healthmedicinet

In our ICU patient group, we observed a very high variability of PIP levels leading to a high percentage of patients with potentially subtherapeutic PIP concentrations. Target attainment was tightly associated with creatinine clearance. Although the strong association between creatinine clearance and piperacillin levels has already been described in several studies of critically ill patients, this work is novel in contemporary literature, given the number of blood-sampling time points, the variability of piperacillin levels observed over several days, the difference of target attainment dependent on both creatinine clearance and commonly used dosage schemes, and the increasing negative association of PIP trough levels with CRP levels during therapy. Our data highlights the concern that patients with mild or moderate renal function impairment are also likely to have subtherapeutic levels over several days with the conventional intermittent dosage scheme of 4.5 g PIP-TAZ TID. This might lead to treatment failure or the selection of drug-resistant strains. In contrast, there might be less risk of subtherapeutic trough levels and treatment failure in ICU patients with severely impaired renal function and use of RRT, even when the dosage is reduced to 4.5 g PIP-TAZ BID.

Previous studies have also described a high dependency of PIP concentrations on creatinine clearance [14, 15, 24–29]. However, only Conil et al. described the effect on target attainment when using this conventional dosing in patients with slightly to moderately impaired renal function [15]. They observed a correlation coefficient of -0.61, whereas we observed an even higher correlation (r?=?-0.837) for patients receiving 4.5 g PIP-TAZ TID. Because Conil et al. determined PIP concentrations at precisely the time point of 24 hours after starting antibiotic treatment, it remained unclear if the observed high percentage of subtherapeutic levels in their study might also have resulted from insufficient loading and how often the target range would be attained at a later time points. The high correlation coefficient we found may open the possibility to develop a pharmacokinetic model, which might help to find adequate dosing especially in dependence of creatinine clearance values. We showed that the percentage of insufficient levels remained high and more or less stable in patients over the course of several days. Moreover, all patients with a creatinine clearance??65 mL/min and approximately half of patients with a creatinine clearance between 30 and 65 mL/min had insufficient levels, even with the lower therapeutic range (therapeutic range 1). This shows that this dosage may be insufficient over several days also for patients who have slightly or moderately impaired renal function. To reach the target range 1, it might be reasonable in cases of slightly to moderately impaired renal function to prescribe the maximum dosage of 4.5 g PIP-TAZ four times daily, as recommended by the prescription drug information. However, occurrence of neurotoxicity, although not clearly observed in our study, should be carefully monitored. Moreover, to the best of our knowledge, we showed for the first time that an adjusted PIP dosage of 4.5 g PIP-TAZ BID for patients with strongly impaired renal function leads to therapeutic levels in critically ill patients much more often (Table 2). Interestingly, for these patients, this was much more dependent on the defined therapeutic range (1 versus 2). Whereas most patients reached therapeutic range 1 (82–100 % at different study days), only 50–64 % reached therapeutic range 2 (Table 2). This might be due to the longer time intervals between consecutive doses in this case, which makes it more difficult to reach a high concentration over a long time interval. There is still a controversial debate about the right target range for critically ill patients [13]. However, the high percentage of patients with severely impaired renal function and reduced dosage reaching at least the target range 1 shows that the problem of underdosing in this patient group is much lower than in patients with slightly or moderately impaired renal function and not an adjusted dosage. This is still important, because many ICU physicians still prescribe PIP-TAZ 4.5 g TID – at least for patients with slightly to severely impaired renal function. Indeed, these dosages are still recommended by the Food and Drug Administration and in expert information.

We also evaluated the influence of RRT on PIP concentrations. This is important as the use of RRT may further alter antibiotic pharmacokinetics [30]. We observed significant higher percentages of T??22.5 mg/L for the patients with RRT. Because of the different RRT methods and the different daily dosages, we only had limited numbers of the specific subgroups. Therefore, we could not evaluate the influence of the different RRT modalities on PIP concentrations.

Considering all patients, we observed a high variability and a high quantity of subtherapeutic levels for PIP, as in other studies [6, 9, 19, 21, 31, 32]. In contrast with the literature, we observed an even higher inter-individual variability for PIP trough levels [6, 9, 19, 21, 33] and a higher percentage of patients with PIP levels below fT??MIC [6, 9, 14] and below the higher target range of 50 % fT??4 × MIC [9, 19, 23]. Sime et al., however, observed a higher percentage of patients with trough levels below the target range [21], which might be due to the average higher creatinine clearance (all patients??50 mL/min) of their study patients. The high inter-individual variability we observed in our study with trough levels varying??100-fold was restricted to patients who received PIP-TAZ TID (Fig. 1), which might be at least in part due to the higher range of creatinine clearance in this group. We also found partly higher intra-patient variability than in the literature: over 4 days, we observed CVs for PIP ranging from 6 to 129 %, whereas Carlier et al. reported CVs of 20–60 % over an entire antibiotic course [6]. The reason for the higher variability observed in our study might be the higher heterogeneity of patient characteristics. As this is typical for ICU patients, our data might support the concept of therapeutic drug monitoring (TDM).

