Abstract
Antipneumococcal activity of BMS 284756 was compared to those of six agents by MIC and time-kill methodologies. BMS 284756 had the lowest MICs compared to those of ciprofloxacin, levofloxacin, and moxifloxacin against quinolone-susceptible (≤0.016 to 0.06 μg/ml) and quinolone-resistant (0.03 to 1 μg/ml) pneumococci. BMS 284756 was bactericidal against 11 of 12 strains at two times the MIC after 24 h.
The incidence of pneumococci resistant to penicillin G and the macrolides has increased dramatically (1, 8, 9). In the United States, a recent survey has shown that penicillin G MICs were increased for 50.4% of 1,476 pneumococci screened; overall, macrolide resistance was 33% (10). Among the quinolones, ciprofloxacin and ofloxacin yield moderate in vitro activity against pneumococci; newer clinically available quinolones with expanded antipneumococcal activity include levofloxacin, gatifloxacin, and moxifloxacin (4, 14, 15, 18, 19, 21).
BMS 284756 (also known as T-3811ME) is a new broad-spectrum des-F(6)-quinolone (6, 20). This study examined the antipneumococcal activity of BMS 284756, ciprofloxacin, levofloxacin, moxifloxacin, cefuroxime, and azithromycin by (i) microdilution testing of 234 quinolone-susceptible strains and 28 strains for which quinolone MICs were elevated, (ii) examination of resistance mechanisms in quinolone-resistant strains, and (iii) time-kill testing of 12 strains. Quinolone-susceptible pneumococci comprised 102 penicillin-susceptible, 61 penicillin-intermediate, and 71 penicillin-resistant strains, all isolated within 2 years of testing. Additionally, 28 strains for which ciprofloxacin MICs were ≥8 μg/ml were tested. For the purposes of this study, strains for which ciprofloxacin MICs were ≥8.0 μg/ml were considered quinolone resistant.
Microbroth MICs were performed according to NCCLS recommendations (12) with cation-adjusted Mueller-Hinton broth with 5% lysed defibrinated horse blood. Standard quality control strains (12) were included in each run. Time-kill testing was performed as described previously (14, 17). Only initial inocula of 5 × 105 to 5 × 106 CFU/ml were acceptable. The lower limit of sensitivity of colony counts in viability testing was 300 CFU/ml (14, 17).
Time-kill results were analyzed by determining the number of strains which yielded a Δlog10 CFU/ml of −1, −2, and −3 at 0, 3, 6, 12, and 24 h, compared to counts at 0 h. Antimicrobials were considered bactericidal at the lowest concentration that reduced the original inoculum by ≥3 log10 CFU/ml (99.9%) at each of the time periods and were considered bacteriostatic if the inoculum was reduced by 0 to <3 log10 CFU/ml. The problem of bacterial carryover was addressed by dilution (14, 17). For macrolide time-kill testing, only the eight strains for which azithromycin MICs were ≤0.125 μg/ml were tested. The one strain for which quinolone MICs were raised was not tested for ciprofloxacin time-kill properties. Time-kill results were analyzed statistically by the Fisher exact test.
For quinolone-resistant strains, a PCR method was used to amplify parC, parE, gyrA, and gyrB with primers and cycling conditions described by Pan et al. and Davies et al. (5, 13). For efflux determinations, MICs were determined in the presence and absence of 10 μg of reserpine (Sigma Chemicals, St. Louis, Mo.)/ml. Strains for which there was a ≥4-fold decrease in MIC were considered to have an efflux mechanism (2, 4,5).
Table 1 lists the results of microdilution MIC testing of the 234 strains for which ciprofloxacin MICs were ≤4.0 μg/ml. BMS 284756 gave the lowest MICs of all quinolones tested, with a range of ≤0.016 to 0.06 μg/ml, followed by moxifloxacin, levofloxacin, and ciprofloxacin. MICs of cefuroxime and azithromycin rose with that of penicillin G (Table 1).
