Annals of Pharmacotherapy

To examine the effect of a computer-assisted antibiotic-dose monitor used to reduce the number of days that patients receive excessive dosages of antibiotics and the number of adverse drug events (ADEs) secondary to antibiotics.

Descriptive epidemiologic study of a two-year preintervention period and one-year intervention period.

The LDS Hospital, a tertiary care center in Salt Lake City, UT.

All patients aged • 18 years, admitted to LDS Hospital from April 1, 1993, to March 31, 1996, who received at least one of five targeted antibiotics (vancomycin, gentamicin, imipenem, cefazolin, cefuroxime), who had a serum creatinine or a urine creatinine clearance test result before antibiotic therapy, and who were never admitted or transferred to the shock/trauma/respiratory intensive care unit.

Each morning during the 12-month intervention period, the antibiotic-dose monitor checked the renal function of all patients who were receiving any of the five antibiotics. Pharmacists received a computer listing of patients who may have been receiving excessive dosages. The antibiotic-dose monitor suggested an alternate dosage and a pharmacikst contacted the patient's physician if the suggested change in the dosage was appropriate.

During the intervention period, 4483 patients received at least one of the five study antibiotics and 1974 (44%) were identified as receiving an excessive dosage, compared with 4494 (50%) of 8901 patients during the preintervention period (p < 0.001). The patients receiving excessive dosages received an excessive dosage for an average of 2.9 days during the intervention period, compared with 4.7 days (p < 0.001) during the preintervention period. In addition, these same patients during the intervention period received fewer doses of antibiotics (10.9 vs. 13.4; p < 0.001), fewer grams of antibiotics (10.4 vs. 12.0; p < 0.02), at less cost ($98 vs. $128; p < 0.004) than the patients during the preintervention period. Moreover, there were 14 ADEs (0.3%) secondary to the five study antibiotics during the intervention period, compared with 82 (0.9%; p < 0.001) for the two-year preintervention period. The study also found that significantly more patients identified as receiving excessive dosages had experienced decreases in renal function, compared with patients who were not identified as receiving excessive dosages (25% vs. 12% during preintervention period and 23% vs. 16% during intervention period; p < 0.001).

Many patients experience decreases in renal function after antibiotics are ordered. The use of the computer-assisted antibiotic-dose monitor appears to be a promising method to help reduce the excessive use and cost of antibiotic therapy and reduce the number of ADEs secondary to antibiotics.

To describe the clinical characteristics and health-related quality of life of family medicine patients with clinically diagnosed gastroesophageal reflux disease (GERD).

The study involved the baseline assessment of 268 patients enrolled in a randomized clinical trial comparing treatments for GERD. The study was conducted in a five-center, university-based family practice in southeastern West Virginia. Patients with a clinical diagnosis of GERD and who had not received treatment in the past 30 days were eligible; pregnant and lactating women and patients with severe renal or hepatic insufficiency were excluded.

Two hundred sixty-eight patients were included in the analysis. Mean ± SD age was 44.9 ± 14.1 years; 61.2% were women and 91.4% were white. Mean ± SD body mass index was 30.3 ± 6 kg/m², and >15.3% of patients had no insurance. One hundred seventy-four (64.9%) patients were enrolled from nonurban primary care clinics. One hundred sixty-four patients (61.2%) were prescribed at least one medication prior to study enrollment (mean ± SD 2.88 ± 1.71; range 1–9). When adjusted for age, gender, comorbidity status, and rural status, severity of GERD was associated with decreased health-related quality of life. GERD patients without comorbidity demonstrated decrements in health-related quality of life when compared with the US general population. When compared with another GERD population, the study patients reported fairly consistent GERD symptomatology and health-related quality of life.

GERD symptom severity was associated with impaired health-related quality of life in a predominantly rural primary care population.

To determine the incidences of serious and nonserious lamotrigine-related rash, determine the risk factors for lamotrigine-related rash, and evaluate the impact on the incidence of rash of the manufacturer's recommendation to reduce the starting dose of lamotrigine.

This was a retrospective case record survey at five tertiary referral epilepsy centers in the UK. The risk factors for lamotrigine-related rash were identified by logistic regression. The independent factors tested were gender, age, epilepsy type, concurrent medication, and starting dose of lamotrigine. The incidences of rash before and after the recommendation of reduction in starting dose were compared by •² analysis.

