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Objectives: Recent recommendations by the Infectious Diseases Society of America for the treatment of Staphylococcus aureus suggest the use of alternative agents when vancomycin MIC values are >or=2 mg/L. This study examines the outcome of patients treated with daptomycin for S. aureus infections with documented vancomycin MICs., Patients and Methods: All patients with skin, bacteraemia and endocarditis infections due to S. aureus with vancomycin MIC values in CORE 2005-08, a retrospective, multicentre, observational registry, were studied. The outcome (cure, improved, failure or non-evaluable) was the investigator assessment at the end of daptomycin therapy. Success was defined as cure or improved., Results: Five hundred and forty-seven clinically evaluable patients were identified with discrete vancomycin MIC values [MIC <2 mg/L: 451 (82%); MIC >or=2 mg/L: 96 (18%)]. The vancomycin MIC groups were well matched for patient characteristics, types of infections, first-line daptomycin use (19%) and prior vancomycin use (58%). Clinical success was reported in 94% of patients. No differences were detected in the daptomycin success rate by the vancomycin MIC group overall or by the infection type. A multivariate logistic regression also failed to identify vancomycin MIC as a predictor of daptomycin failure. Adverse event (AE) rates were not different when analysed by MIC group; both groups had approximately 17% of patients with one AE., Conclusions: In this diverse population, daptomycin was associated with similar outcomes for patients, regardless of whether the vancomycin MIC was categorized as <2 or >or=2 mg/L. Further studies are warranted.

Antibiotic safety is a major determinant in osteomyelitis therapy. Limited data is available describing the long-term safety and efficacy of daptomycin. the safety population was drawn from CORE 2005 and 2006, a retrospective, observational, multicenter study. Clinically evaluable patients received >3 days of daptomycin appropriately adjusted for renal function. three hundred twenty-seven patients were evaluated for safety; 188 (57%) >or=6 mg/kg, 139 (43%) <6 mg/kg. Thirty-one (10%) patients experienced adverse events possibly related to daptomycin and the incidence was similar regardless of dose. No difference was observed in the rate of creatine phosphokinase elevations by dose. A trend toward higher improved rates was noted in patients receiving a final dose of >or=6mg/kg (96% vs. 90%, P=0.08). Daptomycin appeared well-tolerated at doses of 6 mg per kg or greater which were associated with greater clinical improvement. These results require verification via a prospective clinical trial.

Antibiotic treatment for pelvic inflammatory disease (PID) is often broad spectrum and targets a diverse range of vaginal flora. Treatment of PID in nursing mothers presents a particular clinical challenge because use of antimicrobials during breastfeeding poses several potential risks to infants. Excretion of drugs into breast milk can occur through different mechanisms and depends on the characteristics of both the drug and the mother. Whether daptomycin is excreted into breast milk is unknown, as is its subsequent exposure to breastfeeding infants and the associated risks. We describe a case of PID caused by methicillin-resistant Staphylococcus aureus, an uncommon pathogen in PID, in a breastfeeding mother who was successfully treated with daptomycin. Daptomycin concentrations in her breast milk were measured to determine potential exposure to her infant. These concentrations were extremely low, with an estimated milk:plasma ratio of 0.0012. Although additional confirmatory studies are needed, daptomycin may be a reasonable option in the treatment of PID caused by gram-positive organisms that are resistant to other antibiotics.

Gatifloxacin is a new 8-methoxy-fluoroquinolone antibiotic approved for use in the United States in December 1999. It has a broad spectrum of activity with potent activity against gram-positive bacteria, including penicillin-resistant Streptococcus pneumoniae, as well as excellent activity against gram-negative and atypical organisms. Gatifloxacin is available in both oral and injectable forms and is administered once/day. Bioavailability is 96%, with a plasma half-life of approximately 8 hours in individuals with normal renal function. Elimination is primarily renal excretion of unchanged drug with no cytochrome P450-mediated metabolism. The drug is distributed extensively into tissues and fluids and has a favorable pharmacodynamic profile against important pathogens. It had excellent efficacy in clinical studies of acute sinusitis, acute bacterial exacerbations of chronic bronchitis, community-acquired pneumonia, complicated and uncomplicated urinary tract infections and pyelonephritis, skin and skin structure infections, and uncomplicated gonococcal infections. The agent is well tolerated, with no evidence of hepatic, cardiac, or phototoxicity noted thus far. Drug interactions are uncommon; however, like other fluoroquinolones, coadministration with multivalent cations should be avoided due to significantly decreased absorption. Gatifloxacin should prove to be a safe and effective agent for a wide variety of infections.

