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Hosseini S, Alavi Darzam I, Amirdosara M, Zangi M, Sahraei Z. Evaluating the effects of intravenous magnesium sulfate for prevention of colistin induced acute kidney injury: an open-label, placebo-controlled, block randomized clinical trial. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4559-4570. [PMID: 39503756 DOI: 10.1007/s00210-024-03583-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 10/28/2024] [Indexed: 04/10/2025]
Abstract
Colistin, has reinstated as a last-resort antibiotic despite its known nephrotoxicity. The aim of this study was to determine the potential nephroprotective effects of Magnesium (Mg) Sulfate during colistin therapy. This study was an open-label, placebo-controlled, block-randomized clinical trial conducted from January 2023 to February 2024 involving 87 patients eligible for colistin therapy. Patients were randomly assigned to receive either Mg sulfate (16 mEq in 100 mL of normal saline) or 100 mL of normal saline as placebo before each dose of colistin. The primary outcome of the study was the incidence of Acute Kidney Injury (AKI) during the first week of colistin therapy, while the secondary outcomes included colistin dose adjustments, length of stay in the ICU and hospital, and overall mortality. This study was registered in The Iranian Registry of Clinical Trials (IRCT20130917014693N15; 2023-01-12). A total of 87 patients (46 in Mg and 41 in control group) completed the study. Fourteen patients (30.43%) in the Mg group and twenty-one patients (51.21%) in the control group developed AKI during the first week of colistin therapy (p = 0.048). Although AKI incidence was not statistically different between the groups in unadjusted Cox regression model (HR =0.51, 95% CI =0.26-1.01, P =0.057), it became significant after adjusting for confounding factors (HR =0.40,95% CI =0.18-0.86, P =0.021). The length of hospital stay was 48.62 ± 18.82 and 44.82 ± 20.23 days for Mg and control groups respectively (p=0.373). In the Mg group, 25 out of 46 patients (54.34 %) and in the control group, 24 out of 41 patients (58.53%) eventually expired (p=0.694). This study indicates that Mg sulfate significantly reduces AKI rates and prevents hypomagnesemia, optimizing dosing and enhancing patient safety during colistin therapy.
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Affiliation(s)
- Sareh Hosseini
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ilad Alavi Darzam
- Department of Infectious Diseases and Tropical Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Amirdosara
- Department of Anesthesiology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Zangi
- Department of Anesthesiology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Sahraei
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Infectious Diseases and Tropical Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Cho NJ, Jeong I, Ahn SJ, Gil HW, Kim Y, Park JH, Kang S, Lee H. Machine Learning to Assist in Managing Acute Kidney Injury in General Wards: Multicenter Retrospective Study. J Med Internet Res 2025; 27:e66568. [PMID: 40101226 PMCID: PMC11962325 DOI: 10.2196/66568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 01/10/2025] [Accepted: 02/14/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Most artificial intelligence-based research on acute kidney injury (AKI) prediction has focused on intensive care unit settings, limiting their generalizability to general wards. The lack of standardized AKI definitions and reliance on intensive care units further hinder the clinical applicability of these models. OBJECTIVE This study aims to develop and validate a machine learning-based framework to assist in managing AKI and acute kidney disease (AKD) in general ward patients, using a refined operational definition of AKI to improve predictive performance and clinical relevance. METHODS This retrospective multicenter cohort study analyzed electronic health record data from 3 hospitals in South Korea. AKI and AKD were defined using a refined version of the Kidney Disease: Improving Global Outcomes criteria, which included adjustments to baseline serum creatinine estimation and a stricter minimum increase threshold to reduce misclassification due to transient fluctuations. The primary outcome was the development of machine learning models for early prediction of AKI (within 3 days before onset) and AKD (nonrecovery within 7 days after AKI). RESULTS The final analysis included 135,068 patients. A total of 7658 (8%) patients in the internal cohort and 2898 (7.3%) patients in the external cohort developed AKI. Among the 5429 patients in the internal cohort and 1998 patients in the external cohort for whom AKD progression could be assessed, 896 (16.5%) patients and 287 (14.4%) patients, respectively, progressed to AKD. Using the refined criteria, 2898 cases of AKI were identified, whereas applying the standard Kidney Disease: Improving Global Outcomes criteria resulted in the identification of 5407 cases. Among the 2509 patients who were not classified as having AKI under the refined criteria, 2242 had a baseline serum creatinine level below 0.6 mg/dL, while the remaining 267 experienced a decrease in serum creatinine before the onset of AKI. The final selected early prediction model for AKI achieved an area under the receiver operating characteristic curve of 0.9053 in the internal cohort and 0.8860 in the external cohort. The early prediction model for AKD achieved an area under the receiver operating characteristic curve of 0.8202 in the internal cohort and 0.7833 in the external cohort. CONCLUSIONS The proposed machine learning framework successfully predicted AKI and AKD in general ward patients with high accuracy. The refined AKI definition significantly reduced the classification of patients with transient serum creatinine fluctuations as AKI cases compared to the previous criteria. These findings suggest that integrating this machine learning framework into hospital workflows could enable earlier interventions, optimize resource allocation, and improve patient outcomes.
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Affiliation(s)
- Nam-Jun Cho
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
| | - Inyong Jeong
- Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Republic of Korea
| | - Se-Jin Ahn
- Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hyo-Wook Gil
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
| | - Yeongmin Kim
- Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jin-Hyun Park
- Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sanghee Kang
- Department of Surgery, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Hwamin Lee
- Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Republic of Korea
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Pană AG, Șchiopu P, Țoc DA, Neculicioiu VS, Butiuc-Keul A, Farkas A, Dobrescu MȘ, Flonta M, Costache C, Szász IÉ, Junie LM. Clonality and the Phenotype-Genotype Correlation of Antimicrobial Resistance in Acinetobacter baumannii Isolates: A Multicenter Study of Clinical Isolates from Romania. Microorganisms 2025; 13:176. [PMID: 39858944 PMCID: PMC11767935 DOI: 10.3390/microorganisms13010176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/06/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Antibiotic resistance is on the WHO's top 10 list of global public health threats due to its rapid emergence and spread but also because of the high morbidity and mortality associated with it. Amongst the main species driving this phenomenon is A. baumannii, a member of the ESKAPE group of medical assistance-associated infections causing species famous for its extensively drug-resistant phenotypes. Our findings note a 91.52% frequency of extensively drug-resistant carbapenem-resistant A. baumannii (XDR CRAB) phenotype amongst clinical isolates from multiple hospitals in two major cities from northwestern and central Romania, harboring multiple antibiotic resistance genes such as blaOXA-23-like in 108 (91.5%) isolates, blaOXA-24/40-like in 88 (74.6%) isolates, blaNDM in 29 (25%) isolates, ArmA in 75 (63.6%) isolates, and ant(3″)-I in 69 (58.5%) isolates and sul1 in 113 (95.76%) isolates. The isolates, although nearly identical in phenotype, displayed different genotypical profiles, with varying degrees of similarity across hospitals and cities, raising the possibility of both local outbreaks of a single clone and widespread dissemination of resistant isolates.
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Affiliation(s)
- Adrian-Gabriel Pană
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, 4–6 Louis Pasteur Street, 400012 Cluj-Napoca, Romania; (D.A.Ț.); (V.S.N.); (C.C.); (L.-M.J.)
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Pavel Șchiopu
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, 4–6 Louis Pasteur Street, 400012 Cluj-Napoca, Romania; (D.A.Ț.); (V.S.N.); (C.C.); (L.-M.J.)
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Dan Alexandru Țoc
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, 4–6 Louis Pasteur Street, 400012 Cluj-Napoca, Romania; (D.A.Ț.); (V.S.N.); (C.C.); (L.-M.J.)
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Vlad Sever Neculicioiu
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, 4–6 Louis Pasteur Street, 400012 Cluj-Napoca, Romania; (D.A.Ț.); (V.S.N.); (C.C.); (L.-M.J.)
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Anca Butiuc-Keul
- Doctoral School of Integrative Biology, Babeș-Bolyai University, 1 M. Kogalniceanu Street, 400084 Cluj-Napoca, Romania; (A.B.-K.); (A.F.); (M.-Ș.D.)
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babeș-Bolyai University, 1 M. Kogalniceanu Street, 400084 Cluj-Napoca, Romania
- Centre for Systems Biology, Biodiversity and Bioresources, Babes-Bolyai University, 5–7 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Anca Farkas
- Doctoral School of Integrative Biology, Babeș-Bolyai University, 1 M. Kogalniceanu Street, 400084 Cluj-Napoca, Romania; (A.B.-K.); (A.F.); (M.-Ș.D.)
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babeș-Bolyai University, 1 M. Kogalniceanu Street, 400084 Cluj-Napoca, Romania
- Centre for Systems Biology, Biodiversity and Bioresources, Babes-Bolyai University, 5–7 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Matei-Ștefan Dobrescu
- Doctoral School of Integrative Biology, Babeș-Bolyai University, 1 M. Kogalniceanu Street, 400084 Cluj-Napoca, Romania; (A.B.-K.); (A.F.); (M.-Ș.D.)
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babeș-Bolyai University, 1 M. Kogalniceanu Street, 400084 Cluj-Napoca, Romania
- Centre for Systems Biology, Biodiversity and Bioresources, Babes-Bolyai University, 5–7 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Mirela Flonta
- Infectious Disease Clinical Hospital, 23 Iuliu Moldovan Street, 400003 Cluj-Napoca, Romania;
| | - Carmen Costache
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, 4–6 Louis Pasteur Street, 400012 Cluj-Napoca, Romania; (D.A.Ț.); (V.S.N.); (C.C.); (L.-M.J.)
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Cluj-Napoca Emergency Clinical County Hospital, 3–5 Clinicilor Street, 400347 Cluj-Napoca, Romania
| | - Izabella Éva Szász
- Târgu-Mureș Emergency Clinical County Hospital, 50 Gheorghe Marinescu Street, 540136 Târgu-Mureș, Romania;
| | - Lia-Monica Junie
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, 4–6 Louis Pasteur Street, 400012 Cluj-Napoca, Romania; (D.A.Ț.); (V.S.N.); (C.C.); (L.-M.J.)
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
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Samodelov SL, Gai Z, De Luca F, Haldimann K, Hobbie SN, Müller D, Kullak-Ublick GA, Visentin M. L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice. Sci Rep 2024; 14:16444. [PMID: 39013979 PMCID: PMC11252255 DOI: 10.1038/s41598-024-67171-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 07/09/2024] [Indexed: 07/18/2024] Open
Abstract
Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin. The aim of this study was to evaluate whether colistin can directly induce mitochondrial toxicity and, if so, uncover the underlying molecular mechanism. We found that colistin leads to a rapid permeability transition of mitochondria isolated from mouse kidney that was fully prevented by co-incubation of the mitochondria with desensitizers of the mitochondrial transition pore cyclosporin A or L-carnitine. The protective effect of L-carnitine was confirmed in experiments in primary cultured mouse tubular cells. Consistently, the relative risk of colistin-induced kidney damage, calculated based on histological analysis as well as by the early marker of tubular kidney injury, Kim-1, was halved under co-administration with L-carnitine in vivo. Notably, L-carnitine neither affected the pharmacokinetics of colistin nor its antimicrobial activity against relevant bacterial strains. In conclusion, colistin targets the mitochondria and induces permeability transition thereof. L-carnitine prevents colistin-induced permeability transition in vitro. Moreover, L-carnitine co-administration confers partial nephroprotection in mice treated with colistin, without interfering with its pharmacokinetics and antibacterial activity.
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Affiliation(s)
- Sophia L Samodelov
- Department of Clinical Pharmacology and Toxicology, University Hospital Zürich, University of Zürich, 8006, Zürich, Switzerland
| | - Zhibo Gai
- Department of Clinical Pharmacology and Toxicology, University Hospital Zürich, University of Zürich, 8006, Zürich, Switzerland
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Francesca De Luca
- Department of Clinical Pharmacology and Toxicology, University Hospital Zürich, University of Zürich, 8006, Zürich, Switzerland
| | - Klara Haldimann
- Institute of Medical Microbiology, University of Zürich, 8006, Zürich, Switzerland
| | - Sven N Hobbie
- Institute of Medical Microbiology, University of Zürich, 8006, Zürich, Switzerland
| | - Daniel Müller
- Institute of Clinical Chemistry, University Hospital Zürich, University of Zürich, 8006, Zürich, Switzerland
- Laboratory Medicine, University of Basel, 4056, Basel, Switzerland
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zürich, University of Zürich, 8006, Zürich, Switzerland
- Mechanistic Safety, Patient Safety & Pharmacovigilance, Clinical Development and Medical Affairs, Novartis Pharma, 4056, Basel, Switzerland
| | - Michele Visentin
- Department of Clinical Pharmacology and Toxicology, University Hospital Zürich, University of Zürich, 8006, Zürich, Switzerland.
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Soroudi S, Mousavi G, Jafari F, Elyasi S. Prevention of colistin-induced neurotoxicity: a narrative review of preclinical data. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3709-3727. [PMID: 38091077 DOI: 10.1007/s00210-023-02884-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 12/01/2023] [Indexed: 05/23/2024]
Abstract
Polymyxin E or colistin is an effective antibiotic against MDR Gram-negative bacteria. Due to unwanted side effects, the use of this antibiotic has been limited for a long time, but in recent years, the widespread of MDR Gram-negative bacteria infections has led to its reintroduction. Neurotoxicity and nephrotoxicity are the significant dose-limiting adverse effects of colistin. Several agents with anti-inflammatory and antioxidant properties have been used for the prevention of colistin-induced neurotoxicity. This study aims to review the preclinical studies in this field to prepare guidance for future human studies. The data was achieved by searching PubMed, Scopus, and Google Scholar databases. All eligible pre-clinical studies performed on neuroprotective agents against colistin-induced neurotoxicity, which were published up to September 2023, were included. Finally, 16 studies (ten in vitro and eight in vivo) are reviewed. Apoptosis (in 13 studies), inflammatory (in four studies), and oxidative stress (in 14 studies) pathways are the most commonly reported pathways involved in colistin-induced neurotoxicity. The assessed compounds include non-herbal (e.g., ascorbic acid, rapamycin, and minocycline) and herbal (e.g., curcumin, rutin, baicalein, salidroside, and ginsenoside) agents. Besides these compounds, some other measures like transplantation of mitochondria and the use of nerve growth factor and mesenchymal stem cells could be motivating subjects for future research. Based on the data from experimental (in vitro and animal) studies, a combination of colistin with neuroprotective agents could prevent or decrease colistin-induced neurotoxicity. However, well-designed randomized clinical trials and human studies are essential for demonstrating efficacy.
