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Prescribing Ceftolozane/Tazobactam for Pediatric Patients: Current Status and Future Implications

Abstract

Antibiotics are arguably the greatest medical development of the 20th century but these precious resources are being threatened by the continued rise in infections caused by multidrug-resistant bacteria. There is concern that we are on the precipice of a ‘post-antibiotic era’. The situation is exacerbated by a stagnation in the pharmaceutical industry in developing new antibiotics, particularly those with activity against some of the most resistant Gram-negative organisms because of significant economic, scientific, and regulatory barriers. One of the products of recent initiatives to reinvigorate the antibiotic pipeline is the agent ceftolozane/tazobactam. Ceftolozane/tazobactam was approved in December 2014 by the US Food and Drug Administration for the treatment of complicated urinary tract infections and complicated intra-abdominal infections for patients 18 years of age and older. The safety and effectiveness of ceftolozane/tazobactam in pediatric patients has not been established in clinical studies. However, with the rise of highly drug-resistant Gram-negative organisms in children and the current climate of ongoing, multiple, and simultaneous antibiotic shortages—particularly of broad-spectrum antibiotics, the potential off-label role of ceftolozane/tazobactam for children needs to be explored while pediatric studies are ongoing. The objective of this opinion piece is to discuss what is currently known about ceftolozane/tazobactam and its potential implications for use in the pediatric population.

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References

  1. Boucher HW, Talbot GH, Benjamin DK Jr, et al. 10 × ′20 Progress–development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013;56:1685–94.

    PubMed Central  Article  PubMed  Google Scholar 

  2. Generating Antibiotic Incentives Now Act of 2011. https://www.congress.gov/bill/112th-congress/house-bill/2182. Accessed 28 Nov 2015.

  3. Antibiotic Development to Advance Patient Treatment Act of 2013. https://www.congress.gov/bill/113th-congress/house-bill/3742. Accessed 28 Nov 2015.

  4. ZERBAXA (ceftolozane/tazobactam) Current Prescribing Information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206829lbl.pdf. Accessed 28 Nov 2015.

  5. Europeans Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003772/human_med_001917.jsp&mid=WC0b01ac058001d124. Accessed 28 Nov 2015.

  6. Moya B, Zamorano L, Juan C, Ge Y, Oliver A. Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2010;54:3933–7.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  7. Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: a novel cephalosporin/beta-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 2014;74:31–51.

    Article  CAS  PubMed  Google Scholar 

  8. Miller B, Hershberger E, Benziger D, Trinh M, Friedland I. Pharmacokinetics and safety of intravenous ceftolozane/tazobactam in healthy adult subjects following single and multiple ascending doses. Antimicrob Agents Chemother. 2012;56:3086–91.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  9. Craig WA, Andes DR. In vivo activities of ceftolozane, a new cephalosporin, with and without tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae, including strains with extended-spectrum beta-lactamases, in the thighs of neutropenic mice. Antimicrob Agents Chemother. 2013;57:1577–82.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  10. Vanscoy B, Mendes RE, McCauley J, et al. Pharmacological basis of β-lactamase inhibitor therapeutics: tazobactam in combination with cefolozane. Antimicrob Agents Chemother. 2013;2013(57):5924–31.

    Article  Google Scholar 

  11. Wooley M, Miller B, Krishna G, Hershberger E, Chandorkar G. Impact of renal function on the pharmacokinetics and safety of ceftolozane/tazobactam. Antimicrob Agents Chemother. 2014;58:2249–55.

    PubMed Central  Article  PubMed  Google Scholar 

  12. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis. 2015;60:1462–71.

    PubMed Central  PubMed  Google Scholar 

  13. Pharmacokinetic and safety study of ceftolozane/tazobactam in pediatric participants receiving antibiotic therapy for proven or suspected gram-negative infection or for peri-operative prophylaxis (MK-7625A-010). https://clinicaltrials.gov/ct2/show/NCT02266706. Accessed 28 Nov 2015.

  14. Reed MD, Goldfarb J, Yamashita TS, et al. Single-dose pharmacokinetics of piperacillin and tazobactam in infants and children. Antimicrob Agents Chemother. 1994;38:2817–26.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  15. Safety and efficacy study of ceftolozane/tazobactam to treat ventilated nosocomial pneumonia (ASPECT-NP). https://clinicaltrials.gov/ct2/show/NCT02070757. Accessed 28 Nov 2015.

