Abstract
CXA-101, a novel oxyimino-aminothiazolyl cephalosporin, CXA-201 (CXA-101 combined with tazobactam), and various comparators were susceptibility tested by broth microdilution methods against 1,301 well-characterized clinical strains collected worldwide, including ceftazidime-resistant members of the family Enterobacteriaceae and Klebsiella pneumoniae carbapenemase (KPC)- and extended-spectrum β-lactamase (ESBL)-producing strains of Pseudomonas aeruginosa and Bacteroides fragilis. CXA-201 was 2- to 32-fold more active than ceftazidime and piperacillin-tazobactam against ceftazidime-resistant Enterobacteriaceae species but less active than cefepime for some species. CXA-101 and CXA-201 were very active against P. aeruginosa (MIC50, 1 μg/ml for both compounds), including imipenem-resistant strains.
INTRODUCTION
CXA-101 (formerly FR264205), a novel oxyimino-aminothiazolyl cephalosporin, has shown greater activity (compared to ceftazidime) against Pseudomonas aeruginosa (1, 6, 7, 10, 11). CXA-101 has also demonstrated good activity against members of the family Enterobacteriaceae, but similar to other oxyimino-aminothiazolyl cephalosporins, CXA-101 activity can be adversely affected by bacterial production of extended-spectrum β-lactamases (ESBLs) and stably derepressed AmpC β-lactamases (8, 9). Thus, to improve its spectrum against Enterobacteriaceae and some anaerobic species, such as Bacteroides spp., CXA-101 is under clinical development in combination with tazobactam (CXA-201). In the present study, we evaluate the potency and spectrum of activity of CXA-101, with and without tazobactam, and comparator drugs tested against a contemporary collection of clinically derived Enterobacteriaceae and P. aeruginosa possessing selected patterns of antimicrobial resistance, as well as Bacteriodes fragilis wild-type (WT) strains.
The organisms were collected from patients in the United States, Europe, Latin America, and Asia (2006 to 2008) and selected based on previously defined antimicrobial susceptibility patterns. The isolates were recovered from skin and soft tissue samples and respiratory tract and bloodstream infections. Enterobacteriaceae isolates were chosen based on resistance to ceftazidime (strains with a MIC of ≥32 μg/ml), except for Proteus mirabilis where isolates demonstrated an ESBL phenotype, defined as a MIC of ≥2 μg/ml for ceftazidime or ceftriaxone or aztreonam (5). Furthermore, a collection of 53 Klebsiella pneumoniae strains producing K. pneumoniae carbapenemase (KPC) was also included. KPC production was characterized by the modified Hodge test, PCR, and gene sequencing as previously described (2). To better evaluate the activities of CXA-201 (CXA-101 combined with tazobactam) and CXA-101 against β-lactam-resistant P. aeruginosa, strains were stratified by susceptibility pattern to ceftazidime and imipenem.
MIC values for the aerobic bacilli were determined using the reference Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (M07-A8) (4). Quality control (QC) ranges and interpretive criteria for comparator compounds used the CLSI M100-S21 guidelines (5). For B. fragilis, MIC values were determined using the reference CLSI broth microdilution method (M11-A7) (3). CXA-101 (Calixa Therapeutics, San Diego, CA) was tested alone (range, 0.25 to 32 μg/ml) and in combination with tazobactam at a fixed concentration of 2 or 4 μg/ml and at CXA-101/tazobactam ratios of 2:1, 4:1, and 8:1 against Enterobacteriaceae, while P. aeruginosa strains were tested against CXA-101 alone (range, 0.12 to 128 μg/ml) and combined with tazobactam at a fixed concentration of 4 μg/ml (range, 0.12 to 128 μg/ml).
The vast majority of Enterobacteriaceae were resistant to ceftazidime (94.3%) and ceftriaxone (95.3%) as defined by the current CLSI breakpoints (5), and the greatest enhanced effect of tazobactam with CXA-101 was obtained with tazobactam at a fixed concentration of 4 μg/ml (CXA-201; MIC50 of 4/4 μg/ml; Table 1). CXA-201 was 2-fold more potent than cefepime (MIC50 of 8 μg/ml; 55.6% susceptible) and 8-fold more active than piperacillin-tazobactam (MIC50 of 32 μg/ml; 48.2% susceptible) against this highly resistant collection of Enterobacteriaceae. The carbapenems (imipenem and meropenem) were the most active β-lactams tested against these Enterobacteriaceae; however, only 80.4 and 91.6% of strains were susceptible to imipenem and meropenem, respectively (Table 1).
