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Safety and Efficacy of Ceftazidime–Avibactam in the Treatment of Children ≥3 Months to <18 Years With Complicated Urinary Tract Infection

Results from a Phase 2 Randomized, Controlled Trial

Bradley, John S. MD*; Roilides, Emmanuel MD, PhD; Broadhurst, Helen MSc; Cheng, Karen MB, ChB§; Huang, Li-Min MD; MasCasullo, Veronica MD; Newell, Paul MBBS; Stone, Gregory G. PhD**; Tawadrous, Margaret MD**; Wajsbrot, Dalia MSc††; Yates, Katrina PhD; Gardner, Annie MS‡‡

The Pediatric Infectious Disease Journal: September 2019 - Volume 38 - Issue 9 - p 920–928
doi: 10.1097/INF.0000000000002395
Antimicrobial Reports
Open
SDC

Background: Ceftazidime–avibactam is effective and well tolerated in adults with complicated urinary tract infection (cUTI), but has not been evaluated in children with cUTI.

Methods: This single-blind, multicenter, active-controlled, phase 2 study (NCT02497781) randomized children ≥3 months to <18 years with cUTI (3:1) to receive intravenous (IV) ceftazidime–avibactam or cefepime for ≥72 hours, with subsequent optional oral switch. Total treatment duration was 7–14 days. Primary objective was assessment of safety. Secondary objectives included descriptive efficacy and pharmacokinetics. A blinded observer determined adverse event (AE) causality and clinical outcomes up to the late follow-up visit (20–36 days after the last dose of IV/oral therapy).

Results: In total, 95 children received ≥1 dose of IV study drug (ceftazidime–avibactam, n = 67; cefepime, n = 28). The predominant baseline Gram-negative uropathogen was Escherichia coli (92.2%). AEs occurred in 53.7% and 53.6% patients in the ceftazidime–avibactam and cefepime groups, respectively. Serious AEs occurred in 11.9% (ceftazidime–avibactam) and 7.1% (cefepime) patients. One serious AE (ceftazidime–avibactam group) was considered drug related. In the microbiologic intent-to-treat analysis set, favorable clinical response rates >95% were observed for both groups at end-of-IV and remained 88.9% (ceftazidime–avibactam) and 82.6% (cefepime) at test-of-cure. Favorable per-patient microbiologic response at test-of-cure was 79.6% (ceftazidime–avibactam) and 60.9% (cefepime).

Conclusions: Ceftazidime–avibactam was well tolerated in children with cUTI, with a safety profile consistent with that of adults with cUTI and of ceftazidime alone, and appeared effective in children with cUTI due to Gram-negative pathogens.

From the *Rady Children’s Hospital/UCSD, San Diego, CA

3rd Department of Pediatrics, Aristotle University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece

AstraZeneca, Alderley Park, Cheshire, United Kingdom

§Pfizer, Sandwich, Kent, United Kingdom

National Taiwan University Hospital, Taipei, Taiwan

Allergan plc, Madison, NJ

**Pfizer, Groton, CT

††Pfizer, New York, NY

‡‡Pfizer, Cambridge, MA.

Accepted for publication April 8, 2019.

This study was originally sponsored by AstraZeneca. AstraZeneca’s rights to ceftazidime–avibactam were acquired by Pfizer in December 2016. The study is now funded by Pfizer and Allergan.

J.S.B.’s, E.R.’s and L.-M.H.’s institutions received funds from AstraZeneca and Pfizer to conduct and consult on this study; J.S.B., E.R. and L.-M.H. received no funds for the creation of this manuscript. E.R. has received research grants from Astellas, Gilead and Pfizer Inc; and is a scientific advisor and member of speaker bureau for Astellas, Gilead, Merck and Pfizer Inc. H.B. and P.N. are former employees of AstraZeneca and P.N. is a current shareholder in AstraZeneca. P.N is a current employee of F2G Ltd, Manchester, United Kingdom. K.C., M.T., D.W., G.G.S. and A.G. are employees of Pfizer, all of whom may own stocks and options from Pfizer. V.M.C. is an employee of Allergan. K.Y. was a contractor to AstraZeneca at the time of study conduct.

