Vancomycin area under the curve to minimum inhibitory concentration ratio predicting clinical outcome: a systematic review and meta-analysis with pooled sensitivity and specificity.

BACKGROUND: Vancomycin is a first-line antibiotic for methicillin-resistant Staphylococcus aureus infections or other Gram-positive infections. The area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio is proposed as a therapeutic drug-monitoring parameter. How well clinical efficacy is predicted by this measure has not been established. OBJECTIVE: Determine the test performance characteristics (TPC) of AUC:MIC of vancomycin for prediction of positive outcome. DATA SOURCES: PubMed and Ovid Medline (1946 to 2018) and EMBASE (1974 to 2018). Study Eligibility Criteria and Participants: Studies of patients treated with vancomycin for any type of infection in peer reviewed publications. All patient populations were included. INTERVENTIONS: Vancomycin AUC:MIC or AUC was related to patient clinical outcome. METHODS: Searches of medical databases using relevant terms were performed. Screening, study reviewing, data extracting and assessing data quality was performed independently by two reviewers. Studies were stratified by type of primary outcome for calculation of pooled sensitivity, specificity and construction of hierarchical summary receiver operating characteristic (HSROC) curves. RESULTS: Nineteen studies including 1699 patients were meta-analysed. Pooled sensitivity and specificity were 0.77 (95% CI 0.67-0.84) and 0.62 (95% CI 0.53-0.71) respectively for the seven studies with primary outcome of mortality and 0.65 (95% CI 0.53-0.75), 0.58 (95% CI 0.48-0.67) for studies with composite or clinical cure outcome (n = 12). HSROC curves suggested considerable heterogeneity. An additional 11 studies were described but could not be included for meta-analysis because data were not available. The majority of these studies (9/11) failed to demonstrate a relationship between AUC:MIC and positive clinical outcome. CONCLUSIONS: Vancomycin AUC:MIC performance was modest and inconsistent. Analysis was limited by studies without sufficient data; therefore, meta-analytic results may overestimate TPC values. Given this, as well as the lack of standardization of methods, widespread adoption of AUC:MIC as the preferred vancomycin monitoring parameter may be premature.

A Phase I trial of bryostatin-1 in children with refractory solid tumors: a Pediatric Oncology Group study.

Bryostatin-1, a macrocyclic lactone, appears to elicit a wide range of biological responses including modulation of protein kinase C (PKC). PKC, one of the major elements in the signal transduction pathway, is involved in the regulation of cell growth, differentiation, gene expression, and tumor promotion. Because of the potential for a unique mechanism of interaction with tumorgenesis, a Phase I trial of bryostatin-1 was performed in children with solid tumors to: (a) establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); (b) establish the pharmacokinetic profile in children; and (c) document any evidence of antitumor activity. A 1-h infusion of bryostatin-1 in a PET formulation (60% polyethylene glycol 400, 30% ethanol, and 10% Tween 80) was administered weekly for 3 weeks to 22 children (age range, 2-21 years) with malignant solid tumors refractory to conventional therapy. Doses ranged from 20 to 57 microg/m2/ dose. Pharmacokinetics were performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. Twenty-two patients on five dose levels were evaluable for toxicities. At the 57 microg/m2/dose level dose-limiting myalgia (grade 3) was observed in three patients; two of those patients also experienced photophobia or eye pain, and one experienced headache. Symptoms occurred in all patients within 24-72 h after the second dose of bryostatin-1 with resolution within 1 week of onset. Other observed toxicities (grades 1 and 2) included elevation in liver transaminases, thrombocytopenia, fever, and flu-like symptoms. The bryostatin-1 infusion was typically well tolerated. Although stable disease was noted in several patients, no complete or partial responses were observed. The recommended Phase II dose of bryostatin-1 administered as a 1-h infusion weekly for 3 of every 4 weeks to children with solid tumors is 44 microg/m2/dose. Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.