A total of 1050 patients were included. The incidences of serious and nonserious rash were 1.1% (95% CI 0.5% to 1.8%) and 7% (95% CI 5.5% to 8.6%), respectively. Females were at higher risk of developing rash than were males, with a relative risk of 1.8 (95% CI 1.2 to 2.8). The starting dose of lamotrigine was reduced in response to the manufacturer's recommendation, and there was a significant reduction (p = 0.045) in the incidence of serious rash, from 1.5% (12/805) to 0% (0/245). However, there was no reduction in the overall incidence of lamotrigine-related rash, with 63/805 (8%) before and 23/245 (9%) after the recommendation.

Failure to detect a reduction in the incidence of lamotrigine-related rash since the new (reduced) recommended starting dose of lamotrigine may arise from failure to reduce the starting dose below a critical threshold level, incomplete compliance with current recommendations, or insufficient sample size. The results of this and other studies show that the starting dose of lamotrigine is a significant factor affecting the incidence of rash; furthermore, this study also shows that significant reduction in the incidence of serious rash can be achieved by reducing the starting dose. Therefore, clinicians should not deviate from the recommendations.

To report a case of vancomycin-induced anaphylaxis (or anaphylactoid reaction) in a patient with a fever of unrecognized noninfectious origin.

An 83-year-old white man, who was a patient of the Veterans Affairs Medical Center, developed a serious anaphylactic (or anaphylactoid) reaction while receiving intravenous vancomycin as empiric therapy for a nosocomial fever of unknown origin. The fever was subsequently proved to have been due to acute polyarticular gout rather than an infection.

This patient developed respiratory distress and an increased serum troponin concentration, suggestive of a myocardial enzymatic leak as a result of vancomycin therapy. Vancomycin was given before the noninfectious cause of his fever was recognized.

Even with cautious slow infusion, intravenous vancomycin can precipitate life-threatening infusion-related reactions in some patients. Because of this, and to reduce selective pressure for vancomycin resistance, sources of fever that do not require treatment with vancomycin should be diligently investigated prior to the institution of empiric vancomycin therapy in febrile patients, particularly when the past medical history is suggestive of an alternative diagnosis.

To report a case of torsade de pointes related to the administration of high-dose intravenous haloperidol for the treatment of severe agitation.

Reports in the literature of intravenous haloperidol-induced torsade de pointes are rare. We describe the case of a 41-year-old white woman with no predisposing factors who developed torsade de pointes 55 minutes after a dose of intravenous haloperidol 80 mg (total dosage 915 mg over 7 d). The results of the electrocardiogram were consistent with torsade de pointes and showed a prolonged QTc interval of 610 milliseconds. Intravenous magnesium sulfate 2 g/100 mL NaCl 0.9% was administered, which controlled the arrhythmia. The patient received one additional 80-mg haloperidol dose six hours after the arrhythmia-triggering dose, without reoccurrence of torsade de pointes. Haloperidol was then discontinued, and the patient had no further arrhythmias.

Our case report and others from the literature suggest that intravenous haloperidol administration may prolong QT intervals in some patients, precipitating the potentially life-threatening arrhythmia torsade de pointes. Clinicians should be aware of haloperidol's potential to induce torsade de pointes, since it is used regularly for agitation and delirium in the critical care arena.

To report two cases of chronic constrictive pericarditis that appear to be related to the intake of bromocriptine for Parkinson's disease.

Two white men (aged 63 and 69 y) were treated with bromocriptine for four (40 mg/d) and two years (30 mg/d), respectively, with a cumulative dose intake of 58.4 and 21.9 g, respectively. The patients experienced dyspnea with bilateral lower-limb edema and pleural effusion, suggesting right cardiac dysfunction. Echocardiography, computed tomography, and cardiac catheterization results were compatible with a diagnosis of constrictive pericarditis, so pericardectomy was performed on both patients. The anatomic pathology examination showed a fibrous pericardium; cultures were sterile. In the first case, pleural effusion recurred seven months after the pericarditis; bromocriptine was suspected and treatment was discontinued. In the second case, just prior to the pericardectomy, an episode of mental confusion occurred and prompted the cessation of bromocriptine therapy.

