Complicated intra-abdominal infections (cIAIs) are serious bacterial infections extending beyond the bowel wall into the peritoneal space and are associated with significant morbidity and mortality.1,2 In children, cIAIs frequently arise from acute appendicitis and are caused by mixed aerobic/anaerobic enteric flora.3 The most common pathogens in children with cIAI are similar to those reported in adults4,5 and include Enterobacteriaceae, particularly Escherichia coli, as well as Pseudomonas aeruginosa, facultative anaerobes and Gram-positive cocci.6,7 Prompt surgical intervention, usually with percutaneous or surgical drainage, and initiation of appropriate antimicrobial therapy against the etiologic pathogens are essential to improve patient outcomes.2
β-lactam antibiotics are widely used for the treatment of Gram-negative infections including cIAI. However, their usefulness for empiric therapy has been significantly reduced by the increasing incidence of infections caused by β-lactam-resistant pathogens.2,8 Treatment options for multidrug-resistant Gram-negative infections are becoming increasingly limited, and there is a need for new, safe and effective treatment options.9–11
Avibactam is a non-β-lactam β-lactamase inhibitor that exhibits broad-spectrum inhibition of clinically relevant class A, C and some class D serine β-lactamases, including extended-spectrum β-lactamases, AmpC cephalosporinases and Klebsiella pneumoniae serine-carbapenemases, but not metallo-β-lactamases.12–14 In combination, avibactam restores ceftazidime efficacy against most ceftazidime-non-susceptible Gram-negative pathogens.15,16
Ceftazidime-avibactam plus metronidazole is effective and well tolerated in adults with cIAI caused by Gram-negative pathogens, and has demonstrated activity against many ceftazidime-non-susceptible β-lactamase-producing strains.4,5,15,16 In addition, ceftazidime-avibactam plus metronidazole has been shown in adult phase 3 studies to be noninferior to meropenem in patients with cIAI,4,5 and is approved for this indication in adults in Europe and the United States.17,18
Ceftazidime, a β-lactam that has been in clinical use for several decades, is well tolerated in children with Gram-negative infections19 and is approved for the treatment of bacterial infections across multiple body sites, including cIAI in children.20,21 In addition, contemporary surveillance data have shown potent in vitro activity of ceftazidime-avibactam against Enterobacteriaceae isolates obtained from children, including E. coli, and P. aeruginosa isolates.22 Therefore, pediatric intra-abdominal infections, including complicated appendicitis, provide an opportunity to assess the safety and efficacy of ceftazidime-avibactam in children with serious bacterial infections caused by Gram-negative pathogens, including ceftazidime-non-susceptible isolates.
The pharmacokinetics, safety and tolerability of a single dose of ceftazidime-avibactam have been investigated in a phase 1 study of children (≥3 months to <18 years), hospitalized with an infection and receiving systemic antibiotic therapy.23 However, safety and efficacy of ceftazidime-avibactam in children with cIAI have not been evaluated previously. The current study was conducted as part of the global clinical development program for ceftazidime-avibactam, which included postapproval commitments to regulatory authorities in the United States and Europe to conduct a study of ceftazidime-avibactam plus metronidazole in pediatric patients with cIAI to support extension of the current labeled indication for ceftazidime-avibactam plus metronidazole in adults to pediatric patients with cIAI.24,25
MATERIALS AND METHODS
Study Design and Treatment
This phase 2, single-blind, randomized, multicenter, active-controlled study (NCT02475733) was designed to evaluate the safety, tolerability, descriptive efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole versus meropenem in children diagnosed with cIAI (extension of infection through the appendix/bowel wall with evidence of peritonitis).
Infants and children (≥3 months to <18 years), who by judgment of the investigator required hospitalization and intravenous (IV) antibacterial therapy for cIAI, were enrolled either preoperatively or within 24 hours of surgical intervention. Preoperative study enrollment included patients requiring surgical intervention (laparotomy, laparoscopy or percutaneous drainage) for cIAI within 24 hours of enrollment, with evidence of a systemic inflammatory response and physical findings consistent with intra-abdominal infection (IAI).
Intraoperative/postoperative study enrollment <24 hours after the time of incision required visual confirmation of IAI with associated peritonitis and a diagnosis of appendiceal perforation, periappendiceal abscess, traumatic perforation of the intestines (operated on >12 hours after perforation) and/or secondary peritonitis.
