The OPTAMA programme: utilizing MYSTIC (2002) to predict critical pharmacodynamic target attainment against nosocomial pathogens in Europe

Robert G. Masterton1,*, Joseph L. Kuti2, Philip J. Turner3 and David P. Nicolau2

1 Ayrshire and Arran Acute Hospitals Trust, Crosshouse Hospital, Kilmarnock, Ayrshire KA2 0BE; 3 AstraZeneca, Macclesfield, Cheshire, UK; 2 Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA

Received 13 May 2004; returned 6 August 2004; revised 10 October 2004; accepted 23 October 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives: The Optimising Pharmacodynamic Target Attainment using the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) Antibiogram (OPTAMA) programme identifies antibiotic regimens with the highest probability of attaining critical pharmacodynamic targets, accounting for the inherent variability in pharmacokinetics, dosages and MIC distributions.

Methods: European MIC data were obtained from the MYSTIC programme. Pharmacodynamic target attainment was calculated by Monte Carlo simulation for meropenem, imipenem, ceftazidime, cefepime, piperacillin/tazobactam and ciprofloxacin against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.

Results: Significant differences in probability of target attainment were found, with Northern Europe demonstrating the highest probabilities of target attainment and Eastern Europe the lowest. The carbapenems had the highest target attainments and susceptibility levels across all regions and pathogens. The cephalosporins demonstrated high target attainments and susceptibility results against E. coli and K. pneumoniae in Northern and Southern Europe. Piperacillin/tazobactam and ciprofloxacin had the lowest levels for both parameters in all regions. Desirable target attainment was not achieved (except for carbapenems in Northern Europe) for A. baumannii and P. aeruginosa; thus, combination therapy may be appropriate empirical therapy for these pathogens in Southern and Eastern Europe. The closest correlations between target attainment and susceptibility were for meropenem 1 g every 8 h, imipenem 0.5 g every 6 h and ceftazidime 1 g every 8 h.

Conclusions: The study highlighted significant overestimations between the probability of target attainment and the reported percentage susceptibility, particularly for piperacillin/tazobactam and ciprofloxacin. The approach of the OPTAMA programme provides a novel tool which complements susceptibility data to help in the selection of appropriate empirical antibiotic therapy.

Keywords: Monte Carlo simulation , pharmacodynamics , nosocomial infections , surveillance


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The goal of antimicrobial therapy is to successfully treat infections. In mild to moderate sepsis, inappropriate initial treatment can be compensated for by the body's natural defences successfully combating the disease, as well as through opportunities to change therapy depending upon clinical progress and laboratory results. However, it is now recognized that to improve survival and reduce morbidity in serious sepsis, it is important to start treatment with the right antibiotic at the right dose and as early as possible.1,2

The selection of antibiotics for empirical therapy is based on results from surveillance studies and significant local and international variations in resistance rates have been found.3,4 Once a pathogen is isolated, the organism susceptibility determined in the laboratory drives the choice of antibiotic. Although good surveillance studies usually depend upon a quantitative assessment of susceptibility, such as the MIC, in clinical practice a qualitative evaluation into susceptible, intermediate and resistant categories is frequently made.57 Both of these methods can provide reasonable treatment guidance but neither provides information on the effectiveness of antibiotics in the body, as they do not take into account the pharmacokinetic profile and the manner by which different antibiotics exert their bactericidal effect. Thus, susceptibility data, even at the accuracy of a defined MIC value, does not guarantee choosing either an appropriate antibiotic or the dose necessary for a successful clinical outcome.5,8 Instead, susceptibility estimation should be supported by pharmacodynamic and pharmacokinetic data.9 The goal of maximum bacterial kill is correlated to an individual antibiotic's pharmacodynamic profile. For the ß-lactam antibiotics (penicillins, cephalosporins and carbapenems), which employ concentration-independent killing, clinical success correlates best with concentrations of free antibiotic above the MIC for approximately 40–50% of the dosing interval (%T > MIC).10,11 Conversely, with fluoroquinolones, which display concentration-dependent bactericidal activity, bacterial eradication and clinical success against Gram-negative pathogens relates best to an AUC0–24/MIC ratio greater than 125.12