Table 1.
MIC distribution for CXA-101 alone and in combination with tazobactam and various comparator agents tested against selected Enterobacteriaceae species, K. pneumoniae strains, and P. mirabilis strainsa
| Antimicrobial agent(s)b | No. of isolates (cumulative %) inhibited at the following concn (μg/ml) of CXA-101 or comparator agentc: |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 or >16 | 64 or >32 | >64 | |
| CXA-101 | 2 (0.3) | 6 (1.0) | 5 (1.6) | 11 (3.0) | 35 (7.3) | 78 (16.9) | 109 (30.33) | 136 (47.10) | 429 (100.0) | — | |
| CXA-101 combinations | |||||||||||
| CXA-TAZ4 | 4 (0.5) | 36 (4.9) | 102 (17.5) | 143 (35.1) | 83 (45.4) | 95 (57.1) | 63 (64.9) | 95 (76.6) | 190 (100.0) | — | — |
| CXA-TAZ2 | 0 (0.0) | 24 (3.0) | 60 (10.4) | 107 (23.6) | 76 (32.9) | 71 (41.7) | 65 (49.7) | 128 (65.5) | 280 (100.0) | — | — |
| CXA-TAZ(2:1) | 0 (0.0) | 2 (0.3) | 13 (1.9) | 21 (4.4) | 91 (15.7) | 209 (41.4) | 190 (64.9) | 163 (85.0) | 122 (100.0) | — | — |
| CXA-TAZ(4:1) | 0 (0.0) | 2 (0.3) | 8 (1.2) | 19 (3.6) | 43 (8.9) | 118 (23.4) | 225 (51.2) | 209 (76.9) | 187 (100.0) | — | — |
| CXA-TAZ(8:1) | 0 (0.0) | 1 (0.1) | 8 (1.1) | 13 (2.7) | 24 (5.7) | 68 (14.1) | 159 (33.7) | 247 (64.1) | 291 (100.0) | — | — |
| Comparator agents | |||||||||||
| Ceftazidime | — | — | — | — | — | 39 (4.8) | 7 (5.7) | 4 (6.2) | 66 (14.3) | 204 (39.5) | 491 (100.0) |
| Ceftriaxone | — | 11 (1.4) | 4 (1.9) | 6 (2.6) | 17 (4.7) | 33 (8.8) | 53 (15.3) | 102 (27.9) | 128 (43.7) | 457 (100.0) | — |
| Cefepime | 44 (5.4) | 40 (10.4) | 81 (20.6) | 98 (32.4) | 91 (43.7) | 51 (49.9) | 46 (55.6) | 58 (62.8) | 302 (100.0) | — | — |
| Imipenem | — | — | 548 (67.6) | 104 (80.4) | 74 (89.5) | 24 (92.5) | 13 (94.1) | 48 (100.0) | — | — | — |
| Meropenem | 685 (79.4) | 38 (89.3) | 14 (91.0) | 5 (91.6) | 7 (92.5) | 7 (93.3) | 10 (94.6) | 44 (100.0) | — | — | — |
| Piperacillin-tazobactam | — | — | — | 78 (9.6) | 51 (15.9) | 78 (25.5) | 74 (34.7) | 110 (48.2) | 93 (59.7) | 95 (71.4) | 232 (100.0) |
CXA-101 alone and in combination with tazobactam and various comparator agents were tested against 690 ceftazidime-resistant strains from selected Enterobacteriaceae species, 53 KPC-producing K. pneumoniae strains, and 68 ESBL-producing P. mirabilis strains. The selected Enterobacteriaceae species include E. coli (224 strains), K. pneumoniae (186 strains), indole-positive Proteus (82 strains), Enterobacter spp. (90 strains), and Citrobacter spp. (108 strains).