Upon request, and subject to certain criteria, conditions and exceptions see (https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the United States and/or EU or (2) in programs that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Clinical Trial registry name and registration number: https://clinicaltrials.gov/ (identifier: NCT02497781)

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: John Bradley, MD, Rady Children’s Hospital, 3020 Children’s Way, MC 5041, San Diego, CA 92123. E-mail: jsbradley@ucsd.edu

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

There is an increasing prevalence of multidrug-resistant (MDR) uropathogens that are resistant to commonly prescribed antibiotics, such as ampicillin, cephalosporins and trimethoprim–sulfamethoxazole.1–4 The occurrence of extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae and MDR Pseudomonas aeruginosa are of particular concern,5 and highlight the need for novel therapeutics that have activity against MDR Gram-negative pathogens.

Ceftazidime–avibactam combines ceftazidime (a third-generation cephalosporin with activity against Pseudomonas spp.) with avibactam (a non-β-lactam β-lactamase inhibitor). Avibactam has potent activity against serine-based Ambler class A and class C β-lactamases (both intrinsic and plasmid mediated), as well as some class D enzymes.6 Therefore, combination with avibactam restores the spectrum of activity of ceftazidime against many strains of previously resistant Enterobacteriaceae and Pseudomonas spp.7

Urinary tract infections (UTIs) are relatively common in children.2 Recurrent UTIs are observed in 30%–50% of children after initial infection, are especially common in patients with abnormal urinary tract pathology, such as obstructive uropathy, and can be associated with significant morbidity.8 The most common bacterial pathogen associated with pediatric UTIs is Escherichia coli,1 with other Gram-negative pathogens less frequently isolated including Proteus spp., Klebsiella spp., Enterobacter spp., Pseudomonas spp. and Enterococcus spp.1,9

The safety and efficacy of ceftazidime–avibactam in adults with complicated UTIs (cUTIs), including those caused by ceftazidime–non-susceptible Gram-negative pathogens, have been demonstrated in the phase 3 REPRISE and RECAPTURE studies,10,11 and a phase 1 study investigated the pharmacokinetics and safety of ceftazidime–avibactam in 32 hospitalized children.12

This phase 2 study was conducted as part of the global clinical development program for ceftazidime–avibactam, which included postapproval regulatory commitments in the United States and Europe to evaluate ceftazidime–avibactam in pediatric patients with cUTI to support extension of the current labeled indication for ceftazidime–avibactam in adults to pediatric patients with cUTI.13,14 The primary objective was to evaluate the safety and tolerability of ceftazidime–avibactam versus cefepime in hospitalized children ≥3 months to <18 years with cUTI. Secondary objectives were to evaluate the efficacy and pharmacokinetics of ceftazidime–avibactam in this patient population.

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MATERIALS AND METHODS

Study Design and Patients

This single-blind, randomized, multicenter, active-controlled, phase 2 study (NCT02497781) was conducted between September 2015 and September 2017 at 25 study sites in 9 countries in compliance with regulatory agency guidelines for pediatric clinical trials. Eligible subjects were hospitalized children ≥3 months to <18 years who were diagnosed with cUTI, including acute pyelonephritis, that required treatment with intravenous (IV) antibiotics. Diagnosis of acute pyelonephritis was according to investigators’ judgment. Full inclusion and exclusion criteria, as assessed at screening, are provided in the Text, Supplemental Digital Content 1, http://links.lww.com/INF/D522. The study was carried out in accordance with good clinical practice guidelines and the Declaration of Helsinki. Written informed consent was obtained before screening from parents/caregivers, and informed assent from patients (if age appropriate). The final study protocol was approved by the relevant independent ethics committees and/or institutional review boards.