With the aim of improving antibiotic prescribing, this study presents a more developed tool that complements susceptibility reporting for the prediction of the effect of an antibiotic on the outcome of infection. Through the use of Monte Carlo simulation, the Optimising Pharmacodynamic Target Attainment using the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) Antibiogram (OPTAMA) programme incorporates pharmacokinetic parameter estimates, dosing regimens and regional MIC distribution data to calculate the probability of reaching the critical pharmacodynamic target set to ensure maximal bacterial killing and, therefore, the best chance of a clinically successful outcome.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Pharmacodynamic model

Pharmacodynamic exposures, as measured by percentage time above the MIC (%T > MIC) for free (unbound) antibiotic, were modelled for intravenous (iv) bolus regimens of meropenem 0.5 g every 8 h, meropenem 1 g every 8 h, imipenem 0.5 g every 6 h, ceftazidime 1 g every 8 h, cefepime 2 g every 12 h, and piperacillin/tazobactam 4.5 g every 8 h for all pathogens tested. An additional dosing regimen for ceftazidime 2 g every 8 h was modelled against Acinetobacter baumannii and Pseudomonas aeruginosa isolates only, and cefepime 1 g every 12 h was tested against Escherichia coli and Klebsiella pneumoniae isolates only. These regimens were selected as they are in common use in Europe. Pharmacodynamic exposures for ciprofloxacin 0.4 g every 12 h (all pathogens) and 0.4 g every 8 h (against A. baumannii and P. aeruginosa only) were measured by calculation of the total antibiotic AUC0–24/MIC ratio. Dosage regimens were chosen based on the most common regimens used in Europe. A one-compartment iv bolus equation was used to calculate %T > MIC for the ß-lactams:

(Eqn 1)
where Ln is the natural logarithm, f is the fraction of unbound antibiotic, V is the volume of distribution (L) as calculated from the ß phase of the elimination slope, CLT is the total body clearance (L/h) and DI is the dosing interval for the regimen.

Total antibiotic AUC for ciprofloxacin regimens were calculated by the following equation:

(Eqn 2)
The total antibiotic AUC/MIC ratio was used instead of free antibiotic because the original studies evaluating the pharmacodynamic breakpoint for ciprofloxacin did not account for free antibiotic in those patients.11 The AUC/MIC ratio was then calculated by the following:

(Eqn 3)

Microbiology

Microbiology data used during the pharmacodynamic analyses were derived from the MYSTIC database (2002). The MYSTIC database contains a large set of MIC data for hospital, clinically relevant isolates identified to species level by participant laboratories. The MYSTIC programme is a global, multicentre surveillance study that compares the activity of meropenem, in centres that actively use this antimicrobial, against that of imipenem, ceftazidime, cefepime, piperacillin/tazobactam and ciprofloxacin.13 Multiple isolates of the same species from the same patient are excluded.

The data aggregated in this study were generated from isolates collected consecutively in the MYSTIC programme in Europe during 2002. Europe was divided into three regions: Northern Europe (Sweden, Finland, Belgium, Germany and the UK); Southern Europe (Portugal, Spain, Italy, Malta, Greece and Switzerland); and Eastern Europe (Croatia, the Czech Republic, Poland, Turkey and Russia). The total number of pathogens studied throughout Europe included 1740 E. coli isolates (902, 444 and 394 for Northern, Southern and Eastern Europe, respectively), 999 K. pneumoniae isolates (489, 203 and 307, respectively), 580 A. baumannii isolates (185, 111 and 284, respectively) and 1816 P. aeruginosa isolates (1002, 394 and 420, respectively).

The MICs and susceptibility assessments of meropenem, imipenem, ceftazidime, cefepime, piperacillin/tazobactam and ciprofloxacin were determined at each centre by broth microdilution or agar dilution according to National Committee for Clinical Laboratory Standards.14 Control strains of E. coli (ATCC 25922) and P. aeruginosa (ATCC 27853) were run with each set of MIC determinations. Discrete MIC distributions were built for each population of bacteria based on the MIC frequencies in the MYSTIC study using Crystal Ball 2000 (Decisioneering, Inc., Denver, CO, USA), whereby the percentage of bacteria at each MIC is treated as a frequency and values in between the MIC do not exist.

