Increasing antibacterial resistance among Gram-negative pathogens is a major concern worldwide that needs to be urgently addressed. Infections caused by drug-resistant Gram-negative bacteria are associated with increased mortality, longer hospital stays, and increased hospital costs.1 The prevalence of these infections, especially due to multidrug-resistant (MDR) Pseudomonas aeruginosa and extended spectrum β-lactamase–producing Enterobacteriaceae, have significantly increased in recent decades.2,3 This trend is also evident in children.4,5 Development of new antibacterial agents, both for adults and children, is necessary to address this unmet medical need.6
Ceftolozane is a novel antipseudomonal cephalosporin that is structurally similar to ceftazidime, common resistance mechanisms (i.e., porin loss and hydrolysis by AmpC).7 The addition of tazobactam, a well-established β-lactamase inhibitor, improves the coverage of ceftolozane to include select extended spectrum β-lactamase–producing Enterobacteriaceae. This β-lactam/β-lactamase inhibitor combination has broad-spectrum activity against Gram-negative pathogens, including many strains of MDR P. aeruginosa.7 Ceftolozane/tazobactam is available for intravenous (IV) use only, exhibits dose-independent linear kinetics, and requires dose adjustment in patients with impaired renal function; of note, there are no pharmacokinetic (PK) interactions between the ceftolozane and tazobactam components.7–10 Safety and efficacy of ceftolozane/tazobactam in adults was demonstrated in large phase 3 trials for treatment of complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI), in which ceftolozane/tazobactam met primary and key secondary efficacy and safety endpoints.11,12
Ceftolozane/tazobactam was first approved in 2014 in the United States for treatment of cUTI (including pyelonephritis) and cIAI (in combination with metronidazole) in adults, at a dose of 1.5 g (1,000 mg ceftolozane with 500 mg tazobactam) via 1-hour infusion every 8 hours.13 It was subsequently approved in the European Union and multiple countries worldwide. The safety and efficacy data obtained thus far in adults support the continued clinical investigation of ceftolozane/tazobactam in children.
Published literature on the PK of antibiotics appropriate for treating MDR Gram-negative infections is scant in children, especially neonates. Multiple PK parameters can be affected by development and maturation processes across the pediatric age spectrum, and the associated anatomical, physiologic, and biochemical changes of growing children.14 Since these differences between children and adults can potentially result in differences in drug exposure linked to microbiologic and clinical outcomes, studies are necessary to determine the PK and safety of new antibiotics in children.14 We, therefore, conducted a phase 1 study to evaluate the PK, safety and tolerability of single IV doses of ceftolozane/tazobactam in children from birth (7 days postnatal) to < 18 years of age and to obtain data that could be incorporated into future pediatric population PK models.
MATERIALS AND METHODS
Protocol MK-7625A-010 was a phase 1, open-label, multicenter study to characterize PK, safety and tolerability of single IV doses of ceftolozane/tazobactam in children with proven/suspected Gram-negative infection or receiving perioperative prophylaxis, conducted at 18 centers in the United States between November 2014 and June 2017 (clinicaltrials.gov NCT02266706). This study was part of a pediatric study plan/pediatric investigation plan developed in conjunction with regulatory agencies. The study was conducted in accordance with principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies.
The age groups defined for this study were (Table 1): group 1 (≥ 12 to < 18 years), group 2 (≥ 7 to < 12 years), group 3 (≥ 2 to < 7 years), group 4 (≥ 3 months to < 2 years), group 5 (birth [7 days postnatal, > 32 weeks gestation] to < 3 months), and group 6 (birth [7 days postnatal, ≤ 32 weeks gestation] to < 3 months). Enrollment began with groups 1–4; groups 5 and 6 were only enrolled after an interim analysis of group 4. Patients from birth (7 days postnatal) to < 18 years of age were eligible for inclusion. Patients needed to be receiving standard-of-care antibiotic therapy for a proven/suspected Gram-negative infection or for perioperative prophylaxis. Estimated glomerular filtration rate (eGFR) was required to be ≥ 80 mL/min/1.73 m2 (groups 1–4), ≥ 50 mL/min/1.73 m2 (group 5), and ≥ 20 mL/min/1.73 m2 (group 6).15 Lower eGFR thresholds were allowed in groups 5 and 6 due to the immature renal function in children < 3 months old, particularly preterm neonates with ≤ 32 weeks gestation. Key exclusion criteria included known allergy/hypersensitivity to any β-lactam antibiotic; planned blood transfusion or receipt of piperacillin/tazobactam within 24 hours of study drug administration; use of medications known to inhibit tubular secretion of renally excreted drugs (such as piperacillin, probenecid, cimetidine, diclofenac, indomethacin, mycophenolate, and olmesartan); and height or weight outside the 5th to 95th percentile.
