Treatment of invasive IMP-4 Enterobacter cloacae infection in transplant recipients using ceftazidime/avibactam with aztreonam: A case series and literature review.

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat in both solid organ and stem cell transplant recipients. Invasive CPE infections in transplant recipients are associated with a high mortality, often due to limited therapeutic options and antibacterial toxicities. One of the most therapeutically challenging group of CPE are the metallo-ß-lactamase (MBL)-producing Gram-negative bacteria, which are now found worldwide, and often need treatment with older, highly toxic antimicrobial regimens. Newer ß-lactamase inhibitors such as avibactam have well-established activity against certain carbapenemases such as Klebsiella pneumoniae carbapenemases (KPC), but have no activity against MBL-producing organisms. Conversely, aztreonam has activity against MBL-producing organisms but is often inactivated by other co-existing ß-lactamases. Here, we report four cases of invasive MBL-CPE infections in transplant recipients caused by IMP-4-producing Enterobacter cloacae who were successfully treated with a new, mechanism-driven antimicrobial combination of ceftazidime/avibactam with aztreonam. This novel antimicrobial combination offers a useful treatment option for high-risk patients with CPE infection, with reduced drug interactions and toxicity.

Dementia-Like Symptoms Associated With Posaconazole.

Posaconazole is widely used in lung transplant recipients as pre-emptive therapy or universal fungal prophylaxis. In this patient group, posaconazole is increasingly used instead of voriconazole due to the concerns of an increased risk of squamous cell carcinoma (SCC) with voriconazole, particularly with its long-term use. Dose dependent toxicity has not been identified for posaconazole in the registration trials of intravenous (IV) and modified-release tablet formulations. This is supported by post-marketing experience. We describe a lung transplant recipient who experienced dementia-like symptoms almost 3 years after commencing posaconazole for treatment of Aspergillus fumigatus complex and Lomentospora prolificans (formerly Scedosporium prolificans) fungal infections. Symptoms resolved upon discontinuation of posaconazole, but recurred when re-challenged at a lower dose more than a year later. To the best of our knowledge, this is the first case reporting a dementia-like state with posaconazole.

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.

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/m(2)) 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.

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

GOALS OF WORK: An 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 METHODS: A 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 RESULTS: Data 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). CONCLUSIONS: Clinical 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.

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 10 wk). 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.

Postoperative Bleeding After Administration of a Single Dose of Rivaroxaban to a Patient Receiving Antiretroviral Therapy.

A 62-year-old man was admitted to hospital for elective revision of a left total hip arthroplasty. His history was significant for human immunodeficiency virus (HIV) infection for which he was taking the following antiretroviral agents (ARVs): etravirine, ritonavir, darunavir, raltegravir and tenofovir/emtricitabine. Rivaroxaban 10 mg daily was commenced on the second postoperative day for venous thromboembolism (VTE) prophylaxis. Approximately 24 h later, the patient developed hypotension and anaemia, accompanied by thigh swelling due to bleeding at the surgical site. Fluid resuscitation was commenced with red cell transfusion. The prothrombin time (PT) was prolonged at 24.3 (10.6-15.3) s, and a rivaroxaban level taken 24 h after administration was 75 ng/mL. Rivaroxaban was ceased, the PT normalised within 24 h of stopping the drug, and the patient made an uneventful recovery. None of the other coadministered drugs are known to interact with rivaroxaban, or are likely to, based on their metabolic pathways. Rivaroxaban, a substrate for cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), is contraindicated in patients concomitantly treated with strong inhibitors of both these systems, e.g. protease inhibitors (PIs) such as ritonavir (based on in vitro data and a pharmacokinetic study in healthy volunteers). No published data are available on the PI darunavir, a moderate inhibitor; however, concomitant use with rivaroxaban should also be avoided. A prolonged PT and a rivaroxaban trough level greater than eight times that predicted from pharmacokinetic modelling suggests that bleeding was due to increased exposure to rivaroxaban, probably due to an interaction with ritonavir and darunavir. This is supported by a Drug Interaction Probability Scale (DIPS) score of 8. An interaction between a single dose of rivaroxaban and ARVs may be clinically significant; therefore, the patient's medication history should be extensively evaluated to identify any potential interactions.

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 antiinflammatory agents. We describe a patient who developed a generalized desquamating rash after therapy with celecoxib.

Profound hypokalaemia due to Nurofen Plus and Red Bull misuse.

We report an unusual and emerging cause of profound hypokalaemia associated with a severe myopathy, attributable to misuse of Nurofen Plus, a readily available over-the-counter medication containing ibuprofen and codeine, and excessive ingestion of the caffeine-containing energy drink, Red Bull. The mechanism of the hypokalaemia may be ascribed to ibuprofen-mediated type 2 renal tubular acidosis, and caffeine-mediated antagonism of adenosine receptors or intercompartmental shift of potassium into the intracellular space. Practitioners should be aware that patients with codeine addiction who misuse Nurofen Plus may present with severe hypokalaemia complicated by myopathy.

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 micromol/L(normal range 522 micromol/L). All other liver function tests (LFT) were normal. This isolated hyperbilirubinemia remained for the rest of the patient's admission, peaking on day 26, with a level of 255 micromol/L. After a stay in the intensive care unit, the patient was discharged on day 45 with a bilirubin level of 33 micromol/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 micromol/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.

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.

Atypical neuroleptic malignant syndrome with long-term clozapine.

Clozapine-induced neuroleptic malignant syndrome (NMS) may present differently from NMS associated with traditional antipsychotic agents, with fewer clinical features, particularly fewer extrapyramidal manifestations. The risk of developing NMS with clozapine does not appear dose-related. In half of cases, it occurs within 2 weeks of beginning clozapine therapy, but it can develop at any stage, especially with long-term use. We describe a patient who presented with atypical NMS after more than 10 years of clozapine treatment, and who was safely re-challenged with the same drug.