efficacy and safety of ceftazidime–avibactam versus imipenem–cilastatin in the treatment of...

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Current Medical Research & Opinion Vol. 28, No. 12, 2012, 1921–1931

0300-7995 Article FT-0342.R1/748653

doi:10.1185/03007995.2012.748653 All rights reserved: reproduction in whole or part not permitted

Original articleEfficacy and safety of ceftazidime–avibactamversus imipenem–cilastatin in the treatment ofcomplicated urinary tract infections, includingacute pyelonephritis, in hospitalized adults:results of a prospective, investigator-blinded,randomized study

Jose A. VazquezDivision of Infectious Diseases, Henry Ford Hospital,

Detroit, MI, USA

Luis Demetrio Gonzalez PatzanCentro Medico Militar, Guatemala City, Guatemala

David StricklinFour Rivers Clinical Research Inc., Paducah, KY, USA

Dipesh D. DuttaroyMedical College Baroda and Sir Sayajirao General

Hospital, Vadodara, India

Zouheir KreidlyMakassed General Hospital, Beirut, Lebanon

Joy LipkaCarole SableAstraZeneca, Wilmington, DE, USA

Address for correspondence:J.A. Vazquez, Division of Infectious Diseases,

Henry Ford Hospital, 2799 West Grand Boulevard,

CFP 202, Detroit, MI 48202, USA.

Tel.: þ1 313 916 2361; Fax: þ1 313 916 3797;

[email protected]

Keywords:Ceftazidime-resistant – Microbiological response –

uropathogens

Accepted: 7 November 2012; published online: 21 November 2012

Citation: Curr Med Res Opin 2012; 28:1921–31

Abstract

Objectives:

The aim of this prospective phase II, randomized, investigator-blinded study (NCT00690378) was to

compare the efficacy and safety of ceftazidime–avibactam and imipenem–cilastatin in hospitalized adults

with serious complicated urinary tract infection (cUTI) due to Gram-negative pathogens.

Patients and methods:

Patients aged between 18 and 90 years with cUTI were enrolled and stratified by infection type (acute

pyelonephritis or other cUTI) and randomized 1:1 to receive intravenous ceftazidime 500 mg plus avibactam

125 mg every 8 hours or imipenem–cilastatin 500 mg every 6 hours. Patients meeting pre-specified

improvement criteria after 4 days could be switched to oral ciprofloxacin. Patients were treated for a

total of 7–14 days. The primary efficacy objective was a favorable microbiological response at the test-

of-cure (TOC) visit 5–9 days post-therapy in microbiologically evaluable (ME) patients.

Results:

Overall, 135 patients received study therapy (safety population); 62 were included in the ME population

(ceftazidime–avibactam, n¼ 27; imipenem–cilastatin, n¼ 35). The predominant uropathogen was

Escherichia coli. Favorable microbiological response was achieved in 70.4% of ME patients receiving

ceftazidime–avibactam and 71.4% receiving imipenem–cilastatin at the TOC visit (observed difference

�1.1% [95% CI: �27.2%, 25.0%]). Among ME patients with ceftazidime-resistant uropathogens,

response was observed in 6/7 (85.7%) receiving ceftazidime–avibactam. Adverse events were observed

in 67.6% and 76.1% of patients receiving ceftazidime–avibactam and imipenem–cilastatin, respectively.

Limitations of the study include the small number of patients in the ME population.

Conclusion:

The results suggest that the efficacy and safety of ceftazidime–avibactam may be similar to that of

imipenem–cilastatin.

Current address: Cerexa Inc., Oakland, CA, USA

(Joy Lipka) and Merck & Co. Inc., Upper Gwynned,

PA, USA (Carole Sable)

! 2012 Informa UK Ltd www.cmrojournal.com Ceftazidime–avibactam in complicated UTI Vazquez et al. 1921

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Introduction

Urinary tract infections (UTIs) are among themost common bacterial infections1. Although manyUTIs are community acquired2, UTIs are also themost frequently reported hospital-acquired infections,with the majority occurring in patients with a urinarycatheter1.

Complicated UTIs (cUTIs) carry a greater risk of mor-bidity and mortality when compared with uncomplicatedUTIs. Potential complications include life-threateningbacteremia, sepsis, septic shock, renal failure, anddeath2–4. These infections generally involve Gram-nega-tive pathogens, most commonly Escherichia coli, and fre-quently require hospitalization and prolonged treatmentwith intravenous (iv) antibiotics2.

The prevalence of multi-drug resistant (MDR) Gram-negative pathogens is increasing worldwide, largely as aresult of bacterial production of �-lactamases. Theseenzymes include extended-spectrum �-lactamases(ESBLs), which are increasingly seen in Gram-negativepathogens that represent important microbiologic etiolo-gies of community-acquired UTIs5,6.

Carbapenems, because of their broad spectrum of activ-ity and relatively low occurrence of resistance, are cur-rently considered to be the antibiotics of choice for thetreatment of serious infections caused by ESBL-producingorganisms6. However, the production of carbapenemasesby some Enterobacteriaceae and some non-fermentingGram-negative bacteria, such as Acinetobacter baumanniiand Pseudomonas aeruginosa, is now emerging as an impor-tant resistance mechanism to these agents7–9. In addition,Klebsiella pneumoniae carbapenemases (KPC) and OXA-type enzymes degrade not only carbapenems but alsomany of the other currently available �-lactams8,10.KPCs in particular represent a rapidly growing threatworldwide, and the widespread and increased use of carba-penems may lead to further emergence of resistant bacte-rial strains9,11,12. Therefore, there is a growing need formore effective drugs or drug combinations for the treat-ment of infections caused by these �-lactamase-producingpathogens.

