Rates Of Nephrotoxicity Research Articles

A Retrospective Study Evaluating the Safety and Clinical Impact of High Dose (6.75grams) Piperacillin-Tazobactam Dosing in Critically Ill Obese Patients for Pneumonia.

Background: Piperacillin-tazobactam (PTZ) demonstrates time-dependent bactericidal activity, potentially increasing the need for higher dosing in obese and critically ill patients. However, limited information is available on the safety of higher dosing strategies. Objective: To evaluate the safety and clinical impact of high dose 6.75g IV PTZ for the treatment of pneumonia in critically ill, obese (≥120kg) patients vs standard dose 4.5g IV PTZ. Methods: Retrospective, cohort study, multicenter in health-system consisting of four acute-care teaching hospitals. Adult patients weighing at least 120kg on PTZ for pneumonia in the intensive care unit (ICU) from January 2013 to September 2018 were included. The primary outcome of the study was acute nephrotoxicity defined as initiation of renal replacement therapy and/or serum creatinine increase within 48hours of last PTZ dose. Secondary outcomes included thrombocytopenia, 14-day all-cause mortality, and ICU length of stay (LOS). Results: One hundred thirty-six patients were included with 52 and 84 in 4.5g PTZ and 6.75g PTZ respectively. The rate of acute nephrotoxicity was comparable between cohorts (50% 4.5g vs 40.5% 6.75g, P = 0.277). High dose PTZ was not independently associated with acute nephrotoxicity after control for selected confounders. All secondary outcomes were similar. Concomitant vancomycin and calculated supratherapeutic vancomycin area under curve were not independently associated with increased nephrotoxicity. Conclusions: High dose PTZ was not associated with increased acute nephrotoxicity, thrombocytopenia, 14-day all-cause mortality, or ICU LOS. Additionally, more robust trials are needed to fully assess the clinical impact of 6.75g PTZ dosing for critically ill, obese patients, for pneumonia.

Treatment success prediction in patients with methicillin-resistant coagulase-negative staphylococci infections, using vancomycin AUC24/MIC ratio: a multicentre retrospective cohort study.

Although vancomycin is commonly used to treat methicillin-resistant coagulase-negative staphylococci (MRCoNS) infections, there are no clear guidelines for the optimal 24 h AUC24/MIC ratio. This study aimed to determine the target AUC24/MIC ratio associated with vancomycin-treated MRCoNS infection outcomes. This multicentre retrospective cohort study included adult patients who received vancomycin for ≥5 days for bloodstream infections caused by MRCoNS between January 2018 and December 2023. Primary outcome was treatment success, defined as a composite of survival beyond 30 days, clinical success and microbiological eradication. Secondary outcomes included 30-day mortality, clinical success, microbiological eradication and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cut-off for treatment success. Multivariate regression analysis was used to determine the association between AUC24/MIC and outcomes. This study included 147 patients. ROC analysis identified a target AUC24/MIC ≥373 for treatment success. The overall treatment success rate (70.1%) was significantly higher in the above-average AUC24/MIC cut-off group (83.1%) than that in the below AUC24/MIC cut-off group (57.9%). Multivariate analysis confirmed that AUC24/MIC ≥373 was an independent predictor (adjusted OR = 10.227; 95% CI = 3.585-29.171). The 30-day mortality and microbiological eradication rates differed significantly between the below- and above-cut-off groups, whereas nephrotoxicity rates were comparable among the groups. In treating MRCoNS infections, vancomycin AUC24/MIC ratio ≥373 was independently associated with favourable treatment outcomes. However, further prospective studies are required to confirm this target owing to the retrospective nature of this study.

Volumetric modulated arc therapy total body irradiation improves toxicity outcomes compared to 2D total body irradiation.

