OBJECTIVE: To compare the pharmacodynamics of several dosing regimens of piperacillin/tazobactam administered by intermittent and prolonged infusion using pharmacokinetic data from hospitalized patients.

METHODS: Steady-state pharmacokinetic data were obtained from 13 patients who received piperacillin/tazobactam 4.5 g every 8 hours, infused over 4 hours. Monte Carlo simulations (10,000 pts.) were performed to calculate pharmacodynamic exposures at 50% fT>MIC for 4 intermittent-infusion regimens (3.375 g every 4 and 6 h, 4.5 g every 6 and 8 h) and 4 prolonged-infusion regimens (2.25 g, 3.375 g, 4.5 g, and 6.75 g every 8 h [4-h infusion]) of piperacillin/tazobactam using pharmacokinetic data for piperacillin. Cumulative fraction of response (CFR) was calculated using MIC data for 6 gram-negative pathogens (Meropenem Yearly Susceptibility Test Information Collection, 2004–2007), and probability of target attainment (PTA) was calculated at MICs ranging from 1 µg/mL to 64 µg/mL.

RESULTS: The CFR for 3.375 g every 4 hours (intermittent infusion) and 3.375–4.5 g every 8 hours (prolonged infusion) greater than or equal to 90.3% for Escherichia coli, Serratia marcescens, and Citrobacter spp. Increasing the prolonged-infusion dose to 6.75 g improved the CFR to greater than 90% for Enterobacter spp. For every regimen evaluated, the CFR was less than 90% for Klebsiella pneumoniae and Pseudomonas aeruginosa. At an MIC of 16 µg/mL, PTA was greater than 90% for one intermittent-infusion regimen (3.375 g every 4 h) and 3 prolonged-infusion regimens (≥3.375 g every 8 h), but no regimen achieved a PTA greater than 90% at an MIC of 64 µg/mL.

CONCLUSIONS: At doses greater than or equal to 3.375 g every 8 hours, 4-hour infusions of piperacillin/tazobactam achieved excellent target attainment with lower daily doses compared with standard regimens at MICs less than or equal to 16 µg/mL.

OBJECTIVE: To identify the patient-, environment-, and medication-related factors involving unexplained medication discrepancies across transition points after ED presentation.

METHODS: Using a retrospective chart review design, a stratified, random sampling of data was undertaken over a 12-month period. Information was obtained from an electronic administrative database and medical records as patients moved from the ED to another transition point of care. Medication discrepancies were classified into 2 outcome groups: (1) no discrepancies and situations in which discrepancies were adequately explained and (2) discrepancies that had no adequate explanation.

RESULTS: For the 12-month period, 210 randomly selected patients were included; 73 (34.8%) had at least one unexplained medication discrepancy. Binary logistic regression modeling showed 4 factors that were statistically significant in determining the incidence of at least one unexplained medication discrepancy. Benefit card holders (individuals who receive benefits from government insurance programs comparable to the US-based Medicare and Medicaid initiatives, which include the elderly, the disabled, low income earners, and unemployed persons) had 3.73 greater odds of experiencing an unexplained medication discrepancy (95% CI 1.72 to 8.07; p = 0.001). Patients prescribed 5 or more drugs at discharge from the ED had 12.22 greater odds of having at least one unexplained medication discrepancy (95% CI 5.52 to 27.08; p < 0.001). Patients who were first seen by a physician within 1 hour of a change in working shift had 3.70 greater odds of having an unexplained medication discrepancy (95% CI 1.67 to 8.18; p = 0.001). For each additional minute of wait time for a physician, the odds of having an unexplained medication discrepancy increased by a factor of 1.01 (95% CI 1.00 to 1.01; p = 0.042).

CONCLUSIONS: Patient-, environment-, and drug-related factors contribute to the risk of medication discrepancies across transition points from the ED.

OBJECTIVE: To study the rates of hospitalization for gastrointestinal (GI) bleeding events in 3 groups of patients: those taking warfarin only, those taking warfarin plus a nonselective NSAID, and those taking warfarin plus a selective COX-2 inhibitor.

METHODS: This was a retrospective cohort analysis in a large nonprofit health maintenance organization. All warfarin users from January 1, 2000, to December 31, 2005, were eligible for inclusion in the study. Eligible patients were grouped by their exposure time to warfarin only, warfarin plus nonselective NSAIDs, or warfarin plus selective COX-2 inhibitor. The study endpoint was hospitalization for a GI bleed. Patients were matched using a propensity scoring methodology. A multivariate Cox proportional hazards model was used to estimate the hazard ratio for GI bleeding between patient cohorts, controlling for age, sex, baseline medical conditions, prior history of GI bleeding, and prescription drug use.

