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