Volumetric modulated arc therapy (VMAT) total body irradiation (TBI) allows for greater organ sparing with improved target coverage compared to 2D-TBI. However, there is limited evidence of whether improved organ sparing translates to decreases in toxicities and how its toxicities compare to those of the 2D technique. We aimed to compare differences in toxicities among patients treated with TBI utilizing VMAT and 2D techniques. A matched-pair single-institution retrospective analysis of 200 patients treated with TBI from 2014 to 2023 was performed. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and compared using log-rank tests. Differences in characteristics and toxicities between the VMAT and 2D cohorts were compared using Fisher's exact test. Of the 200 patients analyzed, 100 underwent VMAT-TBI, and 100 underwent 2D-TBI. The median age for VMAT-TBI and 2D-TBI patients was 13.7 years and 16.2 years, respectively (p = 0.25). In each cohort, 53 patients were treated with myeloablative regimens (8-13.76 Gy), and 47 were treated with non-myeloablative regimens (2-4 Gy). For the entire VMAT-TBI cohort, lung Dmean, kidney Dmean, and lens Dmax were spared to 60.6% ± 5.0%, 71.0% ± 8.5%, and 90.1% ± 3.5% of prescription, respectively. For the non-myeloablative VMAT-TBI cohort, testis/ovary Dmax, brain, and thyroid Dmean were spared to 33.4% ± 7.3%, 75.4% ± 7.0%, and 76.1% ± 10.5%, respectively. For 2D-TBI, lungs were spared using partial-transmission lung blocks for myeloablative regimens. The VMAT-TBI cohort experienced significantly lower rates of any grade of pneumonitis (2% vs. 12%), nephrotoxicity (7% vs. 34%), nausea (68% vs. 81%), skin (16% vs. 35%), and graft versus host disease (GVHD) (42% vs. 62%) compared to 2D-TBI patients. For myeloablative regimen patients, rates of pneumonitis (0% vs. 17%) and nephrotoxicity (9% vs. 36%) were significantly lower with VMAT-TBI versus 2D-TBI (p < 0.01). Median follow-up was 14.3 months, and neither median OS nor PFS for the entire cohort was reached. In the VMAT versus 2D-TBI cohort, the 1-year OS was 86.0% versus 83.0% (p = 0.26), and the 1-year PFS was 86.6% and 80.0% (p = 0.36), respectively. Normal tissue sparing with VMAT-TBI compared to the 2D-TBI translated to significantly lower rates of pneumonitis, renal toxicity, nausea, skin toxicity, and GVHD in patients, while maintaining excellent disease control.

Teicoplanin in peritoneal dialysis: efficacy, safety, and pharmacological considerations.

Peritoneal dialysis (PD) is a vital treatment modality for renal failure patients, facilitating the removal of excess fluid and unwanted substances. However, peritonitis, a significant complication experienced by PD patients, necessitates careful selection of antibiotics to ensure successful treatment. Commonly used antibiotics in PD patients, such as cephalosporins and glycopeptides like vancomycin, have been associated with undesirable side effects and high failure rates. In response to these challenges, teicoplanin, a novel glycopeptide antibiotic, has gained attention due to its similar range of activity to vancomycin, extended half-life, reduced side effects, and improved elimination. The objective of this study is to comprehensively review the efficacy, mechanism of action, adverse effects, and pharmacological benefits of teicoplanin in peritoneal dialysis patients. Our research involved an extensive review of 21 articles from reputable databases, including Google Scholar, PubMed, and ScienceDirect. The data extracted from these studies was meticulously evaluated to comprehensively understand teicoplanin's clinical profile in this specific patient population. Major findings of these studies are that glycopeptide-based regimens have higher cure rates over first-generation cephalosporins or fluoroquinolones, and teicoplanin demonstrated several advantages over vancomycin, such as a higher therapeutic index, good tolerance, longer half-life, lower rates of nephrotoxicity, improved elimination while being equally effective. Teicoplanin is typically administered to peritoneal dialysis patients with a loading dose of 400mg, aiming to achieve a trough concentration of 10-15mg/dl. Teicoplanin's improved tolerability and lack of regular serum level monitoring requirements make it a promising alternative to traditional antibiotics for clinical use.

Treatment Outcomes and Associated Factors of Intravenous Colistin for Nosocomial Infections in Pediatric Patients: A Retrospective Study in a University Hospital in Thailand.