Children were randomized 3:1 to receive IV infusions of either ceftazidime–avibactam or cefepime (see Table 1 and Figure, Supplemental Digital Content 2, http://links.lww.com/INF/D523 for dosing information). IV treatment was administered for ≥3 days, with an optional switch to oral therapy at the investigators’ discretion on day 4, provided the patient had demonstrated sufficient clinical response and tolerance to oral fluids and/or food (subject to investigators’ interpretation). Planned total duration of treatment (IV ± optional oral switch) was 7–14 days. Randomization was stratified by age, with patients assigned to 1 of 4 age- and weight-based dosage cohorts, with adjustment for renal function (Table 1). Although prophylactic antibiotic use was prohibited between the time of the first dose of study drug and the end-of-treatment (EOT) assessment, prophylactic use was permitted after EOT until the end of the study.

TABLE 1

TABLE 1

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Study Assessments

Safety and tolerability data were captured from the time of informed consent up to the late follow-up (LFU) visit (20–36 days after the last dose of IV or oral study drug) and included adverse events (AEs), vital signs, electrocardiogram and physical examinations and laboratory evaluations. All reported AEs were coded from the verbatim terms reported by study site personnel to the appropriate MedDRA (version 20.0) preferred term. A blinded observer at the site determined AE causality.

Efficacy assessments performed by the site-specific blinded-observer, included clinical outcomes at the end of 72 hours of treatment, end-of-IV treatment (EOIV; within 24 hours of last dose), EOT (within 48 hours of completion of the last dose of oral therapy for patients who switched, or within 24 hours of last infusion of study drug for those who did not receive oral therapy) and test-of-cure (TOC; 8–15 days after the last dose of study drug) visits (see Table, Supplemental Digital Content 3, http://links.lww.com/INF/D524). Children who were considered clinically cured at TOC were reassessed at LFU for evidence of clinical relapse (20–36 days after the last dose of study drug). Microbiologic response was assessed at EOIV, EOT, TOC and LFU visits (see Table, Supplemental Digital Content 4, http://links.lww.com/INF/D525). Efficacy assessments also included the combined clinical and microbiologic responses at EOIV and TOC visits, and the occurrence of emergent infections.

Blood samples were taken from patients treated with ceftazidime–avibactam on day 3 for determination of ceftazidime and avibactam plasma concentrations. Urine samples were also taken for culture and routine urinalysis at baseline and at EOIV, EOT, TOC and LFU visits. The LFU visit could be carried out via telephone for any patient who had not experienced clinical relapse, did not have ongoing AEs at TOC, or did not develop AEs since TOC. Therefore, urine culture was only carried out for those patients who had an in-person LFU visit, with the TOC urine culture representing the final microbiologic assessment in most children. If clinically indicated, blood samples were obtained for culture and routine analysis at baseline and at any time until LFU.

Characterization of β-lactam resistance mechanisms was performed for selected isolated pathogens (see Text, Supplemental Digital Content 5, http://links.lww.com/INF/D526).

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Statistical Analyses

The study was not powered for inferential statistical comparisons between treatment groups; descriptive statistics were used to summarize safety and efficacy data. Sample size calculation was determined by likelihood of observing AEs and is described in the Text, Supplemental Digital Content 6, http://links.lww.com/INF/D527. Safety was assessed for the Safety Analysis Set, which comprised all randomized patients who received ≥1 dose of IV study drug. The analysis sets used to assess the study endpoints are described in Table, Supplemental Digital Content 7, http://links.lww.com/INF/D528.