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Affiliation(s)
- Setareh Soroudi
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box, Mashhad, 91775-1365, Iran
| | - Ghazal Mousavi
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box, Mashhad, 91775-1365, Iran
| | - Fatemeh Jafari
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box, Mashhad, 91775-1365, Iran
| | - Sepideh Elyasi
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box, Mashhad, 91775-1365, Iran.
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Onorato L, de Luca I, Monari C, Coppola N. Cefiderocol either in monotherapy or combination versus best available therapy in the treatment of carbapenem-resistant Acinetobacter baumannii infections: A systematic review and meta-analysis. J Infect 2024; 88:106113. [PMID: 38331328 DOI: 10.1016/j.jinf.2024.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 01/21/2024] [Accepted: 01/28/2024] [Indexed: 02/10/2024]
Abstract
BACKGROUND The best treatment for carbapenem-resistant Acinetobacter baumannii (CRAB) infections is still a matter of debate. OBJECTIVES To describe the outcomes of patients treated with cefiderocol for CRAB infections, and to compare the efficacy of cefiderocol versus best available therapy (BAT). DATA SOURCES We searched MEDLINE, the Cochrane Library and EMBASE to screen original reports published up to September 2023. STUDY ELIGIBILITY CRITERIA Randomized controlled trials (RCTs) and observational studies investigating 30-day mortality, clinical failure, microbiological failure or rate of adverse drug reactions of patients treated with cefiderocol or BAT. PARTICIPANTS Patients with infections due to CRAB. INTERVENTIONS Cefiderocol in monotherapy or in combination with other potentially active agents or BAT. ASSESSMENT OF RISK OF BIAS We used the Cochrane Risk of Bias Tool for RCTs, and the Newcastle Ottawa scale for observational studies. METHODS OF DATA SYNTHESIS We conducted a meta-analysis pooling risk ratios (RRs) through random effect models. RESULTS We screened 801 original reports, and 18 studies (2 RCTs, 13 cohort studies and 3 case-series) were included in the analysis, for a total 733 patients treated with cefiderocol, and 473 receiving the BAT. Among patients receiving cefiderocol, the 30-day mortality rate was 42% (95% CI 38-47%), the rate of microbiological failure 48% (95% CI 31-65%), the clinical failure rate 43% (95% CI 32-55%), and the rate of ADRs was 3% (95% CI 1-6%). A lower mortality rate was observed among patients receiving cefiderocol monotherapy as compared to those treated with combination regimens (RR: 0.64; 95% CI: 0.43-0.94, p = 0.024). We found a significantly lower mortality rate (RR: 0.74; 95% CI: 0.57-0.95, p = 0.02) and a lower rate of ADRs (RR: 0.28; 95% CI: 0.09-0.91, p = 0.03) in the group treated with cefiderocol as compared to BAT. No difference was observed in microbiological and clinical failure rate. CONCLUSIONS Our data strengthen the efficacy and safety profile of cefiderocol in CRAB infections.
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Affiliation(s)
- Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Ilaria de Luca
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Caterina Monari
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy.
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Joo L, Jeong HY, Bae DH, Jee JH, Choi WH, Kim HY, Kim S, Yang DH, Gee HY, Jeon S, Roh YG, Yoo J. Prostaglandin F2α analogue, bimatoprost ameliorates colistin-induced nephrotoxicity. Biomed Pharmacother 2023; 168:115446. [PMID: 37918255 DOI: 10.1016/j.biopha.2023.115446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 08/21/2023] [Accepted: 09/04/2023] [Indexed: 11/04/2023] Open
Abstract
Colistin (polymyxin E) is an antibiotic that is effective against multidrug-resistant gram-negative bacteria. However, the high incidence of nephrotoxicity caused by colistin limits its clinical use. To identify compounds that might ameliorate colistin-induced nephrotoxicity, we obtained 1707 compounds from the Korea Chemical Bank and used a high-content screening (HCS) imaging-based assay. In this way, we found that bimatoprost (one of prostaglandin F2α analogue) ameliorated colistin-induced nephrotoxicity. To further assess the effects of bimatoprost on colistin-induced nephrotoxicity, we used in vitro and in vivo models. In cultured human proximal tubular cells (HK-2), colistin induced dose-dependent cytotoxicity. The number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, indicative of apoptosis, was higher in colistin-treated cells, but this effect of colistin was ameliorated by cotreatment with bimatoprost. The generation of reactive oxygen species, assessed using 2,7-dichlorodihydrofluorescein diacetate, was less marked in cells treated with both colistin and bimatoprost than in those treated with colistin alone. Female C57BL/6 mice (n = 10 per group) that were intraperitoneally injected with colistin (10 mg/kg/12 hr) for 14 days showed high blood urea nitrogen and serum creatinine concentrations that were reduced by the coadministration of bimatoprost (0.5 mg/kg/12 hr). In addition, kidney injury molecule-1 (KIM1) and Neutrophil gelatinase-associated lipocalin (NGAL) expression also reduced by bimatoprost administration. Further investigation in tubuloid and kidney organoids also showed that bimatoprost attenuated the nephrotoxicity by colistin, showing dose-dependent reducing effect of KIM1 expression. In this study, we have identified bimatoprost, prostaglandin F2α analogue as a drug that ameliorates colistin-induced nephrotoxicity.
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Affiliation(s)
- Lina Joo
- Department of Microbiology, CHA University School of Medicine, Seongnam, the Republic of Korea; CHA Organoid Research Center, CHA University, Seongnam, the Republic of Korea
| | - Hye Yun Jeong
- Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, the Republic of Korea
| | - Dong Hyuck Bae
- Department of Microbiology, CHA University School of Medicine, Seongnam, the Republic of Korea; CHA Organoid Research Center, CHA University, Seongnam, the Republic of Korea
| | - Joo Hyun Jee
- Department of Microbiology, CHA University School of Medicine, Seongnam, the Republic of Korea; CHA Organoid Research Center, CHA University, Seongnam, the Republic of Korea
| | - Woo Hee Choi
- Department of Microbiology, CHA University School of Medicine, Seongnam, the Republic of Korea; CHA Organoid Research Center, CHA University, Seongnam, the Republic of Korea; R&D Institute, ORGANOIDSCIENCES LTD., Seongnam, the Republic of Korea
| | - Hye-Youn Kim
- Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, the Republic of Korea
| | - Sejoong Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonnggi-do 13620, the Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine Seoul, 03080, the Republic of Korea
| | - Dong-Ho Yang
- Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, the Republic of Korea
| | - Heon Yung Gee
- Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, the Republic of Korea
| | - SeongGyeong Jeon
- Department of Microbiology, CHA University School of Medicine, Seongnam, the Republic of Korea; CHA Organoid Research Center, CHA University, Seongnam, the Republic of Korea
| | - Yun-Gil Roh
- Program in Health Policy, Chung-Buk National University, Republic of Korea
| | - Jongman Yoo
- Department of Microbiology, CHA University School of Medicine, Seongnam, the Republic of Korea; CHA Organoid Research Center, CHA University, Seongnam, the Republic of Korea; R&D Institute, ORGANOIDSCIENCES LTD., Seongnam, the Republic of Korea.
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Kilic I, Ayar Y, Ceylan İ, Kaya PK, Caliskan G. Nephrotoxicity caused by colistin use in ICU: a single centre experience. BMC Nephrol 2023; 24:302. [PMID: 37833622 PMCID: PMC10576281 DOI: 10.1186/s12882-023-03334-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 09/17/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND We aimed to determine the risk factors that may be associated with colistin-induced acute kidney injury (AKI) to promote the safer use of colistin in the treatment of nosocomial infections caused by multidrug-resistant Gram-negative bacteria in intensive care units. MATERIALS AND METHODS This retrospective observational study was conducted among adult patients who received a minimum of 48 h of intravenous colistin from January 2020 to December 2020 at the intensive care unit of a tertiary care hospital. AKI diagnosis and staging were made based on the Kidney Disease Improving Global Outcome Criteria. RESULTS Of 148 patients who received intravenous colistin at a daily dose of 9 million IU, 54 (36%) developed AKI. In the univariate analysis, age, Charlson comorbidity index, APACHE II score, duration of colistin treatment, basal creatinine level, use of vasopressors, and vancomycin were significantly associated with AKI (p < 0.05). The multivariate analysis revealed that the independent predictor of AKI was the use of vasopressors (OR: 3.14; 95% confidence interval: 1.39-97.07; p = 0.06). CONCLUSION The use of vasopressors in critically ill patients was independently associated with AKI developing during colistin treatment.
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Affiliation(s)
- Isa Kilic
- Department of Anesthesiology and Intensive Care, Ministry of Health, Bursa City Hospital , Bursa, Turkey.
| | - Yavuz Ayar
- Department of Nephrology and Internal Medicine, Health Sciences University, Bursa City Hospital, Bursa, Turkey
| | - İlkay Ceylan
- Department of Anesthesiology and Intensive Care, Ministry of Health, Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Pınar Kucukdemirci Kaya
- Department of Anesthesiology and Intensive Care, Bursa Uludag University, Faculty of Medicine, Bursa, Turkey
| | - Gulbahar Caliskan
- Department of Anesthesiology and Intensive Care, Ministry of Health, Bursa City Hospital , Bursa, Turkey
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9
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Lin ZY, Liang YY, Wang R, Hu B, He WJ, Li JK, Ding ZA, Lin ZY, Zhang S. Dietary magnesium is able to influence the relationship between vitamin C and estimated glomerular filtration rate: A cross-sectional study. Food Sci Nutr 2023; 11:4773-4780. [PMID: 37576036 PMCID: PMC10420853 DOI: 10.1002/fsn3.3456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 05/08/2023] [Accepted: 05/13/2023] [Indexed: 08/15/2023] Open
Abstract
The estimated glomerular filtration rate (eGFR) is a comprehensive index that is widely used to assess renal function. Although studies have confirmed a correlation between eGFR and dietary vitamin C, the impact of varying levels of vitamin C on eGFR remains unclear. Additionally, the interaction between dietary magnesium intake and vitamin C concentration on eGFR is not well understood. As such, the objective of this study was to investigate the relationship between dietary magnesium intake and vitamin C in relation to eGFR. This study analyzed the data of consecutive NHANES from 2005 to 2018. We included 17,633 participants aged 20 or older and used multiple linear regression analysis to evaluate the relationship between dietary vitamin C and eGFR. Dietary Mg intake from experimental data was dichotomized into a low dietary Mg intake group (≤254 mg/day) and a normal dietary Mg intake group (>254 mg/day). To evaluate the impact of dietary magnesium intake on eGFR, a multivariable linear regression was conducted utilizing an interaction test between dietary vitamin C and eGFR. We discovered a positive association between dietary vitamin C content and eGFR. The relationship between dietary vitamin C levels and eGFR differed between individuals with low Mg intake and those with normal Mg intake (β: 2.96 95% CI:1.63 ~ 4.29 vs. β: 1.05 95% CI: -0.15 to 2.25), and the positive association of high dietary vitamin C content with eGFR was stronger in the low Mg intake group. Furthermore, we observed that dietary magnesium intake significantly altered the positive association between dietary vitamin C and eGFR (interaction value of 0.020). Our experimental study revealed that the interaction between dietary magnesium and dietary vitamin C can significantly impact eGFR. This finding carries significant implications for the treatment of diseases resulting from abnormal eGFR, as well as the selection of clinically relevant drugs.
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Affiliation(s)
- Zheng-Yang Lin
- Department of Clinical Medicine The Second Clinical School of Guangzhou Medical University Guangzhou China
| | - Yong-Yi Liang
- Department of Preventive Medicine School of Public Health, Guangzhou Medical University Guangzhou China
| | - Ru Wang
- Department of Medical Imaging The Second Clinical School of Guangzhou Medical University Guangzhou China
| | - Biao Hu
- Department of Clinical Medicine The Second Clinical School of Guangzhou Medical University Guangzhou China
| | - Wen-Ju He
- Department of Clinical Medicine The Second Clinical School of Guangzhou Medical University Guangzhou China
| | - Jun-Kui Li
- Department of Clinical Medicine The Second Clinical School of Guangzhou Medical University Guangzhou China
| | - Zi-Ang Ding
- Department of Clinical Medicine The First Clinical School of Guangzhou Medical University Guangzhou China
| | - Zhuo-Yuan Lin
- Department of Urology The Second Affiliated Hospital of Guangzhou Medical University Guangzhou Medical University Guangzhou China
| | - Shi Zhang
- Department of Gastrointestinal Surgery The Second Affiliated Hospital of Guangzhou Medical University Guangzhou China
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10
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Shi AX, Qu Q, Zhuang HH, Teng XQ, Xu WX, Liu YP, Xiao YW, Qu J. Individualized antibiotic dosage regimens for patients with augmented renal clearance. Front Pharmacol 2023; 14:1137975. [PMID: 37564179 PMCID: PMC10410082 DOI: 10.3389/fphar.2023.1137975] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 07/12/2023] [Indexed: 08/12/2023] Open
Abstract
Objectives: Augmented renal clearance (ARC) is a state of enhanced renal function commonly observed in 30%-65% of critically ill patients despite normal serum creatinine levels. Using unadjusted standard dosing regimens of renally eliminated drugs in ARC patients often leads to subtherapeutic concentrations, poor clinical outcomes, and the emergence of multidrug-resistant bacteria. We summarized pharmaceutical, pharmacokinetic, and pharmacodynamic research on the definition, underlying mechanisms, and risk factors of ARC to guide individualized dosing of antibiotics and various strategies for optimizing outcomes. Methods: We searched for articles between 2010 and 2022 in the MEDLINE database about ARC patients and antibiotics and further provided individualized antibiotic dosage regimens for patients with ARC. Results: 25 antibiotic dosage regimens for patients with ARC and various strategies for optimization of outcomes, such as extended infusion time, continuous infusion, increased dosage, and combination regimens, were summarized according to previous research. Conclusion: ARC patients, especially critically ill patients, need to make individualized adjustments to antibiotics, including dose, frequency, and method of administration. Further comprehensive research is required to determine ARC staging, expand the range of recommended antibiotics, and establish individualized dosing guidelines for ARC patients.