Pharmacokinetics

Pharmacokinetic data were obtained from previously published studies in healthy volunteers.1519 For studies to be considered, they had to: (i) be conducted in at least 10 healthy volunteers; (ii) describe the assay used to determine antibiotic concentrations; (iii) use clinically relevant dosing regimens; (iv) carry out an adequate pharmacokinetic analysis as determined by the OPTAMA investigators (J.L.K., D.P.N.); and (v) present means and standard deviations for CLT and V. No published report in at least 10 healthy volunteers was found for cefepime or ceftazidime, so studies that determined the pharmacokinetics of these agents in six and eight healthy volunteers, respectively, and that met all other criteria were used.17,18 Values for these parameters are listed in Table 1. Log-Gaussian probability distributions for CLT and V were developed using Crystal Ball 2000.


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Table 1. Summary of pharmacokinetic parameters and variability for antimicrobials used in the Monte Carlo simulation

 
Estimates of the fraction of unbound antibiotic for meropenem, imipenem, ceftazidime, cefepime and piperacillin/tazobactam were derived from the package insert for each antibiotic among the other studies previously described. The unbound fractions for these agents were treated as ranges (Table 1). Uniform distributions for the unbound fraction were developed using Crystal Ball 2000.

Monte Carlo simulation

A 5000-patient Monte Carlo simulation (Crystal Ball 2000) was conducted to calculate estimates of %T > MIC or AUC/MIC ratio for each antibiotic regimen/bacterial population combination. During each iteration, different values for CLT, V, f and MIC were substituted into the appropriate equations based on the probability distributions for each, thereby resulting in 5000 estimates of pharmacodynamic exposure for each antibiotic regimen against each bacterium. Values for %T > MIC and AUC/MIC were plotted on frequency curves for further analysis. For comparative purposes, bactericidal pharmacodynamic breakpoints were considered to be 40%T > MIC for meropenem and imipenem, 50%T > MIC for ceftazidime, cefepime and piperacillin/tazobactam, and an AUC/MIC ratio of 125 for ciprofloxacin.912,20

Statistics

The agreement between the probability of bactericidal target attainment and percentage susceptibility was assessed by the methods of Bland & Altman21 and is reported as the mean difference with 95% confidence interval of the difference. Percentage susceptibility is the percentage of isolates that were susceptible to an antibiotic at the NCCLS breakpoint. The two methods were considered to be in agreement when the lower and upper values of the 95% CI of the difference were within –5 and 5, respectively.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The simulated distributions for all pharmacokinetic parameters and MICs were consistent with log-Gaussian (CLT and V), uniform (f) and discrete distributions (MICs) in accordance with the data inputted into the models.

Tables 2 and 3 demonstrate the probabilities of bactericidal pharmacodynamic target attainment for the antimicrobial regimens tested and compare these with the percentage susceptibility results against the enterobacterial and non-fermentative organisms studied. There were no apparent regional effects for the carbapenems against the Enterobacteriaceae tested. In all other antibiotic–organism comparisons evaluated, regional variations were observed, although the range of these variations was less for the carbapenems than for the other antibiotics studied. The highest susceptibility levels and probability of target attainment for all antimicrobial regimens were seen in Northern Europe, followed by Southern Europe. Eastern Europe had the lowest equivalent values for all antibiotic regimens tested. All antibiotic regimens analysed demonstrated higher target attainment and susceptibility throughout Europe for E. coli and K. pneumoniae than for A. baumannii and P. aeruginosa.


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Table 2. Antimicrobial activity and probabilities of target attainment against E. coli and K. pneumoniae in Europe

 

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Table 3. Antimicrobial activity and probabilities of target attainment against A. baumannii and P. aeruginosa in Europe

 
The carbapenem regimens demonstrated the highest target attainment and susceptibility results against E. coli and K. pneumoniae through Northern and Southern Europe, followed by the higher dose cefepime regimen, the lower dose cefepime regimen and ceftazidime. With the exception of an inversion of the lower dose cefepime and ceftazidime regimens for E. coli, these posologies maintained the same order against the identical pathogens from Eastern Europe. Excellent consistency in all regions between the target attainment levels and percentage susceptibility results against the Enterobacteriaceae tested was observed for these regimens. Piperacillin/tazobactam and ciprofloxacin demonstrated the same regional pattern of results but at lower levels of activity, whether assessed by target attainment or susceptibility. Ciprofloxacin was the least potent antibiotic studied. For both these agents, marked variations were found across all regions between the target attainment and susceptibility values, with piperacillin/tazobactam showing less variation than ciprofloxacin.

