CAMEL
Ceftazidime-Avibactam versus Meropenem-vaborbactam for the treatment of bloodstream infections and/or pneumonia due to carbapenem-resistant EnterobacteraLes
Background
Infections caused by carbapenem-resistant Enterobacterales (CRE) are a threat to global public health. Historically, treatment options for CRE infection were limited to poorly effective and highly toxic agents resulting in mortality rates for invasive CRE infections that ranged from 26% to 44%.1 The U.S. Centers for Disease Control and Prevention estimates that more than 13,000 people are infected in the United States and 1,100 die due to CRE infections each year.2 Resistance to carbapenems is mediated by multiple resistance mechanisms, but the most concerning is production of carbapenemase enzymes that are acquired via mobile genetic elements. The most prominent type of carbapenemase in the U.S. is Klebsiella pneumoniae carbapenemase (KPC), an Ambler class A enzyme. In a multicenter study in the U.S. from over 800 patients with confirmed CRE infection or colonization during 2016-2017, carbapenem-resistance due to carbapenemase production was found in 76% of isolates, 93% of which expressed KPC. 3
Given the poor historic outcomes in patients with carbapenemase producing organisms, novel therapies have been developed to treat CRE infections more effectively and safely. These efforts lead to the development of new agents, including ceftazidime-avibactam and meropenem-vaborbactam, which are now the guideline recommended agents for the treatment of KPC infections. Compared to historic treatment options, treatment with either ceftazidime-avibactam or meropenem-vaborbactam has been associated with improved clinical outcomes for patients with infections due to KPC-producing Enterobacterales. 4-7
To date, there are limited data assessing the comparative efficacy of ceftazidime-avibactam and meropenem-vaborbactam against KPC infection. 8,9 Observational experiences suggest decreased resistance development with meropenem-vaborbactam compared to ceftazidime-avibactam, but comparative data is lacking. 8,10-14
CAMEL is a retrospective, multicenter, observational study seeking to compare the clinical efficacy of ceftazidime-avibactam and meropenem-vaborbactam for the treatment of CRE in the United States. Across 500 patients, we will measure clinical outcomes of patients over 90 days from study treatment initiation. We will use inverse probability of treatment weighting to adjust for baseline confounders across patient cohorts and conduct a predefined desirability of outcome ranking (DOOR) analysis.
Whenever available, isolates will be collected from participating sites for molecular characterization, identification of resistance mechanisms, and broth microdilution susceptibility testing.
Details
Progress
Sites are being screened for potential participation. Onboarding will begin soon. Stay tuned for announcements of preliminary data reports.
References:
1. Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis 2014; 20(7): 1170-5.
2. CDC. Antibiotic Resistance Threats in the United States. Atlanta, GA: US Department of Health and Human Services 2019.
3. van Duin D, Arias CA, Komarow L, et al. Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study. Lancet Infect Dis 2020; 20(6): 731-41.
4. Hakeam HA, Alsahli H, Albabtain L, Alassaf S, Al Duhailib Z, Althawadi S. Effectiveness of ceftazidime-avibactam versus colistin in treating carbapenem-resistant Enterobacteriaceae bacteremia. Int J Infect Dis 2021; 109: 1-7.
5. van Duin D, Lok JJ, Earley M, et al. Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae. Clin Infect Dis 2018; 66(2): 163-71.
6. Almangour TA, Ghonem L, Aljabri A, et al. Ceftazidime-Avibactam versus Colistin for the Treatment of Infections Due to Carbapenem-Resistant Enterobacterales: A Multicenter Cohort Study. Infect Drug Resist 2022; 15: 211-21.
7. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infect Dis Ther 2018; 7(4): 439-55.
8. Ackley R, Roshdy D, Meredith J, et al. Meropenem-Vaborbactam versus Ceftazidime-Avibactam for Treatment of Carbapenem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother 2020; 64(5).
9. Shields RK, McCreary EK, Marini RV, et al. Early Experience With Meropenem-Vaborbactam for Treatment of Carbapenem-resistant Enterobacteriaceae Infections. Clin Infect Dis 2020; 71(3): 667-71.
10. Iannaccone M, Boattini M, Bianco G, Corcione S, Cavallo R, Costa C. Ceftazidime-avibactam susceptible to resistant KPC-producing Enterobacterales bloodstream infections: an observational study. J Chemother 2020; 32(3): 160-2.
11. Karaiskos I, Daikos GL, Gkoufa A, et al. Ceftazidime/avibactam in the era of carbapenemase-producing Klebsiella pneumoniae: experience from a national registry study. J Antimicrob Chemother 2021; 76(3): 775-83.
12. Shields RK, Nguyen MH, Chen L, Press EG, Kreiswirth BN, Clancy CJ. Pneumonia and Renal Replacement Therapy Are Risk Factors for Ceftazidime-Avibactam Treatment Failures and Resistance among Patients with Carbapenem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother 2018; 62(5).
13. Shields RK, Potoski BA, Haidar G, et al. Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections. Clin Infect Dis 2016; 63(12): 1615-8.
14. Tumbarello M, Raffaelli F, Giannella M, et al. Ceftazidime-Avibactam Use for Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Infections: A Retrospective Observational Multicenter Study. Clin Infect Dis 2021; 73(9): 1664-76.