Is continuous infusion of beta-lactam antibiotics worthwhile?--efficacy and pharmacokinetic considerations

The most important pharmacodynamic parameter for beta-lactam antibiotics has been shown to be the time above the MIC, which is used as an argument to administer beta-lactam antibiotics by continuous infusion. Studies in vitro and in laboratory animals comparing efficacy of continuous an

Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model

An in vitro pharmacokinetic model mimicking human serum drug concentrations, based on a dialyzer unit, was developed to study the efficacies of continuous infusion and intermittent administration of ceftazidime over a period of 36 h. The daily dose of ceftazidime was 300 mg/liter/24 h given either as a continuous infusion or as three bolus doses. The intermittent dosing regimen yielded peak and trough concentrations after the fourth dose of 92.3 (standard deviation, 8.0) and 1.4 (standard deviation, 0.9) mg/liter, respectively. Continuous administration yielded concentrations of approximately 20 mg/liter. To study efficacy, three Pseudomonas aeruginosa strains, ATCC 27853, CF4, and CF16, were used. The MICs of ceftazidime for these strains were 1, 4, and 16 mg/liter, respectively. Strain CF16 was killed initially during both regimens and then started to regrow. At the end of the fourth dosing interval, i.e., after 32 h, viable counts showed no difference between the regimens. Strains ATCC 27853 and CF4 were killed initially during both dosing schedules, and after the first dosing interval viable counts were similar. However,

Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion

We developed and applied pharmacokinetic-pharmacodynamic (PK-PD) models to characterize in vitro bacterial rate of killing as a function of ceftazidime concentrations over time. For PK-PD modeling, data obtained during continuous and intermittent infusion of ceftazidime in Pseudomonas aeruginosa killing experiments with an in vitro pharmacokinetic model were used. The basic PK-PD model was a maximum-effect model which described the number of viable bacteria (N) as a function of the growth rate (lambda) and killing rate (epsilon) according to the equation dN/dt = [lambda - epsilon x [Cgamma(EC50gamma + Cgamma)]] N, where gamma is the Hill factor, C is the concentration of antibiotic, and EC50 is the concentration of antibiotic at which 50% of the maximum effect is obtained. Next, four different models with increasing complexity were analyzed by using the EDSIM program (MediWare, Groningen, The Netherlands). These models incorporated either an adaptation rate factor and a maximum number of bacteria (Nmax) factor or combinations of the two parameters. In addition, a two-population model was evaluated. Model discrimination was by Akaike's information criterion. The experimental data were best described by the model which included an Nmax term and a rate term for adaptation for a period up to 36 h. The absolute values for maximal growth rate and killing rate in this model were different from those in the original experiment, but net growth rates were comparable. It is concluded that the derived models can describe bacterial growth and killing in the presence of antibiotic concentrations mimicking human pharmacokinetics. Application of these models will eventually provide us with parameters which can be used for further dosage optimization

Pharmacokinetic and pharmacodynamic studies of beta-lactam antibiotics in volunteers and patients with cystic fibrosis

In tbe studies presented in this thesis, the problems encountered in antibacterial tberapy were approached from different angles; the objectives of tbe studies were tbreefoldThe first objective concerns the emergence and prevalence of resistance to antibiotics of bacteria isolated from CF patients. Since CF patients are repeatedly treated witb antibiotics, emerging resistaoce is becoming, or is already, one of tbe major difficulties in treating these patients. In Chapter 4, tbe focus is on Staphylococcus aureus. The resistaoce of S. aureus to several antibiotics was surveyed in strains isolated from CF patients. Furtbermore, tbe frequency of tolerant strains was evaluated. Tolerance is a type of resistaoce in which beta-Iactam antibiotics and in some cases vancomycin, inhibit growtb of the micro-organisms witbout killing tbem. It could be speculated tbat, due to repeated antimicrobial treatment of CF patients, tolerance of S. aureus is induced, or tolerant strains are selected. In Chapter 5, the emergence of resistance in Pseudomonas aeruginosa is studied over a period of several years. Although an association between the use of antibiotics and increase of resistance bas been repeatedly observed in populations as a whole, few, if any data exist on individual patients. Since CF patients harbour the same strain for several years, it is possible to study emergence of resistance in the individual patient, and correlate this with antimicrobial treatment. Furthermore, to study the linkage between the emergence of resistance to different antibiotics, pattern analysis could be usedThe second objective was to study the pharmacokinetics of beta-lactams duting continuous and intermittent infusion. As outlined above, an increase of resistance and altered pharmacokinetics both lead to treatmeThe third part of this thesis focuses on the interaction between P. aeruginosa and ceftazidime in vitro during continuous and intermittent infusion. As indicated above, continuous infusion may be more efficacious than intermittent infusion. However, few in vitro data exist where continuous infusion is compared with intermittent administration. Determinations of the susceptibility of a nticro-organism, usually as a ntinimal inhibitory concentration (MIC) or a killing curve, do not take the fluctuation of antibiotic concentrations due to intermittent dosing into account, as usually occurs when patients are treated. The first part of Chapter 10 discusses this problem, and a brief review of the literature describing in vitro pharmacokinetic models is given. In the second part of this Chapter, an in vitro pharmacokinetic model is described, and the results of intermittent and continuous infusion of ceftazidime on the kiiiing of P. aeruginosa are presente

