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Purpose To assess efficacy and safety of a new dry powder formulation of inhaled colistimethate sodium in patients with cystic fibrosis (CF) aged ≥6 years with chronic Pseudomonas aeruginosa lung infection. Study design and methods A prospective, centrally randomised, phase III, open-label study in patients with stable CF aged ≥6 years with chronic P aeruginosa lung infection. Patients were randomised to Colobreathe dry powder for inhalation (CDPI, one capsule containing colistimethate sodium 1 662 500 IU, twice daily) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution (TIS). Study duration was 24 weeks. Results 380 patients were randomised. After logarithmic transformation of data due to a non-normal distribution, adjusted mean difference between treatment groups (CDPI vs TIS) in change in forced expiratory volume in 1 s (FEV1% predicted) at week 24 was −0.98% (95% CI −2.74% to 0.86%) in the intention-to-treat population (n=373) and −0.56% (95% CI −2.71% to 1.70%) in the per protocol population (n=261). The proportion of colistin-resistant isolates in both groups was ≤1.1%. The number of adverse events was similar in both groups. Significantly more patients receiving CDPI rated their device as ‘very easy or easy to use’ (90.7% vs 53.9% respectively; p<0.001). Conclusion CDPI demonstrated efficacy by virtue of non-inferiority to TIS in lung function after 24 weeks of treatment. There was no emergence of resistance of P aeruginosa to colistin. Overall, CDPI was well tolerated. Trial Reg No EudraCT 2004-003675-36.

Background: This study assessed the ease of use of tobramycin inhalation powder (TIP) administered via T-326 inhaler versus tobramycin inhalation solution (TIS) and colistimethate sodium (COLI), both administered via nebulizers, for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF). Methods: A real-world, open-label, crossover, interventional phase IV study was conducted in CF patients aged ⩾6 years with forced expiratory volume in 1 second (FEV1) ⩾25% to ⩽90% predicted. Patients were assigned to one of the three treatment arms in Cycle 1; all patients received TIP in Cycle 2. Each cycle consisted of 28 days on and 28 days off the treatment. Results: A total of 60 patients [mean (standard deviation) age, 27.6 (8.4) years] were allocated to three treatment arms [TIS/TIP (n = 14); COLI/TIP (n = 28); TIP/TIP (n = 18)] in Cycle 1. The mean total administration time, which included device setup and cleaning, in Cycle 1 versus Cycle 2 for TIS/TIP, COLI/TIP, and TIP/TIP arms were 37.0 versus 5.0 min, 16.4 versus 3.8 min, and 4.2 versus 3.4 min, respectively. The difference in mean total administration time was significantly shorter in Cycle 2 than in Cycle 1 for TIS/TIP (p = 0.0112) and COLI/TIP (p = 0.0016) arms. Overall, 12 patients were found to have contaminated devices across the two treatment cycles. In the TIP/TIP arm, no contamination of the T-326 inhaler was observed in either cycle. Treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication and ACCEPT® questionnaire, was better overall for TIP compared with TIS and COLI. There were no unexpected adverse events and most were mild or moderate in intensity. Conclusion: The T-326 inhaler used to deliver TIP was easy to use, required shorter total administration time, and was much less frequently contaminated than the nebulizers. The safety findings observed for TIP were generally consistent with its established safety profile.

