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Jagua-Gualdrón A, García-Reyes NA, Africano-Lopez HL. Apitherapy for drug-induced kidney disease: a narrative review on its mechanisms. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2025:jcim-2025-0082. [PMID: 40178599 DOI: 10.1515/jcim-2025-0082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 03/12/2025] [Indexed: 04/05/2025]
Abstract
OBJECTIVES The use of medications for the treatment of various diseases often results in kidney damage. Apitherapy is a natural therapeutic tool with potential utility for this purpose. This narrative review analyzes and summarizes the scientific evidence on the use of apitherapy in drug-induced kidney disease. CONTENT This review summarizes and analyzes recent advances in drug-induced kidney disease and explores, based on the available scientific evidence, how apitherapy can modify these mechanisms and be utilized for prevention and treatment. SUMMARY Apitherapy (the complementary and integrative use of beehive products) is a potentially useful therapeutic system for the treatment of various diseases. This review examines the preclinical and clinical evidence available regarding its potential use in drug-induced kidney disease. OUTLOOK Apitherapy has effects on various pathophysiological mechanisms of drug-induced kidney disease, including oxidative stress, inflammation, decreased renal blood flow, glomerular damage, increased membrane permeability, activity of the renin-angiotensin-aldosterone axis, mitochondrial dysfunction, and apoptosis. Further studies in humans are needed to evaluate its efficacy in the clinical setting, but the available evidence is promising.
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Affiliation(s)
- Andrés Jagua-Gualdrón
- National University of Colombia, Bogotá D.C., Colombia
- International Institute for Complementary and Alternative Medicine-IIMAN, Bogotá D.C., Colombia
- International College of Apitherapy, Bogotá D.C., Colombia
| | - Nicolai Andrés García-Reyes
- National University of Colombia, Bogotá D.C., Colombia
- International Institute for Complementary and Alternative Medicine-IIMAN, Bogotá D.C., Colombia
| | - Holman Leonardo Africano-Lopez
- Fundación Universitaria de Ciencias de la Salud, Sociedad de Cirugía de Bogotá, Hospital San José Sede Centro, Bogotá D.C., Colombia
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Yu Z, Hu H, Liu X, Liu J, Yu L, Wei A, Xin C, Gan Y, Lei S, Zhuang L, Shen Y, Du X, Zhu J, Yang Y, Liang G, Guo F, Zhang J, Yu Y. Clinical outcomes and pharmacokinetics/pharmacodynamics of intravenous polymyxin B treatment for various site carbapenem-resistant gram-negative bacterial infections: a prospective observational multicenter study. Antimicrob Agents Chemother 2025; 69:e0185924. [PMID: 40047414 PMCID: PMC11963601 DOI: 10.1128/aac.01859-24] [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: 12/12/2024] [Accepted: 02/05/2025] [Indexed: 04/03/2025] Open
Abstract
Polymyxin B, a last resort for carbapenem-resistant gram-negative bacteria (CRGNB) infections, has infection site-specific pharmacokinetic/pharmacodynamic (PK/PD) properties. However, there is little clinical evidence to support optimal exposures of polymyxin B for different site infections. We performed a prospective, observational, multicenter study to evaluate the clinical outcomes and PK/PD of intravenous polymyxin B treatment for various site CRGNB infections. The main clinical outcomes were 14-day all-cause mortality and nephrotoxicity, and the secondary outcomes were 28-day mortality and clinical response. The area under curves (AUCs) of polymyxin B were determined, and their associations with clinical outcomes were analyzed by stratification based on the infection site. A total of 312 patients were ultimately enrolled from 10 research centers. The overall 14-day mortality was 29.5%, and those of patients with lower respiratory tract infection (LRTI), intra-abdominal infection (IAI), and bloodstream infection (BSI) were 32.3%, 19.7%, and 30.3%, respectively. The 28-day mortality rate was 38.1%, while LRTI patients had the highest mortality (41.4%) and IAI patients lowest (34.8%). The clinical response rate was 46.2%, which was similar among the subgroups. The overall AKI rate was 60.9%. An AUC greater than 50 mg∙h/L was related to lower mortality in IAI patients but not in LRTI patients, which led to a lower but not significant difference in the overall analysis. The AUC of polymyxin B was an independent risk factor for 14-day mortality in IAI patients, and the cutoff value was 76 mg∙h/L. The results would be helpful for personalized dosing and monitoring of polymyxin B.CLINICAL TRIALSThis study is registered with the Chinese Clinical Trial Registry as ChiCTR2200056667.
