Probability of pharmacological target attainment with flucloxacillin in Staphylococcus aureus bloodstream infection: a prospective cohort study of unbound plasma and individual MICs.

OBJECTIVES: MSSA bloodstream infections (BSIs) are associated with considerable mortality. Data regarding therapeutic drug monitoring (TDM) and pharmacological target attainment of the ß-lactam flucloxacillin are scarce. PATIENTS AND METHODS: We determined the achievement of pharmacokinetic/pharmacodynamic targets and its association with clinical outcome and potential toxicity in a prospective cohort of 50 patients with MSSA-BSI. Strain-specific MICs and unbound plasma flucloxacillin concentrations (at five different timepoints) were determined by broth microdilution and HPLC-MS, respectively. RESULTS: In our study population, 48% were critically ill and the 30 day mortality rate was 16%. The median flucloxacillin MIC was 0.125 mg/L. The median unbound trough concentration was 1.7 (IQR 0.4-9.3), 1.9 (IQR 0.4-6.2) and 1.0 (IQR 0.6-3.4) mg/L on study day 1, 3 and 7, respectively. Optimal (100% fT>MIC) and maximum (100% fT>4×MIC) target attainment was achieved in 45 (90%) and 34 (68%) patients, respectively, throughout the study period. Conversely, when using the EUCAST epidemiological cut-off value instead of strain-specific MICs, target attainment was achieved in only 13 (26%) patients. The mean unbound flucloxacillin trough concentration per patient was associated with neurotoxicity (OR 1.12 per 1 mg/L increase, P = 0.02) and significantly higher in deceased patients (median 14.8 versus 1.7 mg/L, P = 0.01). CONCLUSIONS: Flucloxacillin pharmacological target attainment in MSSA-BSI patients is frequently achieved when unbound flucloxacillin concentrations and strain-specific MICs are considered. However, currently recommended dosing regimens may expose patients to excessive flucloxacillin concentrations, potentially resulting in drug-related organ damage.

Screening of middle ear effusion for the common sinus pathogen Bipolaris.

Recently, a third of middle ear effusions have been shown to harbor fungal DNA by polymerase chain reaction (PCR). This suggests that fungi, in addition to being an important sinus pathogen, may also play an important role in acute and serous otitis media. Bipolaris is an important sinus pathogen whose role in infections of the ear is unknown. In this study, we assessed if Bipolaris DNA was present in 19 middle ear effusions that were PCR positive for the presence of fungi. Primer pair specific for Bipolaris spicifera was tested against DNA from various bacterial and fungal species to demonstrate its specificity and was subsequently used on DNA isolated from effusions to determine if Bipolaris-specific DNA was present. None of the nineteen specimens tested positive for Bipolaris by PCR or standard culture technique. This suggests that while fungi may play an important role in otitis media, this study does not support a role for Bipolaris as a middle ear pathogen and may reflect regional differences in its prevalence.