Showing papers in "Pharmacotherapy in 2010"

Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing.

Abstract: Colistin is a polymyxin antibiotic that was discovered in the late 1940s for the treatment of gram-negative infections. After several years of clinical use, its popularity diminished because of reports of significant nephrotoxicity and neurotoxicity. Recently, the antibiotic has resurfaced as a last-line treatment option for multidrug-resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The need for antibiotics with coverage of these gram-negative pathogens is critical because of their high morbidity and mortality, making colistin a very important treatment option. Unfortunately, however, resistance to colistin has been documented among all three of these organisms in case reports. Although the exact mechanism causing colistin resistance has not been defined, it is hypothesized that the PmrA-PmrB and PhoP-PhoQ genetic regulatory systems may play a role. Colistin dosages must be optimized, as colistin is a last-line treatment option; in addition, suboptimal doses have been linked to the development of resistance. The lack of pharmacokinetic and pharmacodynamic studies and no universal harmonization of dose units, however, have made it difficult to derive optimal dosing regimens and specific dosing guidelines for colistin. In critically ill patients who may have multiorgan failure, renal insufficiency may alter colistin pharmacokinetics. Therefore, dosage alterations in this patient population are imperative to achieve maximal efficacy and minimal toxicity. With regard to colistin toxicity, most studies show that nephrotoxicity is reversible and less frequent than once thought, and neurotoxicity is rare. Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns.

Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.

Abstract: Type 2 diabetes mellitus traditionally has been characterized by insulin resistance and beta-cell dysfunction, leading to hyperglycemia and eventual micro- and macrovascular complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of drugs available for the management of type 2 diabetes. In order to provide a comprehensive evaluation and comparison of the pharmacology, pharmacokinetics, efficacy, and safety of the DPP-4 inhibitors-sitagliptin, vildagliptin, saxagliptin, and alogliptin-in the treatment of type 2 diabetes, we conducted a MEDLINE search (1966-July 2009) for pertinent English-language articles. Abstracts of the annual meetings of the American Diabetes Association and European Association for the Study of Diabetes from 2005-2009 were also searched. As a drug class, the DPP-4 inhibitors have become widely accepted in clinical practice because of their low risk of hypoglycemia, favorable adverse-effect profile, and once-daily dosing. They are weight neutral (do not cause weight gain or loss) and appear to decrease beta-cell apoptosis and increase beta-cell survival. Because clinical studies directly comparing agents from this class have not, to our knowledge, been conducted, making comparisons in terms of efficacy and safety will become difficult for clinicians as more agents become available. Based on information from preclinical, clinical, and postmarketing data, there does not appear to be a compelling advantage of one DPP-4 inhibitor over another in terms of efficacy, safety, or ease of clinical use. Although theoretical advantages exist for agents with a higher specificity for DPP-4 inhibition versus inhibition of other isoenzymes associated with toxicity, comparative studies and/or increased clinical experience with this class of drug will determine the clinical advantages, if any, of one agent over another.

Meta-analysis of the Efficacy and Safety of Adalimumab, Etanercept, and Infliximab for the Treatment of Rheumatoid Arthritis

Abstract: Study Objective. To evaluate the efficacy and safety of using the anti-tumor necrosis factor-α (anti-TNF-α) drugs adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis. Design. Systematic review and meta-analysis of 21 randomized, placebo-controlled trials (eight adalimumab, seven infliximab, six etanercept). Patients. Adults with rheumatoid arthritis who received adalimumab (1524 patients), infliximab (1116 patients), etanercept (1029 patients), or placebo (2834 patients) with or without concomitant methotrexate in all groups. Measurements and Main Results. A literature search of several databases from January 1995-December 2008 was performed. There were no restrictions based on language or date of publication, and low-quality studies (based on Jadad score) were excluded. American College of Rheumatology (ACR) 20% improvement criteria (ACR20), 50% improvement criteria (ACR50), and 70% improvement criteria (ACR70) were used to compare treatment efficacy. Safety was compared based on frequency of serious adverse events, serious infections, malignancy, and death. Withdrawals due to adverse events and lack of efficacy were also evaluated. With short-term treatment (12–30 wks), etanercept demonstrated the highest risk ratios (RRs) for reaching ACR20 and ACR50: 2.94 (95% confidence interval [CI] 2.27–3.81) and 5.28 (95% CI 3.12–8.92), respectively. Adalimumab demonstrated the highest RR for achieving ACR70 (5.36, 95% CI 3.76– 7.64). Over a long-term treatment course (1–3 yrs), adalimumab demonstrated the highest RRs (95% CIs) for these parameters: 1.85 (1.07–3.19), 2.80 (1.16–6.77), and 3.23 (1.37–7.61) for ACR20, ACR50, and ACR70, respectively. No statistically significant differences were noted in the safety of any of the three drugs compared with placebo. Infliximab had the highest RRs for withdrawing from the study due to lack of efficacy (2.05, 95% CI 1.33–3.16) and adverse events (0.41, 95% CI 0.18–0.95). Conclusion. With short-term treatment, etanercept and adalimumab had higher efficacy results; with long-term treatment, adalimumab appeared to be the most effective. Clinicians should be aware that each of the three drugs has different rates of efficacy and different safety considerations that must be taken into account when selecting the best treatment for an individual with rheumatoid arthritis.