TABLE 1.
Microbroth dilution MICs for 234 quinolone- susceptible pneumococcal strainsa
| Drug | MIC (μg/ml)
|
||
|---|---|---|---|
| Range | 50% | 90% | |
| Penicillin | |||
| Penicillin S | ≤0.016–0.06 | ≤0.016 | 0.06 |
| Penicillin I | 0.125–1.0 | 0.25 | 1.0 |
| Penicillin R | 2.0–4.0 | 2.0 | 4.0 |
| BMS 284756 | |||
| Penicillin S | ≤0.016–0.06 | 0.03 | 0.03 |
| Penicillin I | ≤0.016–0.06 | 0.03 | 0.06 |
| Penicillin R | ≤0.016–0.06 | 0.03 | 0.06 |
| Ciprofloxacin | |||
| Penicillin S | ≤0.125–4.0 | 1.0 | 2.0 |
| Penicillin I | 0.5–4.0 | 1.0 | 2.0 |
| Penicillin R | 0.5–4.0 | 1.0 | 2.0 |
| Levofloxacin | |||
| Penicillin S | 0.25–2.0 | 1.0 | 1.0 |
| Penicillin I | 0.5–1.0 | 1.0 | 1.0 |
| Penicillin R | 0.25–2.0 | 1.0 | 1.0 |
| Moxifloxacin | |||
| Penicillin S | ≤0.06–0.25 | 0.125 | 0.125 |
| Penicillin I | ≤0.06–0.25 | 0.06 | 0.125 |
| Penicillin R | ≤0.06–0.25 | 0.125 | 0.125 |
| Cefuroxime | |||
| Penicillin S | ≤0.016–4.0 | 0.03 | 0.125 |
| Penicillin I | 0.06–>16.0 | 0.5 | 4.0 |
| Penicillin R | 4.0–>16.0 | 8.0 | 8.0 |
| Azithromycin | |||
| Penicillin S | ≤0.06–>32.0 | 8.0 | >32.0 |
| Penicillin I | ≤0.06–>32.0 | >32.0 | >32.0 |
| Penicillin R | ≤0.06–>32.0 | >32.0 | >32.0 |
Pencillin S, penicillin susceptible; Penicillin I, Penicillin intermediate; Penicillin R, penicillin resistant; 50% and 90%, MICs at which 50 and 90% of strains, respectively, are inhibited. Ciprofloxacin MICs of ≤4.0 μg/ml as shown.
Against 28 strains for which ciprofloxacin MICs were ≥8 μg/ml, BMS 284756 had the lowest MICs (0.03 to 1.0 μg/ml), compared with MICs ranging between 0.125 to 64.0 μg/ml for the other quinolones, with moxifloxacin, levofloxacin, and ciprofloxacin, in ascending order, giving the next lowest MICs (Table 2). Type II topoisomerase mutations of quinolone resistance are presented in Table 3. Increased quinolone MICs were associated with mutations in the quinolone resistance-determining region, mainly in ParC and GyrA, but also in ParE and GyrB (Table 3).
TABLE 2.
Quinolone microbroth dilution MICs for 28 pneumococcal strains not susceptible to ciprofloxacina
| Drug | MIC (μg/ml)
|
||
|---|---|---|---|
| Range | 50% | 90% | |
| Quinolone | |||
| BMS 284756 | 0.03–1.0 | 0.25 | 1.0 |
| Ciprofloxacin | 8.0–64.0 | 16.0 | 64.0 |
| Levofloxacin | 1.0–32.0 | 8.0 | 16.0 |
| Moxifloxacin | 0.125–4.0 | 2.0 | 4.0 |
50% and 90%, MICs at which 50 and 90% of strains, respectively, are inhibited. Ciprofloxacin MICs are ≥8.0 μg/ml.
TABLE 3.
