Cost-effectiveness analysis of linezolid vs. vancomycin in treating methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections using a decision analytic model.

PURPOSE: To evaluate the cost-effectiveness of vancomycin vs. linezolid in complicated skin and soft tissue infections (cSSTIs) with methicillin-resistant Staphylococcus aureus (MRSA) using a decision analytic (DA) model. METHODS: A DA model was created to evaluate the cost-effectiveness of four treatment strategies in the treatment of MRSA cSSTIs: linezolid intravenous (i.v.) to oral (LIN), vancomycin i.v. inpatient treatment (VAN-1), vancomycin i.v. switch to oral linezolid (VAN-2) and vancomycin i.v. switch to outpatient vancomycin i.v. (VAN-3). Probabilities were determined from published clinical trials. Incremental cost-effectiveness ratios for the various strategies were the primary outcome. Univariate (one-way) sensitivity analysis and second-order Monte Carlo simulation (using 10,000 trials) were conducted for all parameters used in the model. RESULTS: The DA model predicted that VAN-3 was the most cost-effective strategy from the base-case analysis. Average cost-effectiveness ratio for this strategy was $26,831.42/cure. Univariate sensitivity analysis revealed that the model was sensitive to linezolid duration of inpatient stay and duration of i.v. vancomycin before switching to an oral agent or discharged with outpatient i.v. administration with vancomycin. Probabilistic sensitivity analysis showed that VAN-1 was dominated by LIN, but LIN was only 30% cost-effective compared with VAN-3. Acceptability curve showed that the probability of choosing LIN as a cost-effective strategy compared with VAN-1, VAN-2 and VAN-3 increased as the willingness-to-pay (WTP) increased. CONCLUSION: Alternative vancomycin strategies (VAN-2 and VAN-3) that take advantage of early discharge opportunities were cost-effective compared with LIN. However, LIN's higher efficacy would make it cost-effective for payers with a high WTP threshold.

Pharmacoeconomic evaluation of a pharmacist-managed hypertension clinic.

STUDY OBJECTIVE: To measure clinical, economic, and humanistic outcomes associated with a pharmacist-managed hypertension clinic compared with physician-managed clinics. DESIGN: Prospective, randomized, comparative study. SETTING: Managed care organization. PATIENTS: A total of 330 patients with mild-to-moderate essential hypertension. INTERVENTION: Hypertension care provided by either the pharmacist-managed hypertension clinic or physician-managed general medical clinics. MEASUREMENTS AND MAIN RESULTS: Baseline and 6-month evaluations consisted of systolic and diastolic blood pressure measurements, a short-form health survey, and collection of health care utilization information. After treatment, blood pressure measurements were significantly lower (p<0.001) in the pharmacist-managed hypertension clinic group than in the physician-managed clinic group. Patient satisfaction was significantly higher in the hypertension clinic group. Total costs for the hypertension clinic group were not different from those of the physician-managed clinic group ($242.46 vs $233.20, p=0.71), but cost:effectiveness ratios were lower in the hypertension clinic group ($27 vs $193/mm Hg for systolic blood pressure readings, and $48 vs $151/mm Hg for diastolic blood pressure readings). CONCLUSION: In a hypertension clinic, pharmacists can be a cost-effective alternative to physicians in management of patients, and they can improve clinical outcomes and patient satisfaction.

Cefepime: a new fourth-generation cephalosporin.