This study aimed to investigate the efficacy and safety of intravenous colistin in pediatric patients with nosocomial gram-negative bacteria infections and to determine factors associated with treatment outcomes. This retrospective study recruited patients aged <18 years receiving intravenous colistin between January 2014 and December 2018. Clinical data and treatment outcomes were reviewed, and factors associated with treatment outcomes were assessed. This study included 178 patients with a median age of 3.4 years (range, 0.1-17.8). The mean ± SD dose of colistin prescribed to patients without renal impairment was 5.1 ± 0.6 mg/kg/day. The clinical response rate was 70.8% in patients receiving colistin for specific treatment. Infection-related mortality and crude mortality were 17.5% and 19.7%, respectively. The nephrotoxicity rate was 29.8%; approximately 70% of the episodes occurred between the 3rd and 7th day of treatment. The presence of at least 2 organ dysfunctions [adjusted hazard ratio (aHR): 7.17; 95% CI: 1.64-31.40], septic shock (aHR: 2.69; 95% CI: 1.36-5.32) and receiving chemotherapy/immunosuppressants (aHR: 2.68; 95% CI: 1.36-5.25) were observed to be associated with clinical failure. The factors observed to be associated with nephrotoxicity included hypoalbuminemia (aHR: 2.93; 95% CI: 1.26-6.78), receiving amphotericin B (aHR: 2.29; 95% CI: 1.16-4.52), vancomycin (aHR: 3.36; 95% CI: 1.50-7.56) and vasopressors (aHR: 2.57; 95% CI: 1.27-5.21). Colistin is generally effective in the treatment of nosocomial gram-negative bacteria infections in pediatric patients. Close monitoring of renal function should be considered, especially in high-risk patients. Optimal dosage regimens for pediatric populations to promote more favorable clinical outcomes and minimize nephrotoxicity require further investigation.

Predictive Value of Vancomycin AUC24/MIC Ratio for 30-day Mortality in Patients with Severe or Complicated Methicillin-Resistant Staphylococcus aureus Infections: A Multicenter Retrospective Study.

Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC24/MIC ratio associated with treatment outcomes of infections treated with vancomycin. This retrospective multicenter cohort study included adult patients receiving ≥ 5days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC24/MIC and outcomes. This study included 82 patients. ROC identified a target AUC24/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC24/MIC cutoff (34.1%) than for above AUC24/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC24/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335-18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups. In treating severe/complicated MRSA infections, vancomycin AUC24/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC24/MIC ratios.

A Retrospective Study Evaluating Neonatal Vancomycin Loading Doses to Achieve a Therapeutic Target

Background: Vancomycin is a glycopeptide antibiotic that has been used to treat hospital-acquired gram-positive infections for more than 5 decades. However, the literature is divided regarding the therapeutic advantages of vancomycin loading doses in neonates. Objectives: This study aimed to investigate the effect of vancomycin loading doses on therapeutic target attainment in neonates with sepsis. Methods: A retrospective cohort study was conducted to compare the vancomycin target attainment (area under the curve 0–24 hours/minimum inhibitory concentration ≥400) in neonates before and after the 2019 change in vancomycin prescription guidelines at a neonatal unit in Cape Town, South Africa. As the standard of care, Bayesian modelling software was used to compute the area under the curve from the trough concentrations. Results: Two hundred ten neonates were included. Multivariate regression analysis showed a 2-fold increase in the odds of target attainment among neonates receiving a loading dose of vancomycin. Early target attainment (within 8–12 hours of treatment initiation) was significantly higher in the loading dose group compared with the no loading dose group [97/105 (92.4%) versus 64/105 (61.0%); P &lt; 0.001]. However, the overall proportion of neonates achieving target attainment at 24 hours was similar between groups [73/105 (69.5%) in the loading dose group versus 62/105 (59.0%) in the no loading dose group; P = 0.110]. The nephrotoxicity rates were low [2/105 (1.9%) in the loading dose group and 2/105 (1.9%) in the no loading dose group]. Conclusions: The addition of a vancomycin loading dose to neonates may facilitate early therapeutic target attainment.

Efficiency of polymyxin B treatment against nosocomial infection: a systematic review and meta-analysis.

