Burden of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay associated with bloodstream infections due to Escherichia coli resistant to third-generation cephalosporins.

OBJECTIVES: This study determined excess mortality and length of hospital stay (LOS) attributable to bloodstream infection (BSI) caused by third-generation-cephalosporin-resistant Escherichia coli in Europe. METHODS: A prospective parallel matched cohort design was used. Cohort I consisted of patients with third-generation-cephalosporin-resistant E. coli BSI (REC) and cohort II consisted of patients with third-generation-cephalosporin-susceptible E. coli BSI (SEC). Patients in both cohorts were matched for LOS before infection with patients free of the respective BSI. Thirteen European tertiary care centres participated between July 2007 and June 2008. RESULTS: Cohort I consisted of 111 REC patients and 204 controls and cohort II consisted of 1110 SEC patients and 2084 controls. REC patients had a higher mortality at 30 days (adjusted odds ratio = 4.6) and a higher hospital mortality (adjusted hazard ratio = 5.7) than their controls. LOS was increased by 8 days. For SEC patients, these figures were adjusted odds ratio = 1.9, adjusted hazard ratio = 2.0 and excess LOS = 3 days. A 2.5 times [95% confidence interval (95% CI) 0.9-6.8] increase in all-cause mortality at 30 days and a 2.9 times (95% CI 1.2-6.9) increase in mortality during entire hospital stay as well as an excess LOS of 5 days (95% CI 0.4-10.2) could be attributed to resistance to third-generation cephalosporins in E. coli BSI. CONCLUSIONS: Morbidity and mortality attributable to third-generation-cephalosporin-resistant E. coli BSI is significant. If prevailing resistance trends continue, high societal and economic costs can be expected. Better management of infections caused by resistant E. coli is becoming essential.

Prioritizing research areas for antibiotic stewardship programmes in hospitals: a behavioural perspective consensus paper.

SCOPE: Antibiotic stewardship programmes (ASPs) are necessary in hospitals to improve the judicious use of antibiotics. While ASPs require complex change of key behaviours on individual, team organization and policy levels, evidence from the behavioural sciences is underutilized in antibiotic stewardship studies across the world, including high-income countries (HICs). A consensus procedure was performed to propose research priority areas for optimizing effective implementation of ASPs in hospital settings using a behavioural perspective. METHODS: A workgroup for behavioural approaches to ASPs was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). Eighteen clinical and academic specialists in antibiotic stewardship, implementation science and behaviour change from four HICs with publicly funded healthcare systems (e.g. Canada, Germany, Norway and the UK) met face-to-face to agree on broad research priority areas using a structured consensus method. Question addressed and recommendations: The consensus process assessing the ten identified research priority areas resulted in recommendations that need urgent scientific interest and funding to optimize effective implementation of ASPs for hospital inpatients in HICs with publicly funded healthcare systems. We suggest and detail behavioural science evidence-guided research efforts in the following areas: (a) comprehensively identifying barriers and facilitators to implementing ASPs and clinical recommendations intended to optimize antibiotic prescribing; (b) identifying actors ('who') and actions ('what needs to be done') of ASPs and clinical teams; (c) synthesizing available evidence to support future research and planning for ASPs; (d) specifying the activities in current ASPs with the purpose of defining a control group for comparison with new initiatives; (e) defining a balanced set of outcomes and measures to evaluate the effects of interventions focused on reducing unnecessary exposure to antibiotics; (f) conducting robust evaluations of ASPs with built-in process evaluations and fidelity assessments; (g) defining and designing ASPs; (h) establishing the evidence base for impact of ASPs on resistance; (i) investigating the role and impact of government and policy contexts on ASPs; and (j) understanding what matters to patients in ASPs in hospitals. CONCLUSIONS: Assessment, revisions and updates of our priority-setting exercise should be considered at intervals of 2 years. To propose research priority areas in low- and middle-income countries, the methodology reported here could be applied.

Appropriate vs. inappropriate antimicrobial therapy.