The chemistry, pharmacology, antimicrobial spectrum, pharmacokinetics, clinical efficacy, adverse effects, and dosage of cefepime are reviewed. Fourth-generation cephalosporins, such as cefepime, have a quaternary nitrogen that is positively charged at the 3-position, providing the properties of a zwitterion. A 2-aminothiazolyl-acetamido group in the side chain at the 7-position with an alpha-oxyimino substitution may enhance stability against beta-lactamases by preventing the enzymes' approach to the main nucleus. Cefepime may exert its antimicrobial effect by attaching to specific penicillin-binding proteins, disrupting cell-wall synthesis. Cefepime has good activity against gram-positive organisms, such as Staphylococcus aureus, and gram-negative organisms, such as Pseudomonas aeruginosa. Cefepime is not active in vitro against Enterococcus faecalis, Clostridium difficile, and methicillin- and cefazolin-resistant Staph. aureus. Cefepime's activity against gram-negative organisms is similar to that of most third-generation cephalosporins. The agent has poor activity against Bacteroides species. The most common mechanism of resistance to cefepime is the excess production of beta-lactamases. Maximum peak plasma concentrations are two to three times higher after i.v. administration than after intramuscular administration. In healthy adults, the volume of distribution is 13-22 L and the elimination half-life is 2-2.3 hours. Clinical studies show that cefepime is as effective as cefotaxime or ceftazidime in patients with infections of the lower respiratory tract, skin and skin structures, urinary tract, or female reproductive system. Cefepime reduces fever as effectively as ceftazidime or piperacillin plus gentamicin in neutropenic patients. The most common adverse effects of cefepime are headache (2.4%), nausea (1.8%), rash (1.8%), and diarrhea (1.7%). Depending on creatinine clearance, the dosage of cefepime is 1000-2000 mg i.v. every 8-24 hours for life-threatening infections and 500-2000 mg i.v. every 12-24 hours for severe infections. Cefepime's clinical efficacy is comparable to that of ceftazidime and cefotaxime.

Pharmacokinetics of meropenem in patients with intra-abdominal infections.

Noncompartmental and compartmental analyses of meropenem disposition in patients receiving 1-g intravenous intermittent infusions every 8 h were performed. Twelve patients (one woman and 11 men) participated in the meropenem pharmacokinetic analysis. Operative findings included perforated appendicitis (five patients), gangrenous appendicitis (five patients), peri-appendical abscess (one patient), and gunshot wound to the abdomen (one patient). The most common associated adverse drug reactions to meropenem were diarrhea and increased liver enzymes. The estimated noncompartmental pharmacokinetic parameters, mean +/- standard deviation, are as follows: maximum drug concentration in plasma, 47.58 +/- 17.59 micrograms/ml; half-life, 1.04 +/- 0.19 h; elimination rate constant, 0.68 +/- 0.12 h-1; area under the concentration-time curve from 0 h to infinity, 57.5 +/- 20.12 micrograms x ml/h; total plasma clearance, 315.40 +/- 71.94 ml/min; renal clearance, 136.7 +/- 89.20 ml/min; volume of distribution at steady state, 26.68 +/- 6.88 liters; and mean residence time, 1.47 +/- 0.28 h. The two-compartment model best described meropenem disposition in our patients. Our findings differed from estimates for healthy volunteers possibly because of the physiologic changes as a result of surgery. Our findings suggest that meropenem (1,000 mg) administered intravenously every 8 h provides adequate concentrations for most intra-abdominal infections.

Effect of antihypertensive formulation on health service expenditures.

A major barrier to the management of hypertension is the extent to which patients comply with the treatment regimen. Herein we report the findings of a retrospective analysis designed to discern the relationship between antihypertensive formulation, regimen compliance and the utilization of health care services. Data for this analysis were derived from the state of South Carolina's Medicaid computer archive. The study population consisted of 1,000 randomly selected beneficiaries initially prescribed one of the following antihypertensive regimens as monotherapy: atenolol (daily); captopril (twice daily); oral clonidine (twice daily); transdermal clonidine (once a week); diltiazem (twice daily); enalapril (twice daily); metoprolol (twice daily); prazosin (twice daily); terazosin (daily); and verapamil-SR (daily). Multivariate regression analysis was used to determine the incremental influence of selected demographic characteristics, utilization of medical services prior to diagnosis for hypertension, initial antihypertensive medication, medication possession ratio for antihypertensive therapy, and the number of maintenance medications for disease state processes other than hypertension on post-period health care expenditure. Results indicate that patients initially prescribed antihypertensive medication requiring daily or weekly administration experience infrequent changes in their therapeutic regimen, far less use of concomitant therapy for blood pressure control, an increased utilization of antihypertensive medication, and a decrease in the use and cost of physician, hospital and laboratory services.