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Affiliation(s)
- A-Xi Shi
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China
| | - Qiang Qu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
| | - Hai-Hui Zhuang
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Xin-Qi Teng
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wei-Xin Xu
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Yi-Ping Liu
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Yi-Wen Xiao
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Jian Qu
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
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11
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Dalfino L, Stufano M, Bavaro DF, Diella L, Belati A, Stolfa S, Romanelli F, Ronga L, Di Mussi R, Murgolo F, Loconsole D, Chironna M, Mosca A, Montagna MT, Saracino A, Grasso S. Effectiveness of First-Line Therapy with Old and Novel Antibiotics in Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii: A Real Life, Prospective, Observational, Single-Center Study. Antibiotics (Basel) 2023; 12:1048. [PMID: 37370367 DOI: 10.3390/antibiotics12061048] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Evidence-based, standard antibiotic therapy for ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) is a relevant unmet clinical need in the intensive care unit (ICU). We aimed to evaluate the effectiveness of first-line therapy with old and novel CRAB active antibiotics in monomicrobial VAP caused by CRAB. A prospective, observational study was performed in a mixed non-COVID-19 ICU. The primary outcome measure was clinical failure upon first-line targeted therapy. Features independently influencing failure occurrence were also investigated via Cox proportional multivariable analysis. To account for the imbalance in antibiotic treatment allocation, a propensity score analysis with an inverse probability treatment weighting approach was adopted. Of the 90 enrolled patients, 34 (38%) experienced clinical failure. Compared to patients who experienced a clinical resolution of VAP, those who had clinical failure were of an older age (median age 71 (IQR 64-78) vs. 62 (IQR 52-69) years), and showed greater burden of comorbidities (median Charlson comorbidity index 8 (IQR 6-8) vs. 4 (IQR 2-6)), higher frequency of immunodepression (44% vs. 21%), and greater clinical severity at VAP onset (median SOFA score 10 (IQR 9-11) vs. 9 (IQR 7-11)). Lower rates of use of fast molecular diagnostics for nosocomial pneumonia (8.8% vs. 30.3%) and of timely CRAB active therapy administration (65% vs. 89%), and higher rates of colistin-based targeted therapy (71% vs. 46%) were also observed in patients who failed first-line therapy. Overall, CRAB active iv regimens were colistin-based in 50 patients and cefiderocol-based in 40 patients, both always combined with inhaled colistin. According to the backbone agent of first-line regimens, clinical failure was lower in the cefiderocol group, compared to that in the colistin group (25% vs. 48%, respectively). In multivariable Cox regression analysis, the burden of comorbid conditions independently predicted clinical failure occurrence (Charlson index aHR = 1.21, 95% CI = 1.04-1.42, p = 0.01), while timely targeted antibiotic treatment (aHR = 0.40, 95% CI = 0.19-0.84, p = 0.01) and cefiderocol-based first-line regimens (aHR = 0.38, 95% CI = 0.17-0.85, p = 0.02) strongly reduced failure risk. In patients with VAP caused by CRAB, timely active therapy improves infection outcomes and cefiderocol holds promise as a first-line therapeutic option.
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Affiliation(s)
- Lidia Dalfino
- Intensive Care Unit II, Department of Precision Medicine, Ionic Area, University of Bari "A. Moro", 70124 Bari, Italy
| | - Monica Stufano
- Intensive Care Unit II, Department of Precision Medicine, Ionic Area, University of Bari "A. Moro", 70124 Bari, Italy
| | - Davide Fiore Bavaro
- Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro", 70124 Bari, Italy
| | - Lucia Diella
- Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro", 70124 Bari, Italy
| | - Alessandra Belati
- Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro", 70124 Bari, Italy
| | - Stefania Stolfa
- Microbiology and Virology Unit, Department of Interdisciplinary Medicine, University of Bari "A. Moro", 70124 Bari, Italy
| | - Federica Romanelli
- Microbiology and Virology Unit, Department of Interdisciplinary Medicine, University of Bari "A. Moro", 70124 Bari, Italy
| | - Luigi Ronga
- Microbiology and Virology Unit, Department of Interdisciplinary Medicine, University of Bari "A. Moro", 70124 Bari, Italy
| | - Rosa Di Mussi
- Intensive Care Unit II, Department of Precision Medicine, Ionic Area, University of Bari "A. Moro", 70124 Bari, Italy
| | - Francesco Murgolo
- Intensive Care Unit II, Department of Precision Medicine, Ionic Area, University of Bari "A. Moro", 70124 Bari, Italy
| | - Daniela Loconsole
- Hygiene Section, Department of Interdisciplinary Medicine, University of Bari "A. Moro", 70124 Bari, Italy
| | - Maria Chironna
- Hygiene Section, Department of Interdisciplinary Medicine, University of Bari "A. Moro", 70124 Bari, Italy
| | - Adriana Mosca
- Microbiology and Virology Unit, Department of Interdisciplinary Medicine, University of Bari "A. Moro", 70124 Bari, Italy
| | - Maria Teresa Montagna
- Hygiene Section, Department of Interdisciplinary Medicine, University of Bari "A. Moro", 70124 Bari, Italy
| | - Annalisa Saracino
- Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro", 70124 Bari, Italy
| | - Salvatore Grasso
- Intensive Care Unit II, Department of Precision Medicine, Ionic Area, University of Bari "A. Moro", 70124 Bari, Italy
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12
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Shen H, Na W, Li Y, Qu D. The clinical significance of renal resistance index (RRI) and renal oxygen saturation (RrSO2) in critically ill children with AKI: a prospective cohort study. BMC Pediatr 2023; 23:224. [PMID: 37149642 PMCID: PMC10163685 DOI: 10.1186/s12887-023-03941-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 03/02/2023] [Indexed: 05/08/2023] Open
Abstract
OBJECTIVE The purpose of this study was to look into the clinical significance of the renal resistance index (RRI) and renal oxygen saturation (RrSO2) in predicting the development of acute kidney injury (AKI) in critically ill children. A new non-invasive method for the early detection and prediction of AKI needs to develop. METHODS Patients admitted to the pediatric intensive care unit (PICU) affiliated with the capital institute of pediatrics from December 2020 to March 2021 were enrolled consecutively. Data of clinical information, renal Doppler ultrasound, RrSO2, and hemodynamic index within 24 h of admission were prospectively collected. Patients were divided into two groups: the study group was AKI occurred within 72 h, while the control group did not. SPSS (version 25.0) was used to analyze the data, and P < 0.05 was considered a statistical difference. RESULTS 1) A total of 66 patients were included in this study, and the incidence of AKI was 19.70% (13/66). The presence of risk factors (shock, tumor, severe infection) increased the incidence of AKI by three times. 2) Univariate analysis showed significant differences in length of hospitalization, white blood cells (WBC), C-reactive protein (CRP), renal resistance index (RRI), and ejection fraction (EF) between the study and control groups (P < 0.05). There were no significant differences in renal perfusion semi-quantitative score (P = 0.053), pulsatility index (P = 0.051), pediatric critical illness score (PCIS), and peripheral vascular resistance index (P > 0.05). 3) Receiver operating characteristic (ROC) curve showed that if RRI > 0.635, the sensitivity, specificity, and AUC for predicting AKI were 0.889, 0.552, and 0.751, respectively; if RrSO2 < 43.95%, the values were 0.615, 0.719 and 0.609, respectively; if RRI and RrSO2 were united, they were 0.889, 0.552, and 0.766, respectively. CONCLUSIONS The incidence of AKI is high in PICU patients. And infection, RRI, and EF are risk factors for AKI in PICU patients. RRI and RrSO2 have certain clinical significance in the early prediction of AKI and may provide a new non-invasive method for early diagnosis and prediction of AKI.
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Affiliation(s)
- Huili Shen
- Pediatric Intensive Care Unit, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
- Pediatric Critical Medicine Department, Children's Hospital of Capital Institute of Pediatric, Beijing, China
| | - Weilan Na
- Pediatric Critical Medicine Department, Children's Hospital of Capital Institute of Pediatric, Beijing, China
| | - Yichu Li
- Pediatric Intensive Care Unit, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Dong Qu
- Pediatric Critical Medicine Department, Children's Hospital of Capital Institute of Pediatric, Beijing, China.
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13
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Tran TT, Cabrera NL, Gonzales-Luna AJ, Carlson TJ, Alnezary F, Miller WR, Sakurai A, Dinh AQ, Rydell K, Rios R, Diaz L, Hanson BM, Munita JM, Pedroza C, Shelburne SA, Aitken SL, Garey KW, Dillon R, Puzniak L, Arias CA. Clinical characteristics, microbiology and outcomes of a cohort of patients treated with ceftolozane/tazobactam in acute care inpatient facilities, Houston, Texas, USA. JAC Antimicrob Resist 2023; 5:dlac131. [PMID: 36601551 PMCID: PMC9806660 DOI: 10.1093/jacamr/dlac131] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 11/25/2022] [Indexed: 01/04/2023] Open
Abstract
Background Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination with activity against a variety of Gram-negative bacteria, including MDR Pseudomonas aeruginosa. This agent is approved for hospital-acquired and ventilator-associated bacterial pneumonia. However, most real-world outcome data come from small observational cohorts. Thus, we sought to evaluate the utilization of ceftolozane/tazobactam at multiple tertiary hospitals in Houston, TX, USA. Methods We conducted a multicentre retrospective study of patients receiving at least 48 h of ceftolozane/tazobactam therapy from January 2016 through to September 2019 at two hospital systems in Houston. Demographic, clinical and microbiological data were collected, including the infecting bacterial isolate, when available. The primary outcome was composite clinical success at hospital discharge. Secondary outcomes included in-hospital mortality and clinical disposition at 14 and 30 days post ceftolozane/tazobactam initiation. Multivariable logistic regression analysis was used to identify predictors of the primary outcome and mortality. Recovered isolates were tested for susceptibility to ceftolozane/tazobactam and underwent WGS. Results A total of 263 patients were enrolled, and composite clinical success was achieved in 185 patients (70.3%). Severity of illness was the most consistent predictor of clinical success. Combination therapy with ceftolozane/tazobactam and another Gram-negative-active agent was associated with reduced odds of clinical success (OR 0.32, 95% CI 0.16-0.63). Resistance to ceftolozane/tazobactam was noted in 15.4% of isolates available for WGS; mutations in ampC and ftsI were common but did not cluster with a particular ST. Conclusions Clinical success rate among this patient cohort treated with ceftolozane/tazobactam was similar compared with previous experiences. Ceftolozane/tazobactam remains an alternative agent for treatment of susceptible isolates of P. aeruginosa.
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Affiliation(s)
- Truc T Tran
- Center for Infectious Diseases Research, Houston Methodist Research Institute, Houston, TX, USA
- Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Nicolo L Cabrera
- Division of Infectious Diseases, John T. Milliken Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Anne J Gonzales-Luna
- Department of Pharmacy, Baylor St. Luke’s Medical Center, CHI St. Luke’s Health, Houston, TX, USA
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
| | - Travis J Carlson
- Department of Clinical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, NC, USA
| | - Faris Alnezary
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
- Department of Clinical and Hospital Pharmacy, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - William R Miller
- Center for Infectious Diseases Research, Houston Methodist Research Institute, Houston, TX, USA
- Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Aki Sakurai
- Department of Infectious Diseases and Microbiology, Fujita Health University School of Medicine, Aichi, Japan
| | - An Q Dinh
- Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Kirsten Rydell
- Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Rafael Rios
- Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia
| | - Lorena Diaz
- Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia
- Genomics and Resistant Microbes Group, Facultad de Medicina Clinica Alemana, Universidad del Desarrollo and Millennium Initiative for Collaborative Research On Bacterial Resistance (MICROB-R), Santiago, Chile
| | - Blake M Hanson
- Center for Infectious Diseases, University of Texas Health Science Center School of Public Health, Houston, TX, USA
| | - Jose M Munita
- Genomics and Resistant Microbes Group, Facultad de Medicina Clinica Alemana, Universidad del Desarrollo and Millennium Initiative for Collaborative Research On Bacterial Resistance (MICROB-R), Santiago, Chile
| | - Claudia Pedroza
- Center for Clinical Research and Evidence-Based Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Samuel A Shelburne
- Department of Infectious Diseases, Infection Control & Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Samuel L Aitken
- Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kevin W Garey
- Department of Pharmacy, Baylor St. Luke’s Medical Center, CHI St. Luke’s Health, Houston, TX, USA
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
| | - Ryan Dillon
- Center for Observational and Real-World Evidence (CORE), Merck and Co., Inc., Kenilworth, NJ, USA
| | - Laura Puzniak
- Center for Observational and Real-World Evidence (CORE), Merck and Co., Inc., Kenilworth, NJ, USA
| | - Cesar A Arias
- Center for Infectious Diseases Research, Houston Methodist Research Institute, Houston, TX, USA
- Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
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14
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Rigatto MH, Bergo P, Baldissera G, Beck E, David L, Santoro L, Barros A, Zanin R, Budelon Gonçalves JI, Falci D, Caumo W, Zavascki AP. Melatonin for prevention of acute kidney injury in patients treated with intravenous polymyxin B: a double-blind, placebo-controlled randomized clinical trial. Clin Microbiol Infect 2022; 29:623-628. [PMID: 36586514 DOI: 10.1016/j.cmi.2022.12.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/29/2022]
Abstract
OBJECTIVES To evaluate the effect of melatonin versus placebo on the incidence of acute kidney injury (AKI) in patients treated with polymyxin B. METHODS We performed a single-centre, double-blind, randomized clinical trial (NCT03725267) of 30-mg oral melatonin versus placebo for patients treated with intravenous polymyxin B. Patients aged ≥18 years receiving polymyxin B for ≤48 hours were eligible. Melatonin or placebo pills were administered until the end of polymyxin B treatment or for a maximum of 14 days. The main outcome was any level of AKI. RESULTS Eighty-eight patients were randomized: 44 in the melatonin group and 44 in the placebo group. The study ended prematurely because of polymyxin B shortage during the COVID-19 pandemic. The patients' mean age was 63.6 ± 17.3 years, and 60.2% of the patients were men. Forty-six (52.3%, 23 in each group) patients developed AKI during the follow-up period. The incidence rate of AKI was 81.9/1000 and 77.4/1000 patients per day in melatonin and placebo groups, respectively (hazard ratio, 1.09; 95% CI, 0.61-1.94; p 0.78). Renal failure and 30-day mortality were similar between the groups. Moreover, the incidence of AKI was not different in pre-specified sub-groups. DISCUSSION Melatonin initiated in the first 48 hours of therapy did not reduce the incidence of AKI in patients treated with polymyxin B.