Nephrotoxicity has seriously affected the clinical application of colistin methanesulphonate (CMS). Colistin B methanesulphonate (CMS-E2) is a novel polymyxin developed and aimed to have lower nephrotoxicity. This study aimed to investigate the relationships between pharmacokinetics (PK) and nephrotoxicity of CMS and CMS-E2 and compare the toxicity of the two drugs in rats. Rats were treated intraperitoneally with a single dose of saline, CMS [10, 20 mg/kg of colistin base activity (CBA)], and CMS-E2 (20, 40 mg/kg CBA). An LC-MS/MS method was developed to determine plasma and renal tissue concentrations of CMS/CMS-E2 and colistin/colistin B. The severity of renal injuries was examined both biochemically and histologically. The PK-toxicodynamic (TD) model was evaluated to characterize the PK of CMS/CMS-E2 and colistin/colistin B in plasma as well as its relationship with nephrotoxicity. Creatinine (CR) and blood urea nitrogen (BUN) profiles were described using an indirect link PK-TD model, with linear-effect relationship. Both the slope between colistin or colistin B concentrations in the effect compartment and CR, BUN was significantly lower for CMS-E2 compared with CMS (CR: P  = 0.027, BUN: P  = 0.043). The concentrations of colistin and colistin B in kidneys were correlated with CR, BUN values, and histologic examination scores. The regression coefficient of CMS-E2 between the colistin B concentrations in renal tissues and CR, BUN values were lower, as well (CR: P  = 0.003, BUN: P  = 0.001). The renal injuries induced by CMS and CMS-E2 lagged behind the change of plasma colistin or colistin B concentrations and correlated to those in kidneys. CMS-E2 showed significantly lower nephrotoxicity compared to CMS in vivo.

Nephrotoxicity was assessed in 173 critically ill patients receiving intravenous colistin or polymyxin B; it occurred in 60.4% and 41.8%, respectively. Further investigation is necessary to elucidate the reason for the difference in nephrotoxicity observed between the groups and to assess the impact of severity of illness and dosing/administration.

Background The nephrotoxicity associated with polymyxins is a critical safety concern in clinical practice. The aim of this study was to compare the nephrotoxicity of patients treated with colistin sulfate (CS) and colistin methanesulfonate (CMS). Methods Data on inpatients who received intravenous colistin (CS) or colistin methanesulfonate (CMS) for over 72 h were collected from January to December 2023. The primary outcome was the incidence of acute kidney injury (AKI) associated with polymyxins, while the secondary outcome was 30-day all-cause mortality. Furthermore, Cox proportional hazard regression analysis was used to identify the risk factors of polymyxin-induced AKI. Results A total of 291 patients were included in this study. The overall incidence of AKI was significantly higher in patients who received CMS compared to those who received CS in the unmatched cohort (29.70% vs. 7.37%) and in the propensity score matching (PSM) cohort (26.30% vs. 10.00%), respectively. However, 30-day all-cause mortality was significantly higher in the CS cohort than in the CMS cohort before (27.37% vs. 15.84%) and after (33.75% vs. 15.00%) PSM. CMS therapy and a lower baseline estimated glomerular filtration rate (eGFR) were identified as independent risk factors for polymyxin-induced AKI. Conclusions This was the first study to investigate the nephrotoxicity difference between CS and CMS to our best knowledge. In this study, the incidence rate of AKI was significantly lower in the CS cohort compared with the CMS cohort, however, 30-day all-cause mortality rate was significantly higher in the CS cohort than in the CMS cohort. Further validation of these findings requires more prospective multicentre studies with a large sample size.

The incidence of acute renal failure, defined by the risk, injury, or failure criteria of the RIFLE criteria (risk, injury, failure, loss, and end-stage kidney disease), in 66 patients who received colistimethate sodium was 45%, and 21% of patients stopped therapy because of nephrotoxicity. The RIFLE criteria should be used in the future to allow for comparison of nephrotoxicity among studies.

To evaluate the cost-effectiveness of two available options for inhaled antibiotic treatment for patients with Bronchiectasis (BE) with Pseudomonas aeruginosa (PA) infections from the perspective of China's healthcare system. A four-state Markov model was developed over a one-year horizon to simulate the cost-effectiveness of two inhaled antibiotic strategies: Tobramycin inhalation solution (TIS) versus nebulized colistimethate sodium (CMS). The inputs for the model were derived from phase III clinical trials and published literature, with cost data were sourced from public and real-world databases, etc. The incremental cost-effectiveness ratio (ICER) was assessed, setting the willingness-to-pay threshold at one times the per capita GDP of China. Scenario and sensitivity analyses were performed to explore the impact of uncertainties in input parameters. Over a one-year period, TIS was found to dominate CMS, resulting in a cost saving of CNY 41,109.53 (USD 5,689.27) and an increase of 0.0048 quality-adjusted life years (QALYs) per patient. Sensitivity analyses confirmed the robustness of these findings, which remained consistent under various scenarios. TIS reduces healthcare costs and improves clinical outcomes compared to CMS in managing BE with PA infections in China. This study supports the inclusion of TIS in clinical guidelines for managing BE with PA infections, considering both economic benefits and health outcomes.

