avycaz™...both drugs were approved february 2015 and december 2014, respectively. both drugs have...

RISK MANAGEMENT/QUALITY IMPROVEMENT WORK PRODUCT DO NOT PLACE IN MEDICAL RECORD

CONFIDENTIAL PURSUANT TO RCW 4.24.240-250 & 70.41.200 1

Pharmacy and Therapeutics Committee UW Medicine May 27

th, 2015

Generic Name i. Ceftazidime/avibactam ii. Ceftolozane/tazobactam

Proprietary Name/Manufacturer

i. Avycaz™ (Actavis) ii. Zerbaxa™ (Cubist Pharmaceuticals)

Similar Formulary Medications: piperacillin/tazobactam, meropenem, ceftazidime, cefepime, polymyxin B Requestor: Tim Dellit, MD

Executive Summary Ceftazidime/avibactam (Avycaz™) and ceftolozane/tazobactam (Zerbaxa™) are combination cephalosporin-class antibiotics with beta lactamase inhibitors indicated for the treatment of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI), including pyelonephritis. Both drugs were approved February 2015 and December 2014, respectively. Both drugs have shown in vitro activity against Enterobacteriaceae and P. aeruginosa even in the presence beta-lactamases such as TEM, SHV, CTX-M, and select oxacillinases (OXA). Ceftazidime/avibactam and ceftolozane/tazobactam are used in combination with metronidazole for cIAI. In cUTI, both drugs are used as monotherapy, dosed 2.5 g every 8 hours and 1.5 g every 8 hours, respectively.

In Phase 2 clinical trials, ceftazidime/avibactam (plus metronidazole in cIAI) was shown to be safe and effective when compared to meropenem and imipenem-cilastatin for cIAI and cUTI, respectively. In Phase 3 clinical trials, ceftolozane/tazobactam (plus metronidazole in cIAI) was shown to be non-inferior to its comparator drugs, meropenem and levofloxacin for cIAI and cUTI, respectively. In the latter Phase 3 trial comparing ceftolozane/tazobactam and levofloxacin, 26.5% (212/800) of the pathogens were not susceptible to levofloxacin which may account for the statistical significance found in the primary endpoint. While ceftazidime/avibactam and ceftolozane/tazobactam both have proven safety and efficacy, neither agents have proven superiority over its comparator drugs. Phase 3 clinical trials for ceftazidime/avibactam have been completed but not yet published or available to the public. Preliminary reports for the Phase 3 cIAI trial report that ceftazidime-avibactam plus metronidazole compared to meropenem had increased mortality rates, 2.5% (13/529) versus 1.5% (8/529), respectively. Despite the lack of Phase 3 clinical trial data, the novel component in ceftazidime/avibactam has a potential role in treatment for refractory multi-drug resistant systemic infections, specifically carbapenemase producing organisms. In vitro studies have demonstrated that the addition of avibactam to ceftazidime improves the activity against most Enterobacteriaceae and Pseudomonas aeruginosa. Currently, there are no commercially available susceptibility testing methods for ceftazidime/avibactam. FDA approved testing methods are projected to be available in January 2016. Ceftolozane/tazobactam demonstrated in vitro activity against Enterobactericeae with beta lactamases and ESBLs such as: TEM, SHV, CTX-M, and select oxacillinases (OXA). Even though there are no commericially available susceptibility testing methods for cefotolozane/tazobactam, it may have a potential role as salvage therapy for refractory multi-drug resistant infections. The recommendation is to ADD both cefazidime/avibactam and ceftolozane/tazobactam to the formulary with restricted use by infectious disease consult and guidance by antimicrobial stewardship. Due to cost and current lack of susceptibility testing, ceftazidime/avibactam or ceftolozane/tazobactam should only be used for salvage therapy against multi-drug resistant organisms when other treatments modalities have failed.



Clinical Indication1,2,

i. Ceftazidime/avibactam is indicated for the treatment of complicated intra-abdominal infections (cIAI) when used in combination with metronidazole and for complicated urinary tract infections (cUTI), including pyelonephritis. ii. Ceftolozane/tazobactam is indicated for the treatment of complicated intra-abdominal infections when used in combination with metronidazole and for complicated urinary tract infections (cUTI), including pyelonephritis. Pharmacology/Mechanism of Action

1,2,

i. Ceftazidime/avibactam contains a cephalosporin component (ceftazidime) that exhibits

bactericidal activity through binding to the penicillin-binding protein (PBPs), leading to inhibition of cell wall biosynthesis. Avibactam is a non-beta lactam beta-lactamase inhibitor that covalently inactivates Amber class A and C and a few of Amber class D enzymes. Avibactam significantly improves the activity of ceftazidime against most Enterobacteriaceae and Pseudomonas aerugionosa. Cefazidime/avibactam has demonstrated in vitro activity in Enterobactericeae with beta lactamases and extended-spectrum beta-lactamases (ESBLs) such as: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC, and select oxacilinases (OXA). It has also shown in vitro activity against Pseudomonas aeruginosa with AmpC beta-lactamases and strains without outer membrane porins (OprD). The addition is thought to improve ceftazidime’s activity against Pseudomonas by a fourfold reduction in MIC. Ceftazidime/avibactam is not active against bacteria with metallo-beta lactamases such as New Delhi MBL (NDM) and gram-negative bacteria with efflux pump mutations, such as Stenotrophomonas spp. Avibactam significantly improves the activity of ceftazidime against Bacteriodes fragilis, Clostridium perfingens and organisms from the Provetella and Porphyromonas spp., but not for other anaerobes or Acinetobacter. No data have been published on the activity of ceftazidime/avibactam versus gram-positive organisms. Currently, there are no commercially available susceptibility testing methods for ceftazidime/avibactam. FDA approved testing methods are projected to be available in January 2016.

ii.