Avibactam (formerly known as NXL104) is a novelnon-�-lactam �-lactamase inhibitor that is not susceptibleto inhibition by classic �-lactamases. Avibactam alone haslittle intrinsic antimicrobial activity, but when adminis-tered in combination with ceftazidime, a broad-spectrumcephalosporin, it restores the in vitro activity of ceftazidimeagainst bacteria producing Ambler class A and C �-lacta-mases13–17.

The objective of the current study was to evaluate theefficacy, safety and tolerability of ceftazidime–avibactamcompared to imipenem–cilastatin for the treatment ofcUTI, including acute pyelonephritis, in hospitalizedadults.

Patients and methods

Study design

This was a phase II, prospective, multicenter, investigator-and patient-blinded, randomized comparative study(Clinicaltrials.gov identifier: NCT00690378). It was per-formed in accordance with International Conference onHarmonisation/Good Clinical Practice guidelines anddesigned following guidelines for studies of cUTIs18.Each patient provided written informed consent. Thetrial involved a total of 26 participating centers in fivecountries (Guatemala, India, Jordan, Lebanon and theUnited States).

Eligible patients were enrolled by the study investigatorat each site. They were stratified based on infectiontype (acute pyelonephritis or other cUTI withoutpyelonephritis) and randomized 1:1 by a central random-ization process to receive either ceftazidime–avibactam orimipenem–cilastatin. At each site, the study pharmacistwas informed of the patient enrolment and infectiontype, and he/she then contacted the randomizationcenter using an interactive voice response system(IVRS). The IVRS then assigned a randomizationnumber to the patient. Each patient received only thestudy medication associated with his/her randomizationnumber.

Investigator and patient blinding was achieved by prep-aration and administration of the iv study antibiotics bysomeone other than the person who evaluated the patientfor clinical response and safety. Furthermore, becausethe schedule of infusions differed between ceftazidime–avibactam and imipenem–cilastatin, the infusion set-upwas masked by covering the iv infusion bags and portswith suitable covers. The study pharmacist (or other desig-nated person) who received the clinical supplies and theperson who administered the treatment were not blindedto study treatment, and were not permitted to informthe investigator or the patients about which treat-ment was being administered. Study treatments weresupplied to the investigator site based on enrolment inthe study.

Study population

Male and female patients between the ages of 18 and 90years were eligible for inclusion in the study if they werediagnosed with either acute pyelonephritis or other cUTIdue to Gram-negative pathogens that was judged by theinvestigator to be serious (requiring parenteral therapy).Subjects were treated for 7–14 days with study drug. Acutepyelonephritis was defined as the presence of fever(defined as body temperature 437.8�C orally, 438.2�Cby tympanic, or438.4�C by rectal measurement) and/orchills documented within 12 hours of entry into the study,

Current Medical Research & Opinion Volume 28, Number 12 December 2012

1922 Ceftazidime–avibactam in complicated UTI Vazquez et al. www.cmrojournal.com ! 2012 Informa UK Ltd

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and flank pain, pyuria (determined by a mid-stream, clean-catch or catheterized urine specimen with �10 whiteblood cells [WBC] per high power field on standard exam-ination of urine sediment or �10 WBC/mm3 in unspunurine) and a positive urine culture (containing �105

colony-forming units [CFU]/mL of a uropathogen pre-sumed or known to be susceptible to study drugs).

Other cUTIs were those confirmed by signs and symp-toms consistent with a UTI (defined as body temperature437.8�C orally, 438.2�C by tympanic measurement, or438.4�C by rectal measurement, chills, flank pain, costo-vertebral angle tenderness, dysuria, urgency, frequency,incontinence, suprapubic pain, nausea or vomiting),pyuria (�10 WBC/mm3), and a positive urine culture(�105 CFU/mL of a uropathogen presumed or known tobe susceptible to study drugs). Male patients with othercUTIs were also required to have a diagnosis of acute pros-tatitis excluded by physical examination. Female patientswith other cUTIs were also required to have a history orclinical evidence of one or more urological abnormalities(indwelling or intermittent use of bladder catheter, instru-mentation of urinary tract, including urogenital surgery inthe 7 days prior to study entry) and/or functional or ana-tomical abnormalities of the urinary tract.

Patients were excluded from the study if the cUTI wascaused by a uropathogen known to be resistant to one orboth study drugs, or if they had received more than onedose of another potentially effective systemic antibioticwithin 48 hours prior to the admission urine culture (orone or more doses of an antibiotic after obtaining the urineculture for admission to the study). Other exclusion crite-ria included the presence of ileal loops or vesicoureteralreflux, complete obstruction of the urinary tract, perineph-ric or intrarenal abscess, or fungal UTI. Patients with apermanent indwelling catheter or instrumentation,including nephrostomy, were excluded unless the devicewas removed within 48 hours of study entry. Pregnant orbreast-feeding women, patients considered unlikely to sur-vive the study period, and patients with a history of hyper-sensitivity to study medication were also excluded.

Study treatment

Patients received either ceftazidime 500 mg plus avibac-tam 125 mg iv (30-minute infusion) every 8 hours orimipenem–cilastatin 500 mg iv (30-minute infusion)every 6 hours, according to randomization.

Patients who met pre-specified criteria for clinicalimprovement (afebrile for �24 hours, with resolution ofnausea and vomiting, and improved signs and symptoms)after at least 4 days of iv treatment, and who had pathogensthat were susceptible to both study antibiotics, were per-mitted to switch to oral ciprofloxacin 500 mg twice daily(or alternative oral therapy if the patient was intolerant of

ciprofloxacin or had a ciprofloxacin-resistant baselinepathogen) for the remaining treatment course. The overalltreatment duration was a minimum of 7 days and a max-imum of 14 days (iv plus oral antibiotics).

