Carmela E Corallo

Vancomycin Dosing: Assessment of Time to Therapeutic Concentration and Predictive Accuracy of Pharmacokinetic Modeling Software

BACKGROUND: Therapeutic drug monitoring is usually required for safe and effective administration of vancomycin. However, dosing recommendations from published guidelines are not suitable in achieving therapeutic vancomycin concentrations in a timely manner in patients with normal renal function. OBJECTIVE: To audit vancomycin dosing and concentrations at our institution and evaluate the predictive accuracy of a pharmacokinetic simulation program, with a view to implementing a pharmacy-based pharmacokinetic service for vancomycin monitoring. METHODS: Patients receiving vancomycin were identified prospectively through the therapeutic drug monitoring archives. Patient information was obtained from medication charts and medical records that were located on wards. Data were entered into the MM-USC*Pack program (Jelliffe R, University of Southern California, 2008, version 12.10). This software was used to predict initial and subsequent concentrations of vancomycin based on patient parameters. The predictive accuracy of this software was evaluated by comparing the predicted concentrations to the observed concentrations. RESULTS: During a 6-week period, 204 concentrations were measured in 77 patients. The most common dosing regimen was 1 g every 12 hours. Overall, initial trough concentrations were subtherapeutic (<10 mg/L) in 58% of patients and trough concentrations did not become therapeutic at any stage throughout therapy in 25% of patients. The pharmacokinetic modeling software demonstrated little systematic bias (−3.1%), but the precision (median prediction error) was 23% (interquartile range, 11-45%). Predictions were poorer in obese patients (body mass index >35 kg/m2) and in patients with unstable renal function. CONCLUSIONS: A delay in attaining target trough concentrations was observed in a significant proportion of patients. Pharmacokinetic modeling software is a potential tool to improve the timeliness of achieving adequate dosing by allowing concentrations to be determined prior to steady-state. The program was able to predict vancomycin concentrations across a heterogeneous patient population with little systematic bias, but only moderate precision.

Toxic epidermal necrolysis after celecoxib therapy.

Toxic epidermal necrolysis (TEN) is a rare disease that is defined by extensive detachment of full‐thickness epidermis. It most often is related to an adverse drug reaction. The drugs implicated in most cases of TEN have been sulfonamides, anticonvulsants, allopurinol, and some of the conventional nonsteroidal anti‐inflammatory agents. We describe a patient who developed a generalized desquamating rash after therapy with celecoxib.

Evaluation of the Accuracy of a Pharmacokinetic Dosing Program in Predicting Serum Vancomycin Concentrations in Critically Ill Patients

BACKGROUND Optimization of the timing of appropriate antibiotics is crucial to improve the management of patients in severe sepsis and septic shock. Vancomycin is commonly used empirically in cases of nosocomial infections in critically ill patients. Therefore, early optimization of vancomycin pharmacokinetics is likely to improve outcomes. OBJECTIVE To evaluate a pharmacokinetic program to predict serum vancomycin concentrations in accordance with administered dose, weight, height, and creatinine clearance in a critically ill population. METHODS We conducted a prospective observational single-center study in a 45-bed intensive care unit (ICU). All patients hospitalized in the ICU requiring intravenous treatment with vancomycin for a suspected infection were enrolled. The modalities of vancomycin therapy and the monitoring of serum concentrations were left to the discretion of the treating clinician. We compared the measured serum vancomycin concentrations with those predicted by the MM-USCPACK program and analyzed the factors influencing the prediction. RESULTS Fifty-four intravenous vancomycin courses were administered in 48 critically ill patients over the 3-month study. The precision was considered acceptable, based on a relative precision equal to 8.9% (interquartile range 3.5-18.9%) and the relative bias for all predictions was equal to -1.3%. Overall, 77.3% of predictions were within 20% of observed concentrations; factors correlating with a poorer prediction were a change in renal function, obesity, and the magnitude of organ dysfunction on initiation of vancomycin (expressed by a Systemic Organ Failure Assessment score >11). CONCLUSIONS The MM-USCPACK program is a useful and reliable tool for prediction of serum vancomycin concentrations in patients hospitalized in ICU and likely reflects the close monitoring of renal function in this setting. For some patients (more severely ill, obese, or significant change in renal function during vancomycin therapy), predictions were less precise.

