Continuous infusion of cefiderocol in a critically ill patient with continuous venovenous haemofiltration

Cefiderocol is a broad-spectrum cephalosporin antibiotic and is indicated in patients with difficult-to-treat Gram-negative bacterial infections. Cefiderocol is applied as a 2–4-times daily prolonged 3-h infusion. The therapeutic target of cefiderocol suggests that continuous infusion (CI) may be advantageous, since it is more likely to achieve 100% of time of the unbound concentration above the minimal inhibitory concentration (MIC). However, limited information on cefiderocol as CI has been assessed. We present a case of a critically ill 37-year-old woman with continuous venovenous haemofiltration (CVVH) treated with a CI of cefiderocol for multidrug-resistant Pseudomonas aeruginosa. She received 4 g per 24 h, in accordance with the recommendations for the total daily dose during CVVH with an effluent flow rate of 2.1–3 L/h. We evaluated intraperitoneal, plasma arterial pre- and postfilter and ultrafiltrate (urine) total cefiderocol concentrations and discussed the pharmacokinetics in respect to the CVVH settings. The predicted unbound plasma concentrations during CI resulted in 6.8–9.5-fold higher concentrations than the adopted MIC of 2 mg/L for cefiderocol against P. aeruginosa. The optimal time of the unbound concentration >MIC target of cefiderocol was met during the sampling period, suggesting adequate exposure during the total treatment period. The obtained intraperitoneal concentration indicated adequate cefiderocol exposure at the site of infection. Continuous infusion of 4 g cefiderocol per 24 h led to sufficient plasma concentrations in our anuric critically ill patient treated with CVVH. This case is supportive to the use of cefiderocol as continuous infusion

Tacrolimus Variability and Clinical Outcomes in the Early Post-lung Transplantation Period: Oral Versus Continuous Intravenous Administration

Background and Objective: High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx. Methods: Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission. Results: We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9–14.6; p < 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI − 11.3 to − 3.4; p < 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8–1.8; p = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0–2.3; p = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar. Conclusions: Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection

Tacrolimus Variability and Clinical Outcomes in the Early Post-lung Transplantation Period: Oral Versus Continuous Intravenous Administration

Background and Objective: High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx. Methods: Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission. Results: We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9–14.6; p < 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI − 11.3 to − 3.4; p < 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8–1.8; p = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0–2.3; p = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar. Conclusions: Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection

Influence of a strict glucose protocol on serum potassium and glucose concentrations and their association with mortality in intensive care patients

INTRODUCTION: Tight glucose control therapy (TGC) has been implemented to control hyperglycemia in ICU patients. TGC may also influence serum potassium concentrations. We therefore investigated the influence of TGC on both serum glucose and serum potassium concentrations and associated mortality. METHOD: We performed a retrospective analysis including all patients admitted to the ICU of a tertiary hospital for 24 hours or more and with at least three serum glucose and serum potassium concentrations between 1999-2001 (conventional period), 2002-2006 (implementation period) or 2007-2009 (TGC period). Segmented regression analysis was used to estimate changes in outcomes that occurred after the intervention controlling for pre-intervention trends. Means and standard deviations (SDs) of serum glucose and serum potassium concentrations, and rate of severe hypoglycemia (≤ 2.2 mmol/L) and hypokalemia (≤ 3 mmol/L), were compared between the TGC and conventional period. RESULTS: Although mean serum glucose concentrations dropped 2.1 mmol/L (95% CI =-1.8 to -2.3 mmol/L, p<0.002), mean serum potassium concentrations did not change (absolute increase 0.02 mmol/L; 95% CI = -0.06 to 0.09 mmol/L, p=0.64). The rate of severe hypoglycemia increased with 5.9% (95% CI=-3.0 to -8.9, p<0.002), but the rate of hypokalemia remained equal (absolute reduction 4.8%; 95% CI = -11.1% to 1.5%, p=0.13). The SD of serum glucose concentrations within a patient did not change, while the SD of serum potassium concentrations even decreased 0.04 mmol/L (95% CI = -0.01 to -0.07, p = 0.01). ICU mortality decreased but this decrease was not significant (absolute difference -3.63%; 95% CI = -9.33 to 2.09, p = 0.20). Mean serum glucose concentrations, mean serum potassium concentrations and SDs of both serum glucose and serum potassium concentrations were all independently associated with ICU mortality. Highest mortality rates were seen at both the lowest and highest mean values (U/J-shaped association) and mortality rates increased with increasing variability (SDs) for both serum glucose and serum potassium concentrations. CONCLUSION: Our study shows that a TGC was not associated with an increased risk of serum potassium related events. Low and high mean values and high variability of both serum glucose and serum potassium concentrations are predictors for high ICU mortality