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Affiliation(s)
- Maria H Rigatto
- Medical School and Medical Sciences Post-Graduation Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Infectious Diseases Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Pedro Bergo
- Pontifícia Universidade Católica do Rio Grande do Sul Medical School, Porto Alegre, Brazil
| | - Giulia Baldissera
- Infectious Diseases Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Eduarda Beck
- Pontifícia Universidade Católica do Rio Grande do Sul Medical School, Porto Alegre, Brazil
| | - Leonardo David
- Pontifícia Universidade Católica do Rio Grande do Sul Medical School, Porto Alegre, Brazil
| | - Lucas Santoro
- Pontifícia Universidade Católica do Rio Grande do Sul Medical School, Porto Alegre, Brazil
| | - Andressa Barros
- Infection Control Service, Hospital São Lucas da PUCRS, Porto Alegre, Brazil
| | - Rafael Zanin
- Pontifícia Universidade Católica do Rio Grande do Sul, Health and Life Sciences School, Porto Alegre, Brazil
| | - João I Budelon Gonçalves
- Pontifícia Universidade Católica do Rio Grande do Sul, Health and Life Sciences School, Porto Alegre, Brazil
| | - Diego Falci
- Infectious Diseases Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Pontifícia Universidade Católica do Rio Grande do Sul Medical School, Porto Alegre, Brazil; Infection Control Service, Hospital São Lucas da PUCRS, Porto Alegre, Brazil
| | - Wolnei Caumo
- Medical School and Medical Sciences Post-Graduation Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Pain and Palliative Care Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Alexandre P Zavascki
- Infectious Diseases Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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15
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Al Sulaiman K, Aljuhani O, Alhammad AM, Al Aamer K, Alshehri S, Alhuwahmel A, Kharbosh A, Alshehri A, Alshareef H, Al Sulaihim I, Alghamdi A, Al Harbi S, Vishwakarma R, Alabdan N, Alrajhi Y, Al Katheri A, Alenazi AA, Alalawi M, Al Ghamdi G. The potential role of adjunctive ascorbic acid in the prevention of colistin-induced nephrotoxicity in critically ill patients: A retrospective study. Saudi Pharm J 2022; 30:1748-1754. [PMID: 36601502 PMCID: PMC9805966 DOI: 10.1016/j.jsps.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 10/03/2022] [Indexed: 11/07/2022] Open
Abstract
Background Colistin is considered a valuable and last-resort therapeutic option for MDR gram-negative bacteria. Nephrotoxicity is the most clinically pertinent adverse effect of colistin. Vivo studies suggest that administering oxidative stress-reducing agents, such as ascorbic acid, is a promising strategy to overcome colistin-induced nephrotoxicity (CIN). However, limited clinical data explores the potential benefit of adjunctive ascorbic acid therapy for preventing CIN. Therefore, this study aims to assess the potential nephroprotective role of ascorbic acid as adjunctive therapy against CIN in critically ill patients. Method This was a retrospective cohort study at King Abdulaziz Medical City (KAMC) for all critically ill adult patients who received IV colistin. Eligible patients were classified into two groups based on the ascorbic acid use as concomitant therapy within three days of colistin initiation. The primary outcome was CIN odds after colistin initiation, while the secondary outcomes were 30-day mortality, in-hospital mortality, ICU, and hospital LOS. Propensity score (PS) matching was used (1:1 ratio) based on the patient's age, SOFA score, and serum creatinine. Results A total of 451 patients were screened for eligibility; 90 patients were included after propensity score matching based on the selected criteria. The odds of developing CIN after colistin initiation were similar between patients who received ascorbic acid (AA) as adjunctive therapy compared to patients who did not (OR (95 %CI): 0.83 (0.33, 2.10), p-value = 0.68). In addition, the 30-day mortality, in-hospital mortality, ICU, and hospital LOS were similar between the two groups. Conclusion Adjunctive use of Ascorbic acid during colistin therapy was not associated with lower odds of CIN. Further studies with a larger sample size are required to confirm these findings.
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Key Words
- AA, Ascorbic Acid
- AKI, Acute Kidney Injury
- Ascorbic Acid
- CIN, Colistin-induced Nephrotoxicity
- CKD, Chronic kidney disease
- Colistin
- Colistin-induced nephrotoxicity
- HD, Hemodialysis
- ICU, Intensive Care Unit
- LOS, Length of Stay
- MDR, Multiple drug resistance
- Mortality
- Nephrotoxicity
- PS, Propensity Score
- Vitamin C
- XDR, Extensively drug-resistant
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Affiliation(s)
- Khalid Al Sulaiman
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia,College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia,Department of Pharmacy Practice, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O.Box 84428, Riyadh 11671, Saudi Arabia,Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia,Corresponding author at: King Abdulaziz Medical City (KAMC) - Ministry of National Guard Health Affairs (MNGHA), King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, 11426 Riyadh, Saudi Arabia.
| | - Ohoud Aljuhani
- Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdullah M. Alhammad
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Kholoud Al Aamer
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Sara Alshehri
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Abdulmohsen Alhuwahmel
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Abdullah Kharbosh
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | | | - Hanan Alshareef
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Ibrahim Al Sulaihim
- Pharmaceutical Care Department, Presidency of State Security, Central Security Hospitals, Riyadh, Saudi Arabia
| | - Albandari Alghamdi
- Department of Pharmacy Practice, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O.Box 84428, Riyadh 11671, Saudi Arabia
| | - Shmeylan Al Harbi
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia,College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Ramesh Vishwakarma
- Statistics Department, European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
| | - Numan Alabdan
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia,College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Yousef Alrajhi
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia,College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Abdulmalik Al Katheri
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia,College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Abeer A. Alenazi
- Pharmaceutical Care Department, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Mai Alalawi
- Department of Pharmaceutical Sciences, Fakeeh College of Medical Sciences, Jeddah, Saudi Arabia
| | - Ghassan Al Ghamdi
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia,Intensive Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia,College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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16
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Juneja D, Nasa P, Jain R. Current role of high dose vitamin C in sepsis management: A concise review. World J Crit Care Med 2022; 11:349-363. [PMID: 36439321 PMCID: PMC9693906 DOI: 10.5492/wjccm.v11.i6.349] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/08/2022] [Accepted: 09/09/2022] [Indexed: 02/05/2023] Open
Abstract
Sepsis and septic shock are common diagnoses for patients requiring intensive care unit admission and associated with high morbidity and mortality. In addition to aggressive fluid resuscitation and antibiotic therapy, several other drugs have been tried as adjuvant therapies to reduce the inflammatory response and improve outcomes. Vitamin C has been shown to have several biological actions, including anti-inflammatory and immunomodulatory effects, which may prove beneficial in sepsis management. Initial trials showed improved patient outcomes when high dose vitamin C was used in combination with thiamine and hydrocortisone. These results, along with relative safety of high-dose (supra-physiological) vitamin C, encouraged physicians across the globe to add vitamin C as an adjuvant therapy in the management of sepsis. However, subsequent large-scale randomised control trials could not replicate these results, leaving the world divided regarding the role of vitamin C in sepsis management. Here, we discuss the rationale, safety profile, and the current clinical evidence for the use of high-dose vitamin C in the management of sepsis and septic shock.
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Affiliation(s)
- Deven Juneja
- Institute of Critical Care Medicine, Max Super Speciality Hospital, New Delhi 110017, India
| | - Prashant Nasa
- Department of Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
| | - Ravi Jain
- Department of Critical Care Medicine, Mahatma Gandhi Medical College and Hospital, Jaipur 302022, Rajasthan, India
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17
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Wang JL, Xiang BX, Song XL, Que RM, Zuo XC, Xie YL. Prevalence of polymyxin-induced nephrotoxicity and its predictors in critically ill adult patients: A meta-analysis. World J Clin Cases 2022; 10:11466-11485. [PMID: 36387815 PMCID: PMC9649555 DOI: 10.12998/wjcc.v10.i31.11466] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/15/2022] [Accepted: 09/23/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Polymyxin-induced nephrotoxicity is a major safety concern in clinical practice due to long-term adverse outcomes and high mortality.
AIM To conducted a systematic review and meta-analysis of the prevalence and potential predictors of polymyxin-induced nephrotoxicity in adult intensive care unit (ICU) patients.
METHODS PubMed, EMBASE, the Cochrane Library and Reference Citation Analysis database were searched for relevant studies from inception through May 30, 2022. The pooled prevalence of polymyxin-induced nephrotoxicity and pooled risk ratios of associated factors were analysed using a random-effects or fixed-effects model by Stata SE ver. 12.1. Additionally, subgroup analyses and meta-regression were conducted to assess heterogeneity.
RESULTS A total of 89 studies involving 12234 critically ill adult patients were included in the meta-analysis. The overall pooled incidence of polymyxin-induced nephrotoxicity was 34.8%. The pooled prevalence of colistin-induced nephrotoxicity was not higher than that of polymyxin B (PMB)-induced nephrotoxicity. The subgroup analyses showed that nephrotoxicity was significantly associated with dosing interval, nephrotoxicity criteria, age, publication year, study quality and sample size, which were confirmed in the univariable meta-regression analysis. Nephrotoxicity was significantly increased when the total daily dose was divided into 2 doses but not 3 or 4 doses. Furthermore, older age, the presence of sepsis or septic shock, hypoalbuminemia, and concomitant vancomycin or vasopressor use were independent risk factors for polymyxin-induced nephrotoxicity, while an elevated baseline glomerular filtration rate was a protective factor against colistin-induced nephrotoxicity.
CONCLUSION Our findings indicated that the incidence of polymyxin-induced nephrotoxicity among ICU patients was high. It emphasizes the importance of additional efforts to manage ICU patients receiving polymyxins to decrease the risk of adverse outcomes.
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Affiliation(s)
- Jiang-Lin Wang
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Bi-Xiao Xiang
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Xiao-Li Song
- Department of Pharmacy, Sanya Central Hospital, Sanya 572000, Hainan Province, China
| | - Rui-Man Que
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Xiao-Cong Zuo
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Yue-Liang Xie
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
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18
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Alshaya AI, Bin Saleh K, Aldhaeefi M, Baderldin HA, Alamody FO, Alhamdan QA, Almusallam MA, Alshaya O, Al Sulaiman K, Alshareef S, Alowais SA, Al Harbi SA, Alghamdi G. Colistin Loading Dose in Septic Patients with Gram Negative Infections. Infect Drug Resist 2022; 15:2159-2166. [PMID: 35498632 PMCID: PMC9048962 DOI: 10.2147/idr.s361244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/08/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Intravenous (IV) colistin is commonly used to treat multidrug-resistant gram-negative infections. It is primarily eliminated renally and may induce acute kidney injury (AKI) at a rate of up to 53%. Consequently, septic patients who require colistin administration have an additional risk of developing AKI. The aim of this study is to investigate clinical failure and AKI predictors for septic patients treated with IV colistin. Methods This retrospective cohort study was conducted at a tertiary teaching hospital in Saudi Arabia. Adult septic patients with suspected or confirmed gram-negative infections who received colistin admitted to the hospital between May 2016 and December 2020 were screened after obtaining IRB approval. AKI was defined based on the AKI Network criteria. We investigated the incidence of clinical failure based on colistin dosing and AKI risk factors, such as the development of septic shock, severity of illness, and medication co-administration using a multiple logistic regression model. Results After screening 163 patients, 103 patients were included in the analysis. No difference was observed between the colistin dosing strategies for clinical failure. Of the included predictors, development of septic shock (OR: 3.75; 95% CI 1.18-13.15), carbapenem co-administration (OR, 3.96; 95% CI, 1.134-15.57) were associated with an increased risk of AKI. The other factors were not significant predictors. Conclusion Clinical failure was not affected by colistin dosing strategies in our cohort of patients with sepsis. Moreover, the co-administration of carbapenems and the development of septic shock may increase the risk of inducing AKI in adult septic patients treated with IV colistin. Further studies are required to confirm these findings.
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Affiliation(s)
- Abdulrahman I Alshaya
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.,Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Khalid Bin Saleh
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.,Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Mohammed Aldhaeefi
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.,Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Hisham A Baderldin
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.,Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Farris O Alamody
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Qusai A Alhamdan
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Mohammed A Almusallam
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Omar Alshaya
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.,Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Khalid Al Sulaiman
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.,Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Shaima Alshareef
- Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Shuroug A Alowais
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.,Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Shmeylan A Al Harbi
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.,Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Ghassan Alghamdi
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.,College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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19
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Sistanizad M, Hassanpour R, Pourheidar E. Are Antibiotics Appropriately Dosed in Critically Ill Patients with Augmented Renal Clearance? A Narrative Review. Int J Clin Pract 2022; 2022:1867674. [PMID: 35685541 PMCID: PMC9159163 DOI: 10.1155/2022/1867674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/17/2021] [Accepted: 12/03/2021] [Indexed: 11/18/2022] Open
Abstract
AIMS Augmented renal clearance (ARC), which is commonly defined as increased renal clearance above 130 ml/min/1.73 m2, is a common phenomenon among critically ill patients. The increased elimination rate of drugs through the kidneys in patients with ARC can increase the risk of treatment failure due to the exposure to subtherapeutic serum concentrations of medications and affect the optimal management of infections, length of hospital stay, and outcomes. The main goal of this review article is to summarize the recommendations for appropriate dosing of antibiotics in patients with ARC. METHODS This article is a narrative review of the articles that evaluated different dosing regimens of antibiotics in patients with ARC. The keywords "Augmented Renal Clearance," "Critically ill patients," "Drug dosing," "Serum concentration," "Beta-lactams," "Meropenem," "Imipenem," "Glycopeptide," "Vancomycin," "Teicoplanin," "Linezolid," "Colistin," "Aminoglycosides," "Amikacin," "Gentamycin," "Fluoroquinolones," "Ciprofloxacin," and "Levofloxacin" were searched in Scopus, Medline, PubMed, and Google Scholar databases, and pediatric, nonhuman, and non-English studies were excluded. RESULTS PK properties of antibiotics including lipophilicity or hydrophilicity, protein binding, the volume of distribution, and elimination rate that affect drug concentration should be considered along with PD parameters for drug dosing in critically ill patients with ARC. CONCLUSION This review recommends a dosing protocol for some antibiotics to help the appropriate dosing of antibiotics in ARC and decrease the risk of subtherapeutic exposure that may be observed while receiving conventional dosing regimens in critically ill patients with ARC.
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Affiliation(s)
- Mohammad Sistanizad
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Prevention of Cardiovascular Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rezvan Hassanpour
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Pourheidar
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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20
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Prasannan BK, Mukthar FC, Unni VN, Mohan S, Vinodkumar K. Colistin Nephrotoxicity-Age and Baseline kidney Functions Hold the Key. Indian J Nephrol 2021; 31:449-453. [PMID: 34880554 PMCID: PMC8597794 DOI: 10.4103/ijn.ijn_130_20] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/11/2020] [Accepted: 11/03/2020] [Indexed: 11/28/2022] Open
Abstract
Introduction: With the emergence of multidrug-resistant gram-negative bacterial infections, there has been a surge in the use of Colistin in recent times. The most important side effect of Colistin use is its nephrotoxicity. The study was designed to assess the effect on kidney function and the risk factors for nephrotoxicity in patients treated with Colistin. Methods: The study is a retrospective one, which included patients who received Colistin for more than 48 hours. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) four-variable equation and acute kidney injury (AKI) was diagnosed as per the Kidney Disease Improving Global Outcome (KDIGO) criteria. Results: Of the 150 patients studied, 59 patients (39.2%) developed AKI within a median period of 4 days (Range 2–20 days) of initiation of Colistin. Age, eGFR at the start of therapy and requirement of vasopressor support for treatment of septic shock were the most important risk factors associated with nephrotoxicity. Among patients with AKI, nearly half had only mild worsening of renal functions to KDIGO AKI stage 1. Nearly 75% of patients with AKI had complete or partial recovery of renal functions after stopping Colistin. Conclusion: Colistin has significant nephrotoxicity, the risk being higher with older age and baseline renal dysfunction. It is important to monitor renal functions early and at regular intervals after initiating therapy.