Levofloxacin, levo-isomer of the D,L-racemate ofloxacin, is a new fluoroquinolone antibiotic approved for use in the United States in December 1996. It has an extended spectrum of activity compared with older-generation fluoroquinolones (ciprofloxacin, ofloxacin), with improved activity against gram-positive bacteria and excellent activity against gram-negative bacteria and atypical organisms. Although its activity against anaerobic organisms is improved over that of earlier fluoroquinolones, levofloxacin should not be considered a first-line anaerobic agent. It is available in an injectable form, as well as an oral formulation with virtually 100% oral bioavailability. The plasma elimination half-life ranges from 6-8 hours in individuals with normal renal function. Approximately 80% of drug is eliminated unchanged in urine through glomerular filtration and tubular secretion. The pharmacokinetics are not appreciably affected by age, gender, or race when differences in renal function and body mass and composition are taken into account. Levofloxacin had impressive efficacy in clinical studies of community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, acute sinusitis, skin and skin structure infections, and complicated urinary tract infections and pyelonephritis. It is well tolerated; its adverse event profile is similar to that of other fluoroquinolones, with gastrointestinal and central nervous system effects reported most commonly. Drug interactions are uncommon with levofloxacin; however, coadministration with antacids or with other agents containing divalent or trivalent cations reduces levofloxacin absorption. The agent should prove to be more effective than older fluoroquinolones, especially for infections caused by pneumococci highly resistant to penicillin.

In light of the tremendous expansion in the number of selective serotonin reuptake inhibitors available to the clinician, the Pharmacy and Therapeutics Committee of the Denver Veterans Affairs Medical Center considered the advantages and disadvantages of fluoxethine, paroxetine, and sertraline, to determine which agent or agents would be carried on the formulary. The committed recommended sertraline as the preferred agent for the treatment of depression, panic disorders, and obsessive-compulsive disorders. The purpose of this retrospective study was to assess the economic outcome of that decision. The study population consisted of patients at the medical center who were receiving selective serotonin reuptake inhibitors during January through March of 1994 and those were receiving these agents between September 1995 and January 1996. The expanded collection period in 1995-96 was due to a relatively new medical center policy to offer 90-day fills on medication to reduce costs. The extended collection period assured a 100% sample of patients receiving these agents. The 1994 fluoxetine to sertraline dosage equivalency ratio was 20 mg:55.6 mg, based on average daily doses of fluoxetine and sertraline of 32.7 and 90.9 mg, respectively. The cost to the medical center for an average daily dose of fluoxetine was $1.86; sertraline cost $1.22 per day. The 1996 fluoxetine to sertraline dosage equivalency ratio (20 mg:51.3 mg) had not changed significantly since 1994, indicating that the dose of 20 mg of fluoxetine remained very close to a 50-mg dose of sertraline. The average daily doses of fluoxetine and sertraline (34.9 mg and 89.7 mg, respectively) were not significantly different than the 1994 doses. Only 33 patients had been prescribed paroxetine (average daily dose, 32.4 mg). On the basis of these values, the average daily cost of fluoxetine to the medical center was $2.01, compared with $1.18 for sertraline and $1.24 for paroxetine. This $0.83 per patient per day drug acquisition cost difference between fluoxetine and sertraline results in a drug cost reduction of $302,674 per year.

Objective: To evaluate the economic benefit associated with the early conversion of therapy from intravenous ceftiaxone to the comparable oral third-generation cephalosporin, cefpodoxime proxetil., Design: Open-label, unblind, nonrandomized clinical trial., Setting: A 360-bed Veterans Affairs Medical Center., Patients: Forty patients who began receiving intravenous ceftriaxone for either a community-acquired pneumonia or a complicated urinary tract infection., Intervention: twenty patients were selected, based on clinical assessment, to be converted from intravenous ceftriaxone to oral cefpodoxime proxetil. Twenty other comparable patients who would have been appropriate for step-down therapy, did not receive pharmacy intervention and were used as a control group., Measurements: Both groups were assessed and compared for length of ceftiaxone therapy, length of oral follow-up therapy (if any), length of hospitalization, results of culture and sensitivity testing, treatment success and readmissions, and cost of respective therapeutic regimens., Results: In the cefpodoxime study group, the average time receiving intravenous and oral antibiotics was 9.1 days at a total cost of $3040.26 for the 20 patients. In the control group, the average time receiving intravenous and oral antibiotics was 11.9 days at a total cost of $3961.26. A savings of $46.05 per patient was achieved. Patients receiving step-down therapy averaged 1 fewer day of hospitalization., Conclusion: Pharmacist intervention and cefpodoxime step-down therapy were associated with decreased overall antibiotic costs in our intravenous-to-oral program.

