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.

Combined therapy with an angiotensin II receptor blocker and an angiotensin-converting enzyme inhibitor in heart failure.

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of chronic combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) in the management of heart failure. DATA SOURCES: Clinical literature was accessed through MEDLINE (January 1966-June 2000). Key search terms included angiotensin-converting enzyme inhibitor; losartan; combined modality therapy; drug effects; heart failure, congestive; and receptors, angiotensin. DATA SYNTHESIS: Heart failure is widely prevalent and continues to be associated with high morbidity and mortality, even with currently recommended care. At the moderate doses studied for patients with mild heart failure in brief trials, combined ACE inhibitor and ARB therapy was well tolerated and had an additive effect in reducing blood pressure and relieving symptoms of heart failure. CONCLUSIONS: An ARB combined with an ACE inhibitor may benefit heart failure patients who are receiving all other recommended therapies. Further trials are needed to evaluate long-term safety effectiveness, quality of life, and survival before the combination can be recommended for routine use.

Tolterodine-warfarin drug interaction.

OBJECTIVE: To report two cases of warfarin therapy in which the addition of tolterodine resulted in prolonged international normalized ratios (INRs). CASE SUMMARY: Two patients, each receiving warfarin for stroke prophylaxis in association with chronic atrial fibrillation, developed adverse effects after the initiation of tolterodine for urinary disorders. Other medications for concurrent medical diagnoses had remained unchanged. One patient had an episode of prostatitis, which was treated with levofloxacin immediately prior to tolterodine initiation. The warfarin dosage had remained constant for many weeks in both patients prior to and during the tolterodine trials. In each patient, the initiation of tolterodine was associated with a significant increase in the patient's INR measured 10-14 days later. Thus, tolterodine was ineffective in both patients and was discontinued one to two days before the elevated INRs were determined during routine clinic visits. INRs determined approximately two weeks after tolterodine was discontinued were similar to those obtained during the period before the use of the drug; the warfarin dosage remained unchanged. Rechallenge with tolterodine was not attempted in either patient. DISCUSSION: Several aspects of the reported cases support the validity of a proposed drug interaction when tolterodine is initiated in a patient stabilized on warfarin therapy. The temporal association of the course of tolterodine with an elevated INR, the return to the previous warfarin dose-INR response relationship after tolterodine discontinuation, and the absence of other causes for the elevated INR were factors found in both patients. Possible mechanisms to explain the suggested drug interaction are explored. CONCLUSIONS: Until further data are available, clinicians should be vigilant for a possible drug interaction when tolterodine therapy is initiated in a patient maintained on warfarin therapy.

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.

Pharmacy-managed, weight-based heparin protocol.

A revised protocol for heparin therapy, in which dosing was based on the patient's weight and the pharmacy staff assumed responsibility for management of the treatment protocol, was evaluated. A fixed-dose protocol for heparin therapy, in which an initial loading dose and infusion rate were specified by physicians and partial thromboplastin times (PTTs) were determined every 12 hours, was revised to determine dosing based on patient weight and diagnosis and to include more levels of dose adjustment and additional laboratory tests. Data on demographic characteristics of patients, heparin therapy, laboratory monitoring, conversion to warfarin therapy, and protocol management were collected for the patients receiving heparin under the revised protocol. Results were compared with those obtained for the old, fixed-dose protocol, which was managed by nursing staff. The revised protocol showed improvements in heparin therapy according to commonly accepted treatment criteria, including dosages, time to achieve a PTT associated with therapeutic anticoagulation, and the time a patient was in the target PTT range. The new protocol was also significantly more effective in avoiding low as well as high PTT ratios. The laboratory monitoring mandated by the revised protocol enhanced the monitoring of heparin therapy, and pharmacy management improved the accuracy and documentation of heparin therapy. Under the revised protocol, anticoagulation goals were attained more rapidly, and dosing changes were more likely to be correct and appropriately documented.

Evolution of a neonatal gentamicin dosing protocol in a small community hospital.