CXA-101 alone and in combination with tazobactam (TAZ) were tested as follows: CXA-TAZ4 and CXA-TAZ2, CXA-101 and tazobactam with taxobactam at a fixed concentration of 4 μg/ml and 2 μg/ml, respectively; CXA-TAZ(2:1), CXA-TAZ(4:1), and CXA-TAZ(8:1), CXA-101 and tazobactam at ratios of 2:1, 4:1, and 8:1, respectively.
The MIC50s are underlined. —, concentration not tested.
CXA-201 showed good in vitro activity against ceftazidime-resistant Escherichia coli (MIC50, 1 μg/ml) and K. pneumoniae (MIC50, 4 μg/ml). Ceftriaxone (0.0 to 1.6% susceptible), cefepime (33.5 to 53.2% susceptible), and piperacillin-tazobactam (MIC50, 16 to 32 μg/ml; 45.2 to 59.4% susceptible) exhibited limited activity, while imipenem and meropenem retained good activity against these organisms (≥97.3% susceptible). The KPC-producing K. pneumoniae strains were highly resistant to all β-lactam agents tested (Table 2).
Table 2.
MIC distributions of CXA-201 tested against ceftazidime-resistant Enterobacteriaceae, ESBL-producing P. mirabilis, P. aeruginosa, and B. fragilisa
| Organism (no. tested)b | No. of isolates (cumulative %) inhibited at the following CXA-101–tazobactam MIC (μg/ml)c: |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| ≤0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | >16 | |
| E. coli, CAZ-R (224) | 2 (0.9) | 5 (3.1) | 42 (21.9) | 72 (54.0)b | 35 (69.6) | 18 (77.7) | 18 (85.7) | 14 (92.0) | 18 (100.0) |
| K. pneumoniae strains | |||||||||
| CAZ-R (186) | 2 (1.1) | 6 (4.3) | 20 (15.1) | 33 (32.8) | 18 (42.5) | 22 (54.3) | 10 (59.7) | 16 (68.3) | 59 (100.0) |
| KPC producers (53) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (3.8) | 51 (100.0) |
| Proteus, indole positive, CAZ-R (82) | 0 (0.0) | 12 (14.6) | 8 (24.4) | 10 (36.6) | 15 (54.9) | 12 (69.5) | 7 (78.0) | 5 (84.1) | 13 (100.0) |
| Enterobacter spp., CAZ-R (90) | 0 (0.0) | 6 (6.7) | 2 (8.9) | 6 (15.6) | 3 (18.9) | 16 (36.7) | 11 (48.9) | 25 (76.7) | 21 (100.0) |
| Citrobacter spp., CAZ-R (108) | 0 (0.0) | 2 (1.9) | 2 (3.7) | 7 (10.2) | 5 (14.8) | 22 (35.2) | 13 (47.2) | 31 (75.9) | 26 (100.0) |
| P. mirabilis with the ESBL phenotype (68) | 0 (0.0) | 5 (7.3) | 28 (48.5) | 15 (70.6) | 7 (80.9) | 5 (88.2) | 4 (94.1) | 2 (97.1) | 2 (100.0) |
| P. aeruginosa (449) | 0 (0.0) | 7 (1.6) | 131 (30.7) | 113 (55.9) | 84 (74.6) | 57 (87.3) | 25 (92.9) | 8 (94.7) | 24 (100.0) |
| CAZ-S, IMI-S (54) | 0 (0.0) | 6 (11.1) | 45 (94.4) | 2 (98.2) | 1 (100.0) | ||||
| CAZ-S, IMI-NS (143) | 0 (0.0) | 3 (2.1) | 75 (54.6) | 58 (95.1) | 3 (97.2) | 0 (0.0) | 3 (99.3) | 1 (100.0) | |
| CAZ-NS, IMI-S (39) | 0 (0.0) | 0 (0.0) | 1 (2.6) | 10 (28.2) | 13 (61.5) | 7 (79.5) | 2 (84.6) | 1 (87.2) | 5 (100.0) |
| CAZ-NS, IMI-NS (213) | 0 (0.0) | 0 (0.0) | 5 (2.4) | 38 (20.2) | 60 (48.4) | 58 (75.6) | 24 (86.9) | 7 (90.9) | 21 (100.0) |
| B. fragilis (41) | 1 (7.4) | 4 (12.2) | 5 (24.4) | 15 (61.0) | 4 (70.7) | 0 (70.7) | 2 (75.6) | 2 (80.5) | 8 (100.0) |
In this experiment, the concentration of tazobactam was fixed at 4 μg/ml.