Objective: To report a case of ketorolac tromethamine-induced acute renal failure and to discuss the risk factors that make patients more susceptible to the renal effects of nonsteroidal antiinflammatory drugs (NSAIDs)., Data Sources: Case reports and review articles identified by MEDLINE. Indexing terms included ketorolac, renal failure, and NSAIDs., Data Extraction: Data were abstracted from pertinent published English-language sources and were reviewed by all authors., Data Synthesis: Ketorolac is an intramuscularly administered NSAID with many of the same adverse effects associated with other oral NSAIDs. Although reversible depression of renal function has been associated with several NSAIDs, to date there have been no published reports of acute renal failure secondary to ketorolac administration. A 71-year-old woman received three doses of ketorolac to control the pain associated with pelvic and T11-T12 compression fractures. Over the next two days, the patient developed signs and symptoms of acute renal failure, including significant increases in blood urea nitrogen, serum creatinine, and peripheral edema. These signs and symptoms resolved over the next three to four days. Certain risk factors, several of which were present in this woman, make individual patients more susceptible to the renal affects of NSAIDs. These risk factors include advanced age, cirrhosis, volume depletion, congestive heart failure, gastrointestinal bleeding, and preexisting mild renal dysfunction., Conclusions: Caution should be taken when initiating ketorolac or any NSAID therapy with specific attention to risk factors that predispose a patient to renal dysfunction.

Anistreplase, a modified congener of streptokinase, is a recently approved thrombolytic agent used in the treatment of acute myocardial infarction (AMI). Clinical studies have demonstrated anistreplase to be equally efficacious as intracoronary streptokinase when given within four hours of the onset of chest pain. Thirty units, given as a single bolus intravenous injection, result in reperfusion rates of approximately 60-70 percent. The adverse-effect profile of anistreplase compares favorably with that of streptokinase, with hemorrhagic complications being the most serious. Anistreplase has two distinct advantages over both streptokinase and alteplase: (1) it can be administered as a single bolus intravenous injection and (2) it has a longer half-life which may result in decreased reocclusion rates. Anistreplase therapy is associated with reductions in both short- and long-term mortality and has been shown to preserve left ventricular function. A large, long-term, comparative clinical trial (Third International Study of Infarct Survival or ISIS-III) investigating morbidity and mortality rates with streptokinase, alteplase, and anistreplase is ongoing, as is a direct comparative study against alteplase alone (TEAM-3, Multicenter Thrombolytic Trials of Eminase in Acute Myocardial Infarction).

The effect of orally administered activated charcoal on the absorption of acetylcysteine in three men was studied. Each of the three volunteers was given 140 mg/kg acetylcysteine as a single oral dose. Blood samples were taken at 0, 0.5, 1, 1.5, 2, 4, 6, and 8 hours after acetylcysteine ingestion. Following a one-week washout period, each subject was given orally 50 g of Activated Charcoal, USP, 15 minutes before a 140-mg/kg acetylcysteine oral dose. Blood samples were taken. Acetylcysteine content in the plasma was determined with a high-pressure ion-exchange chromatography system using a gold-mercury electrochemical cell. No statistically significant differences were found between total areas under the curves, peak concentrations, or time of peak concentrations of acetylcysteine given with or without charcoal. Although acetylcysteine absorption was delayed in two patients, the differences were not significant. These data suggest that acetylcysteine absorption is not impaired by activated charcoal administration. This conflicts with previously published in vitro data; therefore, it is recommended that activated charcoal should not be administered concomitantly with acetylcysteine as a usual procedure until more data are available.

The effects of in situ-produced oil shale retort water on the metabolism of various substrates was studied both in vivo and in vitro. The induction observed in rats was classified as Type I due to an increase in metabolism of hexobarbital and ethylmorphine without subsequent increases in zoxazolamine metabolism. The maximal absorption of the cytochrome-P450-CO complex was observed to be 450 millimicron, also consistent with Type I inducers. Cytochrome P-450 levels were also significantly increased over controls.

