tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012).

YJINF3306_proof ■ 29 April 2014 ■ 1/12 Journal of Infection (2014) xx, 1e12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

www.elsevierhealth.com/journals/jinf

Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012) Q5

Helio S. Sader*, David J. Farrell, Robert K. Flamm, Ronald N. Jones JMI Laboratories, North Liberty, IA, USA Accepted 19 April 2014 Available online - - -

KEYWORDS Ceftolozane/ tazobactam; Urinary tract infections

Summary Ceftolozane/tazobactam is under clinical development for treatment of complicated intra-abdominal infections (IAI), complicated urinary tract infections (UTI) and ventilatorassociated pneumonia. We evaluated the in vitro activity of ceftolozane/tazobactam and comparator agents tested against Gram-negative aerobic bacteria causing IAI and healthcare-associated UTI (HCA-UTI). The organisms were consecutively collected from January to December 2012 from 59 medical centers located in the United States (USA) and 15 European countries by the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS). The collection included 809 organisms from IAI and 2474 organisms from HCA-UTI, and susceptibility testing was performed by reference broth microdilution methods as described by the Clinical and Laboratory Standards Institute (CLSI) M07-A9 document. Overall, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were the most frequently isolated pathogens from both infection types. Ceftolozane/tazobactam was very active against E. coli (MIC50/90, 0.25/0.5 mg/L; 98.5e99.9% inhibited at an MIC of 8 mg/ L) and retained activity against many of the multidrug-resistant (MDR; MIC50/90, 0.5/2e>32 mg/L) and ESBL-phenotype strains (MIC50/90, 0.5/2e32 mg/L). Ceftolozane/tazobactam was active against most K. pneumoniae strains (MIC50/90, 0.25/16 mg/L, 88.9e89.6% inhibited at an MIC of 8 mg/L), but some ESBL-phenotype (MIC50/90, 4e8/>32 mg/L) and MDR (MIC50/90, 16/>32 mg/ L) isolates exhibited elevated MIC values. Ceftolozane/tazobactam was the most active agent tested against P. aeruginosa (MIC50/90, 0.5/4 mg/L; 93.4e95.7% inhibited at 8 mg/L) and retained potency against many MDR (MIC50/90, 2e4/>32 mg/L), ceftazidime-nonsusceptible (MIC50/90, 2e4/

* Corresponding author. JMI Laboratories, 345 Beaver Kreek Ctr, Ste A, North Liberty, IA 52317, USA. Tel.: þ1 319 665 3370; fax: þ1 319 665 3371. Q1 E-mail address: [email protected] (H.S. Sader). 0163-4453/$36 ª 2014 Published by Elsevier Ltd on behalf of The British Infection Association. http://dx.doi.org/10.1016/j.jinf.2014.04.004 Please cite this article in press as: Sader HS, et al., Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012), J Infect (2014), http:// dx.doi.org/10.1016/j.jinf.2014.04.004

61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122

YJINF3306_proof ■ 29 April 2014 ■ 2/12

2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

H.S. Sader et al. >32 mg/L) and meropenem-nonsusceptible (MIC50/90, 2/>32 mg/L) strains. Ceftolozane/tazobactam was also active against Klebsiella oxytoca (MIC50/90, 0.12e0.25/0.5e1 mg/L), Enterobacter spp. (MIC50/90, 0.25e0.5/4e8 mg/L), Citrobacter spp. (MIC50/90, 0.25/2e32 mg/L), Proteus mirabilis (MIC50/90, 0.5/0.5 mg/L), indole-positive Proteae (MIC50/90, 0.25/0.5e1 mg/L), and Serratia spp. (MIC50/90, 0.5/1e2 mg/L). In summary, ceftolozane/tazobactam demonstrated potent in vitro activity when tested against contemporary aerobic Gram-negative pathogens causing IAI and HCAUTI in USA and European medical centers. ª 2014 Published by Elsevier Ltd on behalf of The British Infection Association.

Introduction

Susceptibility testing

Ceftolozane is a novel cephalospirin that is currently under clinical development in combination with the b-lactamase inhibitor tazobactam for treatment of complicated intraabdominal infections (IAI; http://clinicaltrials.gov, identifiers NCT01147640, NCT01445665 and NCT01445678), complicated urinary tract infections (UTI; NCT01345955, NCT01345929 and NCT00921024) and ventilator-associated pneumonia (VAP; NCT01853982). This compound has shown remarkable stability against various resistance mechanisms employed by Pseudomonas aeruginosa to other b-lactam compounds, and has demonstrated activity against ceftazidime-resistant, as well as meropenem-resistant strains.1e3 Ceftolozane has also demonstrated good activity against members of the Enterobacteriaceae, but similar to other established oxyimino-cephalosporins, its activity can be compromised by production of extended-spectrum b-lactamases (ESBLs), carbapenemases and, to some degree, hyperproduction of AmpC b-lactamases. Thus, the addition of tazobactam, a well-established b-lactamase inhibitor, broadens the spectrum of ceftolozane activity to include many ESBL-producing organisms as well as some anaerobes, such as Bacteroides spp.4e6 In this study, we evaluated the activity of ceftolozane/ tazobactam and comparator agents tested against Gramnegative aerobic bacteria causing IAI and healthcareassociated UTI (HCA-UTI) in United States (USA) and European hospitals during 2012.

Isolates were tested for susceptibility to multiple antimicrobial agents at a reference laboratory (JMI Laboratories) by standardized broth microdilution methods as described by the Clinical and Laboratory Standards Institute (CLSI) M07-A9 document.7 Minimum inhibitory concentration (MIC) results were interpreted according to CLSI criteria in M100S23,8 as well as EUCAST breakpoint tables (version 3.0).9 Escherichia coli and Klebsiella pneumoniae isolates were grouped as “ESBL-phenotype” based on the CLSI screening criteria for potential ESBL production, ie, MIC of 2 mg/L for ceftazidime or ceftriaxone or aztreonam.8 Although the “ESBL-phenotype” strains were not submitted to an ESBL confirmation test, and other b-lactamases, such as AmpC and K. pneumoniae carbapenemases (KPC), may also produce an “ESBL-phenotype,” these strains were grouped together because they usually demonstrate resistance to various broad-spectrum b-lactam compounds. Meropenem-nonsusceptible K. pneumoniae indicates a meropenem MIC of 4 mg/L.8 Multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria were classified per recently recommended guidelines10 using the following antimicrobial class representative agents and EUCAST interpretive criteria9: i) for P. aeruginosa e ceftazidime (16 mg/L), meropenem (4 mg/L), piperacillin/ tazobactam (32/4 mg/L), levofloxacin (2 mg/L), gentamicin (8 mg/L), and colistin (4 mg/L); and ii) for Enterobacteriaceae e ceftriaxone (2 mg/L), meropenem (4 mg/L), piperacillin/tazobactam (16/4 mg/L), levofloxacin (2 mg/L), gentamicin (4 mg/L), tigecycline (2 mg/L), and colistin (4 mg/L). Classifications were based on the following recommended parameters: MDR Z nonsusceptible to 1 agent in 3 antimicrobial classes; XDR Z nonsusceptible to 1 agent in all but 2 antimicrobial classes; pandrug-resistant (PDR) Z nonsusceptible to all antimicrobial classes tested.10 Quality control (QC) was performed according to CLSI8 methods. E. coli ATCC 25922 and 35218 and P. aeruginosa ATCC 27853 strains were used all QC results were within the published ranges.8

Material and methods Bacterial isolates The organism collection included only aerobic Gramnegative bacilli collected from hospitalized patients with a diagnosis of IAI or HCA-UTI. The organisms were consecutively collected from January to December 2012 from 28 medical centers located in the USA and 31 medical centers in 15 European countries by the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS). A total of 809 organisms from IAI and 2474 organisms from UTI were included in this investigation. Species identification was performed at each participating medical center and confirmed at the monitoring laboratory (JMI Laboratories, North Liberty, Iowa, USA) using the VITEK 2 System (bioMerieux, Hazelwood, Missouri, USA) or MALDI-TOF (Bruker, Billerica, Massachusetts, USA), when necessary. Only one strain per patient infection episode was included in this surveillance study.