Abbreviations: CAZ-R, ceftazidime-resistant; KPC, Klebsiella pneumoniae carbapenemase; ESBL, extended-spectrum β-lactamase (5); CAZ-S, ceftazidime-susceptible; CAZ-NS, ceftazidime-nonsusceptible; IMI-S, imipenem-susceptible; IMI-NS, imipenem-nonsusceptible.
The MIC50s are underlined.
When tested against ceftazidime-resistant strains of Enterobacter and Citrobacter spp., CXA-201 (MIC50, 16 μg/ml for both organism groups) exhibited greater activity than piperacillin-tazobactam (MIC50, 64 μg/ml for both organism groups), ceftriaxone (MIC50, 32 to >32 μg/ml), and ceftazidime (MIC50, >64 μg/ml for both organism groups), but it was less active than cefepime (MIC50, 1 to 2 μg/ml), imipenem (MIC50, ≤0.5 μg/ml for both organism groups), and meropenem (MIC50, ≤0.12 μg/ml for both organism groups) (Table 2). These strains produced presumptive AmpC enzymes.
CXA-201 activity against P. mirabilis strains with ESBL phenotype (MIC50 of 1 μg/ml and MIC90 of 8 μg/ml) was comparable to that of piperacillin-tazobactam (MIC50 of 1 μg/ml and MIC90 of 8 μg/ml; 97.1% susceptible; Table 2). Ceftazidime (MIC50, 32 μg/ml) and CXA-101 (MIC50, >32 μg/ml) exhibited limited activity against B. fragilis. In contrast, CXA-201 inhibited 70.7% of strains at 2 and 4 μg/ml or less for its components, CXA-101 and taxobactam, respectively (Tables 1 and 2).
CXA-101 demonstrated potent in vitro activity against P. aeruginosa strains, and the addition of tazobactam did not produce significant enhancement of activity (Table 3). CXA-101 and CXA-201 (MIC50 of 1 μg/ml and MIC90 of 8 μg/ml) were at least 8-fold more active than ceftazidime (MIC50 of 8 μg/ml and MIC90 of 128 μg/ml) and doripenem (MIC50 of 8 μg/ml and MIC90 of 16 μg/ml) when tested against the entire collection of P. aeruginosa strains (Table 3). When tested against P. aeruginosa strains susceptible to ceftazidime and imipenem, CXA-201 (MIC50 and MIC90 of 0.5 μg/ml) was 4- to 8-fold more active than ceftazidime and cefepime (MIC50 of 2 μg/ml and MIC90 of 4 μg/ml), 8- to 16-fold more active than piperacillin-tazobactam (MIC50 of 4 μg/ml and MIC90 of 8 μg/ml), and 2- to 4-fold more active than imipenem (MIC50 of 1 μg/ml and MIC90 of 2 μg/ml) while demonstrating activity comparable to that of doripenem (MIC50 of 0.25 μg/ml and MIC90 of 1 μg/ml). P. aeruginosa strains that were not susceptible to imipenem and susceptible to ceftazidime remained highly susceptible to CXA-201 and CXA-101 (MIC50 of 0.5 μg/ml and MIC90 of 1 μg/ml) (Table 3).
Table 3.
