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.

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.

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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.