Endpoints

The primary efficacy endpoint was a favorable microbio-logical response at the test-of-cure (TOC) visit, 5–9 daysafter the last dose of the study therapy, in the microbio-logically evaluable (ME) population. Favorable microbio-logical response was defined as eradication of alluropathogens (reduction of the urine pathogen from�105 CFU/mL to 5104 CFU/mL, with no pathogen pre-sent in the blood). The ME population was defined aspatients who had no major protocol violations, had a pos-itive urine culture on enrolment that contained�105 CFU/mL (4104 CFU/mL if bacteremic) of at leastone uropathogen presumed or known to be susceptible tothe study antibiotics, had a clinical and microbiologicalassessment at the TOC visit (including a quantitativeurine culture), and had either received at least 7 days ofstudy therapy (iv or iv plus oral), or were classified as fail-ures after completing at least 48 hours of iv therapy.

Secondary endpoints included microbiological responseat the end of iv therapy and at the late follow-up (LFU)visit, 4–6 weeks post-therapy in the ME population.Clinical response at the end of iv therapy, at the TOCand at LFU visits was also assessed in the clinically evalu-able (CE) population. Clinical response was defined asresolution of all or most pre-therapy signs and symptomswith no further requirement for antibiotics. The CE pop-ulation was defined as patients who had clinical evidenceof cUTI, were compliant with study drug therapy (receivedat least 7 days of study antibiotic), or were classed asan evaluable clinical failure after completing at least48 hours of iv study therapy, and had a clinical outcomeassessment at the TOC visit. ME patients were alsoassessed for microbiological responses according to the pri-mary diagnosis, baseline uropathogen isolated, and pres-ence of ceftazidime-resistant pathogens. Microbiologicalresponse was also assessed for the modified intent-to-treat (MITT) population, comprising all patients whoreceived at least one dose of study medication and whohad a pre-treatment urine culture containing4105 CFU/mL of at least one uropathogen. Susceptibility to compar-ator antibacterial agents was interpreted based on Clinicaland Laboratory Standards Institute (CLSI) 2010 interpre-tive standards19.

Safety and tolerability were determined for the safetypopulation (all patients who received at least one dose ofstudy medication) by assessment of treatment-emergent adverse events (AEs), local tolerability, vital



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signs, physical examination, electrocardiogram and labo-ratory tests.

Statistical analysis

Formal sample size calculation was not performed sincethis was the initial study for ceftazidime–avibactam inpatients with cUTI. While this phase II study was notstatistically powered to demonstrate non-inferiority, apopulation of 150 patients (75 in each treatment arm)was considered sufficient to provide an estimate of theefficacy and safety of ceftazidime–avibactam as comparedto imipenem–cilastatin in patients with cUTI.Microbiological and clinical outcomes were summarizedand compared using descriptive statistics for each treat-ment arm at the end of iv treatment, and at the TOCand LFU visits. For differences in microbiological responserates, two-sided 95% exact confidence intervals (CIs) werecalculated.

A synopsis of the study protocol is available atClinicalTrials.gov (NCT00690378).

Results

Study population

The study was performed between 6 November 2008(first patient in) and 15 June 2010 (after completionof enrolment and last patient follow-up visit). A totalof 137 patients were randomized to receive eitherceftazidime–avibactam (n¼ 69) or imipenem–cilastatin(n¼ 68). Two patients (one in each study arm) did notreceive any study medication and were excluded from thesafety population, which therefore comprised 135 patients(Figure 1). The majority of patients, 71.0% (49/69) in theceftazidime–avibactam arm and 79.4% (54/68) in the imi-penem–cilastatin arm, completed the study. Most of thepatients who were discontinued had been enrolled on thebasis of Gram-stain results, which initially showed Gram-negative bacteria, but who subsequently had a negativeculture at baseline: 13 (18.8%) and 11 (16.2%) patientsin the ceftazidime–avibactam and imipenem–cilastatinarms, respectively.

Randomized patientsn = 69*

Ceftazidime-avibactam

Safety populationn = 68

Completedn = 49

Reasons forwithdrawal:

• Did not meet inclusion/ exclusion criteria (13)• Discontinued due to SAE (1)• Withdrew consent (2)• Protocol deviation (1)• Lost to follow-up (2)• Other (1)

• No valid pathogen isolated (23)• Protocol violation (12)• Did not meet cUTI/ pyelonephritis definition (4)• Withdrew consent (2)• Insufficient data to make assessment (1)

• No valid pathogen isolated (23)• Protocol violation (12)• Did not meet cUTI/ pyelonephritis definition (4)• Withdrew consent (2)

• No valid pathogen isolated (22)• Withdrew consent (1)

Reasons forexclusion:



MITTpopulation

n = 46

MEpopulation

n = 27

CEpopulation

n = 28

(All patients who received ≥1 doseof study therapy)

Completedn = 54

Reasons forwithdrawal:• Did no meet inclusion/ exclusion criteria (11)• Lost to follow-up (3)

MITTpopulation

n = 49Reasons forexclusion:• No valid pathogen isolated (18)• No study medication received (1)

MEpopulation

n = 35Reasons forexclusion:• No valid pathogen isolated (19)

• No valid pathogen isolated (18)

• Protocol violation (6)

• Protocol violation (6)

• Did not meet cUTI/ pyelonephritis definition (4)

• Did not meet cUTI/ pyelonephritis definition (4)

• Lost to follow-up (2)

• Lost to follow-up (2)

• Did not meet inclusion/ exclusion criteria (1)

• Did not meet inclusion/ exclusion criteria (1)

• Insufficient data to make assessment (1)

• Insufficient data to make assessment (1)

CEpopulation

n = 36Reasons forexclusion:

Patients randomizedN = 137

Imipenem-cilastatin Randomized patients

n = 68*Safety population

n = 67(All patients who received ≥1 dose

of study therapy)

Figure 1. Patient flow through the study. *One patient in each group did not receive a dose of study medication. MITT, modified intent-to-treat;ME, microbiologically evaluable; CE, clinically evaluable.



