Abstract
Ceftolozane/tazobactam, a novel antimicrobial agent with activity against Pseudomonas aeruginosa (including drug-resistant strains) and other common Gram-negative pathogens (including most extended-spectrum-β-lactamase [ESBL]-producing Enterobacteriaceae strains), and comparator agents were susceptibility tested by a reference broth microdilution method against 7,071 Enterobacteriaceae and 1,971 P. aeruginosa isolates. Isolates were collected consecutively from patients in 32 medical centers across the United States during 2011 to 2012. Overall, 15.7% and 8.9% of P. aeruginosa isolates were classified as multidrug resistant (MDR) and extensively drug resistant (XDR), and 8.4% and 1.2% of Enterobacteriaceae were classified as MDR and XDR. No pandrug-resistant (PDR) Enterobacteriaceae isolates and only one PDR P. aeruginosa isolate were detected. Ceftolozane/tazobactam was the most potent (MIC50/90, 0.5/2 μg/ml) agent tested against P. aeruginosa and demonstrated good activity against 310 MDR strains (MIC50/90, 2/8 μg/ml) and 175 XDR strains (MIC50/90, 4/16 μg/ml). Ceftolozane/tazobactam exhibited high overall activity (MIC50/90, 0.25/1 μg/ml) against Enterobacteriaceae and retained activity (MIC50/90, 4/>32 μg/ml) against many 601 MDR strains but not against the 86 XDR strains (MIC50, >32 μg/ml). Ceftolozane/tazobactam was highly potent (MIC50/90, 0.25/0.5 μg/ml) against 2,691 Escherichia coli isolates and retained good activity against most ESBL-phenotype E. coli isolates (MIC50/90, 0.5/4 μg/ml), but activity was low against ESBL-phenotype Klebsiella pneumoniae isolates (MIC50/90, 32/>32 μg/ml), explained by the high rate (39.8%) of meropenem coresistance observed in this species phenotype. In summary, ceftolozane/tazobactam demonstrated high potency and broad-spectrum activity against many contemporary Enterobacteriaceae and P. aeruginosa isolates collected in U.S. medical centers. Importantly, ceftolozane/tazobactam retained potency against many MDR and XDR strains.
INTRODUCTION
Ceftolozane/tazobactam is a novel antibacterial agent with activity against Pseudomonas aeruginosa, including drug-resistant strains, and other common Gram-negative pathogens, including most extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae strains (1). Ceftolozane is a novel antibacterial agent with potent activity (compared with ceftazidime) against P. aeruginosa, including drug-resistant strains, and Enterobacteriaceae (with potency similar to that of other oxyimino-aminothiazolyl cephalosporins) (1–6). However, as with other cephalosporins, ceftolozane's activity is compromised in bacteria producing ESBLs, stably derepressed AmpC β-lactamases, and carbapenemases (1, 7). Tazobactam, a penicillanic acid-sulfone, is a well-established β-lactamase inhibitor that broadens the coverage of β-lactam agents (8). Unlike clavulanate and sulbactam, tazobactam is a moderate inhibitor of inducibly and constitutively expressed AmpC enzymes, although this activity is strain dependent and is less potent against strains with totally derepressed AmpC β-lactamases (9).
During the past decade, nosocomial infections caused by Enterobacteriaceae and P. aeruginosa in intensive care units worldwide have been increasing in prevalence along with increases in antimicrobial resistance and associated increases in morbidity and mortality (10, 11). Empirical and targeted therapies to cover infections with these organisms are increasingly limited. Ceftolozane/tazobactam exploits ceftolozane's potent activity against P. aeruginosa and Enterobacteriaceae and broadens ceftolozane's spectrum of activity against Enterobacteriaceae (1), hence making it an attractive option for clinical development for treatment of some infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Ceftolozane/tazobactam is currently in phase III trials for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and nosocomial bacterial pneumonia. In the present study, we evaluated the potency of ceftolozane/tazobactam and comparator drugs tested for the first time against a large, contemporary (2011–2012) collection of clinically collected Enterobacteriaceae and P. aeruginosa isolates obtained from patients in U.S. hospitals.
MATERIALS AND METHODS
Sampling sites and organisms.
A total of 7,071 Enterobacteriaceae and 1,971 P. aeruginosa isolates were consecutively collected over 2 years (January 2011 to December 2012) from 32 medical centers located across all nine U.S. census regions. All organisms were isolated from documented infections, and only one strain per patient infection episode was included in the surveillance collection. The isolates were derived primarily from bloodstream infections, skin and skin-structure infections (SSSI), and pneumonia in hospitalized patients, urinary tract infections in hospitalized patients, and intra-abdominal infections according to a common surveillance design.
Antimicrobial susceptibility testing.
MIC values were determined using the reference Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (M07-A9) (12). Quality control (QC) ranges and interpretive criteria for comparator compounds used the CLSI M100-S23 guidelines (13). The ESBL phenotype was defined as a MIC of ≥2 μg/ml for ceftazidime or ceftriaxone or aztreonam (13). To better evaluate the activities of ceftolozane/tazobactam against β-lactam-resistant Enterobacteriaceae and P. aeruginosa, strains were stratified by patterns of susceptibility to ceftazidime and meropenem. MDR, extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacteria were classified as such per recently recommended guidelines (14) using the following antimicrobial class representative agents and CLSI interpretive criteria (13): for P. aeruginosa, ceftazidime (MIC of ≥16 μg/ml), meropenem (≥4 μg/ml), piperacillin-tazobactam (≥32/4 μg/ml), levofloxacin (≥4 μg/ml), gentamicin (≥8 μg/ml), and colistin (≥4 μg/ml); and for Enterobacteriaceae, ceftriaxone (≥2 μg/ml), meropenem (≥2 μg/ml), piperacillin-tazobactam (≥32/4 μg/ml), levofloxacin (≥4 μg/ml), gentamicin (≥8 μg/ml), tigecycline (≥4 μg/ml), and colistin (≥4 μg/ml). Classifications were based on the following recommended parameters: MDR = nonsusceptible to ≥1 agent in ≥3 antimicrobial classes; XDR = nonsusceptible to ≥1 agent in all but ≤2 antimicrobial classes; PDR = nonsusceptible to all antimicrobial classes (14).