Background. Gram-negative bacteria susceptible only to colistin (COS) are emerging causes of severe nosocomial infections, reviving interest in the use of colistin. However, consensus on the most effective way to administer colistin has not yet been reached. Methods. All patients who had sepsis due to COS gram-negative bacteria or minimally susceptible gram-negative bacteria and received intravenous colistimethate sodium (CMS) were prospectively enrolled. The CMS dosing schedule was based on a loading dose of 9 MU and a 9-MU twice-daily fractioned maintenance dose, titrated on renal function. For each CMS course, clinical cure, bacteriological clearance, daily serum creatinine clearance, and estimated creatinine clearance were recorded. Results. Twenty-eight infectious episodes due to Acinetobacter baumannii (46.4%), Klebsiella pneumoniae (46.4%), and Pseudomonas aeruginosa (7.2%) were analyzed. The main types of infection were bloodstream infection (64.3%) and ventilator-associated pneumonia (35.7%). Clinical cure was observed in 23 cases (82.1%). Acute kidney injury developed during 5 treatment courses (17.8%), did not require renal replacement therapy, and subsided within 10 days from CMS discontinuation. No correlation was found between variation in serum creatinine level (from baseline to peak) and daily and cumulative doses of CMS, and between variation in serum creatinine level (from baseline to peak) and duration of CMS treatment. Conclusions. Our study shows that in severe infections due to COS gram-negative bacteria, the high-dose, extended-interval CMS regimen has a high efficacy, without significant renal toxicity.

Colistin, a multidrug-resistant gram-negative bacterial infection medication, has been associated with renal impairment and failure. Trans-sodium crocetinate (TSC), a saffron-derived chemical recognized for its antioxidant and nephroprotective properties, was studied in this study to determine its potential to alleviate the nephrotoxic effects of colistin. Forty-two male Wistar rats were randomly classified into seven groups ( n = 6): (1) control (normal saline, 12 days, i.p.), (2) colistin (22 mg/kg, 7 days, i.p.), (3–5) colistin + TSC (25, 50, and 100 mg/kg, 12 days, i.p., starting from 5 days before colistin), (6) TSC (100 mg/kg, 12 days, i.p.), (7) colistin + vitamin E (100 IU/kg, 12 days, i.p). On day 13, the rats were euthanized and the serum content of creatinine, BUN, Na + , and K + , as well as oxidative stress (GSH, MDA, SOD, CAT), inflammatory (IL-1β), apoptotic (Bax, Bcl-2, caspase-3, 8, 9), and autophagy (Beclin-1, LC3) markers, NGAL, and histopathological changes in the kidney were measured. Colistin significantly increased serum creatinine, BUN, MDA, IL-1β, caspase-3,8,9, Bax, Beclin-1, LC3, and NGAL levels in kidney tissue. It also caused inflammation, focal necrosis of tubular epithelial cells, protein cast, and acute tubular necrosis. Furthermore, colistin decreased SOD, CAT, GSH, and Bcl-2 levels. TSC and vitamin E administration along with colistin restored most of the alterations induced by colistin. Overall, it could be concluded that colistin induces oxidative stress, inflammation, autophagy, and apoptosis, which can cause kidney injury. However, TSC can also be used as a therapeutic agent to reduce injuries caused by colistin. Graphical Abstract TSC, trans-sodium crocetinate; BUN, blood nitrogen urea; Cr, creatinine; GFR, glomerular filtration rate