Counting the costs of drug-related adverse events.

Adverse drug events occur frequently and lead to a significant number of fatalities each year. It has been estimated that fatalities directly attributable to adverse drug reactions are the fourth to sixth leading cause of death in US hospitals, exceeding deaths caused by pneumonia and diabetes. The economic burden resulting from drug-related morbidity and mortality is equally significant and has been conservatively estimated at $US30 billion dollars annually, and could exceed $US130 billion in a worst-case scenario. Since many adverse drug events are considered preventable, increased efforts should be made to avoid classes of drugs that are problem-prone and to initiate diligent monitoring of drugs with predictable toxicities. Programmes should also be implemented that improve medication use practices within institutions. Although nearly all drugs are capable of producing an injury, certain drugs are more likely to do so. Prevention of drug-related morbidity and mortality has become an increasingly important requirement for reducing healthcare expenditures. This article will review studies that examine the economic implications of drug-related adverse events.

Predictive performance of a vancomycin-aminoglycoside population model.

OBJECTIVE: To evaluate the Wragge-Cooper method of predicting vancomycin serum concentrations utilizing knowledge of aminoglycoside pharmacokinetic parameters in general medicine and intensive care unit populations, and to develop a revised model if necessary. DESIGN: This study consists of two phases evaluating 50 adults receiving concurrent vancomycin and aminoglycoside therapy. Patients were identified by a retrospective review of medical records. Bayesian analysis of measured serum aminoglycoside and vancomycin concentrations was performed to determine the individualized pharmacokinetic parameters. Phase I of the study tested the predictive performance of a published model incorporating aminoglycoside elimination (Wragge-Cooper) in 25 patients (group 1), and a revised model was developed. Phase II determined the predictive performance of the revised model (revised) and its performance relative to the Wragge-Cooper model and a traditional model incorporating estimated creatinine clearance (traditional) in an additional 25 patients (group 2). SETTING: Two tertiary care university teaching hospitals. MAIN OUTCOME MEASURES: The predictive performance of the models was determined by comparing predicted with measured vancomycin serum concentrations. Bias and precision were evaluated by calculating the mean prediction error (ME) and mean absolute error (MAE), respectively. Linear regression was performed to determine relationships between parameters. RESULTS: The Wragge-Cooper model consistently underpredicts vancomycin serum concentrations in general medicine and intensive care unit populations (ME = -5.18, MAE = 6.63). Relative predictive performance analysis indicates no significant difference in bias or precision between the traditional and Wragge-Cooper models (delta ME 1.17, delta MAE -0.80). Regression analysis of individualized aminoglycoside and vancomycin elimination derived from patients in group 1 reveals the following relationship: vancomycin k10 (1/h) = 0.081 + 1.037ke,amg, r = 0.73. The revised model is significantly less biased and more precise compared with the traditional model (delta ME -4.48; delta MAE 1.22), and is significantly less biased (delta ME 4.29) but no more precise than the Wragge-Cooper model (delta MAE -0.58), using patients from group 2. CONCLUSIONS: The revised model is an accurate method of predicting vancomycin serum concentrations in both general medicine and intensive care unit populations. Use of this model enables individualization of vancomycin dosage in patients receiving concurrent aminoglycoside therapy and minimizes vancomycin serum concentration monitoring.

Economic aspects of antibacterial adverse effects.