Impact of Proton Pump Inhibitors on the Effectiveness of Clopidogrel After Coronary Stent Placement: The Clopidogrel Medco Outcomes Study

Abstract: Study Objective. To investigate the potential impact of proton pump inhibitors (PPIs) on the effectiveness of clopidogrel in preventing recurrent ischemic events after percutaneous coronary intervention (PCI) with stent placement. Design. Population-based, retrospective cohort study. Data Source. National medical and pharmacy benefit claims database comprising approximately 19 million members. Patients. A total of 16,690 patients who had undergone PCI with stent placement and who were highly adherent to clopidogrel therapy alone (9862 patients) or to clopidogrel with a PPI (6828 patients) between October 1, 2005, and September 30, 2006. Measurements and Main Results. The primary end point was the occurrence of a major adverse cardiovascular event during the 12 months after stent placement. These events were defined as hospitalization for a cerebrovascular event (stroke or transient ischemic attack), an acute coronary syndrome (myocardial infarction or unstable angina), coronary revascularization (PCI or coronary artery bypass graft), or cardiovascular death. A composite event rate was compared between patients who received clopidogrel alone and those who received concomitant clopidogrel-PPI therapy. Baseline differences in covariates were adjusted by using Cox proportional hazards models. In the 9862 patients receiving clopidogrel alone, 1766 (17.9%) experienced a major adverse cardiovascular event compared with 1710 patients (25.0%) who received concomitant clopidogrel-PPI therapy (adjusted hazard ratio 1.51, 95% confidence interval 1.39–1.64, p<0.0001). Similar associations of increased risk were observed for each PPI studied (omeprazole, esomeprazole, pantoprazole, and lansoprazole). Conclusion. Concomitant use of a PPI and clopidogrel compared with clopidogrel alone was associated with a higher rate of major adverse cardiovascular events within 1 year after coronary stent placement.

Ferumoxytol: a new intravenous iron preparation for the treatment of iron deficiency anemia in patients with chronic kidney disease.

Abstract: Ferumoxytol is an intravenous iron preparation for treatment of the anemia of chronic kidney disease (CKD). It is a carbohydrate-coated, superparamagnetic iron oxide nanoparticle. Because little free iron is present in the preparation, doses of 510 mg have been administered safely in as little as 17 seconds. Two prospective, randomized studies compared two doses of ferumoxytol 510 mg given in 5 +/- 3 days with 3 weeks of oral iron 200 mg/day (as ferrous fumarate) in anemic patients with CKD. One study enrolled 304 patients with stages 1-5 CKD (predialysis), and the other study enrolled 230 patients with stage 5D CKD (undergoing hemodialysis). In both studies, a greater increase in hemoglobin level from baseline to end of study (day 35) was noted in patients who received ferumoxytol compared with those who received oral iron (mean +/- SD 0.82 +/- 1.24 vs 0.16 +/- 1.02 g/dl in patients with stages 1-5 CKD and 1.02 +/- 1.13 vs 0.46 +/- 1.06 g/dl in patients with stage 5D CKD, p<0.001). A greater proportion of both predialysis and hemodialysis patients who received ferumoxytol had hemoglobin level increases from baseline of 1 g/dl or more compared with those who received oral iron (p<0.001). In a prospective, double-blind, crossover study of more than 700 patients with CKD stages 1-5D that compared the safety of ferumoxytol with normal saline injection, the rates of treatment-related adverse events were 5.2% and 4.5%, respectively. Serious treatment-related adverse events were seen in one patient in each treatment group. The most common adverse events with ferumoxytol occurred at the injection site (bruising, pain, swelling, erythema). Dizziness, nausea, pruritus, headache, and fatigue occurred in less than 2% of patients receiving ferumoxytol, with a similar frequency noted after administration of normal saline. In short-term studies, intravenous ferumoxytol was safely and rapidly administered, and was more effective than oral iron therapy in increasing hemoglobin levels in anemic patients with CKD. Long-term clinical trials with clinical outcomes and studies comparing ferumoxytol with other parenteral iron agents will help define the role of ferumoxytol in treating the anemia of CKD.

Management of Drug and Food Interactions with Azole Antifungal Agents in Transplant Recipients

Abstract: Azole antifungal agents are frequently used in hematopoietic stem cell and solid organ transplant recipients for prevention or treatment of invasive fungal infections. However, because of metabolism by or substrate activity for various isoenzymes of the cytochrome P450 system and/or P-glycoprotein, azole antifungals have the potential to interact with many of the drugs commonly used in these patient populations. Thus, to identify drug interactions that may result between azole antifungals and other drugs, we conducted a literature search of the MEDLINE database (1966-December 2009) for English-language articles on drug interaction studies involving the azole antifungal agents fluconazole, itraconazole, voriconazole, and posaconazole. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity. The magnitude and duration of an interaction between azoles and immunosuppressants are not class effects of the azoles, but differ between drug combinations and are subject to interpatient variability. Drug interactions in the transplant recipient receiving azole therapy may also occur with antibiotics, chemotherapeutic agents, and acid-suppressive therapies, among other drugs. Initiation of an azole antifungal in transplant recipients nearly ensures a drug-drug interaction, but often these drugs are required. Management of these interactions first involves knowledge of the potential drug interaction, appropriate dosage adjustments when necessary, and therapeutic or clinical monitoring at an appropriate point in therapy to assess the drug-drug interaction (e.g., immunosuppressive drug concentrations, signs and symptoms of toxicity). These aspects of drug interaction management are essential not only at the initiation of azole antifungal therapy, but also when these agents are removed from the regimen.

A Comparative Review of the Lipoglycopeptides: Oritavancin, Dalbavancin, and Telavancin

Abstract: Resistance to antibiotics among gram-positive bacteria, especially enterococci and staphylococci, has led to the need to develop new antibiotics. Vancomycin, a glycopeptide antibiotic, has been used for over 3 decades to treat serious methicillin-resistant Staphylococcus aureus infections. The increased frequency of multidrug-resistant bacteria, especially vancomycin-resistant strains, has focused interest on three new lipoglycopeptides for the treatment of infections caused by gram-positive bacteria: oritavancin, dalbavancin, and telavancin. Although oritavancin and dalbavancin are still in development, telavancin received approval from the United States Food and Drug Administration in September 2009 for treatment of complicated skin and skin structure infections. Structurally different from vancomycin and teicoplanin, all three lipoglycopeptides have greater potency and less potential for development of resistant organisms. Of particular importance is the activity of oritavancin, dalbavancin, and telavancin against vancomycin-resistant organisms. In addition, the pharmacokinetic properties of these new antimicrobials substantially differ from those of vancomycin. Both oritavancin and dalbavancin have long terminal half-lives, which may allow for infrequent dosing. In addition, oritavancin is primarily cleared through hepatic pathways, which makes it potentially useful in patients with renal compromise. In animal models, these new lipoglycopeptides were effective in treating serious gram-positive infections, including complicated skin and skin structure infections, endocarditis, bacteremia, and pneumonia; in clinical studies, however, efficacy was shown only in complicated skin and skin structure infections for all three agents. According to preliminary data, the adverse-effect profile of these lipoglycopeptides is generally similar to that of drugs currently used to treat severe gram-positive infections. However, further evaluation and monitoring is necessary as more patients are exposed to these agents. As antimicrobial resistance continues to increase worldwide, the lipoglycopeptides may provide clinicians with a useful antimicrobial in the continued fight against multidrug-resistant gram-positive bacteria.