RESULTS
Ceftolozane/tazobactam activity against Enterobacteriaceae.
Ceftolozane/tazobactam demonstrated high overall activity (MIC50, 0.25 μg/ml; MIC90, 1 μg/ml) against 7,071 Enterobacteriaceae isolates collected in the United States during 2011 to 2012 (Table 1 and Table 2). Using MIC90 values, ceftolozane/tazobactam showed potency identical to that of cefepime, was 16-fold more active than ceftazidime and piperacillin-tazobactam (MIC90 for both, 16 μg/ml), was at least 16-fold more potent than ceftriaxone (MIC90, >8 μg/ml), and was second in potency against all tested compounds only to meropenem (MIC90, ≤0.06 μg/ml; Table 2). Against 601 (8.5%) MDR isolates, meropenem (MIC50/90, ≤0.06/>8 μg/ml; 77.0% susceptible), ceftolozane/tazobactam (MIC50/90, 4/>32 μg/ml), tigecycline (MIC50/90, 0.5/2 μg/ml; 92.3% susceptible), and colistin (MIC50/90, 0.5/>4 μg/ml) were the only agents tested to retain activity at the MIC50 level (Table 2). Ceftolozane/tazobactam was not active against most XDR strains (n = 86; 1.2%) (MIC50/90, >32/>32 μg/ml), with tigecycline being the most active agent (87.1% susceptible), followed by meropenem and gentamicin, with low susceptibility rates of only 22.1% and 20.9%, respectively (Table 2). No PDR Enterobacteriaceae isolates were collected in this study.
Table 1.
Cumulative MIC distributions of ceftolozane/tazobactam against Enterobacteriaceae by resistance phenotype
| Organisma (n) | No. of isolates (cumulative %) inhibited at ceftolozane/tazobactam MIC (μg/ml) of: |
MIC50 | MIC90 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | >32 | |||
| Enterobacteriaceaeb (7,071) | 3 (0.0) | 15 (0.3) | 1,536 (22.0) | 2,977 (64.1) | 1,495 (85.2) | 432 (91.3) | 139 (93.3) | 100 (94.7) | 97 (96.1) | 66 (97.0) | 82 (98.2) | 129 (100.0) | 0.25 | 1 |
| MDR (601) | 0 (0.0) | 0 (0.0) | 2 (0.3) | 41 (7.2) | 117 (26.6) | 60 (36.6) | 47 (44.4) | 58 (54.1) | 52 (62.7) | 34 (68.4) | 68 (79.7) | 122 (100.0) | 4 | >32 |
| XDR (86) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (2.3) | 2 (4.7) | 3 (8.1) | 4 (12.8) | 6 (19.8) | 15 (37.2) | 54 (100.0) | >32 | >32 |
| Escherichia coli (2,691) | 1 (0.0) | 6 (0.3) | 999 (37.4) | 1,301 (85.7) | 256 (95.2) | 61 (97.5) | 29 (98.6) | 11 (99.0) | 9 (99.3) | 6 (99.6) | 7 (99.8) | 5 (100.0) | 0.25 | 0.5 |
| Non-ESBL phenotype (2,364) | 1 (0.0) | 6 (0.3) | 990 (42.2) | 1,208 (93.3) | 150 (99.6) | 8 (100.0) | 1 (100.0) | 0.25 | 0.25 | |||||
| ESBL phenotype (327) | 0 (0.0) | 0 (0.0) | 9 (2.8) | 93 (31.2) | 106 (63.6) | 53 (79.8) | 28 (88.4) | 11 (91.7) | 9 (94.5) | 6 (96.3) | 7 (98.5) | 5 (100.0) | 0.5 | 4 |
| MEM-S (2,683) | 1 (0.0) | 6 (0.3) | 999 (37.5) | 1,301 (86.0) | 256 (95.5) | 61 (97.8) | 29 (98.9) | 10 (99.3) | 8 (99.6) | 2 (99.6) | 6 (99.9) | 4 (100.0) | 0.25 | 0.5 |
| MEM-NS (8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (12.5) | 1 (25.0) | 4 (75.0) | 1 (87.5) | 1 (100.0) | 16 | |
| Klebsiella spp. (1,589) | 1 (0.1) | 5 (0.4) | 342 (21.9) | 682 (64.8) | 243 (80.1) | 104 (86.7) | 30 (88.5) | 23 (90.0) | 13 (90.8) | 12 (91.6) | 42 (94.2) | 92 (100.0) | 0.25 | 8 |
| K. pneumoniae (1,298) | 0 (0.0) | 5 (0.4) | 231 (18.2) | 566 (61.8) | 205 (77.6) | 96 (85.0) | 25 (86.9) | 15 (88.1) | 13 (89.1) | 12 (90.0) | 41 (93.1) | 89 (100.0) | 0.25 | 32 |
| Non-ESBL phenotype (1,054) | 0 (0.0) | 5 (0.5) | 229 (22.2) | 557 (75.0) | 186 (92.7) | 72 (99.5) | 5 (100.0) | 0.25 | 0.5 | |||||
| ESBL phenotype (244) | 0 (0.0) | 0 (0.0) | 2 (0.8) | 9 (4.5) | 19 (12.3) | 24 (22.1) | 20 (30.3) | 15 (36.5) | 13 (41.8) | 12 (46.7) | 41 (63.5) | 89 (100.0) | 32 | >32 |