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Affiliation(s)
| | - Faiz C Mukthar
- Department of Nephrology, Aster Medcity, Kochi, Kerala, India
| | | | - Shilpa Mohan
- Department of Nephrology, Aster Medcity, Kochi, Kerala, India
| | - K Vinodkumar
- Department of Nephrology, Aster Medcity, Kochi, Kerala, India
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21
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Haseeb A, Faidah HS, Alghamdi S, Alotaibi AF, Elrggal ME, Mahrous AJ, Almarzoky Abuhussain SS, Obaid NA, Algethamy M, AlQarni A, Khogeer AA, Saleem Z, Sheikh A. Dose Optimization of Colistin: A Systematic Review. Antibiotics (Basel) 2021; 10:antibiotics10121454. [PMID: 34943666 PMCID: PMC8698549 DOI: 10.3390/antibiotics10121454] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/13/2021] [Accepted: 11/16/2021] [Indexed: 11/16/2022] Open
Abstract
Colistin is considered a last treatment option for multi-drug and extensively resistant Gram-negative infections. We aimed to assess the available data on the dosing strategy of colistin. A systematic review was performed to identify all published studies on the dose optimization of colistin. Grey literature and electronic databases were searched. Data were collected in a specified form and the quality of the included articles was then assessed using the Newcastle-Ottawa scale for cohort studies, the Cochrane bias tool for randomized clinical trials (RCT), and the Joanna Briggs Institute (JBI) critical checklist for case reports. A total of 19 studies were included, of which 16 were cohort studies, one was a RCT, and two were case reports. A total of 18 studies proposed a dosing regimen for adults, while only one study proposed a dosing schedule for pediatric populations. As per the available evidence, a loading dose of 9 million international units (MIU) of colistin followed by a maintenance dose of 4.5 MIU every 12 h was considered the most appropriate dosing strategy to optimize the safety and efficacy of treatment and improve clinical outcomes. This review supports the administration of a loading dose followed by a maintenance dose of colistin in severe and life-threatening multi-drug Gram-negative bacterial infections.
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Affiliation(s)
- Abdul Haseeb
- Department of Clinical Pharmacy, College of Pharmacy, Umm Al Qura University, Makkah 24382, Saudi Arabia; (A.F.A.); (M.E.E.); (A.J.M.); (S.S.A.A.)
- Correspondence: ; Tel.: +96-656-856-0776
| | - Hani Saleh Faidah
- Department of Microbiology, Faculty of Medicine, Umm Al Qura University, Makkah 24382, Saudi Arabia;
| | - Saleh Alghamdi
- Department of Clinical Pharmacy, Faculty of Clinical Pharmacy, Al Baha University, Al Baha 65779, Saudi Arabia;
| | - Amal F. Alotaibi
- Department of Clinical Pharmacy, College of Pharmacy, Umm Al Qura University, Makkah 24382, Saudi Arabia; (A.F.A.); (M.E.E.); (A.J.M.); (S.S.A.A.)
| | - Mahmoud Essam Elrggal
- Department of Clinical Pharmacy, College of Pharmacy, Umm Al Qura University, Makkah 24382, Saudi Arabia; (A.F.A.); (M.E.E.); (A.J.M.); (S.S.A.A.)
| | - Ahmad Jamal Mahrous
- Department of Clinical Pharmacy, College of Pharmacy, Umm Al Qura University, Makkah 24382, Saudi Arabia; (A.F.A.); (M.E.E.); (A.J.M.); (S.S.A.A.)
| | - Safa S. Almarzoky Abuhussain
- Department of Clinical Pharmacy, College of Pharmacy, Umm Al Qura University, Makkah 24382, Saudi Arabia; (A.F.A.); (M.E.E.); (A.J.M.); (S.S.A.A.)
| | - Najla A. Obaid
- Department of Pharmaceutics, College of Pharmacy, Umm Al Qura University, Makkah 24382, Saudi Arabia;
| | - Manal Algethamy
- Alnoor Specialist Hospital, Department of Infection Prevention & Control Program, Makkah 24382, Saudi Arabia;
| | - Abdullmoin AlQarni
- Alnoor Specialist Hospital, Infectious Diseases Department, Makkah 24382, Saudi Arabia;
| | - Asim A. Khogeer
- Plan and Research Department, General Directorate of Health Affairs of Makkah Regiona, Ministry of Health, Makkah 24382, Saudi Arabia;
- Medical Genetics Unit, Maternity & Children Hospital, Makkah Healthcare Cluster, Ministry of Health, Makkah 24382, Saudi Arabia
| | - Zikria Saleem
- Department of Pharmacy Practice, Faculty of Pharmacy, The University of Lahore, Lahore 54000, Pakistan;
| | - Aziz Sheikh
- Usher Institute, The University of Edinburgh, Teviot Place, Edinburgh EH16 4UX, UK;
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22
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Jafari F, Elyasi S. Prevention of colistin induced nephrotoxicity: a review of preclinical and clinical data. Expert Rev Clin Pharmacol 2021; 14:1113-1131. [PMID: 34015235 DOI: 10.1080/17512433.2021.1933436] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Introduction: The emergence of antimicrobial resistance in Gram-negative bacteria is a concerning challenge for health systems. The polymyxins, including colistin, are one of the limited available options these pathogens management. Nephrotoxicity, beside neurotoxicity is the major dose-limiting adverse reaction of polymyxins, with an up to 60% prevalence. As oxidative stress, inflammatory pathways and apoptosis are considered as the main mechanisms of colistin-induced kidney damage, various studies have evaluated antioxidant and/or antiapoptotic compounds for its prevention. In this article, we reviewed animal and human studies on these probable preventive measures.Area covered: PubMed, Scopus, and google scholar databases were searched using several combination of 'colistin', 'polymyxin E', 'CMS', 'Colistimethate sodium', 'nephrotoxicity', 'kidney injury', 'kidney damage', 'renal injury', 'renal damage', 'nephroprotectants', 'renoprotective', 'nephroprotective', and 'prevention'. All eligible articles including animal and human studies up to the end of 2020 were included.Expert opinion: Most of available studies are in vivo researches on anti-oxidant and anti-apoptotic agents like NAC, vitamin C and E, silymarin, and curcumin which mostly showed promising findings. However, limited human studies on NAC and vitamin C did not demonstrate considerable efficacy. So, before proposing these compounds, further well-designed randomized clinical trials are necessary.
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Affiliation(s)
- Fatemeh Jafari
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sepideh Elyasi
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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23
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Gunay E, Kaya S, Baysal B, Yuksel E, Arac E. Evaluation of prognosis and nephrotoxicity in patients treated with colistin in intensive care unit. Ren Fail 2021; 42:704-709. [PMID: 32703065 PMCID: PMC7470093 DOI: 10.1080/0886022x.2020.1795878] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Introduction Nephrotoxicity is the most important adverse effect of colistin therapy. We investigated the frequency of nephrotoxicity, risk factors related to nephrotoxicity, and its relationship with mortality in patients who received intravenous colistin in intensive care units (ICUs). Materials and methods We retrospectively reviewed the data of patients who received intravenous colistin in ICUs between 2011 and 2017. Acute kidney injury (AKI) diagnosis and staging were made based on the Kidney Disease Improving Global Outcome criteria. Results There were 149 patients included in the study with 61% being male. The mean age was 58.7 ± 20.3 years. AKI was detected in 96 (64.4%) patients. There were 25 patients with AKI stage 1 (16.8%) and 71 patients with AKI stage 2 or 3 (47.7%). Advanced age (65.0 vs. 47.4 years; p < .001), diabetes mellitus (p < .001), heart failure (p = .01), high APACHE II score (31.7 vs. 28.08, p = .019), and inotrope usage (p = .01) were found as risk factors for AKI. The 14-day mortality rate was higher in the AKI group (p = .027). Discussion Higher AKI and mortality rates are observed in patients with diabetes, heart failure, advanced age and the hemodynamically impaired. However, it is a fact that there are no alternative therapies other than colistin in the treatment of multidrug-resistant Gram-negative bacterial infections. Therefore, the development of AKI in this patient group should not be considered a sufficient reason for discontinuing colistin treatment. Understanding the risk factors in this potential nephrotoxic treatment can provide a more careful patient follow-up.
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Affiliation(s)
- Emrah Gunay
- Department of Nephrology, University of Health Sciences, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey
| | - Safak Kaya
- Department of Infectious Diseases and Clinical Microbiology, University of Health Sciences, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey
| | - Birol Baysal
- Department of Gastroenterology, Memorial Sisli Hospital, Istanbul, Turkey
| | - Enver Yuksel
- Department of Nephrology, University of Health Sciences, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey
| | - Esref Arac
- Department of Internal Medicine, University of Health Sciences, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey
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The effects of vitamin E on colistin-induced nephrotoxicity in treatment of drug-resistant gram-negative bacterial infections: A randomized clinical trial. J Infect Chemother 2021; 27:1181-1185. [PMID: 33863635 DOI: 10.1016/j.jiac.2021.03.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Nephrotoxicity remains a major long-standing concern for colistin, and it is critical to find agents that can prevent it. The present study aims to investigate the effect of vitamin E on the prevention of colistin-induced nephrotoxicity based on its antioxidant and free radical scavenging properties. METHODS A randomized clinical trial was designed for 52 patients taking colistin. These patients were categorized into two groups of equal size, receiving colistin or colistin plus vitamin E (α-Tocopherol). Vitamin E with doses of 400 units was administrated daily either orally or by a nasogastric tube if needed. The incidence of Acute Kidney Injury (AKI) and its duration was recorded based on RIFLE criteria. RESULTS The Incidence of AKI based on RIFLE criteria was 42.3% and 46.2% in intervention and control groups, respectively. The analysis showed no significant difference in the prevalence of AKI for the two groups (P = 0.78). There was no significant difference in the duration of AKI neither (P = 0.83). CONCLUSION Although vitamin E is a powerful biological antioxidant, the effects of Vitamin E prophylaxis on colistin-induced nephrotoxicity was not taken into consideration in this study.
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Abstract
Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales. Polymyxins were first discovered in the late 1940s but were abandoned soon after their approval in the late 1950s as a result of toxicities (e.g., nephrotoxicity) and the availability of "safer" antibiotics approved at that time. Therefore, knowledge on polymyxins had been scarce until recently, when enormous efforts have been made by several research teams around the world to elucidate the chemical, microbiological, pharmacokinetic/pharmacodynamic, and toxicological properties of polymyxins. One of the major achievements is the development of the first scientifically based dosage regimens for colistin that are crucial to ensure its safe and effective use in patients. Although the guideline has not been developed for polymyxin B, a large clinical trial is currently being conducted to optimize its clinical use. Importantly, several novel, safer polymyxin-like lipopeptides are developed to overcome the nephrotoxicity, poor efficacy against pulmonary infections, and narrow therapeutic windows of the currently used polymyxin B and colistin. This review discusses the latest achievements on polymyxins and highlights the major challenges ahead in optimizing their clinical use and discovering new-generation polymyxins. To save lives from the deadly infections caused by Gram negative "superbugs," every effort must be made to improve the clinical utility of the last-line polymyxins. SIGNIFICANCE STATEMENT: Antimicrobial resistance poses a significant threat to global health. The increasing prevalence of multidrug-resistant (MDR) bacterial infections has been highlighted by leading global health organizations and authorities. Polymyxins are a last-line defense against difficult-to-treat MDR Gram negative pathogens. Unfortunately, the pharmacological information on polymyxins was very limited until recently. This review provides a comprehensive overview on the major achievements and challenges in polymyxin pharmacology and clinical use and how the recent findings have been employed to improve clinical practice worldwide.
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Affiliation(s)
- Sue C Nang
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia (S.C.N., M.A.K.A., J.L.); Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia (T.V.); and Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana (Q.T.Z.)
| | - Mohammad A K Azad
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia (S.C.N., M.A.K.A., J.L.); Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia (T.V.); and Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana (Q.T.Z.)
| | - Tony Velkov
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia (S.C.N., M.A.K.A., J.L.); Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia (T.V.); and Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana (Q.T.Z.)
| | - Qi Tony Zhou
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia (S.C.N., M.A.K.A., J.L.); Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia (T.V.); and Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana (Q.T.Z.)
| | - Jian Li
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia (S.C.N., M.A.K.A., J.L.); Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia (T.V.); and Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana (Q.T.Z.)
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Wagenlehner F, Lucenteforte E, Pea F, Soriano A, Tavoschi L, Steele VR, Henriksen AS, Longshaw C, Manissero D, Pecini R, Pogue JM. Systematic review on estimated rates of nephrotoxicity and neurotoxicity in patients treated with polymyxins. Clin Microbiol Infect 2021; 27:S1198-743X(20)30764-3. [PMID: 33359542 DOI: 10.1016/j.cmi.2020.12.009] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 11/03/2020] [Accepted: 12/10/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Nephrotoxicity and neurotoxicity are commonly associated with polymyxin treatment; however, the emergence of multidrug-resistant Gram-negative bacteria with limited therapeutic options has resulted in increased use of polymyxins. OBJECTIVES To determine the rates of nephrotoxicity and neurotoxicity during polymyxin treatment and whether any factors influence these. DATA SOURCES Medline, Embase and Cochrane Library databases were searched on 2 January 2020. STUDY ELIGIBILITY CRITERIA Studies reporting nephrotoxicity and/or neurotoxicity rates in patients with infections treated with polymyxins were included. Reviews, meta-analyses and reports not in English were excluded. PARTICIPANTS Patients hospitalized with infections treated with systemic or inhaled polymyxins were included. For comparative analyses, patients treated with non-polymyxin-based regimens were also included. METHODS Meta-analyses were performed using a random-effects model; subgroup meta-analyses were conducted where data permitted using a mixed-effects model. RESULTS In total, 237 reports of randomized controlled trials, cohort and case-control studies were eligible for inclusion; most were single-arm observational studies. Nephrotoxic events in 35,569 patients receiving polymyxins were analysed. Overall nephrotoxicity rate was 0.282 (95% confidence interval (CI) 0.259-0.307). When excluding studies where >50% of patients received inhaled-only polymyxin treatment or nephrotoxicity assessment was by methods other than internationally recognized criteria (RIFLE, KDIGO or AKIN), the nephrotoxicity rate was 0.391 (95% CI 0.364-0.419). The odds of nephrotoxicity were greater with polymyxin therapies compared to non-polymyxin-based regimens (odds ratio 2.23 (95% CI 1.58-3.15); p < 0.001). Meta-analyses showed a significant effect of polymyxin type, dose, patient age, number of concomitant nephrotoxins and use of diuretics, glycopeptides or vasopressors on the rate of nephrotoxicity. Polymyxin therapies were not associated with a significantly different rate of neurotoxicity than non-polymyxin-based regimens (p 0.051). The overall rate of neurotoxicity during polymyxin therapy was 0.030 (95% CI 0.020-0.043). CONCLUSIONS Polymyxins are associated with a higher risk of nephrotoxicity than non-polymyxin-based regimens.