Some cohort studies have explored the effects and safety of polymyxin B (PMB) in comparison to other antibiotics for the treatment of nosocomial infections, yielding inconsistent results. This systematic review aims to explore the effectiveness and safety of PMB and compared it with other antibiotics. A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, and Web of Science, searching specific terms to identify quantitative cohort studies or RCTs that compared the effects of PMB with other antibiotics in terms of their efficacy and safety. The Newcastle-Ottawa Scale (NOS) was conducted to evaluate the risk of bias of observational studies. Odds ratios with 95% confidence intervals were used for outcome assessment. We evaluated heterogeneity using the I 2 test. A total of 22 observational trials were included in the analysis. The PMB group had a higher mortality rate compared to the control group (odds ratio: 1.84, 95% CI: 1.36-2.50, p<0.00001, I 2 = 73%). while, the ceftazidime-avibactam group demonstrated a distinct advantage with lower mortality rates, despite still exhibiting high heterogeneity (odds ratio 2.73, 95% confidence interval 1.59-4.69; p = 0.0003; I 2 = 53%). Additionally, the PMB group had a lower nephrotoxicity rate compared to the colistin group but exhibited high heterogeneity in the results (odds ratio 0.58, 95% CI 0.36-0.93; p = 0.02; I 2 = 73%). In patients with nosocomial infections, PMB is not superior to other antibiotics in terms of mortality, specifically when compared to ceftazidime-avibactam. However, PMB demonstrated an advantage in terms of nephrotoxicity compared to colistin.

Safety of Cidofovir Treatment for Suspected or Confirmed Adenovirus Infection in Immunocompetent Pediatric Population.

Cidofovir (CDV), a nucleoside phosphonate analogue, exhibits activity against severe cytomegalovirus and adenoviral (ADV) infection. Nevertheless, reports of elevated nephrotoxicity rates limited its use to highly vulnerable cases, mainly immunocompromised children with fulminant infection. Limited data exists regarding CDV safety in immunocompetent children. To evaluate CDV-related toxicity, mainly nephrotoxicity, in immunocompetent children with severe ADV/cytomegalovirus infection. We conducted a retrospective review of medical records for all immunocompetent children under 18 years of age treated with intravenous CDV from January 2005 to December 2019. Among the 23 patients identified, 21 were diagnosed with severe ADV infection. Median age was 15 months. Twenty-one (91%) children were admitted to the pediatric intensive care unit. Eighteen patients (78%) received standard CDV protocol (5 mg/kg CDV weekly for 2 weeks), 4 (17%) according to nephroprotective low-dose protocol and 1 patient transitioned. The median duration of CDV treatment was 14 days (range: 1-21 days). All patients received hyperhydration and probenecid with each infusion. Acute kidney injury was recorded in 1 patient (with concurrent septic shock) during CDV treatment. Two children exhibited acute kidney injury before CDV initiation, but renal function normalized during CDV treatment. One patient developed transient neutropenia (600 cells/L), apparently as a result of sepsis. No other major adverse effects were noted. Mortality rate was 3/23 (13%), unrelated to CDV toxicity. Our findings suggest that CDV-related nephrotoxicity rate in immunocompetent children may be lower than previously reported, perhaps lower than in the severely immunocompromised population.

Battle of polymyxin induced nephrotoxicity: Polymyxin B versus colistin

ObjectivesNephrotoxicity is the most serious and common adverse effect that limits the use of polymyxins. This study compared polymyxin E (colistin) and polymyxin B regarding drug-related nephrotoxicity. MethodsThis study was conducted as a retrospective cohort study in a university hospital between January 2020 and July 2022. Patients older than 18 years and who received colistin or polymyxin B were identified using electronic hospital records. Kidney disease improving global outcome criteria were used for assessing nephrotoxicity. ResultsA total of 190 patients, 95 in both groups, were evaluated. The incidence of acute kidney injury during the treatment was higher in the colistin group [52.6% (n = 50) and 34.7% (n = 33), P = 0.013]. In patients who were exposed to high-dose, the rate of nephrotoxicity was higher in patients receiving colistin [25% (n = 3) vs. 76.9% (n = 10); P = 0.017]. Nephrotoxicity was reversible in 64.4% (n = 38) of patients and the reversibility rate was similar (70% and 52.6% for colistin and polymyxin; P = 0.248). In the multivariable analysis, colistin treatment [odds ratio (OR): 3.882, 95% confidence interval (95% CI) = (1.829–8.241)], concomitant vasopressor use (OR = 2.08, CI: 1.036–4.179), and age (OR=1.036, CI: 1.014–1.058) were found to be independent markers of nephrotoxicity. ConclusionNephrotoxicity was more common in patients receiving high-dose colistin than polymyxin B. Therefore, the use of appropriate doses of colistin is important in terms of preventing nephrotoxicity. In addition, advancing age and concomitant use of vasopressors contribute to polymyxin-related nephrotoxicity.

