Linezolid: an oxazolidinone antimicrobial agent.

BACKGROUND: Linezolid is the first oxazolidinone anti-infective agent marketed in the United States. It is indicated for the treatment of nosocomial pneumonia, complicated skin and skin-structure infections caused by methicillin-sensitive or methicillin-resistant Staphylococcus aureus and other susceptible organisms, and vancomycin-resistant Enterococcus faecium infections. It also is indicated for the treatment of uncomplicated skin and skin-structure infections caused by methicillin-sensitive S. aureus or Streptococcus pyogenes, and community-acquired pneumonia caused by penicillin-sensitive Streptococcus pneumoniae. OBJECTIVE: This article reviews the pharmacologic properties and clinical usefulness of linezolid. METHODS: Using the terms linezolid, PNU-100766, and oxazolidinone, we performed a literature search of the following databases: MEDLINE (1966 to September 2000), HealthSTAR (1993 to September 2000), Iowa Drug Information Service (1966 to September 2000), International Pharmaceutical Abstracts (1970 to September 2000), PharmaProjects (January 2000 version), and meeting abstracts of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996 to 2000). RESULTS: Linezolid has a unique structure and mechanism of action, which targets protein synthesis at an exceedingly early stage. Consequently, cross-resistance with other commercially available antimicrobial agents is unlikely. It is primarily effective against gram-positive bacteria. To date, resistance to linezolid has been reported in patients infected with enterococci. The pharmacokinetic parameters of linezolid in adults are not altered by hepatic or renal function, age, or sex to an extent requiring dose adjustment. Linezolid is metabolized via morpholine ring oxidation, which is independent of the cytochrome P450 (CYP450) enzyme system; as a result, linezolid is unlikely to interact with medications that stimulate or inhibit CYP450 enzymes. Compassionate-use trials and other clinical studies involving mainly adult hospitalized patients with gram-positive infections have shown that linezolid administered intravenously or orally is effective in a variety of nosocomial and community-acquired infections, including those caused by resistant gram-positive organisms. Reported adverse effects include thrombocytopenia. diarrhea, headache, nausea, vomiting, insomnia, constipation, rash, and dizziness. Preliminary pharmacoeconomic data indicate that a significantly higher percentage of patients receiving linezolid therapy versus comparator could be discharged from the hospital by day 7 (P = 0.005). CONCLUSIONS: Linezolid appears to be effective while maintaining an acceptable tolerability profile. Due to the risk of bacterial resistance, linezolid should be reserved for the treatment of documented serious vancomycin-resistant enterococcal infections.

Amprenavir: a new human immunodeficiency virus type 1 protease inhibitor.

OBJECTIVE: This paper reviews the pharmacologic properties and clinical usefulness of amprenavir, a new human immunodeficiency virus type 1 (HIV-1) protease inhibitor. BACKGROUND: Amprenavir, the most recent HIV-1 protease inhibitor to receive marketing approval from the US Food and Drug Administration, is a potent competitive inhibitor of HIV-1 protease and a relatively weak inhibitor of HIV-2 protease. Inhibition of the HIV-1 protease enzyme results in immature and noninfectious viral particles. Amprenavir is rapidly absorbed following oral administration. The time to peak concentration (Tmax) in adults is between 1 and 2 hours, the area under the plasma concentration versus time curve is roughly proportional to the dose, the half-life is approximately 8 hours, and the volume of distribution is approximately 430 L. The Tmax in children 4 to 12 years of age is between 1.1 and 1.4 hours. The bioavailability of the solution is 86% relative to the capsule formulation. It is metabolized by the cytochrome P-450 isozyme CYP3A4 and to a lesser extent by CYP2D6 and CYP2C9. METHODS: We searched MEDLINE (1966 to January 2000), AIDSLINE (1980 to January 2000), International Pharmaceutical Abstracts (1970 to January 2000), PharmaProjects (January 2000 version), and Web sites of major HIV/acquired immunodeficiency syndrome conferences for appropriate published references (1996 to February 2000). RESULTS: Data reported to date indicate that amprenavir is efficacious in the treatment of HIV disease in patients with primary HIV infection, antiretroviral-naïve patients, protease inhibitor-naïve patients, protease inhibitor-experienced patients, and pediatric patients. Adverse effects were usually of early onset (range, 2 to 21 days) and transient (range, 3 to 46 days), although the incidence of metabolic abnormalities such as lipodystrophy, hyperlipidemia, and diabetes mellitus has not yet been defined. Amprenavir should be avoided in patients with a known sulfonamide allergy. Concomitant use of other medications that are CYP3A4 inducers or inhibitors should be done cautiously and only if the potential benefit clearly outweighs potential risk. The dose should be reduced in patients with significant hepatic impairment (Child-Pugh score, > or = 5). Amprenavir probably should not be administered with rifabutin, rifampin, astemizole, midazolam , triazolam, bepridil, dihydroergotamine, ergotamine, or cisapride. The recommended adult dose is 1200 mg twice daily. For patients between 4 and 12 years of age or between 13 and 16 years of age who weigh < 50 kg, the recommended dosage of the capsule form is 20 mg/kg (22.5 mg/kg for oral solution) twice daily or 15 mg/kg (17 mg/kg for oral solution) 3 times a day to a maximum dose of 2400 mg (2800 mg for oral solution). Patients should not take vitamin E supplements because amprenavir is formulated with a large amount of vitamin E (109 IU/capsule and 46 IU/mL oral solution) to improve oral absorption. Amprenavir may be administered with or without food, but a high-fat meal (> 67 g fat) should be avoided. CONCLUSIONS: Published clinical data are limited, but amprenavir appears to be efficacious and generally well tolerated in patients with HIV infection. Pharmacoeconomic data are not yet available. The introduction of amprenavir appears to be important, since it provides an additional treatment option as a component of both initial and salvage combination therapies for patients with HIV.