Antimicrobial activity of CXA-101 alone or combined with tazobactam at a fixed concentration of 4 μg/ml and various comparator agents
| Organism (no. tested) and antimicrobial agent(s) | MIC50 (μg/ml) | MIC90 (μg/ml) | MIC range (μg/ml) | % susceptiblea | % resistanta |
|---|---|---|---|---|---|
| E. coli, ceftazidime-resistant strains (224) | |||||
| CXA-TAZ4b | 1 | 16 | ≤0.12–>16 | — | — |
| CXA-101 | >32 | >32 | 1–>32 | — | — |
| Ceftazidime | 64 | >64 | 32–>64 | 0.0 | 100.0 |
| Ceftriaxone | >32 | >32 | 1–>32 | 0.0 | 99.5 |
| Cefepime | >16 | >16 | 0.25–>16 | 33.5 | 59.4 |
| Imipenem | ≤0.5 | ≤0.5 | ≤0.5–>8 | 98.2 | 0.5 |
| Meropenem | ≤0.12 | ≤0.12 | 0.015–8 | 98.7 | 0.9 |
| Piperacillin-tazobactam | 16 | >64 | 1–>64 | 59.4 | 17.4 |
| K. pneumoniae, ceftazidime-resistant strains (186) | |||||
| CXA-TAZ4 | 4 | >16 | ≤0.12–>16 | — | — |
| CXA-101 | >32 | >32 | 4–>32 | — | — |
| Ceftazidime | >64 | >64 | 32–>64 | 0.0 | 100.0 |
| Ceftriaxone | >32 | >32 | 0.5–>32 | 1.6 | 97.3 |
| Cefepime | 8 | >16 | 0.25–>16 | 53.2 | 39.2 |
| Imipenem | ≤0.5 | ≤0.5 | ≤0.5–>8 | 97.9 | 2.1 |
| Meropenem | ≤012 | ≤0.12 | ≤0.12–>8 | 97.3 | 1.6 |
| Piperacillin-tazobactam | 32 | >64 | 1–>64 | 45.2 | 33.9 |
| K. pneumoniae, KPC-producing strains (53) | |||||
| CXA-TAZ4 | >16 | >16 | 16–>16 | — | — |
| CXA-101 | >32 | >32 | 32–>32 | — | — |
| Ceftazidime | >64 | >64 | 64–>64 | 0.0 | 100.0 |
| Ceftriaxone | >32 | >32 | 16–>32 | 0.0 | 100.0 |
| Cefepime | >16 | >16 | 4–>16 | 11.3 | 71.7 |
| Imipenem | >8 | >8 | 4–>8 | 0.0 | 100.0 |
| Meropenem | >8 | >8 | 2–>8 | 0.0 | 98.1 |
| Piperacillin-tazobactam | >64 | >64 | >64 | 0.0 | 100.0 |
| Proteus, indole-positive, ceftazidime-resistant strains (82) | |||||
| CXA-TAZ4 | 2 | >16 | 0.25–>16 | — | — |
| CXA-101 | >32 | >32 | 4–>32 | — | — |
| Ceftazidime | 64 | >64 | 32–>64 | 0.0 | 100.0 |
| Ceftriaxone | 8 | >32 | ≤0.25–>32 | 2.4 | 87.8 |
| Cefepime | 0.5 | 16 | ≤0.12–>16 | 86.6 | 8.5 |
| Imipenem | 2 | 4 | ≤0.5–>8 | 34.2 | 14.6 |
| Meropenem | ≤0.12 | 0.25 | ≤0.12–2 | 97.6 | 0.0 |
| Piperacillin-tazobactam | 4 | 64 | ≤0.25–>64 | 70.7 | 8.5 |
| Enterobacter spp., ceftazidime-resistant strains (90) | |||||
| CXA-TAZ4 | 16 | >16 | 0.25–>16 | — | — |
| CXA-101 | >32 | >32 | 4–>32 | — | — |
| Ceftazidime | >64 | >64 | 32–>64 | 0.0 | 100.0 |
| Ceftriaxone | >32 | >32 | 8–>32 | 0.0 | 100.0 |
| Cefepime | 2 | >16 | 0.25–>16 | 71.1 | 20.0 |
| Imipenem | ≤0.5 | 1 | ≤0.5–>8 | 95.6 | 3.3 |
| Meropenem | ≤0.12 | 0.25 | ≤0.12–4 | 96.7 | 2.2 |
| Piperacillin-tazobactam | 64 | >64 | 2–>64 | 16.7 | 38.9 |
| Citrobacter spp., ceftazidime-resistant strains (108) | |||||