Results Intra-abdominal infections The aerobic Gram-negative bacilli most frequently isolated from IAI were E. coli (42.2%), K. pneumoniae (15.6%) and P. aeruginosa (14.2%). Ceftolozane/tazobactam was very active (MIC50/90, 0.25/0.5 mg/L) against 341 E. coli isolates and retained activity against many of the 16 (4.7%) MDR

Please cite this article in press as: Sader HS, et al., Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012), J Infect (2014), http:// dx.doi.org/10.1016/j.jinf.2014.04.004

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124


Ceftolozane/tazobactam activity against Gram-negative 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

isolates (MIC50/90, 0.5/>32 mg/L; 75.0% of isolates inhibited at an MIC of 8 mg/L) and 38 (11.1%) ESBL-phenotype strains (MIC50/90, 0.5/32 mg/L; 86.8% of isolates inhibited at an MIC of 8 mg/L; Table 1). Meropenem was the most potent (MIC50/90, 0.06/0.06 mg/L) agent overall against E. coli. Susceptibility rates (EUCAST) ranged from 80.0% for levofloxacin to 100.0% for colistin, meropenem and tigecycline (Table 2). Ceftolozane/tazobactam was also active against most K. pneumoniae strains (MIC50/90, 0.25/16 mg/L, 88.9% inhibited at an MIC of 8 mg/L; Tables 1 and 2). Ceftolozane/tazobactam exhibited potent activity against 96 non-ESBL-phenotype K. pneumoniae (MIC50/90, 0.25/ 0.5 mg/L; data not shown), but showed limited activity against 21 MDR (MIC50/90, 16/>32 mg/L) and four XDR K. pneumoniae strains when compared with the E. coli MDR population (Table 1). Although ceftolozane/tazobactam was active against many meropenem-susceptible ESBLphenotype K. pneumoniae (MIC50, 1 mg/L and MIC90, >32 mg/L), it was inactive (MIC50, >32 mg/L) against nine meropenem-nonsusceptible isolates (Table 2). Ceftolozane/tazobactam also demonstrated good activity against other Enterobacteriaceae, such as Enterobacter spp. (MIC50/90, 0.5/8 mg/L), Citrobacter spp. (MIC50/90, 0.25/32 mg/L), Klebsiella oxytoca (MIC50/90, 0.25/1 mg/ L), Proteus mirabilis (MIC50/90, 0.5/0.5 mg/L), and indole-positive Proteae (MIC50/90, 0.25/0.5 mg/L; Table 1). Ceftolozane/tazobactam was the most active agent tested against 115 P. aeruginosa (MIC50/90, 0.5/4 mg/L; 95.7% inhibited at 8 mg/L; Tables 1 and 2), demonstrating at least four-fold greater activity than ceftazidime (MIC50/ 90, 2/32 mg/L; 77.4% susceptible) and cefepime (MIC50/90, 2/>16 mg/L; 76.5% susceptible), at least 16-fold greater activity than piperacillin/tazobactam (MIC50/90, 8/ >64 mg/L; 72.2% susceptible), and up to two-fold greater activity than meropenem (MIC50/90, 0.5/8 mg/L; 79.1% susceptible; Table 2). Furthermore, most isolates were susceptible to colistin (98.3% susceptible) and amikacin (93.9e95.7% susceptible), whereas levofloxacin susceptibility was only 75.7e80.0% (Table 2). Importantly, ceftolozane/tazobactam retained potency against many MDR (MIC50/90, 4/>32 mg/L; 73.7% inhibited at 8 mg/L), ceftazidime-nonsusceptible (MIC50/90, 2/ >32 mg/L; 80.8% inhibited at 8 mg/L), and meropenemnonsusceptible (MIC50/90, 2/>32 mg/L; 79.2% inhibited at 8 mg/L) strains of P. aeruginosa. Good activity was also observed against 13 XDR strains (MIC50/90, 4/>32 mg/L) with 61.5% of XDR isolates inhibited at a ceftolozane/tazobactam MIC of 8 mg/L (Table 1). In contrast, ceftolozane/ tazobactam had variable activity against the limited number of Acinetobacter spp. (MIC50/90, 8/>32 mg/L) and Stenotrophomonas maltophilia (MIC50/90, 4/>32 mg/L) collected from patients with IAI (Table 1).

Urinary tract infections E. coli was the most frequent (53.9%) HCA-UTI pathogen isolated in this combined study of USA and European hospitals during 2012, followed by K. pneumoniae (12.8%), P. aeruginosa (8.6%), Enterobacter spp. (5.9%) and P.

3 mirabilis (4.7%). Ceftolozane/tazobactam was very active against E. coli (MIC50/90, 0.25/0.5 mg/L; 99.9% inhibited at 8 mg/L) and retained activity against 69 (5.2%) isolates that were MDR (MIC50/90, 0.5/2 mg/L; 98.6% inhibited at 8 mg/L) and 170 (12.8%) isolates with an ESBLphenotype (MIC50/90, 0.5/2 mg/L; 99.4% inhibited at 8 mg/L; Table 1). Meropenem was the most potent (MIC50/90, 0.06/0.06 mg/L; 100.0% susceptible) agent overall against E. coli (including MDR and ESBL-phenotype strains; Table 2). Against all 1333 E. coli collected from patients with HCA-UTI, susceptibility ranged from 75.0% (EUCAST) for levofloxacin to 100.0% (EUCAST) for meropenem (Table 2). Ranked after meropenem, ceftolozane/tazobactam and colistin were the most active agents tested against MDR and ESBL-phenotype subpopulations of E. coli (Table 2). Only one XDR E. coli strain was detected and the ceftolozane/tazobactam MIC for that organism was 16 mg/L (Table 1). Most K. pneumoniae strains isolated from HCA-UTI exhibited low ceftolozane/tazobactam MIC values (MIC50/90, 0.25/16 mg/L, 89.6% inhibited at an MIC of 8 mg/L; Table 1). Ceftolozane/tazobactam was most active against 230 non-ESBL-phenotype K. pneumoniae (MIC50/90, 0.25/ 0.5 mg/L; highest MIC, 2 mg/L; data not shown), but showed limited activity against MDR (MIC50/90, 16/ >32 mg/L) and XDR (MIC50/90, >32/>32 mg/L) strains (Table 1). Furthermore, ceftolozane/tazobactam demonstrated good activity against most meropenem-susceptible ESBL-phenotype K. pneumoniae (MIC50, 2 mg/L and MIC90, >32 mg/L; Table 1). Ceftolozane/tazobactam was also active against other prevalent Enterobacteriaceae, including K. oxytoca (MIC50/ 90, 0.12/0.5 mg/L), Enterobacter spp. (MIC50/90, 0.25/ 4 mg/L), Citrobacter spp. (MIC50/90, 0.25/2 mg/L), P. mirabilis (MIC50/90, 0.5/0.5 mg/L), indole-positive Proteae (MIC50/90, 0.25/1 mg/L), and Serratia spp. (MIC50/90, 0.5/ 2 mg/L; Table 1). Overall, ceftolozane/tazobactam was very active when tested against P. aeruginosa (MIC50/90, 0.5/4 mg/L; 93.4% inhibited at 8 mg/L; Table 1), demonstrating greater activity than ceftazidime (MIC50/90, 2/32 mg/L), cefepime (MIC50/90, 2/>16 mg/L), piperacillin/tazobactam (MIC50/ 90, 8/>64 mg/L) and meropenem (MIC50/90, 0.5/8 mg/L; Table 2). Susceptibility rates for b-lactam agents tested ranged from 75.0% for meropenem to 83.5% for ceftazidime (Table 2). Many isolates were susceptible to colistin (98.1% susceptible) and amikacin (92.0e96.7% susceptible) with levofloxacin susceptibility rate being the lowest among agents tested (64.6e67.9%; Table 2). Ceftolozane/tazobactam retained good in vitro activity against many MDR (MIC50/90, 2/>32 mg/L; 65.0% inhibited at 8 mg/L), ceftazidime-nonsusceptible (MIC50/90, 4/>32 mg/L; 60.0% inhibited at 8 mg/L), and meropenem-nonsusceptible (MIC50/90, 2/>32 mg/L; 75.5% inhibited at 8 mg/L) strains of P. aeruginosa. Although activity was lower overall against XDR strains (MIC50/90, 8/>32 mg/L), 56.7% of XDR isolates were inhibited at a ceftolozane/tazobactam MIC of 8 mg/L (Table 2). Ceftolozane/tazobactam exhibited limited activity against the small number (29 isolates) of Acinetobacter spp. (MIC50/90, 16/>32 mg/L) and S. maltophilia (MIC50, 16 mg/L) strains tested (Table 1).