Inappropriate antimicrobial treatment (defined as use of antimicrobial agent to which a pathogen is resistant) or a delay in starting appropriate treatment are both associated with increased morbidity and mortality. Studies of ventilator-associated pneumonia, intra-abdominal infections or bacteraemia document higher mortality in patients who received inappropriate therapy. In addition, the outcome in patients switched from inappropriate to appropriate therapy is better than for patients who remained on inappropriate therapy, but the benefit is not as great as for those who were started on appropriate therapy initially. While inappropriate therapy undoubtedly has an important influence on outcomes, it needs to be considered in the context of other patient risk-factors, such as co-morbid conditions, severity score measures, and functional status. When assessing the impact of inappropriate therapy on outcomes such as length of hospital stay, it is important to be as precise as possible about the time of onset of infection. Failure to do so may lead to inaccurate estimation of the effect of inappropriate therapy. While the likelihood that resistant pathogens can increase costs throughout the healthcare system is generally recognised, an under-appreciated aspect of resistance is its consequences for patients and their carers. Initiatives are underway to gauge the impact of resistance and strategies to combat its spread.

The effect of streptozotocin diabetes on insulin binding by isolated rat kidney tubules.

Preparations of kidney tubules were isolated from rat kidney cortex and were demonstrated to possess specific binding sites for insulin. The binding was time-and temperature-dependent and the label was displaced by bovine insulin, A1-B29 dodecoyl insulin, proinsulin and insulin A- and B-chains in proportion to their relative activity. Cell-associated degradation was studied by incubating tubules in the presence of fatty-acid-free albumin. The tubules showed high insulin-degrading activity, which was dependent on temperature, time and cell concentration. The number and affinity of insulin receptors on tubules isolated from kidneys taken from streptozotocin-diabetic rats was not significantly different from tubules isolated from untreated control or insulin-treated diabetic rats. Diabetes did not alter the kinetics of insulin degradation by the tubules. This lack of response by the tubules to changes in the concentration of circulating insulin supports the hypothesis that the kidneys do not play an active role in modulating the rate of insulin removal from the circulation.

Selegiline and mortality in subjects with Parkinson's disease: a longitudinal community study.

OBJECTIVE: To estimate mortality by drug use in a cohort of patients with PD relative to age- and sex-matched comparators. METHODS: two longitudinal cohorts of patients with 7 and 11 years' duration of PD were constructed with matched comparators in Tayside, Scotland. Subjects were eligible for inclusion if they received a first prescription for an anti-Parkinson's drug from July 1989 to December 1995, with no PD drug prescription in the previous 6 months. Those who had previously taken a neuroleptic drug or were younger than 40 years of age were excluded. RESULTS: Overall, subjects with PD in relation to comparators had higher mortality with a rate ratio (RR) of 1.76 (95% CI 1.11, 2.81) in the 7-year cohort. There was significantly greater mortality in patients with PD who received levodopa monotherapy (RR = 2.45, 95% CI 1.42, 4.23) relative to the comparators, adjusting for previous cardiovascular drug use and diabetes. However, there was no significant difference in mortality in those with PD receiving combination therapy of selegiline with levodopa and other drugs in relation to the comparators (RR = 0.92, 95% CI 0.37, 2.31). CONCLUSIONS: Subjects with PD had twice the rate of mortality relative to age- and sex-matched comparators. However, those subjects who received selegiline at any time in combination with co-careldopa or co-beneldopa showed no significant difference in mortality compared with the comparators. Monotherapy with levodopa was associated with the highest mortality.

Efficacy of temafloxacin versus ciprofloxacin or amoxicillin for lower respiratory tract infections in smokers and the elderly.