Children were not to be included if they were unlikely to survive the 6–8 week study period or respond to 7–15 days of treatment with antibiotics, were known to have had cIAI caused by pathogens resistant to either study drug, received nonstudy systemic antibacterial drugs for the treatment of cIAI for >24 hours during 72 hours before the first IV study drug administration, and/or they had a creatinine clearance <30 mL/min/1.73 m2 (see Text, Supplemental Digital Content 1, http://links.lww.com/INF/D511 for complete inclusion and exclusion criteria).
This study was undertaken in accordance with good clinical practice guidelines and the Declaration of Helsinki. Written informed consent was obtained before screening from parents/caregivers, and the patient if appropriate. Independent ethics committees and/or institutional review boards approved the final study protocol.
Children were randomized 3:1 to receive IV ceftazidime-avibactam plus metronidazole or meropenem every 8 hours (see Figure, Supplemental Digital Content 2, http://links.lww.com/INF/D512 for dosage regimens). Metronidazole was administered ≤30 minutes after ceftazidime-avibactam for coverage of anaerobic pathogens. Minimum IV study treatment duration was 72 hours (9 doses of either drug regimen), with optional switch to oral therapy thereafter at the investigators’ discretion. Oral therapy comprised amoxicillin/clavulanic acid, ciprofloxacin plus metronidazole or other pathogen culture-based therapy (subject to local guidelines, administered per standard of care). Total treatment duration (IV ± optional oral switch) was to be 7–15 days. Open-label vancomycin, linezolid or daptomycin were permitted for coverage of Gram-positive pathogens (Enterococcus spp. or methicillin-resistant Staphylococcus aureus [MRSA]) at the investigators’ discretion.
Randomization was stratified by age across 4 cohorts: 12 to <18 years; 6 to <12 years; 2 to <6 years and 3 months to <2 years.
The primary objective was to evaluate the safety and tolerability of ceftazidime-avibactam plus metronidazole versus meropenem, in the safety analysis set (all randomized patients who received any amount of IV study drug). Safety and tolerability data were captured from the time of informed consent up to the late follow-up (LFU) visit (20–35 days after the last dose of IV or oral study drug) and included assessment of adverse events (AEs), vital signs, physical examination, laboratory parameters, creatinine clearance (estimated using the bedside Schwartz formula26) and electrocardiogram data (Table, Supplemental Digital Content 3, http://links.lww.com/INF/D513). 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 investigational site determined AE causality.
Evaluation of clinical and microbiologic outcomes to provide a descriptive estimate of efficacy was an important secondary objective. Efficacy assessments included clinical response and microbiologic response at each study visit: end of 72 hours of treatment, end-of-IV therapy (EOIV), end-of-treatment, test-of-cure (TOC) visit (8–15 days after the last dose of study drug) and LFU visit.
Clinical outcomes were assessed by a site-specific blinded observer as clinical improvement (end of 72 hours and EOIV visits only), clinical cure, clinical failure or indeterminate (defined in Table, Supplemental Digital Content 4, http://links.lww.com/INF/D514), and were evaluated in the intent-to-treat (ITT), microbiologic-ITT (micro-ITT), clinically evaluable and microbiologically evaluable analysis sets (defined in Table, Supplemental Digital Content 5, http://links.lww.com/INF/D515) at each study visit.
Intra-abdominal fluid/tissue samples were collected at the time of surgical intervention (laparatomy, laparoscopy or percutaneous drainage) for aerobic and anaerobic culture at baseline and as clinically indicated up to the LFU visit for identification of etiologic pathogen(s). Gram-negative isolates meeting phenotypic criteria suggestive of the presence of a β-lactamase enzyme underwent further genotypic characterization (See Text, Supplemental Digital Content 6, http://links.lww.com/INF/D516).
Per-patient and per-pathogen microbiologic outcomes (defined in Table, Supplemental Digital Content 7, http://links.lww.com/INF/D517) in the micro-ITT and microbiologically evaluable analysis sets were assessed with respect to the pathogen(s) isolated at baseline as favorable (eradication/presumed eradication), unfavorable (persistence/presumed persistence/persistence with increasing minimal inhibitory concentration [MIC]) or indeterminate.
Blood samples (1 mL per sample for cohorts 1 and 2, and 0.5 mL per sample for cohorts 3 and 4) for determination of plasma concentrations of ceftazidime and avibactam were collected on Day 3 from ceftazidime-avibactam plus metronidazole-treated patients (pharmacokinetic analysis set).
