Evaluation of Linezolid Pharmacokinetics in Critically Ill Obese Patients with Severe Skin and Soft Tissue Infections.

Linezolid standard dosing is fixed at 600 mg every 12 h (q12h) for adults. Literature suggests critically ill, obese patients require higher doses. The study aim is 2-fold: (i) to describe linezolid pharmacokinetics (PK), and (ii) to evaluate if PK/pharmacodynamic (PD) target attainment is achieved with standard dosing in critically ill, obese patients with severe skin and soft tissue infections (SSTIs). Adult patients with a body mass index (BMI) of ≥30 kg/m2 and receiving intravenous (i.v.) linezolid from August 2018 to April 2019 were eligible for consent in this prospective study. Severe SSTIs were defined as necrotizing fasciitis, myonecrosis, or SSTI with sepsis syndrome. Four blood samples were collected at steady state at 1, 3, 5 h postinfusion and as a trough. Target attainment was defined as achieving area under the concentration-time curve from 0 to 24 h to MIC (AUC0-24h/MIC) of ≥100 h*mg/liter. Monte Carlo simulations were used to determine the probability of target attainment (PTA). Eleven patients were included in the study. The median BMI was 45.7 kg/m2, and median total body weight (TBW) was 136.0 kg. Seven patients received standard linezolid doses, and four received 600 mg q8h. A one-compartment model described linezolid PK. Based on AUC0-24h/MIC targets, for noncirrhotic patients at 140 kg, the PTA with standard linezolid doses was 100%, 98.8%, 34.1%, and 0% for MICs of 0.5, 1, 2, and 4 mg/liter, respectively. In conclusion, target attainment of ≥90% is not achieved with standard linezolid doses for noncirrhotic patients ≥140 kg with MICs of ≥2 mg/liter. This study adds to accumulating evidence that standard linezolid doses may not be adequate for all patients.

Statin gap in patients living with HIV: assessing dose appropriateness.

OBJECTIVES: Patients living with HIV (PLWH) are predisposed to atherosclerotic cardiovascular disease (ASCVD), resulting in concomitant antiretroviral and statin use. A statin prescribing gap for PLWH has been reported, but appropriateness of statin selection and dosing (ASD) has not been described. METHODS: This is a comparative, retrospective study reviewing ASD in PLWH vs. uninfected patients at two outpatient clinics within an academic medical centre. Adults > 21 years old indicated for statin therapy were included. The primary outcome was percentage of PLWH prescribed an appropriately dosed statin, accounting for clinical- and patient-related variables, compared with uninfected patients. The secondary outcome was to identify patient characteristics associated with inappropriately dosed statins. RESULTS: After propensity score matching, 879 PLWH and 879 uninfected patients were included for analysis. Fewer PLWH (27.8%, n = 244) were prescribed an ASD compared with uninfected patients (40.5%, n = 356, P < 0.001). Similar rates of statin omission were seen in both populations (P = 0.11). More PLWH received too low a dose compared with the uninfected population (P < 0.0064). There were lower ASD rates in PLWH for subgroups of patients with clinical ASCVD (P = 0.00013) and 10-year ASCVD risk ≥7.5% (P = 0.00055), but not in patients with low-density lipoprotein cholesterol ≥190 mg/dL or diabetes. CONCLUSIONS: Although a statin gap exists in both PLWH and uninfected patients, the clinical significance may be greater for PLWH given the increased risk of ASCVD. This study confirms a larger statin gap in PLWH, particularly when underdosing of statin medications is considered. Additional analysis is warranted to investigate reasons for the ASD gap and beneficial clinical interventions.

The value of fixed rasburicase dosing versus weight-based dosing in the treatment and prevention of tumor lysis syndrome.