Treatment and Dose Evaluations
Ceftolozane/tazobactam was administered as single, 60 (±10) minute infusions. The fixed 2:1 ratio of ceftolozane:tazobactam approved in adults was maintained throughout this study. Age-based doses (Table 1) were chosen based on adult PK data, aiming to achieve the exposure levels seen in adults. Since ceftolozane/tazobactam is primarily renally eliminated, initial doses proposed for this study were determined by adapting an adult population PK analysis10 with allometric scaling by body weight and a pediatric renal maturation function16 (data on file). After 3 patients in each age group received the initially selected dose, an interim analysis of PK and safety data were conducted to determine whether the initial dose was appropriate and to adjust the dose if needed, based upon the following criteria:
- Absence of a safety signal, for example, no serious adverse events (SAEs) related to study drug or 2 reports of the same nonserious adverse event (AE) considered to be study drug-related.
- Acceptable ceftolozane PK/pharmacodynamics (PD) exposure defined as the % time of the dosing interval that free concentrations (%fT) were greater than a minimum inhibitory concentration (MIC) of 8 µg/mL.17 This value was selected based on current Food and Drug Administration–approved breakpoints defining resistance as ≥ 8 µg/mL for Enterobacteriaceae and ≥ 16 µg/mL for P. aeruginosa.
- Acceptable safety exposure, that is, area under the concentration-time curve (AUC) approximating the typical AUC observed in healthy adult volunteers and adult patients with cUTI and cIAI, that did not exceed the maximum exposure previously demonstrated to be safe in adults8; no statistical tests were performed due to the small sample size.
Ceftolozane and tazobactam plasma concentrations were measured at MicroConstants, Inc. (San Diego, CA), using a validated high performance liquid chromatographic tandem mass spectrometric method. Plasma samples (20 µl) with internal standards sulbactam and d7-labeled propylchloroformate ceftolozane-derivative were reacted with nonlabeled propylchloroformate to derivatize ceftolozane. Excess reagent was quenched with benzylamine, and samples then underwent solvent extraction. The final extract was analyzed by 2 separate liquid chromatographic tandem mass spectrometric systems: (a) Phenomenex Synergi Max RP analytical column and electrospray-positive ionization for ceftolozane (detectable range, 0.250–150 µg/mL); (b) ThermoPrism RP analytical column and electrospray negative ionization for tazobactam (detectable range, 0.100–60.0 µg/mL). Blood samples (0.5 mL) were collected at 6 of the following time points for groups 1–4: predose, 0.5 h (±5 min), 1 h (end of study drug infusion + 5 min), 2 h (±10 min), 4 h (±10 min), and 6 h (±20 min) after the start of infusion. In groups 5 and 6, blood samples were collected at only the following 3 time points: 1 h (end of study drug infusion + 5 min), 2 h (±10 min), and 6 h (±20 min) after the start of infusion. Blood draw sampling methods (e.g., peripherally inserted central catheter line, indwelling catheter access, individual peripheral phlebotomies, perioperatively placed arterial line, or heel stick) were at the investigator’s discretion.
Ceftolozane and tazobactam PK parameters were determined using noncompartmental methods with WinNonlin Phoenix version 6.30 (Certara, Princeton, NJ). AUC was determined using the linear up/log down trapezoidal rule. The following PK/PD endpoints were evaluated for each group: ceftolozane %fT > MIC of ≥ 30% (for an MIC of 8 µg/mL), that is, free ceftolozane plasma concentration of ≥ 8 µg/mL for at least the first 2.4 hours (30% of an 8 hour dosing interval), and tazobactam %fT > threshold concentration (Ct) of ≥ 20% (for a Ct of 1 µg/mL), that is, free tazobactam plasma concentration of ≥ 1 µg/mL for at least the first 1.6 hours (20% of an 8-hour dosing interval).17,18 Attainment of the PK/PD targets was assessed visually using free concentration-time curves for ceftolozane and tazobactam. Plasma concentrations of unbound ceftolozane and tazobactam were derived using protein binding values of 21% (ceftolozane) and 30% (tazobactam).13
Screening assessments occurred within 48 hours of study drug administration and included reviews of medical/surgical history and concomitant/prior medication use, as well as the following safety evaluations: full physical examination, vital signs, electrocardiogram (ECG), chemistry and hematology laboratory tests, direct Coombs test, and urinalysis. Patient safety was monitored for 24 hours after study drug infusion. Then, patients and/or parents (or legal representatives) were contacted via telephone 8 (±2) days later for an assessment of AEs and review of concomitant medications and procedures.