Selective cyclooxygenase-2 inhibitors for the treatment of arthritis.

The purpose of this paper is to review the rationale for a new class of nonsteroidal anti-inflammatory drugs (NSAIDs) known as selective cyclooxygenase (COX)-2 inhibitors and to present preliminary clinical data on 2 COX-2 inhibitors that are approved for use in the United States. The primary mechanism of NSAIDs in the treatment of inflammation is the inhibition of COX, which exists in 2 forms. COX-I appears to regulate many normal physiologic functions, and COX-2 mediates the inflammatory response. Theoretically, an NSAID that inhibits COX-2 selectively should decrease inflammation but not influence normal physiologic functions and thus should cause fewer gastrointestinal side effects. Preliminary data suggest that celecoxib, a highly selective COX-2 inhibitor, is superior to placebo and similar to traditional NSAIDs in the short-term treatment of pain due to osteoarthritis, although it has been associated with adverse effects such as headache, change in bowel habits, abdominal discomfort, and dizziness. Celecoxib also has been shown to be as effective as traditional NSAIDs in the treatment of rheumatoid arthritis, but it may cause fewer adverse effects, including endoscopically documented ulcers. Celecoxib is metabolized in the liver by the cytochrome P-450 isozyme CYP2C9, and thus serious drug interactions are possible. In the treatment of osteoarthritis, rofecoxib has been shown to be as effective as traditional NSAIDs and may cause fewer endoscopically documented ulcers, but its complete adverse-effect profile is not known. Until the selective COX-2 inhibitors are widely used and more clinical as well as pharmacoeconomic studies are published, the exact role of COX-2 therapy cannot be determined. words: cyclooxygenase, celecoxib, rofecoxib, rheumatoid arthritis, osteoarthritis.

Treatment regimens for patients with toxoplasmic encephalitis.

Toxoplasma gondii is an obligate intracellular parasitic protozoan that infects a variety of warm-blooded animals, including humans. Infection is usually asymptomatic in immunocompetent individuals but may be devastating in immunocompromised individuals such as those with acquired immunodeficiency syndrome (AIDS). Clinical manifestations of infection in immunocompromised patients include the development of encephalitis. It has been estimated that approximately 30% of patients with AIDS who are latently infected will eventually develop toxoplasmic encephalitis. The most common regimen used to treat toxoplasmic encephalitis is a combination of pyrimethamine 50 to 100 mg/d and sulfadiazine 4 to 8 g/d, with or without folinic acid 10 mg/d. This regimen, however, commonly leads to adverse effects or relapses. Other pharmacologic approaches include the use of clindamycin rather than sulfadiazine, the macrolide antibiotics, atovaquone, 5-fluorouracil, trimethoprim/sulfamethoxazole, minocycline or doxycycline, trimetrexate with folinic acid, dapsone, rifabutin, pentamidine, and diclazuril. None of these alternative regimens has been proven to be more effective than the standard pharmacologic therapy. An evolving approach is the use of immunotherapy, such as interleukin-2, -6, and -12; interferon-gamma; and alpha-tumor necrosis factor. Restoring a competent immune system may be the only cure for toxoplasmosis and other opportunistic infections.

Pharmacist-operated drug information centers in the United States.

Pharmacist-operated drug information centers (DICs) in the United States were surveyed to obtain current information on the availability and scope of their services. Questionnaires were mailed in late 1991 to 179 institutions believed to have organized DICs. Topics covered in the questionnaire included staffing, resources, funding, and services provided. The results were compared with previous survey results to identify trends. Through 1992, 120 usable responses were received. Compared with findings from earlier surveys, DICs' affiliations with medical centers and hospitals have declined and affiliations with pharmacy schools have increased. More personnel work in DICs than ever. Computers are now used by nearly every DIC, there is an increased emphasis on quality-assurance programs for services rendered, and many DICs have increased revenue with new and expanded services. Although DICs are no longer increasing in number, their services are becoming more sophisticated.

Clinical experience with sotalol in the treatment of cardiac arrhythmias.