| MEM-S (1,198) | 0 (0.0) | 5 (0.4) | 231 (19.7) | 566 (66.9) | 205 (84.1) | 96 (92.1) | 25 (94.2) | 15 (95.4) | 9 (96.2) | 5 (96.6) | 10 (97.4) | 31 (100.0) | 0.25 | 1 |
| MEM-NS (100) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 4 (4.0) | 7 (11.0) | 31 (42.0) | 58 (100.0) | >32 | >32 |
| K. oxytoca (283) | 1 (0.4) | 0 (0.4) | 110 (39.2) | 112 (78.8) | 36 (91.5) | 7 (94.0) | 5 (95.8) | 8 (98.6) | 0 (98.6) | 0 (98.6) | 1 (98.9) | 3 (100.0) | 0.25 | 0.5 |
| Non-ESBL phenotype (244) | 1 (0.4) | 0 (0.4) | 109 (45.1) | 109 (89.8) | 22 (98.8) | 3 (100.0) | 0.25 | 0.5 | ||||||
| ESBL phenotype (39) | 0 (0.0) | 0 (0.0) | 1 (2.6) | 3 (10.3) | 14 (46.2) | 4 (56.4) | 5 (69.2) | 8 (89.7) | 0 (89.7) | 0 (89.7) | 1 (92.3) | 3 (100.0) | 1 | 32 |
| Enterobacter spp. (1,029) | 1 (0.1) | 2 (0.3) | 93 (9.3) | 457 (53.7) | 205 (73.7) | 57 (79.2) | 46 (83.7) | 45 (88.0) | 56 (93.5) | 32 (96.6) | 17 (98.3) | 18 (100.0) | 0.25 | 8 |
| CAZ-S (766) | 1 (0.1) | 2 (0.4) | 91 (12.3) | 443 (70.1) | 188 (94.6) | 35 (99.2) | 6 (100.0) | 0.25 | 0.5 | |||||
| CAZ-NS (249) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 5 (2.0) | 16 (8.4) | 22 (17.3) | 40 (33.3) | 45 (51.4) | 55 (73.5) | 31 (85.9) | 17 (92.8) | 18 (100.0) | 4 | 32 |
| Citrobacter spp. (381) | 0 (0.0) | 1 (0.3) | 59 (15.7) | 207 (70.1) | 52 (83.7) | 7 (85.6) | 5 (86.9) | 9 (89.2) | 9 (91.6) | 13 (95.0) | 11 (97.9) | 8 (100.0) | 0.25 | 8 |
| Proteus mirabilis (414) | 0 (0.0) | 0 (0.0) | 3 (0.7) | 126 (31.2) | 260 (94.0) | 24 (99.8) | 1 (100.0) | 0.5 | 0.5 | |||||
| Non-ESBL phenotype (398) | 0 (0.0) | 0 (0.0) | 3 (0.8) | 125 (32.2) | 250 (95.0) | 20 (100.0) | 0.5 | 0.5 | ||||||
| ESBL phenotype (16) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (6.3) | 10 (68.8) | 4 (93.8) | 1 (100.0) | 0.5 | 1 | |||||
| Indole-positive Proteus spp. (368) | 0 (0.0) | 1 (0.3) | 33 (9.2) | 169 (55.2) | 103 (83.2) | 27 (90.5) | 12 (93.8) | 6 (95.4) | 6 (97.0) | 3 (97.8) | 4 (98.9) | 4 (100.0) | 0.25 | 1 |
| Serratia spp. (573) | 0 (0.0) | 0 (0.0) | 2 (0.3) | 24 (4.5) | 366 (68.4) | 152 (94.9) | 16 (97.7) | 6 (98.8) | 4 (99.5) | 0 (99.5) | 1 (99.7) | 2 (100.0) | 0.5 | 1 |
Abbreviations: MDR, multidrug-resistant; XDR, extensively drug resistant; PDR, pan-drug resistant; NS, nonsusceptible; R, resistant; S, susceptible; CAZ, ceftazidime; CAZ, ceftazidime; CAZ, ceftazidime; MEM, meropenem; MEM, meropenem; ESBL, extended-spectrum β-lactamase.
Includes (number of isolates) Citrobacter amalonaticus (9), Citrobacter braakii (12), Citrobacter farmeri (1), Citrobacter freundii (174), Citrobacter koseri (138), Citrobacter sedlakii (2), Citrobacter youngae (3), Enterobacter aerogenes (265), Enterobacter amnigenus (1), Enterobacter asburiae (15), Enterobacter cloacae (730), Enterobacter cloacae complex (1), Enterobacter intermedius (1), Enterobacter sakazakii (4), Escherichia coli (2691), Klebsiella oxytoca (283), Klebsiella ozaenae (3), Klebsiella planticola (1), Klebsiella pneumoniae (1298), Morganella morganii (256), Pantoea agglomerans (14), Proteus mirabilis (414), Proteus vulgaris (38), Providencia rettgeri (34), Providencia stuartii (37), Salmonella enteritidis (1), Salmonella typhi (2), Serratia liquefaciens (14), Serratia marcescens (552), Serratia odorifera (1), Serratia rubidaea (3), group B Salmonella (1), group D Salmonella (1), non-species-identified Citrobacter (42), non-species-identified Enterobacter (12), non-species-identified Klebsiella (4), non-species-identified Proteus (3), non-species-identified Salmonella (7), and non-species-identified Serratia (3).
Table 2.
