Antimicrobial Revision in Persistent Febrile Neutropenia

Febrile Neutropenia Clinical Trial

Official title:

Antimicrobial Revision in Patients With Persistent Febrile Neutropenia: A Prospective, Randomized Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05784844
• Other study ID #: IRB00088805
• Status: Recruiting
• Phase: Phase 4
• Start date: August 2024
• Est. completion date: April 2025

Study information

• Verified date: February 2024
• Source: Wake Forest University Health Sciences
• Contact: John Williamson, PharmD
• Phone: 336-713-3431
• Email: johnwill[@]wakehealth.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Febrile neutropenia is often seen in patients with hematologic malignancies who receive cytotoxic chemotherapy. These patients are usually placed on posaconazole prophylaxis upon starting chemotherapy. If an episode of febrile neutropenia occurs, generally an anti-pseudomonal beta lactam, like cefepime or piperacillin-tazobactam, is initiated. In patients who continue to fever on these agents, the optimal method of antimicrobial revision has yet to be determined.

Description:

In this prospective, randomized, open-label, single-center trial, the primary objective is to compare the clinical efficacy of two approaches to antimicrobial revision among patients with persistent febrile neutropenia. Neutropenic patients on cefepime or piperacillin-tazobactam who continue to fever for greater than 96 hours will be randomized to receive either meropenem or micafungin dosed according to local guidelines. The primary outcome is a global success rate including a composite of defervescence within 72 hours of meropenem or micafungin initiation, absence of signs or symptoms of infection, and no modification to antimicrobial regimen after initiation of meropenem or micafungin. The secondary outcomes to be collected include in-hospital mortality or discharge to hospice, hospital length of stay, time to defervescence, days of therapy of meropenem or micafungin, rate of Clostridioides difficile infection on meropenem or micafungin, and cause of any proven breakthrough infection while on meropenem or micafungin.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: April 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• = 18 years of age

• Diagnosis of hematologic malignancy

• Receiving chemotherapy as treatment of hematologic malignancy

• Neutropenia defined as an absolute neutrophil count (ANC) = 500 cells/mm3 or an ANC = 1000 cells/mm3 with a predicted decline to < 500 cells/mm3 within 48 hours

• Prescribed cefepime or piperacillin-tazobactam as initial treatment for febrile neutropenia

• Persistent fever for = 96 hours since initiation of cefepime or piperacillin-tazobactam OR recurrent fever that occurs = 96 hours since initiation of cefepime or piperacillin-tazobactam (fever defined as single temperature of = 38.3°C (101°F) or a temperature of = 38°C (100.4°F) on two consecutive measures separated by at least one hour)

• Receipt of posaconazole as neutropenia prophylaxis for at least 3 calendar days

Exclusion Criteria:

• Clinically or microbiologically confirmed infection at time of enrollment, For example, a positive culture or rapid diagnostic test, positive imaging (X-ray, CT, MRI) or biomarker, such as galactomannan, that is consistent with infection

• History of infection with organism known to be resistant to meropenem or micafungin

• Documented allergy to carbapenems or echinocandins

• Concomitant use of valproic acid

• Uncontrolled seizure disorder

• Pregnancy

• Previous enrollment in this study

Related Conditions & MeSH terms

• Febrile Neutropenia
• Fever
• Hyperthermia
• Neutropenia

Intervention

Drug:
• Meropenem
Carbapenem antibiotic
• Micafungin
Echinocandin antifungal

Locations

Country	Name	City	State
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Wake Forest University Health Sciences

Country where clinical trial is conducted

United States, 

References & Publications (11)

Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, Gyssens IC, Kern WV, Klyasova G, Marchetti O, Engelhard D, Akova M; ECIL4, a joint venture of EBMT, EORTC, ICHS, ESGICH/ESCMID and ELN. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013 Dec;98(12):1826-35. doi: 10.3324/haematol.2013.091025. Erratum In: Haematologica. 2014 Feb;99(2):400. — View Citation

Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011 Feb 15;52(4):e56-93. doi: 10.1093/cid/cir073. — View Citation

Nakagawa Y, Suzuki K, Ohta K, Hino M, Ohyashiki K, Kanamaru A, Tamura K, Urabe A, Masaoka T; Japan Febrile Neutropenia Study Group. Prospective randomized study of cefepime, panipenem, or meropenem monotherapy for patients with hematological disorders and febrile neutropenia. J Infect Chemother. 2013 Feb;19(1):103-11. doi: 10.1007/s10156-012-0466-8. Epub 2012 Sep 5. — View Citation

