Antibacterial prophylaxis in pediatric patients with leukemia.

BACKGROUND: Bacterial infections in pediatric patients with leukemia are associated with increased risks for morbidity and mortality. Few Recommendations have been made on the use of antibacterial prophylaxis in pediatrics with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). OBJECTIVES: To determine the role of antibacterial prophylaxis in pediatric patients with leukemia and the most appropriate regimen that can be safely and effectively used. METHODS: Literature search was conducted independently by 3 reviewers to find studies on the safety and effectiveness of antibacterial prophylactic regimens. RESULTS: The search strategy resulted in 13 studies; most of them were observational studies. The available evidence recommends use of antibiotics with Gram-positive bacterial coverage in AML patients. In ALL patients, prophylaxis was used during the intensive phases of chemotherapy with ciprofloxacin being recommended most commonly. CONCLUSION: Antibacterial prophylaxis mainly with coverage against Gram-positive bacteria is recommended in pediatric patients with AML. For ALL patients, prophylaxis may be considered for patients who are undergoing intensive chemotherapy phases and are at high risk for infections with ciprofloxacin being the most commonly used agent. In general more studies are needed to determine the role of antibacterial prophylaxis in pediatric patients with leukemia.

Genetic Polymorphism of Thiopurine S-methyltransferase in Children with Acute Lymphoblastic Leukemia in Jordan

Background and Aims: It has been demonstrated that homozygote and heterozygote mutant allele carriers for thiopurine S-methyltransferase (TPMT) are at high risk of developing myelosuppression after receiving standard doses of 6-mercaptopurine (6-MP). The aim of this study was to determine the frequency of TPMT deficient alleles in children with acute lymphoblastic leukemia (ALL) in Jordan and to compare it with other ethnic groups. Methods: We included 52 ALL childhood cases from King Hussein Cancer Research Center in Jordan. Genotyping of the rs1800460, rs1800462, and rs1142345 SNPs was performed by polymerase chain reaction (PCR) followed by sequencing. Comparisons were made with historical data for controls and for both volunteers and cases from other middle-eastern countries. Results: Mutant TPMT alleles were present in 3.8% (2/52) of patients. Allelic frequencies were 1.0% for both TPMT*B and TPMT*C. None of the patients were heterozygous or homozygous for TPMT*3A or TPMT *2. We did not find statistically significant differences in the distribution of mutant alleles between Jordan and other middle-eastern countries for both healthy volunteers or ALL patients. Conclusions: The overall frequency of TPMT mutant alleles was low and did not exhibit differences compared to other middle-eastern countries, including Jordanian studies assessing TPMT mutant alleles in healthy volunteers. The current results question the value of TPMT genotyping in the Jordanian population.

Adherence to 6-Mercaptopurine in children and adolescents with Acute Lymphoblastic Leukemia.

OBJECTIVE: Studies on children with Acute Lymphoblastic Leukemia (ALL) reported non-adherence in 2-54% of cases. The primary objective of this study was to assess rates of adherence to 6-MP using two different methods in children and adolescents with ALL. Secondary aim was to identify factors that influence adherence to 6-MP in children with ALL. METHODS: All eligible children with ALL who are (≤ 19) years old and receive 6-MP therapy for at least 1 month were approached to participate in the study. A total of 52 children with ALL and their primary caregivers were recruited. Adherence measures included an objective method (measuring 6-MP metabolites in packed Red Blood Cells (RBCs)) and a subjective method (using parent and child self-report via the Medication Adherence Report Scale; MARS; Adherence was defined as 90% or greater). RESULTS: Rates of adherence varied across the measurement methods. Packed RBCs sample analysis indicated forty-four patients (84.6%) to be adherent. Using the MARS questionnaires, a total of 49 children (94.2%) were classified as being adherent according to the parental MARS questionnaire scores, while all the 15 children (100%) who answered the MARS (child) questionnaire were classified as adherent. Overall adherence rate was 80.8% within the studied population. CONCLUSION: MARS scale was shown to overestimate adherence compared to measurement of 6-MP metabolites in the blood. A combination of both methods led to increased detection of non-adherence to thiopurine in children with ALL.

Bacterial Infections in Children With Acute Myeloid Leukemia Receiving Ciprofloxacin Prophylaxis.