Against isolates of A. baumannii and P. aeruginosa, the highest susceptibility results and probability of target attainment for all antimicrobial regimens were seen in Northern Europe, followed by Southern Europe. However, desirable target attainments (see discussion for definition) and susceptibility levels against both A. baumannii and P. aeruginosa were found only for the carbapenems in Northern Europe. The cephalosporins demonstrated reasonable activity against P. aeruginosa in Northern Europe. All other antibiotic–organism comparisons demonstrated very low levels of activity across all regions tested, although in the same geographical pattern as for the Enterobacteriaceae. The poorest results were observed with piperacillin/tazobactam and ciprofloxacin regimens, with equivalent low activity against A. baumannii and low-dose ciprofloxacin the least active against P. aeruginosa. Greater variability between target attainment and susceptibility results was seen in the regional results for A. baumannii and P. aeruginosa. For the cephalosporins, target attainment was consistently slightly greater than susceptibility; for piperacillin/tazobactam and ciprofloxacin the reverse was noted and the differences were more marked. Consistent with the findings in Enterobacteriaceae, this effect was most evident in the mid-range of susceptibilities (30–80%). A difference of 50% for piperacillin/tazobactam against P. aeruginosa was seen in one sample from Southern Europe.

Overall, there was excellent agreement between the probability of bactericidal target attainment and percentage susceptibility for imipenem 0.5 g every 6 h and meropenem 1 g every 8 h. The agreements were 0.17 (95% CI –1.24, 1.58) and 0.25 (95% CI –1.65, 2.15), respectively. For the lower dose meropenem (0.5 g every 8 h), slightly less agreement was recorded, with a difference of –3.5 (95% CI –12.28, 5.28). For the cephalosporins studied, ceftazidime at 1 g every 8 h, with a difference of –0.42 (95% CI –1.73, 0.89), also demonstrated excellent agreement with percentage susceptibility. The lower dose of cefepime (1 g every 12 h) showed agreement according to our definition [–1 (95% CI –4.04, 2.04)], but this dosage regimen was not evaluated against the non-fermentative species studied which harbour more resistance.

In contrast, the higher dose cefepime (2 g every 12 h), with a difference of 4.58 (95% CI –4.40, 13.56), and the higher dose of ceftazidime (2 g every 8 h), with a difference of 7.83 (95% CI 0.46, 15.23), yielded positive differences in favour of target attainment when compared with percentage susceptibility. Piperacillin/tazobactam [difference –22.42 (95% CI –47.12, 2.28)] and ciprofloxacin 0.4 g every 12 h [difference –19.5 (95% CI –39.88, 0.88)] and 0.4 g every 8 h [difference –17.5 (95% CI –34.53, –0.47)], demonstrated large negative differences between the probabilities of bactericidal target attainment and percentage susceptibility.

For all antimicrobials tested with multiple dosing regimens, the use of a higher dose of agent produced a higher probability of target attainment in all regions. These increases were usually ≤10% and always tended to be small where target attainment was already high (>80%). The greatest improvements in target attainment were at 16% and were seen for ceftazidime and meropenem against A. baumannii in Southern Europe.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
In recent years, a concentrated effort had been made to improve the effectiveness and appropriateness of antibiotic administration due to the rising tide of resistance associated with increasing and broader antimicrobial usage. More recently, the knowledge that in severe sepsis, mortality and morbidity are significantly improved by starting the right antibiotic as soon as possible has added impetus to achieving these goals.1,2 To date, simple susceptibility testing has been the only available tool to guide both empirical and targeted antibiotic selection; however, this simplistic approach has significant shortcomings.

Qualitative laboratory susceptibility data are poor markers when used alone to predict clinical success. The widespread methodology of trimming results to report them as susceptible, intermediate or resistant according to breakpoints, with many laboratories including the intermediate category within the resistant cohort, means that doctors are managing infections without a true understanding of the degree of susceptibility of the pathogen they are trying to eradicate. Consequently, they are unsure what dose of antibiotic is appropriate.