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Affiliation(s)
- Zhenwei Yu
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huangdu Hu
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Xiaofen Liu
- Institute of Antibiotics, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China
| | - Jieqiong Liu
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lingyan Yu
- Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Anqi Wei
- Department of Intensive Care Unit, Hangzhou Red-Cross Hospital, Hangzhou, China
| | - Chuanwei Xin
- Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Yongxiong Gan
- The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Shu Lei
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Li Zhuang
- Shulan (Hangzhou) Hospital, Hangzhou, China
| | | | - Xiaoxing Du
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianping Zhu
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi Yang
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Gang Liang
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Feng Guo
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Zhang
- Institute of Antibiotics, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China
| | - Yunsong Yu
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
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Stabler AV, Huynh-Phan R, Amin K, Lin K, Patel S, Zaidan N, Stramel S, Thomas JL. Significant Publications on Infectious Diseases Pharmacotherapy in 2023. J Pharm Pract 2025:8971900251318816. [PMID: 39911096 DOI: 10.1177/08971900251318816] [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: 02/07/2025]
Abstract
Purpose: To provide a summarization of the most significant infectious diseases (ID) pharmacotherapy articles published in peer-reviewed literature in 2023. Summary: Members of the Houston Infectious Diseases Network (HIDN) nominated notable articles providing significant contributions to ID pharmacotherapy in 2023. Article nominations included those pertaining to general ID and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pharmacotherapy. Out of the 31 articles nominated by HIDN members, 22 pertained to general ID pharmacotherapy, and 9 pertained to HIV/AIDS pharmacotherapy. To aid selection of the most notable articles of 2023, a survey was created and distributed to members of the Society of Infectious Diseases Pharmacists (SIDP). Of the 153 SIDP members who participated in the survey, there were 118 recorded votes for the top 10 general ID pharmacotherapy articles and 55 votes were recorded for the top HIV/AIDS article. The most notable publications are summarized. Conclusion: Advances in antimicrobial stewardship and infectious disease states continue to occur. Sustained growth in the publication of ID-related articles over the past year contributed to this review's aim to aid clinicians in remaining current on potentially practice-changing ID pharmacotherapy publications from 2023. This review provides a summary of recently published ID literature, including emphasis on antimicrobial stewardship, appropriate treatment durations, new antimicrobials, and drug-resistant organisms.
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Affiliation(s)
- Alex V Stabler
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ricky Huynh-Phan
- Department of Pharmacy, Baylor St. Luke's Medical Center, Houston, TX, USA
| | - Khyati Amin
- Department of Pharmacy, The University of Texas Medical Branch, Galveston, TX, USA
| | - Kevin Lin
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shivani Patel
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
| | - Noor Zaidan
- Department of Pharmacy, The University of Texas Medical Branch, Galveston, TX, USA
| | - Stefanie Stramel
- Department of Pharmacy, Memorial Hermann Memorial City Medical Center, Houston, TX, USA
| | - Jamie L Thomas
- Department of Pharmacy, Memorial Hermann Southwest, Houston, TX, USA
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Cui AL, Yang HX, Yi H, Lv M, Peng XJ, Zheng GH, Li ZR. Design, synthesis, and bioactivity investigation of novel cyclic lipopeptide antibiotics targeting top-priority multidrug-resistant gram-negative bacteria. Eur J Med Chem 2024; 280:116924. [PMID: 39383655 DOI: 10.1016/j.ejmech.2024.116924] [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: 07/16/2024] [Revised: 09/09/2024] [Accepted: 09/26/2024] [Indexed: 10/11/2024]
Abstract