The primary endpoints were AUC and Cmax for ceftolozane and tazobactam in the PK population, that is, all patients who received one full ceftolozane/tazobactam dose and provided blood samples with quantifiable plasma levels at the approximate Cmax (that is, end of 1-hour infusion) and ≥ 2 time points after Cmax. Safety and tolerability were secondary endpoints and were evaluated in the safety population (all patients who received any dose) by examining incidence, severity and type of AEs, changes in any clinical laboratory evaluations, and changes from baseline in ECGs, vital signs and physical examinations. PK/PD targets (%fT > MIC for ceftolozane and %fT > threshold concentration for tazobactam) were assessed visually on time versus plasma concentration plots in all patients.
Data were evaluated with summary statistics; no formal hypothesis testing was planned or performed. Safety analyses included a summarization of exposure, AEs and tabulation of changes from baseline in clinical laboratory data, vital signs, and concomitant medications. All statistical analyses were performed using SAS statistical software Version 9.4.
A sample size of 36 patients (6 patients per age group) was planned, primarily based on empirical considerations and feasibility, and was considered sufficient to meet the study objectives and regulatory requirements. With 6 patients per age group, the probability of detecting ≥ 1 AE with a true event rate of 5% was 26%. With a total of 36 patients across all age groups, the probability of detecting ≥ 1 AE with a true event rate of 5% was 84%.
Of the participating centers, 11 centers enrolled patients (between 1 and 8 patients each). Thirty-seven patients were enrolled and given ceftolozane/tazobactam (safety population); 34 patients comprised the PK population, 9 of whom had a diagnosis of cystic fibrosis (CF). Demographics and baseline characteristics of the safety population are presented in (Table, Supplemental Digital Content 1, http://links.lww.com/INF/D254). Median (range) gestational age was 38.0 (35.0–41.0) weeks in group 5, 28.9 weeks (23.6–31.0) in group 6 (with eGFR ≥ 50 mL/min/1.73 m2), and 26.7 weeks (26.0–27.4) in group 6 (with eGFR ≥ 20–49 mL/min/1.73m2).
Treatment and Dose Evaluations
Details and patient numbers for the interim analyses, which evaluated safety, AUC0-∞, and T > MIC for the initially selected doses, are in Table 1. The interim analyses for group 1 (12 to < 18 years) and group 2 (7 to < 12 years) demonstrated that the initial ceftolozane/tazobactam doses were appropriate, based on achieving exposures in the expected range, and no dose changes were made. The interim analysis for group 3 (2 to < 7 years) indicated that exposures in this group at 18/9 mg/kg ceftolozane/tazobactam were lower than the target AUC0-∞; therefore, the dose was increased to 30/15 mg/kg ceftolozane/tazobactam (the maximum permitted weight-based dose for all age groups as per protocol) for the remaining patients in group 3 and group 4 (3 months to < 2 years).
Following the group 4 interim analysis, the starting dose for group 5 (> 32 weeks gestation, 7 days postnatal to < 3 months) was increased from the initially proposed 12/6 mg/kg ceftolozane/tazobactam to 20/10 mg/kg ceftolozane/tazobactam. The group 5 interim analysis confirmed this adjusted dose as appropriate, and the remaining 3 patients in that group also received 20/10 mg/kg ceftolozane/tazobactam. Similarly, following the group 4 interim analysis, the dose for group 6 (≤ 32 weeks gestation, 7 days postnatal to < 3 months) was also adjusted to 20/10 mg/kg ceftolozane/tazobactam for patients with eGFR values ≥ 50 mL/min/1.73 m.2 For group 6 patients with eGFR between 20 and 49 mL/min/1.73 m,2 a dose of 12/6 mg/kg ceftolozane/tazobactam was selected. The group 6 interim analysis showed that the adjusted doses were appropriate.
