Expanded Treatment Options for Multi-Drug Resistant Infections in Children

The incidence of multi-drug resistant (MDR) infections in children is increasing.^1-2 Fortunately, novel therapeutic options have recently evolved, transforming the treatment of infections due to MDR organisms. However, optimal use of newer antibiotics in children is challenging due to limited pediatric-specific data.

Ceftazidime-avibactam, approved for use in adults in 2015, combines a third-generation cephalosporin with activity against Pseudomonas species with a non-β-lactam β-lactamase inhibitor with potent activity against serine-based Ambler class A and C β-lactamases and some class D enzymes.³

The drug received extended approval by the Food and Drug Administration (FDA) in 2019 at a dose of 50 mg/kg/dose (ceftazidime component) intravenously every 8 hours (q8h) for the treatment of complicated urinary tract infections (cUTI) or complicated intra-abdominal infections (cIAI) in children ≥ 3 months old.⁴ The extended approval was based on two studies in children ≥ 3 months to < 18 years of age.

The first was a cUTI study, which demonstrated a safety profile consistent with adults and a favorable microbiologic response at test of cure.⁵ The second was a cIAI study, which demonstrated a similar safety profile, as well as a favorable clinical and microbiological response (combined with metronidazole) at the end of treatment and test of cure.⁶ A Phase 1, open label, multi-center study is ongoing to evaluate the safety and pharmacokinetics of ceftazidime-avibactam in children with pneumonia.⁷ Outside of clinical trials, reports of real-world experiences with ceftazidime-avibactam in children are limited to case reports or series.^8-10

Ceftolozane-tazobactam combines a fifth-generation cephalosporin with a β-lactamase inhibitor that exhibits strong activity against Pseudomonas aeruginosa and many serine-based Ambler class A and C β-lactamases.¹¹ This antimicrobial combination notably lacks activity against class A carbapenemases (KPC) and metallo-β-lactamases (NDM-1, IMP, and VIM).¹² The drug was approved in 2014 for the treatment of cIAI and cUTI, and later in 2019 for hospital-acquired and ventilator-associated bacterial pneumonia in adults.¹³ However, it has yet to receive FDA approval in children.

A population PK model helped guide the following dosing recommendations used in phase 2 clinical trials for cUTI and cIAI: 1.5 grams ceftolozane/tazobactam IV q8h (12 to 18 years old) and 20 mg/kg (ceftolozane component) IV q8h (< 12 years old).^14-17

A phase 1, open label, multi-center study is ongoing to evaluate the safety and pharmacokinetics of 3 grams (12 to < 18 years old) or 40 mg/kg (ceftolozane component) (< 12 years old) in children with nosocomial pneumonia.¹⁸ Real world data are limited to case reports, which suggest the use of higher doses (50 mg/kg), more frequent administration (q6h), and/or prolonged infusions (over 3 hours) may be necessary to achieve treatment success for more invasive infections or those with a high MIC.^19-20

Overall, ceftazidime-avibactam and ceftolozane-tazobactam provide new options for the treatment of MDR infections in children. Ceftazidime-avibactam is considered safe and effective in children as young as 3 months of age with cUTI or cIAI. Results from ceftolozane-tazobactam clinical trials will help further define its safety and efficacy profile in this specialty population.

Tracy Zembles, PharmD is the lead antimicrobial stewardship pharmacist at Children’s Wisconsin.Dr. Zembles’ clinical interests include implementation of handshake stewardship, evaluation of extended infusion beta lactams in children, and penicillin allergy delabeling.

Meredith Oliver PharmD, BCIDP, is a clinical pharmacy specialist in pediatric antimicrobial stewardship/infectious diseases at M Health Fairview University of Minnesota Masonic Children’s Hospital in Minneapolis, MN. Dr. Oliver’s interests include neonatal antimicrobial stewardship, antimicrobial pharmacokinetics/dynamics, and immunocompromised infectious diseases.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.

References:

1. Medernach RL, Logan LK. The growing threat of antibiotic resistance in children. Infect Dis Clin North Am 2018;32(1):1-17.

2. Meropol SB, Haupt AA, Debanne SM. Incidence and outcomes of infections cause by multidrug-resistant Enterobacteriaceae in children, 2007-2015. J Pediatric Infect Dis Soc 2018;7(1):36-45.