Table 1. MIC distributions for ceftazidime-avibactam from gram-negative

organisms collected from US Hospitals in 20129

Organism (number of isolates) MIC50 MIC90

Enterobacteriaceae (8,640) 0.12 0.25

E.coli (2,767) 0.06 0.12

ESBL phenotype (328) 0.12 0.25

Klebsiella spp (1,589) 0.25 8

K.pneumoniae (1,847) 0.12 0.5

ESBL phenotype (296) 0.5 1

MEM-NS(115) 0.5 2

K.oxytoca (442) 0.06 0.25


Enterobacter cloacae spp (951) 0.12 0.5

CAZ-NS (249) 0.5 1

Serratia spp (506) 0.12 0.5

P.aeruginosa (1,967) 2 4

MEM-NS (354) 4 16

CAZ-NS (330) 4 16

Acinetobacter spp (321) 16 >32 Abbreviations: ESBL: extended spectrum beta-lactamases; MDR, multidrug resistant ( non-susceptible to >1 agent in >3 antimicrobial classes); XDR (extensively drug-resistant): non-susceptible to >1 agent in all but <2 antimicrobial classes; PDR, pan-drug resistant; NS, nonsusceptible; R, resistant; S, susceptible; CAZ, ceftazidime; MEM, meropenem; P/T, piperacillin-tazobactam.



Table 2. FDA breakpoints for susceptibility for ceftazidime/avibactam*

1

Pathogen Minimum inhibitory concentration (mg/L)

Disk diffusion zone diameter (mm)

S R S R

Enterobacteriaceae ≤ 8/4 ≥ 16/4 ≥ 21 ≤ 20

Pseudomonas aeruginosa ≤ 8/4 ≥ 16/4 ≥ 18 ≤ 17 *S = susceptible, R = resistant / CLSI and EUCAST breakpoints have not been established’

Table 3. Summary of ceftazidime-avibactam activity tested against P. aeruginosa isolates from U.S.

hospitals (2012-2013), including antimicrobial-resistant subsets9

Organism (no. tested)a

No. of P.aeruginosa isolates (cumulative %) inhibited at ceftazidime-avibactam MIC (μg/ml) of: MIC

≤0.25 0.5 1 2 4 8 16 32 >32 50% 90%

All isolates (3,902) 60 (1.5)

194 (6.5)

1,523 (45.5)

1,217 (76.7)

563 (91.2)

223 (96.9

b)

74 (98.8)

23 (99.4)

25 (100.0)

2 4

CAZ-NS (634) 1 (0.2)

41 (6.6)

149 (30.1)

181 (58.7)

141 (80.9

b)

73 (92.4)

23 (96.1)

25 (100.0)

4 16

MEM-NS (702) 8 (1.1)

63 (10.1)

172 (34.6)

218 (65.7)

146 (86.5

b)

54 (94.2)

18 (96.7)

23 (100.0)

4 16

P-T-NS (837) 4 (0.5)

62 (7.9)

189 (30.5)

267 (62.4)

196 (85.8

b)

72 (94.4)

22 (97.0)

25 (100.0)

4 16

MER-NS, CAZ-NS, and P-T-NS (330)

1 (0.3)

4 (1.5)

45 (15.2)

87 (45.1)

100 (71.8

b)

53 (87.9)

17 (93.0)

23 (100.0)

8 32

MDR (580) 1 (0.2)

3 (0.7)

31 (6.0)

113 (25.5)

174 (55.5)

148 (81.0

b)

64 (92.1)

21 (95.7)

25 (100.0)

4 16

XDR (338) 1 (0.3)

8 (2.7)

51 (17.8)

88 (43.8)

101 (73.7

b)

46 (87.3)

18 (92.6)

25 (100.0)

8 32

↵a CAZ, ceftazidime; MEM, meropenem; P-T, piperacillin-tazobactam; NS, nonsusceptible; MDR, multidrug resistant ( non-

susceptible to >1 agent in >3 antimicrobial classes); XDR (extensively drug-resistant): non-susceptible to >1 agent in all but <2 antimicrobial classes, ↵b

Percent susceptible according to the U.S. FDA breakpoint criteria

iii. Ceftolozane exhibits bactericidal activity through binding to the PBPs and inhibition of cell wall

biosynthesis. Ceftolozane specifically inhibits PBP1b, PBP1c and PBP3, which are PBPs found on P. aeruginosa and E. coli, respectively. Tazobactam is an irreversible inhibitor of several beta-lactamases and binds covalently to chromosomal and plasmid-mediated bacterial beta lactamases. Ceftolozane/tazobactam has demonstrated in vitro activity against Enterobactericeae with beta lactamases and ESBLs such as: TEM, SHV, CTX-M, and select oxacillinases (OXA). It is not active against bacteria producing KPCs and metallo-beta lactamases. Ceftolozane/tazobactam has shown in vitro activity against P.aeruginosa isolates with chromosomal AmpC, loss of outer membrane porin (OprD), or up-regulation of efflux pumps (MexXY, MexAB). Currently, there are no commercially available susceptibility testing methods for ceftolozane/tazobactam.

iv.