The effects of cimetidine and ranitidine on tocainide pharmacokinetics were assessed in seven healthy subjects, using a randomized, double-blind, placebo-controlled, cross-over study design. After a 400-mg oral dose of tocainide, the area under the concentration-time curve decreased from (mean +/- SD) 31.64 +/- 14.16 micrograms.hr/mL during placebo, to 23.10 +/- 7.33 micrograms.hr/mL during cimetidine (P less than .05). Similarly, the peak tocainide concentrations were 2.81 +/- 0.89 micrograms/mL and 1.70 +/- 0.44 micrograms/mL with placebo and cimetidine, respectively (P less than .05). There was no change in the above parameters between ranitidine and placebo. The terminal half-life and renal clearance of tocainide were not altered by either H2-receptor antagonists, compared with placebo. However, the total amount of tocainide excreted unchanged in the urine, decreased from 159.8 +/- 14.7 mg with placebo to 136.8 +/- 26.8 mg with cimetidine (P less than .05), whereas there was no change with ranitidine. These data indicate that cimetidine, but not ranitidine, causes a decrease in the bioavailability of tocainide and that neither agent alters the apparent elimination rate of tocainide.

The effect of activated charcoal on ethanol blood levels following oral administration of ethanol was studied. Six healthy laboratory dogs were administered 2 ml/kg of 95% ethanol diluted to a 20% solution. Blood ethanol concentrations were measured at 0.5, 1.2, and 3 hours after dosing. After a one-week washout period, the same animals received an identical dose of ethanol preceded by 50 g of activated charcoal in a water slurry. Blood ethanol concentrations were again determined. Absorption of ethanol was significantly (p less than 0.005) inhibited by activated charcoal during the first hour after administration. Blood ethanol levels remained significantly lower (p less than 0.025) throughout the study in the activated charcoal group. Especially during the initial, critical hours of therapy, activated charcoal can significantly reduce the desired blood ethanol concentration required when ethanol is used as an emergency antidote for methanol or ethylene glycol poisonings. The use of activated charcoal is discouraged in poisoning emergencies where such oral-antidote therapy is necessary.

A significant drug interaction between verapamil and digoxin, resulting in elevated serum digoxin concentrations, has been well documented in the medical literature. However, a similar interaction between digoxin and the calcium channel blockers nifedipine and diltiazem has not been conclusively established. This study investigated the influence of diltiazem hydrochloride on trough serum concentrations of concurrently administered digoxin in eight healthy volunteers. During the control phase of the study, volunteers were administered digoxin 0.25 mg/d for 13 days, and subsequently judged to be at steady state by serial determinations of digoxin serum concentrations. Twenty-four hour urine collections were done for creatinine clearance and urinary digoxin clearance determinations. Phase II of the study involved the addition of diltiazem hydrochloride 30 mg qid to the on-going, daily regimen of digoxin. After 14 days of concomitant therapy, steady-state trough digoxin concentrations were again determined, as well as creatinine clearances and urinary digoxin clearances. This investigation demonstrates that concomitant administration of diltiazem hydrochloride with digoxin results in significantly elevated steady-state trough digoxin concentrations (0.32 +/- 0.07 ng/ml increasing to 0.48 +/- 0.06 ng/ml, p less than 0.01). Urinary digoxin clearance decreased from 223.5 +/- 35.7 ml/min to 153.4 +/- 17.5 ml/min (p less than 0.05). Creatinine clearances were unaltered. A review of the current literature on this topic is included.

Home monitors of blood glucose (HMBGs) are gaining acceptance as part of the standard of care for ambulatory self-monitoring and treatment of diabetic patients. Currently there are several HMBGs marketed in the United States, each claiming reliability, accuracy, and "user friendliness," with most of these claims largely unsubstantiated. The objective of our study was to analyze and statistically compare the accuracy and precision of the HMBGs produced by the major competitors in this ever-expanding medical field. Accuracy of each monitor was studied by comparing the glucose value reported by each HMBG with that determined by a reference method (YSI 23A). Precision or reproducibility of results was performed by testing a single, known whole-blood glucose sample 20 times on each monitor. The precision of each device was tested on known low, normal, and elevated samples. Actual and absolute deviations from the reference standard demonstrate that the Accuchek bG and Glucoscan 2000 monitors provide relatively unbiased estimates of blood glucose, whereas the Glucokey, Glucochek II, Glucometer II, and Trendsmeter generally underestimate the true values. The Diascan and Accuchek II monitors, in a separate evaluation, demonstrated acceptable accuracy and precision. We conclude that the Accuchek bG and Glucoscan 2000 statistically are the most accurate and precise HMBGs.