Abstract
PurposeStandard dosing and intermittent bolus application (IB) are important risk factors for pharmacokinetic (PK) target non-attainment during empirical treatment with β-lactams in critically ill patients, particularly in those with sepsis and septic shock. We assessed the effect of therapeutic drug monitoring-guided (TDM), continuous infusion (CI) and individual dosing of piperacillin/tazobactam (PIP) on PK-target attainment in critically ill patients.MethodsThis is a retrospective, single-center analysis of a database including 484 patients [933 serum concentrations (SC)] with severe infections, sepsis and septic shock who received TDM-guided CI of PIP in the intensive care unit (ICU) of an academic teaching hospital. The PK-target was defined as a PIP SC between 33 and 64 mg/L [fT > 2–4 times the epidemiological cutoff value (ECOFF) of Pseudomonas aeruginosa (PSA)].ResultsPK-target attainment with standard dosing (initial dose) was observed in 166 patients (34.3%), whereas only 49 patients (10.1%) demonstrated target non-attainment. The minimum PK-target of ≥ 33 mg/L was overall realized in 89.9% (n = 435/484) of patients after the first PIP dose including 146 patients (30.2%) with potentially harmful SCs ≥ 100 mg/L. Subsequent TDM-guided dose adjustments significantly enhanced PK-target attainment to 280 patients (62.4%) and significantly reduced the fraction of potentially overdosed (≥ 100 mg/L) patients to 4.5% (n = 20/449). Renal replacement therapy (RRT) resulted in a relevant reduction of PIP clearance (CLPIP): no RRT CLPIP 6.8/6.3 L/h (median/IQR) [SCs n = 752, patients n = 405], continuous veno-venous hemodialysis (CVVHD) CLPIP 4.3/2.6 L/h [SCs n = 160, n = 71 patients], intermittent hemodialysis (iHD) CLPIP 2.6/2.3 L/h [SCs n = 21, n = 8 patients]). A body mass index (BMI) of > 40 kg/m2 significantly increased CLPIP 9.6/7.7 L/h [SC n = 43, n = 18 patients] in these patients. Age was significantly associated with supratherapeutic PIP concentrations (p < 0.0005), whereas high CrCL led to non-target attainment (p < 0.0005). Patients with target attainment (33–64 mg/L) within the first 24 h exhibited the lowest hospital mortality rates (13.9% [n = 23/166], p < 0.005). Those with target non-attainment demonstrated higher mortality rates (≤ 32 mg/L; 20.8% [n = 10/49] ≥ 64 mg/L; 29.4% [n = 79/269]).ConclusionTDM-guided CI of PIP is safe in critically ill patients and improves PK-target attainment. Exposure to defined PK-targets impacts patient mortality while lower and higher than intended SCs may influence the outcome of critically ill patients. Renal function and renal replacement therapy are main determinants of PK-target attainment. These results are only valid for CI of PIP and not for prolonged or intermittent bolus administration of PIP.
Highlights
BackgroundEarly effective antibiotic treatment is a fundamental mainstay in sepsis therapy and should be initiated as soon as possible [1, 2] to reduce patient mortality [2,3,4]. β-lactams like PIP are frequently used antibiotics for empiric treatment of severe infections in the ICU [5]
Β-lactams and PIP especially are prone to rapid changes in renal function and volume of distribution both of which frequently occur in patients with sepsis and septic shock [11]
CI infusion represents a reasonable approach of customized drug dosing in the ICU as to extend the time that the unbound fraction of PIP remains above the pathogen-specific minimum inhibitory concentration (MIC) [6, 7, 13, 14] up to 100% of the dosing interval [10, 12, 15]
Summary
BackgroundEarly effective antibiotic treatment is a fundamental mainstay in sepsis therapy and should be initiated as soon as possible [1, 2] to reduce patient mortality [2,3,4]. β-lactams like PIP are frequently used antibiotics for empiric treatment of severe infections in the ICU [5]. Β-lactams like PIP are frequently used antibiotics for empiric treatment of severe infections in the ICU [5]. Intermittent bolus applications (IB) of standard doses are recognized as a main contributor for target non-attainment and potentially unfavorable patient outcome [9, 10]. Given their hydrophilic properties, β-lactams and PIP especially are prone to rapid changes in renal function and volume of distribution both of which frequently occur in patients with sepsis and septic shock [11]. The demand for dose optimization and TDM-guided individual dosing strategies grows [12, 23, 24]
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