1% resistant population of Mycobacterium tuberculosis. J Clin Microbiol 1985; 21:941-6. 16. Chen C, Shih GF, Lindholm-Levy PJ, Heifets L. Minimal inhibitory concentrations of rifabutin, ciprofloxacin and ofloxacin against Mycobacterium tuberculosis isolated before treatment of patients in Taiwan. Am Rev Respir Dis 1989; 140: 987-9. 17. Wise R, Lister D, McNulty CAM, Griggs D, Andrews JM. The comparative pharmacokinetics of five quinolones. J Antimicrob Chemother 1986; 18(suppl D):71-8. 18. Fong IW, Ledbetter WH, Vandenbroucke AC, Simbul M, Raham V.Ciprofloxacin concentrations in bone and muscle after oral dosing. Antimicrob Agents Chemother 1986; 29:405-8.