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RESULTS

Patients

Overall, 101 children were enrolled and 97 were randomized (ceftazidime–avibactam, n = 68; cefepime, n = 29) (Fig. 1). The safety analysis set comprised 95 randomized patients who received IV study drug (ceftazidime–avibactam, n = 67; cefepime, n = 28) (Fig. 1); cohorts 1, 2, 3 and 4 included 19 (20.0%), 22 (23.2%), 18 (18.9%) and 36 (27.4%) patients, respectively (Table 2). Overall, 88 (90.7%) patients completed IV study drug treatment, and 90 (92.8%) patients completed the study up to the TOC visit. Three patients discontinued study treatment due to AEs (detailed below). In addition, in the ceftazidime–avibactam group, 1 patient (cohort 4) discontinued IV study treatment due to patient/parent/legal representative decision after 3 days, and in the cefepime group, 2 patients (both in cohort 3) discontinued study treatment due to enrollment culture/susceptibility results after 2 and 3 days, respectively, and 1 patient (cohort 1) discontinued IV treatment after 13 days. Across all cohorts, the median (range) exposure to IV-only study drugs was 4.0 (1–11) days for ceftazidime–avibactam and 4.0 (2–11) days for cefepime. Of the randomized patients, 60/69 (90.0%) and 26/28 (93.0%) in the ceftazidime–avibactam and cefepime groups, respectively, were switched to oral therapy. The median (range) exposure to IV ± optional oral therapy was 11.0 (1–17) days for ceftazidime–avibactam and 11.5 (2–27) days for cefepime. Overall, ~88% of patients received 8–15 calendar days IV ± optional oral therapy. Proportions of patients receiving IV-only and IV ± optional oral therapy by treatment duration categories (1–3; 4–6; 7–10; 11–15 and >15 days) are shown in the Figure, Supplemental Digital Content 8, http://links.lww.com/INF/D529.

TABLE 2

TABLE 2

FIGURE 1

FIGURE 1

Patient demographics and baseline characteristics for the safety analysis set are shown in Table 2 and were generally balanced across treatment groups within each cohort. A total of 79 (83.2%) patients had a diagnosis of acute pyelonephritis at screening. Among 21 (22.1%) patients with ≥1 complicating factor at screening (Table 2), the most frequent was a functional or anatomical abnormality of the urogenital tract [n = 11 (1.6%)]. A total of 15 (15.8%) patients [ceftazidime–avibactam: 9 (13.4%); cefepime: 6 (21.4%)] had urologic abnormalities.

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Baseline Uropathogens

Overall, 77 of 97 randomized patients were included in the microbiologic intent-to-treat (micro-ITT) set (Fig. 1). Twenty of 97 randomized patients [14 (20.6% ceftazidime–avibactam); 6 (20.7% cefepime)] did not have a study-qualifying baseline pathogen and were therefore excluded from the micro-ITT analysis set; of the 20 patients excluded, 3 (4.4%) patients in the ceftazidime–avibactam group and 1 (3.4%) patient in the cefepime group were also excluded from the micro-ITT analysis set due to having a Gram-positive pathogen identified at baseline (Fig. 1). Baseline Gram-negative uropathogens were typical of those found in cUTI. In the micro-ITT analysis set, all reported Gram-negative pathogens were Enterobacteriaceae, with E. coli [identified in 71/77 (92.2%) patients overall] being the most commonly reported across all cohorts (see Table, Supplemental Digital Content 9, http://links.lww.com/INF/D530). In total, 54 of 77 children in the micro-ITT analysis set [37 (68.5%) ceftazidime–avibactam; 17 (73.9% cefepime)] had blood cultures performed at baseline; no patients had concomitant baseline Gram-negative bacteremia.