Vancomycin versus daptomycin for the treatment of confirmed gram-positive catheter-related bloodstream infections in oncology patients

ObjectiveTo analyse the effectiveness and safety of daptomycin versus vancomycin on the management catheter-related bloodstream infections in oncology patients. MethodA retrospective study was carried out including all patients admitted at the Medical Oncology Unit between 2010 and 2018 with positive blood cultures confirmed catheter-related bloodstream infections due to gram-positive microorganism, who were treated with either vancomycin or daptomycin. The primary end point was all cause 30-days mortality, 30-days hospital readmission and length of hospital stay (length of hospital stay). ResultsA total of 70 patients with catheter-related bloodstream infections were included in the present study: vancomycin was administered to 61.4% (n = 43) and daptomycin to 38.6% (n = 27) of patients. 78.5% (n = 55) of isolated bacteria showed a vancomycin minimum inhibitory concentration ≤ 1 µg/ml. No differences were observed between the two groups of patients regarding the 30-day mortality rate rate (32.6% [n = 14] versus 29.6% [n = 8]; p = 0.797), the 30-day re-admission rate (30.2% [n = 13] versus 29.6°% [n = 8]; p = 0.957) or the length of hospital stay (18.9 versus 16.5 days; p = 0.562). Nephrotoxicity rate was equivalent in both groups: a 7% (n = 3) of vancomycin goup versus a 7.4% (n = 2) of daptomycin group (p = 0.946). ConclusionsOur results show that both antibiotics are equivalent in their safety and effectiveness. Therefore, vancomycin should continue being the treatment of chose for gram-positive catheter-related bloodstream infections, in particular at hospital centres with a low prevalence of strains that show diminished susceptibility to vancomycin.

Delivery and Transcriptome Assessment of an In Vitro Three-Dimensional Proximal Tubule Model Established by Human Kidney 2 Cells in Clinical Gelatin Sponges.

The high prevalence of kidney diseases and the low identification rate of drug nephrotoxicity in preclinical studies reinforce the need for representative yet feasible renal models. Although in vitro cell-based models utilizing renal proximal tubules are widely used for kidney research, many proximal tubule cell (PTC) lines have been indicated to be less sensitive to nephrotoxins, mainly due to altered expression of transporters under a two-dimensional culture (2D) environment. Here, we selected HK-2 cells to establish a simplified three-dimensional (3D) model using gelatin sponges as scaffolds. In addition to cell viability and morphology, we conducted a comprehensive transcriptome comparison and correlation analysis of 2D and 3D cultured HK-2 cells to native human PTCs. Our 3D model displayed stable and long-term growth with a tubule-like morphology and demonstrated a more comparable gene expression profile to native human PTCs compared to the 2D model. Many missing or low expressions of major genes involved in PTC transport and metabolic processes were restored, which is crucial for successful nephrotoxicity prediction. Consequently, we established a cost-effective yet more representative model for in vivo PTC studies and presented a comprehensive transcriptome analysis for the systematic characterization of PTC lines.

Risks of Polymyxin B Nephrotoxicity and Its Precursors in the Intensive Care Unit: A Retrospective Cohort Study.

