Consider the MIC: Treating Respiratory Infections Caused by Pseudomonas aeruginosa With Ceftolozane/Tazobactam

Highlighted Study:

Higher MICs (>2 mg/L) predict 30-day mortality in patients with lower respiratory tract infections caused by Pseudomonas aeruginosa treated with ceftolozane/ tazobactam.

Rodríguez-Núñez O, Periañez-Parraga L, Oliver A, et al. Open Forum Infect Dis. 2019;6(10):ofz416. doi: 10.1093/ofid/ofz416.

Ceftolozane/tazobactam (Zerbaxa) is a β- lactam/β-lactamase inhibitor combination that first entered the market after receiving US Food and Drug Administration approval on December 19, 2014, for the treatment of complicated intra-abdominal and urinary tract infections. The labeled dose for these infections is 1.5 grams every 8 hours intravenously, with an infusion time of 1 hour. Dose adjustments are recommended for patients with renal dysfunction. With increasing concern for antibiotic-resistant bacteria, ceftolozane/tazobactam is a potential treatment option for β-lactamase—producing organisms including Pseudomonas aeruginosa with derepressed class C cephalosporinase production.¹

As a time-dependent agent, the activity of ceftolozane/tazobactam is best predicted by the time of antibiotic concentration greater than the minimum inhibitory concentration (MIC). Pharmacokinetic models have demonstrated that for P aeruginosa strains with MICs up to 8 mg/L, a higher ceftolozane/tazobactam dose of 3 grams every 8 hours achieves more than 90% probability of attaining a 50% time >MIC in the lung epithelial lining fluid.² This higher dose was employed in the ASPECT-NP phase 3 trial of ceftolozane/tazobactam versus meropenem for nosocomial pneumonia, which led to the FDA approval for ceftolozane/tazobactam for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia on June 3, 2019.³

Prior to the publication of the ASPECT-NP trial, Rodríguez-Núñez et al conducted this retrospective, observational study in 90 patients who received treatment with ceftolozane/tazobactam for a lower respiratory tract infection with susceptible P aeruginosa isolated from at least 1 respiratory or blood culture.⁴ The study enrolled patients across 13 hospitals in the United States, the United Kingdom, Spain, and France from 2016 to 2018. Susceptibility to ceftolozane/tazobactam was defined as an MIC ≤4 mg/L by Epsilometer test, in concordance with the breakpoints established by the Clinical and Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing. Patients who received <72 hours of ceftolozane/tazobactam were excluded from the analysis. Standard ceftolozane/tazobactam dose was defined as the labeled dose for intra-abdominal/urinary tract infections (1.5 g every 8 hours for normal renal function), whereas high dose was defined as at least twice the standard dose (Table).⁵ The primary outcome was 30-day mortality after ceftolozane/tazobactam therapy was initiated. Univariate and multivariate analyses were conducted to identify risk factors associated with mortality.

The study enrolled 90 patients with a median age of 65 years; their comorbidities included chronic lung disease (43.3%), vascular disease (28.9%), diabetes (16.7%), receipt of a solid organ transplant (8.9%) including lung transplant (5.6%), and cystic fibrosis (6.7%). Pneumonia was the most common lower respiratory tract infection. In terms of illness severity, the cohort had a median Charlson Comorbidity Index score of 5. Of all infections, 36.7% were ventilator associated; 34.4% of patients presented with septic shock, and 12.2% required continuous renal replacement therapy. As for P aeruginosa MIC distribution, 24.4% of patients had isolates with an MIC ≤1 mg/L, 51.1% had isolates with an MIC 1-2 mg/L, and 24.4% had isolates with an MIC of 4 mg/L.

The overall 30-day mortality rate was 27.8%. In the univariate analysis, 2 factors were identified to be associated with increased mortality: a higher Charlson Comorbidity Index score (OR, 1.2; P = .029) and septic shock (OR, 5.9; P <.001). Decreased mortality was observed in patients who received high-dose ceftolozane/tazobactam with a corresponding MIC ≤2 mg/L (OR, 0.3; P = .033). A mortality benefit was not seen with standard ceftolozane/tazobactam dosing for MIC ≤2 mg/L (OR, 1.1; P = .847). Although the use of high-dose ceftolozane/tazobactam trended toward decreased mortality for MIC ≤1 mg/L, MIC 1-2 mg/L, and MIC 3-4 mg/L, the differences were not statistically significant. The multivariate analysis demonstrated similar results as the univariate analysis: a higher Charlson Comorbidity Index score (OR, 1.27; P = .019), septic shock (OR, 7.96; P <.0001), and a ceftolozane/tazobactam MIC >2 mg/L (OR, 3.33; P = .045) were independently associated with 30-day mortality. Four adverse events attributable to ceftolozane/tazobactam occurred,: leukopenia, encephalopathy with myoclonus, renal failure, and hepatitis.