OBJECTIVES Polymyxins are the last-line therapy for top-priority multidrug-resistant (MDR) gram-negative bacteria. However, polymyxin nephrotoxicity impedes its clinical application. This study aimed to design, synthesize, and identify a novel and promising polymyxin derivative with high efficacy and low toxicity. METHODS To design polymyxin derivatives, we reduced the hydrophobicity of the two hydrophobic domains (fatty acyl chain and D-Phe6-L-Leu7) and modified the positive charged L-2,4-diaminobutyric acid (Dab) residues. Twenty-five derivatives were synthesized, and their antibacterial activities in vitro and renal cytotoxicities were determined. The nephrotoxicity and pharmacokinetic parameters of compound 12 were examined in rats. Antibacterial efficacy in vivo was evaluated using a mouse systemic infection model. Surface plasmon resonance analysis, compound 12-rifampicin combination therapy, and scanning electron microscopy were used to study the mechanism of action of compound 12. RESULTS This research found a new compound, identified as compound 12, which showed similar or increased antibacterial activity against all tested sensitive and carbapenem-resistant gram-negative bacteria. It exhibited reduced renal cytotoxicity and nephrotoxicity, a favorable pharmacokinetic profile, and maintained or improved antibacterial efficacy in vivo. Importantly, its anti-Pseudomonas aeruginosa activity significantly improved. Compound 12, when combined with rifampicin, enhanced the activity of rifampin against gram-negative bacteria. Compound 12 also showed a high affinity for lipopolysaccharide and disrupted cell membrane integrity. CONCLUSION Reducing the hydrophobicity of the two domains reduced renal cytotoxicity and nephrotoxicity. Shortening the side chain of Dab3 by one carbon maintained or increased its antibacterial activity both in vitro and in vivo. Furthermore, only the length of the side chain of Dab9 could be shortened by one carbon among the Dab1,5 and Dab8,9 residues. The bactericidal effects of compound 12 were related to the disruption of cell membrane integrity. Compound 12 may be a promising candidate for combating sensitive and carbapenem-resistant gram-negative bacterial infections, especially Pseudomonas aeruginosa.
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Affiliation(s)
- A-Long Cui
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - He-Xian Yang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Hong Yi
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Miao Lv
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Xiao-Jiong Peng
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Guang-Hui Zheng
- Laboratory of Beijing Tiantan Hospital, Capital Medical University, Beijing, 100076, China.
| | - Zhuo-Rong Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
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Roque-Borda CA, Primo LMDG, Franzyk H, Hansen PR, Pavan FR. Recent advances in the development of antimicrobial peptides against ESKAPE pathogens. Heliyon 2024; 10:e31958. [PMID: 38868046 PMCID: PMC11167364 DOI: 10.1016/j.heliyon.2024.e31958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 05/23/2024] [Accepted: 05/24/2024] [Indexed: 06/14/2024] Open
Abstract
Multi-drug resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a global health threat. The severity of the problem lies in its impact on mortality, therapeutic limitations, the threat to public health, and the costs associated with managing infections caused by these resistant strains. Effectively addressing this challenge requires innovative approaches to research, the development of new antimicrobials, and more responsible antibiotic use practices globally. Antimicrobial peptides (AMPs) are a part of the innate immune system of all higher organisms. They are short, cationic and amphipathic molecules with broad-spectrum activity. AMPs interact with the negatively charged bacterial membrane. In recent years, AMPs have attracted considerable interest as potential antibiotics. However, AMPs have low bioavailability and short half-lives, which may be circumvented by chemical modification. This review presents recent in vitro and in silico strategies for the modification of AMPs to improve their stability and application in preclinical experiments.
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Affiliation(s)
- Cesar Augusto Roque-Borda
- São Paulo State University (UNESP), Tuberculosis Research Laboratory, School of Pharmaceutical Sciences, Araraquara, Brazil
- Universidad Católica de Santa María, Vicerrectorado de Investigación, Arequipa, Peru
| | | | - Henrik Franzyk
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Denmark
| | - Paul Robert Hansen
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Denmark
| | - Fernando Rogério Pavan
- São Paulo State University (UNESP), Tuberculosis Research Laboratory, School of Pharmaceutical Sciences, Araraquara, Brazil
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Mathew SK, Chapla A, Venkatesan P, Eriyat V, Aruldhas BW, Prabha R, Neely M, Rao SV, Kandasamy S, Mathew B. Genetic predisposition and high exposure to colistin in the early treatment period as independent risk factors for colistin-induced nephrotoxicity. Clin Transl Sci 2024; 17:e13764. [PMID: 38476095 PMCID: PMC10933594 DOI: 10.1111/cts.13764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 01/29/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium.