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Affiliation(s)
- Florian Wagenlehner
- Clinic for Urology, Pediatric Urology and Andrology, Justus-Liebig-University, Giessen, Germany
| | - Ersilia Lucenteforte
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Federico Pea
- Department of Medicine, University of Udine and Institute of Clinical Pharmacology, SM Misericordia University Hospital, ASUIUD, Udine, Italy
| | - Alex Soriano
- Infectious Diseases Department, Hospital Clínic of Barcelona, University of Barcelona IDIBAPS, Barcelona, Spain
| | - Lara Tavoschi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | | | | | | | - Davide Manissero
- University College of London, Institute for Global Health, London, UK
| | | | - Jason M Pogue
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
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Zhao S, Chen F, Yin Q, Wang D, Han W, Zhang Y. Reactive Oxygen Species Interact With NLRP3 Inflammasomes and Are Involved in the Inflammation of Sepsis: From Mechanism to Treatment of Progression. Front Physiol 2020; 11:571810. [PMID: 33324236 PMCID: PMC7723971 DOI: 10.3389/fphys.2020.571810] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/30/2020] [Indexed: 12/13/2022] Open
Abstract
Over the past 10 years, the crisis of sepsis has remained a great challenge. According to data from 2016, the sepsis-related mortality rate remains high. In addition, sepsis consumes extensive medical resources in intensive care units, and anti-inflammatory agents fail to improve sepsis-associated hyperinflammation and symptoms of immunosuppression. The specific immune mechanism of sepsis remains to be elucidated. Reactive oxygen species (ROS) are triggered by energy metabolism and respiratory dysfunction in sepsis, which not only cause oxidative damage to tissues and organelles, but also directly and indirectly promote NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. NLRP3 inflammasomes enlarge the inflammatory response and trigger apoptosis of immune cells to exacerbate sepsis progression. Inhibiting the negative effects of ROS and NLRP3 inflammasomes therefore provides the possibility of reversing the excessive inflammation during sepsis. In this review, we describe the interaction of ROS and NLRP3 inflammasomes during sepsis, provide prevention strategies, and identify fields that need further study.
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Affiliation(s)
- Shuai Zhao
- Department of Anesthesiology, First Hospital of Jilin University, Changchun, China
| | - Fan Chen
- Department of Neurosurgery, University Medicine Greifswald, Greifswald, Germany
| | - Qiliang Yin
- Department of Oncology, First Hospital of Jilin University, Changchun, China
| | - Dunwei Wang
- Department of Anesthesiology, First Hospital of Jilin University, Changchun, China
| | - Wei Han
- Department of Anesthesiology, First Hospital of Jilin University, Changchun, China
| | - Yuan Zhang
- Department of Anesthesiology, First Hospital of Jilin University, Changchun, China
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Aitullina A, Purviņa S, Krūmiņa A. Colistin co-administration with other nephrotoxins: experience of teaching hospital of Latvia. Int J Clin Pharm 2020; 43:509-517. [PMID: 32996073 DOI: 10.1007/s11096-020-01154-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 09/14/2020] [Indexed: 12/30/2022]
Abstract
Background Colistin is a potentially nephrotoxic antibiotic used for the management of multidrug-resistant bacterial infections in critically ill patients. Co-administration with other nephrotoxins was reported as a potentially modifiable risk factor of colistin acute kidney injury. Objective To establish the role of colistin dosing and co-medications in development of colistin kidney injury. Setting Community teaching hospital in Latvia. Method Adult patients from intensive care units with diagnosed Gram-negative bacterial infections, undergoing colistin treatment for longer than 72 h, and not receiving renal replacement therapy were included in this retrospective study. Main outcome measure Colistin nephrotoxicity was defined as an increase in the serum creatinine level by at least 50% from the baseline after ≥ 48 h. Results In 73 of 87 cases, Acinetobacter baumannii pneumonia was diagnosed. The nephrotoxicity rate was 27.6% with a median onset of 8 days. In 79% of the cases, colistin was co-administrated with at least one potentially nephrotoxic agent. The most used nephrotoxins were loop diuretics (44 cases), non-steroidal anti-inflammatory drugs (19 cases) and vancomycin (11 cases). The use of nephrotoxins was similar in patients with colistin nephrotoxicity (group-1) and without it (group-2). Carbapenems were more common in group-2 (37% vs 62%, p = 0.004) and a colistin loading dose of 9 MU in group-1 (87% vs 62%, p = 0.027). However, in the multifactor regression analysis, the protective role of carbapenems was not confirmed. Conclusion Potentially nephrotoxic agents are commonly co-administrated with colistin. This study failed to prove their role in the development of acute kidney injury.
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Affiliation(s)
- Aleksandra Aitullina
- Department of Pharmacology, Riga Stradins University, 13 Pilsonu St., Riga, 1002, Latvia. .,Paul Stradins Clinical University Hospital, Riga, Latvia.
| | - Santa Purviņa
- Department of Pharmacology, Riga Stradins University, 13 Pilsonu St., Riga, 1002, Latvia.,Paul Stradins Clinical University Hospital, Riga, Latvia
| | - Angelika Krūmiņa
- Department of Infectology, Riga Stradins University, 3 Linezera St., Riga, 1006, Latvia.,Riga East Clinical University Hospital, Riga, Latvia
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29
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Temboot P, Kaewpaiboon S, Tinpun K, Nakpeng T, Khalil R, Ul-Haq Z, Thamlikitkul V, Tiengrim S, Srichana T. Potential of sodium deoxycholate sulfate as a carrier for polymyxin B: Physicochemical properties, bioactivity and in vitro safety. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101779] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Choe J, Sohn YM, Jeong SH, Park HJ, Na SJ, Huh K, Suh GY, Jeon K. Inhalation with intravenous loading dose of colistin in critically ill patients with pneumonia caused by carbapenem-resistant gram-negative bacteria. Ther Adv Respir Dis 2020; 13:1753466619885529. [PMID: 31680646 PMCID: PMC6852352 DOI: 10.1177/1753466619885529] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: Despite the increasing use of colistin in clinical practice, the optimal
dosing, and administration route have not been established. This study aimed
to evaluate the clinical outcome and safety of intravenous (IV) colistin
with a loading dose (LD) and adjunctive aerosolized (AS) colistin
administration in critically ill patients with hospital-acquired pneumonia
(HAP) or ventilator-associated pneumonia (VAP) caused by
carbapenem-resistant gram-negative bacteria (CRGNB). Methods: We retrospectively reviewed 191 critically ill patients who received colistin
for the treatment of HAP or VAP caused by CRGNB. Patients were divided into
three groups: non-LD IV (patients received only IV colistin without LD), LD
IV (patients received only IV colistin with LD), and AS–LD (patients
received IV colistin with LD and adjunctive AS colistin). Results: There was no difference in clinical response between the three groups.
However, the rate of microbiological eradication was significantly higher in
the AS–LD group (60%) than in the non-LD IV (31%), and LD IV (33%) groups
(p = 0.010). Patients treated with adjunctive AS
colistin in combination with LD IV had significantly lower 30-day mortality
rates than patients treated with IV colistin alone
(p = 0.027). After adjusting for potential confounding
factors, adjunctive AS colistin was still significantly associated with
lower mortality (adjusted OR 0.338, CI 95% 0.132–0.864,
p = 0.024). However, nephrotoxicity did not change
according to the use of LD regimen and AS colistin administration
(p = 0.100). Conclusions: Adjunctive AS colistin in combination with IV colistin with LD was related to
an improved 30-day mortality and microbiological outcome without an increase
in nephrotoxicity in critically ill patients with HAP and VAP caused by
CRGNB. The reviews of this paper are available via the supplemental
material section.
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Affiliation(s)
- Junsu Choe
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - You Min Sohn
- Department of Pharmaceutical Services, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Suk Hyeon Jeong
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hyo Jung Park
- Department of Pharmaceutical Services, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Soo Jin Na
- Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyungmin Huh
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Gee Young Suh
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyeongman Jeon
- Department of Critical Care Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
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31
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Heybeli C, Canaslan K, Oktan MA, Yıldız S, Arda HÜ, Çavdar C, Çelik A, Gökmen N, Cömert B. Acute kidney injury following colistin treatment in critically-ill patients: may glucocorticoids protect? J Chemother 2020; 33:85-94. [PMID: 32500843 DOI: 10.1080/1120009x.2020.1770027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Nephrotoxicity following colistin administration is common and factors alleviating nephrotoxicity are yet to be determined. We retrospectively evaluated outcomes of subjects who were treated with colistin (n = 133) and with antibiotics other than colistin (control, n = 133) in intensive care units. Acute kidney injury (AKI) occurred in 69.2% and 29.3% of patients in colistin and control groups, respectively (p < 0.001). In the colistin group, glucocorticoid exposure was more common in subjects who did not develop AKI (p < 0.001). This was not the case in the control group. In the colistin cohort, older age (per 10 years, odds ratio [OR] 1.41, 95% CI 1.05-1.91; p = 0.025), PPI use (OR 3.30, 95% CI 1.18-9.23; p = 0.023) and furosemide treatment (OR 2.66, 95% CI 1.01-6.98; p = 0.047) were independently associated with the development of AKI while glucocorticoid treatment (OR 0.23, 95% CI 0.10-0.53; p = 0.001) was independently associated with reduced risk of AKI. Mortality was observed in 74 patients in the colistin cohort (55.6%). A higher APACHE-II score (OR 1.17, 95% CI 1.08-1.26; p < 0.001) was independently associated with mortality while a higher serum albumin level (per 1 g/dL increase, OR 0.20, 95% CI 0.070-0.60; p = 0.004) was associated with a lower risk of mortality. In conclusion, glucocorticoid exposure is associated with a lower risk of AKI caused by colistin therapy in critically-ill patients. Prospective studies are needed to confirm these findings and determine the optimal type, dose and duration of glucocorticoid therapy.
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Affiliation(s)
- Cihan Heybeli
- Department of Internal Medicine, Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Kübra Canaslan
- Department of Internal Medicine, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Mehmet Ası Oktan
- Department of Internal Medicine, Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Serkan Yıldız
- Department of Internal Medicine, Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Hayri Üstün Arda
- Department of Internal Medicine, Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Caner Çavdar
- Department of Internal Medicine, Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Ali Çelik
- Department of Internal Medicine, Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Necati Gökmen
- Department of Anesthesiology and Reanimation, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Bilgin Cömert
- Department of Internal Medicine, Division of Intensive Care Medicine, Dokuz Eylül University School of Medicine, Izmir, Turkey
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Pampa-Saico S, Pintado V, Muriel A, Caravaca-Fontan F, Yerovi-León E, Rojo-Sanchis A, Del Rey JM, Teresa Tenorio M, Liaño F. Colistimethate sodium and acute kidney injury: Incidence, risk factors, outcome and prognosis of renal function. Nefrologia 2020; 40:647-654. [PMID: 32473742 DOI: 10.1016/j.nefro.2020.04.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/12/2020] [Accepted: 04/02/2020] [Indexed: 10/24/2022] Open
Abstract
BACKGROUND Colistimethate sodium (CMS) treatment has increased over the last years, being acute kidney injury (AKI) its main drug-related adverse event. Therefore, this study aimed to evaluate the incidence and risk factors associated with AKI, as well as identifying the factors that determine renal function (RF) outcomes at six months after discharge. MATERIALS AND METHODS This retrospective study included adult septic patients receiving intravenous CMS for at least 48h (January 2007-December 2014). AKI was assessed using KDIGO criteria. The glomerular filtration rate (GFR) was estimated by the 4-variable MDRD equation. Logistic and linear models were performed to evaluate the risk factors for AKI and chronic kidney disease (CKD). RESULTS Among 126 patients treated with CMS; the incidence of AKI was 48.4%. Sepsis-severe sepsis (OR 8.07, P=0.001), sepsis-septic shock (OR 42.9, P<0.001), and serum creatinine (SCr) at admission (OR 6.20, P=0.009) were independent predictors. Eighty-four patients survived; the main factors for RF evolution at the 6-month follow-up was baseline eGFR (0.58, P<0.001) and at discharge (0.34, P<0.001). Fifty-six percent (34/61) of the patients that developed AKI survived. At six months, 32% had CKD. CONCLUSIONS The development of AKI in septic patients with CMS treatment was associated with sepsis severity and SCr at admission. Baseline eGFR and eGFR at discharge were and important determinant of the RF at the 6-month follow-up. These predictors may assist in clinical decision making for this patient population.
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Affiliation(s)
- Saúl Pampa-Saico
- Department of Nephrology, Hospital Universitario Ramón y Cajal, Madrid, Spain.
| | - Vicente Pintado
- Department of Infectious Diseases, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Alfonso Muriel
- Department of Clinical Biostatistics, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRyCis), RedinRenISCIII (ERC 10 RD12/0021/0020), Madrid, Spain
| | | | | | | | - José M Del Rey
- Department of Biochemistry, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - M Teresa Tenorio
- Department of Nephrology, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Fernando Liaño
- Department of Nephrology, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRyCis), RedinRenISCIII (ERC 10 RD12/0021/0020), Madrid, Spain
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Comparison of Treatment Outcomes between Analysis Populations in the RESTORE-IMI 1 Phase 3 Trial of Imipenem-Cilastatin-Relebactam versus Colistin plus Imipenem-Cilastatin in Patients with Imipenem-Nonsusceptible Bacterial Infections. Antimicrob Agents Chemother 2020; 64:AAC.02203-19. [PMID: 32094127 DOI: 10.1128/aac.02203-19] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 02/13/2020] [Indexed: 02/07/2023] Open
Abstract
The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.).
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Bellos I, Pergialiotis V, Frountzas M, Kontzoglou K, Daskalakis G, Perrea DN. Efficacy and safety of colistin loading dose: a meta-analysis. J Antimicrob Chemother 2020; 75:1689-1698. [DOI: 10.1093/jac/dkaa064] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/22/2020] [Accepted: 02/04/2020] [Indexed: 11/12/2022] Open
Abstract
Abstract
Objectives
Colistin represents a polypeptide used for the treatment of MDR microorganisms, although the optimal dosing strategy is under investigation. The present meta-analysis aims to determine whether the administration of a colistin loading dose in patients receiving high-dose maintenance regimens changes the rates of treatment success and the risk of nephrotoxicity.