63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 4

Infection type/organisma

Number of isolates (cumulative %) inhibited at ceftolozane/tazobactam MIC (mg/L) of 0.12

0.25

0.5

341 16 38 126 21 4 21 9 30 82 33 38 24 24 11 115 19 13 26 24 11 7

108 e e 16 e e 1 e 10 4 e 4 e e e e e e e e 1 e

178 2 9 60 1 e 5 e 13 27 e 21 6 12 1 5 e e e e 0 e

39 6 13 25 1 e 3 e 3 15 2 4 18 10 6 56 1 1 e 3 1 e

1333 69 1 170 316 57 11 67 19 44 146 45 113 117 118 44

383 2 e 4 53 e e e e 17 12 e 12 e 13 e

(31.7)

(12.7)

(4.5) (33.3) (4.9) (10.5)

(9.1)

(28.7) (2.9) (2.4) (16.8)

(38.6) (8.2) (10.6) (11.0)

762 15 e 48 139 2 e 9 e 16 67 2 67 32 51 4

(83.9) (12.5) (23.7) (60.3) (4.8) (27.3) (76.7) (37.8) (65.8) (25.0) (50.0) (9.1) (4.3)

(9.1)

(85.9) (24.6) (30.6) (60.8) (3.5) (13.4) (75.0) (54.1) (4.4) (69.9) (27.4) (54.2) (9.1)

146 34 e 80 52 1 e 13 e 8 27 6 16 78 38 23

1 (95.3) (50.0) (57.9) (80.2) (9.5) (40.9) (86.7) (56.1) (6.1) (76.3) (100.0) (91.7) (63.6) (53.0) (5.3) (7.7) (12.5) (18.2)

(96.8) (73.9) (77.6) (77.2) (5.3) (32.8) (93.2) (72.6) (17.8) (84.1) (94.0) (86.4) (61.4)

6 1 6 5 2 e 3 e 2 9 5 3 e 1 4 28 1 0 3 3 1 2 23 9 e 20 16 4 e 9 e 0 9 8 2 6 7 12

2 (97.1) (56.3) (73.7) (84.1) (19.0) (54.5) (93.3) (67.1) (21.2) (84.2) (95.8) (100.0) (77.4) (10.5) (7.7) (11.5) (25.0) (27.3) (28.6) (98.6) (87.0) (89.4) (82.3) (12.3) (46.3) (93.2) (78.8) (35.6) (85.8) (99.1) (92.4) (88.6)

2 1 2 4 2 e 2 e 1 7 6 0 e 0 e 13 6 4 10 8 2 1 14 6 e 13 10 7 e 9 e 1 7 6 6 1 2 5

4 (97.7) (62.5) (78.9) (87.3) (28.6) (63.6) (96.7) (75.6) (39.4) (84.2) (95.8) (88.7) (42.1) (38.5) (50.0) (58.3) (45.5) (42.9) (99.6) (95.7) (97.1) (85.4) (24.6) (59.7) (95.5) (83.6) (48.9) (91.2) (100.0) (94.1) (100.0)

3 2 3 0 0 e 0 e 0 3 3 0 e 0 e 6 4 2 6 3 0 1 1 0 e 1 13 11 1 13 e 1 12 11 1 e 1 e

(98.5) (75.0) (86.8) (87.3) (28.6) (63.6) (96.7) (79.3) (48.5) (84.2) (95.8) (93.9) (63.2) (53.8) (73.1) (70.8) (45.5) (57.1) (99.7) (95.7) (97.6) (89.6) (43.9) (9.1) (79.1) (97.7) (91.8) (73.3) (92.0) (94.9)

8

16

32

>32

0 (98.5) 0 (75.0) 0 (86.8) 2 (88.9) 2 (38.1) e 2 (72.7) e 0 (96.7) 9 (90.2) 9 (75.8) 0 (84.2) e 0 (95.8) e 2 (95.7) 2 (73.7) 1 (61.5) 2 (80.8) 2 (79.2) 2 (63.6) 1 (71.4)

1 (98.8) 1 (81.3) 1 (89.5) 4 (92.1) 3 (52.4) 1 (25.0) 2 (81.8) 2 (22.2) 1 (100.0) 6 (97.6) 6 (93.9) 2 (89.5) e 0 (95.8) e 0 (95.7) 0 (73.7) 0 (61.5) 0 (80.8) 0 (79.2) 1 (72.7) 1 (85.7)

2 (99.4) 1 (87.5) 2 (94.7) 1 (92.9) 1 (57.1) 0 (25.0) 0 (81.8) 1 (33.3) e 2 (100.0) 2 (100.0) 1 (92.1) e 0 (95.8) e 2 (97.4) 2 (84.2) 2 (76.9) 2 (88.5) 2 (87.5) 1 (81.8) 0 (85.7)

2 2 2 9 9 3 3 6 e e e 3 e 1 e 3 3 3 3 3 2 1

3 (99.9) 2 (98.6) e 3 (99.4) 0 (89.6) 0 (43.9) 0 (9.1) 0 (79.1) e 1 (100.0) 5 (95.2) 5 (84.4) 2 (93.8) e 2 (96.6) e

1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 4 (90.8) 4 (50.9) 0 (9.1) 3 (83.6) 1 (5.3) e 3 (97.3) 3 (91.1) 3 (96.5) e 1 (97.5) e

e e e e 8 (93.4) 8 (64.9) 2 (27.3) 1 (85.1) 7 (42.1) e 2 (98.6) 2 (95.6) 1 (97.3) e 2 (99.2) e

e e e e 21 20 8 10 11 e 2 2 3 e 1 e

(100.0) (100.0) (100.0) (100.0) (100.0) (100.0) (100.0) (100.0)

(100.0) (100.0) (100.0) (100.0) (100.0) (100.0) (100.0) (100.0) (100.0)

(100.0) (100.0) (100.0) (100.0) (100.0) (100.0) (100.0) (100.0) (100.0)


Intra-abdominal infections Escherichia coli MDR ESBL-phenotype Klebsiella pneumoniae MDR XDR MER-S ESBL-phenotype MER-NS Klebsiella oxytoca Enterobacter spp. CAZ-NS Citrobacter spp. Proteus mirabilis Indole-positive Proteae. Serratia spp. Pseudomonas aeruginosa MDR XDR CAZ-NS MER-NS Acinetobacter spp. Stenotrophomonas maltophilia Urinary tract infections Escherichia coli MDR XDR ESBL-phenotype Klebsiella pneumoniae MDR XDR MER-S ESBL-phenotype MER-NS Klebsiella oxytoca Enterobacter spp. CAZ-NS Citrobacter spp. Proteus mirabilis Indole-positive Proteae Serratia spp.

