Evaluation of target attainment of oral posaconazole suspension in immunocompromised children

Background Posaconazole is a broad-spectrum antifungal that is not licensed for use in children <13 years of age. Despite this and by necessity, it is used extensively in paediatric hospitals for prophylaxis of invasive fungal disease. Objectives To determine whether initial prophylactic dosing recommendations attain a posaconazole plasma concentration of ≥700 ng/mL in immunocompromised children <13 years of age. Patients and methods We performed a retrospective study of immunocompromised children <13 years of age receiving posaconazole suspension prophylaxis at a starting dose of 5 mg/kg every 8 h for ≥7 days and who had a posaconazole concentration measured after ≥7 days. Posaconazole plasma concentrations and rate of breakthrough infection were recorded. Results A total of 70 patients were included with a median age of 5 years (range 3 months to 12 years). The mean posaconazole plasma concentration was 783.4 ng/mL (IQR 428.3–980 ng/mL) and the percentage of patients with a posaconazole plasma concentration ≥700ng/mL was 47.9%. Patients who were on a proton pump inhibitor, a histamine H2 antagonist or metoclopramide, had mucositis or were enterally fed had a lower posaconazole plasma concentration compared with patients without these co-administered drugs/mucositis/enteral feeding (542.3 versus 1069.8 ng/mL; P<0.001). The breakthrough invasive fungal infection rate was 4.3% (3/70). Conclusions The studied 5 mg/kg posaconazole suspension every 8 h resulted in target concentrations in only 47.9% of patients and further studies looking at newer posaconazole formulations are needed.

Neuroimmune communication in the submucous plexus of guinea pig colon after sensitization to milk antigen

We investigated electrical and synaptic behavior of neurons in the colonic submucous plexus during exposure to beta-lactoglobulin in guinea pigs sensitized by ingestion of milk. Microelectrodes were used to record electrical and synaptic behavior in neurons from milk-sensitized and nonsensitized age-matched animals during exposure to beta-lactoglobulin. Neurons in sensitized animals were hyperexcitable. Application of the histamine H2 antagonist cimetidine reversed the hyperexcitability, suggesting endogenously released histamine as one of the responsible factors. Antigenic exposure suppressed stimulus-evoked nicotinic cholinergic fast excitatory postsynaptic potentials (EPSPs). This was blocked by the selective histamine H3 antagonist burimamide. Suppression of the EPSPs resulted from presynaptic inhibition of acetylcholine release. Increased neuronal excitability and suppression of synaptic transmission was only found in milk-sensitized intestine, not in the intestine from age-matched nonsensitized animals. We concluded that signaling from mucosal mast cells to the enteric nervous system is important in colonic defense against antigenic threats. Histamine is a paracrine messenger in the communication network.