Thresholds of both target ranges for unbound PIP were defined as in other studies [6, 9, 14, 19, 21, 23]. A traditional target for this antibiotic is 40–50 %fT??MIC [34]. However, a higher target range might be more appropriate for ICU patients [31] because of the critical illnesses of these patients. Therefore, we chose 100 %fT??MIC in accordance with most other studies [6, 9, 14, 21]. Indeed, different studies demonstrated that for beta-lactam antibiotics, maximum killing is often only achieved when the T??MIC approaches 90–100 % of the dosing interval [35]. The higher target range (50 %fT??4 × MIC) was chosen in accordance with other studies [19, 23], because antibacterial killing of beta-lactam antibiotics might be maximal when the antibiotic is 4–5 × MIC [36]. A long time-interval above such a higher threshold might also be positive to reduce the development of antibiotic resistance [3]. However, it should be noted that even higher target ranges (i.e., 100 %fT??4 × MIC) might be useful to maximize the antimicrobial effect and minimize the development of resistance in these patients [3, 19]. Target attainment might also vary in dependence of microorganism idiosyncrasies such as inoculum [37]. Future prospective interventional studies are required to investigate which target ranges are associated with the best outcome for patients, thereby also minimizing the risk for the development of antibiotic resistance in the intensive care unit.

Outcome parameters such as alive ICU-free days, 28-day mortality, or occurrence of adverse reactions did not correlate with PIP levels in all patients. However, because of the patient number and the heterogeneous patient group used, short-term effects of antimicrobial therapy on alive ICU-free days and 28-day mortality might not be visible in this group. We therefore also correlated CRP concentrations in both all patients and in the outcome group. In the outcome group, we found a negative correlation of CRP concentrations at day 4 with PIP trough levels (p??0.05). Furthermore, a trend to a faster CRP decrease in cases of high PIP trough levels was also observed at day 3 and 4 (both p??0.1, Table 3). We thought that it might be important to define an outcome group, because we wanted to evaluate only relevant patients, where PIP-TAZ was the only antimicrobial therapy effective against the causative pathogens. As it has not yet been shown in the literature for piperacillin that target attainment of our targets correlates with a positive clinical or microbiological outcome, the targets used in our study have to be regarded only as a limited approach. However, our data indicate that at least higher concentrations of PIP might be associated with a faster decrease of the inflammation parameter CRP.

This study has some limitations. (1) The data were drawn from a single center. Indeed, PIP pharmacokinetics might be different among patients from different ICUs. To minimize this limitation, we included a relatively high number of patients and allowed a high heterogeneity of patient characteristics to best represent the full spectrum of different patients in ICUs. (2) We did not measure the unbound fraction of PIP from stored serum samples, e.g., via centrifugal filter devices. Indeed, it remains unclear if PIP might be bound to the filter in a relevant percentage and if freeze-thaw cycles might alter the protein-binding fraction. However, we considered a fixed protein-binding fraction of 30 % in the definitions of the target ranges. This may be a problem in individual patients, because unbound PIP fractions may differ substantially in individual critically ill patients, especially in those with altered protein levels. (3) Higher thresholds of the target ranges were not defined, as no robust data are existent. However, definition of such thresholds may also be important because it has been shown that the neurotoxicity of some beta-lactam antibiotics may be probably underestimated in critically ill patients [38]. (4) Only two different dosing schemes were evaluated. Some authors have used higher doses for critically ill patients [6, 14]; however, the dosage schemes used in our study are still recommended by the Food and Drug Administration and in expert information. Prolonged or continuous infusions have also been recommended [34]. Indeed, it has been shown by Abdul-Aziz et al. that prolonged infusion of piperacillin can be associated with a better outcome [39] but no difference in the clinical outcome was observed in other studies [40, 41]. Moreover, some authors also write that a prolonged or continuous infusion eventually promotes that resistant mutants are selectively amplified, and that these mutants therefore might become the dominant bacterial population [2] (5) Finally, we did not use pharmacokinetic modeling to describe %T??90 mg/L or trough levels. Such models are especially relevant if only few samples per patient are available or if concentrations around the peak value have to be described. We did not perform pharmacokinetic modeling because we collected multiple blood samples between consecutive antibiotic administrations (Additional file 1), and we only described the %T??90 mg/L and the trough levels, which were always on the descending concentration time curves. Indeed, imprecise individual predictions might occasionally occur with pharmacokinetic modeling if the individual estimated parameter values vary substantially from those of the typical population, which might be a problem in a highly heterogeneous patient group as in our study [42].