No. of isolates

H.S. Sader et al.


Table 1 Cumulative MIC distributions of ceftolozane/tazobactam tested against aerobic Gram-negative bacilli isolated from intra-abdominal and urinary tract infections in the USA and Europe during 2012.

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124


Ceftolozane/tazobactam activity against Gram-negative

(93.4) (65.0) (56.7) (60.0) (75.5) (72.0) (75.0)

4 4 4 4 4 1 0

(95.3) (75.0) (70.0) (71.4) (83.0) (76.0) (75.0)

10 10 9 10 9 6 1

(100.0) (100.0) (100.0) (100.0) (100.0) (100.0) (100.0)

Susceptibility rates by geographic region

a

(26.4) (12.0) e

2 (8.0)

MDR Z multidrug-resistant; XDR Z extensively drug-resistant; CAZ-NS Z ceftazidime-nonsusceptible; MER-NS Z meropenem-nonsusceptible; and ESBL Z extended-spectrum b-lactamase.8,10

0 0 0 0 0 8 2 (93.4) (65.0) (56.7) (60.0) (75.5) (40.0) (25.0) 4 3 3 3 3 1 0 (91.5) (57.5) (46.7) (51.4) (69.8) (36.0) (25.0) 5 3 2 5 3 4 0 (89.2) (50.0) (40.0) (37.1) (64.2) (20.0) (25.0) 14 11 6 8 10 2 1 (82.5) (22.5) (20.0) (14.3) (45.3) (12.0) 49 7 5 5 10 0 e (59.4) (5.0) (3.3)

114 2 1 e 13 0 e 11 (5.7) e e e 1 (1.9) 1 (12.0) e 1 (0.5) e e e e

212 40 30 35 53 25 4 Pseudomonas aeruginosa MDR XDR CAZ-NS MER-NS Acinetobacter spp. Stenotrophomonas maltophilia

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

5

Antimicrobial susceptibilities for E. coli, K. pneumoniae and P. aeruginosa stratified by site of infection and geographic region are presented in Table 3. Among E. coli isolates from IAI, susceptibility rates were similar in both geographic regions for all antimicrobials except gentamicin, for which susceptibility rate was markedly higher in Europe (95.9% [CLSI]) compared to USA (89.1% [CLSI], p < 0.05). In contrast, among E. coli isolates from UTI, susceptibility rates were higher for ceftazidime, cefepime and levofloxacin in the USA (94.8, 95.7 and 77.8%, respectively [CLSI criteria]) compared to Europe (88.8, 90.0 and 72.7%, respectively [CLSI criteria]; p < 0.05). Among K. pneumoniae and P. aeruginosa, susceptibility rates were generally higher in the USA compared to Europe for IAI and UTI, with the only exceptions being meropenem when tested against K. pneumoniae from UTI and levofloxacin when tested against P. aeruginosa also from UTI. In these two occasions, susceptibility rates were slightly higher in Europe (95.2 and 68.8%, respectively) compared to USA (93.2 and 67.0%, respectively; Table 3).

Discussion Most complicated IAI are polymicrobial, and enteric Gramnegative bacilli, Gram-positive cocci and anaerobic organisms are the predominant pathogens.11,12 E. coli is the most common organism, but other Enterobacteriaceae, such as Klebsiella spp. and Enterobacter spp., and P. aeruginosa are also frequently isolated from patients with complicated IAI. Obligate anaerobic organisms are important components of most IAI, even though microbiology laboratories may not recover or report these organisms. The most prevalent anaerobic organism in IAI is Bacteroides fragilis, whereas among the Gram-positive cocci, viridans group streptococci and enterococci can be the predominant pathogens.11 Complicated UTI represents a major source of Gramnegative bacteremias, and E. coli is the most common pathogen of community-associated UTI as well as HCA-UTI.13,14 Nevertheless, in recurrent HCA-UTI, especially in the presence of anatomic abnormalities of the urinary tract, the relative frequency of Klebsiella spp., Proteus spp., Pseudomonas spp. and Enterobacter spp. increases. Since instrumentation and repeat courses of antimicrobial therapy are common in these complicated patients, antimicrobialresistant isolates should be expected.13,15 Antimicrobial-resistant strains that produce ESBLs have emerged among Enterobacteriaceae, predominantly E. coli and Klebsiella spp., and have become endemic in hospitals at varying levels of intensity.15,16 P. aeruginosa also represents a major cause of HCA-UTI and complicated IAI, and often demonstrates decreased susceptibility to various antimicrobial agents.12,14 In recent years, the occurrence of MDR P. aeruginosa has increased, and this reduces the probability of appropriate empiric therapy. Furthermore, delay in the initiation of appropriate antimicrobial therapy has been shown to be associated with increased morbidity and mortality in patients with severe infections, particularly those caused by E. coli and P. aeruginosa.17,18


63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124


6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

H.S. Sader et al. Table 2 Antimicrobial activity of ceftolozane/tazobactam and various comparator agents tested against selected organisms isolated from intra-abdominal and urinary tract infections collected in the USA and Europe during 2012. Infection type/organism or resistant subset (no. tested)/ antimicrobial agenta

MIC (mg/L) 50%

%S/%I/%R 90%

b

Range

CLSIb

EUCASTb

Intra-abdominal infections Escherichia coli (341) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Tigecyclined Colistin

0.25 0.06 0.12 0.5 0.06 2 0.12 1 0.12 0.25

0.5 >8 1 2 0.06 16 >4 2 0.12 0.5

0.12e>32 0.06e>8 0.06e>32 0.5e>16 0.06e0.25 0.5e>64 0.12e>4 1e>8 0.03e0.5 0.12e1

-/-/88.9/0.0/11.1 92.1/1.4/6.5 92.1/0.5/7.4 100.0/0.0/0.0 92.7/2.9/4.4 80.3/2.1/17.6 93.0/0.3/6.7 100.0/0.0/0.0 -/-/-

-/-/88.9/0.0/11.1 90.0/2.1/7.9 89.7/2.4/7.9 100.0/0.0/0.0 89.7/3.0/7.3 80.0/0.3/19.7 92.1/0.9/7.0 100.0/0.0/0.0 100.0/0.0/0.0

MDR (16) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Tigecyclined Colistin

0.5 >8 32 >16 0.06 32 >4 >8 0.12 0.25

>32 >8 >32 >16 0.06 >64 >4 >8 0.25 0.5

0.25e>32 4e>8 1e>32 0.5e>16 0.06e0.12 2e>64 >4 1e>8 0.03e0.25 0.25e0.5

-/-/0.0/0.0/100.0 12.5/18.7/68.8 18.8/0.1/81.3 100.0/0.0/0.0 37.5/25.0/37.5 0.0/0.0/100.0 31.3/0.1/68.8 100.0/0.0/0.0 -/-/-

-/-/0.0/0.0/100.0 6.3/6.2/87.5 6.3/12.4/81.3 100.0/0.0/0.0 31.3/6.2/62.5 0.0/0.0/100.0 31.3/0.1/68.8 100.0/0.0/0.0 100.0/0.0/0.0