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Affiliation(s)
- Sumith K. Mathew
- Department of Pharmacology and Clinical PharmacologyChristian Medical College & HospitalVelloreTamilnaduIndia
| | - Aaron Chapla
- Department of Endocrinology, Diabetes & MetabolismChristian Medical College & HospitalVelloreTamilnaduIndia
| | | | - Vishnu Eriyat
- Department of Pharmacology and Clinical PharmacologyChristian Medical College & HospitalVelloreTamilnaduIndia
| | - Blessed Winston Aruldhas
- Department of Pharmacology and Clinical PharmacologyChristian Medical College & HospitalVelloreTamilnaduIndia
| | - Ratna Prabha
- Department of Pharmacology and Clinical PharmacologyChristian Medical College & HospitalVelloreTamilnaduIndia
| | - Michael N. Neely
- Department of Pediatrics, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
- Division of Infectious DiseasesChildren's Hospital Los AngelesLos AngelesCaliforniaUSA
| | - Shoma V. Rao
- Surgical Intensive Care Unit and Division of Critical CareChristian Medical College & HospitalVelloreTamilnaduIndia
| | - Subramani Kandasamy
- Surgical Intensive Care Unit and Division of Critical CareChristian Medical College & HospitalVelloreTamilnaduIndia
| | - Binu Susan Mathew
- Department of Pharmacology and Clinical PharmacologyChristian Medical College & HospitalVelloreTamilnaduIndia
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Wu M, Zhao J, Liu Z, Zhang H. Intrathecal Injection of Polymyxin B in a Child with Meningitis Caused by Carbapenem-Resistant Pseudomonas aeruginosa: A Case Report and Literature Review. Infect Drug Resist 2024; 17:249-258. [PMID: 38283113 PMCID: PMC10822138 DOI: 10.2147/idr.s445416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 01/20/2024] [Indexed: 01/30/2024] Open
Abstract
Background Clinically, Carbapenem-resistant Pseudomonas aeruginosa (CRPA) meningitis is extremely difficult to cure and has a high mortality rate. Intrathecal injection of polymyxins B is suggested to be an effective anti-infective means to treat intracranial infection with CRPA. However, due to the potential drug toxicity of polymyxin B in children, this regimen has rarely been reported in pediatrics. Case Description A 5-year-old male patient diagnosed with Epstein-Barr virus-induced hemophagocytic syndrome (HPS) exhibited persistent fever for over a month despite antibacterial and chemotherapy regimens. During hospitalization, the patient presented with unconsciousness, nystagmus, and myasthenia. Cerebrospinal fluid (CSF) analysis indicated elevated leukocyte counts and protein levels. Sputum and blood cultures, as well as metagenomic next-generation sequencing (mNGS) of CSF, identified CRPA. Intravenous and intrathecal polymyxin B administration resulted in temperature normalization and amelioration of consciousness disturbances and nystagmus. Subsequent CSF analysis yielded normal results, while polymyxin B treatment exhibited no nephrotoxicity or neurotoxicity. Conclusion Intrathecal injection of polymyxin B in children with meningitis caused by CRPA is an effective treatment without remarkable adverse events.