Table 4. MIC distribution of ceftolozane/tazobactam from US Hospitals in

2011-201210

Organism MIC50 MIC90

Enterobacteriaceae (7,017) 0.25 1

MDR (601) 4 >32

XDR (86) >32 >32

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E.coli (2,691) 0.25 0.5

Non-ESBL phenotype (2,364) 0.25 0.25


Klebsiella spp (1,589) 0.25 8

K.pneumoniae (1,298) 0.25 8

Non-ESBL (1,054) 0.25 0.5

ESBL phenotype (244) 32 >32

K.oxytoca (283) 0.25 0.5

Non-ESBL phenotype (244) 0.25 0.5

ESBL phenotype (39) 1 32

Enterobacter spp (1,029) 0.25 8

CAZ-S(766) 0.25 0.5

CAZ-NS (249) 4 32

Serratia spp (573) 0.5 1

P.aeruginosa (1,971) 0.5 2

CAZ-NS (338) 4 8

MEM-NS (388) 1 8 Abbreviations: ESBL: extended spectrum beta-lactamase; MDR, multidrug resistant ( non-susceptible to >1 agent in >3 antimicrobial classes); XDR (extensively drug-resistant): non-susceptible to >1 agent in all but <2 antimicrobial classes; PDR, pan-drug resistant; NS, nonsusceptible; R, resistant; S, susceptible; CAZ, ceftazidime; MEM, meropenem; P/T, piperacillin-tazobactam;

Table 5. FDA breakpoint criteria for ceftolozane/tazobactam

2

Pathogen Minimum inhibitory concentration (mcg/L)

Disk diffusion zone diameter (mm)

S I R S

I R

Enterobacteriaceae ≤ 2/4 4/4 ≥ 8/4 - - -

Pseudomonas aeruginosa ≤ 4/4 8/4 ≥ 16/4 ≥ 21 17 – 20 ≤ 16

Streptococcus anginosus Streptococcus constellatus Streptococcus salivarius

≤ 4/4 16/4 ≥ 32/4 - - -

B. fragilis ≤ 8/4 16/4 ≥ 32/4 - - - S = susceptible, R = resistant / CLSI and EUCAST breakpoints have not been established

Table 6. Cumulative MIC distributions of ceftolozane/tazobactam against P. aeruginosa by resistance

phenotype10

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




Table 6. Cumulative MIC distributions of ceftolozane/tazobactam against P. aeruginosa by resistance

phenotype10

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

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

↵a Abbreviations: MDR, multidrug resistant ( non-susceptible to >1 agent in >3 antimicrobial classes); XDR (extensively

drug-resistant): non-susceptible to >1 agent in all but <2 antimicrobial classes; PDR, pan-drug resistant; NS, nonsusceptible; R, resistant; S, susceptible; CAZ, ceftazidime; MEM, meropenem; P/T, piperacillin-tazobactam.

Dosing Regimen (Dosage and Administration)

1,2

i. Ceftazidime/avibactam should be given every 8 hours by intravenous infusion over 2 hours for patients with CrCl above 50 ml/min.

Table 7. Dosage of ceftazidime/avibactam by indication

Infection Dose Frequency Infusion time (hours)

Duration of treatment

Complicated intra-abdominal infection

2.5 g (2 g/0.5 g)

Every 8 hours 2 5 to 14 days

Complicated urinary tract infection, including

pyelonephritis

2.5 g 2 g/0.5g)

Every 8 hours 2 7 to 14 days

The following recommendations are dosage adjustments for renal impairment:

Table 8. Recommended ceftazidime/avibactam dosage adjustment for renal impairment

Estimated CrCl (ml/min) Recommended dosing regimen

31 to 50 ml/min 1.25 g every 8 hours



Less than or equal to 5 ml/min 0.94 g every 48 hours

ii. Ceftolozane/tazobactam should be given every 8 hours by intravenous infusion over 1 hour for patients with CrCl above 50 ml/min.

Table 9. Dosage of ceftolozane/tazobactam by indication

Infection Dose Frequency Infusion time (hours)

Duration of treatment

Complicated intra- 1.5 g Every 8 hours 1 4-14 days


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abdominal infection (1 g/0.5 g)

Complicated urinary tract infections, including

pyelonephritis

1.5 g 1 g/0.5 g)

Every 8 hours 1 7 days

The following recommendations are dosage adjustments for renal impairment:

Table 10. Recommended ceftolozane/tazobactam dosage adjustment for renal impairment

Estimated CrCl (ml/min) Recommended dosing regimen

30 to 50 ml/min 750 mg every 8 hours

15 to 29 ml/min 375 mg every 8 hours

Hemodialysis 750 mg loading dose once, then 150 mg every 8 hours, preferably after dialysis

Pharmacokinetics

1,2

The pharmacokinetics are similar between ceftazidime/avibactam and ceftolozane/tazobactam between single and multiple doses alike. For both drugs, Cmax and AUC increase in proportion to dose. Ceftazidime is less than 10% protein bound, while avibactam is 5.7 to 8.2% protein bound. Ceftolozane is 16 to 21% protein bound, while tazobactam is 30% bound. Eighty to 90% of ceftazidime/avibactam is renally eliminated unchanged. Eighty to 95% of ceftolozane/tazobactam is mainly renally excreted unchanged. Twenty percent of tazobactam is metabolized to its metabolite M1. i. The following is ceftazidime/avibactam’s pharmacokinetic parameters following intravenous administration of a 2.5 g single dose and multiple doses:

Table 11. Ceftazidime/avibactam pharmacokinetic parameters (2.5 g every 8 hours)

Ceftazidime Avibactam

Parameter Single 2.5 g Dose over 2-hour infusion

(n=16)

Multiple 2.5 g Dose every 8 hours over 2 hour infusion for 11

days (n=16)

Single 2.5 g Dose over 2-hour

infusion (n=16)

Multiple 2.5 g Doses every 8 hours over 2-

hour infusion for 11 days (n=16)

Cmax (mg/L) 88.1 (14) 90.4 (16) 15.2 (14) 14.6 (17)

AUC (mgh/L)

289 (15) 291 (15) 42.1 (16) 38.2 (19)

T1/2 (h) 3.27 (33) 2.76 (7) 2.22 (31) 2.71 (25)

CL (L/h) 6.93 (15) 6.86 (15) 11.9 (16) 13.1 (19)