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The ME population consisted of 27 patients in theceftazidime–avibactam arm and 35 in the imipenem–cilastatin arm. The CE population consisted of 28 and 36patients in each treatment arm, respectively. The MITTpopulation consisted of 46 and 49 patients in each arm,respectively. The main reason for exclusion from the ME,CE and the MITT populations was the absence of a validbaseline pathogen (Figure 1).

Patient characteristics

In the safety population, baseline demographics were sim-ilar in both treatment arms (Table 1). Mean age was46.4 and 48.2 years in the ceftazidime–avibactam andimipenem–cilastatin arms, respectively, while 75.0% and73.1% were female, respectively. The primary diagnosiswas acute pyelonephritis in 64.7% and 61.2% of patientsin the ceftazidime–avibactam and imipenem–cilastatinarms, respectively. Only a small number of patients ineach treatment arm had a positive blood culture (threein the ceftazidime–avibactam arm and four in the imi-penem–cilastatin arm). In the ME population, the mostcommon uropathogen isolated was E. coli, recoveredfrom 25/27 (92.6%) patients in the ceftazidime–avibactam

arm and 33/35 (94.3%) patients in the imipenem–cilastatin arm (Table 2). Additionally, all blood pathogenswere identified as E. coli.

Table 3 summarizes the in vitro susceptibilities of base-line pathogens to a range of antibiotics, using CLSI crite-ria, in the ME population. All 63 micro-organisms weresusceptible to imipenem. However, 20 were found to beresistant to ceftazidime alone. These included eight iso-lates (all E. coli) from the ceftazidime–avibactam treat-ment arm, seven of which were classified as resistant toceftazidime (minimum inhibitory concentration [MIC]48 mg/L) and one as intermediate (MIC 8 mg/L). Therewere 12 ceftazidime-non-susceptible isolates from theimipenem–cilastatin arm, including 11 E. coli (10 resistantand one intermediate) and one Enterobacter cloacae (resis-tant); all were susceptible to imipenem. All pathogens (E.coli) recovered from the bloodstream were susceptible toimipenem, and only one (from a patient in the imipenem–cilastatin arm) was resistant to ceftazidime alone.

Most patients received 7–14 days of antibiotic therapy(iv and oral combined): 45/68 (66.2%) patients in theceftazidime–avibactam arm, and 52/67 (77.6%) in theimipenem–cilastatin arm. As noted previously, most ofthe patients who were discontinued from the study, andtherefore did not receive the full course of antimicrobialtherapy, had been enrolled on the basis of a positive urineGram-stain result but had a negative culture at baseline.The median duration of iv therapy was 5 and 6 days in eachtreatment arm, respectively. The median duration of ivplus oral therapy was 11 and 12 days, respectively.

Efficacy

Favorable microbiological response in the ME populationat the TOC visit was observed in 19/27 (70.4%) patients inthe ceftazidime–avibactam arm and 25/35 (71.4%) in theimipenem–cilastatin arm (observed difference �1.1%[95% CI: �27.2%, 25.0%]) (Figure 2). Favorable microbi-ological response rates at the end of iv therapy were 25/26(96.2%) and 34/34 (100%) in the ceftazidime–avibactam

Table 1. Summary of baseline demographics, patient characteristics andprimary diagnosis (safety population).

Ceftazidime–avibactam(n¼ 68)

Imipenem–cilastatin(n¼ 67)

Age, years; mean (SD) 46.4 (18.2) 48.2 (18.4)18–44 31 (45.6) 26 (38.8)45–64 26 (38.2) 29 (43.3)65–74 5 (7.4) 2 (3.0)75–90 6 (8.8) 10 (14.9)

Gender, n (%)Male 17 (25.0) 18 (26.9)Female 51 (75.0) 49 (73.1)

Ethnicity, n (%)Hispanic or Latino 18 (26.5) 18 (26.9)Not Hispanic or Latino 50 (73.5) 49 (73.1)White 40 (58.8) 41 (61.2)Black 2 (2.9) 5 (7.5)Asian 8 (11.8) 5 (7.5)Other (inc. Mexican, MexicanAmerican and multiracial)

18 (26.5) 16 (23.9)

Height (cm), mean (SD) 161.4 (9.9) 161.6 (8.5)Weight (kg), mean (SD) 73.0 (19.5) 74.3 (18.6)Primary diagnosis, n (%)

Acute pyelonephritis 44 (64.7) 41 (61.2)Other cUTI (without acute

pyelonephritis)24 (35.3) 26 (38.8)

Baseline uropathogen level:Met entry criterion of �105 CFU/mL 46 (67.6) 49 (73.1)Did not meet entry criterion 22 (32.4) 18 (26.9)

Positive blood culture, n (%)Present 3 (4.4) 4 (6.0)Absent 65 (95.6) 63 (94.0)

cUTI, complicated urinary tract infection; CFU, colony-forming units.

Table 2. Baseline uropathogen isolated (microbiologically evaluablepopulation).

Ceftazidime–avibactam*

(n¼ 27)


E. coli 25 (92.6) 33 (94.3)P. aeruginosa 2 (7.4) 0C. koseri 1 (3.7) 0E. cloacae 0 1 (2.9)P. mirabilis 0 1 (2.9)

*One patient in the ceftazidime–avibactam arm had two organisms isolated(E. coli and C. koseri).