As the study was not powered for inferential statistical comparisons between treatment groups, descriptive statistics were used to summarize all variables. The sample size calculation is described in the supplementary methods (see Text, Supplemental Digital Content 8, http://links.lww.com/INF/D518).
Between August 2015 and June 2017, 83 patients from 10 countries (see Table, Supplemental Digital Content 9, http://links.lww.com/INF/D519) were randomized and received any amount of IV study drug (Fig. 1), and comprised the safety analysis set (ceftazidime-avibactam plus metronidazole, n = 61; meropenem, n = 22). Among these 83 patients, 79 (95.2%) completed IV study treatment (Fig. 1).
Across all cohorts, the median (range) exposure to IV study drugs was 7 (2–13) days for both treatment groups. Overall, 69% and 68% of children in the ceftazidime-avibactam plus metronidazole and meropenem study arms, respectively, switched to oral therapy. The median (range) duration of total therapy (IV ± optional oral therapy) was 12 (2–17) and 13 (6–20) days for the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively; the majority (67/83 [72.3%]) of children across both groups received 8–15 days of IV ± optional oral therapy, consistent with the protocol recommended treatment duration of 7–15 days (IV ± oral therapy combined). Durations of exposure for IV-only and IV ± optional oral therapy are summarized in the Figure, Supplemental Digital Content 10, http://links.lww.com/INF/D520). Three of 61 (4.9%) patients in the ceftazidime-avibactam plus metronidazole group received vancomycin for coverage of Gram-positive pathogens as allowed per protocol.
Baseline patient characteristics are presented in Table 1. The mean age across cohorts was 10.3 years for both treatment groups. Most patients (88% [73/83]) were randomized to cohorts 1 and 2 (6 to <18 years); only 1 child (age 21 months; meropenem group) was randomized to cohort 4. In the ceftazidime-avibactam plus metronidazole group, most patients were male (72.1% [44/61]), whereas in the meropenem group there were slightly more females (59.1% [13/22]) than males. Otherwise, baseline characteristics were generally similar across treatment groups. Approximately, 90% (75/83) of children had appendicitis at screening and in 86.7% (72/83) cIAI was confirmed to be associated with appendiceal perforation or periappendiceal abscess.
Overall, 69/83 (83.1%) randomized patients had an etiologic cIAI pathogen isolated from the baseline culture and comprised the micro-ITT analysis set (ceftazidime-avibactam plus metronidazole, n = 50; meropenem, n = 19). From these 69 children, the most frequently isolated Gram-negative baseline pathogens were E. coli (79.7% [55/69]) and P. aeruginosa (33.3% [23/69]) (see Table, Supplemental Digital Content 11, http://links.lww.com/INF/D521). Gram-positive pathogens were isolated from 37/69 (53.6%) patients in the micro-ITT analysis set, most frequently Streptococcus anginosus (47.8% [33/69]; see Table, Supplemental Digital Content 11, http://links.lww.com/INF/D521emental). Anaerobic pathogens were isolated from 36 (52.2%) children in the micro-ITT analysis set, most commonly Bacteroides fragilis (21/69 [30.4%]). In total, 52 (75.4%) children in the micro-ITT analysis set had polymicrobial infections (Gram-negative and/or Gram-positive aerobes and/or anaerobes): 35/50 (70.0%) and 17/19 (89.5%) children in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Overall, 9/69 children had mixed Gram-negative and Gram-positive aerobic infections: 6/50 (12.0%) and 3/19 (15.8%) in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively.
All Gram-negative baseline pathogens were susceptible in vitro to both ceftazidime-avibactam and meropenem based on Food and Drug Administration and Clinical and Laboratory Standards Institute (CLSI) interpretative criteria.18,27,28 Two patients in the ceftazidime-avibactam plus metronidazole group and none in the meropenem group had ceftazidime-non-susceptible E. coli isolates at baseline, as determined by CLSI criteria (MIC > 4 mg/L).27
In the safety analysis set, 32/61 (52.5%) children in the ceftazidime-avibactam plus metronidazole group and 13/22 (59.1%) children in the meropenem group experienced ≥1 treatment-emergent AE (Table 2). The most common AEs in the ceftazidime-avibactam plus metronidazole group were vomiting (14.8%), infusion site phlebitis (6.6%) and seroma (4.9%). Vomiting, cough and abdominal pain (each occurring in 9.1% of children) were the most common AEs in the meropenem group. The majority of AEs reported were of mild intensity; 4/61 children (6.6%) in the ceftazidime-avibactam plus metronidazole group and 1/22 (4.5%) child in the meropenem group experienced ≥1 severe AE. None of the reported severe AEs were considered related to study drug by the blinded observer and all resolved. There were no specific AEs of either moderate or severe intensity reported in >1 child. One child in the ceftazidime-avibactam plus metronidazole group (who experienced moderate vomiting) and 2 in the meropenem group (1 with mild vomiting and moderate nausea and 1 with mild rash) had AEs assessed by the blinded observer as potentially drug related; all of these AEs resolved.