The treatment of cardiac arrhythmias has changed over the past several years, as concerns have grown about proarrhythmias and increased mortality associated with certain antiarrhythmic agents. Sotalol, a unique racemic compound with both Class II (beta-blocking) and Class III (repolarization-prolonging) properties, effectively controls life-threatening arrhythmias and has a favorable safety profile, especially when compared with traditional antiarrhythmic drugs. A review of clinical trials demonstrates that sotalol is an effective treatment for premature ventricular complexes, ventricular tachycardia, and ventricular fibrillation. Moreover, it significantly reduces cardiac and all-cause mortality in these patient populations. Although sotalol currently is approved in the United States only for the treatment of life-threatening ventricular arrhythmias, it also is active against several supraventricular arrhythmias. Sotalol is safe and generally well tolerated; most of the adverse effects experienced with its use are related to its beta-blocking activity. However, sotalol has been associated with life-threatening proarrhythmias, including torsades de pointes, but the incidence of this adverse effect is low. Unlike pure Class II agents, sotalol usually is well tolerated in patients with mild-to-moderate left ventricular dysfunction and rarely causes new or worsening congestive heart failure. Sotalol represents an advance in the treatment and prevention of symptomatic ventricular arrhythmias and appears to be a reasonable first-line choice when the arrhythmia is life threatening.

Pharmacist-operated drug information centers in the United States--1986.

Pharmacist-operated drug information centers (DICs) were surveyed early in 1986 to obtain current information concerning the status, availability, and scope of their services. Questionnaires were sent to 191 institutions believed to be active in disseminating drug information; 127 responses were usable. Descriptive information on the respondents is tabulated, and a comprehensive directory of pharmacist-operated DICs is provided. Significant changes have occurred in the affiliations of DICs since previous surveys, and sources of DIC funding seem to be related to these affiliations. Many DICs appear to have the potential to answer more questions than they actually answer. Since few of them are self-sustaining, DICs should attempt to document how their activities affect prescribing practices and, hence, overall hospital finances.

Elderly ambulatory care patients' knowledge about drugs.

The extent of knowledge that elderly ambulatory clinic patients possessed about their maintenance prescription and nonprescription medications was determined using 17 selected questions. Information was obtained by using structured interviews from 100 subjects, 65 years of age or older, selected from a general medicine clinic using the simple two-stage cluster sampling method. The medical charts and various medication teaching manuals were used as criteria to determine whether or not the questions were answered correctly. The questions bout adverse reactions, nonprescription medications to avoid, and activities to avoid or perform with caution were answered correctly less than 30% of the time. Thus, practitioners should not assume that elderly ambulatory patients on maintenance drug therapy possess sufficient knowledge to use their medications safely and effectively.

Educational programs offered by colleges of pharmacy and drug information centers within the United States.

The purpose of this investigation was to determine the scope of drug information educational programs offered by formalized DICs and colleges of pharmacy to pharmacy students. Data were collected from surveys mailed October and December 1982 to 120 institutions known to be active in disseminating drug information as well as the 72 colleges of pharmacy located in the United States and Puerto Rico. A total of 109 questionnaires (91 percent response rate) were returned from the DICs, and 67 questionnaires (93 percent response rate) were returned from colleges of pharmacy. Seventy-four of the DICS and 63 colleges of pharmacy indicated that they provide required and/or elective didactic or experiential drug information training for pharmacy students. These experiences were offered predominantly to fifth year baccalaureate candidates and PharmD candidates. Thirty-two colleges reported that drug information training is a required component of baccalaureate externship-clerkship experiences although most students receive fewer than 40 hours of training. Forty-seven DICs and 20 colleges are affiliated with ASHP approved residency programs. The amount of drug information exposure each resident obtains was highly variable. This survey indicates that many of today's pharmacy students may not be receiving sufficient drug information training to respond to the drug information needs of other health professionals and the lay public.

Comparative content evaluation of the de Haen and Drugdex drug information systems.

The Missouri evaluation protocol was used for comparing the contents of the Drugdex and de Haen drug information systems. Criteria for evaluating (1) general information content and (2) content of drug-drug interactions are given in the Missouri protocol. To check the two drug information systems for content, 113 sample drugs were randomly selected to represent all pharmacologic-therapeutic categories of the American Hospital Formulary Service. A list of 215 sample drug-drug interactions was randomly selected from Hansten's Drug Interactions. Each system was then search, applying each general content criterion and drug interaction criterion to each sample drug and sample interaction, respectively. Raw data were transformed into the Missouri protocol's seven weighted variables, and aggregate scores were obtained by summing the weighted scores for the variables. All scoring measurements were done by one investigator. Both raw (unweighted) and weighted scores were analyzed. Aggregate scores showed no significant differences between Drugdex and de Haen for either general information content or content of drug-drug interactions. However, analysis of raw data contradicted these results by showing differences between systems for several variables. The de Haen system included general information on a greater percentage of the sample drugs, but Drugdex covered more information criteria per drug. Drugdex contained a greater percentage of the sample drug-drug interactions, but de Haen covered more criteria for a listed interaction. The results of this study suggest that neither Drugdex nor the de Haen system can be recommended for use in lieu of the other. The Missouri protocol has flaws that preclude its routine use for comparative evaluation of drug information systems.