Phase I therapy trials in children with cancer.

PURPOSE: This study examined the response and toxicity rates of antineoplastic drugs evaluated in phase I clinical trials in children to identify trends in response and toxicity over time. PATIENTS AND METHODS: Full length, peer-reviewed articles describing the results of single agent phase I therapy trials in children younger than 21 years with cancer were reviewed. Tumor-specific response data and doses of drugs that resulted in objective responses were noted. Deaths that occurred on study caused by drug toxicity, progressive disease (PD), or complications of marrow aplasia were identified, along with drug doses that resulted in toxic death. Temporal trends in response rates, toxicity, and number of patients entered in trials were examined. RESULTS: A total of 1,606 patients with cancer were enrolled in 56 single-agent pediatric phase I therapy trials published between 1978 and 1996. Of these, 1,257 were evaluated for response by tumor type. The overall objective response rate was 7.9%. Response rates were highest for patients with neuroblastoma (17.7%) and acute myelogenous leukemia (11.6%). Patients with osteosarcoma and rhabdomyosarcoma had response rates of < 3%. Sixty percent of responses in patients with solid tumors occurred at 81 to 100% of the maximum tolerated dose (MTD), although 42% of responses in patients with leukemia occurred at > 100% of the MTD. Death on study was noted in 7.0% of all patients entered in trials. Only 0.7% of patients experienced a death related to drug toxicity. PD accounted for the death of 5.6% of study participants. A trend of increasing response rate despite smaller trial size was noted over the last 7 years of this period. CONCLUSION: Phase I trials in children with cancer represent a safe mechanism to determine the MTD, toxicity profile, and pharmacokinetics of new agents for use in children with cancer.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

PURPOSE: A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS: A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS: Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION: The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Neuroblastoma presenting as acute monoblastic leukemia.

PURPOSE: We report a 5-year-old boy with stage 4 neuroblastoma initially diagnosed as having acute monoblastic leukemia (FAB M5A, AMoL), based on bone marrow morphology, histochemistry, immunocytochemistry, immunophenotyping and cytogenetics, all consistent with AMoL. The patient also had circulating blasts at diagnosis. After failing initial therapy for AMoL and because of concerns about residual blasts with a clumped appearance in the bone marrow, urinary homovanillic acid (HVA) and vanillylmandelic acid (VMA) and N-myc amplification in tumor cells were evaluated and found to be positive, resulting in the diagnosis of neuroblastoma. Abdominal computerized tomography showed a left adrenal mass. A review of 10 reported cases of neuroblastoma with leukemic features showed that seven of them were misdiagnosed as having leukemia, and in six of the seven, the diagnosis of neuroblastoma was made postmortem. CONCLUSION: Neuroblastoma may be confused with acute leukemia, even with the use of modern techniques.

A phase I study of acivicin in refractory pediatric solid tumors. A Pediatric Oncology Group study.

Forty-two patients with progressive solid tumors and brain tumors were entered in this Phase I study of the glutamine antagonist acivicin given intravenously over thirty minutes daily for five days. The major toxicities encountered were myelosuppression and central nervous system toxicity (nightmares and somnolence). The maximum tolerated dosage on this schedule was 26 mg/M2 daily for five days. Six patients including three patients with brain tumor had stable disease.

Transient secretory IgA deficiency in mice after cyclophosphamide treatment.

Cyclophosphamide (Cy), an alkylating agent widely used in chemotherapy of leukemia and cancer, causes a well-documented toxicity on hematopoietic and lymphoid cells. Neutropenia is thought to be the main factor involved in infectious complications following antimitotic chemotherapy. Little is known on the effects of these therapies on the mucosal associated lymphoid system which is one of the main barriers against environmental pathogenic agents. The present study examined the effects of a single administration of Cy (200 mg/kg) on murine T and B cell populations of Peyer's patches (PPs), IgA secretion in the proximal part of the small intestine, and plasma cells of the lamina propria. Cy induced in mice a transient decrease in the T and B cell populations of the PPs with a drastic fall of B cell counts and a profound decrease of intestinal IgA secretion due to a reduction of lamina propria plasma cells. This transient secretory IgA deficiency may contribute to the infectious complications following antimitotic chemotherapy.