The purpose of this study was to determine the effects of smoking history and age on the efficacy and safety of temafloxacin versus ciprofloxacin or amoxicillin in patients with lower respiratory tract infections (LRTIs). Data were pooled from six clinical trials designed to evaluate the efficacy and safety of temafloxacin in bacterial infections of the lower respiratory tract. Patients were selected for this analysis based on smoking history (n = 256) and age (greater than or equal to 65 years of age [n = 328]). Results in the smoker and elderly subgroups were compared between treatment groups and with those in nonsmoker and nonelderly subgroups. Temafloxacin 300 mg or 600 mg b.i.d., ciprofloxacin 500 mg or 750 mg b.i.d., or amoxicillin 500 mg t.i.d. was administered orally for 7-14 days. Patients were assessed at enrollment, on study days 3-7, 24-72 hours post-treatment, and at 5-9 days post-treatment. Temafloxacin and the reference drugs demonstrated comparable clinical efficacy for treatment of LRTI in smokers (93.7% and 92.5%, respectively) and the elderly (94.6% and 89.3%, respectively). However, eradication of baseline pathogens in individual patients was significantly more common after temafloxacin therapy than that following treatment with the reference drugs in both smokers (99.2% versus 91.2%, p = 0.006) and elderly patients (97.5% versus 91.5%, p = 0.028). Overall, eradication rates for pretreatment pathogens were also significantly higher in smokers (99.3% versus 91.8%, p = 0.006) and in the elderly (97.8% versus 92.3%, p = 0.027). Neither age nor smoking status had a consistent effect on the rate of premature discontinuation of study drugs. Adverse events occurred at a similar rate between treatment groups in the elderly and in the smokers. Temafloxacin appears to be a promising alternative to therapy with either ciprofloxacin or amoxicillin in the treatment of respiratory infections in high-risk patients, smokers, and the elderly.

Cost management in community-acquired lower respiratory tract infection.

Pharmacoeconomic analysis must determine a credible cost model, including healthcare-related, non-healthcare-related, and intangible costs, and must identify important treatment outcomes. Outcomes can be ranked in terms of their sensitivity to different treatments or weighted in terms of cost. Two recent studies of community-acquired lower respiratory tract infection have shown that inadequate treatment is a frequent cause of repeat visits to the physician's office, involving extra costs that could presumably be avoided by more effective first-line treatment. When economic data are to be incorporated into clinical trials, it is important to collect data outside as well as within the trial center and to concentrate on data likely to be of significance to the decision makers the trial is designed to influence. The best way of achieving internal validity in such trials is through randomization, which minimizes bias, chance imbalance, and confounding factors. The three major determinants of the cost-effectiveness of treatment are efficacy, the value attached to preventing treatment failure, and the accuracy of diagnosis. The latter is important because a drug can only benefit patients if they have the disease for which it is an effective treatment.

A patch clamp study of the effects of ciprofloxacin and biphenyl acetic acid on rat hippocampal neurone GABAA and ionotropic glutamate receptors.

The neurotoxic effects of 4-quinolones alone and in combination with certain non-steroidal anti-inflammatory drugs (NSAIDs) may be related to an interaction at GABAA and/or ionotropic glutamate receptors. In the present study, the effects of the fluoroquinolone, ciprofloxacin, alone and in combination with the NSAID, biphenyl acetic acid (BPAA), were examined on GABAA-, NMDA-, AMPA-, and kainate-evoked current responses recorded from cultured rat hippocampal neurones, using the whole cell patch clamp technique. GABA-evoked currents were reversibly inhibited by bicuculline (3 microM) and ciprofloxacin (100 microM) to 11 +/- 5 and 38 +/- 7% of control, respectively. BPAA (100 microM) had little affect on the GABA current (the response was 82 +/- 4% of control) but enhanced the inhibitory potency of ciprofloxacin by approx. 3000-fold. The antagonist effects of ciprofloxacin (30 microM) and ciprofloxacin (0.03 microM) together with BPAA (100 microM) on the GABA-evoked current were not voltage-dependent. Whole cell currents evoked by NMDA, AMPA or kainate were little influenced by ciprofloxacin (100 microM), BPAA (100 microM), or ciprofloxacin plus BPAA (both at 100 microM); the responses being > or = 90% of control in all cases. These data suggest that the proconvulsant effects of quinolones when combined with BPAA may be related to antagonism of central GABAA receptors but not to an interaction at ionotropic glutamate receptors.

Safe withdrawal of monotherapy for hypertension is poorly effective and not likely to reduce health-care costs.