The economic impact of adverse effects is often understated. Increased hospitalisations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Although most classes of antibacterials are well tolerated, severe reactions do occur and can add significantly to the cost of care. Among hospitalised patients, antibacterial adverse effects account for nearly 25% of adverse drug reactions. Published pharmacoeconomic data on direct and indirect costs of antibacterial adverse effects are lacking. The importance of determining the most cost-effective treatment regimen is becoming more apparent due to limited resources available within the healthcare system. When considering the cost of new antibacterials, a simple comparison of acquisition costs may not accurately reflect the true costs of treatment. A drug with a lower acquisition cost may be more toxic and/or less effective, resulting in higher complication rates and/or treatment failures, thus leading to a higher overall treatment cost. In addition, nephrotoxic agents such as aminoglycosides and vancomycin often require close monitoring of serum drug concentrations and creatinine levels, which also contributes to the total cost of therapy. Indirect costs as a result of reduced quality of life or loss of productivity are certainly not reflected in the acquisition costs of antimicrobials. Institutions must evaluate a drug's potential for causing and adverse event, among various other factors, when considering drugs for inclusion on their formularies. Drugs with good safety profiles may minimise hospitalisation or facilitate early discharge. Thus, the adverse effect profile of an antimicrobial agent can contribute significantly to its overall direct costs, primarily as a result of higher monitoring costs and additional days of hospitalisation. For example, in the US, the cost associated with adverse effects, such as nephrotoxicity, observed with aminoglycosides and vancomycin, may add approximately $US2500 per patient with nephrotoxicity (1990 values). Indirect costs can also be substantial as a result of reduced productivity. Many adverse effects of antibacterial agents are predictable and may be minimised with appropriate monitoring and care. This article reviews the pharmacoeconomic aspects of adverse effects associated with some of the more important antibacterial classes such as the beta-lactams, aminoglycosides, vancomycin, macrolides and fluoroquinolones.

A 5-year retrospective analysis of alpha-interferon usage.

Alpha interferon is an immune modulator used in the treatment of hematologic malignancies and immunosuppressive diseases. While many of the clinical indications for interferon have been well described and are FDA-approved, a large number of clinical uses of interferon are being developed. This study evaluated the appropriateness, efficacy, and safety of interferon therapy at our institution from 1987 to 1991. Data were collected by chart review. Response rates of patients in this hospital were compared to those published in the literature. Twenty-six patients were prescribed alpha interferon. Ten patients (38%) demonstrated a partial response, the highest responses seen in Hairy cell leukemia (67%) and chronic myelogenous leukemia (57%). Response rates for each disease compared favorably to those predicted from the literature. Twelve patients (46%) demonstrated intolerance. Overall five patients (19%) remain on therapy. While interferon appears to be moderately effective in certain diseases, intolerance to interferon seems to be the major limiting factor to its clinical application.

Considerations in antimicrobial prescribing.

Soon after antimicrobial drugs became available, it was recognized that they were being overused and misused. Reasons for concern about the inappropriate use of antimicrobials include the emergence of resistant nosocomial bacteria, which have been identified in every hospital nationwide. The presence of resistant nosocomial bacteria presents the physician with a clinical problem and increases the cost of therapy. It is clear that methods need to be implemented to help physicians improve prescribing of antimicrobial agents. As health care practitioners in all fields strive to make patient care more cost-effective, one observation has become evident: The successfully treated patient consumes fewer resources and subsequently costs the hospital less than an otherwise similar, unsuccessfully treated patient. The goal in the 1990s is to provide optimal, cost-effective care for patients without compromising quality. This goal can be achieved by collaborative efforts of physicians, pharmacists, and microbiologists working together as a team to promote quality patient care.

Effect of impaired renal function on the pharmacokinetics of coadministered cefoperazone and sulbactam.

The pharmacokinetics of cefoperazone 2 g combined with sulbactam 1 g after a single dose administered intravenously were evaluated in 24 subjects with normal and impaired renal function. Subjects were categorized into four groups based on endogenous creatinine clearance Clcr. Patients in groups 1, 2 and 3 had ClcrS of greater than 60, 31 to 60, and 10 to 30 mL/min/1.73 m2, respectively. Patients in group 4 required maintenance haemodialysis and were assumed to have Clcr less than 10 mL/min/1.73 m2. Pharmacokinetic parameters were determined by noncompartmental methods. No significant differences (P greater than 0.05) in mean peak serum cefoperazone-sulbactam concentrations for group 1 (208.4/29.0 mg/L), group 2 (199.0/34.1 mg/L), group 3 (163.2/35.0 mg/L), and group 4 (234.0/66.0 mg/L) were noted. Correlations between both total serum (r = 0.58) and renal (r = 0.35) clearance and creatinine clearances were negative for cefoperazone, although both were shown to decline with diminished renal function. Correlations between serum (r = 0.85) and renal (r = 0.72) clearances and creatinine clearance for sulbactam were, on the other hand, both positive and declined in a linear fashion. No significant differences in steady state volumes of distribution were noted for either cefoperazone (P = 0.53) or sulbactam (P = 0.85) amongst the four groups. After 24 h, urinary recovery was also comparable for both cefoperazone (P = 0.64) and sulbactam (P = 0.85) amongst the four groups. The concentrations of cefoperazone and sulbactam remained at or above the MICs (16/8 mg/L) for common bacterial pathogens for 2.5, 3, 7 and 14 h in groups 1, 2, 3 and 4, respectively.