Correlation of quinolone MIC and mutation in quinolone-resistant pneumococcal strains
| Strain(s) | MIC range (μg/ml) of:
|
Mutation in QRDRa of:
|
||||||
|---|---|---|---|---|---|---|---|---|
| BMS 284756 | Ciprofloxacin | Levofloxacin | Moxifloxacin | ParC | ParE | GyrA | GyrB | |
| 1–6 | 0.25–0.5 | 8.0–16.0 | 1.0–16.0 | 1.0–2.0 | S79-F, K137-N | 1460-V | S81-F | None |
| 7, 8 | 1.0 | 32.0 | 16.0–32.0 | 4.0 | S79-Y, K-137-N | 1460-V | E85-K | None |
| 9 | 0.06 | 8.0 | 4.0 | 0.25 | S79-F, K137-N | 1460-V | None | E474-K |
| 10 | 0.25 | 32.0 | 8.0 | 2.0 | D83-G, N91-D | None | S81-F | None |
| 11 | 0.5 | 64.0 | 16.0 | 2.0 | D83-G, N91-D | None | S81-F S114-G | None |
| 12 | 0.125 | 8.0 | 2.0 | 0.25 | S79-Y | 1460-V | None | None |
| 13 | 0.5 | 16.0 | 8.0 | 2.0 | D83-N | 1460-V | S81-F | None |
| 14–18 | 0.5–1.0 | 32.0–64.0 | 16.0 | 2.0–4.0 | S79-Y | 1460-V | S81-F | None |
| 19 | 0.125 | 8.0 | 8.0 | 1.0 | R95-C | D435-N | S81-F | None |
| 20 | 0.06 | 8.0 | 2.0 | 0.25 | None | 1460-V | None | None |
| 21 | 0.25 | 32.0 | 8.0 | 1.0 | D83-N | None | S81-F | None |
| 22 | 0.5 | 64.0 | 16.0 | 2.0 | S79-F | 1460-V | S81-Y | None |
| 23 | 0.25 | 64.0 | 8.0 | 1.0 | S79-Y | None | S81-A | None |
| 24 | 0.25 | 32.0 | 8.0 | 1.0 | D83-N | None | S81-F | None |
| 25, 26 | 0.03–0.125 | 8.0–16.0 | 1.0–4.0 | 0.125–0.25 | S79-Y | None | None | None |
| 27 | 0.25 | 16.0 | 8.0 | 1.0 | S79-F | 1460-V | S81-C | None |
| 28 | 0.5 | 16.0 | 16.0 | 2.0 | S79-F | 1460-V | None | D435-N |
QRDR, quinolone resistance-determining region.
In the presence of reserpine, ciprofloxacin MICs for 12 strains were lower (4 to 16 times lower); levofloxacin MICs for 2 strains were lower (4 times lower); BMS 284756 MICs were lower for 1 strain (4 times lower), and moxifloxacin MICs were lower for 1 strain (4 times lower). MICs were lower for three strains in the presence of reserpine with two agents and one strain with three agents.
Time-kill results (Table 4) showed that BMS 284756, at two times the MIC, was bactericidal against 11 of 12 strains after 24 h and was bactericidal against all 12 strains after 24 h at four times the MIC. At ≤0.5 μg/ml, BMS 284756 was bactericidal against all 11 quinolone-susceptible strains after 24 h; BMS 284756 was bactericidal against 1 strain for which the quinolone MIC was elevated (1.0 μg/ml) after 24 h. Slower kill kinetics were observed at earlier time periods, with 90% killing of all strains at two times the MIC after 12 h. Kill kinetics for other quinolones were similar to those of BMS 284756. β-Lactams were bactericidal against 9 to 12 strains at two times the MIC after 24 h, while azithromycin showed bactericidal activity against 6 of 8 susceptible strains at two times the MIC after 24 h. Statistical analysis showed no significant difference in kill kinetics between different strains at different time periods by the different antibiotics.