BACKGROUND: Rasburicase is a recombinant urate oxidase enzyme used for the treatment and prevention of tumor lysis syndrome. Our objective was to assess the efficacy of indication-based, low-dose rasburicase administration compared to the Food and Drug Administration-approved weight-based dosing. METHODS: This was a retrospective cohort study utilizing data from a tertiary medical center including patients admitted from 2012 to 2016, who received at least one dose of rasburicase. The primary outcome was achieving a uric acid level less than 7.5 mg/dl after a single dose of rasburicase in the preprotocol (Food and Drug Administration-approved weight-based dosing) and postprotocol (indication-based, low-dose) groups. Secondary outcomes included the change in uric acid levels between the pre- and postprotocol groups, adherence to the new institutional protocol, need for repeat rasburicase doses, and a cost analysis. RESULTS: Sixty-four patients received at least one dose of rasburicase between 1 January 2012 and 1 December 2016. Twenty-seven (79.4%) doses in the preprotocol group and 28 (82.4%) doses in the postprotocol group successfully achieved a uric acid level less than 7.5 mg/dl after a single dose of rasburicase (p=1.000). The average total monthly cost of rasburicase was reduced by 59.9% after adoption of the new protocol. CONCLUSIONS: Indication-based, low-dose rasburicase displayed significantly more value when compared to weight-based dosing as shown by achieving cost savings without compromising clinical efficacy.

Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: A case report and review of the literature.

Asparaginase is a chemotherapeutic agent that is commonly used in combination with other medications for the treatment of acute lymphoblastic leukemia. An adverse effect of asparaginase includes hepatotoxicity, which can lead to severe liver failure and death. Several reports have documented successful treatment of asparaginase-induced hepatotoxicity using levocarnitine (l-carnitine) and vitamin B complex. Herein, we report a patient with acute lymphoblastic leukemia that experienced acute liver injury following pegaspargase administration. Our patient was successfully treated with l-carnitine and vitamin B complex for 8 days and achieved recovery of hepatic function. Furthermore, we review the current literature and provide a recommendation on a regimen that can be used as an option for the treatment of asparaginase-induced hepatic injury.

Synergistic inhibition of the lethal fungal pathogen Batrachochytrium dendrobatidis: the combined effect of symbiotic bacterial metabolites and antimicrobial peptides of the frog Rana muscosa.

A powerful mechanism for protection against disease in animals is synergy between metabolites present in the natural microbiota of the host and antimicrobial peptides (AMPs) produced by the host. We studied this method of protection in amphibians in regard to the lethal disease chytridiomycosis, which is caused by Batrachochytrium dendrobatidis (Bd). In this study, we show that the AMPs of Rana muscosa, as well as the metabolite 2,4-diacetylphloroglucinol (2,4-DAPG) from Pseudomonas fluorescens, a bacterial species normally found on the skin of R. muscosa, were inhibitory to the growth of Bd in vitro. When both AMPs and 2,4-DAPG were used in growth inhibition assays, they worked synergistically to inhibit the growth of Bd. This synergy resulted in reduced minimum concentrations necessary for inhibition by either 2,4-DAPG or AMPs. This inhibitory concentration of AMPs did not inhibit the growth of a P. fluorescens strain that produced 2,4-DAPG in vitro, although its growth was inhibited at higher peptide concentrations. These data suggest that the AMPs secreted onto frog skin and the metabolites secreted by the resident beneficial bacteria may work synergistically to enhance protection against Bd infection on amphibian skin. These results may aid conservation efforts to augment amphibian skins' resistance to chytridiomycosis by introducing anti-Bd bacterial species that work synergistically with amphibian AMPs.

Evaluation of Intra-Operative Topical Vancomycin and the Incidence of Acute Kidney Injury.

Background: Intra-operative topical vancomycin (VAN) is a strategy used to prevent surgical site infections (SSI). Although evidence supporting efficacy in SSI prevention is evolving, data describing safety, specifically acute kidney injury (AKI), are limited. The purpose of this study was to determine AKI incidence in patients who received intra-operative topical VAN. Patients and Methods: This is a retrospective study of adult inpatient encounters in which topical VAN was administered intra-operatively as powder/paste, beads, rods/cement/spacers, or unspecified topical route from February to July 2018. Patients were excluded for AKI or renal replacement therapy (RRT) at baseline or ≤2 serum creatinine (SCr) values post-surgery. The primary outcome was AKI incidence after intra-operative topical VAN, defined as increase in SCr ≥50% or 0.5 mg/dL from baseline or RRT initiation. Secondary outcomes included analysis of AKI risk factors and SSI incidence. Acute kidney injury risk factors were analyzed using multivariable logistic regression. Results: Five hundred thirty-four patient encounters met study criteria. Powder/paste were the most common topical VAN formulations (44.8%) with median doses of 2,000 (range, 1,000-26,000) mg. Acute kidney injury incidence was 8.8%. Independent risk factors for AKI were higher Charlson comorbidity index (adjusted odds ratio [aOR], 1.20 [range, 1.06-1.36]), concomitant systemic VAN (aOR, 2.44 [range, 1.29-4.58]), and doubling of total topical VAN dose (aOR, 1.51 [range, 1.13-2.03]). Conclusions: The incidence of AKI with intra-operative topical VAN is comparable to reported rates as systemic VAN. Clinicians may consider total topical VAN dose and concomitant systemic VAN to limit AKI incidence with topical VAN use.