Implementation of a pharmacist-initiated pharmaceutical handover for oncology and haematology patients being transferred to critical care units

Goals of workAn information gap with respect to specific therapies was identified when patients were transferred from the oncology and haematology unit (OHU) to the critical care units. The goal was to implement and evaluate the effectiveness of a pharmacist-initiated pharmaceutical handover (PIPH) for patients being transferred from the OHU to the critical care units at a major teaching hospital.Patients and methodsA PIPH process for the specific therapies of mouthcare, chemotherapy regimen, growth factors and antibiotics was developed. The PIPH was delivered in written format or combined written and verbal format. The impact of the PIPH was by assessment of recorded clinical pharmacist interventions. Data were analysed to evaluate any difference in the number of interventions relating to and the time to administration of the specific therapies.Main resultsData were available for 30 patient transfers in the pre-implementation group, with 22 transfers available in the post-implementation period. The number of interventions relating to the specific therapies was significantly reduced in the post-implementation group (144 vs 26; p < 0.0001). A significantly greater proportion of the specific therapies were administered on time in the post-implementation group (57% vs 96%; p < 0.0001).ConclusionsClinical pharmacists in the specialty area of oncology and haematology can improve the continuum of care when their patients are transferred to other units. By providing an accurate handover about specific therapies, there is an overall improvement in the prescribing and timely administration of these therapies.

Anticholinergic syndrome following an unintentional overdose of scopolamine.

Scopolamine hydrobromide (hyoscine) is an antimuscarinic drug which is primarily used in the prophylaxis and treatment of motion sickness and as a premedication to dry bronchial and salivary secretions. In acute overdosage, the main clinical problem is central nervous system (CNS) depression. In Australia, tablets containing scopolamine hydrobromide 0.3 mg are available over the counter in packs of ten. The recommended dose for adults is one to two tablets as a single dose, repeated four to six hours later, if required. The maximum dose stated on the pack is four tablets over a 24-hour period with a caution regarding drowsiness and blurred vision. We describe a patient who presented with symptoms of anticholinergic syndrome secondary to an unintentional overdose of scopolamine. Whilst at work, the patient noticed that he had forgotten his prescribed medication, domperidone, at home; a friend gave him some travel sickness medication which contained scopolamine for relief of nausea. On a previous occasion, he had experienced a similar, less severe reaction with another anticholinergic agent, loperamide. This report highlights the need to consider nonprescription products, ie, over the counter medications, herbal/nutritional supplements as causes of anticholinergic syndrome when a patient presents with symptoms suggestive of this diagnosis.

Sibutramine-Associated QT Interval Prolongation and Cardiac Arrest

Objective: To report on a probable association between sibutramine and QT interval prolongation leading to ventricular fibrillation and cardiac arrest. Case Summary: A previously well 51-year-old woman with obesity but no other relevant past medical history or cardiac risk factors was prescribed sibutramine (initial dose 10 mg daily, increased to 15 mg daily after 10wk). Four months after initiation of therapy, the woman developed ventricular fibrillation and was successfully resuscitated. On admission, an electrocardiogram (ECG) demonstrated sinus tachycardia without any ischemic changes and a prolonged QTc interval (545 msec). A subsequent coronary angiogram revealed normal coronary arteries and no other abnormalities. Her QTc interval returned to normal (432 msec) by day 2 and remained within normal limits (<440 msec) thereafter. Due to a favorable neurologic recovery and the absence of any cardiac structural abnormality, the patient was readmitted for implantation of an automatic implantable cardioverter-defibrillator on day 35 and remained well from a cardiac and neurologic standpoint at a 2-year follow-up examination. Discussion: Sibutramine acts centrally to inhibit noradrenaline, dopamine, and serotonin reuptake, thereby sharing similar actions of other QT interval-prolonging drugs. Therefore, sibutramine might be anticipated to also share a tendency to QT interval prolongation. The current prescribing information for sibutramine does not specifically list any precautions or adverse reactions related to QT interval prolongation. QT interval prolongation associated with sibutramine in this case is considered probable based on the Naranjo probability scale. Conclusions: Clinicians prescribing sibutramine should monitor their patients for ECG abnormalities and be cautious in coprescribing drugs known to prolong the QT interval.