Use of pharmacodynamic parameters to predict efficacy of combination therapy by using fractional inhibitory concentration kinetics

Combination therapy with antimicrobial agents can be used against bacteria that have reduced susceptibilities to single agents. We studied various tobramycin and ceftazidime dosing regimens against four resistant Pseudomonas aeruginosa strains in an in vitro pharmacokinetic model to determine the usability of combination therapy for the treatment of infections due to resistant bacterial strains. For the selection of an optimal dosing regimen it is necessary to determine which pharmacodynamic parameter best predicts efficacy during combination therapy and to find a simple method for susceptibility testing. An easy-to-use, previously described E-test method was evaluated as a test for susceptibility to combination therapy. That test resulted in a MICcombi, which is the MIC of, for example, tobramycin in the presence of ceftazidime. By dividing the tobramycin and ceftazidime concentration by the MICcombi at each time point during the dosing interval, fractional inhibitory concentration (FIC) curves were constructed, and from these curves new pharmacodynamic parameters for combination therapy were calculated (i.e., AUCcombi, Cmax-combi, T>MIC-combi, and T>FICi, where AUCcombi, Cmax-combi, T>MIC-combi, and T>FICi are the area under the FICcombi curve, the peak concentration of FICcombi, the time that the concentration of the combination is above the MICcombi, and the time above the FIC index, respectively). By stepwise multilinear regression analysis, the pharmacodynamic parameter T>FICi proved to be the best predictor of therapeutic efficacy during combination therapy with tobramycin and ceftazidime (R2 = 0.6821; P < 0.01). We conclude that for combination therapy with tobramycin and ceftazidime the T>FICi is the parameter best predictive of efficacy and that the E-test for susceptibility testing of combination therapy gives promising results. These new pharmacodynamic parameters for combination therapy promise to provide better insight into the rationale behind combination therapy