BACKGROUND: The aim of the study was to describe the incidence and type of bacterial infections associated with the use of ciprofloxacin prophylaxis as single agent in pediatric patients with acute myeloid leukemia (AML). PROCEDURE: This was a retrospective review of all patients with AML, who were treated according to the AML02 protocol between 2011 and 2015. The medical records were reviewed for any positive cultures from the initiation of the protocol until death or protocol discontinuation. Patient demographics, type of infections, type of isolated bacteria, and intensive care unit admissions were recorded. RESULTS: A total of 50 patients were evaluated, who were of a mean age of 8 years±5.1 (SD). We identified 77 episodes of bacterial infections in 42 (84%) patients. Among those bacterial infections, 73 episodes were with bacteremia and included 45 (62%) gram-positive bacterial infections, 24 (33%) gram-negative bacterial infections, and 4 (6%) mixed gram-negative and gram-positive bacterial infections. Coagulase-negative Staphylococcus and Viridans streptococci were the most commonly isolated bacteria in 33% and 30% of the episodes, respectively. Seventeen (45%) patients with bacteremia required intensive care unit admission. CONCLUSIONS: A high rate of bacterial infection was detected in patients who received the AML02 protocol, mainly gram-positive bacterial infections. The prophylactic regimen should be reconsidered for its efficacy, and other antibacterial prophylaxis may be used.

Vancomycin pharmacokinetics and predicted dosage requirements in pediatric cancer patients.

PURPOSE: To determine the pharmacokinetic parameters and compare pharmacodynamic target attainment at different dosing strategies of vancomycin in pediatric cancer patients. METHODS: Pediatric patients who received vancomycin and had at least two steady-state concentrations taken within the same dosing interval were identified. Vancomycin minimum inhibitory concentrations (MICs) for methicillin resistant staphylococcus aureus (MRSA) isolates from our institution were determined using E-test. The population-based pharmacokinetic modeling was performed using NONMEM 7.2. A one-compartment model with first-order kinetics was used to estimate clearance (CL) and volume of distribution (Vd). Monte Carlo simulations (N = 9800) were performed to compare area-under-the-curve over 24 h (AUC24)/MIC and trough concentration at different doses. RESULTS: Forty-nine patients, with 120 vancomcyin serum concentrations, were included in the analysis, mean age was 6 ± 2.5 (SD) years, mean weight was 19.6 ± 6.9(SD) kg, mean baseline serum creatinine was 0.4 ± 0.11(SD) mg/dl, and mean initial vancomycin dose was 205 mg/day (range 100-460). Final model pharmacokinetic parameters were: CL (L/h) = 0.381 × weight(0.75) and Vd (L) = 0.663 × weight. Mean baseline (±SD) vancomycin CL was 0.20 ± 0.07 L/h/kg and Vd 0.66 ± 0.001 L/kg. . Renal function, sex, age, stay in the intensive care unit, and co-administration of nephrotoxic medications did not have an effect on the calculated parameters. Using Monte Carlo simulation with reported MICs, a dose of 60 mg/kg/day achieved AUC24/MIC ≥400 and trough concentration ≥15 mcg/mL in only 21.5% and 11% of virtual subjects, respectively. CONCLUSIONS: Higher than usual vancomycin doses may be required to treat serious MRSA infections in pediatric patients. The currently recommended dose of 60 mg/kg/day is unlikely to achieve the targets in most subjects. The optimal vancomycin dosing in pediatric cancer patients requires further investigations.

Safety of inadvertent administration of overdose of intrathecal Cytarabine in a pediatric patient.

PURPOSE: To describe a medication error of intrathecal Cytarabine overdose that was managed conservatively with no apparent toxicities. SUMMARY: An 11-year-old girl was diagnosed with bone marrow relapsed precursor B-cell acute lymphoblastic leukemia. According to her chemotherapy protocol, she was started on triple intrathecal chemotherapy consisting of Methotrexate, Cytarabine and Hydrocortisone on day 1 of the protocol. After the intrathecal therapy being administered to the patient, the pharmacist who checked the medication realized that the wrong formulation of Cytarabine was used to prepare the intrathecal therapy; this error resulted in five times overdose of Cytarabine. The patient was then managed conservatively without cerebrospinal fluid exchange. Our patient remained clinically and neurologically stable without apparent toxicities and was discharged safely from hospital. CONCLUSION: Supportive care without the need for invasive procedures such as cerebrospinal fluid exchange may be adequate for managing intrathecal Cytarabine overdose.