Serious AEs were reported in 5 children (8.2%) and 1 child (4.5%) in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively (Table 2); none occurred in more than 1 patient and none was considered study drug related by the blinded observer. There were no cases of Clostridium difficile infection or serious hypersensitivity/anaphylaxis reactions identified during this study. Furthermore, there were no deaths or discontinuations of study drug due to an AE (Table 2).
Analyses of other safety variables (electrocardiogram, physical examination, vital signs and laboratory parameters) revealed no trends or safety signals. Observed changes from baseline during the study were considered clinically insignificant and/or consistent with the underlying illness. Two patients in the ceftazidime-avibactam plus metronidazole group had potentially clinically significant postbaseline elevated platelet concentrations (2.4 and 2.6 × upper limit of normal [ULN]), 1 had elevated alanine aminotransferase (4 × ULN) and 1 had elevated aspartate aminotransferase (3.3 × ULN) at the EOIV visit. Furthermore, 1 patient receiving total parenteral nutrition had decreased serum calcium levels (0.62 × lower limit of normal) on Day 7 and at the EOIV visit. None of these postbaseline abnormalities were reported as AEs and all normalized or had started to normalize by the TOC visit. Two patients (1 from each treatment group) had a postbaseline positive Coombs seroconversion test result at the TOC visit; there was no evidence of hemolytic anemia in either case.
In both treatment groups, per-patient favorable clinical and microbiologic response rates were ≥90% across all analysis sets early in the course of treatment and were sustained through to the TOC visit (Table 3). There were no clinical relapses at the LFU visit and no emergent infections throughout the study duration in either group. As collection of intra-abdominal cultures requires an invasive procedure, postbaseline cultures were obtained only if clinically indicated (ie, follow-up surgical procedure). Thus, for most patients, microbiologic outcomes were presumed based on clinical outcome. Accordingly, per-patient microbiologic response rates in the micro-ITT analysis set were identical to the per-patient clinical responses at each time point.
Two children in the ceftazidime-avibactam plus metronidazole group and none in the meropenem group had cIAI due to ceftazidime-non-susceptible E. coli, as determined by CLSI criteria (MIC > 4 mg/L).27 One isolate with a ceftazidime MIC of 16 mg/L (ceftazidime-avibactam MIC of 0.12 mg/L) from a patient in Taiwan expressed TEM-1 (class A β-lactamase) and CMY-2 (a plasmidic AmpC) enzymes. The other isolate with a ceftazidime MIC of 32 mg/L (ceftazidime-avibactam MIC of 0.12) from a patient in Turkey expressed CTX-M-15 extended-spectrum β-lactamase. Both of these children were treated successfully with ceftazidime-avibactam.
Two ceftazidime-avibactam plus metronidazole-treated children had bacteremia at baseline, one due to E. coli and one due to P. aeruginosa; clinical/microbiologic outcomes at TOC for these patients were favorable and indeterminate, respectively.
Only 1 child, who had a polymicrobial infection (including Bacteroides caccae, B. fragilis, Clostridium ramosum, Eggerthella lenta, E. coli and S. anginosus group), discontinued ceftazidime-avibactam plus metronidazole treatment at the end of 72-hour assessment due to lack of therapeutic response.
In the micro-ITT analysis set, favorable per-pathogen microbiologic response rates at TOC among baseline Enterobacteriaceae isolates were 90.5% (38/42) and 92.9% (13/14) in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively (Table 4). Similarly, among P. aeruginosa isolates at baseline, 85.7% (12/14) and 88.9% (8/9), respectively, had a favorable microbiologic response. Per-pathogen favorable microbiologic response rates among Gram-positive and anaerobic pathogens exceeded 91% in both treatment groups (Table 4).
Of note, 4 patients in the ceftazidime-avibactam plus metronidazole group had polymicrobial infections including Enterococcus spp. isolates, but did not receive concomitant therapy against Enterococcus spp. yet experienced a favorable clinical response from the end of 72-hour visit through the TOC visit, suggesting that surgical drainage and study drug treatment of their susceptible Gram-negative pathogens allowed clearance of the enterococcal infection in the absence of targeted therapy for this organism.