Phase I and clinical pharmacology trial of 502U83 using a monthly single dose schedule.

502U83 is an arylmethylaminopropanediol derivative exhibiting significant antineoplastic activity in a number of murine and human tumor models. In this Phase I trial, a 1-h or 4-h infusion of the agent was administered i.v. in 250 ml of 5% dextrose in water every 28 days. Fifty-three courses at doses of 25 to 2000 mg/m2 were administered to 36 patients with refractory solid tumors. Prolongation of the PR, QRS, and QT intervals on electrocardiograms was dose limiting at 2000 mg/m2. This prolongation appeared dose related and was reversible upon discontinuation of the infusion. No hematological toxicity was observed. Other toxicities included only sporadic and mild to moderate nausea and vomiting. No tumor responses were noted. 502U83 plasma concentrations were determined by high-pressure liquid chromatography. Complete pharmacokinetic profiles were obtained for 21 of the 36 patients. After infusion, plasma concentrations declined in a biexponential or in a triexponential manner with a harmonic mean terminal t 1/2 of 8.83 h. Using a three-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 195 liters/m2 and 42.5 liters/h/m2, respectively, indicative of extensive tissue distribution. No correlation could be found between the pharmacokinetic parameters and prolongation of the cardiac conduction intervals. Because of the cardiac effects with the drug, the schedule of administration of 502U83 used in this study cannot be recommended.

Diurnal variation in the pharmacokinetics and myelotoxicity of mercaptopurine in children with acute lymphocytic leukemia.

During their maintenance therapy, children with acute lymphoblastic leukemia are treated with a daily dose of mercaptopurine for several years. A recent retrospective analysis has suggested that administration of the drug in the evening results in a better prognosis. We compared the disposition pharmacokinetics of mercaptopurine administered in the morning vs in the evening in 13 children with acute lymphoblastic leukemia. Elimination half-life of mercaptopurine was significantly longer in the evening than during the day (423 +/- 142 minutes vs 176 +/- 22 minutes, mean +/- SEM). The area under the concentration-time curve (AUC0-infinity) was significantly larger in the evening (24,713 +/- 3536 ng/mL per minute vs 17,120 +/- 1474 ng/mL per minute). These differences were even more pronounced when comparing the area under the curve of the postdistributive phase (AUC300 min-infinity, 7724 +/- 2955 ng/mL per minute in the evening vs 2597 +/- 712 ng/mL per minute during the day). In a second study, 12 children with acute lymphoblastic leukemia receiving mercaptopurine in the morning had their medication administration switched to the evening. Within 2 weeks there was a sharp fall in peripheral white blood cell counts in all patients (from 4.1 x 10(9)/L to 2.2 x 10(9)/L) mainly due to a drop in polymorphonuclear lymphocytes (from 2.78 x 10(9)/L to 1.05 x 10(9)/L). We conclude that the diurnal variations of mercaptopurine disposition result in clinically important myelotoxicity of the drug.

Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children.

BACKGROUND: Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse. METHODS: To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted. RESULTS: There was a significant difference in the mean (+/- SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636 +/- 197 nmol per liter x minutes in those who relapsed, as compared with 2424 +/- 177 nmol per liter x minutes in those who did not (P less than 0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043 +/- 12,812 nmol per liter x minutes) than in those who did not (168,862 +/- 18,830 nmol per liter x minutes) (P less than 0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan-Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter x minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P less than 0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter x minutes had a significantly better prognosis than those with a lower exposure (P less than 0.005). CONCLUSIONS: Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure.

Adriamycin and cis-platinum administered by continuous infusion preoperatively in hepatoblastoma unresectable at presentation.