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Safety

Overall, AEs, whether believed to be related to therapy or not, occurred in 36/67 patients (53.7%) in the ceftazidime–avibactam group and in 15/28 patients (53.6%) in the cefepime group (Table 3). The most frequently reported AEs up to the LFU visit were diarrhea and UTI (5 [7.5%] patients each) for the ceftazidime–avibactam group, and diarrhea (3 [10.7%]) for the cefepime group (Table 3). No AEs indicative of UTI were reported up to the end of IV study therapy; however, 7 (10.4%) and 2 (7.1%) patients in the ceftazidime–avibactam and cefepime groups, respectively, had UTI, pyelonephritis acute or cystitis which occurred 7–41 days after completion of IV study therapy, and which were not considered study drug related. On further assessment of these 9 patients, 5 (4 in the ceftazidime–avibactam and 1 in the cefepime group, respectively) had functional or anatomical urinary tract abnormalities, 1 had a history of recurrent pyelonephritis and 3 (2 and 1 in the ceftazidime–avibactam and cefepime groups, respectively) had a history of pyelonephritis. Hence, AEs of cUTIs that occurred after completion of study therapy were considered reflective of the natural history of the underlying condition in this patient population, in which recurrence of a de novo infection may occur due to underlying risk factors (eg, abnormal genitourinary anatomy) rather than acute treatment failure.

TABLE 3

TABLE 3

The majority of AEs were nonserious and considered by the observer to be of mild intensity. Six of 67 (9.0%) patients in the ceftazidime–avibactam arm had ≥1 AE of severe intensity. These were 1 case each of abdominal pain, constipation, nephrolithiasis, nervous system disorder, tachycardia and viral infection, and 2 cases of pyelonephritis acute. Two of 28 (7.1%) patients in the cefepime arm had AEs of severe intensity: 1 case each of cystitis and pyelonephritis acute. In the ceftazidime–avibactam group, 7 (10.4%) patients had AEs that were considered by blinded observer to be possibly related to the study drug: 1 patient had moderate nausea, vomiting and dizziness; 2 had mild diarrhea; 1 had severe Nervous system disorder (only considered to be temporally related); 1 had mild dermatitis diaper; 1 had mild rash and 1 had moderate rash. In the cefepime group, 1 (3.6%) patient had moderate diarrhea and mild intertrigo considered possibly study drug related. There were no AEs with an outcome of death. Overall, serious adverse events (SAEs) occurred in 8/67 (11.9%) patients in the ceftazidime–avibactam group and 2/28 (7.1%) in the cefepime group (Table 3). One SAE was considered possibly drug related; the patient (ceftazidime–avibactam arm; cohort 1) had a severe event of nervous system disorder, occurring 2 days after the start of IV study drug infusion. This patient had an ongoing medical history of anxiety, depression and hypertension secondary to polycystic kidney disease, and had experienced similar symptoms before enrollment in the study. The event led to discontinuation from the study and resolved on study day 3. All other events considered treatment related by the blinded observer were known adverse drug reactions for the study therapies. In addition to the patient described above, 2 further patients in the ceftazidime–avibactam arm had AEs leading to treatment discontinuation: the first was a patient (cohort 1) who experienced moderate dizziness, nausea and vomiting on day 2 that was considered possibly study drug related; in addition to study medication, this patient received a dose of 1 g ceftriaxone sodium (received day −1 to day 1) for treatment of the underlying disease. The second was a patient (cohort 2) who experienced severe asymptomatic tachycardia of 150 bpm, 2 hours after start of IV study drug infusion, which was considered unrelated by the blinded observer. No patient in the cefepime arm had an AE that led to discontinuation of treatment. All AEs that led to study discontinuation resolved.

No new clinically significant changes in laboratory parameters, vital signs, electrocardiogram or physical examination data were identified, and no patients met laboratory criteria for potential Hy Law, which assesses hepatic function for drug toxicity.

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Efficacy

The per-patient favorable clinical, microbiologic and combined responses at TOC are shown in Table 4 for the micro-ITT analysis set. At the earliest assessment (end of 72 hours), 49/54 (90.7%) patients in the ceftazidime–avibactam group and 22/23 (95.7%) in the cefepime group had a favorable clinical response (micro-ITT analysis set). Favorable clinical response was sustained at the TOC visit [48/54 (88.9%) overall for ceftazidime–avibactam and 19/23 (82.6%) overall for cefepime]. At LFU, 81.5% (44/54) patients in the ceftazidime–avibactam group and 82.6% (19/23) patients in the cefepime group had a favorable outcome; 11.1% (6/54) and 17.4% (4/23) patients, respectively, did not have clinical outcome assessed at LFU because they were not assessed as clinical cures at the TOC visit.

