A recent analysis reported that of 6.3 million children who died before age 5 years in 2013, just over half died from infectious causes.1 Because of the spread of antibiotic-resistant bacteria, a continued need exists for therapies effective against multidrug resistant (MDR) organisms, including among children and newborns, where MDR Klebsiella spp., Acinetobacter spp. and Escherichia coli cause significant morbidity and mortality.2 Cystic fibrosis studies demonstrate growing rates of MDR infections caused by Pseudomonas aeruginosa, Staphylococcus aureus, Bulkholderia species, Stenotrophomonas maltophilia3 and rapid-growing mycobacteria.
Tigecycline, a semisynthetic tetracycline, has demonstrated antibacterial activity across a broad spectrum of Gram-positive, Gram-negative, anaerobic and atypical bacteria (Summary of Product Characteristics and the US Prescription Information).4,5 In the United States, tigecycline (Tygacil) was approved by the US Food and Drug Administration (FDA) for complicated skin and skin-structure infections (cSSSI), complicated intra-abdominal infections (cIAI) and community-acquired bacterial pneumonia (CAP) for patients 18 years of age and older.5 The European Medicines Agency (EMA)-approved Summary of Product Characteristics states that tigecycline is indicated in adults and children from the age of 8 years for treatment of cIAI and complicated skin and soft-tissue infections (cSSTI), with the exception of diabetic foot infections.4
A mortality imbalance in adults has been demonstrated in meta-analyses of phase 3 and phase 4 active controlled tigecycline clinical trials in adults. This is reflected in tigecycline labels, and should be considered when contemplating pediatric use. Also, tigecycline is not generally recommended in patients <8 years because of potential effects on tooth development, a class effect of tetracyclines, although clearly the risk–benefit ratio needs to be considered when treating MDR infections. The product label indicates tigecycline should be avoided in patients <18 years old unless no alternatives are available.5 Proposed pediatric dosing recommendations have been developed through simulations comparing therapeutic target attainment of twice daily doses ranging from 0.75 to 1.25 mg/kg. These simulations were based upon pharmacokinetic (PK) data from children,6 and exposures in adults enrolled in phase 2 and 3 trials.7,8
In the European Union (EU), the Pediatric Committee accepted limited tigecycline clinical data to support a pediatric indication (for children from the age of 8 years) based on the limited therapeutic options available and the obvious unmet clinical needs. This resulted in a restricted pediatric indication for tigecycline to treat cSSTI and cIAI by the EMA only in situations in which other antibiotics are not suitable.
The restricted pediatric indication was based on the recent Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections,9 which provides approval guidelines for medications with limited pediatric clinical data for treatment of infections caused by MDR organisms for which there are few therapeutic options. Of note, Mycobacterium is not listed in the tigecycline European label. However, rapid-growing mycobacteria are included in in vitro activity in the US label. Clinical Mycobacterium infections treated with tigecycline are described.10
Although there are currently no plans for further pediatric clinical trials, it was recognized that therapeutic options to treat MDR infections in children are limited, and tigecycline is used off-label by clinicians. This report provides comprehensive information on tigecycline use in pediatrics, specifically with regard to available clinical data (including PK and safety information) and clinical use (real-world/outcomes data and reporting), both on-label and off-label.
Available data were identified from published and unpublished sources including clinical trials, expanded access and compassionate use programs, healthcare record databases and patient safety monitoring. This information was summarized and presented here.
A phase 1 ascending single dose study (Study P110) enrolled 24 children age 8–16 years (Table 1), recently recovered from infections. A single dose of tigecycline was administered to 3 dose groups: 0.5 mg/kg (maximum of 50 mg), 1 mg/kg (maximum of 100 mg) and 2 mg/kg (maximum of 150 mg) administered intravenously over 30 minutes. Sampling for PK analyses occurred before and at 0.5, 0.75, 1, 2, 4, 8, 12, 24, 36 and 48 hours after dose administration. As with adults, a distinctively 2-compartment concentration-time curve was observed. The PK parameters were similar to those seen in adults, but with wider intersubject variability. Renal clearance was low compared with the total clearance (9.8%–39%).