Although this study was retrospective and observational in nature, the cohort included patients with multidrug-resistant and extensively drug-resistant P aeruginosa respiratory tract infections with significant comorbidities and severity-of-illness indicators. The mortality benefit of high-dose ceftolozane/tazobactam in patients with MICs ≤2 mg/L strengthens the case for the higher dose of ceftolozane/tazobactam for respiratory tract infections, now FDA approved. In this study, MIC >2 mg/L was a stronger predictor for increased mortality than was the ceftolozane/tazobactam dosing strategy, reinforcing the difficulty of treating patients who have these resistant organisms. The association of increased MIC with risk of clinical failure has been described in other studies as well.⁶ Further research on strategies to optimize the pharmacokinetic and pharmacodynamic parameters of these novel agents in the age of antimicrobial resistance is needed to improve outcomes. When using ceftolozane/ tazobactam to treat patients with P aeruginosa respiratory tract infections, the use of extended or continuous antibiotic infusion and/or combination therapy with other active antibiotic agents should be considered, particularly if targeting higher MIC values.^7-9

Catherine Li, PharmD, is currently a PGY-2 infectious diseases pharmacy resident at Beth Israel Deaconess Medical Center in Boston, MA. Her clinical interests include antimicrobial stewardship, antimicrobial resistance, and transitions of care.

* indicates active member of the Society of Infectious Diseases Pharmacists

References

1. Moya B, Zamorano L, Juan C, Pérez JL, Ge Y, Oliver A. Activity of a new cephalosporin, CXA-101 (FR264205), against beta-lactam-resistant Pseudomonas aeruginosa mutants selected in vitro and after antipseudomonal treatment of intensive care unit patients. Antimicrob Agents Chemother. 2010;54(3):1213-1217. doi: 10.1128/AAC.01104-09.
2. Xiao AJ, Miller BW, Huntington JA, Nicolau DP, Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol. 2016;56(1):56-66. doi: 10.1002/jcph.566.
3. Kollef MH, Nová&#269;ek M, Kivistik Ü, et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2019;19(12):1299-1311. doi: 10.1016/S1473-3099(19)30403-7.
4. Rodríguez-Núñez O, Periañez-Parraga L, Oliver A, et al. Higher MICs (>2 mg/L) predict 30-day mortality in patients with lower respiratory tract infections caused by multidrug- and extensively drug-resistant Pseudomonas aeruginosa treated with ceftolozane/tazobactam. Open Forum Infect Dis. 2019;6(10):ofz416. doi: 10.1093/ofid/ofz416.
5. Zerbaxa [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2019.
6. Escola-Verge L, Pigrau C, Los-Arcos I, et al. Ceftolozane/tazobactam for the treatment of XDR Pseudomonas aeruginosa infections. Infection. 2018;46(4):461-468. doi: 10.1007/s15010-018-1133-5.
7. Pilmis B, Petitjean G, Lesprit P, et al. Continuous infusion of ceftolozane/tazobactam is associated with a higher probability of target attainment in patients infected with Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis. 2019;38(8):1457-1461. doi: 10.1007/s10096-019-03573-4.
8. Davis SE, Ham J, Hucks J, et al. Use of continuous infusion ceftolozane—tazobactam with therapeutic drug monitoring in a patient with cystic fibrosis. Am J Health Syst Pharm. 2019;76(8):501-504. doi: 10.1093/ajhp/zxz011.
9. Natesan S, Pai MP, Lodise TP. Determination of alternative ceftolozane/tazobactam dosing regimens for patients with infections due to Pseudomonas aeruginosa with MIC values between 4 and 32&thinsp;mg/L. J Antimicrob Chemother. 2017;72(10):2813-2816. doi: 10.1093/jac/dkx221

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