Vss (L) 18.1 (20) 17 (16) 23.2 (23) 22.2 (18)

ii. Ceftolozane/tazobactam pharmacokinetic parameters following intravenous administration of 1.5 grams on day 1 and day 10:

Table 12. Ceftolozane/tazobactam pharmacokinetic parameters

Parameter Ceftolozane Tazobactam

1g/0.5g every 8 hours on day 1

(n=9)a


(n=10)


(n=9)


(n=10)

Cmax (mcg/L) 69.1 (11) 74.4 (14) 18.4 (16) 18 (8)

Tmax (h)b 1.02 (1.01, 1.1) 1.07 (1, 1.1) 1.02 (0.99, 1.03) 1.01 (1, 1.1)

AUC (mcgh/L)c 172 (14) 182 (15) 24.4 (18) 25 (15)

T1/2 (h) 2.77 (30) 3.12 (22) 0.91 (26)d 1.03 (19)

a N=9, one outlier subject excluded from descriptive statistics



b Median (minimum, maximum) presented

c AUC for day 1= AUC last and AUC for Day 10 = steady state AUC (AUCτ,SS). Daily AUC at steady state is calculated by multiplying

the Day 10 AUC values by three (e.g. 546 mcgh/mL) for ceftolozane and 75 mcgh/ml for tazobactam) d N=8, one subject excluded from descriptive statistics as the concentration-time profile did not exhibit a terminal log-linear phase

and t1/2 could not be calculated Storage

1,2

i. After dilution, ceftazidime-avibactam should be used within 12 hours when stored at room temperature.

Diluted infusion bags may be refrigerated at 2 to 8°C (36 to 46°F) for up to 24 hours and used within 12

hours at room temperature. ii. After dilution, ceftolozane/tazobactam should be stored at room temperature for up to 24 hours. Diluted

ceftolozane/tazobactam can be refrigerated at 2 to 8°C (36 to 46°F) for up to 7 days. Reconstituted and

diluted ceftolozane/tazobactam should not be frozen. Contraindications

1,2

i. Ceftazidime/avibactam is contraindicated in patients who have a known serious hypersensitivity to either component of this medication or other cephalosporins. ii. Ceftolozane/tazobactam is contraindicated in patients who have a known serious hypersensitivity to either component of this medication or other beta lactams. Precautions

1,2

Both drugs Decreased clinical response in patients with renal insufficiency of 30 to 50 mL/min In both Phase 3 cIAI trials, clinical cure rates were lower in patients with CrCl of 30 to 50 mL/min. In the ceftazidime/avibactam plus metronidazole Phase 3 cIAI trial, patients in the study drug group with CrCl of 30 to 50 mL/min had 33% lower daily dose than what is recommended. Similarly, in a subgroup analysis of a Phase 3 cIAI trial, clinical cure rates were lower in patients with baseline CrCl of 30 to ≤50 mL/min. The reduction in clinical cure rates was more marked in the ceftolozane/tazobactam plus metronidazole arm (11/23, 48%) compared to the meropenem arm (9/13, 69%). A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust dosage as needed. Hypersensitivity Reactions

Serious and potentially fatal hypersensitivity (anaphylactic) reactions have been reported for beta-lactam antibiotics. Careful review of previous hypersensitivity reactions to cephalosporins, penicillins and carbapenems should be done. Discontinue drug if an anaphylactic reaction occurs.

Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial drugs, including ceftazidime/avibactam and ceftolozane/tazobactam. Severity for both drugs range from mild diarrhea to fatal colitis. Development of Drug-Resistant Bacteria

Prescribing ceftazidime/avibactam and ceftolozane/tazobactam in the absence of a proven or strongly suspected bacterial infection is unlikely to provide clinical benefit to the patient and increases the risk of developing drug-resistant bacteria. Central Nervous System Reactions Patients treated with ceftazidime have been reported to experience seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability and myoclonia, particularly in renal impairment. Adjust doses according to creatinine clearance. Adverse Effects

1,2

i. The safety information for Ceftazidime/avibactam was generated from two active-controlled Phase 2 clinical trials for cIAI and cUTI, including pyelonephritis. In the cIAI Phase 2 trial, 9/101 (8.9%) and 11/102



(10.8%) patients had serious adverse events to ceftazidime/avibactam plus metronidazole and meropenem, respectively. In the ceftazidime/avibactam plus metronidazole group, discontinuation rates were highest for skin and subcutaneous tissue disorders (3%). Nausea and vomiting occurred in 10% or more of patients taking ceftazidime/avibactam. In the cUTI Phase 2 trial, 6/68 (8.8%) and 2/67 (3.0%) patients had serious adverse events to ceftazidime/avibactam plus metronidazole and meropenem, respectively. Constipation and anxiety occurred in 10% or more of patients taking ceftazidime/avibactam. The most common adverse reactions are listed in the following table:

Table 13. Incidence of adverse drug reactions for ceftazidime/avibactam in the phase 2 clinical

trials

Complicated intra-abdominal infections

Complicated urinary tract infections, including pyelonephritis

Ceftazidime/avibactam plus metronidazole

(N=101)

Meropenem (N=102)

Ceftazidime/avibactam (N=68)

Imipenem-cilastatin

(N=67)