  16. Chandorkar G, Huntington JA, Gotfried MH, Rodvold KA, Umeh O. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects. J Antimicrob Chemother. 2012;67:2463–9.

    Article  CAS  PubMed  Google Scholar 

  17. Xiao AJ, Miller BW, Huntington JA, et al. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol. 2015. doi:10.1002/jcph.566. [Epub ahead of print].

  18. Melchers MJ, Mavridou E, Seyedmousavi S, et al. Plasma and epithelial lining fluid pharmacokinetics of ceftolozane and tazobactam alone and in combination in mice. AAC. 2015;59:3373–6.

    Article  CAS  Google Scholar 

  19. Gelfand MS, Cleveland KO. Ceftolozane/tazobactam therapy of respiratory infections due to multidrug-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2015;61:853–5.

    Article  PubMed  Google Scholar 

  20. Population pharmacokinetics and safety of intravenous ceftolozane/tazobactam in adult cystic fibrosis patients. https://clinicaltrials.gov/ct2/show/NCT02421120. Accessed 28 Nov 2015.

  21. Snydman DR, McDermott LA, Jacobus NV. Activity of ceftolozane/tazobactam against a broad spectrum of recent clinical anaerobic isolates. Antimicrob Agents Chemother. 2014;58:1218–23.

    PubMed Central  Article  PubMed  Google Scholar 

  22. Lucasti C, Hershberger E, Miller B, et al. Multicenter, double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane/tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections. Antimicrob Agents Chemother. 2014;58:5350–7.

    PubMed Central  Article  PubMed  Google Scholar 

  23. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the surgical infection society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:133–64.

    Article  PubMed  Google Scholar 

  24. Centers for diseases control and prevention. Get smart for healthcare. http://www.cdc.gov/getsmart/healthcare/implementation/core-elements.html. Accessed 28 Nov 2015.

  25. Snydman DR, Jacobus NV, McDermott LA, et al. Lessons learned from the anaerobe survey: historical perspective and review of the most recent data (2005–2007). Clin Infect Dis. 2010;50(Suppl 1):S26–33.

    Article  PubMed  Google Scholar 

  26. Package insert for Zosyn (Piperacillin and tazobactam for injection, USP). http://labeling.pfizer.com/showlabeling.aspx?id=416. Accessed 28 Nov 2015.

  27. Smith JM, Avdic E, Tamma PD, et al. Risk factors for resistance to β-lactam/β-lactamase inhibitors and ertapenem in Bacteroides bacteremia. Antimicrob Agents Chemother. 2015;59:5049–51.

    Article  CAS  PubMed  Google Scholar 

  28. Sader HS, Farrell DJ, Castanheira M, Flamm RK, Jones RN. Antimicrobial activity of ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011–12). J Antimicrob Chemother. 2014;69:2713–22.

    Article  CAS  PubMed  Google Scholar 

  29. Farrell DJ, Sader HS, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012). Int J Antimicrob Agents. 2014;43:533–9.

    Article  CAS  PubMed  Google Scholar 

  30. Sader HS, Farrell DJ, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012). J Infect. 2014;69:266–77.

    Article  PubMed  Google Scholar 

  31. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane/tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in US Hospitals (2011–2012). Antimicrob Agents Chemother. 2013;57:6305–10.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  32. Walkty A, Karlowsky JA, Adam H, et al. In vitro activity of ceftolozane/tazobactam against Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals in the CANWARD study, 2007 to 2012. Antimicrob Agents Chemother. 2013;57:5707–9.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  33. Bush K, Jacoby GA. Updated functional classification of beta-lactamases. Antimicrob Agents Chemother. 2010;54:969–76.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  34. Bush K, Macalintal C, Rasmussen BA, Lee VJ, Yang Y. Kinetic interactions of tazobactam with beta-lactamases from all major structural classes. Antimicrob Agents Chemother. 1993;37:851–8.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  35. Zimhony O, Chmelnitsky I, Bardenstein R, et al. Endocarditis caused by extended-spectrum-beta-lactamase-producing Klebsiella pneumoniae: emergence of resistance to ciprofloxacin and piperacillin-tazobactam during treatment despite initial susceptibility. Antimicrob Agents Chemother. 2006;50:3179–82.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  36. Thomson KS, Moland ES. Cefepime, piperacillin-tazobactam, and the inoculum effect in tests with extended-spectrum beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2001;45:3548–54.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  37. Tamma PD, Han JH, Rock C, et al. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum beta-lactamase bacteremia. Clin Infect Dis. 2015;60:1319–25.