Antimicrobial activity of ceftolozane/tazobactam and various comparator agents against Enterobacteriaceae collected in the U.S. during 2011 to 2012
| Organism(s) and antimicrobial agenta (no. tested) | MIC50 | MIC90 | % susceptibleb | % resistantb |
|---|---|---|---|---|
| Enterobacteriaceae—all isolates (7,071) | ||||
| Ceftolozane/tazobactam | 0.25 | 1 | —c | — |
| Ceftazidime | 0.12 | 16 | 88.1 | 10.5 |
| Ceftriaxone | ≤0.06 | >8 | 85.2 | 13.8 |
| Cefepime | ≤0.5 | 1 | 94.0 | 5.0 |
| Meropenem | ≤0.06 | ≤0.06 | 98.0 | 1.8 |
| Piperacillin-tazobactam | 2 | 16 | 90.9 | 5.8 |
| Aztreonam | ≤0.12 | 16 | 88.0 | 10.5 |
| Levofloxacin | ≤0.12 | >4 | 81.9 | 16.1 |
| Gentamicin | ≤1 | 4 | 90.7 | 8.2 |
| Tigecyclined | 0.25 | 1 | 98.2 | 0.1 |
| Colistin | 0.5 | >4 | — | — |
| Enterobacteriaceae—MDR (601) | ||||
| Ceftolozane/tazobactam | 4 | >32 | — | — |
| Ceftazidime | 32 | >32 | 22.0 | 71.7 |
| Ceftriaxone | >8 | >8 | 11.0 | 87.7 |
| Cefepime | 16 | >16 | 46.9 | 44.1 |
| Meropenem | ≤0.06 | >8 | 77.0 | 20.5 |
| Piperacillin-tazobactam | 64 | >64 | 34.6 | 46.3 |
| Aztreonam | >16 | >16 | 22.0 | 74.2 |
| Levofloxacin | >4 | >4 | 17.8 | 72.9 |
| Gentamicin | >8 | >8 | 40.8 | 50.1 |
| Tigecyclined | 0.5 | 2 | 92.3 | 0.2 |
| Colistin | 0.5 | >4 | — | — |
| Enterobacteriaceae—XDR (86) | ||||
| Ceftolozane/tazobactam | >32 | >32 | — | — |
| Ceftazidime | >32 | >32 | 2.3 | 96.5 |
| Ceftriaxone | >8 | >8 | 0.0 | 100.0 |
| Cefepime | >16 | >16 | 15.1 | 73.3 |
| Meropenem | >8 | >8 | 22.1 | 70.9 |
| Piperacillin-tazobactam | >64 | >64 | 2.3 | 81.4 |
| Aztreonam | >16 | >16 | 3.5 | 93.0 |
| Levofloxacin | >4 | >4 | 0.0 | 93.0 |
| Gentamicin | >8 | >8 | 20.9 | 61.6 |
| Tigecyclined | 0.5 | 4 | 87.1 | 0.0 |
| Colistin | >4 | >4 | — | — |
| E. coli, ESBL phenotype (327) | ||||
| Ceftolozane/tazobactam | 0.5 | 4 | — | — |
| Ceftazidime | 16 | >32 | 31.8 | 55.7 |
| Ceftriaxone | >8 | >8 | 8.3 | 90.2 |
| Cefepime | 16 | >16 | 44.5 | 48.8 |
| Meropenem | ≤0.06 | >8 | 97.6 | 1.5 |
| Piperacillin-tazobactam | 8 | >64 | 77.4 | 13.5 |
| Aztreonam | >16 | >16 | 23.2 | 63.9 |
| Levofloxacin | >4 | >4 | 22.6 | 75.5 |
| Gentamicin | 2 | >8 | 63.0 | 36.7 |
| Tigecyclined | 0.12 | 0.25 | 100.0 | 0.0 |
| Colistin | ≤0.25 | 0.5 | — | — |
| K. pneumoniae, ESBL phenotype (244) | ||||
| Ceftolozane/tazobactam | 32 | >32 | — | — |
| Ceftazidime | >32 | >32 | 5.3 | 88.5 |
| Ceftriaxone | >8 | >8 | 5.3 | 93.4 |
| Cefepime | >16 | >16 | 27.9 | 60.7 |
| Meropenem | ≤0.06 | >8 | 59.0 | 39.8 |
| Piperacillin-tazobactam | >64 | >64 | 25.4 | 65.2 |
| Aztreonam | >16 | >16 | 7.8 | 91.0 |
| Levofloxacin | >4 | >4 | 20.1 | 76.6 |
| Gentamicin | 4 | >8 | 50.8 | 39.8 |
| Tigecyclined | 0.5 | 2 | 97.1 | 0.0 |
| Colistin | 0.5 | >4 | — | — |
| Enterobacter spp. (1,029) | ||||
| Ceftolozane/tazobactam | 0.25 | 8 | — | — |
| Ceftazidime | 0.25 | >32 | 75.6 | 22.1 |
| Ceftriaxone | 0.25 | >8 | 71.6 | 25.9 |
| Cefepime | ≤0.5 | 2 | 96.3 | 2.6 |
| Meropenem | ≤0.06 | ≤0.06 | 98.6 | 1.1 |
| Piperacillin-tazobactam | 4 | 64 | 81.5 | 8.1 |
| Aztreonam | ≤0.12 | >16 | 76.9 | 19.2 |
| Levofloxacin | ≤0.12 | 0.5 | 94.7 | 3.9 |
| Gentamicin | ≤1 | ≤1 | 94.8 | 4.3 |
| Tigecyclined | 0.25 | 0.5 | 98.5 | 0.0 |
| Colistin | 0.5 | >4 | — | — |
| Citrobacter spp. (381) | ||||
| Ceftolozane/tazobactam | 0.25 | 8 | — | — |
| Ceftazidime | 0.25 | >32 | 84.8 | 15.2 |
| Ceftriaxone | 0.12 | >8 | 84.3 | 15.2 |
| Cefepime | ≤0.5 | 1 | 97.4 | 1.1 |
| Meropenem | ≤0.06 | ≤0.06 | 97.9 | 1.8 |
| Piperacillin-tazobactam | 2 | 64 | 87.1 | 7.9 |
| Aztreonam | ≤0.12 | >16 | 84.8 | 13.4 |
| Levofloxacin | ≤0.12 | 2 | 91.9 | 5.0 |
| Gentamicin | ≤1 | ≤1 | 95.5 | 4.2 |
| Tigecyclined | 0.12 | 0.5 | 100.0 | 0.0 |
| Colistin | 0.5 | 1 | — | — |
| Serratia spp. (573) | ||||
| Ceftolozane/tazobactam | 0.5 | 1 | — | — |
| Ceftazidime | 0.25 | 0.5 | 97.7 | 1.7 |
| Ceftriaxone | 0.25 | 1 | 91.4 | 6.8 |
| Cefepime | ≤0.5 | ≤0.5 | 99.1 | 0.3 |
| Meropenem | ≤0.06 | ≤0.06 | 99.1 | 0.5 |
| Piperacillin-tazobactam | 2 | 4 | 96.9 | 0.9 |
| Aztreonam | ≤0.12 | 0.5 | 97.5 | 2.3 |
| Levofloxacin | ≤0.12 | 0.5 | 96.5 | 1.0 |
| Gentamicin | ≤1 | 2 | 97.7 | 2.3 |
| Tigecyclined | 0.5 | 1 | 99.0 | 0.3 |
| Colistin | >4 | >4 | — | — |
Abbreviations: MDR, multidrug resistant; XDR, extensively drug resistant; PDR, pan-drug resistant; ESBL, extended-spectrum β-lactamase.