Vomiting 14% 5% 0% 0%

Nausea 10% 6% 2% 5%

Constipation 4% 1% 10% 3%

Abdominal pain 8% 3% 7% 5%

Upper abdominal pain

1% 0% 7% 2%

Increased blood alkaline phosphatase

9% 7% 3% 2%

Increased alanine aminotransferase

8% 13% 3% 6%

Dizziness 0% 2% 6% 9%

Anxiety 5% 1% 10% 8%

Other adverse reactions reported in the ceftazidime/avibactam Phase 2 trials, but at a rate of less than 5% were eosinophilia, thrombocytopenia, increased gamma-glutamyltransferase, prolonged prothrombin time, hypokalemia, acute renal failure, renal impairment and rash. ii. The safety information for Ceftolozane/tazobactam is from Phase 3 cIAI and cUTI comparator-controlled trials. A total of 1,015 patients were treated with ceftolozane/tazobactam and 1,013 were treated with comparator drugs (levofloxacin or meropenem) for up to 7 to 14 days. The most common adverse effects occurring in at least 5% or greater patients who received ceftolozane/tazobactam were nausea, diarrhea, headache, and pyrexia. The most common adverse reactions are listed in the following table:

Table 14. Adverse reactions for ceftolozane/tazobactam in phase 3 clinical trials

Complicated intra-abdominal infections

Complicated urinary tract infections, including pyelonephritis

Ceftolozane/tazobactam

(N=482)

Meropenem (N=497)

Ceftolozane/tazobactam

(N=533)

Levofloxacin (N=535)

Nausea 38 (7.9) 29 (5.8) 15 (2.8) 9 (1.7)

Headache 12 (2.5) 9 (1.8) 31 (5.8) 26 (4.9)

Diarrhea 30 (6.2) 25 (5) 10 (1.9) 23 (4.3)

Pyrexia 27 (5.6) 20 (4) 9 (1.7) 5 (0.9)

Constipation 9 (1.9) 6 (1.2) 21 (3.9) 17 (3.2)

Insomnia 17 (3.5) 11 (2.2) 7 (1.3) 14 (2.6)

Vomiting 16 (3.3) 20 (4) 6 (1.1) 6 (1.1)

Hypokalemia 16 (3.3) 10 (2) 4 (0.8) 2 (0.4)



ALT increased 7 (1.5) 5 (1) 9 (1.7) 5 (0.9)

AST increased 5 (1) 3 (0.6) 9 (1.7) 5 (0.9)

Anemia 7 (1.5) 5 (1) 2 (0.4) 5 (0.9)

Thrombocytopenia 9 (1.9) 5 (1) 2 (0.4) 2 (0.4)

Abdominal pain 6 (1.2) 2 (0.4) 4 (0.8) 2 (0.4)

Anxiety 9 (1.9) 7 (1.4) 1. (0.2) 4 (0.7)

Dizziness 4 (0.8) 5 (1) 6 (1.1) 1 (0.2)

Hypotension 8 (1.7) 4 (0.8) 2 (0.4) 1 (0.2)

Atrial fibrillation 6 (1.2) 3 (0.6) 1 (0.2) 0

Rash 8 (1.7) 7 (1.4) 5 (0.9) 2 (0.4)

Less common adverse reactions occurring in less than 1% was tachycardia, angina pectoris, gastritis, abdominal distention, dyspepsia, flatulence, paralytic ileus, infusion site reactions, oropharyngeal candidiasis, fungal urinary tract infection, increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase, hyperglycemia, hypomagnesemia, hypophosphatemia, ischemic stroke, and renal failure. Drug Interactions

1,2

i. Avibactam is an OAT1 and OAT3 substrate in vitro which may lead to uptake from the serum and excretion. Probenecid, which is a potent OAT inhibitor in vitro, may potentially decrease elimination of avibactam. Since ceftazidime/avibactam and probenecid have not been tested for drug interactions, co-administration is not recommended. ii. Ceftolozane/tazobactam There are no anticipated drug interactions between ceftolozane/tazobactam and substrates, inhibitors and inducers of cytochrome P450 enzymes. Use in Pregnancy/Lactation

Pregnancy1,2

i. Ceftazidime/avibactam is a Category B drug. There are no adequate or well-controlled studies of cefatazidime/avibactam in pregnant women. In animal model studies with mice and rats, ceftazidime at doses as high as 40 times that of human doses, showed no evidence of harm. Avibactam studied in rats and rabbits did not show evidence of embryofetal toxicity. Due to lack of evidence in pregnant women, this drug should only be used in pregnant women if the benefit outweighs the potential risk. ii. Ceftolozane/tazobactam is a Category B drug. There are no adequate or well-controlled trials in pregnant women with either component. No evidence of harm was shown in mice and rats when ceftolozane was given up to doses of 2000 and 1000 mg/kg/day. These doses are 4 to 7 times the mean daily human exposure to ceftolozane. In pre-postnatal rat studies, IV ceftolozane (300 mg/kg/day) during pregnancy and lactation was associated with decrease in auditory startle response at day 60 male pups. It is unknown if ceftolozane crosses the placenta in animals. When tazobactam was administered to rats at doses of up to 3000 mg/kg/day, maternal toxicity (decreased food consumption and body weight gain) but no fetal toxicity occurred. In pre-postnatal study of rats, tazobactam given intraperitoneally twice daily at gestation and during lactation caused decrease in maternal food consumption, body weight gain and more stillbirths. There was no effect on development or function. Tazobactam was shown to cross the placenta in rats. This combination drug should only be used in pregnant women if the benefit outweighs the potential risk. Lactation