To the best of our knowledge, only one case of constrictive pericarditis induced by bromocriptine therapy has previously been described in the literature.

Our cases call attention to a possible association between bromocriptine use in patients who have Parkinson's disease and constrictive pericarditis.

To describe the use of intravenous immune globulin (IVIG) to treat Wegener's granulomatosis (WG) in an adolescent female with an abnormal magnetic resonance imaging (MRI) scan and electroencephalogram (EEG), as well as central nervous system involvement manifesting as generalized seizures.

A 15-year-old white girl diagnosed with WG and receiving prednisone and cyclophosphamide was admitted with new-onset tonic–clonic seizures. The patient received phenobarbital and phenytoin to control seizures and was receiving cyclophosphamide and corticosteroids for WG. She developed cyclophosphamide-induced cystitis and was started on a four-day therapeutic course of IVIG following the discontinuation of cyclophosphamide. After 16 days of hospitalization, repeat EEG and MRI were within normal limits, and laboratory and clinical improvement was evident in at least nine of the affected organ systems including pulmonary, hematologic, renal, ocular, cutaneous, musculoskeletal, central nervous system, gastrointestinal, and genitourinary. The patient was discharged with clinical involvement of WG documented in two organ systems, hematologic and renal.

WG is a form of vasculitis believed to develop due to an autoimmune disorder. The diagnosis is based on radiographic and histopathologic findings, as well as the presence of elevated antineutrophil cytoplasmic antibodies and a suggestive clinical presentation. The presentation is widely variable and is most commonly associated with upper-airway involvement such as sinusitis, cough, pulmonary infiltrates, and cavitary nodules. Renal involvement signifies generalized disease. Conventional treatment for WG includes cyclophosphamide and prednisone. Little information is available describing therapeutic alternatives. Cytotoxicity related to immunosuppressant regimens limits continuous treatment and may necessitate the use of alternative agents.

This case describes the use of IVIG in an adolescent patient presenting with WG as a generalized, active disease with neurologic complications. IVIG may be useful in generalized, active WG complicated by intolerance to cyclophosphamide and seizures, but further study is necessary to define its role.

To report a case of oxacillin-induced tissue necrosis in which recommended concentration guidelines for dilution and administration were used. Oxacillin concentration data, potential risk factors, and treatment options for extravasation injuries are also briefly reviewed.

Oxacillin was infused peripherally by infusion pump in a 79-year-old white woman as prophylactic antibiotic coverage for permanent pacemaker placement. Oxacillin extravasation occurred after the second postoperative dose. A dimesized area of necrosis was noted at the heparinlock insertion site.

Only one case of oxacillin-induced necrosis has been reported. The degree of damage and concentration of drug used were not specifically described. Concentration may play a role in the appearance or absence of tissue damage after an antibiotic extravasation and should be taken into consideration when evaluating a drug's tissue toxicity potential.

The potential exists for oxacillin 50 mg/mL to cause tissue damage in humans if an extravasation occurs. This reaction may be avoided with use of a less-concentrated preparation, avoidance of infusion pump administration, and identification of high-risk patients.

To review the published data and clinical guidelines on the use of β-blockers in myocardial infarctions (MIs) and contrast that with actual clinical practice.

A MEDLINE search (January 1970–June 1999) was performed to identify all relevant articles. References from these articles were also evaluated for review if deemed important.

Intravenous and oral β-blockers have been proven to improve outcomes in patients with MIs in numerous clinical trials. In current clinical practice, only 15% of MI patients receive intravenous β-blockers and long-term β-blocker therapy is used in <40% of patients without contraindications. However, they could be safely administered to 40% and 70% of these patients, respectively. Furthermore, most of these patients are receiving doses far below those found beneficial in clinical trials. Many of the real and perceived contraindications to β-blockers are reviewed to allow the practitioner to identify patients who are incorrectly excluded from β-blocker therapy. Also discussed are special clinical situations in which the benefits observed during clinical trials may not apply.