3. Zasowski EJ, Rybak JM, Rybak MJ. The β-lactams strike back: ceftazidime-avibactam. Pharmacotherapy 2015;35(8):755-770.

4. Pfizer. Ceftazidime-avibactam [package insert]. US Food and Drug administration website. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/206494s005,s006lbl.pdf. Revised [3/2019]. Accessed [7/20/2021].

5. Bradley JS, Roilides E, Broadhurst H, et al. Safety and efficacy of ceftazidime-avibactam in the treatment of children ≥ 3 months to < 18 years with complicated urinary tract infection: results from a phase 2 randomized, controlled trial. Pediatr Infect Dis J 2019;38(9):920-928.

6. Bradley JS, Broadhurst H, Cheng K, et al. Safety and efficacy of ceftazidime-avibactam plus metronidazole in the treatment of children ≥ 3 months to < 18 years with complicated intra-abdominal infection: results from a phase 2 randomized, controlled trial. Pediatr Infect Dis J 2019;38(8):816-824.

7. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT 04040621, Single-dose PK study of ceftazidime-avibactam in hospitalized children receiving systemic antibiotics for nosocomial pneumonia. URL: https://clinicaltrials.gov/ct2/show/NCT04040621. Accessed [7/20/2021].

8. Tamma PD, Fan Y, Bergman Y, et al. Successful treatment of persistent Burkholderia cepacia complex with ceftazidime-avibactam. Antimicrobl Agents Chemother 2018;62:e02213-17.

9. Hobson CA, Bonacorsi S, Fahd M, et al. Successful treatment of bacteremia due to NDM-1-producing Morganelle morganii with aztreonam and ceftazidime-avibactam combination in a pediatric patient with hematologic malignancy. Antimicrob Agents Chemother 2019;63:e02463-18.

10. Iosifidis E, Chorafa E, Agakidou E, et al. Use of ceftazidime-avibactam for the treatment of extensively drug-resistant or pan drug-resistant Klebsiella pneumoniae in neonates and children < 5 years of age. Pediatr Infect Dis J 2019;38(8):812-815.

11. Cho JC, Fiorenza MA, Estrada SJ. Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination. Pharmacotherapy 2015;35(7):701-715.

12. Rodriguez BA, Girotto JE, Nicolau DP. Ceftazidime/avibactam and ceftolozane/tazobactam: novel therapy for multidrug resistant gram-negative infections in children. Curr Pediatr Rev 2018;14(2):97-109.

13. Merck Sharp & Dohme Corp. Ceftolozane-tazobactam [package insert]. US Food and Drug administration website. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/206829s008lbl.pdf Revised [6/2019]. Accessed [7/29/2021].

14. Bradley JS, Ang JY, Arrieta AC, et al. Pharmacokinetics and safety of single intravenous doses of ceftolozane/tazobactam in children with proven or suspected gram-negative infection. Pediatr Infect Dis J. 2018;37(11):1130-1136.

15. Larson KB, Patel YT, Willavize S, et al. Ceftolozane-tazobactam population pharmacokinetics and dose selection for further clinical evaluation in pediatric patients with complicated urinary tract or complicated intra-abdominal infections. Antimicrob Agents Chemother 2019;63(6):e02578-18.

16. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03230838, MK-7625A versus meropenem in pediatric participants with complicated urinary tract infection. URL: https://clinicaltrials.gov/ct2/show/NCT03230838. Accessed [7/29/2021].

17. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03217136, MK-7625A plus metronidazole versus meropenem in pediatric participants with complicated intra-abdominal infection. URL: https://clinicaltrials.gov/ct2/show/NCT03217136. Accessed [7/29/2021].

18. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT04223752, Safety and pharmacokinetics of ceftolozane/tazobactam in pediatric participants with noscomial pneumonia. URL: https://clinicaltrials.gov/ct2/show/NCT04223752. Accessed [7/29/2021].

19. Aitken SL, Kontoyiannis DP, DePombo AM, et al. Use of ceftolozane/tazobactam in the treatment of multidrug-resistant pseudomonas aeruginosa bloodstream infection in a pediatric leukemia patient. Pediatr Infect Dis J 2016;35:1040-1042.

20. Martin-Cazana M, Grau S, Epalza C, et al. Successful ceftolozane-tazobactam rescue therapy in a child with endocarditis caused by multidrug-resistant pseudomonas aeruginosa. J Paediatr Child Health 2019;55(8):985-987.