Comparison of two different models of anticoagulation management services with usual medical care.

Abstract: Study Objective. To evaluate the safety and economic impact of three models of anticoagulation management services: usual medical care, a nurse-managed service, and a pharmacist-managed service. Design. Retrospective medical record review. Setting. An eight-county health care system in central New York State. Patients. Nine hundred ninety-six patients (age range 19–99 yrs) who were receiving warfarin therapy for at least 6 months and who had three or more international normalized ratio (INR) values reported during the 1-year study period; 489 patients (6243 INR values) were in the pharmacist-managed group, 307 patients (3618 INR values) were in the nurse-managed group, and 200 patients (3142 INR values) were in the usual care group. Measurements and Main Results. All INR measurements were performed by the central laboratory or by on-site point-of-care testing. Data were queried from calendar year 2003 for the usual care and nurse-managed services and calendar year 2006 for the pharmacist-managed service. Anticoagulation indication, INR goal, baseline characteristics, and rates and costs of hospitalization and emergency department visits directly related to anticoagulation therapy were extracted from the medical record. If the INR goal was not documented, a range was assigned as appropriate from the American College of Chest Physicians anticoagulation guidelines. Markers of anticoagulation control—time in range (percentage of time a patient is maintained within their therapeutic range) and percentage of INR values in range—were calculated for each study group. Baseline characteristics were similar among all study groups. The pharmacist-managed service yielded the lowest rates of hospitalization and emergency department visits, with hospitalizations reduced by 56% versus nurse-managed service and 61% versus usual care (p<0.01). Emergency department visits were reduced by 78% in both the nurse-managed and usual care models (p<0.002). Based on visit rates, the pharmacist-managed service averted $141,277.34 in hospitalization costs and $10,183.76 in emergency department visit costs versus the nurse-managed service and $95,579.08 in hospitalization costs and $5511.21 in emergency department costs compared with the usual care model. Conclusion. Pharmacist-managed anticoagulation management services reduced the rates of anticoagulation-related emergency department visits and hospitalizations, with significant financial impact. Based on results of this study, a collaborative clinic using pharmacists, nurses, and physicians may be the optimal structure for an anticoagulation management service, with these results verified in future prospective randomized studies.

Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology.

Abstract: Everolimus, a proliferation signal inhibitor in the mammalian target of rapamycin (mTOR) drug class, has many clinical applications, including in organ transplantation, oncology, and cardiology. It currently has United States Food and Drug Administration (FDA) approval for prophylaxis against rejection in de novo renal transplant recipients, treatment of renal cell carcinoma, and use as a drug-eluting stent. To review the pharmacology, pharmacokinetics, efficacy, and safety of everolimus, we performed a search of the MEDLINE database (January 1997-April 2010) for all English-language articles of in vitro and in vivo studies that evaluated everolimus, as well as abstracts from recent scientific meetings and the manufacturer. In transplantation, everolimus demonstrates immunosuppressive properties and has been used to prevent acute rejection in cardiac, liver, lung, and renal transplant recipients. It appears that this agent may be potent enough to allow for the minimization or removal of calcineurin inhibitors in the long-term management of renal transplant recipients. In oncology, everolimus has been proven effective for the management of treatment-resistant renal cell carcinoma. In cardiology, everolimus is available as a drug-coated stent and is used in percutaneous coronary interventions for prevention of restenosis. In transplant recipients and patients with renal cell carcinoma, everolimus appears to have an extensive adverse-event profile. The pharmacologic properties of everolimus differentiate this agent from other drugs used in these clinical areas, and its pharmacokinetic properties differentiate it from sirolimus.

Role of Lactobacillus in the prevention of antibiotic-associated diarrhea: a meta-analysis.

Abstract: Study Objective. To evaluate the efficacy of a Lactobacillus probiotic singleagent regimen in preventing antibiotic-associated diarrhea (AAD). Design. Meta-analysis of 10 randomized, blinded, placebo-controlled trials. Patients. A total of 1862 pediatric and adult patients who received a Lactobacillus single-agent regimen or placebo for the prevention of AAD. Measurements and Main Results. The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception through May 2008 by two investigators independently using the following key words: probiotic, Lactobacillus, antibiotic-associated diarrhea. Full reports published in English were included if the studies were randomized, blinded, and placebo-controlled trials that evaluated the efficacy of Lactobacillus single-agent regimens versus placebo in the prevention of AAD. Bibliographies of recent review articles and systematic reviews were hand searched. Quality of the studies was assessed by using the Jadad scoring system. Number of subjects, age, Lactobacillus regimen, follow-up period, and occurrence of AAD were extracted into a standardized data collection form. Overall impact of Lactobacillus on AAD was compared with placebo by using a random-effects model. Ten studies with a total of 1862 patients (50.4% male) met all criteria. Six studies included patients aged 18 years or older, whereas four included patients younger than 18 years (range 2 wks-14 yrs). Jadad scores ranged from 2–5 (out of 5). The total daily dose of Lactobacillus ranged from 2 times 109 −4 times 1010 colony-forming units and was administered throughout the entire antibiotic treatment (5–14 days) for all patients. The follow-up period varied from 2 days-3 months after the end of the probiotic regimen. The combined risk ratio (RR) of developing AAD was significantly lower with Lactobacillus compared with placebo (RR 0.35, 95% confidence interval [CI] 0.19-0.67). In a subgroup analysis, this held true for adults but not pediatric patients (RR 0.24, 95% CI 0.08-0.75 and RR 0.44, 95% CI 0.18-1.08, respectively). Conclusion. Administration of a Lactobacillus single-agent regimen as a prophylactic agent during antibiotic treatment reduced the risk of developing AAD compared with placebo in adults but not pediatric patients.