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Affiliation(s)
- Mei Wu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, People’s Republic of China
| | - Jingui Zhao
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, People’s Republic of China
| | - Zhongqiang Liu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, People’s Republic of China
| | - Haiyang Zhang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, People’s Republic of China
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Wu Y, Jiang S, Li D, Wu Y, Li Q, Wang X, Liu B, Bao H, Wu D, Hu X. Clinical Efficacy and Safety of Colistin Sulfate in the Treatment of Carbapenem-Resistant Organism Infections in Patients with Hematological Diseases. Infect Dis Ther 2024; 13:141-154. [PMID: 38212555 PMCID: PMC10828183 DOI: 10.1007/s40121-023-00909-8] [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: 10/06/2023] [Accepted: 12/15/2023] [Indexed: 01/13/2024] Open
Abstract
INTRODUCTION Carbapenem-resistant organisms (CRO) have emerged as a significant worldwide issue. However, the availability of efficacious antibiotics for treating CRO infections remains limited. Polymyxins, including colistin sulfate, represent the last-line therapeutic option against CRO infections. This study aims to retrospectively evaluate the clinical effectiveness and safety of colistin sulfate in managing CRO infections among patients with hematological diseases. METHODS Between April 2022 and January 2023, a total of 118 hematological patients diagnosed with CRO infection were treated with colistin sulfate at Suzhou Hongci Hospital of Hematology. The assessment encompassed the clinical efficacy, bacterial clearance rate, adverse reactions, and 30-day all-cause mortality. RESULTS The study found that the total effective rate of colistin sulfate in the treatment of CRO infection was 74.6%, with a bacterial clearance rate of 72.6%. Throughout the treatment, nephrotoxicity occurred in 7.6% of cases, neurotoxicity in 2.5% of cases, and the 30-day all-cause mortality rate was 22.9%. Multivariate logistic analysis revealed that the treatment course and combination medication with other antimicrobials were independent factors affecting the clinical efficacy of colistin sulfate. CONCLUSION Our study demonstrates that the treatment of colistin sulfate can achieve high clinical efficacy and microbial responses, with a low risk of nephrotoxicity. This study provides evidence of the positive clinical efficacy and safety of colistin sulfate treatment in these patients. High-quality randomized controlled trials are still needed to further confirm the beneficial role of colistin sulfate.
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Affiliation(s)
- Yuanbing Wu
- Department of Hematology, The Hospital of Suzhou Hongci Hematology, Suzhou, 215000, Jiangsu, China
| | - Shanshan Jiang
- Department of Hematology, The Hospital of Suzhou Hongci Hematology, Suzhou, 215000, Jiangsu, China
| | - Dongyang Li
- Department of Hematology, The Hospital of Suzhou Hongci Hematology, Suzhou, 215000, Jiangsu, China
| | - Yaxue Wu
- Department of Hematology, The Hospital of Suzhou Hongci Hematology, Suzhou, 215000, Jiangsu, China
| | - Qian Li
- Department of Hematology, The Hospital of Suzhou Hongci Hematology, Suzhou, 215000, Jiangsu, China
| | - Xing Wang
- Department of Hematology, The Hospital of Suzhou Hongci Hematology, Suzhou, 215000, Jiangsu, China
| | - Bin Liu
- Department of Hematology, The Hospital of Suzhou Hongci Hematology, Suzhou, 215000, Jiangsu, China
| | - Haiyan Bao
- Department of Hematology, National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, 215000, Jiangsu, China
| | - Depei Wu
- Department of Hematology, National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, 215000, Jiangsu, China.
| | - Xiaohui Hu
- Department of Hematology, National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, 215000, Jiangsu, China.
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Xia GL, Xu X, You XB, Wang X, Feng DD, Lei S, Jiang RL. Efficacy and nephrotoxicity of polymyxin B in elderly patients with carbapenem resistant bacterial infection. Ann Clin Microbiol Antimicrob 2023; 22:101. [PMID: 37968642 PMCID: PMC10652515 DOI: 10.1186/s12941-023-00647-2] [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: 07/28/2023] [Accepted: 10/24/2023] [Indexed: 11/17/2023] Open
Abstract
BACKGROUND To study the efficacy and nephrotoxicity of polymyxin B in the treatment of elderly patients with carbapenem-resistant organism (CRO) infection. METHODS The clinical and microbiological data of patients with CRO-infected sepsis treated with polymyxin B were retrospectively analyzed. The effective rate, bacterial clearance, incidence and recovery rate of acute renal injury (AKI) and prognosis-related indicators in AKI at different stages were compared. RESULTS The effective rate of 215 elderly patients with CRO infection treated with polymyxin was 50.7%. The total bacterial clearance rate was 44.2%, the total incidence of AKI was 37.2%, the recovery rate of AKI was 35%, and the incidence range of polymyxin B-related AKI was 10.2-37.2%. Logistic multivariate regression analysis showed that the predictors of AKI in elderly patients were high APACHE II score, long duration of polymyxin, chronic renal insufficiency and ineffective outcome; the ROC curve showed that the cutoff value for predicting AKI was a serum creatinine concentration of 73 mmol/L before polymyxin B use, and the AUC was 0.931. CONCLUSIONS Rational use of polymyxin B is safe and effective in elderly patients with CRO infection, and its effective outcome can improve the recovery rate of AKI.