Evaluation of a Community-wide Diabetes Prevention Program

This thesis is an evaluation of the effectiveness of a community-wide diabetes prevention program conducted in three Divisions of General Practice in Sydney, Australia. The aims were to assess whether translation of diabetes prevention programs was feasible in real-life settings and whether results achieved were comparable with those of randomised trials on which this intervention was based. Its primary goals were to assess whether the lifestyle intervention could increase participation in moderate-to-vigorous physical activity to 210 minutes per week, reduce total fat and saturated fat consumption to 30% and 10% of total daily energy intake, increase fibre consumption to 15 g/1,000 kcal/day, and lead to 5% weight loss over one year. The background section covers the physiopathology of type 2 diabetes, its risk factors, and the available population screening tools to identify people at risk. The growing morbidity and mortality burden, the economic implications of this public health problem, and the importance and feasibility of preventing or delaying the onset by intervening in the precursor stages are then summarised. Evidence for preventability is examined through a literature review of lifestyle interventions in research settings comprising highly structured and closely monitored physical activity and dietary programs under controlled conditions. Examples of the effectiveness of translation of randomised controlled trials (RCTs) into less stringent programs in community settings such as workplaces, churches, indigenous communities and whole-of-country initiatives are presented. A systematic review and meta-analysis of effectiveness of the lifestyle approaches in routine clinical practice supplements the evidence for application of prevention principles in real-life settings. The main chapters of the thesis centre on process and impact evaluation of the semi-structured Sydney-based intervention, which recruited 1,250 participants from the mainstream Australian 29 public using general practitioner services in the study area, who were followed for 12 months. The intervention’s goals aligned with those of the Finnish Diabetes Prevention Program but with less stringent entry criteria and less intensive intervention components delivered by purpose-trained lifestyle officers. The Program included an initial individual assessment and coaching session, three subsequent group sessions in the following three months, then three follow-up coaching calls at three, six and nine months. A final assessment at one year, using the same objective and self-reported measures as in the initial assessment, captured changes in body weight, physical activity and dietary habits. The process evaluation showed that it is feasible and effective to use targeted screening to identify and recruit high-risk individuals into a free-of-charge program in the general practice setting, however a quarter of participants were lost to follow-up by one year. While minor variations in aspects of the Program were required to meet local need, Program fidelity in delivering components, and self-reported adherence to diet and physical activity was high. Using a before-after study design, the impact evaluation measured 1-year changes in key Program parameters in relation to baseline. These comprised: measured weight, waist circumference, BMI, and glycaemia measurements; and self-reported dietary intake and structured physical activity, using a 3-day food record and the Physical Activity Scale for the Elderly (PASE) questionnaire, respectively. The main findings at 12 months for the 586 completers as at December 2010 were: a mean weight loss of 2.1 kg; waist circumference reduction of 2.5 cm; no significant change in glycaemia; 3% reduction of fat and saturated fat intake; 16% increase in fibre intake; and mean increase in moderate-to-vigorous physical activity of 13.7 minutes/week. All these changes were smaller than those achieved by the RCTs in research settings, most likely due to the lower intensity and monitoring of the Sydney intervention. Weight loss and waist circumference reductions were similar for participants in 30 group session and those who received telephone-only coaching. Diabetes incidence was 1% at the end of the first year. An economic appraisal of the Program implementation completes the evaluation. A cost of A$400 per kg lost among people achieving the weight goal was estimated on Program completion, but the cost was double for the overall group that included non weight losers. The cost of achieving the physical activity goal and the dietary goals was not feasible or sustainable with resources available in routine clinical settings. The costs per outcome were similar for participants not attending group sessions, who received only telephone coaching. Hence it is worth exploring this less labour-intensive modality if a general practice based Program were to be delivered as routine preventive care. In sum, the evaluation of this community-wide diabetes prevention program showed that translation of diabetes prevention programs into routine practice, while feasible at less intensive levels than in RCTs, has a somewhat lower effect on diabetes risk reduction and it can still be a financial burden in clinical settings. However, given the potential for population-wide benefit, the effectiveness of alternative delivery modes, number and duration of program components and more targeted patient sub-groups should be investigated.The Sydney Diabetes Prevention Program was funded by New South Wales Health as part of the Australian Better Health Initiative. Financial contribution and other in-kind support were provided by the Sydney South West Area Health Service and the Australian Diabetes Council -NSW

Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study

Item does not contain fulltextPURPOSE: Tobramycin is an aminoglycoside antibiotic of which the 24 h exposure correlates with efficacy. Recently, we found that clearance of the aminoglycoside gentamicin correlates with total body weight (TBW). In this study, we investigate the full pharmacokinetic profile of tobramycin in obese and non-obese individuals with normal renal function. METHODS: Morbidly obese individuals (n = 20) undergoing bariatric surgery and non-obese healthy volunteers (n = 8), with TBW ranging 57-194 kg, received an IV dose of tobramycin with plasma concentrations measured over 24 h (n = 10 per individual). Statistical analysis, modelling and simulations were performed using NONMEM. RESULTS: In a two-compartment model, TBW was the best predictor for central volume of distribution (p &lt; 0.001). For clearance, MDRD (de-indexed for body surface area) was identified as best covariate (p &lt; 0.001), and was superior over TBW ((p &lt; 0.05). Other renal function estimates (24 h urine GFR and de-indexed CKD-EPI) led to similar results as MDRD (all p &lt; 0.001)). CONCLUSIONS: In obese and non-obese individuals with normal renal function, renal function estimates such as MDRD were identified as best predictors for tobramycin clearance, which may imply that other processes are involved in clearance of tobramycin versus gentamicin. To ensure similar exposure across body weights, we propose a MDRD-based dosing nomogram for obese patients