Statin-associated muscle-related adverse effects: a case series of 354 patients.

Abstract: Study objective: To characterize the properties and natural history of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-associated muscle-related adverse effects (MAEs). Design: Patient-targeted postmarketing adverse-effect surveillance approach coupling survey design with an open-ended narrative. Setting: University-affiliated health care system. Subjects: Three hundred fifty-four patients (age range 34-86 yrs) who self-reported muscle-related problems associated with statin therapy. Measurements and main results: Patients with perceived statin-associated MAEs completed a survey assessing statin drugs and dosages; characteristics of the MAEs; time course of onset, resolution, or recurrence; and impact on quality of life (QOL). Cases were assessed for putative drug adverse-effect causality by using the Naranjo adverse drug reaction probability scale criteria and were evaluated for inclusion in groups for which mortality benefit with statins has been shown. Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p<0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p<0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and QOL domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy. Conclusion: This study complements available information on the properties and natural history of statin-associated MAEs, affirming dose dependence and strong QOL impact. The data indicating a dose-dependent relationship between MAE risk and recurrence suggest lower potency statins or discontinuation may bear consideration for ameliorating symptoms.

Hospital resource utilization and costs of inappropriate treatment of candidemia.

Abstract: Study Objectives. To evaluate the impact of inappropriate therapy—defined as delayed antifungal therapy beyond 24 hours from culture collection, inadequate antifungal dosage, or administration of an antifungal to which an isolate was considered resistant—on postculture hospital length of stay and costs, and to evaluate the relationship between modifiable risk factors, including failure to remove a central venous catheter, antifungal delay, and inadequate dosage, for an additive effect on hospital length of stay and costs. Design. Single-center retrospective cohort study. Setting. 1250-bed academic medical center. Patients. One hundred sixty-seven consecutive adult patients admitted between January 2004 and May 2006 with culture-confirmed Candida bloodstream infections that occurred within 14 days of hospital admission and who received at least one dose of antifungal treatment. Measurements and Main Results. Patients were stratified according to appropriateness of antifungal therapy. Appropriate therapy was defined as initiation of an antifungal to which the isolated pathogen was sensitive in vitro within 24 hours of positive culture collection, in addition to receipt of an adequate dose as recommended by the Infectious Diseases Society of America and the antifungal package insert. Postculture length of stay was the primary outcome and hospital costs the secondary outcome. An evaluation of modifiable risk factors was performed separately. Data were analyzed for 167 patients (22 in the appropriate therapy group and 145 in the inappropriate therapy group). Postculture length of stay was shorter in the appropriate therapy group (mean 7 vs 10.4 days, p=0.037). This correlated with total hospital costs that were lower in the appropriate therapy group (mean $15,832 vs $33,021, p<0.001.) A graded increase in costs was noted with increasing number of modifiable risk factors (p=0.001). Conclusion. Inappropriate therapy for Candida bloodstream infection occurring within 14 days of hospitalization was associated with prolonged postculture length of stay and increased costs. A rise in costs, but not length of stay, was noted with increasing modifiable risk factors.

Ceftaroline: a new cephalosporin with activity against resistant gram-positive pathogens.

Abstract: Ceftaroline is a novel, broad-spectrum, advanced-generation cephalosporin whose action is mediated by binding to penicillin-binding proteins in bacteria, consistent with other beta-lactam antibiotics. Ceftaroline is distinct in that it has antimicrobial activity against multidrug-resistant Staphylococcus aureus (including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus [VISA], heteroresistant VISA, and vancomycin-resistant S. aureus), Streptococcus pneumonia (including drug-resistant strains), and respiratory gram-negative pathogens such as Moraxella catarrhalis and Haemophilus influenzae (including beta-lactamase-positive strains). Development of resistance to ceftaroline occurs rarely in gram-positive bacteria and at a similar rate to that of other oxyimino-cephalosporins in gram-negative bacteria. The inactive prodrug, ceftaroline fosamil, is administered by intravenous infusion and rapidly undergoes biotransformation to ceftaroline. Ceftaroline then follows a two-compartment pharmacokinetic model and is eliminated primarily by renal excretion, with a half-life of approximately 3 hours. Similar to other cephalosporins, time above the minimum inhibitory concentration is the pharmacodynamic parameter that best predicts efficacy for ceftaroline. Ceftaroline 600 mg intravenously every 12 hours has been shown to have similar efficacy to vancomycin plus aztreonam for the treatment of complicated skin and skin structure infections and to ceftriaxone for the treatment of community-acquired bacterial pneumonia in phase III clinical trials. Ceftaroline displayed a safety profile similar to that of other cephalosporins in clinical trials. Dosage adjustment is required for moderate renal impairment and for patients receiving hemodialysis. Ceftaroline breakpoints have been proposed but not confirmed. Ceftaroline is a renally excreted broad-spectrum cephalosporin that is clinically effective for the treatment of complicated skin and skin structure infections and community-acquired bacterial pneumonia, and it has distinctive activity against some difficult-to-treat multidrug-resistant gram-positive organisms.

Vancomycin-Resistant Enterococcal Urinary Tract Infections

Abstract: Enterococci are a common cause of urinary tract infections (UTIs) among hospitalized patients. The rising prevalence of vancomycin-resistant enterococci (VRE) is of particular concern within many institutions because of its association with increased mortality and health care costs, as well as limited treatment options. Clinicians need to differentiate between VRE-associated urinary colonization, asymptomatic bacteriuria, and UTIs in order to determine the need for treatment, optimal therapeutic options, and length of therapy. Unnecessary use of antibiotics in patients simply colonized and not infected with VRE in the urine has become a large problem in both hospitals and long-term care facilities. A PubMed-MEDLINE search was conducted to identify all English-language literature published between January 1975 and March 2010 in order to summarize diagnostic criteria and treatment options for VRE UTIs. Several antimicrobials are discussed, with the specific focus on those with the potential to treat VRE UTIs and susceptibility patterns of VRE from urinary sources: ampicillin, amoxicillin, daptomycin, doxycycline, fosfomycin, imipenem-cilastatin, linezolid, nitrofurantoin, penicillin, piperacillin, quinupristin-dalfopristin, tetracycline, and tigecycline. Recommendations for empiric treatment of enterococcal UTIs and definitive treatment of VRE UTIs, including an evidence-based treatment algorithm, are proposed. Ampicillin generally is considered the drug of choice for ampicillin-susceptible enterococcal UTIs, including VRE. Nitrofurantoin, fosfomycin, and doxycycline have intrinsic activity against enterococci, including VRE, and are possible oral options for VRE cystitis. Linezolid and daptomycin should be reserved for confirmed or suspected upper and/or bacteremic VRE UTIs among ampicillin-resistant strains. Use of other antimicrobials, such as quinupristin-dalfopristin and tigecycline, should be evaluated on a case-by-case basis due to concerns of toxicity, resistance, and insufficient supportive data. Additional clinical data are needed to determine the optimal management and duration of therapy for VRE UTIs.