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and imipenem–cilastatin arms, respectively, and 15/26(57.7%) and 18/30 (60.0%) at the LFU visit (Figure 2).At the LFU visit, 3/26 (11.5%) and 2/30 (6.7%) patients inthe ceftazidime–avibactam and imipenem–cilastatin arms,respectively, reported a recurrence, while 8/26 (30.8%)and 10/30 (33.3%), respectively, were diagnosed with per-sistent infections.

Favorable microbiological response rates in the MEpopulation were also similar in both treatment armswhen stratified by primary diagnosis (acute pyelonephritisor other cUTI) and by baseline pathogen (Table 4).Among patients with acute pyelonephritis, 13/18(72.2%) and 14/19 (73.7%) had a favorable micro-biological response in the ceftazidime–avibactam andimipenem–cilastatin arms, respectively. Among patientswith other cUTIs, 6/9 (66.7%) and 11/16 (68.8%) dem-onstrated a favorable microbiological response in theceftazidime–avibactam and imipenem–cilastatin arms,respectively. In cases where E. coli was identified as theuropathogen, 19/25 (76%) of patients in the ceftazidime–avibactam arm and 23/33 (69.7%) of patients in theimipenem/-cilastatin arm had a favorable microbiologicalresponse (Table 4). In the ceftazidime–avibactam arm, the

two patients with P. aeruginosa infection had a persistentinfection at the TOC visit, while the single patient withCitrobacter koseri showed eradication of infection at theTOC visit. In the imipenem–cilastatin arm, one patienteach had infection with E. cloacae and Proteus mirabilis,both of which had a favorable microbiological responseat the TOC visit (Table 4).

Among patients with ceftazidime-resistant uropatho-gens, favorable microbiological response at the TOCvisit was achieved in 6/7 (85.7%) and 9/11 (81.8%)patients in the ceftazidime–avibactam and imipenem–cilastatin arms, respectively (Table 4).

In the CE population, a favorable clinical response wasobserved in all patients in both treatment arms at the endof iv therapy (Figure 3). At the TOC visit, clinicalresponse was maintained in 24/28 (85.7%) and 29/36(80.6%) of patients in the ceftazidime–avibactam and imi-penem–cilastatin arms, respectively (observed difference5.2 [95% CI:�16.3%, 26.6%]). At the LFU visit, sustainedclinical responses were achieved in 20/27 (74.1%) and 24/36 (66.7%) patients in the ceftazidime–avibactam andimipenem–cilastatin arms, respectively (observed differ-ence 7.4 [95% CI: �18.4%, 33.2%]).

Overall, both favorable microbiological and clinicalresponses were achieved in 18/27 (66.7%) ME patientstreated with ceftazidime–avibactam, and 21/35 (60.0%)ME patients treated with imipenem–cilastatin at theTOC visit (observed difference 6.7 [95% CI: �17.4%,30.7%]). At the LFU visit, 14/26 (53.8%) and 18/30(60%) of patients treated with ceftazidime–avibactamand imipenem–cilastatin, respectively, had favorablemicrobiological and clinical responses (observed differ-ence �6.2 [95% CI: �32.1%, 19.8%]).

In the MITT population, favorable microbiologicalresponse (eradication) at the end of iv therapy wasachieved in 40/46 (87.0%) of patients in the ceftazi-dime–avibactam group and 45/49 (91.8%) of patients inthe imipenem–cilastatin group (observed difference �4.0[95% CI: �19.4%, 9.6%]) (Figure 4). At the TOC visit,

Table 3. In-vitro susceptibility* of baseline pathogens isolated from urine and blood (microbiologically evaluable populationy).

Pathogen n/m (%) Imipenem Amoxicillinþclavulanate

Cefotaxime Ceftazidime Ciprofloxacin PiperacillinþTazobactam

Tigecycline

E. coliUropathogen 58/58 (100.0) 26/58 (44.8) 35/58 (60.3) 39/58 (67.2) 25/58 (43.1) 53/58 (91.4) 58/58 (100.0)Blood pathogenz 5/5 (100.0) 4/5 (80.0) 4/5 (80.0) 4/5 (80.0) 4/5 (80.0) 5/5 (100.0) 5/5 (100.0)

P. aeruginosa 2/2 (100.0) NT 0/2 (0.0) 2/2 (100.0) 0/2 (0.0) 2/2 (100.0) NTC. koseri 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) 1/1 (100.0)E. cloacae 1/1 (100.0) 0/1 (0.0) 0/1 (0.0) 0/1 (0.0) 0/1 (0.0) 0/1 (0.0) NTP. mirabilis 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) 1/1 (100.0)

*Antibacterial susceptibility was defined according to Clinical and Laboratory Standards Institute interpretive criteria19.yOne patient had two uropathogens.zAll blood pathogens isolated were identified as E. coli. All other pathogens listed are uropathogens.n, number of susceptible pathogens; m, number of patients with the pathogen; NT, not tested.

100

Res

pons

e ra

te (

%)

9080706050403020100

End iv TOC visit LFU visit

Ceftazidime-avibactam(n = 27)

Imipenem-cilastatin(n = 35)

96.2

(80

.4, 9

9.9)

70.4

(49

.8, 8

6.2)

57.7

(36

.9, 7

6.6)

71.4

(53

.7, 8

5.4)

100.

0 (8

9.7,

100

.0)

60.0

(60

.0, 7

7.3)

Figure 2. Percentage (95% confidence interval) of patients with favorablemicrobiological response (microbiologically evaluable population).iv, intravenous; TOC, test-of-cure; LFU, late follow-up.



