Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia

Alan J Xiao, Benjamin W Miller, Jennifer A Huntington, David P Nicolau, Alan J Xiao, Benjamin W Miller, Jennifer A Huntington, David P Nicolau

Abstract

Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a > 90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve > 90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a > 90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of ≤ 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs.

Keywords: Pseudomonas aeruginosa; ceftolozane/tazobactam; dose justification; epithelial lining fluid; nosocomial pneumonia; probability of target attainment.

© 2015 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Observed individual ceftolozane (A) and tazobactam (B) concentrations in plasma (×) and ELF (о) in 25 healthy subjects following the third dose of 1.5 g ceftolozane/tazobactam administered as a 60‐minute intravenous infusion every 8 hours.
Figure 2
Figure 2
Ceftolozane/tazobactam plasma‐ELF PK model structure.
Figure 3
Figure 3
Fit of the PK model to the observed concentrations in both plasma (×) and ELF (о) for ceftolozane (A) and tazobactam (B); the dashed line represents unity.
Figure 4
Figure 4
Simulated ceftolozane (A) and tazobactam (B) steady‐state concentration–time profiles in plasma and ELF in nosocomial pneumonia patients with normal renal function following 3 g ceftolozane/tazobactam administered as a 60‐minute intravenous infusion every 8 hours.
Figure 5
Figure 5
MIC distribution of Enterobacteriaceae and P. aeruginosa isolates from hospitalized patients with pneumonia from 2012 US/European Union surveillance data7 and simulated PTA of ceftolozane in plasma (A) and ELF (B) in patients with normal renal function following 3 g ceftolozane/tazobactam administered as a 60‐minute intravenous infusion every 8 hours.
Figure 6
Figure 6
MIC distribution of Enterobacteriaceae and P. aeruginosa isolates from hospitalized patients with pneumonia from 2012 US/European Union surveillance data7 and simulated PTA of ceftolozane in plasma (A) and ELF (B) in patients with normal renal function following 1.5 g ceftolozane/tazobactam administered as a 60‐minute intravenous infusion every 8 hours.
Figure 7
Figure 7
Simulated PTA of tazobactam in plasma (A) and ELF (B) in patients with normal renal function following 3 g ceftolozane/tazobactam administered as a 60‐minute intravenous infusion every 8 hours.