| CXA-TAZ4 | 16 | >16 | 0.25–>16 | — | — |
| CXA-101 | 32 | >32 | 1–>32 | — | — |
| Ceftazidime | >64 | >64 | 32–>64 | 0.0 | 100.0 |
| Ceftriaxone | 32 | >32 | 4–>32 | 3.7 | 44.4 |
| Cefepime | 1 | 16 | ≤0.12–>16 | 88.9 | 7.4 |
| Imipenem | ≤0.5 | 1 | ≤0.5–8 | 99.1 | 0.0 |
| Meropenem | ≤0.12 | ≤0.12 | ≤0.12–4 | 100.0 | 0.0 |
| Piperacillin-tazobactam | 64 | >64 | 1–>64 | 32.4 | 32.4 |
| P. mirabilis strains with ESBL phenotype (68) | |||||
| CXA-TAZ4 | 1 | 8 | 0.25–>16 | — | — |
| CXA-101 | 8 | >32 | ≤0.25–>32 | — | — |
| Ceftazidime | ≤4 | >64 | ≤4–>64 | 57.4 | 32.4 |
| Ceftriaxone | 8 | >32 | ≤0.25–>32 | 23.5 | 64.7 |
| Cefepime | 4 | >16 | ≤0.12–>16 | 58.8 | 36.8 |
| Imipenem | 2 | 4 | ≤0.5–4 | 45.6 | 14.7 |
| Meropenem | ≤0.12 | ≤0.12 | ≤0.12–8 | 98.5 | 1.5 |
| Piperacillin-tazobactam | 1 | 8 | ≤0.5–32 | 97.1 | 0.0 |
| P. aeruginosa | |||||
| All strains (449) | |||||
| CXA-TAZ4 | 1 | 8 | 0.25–>128 | — | — |
| CXA-101 | 1 | 8 | 0.25–>128 | — | — |
| Ceftazidime | 16 | 128 | 1–>128 | 43.9 | 46.3 |
| Cefepime | 8 | >16 | 0.5–>16 | 51.2 | 24.7 |
| Imipenem | >8 | >8 | 0.5–>8 | 20.7 | 59.7 |
| Doripenem | 8 | 16 | 0.06–>32 | 21.2 | 52.8 |
| Piperacillin-tazobactam | 32 | >64 | 1–>64 | 62.6 | 37.4 |
| Ceftazidime- and imipenem-susceptible strains (54) | |||||
| CXA-TAZ4 | 0.5 | 0.5 | 0.25–2 | — | — |
| CXA-101 | 0.5 | 0.5 | 0.25–2 | — | — |
| Ceftazidime | 2 | 4 | 1–8 | 100.0 | 0.0 |
| Cefepime | 2 | 4 | 0.5–16 | 98.2 | 0.0 |
| Imipenem | 1 | 2 | 0.5–4 | 100.0 | 0.0 |
| Doripenem | 0.25 | 1 | 0.06–1 | 100.0 | 0.0 |
| Piperacillin-tazobactam | 4 | 8 | 1–32 | 100.0 | 0.0 |
| Ceftazidime-susceptible, imipenem-nonsusceptible strains (143) | |||||
| CXA-TAZ4 | 0.5 | 1 | 0.25–8 | — | — |
| CXA-101 | 0.5 | 1 | 0.25–16 | — | — |
| Ceftazidime | 8 | 8 | 2–8 | 100.0 | 0.0 |
| Cefepime | 8 | 16 | 1–>16 | 87.4 | 3.5 |
| Imipenem | >8 | >8 | 8–>8 | 0.0 | 72.0 |
| Doripenem | 4 | 8 | 2–16 | 3.5 | 35.7 |
| Piperacillin-tazobactam | 16 | 64 | 2–>64 | 90.9 | 9.1 |
| Ceftazidime-nonsusceptible, imipenem-susceptible strains (39) | |||||
| CXA-TAZ4 | 2 | 64 | 0.5–>128 | — | — |
| CXA-101 | 2 | 128 | 0.25–>128 | — | — |
| Ceftazidime | 64 | >128 | 16–>128 | 7.7 | 92.3 |
| Cefepime | 16 | >16 | 4–>16 | 25.6 | 41.0 |
| Imipenem | 1 | 4 | 0.5–4 | 100.0 | 0.0 |
| Doripenem | 1 | 4 | 0.25–8 | 87.2 | 5.1 |
| Piperacillin-tazobactam | 64 | >64 | 16–>64 | 59.0 | 41.0 |
| Ceftazidime- and imipenem-nonsusceptible strains (213)c | |||||
| CXA-TAZ4 | 2 | 16 | 0.5–>128 | — | — |
| CXA-101 | 4 | 16 | 0.5–>128 | — | — |
| Ceftazidime | 64 | >128 | 16–>128 | 0.0 | 80.7 |