Cefepime clinical pharmacokinetics.

Cefepime is a new parenteral cephalosporin with antimicrobial activity similar to third-generation cephalosporins. It acts against the Enterobacteriaceae family, and Pseudomonas aeruginosa, but maintains Gram-positive activity similar to that of first- or second-generation cephalosporins. Cefepime has in vitro activity against many bacterial isolates resistant to ceftazidime and cefotaxime, is stable against chromosomally mediated beta-lactamases, demonstrates lower affinity for these enzymes and shows a high resistance to enzymatic hydrolysis. Clinical uses thus far include treatment of lower respiratory tract, intra-abdominal and urinary tract infections, skin and soft tissue infections and for prophylaxis in biliary tract and prostate surgery. Pharmacokinetic studies indicate that cefepime exhibits linear pharmacokinetic behaviour. Pharmacokinetic variables are not significantly different between single- and multiple-dose administration, indicating a lack of drug accumulation in patients with normal renal function. Cefepime is not highly bound to plasma proteins, with binding values of approximately 16 to 19%. The drug is widely distributed in various biological tissues and fluids. The primary route of elimination is from the kidneys, with over 80% of the drug recovered in the urine as unchanged drug in patients with normal renal function. Total drug clearance and renal clearance are similar to creatinine clearance, and glomerular filtration is thought to be the primary mechanism of renal excretion. The elimination half-life is approximately 2 to 2.5 h in patients. Cefepime is removed by haemodialysis (over 3h) and peritoneal dialysis (over 72h) to an appreciable extent, with 40 to 68% and 26% of the drug removed, respectively. Overall, cefepime is well tolerated by patients and no significant drug interactions have been reported to date.

Effect of pharmaceutical formulation for antihypertensive therapy on health service utilization.

A significant factor in the management of hypertension is the extent to which patients comply with the treatment regimen. A retrospective analysis was undertaken to determine the relationship between antihypertensive formulation, regimen compliance, and the utilization of health care services. Data for this analysis were derived from the state of South Carolina's Medicaid computer archive. The study population consisted of 1000 randomly selected patients initially prescribed one of the following antihypertensive regimens as monotherapy: atenolol once daily, captopril BID, oral clonidine BID, transdermal clonidine once weekly, diltiazem BID, enalapril BID, metoprolol BID, prazosin BID, terazosin once daily, and sustained-release verapamil once daily. Multivariate regression analysis was used to determine the incremental influence of selected demographic characteristics, use of medical services before diagnosis of hypertension, initial antihypertensive medication, medication possession ratio for antihypertensive therapy, and number of maintenance medications for diseases other than hypertension on post-period health care expenditures. The results indicated that patients initially prescribed antihypertensive medication requiring once-daily or once-weekly administration experienced an increased utilization of antihypertensive medication, needed fewer changes in their therapeutic regimen, and far less need for concomitant therapy for blood pressure control compared with those prescribed a BID regimen. Patients in the once-daily or once-weekly groups also used significantly fewer physician, hospital, and laboratory services (P < or = 0.05).

A randomized study of cefepime versus the combination of gentamicin and mezlocillin as an adjunct to surgical treatment in patients with acute cholecystitis.