According to CLSI interpretive criteria (13).
—, no published interpretive criteria.
In the absence of CLSI interpretive criteria, U.S. FDA interpretive criteria were applied (Tygacil Product Insert, 2012).
Ceftolozane/tazobactam was highly potent (MIC50/90, 0.25/0.5 μg/ml), inhibiting 99.0% of 2,691 Escherichia coli isolates at a MIC of ≤4 μg/ml and 100.0% of 2,364 non-ESBL-phenotype isolates at a MIC of ≤2 μg/ml (Table 1). Similarly, ceftolozane/tazobactam activity was high against non-ESBL-phenotype Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis (MIC90 for all three, 0.5 μg/ml; Table 1). Although ceftolozane/tazobactam was active against most ESBL-phenotype E. coli isolates (MIC50/90, 0.5/4 μg/ml), its potency was much lower against ESBL-phenotype K. pneumoniae (MIC50/90, 32/>32 μg/ml; Table 1). This observed lower activity for ceftolozane/tazobactam in ESBL-phenotype K. pneumoniae can be explained by the higher rate of meropenem resistance (i.e., carbapenemases) observed in this phenotype (39.8%) compared with ESBL-phenotype E. coli (1.5%; Table 2), supported by the higher activity (MIC90, 1 μg/ml) observed against meropenem-susceptible K. pneumoniae (Table 1).
Tested against Enterobacter spp., Citrobacter spp., and Serratia spp., ceftolozane/tazobactam exhibited 8-fold-greater activity (MIC50, 0.25 to 0.5 μg/ml) than piperacillin-tazobactam (MIC50, 2 to 4 μg/ml), activity similar to that of ceftriaxone (MIC50, 0.12 to 0.25 μg/ml) and ceftazidime (MIC50, 0.25 μg/ml for all three genera), and activity similar to or lower than that of cefepime (MIC50, ≤0.5 μg/ml; Table 2). Ceftolozane/tazobactam was also very active (MIC50/90, 0.25/1 μg/ml) against 368 indole-positive Proteus spp. (Table 1).
Ceftolozane/tazobactam activity against P. aeruginosa.
Ceftolozane/tazobactam was the most potent (MIC50/90, 0.5/2 μg/ml) agent tested against 1,971 P. aeruginosa isolates, inhibiting 96.1% at a MIC of ≤4 μg/ml (Tables 3 and 4). Ceftolozane/tazobactam was at least 4-fold more active than ceftazidime (MIC50/90, 2/32 μg/ml), at least 8-fold more active than cefepime (MIC50/90, 4/16 μg/ml), at least 16-fold more active than piperacillin-tazobactam (MIC50/90, 8/>64 μg/ml), and slightly more potent than meropenem (MIC50/90, 0.5/8 μg/ml) when tested against the entire collection of P. aeruginosa isolates (Table 4). After colistin (MIC50/90, 1/2 μg/ml; 98.4% susceptible), ceftolozane/tazobactam was the most active (MIC50/90, 2/8 μg/ml) agent tested against 310 MDR P. aeruginosa isolates, with resistance for all other agents ranging from 36.5% for gentamicin to 70.6% for levofloxacin (Table 4). Similarly, against 175 XDR strains, ceftolozane/tazobactam retained activity (MIC50/90, 4/16 μg/ml), whereas resistance to other agents was high—ranging from 49.7% for gentamicin to 88.0% for levofloxacin (Table 4). Most XDR strains remained susceptible to colistin (97.7% susceptible), while in contrast, high levels of resistance to ceftazidime (73.7% resistant) and meropenem (76.0% resistant) were observed (Table 4). Only one PDR P. aeruginosa strain was detected, and ceftolozane/tazobactam demonstrated no observable activity (MIC, >32 μg/ml; Table 3) against this strain. Ceftolozane/tazobactam also had good activity against many ceftazidime-nonsusceptible (MIC50/90, 4/8 μg/ml), meropenem-nonsusceptible (MIC50/90, 1/8 μg/ml), piperacillin-tazobactam-nonsusceptible (MIC50/90, 2/8 μg/ml), cefepime-nonsusceptible (MIC50/90, 4/8 μg/ml), levofloxacin-nonsusceptible (MIC50/90, 1/8 μg/ml), and gentamicin-nonsusceptible (MIC50/90, 1/8 μg/ml) isolates (Table 3). Ceftolozane/tazobactam also had moderate activity against many isolates with combined ceftazidime and meropenem nonsusceptibility (MIC50/90, 4/32 μg/ml) and combined ceftazidime and meropenem and piperacillin-tazobactam nonsusceptibility (MIC50/90, 4/32 μg/ml; Table 3).
