High target attainment for ß-lactam antibiotics in intensive care unit patients when actual minimum inhibitory concentrations are applied.

Patients in the intensive care unit (ICU) are at risk for suboptimal levels of ß-lactam antibiotics, possibly leading to poor efficacy. Our aim was to investigate whether the actual minimum inhibitory concentration (MIC) compared to the more commonly used arbitrary epidemiological cut-off values (ECOFFs) would affect target attainment in ICU patients on empirical treatment with broad-spectrum ß-lactam antibiotics and to identify risk factors for not reaching target. In a prospective, multicenter study, ICU patients ≥18 years old and treated with piperacillin/tazobactam, meropenem, or cefotaxime were included. Clinical and laboratory data were recorded. Serum trough antibiotic levels from three consecutive days were analyzed by liquid chromatography-mass spectrometry (LC-MS). The target was defined as the free trough concentration above the MIC (100% fT>MIC). MICECOFF was used as the target and, when available, the actual MIC (MICACTUAL) was applied. The median age of the patients was 70 years old, 52% (58/111) were males, and the median estimated glomerular filtration rate (eGFR) was 48.0 mL/min/1.73 m2. The rate of patients reaching 100% fT > MICACTUAL was higher (89%, 31/35) compared to the same patients using MICECOFF (60%, p = 0.002). In total, 55% (61/111) reached 100% fT > MICECOFF. Increased renal clearance was independently associated to not reaching 100% fT > MICECOFF. On repeated sampling, >77% of patients had stable serum drug levels around the MICECOFF. Serum concentrations of ß-lactam antibiotics vary extensively between ICU patients. The rate of patients not reaching target was markedly lower for the actual MIC than when the arbitrary MIC based on the ECOFF was used, which is important to consider in future studies.

Associated antimicrobial resistance in Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes.

Associated resistance to four to six related and unrelated antimicrobial agents was investigated in consecutive non-duplicate isolates of Escherichia coli (n = 39 425), Pseudomonas aeruginosa (n = 1070), Staphylococcus aureus (n = 7489), Streptococcus pneumoniae (n = 1604) and Streptococcus pyogenes (n = 2531). In all species, high proportions (76.5-88.9%) of isolates were susceptible to all the drugs investigated. Irrespective of species, isolates resistant to one drug were more likely to be resistant to any of the other drugs than were susceptible isolates. Thus, trimethoprim resistance in E. coli was 38.4% among ampicillin-resistant vs. 3.9% among ampicillin-susceptible isolates, and erythromycin resistance in Strep. pneumoniae was 41% among doxycycline-resistant vs. 1% among doxycycline-susceptible isolates. In all five species investigated, there was also significant associated resistance among unrelated drugs, highlighting the fact that resistance development occurs primarily among bacteria already resistant to one or more antimicrobial agents. For the clinician, pronounced resistance associations mean that when empirical therapy fails because of resistance, there is a reduced chance of choosing an alternative successful empirical agent. For the epidemiologist, who uses routine clinical susceptibility data to describe resistance development, resistance associations mean that if the dataset contains results for isolates selected on the basis of their susceptibility to another drug, structurally related or not, a bias of false resistance is introduced.