OBJECTIVE: To carry out a population-based evaluation of withdrawal of treatment in primary care using repeated ambulatory blood pressure monitoring (ABPM) assessment to avoid subjecting patients to prolonged periods of excess risk. METHOD: Patients from two community practices (total population 11 034 patients) being administered monotherapy for hypertension, were identified and invited to participate. Subjects were withdrawn from treatment if they had no significant co-morbidity and daytime ABPM blood pressure was < or = 150/90 mmHg. Antihypertensive therapy was restarted if daytime ABPM blood pressure was > 150/90 mmHg during weeks 4, 8, 12, 26, 39 and 52. RESULTS: Of 126 eligible patients 53 had a co-morbidity and 37 declined to participate. Of the 36 patients who entered the study 10 were excluded because they had elevated ABPM blood pressures during treatment and one because they had echocardiographic left ventricular hypertrophy. Of the 25 patients from whom monotherapy was withdrawn, we restarted treatment of 19 before week 52. If clinic blood pressure monitoring had been used instead of ABPM, different decisions would have been taken in eight of 25 cases. The costs of the ABPM-determined withdrawal of treatment programme were greater than the expected savings in drug costs, even assuming that all six patients from whom treatment was withdrawn remained without treatment for a further 9 years. This conclusion was not sensitive to reducing the number of ABPM measurements and to inflation in study-drug costs. However, if all patients had been treated with the most expensive drug, then even the full ABPM programme could have saved money within 9 years. CONCLUSIONS: Antihypertensive therapy could be withdrawn from only a small proportion of patients in the community on the basis of ABPM. The costs of the programme are likely to exceed savings unless the cost of drugs administered is substantially higher than that observed in this study.

Cost of gentamicin assays carried out by microbiology laboratories.

AIMS: To assess the current range of prices charged for gentamicin assays in United Kingdom laboratories; and to examine the laboratories' likely response to increases or decreases in the demand for the service. METHODS: A postal survey of the 420 members of the Association of Medical Microbiologists was used to establish the range of prices charged for aminoglycoside assays. Additionally, eight private institutions were contacted to determine what the private sector was charging for aminoglycoside assays. Reagent costs in the NHS laboratories were calculated by dividing the total cost of all aminoglycoside assay kits by the number of samples analysed. RESULTS: The NHS and the private institutions both showed a wide price variation. Prices charged to an in-hospital requester for a peak and trough assay ranged from 5.00 pounds to 68.20 pounds (n = 44), and to an external private hospital, under a bulk service contract, from 5.00 pounds to 96.00 pounds (n = 47). Prices charged by private laboratories ranged from 49.00 pounds to 84.00 pounds (n = 8). There was a log linear correlation in the NHS laboratories between the reagent costs per assay and the number of assays performed per year, and most laboratories thought that their price per assay would be sensitive to increases or decreases in demand. Laboratories which had purchased their assay machines had lower reagent costs per assay but higher repair and maintenance costs. Overall, number of assays performed and method of payment for assay machinery only accounted for 44.8% of the observed variation in assay kit costs. CONCLUSIONS: The price range for gentamicin assays in the United Kingdom is wide and is only partially explained by the number of assays performed. Most laboratories believe that they would experience a reduction in unit cost as output increases. The currently offered range of prices is, in part, due to variation in the laboratories' approach to costing the service provided and some laboratories charge prices which do not even cover the cost of assay kits. Overall, we believe that prices charged should be as close as possible to the marginal cost of the tests performed.

Hypothetical economic analysis of screening for left ventricular hypertrophy in high-risk normotensive populations.

BACKGROUND: Left ventricular hypertrophy (LVH) measured by echocardiography is a powerful independent marker of increased cardiovascular risk. The prevalence of echocardiographic LVH in patients with high cardiovascular risk appears to be high, even in patients currently considered normotensive. AIM: To ascertain the likely costs of screening for and treating echocardiographic LVH in normotensive patients at high risk of cardiovascular events. DESIGN: Hypothetical economic analysis. METHODS: Cost analyses were based on known costs of echocardiography, costs of selected cardiovascular medications and prevalence of normotensive LVH in at-risk populations, combined with treatment effect data from studies of hypertensive patients with echocardiographic LVH. RESULTS: Screening costs per case for echocardiographic LVH are likely to be low, because of the high prevalence of the condition and the low unit cost of echocardiography. Treatment costs are likely to be comparable to those currently deemed acceptable in treating high-risk cardiovascular populations, e.g. the HOPE study population. DISCUSSION: The costs of screening for and treating LVH in normotensive patients at risk of cardiovascular events do not appear to be prohibitively high. Trials of screening and treatment for normotensive LVH seem therefore to be warranted.

The pharmacokinetics of clarithromycin and its 14-OH metabolite.

