Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m² for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (Css) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45⁻95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; p < 0.001). Mean Css was 0.9 (0.2⁻2.9) mg/L, and Css was <2 mg/L in 50 patients (83.3%). Clinical cure was achieved in 43 (72.9%) patients. Worsened renal function at EOT was present in 20 (33.9%) patients and was reversible in 10 (52.6%). The CMS dosages used in this cohort were almost half those currently recommended. The mean achieved Css were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments.

Colistin plasma concentrations are not associated with better clinical outcomes in patients with pneumonia caused by extremely drug-resistant Pseudomonas aeruginosa.

IMPORTANCE: In some cases, colistin is the only treatment option for infections caused by the very drug-resistant Pseudomonas aeruginosa. However, in the past decade, there have been questions concerning its pharmacokinetics and concentration at the site of infection. In this scenario, its use in a difficult-to-treat infection like pneumonia is currently debatable. This is a clinical pharmacokinetic study of colistin in patients with multidrug-resistant P. aeruginosa pneumonia. Our findings demonstrate that colistin exposure is associated with worse clinical outcomes rather than better clinical outcomes, implying that other therapeutic options should be explored in this clinical setting.

Biological agents for rheumatic diseases in the outbreak of COVID-19: friend or foe?

BACKGROUND: The recent outbreak of COVID-19 has raised concerns in the rheumatology community about the management of immunosuppressed patients diagnosed with inflammatory rheumatic diseases. It is not clear whether the use of biological agents may suppose a risk or protection against SARS-CoV-2 infection; however, it has been suggested that severe respiratory forms of COVID-19 occur as a result of exacerbated inflammation status and cytokine production. This prompted the use of interleukin 6 (IL-6) (tocilizumab and sarilumab) and IL-1 inhibitors (anakinra) in severe COVID-19 disease and more recently JAK1/2 inhibitor (baricitinib). Therefore, patients with rheumatic diseases provide a great opportunity to learn about the use of biological agents as protective drugs against SARS-CoV-2. OBJECTIVES: To estimate COVID-19 infection rate in patients treated with biological disease-modifying antirheumatic drugs (bDMARDs) for inflammatory rheumatic diseases (RMD), determine the influence of biological agents treatment as risk or protective factors and study the prognosis of patients with rheumatic diseases receiving biological agents compared to the general population in a third-level hospital setting in León, Spain. METHODS: We performed a retrospective observational study including patients seen at our rheumatology department who received bDMARDs for rheumatic diseases between December 1st 2019 and December 1st 2020, and analysed COVID-19 infection rate. All patients who attended our rheumatology outpatient clinic with diagnosis of inflammatory rheumatic disease receiving treatment with biological agents were included. Main variable was the hospital admission related to COVID-19. The covariates were age, sex, comorbidities, biological agent, duration of treatment, mean dose of glucocorticoids and need for intensive care unit . We performed an univariate and multivariate logistic regression models to assess risk factors of COVID-19 infection. RESULTS: There were a total of 4464 patients with COVID-19 requiring hospitalisation. 40 patients out of a total of 820 patients with rheumatic diseases (4.8%) receiving bDMARDs contracted COVID-19 and 4 required hospital care. Crude incidence rate of COVID-19 requiring hospital care among the general population was 3.6%, and it was 0.89% among the group with underlying rheumatic diseases. 90% of patients receiving bDMARDS with COVID-19 did not require hospitalisation. Out of the 4464 patients, 869 patients died, 2 of which received treatment with biological agents. Patients with rheumatic diseases who tested positive for COVID-19 were older (female: median age 60.8 IQR 46-74; male: median age 61.9 IQR 52-70.3) than those who were negative for COVID-19 (female: median age 58.3 IQR 48-69; male: median age 56.2 IQR 47-66), more likely to have hypertension (45% vs 26%, OR 2.25 (CI 1.18-4.27),p 0.02), cardiovascular disease (23 % vs 9.6%, OR 2.73 (1.25-5.95), p 0.02), be smokers (13% vs 4.6%, OR 2.95 (CI 1.09-7.98), p 0.04), receiving treatment with rituximab (20% vs 8%, 2.28 (CI 1.24-6.32), p 0.02) and a higher dose of glucocorticoids (OR 2.5 (1.3-10.33, p 0.02) and were less likely to be receiving treatment with IL-6 inhibitors (2.5% vs 14%, OR 0.16, (CI 0.10-0.97, p 0.03). When exploring the effect of the rest of the therapies between groups (affected patients vs unaffected), we found no significant differences in bDMARD proportions. IL-1 inhibitors, IL-6 inhibitors, JAK inhibitors and belimumab-treated patients showed the lowest incidence of COVID-19 among adult patients with rheumatic diseases. We found no differences in sex or rheumatological disease between patients who tested positive for COVID-19 and patients who tested negative. CONCLUSIONS: Overall, the use of biological disease-modifying antirheumatic drugs (bDMARDs) does not associate with severe manifestations of COVID-19. Patients with rheumatic disease diagnosed with COVID-19 were more likely to be receiving a higher dose of glucocorticoids and treatment with rituximab. IL-6 inhibitors may have a protective effect.