TABLE 4.
Time-kill results of 12 pneumococcal strainsa
| Drug | No. of strains killed of the following times and indicated inoculumb:
|
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 3 h
|
6 h
|
12 h
|
24 h
|
|||||||||
| −1 | −2 | −3 | −1 | −2 | −3 | −1 | −2 | −3 | −1 | −2 | −3 | |
| BMS 284576 | ||||||||||||
| 8× MIC | 10 | 1 | 0 | 11 | 8 | 0 | 12 | 11 | 6 | 12 | 12 | 12 |
| 4× MIC | 10 | 1 | 0 | 11 | 4 | 0 | 12 | 11 | 6 | 12 | 12 | 12 |
| 2× MIC | 6 | 0 | 0 | 10 | 3 | 0 | 12 | 10 | 4 | 12 | 12 | 11 |
| MIC | 1 | 0 | 0 | 7 | 1 | 0 | 8 | 3 | 1 | 8 | 5 | 3 |
| 0.5× MIC | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0 |
| Ciprofloxacinc | ||||||||||||
| 8× MIC | 9 | 2 | 1 | 11 | 6 | 2 | 11 | 10 | 6 | 11 | 11 | 11 |
| 4× MIC | 8 | 1 | 1 | 11 | 5 | 1 | 11 | 10 | 6 | 11 | 11 | 11 |
| 2× MIC | 6 | 2 | 0 | 11 | 5 | 0 | 11 | 10 | 6 | 11 | 10 | 10 |
| MIC | 4 | 0 | 0 | 5 | 3 | 0 | 7 | 6 | 1 | 5 | 5 | 1 |
| 0.5× MIC | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Levofloxacin | ||||||||||||
| 8× MIC | 12 | 4 | 1 | 12 | 8 | 2 | 12 | 12 | 7 | 12 | 12 | 12 |
| 4× MIC | 11 | 3 | 0 | 12 | 7 | 2 | 12 | 11 | 8 | 12 | 12 | 12 |
| 2× MIC | 7 | 3 | 0 | 12 | 6 | 0 | 12 | 10 | 6 | 12 | 11 | 8 |
| MIC | 3 | 0 | 0 | 5 | 1 | 0 | 6 | 4 | 1 | 5 | 4 | 3 |
| 0.5× MIC | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Moxifloxacin | ||||||||||||
| 8× MIC | 11 | 3 | 0 | 12 | 8 | 3 | 12 | 11 | 8 | 12 | 12 | 12 |
| 4× MIC | 9 | 1 | 0 | 12 | 6 | 2 | 12 | 11 | 5 | 12 | 12 | 12 |
| 2× MIC | 4 | 0 | 0 | 12 | 2 | 0 | 12 | 10 | 4 | 12 | 11 | 8 |
| MIC | 1 | 0 | 0 | 5 | 0 | 0 | 6 | 3 | 0 | 6 | 4 | 3 |
| 0.5× MIC | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Cefuroxime | ||||||||||||
| 8× MIC | 7 | 2 | 0 | 11 | 6 | 1 | 12 | 10 | 8 | 12 | 12 | 12 |
| 4× MIC | 6 | 0 | 0 | 10 | 5 | 1 | 12 | 11 | 6 | 12 | 12 | 11 |
| 2× MIC | 5 | 0 | 0 | 9 | 5 | 3 | 12 | 10 | 6 | 9 | 9 | 9 |
| MIC | 4 | 0 | 0 | 7 | 4 | 1 | 9 | 6 | 3 | 2 | 2 | 2 |
| 0.5× MIC | 2 | 0 | 0 | 2 | 0 | 0 | 2 | 0 | 0 | 1 | 1 | 1 |
| Azithromycind | ||||||||||||
| 8× MIC | 4 | 1 | 0 | 8 | 3 | 1 | 8 | 6 | 4 | 8 | 8 | 8 |
| 4× MIC | 4 | 1 | 0 | 7 | 1 | 1 | 8 | 5 | 4 | 8 | 8 | 7 |
| 2× MIC | 2 | 0 | 0 | 4 | 1 | 1 | 7 | 4 | 3 | 8 | 8 | 6 |
| MIC | 1 | 0 | 0 | 2 | 1 | 0 | 6 | 3 | 1 | 8 | 6 | 6 |
| 0.5× MIC | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
MICs (all values are in micrograms per milliliters are as follows: penicillin G, 0.008 to 4.0; BMS 284756, 0.03 to 1.0; ciprofloxacin, 0.5 to 64.0; levofloxacin, 0.5 to 16.0; moxifloxacin, 0.06 to 2.0; cefuroxime, 0.016 to 4.0; and azithromycin, 0.016 to >32.0.