The effect of veno-arterial extracorporeal oxygenation and nasogastric tube administration on the pharmacokinetic profile of abacavir, lamivudine and dolutegravir: a case report.

BACKGROUND: Pharmacokinetic (PK) changes can affect antiretroviral (ARV) systemic exposure for critically ill patients living with HIV (CI-PLWH). Studies to guide ARV adjustments in this population are limited. METHODS: A PK analysis was conducted in a 44-year-old CI-PLWH who presented for a heart and lung transplant on veno-arterial extracorporeal membrane oxygenation (VA ECMO). Home ARV therapy (ART) of co-formulated abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) was continued. ARV serum concentrations were obtained during and after VA ECMO. Two blood levels were drawn at 1 h, for maximum serum concentration (Cmax) and a serum trough (Ct). ARVs were given as a single tablet crushed via nasogastric tube. RESULTS: Area under the concentration-time curve (AUC0-t) was calculated using non-compartmental analysis. Cmax and AUC0-t were higher during VA ECMO compared with post-decannulation. The Cmax of ABC was >2.5-fold higher than the mean in the reference. Cmax and Ct post VA ECMO were within range of referenced literature for all ARVs. Cmax and AUC0-t of DTG post VA ECMO was approximately four- to fivefold lower than referenced literature. HIV virological suppression was maintained throughout the hospitalization. CONCLUSIONS: ART adjustments would not be required for this patient. Additional studies are needed to assess effects of VA ECMO and crushed tube administration of ARVs in CI-PLWH.

Evaluation of Addition of Intravenous Metronidazole to Oral Vancomycin Therapy in Critically Ill Patients with Non-Fulminant Severe Clostridioides difficile Infection.

BACKGROUND: Data on the impact of combination therapy (intravenous metronidazole [IV MTZ] plus oral vancomycin [PO VAN]) on clinical outcomes in intensive care unit (ICU) patients with severe non-fulminant Clostridioides difficile infection (CDI), including NAP1-positive samples, are lacking. METHODS: Retrospective observational cohort of adult patients who developed CDI in the ICU diagnosed with severe non-fulminant CDI who received PO VAN. Patients with an order for IV MTZ started within 72 hours of PO VAN and who received at least 72 hours of combined therapy composed the combination therapy group. A subset of patients had stool samples collected for NAP1 testing. An additional subset was matched by Acute Physiology and Chronic Health Evaluation (APACHE) II scores. The primary outcome was inpatient all-cause mortality within 30 days of CDI diagnosis. RESULTS: A total of 138 patients were included with 60 (43.5%) patients in the combination group. Compared with the PO VAN group, those in the combination group had higher white blood cell counts at diagnosis (15.9 [interquartile range (IQR) 10.2-21.1] vs 20.9 [IQR 16.2-29] cells/mm3 , p<0.001), respectively. Overall inpatient mortality was higher in the combination group, but 30-day mortality was not significantly different between groups (12.8% monotherapy vs 18.3% combination, p=0.371). This finding was the same for the 96 patients in the APACHE II-matched subgroup, 14.6% monotherapy versus 18.8% combination, p=0.785. NAP1 testing was completed in 42 patients; 11 were positive (26.2%). Patients who were NAP1 positive were more likely to receive IV MTZ (54.5% vs 19.4%, p=0.026). CONCLUSION: Compared with PO VAN, combination therapy with IV MTZ was not associated with better clinical outcomes in severe non-fulminant CDI in ICU patients.