Nakane T, Tamura K, Hino M, Tamaki T, Yoshida I, Fukushima T, Tatsumi Y, Nakagawa Y, Hatanaka K, Takahashi T, Akiyama N, Tanimoto M, Ohyashiki K, Urabe A, Masaoka T, Kanamaru A; Japan Febrile Neutropenia Study Group. Cefozopran, meropenem, or imipenem-cilastatin compared with cefepime as empirical therapy in febrile neutropenic adult patients: A multicenter prospective randomized trial. J Infect Chemother. 2015 Jan;21(1):16-22. doi: 10.1016/j.jiac.2014.08.026. Epub 2014 Sep 17. — View Citation

National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prevention and Treatment of Cancer-Related Infections Version 1.2022. Accessed July 12, 2022. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1457

Oyake T, Kowata S, Murai K, Ito S, Akagi T, Kubo K, Sawada K, Ishida Y. Comparison of micafungin and voriconazole as empirical antifungal therapies in febrile neutropenic patients with hematological disorders: a randomized controlled trial. Eur J Haematol. 2016 Jun;96(6):602-9. doi: 10.1111/ejh.12641. Epub 2015 Aug 26. — View Citation

Oztoprak N, Piskin N, Aydemir H, Celebi G, Akduman D, Keskin AS, Gokmen A, Engin H, Ankarali H. Piperacillin-tazobactam versus carbapenem therapy with and without amikacin as empirical treatment of febrile neutropenia in cancer patients: results of an open randomized trial at a university hospital. Jpn J Clin Oncol. 2010 Aug;40(8):761-7. doi: 10.1093/jjco/hyq046. Epub 2010 Apr 28. — View Citation

Ratliff CM, Beardsley JR, Kennedy L, Ohl C, Johnson JW, Luther VP, William JC. Efficacy of doripenem compared with meropenem for treatment of febrile neutropenia among patients who became febrile while on cefepime or piperacillin-tazobactam. Poster Presented at: Infectious Diseases Society of America Annual Meeting; October 21, 2011; Boston, MA. https://idsa.confex.com/idsa/2011/webprogram/Paper30902.html

Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, Cornely OA, Bourque MR, Lupinacci RJ, Sable CA, dePauw BE. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004 Sep 30;351(14):1391-402. doi: 10.1056/NEJMoa040446. — View Citation

Wang Y, Du Z, Chen Y, Liu Y, Yang Z. Meta-analysis: combination of meropenem vs ceftazidime and amikacin for empirical treatment of cancer patients with febrile neutropenia. Medicine (Baltimore). 2021 Feb 26;100(8):e24883. doi: 10.1097/MD.0000000000024883. — View Citation

Zimmer AJ, Freifeld AG. Optimal Management of Neutropenic Fever in Patients With Cancer. J Oncol Pract. 2019 Jan;15(1):19-24. doi: 10.1200/JOP.18.00269. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Global Success Rate	Percentage of study candidates who meet all of the following criteria: Defervescence, as defined by a temperature < 38°C (100.4°F) sustained for at least 24 consecutive hours, within 72 hours of meropenem or micafungin initiation; Absence of signs or symptoms of infection within 72 hours of meropenem or micafungin initiation including but not limited to hypotension, erythema at catheter sites or cellulitis, positive imaging concerning for infection (e.g., pneumonia, osteomyelitis, abscesses etc.), positive cultures or rapid diagnostic tests, positive biomarkers (e.g. galactomannan), dysuria, hypothermia (= 35°C or = 95°F) etc.; No modification to antimicrobial regimen after initiation of meropenem or micafungin unless the antibiotic modification is considered de-escalation (e.g. discontinuation of vancomycin)	Hour 72
Secondary	Number of Subjects In-hospital mortality or discharge to hospice	Death during in-hospital admission or discharge from in-hospital admission to hospice care	From hospital admission to death/discharge to hospice, up to 4 days
Secondary	Hospital length of stay (days)	Number of days admitted to hospital	From hospital admission to discharge, up to 4 days
Secondary	Time to defervescence (hours)	Time of defervescence defined as the beginning of the 24 consecutive hour afebrile period; Time to defervescence defined as the time in hours from the initial documented fever to the beginning of the 24 consecutive hour afebrile period	through study completion, an average of 4 days
Secondary	Days of therapy of meropenem or micafungin	1 antibiotic x the number of days administered, any calendar day in which at least one dose is given counts as a full day of therapy - Time in days from initiation to discontinuation of meropenem or micafungin	through study completion, an average of 4 days
Secondary	Rate of Clostridioides difficile infection on meropenem or micafungin	Percentage of patients who develop Clostridioides difficile infection while on meropenem or micafungin	through study completion, an average of 4 days
Secondary	Collection of Causes of any proven breakthrough infection while on meropenem or micafungin	Collection of origin of proven breakthrough infection	through study completion, an average of 4 days

External Links

•   National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®)