A phase 2 ascending multiple-dose study (Study 2207) in 58 children (age 8–11 years) included evaluation of steady-state PK parameters6 (Table 1). Children with serious infections (cIAI, cSSSI or CAP) received tigecycline 0.75, 1 or 1.25 mg/kg (maximum of 50 mg) every 12 hours (q12h) intravenously over 30 minutes. The PK parameters were consistent with those observed in the single-dose study and similar to adults with the exception of higher weight-normalized clearance in the younger children. PK data from both pediatric studies were combined to develop a population PK model; only body weight was found to be a significant covariate of tigecycline plasma clearance (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000644/WC500191296.pdf).
In early development, the most informative PK/pharmacodynamic efficacy parameter for tigecycline was the ratio of area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) and was identified in a preclinical model as well as in adults with cSSSI and cIAI.7,8,11 Therefore, assuming bacteria causing infections in children will respond similarly to tigecycline as in adults (ie, assuming similar MICs for both patient groups), it is reasonable to expect similar efficacy in children administered a dose regimen that provides exposure (AUC) that matches the AUC in adults successfully treated. PK/pharmacodynamic simulations evaluated dosing regimens in children and used PK data from the studies in children, available data from adults who had participated in phase 2 and 3 clinical trials and microbiologic data from the Tigecycline Evaluation Surveillance Trial (now part of the Antimicrobial Testing Leadership And Surveillance program: https://atlas-surveillance.com) that was available at the time (2009). Regimens of 1.2 mg/kg (maximum dose 50 mg) q12h in children 8–11 years and 50 mg q12h in children 12 to <18 years were predicted to achieve AUC, and thus AUC/MIC values were similar to adults receiving 50 mg q12h.
A similar clinical efficacy has been observed between adults and children treated with tigecycline.
This study described above was a phase 2, open-label, multicenter study that enrolled 58 children with cSSTI, cIAI and CAP.6 Enrollment was permitted in only 1 dose cohort at a time and enrollment in the subsequent cohort was possible only after review of tolerability in the previous dose level. Overall, clinical cure rates at test-of-cure were 94.1% (16/17), 76.2% (16/21) and 75.0% (15/20) in the 0.75-, 1- and 1.25-mg/kg cohorts, respectively (Table 1).
Compassionate Use Program
A compassionate use program was begun under the auspices of the sponsor’s Clinical Research and Development Department. Available data were obtained from investigating physicians (who also provided narratives) and submitted to the sponsor for compilation and interpretation. In all, 104 adults and children from 15 countries were enrolled. The patient population included 92 adults, 10 with cystic fibrosis. Of the 12 children, 9 had cystic fibrosis (all with mycobacteria), 1 had vasculitis with mycobacteria, 1 had chronic myeloid leukemia with Acinetobacter baumannii and 1 had a sternal wound with A. baumannii (Table 2).
In all pediatric cases (12/104), tigecycline was added after initial failure of other therapies and was used in combination with other agents including macrolides, cephalosporins, penicillins, beta-lactamase inhibitor combinations, aminoglycosides, carbapenems, doxycycline, colistin and linezolid. The therapy duration varied and in some cases was very prolonged. All 12 children survived; 7 achieved clinical improvement, 4 experienced treatment failure and 1 patient had indeterminate response (unpublished data from the compassionate use program) (Table 2). Clinical outcomes could not be attributed to tigecycline alone because numerous antibiotics were used before and concurrent with tigecycline.
Ten of the 12 children who had mycobacteria infection were included, in addition to adult patients from 2 other studies, in a report on the application of tigecycline-containing regimens for salvage treatment of rapidly growing mycobacterial infections; however, no details on these children were described in this report.10
Other Published Reports
Zhu et al12 reported results from a retrospective chart review of 24 children hospitalized with primary or secondary infections and treated with tigecycline; pneumonia was the most common infection (71.4%). The authors found 45.8% of patients had evidence of a response to tigecycline (clinical, microbiologic or both), primarily to infections caused by MDR bacteria. A. baumannii was the most commonly isolated pathogen and was confirmed in 50% of patients. Also, the 5 patients who experienced both clinical and microbiologic responses were infected with A. baumannii. Six patients died because of infection (3) or their primary disease (3), for example, congenital heart disease or hematologic malignancy. The authors noted the contribution of combinations of antibiotics and their synergistic mechanisms of action; tigecycline was most commonly combined with other antibiotics for Gram-negative bacteria. Tigecycline dosing used was considered effective and tolerable: an initial loading dose of 1.5 or 2 mg/kg followed by a maintenance dose of 1 mg/kg/dose q12h.