    PubMed  Google Scholar 

  38. Ofer-Friedman H, Shefler C, Sharma S, et al. Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae. Infect Control Hosp Epidemiol. 2015;36(8):981–5.

  39. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane/tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet. 2015;385:1949–56.

    Article  CAS  PubMed  Google Scholar 

  40. Eckmann C, Solomkin J. Ceftolozane/tazobactam for the treatment of complicated intra-abdominal infections. Expert Opin Pharmacother. 2015;16:271–80.

    Article  PubMed  Google Scholar 

  41. Cabot G, Bruchmann S, Mulet X, et al. Pseudomonas aeruginosa ceftolozane/tazobactam resistance development requires multiple mutations leading to overexpression and structural modification of AmpC. Antimicrob Agents Chemother. 2014;58:3091–9.

    PubMed Central  Article  PubMed  Google Scholar 

  42. Livermore DM, Mushtaq S, Ge Y. Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2010;65:1972–4.

    Article  CAS  PubMed  Google Scholar 

  43. Takeda S, Nakai T, Wakai Y, Ikeda F, Hatano K. In vitro and in vivo activities of a new cephalosporin, FR264205, against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2007;51:826–30.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  44. Livermore DM, Mushtaq S, Ge Y, Warner M. Activity of cephalosporin CXA-101 (FR264205) against Pseudomonas aeruginosa and Burkholderia cepacia group strains and isolates. Int J Antimicrob Agents. 2009;34:402–6.

    Article  CAS  PubMed  Google Scholar 

  45. Castanheira M, Mills JC, Farrell DJ, Jones RN. Mutation-driven beta-lactam resistance mechanisms among contemporary ceftazidime-nonsusceptible Pseudomonas aeruginosa isolates from US hospitals. Antimicrob Agents Chemother. 2014;58:6844–50.

    PubMed Central  Article  PubMed  Google Scholar 

  46. VanScoy B, Mendes RE, Castanheira M, et al. Relationship between ceftolozane–tazobactam exposure and drug resistance amplification in a hollow-fiber infection model. Antimicrob Agents Chemother. 2013;57:4134–8.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  47. Kuti JL, Pettit RS, Neu N, et al. Microbiological activity of ceftolozane/tazobactam, ceftazidime, meropenem, and piperacillin/tazobactam against Pseudomonas aeruginosa isolated from children with cystic fibrosis. Diagn Microbiol Infect Dis. 2015;83:53–5.

    Article  CAS  PubMed  Google Scholar 

  48. Zamorano L, Juan C, Fernandez-Olmos A, Ge Y, Canton R, Oliver A. Activity of the new cephalosporin CXA-101 (FR264205) against Pseudomonas aeruginosa isolates from chronically-infected cystic fibrosis patients. Clin Microbiol Infect. 2010;16:1482–7.

    Article  CAS  PubMed  Google Scholar 

  49. Regulation (EC) No 1901/2006 of the european parliament and of the council of 12 December 2006. http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf. Accessed 28 Nov 2015.

  50. United states food and drug administration. Pediatric development of the drug or biological product. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM338453.pdf. Accessed 28 Nov 2015.

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Correspondence to Pranita D. Tamma.

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This manuscript was funded by Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases. SMT, AJH, and PDT report no conflicts of interest.

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Tamma, S.M., Hsu, A.J. & Tamma, P.D. Prescribing Ceftolozane/Tazobactam for Pediatric Patients: Current Status and Future Implications. Pediatr Drugs 18, 1–11 (2016). https://doi.org/10.1007/s40272-015-0157-x

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  • DOI: https://doi.org/10.1007/s40272-015-0157-x

Keywords

  • Minimum Inhibitory Concentration
  • Levofloxacin
  • Ceftazidime
  • Meropenem
  • Cystic Fibrosis Patient