In patients with acute cholecystitis, antibiotics are used as an adjunct to cholecystectomy to reduce the incidence of postoperative septic complications thought to be related to bactibilia. Combinations of penicillins, or cephalosporins or aminoglycosides, or both, are often used. Cefepime is a fourth-generation cephalosporin with excellent activity against gram-positive and gram-negative bacteria, including Pseudomonas species. It has a prolonged serum half-life, allowing twice-daily dosing, and is not nephrotoxic. This study was undertaken to determine whether or not cefepime was as effective as the combination of gentamicin and mezlocillin in patients with acute cholecystitis. One hundred and forty-nine patients were randomized, two to one, to receive cefepime or gentamicin and mezlocillin. Cefepime was given intravenously at 2 grams every 12 hours; gentamicin, 1.0 to 1.5 milligrams per kilograms every eight hours, and mezlocillin, 3 to 4 grams every four to six hours. All patients underwent cholecystectomy. Bile cultures were obtained, and concentrations of cefepime in blood, bile, peritoneal fluid and gallbladder were determined in a subset of patients. There were 56 evaluable cefepime-treated and 34 evaluable gentamicin and mezlocillin-treated patients. Bactibilia was present in 17 of 56 cefepime-treated patients (30.4 percent) and ten of 34 gentamicin and mezlocillin-treated patients (29.4 percent). Enterococci were recovered in six cefepime-treated patients. Clinical and bacteriologic responses were similar for the cefepime-treated and gentamicin and mezlocillin-treated groups, with one failure in each group, a wound infection in a patient receiving cefepime and a subhepatic abscess in a patients receiving gentamicin and mezlocillin. Other measures of outcome, such as the number of days of fever, days nothing by mouth, days of hospitalization and days of antibiotic therapy were similar in both groups. Cefepime, with every 12 hour dosing, achieved extremely high concentrations in all tissues assayed at the time of the operation, a mean of eight hours after administration. Adverse clinical events were similar in both treatment groups. Cefepime is as effective as gentamicin and mezlocillin in preventing septic complications after cholecystectomy for acute cholecystitis. Cefepime requires fewer doses, does not require drug monitoring, is not associated with nephrotoxicity and may therefore prove to be a cost-effective alternative to combination therapy that uses an aminoglycoside.

Chemical compatibility of cefmetazole sodium with ranitidine hydrochloride during simulated Y-site administration.

The stability of cefmetazole sodium and ranitidine hydrochloride was studied under conditions simulating administration via a Y-injection site into a primary infusion line. Cefmetazole sodium was reconstituted with both 0.9% sodium chloride injection (50 mL or 100 mL) and 5% dextrose injection (50 mL) to produce premixing concentrations of cefmetazole 10 and 20 mg/mL. Ranitidine hydrochloride injection was diluted with 50 mL 0.9% sodium chloride injection to give premixing concentrations of ranitidine 1 mg/mL. To simulate Y-site administration, 2 mL of cefmetazole was mixed with 2 mL of ranitidine in a 10-mL glass test tube. All study mixtures were prepared in triplicate and stored at room temperature (22-23 degrees C) under normal fluorescent room lighting. Samples of these admixtures were inspected for visual changes and tested for pH. The concentrations of two drugs were immediately determined by stability-indicating high-performance liquid chromatographic assay methods after mixing and at 1, 2, and 4 hours. No visual changes were observed. The pH in the admixtures was influenced by concentrations of the two drugs. The pH of each single-drug solution did not change during the study period. On the other hand, the pH of any admixtures of cefmetazole and ranitidine solutions prepared with 0.9% sodium chloride or 5% dextrose injection, decreased. Cefmetazole in any of the admixtures with ranitidine retained greater than 95% of its original concentration for 4 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Stability of ranitidine hydrochloride with aztreonam, ceftazidime, or piperacillin sodium during simulated Y-site administration.

The stability of ranitidine hydrochloride after being mixed with commonly used i.v. beta-lactam antibiotics and administered by simulated Y-site injection was studied. Solutions of ranitidine 1 mg/mL (as the hydrochloride salt), aztreonam 16.7 mg/mL, ceftazidime 20 mg/mL (with sodium carbonate), and piperacillin 30 mg/mL (as the sodium salt) were prepared by reconstitution in i.v. mini-bags. To simulate Y-site injection, 2 mL of ranitidine hydrochloride was mixed with 2 mL of each antibiotic in glass test tubes. These admixtures were prepared in triplicate and stored at room temperature under fluorescent light. Concentrations of each drug in each admixture were determined by stability-indicating high-performance liquid chromatography immediately and after one, two, and four hours. Aztreonam, ceftazidime, and piperacillin each retained more than 95% of the original concentration for at least four hours when mixed 1:1 with ranitidine. Ranitidine retained more than 90% of its original concentration for at least four hours when combined with each of the other drugs. Ranitidine 1 mg/mL (as the hydrochloride salt) and aztreonam 16.7 mg/mL, ceftazidime 20 mg/mL (with sodium carbonate), or piperacillin 30 mg/mL (as the sodium salt) were stable for at least four hours during simulated Y-site administration.