Similarly, Iosifidis et al13 reported a case series of 13 children (median age 8 years) with MDR infections [5 bacteremias, 6 lower respiratory tract infections and 3 other infections (sepsis, septic thrombophlebitis and cSSTI)]. Pathogens were resistant to most or all antibiotics tested except tigecycline. A loading dose (1.8–6.5 mg/kg) was given (in all but 2 cases), followed by maintenance at 1–3.2 mg/kg q12h. No serious adverse events (AEs) were reported. Among tigecycline-treated patients receiving therapy for ≥5 days, clinical and microbiologic improvement was seen in 7 of 11 (64%) and 4 of 7 (57%) patients, respectively; patients with bacteremia did not benefit from addition of tigecycline (3 of 3 clinical failures and death). In contrast, among 8 nonbacteremic patients who received tigecycline, clinical outcome improved in 7 patients (1 patient died) and only 1 experienced clinical failure and died.
In Study P110, no deaths occurred among the 25 children enrolled. Treatment-emergent AEs (TEAEs) occurred in approximately one-third of children and included headache (8%), nausea (12%) and vomiting (16%). One child had vomiting with associated dehydration, a serious AE that resolved during hospitalization. Another child withdrew because of a mild injection site reaction. All TEAEs were observed in other clinical studies of tigecycline (Table 1).
In Study 2207, no deaths occurred. TEAEs were reported in 44 (75.9%) children with nausea (28, 48.3%) and vomiting (27, 46.6%) being the most frequent. Compared with the 0.75-mg/kg group, significantly more children in the 1.25- and 1-mg/kg groups had nausea (60.0% and 61.9% vs. 17.6%; P = 0.018 and P = 0.009, respectively) and more children had vomiting (55.0% and 52.4% vs. 29.4%; difference was not significant). The majority of nausea and vomiting events were mild to moderate. Three (5.2%) children had serious AEs, 1 with cIAI receiving 0.75 mg/kg of tigecycline, 1 with cSSSI receiving 1 mg/kg of tigecycline and 1 with cSSSI receiving 1.25 mg/kg of tigecycline. Two (3.4%) discontinued tigecycline who were withdrawn because of AEs. In addition, children receiving 0.75 mg/kg of tigecycline defervesced, on average, 2 days later than those in the 1- or 1.25-mg/kg groups, suggesting a delayed response to therapy. No potentially clinically important laboratory results, vital signs or electrocardiograms were identified as medically important. No new or unexpected safety concerns were observed with tigecycline (Table 1).
The Tigecycline Post-Authorization Safety Study (PASS) was an observational cohort study that employed retrospective chart abstraction study design in which prerecorded patient-centered data were reviewed (EU registration number EUPAS3674).14 The study enrolled 777 patients from 13 sites in 5 EU countries (2 sites in Austria, 4 in Germany, 3 in Italy, 2 in Greece and 2 in the United Kingdom). The study primary objectives were: (1) to evaluate the effectiveness of risk minimization measures (RMM) for tigecycline by describing prescription patterns among patients treated with any dose of tigecycline for any indication (on- or off-label) in the EU before and following implementation of RMM and (2) to determine the incidence of superinfection and lack of efficacy among adult patients treated with approved doses of tigecycline for cIAI and cSSTI in the EU before and after implementation of RMM. Pediatric data are summarized in Table 3.
Although the number of children treated in the PASS is small, this study was conducted before the approval of a restricted pediatric indication and further supports the need, albeit infrequent, for tigecycline use in children when other therapies are not suitable. This dataset is notable mostly for: (1) small numbers of children and (2) the types of infections for which tigecycline was used. Although not explicitly stated, the children who received tigecycline might have received it because other therapies failed and/or in vitro activity indicated tigecycline was the only agent with activity.
The Pfizer Global Safety Database collects information from a wide range of sources including patient and healthcare professional reports to Pfizer, clinical trials and safety cases reported in the literature. In 2014, there were 82 pediatric cases (149 events). The mean age was 10.2 years. The most frequently reported AEs were off-label use, vomiting and nausea; all other recorded events occurred in <5% of patients (Table 4). In these patients, tigecycline was used most frequently for Gram-negative and mycobacterial infections (Table 5). In cases where dosage information was available, the majority ranged from 25 to 50 mg q12h, consistent with known PK data and proposed dosing in children.