Polymyxin group antibiotics constitute a part of our limited arsenal in the treatment of multidrug-resistant gram-negative bacteria. However, their use is limited especially due to nephrotoxicity and other side effects. In this study, we primarily aimed to determine the effect of polymyxin B on the rate of nephrotoxicity in critically ill patients, and secondly to identify the factors that facilitate nephrotoxicity caused by polymyxin B. The study was designed as a retrospective cohort study and conducted by scanning patients aged 18 years or older who had been admitted to our intensive care unit (ICU) in 2022 and treated with polymyxin B for at least 72 hours. Patients without chronic renal failure and acute kidney injury (AKI) before starting polymyxin B therapy were included and AKI was examined after the use of polymyxin B. The patients were then divided into two groups, those with AKI and those without AKI. We tried to find factors that may facilitate AKI by comparing the two groups. Of the patients, 26 were female and 34 were male. In 21 of the patients (35%), renal damage of varying degrees developed; these patients belonged to the nephrotoxicity (NT) group, while the rest belonged to the non-nephrotoxicity (non-NT) group. We found that advanced age (p=0.008), low baseline GFR (p=0.01), baseline creatinine (p=0.006), BMI (p=0.011), concomitant diseases (p<0.001), and days of use of polymyxin B (p=0.006) were statistically different between the two groups. In multivariate analysis of univariate analysis, we found that duration of polymyxin B use, BMI, and advanced age were independent risk factors for AKI development. We found that 21 (35%) of 60 intensive care unit patients who had no previous history of kidney injury developed kidney injury after being treated with polymyxin B. We identified advanced age, high BMI, and duration of polymyxin B use as independent risk factors. Therefore, we recommend close monitoring of renal function and prompt intervention, particularly in patients with risk factors, during polymyxin B use.

Effect of Genetic Polymorphism on Clinical Efficacy of Tacrolimus in Adult Living Donor-Liver Transplant Patients

Background and Aim The influence of genetic polymorphism on the clinical outcome including response and safety of immunosuppression in liver transplant (LT) recipients remains controversial among different races and ethnicities, especially for calcineurin inhibitors (CNIs). This study aims to evaluate the effect of different genotypes of the single nucleotide polymorphism (SNP) in the genes encoding CYP3A5 on the therapeutic response to the widely used calcineurin inhibitor; tacrolimus. Method In 49 living donor liver transplant (LDLT) recipients with tacrolimus as the backbone immunosuppressive, the rejection, delayed graft function, laboratory evidenced nephrotoxicity, new onset diabetes and hypertension rates were considered the primary therapeutic and safety outcomes of tacrolimus. The biochemical parameters of tacrolimus response and safety as evidence by the status of liver functions, renal functions, complete blood counts and serum electrolytes, as well as the need for Mycophenolate mofetil (MMF) were considered the secondary outcomes. Results the rejection and delayed graft function rates didn’t differ significantly among different genotypes (p = 1), similarly; the incidence of new onset diabetes and hypertension didn’t differ significantly among different genotypes (p = 1, and 0.4143 respectively). Moreover; laboratory evidenced nephrotoxicity rates didn’t differ significantly among different genotypes (p = 0.5040). No significant intergenotype differences were observed in the all biochemical outcomes. However the need for MMF was significantly higher among carriers of the CYP3A5*3 allele. Conclusion different genotypes did not offer an advantage over one another in predicting therapeutic response or toxicity of tacrolimus among LDLT recipients.

Zileuton ameliorates aminoglycoside and polymyxin-associated acute kidney injury in an animal model.

Aminoglycosides and polymyxins are antibiotics with in vitro activity against MDR Gram-negative bacteria. However, their clinical use is hindered by dose-limiting nephrotoxicity. The objective of this project was to determine if zileuton can reduce nephrotoxicity associated with amikacin and polymyxin B in a rat model of acute kidney injury. Sprague Dawley rats (n = 10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 min before antibiotic administration. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥2× elevation of baseline serum creatinine. Time-to-event analysis and log rank test were used to compare the onset of nephrotoxicity in different cohorts. Histopathological analysis was also conducted to characterize the extent of kidney injury. Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100%, respectively. The overall rate was reduced to 30% in animals receiving adjuvant zileuton. The onset of nephrotoxicity associated with amikacin and polymyxin B was also significantly delayed by zileuton at 4 and 10 mg/kg, respectively. Histopathology confirmed reduced kidney injury in animals receiving amikacin concomitant with zileuton. Our pilot data suggest that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat MDR Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and dosing in humans.

A Quasi-Experimental Evaluation of Single Trough-Based Area Under the Curve Guided Dosing on the Incidence of Vancomycin Associated Nephrotoxicity in Veteran Patients.