Determination of fluconazole in human serum by solid-phase extraction and reversed-phase high-performance liquid chromatography.

A simple, rapid, and accurate reversed-phase octadecylsilyl high-performance liquid chromatographic method using solid-phase column extraction is described for measuring fluconazole in human serum. The column eluent was monitored by ultraviolet absorption at 210 nm. Fluconazole was extracted from diluted serum by adsorption on a small Bond-Elut C18 cartridge after the addition of UK48,134 as the internal standard and recovered by elution with methanol. The methanol was then evaporated to dryness and the residue reconstituted in 200 microliters of mobile phase and filtered prior to injecting an aliquot (50 microliters) onto an Adsorbosphere C18 column (4.6 x 250 mm, 5 microns particle size), using a mobile phase of 25 mM tris(hydroxymethyl)aminomethane-phosphate buffer (pH 7.0):acetonitrile (75:25, vol/vol). The retention times were 6.6 min for fluconazole and 9.0 min for the internal standard. The assay was precise, with inter- and intraassay coefficients of variation of less than or equal to 2.9% and less than or equal to 2.1%, respectively, and with good linearity (r = 1.000) in the range of 0.1 to 25 micrograms/ml. The duration of each analysis was 15 min and the minimum detectable serum concentration was 0.1 microgram/ml.

Tissue concentrations of cefepime in acute cholecystitis patients.

Cefepime is a new broad-spectrum cephalosporin with activity against Staphylococcus, Streptococcus, Pseudomonas, and the Enterobacteriaceae. The purpose of this study was to measure cefepime concentrations in plasma, peritoneal fluid, bile fluid and appendix tissue in patients undergoing elective cholecystectomy. Patients were randomly assigned to receive either cefepime, 2 g intravenously in phosphate buffer (IVPB) q 12 h or gentamicin 1.5 mg/kg IVPB q 8 h plus mezlocillin 4 g IVPB q 6 h. During surgery, gall bladder tissue, plasma, peritoneal fluid, and bile fluid samples were obtained at approximately the same time. Thirty-three patients had data acceptable for analysis. Values are given as mean +/- standard deviation. The mean delta time (defined as the time between the administration of cefepime and the time the samples were obtained) was 8.58 +/- 3.53 h. The values for plasma, peritoneal fluid, bile fluid, and gall bladder tissue concentrations were 7.63 +/- 14.17 micrograms/ml, 5.66 +/- 6.80 micrograms/ml, 15.51 +/- 16.94 micrograms/ml, and 5.36 +/- 6.57 micrograms/gm, respectively. The peritoneal fluid/plasma ratio was 2.10 +/- 2.33, the bile fluid/plasma ratio was 14.44 +/- 31.99, and the gall bladder tissue/plasma ratio was 1.44 +/- 1.82. There was a significant correlation between peritoneal fluid and plasma concentration (r = 0.91, p less than 0.0005), and gall bladder tissue and plasma concentration (r = 0.90, p less than 0.0005). There was no correlation between bile fluid and plasma cefepime concentrations. The minimum inhibitory concentration (MIC) data from previous in vitro studies indicate that cefepime concentrations achieved in this patient population would be adequate against typical biliary tract pathogens.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic population parameters for aminoglycosides in cholecystitis patients.

We report the use of a new method to determine patient population pharmacokinetic parameters (nonparametric expected maximum or NPEM). Our purpose was to develop and then analyze the utility of these parameters, compared to a more traditional approach. Nineteen patients with acute cholecystitis made up the control group for defining the parameters via NPEM. The standard of practice was to use a model created from a different intraabdominal infection group (appendicitis), referred to as "surgical patient model." These two models were compared with a group of 23 patients receiving gentamicin for acute cholecystitis. We concluded that the NPEM model was superior to the surgical patient model in predicting gentamicin trough and peak levels with less bias and better precision.