Mean ceftolozane plasma concentration-time profiles were generally comparable across groups 1–4 (Fig. 1A and [Fig., Supplemental Digital Content 2, http://links.lww.com/INF/D255]), while the terminal half-life (t1/2) was slightly greater in groups 5 and 6. The PK parameters of ceftolozane are summarized in Table 2 and were generally similar across groups 1–4. T1/2 and clearance (CL) were slightly different in groups 5 and 6 compared with older patients; CL was slightly decreased in neonates/young infants. For group 6 patients (≤ 32 weeks gestation, 7 days postnatal to < 3 months of age) receiving the 12/6 mg/kg ceftolozane/tazobactam dose, CL was approximately 2-fold lower, consistent with these neonates’ and young infants’ reduced renal function (eGFR, 20–49 mL/min/1.73 m2). Volume of distribution (Vss) was comparable across all age groups, with a slight trend toward increased Vss in groups 5 and 6. These data suggest a trend toward altered PK in neonates and very young infants (birth to < 3 months) compared with older patients.
Following the 1.7-fold dose increase (from 18/9 mg/kg ceftolozane/tazobactam to 30/15 mg/kg ceftolozane/tazobactam) in group 3 after the interim analysis, the ceftolozane AUC increased approximately 1.9-fold, suggesting that the PK of ceftolozane is dose-proportional. Based on unbound concentration-time profiles, all children achieved the PK/PD target for ceftolozane, that is, %fT > MIC of ≥ 30% for an MIC of 8 µg/mL (Fig. 1A).
Mean tazobactam plasma concentration-time profiles are shown in Figure 1B and (Fig., Supplemental Digital Content 2, http://links.lww.com/INF/D255), and the tazobactam PK parameters are summarized in Table 2. Tazobactam AUC0-∞ appeared higher (77.6 µg*h/mL) for group 6 (12/6mg/kg ceftolozane/tazobactam); however, these data represent only a single patient and must be interpreted with caution. With a 1.7-fold ceftolozane/tazobactam dose increase following the group 3 interim analysis, the tazobactam AUC0-∞ increased approximately 1.6-fold, suggesting that tazobactam PK is also dose-proportional. Tazobactam CL was generally comparable across groups 1–4, with a slight trend toward decreasing tazobactam CL in neonates and young infants. Tazobactam Vss was generally comparable across groups 1–6, while Vss in the single group 6 patient who received 12/6 mg/kg ceftolozane/tazobactam was 0.338 L/kg. Taken together, these results suggest variability in the tazobactam data. Based on unbound concentration-time profiles, all children achieved the PK/PD target for tazobactam, that is, %fT > Ct of ≥ 20% for a Ct of 1 µg/mL (Fig. 1B).
Eleven patients (~30%) experienced ≥ 1 treatment-emergent AE; anemia, diarrhea, and hypokalemia were the only AEs reported twice. No deaths, severe AEs, or treatment-related SAEs were reported. Three patients had a treatment-emergent SAE requiring hospitalization. All SAEs were mild to moderate in severity, and resolved: one 16-year old with aggravated pneumonia, one 8-year old with CF pulmonary exacerbation, and one 15-month old (30/15 mg/kg ceftolozane/tazobactam) with device-related sepsis. Two patients had mild treatment-related AEs that resolved by study completion: one 17-year old with dizziness (during the infusion) and one 2-year and 11-months old (30/15 mg/kg ceftolozane/tazobactam) with tachycardia (during the infusion) and bradycardia (on day 2). There were no events indicative of hypersensitivity reactions or hemolytic disorders, nor any events involving Clostridium difficile. Also, no clinically significant laboratory abnormalities or changes in ECGs were observed after study drug administration.
Ceftolozane/tazobactam may be an important new treatment option for children with serious infections caused by susceptible strains of drug-resistant Gram-negative bacteria. This single-dose phase 1 trial was the first study to evaluate the administration of ceftolozane/tazobactam in children of all ages. Obtaining PK and safety data for new drugs in the pediatric population is essential to ensure that healthcare providers have access to accurate dosing information, which can improve clinical outcomes in children.19 One of the major strengths of this study is that we evaluated ceftolozane/tazobactam in neonates from birth to < 3 months old, half of whom were born prematurely at ≤ 32 weeks gestation. For this study, birth was defined as ≥ 7 days postnatal because ceftolozane/tazobactam is primarily renally eliminated, and renal function is lower during the first week of life.
Ceftolozane PK was generally comparable among children older than 3 months (groups 1–4) following administration of single IV doses of ceftolozane/tazobactam. CL of both ceftolozane and tazobactam appeared to be lower, and volume of distribution slightly higher, in young infants and neonates (groups 5 and 6) than older children. These differences are consistent with age-related physiologic changes. Renal function matures through infancy, with CL values reaching adult values around the second year of life. Renal CL of drugs, including those governed by glomerular filtration and/or tubular secretion, such as ceftolozane and tazobactam,8,13,20,21 increases with increasing gestational age and body weight.14 Lower CL in young infants and neonates was therefore likely due to their immature renal function. We mitigated the effect of developmental changes in CL on drug exposure through appropriate initial dose selection individually for each age group and through dose changes informed by interim analyses. As a result, exposures were generally comparable across all age groups (after dose adjustments were made for groups 3 and 4). Increased volume of distribution likely resulted from higher total body and extracellular water in neonates; also, premature neonates have higher extracellular water content than term neonates.14,22 These increases can result in increased volume of distribution of water soluble drugs, such as ceftolozane and tazobactam.
