Extremely high unbound flucloxacillin concentrations in a patient with acute septic renal failure during continuous venovenous hemofiltration: Therapeutic drug monitoring to optimize treatment.

A 75-year-old female orthopedic patient with spondylodiscitis was admitted to the intensive care unit, where she developed severe acute renal injury (AKI) due to a Staphylococcus aureus bloodstream infection. Continuous venovenous hemofiltration (CVVH) was initiated as renal replacement therapy. According to physician experience and based on (inter)national guidelines and the severity of the infection, treatment with intravenous (IV) flucloxacillin at an initial continuous dose of 9 g/24h was started. The dose was increased to 12 g/24h because endocarditis could not be excluded. Therapeutic drug monitoring (TDM) was used to monitor flucloxacillin levels which are related to antibiotic efficacy and toxicity. Total and unbound flucloxacillin concentrations were measured following 24 hours of continuous infusion at three time points before regional citrate anticoagulation (RCA)-CVVH was initiated, at three time points in plasma, pre-filter, and post-filter, and in ultrafiltrate samples during RCA-CVVH treatment and 1 day following cessation of CVVH treatment. Extremely high total (up to 299.8 mg/L) and unbound (up to 155.1 mg/L) flucloxacillin concentrations were found in the plasma. This led to a dose decrease to 6 g/24h and subsequently to 3 g/24h. Antimicrobial target attainment against S. aureus was achieved by dosing IV flucloxacillin based on TDM. Based on these findings, we conclude that current dosing guidelines for flucloxacillin during renal replacement therapy need revision. We suggest a starting dose of 4 g/24h, which should be adjusted based on the TDM of the unbound flucloxacillin concentration.

Study protocol for the randomized controlled EVA (early vascular adjustments) trial: tailored treatment of mild hypertension in pregnancy to prevent severe hypertension and preeclampsia.

BACKGROUND: In contrast to severe gestational hypertension, it is questioned whether antihypertensive medication for mild to moderate gestational hypertension prevents adverse maternal and offspring outcomes. Hypertensive drugs halve the risk of severe hypertension, but do not seem to prevent progression to preeclampsia or reduce the risk of complications in offspring. In fact, beta-blockers, a first line therapy option, are suspected to impair foetal growth. Disappointing effects of antihypertensive medication can be anticipated when the pharmacological mode of action does not match the underlying haemodynamic imbalance. Hypertension may result from 1) high cardiac output, low vascular resistance state, in which beta blockade is expected to be most effective, or 2) low cardiac output, high vascular resistance state where dihydropyridine calcium channel blockers or central-acting alpha agonists might be the best corrective medication. In the latter, beta-blockade might be maternally ineffective and even contribute to impaired foetal growth by keeping cardiac output low. We propose a randomized controlled trial to determine whether correcting the haemodynamic imbalance in women with mild to moderate hypertension reduces the development of severe hypertension and/or preeclampsia more than non-pharmacological treatment does, without alleged negative effects on foetal growth. METHODS: Women diagnosed with mild to moderate hypertension without proteinuria or signs of other organ damage before 37 weeks of pregnancy are invited to participate in this randomized controlled trial. Women randomized to the intervention group will be prescribed tailored antihypertensive medication, using a simple diagnostic and treatment algorithm based on the mean arterial pressure/heart rate ratio, which serves as an easy-to-determine proxy for maternal circulatory state. Women randomized to the control group will receive non-pharmacological standard care according to national and international guidelines. In total, 208 women will be randomized in a 1:1 ratio. The primary outcome is progression to severe hypertension and preeclampsia and the secondary outcomes are adverse maternal and neonatal outcomes. DISCUSSION: This trial will provide evidence of whether tailoring treatment of mild to moderate gestational hypertension to the individual haemodynamic profile prevents maternal disease progression. TRIAL REGISTRATION: NCT02531490 , registered on 24 August 2015.