Background: Two common dosing strategies for vancomycin are trough-based and area under the curve (AUC)-based dosing. Objective: To compare the incidence of nephrotoxicity in trough-based dosing group with the single trough-based AUC dosing at the Salem VA Medical Center. Methods: This retrospective study included patients who received trough-based dosing of vancomycin between January 1, 2017, and January 1, 2019 (preimplementation group) and AUC-based dosing (postimplementation) between October 1, 2019, and October 1, 2021, at the Salem VA Medical Center. The primary outcome was nephrotoxicity at 96 hours, 7 days, and entire hospital length of stay (LOS). Secondary outcomes included 30-day readmission and all-cause mortality rates, cumulative doses at 24, 48, and 72 hours, and percentage of patients considered at goal (AUC 400-600 or trough between 10 and 20 mg/L). Propensity score (PS) matching was utilized to adjust for confounding. Results: After PS matching 100 patients were included in preimplementation and 95 patients in the postimplementation group. The average study patient was a 68-year-old white male. There was significant reduction in the risk of nephrotoxicity in postimplementation cohort at 96 hours (adjusted (a)HR: 0.28, 95% CI (0.12-0.66); 7 days (aHR: 0.39, 95% CI (0.18-0.85); and entire hospital LOS (aHR: 0.46, 95% CI (0.22-0.95). Secondary outcomes showed no difference between the groups except significantly higher proportion of patients were considered at therapeutic goal in the postimplementation cohort compared with pre-implementation cohort. Conclusion: This hypothesis generating study shows that AUC-based dosing calculated using single trough concentration may result in reduced rate of nephrotoxicity than trough-based dosing.

Correlation of Calculated Vancomycin Trough Concentrations and Exposure: A Monte Carlo Simulation.

Current recommendations are to dose vancomycin to target 24-hour area under the curve (AUC) of 400-600 mg·h/L to optimize efficacy and safety. Limited data support AUC monitoring, and some centers continue to use trough concentrations. A target of 10-20 mg/L has been proposed to reduce nephrotoxicity risk. To use previously published pharmacokinetic equations in a Monte Carlo simulation relating AUC exposure to trough concentrations when targeting an AUC between 400 and 600 mg·h/L. Previously published pharmacokinetic data were used as input parameters for a Monte Carlo simulation using previously published formulae to correlate AUC to simulated trough concentrations. Pharmacokinetic parameters were assumed to occur in a normal distribution pattern. We excluded irrelevant simulated cases. Maintenance doses of 15 mg/kg were rounded to the nearest 250 mg. Calculated trough concentrations for AUCs of both 400 and 600 mg·h/L were evaluated in each simulation. A total of 10 000 Monte Carlo simulations were performed. Targeting an AUC of 400 mg·h/L resulted in a mean trough concentration of 10.3 ± 0.8 mg/L. Targeting an AUC of 600 mg·h/L resulted in a mean trough concentration of 15.4 ± 1.2 mg/L. We demonstrate that a lower trough concentration range may be supported by an AUC of 400-600 mg·h/L, which may reduce risk and rates of nephrotoxicity without compromising previously established efficacious target trough concentrations.

Therapeutic Drug Monitoring of Vancomycin Concentrations for the Management of Bone and Joint Infections: An Urgent Need

Vancomycin is used for the treatment of bone and joint infections (BJI), but scarce information is available about its pharmacokinetic/pharmacodynamic (PK/PD) characteristics. We aimed to identify the risk factors associated with the non-achievement of an optimal PK/PD target in the first therapeutic drug monitoring (TDM). Methods: A retrospective study was conducted in a tertiary hospital from January 2020 to January 2022. Patients with BJI and TDM of vancomycin on day 2 of treatment were included. Initial vancomycin fixed doses (1 g every 8 h or 12 h) was decided by the responsible doctors. According to TDM results, dosage adjustments were performed. An AUC24h/MIC < 400 mg × h/L, between 400 and 600 mg × h/L and >600 mg × h/L, were defined as suboptimal, optimal and supratherapeutic, respectively. Patients were grouped into these three categories. Demographic, clinical and PK characteristics were compared between groups. Nephrotoxicity at the end of treatment was assessed. Results: A total of 94 patients were included: 22 (23.4%), 42 (44.7%) and 30 (31.9%) presented an infratherapeutic, optimal and supratherapeutic PK/PD targets, respectively. A younger age and initial vancomycin dose <40 mg/kg/day were predictive factors for achieving a suboptimal PK/PD target, while older age, higher serum-creatinine and dose >40 mg/kg/day were associated with overexposure. The nephrotoxicity rate was 22.7%. More than 50% of patients did not achieve an optimal PK/PD. Considering age, baseline serum-creatinine and body weight, TDM is required to readily achieve an optimal and safe exposure.