Methylene blue for the treatment of septic shock.

Abstract: Septic shock is a major cause of morbidity and mortality in the intensive care unit, and effective therapies are limited. Methylene blue is a selective inhibitor of guanylate cyclase, a second messenger involved in nitric oxide-mediated vasodilation. The use of methylene blue in the treatment of septic shock has been repeatedly evaluated over the past 20 years, but data remain scarce. To evaluate the safety and efficacy of methylene blue for the treatment of septic shock, we conducted a literature search of the EMBASE (1974-June 2009), MEDLINE (1966-June 2009), and International Pharmaceutical Abstracts (1970-June 2009) databases. All available studies published in English were reviewed. Observational studies with methylene blue have demonstrated beneficial effects on hemodynamic parameters and oxygen delivery, but use of methylene blue may be limited by adverse pulmonary effects. Methylene blue administration is associated with increases in mean arterial pressure while reducing catecholamine requirements in patients experiencing septic shock; however, its effects on morbidity and mortality remain unknown. Well-designed, prospective evaluations are needed to define the role of methylene blue as treatment of septic shock.

Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists.

Abstract: Aerosolized delivery of antimicrobial agents is an attractive option for management of pulmonary infections, as this is an ideal method of providing high local drug concentrations while minimizing systemic exposure. With the paucity of consensus regarding the safety, efficacy, and means with which to use aerosolized antimicrobials, a task force was created by the Society of Infectious Diseases Pharmacists to critically review and evaluate the literature on the use of aerosolized antiinfective agents. This article summarizes key findings and statements for preventing or treating a variety of infectious diseases, including cystic fibrosis, bronchiecstasis, hospital-acquired pneumonia, fungal infections, nontuberculosis mycobacterial infection, and Pneumocystis jiroveci pneumonia. Our intention was to provide guidance for clinicians on the use of aerosolized antibiotics through evidence-based pharmacotherapy. Further research with well-designed clinical trials is necessary to elucidate the optimal dosage and duration of therapy and, of equal importance, to appreciate the true risks associated with the use of aerosolized delivery systems.

Urate-Lowering Therapy for Gout: Focus on Febuxostat

Abstract: Gout is a common, painful, and often debilitating rheumatologic disorder that remains one of the few arthritic conditions that can be diagnosed with certainty and cured with appropriate therapy. Allopurinol is the most frequently prescribed agent for gout in the United States. Unfortunately, most patients treated with allopurinol do not achieve target serum uric acid (sUA) levels, possibly due to a perceived intolerability to allopurinol in doses above 300 mg and the need for reduced doses in patients with renal insufficiency. Febuxostat, an orally administered, nonpurine inhibitor of xanthine oxidase, was recently approved by the U.S. Food and Drug administration for chronic management of hyperuricemia in patients with gout. Patients treated with febuxostat achieve rapid and substantial reductions in sUA levels. Compared with allopurinol-treated patients, patients receiving febuxostat 80 mg/day were more likely to achieve sUA concentrations less than 6 mg/dl. In long-term studies (up to 5 yrs), febuxostat demonstrated sustained reductions in sUA levels, nearly complete elimination of gout flares, and a frequency of adverse effects comparable to allopurinol. The most commonly reported adverse effects were liver function abnormalities, rash, nausea, and arthralgias. The recommended starting dose of febuxostat is 40 mg/day, which may be increased to 80 mg/day after 2 weeks if patients do not achieve sUA levels less than 6 mg/dl. Dosage adjustment in mild-to-moderate renal insufficiency is unnecessary; however, data are lacking on the safety of febuxostat in patients with severe renal impairment. Although more costly than allopurinol, febuxostat appears to be an acceptable alternative for the treatment of gout and hyperuricemia, and may be advantageous in patients with renal impairment, intolerance to allopurinol, or the inability to attain sUA levels less than 6 mg/dl despite adequate therapy with available agents.

Methods in epidemiology: observational study designs.

Abstract: This article is the first of a three-part series intended to enhance clinical pharmacists' understanding of methods frequently used in epidemiologic research and their applications. The basic tenets of epidemiology and uses for data derived from epidemiologic studies are given, along with a high-level overview of the differences between experimental and observational study designs. The defining characteristics of each of the observational study designs (case report or case series, ecologic, cross-sectional, cohort, case-control, nested case-control, and case-cohort) and the resultant strengths and limitations of the study designs are presented. Applications for observational studies in pharmacoepidemiology (including the case-crossover and case-time-control study designs) are discussed. Finally, points to consider when evaluating data from observational studies are addressed.

Drug-Induced QT-Interval Prolongation: Considerations for Clinicians

Abstract: Drug-induced proarrhythmia is a frequently encountered clinical problem and a leading cause for withdrawal or relabeling of prescription drugs Suppression of the rapid component of the delayed rectifier potassium current, I(Kr), represents the principal pharmacodynamic mechanism leading to heterogeneous prolongation of the ventricular action potential and prolongation of the QT interval clinically However, the risk of proarrhythmia by QT-interval-prolonging drugs is variable and critically dependent on several factors leading to multiple reductions in the cardiac repolarization reserve As antiarrhythmic drugs that prolong the QT interval are usually aggressively managed with continuous electrocardiogram monitoring and screening for drug interactions when administered to patients who have a high risk of sudden cardiac death, their risk of mortality is not increased However, noncardiovascular QT-interval-prolonging drugs, which often produce less QT-interval prolongation compared with antiarrhythmic drugs, are found to be associated with increased rates of death in patients who have a markedly lower de novo risk of sudden cardiac death Thus, it is important for clinicians, particularly pharmacists, to be cognizant of the levels of risk associated with varying degrees of QT-interval prolongation caused by drugs so that they can develop strategies to either prevent or reduce the risk of proarrhythmias

Drug-induced black hairy tongue.

