O254 1-Hour Oral Session PK/PD-Based Optimized Broad-Spectrum Beta-Lactam Therapy

O254 1-hour Oral Session PK/PD-based optimized broad-spectrum beta-lactam therapy Risk factors for not reaching 100 % time over actual or estimated minimal inhibitory concentrations in intensive care unit patients on broad spectrum beta-lactam antibiotics Hanna Woksepp1, Anita Hällgren2, Sten Borgström3, Anna Wimmerstedt4, Anna Oscarsson Tibblin5, Fredrik Kullberg4, Peter Nordlund6, Maj-Lis Lindholm3, Jonas Bonnedahl7, Björn Carlsson8, Thomas Schön*9 1Department of Clinical Microbiology, Kalmar County Hospital, Kalmar County Hospital, Kalmar, Sweden 2Deparment of Infectious Diseases, Linköping University, Linköping, Sweden 3Department of Intensive Care, Kalmar County Hospital, Kalmar, Sweden 4Department of Intensive Care, Växjö Hospital, Växjö, Sweden 5Department of Intensive Care, Linköping University, Linköping, Sweden 6Department of Intensive Care, Ryhov Hospital, Jönköping, Sweden 7Kalmar County Hospital and Linnaeus University, Department of Infectious Diseases and Centre for Ecology and Evolution in Microbial Model Systems, Kalmar, Sweden 8Department of Clinical Pharmacology, Linköping University, Linköping, Sweden 9Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden Background: Recent studies indicate that patients in the intensive care unit (ICU) are at risk for low levels of broad spectrum beta-lactam antibiotics which may affect treatment outcome and selection of drug resistance. Potential reasons include the increased volume of distribution and renal clearance in ICU patients. However, due to a variation in pharmacokinetics and limited knowledge of the individual risk factors, it is difficult to predict who will suffer from a low antibiotic exposure. Most studies on ICU patients use 100% time over minimal inhibitory concentration (MIC) as the treatment target. However, the actual MICs are rarely determined and instead estimated surrogate cut-offs are used. Thus, our aim was to identify risk factors for achieving free serum concentrations 100% time over the actual and the estimated MIC (100% fT>MIC) in ICU patients treated with broad spectrum beta-lactam antibiotics. Material/methods: In a prospective multicenter study, 111 consecutive ICU patients who were treated with cefotaxime (CTX; n=38), piperacillin (PIP; n=49) or meropenem (MER; n=24) were included at four sites. Extensive clinical and laboratory data were collected including days at ICU and 30 day mortality. None of the sites used continuous infusion for administration and serum samples were taken on ICU admission and on two consecutive days just prior to the next antibiotic dose was given. Serum concentrations of CTX, PIP and MER were analyzed by mass spectrometry (LC-MS/MS), at the Karolinska University Hospital, Huddinge, Sweden. The actual MIC of relevant bacteria, as evaluated by an infectious disease specialist blinded to the results, was determined (E-test). The serum concentrations were compared to the actual MIC if available or to the estimated “worst-case” MIC for susceptible bacteria for CTX, MER or PIP corresponding to 4, 2 and 16 mg/L respectively. Results: The median concentrations of CTX, MER and PIP were 2 (IQR: 0.5-7), 6 (2-14) and 26 (5- 63) mg/L. The rate of patients not reaching 100% fT above the actual MIC was 24% (10/42) and 46% (51/111) for the estimated MIC. Factors significantly associated to not reaching 100% fT above the estimated MIC included lower age, increased GFR, low SAPS-score as well as a lower use of ionotropic drugs or continuous renal replacement therapy (CRRT). No risk factors were identified for not reaching 100% fT above the actual MIC. Conclusions: When the actual MIC could be determined, the rate of ICU patients with an exposure of broad spectrum beta-lactam antibiotics below the target were considerably lower than when an arbitrary, estimated cut-off was used. Although several risk factors such as an increased glomerular filtration rate could be identified in patients not reaching the target in relation to the estimated MIC, no such factors could be identified when the actual MIC was considered. .

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