Values log10 CFU per milliliter lower than the original inoculum (−1, −2, −3) are shown.
Eleven strains for which ciprofloxacin MICs were ≤4.0 μg/ml were tested.
Only eight strains for which macrolide MICs were ≤0.125 μg/ml were tested.
The incidence of quinolone-resistant pneumococci is currently very low in most countries. However, recent reports from Hong Kong (7), Canada (3), and Spain (11) have documented a worrisome increase in pneumococci for which quinolone MICs are increased.
BMS 284756 (6, 20) is a new quinolone with a broad spectrum of activity against gram-positive and -negative organisms. Takahata and coworkers (20) and Fung-Tomc et al. (6) have reported BMS 284756 MIC50 and MIC90 values of 0.025 to 0.125 and 0.05 to 0.125 μg/ml for penicillin-susceptible and penicillin-intermediate and -resistant pneumococcal strains, respectively; BMS 284756 MICs were at least 1 log unit lower than those of ciprofloxacin and levofloxacin, with MICs 1 doubling dilution lower than those of trovafloxacin (6, 20).
In our study, BMS 284756 gave the lowest quinolone MICs against all pneumococcal strains tested, followed by those for moxifloxacin, levofloxacin, and ciprofloxacin. These MICs are similar to those described previously (6, 20). Additionally, MICs of BMS 284756 against highly quinolone-resistant pneumococci were all ≤1.0 μg/ml, irrespective of the quinolone-resistance mechanism. MICs of nonquinolone agents were similar to those described previously (14, 16, 18, 19).
BMS 284756 showed good killing against the 12 strains tested, including the 1 quinolone-resistant strain. At ≤0.5 μg/ml, BMS 284756 was bactericidal against all 11 quinolone-susceptible strains and at 1.0 μg/ml it was bactericidal against the 1 strain for which quinolone MICs were elevated. Kinetics of quinolones and nonquinolones in our study were similar to those described previously (14, 17, 21).
In summary, BMS 284756 was the most potent quinolone tested by MIC and time-kill methods against both quinolone-susceptible and -resistant pneumococci. MICs for both quinolone-susceptible strains and those for which quinolone MICs were raised were similar to those of gemifloxacin (4). With a single oral daily dose of 400 mg, the maximum concentration of BMS 284756 in serum is 6.65 ± 0.99 mg/ml, with a total area under the concentration-time curve of 59.6 ± 11.9 2mg·h/ml and a time to maximum concentration in serum of 1.5 h (D. Grasela, Abstr. 7th Int. Symp. New Quin., abstr. P93, 2001); the drug is 75% protein bound (Bristol Myers Squibb, unpublished data). If the incidence of quinolone-resistant pneuococci increases further, BMS 284756 will be a well-placed therapeutic option. Clinical studies will be necessary to validate this hypothesis.
Acknowledgments
This study was supported by a grant from Bristol Myers Squibb Laboratories, Wallingford, Conn.
We thank D. Felmingham and R. Grüneberg (GR Micro, London, United Kingdom) for the provision of some quinolone-resistant pneumococci.
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