References

    1. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital‐acquired, ventilator‐associated, and healthcare‐associated pneumonia. Am J Respir Crit Care Med 2005;171(4):388–416.
    1. Jones RN. Microbial etiologies of hospital‐acquired bacterial pneumonia and ventilator‐associated bacterial pneumonia. Clin Infect Dis. 2010; 51(suppl 1):S81–S87.
    1. Udy AA, Roberts JA, Lipman J. How should we dose antibiotics for pneumonia in the ICU? Curr Opin Infect Dis. 2013; 26(2):189–195.
    1. Zerbaxa [prescribing information]. Lexington, MA: Cubist Pharmaceuticals Inc. 2014.
    1. 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(6):533–539.
    1. 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(4):1577–1582.
    1. Drusano GL. Antimicrobial pharmacodynamics: critical interactions of “bug and drug” Nat Rev Microbiol. 2004; 2(4):289–300.
    1. Lepak AJ, Reda A, Marchillo K, Van HJ, Craig WA, Andes D. Impact of MIC range for Pseudomonas aeruginosa and Streptococcus pneumoniae on the ceftolozane in vivo pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother. 2014; 58(10):6311–6314.
    1. 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(10):2463–2469.
    1. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta‐lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014; 58(8):1072–1083.
    1. Melhem M, Forrest A, Rubino C. Pharmacokinetic‐pharmacodynamic (PK‐PD) target attainment (TA) analyses supporting the selection of in vitro susceptibility test interpretive criteria for ceftolozane/tazobactam (TOL/TAZ) against Pseudomonas aeruginosa Presented at: European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); May 10‐13, 2014; Barcelona, Spain. Poster 1743.
    1. 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(10):1462–1471.
    1. 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(9):5350–5357.
    1. 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(9981):1940–1956.
    1. Ambrose PG, Bhavnani SM, Ellis‐Grosse EJ, Drusano GL. Pharmacokinetic‐pharmacodynamic considerations in the design of hospital‐acquired or ventilator‐associated bacterial pneumonia studies: look before you leap! Clin Infect Dis 2010;51(suppl 1):S103–S110.
    1. Chandorkar G, Xiao A, Mouksassi S, Hershberger E, Krishna G. Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections. J Clin Pharmacol. 2015; 55(2):230–239.
    1. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard, 9th ed. CLSI document M07‐A9. Clinical and Laboratory Standards Institute, Wayne, PA: 2012.
    1. Vanscoy B, Mendes RE, Nicasio AM, et al. Pharmacokinetics‐pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model. Antimicrob Agents Chemother. 2013; 57(6):2809–2814.
    1. Vanscoy B, Mendes RE, McCauley J, et al. Pharmacological basis of beta‐lactamase inhibitor therapeutics: tazobactam in combination with ceftolozane. Antimicrob Agents Chemother. 2013; 57(12):5924–5930.
    1. Pea F, Viale P. The antimicrobial therapy puzzle: could pharmacokinetic‐pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients? Clin Infect Dis. 2006; 42(12):1764–1771.
    1. Rello J, Ulldemolins M, Lisboa T, et al. Determinants of prescription and choice of empirical therapy for hospital‐acquired and ventilator‐associated pneumonia. Eur Respir J. 2011; 37(6):1332–1339.
    1. Kollef MH, Morrow LE, Niederman MS, et al. Clinical characteristics and treatment patterns among patients with ventilator‐associated pneumonia. Chest. 2006; 129(5):1210–1218.
    1. Tumbarello M, De Pascale G, Trecarichi EM, et al. Clinical outcomes of Pseudomonas aeruginosa pneumonia in intensive care unit patients. Intensive Care Med. 2013; 39(4):682–692.
    1. 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(6):3086–3091.
    1. Siegel RE. The significance of serum vs tissue levels of antibiotics in the treatment of penicillin‐resistant Streptococcus pneumoniae and community‐acquired pneumonia: are we looking in the wrong place? Chest. 1999; 116(2):535–538.
    1. Rodvold KA, George JM, Yoo L. Penetration of anti‐infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents. Clin Pharmacokinet. 2011; 50(10):637–664.
    1. Li C, Du X, Kuti JL, Nicolau DP. Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections. Antimicrob Agents Chemother. 2007; 51(5):1725–1730.
    1. Lodise TP, Sorgel F, Melnick D, Mason B, Kinzig M, Drusano GL. Penetration of meropenem into epithelial lining fluid of patients with ventilator‐associated pneumonia. Antimicrob Agents Chemother. 2011; 55(4):1606–1610.
    1. Felton TW, McCalman K, Malagon I, et al. Pulmonary penetration of piperacillin and tazobactam in critically ill patients. Clin Pharmacol Ther. 2014; 96(4):438–448.
    1. Boselli E, Breilh D, Rimmele T, et al. Alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to patients with ventilator‐associated pneumonia. Crit Care Med. 2008; 36(5):1500–1506.
    1. Muller AE, Schmitt‐Hoffmann AH, Punt N, Mouton JW. Monte Carlo simulations based on phase I studies predict target attainment of ceftobiprole in nosocomial pneumonia patients: a validation study. Antimicrob Agents Chemother. 2013; 57(5):2047–2053.
    1. Roberts JA, Lipman J. Optimal doripenem dosing simulations in critically ill nosocomial pneumonia patients with obesity, augmented renal clearance, and decreased bacterial susceptibility. Crit Care Med. 2013; 41(2):489–495.
    1. Young RJ, Lipman J, Gin T, Gomersall CD, Joynt GM, Oh TE. Intermittent bolus dosing of ceftazidime in critically ill patients. J Antimicrob Chemother. 1997; 40(2):269–273.
    1. Heim‐Duthoy KL, Bubrick MP, Cocchetto DM, Matzke GR. Disposition of ceftazidime in surgical patients with intra‐abdominal infection. Antimicrob Agents Chemother. 1988; 32(12):1845–1847.
    1. de Stoppelaar F, Stolk L, van Tiel F, Beysens A, van der Geest S, de Leeuw P. Meropenem pharmacokinetics and pharmacodynamics in patients with ventilator‐associated pneumonia. J Antimicrob Chemother. 2000; 46(1):150–151.
    1. Binder L, Schworer H, Hoppe S, et al. Pharmacokinetics of meropenem in critically ill patients with severe infections. Ther Drug Monit. 2013; 35(1):63–70.
    1. Bedikian A, Okamoto MP, Nakahiro RK, et al. Pharmacokinetics of meropenem in patients with intra‐abdominal infections. Antimicrob Agents Chemother. 1994; 38(1):151–154.
    1. Bhagunde P, Chang KT, Hirsch EB, Ledesma KR, Nikolaou M, Tam VH. Novel modeling framework to guide design of optimal dosing strategies for beta‐lactamase inhibitors. Antimicrob Agents Chemother. 2012; 56(5):2237–2240.
    1. Rubino C, Bhavnani SM, Steenbergen JN, Krishna G, Ambrose PG. Pharmacokinetic‐ pharmacodynamic (PK‐PD) target attainment analyses supporting the selection of in vitro susceptibility test interpretive criteria for ceftolozane/tazobactam (TOL/TAZ) against Enterobacteriaceae. Presented at: 54th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 5‐9, 2014; Washington, DC. Poster A‐1347.
    1. Melchers MJ, Mavridou E, Seyedmousavi S, van Mil AC, Lagarde C, Mouton JW. Plasma and ELF pharmacokinetics of ceftolozane and tazobactam alone and in combination in mice. Antimicrob Agents Chemother. 2015; 59(6):3373–3376.

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