Single-dose pharmacokinetics of intravenous ampicillin plus sulbactam in healthy elderly and young adult subjects.

The pharmacokinetics of intravenous ampicillin and sulbactam, a beta-lactamase inhibitor, were evaluated in two different age groups. Twelve healthy elderly subjects (age 65-93 years) and 12 healthy young adult subjects (age 20-35 years) received both a dose of ampicillin 1 g plus sulbactam 0.5 g and a higher dose of ampicillin 2 g plus sulbactam 1 g after a one-week period between doses. A reverse-phase high-pressure liquid chromatography method was used for the quantitation of ampicillin and sulbactam in serum and urine. The pharmacokinetic parameters for both ampicillin and sulbactam were calculated by computer-based two-compartment nonlinear model. After a 30-min infusion, serum concentrations of both drugs declined in a biexponential manner for both doses. Elderly subjects demonstrated significantly lower total clearances (Clt) than young adult subjects of ampicillin 1 g (220.0 +/- 104.2 vs 360.0 +/- 95.8 ml/min/1.73 m2), ampicillin 2 g (72.6 +/- 36.6 vs 306.8 +/- 109.77 ml/min/1.73 m2), sulbactam 0.5 g (122.3 +/- 47.8 vs 263.9 +/- 93.7 ml/min/1.73 m2), and sulbactam 1 g (171.2 +/- 85.8 vs 391.7 +/- 70.8 ml/min/1.73 m2), respectively. Significance was defined as P less than 0.05. Renal clearance was also significantly reduced in the elderly subjects. Area under the curve was found to be significantly increased in the elderly subjects compared to the young subjects for both ampicillin and sulbactam as were the beta elimination half-lives. No significant difference in the apparent volume of distribution, when adjusted for body weight, was found for either sulbactam (P greater than 0.95) or ampicillin (P greater than 0.95) between the two groups. Linear regression analysis revealed that age was significantly correlated with the Clt of ampicillin 1 g (r = 0.85, P less than 0.001), ampicillin 2 g (r = 0.90, P less than 0.001), sulbactam 0.5 g (r = 0.80, P less than 0.001), and sulbactam 1 g (r = 0.93, P less than 0.001). A multivariate analysis showed a slight improvement in correlation when creatinine clearance was added to age and compared with Clt. Urinary recovery of both ampicillin and sulbactam was approximately 60% after 14 h.

The effect of control on the pattern of utilization of cefotaxime, moxalactam and cefoperazone in a teaching hospital.

In a 710-bed teaching hospital, the infectious disease section and pharmacy service initiated a joint programme to control and monitor the use of third-generation cephalosporins (TGC): cefotaxime, moxalactam and cefoperazone. The policy requires that an infectious disease physician approve the use of a TGC prior to its administration. This retrospective study sought to assess the pattern of utilization of these agents. From January to December 1983, 109 patient courses of cefotaxime (CT), moxalactam (MX), and cefoperazone (CP) were tabulated. Records from 92 patient courses were available for review (84.4%). The preliminary data show that 46.7% of TGC were used empirically to treat suspected infections without culture and sensitivity data, while 50.0% were used to treat various infections (central nervous system, pulmonary, wound, abdominal, biliary, urinary and blood) after culture and sensitivities were known. Only 3.3% of the TGC were used for surgical prophylaxis. In the empirical treatment group, the leading indications for use of TGC were central nervous system (CT = 40.0%, MX = 48.0%) and biliary (CP = 23.1%) infections. In the treatment group with culture and sensitivity data, the primary uses of TGC were for the treatment of Gram-negative pulmonary (MX = 28.0%, CP = 19.2%) and wound (CP = 15.4%) infections. This study shows that physician and pharmacy control does not eliminate empirical treatment with TGC; but it does narrow their use to situations in which their properties are best exploited.