Table 3.
Cumulative MIC distributions of ceftolozane/tazobactam against P. aeruginosa by resistance phenotype
| P. aeruginosa resistance status (no. of isolates tested)a | No. of isolates (cumulative %) inhibited at ceftolozane/tazobactam MIC (μg/ml) of: |
MIC50 | MIC90 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | >32 | |||
| All isolates (1,971) | 0 (0.0) | 2 (0.1) | 3 (0.3) | 72 (3.9) | 958 (52.5) | 594 (82.6) | 152 (90.4) | 113 (96.1) | 47 (98.5) | 10 (99.0) | 4 (99.2) | 16 (100.0) | 0.5 | 2 |
| MDR (310) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.6) | 9 (3.5) | 79 (29.0) | 81 (55.2) | 74 (79.0) | 35 (90.3) | 10 (93.5) | 4 (94.8) | 16 (100.0) | 2 | 8 |
| XDR (175) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (1.1) | 28 (17.1) | 50 (45.7) | 44 (70.9) | 26 (85.7) | 8 (90.3) | 2 (91.4) | 15 (100.0) | 4 | 16 |
| PDR (1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (100.0) | >32 | >32 |
| CAZ-S (1,633) | 0 (0.0) | 2 (0.1) | 3 (0.3) | 72 (4.7) | 957 (63.3) | 542 (96.5) | 53 (99.8) | 4 (100.0) | 0.5 | 1 | ||||
| CAZ-NS (338) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 52 (15.7) | 99 (45.0) | 109 (77.2) | 47 (91.1) | 10 (94.1) | 4 (95.3) | 16 (100.0) | 4 | 8 |
| MEM-S (1,583) | 0 (0.0) | 2 (0.1) | 3 (0.3) | 69 (4.7) | 899 (61.5) | 450 (89.9) | 80 (94.9) | 60 (98.7) | 18 (99.9) | 1 (99.9) | 0 (99.9) | 1 (100.0) | 0.5 | 2 |
| MEM-NS (388) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (0.8) | 59 (16.0) | 144 (53.1) | 72 (71.6) | 53 (85.3) | 29 (92.8) | 9 (95.1) | 4 (96.1) | 15 (100.0) | 1 | 8 |
| CAZ-NS, MEM-NS (183) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 24 (13.1) | 50 (40.4) | 52 (68.9) | 29 (84.7) | 9 (89.6) | 4 (91.8) | 15 (100.0) | 4 | 32 |
| P/T-S (1,513) | 0 (0.0) | 2 (0.1) | 3 (0.3) | 71 (5.0) | 931 (66.6) | 459 (96.9) | 39 (99.5) | 4 (99.7) | 2 (99.9) | 1 (99.9) | 0 (99.9) | 1 (100.0) | 0.5 | 1 |
| P/T-NS (458) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.2) | 27 (6.1) | 135 (35.6) | 113 (60.3) | 109 (84.1) | 45 (93.9) | 9 (95.9) | 4 (96.7) | 15 (100.0) | 2 | 8 |
| CAZ-NS, MEM-NS, P/T-NS (175) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 22 (12.6) | 47 (39.4) | 51 (68.6) | 29 (85.1) | 8 (89.7) | 4 (92.0) | 14 (100.0) | 4 | 32 |
| Cefepime-S (1,624) | 0 (0.0) | 2 (0.1) | 3 (0.3) | 71 (4.7) | 955 (63.5) | 534 (96.4) | 49 (99.4) | 9 (99.9) | 0 (99.9) | 0 (99.9) | 0 (99.9) | 1 (100.0) | 0.5 | 1 |
| Cefepime-NS (347) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 3 (1.2) | 60 (18.4) | 103 (48.1) | 104 (78.1) | 47 (91.6) | 10 (94.5) | 4 (95.7) | 15 (100.0) | 4 | 8 |
| Levofloxacin-S (1,477) | 0 (0.0) | 2 (0.1) | 3 (0.3) | 62 (4.5) | 866 (63.2) | 403 (90.5) | 69 (95.1) | 51 (98.6) | 17 (99.7) | 0 (99.7) | 2 (99.9) | 2 (100.0) | 0.5 | 1 |
| Levofloxacin-NS (494) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 10 (2.0) | 92 (20.7) | 191 (59.3) | 83 (76.1) | 62 (88.7) | 30 (94.7) | 10 (96.8) | 2 (97.2) | 14 (100.0) | 1 | 8 |
| Gentamicin-S (1,758) | 0 (0.0) | 2 (0.1) | 3 (0.3) | 69 (4.2) | 934 (57.3) | 513 (86.5) | 103 (92.4) | 87 (97.3) | 34 (99.3) | 3 (99.4) | 4 (99.7) | 6 (100.0) | 0.5 | 2 |
| Gentamicin-NS (213) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (1.4) | 24 (12.7) | 81 (50.7) | 49 (73.7) | 26 (85.9) | 13 (92.0) | 7 (95.3) | 0 (95.3) | 10 (100.0) | 1 | 8 |
Abbreviations: MDR, multidrug resistant; XDR, extensively drug resistant; PDR, pan-drug resistant; NS, nonsusceptible; R, resistant; S, susceptible; CAZ, ceftazidime; MEM, meropenem; P/T, piperacillin-tazobactam.
Table 4.