In addition to the Pfizer Global Safety Database, other sources of data regarding tigecycline use in children include the US FDA MedWatch reporting and healthcare or insurance databases on patient outcomes. Limited pediatric data on tigecycline use can be obtained from sources such as Premier (www.premierinc.com/), Arlington Medical Resources (a Decision Resources Group company, https://decisionresourcesgroup.com/solutions/medtech/) and the Pediatric Health Information System (www.childrenshospitals.org/).
This report summarizes data from a wide range of sources to provide a comprehensive description of pediatric tigecycline use. It describes tigecycline as a treatment for children with serious MDR infections and limited therapeutic options. These datasets have strengths and weaknesses. The data available offer important insights into dosing, PK, tolerability and AE profiles, but lack the breadth of information provided by phase 3 clinical trials. Large healthcare databases include greater patient numbers with diverse geographic representation, but are limited in depth of data and outcomes reporting. Published cases offer detailed patient history and response to treatment but are not randomized and controlled.
Clinical trials conducted in adults used loading doses to achieve therapeutic concentrations quickly. However, clinical studies confirmed AUC was most closely related to efficacy,7,8 and multiple- versus single-dose PK data in adults suggested that the steady-state accumulation was less than that predicted. Thus, a loading dose may not be needed. In an effort to improve tolerability, the pediatric phase 2 study conducted by Purdy et al6 did not include a loading dose.
The need for effective treatments against resistant infections in children, is indicated by the Tigecycline Evaluation Surveillance Trial data collection of pediatric isolates and the clinical use of tigecycline in the Compassionate Use Study, PASS, the Pfizer Global Safety Database and case reports, and is supported by data from Arlington Medical Resources, Premier and Pediatric Health Information System. However, there is no standard method of conducting antibiotic pharmacovigilance, particularly for off-label use and treatment of MDR infections.
Consideration of tigecycline’s PK characteristics may assist clinicians in dosing. Taking into account not only physical but physiologic differences between children and adults in drug absorption, distribution, metabolism and elimination are important.15 The volume of distribution of tigecycline is very large and so differences in body composition in very young children are unlikely to significantly affect drug concentrations. Immaturity of the cytochrome P450 enzymes observed in very young infants would not be expected to alter tigecycline PK as it is not metabolized, but eliminated unchanged in bile, nor would the low glomerular filtration rate and immaturity of tubular excretion, because of the very modest excretion in urine.
More data are needed in children but regulatory and logistical challenges remain. The phase 1 and phase 2 Pfizer clinical trials excluded any child under 8 years of age. This exclusion was necessary due to known tetracycline effects discussed above, and these effects, along with the adult mortality imbalance, preclude further clinical trials in children below 8 years of age. The PASS study also had no child under 8 years of age. Only the compassionate use trial had a single child enrolled under age 8 (3 years of age). In view of this lack of clinical data below age 8 years, the current label language should be followed, and use below age 8 years should be at the discretion of the physician when no other alternative is available, and when the benefits are determined to outweigh the risks. A recent systematic review revealed an urgent need for improved harmonization between EMA and FDA on design and conduct of pediatric antibiotics trials.16 However, further clarity may be forthcoming. For instance, as of 2017, the EMA is developing a draft addendum to the guideline on evaluation of medicinal products indicated for treatment of pediatric bacterial infections (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/04/WC500205026.pdf). Collaboration between pharmaceutical companies and pediatric academic specialty networks (as has occurred with pediatric antiretroviral drug registries) should be explored in the setting of antibiotic treatment of serious MDR infections.
Information presented here may help guide the appropriate use of tigecycline in children with MDR infections. Continued pharmacovigilance from real-world observational studies may also further refine appropriate use of tigecycline in this population. The manufacturer and academic collaborators chose to summarize these data to help advance understanding of tigecycline use in pediatrics, a topic that has attracted much investigation.17 We encourage other companies to undertake similar exercises in situations where studies cannot be conducted, particularly for specific patient populations such as neonates and children.
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 deidentified 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 deidentified 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.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
pharmacokinetics; pharmacovigilance; real-world experience