Clarithromycin has been administered to 486 subjects in 23 different Phase I studies. Absorption of clarithromycin is rapid and peak concentrations are reached within 2 h of oral dosing. Bioavailability of clarithromycin is c. 50% after oral dosing. However, additional clarithromycin is absorbed and converted into 14-OH-clarithromycin in the liver before entering the systemic circulation. The antimicrobial activity of 14-OH-(R)-clarithromycin, if anything, is superior to that of the parent compound, so that the total absorption of biologically active substance is more than 50% of the administered dose. Peak serum concentrations after oral administration of a 250 mg, film-coated tablet of clarithromycin are 1.5 mg l-1 clarithromycin and 0.8 mg l-1 of 14-OH-(R)-clarithromycin. Clarithromycin is 72% bound to plasma proteins at a concentration of 0.45 mg l-1 but binding decreases with increasing concentration of clarithromycin. Concentrations of clarithromycin in lung are approximately five-fold greater than serum concentrations. Clarithromycin is metabolized in the liver and in the stomach. Approximately 22% of an oral dose is recovered as parent compound, 18% in the urine and 4% in the faeces. Clearance of clarithromycin decreases with increasing dose, probably because of saturable hepatic metabolism. There is a progressive increase in serum concentrations of clarithromycin and 14-OH-(R)-clarithromycin with renal impairment so that doses may need to be reduced in severe impairment (glomerular filtration rate less than 30 ml min-1). No effect of age on clarithromycin clearance has been demonstrated when clarithromycin clearance is corrected for creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost-effectiveness analysis of the use of chlorhexidine detergent in preoperative whole-body disinfection in wound infection prophylaxis.

A total of 3482 general surgical patients entered a trial in which they had a chlorhexidine or placebo detergent shower three times before elective clean wound or potentially contaminated surgery. Patients who showered with a chlorhexidine detergent (N = 1744) had a significant reduction in skin flora compared with those who showered with a placebo detergent (N = 1738). The majority of wound infections occurred outside hospital (312 outpatient infections vs. 201 inpatient infections). Wound infection rates were similar in the chlorhexidine and placebo groups (5.79% vs. 5.75% for inpatient infections and 8.54% vs. 9.38% for outpatient infections). The average hospital cost of both non-infected and infected patients was higher in the chlorhexidine group. The average cost of a non-infected chlorhexidine patient was 847.95 pounds as opposed to 804.60 pounds for a non-infected placebo patient, whilst the average cost of an infected patient was 1459.70 pounds (chlorhexidine) and 1414.22 pounds (placebo). A cross-match comparison of patients undergoing vascular surgery revealed no statistical significance in the difference between the two experimental groups. Patients were matched for age, sex, type of operation and surgeon. We conclude that preoperative whole-body disinfection with a chlorhexidine detergent is not a cost-effective treatment for reducing wound infection.

Subspecies discrimination of staphylococci from revision arthroplasties by ribotyping.

Sixty-six cultures of Staphylococcus spp. were obtained from bone and tissue samples collected from 37 patients during revision arthroplasties and were speciated and ribotyped to assess strain diversity in each species. There were 10 ribotypes among 51 isolates of S. epidermidis, three among three isolates of S. capitis, two among four isolates of S. aureus and two among two isolates of S. simulans. One ribotype was found among each of: two isolates of S. warneri; two isolates of S. haemolyticus and single isolates of S. cohnii and S. saprophyticus. Low molecular weight bands of ribotype patterns characterized one or two related species whereas high molecular weight bands were useful for distinguishing types within species. Specimens from 17 patients yielded more than one isolate of Staphylococcus spp. In 13 of these patients the isolates were representatives of a single species but in only eight did ribotyping show the isolates to be identical. The findings of multiple species and ribotypes from samples taken from the same patient may have implications for understanding the nature of infection in revision arthroplasty and for antibiotic therapy.

A cost-effectiveness study of the management of intractable urinary incontinence by urinary catheterisation or incontinence pads.