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eradication was reported in 31/46 (67.4%) of patients inthe ceftazidime–avibactam group and in 31/49 (63.3%) ofpatients in the imipenem–cilastatin group (observed dif-ference 4.1 [95% CI: �17.1%, 25.4%]). At the LFU visit,

sustained microbiologic eradication was observed in 23/46(50.0%) of patients and 23/49 (46.9%) of patients in eachgroup, respectively (observed difference 3.1 [95% CI:�19.1%, 25.3%]).

Safety and tolerability

Over the course of the study, AEs were reported in 46/68(67.6%) patients in the ceftazidime–avibactam arm and51/67 (76.1%) patients in the imipenem–cilastatin arm.The most common AEs in both treatment arms includedconstipation, diarrhea, abdominal pain, headache, anxi-ety, and injection/infusion site reactions (Table 5).During iv and oral treatment, drug-related treatment-emergent AEs were reported in 24/68 (35.3%) and 34/67(50.7%) of patients in the ceftazidime–avibactam andimipenem–cilastatin arms, respectively. Headache andinjection/infusion site reactions were the most commondrug-related AEs in both treatment arms (Table 6).Injection/infusion site reactions were reported in fewerpatients in the ceftazidime–avibactam arm than in theimipenem–cilastatin arm (5.9% vs. 22.4%, respectively).

Treatment-emergent serious AEs (SAEs) were reportedin 6/68 (8.8%) and 2/67 (3.0%) of patients in theceftazidime–avibactam and imipenem–cilastatin arms,respectively, during the course of the study (Table 5).Three of the SAEs in the ceftazidime–avibactam armwere considered to be drug-related: renal failure, diarrhea,and accidental overdose of ceftazidime–avibactam (Table6). Although the accidental overdose of ceftazidime–avibactam was recorded as a SAE, there were no AEs asso-ciated with this event. The patient who received the over-dose was found to have been administered ceftazidime2000 mg (instead of 500 mg) and avibactam 1000 mg(instead of 125 mg). Study medication was discontinuedimmediately by the investigator. The patient remained

Table 4. Favorable microbiological response rate at test-of-cure visit according to primary diagnosis and baselineuropathogens (microbiologically evaluable population).



Observeddifference(95% CI)

Primary diagnosis, n (%):Acute pyelonephritis 13/18 (72.2) 14/19 (73.7) �1.5 (�35.5, 32.6)Other cUTI 6/9 (66.7) 11/16 (68.8) �2.1 (�49.0, 44.9)

Baseline uropathogen, n (%)E. coli 19/25 (76.0) 23/33 (69.7) 6.3 (�20.1, 32.8)P. aeruginosa 0/2 (0.0) 0/0 –C. koseri 1/1 (100.0) 0/0 –E. cloacae 0/0 1/1 (100.0) –P. mirabilis 0/0 1/1 (100.0) –

Ceftazidime-resistant pathogens, n (%)E. coli 6/7 (85.7) 8/10 (80.0) –E. cloacae 0/0 1/1 (100) –

n, number of patients; CI, confidence interval; cUTI, complicated urinary tract infection.

100

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e ra

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%)

9080706050403020100


87.0

67.4

50.0

63.3

46.9

91.8



Figure 4. Percentage of patients with favorable microbiological response(modified intent-to-treat population [95% confidence interval were notcalculated for modified intent-to-treat population]). iv, intravenous; TOC,test-of-cure; LFU, late follow-up.

100


Res

pons

e ra

te (

%)

100.0

85.7

74.180.6

66.7

100.0



9080706050403020100

Figure 3. Percentage of patients with clinical response (clinically evaluablepopulation [95% confidence interval were not calculated for clinicalresponse]). iv, intravenous; TOC, test-of-cure; LFU, late follow-up.



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hospitalized and under observation for 2 days, but no lab-oratory abnormalities or AEs were documented. Thepatient was then discharged and followed up as an outpa-tient for 2 weeks, with no clinical sequelae. One patient inthe imipenem–cilastatin arm developed a drug-related

SAE associated with an increase in serum creatininelevel. This patient was discharged on day 7 after initialhospitalization for treatment of cUTI, at which timeserum creatinine was normal (0.71 mg/dL; upper limit ofnormal¼ 0.9 mg/dL). On day 12, the patient was read-mitted to hospital for evaluation and was found to havea serum creatinine level of 2.58 mg/dL. After iv hydrationand insertion of an indwelling catheter, serum creatinineinitially improved but then increased again (from 1.4 to1.61 mg/dL) when a new UTI developed, which wasthought to be secondary to the indwelling catheter. Theorganism was identified as E. coli and the patient was trea-ted with iv amoxicillin and clavulanate, and was dis-charged on day 31 with a normal serum creatinine level(0.83 mg/dL). The investigator considered the event to bemoderate in intensity and probably related to studymedication.

Discussion

The results of this small phase II study provide some indi-cation that that ceftazidime–avibactam may be as effica-cious as imipinem–cilastatin for the treatment of cUTI inadults, including those with ceftazidime-non-susceptiblepathogens. Favorable microbiological response in the MEpopulation at the TOC visit was observed in approxi-mately 70% of patients in both treatment arms, havingreached 96–100% at the end of iv therapy. Similarly, afavorable microbiological response (eradication of patho-gen) in the MITT population was approximately 90% ineach treatment arm at the end of iv therapy, and 63–67%at the TOC visit. The reason for the decline in microbio-logical response rate between visits is uncertain. However,it may simply be a function of the relatively small patientnumbers included in the study. Similarly, we do not havean explanation for the relatively low rates of microbiolog-ical eradication in patients with acute pyelonephritis inboth treatment arms.

