Efficacy of Cefoperazone-Sulbactam as Empirical Monotherapy Therapy for Febrile Neutropenia in Children with Solid Tumors and Lymphomas

Öz

Objective: Monotherapy with a beta lactam or a cephalosporin has become the standard of care for the treatment of febrile neutropenia (FEN). We aimed to evaluate the efficacy of cefoperazone/sulbactam (CS) as empirical monotherapy for febrile neutropenia in children with solid tumors and lymphomas. Material and Methods: Children with FEN received cefaperazone-sulbactam (80 mg/kg/day, every 8 hours). Treatment responses (a) successful, complete resolution of all signs and symptoms of infection at 72 hours and after 7 days of CS treatment; (b) success with modification, change of therapy for viral, parasitic or fungal infection or addition of glycopeptides; (c) failure was defined as the emergence of a new or resistant infection, treatment-resistant bacteremia, the need to switch to carbapenems. Results: Our study included 157 patients and 350 febrile neutropenia episodes. The most common diagnoses were osteosarcoma (35%), Ewing sarcoma (30%), non-hodgkin lymphoma (13%) and rhabdomyosarcoma (9%), respectively. The origin of fever could not be determined in 223 (64%) of FEN episodes, 79 (22%) had microbiologically documented infection (MDI), and 48 (14%) had clinically documented infection (CDI). The success rate was 65% (229), the success rate with modification was 9% (31) and the failure rate was 26% (90). SC monotherapy was successful in 33% of attacks with MDI and in 60% of attacks with CDI. However, SC monotherapy was successful in 82% of febrile episodes of unknown origin. Conclusion: Cefoperazone/sulbactam is effective and safe in febrile neutropenic children with solid tumors and lymphomas for monotherapy.

Anahtar Kelimeler

• Cancer
• Cefoperazone
• Child
• Febrile neutropenia
• Sulbactam

Lenfoma ve Solid Tümörlü Çocuklarda Febril Nötropenide Sefaperazon-Sulbaktam Monoterapisinin Etkinliği

Öz

Amaç: Febril nötropeninin tedavisinde beta laktam veya bir sefalosporin ile monoterapi, standart haline gelmiştir. Bu çalışmada solid tümörlü ve lenfomalı çocuklarda febril nötropeninin ampirik tedavisi olarak sefoperazon/sulbaktamın (SS) etkinliğini değerlendirmeyi amaçladık. Gereç ve Yöntemler: Febril nötropenik çocuk hastalara sefaperazon-sulbaktam (80 mg / kg / gün, 8 saatte bir) başlandı. Tedavi yanıtları (a) başarılı, 72. saatte ve 7 günlük SS tedavisinden sonra enfeksiyonun tüm belirti ve semptomlarının tamamen düzelmesi; (b) modifikasyon ile başarılı, viral, parazitik veya mantar enfeksiyonu için tedavi değişikliği veya glikopeptid ilavesi; (c) başarısızlık, yeni veya dirençli bir enfeksiyonun ortaya çıkması, tedaviye dirençli bakteriyemi, karbapenemlere geçme veya aynı spektrumda bir antibiyotik ekleme ihtiyacı olarak tanımlandı. Bulgular: Yüz elli yedi hastaya ait 350 febril nötropeni atağı (K: 73, E: 84, ortanca yaş: 11.8 yıl (0.6-18)) kaydedildi. En sık tanılar sırasıyla osteosarkom (%35), Ewing sarkomu (%30), non-hodgkin lenfoma (%13) ve rabdomyosarkomdu (%9). Ortanca mutlak nötrofil sayısı 60/mm3 (0-800) ve nötropeni süresi 7 gün (3-60)’dı. Ortanca tedavi süresi 7 gündü (3-30). FEN ataklarının 223’ünde (%64) ateşin kaynağı tespit edilemedi, 79’unda (%22) mikrobiyolojik dokümante enfeksiyon (MDE) vardı ve 48’inde (%14) klinik dokümante enfeksiyon mevcuttu (KDE). Başarı oranı %65 (229), modifikasyon ile başarı oranı % 9 (31) ve başarısızlık oranı %26 (90)’dı. Sefoperazon/sulbaktam monoterapisi MDE olan atakların %33’ünde, KDE olan atakların %60’ında başarılı oldu. Ancak SS monoterapisi nedeni bilinmeyen ateşli atakların %82’sinde başarılı oldu. Sonuç: Sefoperazon/sulbaktam, solid tümör ve lenfomalı çocuklarda nötropenik ateşin tedavisinde monoterapi olarak etkili ve güvenlidir.

