Initiation of Vancomycin Therapy and the First Therapeutic Drug Monitoring

There have been a limited number of studies in Latvia that were focused on vancomycin therapeutic drug monitoring (TDM), especially during the initiation phase of the therapy. The aim of this study was to investigate details of vancomycin therapy in its initiation phase and to analyse the results of the first therapeutic drug monitoring within a multidisciplinary hospital in Latvia. A retrospective observational study was performed in a multidisciplinary hospital in Latvia. Adult patients hospitalised in an intensive care unit and undergoing vancomycin therapy with at least one concentration measurement were included in this study. Data about patients included demographic and clinical data, renal function prior to initiation of vancomycin therapy, data about vancomycin therapy, data about the first TDM, and details about the first measurement of vancomycin concentration according to determined reference range — subtherapeutic, therapeutic and supratherapeutic levels. A total of 60 intensive care unit patients who received vancomycin with at least one concentration measurement were included in this study. Fifty-eight patients received vancomycin as intermittent intravenous infusion. The first measurement of concentration was taken before the 3rd–4th vancomycin dose in 38.3% cases, and in 33.3% cases — before the 2nd dose. Sampling to determine the concentration within 30 minutes before vancomycin administration was performed in zero cases. In 35% cases, sampling was done within 2–5 hours before vancomycin administration and in 23.3% — immediately after or within a few hours after vancomycin infusion. Twelve (20%) patients had a concentration in the subtherapeutic level, and 14 (23.3%) patients had concentrations above the therapeutic level. In 42.8% of patients who had concentrations in supratherapeutic level, sampling had been performed immediately after or within several hours after vancomycin administration. The first concentration measurement was performed more than one hour before an infusion in all cases. Data on concentrations and timing were not adequate to perform appropriate therapy modification. Interpretation of dosing regime and concentration results were not adequate, and therefore correct modification of vancomycin therapy was often not possible. Routines of correct dosing regime and the 1st TDM during the initiation phase of vancomycin therapy can be improved.

1733. Voriconazole Prophylaxis Following Allogeneic Hematopoietic Stem Cell Transplant: How Much Is Enough, Are Low Voriconazole Levels Associated With Opportunistic Infections, and What Are the Reasons for Discontinuation?

Background Patients who undergo allogeneic hematopoietic stem cell transplantation (alloHSCT) are at increased risk for invasive fungal infections with associated high morbidity and mortality that necessitates the use of prophylactic antifungals. Voriconazole is commonly used for prophylaxis, but there are no recommendations for therapeutic drug monitoring. The purpose of this study was to characterize voriconazole therapeutic drug monitoring and associated outcomes in this patient population. Methods AlloHSCT patients receiving voriconazole prophylaxis at the University of Alabama at Birmingham Hospital between March 2015 and March 2018 were included in the analysis. Serum voriconazole levels (SVL) were evaluated to determine what percentage of patients achieved prophylactic or therapeutic concentrations. Incidence of invasive fungal infections (IFI) and voriconazole discontinuation was also assessed. Results Voriconazole prophylaxis was used in 151 of 162 alloHSCT patients, and 120 patients (79%) had SVL drawn correctly (≥4 days after initiation of course). We found that 35 (29%) patients achieved a subtherapeutic level (<0.5 μg/mL), 17 (14%) prophylactic level (0.5 to 1 μg/mL), 68 (57%) therapeutic level (1 to 5.5 μg/mL), and no patients achieved a supratherapeutic level (level ≥5.5 μg/mL). Voriconazole prophylaxis was discontinued early in 60 of 151 patients. Most common etiologies for discontinuation included liver function test abnormalities (44%) and encephalopathy (21%). The average SVL was 1.2 μg/mL in those requiring discontinuation. Four patients (3%) developed an IFI while receiving prophylactic voriconazole, of which only 1 had subtherapeutic level. Conclusion Even though approximately one-third of patients achieved a subtherapeutic SVL, there was no correlation with breakthrough IFI. There was also no linear correlation between SVL and risk of adverse effects requiring discontinuation. Our observational data do not support a need for therapeutic drug monitoring in alloHSCT patients receiving prophylactic voriconazole. Disclosures All authors: No reported disclosures.

Status Epilepticus in Children With Epilepsy: The Role of Antiepileptic Drug Levels in Prevention

Objectives. To determine the association between subtherapeutic antiepileptic drug (AED) levels or AED withdrawal and status epilepticus (SE) in children with epilepsy. Methods. We studied the AED levels at the time of SE in 51 consecutive children with epilepsy. Information about prior AED levels, possible etiology of seizures, and acute precipitants was extracted from medical records. Results. The mean age at the time of SE was 5.7 years (range, 3 months through 18 years). Forty-three patients had history of remote insult, five had history of progressive encephalopathy, and three patients were classified as idiopathic. At the time of SE all AED levels were therapeutic in 34 (66%) patients and at least one level was therapeutic in 42 (82%) patients. All levels were subtherapeutic in 9 (18%) patients. Four patients had their AED reduced or discontinued less than 1 week before SE. Twelve patients with therapeutic AED levels on their most recent clinic visit had at least one subtherapeutic level at the time of SE. Eight (16%) patients were febrile and one was hyponatremic. Of the 51 patients, 31 (61%) had no obvious explanation for the development of SE, as all known AEDs were therapeutic and there were no known acute insults. Conclusions. Neurologically abnormal children with preexisting epilepsy are at high risk for development of SE despite having therapeutic AED levels at that time. Acute precipitants of SE, such as fever or AED withdrawal, may play a role in inducing SE only in a minority of patients.

Interleukin 1-induced, T cell-mediated regression of immunogenic murine tumors. Requirement for an adequate level of already acquired host concomitant immunity.

Intraperitoneal injection of human rIL-1 in a dose of 0.5 microgram daily for 5 d, or 1 microgram daily for 3 d, was capable of causing complete regression of immunogenic SA1 sarcoma growing subcutaneously in syngeneic or semisyngeneic mice. Higher doses of IL-1 were not more therapeutic against the SA1 sarcoma, but needed to be given to cause complete regression of the immunogenic L5178Y lymphoma. On the other hand, the P815 mastocytoma was much less responsive to IL-1 therapy, in that it failed to undergo complete regression in response to doses of IL-1 capable of causing regression of the L5178Y lymphoma. IL-1 caused regression of the SA1 sarcoma when given on days 6-8 of tumor growth, but not when given on days 1-3. This refractoriness of a small tumor to IL-1 therapy suggests that the antitumor action of IL-1 is based on an underlying host-immune response that is not generated until after day 3 of tumor growth. Direct evidence for the participation of host immunity in IL-1-induced tumor regression was supplied by results showing that IL-1 was not therapeutic against the SA1 sarcoma growing in T cell-deficient (TXB) mice, unless these mice were first infused with Ly-2+ and L3T4+ T cells from donor mice bearing an established SA1 sarcoma. In contrast, normal T cells, or T cells from donor mice bearing a YAC-1 lymphoma, failed to provide TXB recipients with the ability to cause regression of their SA-1 sarcoma in response to IL-1 treatment. The results are in keeping with the interpretation that exogenous IL-1, by augmenting the production of tumor-sensitized T cells, converts a subtherapeutic level of host immunity to a therapeutic level. The results suggest, in addition, that IL-1 only stimulates the replication of T cells that are already engaged in the antitumor immune response.