Abstract: Black hairy tongue (BHT) is a benign, self-limiting disorder characterized by abnormally hypertrophied and elongated filiform papillae on the surface of the tongue. The prevalence of BHT is quite variable, ranging from 0-53.8% depending on the population. Many predisposing factors to BHT exist, and several drugs and drug classes have been implicated in causing this disorder. A modified Naranjo adverse drug reaction probability nomogram specific for BHT was used to rate causality for the available published case reports of drug-induced BHT. From the available data, antibiotics and drugs capable of inducing xerostomia are the drug classes that have modest evidence of causality and a rational mechanism. The presence of underlying predisposing factors in these cases along with the variable prevalence of BHT make drawing firm conclusions difficult. Treatment for BHT involves eliminating any predisposing issues and practicing scrupulous oral hygiene. Drug therapy and physical removal of the elongated filiform papillae are available for resistant cases. Clinicians should be aware of the prevalence, the predisposing factors and drug classes that may play a role in the development, and the treatment of BHT.

Evaluation of renal drug dosing: prescribing information and clinical pharmacist approaches.

Abstract: Study Objective. To characterize renal function parameters reported in United States Food and Drug Administration-approved prescribing information (package inserts), to compare dosage recommendations for patients with impaired renal function between prescribing information and tertiary drug dosing references, and to evaluate renal function quantification methods most commonly used by clinical pharmacists to develop dosage regimens. Design. Retrospective analysis and Web-based survey. Data Sources. Prescribing information for all new molecular entities (NMEs) approved from 1998–2007 in which dosing recommendations were proposed for patients with impaired renal function, drug monographs from four tertiary drug dosing references (Micromedex, Lexi-Comp, Epocrates Rx, and American Hospital Formulary Service [AHFS] Drug Information) for all identified NMEs, and a Web-based survey of 204 nephrology and critical care pharmacy practitioners. Measurements and Main Results. A total of 44 NMEs included renal dosing recommendations in their prescribing information. For all 44 NMEs, prescribing information was reviewed to determine methods to quantify renal function, units of measure reported, and use of chronic kidney disease terminology. The most common index of renal function was creatinine clearance; the Cockcroft-Gault equation was specified in the prescribing information of 11 NMEs. Standardization for body weight was inconsistent, with prescribing information for four NMEs reporting renal function in ml/minute/1.73 m2. The prescribing information or tertiary sources did not mention use of estimated glomerular filtration rate (eGFR) or the Modification of Diet in Renal Disease Study (MDRD) equation. Epocrates Rx provided the most abbreviated renal dosing information, whereas AHFS Drug Information was the most comprehensive, and Lexi-Comp includes a renal function calculator. Nearly all (86%) clinical pharmacists indicated that automated eGFR is reported at their institutions, although they do not use these predictions for dosing in patients with impaired renal function, and their approaches to renal function estimation varied widely. Conclusion. Reporting of renal function methods and dosing recommendations for patients with impaired renal function requires standardization in order to ensure optimal dosing. Pharmacy clinicians do not substitute eGFR in place of creatinine clearance for renal dosing, which is consistent with current prescribing information. Studies are needed that will evaluate the validity of using eGFR to predict drug clearance and thereby generate dosage recommendations.

Diverse Effects of Statins on Angiogenesis: New Therapeutic Avenues

Abstract: Angiogenesis is an important process for a variety of physiologic and pathologic conditions. Different angiogenic modulating targets are under extensive investigation both experimentally and clinically. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the first-line agents used in hypercholesterolemia. They are also characterized by having other benefits apart from their lipid-lowering effects. Among these pleiotropic effects are the pro- and antiangiogenic properties of statins. The pleiotropic effects of statins and how they modulate new blood vessel formation are discussed in this review. The currently available data from both animal and human studies regarding the effects of statins on angiogenesis in ischemic heart disease, stroke, ocular diseases, and cancer are also reviewed. Statins are safe, orally available agents that may acquire novel therapeutic indications through their angiogenic modulating effects.

Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter Lopinavir-Ritonavir exposure in healthy subjects

Abstract: Despite the success of potent combination antiretroviral (ARV) therapy, complementary and alternative medications (CAM) remain widely used by patients with HIV infection. Indeed, more than half of HIV infected patients report using CAM at some point in time.1–4 Patients with HIV infection typically use CAM for symptomatic relief of side effects secondary to ARV therapy and/or general health benefits. Unfortunately, the co-administration of CAM and ARV medications can place patients at risk for clinically significant drug drug interactions. Because HIV protease inhibitors are primarily metabolized by cytochrome P450 (CYP) 3A4, herbal preparations that modulate this metabolic pathway have the potential to alter protease inhibitor pharmacokinetics potentially resulting in reduced ARV efficacy or increased toxicity.1 Piscitelli et al. found that St. John’s wort decreased the systemic exposure of the HIV protease inhibitor indinavir by 57% during coadministration.5 In a separate study by the same investigators, three weeks of garlic caplet supplementation decreased the area under the concentration versus time curve (AUC) of saquinavir, another HIV protease inhibitor, by 51%.6 In spite of the potential for clinically relevant interactions between CAM and ARVs, relatively few herbal products have been tested for their effects on ARV drug disposition in vivo; one such herbal supplement that has not been assessed for its influence on ARV pharmacokinetics is Echinacea purpurea. E purpurea is predominantly used to prevent and treat the common cold, influenza, and upper respiratory tract infections.7–9 In the setting of HIV infection, E. purpurea may be taken for its immunomodulatory and antiviral effects.1 Of note, Echinacea products ranked behind garlic as the second top-selling herbal dietary supplement in the food, drug, and mass market channel in the United States in 2005 with over 21 million U.S. dollars in sales.10 At least two studies have assessed the influence of E purpurea root on CYP3A activity in humans.11,12 Using single doses of both oral and iv midazolam as a probe for intestinal and hepatic CYP3A activity, respectively, Gorski et al. observed an 85% increase in the intestinal availability of midazolam (P=0.015) and a 15% reduction in the hepatic availability of the drug (P= 0.006) after 1600 mg (total daily dose) of E purpurea administration for 8 days.11 These data suggest that E purpurea selectively alters the catalytic activity of CYP3A in the liver vs. intestine. Conversely, Gurley et al. found that 28 days of E purpurea whole plant extract administration did not significantly alter CYP3A metabolic serum ratios of 1-hydroxymidazolam:midazolam collected one hr post-dose in 12 healthy volunteers.12 To this end, it is difficult to predict the influence of E purpurea on the pharmacokinetics of CYP3A substrates such as the HIV protease inhibitors. The presence or absence of such interactions may depend on the relative extraction of the coadministered drug by hepatic and intestinal CYP3A. Due to the potentially serious consequences of a drug-drug interaction between E purpurea and HIV protease inhibitors (i.e virologic and/or immunologic failure or drug toxicity) the current study was designed to assess the influence of E purpurea on the steady state pharmacokinetics of lopinavir plus ritonavir in healthy human volunteers.