1,2

i. Small concentrations of ceftazidime have been found in human milk, although not known for avibactam. In rats, avibactam was excreted into milk in a dose dependent fashion. ii. It is not known whether ceftolozane and tazobactam are excreted into human milk. Since many medications are excreted into breast milk, use caution in pregnant women. Clinical Trials



i. Ceftazidime/avibactam

The safety and efficacy of ceftazidime/avibactam in complicated intrabdominal infection (cIAI) and complicated urinary tract infection (cUTI) was studied in two Phase II clinical trials. Both trials were not powered to conclude non-inferiority to their comparator drugs, but sufficient to estimate efficacy and safety of ceftazidime/avibactam. Phase 3 trials have been completed, but the results have not yet been published or available for review. Preliminary reports for the phase 3 cIAI trial report that ceftazidime-avibactam plus metronidazole compared to meropenem had increased mortality, 2.5% (13/529) versus 1.5% (8/529) respectively. Among a subgroup of patients with baseline CrCl 30-50 ml/min, death occurred in 25.8% (8/31) of patients who received ceftazidime/avibactam and in 8.6% (3/35) of patients who received meropenem. Within this subgroup, patients treated with ceftazidime/avibactam received a 33% lower daily dose than is currently recommended. In patients with normal renal function or mild renal impairment (baseline CrCl > 50ml/min), death occurred in 1% (5/498) of patients who received ceftazidime/avibactam and 1% (5/494) of patient who received meropenem. The causes of death varied, and contributing factors included progression of underlying infections, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention.

Complicated Intra-abdominal Infections (cIAI) 1,3,5,8

A total of 204 patients were included in the Phase II, prospective, randomized, double-blind active-controlled trial. Patients were eligible for inclusion if they were aged 18-90 years of age with evidence of cIAI, requiring surgical intervention and antibiotics, caused by organism presumed to be susceptible to ceftazidime/avibactam plus metronidazole or meropenem. Diagnoses included cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall, divertivular disease with perforation or abscess; appendiceal perforation or peri-appendiceal abscess; acute gastric and duodenal perforation (only if operated on greater than 24 hour after perforation occurred); traumatic perforation of the intestines (only if operated on > 12 hours after perforation occurred); secondary peritonitis (but not spontaneous peritonitis associated with cirrhosis and chronic ascites); or intra-abdominal abscess with evidence of intraperitoneal involvement. Patients were excluded if they had any following: abdominal wall abscess, small bowel obstruction or ischemic bowel without perforation; received other systemic antibiotics within 72 hours of the study; concurrent infections that may interfere with the evaluation of the response to study; perinephric infections or infections of the female genital tract; infections known to be resistant to study drugs or sepsis with shock unresponsive to Intravenous fluid challenge or APACHE score > 25; anticipated survival less than period; abnormal liver function tests; abnormal renal function (CrCl < 50 ml/min); immunocompromised status; or body mass index > 45. Patients were randomized to ceftazidime/avibactam plus metronidazole or meropenem plus placebo infusions. The treatment group received 2 g/500 mg of ceftazidime/avibactam plus 500 mg of metronidazole every 8 hours. The comparator group received meropenem 1 gram every 8 hours plus placebo infusions. Treatment duration was anywhere from 5 to 14 days depending on clinical response. A favorable clinical response was defined as complete resolution or improvement in signs and symptoms without surgery or additional antibiotics. No other concomitant antibiotics were allowed except for MRSA and Enterococcus treatment options such as vancomycin, linezolid and daptomycin. The primary efficacy endpoint was clinical response after 2 weeks evaluated at the test-of-cure (TOC) visit in the microbiologically evaluable (ME) population. The ME population comprised of patients who had at least one susceptible pathogen to ceftazidime/avibactam and meropenem. In the ME population, favorable clinical response was 91.2% (62/68) and 93.4% (71/76) in the ceftazidime/avibactam plus metronidazole and meropenem groups, respectively (estimated difference was -2.2%; 95% CI, -20.4%, -12.2%). Clinical response was also evaluated at the end of IV therapy and late follow-up (LFU). After completion of IV therapy, favorable clinical response was 97.1% (66/68) and 97.4% (74/76), respectively (observed difference -0.3%; 95% CI, -17.1%, 15.4%). The clinically evaluable (CE) population included patients who had confirmed cIAI and received 80 to 120% of the scheduled study drug. Clinical response was also evaluated in the CE



population, microbiological modified intent-to-treat (mMITT) and all patients who received at least one dose of the study drug during the TOC and LFU visit. For the CE population, favorable clinical response was 92.0% (80/87) and 94.4% (85/90), for ceftazidime-avibactam and meropenem groups respectively (observed group difference -2.5%; 95% CI, -19.5%, 10.1%). After completion of IV therapy, favorable clinical response for the CE population was 96.6% (84/87) and 97.8% (87/89), respectively. E.coli was the most common pathogen isolated from the site of cIAI and all E.coli isolates were susceptible to either ceftazidime/avibactam and meropenem. Of the other gram-negative organisms, six isolates had resistance to ceftazidime-avibactam, with two of the isolates having meropenem resistance. Observed adverse effects were 64.4% (65/101) and 57.8% (59/102) in the ceftazidime/avibactam plus metronidazole group and meropenem group, respectively. Nausea, vomiting and abdominal pain were common in the ceftazidime/avibactam plus metronidazole group while there were more cases of elevated liver enzymes in the meropenem group. Significant adverse effects was seen in 9 (8.9%) and 11 (10.8%) patients in the ceftazidime/avibactam plus metronidazole and meropenem groups, respectively. Three patients died in the ceftazidime/avibactam group versus two deaths in the meropenem group. Complicated Urinary Tract Infections (cUTI)