| Cefepime | 16 | >16 | 4–>16 | 19.7 | 42.3 |
| Imipenem | >8 | >8 | 8–>8 | 0.0 | 77.5 |
| Doripenem | 8 | 32 | 2–>32 | 0.9 | 86.4 |
| Piperacillin-tazobactam | >64 | >64 | 8–>64 | 34.7 | 65.3 |
| B. fragilis strains (41) | |||||
| CXA-TAZ4 | 1 | >16 | ≤0.12–>16 | — | — |
| CXA-101 | >32 | >32 | 1–>32 | — | — |
| Ceftazidime | 32 | >64 | 8–>64 | — | — |
The percentages of susceptible and resistant organisms according to CLSI breakpoints (5) are shown. —, no published interpretive criteria.
CXA-TAZ4, CXA-101 combined with tazobactam at fixed concentration of 4 μg/ml.
Imipenem MIC of ≥8 μg/ml and ceftazidime MIC of ≥16 μg/ml. CLSI breakpoints (5) were used.
Against ceftazidime-resistant strains, CXA-201 (MIC50 of 2 μg/ml and MIC90 of 16 to 64 μg/ml) was 32-fold more active than ceftazidime (MIC50, 64 μg/ml) and retained good activity against the majority of strains. Interestingly, 75.6 and 85.9% of P. aeruginosa strains resistant to both ceftazidime and imipenem were inhibited at ≤4 and ≤8 μg/ml of CXA-201, respectively (Table 3). CXA-201 (MIC50 of 2 μg/ml and MIC90 of 16 μg/ml) and CXA-101 (MIC50 of 4 μg/ml and MIC90 of 16 μg/ml) were the most active compounds tested against this highly selected group of resistant P. aeruginosa strains, followed in activity by doripenem (MIC50 of 8 μg/ml and MIC90 of 32 μg/ml) and cefepime (MIC50 of 16 μg/ml and MIC90 of >16 μg/ml) (Table 3).
CXA-101 has demonstrated potent anti-P. aeruginosa activity in previous studies (1, 7, 10, 11); however, like long-established oxyimino-cephalosporins, it is compromised by ESBLs, derepressed AmpC enzymes, and carbapenemases, such as KPCs and metallo-β-lactamases (8). To decrease this vulnerability, CXA-101 was combined with tazobactam, a β-lactamase inhibitor with established safety and efficacy when associated with piperacillin. As anticipated, the majority of ceftazidime-resistant Enterobacteriaceae and ESBL-producing P. mirabilis strains exhibited elevated CXA-101 MIC values (only 16.9% of strains inhibited at ≤8 μg/ml of CXA-101). However, the addition of tazobactam (CXA-201) markedly extended the spectrum of CXA-101 against this large collection of β-lactamase-producing strains, and 64.9% of strains were inhibited at ≤8/4 μg/ml (Table 1). Synergism effects were more evident among ESBL-producing organisms, such as E. coli, K. pneumoniae, and P. mirabilis. Some inhibitory activity was also observed with AmpC-derepressed Enterobacter and Citrobacter strains; however, CXA-201 MIC values remained elevated (≥16 μg/ml) for approximately one-half of the tested organisms.