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Affiliation(s)
- G L Xia
- Department of Intensive Care Unit, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), NO.54 Youdian Road, Hangzhou, 310006, China
| | - X Xu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - X B You
- The Third Affiliated Hospital of Zhejiang, Chinese Medical University, Hangzhou, 310009, China
| | - X Wang
- Department of Intensive Care Unit, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), NO.54 Youdian Road, Hangzhou, 310006, China
| | - D D Feng
- Department of Intensive Care Unit, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), NO.54 Youdian Road, Hangzhou, 310006, China
| | - S Lei
- Department of Intensive Care Unit, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), NO.54 Youdian Road, Hangzhou, 310006, China
| | - R L Jiang
- Department of Intensive Care Unit, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), NO.54 Youdian Road, Hangzhou, 310006, China.
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Yang J, Gan Y, Feng X, Chen X, Wang S, Gao J. Effects of melatonin against acute kidney injury: A systematic review and meta-analysis. Int Immunopharmacol 2023; 120:110372. [PMID: 37279642 DOI: 10.1016/j.intimp.2023.110372] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/02/2023] [Accepted: 05/19/2023] [Indexed: 06/08/2023]
Abstract
INTRODUCTION Melatonin is a hormone synthesized by the pineal gland, and has antioxidative effects in reducing acute kidney injury (AKI). In the past three years, an increasing number of studies have evaluated whether melatonin has a protective effect on AKI. The study systematically reviewed and assessed the efficacy and safety of melatonin in preventing AKI. MATERIAL AND METHODS A systematic literature search was conducted in the PubMed, Embase, and Web of Science databases on February 15, 2023. Eligible records were screened according to the inclusion and exclusion criteria. The odds ratio and Hedges' gwith the corresponding 95% confidence intervals were selected to evaluate the effects of melatonin on AKI. We pooled extracted data using a fixed- or random-effects model based on a heterogeneity test. RESULTS There were five studies (one cohort study and four randomized controlled trials) included in the meta-analysis. Although the glomerular filtration rate (GFR) may be significantly improved by melatonin, the incidence of AKI was not significantly decreased in the melatonin group compared with the control group in randomized controlled trials (RCTs). CONCLUSIONS In our study, the present results do not support a direct effect of melatonin use on the reduction of AKI. More well-designed clinical studies with larger sample size are required in the future.
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Affiliation(s)
- Jianhua Yang
- Department of Intensive Care Medicine, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, Chongqing 400016, China.
| | - Yuanxiu Gan
- Department of Intensive Care Medicine, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400016, China.
| | - Xuanyun Feng
- Department of Intensive Care Medicine, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400016, China.
| | - Xiangyu Chen
- Department of Emergency, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
| | - Shu Wang
- Department of Intensive Care Medicine, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, Chongqing 400016, China.