TABLE 4

TABLE 4

Favorable per-patient microbiologic response at TOC was 43/54 (79.6%) in the ceftazidime–avibactam group and 14/23 (60.9%) in the cefepime group (micro-ITT analysis set). For subjects who were doing well clinically, an LFU return visit and urine culture was optional. Therefore, favorable microbiologic response rates were lower at LFU for both groups than at preceding visits [ceftazidime–avibactam: 16/54 (29.6%); cefepime: 4/23 (17.4%)]; this was primarily due to a high percentage of indeterminate responses (ie, urine not collected for culture) at LFU [ceftazidime–avibactam: n = 32/54 (59.3%); cefepime: n = 14/23 (60.9%)]. Per-patient favorable microbiologic response rates at TOC in the microbiologically evaluable (ME) analysis set were 36/41 (87.8%) in the ceftazidime–avibactam arm and 11/16 (68.8%) in the cefepime arm and at LFU were 10/16 (62.5%) and 4/9 (44.4%), respectively.

Two children in the ceftazidime–avibactam group (both in cohort 2) and 1 in the cefepime group (cohort 3) had baseline E. coli isolates that were nonsusceptible to ceftazidime [based on an interpretive criterion of a minimum inhibitory concentration (MIC) >4 mg/L] and to cefepime (MIC >8 mg/L). From the ceftazidime–avibactam group, one isolate, with a ceftazidime MIC of 32 mg/L and a cefepime MIC of >16 mg/L, was from a patient in Taiwan and possessed CTX-M-55, while the other isolate, with a ceftazidime MIC of 64 mg/L and a cefepime MIC of >16 mg/L, was from a patient in Turkey and possessed CTX-M-15 and TEM-1. These 2 patients who received ceftazidime–avibactam were considered clinical cures at TOC and had favorable microbiologic responses at TOC. From the cefepime group, the isolate with MIC of ceftazidime 16 mg/L and of cefepime >16 mg/L was from a patient in Taiwan and possessed CTX-M-55. This patient was a clinical failure at TOC and had an indeterminate microbiologic response at TOC, based on lack of urine culture. All isolates were susceptible to ceftazidime–avibactam in vitro (MIC ≤ 8 mg/L).

Per-pathogen favorable microbiologic response rates at TOC are shown in the Table, Supplemental Digital Content 10, http://links.lww.com/INF/D531. Overall, 86.5% (32/37) of patients treated with ceftazidime–avibactam in the ME analysis set with an E. coli isolate at baseline had a favorable microbiologic response at TOC (including patients with ceftazidime–non-susceptible pathogens).

There were 3 (7%) emergent (new) infections (all 3 were reported as adverse events of “UTI”) at the TOC visit in the ceftazidime–avibactam group and none in the cefepime group in the ME set. Of the 3 new infections, 2 patients were reported to have both underlying urologic abnormalities and complicating factors. For the first of these 2 patients (cohort 2), the underlying diagnosis was cUTI, the baseline pathogen was E. coli and the emergent infection was caused by Enterococcus faecalis. For the second patient (cohort 2), the underlying diagnosis was cUTI, the baseline pathogen was Enterobacter cloacae and the emergent infection was caused by E. coli. The third new infection occurred in a patient enrolled with pyelonephritis (cohort 1); the baseline pathogen was E. coli, and the emergent infections were caused by E. faecalis and Staphylococcus haemolyticus. No antibiotic prophylaxis before emergence of the new infection(s) was reported for any of these 3 patients between EOT and LFU. Baseline isolates were susceptible to both ceftazidime–avibactam and cefepime in all cases.