RESULTS: The eligible population consisted of 35,548 patients undergoing 46,214 courses of warfarin therapy. The adjusted hazard ratio for hospital-associated GI bleeding in the warfarin plus nonselective NSAID group versus warfarin alone was 3.58 (95% CI 2.31 to 5.55; p < 0.01) and for warfarin plus selective COX-2 inhibitor versus warfarin alone was 1.71 (95% CI 0.60 to 4.84; p = 0.31). For nonselective NSAIDs plus warfarin versus selective COX-2 inhibitor plus warfarin, the adjusted hazard ratio was 3.69 (95% CI 1.42 to 9.60; p = 0.01).

CONCLUSIONS: In general, nonselective NSAIDs and selective COX-2 inhibitors should be avoided in patients taking warfarin. In situations where patients require NSAIDs and cannot be managed using other therapies, our results suggest that selective COX-2 inhibitors are associated with fewer hospitalizations for GI bleeding.

OBJECTIVE: To compare traditional sliding scale (SS) with a tight glycemic control (TC) algorithm. The primary endpoint was the percentage of total blood glucose measurements in the target range of 80–150 mg/dL. The secondary endpoint evaluated was safety, defined as percentage of all blood glucose measurements that were 0–60 mg/dL.

METHODS: A 1-year, retrospective analysis from June 1, 2007, to May 31, 2008, was performed evaluating all inpatients with hyperglycemia within the first 48 hours of admission to the Medical Center of Plano, Plano, TX. A cohort of patients managed with SS (n =121) was compared with those treated with TC (n = 210). Patients on SS insulin received a traditional SS regimen with regular insulin or insulin aspart based on physician preference.

RESULTS: Demographics and comorbidities were similar between the 2 groups; however, the TC cohort was younger (64.8 ± 14.1 vs 70.8 ± 13.7 y; p < 0.001). There were more persons with type 2 diabetes mellitus in the TC cohort (81.9%) versus the SS cohort (60.3%; p < 0.001). In the TC cohort, 42.9% of blood glucose measurements were in the target range of 80–150 mg/dL compared with 30.6% of the measurements in the SS cohort (p < 0.001). Regarding safety, 2% of blood glucose measurements of the TC cohort were in the range of 0–60 mg/dL versus 0.3% of the SS cohort (p < 0.001). No clinical sequelae of hypoglycemia were observed. Patients achieved more blood glucose measurements in the target range when treated with TC versus SS insulin, without regard to prior history of diabetes.

CONCLUSIONS: Patients treated with TC experienced more blood glucose measurements in the target range as compared with patients treated with SS with relatively low hypoglycemia rates.

OBJECTIVE: To establish a pharmacist-run osteoporosis service at a family medicine clinic and to evaluate short-term compliance with osteoporosis treatment guidelines before and after initiation of the service.

METHODS: A pharmacist-run osteoporosis service was established in October 2008. Adults with the diagnosis of osteoporosis before initiation of the service were included in evaluation of short-term compliance with treatment guidelines, including appropriate dual-energy X-ray absorptiometry (DEXA) scan frequency, pharmacotherapy, calcium and vitamin D supplementation, and nonpharmacologic education. Of 42 referred patients, 22 were eligible for inclusion. A retrospective chart review was conducted, and patients served as their own controls, with data from before and after establishment of the service evaluated.

RESULTS: Of the 22 patients evaluated, 8 (36%) received DEXA scans at the appropriate frequency before the service was established, versus 18 (82%) after the service was initiated. Seven (32%) patients were taking appropriate pharmacotherapy before the service, versus 17 (77%) after the service. Nine (41%) patients were taking calcium and vitamin D before the service, versus 22 (100%) after the service. Three (33%) of these patients were taking the appropriate dose and salt of calcium before the service, versus 20 (91%) after the service. Five (56%) of the 9 patients were taking the appropriate vitamin D dose before the service, versus 21 (95%) after the service. No patient had documented nonpharmacologic education prior to the service, compared with all patients after the service. All differences were significant (p < 0.05).

CONCLUSIONS: A pharmacist-run osteoporosis service significantly improved short-term compliance with guidelines, including appropriate DEXA scan frequency, pharmacotherapy, calcium and vitamin D supplementation, and nonpharmacologic education.