β-blockers are valuable drugs in the treatment of peri-and post-MI. In clinical practice, most patients are not treated or are inadequately treated with β-blockers. Pharmacists should ensure that such patients actually have an absolute contraindication or unusual situation where therapy is not firmly indicated. Patients without absolute contraindications warrant titration to specific target doses or a target heart rate of 55–60 beats/min.

To describe the pharmacology, pharmacokinetics, clinical efficacy, and safety of tolterodine for the treatment of overactive bladder.

Published articles and abstracts were identified from a MEDLINE search (January 1980–October 1998) using the terms tolterodine, PNU-200583E, urge incontinence, overactive bladder, detrusor instability, detrusor overactivity, and antimuscarinic. Pertinent articles written in English were considered for review. Additional articles were identified from the bibliographies of retrieved articles. Data from the Food and Drug Administration– approved product labeling and the manufacturer were also used in the absence of published data.

Clinical studies of tolterodine involving human subjects were evaluated.

Tolterodine is a competitive muscarinic receptor antagonist with relative functional selectivity for bladder muscarinic receptors. It is metabolized in the liver by CYP2D6 to an active metabolite (DD 01), which is partially responsible for its pharmacologic activity. Those who are genetically devoid of CYP2D6 will have higher concentrations of the parent compound and virtually undetectable concentrations of DD 01; however, the clinical efficacy does not appear to be altered. In dosages of 2 mg twice daily, tolterodine has shown consistent reductions in the number of micturitions per 24 hours and less consistently decreased incontinence episodes in patients with detrusor overactivity. The functional selectivity of tolterodine for bladder muscarinic receptors results in fewer systemic adverse effects, such as dry mouth, than occur with comparable nonselective antimuscarinic agents.

Clinical studies have shown that the effectiveness of tolterodine for symptoms of overactive bladder is similar to that of oxybutynin. The adverse effect profiles of tolterodine and oxybutynin are similar; however, comparative clinical trials have shown significantly fewer patients taking tolterodine require dosage reductions or discontinue therapy due to antimuscarinic adverse effects such as dry mouth. Although more costly than oxybutynin, tolterodine represents a modest improvement over oxybutynin with respect to adverse effect profile, which may allow more patients with incontinence to tolerate therapeutic doses. Further research is necessary to determine whether tolterodine has clinical advantages over similar agents in patients with other muscarinic adverse effects, such as constipation or cognitive impairment.

To review the efficacy and safety of fenofibrate in the management of hyperlipidemias.

A MEDLINE search (1974–October 1998), Current Contents search, additional references from article bibliographies, and the package insert from the manufacturer were used to identify data for evaluation. Studies evaluating fenofibrate (peer-reviewed publications, package insert data) were considered for inclusion. Abstracts and data on file with the manufacturer were not considered for inclusion.

English-language literature was reviewed to evaluate the pharmacology, pharmacokinetics, clinical use, and tolerability of fenofibrate. Data from animals and in vitro systems were included only when necessary to explain the drug's pharmacology.

Micronized fenofibrate is a fibric acid derivative approved by the Food and Drug Administration (FDA) in February 1998 for the treatment of types IV and V hyperlipidemia. Data from the peer-reviewed literature also support the use of fenofibrate in types IIa, IIb, and III hyperlipidemias. Micronized fenofibrate 67–201 mg/d is useful as monotherapy or as an adjunct to other hypolipidemics and dietary therapy. In placebo-controlled clinical trials, regular formulation fenofibrate 300–400 mg/d lowered serum triglyceride (TG) concentrations by 24–55%, total cholesterol by 9–25%, low-density lipoprotein cholesterol (LDL-C) concentrations by 6–35%, and raised high-density lipoprotein cholesterol (HDL-C) concentrations by 8–38%. Few comparative data exist regarding fenofibrate versus clofibrate and gemfibrozil. In noncomparative and comparative clinical trials, fenofibrate appeared to be well tolerated. The most common causally related adverse events were digestive, musculoskeletal, and dermatologic in nature. Concurrent use of fenofibrate and a hydroxymethylglutaryl-coenzyme A inhibitor may increase the risk of myopathy and/or rhabdomyolysis, although recent data suggest that concurrent use of fenofibrate with low-dose simvastatin or pravastatin is safe. Fenofibrate may enhance the effect of oral anticoagulants.