1,7

A total of 137 patients were randomized to the phase II, prospective, multi-center, double-blinded comparative study. Patients were included if between ages of 18-90 and had either acute pyelonephritis or other cUTI due to a gram-negative pathogen requiring IV therapy. Patients were excluded if the cUTI was caused by a uropathogen known to be resistant to one or more of the study drugs or if they received more than one dose of another potentially effective systemic antibiotic within 48 hours prior to admission urine culture. Other exclusions include presence of ileal loops or vesicourtetral reflux, complete obstruction of the urinary tract, perinephric abscess or intrarenal abscess or fungal UTI. Patients with permanent indwelling catheter or instrumentation including nephrostomy, were excluded unless removd within 48 hours of study entry. Sixty-nine patients were randomized to 500 mg/125 mg of ceftazidime/avibactam every 8 hours and sixty-eight patients were randomized impenem-cilastatin for up to 7-14 days. If clinically improved after 4 days of IV treatment to susceptible pathogens, patients were allowed to switch to oral ciprofloxacin 500 mg twice daily. The primary endpoint was evaluated in the ME population for favorable microbiological response at the test-of-cure (TOC) visit, which was 5 to 9 days after completion of antibiotics. A favorable response was defined as eradication of all pathogens in urine and blood. The ME population consisted of patients with positive urine culture that was susceptible to either antibiotics at

enrollment (≥105 CFU/ml or >10

4 CFU/ml if bacteremia present), clinical and microbiological

evaluation at TOC visit, received at least 7 days of antibiotics or treatment failures after 48 hours of IV therapy. Favorable microbiological response in the ME population was 19/27 (70.4%) and 25/35 (71.4%), respectively (observed difference -1.1%; 95% CI -27.2%, 25.0%). There were 19 patients in the imipenem and 23 patients in the ceftazidime-avibactam groups that were excluded in ME analysis because they did not have a valid pathogen isolated (i.e gram-stain result was positive but had a negative culture at baseline). Secondary endpoints looked at microbiological response assessed at end of IV therapy, LFU and clinical response at TOC and LFU visits for the CE population. The CE population consisted of patients who had clinical evidence of cUTI, at least 7 days of study drug or evaluable clinical failure after 48 hours of IV therapy, and clinical outcome assessment at the TOC visit. Clinical response at the end of IV therapy was 15/26 (57.7%) and 18/30 (60.0%), respectively. All 63 organisms isolated were susceptible to imipenem, but 20 organisms were found to be resistant to ceftazidime alone. Among the patients with the ceftazidime-resistant uropathogens, favorable microbiological response was achieved in 6/7 (85.7%) and 9/11 (81.8%) patients in the ceftazidime-avibactam and imipenem groups, respectively.



Adverse effects (AEs) reported were 46/68 (67.6%) and 51/67 (76.1%) in the ceftazidime/avibactam and imipenem/cilastatin groups, respectively. Treatment-emergent serious AEs were reported in 6/68 (8.8%) and 2/67 (3.0%) of patients in the ceftazidime/avibactam and imipenem/cilastatin groups, respectively. For ceftazidime/avibactam, the drug-related significant AEs were renal failure, diarrhea, and unintentional overdose. The most common AEs for both drugs were constipation, diarrhea, abdominal pain, headache, anxiety and injection/infusion site reactions.

ii. Ceftolozane/tazobactam The safety and efficacy of ceftolozane/tazobactam was studied in two Phase 3 clinical trials. The details and major findings of both trials are listed below: Complicated Intra-abdominal Infections (cIAI)

2,3,4

A total of 979 patients were included in this multicenter, prospective, randomized, double-blind, placebo-controlled trial. Patients 18 years of age and older were included if operative or percutaneous drainage of infection was planned or performed with confirmed presence of cIAI. Patients were excluded if fascia was not closed after surgery, there was a high likelihood of poor source control with surgery, creatinine clearance was less than 30 ml/min or antibiotic therapy was administered for more than 24 hours prior to the first dose of study medication unless refractory to treatment. Patients were randomized to ceftolozane/tazobactam plus metronidazole or meropenem plus placebo for 4 to 10 days. The primary endpoint was clinical cure at the TOC visit defined as complete resolution or significant improvement in signs and symptoms since initial infection for the microbiologically intent-to-treat (MITT). Death due to cIAI prior to TOC visit, recurrent infections, addition of antibiotics and/or surgical site infection were categorized as treatment failure. At the TOC visit, clinical cure rates were 83% (323/389) for ceftolozane/tazobactam plus metronidazole and 87.3% (364/417) with meropenem (weighted difference -4.2; 95% CI, -8.91% to .54%). Secondary endpoints looked at the ME population during the TOC visit and clinical cure rates were 94.2% and 94.7% (weighted difference, -1.0%; 95% CI, -4.52 to 2.59), respectively. Statistical non-inferiority was established for the MITT and ME population. After completion of therapy, clinical cure rate was 89.2% and 92.3% (difference, -3.1; 95% CI, -7.23 to .89). Per pathogen cure rates were similar across both groups.

Incidence of adverse effects between ceftolozane/tazobactam plus metronidazole and meropenem were similar at 44% and 42.7%, respectively. The most common lab abnormality was increases in alanine aminotransferase and aspartate aminotransferase. The rate of discontinuation was similar at 0.6% and 0.8%, respectively. Serious adverse events occurred in 39/482 (8.1%) and 36/497 (7.2%) in the ceftolozane/tazobactam plus metronidazole and meropenem group, respectively. One patient in each group had severe Clostridium difficile infection.

Complicated Urinary Tract Infections (cUTI)

2

A total of 1,068 patients with cUTI were included in a multicenter, double-blind trial comparing ceftolozane/tazobactam to levofloxacin. Patients were eligible to participate in the study if they were 18 years or older, had pyuria, pyelonephritis or complicated urinary tract infection, received intravenous antibiotics and a urine culture had been drawn within 36 hours before antibiotics were initiated. Patients were excluded if they were receiving non-study antibiotics that cover gram-negative organisms, another infection necessitated greater than 7 days of treatment, or antibiotics were initiated before cultures were drawn. Patients were randomized to receive ceftolozane/tazobactam 1 g every 8 hours to levofloxacin 750 mg one daily for 7 days. The primary endpoint was improvement in symptoms and complete eradication of pathogens at the TOC visit (7 days after last dose) in the microbiologically modified intent-to-treat (mMITT)



population. The mMITT population includes patients who received medication and had at least 1 pathogen in the urine. In the mMITT population, the clinical cure rate was 76.9% (306/398) and 68.4% (275/402) in the ceftolozane/tazobactam and levofloxacin group, respectively (difference 8.5, 95% CI; 2.3, 14.6). While statistical significance was seen in the primary endpoint, it was noted that up to 26.5% (212/800) of the pathogens were not susceptible to levofloxacin at baseline. For secondary endpoints, the ME population was evaluated for composite microbiological and clinical cure response at the TOC visit. In the ME population, the clinical cure rate was 83.3% (284/341) and 75.4% (266/353), respectively (difference 8.0, 95% CI; 2.0, 14.0). The composite cure rate for ceftolozane/tazobactam in the mMITT population was 79.3% (23/29).