A prospective study of febrile neutropenia in pediatric cancer patients in Jordan.

OBJECTIVE: To describe the characteristics and clinical course of febrile neutropenia (FN) in pediatric patients admitted to a comprehensive cancer center in Jordan. METHODS: This is a 6-month prospective observational study. Patients admitted with FN were identified. Patient demographics, duration since last chemotherapy, use of granulocyte colony-stimulating factor, presence of central lines, transfer to the intensive care unit, length of hospital stay, mortality, and the results of all cultures were recorded. RESULTS: One hundred and nine episodes for 88 patients were included, with a median age of 6 years (range, 1 to 19 y) and 55% were females. Median duration since last chemotherapy was 7 days (range, 1 to 33 d); median duration of hospital stay was 7 days (range, 1 to 81 d). Transfer to the intensive care unit was required for 11% of episodes, and there were no deaths. Positive cultures were reported in 18.4% episodes. Pathogens isolated were gram-positive organisms (50%), gram-negative organisms (20%), viral (25%), and fungal (5%). Positive blood cultures were significantly more in episodes with central lines compared with those with no central lines (P=0.04). CONCLUSIONS: FN episodes had favorable outcomes and were mostly associated with negative cultures. There were differences between the microbiologic profiles reported in this study, compared with what has been previously described.

Clinical pharmacy services in the outpatient pediatric oncology clinics at a comprehensive cancer center.

BACKGROUND: There is a need to expand clinical pharmacy services to cover the ambulatory pediatric cancer patients. There is a paucity of published literature describing pharmacy services in this setting. OBJECTIVE: To describe the development, implementation and the reported interventions of a clinical pharmacy service in the outpatient pediatric hematology-oncology clinics at a comprehensive cancer center in Jordan. METHODS: A stepwise approach was followed to develop and implement the described service. Four goals were set for the service comprising (1) ensure safe medication use (2) improve patient and caregiver education (3) enhance efficiency in medication distribution (4) facilitate the continuity of care across the inpatient and outpatient settings. The interventions collected were categorized into four major classes: clarification, safety, therapeutic and education. RESULTS: A total of 939 interventions were reported. Safety interventions were the highest with 500 (53%), followed by education 247 (26%), clarification 113 (12%) and therapeutic 79 (9%). The most common single interventions were patient counseling 247 (26%) and chemotherapy evaluation 229 (24%). Less frequent interventions were drug interactions and adverse drug reactions with 10 (1%) each. CONCLUSION: Developing pediatric hematology-oncology clinical pharmacy services to cover the outpatient setting is essential to ensure continuity of care and to optimize therapeutics.

Glucarpidase rescue in a patient with high-dose methotrexate-induced nephrotoxicity.

PURPOSE: To describe the successful use of glucarpidase (carboxypeptidase G2) in the treatment of high-dose methotrexate-induced nephrotoxicity in a patient with osteosarcoma. SUMMARY: A 12-year-old female patient who had been diagnosed with low-grade right mandibular osteosarcoma was started on a protocol of cisplatin plus doxorubicin alternating with high-dose methotrexate. Following her first dose of methotrexte, she developed acute renal failure and higher than expected 24h methotrexate level of 478µM/L. High-dose leucovorin rescue was started with vigorous hydra- tion and urine alkalinization together with two sessions of hemodialysis. Because her methotrexate level was persistently high, the investigational drug glucarpidase was administered. Methotrexate level dropped from 65 to 16.3 µM/L after a single dose of glucarpidase measured by fluorescence polarization immunoassay. Leucovorin and urine alkalinization were continued until day 17 when the patient's kidney function normalized and methotrexate level reached 0.05 µM/L. The patient tolerated glucarpidase well without any significant adverse events. CONCLUSION: Glucarpidase is a safe and effective agent in the management of high-dose methotrexate-induced nephrotoxicity and delayed methotrexate elimination.