Clinical relapse at LFU occurred in 4/54 (7.4%) patients in the ceftazidime–avibactam group (1 patient in cohort 2, 1 in cohort 3 and 2 in cohort 4) and no patients in the cefepime group (micro-ITT analysis set) (see Table, Supplemental Digital Content 11, http://links.lww.com/INF/D532). Of the 4 patients with clinical relapse, 3 were reported to have both underlying urologic abnormalities and complicating factors.

The microbiologic outcome of persistence at a particular visit was carried forward to subsequent visits. In the micro-ITT analysis set, 6 patients (11%) in the ceftazidime–avibactam group and 5 (22%) in the cefepime group had persistent infections at LFU, based on the assessment of local culture results by the investigator. Unfortunately, colony counts on urine cultures were not collected in the clinical trial database; therefore, ability to confirm true infection versus colonization/contamination was limited. The baseline pathogen was E. coli in all cases, and all isolates were susceptible to study drug. No persistent infections with increasing MIC were seen.

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Plasma Concentrations

Median plasma concentrations of ceftazidime and avibactam are presented in Figure 2.

FIGURE 2

FIGURE 2

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DISCUSSION

This study is the first prospective, randomized study to report the safety and efficacy of ceftazidime–avibactam in hospitalized children with cUTI (including acute pyelonephritis). Ceftazidime–avibactam was well tolerated in children ≥3 months to <18 years. The overall safety profile was in line with the expected safety profile for ceftazidime–avibactam from adults, the established safety profile of ceftazidime alone and the pattern of AEs expected for this patient population15; no new clinically relevant safety concerns were identified for ceftazidime–avibactam in this study.

Favorable clinical response rates >90% were observed for both treatment groups early during treatment at 72 hours (90.7% for ceftazidime–avibactam and 95.7% for cefepime) and remained >81% for both groups at the LFU visit. Favorable per-patient microbiologic response at TOC was ~80% for the ceftazidime–avibactam group and ~61% in the cefepime group. Of note, there was a high proportion of urine samples not collected at the LFU visit; as this visit could be conducted by telephone for patients without clinical relapse or ongoing or new AEs since TOC. While the investigators assumed that children who had no clinical symptoms should be assigned a favorable response, the definitions for microbiologic response provided at the beginning of the study meant that the urine cultures that were collected at LFU had a greater chance of being positive, in both groups. By definition, those without a culture were considered “indeterminate” (rather than presumed eradication), leading to a high percentage of indeterminate microbiologic responses recorded at the LFU visit (ie, source specimen was not available to culture, so no “favorable” or “presumed favorable” microbiologic response was assumed). Consequently, favorable microbiologic response rates were lower at LFU for both treatment groups than at the preceding visits. While this study was not powered for inferential statistical comparisons between treatment groups, the high clinical/microbiologic response rates observed were consistent with studies of ceftazidime–avibactam conducted in adult patients with cUTI.10,11,16

The most common pathogen isolated was E. coli, which is in line with expectations for patients with cUTI.1,9,17 Favorable per-pathogen microbiologic response at TOC was 86.5% for ceftazidime–avibactam-treated patients with an E. coli isolate at baseline, including patients with ceftazidime- and cefepime-non-susceptible pathogens (ME analysis set). These findings are also similar to those from adult patients with cUTI.10,11 Of note, there were no cases of Pseudomonas in the study. This suggests that the infections were predominantly community acquired in healthy individuals, who had not received extensive antibiotic pretreatment.18