The bacterial epidemiology of the cUTIs in this study isgenerally similar to that reported elsewhere in NorthAmerica, Latin America and Europe1,20. E. coli remainsthe most frequently isolated uropathogen, followed by P.aeruginosa and Proteus spp. The most notable exception inthe present study is the absence of K. pneumoniae in any ofthe ME patients, whereas this organism accounted for 8–12% of uropathogens isolated in the American andEuropean surveys cited above1,20. Again, however, thismay simply be due to the relatively small numbers ofpatients included in this study.

Current treatment options for cUTI due to ESBL-or AmpC-�-lactamase-producing organisms includepiperacillin–tazobactam and carbapenems such as imi-penem, meropenem, and the newer agent doripenem2.Although this was a phase II study and the patient numbers

Table 5. Treatment-emergent adverse events (AEs) (occurring in �5% ofpatients) and serious AEs (SAEs) in each treatment arm during intravenousand oral therapy (safety population).



AE, n (%)Constipation 7 (10.3) 2 (3.0)Diarrhea 6 (8.8) 7 (10.4)Abdominal pain 10 (14.7) 4 (6.0)Abdominal distension 0 5 (7.5)Headache 13 (19.1) 21 (31.3)Dizziness 4 (5.9) 0Chest pain 4 (5.9) 3 (4.5)Injection/infusion site reaction 5 (7.4) 16 (23.9)Anxiety 7 (10.3) 5 (7.5)Insomnia 4 (5.9) 4 (6.0)Alanine aminotransferase increase 2 (2.9) 4 (6.0)Back pain 2 (2.9) 4 (6.0)Hypertension 4 (5.9) 2 (3.0)

SAE, n (%)Renal failure acute 1 (1.5) 0Renal impairment 1 (1.5) 0Atrial fibrillation 1 (1.5) 0Diarrhea 1 (1.5) 0Accidental overdose 1 (1.5) 0Intervertebral disc protrusion 1 (1.5) 0Urosepsis 0 1 (1.5)Blood creatinine increased 0 1 (1.5)

Terms coded in line with Medical Dictionary for Regulatory Activity (MedDRA,Version 12, Chantilly, Virginia, USA).

Table 6. Drug-related adverse events (AEs) occurring in two or morepatients (�3%) and drug-related serious AEs (SAEs) in either treatment armduring intravenous and oral therapy (safety population).



AE, n (%)Diarrhea 3 (4.4) 2 (3.0)Abdominal pain 2 (2.9) 1 (1.5)Nausea 0 2 (3.0)Headache 7 (10.3) 8 (11.9)Dizziness 2 (2.9) 0Chest pain 2 (2.9) 2 (3.0)Injection/infusion site reaction 4 (5.9) 15 (22.4)Alanine aminotransferase increased 1 (1.5) 3 (4.5)Aspartate aminotransferase increased 1 (1.5) 2 (3.0)Anxiety 2 (2.9) 0Blood creatinine increased 0 2 (3.0)Vulvovaginal mycotic infection 0 2 (3.0)

SAE, n (%)Renal failure acute 1 (1.5) 0Diarrhea 1 (1.5) 0Accidental overdose 1 (1.5) 0Blood creatinine increased 0 1 (1.5)



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are relatively small, the results compare favorably withprevious studies in patients with cUTIs, even thoughthere were some differences between the studies. For exam-ple, in the DORI-5 clinical trial, which was a phase IIIdouble-blind study, 753 patients with either cUTIs orpyelonephritis were treated with either doripenem500 mg iv every 8 hours or levofloxacin 250 mg iv every24 hours21. As in the present study, E. coli was the baselineuropathogen isolated most frequently from the MITT pop-ulation (73.6% of patients); other uropathogens includedP. mirabilis (6.5%), K. pneumoniae (4.9%), P. aeruginosa(2.8%) and E. cloacae (2.8%). In both treatment arms,patients could switch to oral levofloxaxin after 3 days ofiv therapy if they demonstrated significant clinical andmicrobiological improvements. All patients were to com-plete a 10-day treatment course. Additionally, as in thepresent study, a high proportion of patients were excludedfrom the ME population, mostly because there were nostudy-qualifying pre-treatment urine cultures (100patients), but also because of TOC window violations,lack of interpretable TOC urine culture assessment (76patients), and non-compliance (51 patients). The micro-biological cure rates in the ME population (n¼ 545) at theTOC visit, 5–11 days after the last dose of antibiotic, were82.1% with doripenem and 83.4% with levofloxacin.Furthermore, in patients with levofloxacin-resistant E.coli at baseline, the microbiological cure rates were only55% and 29%, respectively.

In a non-randomized Japanese study that included 155adults with cUTI, doripenem 250 mg twice daily was foundto be equivalent to meropenem 500 mg twice daily over 5days22. In this study, 45% of cases were due to E. coli, 35%Staphylococcus epidermidis, 20% P. aeruginosa, 18% Serratiamarcescens, and 17% K. pneumoniae. The bacteriologicalresponse (eradication) rates immediately after the end oftreatment were 95.9% and 96.2% in each group,respectively.

In a non-comparative study evaluating piperacillin–tazobactam 4 g/500 mg every 8 hours for at least 5 days inadults with cUTI (47% due to E. coli, 13% due to P.aeruginosa and the remainder due to other pathogens),the bacterial eradication rates were reported in 73% (82/112) of evaluable patients 4–6 weeks after the end of treat-ment23. In a similar non-comparative study employing thesame regimen of piperacillin–tazobactam in 61 evaluableadults with cUTI (including 33 with E. coli, eight with K.pneumoniae, seven with Enterococus spp., six with P. mira-bilis, three with P. aeruginosa, three with Enterobacter spp.and two with Morganella morganii), 85.3% demonstratedbacterial eradication 5–9 days after stopping therapy.This response was sustained in 79.6% of patients afterthe 4 - to 6-week follow-up24.