K. pneumoniae (126) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Tigecyclined Colistin

0.25 0.06 0.25 0.5 0.06 4 0.12 1 0.25 0.5

16 >8 >32 >16 0.12 >64 >4 >8 1 1

0.12e>32 0.06e>8 0.03e>32 0.5e>16 0.06e>8 0.5e>64 0.12e>4 1e>8 0.12e4 0.25e>8

-/-/78.6/0.0/21.4 78.6/2.4/19.0 84.9/4.8/10.3 92.9/0.0/7.1 80.2/8.7/11.1 84.1/0.8/15.1 87.3/1.6/11.1 99.2/0.8/0.0 -/-/-

-/-/78.6/0.0/21.4 76.2/2.4/21.4 80.2/3.1/16.7 92.9/0.0/7.1 75.4/4.8/19.8 82.5/1.6/15.9 86.5/0.8/12.7 93.7/5.5/0.8 97.6/0.0/2.4

MDR (21) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Tigecyclined Colistin

16 >8 >32 >16 0.12 >64 >4 >8 0.5 0.25

>32 >8 >32 >16 >8 >64 >4 >8 1 1

0.25e>32 >8 16e>32 1e>16 0.06e>8 8e>64 0.12e>4 1e>8 0.25e2 0.25e>8

-/-/0.0/0.0/100.0 0.0/0.0/100.0 19.0/23.9/57.1 57.1/0.0/42.9 9.5/33.4/57.1 19.0/0.0/81.0 38.1/9.5/52.4 100.0/0.0/0.0 -/-/-

-/-/0.0/0.0/100.0 0.0/0.0/100.0 4.8/4.7/90.5 57.1/0.0/42.9 9.5/0.0/90.5 19.0/0.0/81.0 38.1/0.0/61.9 95.2/4.8/0.0 90.5/0.0/9.5

Enterobacter spp.f (82) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin

0.5 0.5 0.5 0.5 0.06 4 0.12

8 >8 >32 4 0.12 >64 1

0.12e32 0.06e>8 0.06e>32 0.5e>16 0.06e2 0.5e>64 0.12e>4

-/-/56.1/3.7/40.2 59.8/7.3/32.9 96.3/2.5/1.2 98.8/1.2/0.0 72.0/15.8/12.2 90.2/3.7/6.1

-/-/56.1/3.7/40.2 57.3/2.5/40.2 79.3/14.6/6.1 100.0/0.0/0.0 62.2/9.8/28.0 90.2/0.0/9.8


Q4

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124



7

Table 2 (continued ) Infection type/organism or resistant subset (no. tested)/ antimicrobial agenta Gentamicin Tigecyclined Colistin P. aeruginosa (115) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Amikacin Colistin

MIC (mg/L) 50%

%S/%I/%R 90%

b

Range

CLSIb

EUCASTb

1e>8 0.06e4 0.25e>8

95.1/0.0/4.9 96.3/3.7/0.0 -/-/-

93.9/1.2/4.9 87.7/8.6/3.7 87.7/0.0/12.3

1 0.25 0.5

1 2 8

0.5 2 2 0.5 8 0.5 1 2 1

4 32 >16 8 >64 >4 8 8 2

0.25e>32 1e>32 0.5e>16 0.06e>8 1e>64 0.12e>4 1e>8 0.5e>32 1e4

-/-/-c 77.4/3.5/19.1 76.5/11.3/12.2 79.1/5.2/15.7 72.2/13.9/13.9 80.0/4.3/15.7 88.7/1.7/9.6 95.7/0.8/3.5 98.3/1.7/0.0

-/-/77.4/0.0/22.6 76.5/0.0/23.5 79.1/15.7/5.2 72.2/0.0/27.8 75.7/4.3/20.0 88.7/0.0/11.3 93.9/1.8/4.3 98.3/0.0/1.7

MDR (19) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Amikacin Colistin

4 32 >16 8 >64 >4 >8 8 1

>32 >32 >16 >8 >64 >4 >8 >32 2

0.5e>32 4e>32 8e>16 0.12e>8 32e>64 0.25e>4 1e>8 0.5e>32 1e4

-/-/10.5/10.6/78.9 10.5/31.6/57.9 10.5/15.8/73.7 0.0/36.8/63.2 31.6/10.5/57.9 47.4/0.0/52.6 78.9/5.3/15.8 94.7/5.3/0.0

-/-/10.5/0.0/89.5 10.5/0.0/89.5 10.5/68.4/21.1 0.0/0.0/100.0 31.6/0.0/68.4 47.4/0.0/52.6 68.4/10.5/21.1 94.7/0.0/5.3

XDR (13) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Amikacin Colistin

4 32 >16 8 >64 >4 >8 8 2

>32 >32 >16 >8 >64 >4 >8 >32 2

0.5e>32 4e>32 8e>16 4e>8 32e>64 1e>4 2e>8 0.5e>32 1e4

-/-/15.4/7.7/76.9 15.4/15.4/69.2 0.0/23.1/76.9 0.0/46.2/53.8 15.4/15.4/69.2 23.1/0.0/76.9 69.2/7.7/23.1 92.3/7.7/0.0

-/-/15.4/0.0/84.6 15.4/0.0/84.6 0.0/69.2/30.8 0.0/0.0/100.0 15.4/0.0/84.6 23.1/0.0/76.9 53.8/15.4/30.8 92.3/0.0/7.7

CAZ-NS (26) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Amikacin Colistin

2 32 16 4 >64 1 2 4 1

>32 >32 >16 >8 >64 >4 >8 >32 2

1e>32 16e>32 8e>16 0.12e>8 32e>64 0.25e>4 1e>8 0.5e>32 1e4

-/-/0.0/15.4/84.6 11.5/46.2/42.3 42.3/11.5/46.2 0.0/42.3/57.7 57.7/7.7/34.6 69.2/0.0/30.8 88.5/0.0/11.5 96.2/3.8/0.0

-/-/0.0/0.0/100.0 11.5/0.0/88.5 42.3/46.2/11.5 0.0/0.0/100.0 53.8/3.9/42.3 69.2/0.0/30.8 84.6/3.9/11.5 96.2/0.0/3.8

MER-NS (24) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Amikacin Colistin

2 32 >16 8 64 4 4 8 2

>32 >32 >16 >8 >64 >4 >8 >32 2

0.5e>32 1e>32 1e>16 4e>8 4e>64 0.25e>4 1e>8 0.5e>32 1e4

-/-/-/-/37.5/8.3/54.2 37.5/0.0/62.5 29.2/16.6/54.2 29.2/0.0/70.8 0.0/25.0/75.0 0.0/75.0/25.0 29.2/25.0/45.8 29.2/0.0/70.8 45.8/8.4/45.8 45.8/0.0/54.2 58.3/0.0/41.7 58.3/0.0/41.7 83.3/4.2/12.5 75.0/8.3/16.7 95.8/4.2/0.0 95.8/0.0/4.2 (continued on next page)


63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124


8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

H.S. Sader et al. Table 2 (continued) Infection type/organism or resistant subset (no. tested)/ antimicrobial agenta

MIC (mg/L) 50%

%S/%I/%R 90%

b

Range

CLSIb

EUCASTb

Urinary tract infections E. coli (1333) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Colistin

0.25 0.06 0.12 0.5 0.06 2 0.12 1 0.25

0.5 >8 2 2 0.06 8 >4 >8 0.5

0.03e16 0.06e>8 0.03e>32 0.5e>16 0.06e2 0.5e>64 0.12e>4 1e>8 0.12e>8

-c/-/88.0/0.2/11.8 91.8/2.0/6.2 92.9/1.1/6.0 99.9/0.1/0.0 96.2/2.1/1.7 75.3/1.4/23.3 88.4/0.3/11.3 -/-/-