OBJECTIVE: To investigate the level of completeness of documentation in the EPR after a patient's first visit to a Dutch community pharmacy.

METHODS: In each participating pharmacy, newly enlisted (<3 mo) patients to whom at least one medication had been dispensed were enrolled in this survey. For each patient who could be interviewed, pharmacy master students used a structured questionnaire to gather relevant, mandatory patient data (ie, basic characteristics, current drugs used, diseases, intolerabilities, specific conditions) and nonmandatory patient data (eg, diagnostic and monitoring data, personal experiences and habits, drug use problems) from the patient's EPR and from a structured telephone interview with the patient. Data retrieved from the patient's EPR were compared with data provided by the patient during the telephone interview.

RESULTS: Of 403 selected patients, 154 (38.2%) could be interviewed by telephone. Poor documentation of telephone numbers in the EPR was the main reason for nonresponse (134/249). Interviewers found that 67.7% of prescription drugs, 0% of over-the-counter drugs, 19.6% of diseases, 3.7% of intolerabilities, and none of the specific conditions reported by patients had been documented in the EPR. Nonmandatory data (personal experiences and habits, drug use problems) reported during the patient interview had not been documented in the EPR.

CONCLUSIONS: The EPR after a patient's first visit to the community pharmacy is often incomplete. For new patients, the pharmacist should more proactively and systematically gather patient information, and all relevant information should be recorded, preferably in coded form, in the pharmacy information system to allow more adequate clinical risk management.

OBJECTIVE: An evaluation was conducted to determine whether use of drug information templates by fourth-year pharmacy students during their drug information experiential rotation improved compliance with the modified systematic approach.

METHODS: Fifty documented drug information requests, including 25 prior to template implementation (August 2005–August 2006) and 25 after template implementation (August 2007–August 2008), were randomly selected for evaluation. Each question was evaluated for completeness of background information obtained, categorization and identification of the ultimate question, completeness of references searched, and formulation of a concise response and an evidence-based recommendation.

RESULTS: Background information was complete in 16% of pre-template questions and 92% of post-template questions (p < 0.001). Eighty-four percent of pre-template questions and 96% of post-template questions were appropriately categorized (p = 0.349). The requestor's ultimate question was clearly identified in 68% of pretemplate questions and 92% of post-template questions (p = 0.074). All necessary references were searched in 36% of pre-template questions and 88% of post-template questions (p < 0.001). A concise response was documented in 80% of pretemplate questions and 92% of post-template questions (p = 0.417). In questions determined to require a specific recommendation among the pre-template (n = 20) and post-template groups (n = 14), a clear and evidence-based recommendation was described in 40% (p = 0.038) and 79% (p = 0.038), respectively.

CONCLUSIONS: Use of drug information request templates improves students' compliance with the modified systematic approach, most notably in obtaining background information and searching necessary references including primary literature.

DATA SOURCES: Data were collected from searches of MEDLINE (1966–June 30, 2009), EMBASE (1974–June 30, 2009), bibliographies of manuscripts, and www.fda.gov. Key search terms included fospropofol, Lusedra, Aquavan, sedative–hypnotic, and monitored anesthesia care.

STUDY SELECTION AND DATA EXTRACTION: All Phase 1, Phase 2, and Phase 3 clinical trials studying the safety and efficacy of fospropofol were reviewed.

DATA SYNTHESIS: Fospropofol is a water-soluble prodrug of propofol, a potent sedative–hypnotic agent. Propofol is highly lipophilic and is formulated in lipid-containing solvents, which have known disadvantages, including pain on injection, narrow therapeutic window with the potential to cause deep sedation, high lipid intake during long-term sedation, and risk of infection resulting from bacterial contamination. Due to its water solubility, fospropofol eliminates some of the known lipid emulsion–associated disadvantages of propofol and provides a more predictable peak onset of activity and more gradual recovery to a full state of consciousness. The pharmacokinetic and pharmacodynamic profiles of fospropofol make it an attractive agent for sedation for procedures of short duration. Unfortunately, the number of patients studied has been relatively small and the amount of safety data is limited. Of concern are reports of hypoxemia and hypotension; these reports are limited in number, but the episodes are serious and may require acute intervention. Although fospropofol holds promise for procedural sedation, due to limited safety data, the Food and Drug Administration has limited approval of fospropofol to monitored anesthesia care in patients undergoing diagnostic or therapeutic procedures.