Antimicrobial activity of ceftolozane/tazobactam and various comparator agents against P. aeruginosa isolates collected in the United States during 2011 to 2012
| P. aeruginosa resistance status (no. of isolates tested) and antimicrobial agenta | MIC50 | MIC90 | % susceptibleb | % resistantb |
|---|---|---|---|---|
| All isolates (1,971) | ||||
| Ceftolozane/tazobactam | 0.5 | 2 | —c | — |
| Ceftazidime | 2 | 32 | 82.9 | 13.7 |
| Cefepime | 4 | 16 | 82.4 | 8.6 |
| Meropenem | 0.5 | 8 | 80.3 | 13.9 |
| Piperacillin-tazobactam | 8 | >64 | 76.8 | 13.7 |
| Aztreonam | 8 | >16 | 68.5 | 19.2 |
| Levofloxacin | 0.5 | >4 | 74.9 | 19.1 |
| Gentamicin | ≤1 | 8 | 89.2 | 7.7 |
| Colistin | 1 | 2 | 99.1 | 0.2 |
| MDR (310) | ||||
| Ceftolozane/tazobactam | 2 | 8 | — | — |
| Ceftazidime | 32 | >32 | 22.6 | 60.6 |
| Cefepime | 16 | >16 | 22.5 | 38.7 |
| Meropenem | 8 | >8 | 19.4 | 64.5 |
| Piperacillin-tazobactam | >64 | >64 | 11.0 | 60.0 |
| Aztreonam | >16 | >16 | 9.0 | 69.0 |
| Levofloxacin | >4 | >4 | 15.2 | 70.6 |
| Gentamicin | 4 | >8 | 53.5 | 36.5 |
| Colistin | 1 | 2 | 98.4 | 0.3 |
| XDR (175) | ||||
| Ceftolozane/tazobactam | 4 | 16 | — | — |
| Ceftazidime | 32 | >32 | 9.1 | 73.7 |
| Cefepime | >16 | >16 | 10.9 | 52.0 |
| Meropenem | 8 | >8 | 7.4 | 76.0 |
| Piperacillin-tazobactam | >64 | >64 | 2.3 | 74.9 |
| Aztreonam | >16 | >16 | 4.6 | 72.6 |
| Levofloxacin | >4 | >4 | 2.9 | 88.0 |
| Gentamicin | 8 | >8 | 38.9 | 49.7 |
| Colistin | 1 | 2 | 97.7 | 0.6 |
DISCUSSION
Resistance mechanisms in Enterobacteriaceae and P. aeruginosa are extremely diverse, and there is currently no antimicrobial agent or combination that allows complete coverage of these important pathogens in the hospital setting. In in vitro studies to date, ceftolozane/tazobactam has demonstrated the greatest overall in vitro activity, compared with other agents tested, against this combined group of Gram-negative pathogens (1, 7, 15). The data from this large multicenter U.S. surveillance study confirm the data presented in earlier studies and demonstrate that ceftolozane/tazobactam had high in vitro potency and a broad spectrum of activity against many nosocomial isolates of Enterobacteriaceae and P. aeruginosa circulating in the United States during 2011 and 2012. In addition, this larger set of contemporary data supports the previously reported activity against a collection of ceftazidime- and/or carbapenem-resistant Enterobacteriaceae and P. aeruginosa isolates (1).
For this investigation, as described in Materials and Methods, we classified MDR, XDR, and PDR for both Enterobacteriaceae and P. aeruginosa according to guidelines recently published by an international expert panel (14). To achieve this, we tested representative antimicrobials from different classes in our laboratory to determine nonsusceptibility within each class. In addition, we used current (2013) CLSI MIC interpretive criteria to determine nonsusceptibility (13). It should be noted that current (2013) European Committee on Antimicrobial Susceptibility Testing (EUCAST) interpretive criteria (16) differ from the CLSI interpretive criteria for many of the organism/antimicrobial combinations (for example, for Enterobacteriaceae, nonsusceptibility to meropenem is ≥2 μg/ml by CLSI and ≥4 μg/ml by EUCAST). With these caveats, these data show that, although the level was reduced, ceftolozane/tazobactam retained good activity against MDR and XDR strains of P. aeruginosa and MDR strains of Enterobacteriaceae—but low activity against most strains of XDR Enterobacteriaceae due to the high prevalence of carbapenemase-producing K. pneumoniae in the XDR population (Table 2). This is in contrast to other agents (except colistin) that demonstrated reduced susceptibility (MDR/XDR)—22.6/9.1% ceftazidime-susceptible and 19.4/7.4% meropenem-susceptible P. aeruginosa (Table 3) isolates and 22.0/2.3% ceftazidime-susceptible and 77.0/22.1% meropenem-susceptible Enterobacteriaceae isolates (Table 1). Overall, in this U.S. surveillance study performed from 2011 through 2012, 15.7% of P. aeruginosa isolates were classified as MDR and 8.9% were classified as XDR (Table 3), and 8.4% of Enterobacteriaceae isolates were classified as MDR and only 1.2% as XDR (Table 1). Only one strain was classified as PDR. In this study, ceftolozane/tazobactam activity was most compromised against the XDR Enterobacteriaceae (only 1.2% of Enterobacteriaceae isolates).
In summary, these data for ceftolozane/tazobactam that have been collected over 2 years from 32 medical centers located across all nine U.S. census regions demonstrate high potency and broad-spectrum activity of this antibacterial agent tested against contemporary Enterobacteriaceae and P. aeruginosa strains. Importantly, ceftolozane/tazobactam retained clear activity against many MDR and XDR strains. The in vitro surveillance data presented here, coupled with favorable results published from pharmacokinetic, safety, animal infection, and in vitro studies (15, 17–20), suggest the potential usefulness of ceftolozane/tazobactam for the treatment of some infections caused by MDR Gram-negative organisms and warrant further clinical development.