Utility of a transdermal delivery system for antihypertensive therapy. Part 1.

A retrospective evaluation of patient-level Medicaid claims data from two states was undertaken to discern the fiscal utility of transdermally delivered clonidine versus both the oral formulation of clonidine and oral formulations of eight other antihypertensive agents. In the first phase of our two-part study, we compared paid claims data (n = 1,135) from Florida for transdermal and oral clonidine. Multivariate regression analysis was used to evaluate the incremental impact of six variables on health-care expenditures in the first year after patients were given a diagnosis of hypertension. These variables were: age, gender, prior utilization of medical services, regimen complexity, and dosage formulation. Patients prescribed transdermal clonidine experienced a significant (p less than or equal to 0.001) increase in prescription expenditures and significant reductions in the use of physician (p less than or equal to 0.05), laboratory (p less than or equal to 0.10), and hospital (p less than or equal to 0.05) services. Moreover, savings were maximized (p less than or equal to 0.001) where multi-drug regimens incorporated the transdermal delivery system. In the second phase of our study we compared paid claims data (n = 8,894) from South Carolina for transdermal clonidine and for nine oral antihypertensive agents: atenolol, captopril, clonidine, diltiazem, enalapril, metoprolol, prazosin, terazosin, and verapamil-SR. Once again, regression analysis was used, this time to evaluate the incremental impact of five variables on health-care expenditures in the first year post diagnosis: age, gender, prior utilization of medical services, regimen complexity, and Medication Possession Ratio (MPR), an index of compliance. The data from part 2 of our study revealed that patients assigned a b.i.d. oral antihypertensive agent experienced a significant reduction (p less than or equal to 0.05) in MPR and a significant (p less than 0.05) increase in health-care expenditures when compared to patients prescribed the transdermal delivery system and to patients prescribed once-daily oral medications. These data confirm previous findings concerning the impact of complicated dosing regimens on compliance in hypertensive patients. In this two-part paper we report the data from both phases of our study.

Effect of health education in promoting prescription refill compliance among patients with hypertension.

A multifactorial health-education program designed to enhance compliance with a once-daily regimen of atenolol was evaluated among 453 patients enrolled in health maintenance organizations (HMOs). The initiation of the 180-day study period was used to classify patients as either new or existing cases of hypertension. In turn, patients in these two categories were randomly assigned to a control or an experimental group. Patients assigned to the experimental groups received an enrollment kit upon exercising their initial prescription (new patients) or their first refill request (existing patients). The kit contained: a 30-day supply of atenolol; an educational newsletter about hypertension; information on nutrition and life-style changes; and an explanation of the intent and content of the program. Before the next scheduled prescription-refill date, each patient was contacted by telephone to inquire about his or her experience with the therapy and to stress the importance of adherence to the regimen. Each month thereafter, the newsletter and an enclosed prescription-refill reminder were mailed to each patient. The medication possession ratio, defined as the number of days' supply of atenolol obtained by a patient during the 180-day study period, was significantly (P less than or equal to 0.001) enhanced for the new and existing experimental groups relative to the control groups. Multiple regression analyses revealed that enrollment in the health-education program increased the number of days' supply of atenolol obtained by existing patients by 27 (P less than or equal to 0.001), and by new patients by 40 (P less than or equal to 0.001).

Effectiveness of the C Cap in promoting prescription refill compliance among patients with glaucoma.

In an attempt to increase patient compliance with a dosing regimen, prescriptions for topical solutions of glaucoma medication were refilled using the C Cap, a memory aid designed to help patients to remember to instill the medication as prescribed. A comparison of the number of prescription refills requested by 121 patients with glaucoma showed that patients who received the C Cap requested significantly more refills in the six months after receiving the C Cap than before and requested significantly more refills than did patients who did not receive the C Cap.