Fenofibrate reduces serum TG, total cholesterol, and LDL-C, and raises HDL-C to clinically relevant degrees. Its spectrum of activity appears to exceed that recommended for types IV and V hyperlipidemia to encompass types IIa, IIb, and III hyperlipidemias as well. To this extent, it may be considered a broader-spectrum fibrate than is indicated by its FDA approval. Adverse effects of fenofibrate appear to be similar to those of other fibrates and require routine monitoring (clinical, liver function). Long-term safety data are readily available from drug registries in many countries where the product has been available for nearly two decades. Cost-effectiveness studies comparing fenofibrate with other hypolipidemics demonstrate benefits of fenofibrate over simvastatin in types IIa and IIb hyperlipidemia. The need for dosage titration of the micronized preparation from 67 mg/d upward to a final dose of 200 mg/d is also not supported by peer-reviewed literature (except in the case of renal impairment). Although preliminary data on plaque regression are encouraging, published clinical studies evaluating the impact of fenofibrate on cardiovascular morbidity and mortality are awaited. Micronized fenofibrate is worthy of formulary inclusion.

To examine the evidence regarding the therapeutic effectiveness of lamivudine in the treatment of chronic hepatitis B virus (HBV) infection in immunocompetent patients.

Using chronic hepatitis B and lamivudine as MeSH headings, MEDLINE was searched from 1966 to September 1998 for all published randomized controlled trials evaluating lamivudine in chronic HBV infection. Relevant articles from selected bibliographies were also retrieved.

Only randomized, single- and double-blind trials in human HBV carriers published in the English language were included.

Evidence from the controlled trials suggests that lamivudine has a therapeutic effect in suppressing HBV replication in immunocompetent patients. Lamivudine 100 mg/d appears to suppress HBV replication in as many as 97% of patients within two weeks after the initiation of therapy and is capable of suppressing histologic damages. However, viral suppression is effective only during the therapy; on discontinuation of lamivudine therapy, most patients return to the pretreatment condition. Viral resistance to lamivudine has been observed. Most patients with chronic HBV infection appear to tolerate 100 mg/d of lamivudine therapy.

Evidence has shown that oral lamivudine 100 mg/d will produce rapid and significant suppression of viral replication in immunocompetent patients with chronic HBV infections. Treatment periods up to one year have been effective and well tolerated. The suppression of viral replication may not be sustained after cessation of lamivudine therapy, and very few patients have complete elimination of HBV during therapy. Therefore, long treatment periods may be necessary. Efficacy and tolerability of treatment beyond one year need to be investigated. Resistance to lamivudine has been reported in patients receiving therapy. A combination anti-HBV regimen using lamivudine and other agents with different mechanisms of action should be investigated to maximize the elimination of the viral infection while minimizing or preventing damage to the liver cells and tissues and the development of viral resistance.

To review the use of valproic acid in HIV-positive patients.

Clinical literature was accessed through a MEDLINE search (January 1966–November 1998). Key search terms included HIV, AIDS, seizures, valproic acid, and glutathione.

Patients with HIV often develop neurologic manifestations; therefore, valproic acid may be considered in the management of this population. It has been demonstrated that valproate may increase viral burden by potentiating replication. An evaluation of studies addressing the use of valproic acid in HIV-positive patients was conducted.

The potential for valproate-induced increases in viral replication exists. Although further studies are warranted, clinicians should exercise caution when using valproate in HIV-positive patients.

To review the role of anagrelide in the management of essential thrombocythemia.

A MEDLINE search (January 1966–August 1998) was performed using the key terms anagrelide, thrombocytosis, and essential thrombocythemia. In addition, the package insert, product monograph, and patient information pamphlets were reviewed.

Recently, there has been a trend toward the use of anagrelide in the management of thrombocythemia. Anagrelide lacks leukemogenic and mutagenic potential and possesses a more favorable adverse effect profile compared with other therapeutic agents. At recommended doses, anagrelide induces thrombocytopenia in thrombocythemic patients with a concomitant reduction in the incidence of disease-related symptoms.

Although the treatment of choice for thrombocythemia is still an area of debate, anagrelide has distinct advantages over alternative therapies. Anagrelide represents an important therapeutic option in the treatment of patients with thrombocythemia.