The highest incidence of adverse effects seen in this Phase 3 trial was headache, constipation, nausea and vomiting.

Financial Impact

Medication Strength Outpatient

PHS Inpatient/SCCA Maintenance

Frequency Inpatient Cost per therapy (14

days)

Ceftazidime/avibactam (Avycaz)

2.5 g $208.25/dose $624.75/day

$270.81/dose $812.43/day

cIAI: 2.5 g q8h x 5 to 14 days

cUTI: 2.5 g q8h x 7 to 14 days

$11,374.02

Ceftolozane/tazobactam (Zerbaxa)

1.5 g $60.73/dose $182.19/day

$81.13/dose $243.39/day

cIAI: 1.5 g q8h x 5 to 14 days

cUTI: 1.5 g q8h x 7 to 14 days

$3,407.46

Discussion

In Phase 2 clinical trials, ceftazidime/avibactam (plus metronidazole in cIAI) was shown to be safe and effective when compared to meropenem and imipenem-cilastatin for both cIAI and cUTI. In Phase 3 clinical trials, ceftolozane/tazobactam (plus metronidazole in cIAI) was shown to be non-inferior to its comparator drugs, meropenem and levofloxacin for cIAI and cUTI, respectively. Phase 3 trials of ceftazidime/avibactam have been completed, but the results have not yet been published or available for review. Preliminary reports for the phase 3 cIAI trial report that ceftazidime-avibactam plus metronidazole compared to meropenem had increased mortality, 2.5% (13/259) versus 1.5% (8/529) respectively. The causes of death varied, and contributing factors included progression of underlying infections, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention. Both agents generally have safe profiles of adverse effects, but patients should be monitored for lowering of seizure threshold with ceftazidime/avibactam and gastrointestinal side effects with both medications. In addition, dose adjustments based on renal function need to be more extensively studied in ceftazidime/avibactam, as patients with impaired renal function were not included in phase 2 clinical trials. Despite the lack of published Phase 3 clinical trials, the novel component in ceftazidime/avibactam has a potential role in treatment for refractory multi-drug resistant systemic infections. In vitro studies have demonstrated that the addition of avibactam to ceftazidime improves the activity against most Enterobacteriaceae and Pseudomonas aeruginosa. Currently, there are no clinical susceptibility testing methods available for ceftazidime/avibactam. Testing methods are projected to be available in January 2016. Ceftolozane/tazobactam demonstrated in vitro activity against Enterobactericeae with beta lactamases and ESBLs such as: TEM, SHV, CTX-M, and select oxacillinases (OXA), but it is not active against bacteria producing KPCs and metallo-beta lactamases. However, it may have a potential role as salvage therapy against multi-drug resistant infections. Recommendation



The recommendation is to ADD both ceftazidime/avibactam and ceftolozane/tazobactam to the formulary with restricted use by infectious disease consult and guidance by antimicrobial stewardship. Due to cost and current lack of susceptibility testing, ceftazidime/avibactam and ceftolozane/tazobactam should only be used for salvage therapy against multi-drug resistant organisms in the setting of failure or toxicity to other treatments modalities. Submitted By: Jennifer S. Baik, PharmD, PGY1 Pharmacy Practice Resident Reviewed by: Jeannie Chan, PharmD, MPH and Rupali Jain, PharmD, BCPS References 1. Cetazidime-avibactam (Avycaz™) Package Insert, Actavis. February 2015. 2. Ceftolozane/tazobactam (Zerbaxa™) Package Insert, Cubist Pharmaceuticals. December 2014. 3. Solomkin et al. Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal

Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI). Clin Infect Dis. 2015 Feb 10.

4. Zhanel et al. Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 2014 Jan;74(1):31-51.

5. Zhanel et al. Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs. 2013 Feb;73(2):159-77.

6. Lucasti et al. Double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections. Antimicrob Agents Chemother. 2014 Sep;58(9):5350-7.

7. Vazquez et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012 Dec; 28(12):1921-31.

8. Lucasti et al. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013 May;68(5):1183-92.

9. Sader HS, Castanheira M, Mendes RE, Flamm RK, Farrell DJ, Jones RN.Ceftazidime-Avibactam Activity against Multidrug-Resistant Pseudomonas aeruginosa Isolated in U.S. Medical Centers in 2012 and 2013. Antimicrob Agents Chemother. 2015 Jun;59(6):3656-9.

10. 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 (2011-2012). Antimicrob Agents Chemother. 2013 Dec;57(12):6305-10.

11. Sader HS, Castanheira M, Mendes RE, Flamm RK, Farrell DJ, Jones RN. 2015. Ceftazidime-avibactam activity against multidrug-resistant Pseudomonas aeruginosa isolated in U.S. medical centers in 2012 and 2013. Antimicrob Agents Chemother 59:3656–3659.

http://www.ncbi.nlm.nih.gov/pubmed/25845861






avycaz™...both drugs were approved february 2015 and december 2014, respectively. both drugs have...

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