CONCLUSIONS: Fospropofol is a viable addition to the class of sedative–hypnotic agents due to the minimization of unwanted adverse effects of propofol and maintenance of a favorable pharmacokinetic profile facilitating sedation, anxiolysis, and rapid recovery. However, there are limited safety data to justify its use without the presence of dedicated anesthesia personnel.

DATA SOURCES: A MEDLINE search (1966–July 2009) was conducted using the key words lacosamide, harkoseride, SPM-927, ADD-234037, epilepsy, anticonvulsant, and neuropathic pain. Bibliographies of all articles retrieved were also reviewed.

STUDY SELECTION AND DATA EXTRACTION: All studies including humans and published in English with data describing lacosamide for the adjunctive treatment of partial-onset seizures and for treatment of neuropathic pain were reviewed.

DATA SYNTHESIS: Lacosamide is a functionalized amino acid molecule that selectively enhances the slow inactivation of voltage-gated sodium channels and interacts with the collapsin-response mediator protein-2. With its bioavailability of approximately 100%, minimal protein binding, and few drug–drug interactions, lacosamide has a favorable pharmacokinetic profile. Recent data suggest that lacosamide may have a role as adjunctive treatment of partial-onset seizures. Open-label studies showed a 14–47% reduction in seizure frequency, while placebo-controlled trials demonstrated a 26–40% reduction in seizure frequency. The 50% responder rates ranged from 32.7% to 41.2% with varying doses of lacosamide. Although lacosamide use is not approved by the Food and Drug Administration for treatment of neuropathic pain, studies demonstrated reductions of 2.01–3.60 in pain scale scores. The most common adverse effects, occurring in greater than 10% of subjects in the clinical trials, include arthralgia, ataxia, blurred vision, diplopia, dizziness, fatigue, headache, injection site pain (only in intravenous studies), nausea, tremor, upper respiratory tract infection, and vomiting.

CONCLUSIONS: Lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures. Its exact role in the treatment of neuropathic pain needs to be determined.

DATA SOURCES: Searches of MEDLINE (1966–June 2009) and EMBASE (1974–June 2009) were conducted using the terms efungumab, Mycograb, heat shock protein 90, and invasive candidiasis. Other resources included www.clinicaltrials.gov and article bibliographies.

STUDY SELECTION AND DATA EXTRACTION: All studies and case reports evaluating efungumab use in IC were included. Literature review was limited to the English language.

DATA SYNTHESIS: Efungumab is a monoclonal antibody targeted against heat shock protein 90 (HSP 90). It binds to HSP 90, preventing a conformational change needed for fungal viability. In vitro data show that HSP 90 inhibition may decrease resistance against antifungal agents and increase antifungal activity. Efungumab shows activity against Candida spp. when used alone and synergism when combined with fluconazole, caspofungin, and amphotericin B. A randomized controlled trial evaluated combination therapy of efungumab 1 mg/kg twice daily and liposomal amphotericin B versus amphotericin B therapy alone. At day 10, a favorable response was seen in 84% of patients in the efungumab group compared with 48% of patients in the placebo group (OR 5.76; 95% CI 2.4 to 13.8). Mortality at day 33 was also lower in the efungumab group, 4% versus 18%, respectively (OR 0.168; 95% CI 0.036 to 0.797). Although adverse effects were similar in this trial (10% vs 7%), case reports revealed an increased incidence of blood pressure fluctuations. Cytokine release syndrome has also been linked to efungumab use, warranting further exploration of its safety.

CONCLUSIONS: Efungumab is a new antifungal agent with a novel mechanism of action. Available clinical data and synergy studies support the use of efungumab in combination with other antifungal agents for the treatment of IC. Further safety data are needed before formulary recommendations can be made.

DATA SOURCES: A literature review was performed via MEDLINE (1950–July 1, 2009) and International Pharmaceutical Abstracts (1970–June 2009) searches using the terms post-thrombotic syndrome, post-phlebitic syndrome, deep vein thrombosis, and compression stockings.