Pharmacologic prophylaxis of postoperative atrial fibrillation in patients undergoing cardiac surgery: beyond beta-blockers.

Abstract: Postoperative atrial fibrillation (POAF) is a frequent complication of cardiac surgery that increases patient morbidity, length of stay, and hospital costs. A substantial body of evidence exists evaluating various pharmacologic and nonpharmacologic methods to decrease the occurrence of POAF in an effort to decrease its burden on the health care system. Evidence-based guidelines support the use of beta-blockers as standard prophylaxis of POAF in patients undergoing cardiac surgery. Traditional prophylactic therapy for POAF targets the sympathetic nervous system, refractory period, and atrial conduction. However, associations between the development of POAF and the inflammatory process, oxidative stress, and atrial remodeling have prompted the investigation of novel therapies targeting these processes. To evaluate the role of pharmacologic strategies beyond beta-blockers in the prevention of POAF, we conducted a search of the PubMed database to identify studies published from 1950-February 2009. Emphasis was placed on how these therapies could be used in patients intolerant to beta-blockers or as additive therapy in high-risk patients. We found that sufficient evidence exists to recommend the use of amiodarone, sotalol, and possibly magnesium as monotherapy in patients unable to take beta-blockers or as add-on therapy for the prevention of POAF. Currently, available evidence does not support the use of propafenone, procainamide, digoxin, thiazolidinediones, triiodothyronine, or calcium channel blockers in the prevention of POAF. Preliminary evidence suggests that dofetilide, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), nonsteroidal antiinflammatory drugs, corticosteroids, omega-3 fatty acids, ascorbic acid, N-acetylcysteine, and sodium nitroprusside may be effective in preventing POAF. Additional large-scale, adequately powered clinical studies are needed to determine the benefit of these agents before they can be considered for routine use.

Comparison of bivalirudin and argatroban for the management of heparin-induced thrombocytopenia.

Abstract: Study objectives To compare the effectiveness of bivalirudin and argatroban in achieving anticoagulation goals and to compare clinical outcomes assessing the safety and efficacy in patients with known or suspected heparin-induced thrombocytopenia (HIT). Design Single-center, retrospective analysis. Setting Large tertiary care academic medical center. Patients A total of 138 adults who received either bivalirudin (92 patients) or argatroban (46 patients) for at least 24 hours for known or suspected HIT between January 2007 and July 2008. MEASUREMENTS AND MAIN RESULTS. Data regarding demographics, direct thrombin inhibitor (DTI) dosing and monitoring, and related clinical outcomes were collected; statistical analysis was performed to compare results for patients receiving bivalirudin versus those receiving argatroban. Duration of DTI use ranged from 24-658 hours. At the time of DTI initiation, 108 patients (78%) were in an intensive care unit, with the highest proportion (61/138 [44%]) in the cardiothoracic surgery intensive care unit. The median (interquartile range [IQR]) DTI doses at the time of first reaching therapeutic goal were bivalirudin 0.06 mg/kg/hour (0.04-0.08 mg/kg/hr) and argatroban 1.0 μg/kg/minute (0.5-2.0 μg/kg/min). The median percentage of activated partial thromboplastin time (aPTT) values within therapeutic range while patients were receiving DTI therapy were similar for bivalirudin and argatroban (75% and 70%, respectively, p=0.238). A greater percentage of aPTT values were supratherapeutic with argatroban versus bivalirudin treatment (18% vs 8%, p=0.046). Median time to therapeutic goal was similar for bivalirudin (5.50 hrs [IQR 4-14.5 hrs]) and argatroban (5.75 hrs [IQR 3-17.7 hrs], p=0.499). New thromboembolic events occurred in seven patients (8%) receiving bivalirudin and two (4%) receiving argatroban (p=0.718). Bleeding events occurred at similar rates in both groups (9% for bivalirudin vs 11% for argatroban, p>0.999). Conclusions Bivalirudin and argatroban were similar in achieving and maintaining therapeutic anticoagulation goals, clinical outcomes, and safety. This study suggests that bivalirudin represents an alternative in the management of HIT, but prospective studies are needed.