-/-/88.0/0.2/11.8 88.5/3.3/8.2 89.2/2.5/8.3 100.0/0.0/0.0 92.7/3.5/3.8 75.0/0.3/24.7 87.4/1.0/11.6 98.9/0.0/1.1

MDR (69) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Colistin

0.5 >8 16 >16 0.06 8 >4 >8 0.25

2 >8 >32 >16 0.06 >64 >4 >8 0.5

0.12e16 0.06e>8 0.12e>32 0.5e>16 0.06e2 0.5e>64 1e>4 1e>8 0.12e8

-/-/5.8/1.4/92.8 29.0/14.5/56.5 26.1/8.7/65.2 98.6/1.4/0.0 65.2/21.8/13.0 1.4/4.4/94.2 20.3/1.4/78.3 -/-/-

-/-/5.8/1.4/92.8 10.1/18.9/71.0 5.8/14.5/79.7 100.0/0.0/0.0 50.7/14.5/34.8 1.4/0.0/98.6 20.3/0.0/79.7 95.7/0.0/4.3

K. pneumoniae (316) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Aztreonam Piperacillin/tazobactam Levofloxacin Gentamicin Colistin

0.25 0.06 0.12 0.5 0.06 0.12 4 0.12 1 0.5

16 >8 >32 >16 0.06 >16 >64 >4 >8 1

0.06e>32 0.06e>8 0.03e>32 0.5e>16 0.06e>8 0.12e>16 0.5e>64 0.12e>4 1e>8 0.25e>8

-/-/74.1/0.0/25.9 76.3/3.1/20.6 81.3/2.6/16.1 94.0/0.0/6.0 74.7/1.6/23.7 82.8/3.8/13.4 79.4/3.1/17.5 83.2/1.9/14.9 -/-/-

-/-/74.1/0.0/25.9 73.1/3.2/23.7 74.7/2.8/22.5 94.0/1.3/4.7 74.1/2.2/23.7 78.3/4.5/17.2 77.1/2.3/20.6 82.6/0.6/16.8 95.5/0.0/4.5

MDR (57) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Colistin

16 >8 >32 >16 0.06 >64 >4 >8 0.5

>32 >8 >32 >16 >8 >64 >4 >8 >8

0.25e>32 0.25e>8 0.25e>32 0.5e>16 0.06e>8 2e>64 0.12e>4 1e>8 0.25e>8

-/-/5.3/0.0/94.7 8.8/0.0/91.2 21.1/5.2/73.7 66.7/0.0/33.3 17.5/15.8/66.7 10.5/10.6/78.9 36.8/8.8/54.4 -/-/-

-/-/5.3/0.0/94.7 3.5/5.3/91.2 7.0/1.8/91.2 66.7/7.0/26.3 12.3/5.2/82.5 8.8/1.7/89.5 35.1/1.7/63.2 78.9/0.0/21.1

Enterobacter spp.g (146) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Colistin

0.25 0.25 0.25 0.5 0.06 4 0.12 1 0.5

4 >8 >32 4 0.12 64 2 8 >8

0.12e>32 0.06e>8 0.06e>32 0.5e>16 0.06e8 1e>64 0.12e>4 1e>8 0.12e>8

-/-/65.1/1.3/33.6 69.2/2.0/28.8 93.2/0.6/6.2 98.6/0.0/1.4 81.5/11.7/6.8 93.2/0.6/6.2 88.4/2.0/9.6 -/-/-

-/-/65.1/1.3/33.6 67.1/2.1/30.8 82.2/10.3/7.5 98.6/1.4/0.0 75.3/6.2/18.5 89.7/3.5/6.8 86.3/2.1/11.6 88.1/0.0/11.9

Citrobacter spp.h (113) Ceftolozane/tazobactamc

0.25

2

0.12e>32

-/-/-

-/-/-


63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124



9

Table 2 (continued ) Infection type/organism or resistant subset (no. tested)/ antimicrobial agenta

MIC (mg/L) 50%

%S/%I/%R 90%

b

Range

CLSIb

EUCASTb

Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Colistin

0.12 0.25 0.5 0.06 2 0.12 1 0.5

>8 32 1 0.06 16 4 1 1

0.06e>8 0.06e>32 0.5e>16 0.06e>8 0.5e>64 0.12e>4 1e>8 0.12e1

83.2/0.0/16.8 85.0/0.8/14.2 95.6/0.0/4.4 98.2/0.0/1.8 90.3/2.6/7.1 87.6/3.5/8.9 93.8/0.9/5.3 -/-/-

83.2/0.0/16.8 79.6/5.4/15.0 92.0/3.6/4.4 98.2/0.0/1.8 85.0/5.3/9.7 87.6/0.0/12.4 92.9/0.9/6.2 100.0/0.0/0.0

Proteus mirabilis (117) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Colistin

0.5 0.06 0.06 0.5 0.06 0.5 0.12 1 >8

0.5 0.06 0.12 0.5 0.12 1 >4 >8 >8

0.25e2 0.06e>8 0.03e8 0.5e>16 0.06e0.25 0.5e32 0.12e>4 1e>8 1e>8

-/-/96.6/1.7/1.7 99.1/0.9/0.0 98.3/0.8/0.9 100.0/0.0/0.0 99.1/0.9/0.0 84.6/4.3/11.1 87.2/1.7/11.1 -/-/-

-/-/96.6/1.7/1.7 96.6/2.5/0.9 97.4/0.9/1.7 100.0/0.0/0.0 98.3/0.8/0.9 82.9/1.7/15.4 83.8/3.4/12.8 0.9/0.0/99.1

Indole-positive Proteaei (118) Ceftolozane/tazobactamc Ceftriaxone Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Colistin

0.25 0.06 0.12 0.5 0.06 0.5 0.12 1 >8

1 4 16 0.5 0.12 4 >4 >8 >8

0.06e>32 0.06e>8 0.015e>32 0.5e>16 0.06e0.25 0.5e>64 0.12e>4 1e>8 8e>8

-/-/83.1/2.5/14.4 88.9/0.8/10.3 99.2/0.0/0.8 100.0/0.0/0.0 94.1/3.4/2.5 74.6/10.1/15.3 83.9/2.5/13.6 -/-/-

-/-/83.1/2.5/14.4 81.2/7.7/11.1 95.8/2.5/1.7 100.0/0.0/0.0 94.1/0.0/5.9 66.9/7.7/25.4 72.9/11.0/16.1 0.0/0.0/100.0

4 32 >16 8 >64 >4 8 8 2

0.12e>32 0.5e>32 0.5e>16 0.06e>8 0.5e>64 0.12e>4 1e>8 0.25e>32 0.25e8

-/-/83.5/3.3/13.2 80.7/8.5/10.8 75.0/6.1/18.9 77.4/10.3/12.3 67.9/3.3/28.8 87.7/2.4/9.9 96.7/1.4/1.9 98.1/1.4/0.5

-/-/83.5/0.0/16.5 80.7/0.0/19.3 75.0/15.6/9.4 77.4/0.0/22.6 64.6/3.3/32.1 87.7/0.0/12.3 92.0/4.7/3.3 98.1/0.0/1.9 -/-/30.0/0.0/70.0 20.0/0.0/80.0 7.5/45.0/47.5 17.5/0.0/82.5 2.5/0.0/97.5 45.0/0.0/55.0 62.5/22.5/15.0 92.5/0.0/7.5

P. aeruginosa (212) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Amikacin Colistin

0.5 2 2 0.5 8 0.5 2 2 2

MDR (40) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Amikacin Colistin

2 32 16 8 64 >4 8 8 2

>32 >32 >16 >8 >64 >4 >8 32 2

0.5e>32 2e>32 4e>16 0.25e>8 8e>64 1e>4 1e>8 0.5e>32 0.25e8

-/-/30.0/12.5/57.5 20.0/32.5/47.5 7.5/12.5/80.0 17.5/32.5/50.0 2.5/2.5/95.0 45.0/7.5/47.5 85.0/5.0/10.0 92.5/5.0/2.5

XDR (30) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam

8 32 >16 >8 >64

>32 >32 >16 >8 >64

0.5e>32 4e>32 8e>16 0.25e>8 8e>64

-/-/-/-/16.7/13.3/70.0 16.7/0.0/83.3 16.7/23.3/60.0 16.7/0.0/83.3 6.7/10.0/83.3 6.7/36.6/56.7 6.7/33.3/60.0 6.7/0.0/93.3 (continued on next page)


63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124


10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

H.S. Sader et al.