STUDY OBJECTIVE: The aim was to compare the costs and effects of management of intractable urinary incontinence by urinary catheterisation or incontinence pads. DESIGN: This was a prospective, randomised study comparing catheterisation with pads, supplemented by additional data collected from patients with chronic indwelling catheters. Main outcome measures were costs of equipment, nursing time, patient preference, nursing preference, and clinical and bacteriological assessment of urinary infection. SUBJECTS: 78 intractably incontinent elderly female patients were randomly allocated to management by urinary catheter or pads and toileting. Supplementary data on equipment costs and nursing time were collected from 27 patients, of whom 22 were already catheterised at the time of the randomisation and five were catheterised by the nursing staff after the last date for entry into the randomisation. MAIN RESULTS: Of the 38 patients randomised to catheterisation, 14 refused consent so only 24 were catheterised on day 1 of the study. There was a rapid removal of catheters, especially in the first six weeks of the study and only four of the randomised catheter patients completed the full 26 weeks of the study. However, eight of the pads patients were catheterised between the 7th and 22nd week because of deteriorating general condition and all retained their catheters for the remainder of the study period. Of 35 patients who had experienced catheters and pads, 12 expressed a clear preference for catheters, 12 for pads, and 11 were undecided. Nurses were in favour of the use of pads, mainly because of concerns about urinary infection with catheters. Comparing costs for patients managed with catheters (532 patient weeks) or pads (903 patient weeks), catheter patients required less nursing time (15.4 v 29.0 h per patient per week) but equipment costs were higher (19.20-24.65 pounds v 8.79-11.35 pounds per patient per week), mainly because of the cost of catheter care (12.75 pounds per patient per week). Asymptomatic bacteriuria was prevalent in both groups but 73% of catheterised patients received treatment for clinical signs of infection compared with 40% of pads patients. Only 30% of patients who were treated had any generalised symptoms of infection. CONCLUSIONS: Use of catheters reduces nursing time but may increase weekly equipment costs depending on the cost of laundry. Despite the high dropout rate among patients randomised to catheters a minority of patients (12/35) expressed a clear preference for catheters and we believe that more patients with intractable incontinence should be given a trial of catheterisation to assess acceptability. Bacteriuria was prevalent in pads or catheter patients but no major episodes of invasive infection were noted in either group.

Pharmacoeconomics of intravenous drug administration.

Direct administration of a drug into a vein guarantees bioavailability, i.e. the total amount of drug is fully available to the bloodstream for transport to all areas of the body. What is not ensured is the safety, need and 'value for money' of this route. Few workers would disagree that there is increased morbidity associated with this method of administration. Adverse events range from the painful irritation of veins to life-threatening infection introduced by needle puncture. It is proposed that in many situations the disadvantages of the intravenous (IV) route outweigh the advantages. There are many hidden costs of IV therapy ranging from the adverse events associated with IV administration to the need for specialised equipment, consumables and additional personnel time. Recent studies have shown that the oral route can be substituted in many patients receiving IV therapy without loss of efficacy. The reduction in costs intrinsic to IV therapy is an additional bonus. There is a need to increase the use of alternative routes of administration on the basis of safety, quality of life and cost.

Defining criteria for the pharmacoeconomic evaluation of new oral cephalosporins.

Economic analysis is founded on the assumption that resources are limited and that they should be used in a way that maximises the benefits gained. It should be clear that economic analysis must be based on a consideration of choices for resource utilisation. Pharmacoeconomics extends these assumptions to drug treatment. Therefore, a full pharmacoeconomic analysis must consider two or more alternative treatments and should be founded on measurement of incremental cost, incremental efficacy, and the value of successful outcome. Most doctors would agree that it is easy to choose between two treatments if the least expensive drug is also the most effective. Economic analysis is required whenever the more expensive of two options is also the more effective. In this instance, the decision maker must believe that the value of one additional successful outcome is greater than the investment made in the more effective treatment. This approach would be a suitable model for comparing new oral third generation cephalosporins with cheaper oral drugs such as amoxicillin. Another decision requiring economic analysis is the choice between a new, oral third generation cephalosporin and an older intravenous formulation of a third generation cephalosporin. In this case, the new treatment is cheaper than the old treatment and the decision maker must be convinced that the oral treatment is as effective as the intravenous treatment. Statistically, it is only possible to exclude a difference of a given magnitude.(ABSTRACT TRUNCATED AT 250 WORDS)

Once-daily aminoglycoside administration in gram-negative sepsis. Economic and practical aspects.