DATA SYNTHESIS: PTS is best characterized as a chronic syndrome of clinical signs and symptoms including pain, swelling, parasthesias, and ulceration in the affected limb following deep vein thrombosis (DVT). It occurs in up to half of patients with symptomatic DVT, usually within the first 2 years. Although the pathophysiology of PTS is not well understood, a thrombus may cause venous hypertension and valvular incompetence resulting in edema, tissue hypoxia, and in severe cases, ulceration. Risk factors for PTS include recurrent ipsilateral DVT, obesity, and poor quality of anticoagulant therapy. PTS diagnosis is based on the presence of typical signs and symptoms and may be made using one of several clinical scoring systems. Prevention of PTS should focus on DVT prevention and the use of elastic compression stockings following DVT, while fibrinolysis remains under investigation as an effective method for PTS prevention. The treatment of PTS may include either pharmacologic or mechanical modalities, although none of these regimens has been rigorously tested. Pharmacists have the opportunity to provide more comprehensive antithrombotic management by educating patients and providers on PTS, recommending appropriate preventive therapy, assisting patients in obtaining and adhering to this therapy, and assisting providers with the management of PTS.

CONCLUSIONS: Providers should be proactive in preventing PTS, with pharmacists taking an active role in optimal DVT prevention, identifying patients at risk for PTS, and counseling and directing preventive therapies.

DATA SOURCES: A search of MEDLINE (1966–June 2009) was conducted using the terms furosemide, torsemide, bumetanide, ethacrynic acid, and loop diuretics. Articles were limited to those written in English.

STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed. Studies were eligible if they encompassed pharmacokinetics, comparative safety and efficacy, or comparative costs of the loop diuretics.

DATA SYNTHESIS: In patients with heart failure (HF), torsemide demonstrated decreased mortality compared with furosemide in 1 study (2.2% vs 4.5% in the furosemide group; p < 0.05), decreased hospitalizations in 1 study (23 in the torsemide group vs 61 in the furosemide group; p < 0.01), and improved New York Heart Association functional classifications in 2 studies. In the first, 45.8% with torsemide versus 37.2% with furosemide demonstrated improvement in at least one functional class (p = 0.00017). In the second, 40.2% with torsemide and 30.7% with furosemide demonstrated improvement in at least one functional class (p = 0.014). In 2 of 3 studies of patients with cirrhosis, torsemide increased natriuresis and total volume diuresed compared with furosemide in patients with cirrhosis; however, no significant difference between the agents with respect to plasma renin and aldosterone concentrations was demonstrated. In patients with pulmonary hypertension, central venous pressure, capillary wedge pressure, and stroke volume significantly improved from baseline among patients who received torsemide, but not in those who received furosemide, although the intergroup analysis failed to reach statistical significance. Among patients with chronic kidney disease, no significant differences were noted with respect to natriuresis and blood pressure control between the 2 agents; however, in patients with acute kidney injury, patients who received furosemide had a significant improvement in urine output versus the torsemide group. Additionally, 2 trials comparing bumetanide with furosemide were identified, although the results were conflicting. In patients with nephrotic syndrome, bumetanide significantly improved weight loss in the first 4 weeks and in week 20, compared with furosemide. In patients with HF, significant improvement in dyspnea at rest and on exertion was exhibited in the bumetanide group, but not in the furosemide group; no significant difference was noted between the 2 groups when evaluating global assessment.

CONCLUSIONS: Growing evidence demonstrates more favorable pharmacokinetic profiles of torsemide and bumetanide compared with furosemide. Furthermore, torsemide may be more efficacious and safer than furosemide in patients with HF. A trial comparing all 3 drugs would be required to confirm torsemide as the primary loop diuretic in patients with HF, but based upon limited current evidence, we recommend torsemide over furosemide. Currently, little evidence exists to support either torsemide or bumetanide as first-line treatment over furosemide in patients with other edematous disease states.

DATA SOURCES: Searches of MEDLINE and PubMed (1977–July 2009) were conducted using the key words quetiapine and bipolar depression. The references of literature found were cross-referenced. The pharmaceutical company that produces quetiapine was contacted to obtain the posters for the EMBOLDEN I and EMBOLDEN II trials.

STUDY SELECTION AND DATA EXTRACTION: Only double-blind, placebo-controlled trials were included for review, as well as any subanalyses of the literature that matched this criterion.

DATA SYNTHESIS: There was a total of 5 double-blind, placebo-controlled trials and 5 subanalyses reviewed. The results of these data demonstrated quetiapine's efficacy in the treatment of depressive phases of bipolar disorder, including statistically significant improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS). In the trials reviewed in this article, the change in MADRS scores ranged from –15.4 to –16.94 within the quetiapine groups, and from –10.26 to –11.93 in the placebo groups. There were also statistically significant improvements in the Hamilton Anxiety Rating Scale, the Short Form of the Quality of Life Enjoyment and Satisfaction Questionnaire, the Pittsburgh Sleep Quality Index, and the Sheehan Disability Scale. All of these trials had a duration of 8 weeks and therefore cannot be applied to the long-term use of quetiapine in bipolar depression. The most common adverse events were sedation, somnolence, and dry mouth. The overall dropout rates for the trials reviewed ranged from 24% to 47%.