Table 2 (continued) Infection type/organism or resistant subset (no. tested)/ antimicrobial agenta

MIC (mg/L)

%S/%I/%R Range

CLSIb

EUCASTb

4e>4 1e>8 1e>32 0.25e8

0.0/3.3/96.7 40.0/3.3/56.7 83.3/6.7/10.0 90.0/6.7/3.3

0.0/0.0/100.0 40.0/0.0/60.0 63.3/20.0/16.7 90.0/0.0/10.0

>32 >32 >16 >8 >64 >4 >8 32 2

1e>32 16e>32 8e>16 0.25e>8 8e>64 0.25e>4 1e>8 1e>32 0.25e8

-/-/0.0/20.0/80.0 11.4/37.2/51.4 25.7/8.6/65.7 11.4/28.6/60.0 20.0/2.9/77.1 60.0/2.9/37.1 88.6/5.7/5.7 97.1/0.0/2.9

-/-/0.0/0.0/100.0 11.4/0.0/88.6 25.7/31.4/42.9 11.4/0.0/88.6 20.0/0.0/80.0 60.0/0.0/40.0 71.4/17.2/11.4 97.1/0.0/2.9

>32 >32 >16 >8 >64 >4 >8 16 2

0.25e>32 1e>32 2e>16 4e>8 4e>64 0.25e>4 1e>8 0.25e>32 0.25e8

-/-/50.9/7.6/41.5 43.4/20.8/35.8 0.0/24.5/75.5 43.4/20.8/35.8 15.1/1.9/83.0 64.2/5.6/30.2 90.6/3.7/5.7 94.3/3.8/1.9

-/-/50.9/0.0/49.1 43.4/0.0/56.6 0.0/62.3/37.7 43.4/0.0/56.6 15.1/0.0/84.9 64.2/0.0/35.8 73.6/17.0/9.4 94.3/0.0/5.7

50%

90%

>4 >8 8 2

>4 >8 32 2

CAZ-NS (35) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Amikacin Colistin

4 32 >16 8 >64 >4 4 4 2

MER-NS (53) Ceftolozane/tazobactamc Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin Amikacin Colistin

2 8 16 8 32 >4 4 4 2

Levofloxacin Gentamicin Amikacin Colistin

b

a Abbreviations: MDR Z multidrug-resistant; ESBL Z extended-spectrum b-lactamase; XDR Z extensively drug-resistant; CAZNS Z ceftazidime-nonsusceptible; MER-NS Z meropenem-nonsusceptible.8,10 b Criteria as published by the CLSI (2013) and EUCAST (2013). I Z intermediate; R Z resistant; S Z susceptible.8,9 c - Z breakpoints not available. d In the absence of CLSI breakpoint, US Food and Drug Administration breakpoints were applied when available.19 f Includes: Enterobacter aerogenes (20 strains), and Enterobacter cloacae (62 strains). g Includes: Enterobacter aerogenes (54 strains), E. asburiae (two strains) and E. cloacae (90 strains). h Includes: Citrobacter braakii (two strains), C. farmeri (one strain), C. freundii (57 strains), C. koseri (41 strains) and unspeciated Citrobacter (12 strains). i Includes: Morganella morganii (72 strains), Proteus vulgaris (17 strains), Providencia rettgeri (15 strains) and Providencia stuartii (14 strains).

Table 3 region.

Antimicrobial susceptibility of E. coli, K. pneumoniae and P. aeruginosa according to site of infection and geographic

Organism

% Susceptible by CLSI/EUCAST criteria (no. tested) IAI

UTI

USA

EU

USA

EU

E. coli Ceftolozane/tazobactam Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin

(147) 98.6a 91.2/90.5 91.8/91.1 100.0/100.0 94.6/93.2 78.2/78.2 89.1/89.1

(194) 98.5a 92.8/89.7 92.3/88.7 100.0/100.0 91.2/87.1 81.9/81.4 95.9/94.3

(675) 99.9a 94.8/92.6 95.7/93.8 99.9/100.0 97.5/95.1 77.8/77.3 89.2/88.0

(658) 100.0a 88.8/84.4 90.0/84.5 100.0/100.0 95.0/90.2 72.7/72.5 87.7/86.8

K. pneumoniae Ceftolozane/tazobactam Ceftazidime

(64) 92.2a 87.5/87.5

(62) 85.5a 69.4/64.5

(191) 90.6a 84.8/83.8

(125) 88.0a 63.2/56.8


63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124



11

Table 3 (continued ) Organism

% Susceptible by CLSI/EUCAST criteria (no. tested) IAI

Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin P. aeruginosa Ceftolozane/tazobactam Ceftazidime Cefepime Meropenem Piperacillin/tazobactam Levofloxacin Gentamicin a

UTI

USA

EU

USA

EU

93.8/89.1 95.3/95.3 84.4/79.7 87.5/87.5 90.6/89.1

75.8/71.0 90.3/90.3 75.8/71.0 80.7/77.4 83.9/83.9

86.9/85.3 93.2/93.2 87.4/84.8 84.8/83.3 91.1/90.1

72.8/58.4 95.2/95.2 75.6/68.3 71.0/67.7 71.2/71.2

(70) 100.0a 84.3/84.3 80.0/80.0 84.3/84.3 78.6/78.6 77.1/74.3 91.4/91.4

(45) 88.9a 66.7/66.7 71.1/71.1 81.1/71.1 62.2/62.2 84.4/77.8 84.4/84.4

(103) 98.1a 92.2/92.2 87.4/87.4 76.7/76.7 86.4/86.4 67.0/64.1 91.3/91.3

(109) 89.0a 75.2/75.2 74.3/74.3 73.4/73.4 68.8/68.8 68.8/65.1 84.4/94.4

% inhibited at 8 mg/L.