| | - Junwei Gao
- Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
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11
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Lu J, Zhu Y, Parkington HC, Hussein M, Zhao J, Bergen P, Rudd D, Deane MA, Oberrauch S, Cornthwaite-Duncan L, Allobawi R, Sharma R, Rao G, Li J, Velkov T. Transcriptomic Mapping of Neurotoxicity Pathways in the Rat Brain in Response to Intraventricular Polymyxin B. Mol Neurobiol 2023; 60:1317-1330. [PMID: 36443617 DOI: 10.1007/s12035-022-03140-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 11/17/2022] [Indexed: 11/30/2022]
Abstract
Intraventricular or intrathecal administration of polymyxins are increasingly used to treat multidrug-resistant (MDR) Gram-negative bacteria caused infections in the central nervous system (CNS). However, our limited knowledge of the mechanisms underpinning polymyxin-induced neurotoxicity significantly hinders the development of safe and efficacious polymyxin dosing regimens. To this end, we conducted transcriptomic analyses of the rat brain and spinal cord 1 h following intracerebroventricular administration of polymyxin B into rat lateral ventricle at a clinically relevant dose (0.5 mg/kg). Following the treatment, 66 differentially expressed genes (DEGs) were identified in the brain transcriptome while none for the spinal cord (FDR ≤ 0.05, fold-change ≥ 1.5). DEGs were enriched in signaling pathways associated with hormones and neurotransmitters, including dopamine and (nor)epinephrine. Notably, the expression levels of Slc6a3 and Gabra6 were decreased by 20-fold and 4.3-fold, respectively, likely resulting in major perturbations of dopamine and γ-aminobutyric acid signaling in the brain. Mass spectrometry imaging of brain sections revealed a distinct pattern of polymyxin B distribution with the majority accumulating in the injection-side lateral ventricle and subsequently into third and fourth ventricles. Polymyxin B was not detectable in the left lateral ventricle or brain tissue. Electrophysiological measurements on primary cultured rat neurons revealed a large inward current and significant membrane leakage following polymyxin B treatment. Our work demonstrates, for the first time, the key CNS signaling pathways associated with polymyxin neurotoxicity. This mechanistic insight combined with pharmacokinetic/pharmacodynamic dosing strategies will help guide the design of safe and effective intraventricular/intrathecal polymyxin treatment regimens for CNS infections caused by MDR Gram-negative pathogens.
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Affiliation(s)
- Jing Lu
- Department of Pharmacology & Biochemistry, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.,Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
| | - Yan Zhu
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
| | - Helena C Parkington
- Department of Physiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
| | - Maytham Hussein
- Department of Pharmacology & Biochemistry, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.,Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
| | - Jinxin Zhao
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
| | - Phillip Bergen
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
| | - David Rudd
- Drug Delivery, Disposition and Dynamics, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, 3010, Australia
| | - Mary A Deane
- Department of Physiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
| | - Sara Oberrauch
- Department of Pharmacology & Biochemistry, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Linda Cornthwaite-Duncan
- Department of Pharmacology & Biochemistry, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Rafah Allobawi
- Department of Pharmacology & Biochemistry, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.,Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
| | - Rajnikant Sharma
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27514, USA
| | - Gauri Rao
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27514, USA.
| | - Jian Li
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
| | - Tony Velkov
- Department of Pharmacology & Biochemistry, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia. .,Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
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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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Mahamad Maifiah MH, Zhu Y, Tsuji BT, Creek DJ, Velkov T, Li J. Integrated metabolomic and transcriptomic analyses of the synergistic effect of polymyxin-rifampicin combination against Pseudomonas aeruginosa. J Biomed Sci 2022; 29:89. [PMID: 36310165 PMCID: PMC9618192 DOI: 10.1186/s12929-022-00874-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 10/21/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Understanding the mechanism of antimicrobial action is critical for improving antibiotic therapy. For the first time, we integrated correlative metabolomics and transcriptomics of Pseudomonas aeruginosa to elucidate the mechanism of synergistic killing of polymyxin-rifampicin combination. METHODS Liquid chromatography-mass spectrometry and RNA-seq analyses were conducted to identify the significant changes in the metabolome and transcriptome of P. aeruginosa PAO1 after exposure to polymyxin B (1 mg/L) and rifampicin (2 mg/L) alone, or in combination over 24 h. A genome-scale metabolic network was employed for integrative analysis. RESULTS In the first 4-h treatment, polymyxin B monotherapy induced significant lipid perturbations, predominantly to fatty acids and glycerophospholipids, indicating a substantial disorganization of the bacterial outer membrane. Expression of ParRS, a two-component regulatory system involved in polymyxin resistance, was increased by polymyxin B alone. Rifampicin alone caused marginal metabolic perturbations but significantly affected gene expression at 24 h. The combination decreased the gene expression of quorum sensing regulated virulence factors at 1 h (e.g. key genes involved in phenazine biosynthesis, secretion system and biofilm formation); and increased the expression of peptidoglycan biosynthesis genes at 4 h. Notably, the combination caused substantial accumulation of nucleotides and amino acids that last at least 4 h, indicating that bacterial cells were in a state of metabolic arrest. CONCLUSION This study underscores the substantial potential of integrative systems pharmacology to determine mechanisms of synergistic bacterial killing by antibiotic combinations, which will help optimize their use in patients.