CONCLUSIONS: Based on the literature reviewed here, quetiapine appears to be a safe and efficacious short-term treatment option for bipolar depression. Patients with bipolar type I showed greater improvement on the MADRS than those with bipolar type II. Patients with a rapid-cycling disease course showed an improvement in depressive symptoms, regardless of bipolar type.

DATA SOURCES: Multiple MEDLINE searches were performed using a comprehensive search term list to identify studies for inclusion, including, but not limited to, anemia, erythropoiesis-stimulating agent (ESA), epoetin, darbepoetin, CERA, hemoglobin, CKD, dialysis, end-stage renal disease, quality of life, and pharmacist. Annual data reports and clinical practice guidelines published by the National Kidney Foundation and US Renal Data System were included. Information provided within product package inserts for recombinant human erythropoietin (epoetin alfa; Epogen, Procrit) and darbepoetin alfa (Aranesp) were also included.

STUDY SELECTION AND DATA EXTRACTION: Only articles that were published in English and were relevant for this review were included.

DATA SYNTHESIS: Anemia is a common complication of CKD, with significant impact on patients' quality of life. Anemia of CKD represents a significant burden on the healthcare system, with ESA use resulting in substantial financial costs. As new therapies, formularies, and dosing regimens evolve, the collaborative role of the clinical pharmacist is integral to a multidisciplinary treatment strategy, both in the inpatient and outpatient settings, such as hospitals or dialysis centers, respectively. This review focuses on initial and target hemoglobin (Hb) concentrations, as well as patient characteristics, treatment preferences, and dosing schedules, which are important considerations in managing CKD-associated anemia. To ensure effective therapeutic strategies, a patient-centered approach is required. Pharmacists are ideally positioned to help select ESA therapy, influence formulary use, educate healthcare professionals and patients, develop and implement dosing and monitoring protocols, and possibly promote quality improvement.

CONCLUSIONS: An approach to CKD-associated anemia management that involves collaboration with pharmacists is essential to achieve patient-specific, cost-effective ESA therapy.

DATA SOURCES: A search of MEDLINE from 1948 to August 20, 2009, was performed using the search terms tamoxifen, warfarin, drug interactions, and cytochrome P450 2C9. EMBASE was searched (1980–week 33, 2009), using the search terms tamoxifen and warfarin, for articles limited to use in humans and published in English, then further narrowed to drug interactions. Bibliographic review was conducted but did not reveal any additional references.

STUDY SELECTION AND DATA EXTRACTION: All sources evaluated were published in English and included original case reports, letters, and medical record or database reviews that described an interaction between warfarin and tamoxifen.

DATA SYNTHESIS: Since tamoxifen therapy and cancer increase the risk of venous thromboembolism, warfarin may be prescribed to these patients. However, product information, primary literature, and tertiary literature describe concomitant use of tamoxifen and warfarin as a contraindication since this may increase the level of anticoagulation and the risk of bleeding complications. Although the exact mechanism of the interaction is unknown, one theory is that tamoxifen inhibits CYP2C9, which metabolizes the S-isomer of warfarin. Five publications were identified including 2 letters, 2 individual case reports, and 2 retrospective reviews (1 of the case reports was included in a medical record review). Collectively, these articles described a total of 31 patients taking warfarin and tamoxifen concomitantly, with 8 patients experiencing bleeding complications.

CONCLUSIONS: Although concomitant use of warfarin and tamoxifen is deemed a contraindication, evidence regarding this potential interaction is limited. Therefore, safety of concomitant use of tamoxifen and warfarin may be similar to that of other drugs that interact with warfarin, requiring consistent and careful monitoring. However, more evidence is needed to warrant the routine use of this combination.

DATA SOURCES: Literature was accessed through MEDLINE (1950–June 2009), PubMed (1966–June 2009), and International Pharmaceutical Abstracts (1970–June 2009), with combinations of the following terms: positive inotrope, milrinone, dobutamine, and β-receptor blocker. In addition, reference citations from publications identified were reviewed.

STUDY SELECTION AND DATA EXTRACTION: All articles that examined the effect of combination therapy with a β-blocker and milrinone on clinical endpoints in patients with advanced HF were assessed.