In the present study, we evaluated the antimicrobial susceptibility of a large collection of consecutively collected aerobic Gram-negative organisms from IAI (809) and HCA-UTI (2474) tested against ceftolozane/tazobactam and contemporary broad-spectrum agents. E. coli, K. pneumoniae and P. aeruginosa were the most frequently isolated organisms and represented approximately 75.0% of isolates from both infection types combined. Among these three organisms, the susceptibility rates were generally similar between isolates from IAI and HCA-UTI. ESBL-phenotype rates were 11.1e12.8% and 23.8e27.2% for E. coli and K. pneumoniae, respectively; whereas P. aeruginosa susceptibility rates to meropenem ranged from 75.0 (HCAUTI) to 79.1% (IAI). Our results also indicated that susceptibility rates were generally higher in the USA compared to EU, especially among P. aeruginosa isolates (Table 3). Overall, 97.1% of organisms from these three species combined were inhibited at a ceftolozane/tazobactam MIC of 8 mg/ L and 95.7% were susceptible to the tested carbapenem, meropenem. An important finding of this investigation was the increased rate of MDR organisms among E. coli (4.7e5.2%), K. pneumoniae (16.6e18.0%) and P. aeruginosa (16.0e18.9%). Furthermore, 11.3e14.2% of P. aeruginosa strains exhibited an XDR pattern.10 Among non-b-lactam comparator agents, colistin and tigecycline were the most active agents. Tigecycline exhibited good activity against MDR E. coli and K. pneumoniae, but this compound has very limited activity against P. aeruginosa.19 Although colistin has potent activity against the most frequently isolated organisms, including MDR and XDR strains, this compound possesses limited activity against some Enterobacteriaceae species commonly isolated from IAI and HCA-UTI, including, Enterobacter spp., P. mirabilis, Citrobacter spp. and Serratia spp. In summary, the results of this investigation indicated that ceftolozane/tazobactam has potent in vitro activity when tested against contemporary (2012) aerobic Gramnegative pathogens causing IAI and HCA-UTI in USA and

European medical centers. Ceftolozane/tazobactam was active against most Enterobacteriaceae, including many ESBL-phenotype and MDR strains; and demonstrated potent activity (inhibition at 8 mg/L) against contemporary P. aeruginosa isolates including many MDR, ceftazidimenonsusceptible, and meropenem-nonsusceptible strains. Ceftolozane/tazobactam warrants further study as a valuable treatment addition for IAI and HCA-UTI in the USA and Europe, especially for therapy of MDR Gram-negative pathogens.

Acknowledgments This study was funded by research grants from Cubist Pharmaceuticals (Lexington, MA, USA).

Q2

References 1. Bulik CC, Christensen H, Nicolau DP. In vitro potency of CXA101, a novel cephalosporin, against Pseudomonas aeruginosa displaying various resistance phenotypes, including multidrug resistance. Antimicrob Agents Chemother 2010;54:557e9. 2. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane/tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. hospitals (2011e2012). Antimicrob Q3 Agents Chemother; 2013 [in press]. 3. Sader HS, Rhomberg PR, Farrell DJ, Jones RN. 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 2011; 55:2390e4. 4. Craig WA, Andes DR. 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 2013;57: 1577e82.


63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124


12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

5. Vanscoy B, Mendes RE, McCauley J, Bhavnani SM, Bulik CC, Okusanya OO, et al. Pharmacological basis of b-lactamase inhibitor therapeutics: tazobactam in combination with ceftolozane. Antimicrob Agents Chemother; 2013 [in press]. 6. Snydman DR, McDermott LA, Jacobus NV. Activity of ceftolozane/tazobactam against a broad spectrum of recent clinical anaerobic isolates. Antimicrob Agents Chemother; 2013 [in press]. 7. Clinical and Laboratory Standards Institute M07eA9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard. 9th ed. Wayne, PA: CLSI; 2012. 8. Clinical and Laboratory Standards Institute M100eS23. Performance standards for antimicrobial susceptibility testing: 23rd informational supplement. Wayne, PA: CLSI; 2013. 9. EUCAST. Breakpoint tables for interpretation of MICs and zone diameters. Version 3.0. Available at: http://www.eucast.org/ clinical_breakpoints/; January 2013 [accessed 02.01.13]. 10. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18:268e81. 11. Mazuski JE, Solomkin JS. Intra-abdominal infections. Surg Clin North Am 2009;89:421e37. 12. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010;50:133e64.

H.S. Sader et al. 13. Lane DR, Takhar SS. Diagnosis and management of urinary tract infection and pyelonephritis. Emerg Med Clin North Am 2011; 29:539e52. 14. Wagenlehner FM, Cek M, Naber KG, Kiyota H, BjerklundJohansen TE. Epidemiology, treatment and prevention of healthcare-associated urinary tract infections. World J Urol 2012;30:59e67. 15. Briongos-Figuero LS, Gomez-Traveso T, Bachiller-Luque P, Dominguez-Gil Gonzalez M, Gomez-Nieto A, PalaciosMartin T, et al. Epidemiology, risk factors and comorbidity for urinary tract infections caused by extended-spectrum beta-lactamase (ESBL)-producing enterobacteria. Int J Clin Pract 2012;66:891e6. 16. Park SY, Kang CI, Joo EJ, Ha YE, Wi YM, Chung DR, et al. Risk factors for multidrug resistance in nosocomial bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. Microb Drug Resist 2012;18:518e24. 17. Morata L, Cobos-Trigueros N, Martinez JA, Soriano A, Almela M, Marco F, et al. Influence of multidrug resistance and appropriate empirical therapy on the 30-day mortality rate of Pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother 2012;56:4833e7. 18. Peralta G, Sanchez MB, Garrido JC, De Benito I, Cano ME, Martinez-Martinez L, et al. Impact of antibiotic resistance and of adequate empirical antibiotic treatment in the prognosis of patients with Escherichia coli bacteraemia. J Antimicrob Chemother 2007;60:855e63. 19. Tygacil. Tygacil package insert. Available at: www.tygacil. com; 2012 [accessed January 2013].


32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial skin and skin structure infections in United States medical centers (2010-2012).

Ceftaroline activity against organisms isolated from respiratory tract infections in USA hospitals: results from the AWARE Program, 2009-2011.

Fosfomycin and Comparator Activity Against Select Enterobacteriaceae, Pseudomonas, and Enterococcus Urinary Tract Infection Isolates from the United States in 2012.

tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011-12).

Antimicrobial Activities of Ceftazidime-Avibactam and Comparator Agents against Gram-Negative Organisms Isolated from Patients with Urinary Tract Infections in U.S. Medical Centers, 2012 to 2014.

tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012).

Management of urinary tract infections from multidrug-resistant organisms.

Ceftaroline activity against bacterial organisms isolated from acute bacterial skin and skin structure infections in United States medical centers (2009-2011).

In Vitro Activity of Lefamulin Tested against Streptococcus pneumoniae with Defined Serotypes, Including Multidrug-Resistant Isolates Causing Lower Respiratory Tract Infections in the United States.

Ceftaroline activity tested against bacterial isolates from pediatric patients: results from the assessing worldwide antimicrobial resistance and evaluation program for the United States (2011-2012).

Ceftazidime-avibactam and comparator agents tested against urinary tract isolates from a global surveillance program (2011).

Escherichia coli Isolated from Urinary Tract Infections of Lebanese Patients between 2005 and 2012: Epidemiology and Profiles of Resistance.

Antibiotic Resistance among Urinary Isolates from Female Outpatients in the United States in 2003 and 2012.

Critical evaluation of ceftolozane-tazobactam for complicated urinary tract and intra-abdominal infections.

Comparative Evaluation of Fosfomycin Activity with other Antimicrobial Agents against E.coli Isolates from Urinary Tract Infections.

tazobactam for the treatment of complicated urinary tract and intra-abdominal infections.

Vital signs: disability and physical activity--United States, 2009-2012.

Incidence and Management of Uncomplicated Recurrent Urinary Tract Infections in a National Sample of Women in the United States.

Urinary catheter indications in the United States: results from a national survey of acute care hospitals.

The Increase in Hospitalizations for Urinary Tract Infections and the Associated Costs in the United States, 1998-2011.

Sustained in vitro activity of human albumin microspheres containing chlorhexidine dihydrochloride against bacteria from cultures of organisms that cause urinary tract infections.

Susceptibility to β-lactams and quinolones of Enterobacteriaceae isolated from urinary tract infections in outpatients.

In Vitro Activity of Oral Cephalosporins (Cefprozil and Cefixime) Against Ciprofloxacin-Resistant Enterobacteriaceae from Community-Acquired Urinary-Tract Infections.

Antimicrobial activity of cefepime-tazobactam combination tested against clinical isolates of Enterobacteriaceae.