Time above the MIC of piperacillin/tazobactam as a predictor of outcome in pseudomonas aeruginosa bacteraemia

3 Pseudomonas aeruginosa bacteraemia is an infection associated with high mortality 4 rate. Piperacillin + Tazobactam is a β-lactam β-lactamase inhibitor combination that 5 is frequently used for the management of Pseudomonas aeruginosa . The 6 pharmacokinetic-pharmacodynamic index associated with in-vitro maximal bacterial 7 killing for Piperacillin + Tazobactam is the percentage of time at which the free 8 fraction concentration is above the minimum inhibitory concentration (%fT>MIC). 9 However, the precise %fT>MIC target associated with improved clinical outcomes is 10 unknown. 11 The aim of this study was to investigate the correlation between survival of patients 12 with Pseudomonas aeruginosa bacteraemia and the threshold of Piperacillin + 13 Tazobactam %fT>MIC. This retrospective study included all adult patients 14 hospitalized over an 82 month period with Pseudomonas aeruginosa bacteraemia, 15 and treated with Piperacillin + Tazobactam . Patients with a polymicrobial infection 16 or those who died within 72 hours of culture, were excluded. The %fT>MIC of 17 Piperacillin + Tazobactam associated with in-hospital survival was derived using 18 Classification and Regression Tree analysis. After screening 270 patients, 78 were 19 eligible for inclusion in the study; 18% died during hospitalization. Classification and 20 Regression Tree analysis identified %fT>MIC >60.68% as associated with improved 21 survival, and this remained statistically significant after controlling for clinical 22 covariates (OR= 7.74, 95% CI 1.32-45.2). In conclusion, the findings recommend 23 dosing of Piperacillin + Tazobactam with the aim of achieving a pharmacodynamic 24 target of at least 60% fT>MIC in these patients. 25 3 Introduction 26 27 Pseudomonas aeruginosa (PA) bacteraemia is a common hospital-acquired 28 infection (1), associated with increased mortality, ranging between 18-61% (2). 29 Early appropriate antimicrobial therapy is associated with improved survival (3–8). 30 Piperacillin and the combination of piperacillin and tazobactam (TZP) are extensively 31 used in the treatment of infectious diseases in critically ill patients; specifically, when 32 PA is the causative pathogen (8). Protein binding for piperacillin ranges between 2033 30% and for tazobactam it is approximately 30% (9, 10). Various population 34 pharmacokinetic studies have suggested that the main covariates influencing the 35 volume of distribution and clearance of TZP were weight and creatinine clearance, 36 respectively (11–16). The usual dose of TZP is 4.5g three times daily for most 37 infections and may be increased to 4.5g four times daily in severe health-care 38 acquired infections (17), and in PA infections, as recommended by the European 39 Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and 40 Laboratory Standards Institute (CLSI). Dose adjustments for renal impairment vary 41 widely between sources (9, 17, 18). There is no sufficient data regarding dosing 42 regimens that will achieve pharmacokinetic and pharmacodynamic (PK-PD) targets 43 that are correlated with improved clinical outcomes. 44 Piperacillin, like other β-lactams, exhibits a time-dependent bactericidal activity. In45 vitro and animal studies suggest that the PK-PD parameter for β-lactams that is 46 most predictive of microbiological efficacy, is the percentage of time between doses 47 at which the free fraction concentration remains above the minimum inhibitory 48 concentration (%fT>MIC) (19). For piperacillin, a PK-PD target of 50% fT>MIC is 49 often cited based on studies on other penicillins (20), for example ticarcillin (21, 22). 50 4 There is only one study that reported a relationship between bacterial kill and 51 %fT>MIC with significant thresholds of 27% for bacteriostasis and 75% for 52 bactericidal activity (23). 53 Very few studies have tried to correlate %fT>MIC with clinical outcomes. Among 54 them is the DALI trial, a prospective multinational study that included 361 critically ill 55 patients who were treated with a β-lactam (24). This study concluded that for all β56 lactams a %fT>MIC >50% is associated with better outcomes. Other studies dealt 57 specifically with Meropenem and neutropenic patients (25), and cephalosporins (26, 58 27). 59 Moreover, the need for a clinically driven %fT>MIC target is augmented by the fact 60 that β-lactams display indirect antimicrobial properties. These properties cannot be 61 identified by the standard in-vivo susceptibility testing and include synergy with 62 cationic host defence peptides and action as immune-adjuvants (28). The use of an 63 in-vitro derived PK-PD target for any antimicrobial without clinical validation is highly 64 problematic (29). This observation is especially true in the case of βlactams. 65 The aim of this study was to investigate the correlation between the 66 concentration/time profile of TZP and clinical outcomes in patients with PA 67 bacteraemia. Additionally the study aimed to find if there is a threshold of %fT>MIC 68 that is associated with improved survival at 30 days. 69