DATA SYNTHESIS: A search of the literature revealed 4 studies examining the clinical effects of combination therapy with a β-blocker and milrinone. Three of these studies were retrospective reviews, while one was a post hoc subgroup analysis from the OPTIME-CHF study. Concomitant therapy with milrinone and a β-blocker was well tolerated, with no significant increase in adverse events or deterioration in clinical status in any study. Tolerability rates for combination therapy ranged from 88% to 92%. In 2 of the studies, roughly 50% of the patients in the combination arm were able to be weaned off milrinone. One study suggested a mortality reduction in favor of combination therapy over milrinone alone, while another study suggested no difference in mortality with combination therapy versus milrinone monotherapy. One study suggested a potential increase in mortality when β-blocker therapy was withdrawn in patients who were started on milrinone. None of the studies demonstrated any significant differences in hospitalization rates. All of the studies were limited by their retrospective nature and small sample size.

CONCLUSIONS: Data are insufficient to make firm conclusions on the clinical benefit of combination therapy with a β-blocker and milrinone in patients with advanced HF, although it appears that this regimen is well tolerated and may allow weaning of inotropic support.

OBJECTIVE: To explore variation in pharmacy staff response to requests for nonprescription medicines from different legislative schedules through analysis of data collected using pseudo-patient methods.

METHODS: Consumers posed as pharmacy patrons (ie, pseudo-patients, simulated patients) and requested 1 of 3 specific nonprescription medicines by name. Two of these, ibuprofen and a branded cold and flu medication, could be sold by any pharmacy staff member (these were considered Pharmacy Medicine). The third, a combination analgesic containing paracetamol (acetaminophen), codeine, and doxylamine, required pharmacist involvement in the sale (considered Pharmacist Only Medicine). Pseudo-patient visits measured the service provided in each pharmacy by observing whether staff performed particular behaviors such as providing advice regarding the drugs.

RESULTS: Staff response was generally superior when pseudo-patients requested the combination analgesic that required pharmacist intervention. Medicine advice was provided verbally to 84.9% of pseudo-patients requesting this analgesic compared with 51.1% of those requesting the cold and flu medication. Similar trends were observed for other behaviors.

CONCLUSIONS: Emerging patterns imply that pharmacy staff response may vary according to the medicine requested. It may be that pharmacists and their staff prioritize drugs or behaviors that they consider critically relevant as part of a risk management approach. This has possible implications for future scheduling policy. Further research using a range of scenarios would more fully explore the breadth of such behavior. This would aid identification of medicines that trigger professional intervention and inform development of targeted training programs.

CASE SUMMARY: A 16-day-old infant developed several mild episodes of apnea that culminated in a severe cyanotic episode requiring resuscitation. A thorough examination at the hospital gave no evidence of underlying diseases that could explain the reaction. The mother had used lamotrigine in increasing doses throughout pregnancy, and at the time of the apneic episodes, she used 850 mg/day. The infant was fully breast-fed, and the neonatal lamotrigine serum concentration was 4.87 µg/mL at the time of admission. Breast-feeding was terminated, and the infant fully recovered.

DISCUSSION: Although there are several reports on extensive passage of lamotrigine into breast milk, this is the first published report of a serious adverse reaction in a breast-fed infant. Lamotrigine clearance increases throughout pregnancy, and maternal dose increases are often necessary to maintain therapeutic effect. After delivery, clearance rapidly returns to preconception levels, enhancing the risk of adverse reactions in both mothers and breast-fed infants if the dose is not sufficiently reduced. In this case, the dose was slowly reduced after delivery, and the maternal lamotrigine serum concentration more than doubled in the week before the neonatal apneic episodes. A high lamotrigine concentration was detected in the breast milk, and the neonatal lamotrigine serum concentration was in the upper therapeutic range. The neonatal lamotrigine elimination half-life was approximately twice that seen in adults. The Naranjo probability scale indicated a probable relationship between apnea and exposure to lamotrigine through breast-feeding in this infant.

CONCLUSIONS: Infants can be exposed to clinically relevant doses of lamotrigine through breast-feeding. Individual risk/benefit assessment is important, and close monitoring of both mother and child is advisable, especially during the first 3 weeks postpartum.

CASE SUMMARY: A 29-year-old woman was treated with duloxetine for depression during the second half of an uncomplicated gestation. She gave birth at term to a healthy female infant. A cord blood sample was obtained at birth. The mother continued the antidepressant while exclusively breast-feeding her infant. One month later, we collected blood and milk samples from the mother and a single blood sample from the infant. All samples were analyzed for the presence and concentrations of duloxetine.