Anahtar Kelimeler

• Kanser
• Sefoperazon
• Çocuk
• Febril nötropeni
• Sulbaktam

Kaynakça

1. Ardura M.I KAY. Infectious Complications in Children with Underlying Malignancy. In: Blaney S.M HLJ, Adamson PC, editor. Pizzo and Poplack’s Pediatric Oncology. EIGHT ed. Philadelphia: Wolters Kluwer Health 2021.
2. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. 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;52:e56-93.
3. Anoshirvani AA, Zarinfar N, Rafiee M, Zamani Z. Effect of combination therapy of ceftazidime/amikacin and monotherapy with imipenem on the treatment of fever and neutropenia in patients with cancers. Open Access Maced J Med Sci 2018;6:1423-30.
4. Andreatos N, Flokas ME, Apostolopoulou A, Alevizakos M, Mylonakis E. The dose-dependent efficacy of cefepime in the empiric management of febrile neutropenia: a systematic review and meta-analysis. Open Forum Infect Dis 2017;4: ofx113.
5. Lee NH, Kang JM, Lee JW, Huh HJ, Lee NY, Yoo KH, et al. Cefepime versus cefepime plus amikacin as an initial antibiotic choice for pediatric cancer patients with febrile neutropenia in an era of increasing cefepime resistance. Pediatr Infect Dis J 2020;39:931-6.
6. Kebudi R, Kizilocak H. Febrile neutropenia in children with cancer: approach to diagnosis and treatment. Curr Pediatr Rev 2018;14:204-9.
7. Horita N, Shibata Y, Watanabe H, Namkoong H, Kaneko T. Comparison of antipseudomonal β-lactams for febrile neutropenia empiric therapy: systematic review and network meta-analysis. Clin Microbiol Infect 2017;23:723-9.
8. Xin X, Jian L, Xia X, Jia B, Huang W, Li C, et al. A multicentre clinical study on the injection of ceftriaxone/sulbactam compared with cefoperazone/sulbactam in the treatment of respiratory and urinary tract infections. Ann Clin Microbiol Antimicrob 2013;12:38.

9. Karaman S, Vural S, Yildirmak Y, Emecen M, Erdem E, Kebudi R. Comparison of piperacillin tazobactam and cefoperazone sulbactam monotherapy in treatment of febrile neutropenia. Pediatr Blood Cancer 2012;58:579-83.
10. Lehrnbecher T, Robinson PD, Ammann RA, Fisher B, Patel P, Phillips R, et al. Guideline for the Management of Fever and Neutropenia in Pediatric Patients With Cancer and Hematopoietic Cell Transplantation Recipients: 2023 Update. J Clin Oncol 2023;41:1774-85.
11. Robinson PD, Lehrnbecher T, Phillips R, Dupuis LL, Sung L. Strategies for empiric management of pediatric fever and neutropenia in patients with cancer and hematopoietic stem-cell transplantation recipients: a systematic review of randomized trials. J Clin Oncol 2016;34:2054-60.
12. Horita, N, Shibata Y, Watanabe H, Namkoong H, Kaneko T. Comparison of antipseudomonal β-lactams for febrile neutropenia empiric therapy: systematic review and network meta-analysis. Clin Microbiol Infect 2017;23:723-9.
13. Aynioglu A, Mutlu B, Hacihanefioglu A. A comparison of the efficacy of piperacillin-tazobactam and cefoperazone-sulbactam therapies in the empirical treatment of patients with febrile neutropenia. Rev Esp Quimioter 2016;29:69-75.
14. Demir HA, Kutluk T, Ceyhan M, Yağcı-Küpeli B, Akyüz C, Cengiz B. Comparison of sulbactam-cefoperazone with carbapenems as empirical monotherapy for febrile neutropenic children with lymphoma and solid tumors. Pediatr Hematol Oncol 2011;28:299-310.
15. Demirkaya M, Celebi S, Sevinir B, Hacımustafaoglu M. Randomized comparison of piperacillin-tazobactam plus amikacin versus cefoperazone-sulbactam plus amikacin for management of febrile neutropenia in children with lymphoma and solid tumors. Pediatr Hematol Oncol 2013;30:141-8.
16. Ponraj M, Dubashi B, Harish BH, Kayal S, Cyriac SL, Pattnaik J, et al. Cefepime vs. cefoperazone/sulbactam in combination with amikacin as empirical antibiotic therapy in febrile neutropenia. Support Care Cancer 2018;26:3899-908.
17. Lan SH, Chang SP, Lai CC, Lu LC, Tang HJ. Efficacy and safety of cefoperazone-sulbactam in empiric therapy for febrile neutropenia: A systemic review and meta-analysis. Medicine (Baltimore) 2020;99:e19321.
18. Febrile Neutropenia Study Group. Guidelines for diagnosis and treatment of neutropenic patients. Flora 2004;9:5-28.
19. Kar YD, Özdemir ZC, Bör Ö. Evaluation of febrile neutropenic attacks of pediatric hematology-oncology patients. Turk Pediatri Ars 2017;52:213-20.
20. Uygun V, Karasu GT, Ogunc D, Yesilipek A, Hazar V. Piperacillin/tazobactam versus cefepime for the empirical treatment of pediatric cancer patients with neutropenia and fever: a randomized and open-label study. Pediatr Blood Cancer 2009;53:610-4.
21. Altınel E YN, Işık P, Özkasap S, Bay A, Kara A. Evaluation of febrile neutropenia in children with acute leukemia. Turkish J Pediatr Dis 2012;6:93-100.
22. Meena JP, Brijwal M, Seth R, Gupta AK, Jethani J, Kapil A, et al. Prevalence and clinical outcome of respiratory viral infections among children with cancer and febrile neutropenia. Pediatr Hematol Oncol 2019;36:330-43.
23. Alali M, David MZ, Danziger-Isakov LA, Elmuti L, Bhagat PH, Bartlett AH. Pediatric febrile neutropenia: change in etiology of bacteremia, empiric choice of therapy and clinical outcomes. J Pediatr Hematol Oncol 2020;42:e445-e51.
24. Özdemir ZC, Koç A, Ayçiçek A. Microorganisms isolated from cultures and infection focus and antibiotic treatments in febrile neutropenic children from Şanlıurfa, Turkey. Turk J Pediatr 2016;58:47-53
25. Perdikouri EIA, Arvaniti K, Lathyris D, Apostolidou Kiouti F, Siskou E, Haidich AB, et al. Infections due to multidrug-resistant bacteria in oncological patients: insights from a five-year epidemiological and clinical analysis. Microorganisms 2019;7:277.