ACKNOWLEDGMENTS
We express our appreciation to S. Benning, M. Stilwell, and M. Janecheck in the preparation of the manuscript and to the JMI staff members for scientific assistance in performing this study.
This study was funded by research grants from Cubist Pharmaceuticals (Lexington, MA). Cubist Pharmaceuticals was involved in the study design and decision to present these results. Cubist Pharmaceuticals had no involvement in the collection, analysis, or interpretation of data. JMI Laboratories, Inc., has received research and educational grants in 2009 to 2011 from Achaogen, Aires, American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, Bayer, bioMérieux, Cempra, Cerexa, Contrafect, Cubist Pharmaceuticals, Daiichi, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson, LegoChem Biosciences Inc., Meiji Seika Kaisha, Merck, Nabriva, Novartis, Paratek, Pfizer, PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co., Theravance, ThermoFisher, TREK Diagnostics, and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, J&J, and Theravance. In regard to speaker bureaus and stock options, we declare that we have no conflicts of interest.
Footnotes
Published ahead of print 7 October 2013
REFERENCES
- 1. Sader HS, Rhomberg PR, Farrell DJ, Jones RN. 2011. Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob. Agents Chemother. 55:2390–2394 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Livermore DM, 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]
- 3. Moya B, Zamorano L, Juan C, Perez JL, Ge Y, Oliver A. 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]
- 4. 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]
- 5. Bulik CC, Christensen H, Nicolau DP. 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]
- 6. Giske CG, Ge J, Nordmann P. 2009. Activity of cephalosporin CXA-101 (FR264205) and comparators against extended-spectrum-{beta}-lactamase-producing Pseudomonas aeruginosa. J. Antimicrob. Chemother. 64:430–431 [DOI] [PubMed] [Google Scholar]
- 7. Titelman E, Karlsson IM, Ge Y, Giske CG. 2011. In vitro activity of CXA-101 plus tazobactam (CXA-201) against CTX-M-14- and CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae. Diagn. Microbiol. Infect. Dis. 70:137–141 [DOI] [PubMed] [Google Scholar]
- 8. English AR, Retsema JA, Girard AE, Lynch JE, Barth WE. 1978. CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother. 14:414–419 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Akova M, Yang Y, Livermore DM. 1990. Interactions of tazobactam and clavulanate with inducibly- and constitutively-expressed class I beta-lactamases. J. Antimicrob. Chemother. 25:199–208 [DOI] [PubMed] [Google Scholar]
- 10. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, Gomersall C, Sakr Y, Reinhart K, EPIC II Group of Investigators 2009. International study of the prevalence and outcomes of infection in intensive care units. JAMA 302:2323–2329 [DOI] [PubMed] [Google Scholar]
- 11. Rosenthal VD, Bijie H, Maki DG, Mehta Y, Apisarnthanarak A, Medeiros EA, Leblebicioglu H, Fisher D, Alvarez-Moreno C, Khader IA, Del Rocio Gonzalez Martinez M, Cuellar LE, Navoa-Ng JA, Abouqal R, Guanche Garcell H, Mitrev Z, Pirez Garcia MC, Hamdi A, Duenas L, Cancel E, Gurskis V, Rasslan O, Ahmed A, Kanj SS, Ugalde OC, Mapp T, Raka L, Yuet Meng C, Thu le TA, Ghazal S, Gikas A, Narvaez LP, Mejia N, Hadjieva N, Gamar Elanbya MO, Guzman Siritt ME, Jayatilleke K; INICC members. 2012. International Nosocomial Infection Control Consortium (INICC) report, data summary of 36 countries, for 2004–2009. Am. J. Infect. Control 40:396–407 [DOI] [PubMed] [Google Scholar]
- 12. Clinical and Laboratory Standards Institute 2012. M07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition. Clinical and Laboratory Standards Institute, Wayne, PA [Google Scholar]
- 13. Clinical and Laboratory Standards Institute 2013. M100-S23. Performance standards for antimicrobial susceptibility testing: 23rd informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA [Google Scholar]
- 14. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL. 2012. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect. 18:268–281 [DOI] [PubMed] [Google Scholar]
- 15. Craig WA, Andes DR. 28 December 2012. In vivo activities of ceftolozane, a new cephalosporin, with and without tazobactam against Pseudomonas aeruginosa and enterobacteriaceae, including strains with extended-spectrum beta-lactamases, in the thighs of neutropenic mice. Antimicrob. Agents Chemother. 10.1128/AAC.01590-12 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. EUCAST, January 2013. Breakpoint tables for interpretation of MICs and zone diameters. Version 3.0. http://www.eucast.org/clinical_breakpoints/ Accessed 2 January 2013
- 17. Ge Y, Whitehouse MJ, Friedland I, Talbot GH. 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]
- 18. Chandorkar G, Huntington JA, Gotfried MH, Rodvold KA, Umeh O. 2012. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects. J. Antimicrob. Chemother. 67:2463–2469 [DOI] [PubMed] [Google Scholar]
- 19. Vanscoy B, Mendes RE, Castanheira M, McCauley J, Bhavnani SM, Forrest A, Jones RN, Okusanya OO, Friedrich L, Steenbergen J, Ambrose PG. 2013. Relationship between ceftolozane/tazobactam exposure and drug-resistance amplification in a hollow-fiber infection model. Antimicrob. Agents Chemother. 57:4134–4138 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. VanScoy B, Mendes RE, Nicasio AM, Castanheira M, Bulik CC, Okusanya OO, Bhavnani SM, Forrest A, Jones RN, Friedrich LV, Steenbergen JN, Ambrose PG. 2013. Pharmacokinetics-pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model. Antimicrob. Agents Chemother. 57:2809–2814 [DOI] [PMC free article] [PubMed] [Google Scholar]