The effects of conventional dosage of gentamicin of 2.5 mg/kg given every 12 hours was retrospectively investigated in a small community hospital. Consistent with previous results in large hospitals, the conventional dosage of gentamicin commonly resulted in serum concentrations associated with toxicosis. Results were compared with those obtained prospectively according to a gentamicin dosing protocol that used a formula based on gestational age. The gestational age regimen provided similar peak and significantly lower trough serum concentrations; statistical analysis indicated no demographic differences in the compared groups. Very few neonates who received gentamicin according the gestational age formula were exposed to gentamicin serum concentrations associated with an increased risk of toxicosis. An absence of any significant differences in mean peak and trough serum concentrations in subgroups of neonates treated according to the gestational age formula suggested that use of the gentamicin dosing protocol was appropriate for all neonates. The dose of 3.5 mg/kg used in the gestational age formula was predicted to have resulted in initial gentamicin peak serum concentrations > 5 micrograms/ml in nearly 90% of neonates. The experience obtained with the gestational age formula allowed revision of the gentamicin dosing protocol to provide for more cost-responsible serum concentration monitoring.

Intradermal hepatitis B vaccination.

The availability of vaccine since 1982 for immunization against hepatitis B virus (HBV) has had minimal impact on the disease; mass immunization has been suggested. Intradermal vaccination, which has precedent in prophylaxis of other infectious diseases, has been investigated as a low-cost alternative to traditional intramuscular HBV vaccination. Results of open and comparative trials indicate similar seroconversion rates for intradermal and intramuscular HBV vaccination routes in healthy adults. However, antibody titers and, presumably, duration of antibody protection appear to be decreased with intradermal HBV vaccination. Limited data suggest that demographic factors such as age and gender may affect vaccine responsiveness to intradermal HBV vaccine. Adverse skin reactions are common but do not represent a deterrent to continued intradermal HBV vaccination. There is a need for large-scale prospective comparative trials to substantiate the value of intradermal HBV vaccination. Nevertheless, the potential economic and epidemiologic benefit of intradermal vaccination justifies continued investigation for prevention of HBV infection.

Carbamazepine hypersensitivity reaction.

Carbamazepine is an anticonvulsant that is being used more frequently in the treatment of various psychiatric disorders. The drug has been associated with serious adverse reactions that appear to have an immunological pathogenesis. A case report describing a patient suffering an adverse reaction to carbamazepine is presented, to illustrate the various body systems typically affected in the apparent hypersensitivity reaction. The importance of laboratory and patient monitoring during the initial 3 months of carbamazepine therapy is reinforced.

Utilization of Km for phenytoin dosage after folate addition to patient regimen.

Phenytoin decreases serum and red blood cell folates in 50% of the patients on the anticonvulsant. The supplementation of folic acid changes the disposition of phenytoin, a drug that exhibits Michaelis-Menten kinetics. In a retrospective study at the Veterans Administration Medical Center, seven adult male folate-deficient epileptic patients on phenytoin alone and compliant with the anticonvulsant were supplemented with 1 mg oral folic acid. Before and after the addition of the vitamin, Vmax and Km were calculated for phenytoin. With folic acid, the total serum phenytoin concentration decreased significantly by an average of 22.6 +/- 13.0%. The Km decreased significantly from 6.7 +/- 1.1 to 4.1 +/- 1.5 micrograms/ml. The Vmax remained unchanged. It is hypothesized that folic acid is a cofactor in the metabolism of phenytoin. A cofactor would be expected to alter the affinity (Km) of the enzymes for phenytoin with no change in the liver's total capacity (Vmax) to metabolize phenytoin. This retrospective study in seven male epileptic patients is a convincing argument for the hypothesis.

Clinical and electrophysiologic evaluation of peripheral nerve function in chronic phenytoin therapy.