In the present study, 2 children in the ceftazidime–avibactam group and 1 in the cefepime group had a ceftazidime- and cefepime-non-susceptible pathogen isolated at baseline. Observations from adult studies have previously demonstrated the ability of avibactam to restore the activity of ceftazidime against extended-spectrum β-lactamase-producing ceftazidime-non-susceptible pathogens in a clinical setting.10,11,16 Of note, in a recent systematic review and meta-analysis, the prevalence of extended-spectrum β-lactamase-producing Enterobacteriaceae in 7374 pediatric patients with cUTI was found to be 14%, with vesicoureteral reflux and history of prior UTI identified as risk factors.19 Anatomical abnormalities represent a risk factor for recurrent or more complicated infections in general.20 Four patients in the current study demonstrated clinical relapse at LFU and, of these, 3 were reported to have both underlying urologic abnormalities and complicating factors. Furthermore, of the 3 patients in the ceftazidime–avibactam group with emergent infections, 2 had both underlying urologic abnormalities and complicating factors. Of note, no persistent infections with increasing MIC were seen in this study.

AEs of UTI were reported in 5 (7.5%) children in the ceftazidime–avibactam arm and no patients in the cefepime arm, cystitis in no patients in the ceftazidime–avibactam arm and 1 (3.6%) in the cefepime arm, and pyelonephritis acute in 2 (3.0%) in the ceftazidime–avibactam and 1 (3.6%) in the cefepime arm. In line with Good Clinical Practice, AEs were recorded by investigators regardless of suspected causality; therefore, it was possible for a child with high risk of recurrent UTI to have a subsequent episode within the follow-up period and for this to be recorded as an AE of UTI, cystitis or pyelonephritis acute. As AEs were captured until end of LFU, AE/SAEs classified as UTI, cystitis or pyelonephritis acute could reflect either relapse or a new infection with a new pathogen. Importantly, no AE/SAEs of UTI, cystitis or pyelonephritis acute were considered related to the study drug.

Although this small study was not powered for inferential statistical comparisons between treatment groups, the safety findings in children with cUTI extend the previous determination of the safety profile of ceftazidime–avibactam in adult patients.10,11,16 The safety collection and analysis conducted in this study was appropriate for a phase 2 pediatric study, and the methodology for this was a standard approach to investigation of infections in children.21,22 It is well recognized that most randomized controlled trials are too small to be able to provide more than observational safety data; to be powered for statistical analysis of safety, studies generally require several thousand patients in each arm, and this would still not be sufficiently large for analysis of more rare AEs.23

Population pharmacokinetic modeling for the estimation of pharmacokinetic parameters and probability of pharmacokinetic/pharmacodynamic target attainment are ongoing and will be reported separately.

In addition, alongside the current study in pediatric cUTI patients, the recently completed prospective, randomized phase 2 study in children with cIAI will provide further insight regarding the role of ceftazidime–avibactam in pediatric patients (NCT02475733).24

In conclusion, the safety findings from this study in children with cUTI extend the previous determination of the safety profile of ceftazidime–avibactam in adult patients. Ceftazidime–avibactam was well tolerated, with a safety profile consistent with ceftazidime monotherapy in pediatric patients. Ceftazidime–avibactam appeared effective in the treatment of pediatric cUTI caused by Gram-negative pathogens, with favorable clinical and microbiologic response rates observed against the predominant cUTI pathogen (E. coli), including ceftazidime-non-susceptible isolates. Ceftazidime–avibactam may therefore offer physicians a valuable treatment option in the initial treatment of children with cUTI caused by susceptible pathogens in an era of increasing prevalence of MDR Gram-negative pathogens.

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Acknowledgments

The authors thank the patients and families involved in this study. The authors also thank Rodrigo Mendes, Mariana Castanheira, Leah N. Woosley and Timothy B. Doyle of JMI Laboratories for sequencing of the molecular characterization data. Medical writing support was provided by Melanie More and Mark Waterlow of Prime, Knutsford, Cheshire, United Kingdom, funded by Pfizer. Ultimate responsibility for opinions, conclusions and data interpretation lies with the authors.

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REFERENCES

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Keywords:

ceftazidime–avibactam; cefepime; pediatric; complicated urinary tract infection; phase 2

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