DISCUSSION: Duloxetine crosses the placenta at term and is excreted into breast milk. No evidence of developmental or other type of toxicity was observed in the infant at birth or during the first 32 days after birth. The published literature detailing human pregnancy experience with this antidepressant is limited to 11 cases in which women became pregnant while taking duloxetine. In 10 cases, the drug was discontinued when pregnancy was diagnosed and no outcome data were reported. In the eleventh case, an infant exposed to duloxetine 90 mg/day developed neonatal behavioral syndrome. One study examined the excretion of duloxetine into breast milk, but the mothers discontinued nursing for the study. In the present case, no adverse effects from exposure to the drug in milk were noted in the exclusively breast-fed infant. The possibility of functional/neurobehavioral deficits appearing later in life cannot be excluded because long-term follow-up has not been conducted in infants exposed to duloxetine in utero or during nursing.

CONCLUSIONS: No developmental toxicity or other signs of toxicity were observed in an infant exposed to duloxetine during the second half of gestation and during breast-feeding in the first 32 days after birth. However, the possibility of functional/neurobehavioral deficits appearing later in life cannot be excluded.

CASE SUMMARY: A 64-year-old white female had recently received treatment with bendamustine for stage III follicular lymphoma. After her fourth cycle, she was admitted to an outside facility with severe right upper quadrant pain across her back and findings consistent with obstructive jaundice. She was found to have pancytopenia and elevations in total bilirubin, alkaline phosphatase, and transaminase levels. A bone marrow biopsy showed no evidence of lymphoma and presence of megakaryocytes on 2 occasions. Upon transfer to West Virginia University Hospitals, her haptoglobin was found to be undetectable, total bilirubin 10.3 mg/dL (unconjugated bilirubin 4.9 mg/dL), reticulocyte count 21.4% (reticulocyte index ≥2%), alkaline phosphatase 1125 U/L, and lactate dehydrogenase 421 U/L. The peripheral smear showed evidence of spherocytes and very rare schistocytes. Based on these findings, the woman was diagnosed with hemolytic anemia secondary to bendamustine exposure. She was started on prednisone 1 mg/kg (60 mg) daily and, soon after, her platelets and hemoglobin stabilized.

DISCUSSION: Drug-induced hemolytic anemia is an acquired or extrinsic process that results in antibody-mediated red blood cell destruction. The patient was not taking any medications commonly associated with hemolytic anemia; however, her laboratory test results were consistent with hemolytic anemia. Based on bendamustine's structural similarity to fludarabine and fludarabine's association with causing hemolytic anemia, we considered exposure to bendamustine to be the most likely contributory factor for her diagnosis. According to the Naranjo probability scale, a probable likelihood was reflected in bendamustine causing the hemolytic anemia.

CONCLUSIONS: Continued monitoring of postmarketing data is necessary to correlate this occurrence of hemolytic anemia with bendamustine therapy.

CASE SUMMARY: An 11-day-old term female infant with Hirschsprung enterocolitis and bowel perforation was transferred to our institution on day 4 of hospitalization with septic shock and abdominal compartment syndrome. Initial peritoneal culture at time of colectomy did not grow yeast; however, Candida albicans grew from cultures obtained on abdominal washout 2 days later even while the patient was on treatment with liposomal amphotericin B 5 mg/kg/day. Anidulafungin 1.5 mg/kg/day intravenous therapy was instituted, and within 4 days peritoneal cultures were negative. The patient slowly recovered and, after a prolonged hospitalization, she was discharged home on hospital day 68 on partial parenteral nutrition.

DISCUSSION: Despite the rising incidence of fluconazole-resistant Candida spp., pediatric dosing guidelines, and an adult indication for echinocandin use in candidal peritonitis, there are no reports of echinocandin use for fungal peritonitis in pediatric patients. The echinocandins are rational choices when fluconazole resistance is a concern. Furthermore, the unique clearance profile of anidulafungin makes it an attractive choice in critically ill patients with hepatic and renal dysfunction; the Infectious Diseases Society of America has recommended that an echinocandin be first-line antifungal therapy for moderately or severely ill pediatric or adult patients.

CONCLUSIONS: Peritoneal candidiasis is a common complication of bowel perforation in neonates. Anidulafungin's pharmacokinetic and antifungal properties make it a viable therapeutic option in the treatment of this disease in critically ill infants and children.