Analysis of covariance was employed to explore possible correlations among duration of phenytoin therapy, phenytoin and folate serum concentrations, and clinical and electrophysiologic findings in 32 patients receiving single phenytoin therapy. None of our patients volunteered peripheral nervous system complaints. On examination, 9 of 32 (28%) were found to have signs suggestive of neuropathy (absent knee and/or ankle jerks). Neither phenytoin serum concentration nor duration of phenytoin therapy was found to significantly (p greater than 0.05) affect nerve function after an adjustment for age differences. A test for overall effect of folate serum concentration (grouped greater than or equal to 5 or less than 5 ng/ml) also failed to reach statistical significance (p greater than 0.05). Our findings suggest that phenytoin and folate serum concentrations and duration of phenytoin therapy do not have an important role in the development of clinical neuropathy and electrophysiologic abnormalities.

Dipyridamole: a critical evaluation.

Dipyridamol is a vasodilator that is used primarily in clinical practice as an antiplatelet agent. It increases coronary blood flow and was originally introduced as an antianginal agent. An ability to prolong a shortened platelet survival has been used to justify its value in preventing thromboembolic complications. Conditions characterized by a reduction in platelet survival and where dipyridamole has been used include heart valve replacement, arterial grafting, cerebrovascular disorders, and disorders of peripheral circulation. The in vivo effect of dipyridamole on platelet aggregation has not been well defined and may depend on additional factors. Prostaglandins appear to have important roles in platelet homeostasis; their relationships to the action of dipyridamole are discussed. Dipyridamole usually is combined with aspirin for synergistic anti-aggregatory purposes. However, the nature of the interaction has not been elucidated and benefit from the addition of dipyridamole has not been demonstrated in clinical studies. A review of clinical studies using dipyridamole indicates that it currently has limited value.

Phenytoin-folic acid: a review.

The nutrient-drug interaction between folate and phenytoin is a two-way interaction. Folate deficiency resulting from long-term phenytoin therapy is a common occurrence, but progression of the deficiency to a megaloblastic anemia is rare. However, there are data to suggest nonanemic folate deficiency may be detrimental to the patient. Several mechanisms have been proposed to explain the ability of phenytoin to deplete body folate. The supplementation of folic acid to folate-deficient patients taking phenytoin has been shown to result in lowered serum concentrations of phenytoin, and possibly loss of control of the seizure disorder. Folate appears to be associated with the hepatic metabolism of phenytoin, although the effect of folic acid supplementation on phenytoin elimination kinetics is suggested to be individualized.

Phenytoin and folic acid interaction: a preliminary report.

The effect of folic acid (1 mg/day orally) on phenytoin steady-state pharmacokinetics was studied in four male folate-deficient epileptic patients who were treated with only one anticonvulsant. Each patient served as his own control before and after starting folic acid replacement therapy. The Michaelis-Menten parameters, Vmax and Km, were calculated for each patient, and compliance with the single anticonvulsant drug (phenytoin) regimen was documented. Blood and urine samples were collected just before (day 1) and after 180 or 300 days of vitamin administration. Total and free phenytoin were measured in plasma; and phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin (DHD) were measured in 24-h urine. After the addition of folic acid, total phenytoin plasma concentration decreased 7.5-47.6% in three of the four patients, and the extent of this change correlated with Km (r2 = 0.99). Ratios of urinary metabolites to parent drug increased in those patients showing a decrease in plasma phenytoin caused by folic acid supplementation. This indicated that a folic acid-associated increase in phenytoin oxidative metabolism had occurred.

Phenytoin and folic acid: individualized drug-drug interaction.

The effect of folic acid supplementation on the disposition of phenytoin and the resultant loss of seizure control in a male folate-deficient epileptic is reported. Due to the increase in tonic-clonic seizures after the initiation of folic acid (1 mg, orally) the sodium phenytoin dosage was increased by 130 mg until control was achieved. Because of these dosage changes, the Vmax and Km were calculated before and after initiation of the folic acid. The Vmax remained relatively the same, but the Km decreased after folate supplementation.