[40, 41, 44, 45, 50] Owing to a lack of uniform diagnostic criteria and end-point selection in nosocomial pneumonia trials, close attention must be paid to identify differences that could influence the outcome of trials.[51, 52] One of the retrospective cohort studies compared clinical outcomes of piperacillin�Ctazobactam by EI and bolus dosing in critically ill patients with Pseudomonas aeruginosa infections. In that study, patients receiving EI had a lower 14?day mortality rate and hospital length of stay compared with patients receiving bolus dosing when the Acute Physiology and Chronic Health Evaluation (APACHE) II score was >?17. No difference in clinical outcome was observed when the APACHE score was <?17. Similar results have been reported in other retrospective cohort studies comparing the two administration modalities among patients with ventilator-associated pneumonia. There are several <a href="http://www.selleckchem.com/products/PD-98059.html
">PD98059 mouse issues with the randomized studies conducted thus far that complicate interpretation and mean that a definitive prospective clinical outcome study is still required before it can be concluded that all critically ill patients must receive ��-lactams by prolonged infusion. First, many of the studies do not include patients that are representative of the wider population, with most studies having a patient sample with mortality rates far lower than is reported in the critical care literature. Second, most of the bacterial isolates in the randomized studies were highly susceptible, Decitabine ic50 Tryptophan synthase
meaning that low concentrations achieved during the bolus dosing may still be adequate enough to exceed pathogen MICs for a sufficient period of the dosing interval. This issue was emphasized in retrospective cohort studies that described a higher probability of clinical cure with CI of meropenem or piperacillin�Ctazobactam when the isolated pathogen had a higher MIC, of 8 or 16?mg/L.[44, 45] Third, many of the studies used higher doses in the bolus dosing group and the lower dose may have predisposed to less effective concentrations that may have masked any potential benefits of continuous infusion.[30, 32, 36, 37] Fourth, only a few studies[31, 32, 37] have included the concurrent PK/PD analysis to confirm whether any of the administration modalities were reaching the PD targets. Finally, in most of the studies, patients were given combination therapy with non-��-lactam antibiotics. Although this may reflect clinical practice, it may have also augmented the clinical effects of either bolus or CI strategies.[30, 31, 34, 36-38] Considering the methodological limitations of the clinical studies available to date, a large multicentre randomized controlled study is needed to confirm the benefits of a prolonged infusion approach for ��-lactam antibiotics in critically ill patients.