Historically, the data used to set breakpoints have been limited to interpretation of bimodal MIC population distributions. There has been little influence from either human pharmacokinetic data or clinical trials.8 Until recently, pharmacodynamic data were not considered when determining susceptibility breakpoints.22,23 Consequently, there has been a lack of correlation between clinical outcomes and laboratory reporting of resistance. For example, the laboratory may report resistance when a usual clinical dose is actually high enough to successfully eradicate the organism, as is the case with the reporting of Streptococcus pneumoniae resistance against penicillin.24 More dangerously, if a breakpoint is set too high, pathogens may be reported as susceptible when pharmacodynamic exposure is not sufficient to eradicate the organism. For example, extended spectrum ß-lactamase-producing Enterobacteriaceae that are just within the susceptible range for cephalosporins by MIC testing may not respond to treatment with such antibiotics,25 and the AUC/MIC ratio of fluoroquinolones in nosocomial pneumoniae is much more closely related to clinical outcomes than qualitative susceptibility.26

This problem has been recognized for some time, leading to proposals that pharmacodynamic considerations should be included in antibiotic selection.27 This hypothesis has been demonstrated to be clinically relevant in a limited number of circumstances.28,29 Others have attempted to introduce greater subtlety and achieve greater clinical efficacy by combining pharmacokinetic with pharmacodynamic influences in choosing antibiotic treatments. This methodology has been evaluated to aid posology in difficult-to-treat infections,30 as well as to guide selection within an antibiotic class.31 The same approach could be effective in reducing the burden of evolving bacterial resistance.32 Therefore, a more appropriate measure of true clinical susceptibility related to outcome might be based on pharmacodynamic modelling and calculation of the probability of an antimicrobial regimen achieving optimal bactericidal exposure. Our study explores the utility of this approach in a general clinical setting by measuring the probabilities of attaining target pharmacodynamic exposures between antibiotics of different classes, as well as comparing different dosing regimens for the same agent. Both of these are refinements that cannot be evaluated on susceptibility reports.

The OPTAMA programme was therefore designed to compare pharmacodynamic exposures of differing antimicrobial regimens, taking into consideration the variability of pharmacokinetics among individuals as well as microbiological data specific to various geographical regions. The prediction of probable outcomes from population datasets is accomplished frequently through the use of Monte Carlo simulation.8,22,3235 In this study, thousands of antimicrobial exposure-to-bacterial-MIC scenarios were simulated by computer and analysed to produce a prediction of pharmacodynamic target attainment targets specific to each class of antibiotics. Interpretation of such calculated target attainments is potentially as applicable to empirical antibiotic selection as they are to modification of individual therapy. Target attainments could also help to identify the preferred antibiotic selections and their dosing schedules, even when the consistent picture is of low-level attainment. However, due to the complexity of the process, it is more likely that such methodology would be applied in the case of an individual patient with serious sepsis where clinicians are seeking the greatest possible chance of success. Although no agreed criteria of assessment of susceptibility or target attainment levels exist in these circumstances, it was felt that target attainments of >80% were acceptable, with a desired level of >90%. Dosing alterations that offered a >10% chance of successful target attainment over the standard regimen were viewed as significant.

The European OPTAMA programme studied organisms collected from three regions of Europe during the 2002 MYSTIC programme and used dosing regimens most common to these areas. The bactericidal target attainment results for Europe mirrored those of straight susceptibility testing in demonstrating that there are differences between regions. The probabilities and greatest susceptibility findings were highest in Northern Europe and lowest in Eastern Europe. Overall, bactericidal target attainment was lowest for the piperacillin/tazobactam and ciprofloxacin regimens against all bacterial species in all regions. The NCCLS breakpoints for ciprofloxacin and piperacillin/tazobactam may account for this since they are set too high for the currently used doses of these two antibacterial agents. Against E. coli and K. pneumoniae, all the carbapenem regimens tested and cephalosporins demonstrated high target attainment in Northern and Southern Europe and would be optimal choices for empirical treatment of these organisms. In contrast, only the carbapenems maintained high target attainment against these pathogens in Eastern Europe. For the pathogens A. baumannii and P. aeruginosa, which are known to harbour more resistance, target attainment was generally too low to justify the use of any of these regimens as monotherapy. The exceptions to this were the carbapenem regimens tested and cephalosporins in Northern Europe, where probabilities for higher dosage regimens ranged from 79% to 95% for A. baumannii and 81% to 87% for P. aeruginosa. While larger or more frequent doses of ceftazidime, cefepime and ciprofloxacin against these pathogens resulted in greater probabilities of target attainment, such increases were not high enough by themselves, i.e. did not achieve levels of >80%, to justify the use of any of these agents empirically as monotherapy outside of Northern Europe. These data also belie the confidence with which practising clinicians often intuitively rely upon an escalating dosage approach to deal with difficult-to-treat or non-responsive infections. For all other regimens and regions of Europe, the use of combination therapy to treat these pathogens would seem to be justifiable and may improve outcomes when used empirically. A recent study demonstrated that the use of combination antimicrobial therapy for P. aeruginosa bacteraemia resulted in an improvement in 30 day survival, at least until the antibiotic susceptibility results were available to help guide therapy.36 The application of the OPTAMA approach to combination antibiotic therapy has still to be evaluated.

