Quinupristin/dalfopristin: a therapeutic review.

BACKGROUND: The proliferation of multidrug-resistant gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium (VREF), has created a pressing need for effective alternative antibiotics. Quinupristin/dalfopristin is a new combination streptogramin product with a selective spectrum of antibacterial activity, mainly against gram-positive aerobic bacteria. It has been assessed primarily in emergency-use protocols, in hospitalized patients with skin and skin-structure infections, and in patients with VREF bacteremia. OBJECTIVES: The objectives of this review were to summarize important results of in vitro microbiologic studies; to provide information on relevant pharmacokinetic parameters, drug interactions, and Y-site compatibility; and to assess efficacy and safety data from clinical studies of quinupristin/dalfopristin. METHODS: Articles included in this review were identified by a MEDLINE search of the literature published between 1966 and September 2000 using the terms Synercid, quinupristin, and dalfopristin. Additional articles were retrieved from the reference lists of articles identified in the MEDLINE search. RESULTS: In vitro analysis of the spectrum of activity of quinupristin/dalfopristin has confirmed its relatively selective coverage of gram-positive aerobic bacteria. Both quinupristin and dalfopristin undergo hepatic metabolism and are extensively excreted in the feces. Combination quinupristin/dalfopristin inhibits the cytochrome P450 3A4 pathway, and caution is warranted with concomitant use of other medications eliminated via this pathway. In trials in patients with VREF infections, treatment success with quinupristin/dalfopristin varied depending on the site of infection, ranging from 51.9% in bacteremia of unknown origin to 88.9% in urinary tract infections. The results of comparative clinical trials suggest that quinupristin/dalfopristin has similar efficacy to that of commonly used antibiotics, including cefazolin, oxacillin, and vancomycin, in patients with skin and skin-structure infections or nosocomial pneumonia. The most frequently reported adverse effects with administration of quinupristin/dalfopristin were infusion-site inflammation, pain, and edema; other infusion-site reactions; and thrombophlebitis. Arthralgia, myalgia, nausea, diarrhea, vomiting, and rash occurred in 2.5% to 4.6% of patients and were the most frequently reported systemic adverse events. CONCLUSIONS: Outcomes data from clinical trials indicate that quinupristin/dalfopristin has the potential to play an important role in the treatment of bacteremia, complicated skin and skin-structure infections, and nosocomial pneumonia caused by VREF. Issues of bacterial resistance to quinupristin/dalfopristin and other appropriate uses of this combination agent remain to be elucidated.

Nitroprusside treatment of erythromelalgia in an adolescent female.

OBJECTIVE: To report a case of erythromelalgia in an adolescent patient successfully treated with nitroprusside. CASE SUMMARY: A 15-year-old girl with erythromelalgia resistant to aspirin therapy received an infusion of nitroprusside. The response of the erythromelalgia to nitroprusside was dramatic, with complete pain resolution within 17 hours after the start of therapy. No relapse of erythromelalgia was seen when nitroprusside was discontinued and the patient remained well after 6 months. DISCUSSION: This case adds to existing literature substantiating the benefit of nitroprusside for the treatment of erythromelalgia in pediatric patients. Erythromelalgia in children may represent a different disease entity than that seen in adults, which is commonly responsive to aspirin therapy. The pathogenesis of erythromelalgia is unclear and precludes formulating a proposed mechanism by which nitroprusside has benefit in children. CONCLUSIONS: Nitroprusside is valuable for erythromelalgia resistant to aspirin therapy in pediatric patients. Because of unanswered questions regarding the disease, aspirin remains the agent of first choice in all patients with this rare disease.

Pharmacy-managed protocol for warfarin use in orthopedic surgery patients.

A pharmacy-managed protocol for warfarin use in orthopedic surgery patients was studied. In 1990 a protocol designed to accommodate either protocol- or physician-determined dosing of warfarin for orthopedic antithrombotic prophylaxis (OAP) was implemented at a community hospital. A "protocol" group consisting of patients treated entirely under the protocol-determined dosing option was prospectively identified over a two-year period. A "physician" group consisting of patients treated by physicians in the 10 months immediately preceding implementation of the protocol was also identified. The ability of the protocol to achieve laboratory-test and clinical goals was assessed by comparing the two groups. The proportion of patients who received OAP increased from 89% for the physician group to 98% for the protocol group. Mean prothrombin times (PTs) were significantly higher in the protocol group only on postoperative day 2; 66% of all PTs beyond post-operative day 1 in the protocol group were within the targeted range, which reflected an International Normalized Ratio of 1.6-3.2. The frequencies of clinically apparent postoperative thrombotic events and bleeding episodes were low in each group and comparable to literature values. Analysis of protocol-group patients with PTs of > 20 seconds indicated that lower weight, female sex, and blood loss during surgery were associated with an elevated PT. The protocol was revised to provide for a lower initial warfarin dose in elderly women. A pharmacy-managed protocol for dosing warfarin achieved therapeutic goals and promoted nearly universal use of OAP in patients undergoing high-risk orthopedic surgery.

Alteration of carbamazepine pharmacokinetics in patients with traumatic brain injury.

All patients admitted to a rehabilitation unit with closed-head injury over a 3-year period were reviewed for carbamazepine use exceeding 30 days in the hospital. Nine patients met the study inclusion criteria for age and duration of carbamazepine therapy. On review of the dose:serum concentration relationship, significant changes were noted in four patients. An initial increase in the dose:serum concentration ratio during the first few months of therapy was thought to reflect the well-known auto-induction of carbamazepine metabolism. However, unexplainable decreases in the dose:serum concentration occurred in the following months, and suggested alteration of carbamazepine pharmacokinetics in patients with traumatic brain injury. The finding may be important in determining the optimal approach to therapeutic drug monitoring of carbamazepine in brain-injured patients.

Multiple dose pharmacokinetics of four different doses of nisoldipine in hypertensive patients.

This randomized double-blind parallel group study characterized the pharmacokinetics of the calcium channel antagonist, nisoldipine (core-coat tablets), administered once daily for 7 days in doses of 5 mg (n = 12), 10 mg (n = 13), 20 mg (n = 12), and 30 mg (n = 11) to patients with mild to moderate hypertension. Serial blood samples were obtained from 0 to 24 hours and from 0 to 48 hours after nisoldipine administration on days 1 and 7, respectively. Nisoldipine plasma concentrations were determined by gas chromatography with electron capture detection. No statistically significant difference was found in dose-normalized area under the curve between the four groups. Area under the curve (standardized to body weight) correlated to dose (r = .74, P less than .05). No significant difference existed in oral clearance (L/h/kg) when analyzed for equivalence across the four doses: 8.21 +/- 3.47 (5 mg), 11.84 +/- 13.85 (10 mg), 11.48 +/- 7.49 (20 mg), and 10.36 +/- 5.49 (30 mg). The present investigation characterizes the pharmacokinetics of nisoldipine core-coat tablets in hypertensive patients and demonstrates the dose proportionality or linearity of nisoldipine plasma concentrations and area under the curve, measured over a dose range of 5 to 30 mg.