The doses evaluated in this study (after interim analysis dose adjustments, if any) yielded AUC exposures generally comparable with those previously observed in healthy adult volunteers receiving a single, fixed 1.5 g dose of ceftolozane/tazobactam.8 In addition, these doses readily achieved PK/PD targets for both ceftolozane and tazobactam. The PK/PD index best correlating with ceftolozane in vivo efficacy, as with most beta-lactam antibiotics, is %fT > MIC, with a %fT > MIC of 30% being supported by data from a neutropenic mouse thigh infection model.17 Since tazobactam has limited intrinsic antibacterial activity, target attainment was evaluated using the tazobactam Ct needed to effectively neutralize susceptible bacterial β-lactamases (i.e., Ct of ≥ 1 μg/mL maintained for 20% of the dosing interval), as supported by in vivo models.18 With any beta-lactam antibiotic that demonstrates time-dependent bacterial killing (such as ceftolozane), it is possible to maximize the time that the antibiotic is present at the infection site at sufficiently high concentrations to provide antibacterial activity even against less susceptible pathogen strains with higher MIC values. Approaches to achieve this goal may include: (1) increasing the total daily dose; (2) administering the antibiotic more frequently while keeping the total daily dose unchanged; (3) administering with a prolonged infusion time (e.g., 2 or 3 hours for an antibiotic that is usually dosed every 8 hours); or (4) administering as a continuous infusion after an initial dose.23–25 However, such dosing strategies have not yet been studied for ceftolozane/tazobactam in clinical trials.
Of note, our study enrolled several patients with CF. Patients with CF have been reported to have altered PKs (i.e., larger volume of distribution, increased total body CL of beta lactam antibiotics, smaller AUC, shorter elimination half time and lower antibiotic concentration).26 An exploratory analysis of ceftolozane/tazobactam PK using model-derived parameters suggested that no clinically meaningful differences in the PK of ceftolozane/tazobactam were observed in children with or without CF;27 additional analysis is ongoing to investigate the effects of CF on the PK of ceftolozane/tazobactam in children.
This study comes with several limitations. One limitation is the small sample size, with only 5–6 patients in the PK population in each of the 6 groups. It is well-recognized that pediatric PK studies are difficult to enroll due to scientific, regulatory and ethical challenges.28,29 Limited conclusions can be drawn from the noncompartmental methods used, because sparse PK sampling was conducted in groups 5 and 6 and because PK data were only available for the few group 6 patients who received 12/6 mg/kg ceftolozane/tazobactam. Tazobactam data were further limited by several patients having undetectable concentrations at the 6-hour time point. Nonetheless, the PK data collected were suitable for creation of a preliminary population PK analysis30 that informed dose selection for on-going pediatric phase 2 prospective, comparative clinical trials evaluating ceftolozane/tazobactam for treating cUTI (clinicalTrials.gov NCT03230838) and cIAI (clinicalTrials.gov NCT03217136): 1.5g ceftolozane/tazobactam q8h for patients 12 to < 18 years old and 20/10 mg/kg ceftolozane/tazobactam q8h for patients < 12 years old.
In summary, single doses of ceftolozane/tazobactam in pediatric patients from birth (7 days postnatal) to < 18 years of age were generally well tolerated; no safety concerns were identified. Observed AEs were consistent with those that may be expected in this particular trial population, that is, hospitalized pediatric patients. Our data provide further evidence that CL of beta-lactams is higher in children and adolescents than in adults. The doses evaluated yielded AUC exposures generally comparable with those previously observed in adults. These results support continued development of ceftolozane/tazobactam in ongoing pediatric trials.
The authors thank the patients and their families and caregivers for participating in this study, along with all investigators, research nurses, and other site personnel. Medical writing support was provided by Dominik Wolf, MSc, of Merck & Co., Inc., Kenilworth, NJ, and editorial support by Carol Zecca, BS, of Merck & Co., Inc., Kenilworth, NJ.
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beta-lactamase inhibitor; tolerability; clinical trial; Pseudomonas; children
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