Intravenous Polymyxin B as Adjunctive Therapy to High-Dose Tigecycline for the Treatment of Nosocomial Pneumonia Due to Carbapenem-Resistant Acinetobacter baumannii and Klebsiella pneumoniae: A Propensity Score-Matched Cohort Study.

Although the combination of polymyxin and tigecycline is widely used in treating carbapenem-resistant bacterial infections, the benefit of this combination is still uncertain. To assess whether adding polymyxin B to the high-dose tigecycline regimen would result in better clinical outcomes than the high-dose tigecycline therapy in patients with pneumonia caused by carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii, we conducted a propensity score-matched cohort study in a single center between July 2019 and December 2021. Of the 162 eligible patients, 102 were included in the 1:1 matched cohort. The overall 14-day mortality in the matched cohort was 24.5%. Compared with high-dose tigecycline, the combination therapy was not associated with better clinical outcomes, and showed similar 14-day mortality (OR, 0.72, 95% CI 0.27-1.83, p = 0.486), clinical cure (OR, 1.09, 95% CI 0.48-2.54, p = 0.823), microbiological cure (OR, 0.96, 95% CI 0.39-2.53, p = 0.928) and rate of nephrotoxicity (OR 0.85, 95% CI 0.36-1.99, p = 0.712). Subgroup analyses also did not demonstrate any statistical differences. Based on these results, it is reasonable to recommend against adding polymyxin B to the high-dose tigecycline regimen in treating pneumonia caused by carbapenem-resistant K. pneumoniae and A. baumannii.

Amphotericin B and monoacyl-phosphatidylcholine form a stable amorphous complex

Amphotericin B (AmB) is a “life-saving” medicine for the treatment of invasive fungal infections and visceral leishmaniasis. To date, all marketed AmB formulations require parenteral administration, which causes high rates of acute infusion-related side effects and dose-dependent nephrotoxicity. The development of an oral AmB formulation will entail numerous advantages including increased patient compliance, eliminated infusion-related toxicities and reduced nephrotoxicity. Unfortunately, the gastrointestinal absorption of AmB is negligible due to its extremely low solubility in both aqueous and lipid solvents, and its poor gastrointestinal permeability. Drug-phospholipid complexation is an emerging strategy for oral delivery of poorly soluble drugs. In this study, monoacyl-phosphatidylcholine (MAPC) was complexed with AmB forming an AmB-MAPC complex (APC), to enhance the dissolution rate and aqueous solubility of AmB, in order to enable oral delivery of AmB. X-ray powder diffraction demonstrated that AmB was transformed to its amorphous form following complexation with MAPC, i.e. in the APC. Fourier-transform infrared spectroscopy suggested molecular interactions between AmB and MAPC. Dynamic light scattering indicated formation of colloidal structures after aqueous dispersion of APC; Cryogenic transmission electron microscopy showed that APC formed small round, “rod-like” and “worm-like” micellar structures and Small-angle neutron scattering provided three-dimensional micellar structures formed by APC upon aqueous dispersion, which indicated that AmB was inserted into the micellar mono-layer membrane formed by MAPC. Additionally, APC showed an increased dissolution rate and a higher amount of AmB solubilized in fasted state simulated intestinal fluid, compared to AmB/MAPC physical mixtures and crystalline AmB. In conclusion, an APC exhibiting amorphous properties was developed, the APC showed improved dissolution rate and increased apparent aqueous solubility compared to AmB, indicating that the application of APC could be a promising strategy to enable the oral delivery of AmB.