Methods
Medline, Scopus, CENTRAL, Clinicaltrials.gov and Google Scholar were systematically searched from inception to 18 November 2019. Studies were considered eligible if they reported clinical outcomes among patients receiving high-dose colistin therapy with and without the administration of a loading dose. Meta-analysis was performed by fitting a random-effects model.
Results
Eight (three prospective and five retrospective cohort) studies were included, comprising 1115 patients. The administration of a colistin loading dose was associated with significantly higher microbiological [risk ratio (RR) = 1.23, 95% CI = 1.10–1.39] but not clinical (RR = 1.04, 95% CI = 0.87–1.24) success. No significant associations were calculated for nephrotoxicity (RR = 1.31, 95% CI = 0.90–1.91) and mortality (RR = 1.03, 95% CI = 0.82–1.29) risk. The results remained stable after adjustments for small sample size, credibility ceilings, publication bias and risk of bias.
Conclusions
Observational evidence suggests that the administration of a colistin loading dose in patients receiving high maintenance dosage regimens is significantly associated with higher rates of microbiological response, but does not change clinical cure, mortality or nephrotoxicity risk. The dosing regimen that would provide the optimal balance between treatment efficacy and safety needs to be determined by future randomized controlled trials.
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Affiliation(s)
- Ioannis Bellos
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasilios Pergialiotis
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Maximos Frountzas
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Kontzoglou
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Daskalakis
- First Department of Obstetrics and Gynaecology, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Despina N Perrea
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, Giacobbe DR, Viscoli C, Giamarellou H, Karaiskos I, Kaye D, Mouton JW, Tam VH, Thamlikitkul V, Wunderink RG, Li J, Nation RL, Kaye KS. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy 2020; 39:10-39. [PMID: 30710469 DOI: 10.1002/phar.2209] [Citation(s) in RCA: 593] [Impact Index Per Article: 118.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin-based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.
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Affiliation(s)
- Brian T Tsuji
- School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York
| | | | - Alexandre P Zavascki
- Department of Internal Medicine, Medical School, Universidade Federal, do Rio Grande do Sul, Porto Alegre, Brazil.,Infectious Diseases Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Mical Paul
- Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel.,The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
| | - George L Daikos
- First Department of Propaedeutic Medicine, Laikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Alan Forrest
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Daniele R Giacobbe
- Infectious Diseases Unit, Ospedale Policlinico San Martino-Istituto di Ricovero e Cura a Carattere Scientifico per l'Oncologia, Genoa, Italy.,Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Claudio Viscoli
- Infectious Diseases Unit, Ospedale Policlinico San Martino-Istituto di Ricovero e Cura a Carattere Scientifico per l'Oncologia, Genoa, Italy.,Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Helen Giamarellou
- 1st Department of Internal Medicine, Infectious Diseases, Hygeia General Hospital, Athens, Greece
| | - Ilias Karaiskos
- 1st Department of Internal Medicine, Infectious Diseases, Hygeia General Hospital, Athens, Greece
| | - Donald Kaye
- Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Johan W Mouton
- Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands
| | - Vincent H Tam
- University of Houston College of Pharmacy, Houston, Texas
| | - Visanu Thamlikitkul
- Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Richard G Wunderink
- Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Jian Li
- Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Roger L Nation
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Keith S Kaye
- Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan
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Brown ML, Motsch J, Kaye KS, File TM, Boucher HW, Vendetti N, Aggrey A, Joeng HK, Tipping RW, Du J, DePestel DD, Butterton JR, Paschke A. Evaluation of Renal Safety Between Imipenem/Relebactam and Colistin Plus Imipenem in Patients With Imipenem-Nonsusceptible Bacterial Infections in the Randomized, Phase 3 RESTORE-IMI 1 Study. Open Forum Infect Dis 2020; 7:ofaa054. [PMID: 32154325 PMCID: PMC7052751 DOI: 10.1093/ofid/ofaa054] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 02/18/2020] [Indexed: 11/16/2022] Open
Abstract
Background In the randomized controlled RESTORE-IMI 1 clinical trial (NCT02452047), imipenem/cilastatin (IMI) with relebactam (IMI/REL) was as effective as colistin plus IMI for the treatment of imipenem-nonsusceptible gram-negative infections. Differences in nephrotoxicity were observed between treatment arms. As there is no standard definition of nephrotoxicity used in clinical trials, we conducted analyses to further understand the renal safety profile of both treatments. Methods Nephrotoxicity was retrospectively evaluated using 2 acute kidney injury assessment criteria (Kidney Disease Improving Global Outcomes [KDIGO] and Risk, Injury, Failure, Loss, and End-stage Kidney Disease [RIFLE]). Additional outcomes included time to onset of protocol-defined nephrotoxicity and incidence of renal adverse events. Results Of 47 participants receiving treatment, 45 had sufficient data to assess nephrotoxicity (IMI/REL, n = 29; colistin plus IMI, n = 16). By KDIGO criteria, no participants in the IMI/REL but 31.3% in the colistin plus IMI group experienced stage 3 acute kidney injury. No IMI/REL-treated participants experienced renal failure by RIFLE criteria, vs 25.0% for colistin plus IMI. Overall, the time to onset of nephrotoxicity varied considerably (2–22 days). Fewer renal adverse events (12.9% vs 37.5%), including discontinuations due to drug-related renal adverse events (0% vs 12.5%), were observed in the IMI/REL group compared with the colistin plus IMI group, respectively. Conclusions Our analyses confirm the findings of a preplanned end point and provide further evidence that IMI/REL had a more favorable renal safety profile than colistin-based therapy in patients with serious, imipenem-nonsusceptible gram-negative bacterial infections. ClinicalTrials.gov Identifier NCT02452047.
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Affiliation(s)
| | - Johann Motsch
- Universitätsklinikum Heidelberg, Heidelberg, Germany
| | - Keith S Kaye
- University of Michigan, Ann Arbor, Michigan, USA
| | | | | | | | | | | | | | - Jiejun Du
- Merck & Co., Inc., Kenilworth, New Jersey, USA
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Honore PM, Spapen HD, Marik P, Boer W, Oudemans-van Straaten H. Dosing vitamin C in critically ill patients with special attention to renal replacement therapy: a narrative review. Ann Intensive Care 2020; 10:23. [PMID: 32052229 PMCID: PMC7016079 DOI: 10.1186/s13613-020-0640-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 02/06/2020] [Indexed: 01/02/2023] Open
Abstract
Rationale/methods The primary aim of the present contribution is to find a literature-based agreement on dose adjustments of vitamin C in critically ill patients undergoing renal replacement therapy (RRT). Available data/study results Critical illness is frequently accompanied by severe vitamin C deficiency. High-dose supplementation beneficially affects clinical outcome in small cohorts of patients with sepsis, burn injury, and trauma. There are no specific data on clinical outcomes in patients receiving renal replacement therapy (RRT). Vitamin C plasma concentrations in patients on RRT are comparable to critically ill patients not receiving RRT. Vitamin C is cleared from the circulation during RRT at a rate dependent on the plasma concentration, dose and duration of RRT. Sieving coefficient is about 1. While the dose of RRT is lower than normal renal function, tubular reabsorption is absent. Sparse evidence suggests that vitamin C dosing during continuous RRT should not exceed the dose administered to critically ill patients not receiving continuous RRT. Low plasma concentrations are expected during prolonged RRT because of persistent extracorporeal removal, absent renal reabsorption and enhanced metabolic loss due to circuit-induced oxidative stress. A dosage of twice 1 g vitamin C daily may be necessary to achieve normal plasma concentrations during RRT, but more studies are needed. There is no available evidence that high doses of vitamin C administered over a short period can induce oxalate stones or has pro-oxidant effects. Conclusions Supplementing vitamin C 1 g twice daily to critically ill patients has a solid pathophysiological rationale and a good safety profile. Patients on RRT probably need similar doses as critically ill patients not receiving RRT. Intravenous vitamin C in a dose of 2 g/day may be necessary to achieve normal plasma concentrations during RRT. However, data on dose adjustment of vitamin C during intermittent or chronic RRT are sparse and require more thorough pharmacokinetic and dose–response studies.
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Affiliation(s)
- Patrick M Honore
- ICU Dept, Centre Hospitalier Universitaire Brugmann/Brugmann University Hospîtal, Place Van Gehuchtenplein, 4, 1020, Brussels, Belgium.
| | - Herbert D Spapen
- Development, Ageing & Pathology Research Department, Vrije Universiteit Brussel, Brussels, Belgium
| | - Paul Marik
- Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, 825 Fairfax Av, Suite 410, Norfolk, VA, 23507, USA
| | - Willem Boer
- Dept. of Anesthesiology, Intensive Care Medicine, Emergency Medicine & Pain Medicine, Ziekenhuis Oost-Limburg Genk, Genk, Belgium
| | - Heleen Oudemans-van Straaten
- Department of Intensive Care Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
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Karaiskos I, Lagou S, Pontikis K, Rapti V, Poulakou G. The "Old" and the "New" Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How. Front Public Health 2019; 7:151. [PMID: 31245348 PMCID: PMC6581067 DOI: 10.3389/fpubh.2019.00151] [Citation(s) in RCA: 177] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 05/23/2019] [Indexed: 12/15/2022] Open
Abstract
The recent expansion of multidrug resistant and pan-drug-resistant pathogens poses significant challenges in the treatment of healthcare associated infections. An important advancement, is a handful of recently launched new antibiotics targeting some of the current most problematic Gram-negative pathogens, namely carbapenem-producing Enterobacteriaceae (CRE) and carbapenem-resistant P. aeruginosa (CRPA). Less options are available against carbapenem-resistant Acinetobacter baumannii (CRAB) and strains producing metallo-beta lactamases (MBL). Ceftazidime-avibactam signaled a turning point in the treatment of KPC and partly OXA- type carbapenemases, whereas meropenem-vaborbactam was added as a potent combination against KPC-producers. Ceftolozane-tazobactam could be seen as an ideal beta-lactam backbone for the treatment of CRPA. Plazomicin, an aminoglycoside with better pharmacokinetics and less toxicity compared to other class members, will cover important proportions of multi-drug resistant pathogens. Eravacycline holds promise in the treatment of infections by CRAB, with a broad spectrum of activity similar to tigecycline, and improved pharmacokinetics. Novel drugs and combinations are not to be considered "panacea" for the ongoing crisis in the therapy of XDR Gram-negative bacteria and colistin will continue to be considered as a fundamental companion drug for the treatment of carbapenem-resistant Enterobacteriaceae (particularly in areas where MBL predominate), for the treatment of CRPA (in many cases being the only in vitro active drug) as well as CRAB. Aminoglycosides are still important companion antibiotics. Finally, fosfomycin as part of combination treatment for CRE infections and P. aeruginosa, deserves a greater attention. Optimal conditions for monotherapy and the "when and how" of combination treatments integrating the novel agents will be discussed.
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Affiliation(s)
- Ilias Karaiskos
- First Department of Internal Medicine-Infectious Diseases, Hygeia General Hospital, Athens, Greece
| | - Styliani Lagou
- Third Department of Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Pontikis
- ICU First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasiliki Rapti
- Third Department of Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Garyphallia Poulakou
- Third Department of Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Song Y, Kadiyala U, Weerappuli P, Valdez JJ, Yalavarthi S, Louttit C, Knight JS, Moon JJ, Weiss DS, VanEpps JS, Takayama S. Antimicrobial Microwebs of DNA-Histone Inspired from Neutrophil Extracellular Traps. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1807436. [PMID: 30698844 PMCID: PMC6467213 DOI: 10.1002/adma.201807436] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 01/16/2019] [Indexed: 05/07/2023]
Abstract
Neutrophil extracellular traps (NETs) are decondensed chromatin networks released by neutrophils that can trap and kill pathogens but can also paradoxically promote biofilms. The mechanism of NET functions remains ambiguous, at least in part, due to their complex and variable compositions. To unravel the antimicrobial performance of NETs, a minimalistic NET-like synthetic structure, termed "microwebs," is produced by the sonochemical complexation of DNA and histone. The prepared microwebs have structural similarity to NETs at the nanometer to micrometer dimensions but with well-defined molecular compositions. Microwebs prepared with different DNA to histone ratios show that microwebs trap pathogenic Escherichia coli in a manner similar to NETs when the zeta potential of the microwebs is positive. The DNA nanofiber networks and the bactericidal histone constituting the microwebs inhibit the growth of E. coli. Moreover, microwebs work synergistically with colistin sulfate, a common and a last-resort antibiotic, by targeting the cell envelope of pathogenic bacteria. The synthesis of microwebs enables mechanistic studies not possible with NETs, and it opens new possibilities for constructing biomimetic bacterial microenvironments to better understand and predict physiological pathogen responses.
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Affiliation(s)
- Yang Song
- Wallace H Coulter Department of Biomedical Engineering & Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology & Emory School of Medicine, Atlanta, GA, 30332, USA
| | - Usha Kadiyala
- Department of Emergency Medicine, Michigan Center for Integrative Research in Critical Care, Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Priyan Weerappuli
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jordan J. Valdez
- Emory Antibiotic Resistance Center, Emory Vaccine Center, School of Medicine, Emory University, Atlanta, GA, 30307, USA
| | | | - Cameron Louttit
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jason S. Knight
- Division of Rheumatology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - James J. Moon
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - David S. Weiss
- Emory Antibiotic Resistance Center, Emory Vaccine Center, School of Medicine, Emory University, Atlanta, GA, 30307, USA
| | - J. Scott VanEpps
- Department of Emergency Medicine, Michigan Center for Integrative Research in Critical Care, Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Shuichi Takayama
- Wallace H Coulter Department of Biomedical Engineering & Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology & Emory School of Medicine, Atlanta, GA, 30332, USA
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Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity. Antibiotics (Basel) 2019; 8:antibiotics8010024. [PMID: 30875778 PMCID: PMC6466603 DOI: 10.3390/antibiotics8010024] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/07/2019] [Accepted: 03/11/2019] [Indexed: 12/20/2022] Open
Abstract
Polymyxins are valuable antimicrobials for the management of multidrug-resistant Gram-negative bacteria; however, nephrotoxicity associated with these drugs is a very common side effect that occurs during treatment. This article briefly reviews nephrotoxic mechanisms and risk factors for polymyxin-associated acute kidney injury (AKI) and discusses dosing strategies that may mitigate kidney damage without compromising antimicrobial activity. Polymyxins have a very narrow therapeutic window and patients requiring treatment with these drugs are frequently severely ill and have multiple comorbidities, which increases the risk of AKI. Notably, there is a significant overlap between therapeutic and toxic plasma polymyxin concentrations that substantially complicates dose selection. Recent dosing protocols for both colistin and polymyxin B have been developed and may help fine tune dose adjustment of these antibiotics. Minimizing exposure to modifiable risk factors, such as other nephrotoxic agents, is strongly recommended. The dose should be carefully selected, particularly in high-risk patients. The administration of oxidative stress-reducing drugs is a promising strategy to ameliorate polymyxin-associated AKI, but still requires support from clinical studies.