A fuller understanding of the pharmacodynamics of aminoglycoside antibiotics now exists compared with when they were introduced. Recent findings have shown that once-daily dosage regimens of aminoglycosides are as effective as bd or tid regimens in the treatment of Gram-negative sepsis. However, radical changes in dosage frequency based on this knowledge are resisted by some physicians because of fears about the peak concentration toxicity of aminoglycosides. These fears have been shown to be misplaced. The delay in the translation of research findings into practice may be attributable to the sheer quantity of medical literature and the limited time that clinicians have available to read it. Because healthcare resources are finite, physicians are increasingly becoming aware of the need to use drug therapy in the most cost-effective way. An important component of aminoglycoside therapy that may persuade clinicians to change their practice is the organised consideration of the various costs associated with different administration regimens. This review examines the source of those costs, and endorses once-daily dosage of aminoglycosides from both an economic and practical viewpoint.

Pharmacoeconomics of antibacterial treatment.

Antibacterial drugs account for between 3 and 25% of all prescriptions, between 6 and 21% of the total market value of drugs in a single country, and up to 50% of the drug budget in hospitals. Bacterial infection is widely perceived as disease caused by harmful outside agents which can be isolated and tested to select the best drug for treatment. In fact, the need for any treatment and the pros and cons of different drugs are just as debatable as in any other therapeutic area. Moreover, the bacteria which make up the normal flora of the body fulfil important roles, so that the ecological implications of treatment for the individual and for society should be considered in assessing the costs and consequences of antibacterial treatment. In this review we outline the most important issues relating to the treatment of bacterial infection in the community and in the hospital, contrasting information from developed and developing countries where appropriate. We review the existing literature on economic evaluation, but in general most of the literature deals with containing the costs of antibacterial drugs in hospitals, and there are many gaps in the literature on cost-effectiveness of treatment. Consequently there are still extreme variations in medical practice which present a challenge for future evaluation. As the outcomes of antibacterial treatment are apparent in a few weeks or months, this is an ideal field for testing pharmacoeconomic methodology. The desire to overcome medical practice variation through consensus statements should be avoided. Instead we recommend wider application of decision analysis to acknowledge that choices exist for the diagnosis and treatment of bacterial infection and to gather information about the implications of these choices. Much of the existing literature would be improved by a more explicit definition of costs. Direct costs to the health services should be distinguished from non medical costs. Moreover, the analysis should consider whether savings from one budget result in costs to another health service budget, or to the patient (transfer costs). These deficiencies in cost analysis will be relatively easy to correct. Of more concern is the fact that the efficacy of much antibacterial treatment is either totally debatable, or variable, depending on factors such as the type of patient treated or the quality of delivery of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

The cost effectiveness of amoxicillin/clavulanic acid as antibacterial prophylaxis in abdominal and gynaecological surgery.

The objective of this study was to compare the cost effectiveness of amoxicillin/clavulanic acid with other antibacterial regimens for prophylaxis of infection after elective abdominal or gynaecological surgery. Data from 21 previously published comparative clinical trials were used to calculate statistical confidence intervals for differences in postoperative wound infection rate. A simple model was used to produce a tabular sensitivity analysis of cost effectiveness over a wide range of costs of wound infection and potential differences in efficacy. For more expensive comparator regimens, including combination regimens utilising gentamicin and metronidazole, amoxicillin/clavulanic acid was either likely to be more cost effective or equally cost effective. For example, in trials of colonic surgery the comparators were on average 11.39 pounds more expensive than amoxicillin/clavulanic acid, which was > 95% likely to be more cost effective unless the cost of wound infection was estimated to be > 1519 pounds. Amoxicillin/clavulanic acid was more expensive than only 2 of the 21 comparators. Furthermore, in one of these 2 trials it was also significantly more effective than the comparator. In this trial, amoxicillin/clavulanic acid was > 95% likely to be more cost effective as prophylaxis in hysterectomy than rectal metronidazole, provided that the cost of wound infection was estimated to be > 179 pounds. In conclusion, this analysis shows that amoxicillin/clavulanic acid, given as monotherapy, is likely to be equally or more cost effective than a wide range of comparator regimens for prophylaxis of elective abdominal or gynaecological surgery.