The management of prolonged, isolated hyperbilirubinemia following cytarabine-based chemotherapy for Acute Myeloid Leukaemia

Background. Patients diagnosed with Acute Myeloid Leukaemia (AML) often receive cytarabine-based chemotherapy as standard treatment. Cytarabine is usually given in combination with other agents such as idarubicin. Such treatments are known to cause hepatic dysfunction characterized by a combination of jaundice, hyperbilirubinemia and increases in liver enzymes. Isolated hyperbilirubinemia is rarely reported. It is often difficult to identify a causative agent for the hepatic dysfunction, as there are often complicating factors such as sepsis. Aim: To report a case of isolated hyperbilirubinemia in a patient treated with cytarabine-based chemotherapy for AML. Clinical Details. After a diagnosis of AML the patient was admitted to hospital to receive induction chemotherapy consisting of high-dose cytarabine, idarubicin, and etoposide. All baseline laboratory results were normal, except the full blood evaluation that was consistent with AML. The chemotherapy was delivered over 7 days, and on the eighth day the patient had a bilirubin (BL) level of 27 umol/L (normal range 522 umol/L). All other liver function tests (LFT) were normal. This isolated hyperbilirubinemia remained for the rest of the patients admission, peaking on day 26, with a level of 255 umol/L. After a stay in the intensive care unit, the patient was discharged on day 45 with a bilirubin level of 33 umol/L. All other LFT remained unremarkable. Outcome. The isolated hyperbilirubinemia resolved slowly and on day 68, when the patient was re-admitted for further dose-reduced cytarabine, the BL level was 21 umol/L. The patient was successfully retreated with this lower dose regimen. Conclusion. Isolated hyperbilirubinemia is an uncommon presentation of cytarabine induced liver dysfunction. Resolution does occur but over a prolonged period. A lower dose of cytarabine for future treatment should be considered. J Oncol Pharm Practice (2009) 15: 107—110.

Systemic Absorption of Low-Dose Oral Vancomycin

The absorption of oral vancomycin is usually minimal. However, in the presence of renal impairment and inflammatory disorders of the intestinal mucosa, it may be absorbed to a significant extent. Case reports and literature reviews suggest that this is generally not an issue unless doses of vancomycin above 2 g/day are used for prolonged periods.

Failure to achieve therapeutic levels with high-dose posaconazole tablets potentially due to enhanced clearance

Aim To describe a case of persistent sub-therapeutic posaconazole levels in setting of salvage chemotherapy for relapsed acute myeloid leukemia. Case details A 57-year-old male was admitted for the management of relapsed acute myeloid leukemia and ongoing pulmonary aspergillosis. While continuing on posaconazole tablet 300 mg daily, he received a course of salvage chemotherapy. The initial steady state posaconazole trough level was therapeutic at 0.84 mg/L (target >0.70 mg/L). However, after five days, the level had dropped to 0.40 mg/L, coinciding with hyperbilirubinemia and hypoalbuminemia. Bilirubin level peaked at 36 µm/L (normal high <20 µm/L), albumin levels were consistently low, averaging at 25 g/L (range 33–46 g/L). The patient had been compliant and there were no underlying gastrointestinal conditions identified which might have potentially affected posaconazole absorption. Outcome An increase in posaconazole dose failed to achieve target levels and treatment was changed to voriconazole. However, levels were surprisingly supra-therapeutic, resulting in side effects and substantial dose reduction was required. Conclusion Failure to achieve target posaconazole levels despite increased dosing may be attributed to factors other than impaired oral absorption. Enhanced metabolism and clearance could be associated with hypoalbuminemia and hyperbilirubinemia. Further case studies, including PK modelling, are required to confirm this effect.

Safety of rapid infusion of iron polymaltose: Comparative study in 300 patients

Iron polymaltose is the most cost‐effective and convenient intravenous (IV) iron formulation available in Australia for the treatment of iron deficiency anaemia in hospital inpatients. However, in the ambulatory setting, the requirement for administration over several hours has been a major limitation. Although there is some data on the safety of using a faster infusion rate, further information was required with respect to the administration of higher doses.