Median plasma concentrations for ceftazidime and avibactam were similar across age cohorts 1–3 (Fig. 2). No patients from cohort 4 received ceftazidime-avibactam; therefore, no plasma concentration data are available for this age group.
This is the first prospective, randomized study to evaluate the safety, tolerability and efficacy of ceftazidime-avibactam in hospitalized children with invasive bacterial infections, specifically cIAI. No clinically relevant safety findings for ceftazidime-avibactam plus metronidazole among pediatric patients were identified in this study population. The most commonly reported AEs of any severity were vomiting (14.8%), infusion site phlebitis (6.6%) and seroma (4.9%; ceftazidime-avibactam plus metronidazole) and vomiting, cough and abdominal pain (each occurring in 9.1% of children; meropenem). The pattern of AEs was as expected for the disease under study, and/or the established safety profile of the study therapies in adult and pediatric patients.4,5,15,16,19,29 Moreover, no children discontinued IV study drug due to an AE. Although differences in the clinical presentation of cIAI and underlying comorbidities may limit the direct comparison of adult and pediatric AE data, the overall safety profile of ceftazidime-avibactam in the current trial was consistent with that reported in the pivotal phase 3 randomized RECLAIM clinical trial in adults with cIAI: 52.5% of pediatric and 45.9% of adult patients treated with ceftazidime-avibactam plus metronidazole experienced any AE, and 8.2% and 7.9%, respectively, experienced a serious AE.5
Avibactam is known to be associated with phlebitis (identified from animal data).17 The addition of avibactam in the ceftazidime-avibactam phase 3 clinical development program in adult patients did not result in a clinically significant increase in the phlebitis as known to be associated with ceftazidime.4,5,15,30,31 Of note, an increased risk of infusion site phlebitis has been reported for a variety of drugs administered using peripheral IV catheters as the number of IV infusions increases;32 children receiving ceftazidime-avibactam plus metronidazole in this study received twice the infusions of the comparator; however, the numbers of patients were too small to more fully assess whether this increased the risk of phlebitis. Over the course of the study, 4 children in the ceftazidime-avibactam plus metronidazole group experienced 5 cases of infusion site phlebitis that were temporally related to study drug infusion. However, none of these resulted in discontinuation of therapy and the overall observed frequency was in line with that expected for ceftazidime monotherapy in adults and children.20
Collectively, safety data from the study indicate that ceftazidime-avibactam plus metronidazole is well tolerated with a safety profile consistent with that observed in adult patients with cIAI and for ceftazidime monotherapy in pediatric and adult patients.
The type and distribution of Gram-negative pathogens isolated (predominantly E. coli and P. aeruginosa) were as expected for pediatric patients with cIAI and appendicitis.6,7 In line with the polymicrobial nature of cIAI, approximately 75% of patients in the micro-ITT analysis set were found to be infected with 2 or more pathogens, with most of the polymicrobial infections being with 2 or more Gram-negative species.
The overall favorable clinical/microbiologic response rates at EOIV and TOC were ≥90% for patients receiving either ceftazidime-avibactam plus metronidazole or meropenem across all visits, and notably, responses were sustained at the LFU visit. Likewise, per-pathogen microbiologic response rates at TOC for the predominant pathogens (E. coli and P. aeruginosa) paralleled the overall results. While the study was not powered for inferential statistical comparisons between treatment groups, these data suggest that ceftazidime-avibactam plus metronidazole was effective in the treatment of cIAI in children, similar to meropenem. Again taking into consideration methodologic differences between trials (eg, timing of assessment and definitions of analysis sets) as well as differences between adult and pediatric cIAI patients, the findings from the current study are consistent with the pivotal phase 3 RECLAIM trial in adults with cIAI, which reported noninferiority of ceftazidime-avibactam plus metronidazole versus meropenem based on the Food and Drug Administration-specified 10% noninferiority margin for the difference in clinical cure rates at TOC, with clinical cure rates at TOC of 81.6% and 85.1%, respectively, in the microbiologically modified ITT population.5
Two children were infected by ceftazidime-non-susceptible E. coli at baseline and responded to ceftazidime-avibactam plus metronidazole treatment. Although limited in number, the favorable outcomes observed for these 2 patients offer supportive clinical evidence for pathogens that are ceftazidime-avibactam susceptible, but are ceftazidime-resistant, echoing observations in adult studies which demonstrate the efficacy of ceftazidime-avibactam against these target pathogens of interest.4,5,15,16 The high clinical/microbiologic response rates observed in this study paralleled results from the adult phase 3 cIAI studies of ceftazidime-avibactam plus metronidazole, which reported high favorable clinical/microbiologic response rates against Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, K. oxytoca and P. aeruginosa, including ceftazidime-nonsusceptible strains.4,5,15
Unfortunately, no patients receiving ceftazidime-avibactam plus metronidazole were enrolled into cohort 4, reflecting the epidemiology of cIAI in this very young age group (3 months to <2 years); thus, clinical data for ceftazidime-avibactam in the youngest patients are limited to the safety and pharmacokinetic (PK) data previously reported.23 Of note, a phase 2 study of ceftazidime-avibactam in pediatric patients with cUTI (NCT02497781) was recently completed and should provide additional information on the clinical experience of ceftazidime-avibactam in pediatric patients across all age cohorts.33
Mean plasma concentrations for ceftazidime and avibactam were consistent across cohorts, suggesting that the age- and/or weight-based dose adjustments for ceftazidime-avibactam used in this study were appropriate for the population studied. Further population pharmacokinetic modeling for estimation of pharmacokinetic parameters and probability of pharmacokinetic/pharmacodynamic target attainment are ongoing and will be separately reported.