Our results indicate that CXA-101 alone and CXA-TAZ4 (CXA-101 with taxobactam at a fixed concentration of 4 μg/ml) are more potent than ceftazidime and cefepime against P. aeruginosa (1, 10). Against strains susceptible to ceftazidime and imipenem, CXA-101 and CXA-201 were 4- to 8-fold more active than these commonly used antipseudomonal cephalosporins. Furthermore, the in vitro activities of CXA-101 and CXA-201 were not adversely affected by resistance to the carbapenems. Although CXA-101 and CXA-201 MIC values were higher for ceftazidime-resistant organisms than for their ceftazidime-susceptible counterparts, it appears that these compounds retain activity against some P. aeruginosa strains resistant to ceftazidime. CXA-201 was the most active compound tested against strains resistant to both ceftazidime and imipenem with MIC50s of only 2 and 4 μg/ml for its components, CXA-101 and tazobactam, respectively.
In summary, these data for CXA-201 tested against various β-lactam-resistant strains of Enterobacteriaceae and P. aeruginosa are encouraging; most importantly, CXA-201 demonstrated enhanced anti-P. aeruginosa activity compared to ceftazidime and cefepime. Initial results from pharmacokinetics and safety studies are also promising (6), indicating the potential usefulness of CXA-201 for the treatment of some infections caused by multidrug-resistant (MDR) Gram-negative organisms.
Footnotes
Published ahead of print on 14 February 2011.
REFERENCES
- 1. Bulik C. C., Christensen H., Nicolau D. P. 2010. In vitro potency of CXA-101, a novel cephalosporin, against Pseudomonas aeruginosa displaying various resistance phenotypes, including multidrug resistance. Antimicrob. Agents Chemother. 54:557–559 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Castanheira M., Sader H. S., Jones R. N. 2010. Antimicrobial susceptibility patterns of KPC-producing or CTX-M-producing Enterobacteriaceae. Microb. Drug Resist. 16:61–65 [DOI] [PubMed] [Google Scholar]
- 3. Clinical and Laboratory Standards Institute. 2007. M11-A7. Methods for antimicrobial susceptibility testing of anaerobic bacteria; approved standard: seventh edition. Clinical and Laboratory Standards Institute, Wayne, PA [Google Scholar]
- 4. Clinical and Laboratory Standards Institute. 2009. M07-A8. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: eighth edition. Clinical and Laboratory Standards Institute, Wayne, PA [Google Scholar]
- 5. Clinical and Laboratory Standards Institute. 2011. M100-S21. Performance standards for antimicrobial susceptibility testing: 21st informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA [Google Scholar]
- 6. Ge Y., Whitehouse M. J., Friedland I., Talbot G. H. 2010. Pharmacokinetics and safety of CXA-101, a new antipseudomonal cephalosporin, in healthy adult male and female subjects receiving single- and multiple-dose intravenous infusions. Antimicrob. Agents Chemother. 54:3427–3431 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Juan C., Zamorano L., Perez J. L., Ge Y., Oliver A. 2010. Activity of a new antipseudomonal cephalosporin, CXA-101 (FR264205), against carbapenem-resistant and multidrug-resistant Pseudomonas aeruginosa clinical strains. Antimicrob. Agents Chemother. 54:846–851 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Livermore D. M., Mushtaq S., Ge Y. 2010. Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus beta-lactamase-producing Enterobacteriaceae. J. Antimicrob. Chemother. 65:1972–1974 [DOI] [PubMed] [Google Scholar]
- 9. Livermore D. M., Mushtaq S., Ge Y., Warner M. 2009. Activity of cephalosporin CXA-101 (FR264205) against Pseudomonas aeruginosa and Burkholderia cepacia group strains and isolates. Int. J. Antimicrob. Agents 34:402–406 [DOI] [PubMed] [Google Scholar]
- 10. Moya B., et al. 2010. Activity of a new cephalosporin, CXA-101 (FR264205), against beta-lactam-resistant Pseudomonas aeruginosa mutants selected in vitro and after antipseudomonal treatment of intensive care unit patients. Antimicrob. Agents Chemother. 54:1213–1217 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Takeda S., Ishii Y., Hatano K., Tateda K., Yamaguchi K. 2007. Stability of FR264205 against AmpC beta-lactamase of Pseudomonas aeruginosa. Int. J. Antimicrob. Agents 30:443–445 [DOI] [PubMed] [Google Scholar]