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Prestwood J, Chang D, McGann P, Barsoumian AE. Successful Use of Colistin Monotherapy as Outpatient Parenteral Antibiotic Therapy for XDR Acinetobacter Hepatic Abscesses. Mil Med 2019; 184:e311-e313. [PMID: 30252091 DOI: 10.1093/milmed/usy241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 08/01/2018] [Indexed: 11/13/2022] Open
Abstract
Acinetobacter baumannii is naturally resistant to several classes of antibiotics and readily develops further resistance mechanisms under antibiotic pressure. For patients infected with extremely drug-resistant organisms, effective antibiotic treatments are intravenous and often require inpatient hospitalization for monitoring and dose adjustment. A 31-year-old active duty service member, stationed in Southeast Asia, sustained thermal burns from an electrical arc injury to over 40% of his total body surface area. His hospital course was complicated by multiple extensively drug resistant (XDR) A. baumanii infections including bacteremia and hepatic abscesses. To facilitate discharge to his family, his hepatic abscesses were treated successfully as an outpatient with several weeks of parenteral colistin monotherapy. With regular renal function testing, his dosages were held and/or adjusted to compensate for acute kidney injuries, and he was successfully cleared of his infection. Up to 50% of A. baumannii isolates in American hospitals, including major DOD facilities, are carbapenem resistant. As a result, historically last-line therapies, such as polymyxins, are increasingly used as treatment. New dosing guidance is emphasized to minimize renal toxicities. This case demonstrates the ability to administer parenteral colistin as an outpatient under close supervision.
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Affiliation(s)
- Jackson Prestwood
- Department of Medicine, Brooke Army Medical Center, 3551 Roger Brooke Dr., JBSA- Ft. Sam Houston TX
| | - David Chang
- Department of Medicine, Infectious Disease Service, Landstuhl Regional Medical Center, CMR 402, APO, AE
| | - Patrick McGann
- Multi-Drug Resistant Organism Repository and Surveillance Network (MRSN), Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD
| | - Alice E Barsoumian
- Department of Medicine, Brooke Army Medical Center, 3551 Roger Brooke Dr., JBSA- Ft. Sam Houston TX
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Aitullina A, Krūmiņa A, Svirskis Š, Purviņa S. Colistin Use in Patients with Extreme Renal Function: From Dialysis to Augmented Clearance. ACTA ACUST UNITED AC 2019; 55:medicina55020033. [PMID: 30709064 PMCID: PMC6409577 DOI: 10.3390/medicina55020033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 01/20/2019] [Accepted: 01/28/2019] [Indexed: 11/24/2022]
Abstract
Background and objectives: Colistin is used for the treatment of multidrug-resistant (MDR) Gram-negative bacteria infection in critically ill patients. It is recommended to adjust the dose in cases of renal impairment but not in cases of augmented renal clearance (ARC). The aim of this study was to determine colistin use pattern in patients with different renal functional states. Materials and Methods: Adult patients admitted to intensive care units of single Latvian hospitals in the years 2015–2017 with an MDR Gram-negative bacterial infection and at least 72 h colistin therapy were included in this study. Data were collected retrospectively from medical notes. Colistin use pattern and outcomes were analyzed in patients with different renal function prior to colistin therapy: normal, ARC, impaired, and on renal replacement therapy (RRT). Results: 100 cases of colistin use met the inclusion criteria. The study group was heterogeneous, and patients had different renal function states prior to colistin therapy-from continuous RRT (18 cases) to ARC (16 cases). The standard colistin dose of 9 million units (MU) daily was the most common dose among the patients. In many cases (43%), colistin dose adjustment did not follow the recent recommendations of drug manufacturers-this was mainly in patients with renal impairment prior to colistin therapy. Eighteen cases of colistin acute kidney injury (AKI) were detected, mostly (10 cases) in patients with normal renal function and without ARC prior to colistin therapy. No patients with colistin AKI needed RRT. Conclusions: Colistin doses varied greatly among patients, and in patients with renal function impairment it was commonly not in accordance with the summary of product characteristics (SPC). Patients with ARC mostly received a standard colistin daily dose of 9 MU daily, but the cumulative dose had a tendency to be higher and duration of colistin therapy was longer in comparison with other patient groups. ARC’s role in the development of colistin nephrotoxicity is still unclear.
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Affiliation(s)
- Aleksandra Aitullina
- Department of Pharmacology, Riga Stradins University, Pilsonu Street 13, Riga, LV-1002, Latvia.
| | - Angelika Krūmiņa
- Department of Infectology and Dermatology, Riga Stradins University, Linezera Street 3, Riga, LV-1006, Latvia.
| | - Šimons Svirskis
- Microbiology and Virology Institute, Riga Stradins University, Ratsupites Street 5, LV-1067 Riga, Latvia.
| | - Santa Purviņa
- Department of Pharmacology, Riga Stradins University, Pilsonu Street 13, Riga, LV-1002, Latvia.
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Azad MAK, Nation RL, Velkov T, Li J. Mechanisms of Polymyxin-Induced Nephrotoxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1145:305-319. [PMID: 31364084 DOI: 10.1007/978-3-030-16373-0_18] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Polymyxin-induced nephrotoxicity is the major dose-limiting factor and can occur in up to 60% of patients after intravenous administration. This chapter reviews the latest literature on the mechanisms of polymyxin-induced nephrotoxicity and its amelioration. After filtration by glomeruli, polymyxins substantially accumulate in renal proximal tubules via receptor-mediated endocytosis mainly by megalin and PEPT2. It is believed that subsequently, a cascade of interconnected events occur, including the activation of death receptor and mitochondrial apoptotic pathways, mitochondrial damage, endoplasmic reticulum stress, oxidative stress and cell cycle arrest. The current literature shows that oxidative stress plays a key role in polymyxin-induced kidney damage. Use of antioxidants have a potential in the attenuation of polymyxin-induced nephrotoxicity, thereby widening the therapeutic window. Mechanistic findings on polymyxin-induced nephrotoxicity are critical for the optimization of their use in the clinic and the discovery of safer polymyxin-like antibiotics.
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Affiliation(s)
- Mohammad A K Azad
- Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC, Australia
| | - Roger L Nation
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Melbourne, VIC, Australia
| | - Tony Velkov
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Jian Li
- Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC, Australia.
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Hanedan B, Ozkaraca M, Kirbas A, Kandemir FM, Aktas MS, Kilic K, Comakli S, Kucukler S, Bilgili A. Investigation of the effects of hesperidin and chrysin on renal injury induced by colistin in rats. Biomed Pharmacother 2018; 108:1607-1616. [DOI: 10.1016/j.biopha.2018.10.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 10/01/2018] [Accepted: 10/02/2018] [Indexed: 12/25/2022] Open
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Oliota AF, Penteado ST, Tonin FS, Fernandez-Llimos F, Sanches AC. Nephrotoxicity prevalence in patients treated with polymyxins: a systematic review with meta-analysis of observational studies. Diagn Microbiol Infect Dis 2018; 94:41-49. [PMID: 30635223 DOI: 10.1016/j.diagmicrobio.2018.11.008] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 11/06/2018] [Accepted: 11/12/2018] [Indexed: 12/15/2022]
Abstract
Colistin and polymyxin B are increasingly reintroduced in clinical practice due to the absence of effective antibiotics for the treatment of emerging infections caused by gram-negative bacteria. The synthesis of current evidence on the characteristics of polymyxins, especially regarding nephrotoxicity, is necessary. This study aims to conduct a systematic review and meta-analysis of cohort-type observational studies in order to identify the prevalence of nephrotoxicity in patients treated with either colistin or polymyxin B. PubMed, Scopus, and DOAJ electronic databases were searched, and manual searches were done. Cohort studies evaluating renal damage (nephrotoxicity) in adult patients caused by colistin or polymyxin B were included. Meta-analyses of the prevalence of nephrotoxicity as well as cumulative meta-analysis and meta-regression were conducted. After the systematic searches, 95 cohorts (n = 7911 patients) were included for analysis. The nephrotoxicity prevalence was 26.7% [confidence interval (CI) 95%: 22.8-30.9%] for colistin and 29.8% (CI 23.8-36.7%) for polymyxin B (P = 0.720). The publication year of the studies, the criteria used to classify renal damage, and the nephrotoxicity as primary or secondary outcome showed a significant influence on the adverse event rates.
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Affiliation(s)
- Ana F Oliota
- Center for Medical and Pharmaceutical Sciences, Universidade Estadual do Oeste do Paraná, Cascavel, Brazil
| | - Suelem T Penteado
- Center for Medical and Pharmaceutical Sciences, Universidade Estadual do Oeste do Paraná, Cascavel, Brazil
| | - Fernanda S Tonin
- Postgraduate Program in Pharmaceutical Sciences, Universidade Federal do Paraná, Curitiba, Brazil
| | - Fernando Fernandez-Llimos
- Research Institute for Medicines (iMed.ULisboa), Departament of Social Pharmacy, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
| | - Andreia C Sanches
- Center for Medical and Pharmaceutical Sciences, Universidade Estadual do Oeste do Paraná, Cascavel, Brazil.
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Maniara BP, Healy LE, Doan TL. Risk of Nephrotoxicity Associated With Nonrenally Adjusted Intravenous Polymyxin B Compared to Traditional Dosing. J Pharm Pract 2018; 33:287-292. [PMID: 30253682 DOI: 10.1177/0897190018799261] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Polymyxin B's package insert recommends renal adjustment. Contemporary studies suggest it does not require renal adjustment. OBJECTIVE To determine whether time to acute kidney injury (AKI) differs between renally adjusted and nonadjusted intravenous (IV) polymyxin B. METHODS This retrospective chart review compared time to AKI after renally adjusted and nonadjusted IV polymyxin B administration. It included patients who were 18 years or older, received IV polymyxin B, and had creatinine clearance below 80 mL/min, and excluded ones who had AKI, received renal replacement therapy, or were pregnant. RESULTS Fifty-four patients were included. There was not any statistical association between dosing type and time to AKI (P = .13). Incidence of nephrotoxicity, mortality, and length of stay (LOS) were higher in the renally adjusted arm (21.7% vs 6.5%, 17.4% vs 6.5%, and 16 vs 14 days, respectively). Four patients received concomitant ascorbic acid; not one developed AKI. CONCLUSION A significant association between IV polymyxin B dosing type and time to AKI was not found. Adverse events were higher in the renally adjusted arm. This suggests that nonadjusted IV polymyxin B may be preferred in patients with renal impairment. Ascorbic acid may mitigate IV polymyxin B's nephrotoxic potential. Further studies are needed to corroborate these findings.
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Affiliation(s)
- Bejoy P Maniara
- Department of Pharmacy, PGY-2 Infectious Diseases Resident Pharmacist, James J. Peters VA Medical Center, Bronx, NY, USA
| | - Lauren E Healy
- Medical Intensive Care Unit, Department of Pharmacy, Long Island Jewish Medical Center, New Hyde Park, NY, USA
| | - Thien-Ly Doan
- Infectious Disease, Department of Pharmacy, Long Island Jewish Medical Center, New Hyde Park, NY, USA
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Chuang L, Ratnayake L. Overcoming challenges of treating extensively drug-resistant Acinetobacter baumannii bacteraemic urinary tract infection. Int J Antimicrob Agents 2018; 52:521-522. [PMID: 30081140 DOI: 10.1016/j.ijantimicag.2018.07.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/14/2018] [Accepted: 07/18/2018] [Indexed: 11/17/2022]
Affiliation(s)
- Leyland Chuang
- Department of Medicine, Ng Teng Fong General Hospital, National University Health System, 1 Jurong East Street 21, Singapore 609606.
| | - Lasantha Ratnayake
- Department of Laboratory Medicine, Ng Teng Fong General Hospital, National University Health System, Singapore
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50
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Escolà-Vergé L, Pigrau C, Los-Arcos I, Arévalo Á, Viñado B, Campany D, Larrosa N, Nuvials X, Ferrer R, Len O, Almirante B. Ceftolozane/tazobactam for the treatment of XDR Pseudomonas aeruginosa infections. Infection 2018; 46:461-468. [PMID: 29594953 DOI: 10.1007/s15010-018-1133-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 03/16/2018] [Indexed: 12/01/2022]
Abstract
PURPOSE The aim of this study was to evaluate the effectiveness of ceftolozane/tazobactam (C/T) for treating extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) infections, and to analyze whether high C/T dosing (2 g ceftolozane and 1 g tazobactam every 8 h) and infection source control have an impact on outcome. METHODS Retrospective study of all consecutive patients treated with C/T for XDR-PA infection at a tertiary referral hospital (November 2015-July 2017). Main clinical and microbiological variables were analyzed. RESULTS Thirty-eight patients were included. Median age was 59.5 years and Charlson Comorbidity Index was 3.5. Fourteen (36.8%) patients had respiratory tract infection, six (15.8%) soft tissue, and six (15.8%) urinary tract infection. Twenty-three (60.5%) received high-dose C/T and in 24 (63.2%) C/T was combined with other antibiotics. At completion of treatment, 33 (86.8%) patients showed clinical response. At 90 days of follow-up, 26 (68.4%) achieved clinical cure, and 12 (31.6%) had clinical failure because of persistent infection in one patient, death attributable to the XDR-PA infection in four, and clinical recurrence in seven. All-cause mortality was 5 (13.2%). Lower C/T MIC and adequate infection source control were the only variables significantly associated with clinical cure. CONCLUSIONS C/T should be considered for treating XDR-PA infections, with infection source control being an important factor to avoid failure and resistance.
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Affiliation(s)
- Laura Escolà-Vergé
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.,Spanish Network for Research in Infectious Diseases (REIPI), Madrid, Spain
| | - Carles Pigrau
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.,Spanish Network for Research in Infectious Diseases (REIPI), Madrid, Spain
| | - Ibai Los-Arcos
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
| | - Ángel Arévalo
- Pharmacy Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Belen Viñado
- Microbiology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Spanish Network for Research in Infectious Diseases (REIPI), Madrid, Spain
| | - David Campany
- Pharmacy Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Nieves Larrosa
- Microbiology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Spanish Network for Research in Infectious Diseases (REIPI), Madrid, Spain
| | - Xavier Nuvials
- Intensive Care Department and SODIR Research Group, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ricard Ferrer
- Intensive Care Department and SODIR Research Group, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Oscar Len
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
| | - Benito Almirante
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain. .,Spanish Network for Research in Infectious Diseases (REIPI), Madrid, Spain.
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