In conclusion, results of this phase 2 randomized study extend the prior evidence of safety and efficacy for ceftazidime-avibactam plus metronidazole in the treatment of adult patients with cIAI, to children. Ceftazidime-avibactam plus metronidazole was well tolerated in children with cIAI; safety observations were consistent with the established safety profiles of ceftazidime monotherapy and/or metronidazole in children as well as ceftazidime-avibactam in adults. Likewise, ceftazidime-avibactam plus metronidazole appeared effective in the treatment of pediatric cIAI caused by the predominant aerobic and anaerobic pathogens, including ceftazidime-non-susceptible Gram-negative pathogens. In the context of the increasing prevalence of multidrug-resistant Gram-negative pathogens in children, ceftazidime-avibactam represents a potential new treatment option.
The authors would like to thank the patients and their families, as well as the study coordinators responsible for screening and assisting in the successful completion of this study, including the development of this manuscript, and Sara Hingtgen, RN, MSN, for her input throughout the study duration. The authors also thank all the study investigators who are listed below and JMI for sequencing the molecular characterization data, in particular Rodrigo Mendes, Mariana Castanheira, Leah N. Woosley and Timothy B. Doyle. Medical writing support was provided by Jade Murdoch, MChD, and Mark Waterlow, BSc, CMPP, of Prime, Knutsford, Cheshire, funded by Pfizer. Ultimate responsibility for opinions, conclusions and data interpretation lies with the authors.
The study group investigators are as follows: Argentina: German Ambasch, Angel Minguez, Gonzalo Perez Marc; Chile: Tamara Viviani Salgado, Elba Wu Hupat; Czech Republic: Jiri Biolek, Martin Gregora, Michal Hladik, Rene Hrdlicka, Pavel Mokros, Martin Prchlik, Josef Sykora; Greece: Georgios Tsikopoulos, Alexander Passalides, Athanasios Michos, Garyfallia Syridou; Hungary: Csaba Bereczki, Ferenc Dicso, Marta Nad, Gyorgy Oroszlan, Gabor Simon, Zsuzsanna Korponay, Gergely Toth, Lajos Suranyi, Peter Vajda; Poland: Pawel Nachulewicz, Bartosz Korczowski, Anna Piaseczna Piotrowska; Romania: Eugen Boia, Otilia Marginean, Aurel Mironescu, Constantin Tica, Carmen Ciongradi, Horea Gozar; Russian Federation: Antonina Zuzova, Irina Khodareva; Spain: Maria Mendez, Emilio Monteagudo, Jose Ramos Amador, Ana Jimenez, Claudia Fortuny Guasch; Taiwan: Chia Man Chou, Hsin Chi, Yung Feng Huang; Turkey: Mustafa Celen, Omer Yilmaz, Eda Kadayifci, Derya Alabaz, Nuran Salman, Ener Dinleyici; United States: Norma Perez, Coburn Allen, Delma Nieves, Claudia Espinosa, Roger Barton, Jagmohan Batra, Jeffrey Blumer, John Bradley, Yvonne Bryson, Graham Krasan, Yi Horng Lee, Patricia DeLaMora, David Di John and Shawn St. Peter.
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