Influence of a strict glucose protocol on serum potassium and glucose concentrations and their association with mortality in intensive care patients

INTRODUCTION: Tight glucose control therapy (TGC) has been implemented to control hyperglycemia in ICU patients. TGC may also influence serum potassium concentrations. We therefore investigated the influence of TGC on both serum glucose and serum potassium concentrations and associated mortality. METHOD: We performed a retrospective analysis including all patients admitted to the ICU of a tertiary hospital for 24 hours or more and with at least three serum glucose and serum potassium concentrations between 1999-2001 (conventional period), 2002-2006 (implementation period) or 2007-2009 (TGC period). Segmented regression analysis was used to estimate changes in outcomes that occurred after the intervention controlling for pre-intervention trends. Means and standard deviations (SDs) of serum glucose and serum potassium concentrations, and rate of severe hypoglycemia (≤ 2.2 mmol/L) and hypokalemia (≤ 3 mmol/L), were compared between the TGC and conventional period. RESULTS: Although mean serum glucose concentrations dropped 2.1 mmol/L (95% CI =-1.8 to -2.3 mmol/L, p<0.002), mean serum potassium concentrations did not change (absolute increase 0.02 mmol/L; 95% CI = -0.06 to 0.09 mmol/L, p=0.64). The rate of severe hypoglycemia increased with 5.9% (95% CI=-3.0 to -8.9, p<0.002), but the rate of hypokalemia remained equal (absolute reduction 4.8%; 95% CI = -11.1% to 1.5%, p=0.13). The SD of serum glucose concentrations within a patient did not change, while the SD of serum potassium concentrations even decreased 0.04 mmol/L (95% CI = -0.01 to -0.07, p = 0.01). ICU mortality decreased but this decrease was not significant (absolute difference -3.63%; 95% CI = -9.33 to 2.09, p = 0.20). Mean serum glucose concentrations, mean serum potassium concentrations and SDs of both serum glucose and serum potassium concentrations were all independently associated with ICU mortality. Highest mortality rates were seen at both the lowest and highest mean values (U/J-shaped association) and mortality rates increased with increasing variability (SDs) for both serum glucose and serum potassium concentrations. CONCLUSION: Our study shows that a TGC was not associated with an increased risk of serum potassium related events. Low and high mean values and high variability of both serum glucose and serum potassium concentrations are predictors for high ICU mortality

Oral dexamethasone pulse therapy versus daily prednisolone in sub-acute onset myositis, a randomised clinical trial

To determine if high-dose pulsed dexamethasone is more effective and safer than daily high-dose prednisolone in treatment-naive adult patients with inflammatory myopathies (sporadic inclusion body myositis excluded) we performed a multicenter, double-blind randomised controlled clinical trial with 18 months follow-up. Sixty-two patients were randomised into 28-day cycles of oral high-dose dexamethasone or daily high-dose prednisolone. Primary outcome measures included (1) seven point composite score of six clinically relevant outcomes and (2) (time-to) remission and (time-to) relapse. No difference between both treatment groups on the composite score was found. Side-effects occurred significantly less frequently in the dexamethasone group. Median time to relapse was 60 (2.9) weeks in the prednisolone and 44 (4.7) weeks in the dexamethasone group (log-rank test p = 0.03). In conclusion, pulsed high-dose oral dexamethasone is not superior to daily prednisolone as first-line treatment of idiopathic inflammatory myopathies, but is a good alternative by causing substantially fewer side-effects. (C) 2010 Elsevier B.V. All rights reserve