الفهرس 
Review of LiteratureOnly 14 pages are availabe for public view
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Abstract
Febrile neutropenia (FN) is common in hematological and solid malignancies as a consequence of cytotoxic chemotherapy and is an important cause of death in children. About one-third of children treated with these cytotoxic drugs experienced FN during the neutropenic period. During FN, there are bloodstream infections with multidrug-resistant gram-negative bacteria (MDR-GNB), and the defective inflammatory and immunologic responses lead to sepsis and death (Hsu and Tamma, 2014). Consequently, a medical emergency mandates the prompt administration of antibiotic therapy to treat these patients (Zimmer and Freifeld, 2019).
Colistin was initially discovered in the 1940s and was used in several countries. However, its association with nephrotoxicity and neurotoxicity limited its use. Colistin, a member of the polymyxin family of antibiotics, has been reintroduced to clinical practice after the increased incidence of infections caused by MDR-GNB (Li et al., 2006). Colistin methanesulphonate (CMS) is a prodrug of colistin that hydrolyses in vivo, yielding the active colistin base (Fan et al., 2022). Colistin is now used as 2nd line agent in the treatment of carbapenem-resistant Enterobacteriaceae (CRE) and MDR-GN infections (Hsu and Tamma, 2014). Its effectiveness against most gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii, is well documented (Zimmer and Freifeld, 2019). An excellent index to measure the efficacy of colistin is the pharmacokinetic/pharmacodynamic index (PK/PD), defined as the ratio of the area under the concentration-time curve from 0 to 24hr (AUC24) to the minimum inhibitory concentration (MIC). In 2019 International Consensus Guidelines for the Optimal Use of the Polymyxins recommended a target AUC≥ 50 mg.hr/L to equate to a target steady-state concentration of 2mg/L. However, lower respiratory tract infection may require a higher target AUC24. It is recommended to consider the dose that provides the maximum exposure to colistin with the least side effect (Tsuji et al., 2019).
Currently, the FDA-recommended doses for pediatric patients are 2.5 - 5 mg/kg /day of CBA in 2-4 divided doses (Tsuji et al., 2019). However, pharmacodynamic and pharmacokinetic data in the pediatric population are still lacking.
In this study, we aimed to study the pharmacokinetic/pharmacodynamic of the two currently used doses of colistin to evaluate their effectiveness, treatment outcomes, and incidence of nephrotoxicity in pediatric oncology patients suffering from febrile neutropenia caused by MDR-GN infection.
The study was a prospective, randomized clinical study comparing two different colistin doses in pediatric cancer patients with MDR gram-negative infection. Patients were recruited at the Pediatric Oncology Unit and the Pediatric Intermediate Care Unit at the National Cancer Institute, Cairo University. Enrolled patients were randomized to receive either a low dose (Loading dose of 2.5 mg/kg followed by a maintenance dose of 1.25 mg/kg as a short infusion every 12 hr.) or a high dose (Loading dose of 5 mg/kg followed by a maintenance dose of 2.5 mg/kg as a short infusion for 30min every 12 hr.).
All patients’ data were collected from the patient’s files, including demographic and clinical characteristics. Other clinical data included clinical cure (resolution of clinical signs and symptoms of infections), time to defervescence(fever resolution), microbiological clearance (disappearance of MDR-GN bacterial isolates on follow-up cultures), time to microbiological clearance (Dalfino et al., 2012), mortality, the development of nephrotoxicity (assessed and graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC AE) v5.0) and length of hospital stay and adjusted length of stay (time from the start of colistin till the discharge of the hospital or death). Blood samples were withdrawn from the patients after reaching a steady state (after 4 days) of CMS therapy. Two blood samples (3 mL) of venous blood were drawn into a heparinized tube, the trough concentrations (Cmin) were collected just before the next dose, and peak concentrations (Cmax) were collected 30 minutes after the end of the CMS infusion.
This study showed that both groups, had comparable baseline demographic characteristics, clinical, microbiological and laboratory as well as clinical scoring systems, the sequential organ failure assessment score [SOFA] and the pediatric risk of mortality III score [ PRISM III]. Comparable rate of clinical cure was observed in both arms of the study with 85.2 % in the LD group vs 82.1% in the HD group. Microbiological clearance was detected in 95.7 %vs 91.6% in the LD and HD groups respectively. However, the LD group had a lower number of days to microbiological clearance versus the HD group (4 vs. 6 days p= 0.007). The mortality rate was comparable in LD and HD groups. Both colistin doses triggered grade 1-2 nephrotoxicity in 6(22.2%) and 5(17.9%) patients in LD and HD groups, respectively, p=0.686. Those with TLC<1000(x103cells/µl) and ANC<100 (x103cells/µl) declined significantly in LD.
Total colistin trough plasma concentration (Cmin) was evaluated and showed a significantly higher level [1.16(0.2-3.51)g/mL] in the HD group compared to [0.54(0.0-1.71) g/mL]in the LD group. In contrast, the peak concentration (Cmax) showed no significant difference between both groups, [10.6(2.22-18.52)]vs [7.52(0.99-18.84) g/mL]in the LD and HD group, respectively. The observed median AUC 24 was [ 37.9(11.4-75.97) g.hr/mL] in the LD group compared to [44.19(11.14-98.74)g.hr/mL]in the HD group, with no significant difference. in addition, a non-significant difference existed between the median AUC/MIC in both groups, the LD group showed a median of [47.2(14.7-131.7)] compared to [45.1(6.2-131.7)] in the HD group. Four (25%) patients vs. 4(33.3%) in the LD and HD group (p-value 0.69) attained an optimal plasma AUC/MIC, while the therapeutic level of colistin was reached in all patients in the LD group compared to 14/16 (87.5%) in the HD group.
In conclusion, the current study suggests that both doses are adequately effective and safe in treating infections caused by MDR gram-negative bacteria in children with cancer, with a slightly more favorable outcome with the LD group. These favorable effects were evident in the time to clearance of the microorganism and in those recovering from low TLC and ANC.