Hepatoblastoma deemed surgically unresectable at presentation is fatal unless conversion to resectability is attained. We report a series of six consecutive patients, ranging in age from newborn to 5.75 years with hepatoblastoma unresectable at presentation, either because of size of tumor or its anatomical boundaries, or because of metastatic disease. All were treated with preoperative continuous infusions of cis-platinum and Adriamycin. All achieved resectability, and there was only one operative death. The five surviving patients are alive and free of disease off therapy. Potential benefit may accrue from preoperative chemotherapy in most cases of hepatoblastoma.

Preoperative chemotherapy in 'unresectable' hepatoblastoma.

Chemotherapy was used to treat 11 children with hepatoblastoma that was judged to be unresectable because of tumor tissue in both lobes of the liver (eight patients) or because of size of the primary tumor (three patients). Three with bilobar involvement also had metastatic disease. Adriamycin was used in all patients. In nine, it was used in combination with cisplatin. A combination of other agents was used in four of these children. After two to six cycles (mean, 4 cycles), eight primary tumors exhibited marked response with greater than 50% reduction in size. Metastases disappeared in two patients. Complete resection of residual tumor was attempted in eight cases, and was successful in seven. One patient died at the time of surgery during an extended right hepatectomy. Two children had anaplastic hepatoblastomas that did not respond to chemotherapy, and the children died. One responder with giant cell hepatitis died from a severe coagulopathy and bleeding during chemotherapy before surgery. With preoperative chemotherapy, seven of 11 children with "unresectable" hepatoblastoma are now alive without disease 4 to 42 months following successful resection.

Nutritional vitamin B12 deficiency in infancy: three case reports and a review of the literature.

Three cases of vitamin B12 deficiency that occurred during infancy are presented. These cases appeared to be the result of pre-existing maternal deficiency. All three infants demonstrated evidence of neurodevelopmental delay at presentation, and one had sustained loss of milestones and developed involuntary motor movements. Prior to the initiation of therapy, all three infants were anemic: one was thrombocytopenic and one pancytopenic. In all three cases the hematologic and neurologic abnormalities were corrected with vitamin B12 therapy. The literature is reviewed and discussed with respect to the mechanism of the infants' vitamin B12 deficiency and neurodevelopmental manifestations.

[Serial determination of anthracycline poisoning in children]. / Serielle Bestimmung der Anthrazyklintoxizität bei Kindern.

Dose-related cardiotoxicity limits enthracycline administration in patients with solid tumours or leukaemia. Many patients (70%) would probably benefit by receiving more than a total accumulative dose of 500 mg/m2. As a measure of myocardial function the left ventricular ejection fractions (EF) were determined from serial radionuclide angiograms in 62 children who had at least 3 studies (mean age 8.4 +/- 5.4 years). Seven patients who had clinical evidence of cardiac involvement and/or a marked decline in their EF underwent endmyocardial biopsy (9 x). The EF declined progressively from 63 +/- 7% prior to chemotherapy to 60 +/- 5%, 58 +/- 7% and 54 +/- 7% after low, medium and high-dose anthracycline, respectively in the non-biopsied children vs 58 +/- 4%, 54 +/- 7% and 48 +/- 4% in the biopsied patients. Anthracycline dosage was 129 +/- 42, 307 +/- 68 and 471 +/- 61 mg/m2 and 103 +/- 64, 303 +/- 73 and 536 +/- 93 mg/m2, respectively. The biopsies were obtained at a mean anthracycline dose of 408 mg/m2 when the EF was 46 +/- 5%, and graded according to the modified Billingham score; grade 1 (6 x), 1.5 (2 x) and 2.5 (1 x). A decline in the EF was seen in 89% of our patients throughout their chemotherapy course, with a statistical significance of p less than 0.02 in the biopsied patients after medium dose therapy which was not seen in the non-biopsied children until they were receiving anthracyclines.