Use of Cytomegalovirus Intravenous Immune Globulin for the Adjunctive Treatment of Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients

Abstract: Study Objective. To describe the characteristics and clinical outcomes of hematopoietic stem cell transplant (HSCT) recipients who received adjunctive cytomegalovirus intravenous immune globulin (CMV-IVIG) for probable or proven CMV disease. Design. Retrospective cohort study. Setting. Large, university-affiliated, tertiary-care medical center. Patients. Thirty-five adult HSCT recipients who received at least one dose of CMV-IVIG for adjunctive treatment of probable or proven CMV disease between January 1, 1999, and December 31, 2007. Measurements and Main Results. All-cause mortality at hospital discharge was the primary outcome. All patients received an allogeneic HSCT. Twenty-six patients (74%) had pneumonitis, nine (26%) had enteritis, and 29 (83%) had CMV viremia. All patients received concomitant antiviral therapy; 31 (89%) received ganciclovir, and 14 (40%) received foscarnet. All-cause mortality at hospital discharge was 49% (17 patients). Patient characteristics associated with mortality included requiring intubation for CMV pneumonia (11 [79%] of 14 nonsurvivors vs 3 (25%) of 12 survivors, p=0.016) and earlier disease onset after HSCT (median 48 days for nonsurvivors vs 106 days for survivors, p<0.001). In the multivariate analysis, only requiring intubation for CMV pneumonia remained a significant risk factor for increased mortality. A low rate of adverse events was attributed to CMV-IVIG, with mild hypertension (two patients [6%]) and erythema and chills (one patient [3%]) being the most common. Conclusion. The mortality rate in our study population was similar to previous reports in the literature and may be somewhat lower than rates reported with antiviral monotherapy. Our analysis suggests that factors associated with mortality include the need for intubation and, possibly, earlier onset of CMV disease after HSCT. Treatment with CMV-IVIG appears to be well tolerated in HSCT recipients. These findings support further trials of CMV-IVIG efficacy in this setting.

Deterioration of blood pressure control after discontinuation of a physician-pharmacist collaborative intervention.

Abstract: Study Objective To evaluate blood pressure (BP) control following discontinuation of a physician\pharmacist collaborative intervention.

Treatment options for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.

Abstract: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare neurodegenerative disease caused by the decreased ability of cells to produce sufficient energy in the form of adenosine 5'-triphosphate. Although it is one of the most common maternally inherited mitochondrial disorders, its exact incidence is unknown. Caused most frequently by an A-to-G point mutation at the 3243 position in the mitochondrial DNA, MELAS syndrome has a broad range of clinical manifestations and a highly variable course. The classic neurologic characteristics include encephalopathy, seizures, and stroke-like episodes. In addition to its neurologic manifestations, MELAS syndrome exhibits multisystem effects including cardiac conduction defects, diabetes mellitus, short stature, myopathy, and gastrointestinal disturbances. Unfortunately, no consensus guidelines outlining standard drug regimens exist for this syndrome. Many of the accepted therapies used in treating MELAS syndrome have been identified through a small number of clinical trials or isolated case reports. Currently, the drugs most often used include antioxidants and various vitamins aimed at minimizing the demands on the mitochondria and supporting and maximizing their function. Some of the most frequently prescribed agents include coenzyme Q(10), l-arginine, B vitamins, and levocarnitine. Although articles describing MELAS syndrome are available, few specifically target education for clinical pharmacists. This article will provide pharmacists with a practical resource to enhance their understanding of MELAS syndrome in order to provide safe and effective pharmaceutical care.

Pharmacologic Options for Reducing the Shivering Response to Therapeutic Hypothermia

Abstract: Recent literature has demonstrated significant improvements in neurologic outcomes in patients who have received induced hypothermia in the setting of out-of-hospital cardiac arrest. Through multiple metabolic mechanisms, the induction of hypothermia slows the progression and devastation of transient cerebral hypoxia. Despite these benefits, the desired reduction in core temperature is often a challenging venture as the body attempts to maintain homeostasis through the induction of thermoregulatory processes aimed at elevating body temperature. Shivering is an involuntary muscular activity that enhances heat production in an attempt to restore homeostasis. For successful induction and maintenance of induced hypothermia, shivering, as well as other thermoregulatory responses, must be overcome. Several pharmacologic options are available, either used alone or in combination, that safely and effectively prevent or treat shivering after the induction of hypothermia. We conducted a PubMed search (1966-March 2009) to identify all human investigations published in English that discussed pharmacologic mechanisms for the control of shivering. Among these options, clonidine, dexmedetomidine, and meperidine have demonstrated the greatest and most clinically relevant impact on depression of the shivering threshold. More research in this area is needed, however, and the role of the clinical pharmacist in the development and implementation of this therapy needs to be defined.

Severe lactic acidosis after an iatrogenic propylene glycol overdose.

Abstract: Propylene glycol is a diluent found in many intravenous and oral drugs, including phenytoin, diazepam, and lorazepam. Propylene glycol is eliminated from the body by oxidation through alcohol dehydrogenase to form lactic acid. Under normal conditions, the body converts lactate to pyruvate and metabolizes pyruvate through the Krebs cycle. Lactic acidosis has occurred in patients, often those with renal dysfunction, who were receiving prolonged infusions of drugs that contain propylene glycol as a diluent. We describe a 50-year-old man who experienced severe lactic acidosis after receiving an accidental overdose of lorazepam, which contains propylene glycol. The patient was acutely intoxicated, with a serum ethanol concentration of 406 mg/dl. He had choked on a large piece of meat and subsequently experienced pulseless electrical activity with ventricular fibrillation cardiac arrest. He was brought to the emergency department; within 2 hours, he was admitted to the intensive care unit for initiation of the hypothermia protocol. The patient began to experience generalized tonic-clonic seizures 12 hours later, which resolved after several boluses of lorazepam. A lorazepam infusion was started; however, it was inadvertently administered at a rate of 2 mg/minute instead of the standard rate of 2 mg/hour. Ten hours later, the administration error was recognized and the infusion stopped. The patient's peak propylene glycol level was 659 mg/dl, pH 6.9, serum bicarbonate level 5 mEq/L, and lactate level 18.6 mmol/L. Fomepizole was started the next day and was continued until hospital day 3. Continuous renal replacement therapy was started and then replaced with continuous venovenous hemofiltration (CVVH) for the remainder of the hospital stay. The patient's acidosis resolved by day 3, when his propylene glycol level had decreased to 45 mg/dl. Fomepizole was discontinued, but the patient's prognosis was poor (anoxic brain injury); thus care was withdrawn and the patient died. Although the patient's outcome was death, his lactic acidosis was treated successfully with fomepizole and CVVH. Clinicians should be aware that an iatrogenic overdose of lorazepam may result in severe propylene glycol toxicity, which may be treated with fomepizole and CVVH.