In the present study, a favorable microbiologicalresponse in the ME population was observed at the TOCvisit in 6/7 (85.7%) patients with ceftazidime-resistant

uropathogens in the ceftazidime–avibactam arm.Although the numbers are small, the cure rates are prom-ising, particularly in the current environment, in whichthere is an increasing prevalence of MDR pathogens ascauses of UTIs.

While carbapenems are one of the current treatments ofchoice for patients with community- or hospital-acquiredUTIs caused by MDR pathogens, recent epidemiologicstudies indicate increasing numbers of carbapenemase-producing Gram-negative pathogens7–9. The availabilityof a new, effective and well tolerated antibacterial drugcombination would therefore represent an importantadvance in the treatment of patients with cUTIs.

In the current clinical trial, ceftazidime–avibactam wasgenerally well tolerated in patients with cUTI. The mostcommon AEs in both treatment arms were gastrointestinaldisorders, headache, anxiety and injection/infusion sitereactions. Moreover, the frequency of injection site reac-tions was considerably lower in the ceftazidime–avibactamarm than the imipenem–cilastatin arm. It should be noted,however, that patients in the ceftazidime–avibactam armreceived three infusions per day, while those in theimipenem–cilastatin arm received four infusions per day.

Limitations of the study include the small size of theoverall patient population, and the relatively small per-centage of patients with a pathogen isolated at baselineand who were included in the ME population in each treat-ment arm. Furthermore, the number of patients with cef-tazidime-resistant bacteria was small, and there were veryfew patients with P. aeruginosa infections. Nevertheless,the results provide promising evidence that ceftazidime–avibactam may be effective in patients with cUTI, includ-ing some with ceftazidime-resistant pathogens.

It should also be mentioned that, based on currenttreatment practices, a variety of agents might have beenchosen as the comparator compound in this study.Imipenem–cilastatin was selected because carbapenemsare currently the treatment of choice in cUTI, and becauseit has been shown to have excellent efficacy against Gram-negative pathogens, and is approved for use and has beenwidely used in the treatment of cUTI25,26. Furthermore,like ceftazidime–avibactam, imipenem–cilastatin is a com-bination of an antibiotic and a chemical compound thatinhibits the enzyme responsible for inactivating the anti-biotic – in this case, dehydropeptidase27.

Conclusion

The results of this small phase II study suggest that theefficacy of ceftazidime–avibactam may be similar to thatof imipenem–cilastatin in adults with cUTI. In addition,among subjects with ceftazidime-resistant uropathogens,six of seven cases treated with ceftazidime–avibactamhad a favorable microbiological response. In general,



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ceftazidime–avibactam was well tolerated in this popula-tion, with a favorable safety profile. Overall, ceftazidime–avibactam shows promise as an agent for the treatment ofcUTIs, including those caused by ceftazidime-resistantpathogens. Further evaluation is required to better under-stand how ceftazidime–avibactam should be used. In thefuture, larger studies should attempt to include highernumbers of patients infected with P. aeruginosa thanwere included in the present study in order to determinemore clearly the effectiveness of ceftazidime–avibactamagainst this virulent and resistant pathogen. Two largephase III studies are ongoing comparing ceftazidime–avibactam with doripenem in patients with cUTI, includ-ing acute pyelonephritis.

TransparencyDeclaration of fundingThis study was led by Novexel and ceftazidime-avibactam is nowbeing developed by AstraZeneca and Forest-Cerexa. The designand conduct of the study, as well as analysis of the study data andopinions, conclusions, and interpretation of the data, are theresponsibility of the authors.

Declaration of financial/other relationshipsJ.A.V., L.D.G.P. and D.S. have disclosed that they have no sig-nificant relationships with or financial interests in any commer-cial companies related to this study or article. D.D.D. received astudy grant from Novexel & Trident Clinical Research for theconduct of the study. Z.K. received a study grant from Novexel.At the time this study was conducted, J.L. and C.S. were employ-ees of Novexel/AstraZeneca.

CMRO peer reviewers on this manuscript have received hon-oraria for their review work, but have no other relevant financialrelationships to disclose.

Author contributionsC.S. designed the study, J.A.V. was International Co-ordinatingInvestigator and is guarantor for the study data, and all authorswere involved in all diverse phases of the study (including enrol-ment of patients) and writing and editing the manuscript.

AcknowledgementsMedical writing support was provided by Liz Anfield, PrimeMedica Ltd, Knutsford, Cheshire, and was funded byAstraZeneca. She prepared a preliminary outline and subsequentrevisions of the manuscript based on extensive critical input fromall the authors.

Study investigators (in addition to authors): Guatamala:Magdalena Gonzalez, Gilberto Recinos, Rodolfo Sanchez, LuisJuarez. India: Shriniwas Ambike, Jaydeep Date, Bharat Kalambe,Guntupalli Malakondaiah, Anthony Rozario. Jordan: IbrahimBaniHani, Mamum Ezzibdeh, Ghazi Al-Edwan. Lebanon:Ghenwa El-Dakdouki, Ahmad Fawaz, Ahmad Moussa, ZouayrTabbarah, Walid Alame. US: Salah Bibi, Ravi Kamepalli,Stanley Link, Carol Tanner-St James.

A preliminary report of these results was presented at theEuropean Congress of Clinical Microbiology and InfectiousDiseases (ECCMID), Milan, Italy, May 2011 (PosterPresentation [P1533]).

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efficacy and safety of ceftazidime–avibactam versus imipenem–cilastatin in the treatment of...

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