Importantly, this study revealed that the probability of attaining bactericidal exposure did not always correspond with the reported percentage susceptibility. Susceptibility rates underestimate the predicted bactericidal effect of some antibiotics (including higher doses of ceftazidime and cefepime), while overestimating the potential impact of other antibiotics (including piperacillin/tazobactam and ciprofloxacin). For the latter two agents, probabilities differed by an average of 17.5–22.42%, with large variability around calculation of the mean. Clinically, this suggests an increased likelihood of unsuccessful bactericidal outcomes for pathogens reported as susceptible when treated with standard dosing regimens for these agents. While pharmacodynamic exposure for cefepime 1 g every 12 h was found to be in agreement with percentage susceptibility, this dosing regimen was not simulated against A. baumannii and P. aeruginosa, where MICs are generally higher. In separate studies, the target attainment levels for cefepime 1 g every 12 h did not correspond with the percentage susceptibility values when evaluated against all pathogens.37,38 In general, more disagreement will be apparent if a greater number of pathogens with higher MICs are used in the analysis, particularly for those agents where the susceptibility breakpoint may be too high or too low.

It is important to note some assumptions and potential limitations in the OPTAMA analysis. First, the MIC distributions used are regionally specific to Northern, Southern, and Eastern Europe as reported in the MYSTIC programme. Locally derived institutional data may differ. Ideally, surveillance data should be unit specific for an institution, which will result in the most accurate estimation of pharmacodynamic exposure of different antimicrobial regimens. However, the percentage susceptibility reported in the MYSTIC programme is consistent with other surveillance studies in these regions.39,40 Another assumption is that it is reasonable to use healthy volunteer pharmacokinetic data to calculate pharmacodynamic exposure in actual patients. This approach has the advantage that the use of healthy volunteer data allows comparison of the antibiotics in similar populations.1519 Conversely, although patient data would be more appropriate, no comparable pharmacokinetic studies have studied all these antibiotics in the same patient population (e.g. a surgical intensive care unit), thus making comparisons of exposure between agents difficult. Additionally, a recent report for the ß-lactams has shown that the use of healthy volunteer data during Monte Carlo simulation is predictive of target attainment in varying patient populations.41 This is because although patients tend to have a larger volume of distribution, most also have a reduced clearance which compensates for any loss in time above the MIC exposure. Since clearance is the only pharmacokinetic parameter estimate used to calculate AUC/MIC exposure for ciprofloxacin, the reported results may be a conservative estimate of ciprofloxacin target attainment. A potential limitation of the study is that antibiotic plasma data were used rather than tissue levels at the site of infection. However, for most infection sites, the pharmacodynamic exposure that is achieved in serum has been used as a good marker for tissue. Another potential limitation relates to the use of defined pharmacodynamic breakpoints rather than a range of %T > MIC and AUC/MIC ratio as in other studies.37,38 This might affect the target attainment for the cephalosporins since the bactericidal exposure for the cephalosporins seems to vary depending on the specific agent and bacteria studied, and higher targets, such as 70% have been reported.

In conclusion, this study has demonstrated that it is possible to use surveillance programmes to rank antimicrobial agents according to which would be most likely to achieve a desired pharmacodynamic endpoint. This offers a new approach to the production of both empirical antimicrobial regimens and individually tailored antibiotic management in severe sepsis, with the dual goals of improving antibiotic prescribing and clinical outcomes. Furthermore, the study highlighted significant discrepancies between the probability of pharmacodynamic target attainment and the reported percentage susceptibility for individual antibiotics. This indicates that, compared with estimation of target attainment, traditional surveillance methods might underestimate or, more importantly, overestimate the clinical effectiveness of some agents at particular dosing regimens. The usefulness of this methodology needs to be tested in clinical trials.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was sponsored by AstraZeneca.


    Footnotes
 
* Corresponding author. Tel: +44-1563-577004; Email: robert.masterton{at}aaaht.scot.nhs.uk


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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