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Affiliation(s)
- Mohd Hafidz Mahamad Maifiah
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia
- International Institute for Halal Research and Training, International Islamic University Malaysia, 50728, Kuala Lumpur, Malaysia
| | - Yan Zhu
- Infection Program and Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
| | - Brian T Tsuji
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Darren J Creek
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia
| | - Tony Velkov
- Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Jian Li
- Infection Program and Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
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Xu Y, Liang P, Liu N, Dong D, Gu Q, Wang X. Correlation between the drug concentration of polymyxin B and polymyxin B-associated acute kidney injury in critically ill patients: A prospective study. Pharmacol Res Perspect 2022; 10:e01010. [PMID: 36206131 PMCID: PMC9542723 DOI: 10.1002/prp2.1010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/30/2022] [Indexed: 11/12/2022] Open
Abstract
In recent years, polymyxin B-associated acute kidney injury (PB-AKI) in critically ill patients has been reported frequently, but polymyxin B (PB) is mainly cleared through non-renal pathways, and the reasons of PB-AKI remain unclear. The aim of this study was to investigate the relationship between the serum concentration of PB and PB-AKI. We conducted a prospective cohort study in an intensive care unit between May 2019 and July 2021. Over the study period, 52 patients were included and divided into an AKI group (n = 26) and a non-AKI group (n = 26). The loading dose of PB in the AKI group was significantly higher than that in the non-AKI group. The C1/2 , Cmin , and estimated area under the concentration-time curve (AUC)0-24 of PB in the AKI group were dramatically increased compared with those in the non-AKI group, but the Cmax between the two groups showed no differences. Upon obtaining the ROC curve, the areas for the C1/2 , Cmin , and estimated AUC0-24 were 0.742, 0.710, and 0.710, respectively. The sensitivity was ascertained to be 61.54%, and the specificity was 76.92% when the cutoff value for the estimated AUC0-24 of 97.72 mg·h/L was used preferentially. The incidence of PB-AKI is high and related to the loading dose of PB. PB-AKI could be predicted when the estimated AUC0-24 of PB was greater than 97.72 mg·h/L.
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Affiliation(s)
- Ying Xu
- Surgical Intensive Care Unit (SICU), Department of General SurgeryJinling Hospital of Nanjing Medical UniversityNanjingChina,Intensive Care UnitDrum Tower Hospital Affiliated to Nanjing University School of MedicineNanjingJiangsuChina
| | - Pei Liang
- Department of PharmacyDrum Tower Hospital Affiliated to Nanjing University School of MedicineNanjingChina
| | - Ning Liu
- Intensive Care UnitDrum Tower Hospital Affiliated to Nanjing University School of MedicineNanjingJiangsuChina
| | - Danjiang Dong
- Intensive Care UnitDrum Tower Hospital Affiliated to Nanjing University School of MedicineNanjingJiangsuChina
| | - Qin Gu
- Intensive Care UnitDrum Tower Hospital Affiliated to Nanjing University School of MedicineNanjingJiangsuChina
| | - Xinying Wang
- Surgical Intensive Care Unit (SICU), Department of General SurgeryJinling Hospital of Nanjing Medical UniversityNanjingChina
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15
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Mally A, Jarzina S. Mapping Adverse Outcome Pathways for Kidney Injury as a Basis for the Development of Mechanism-Based Animal-Sparing Approaches to Assessment of Nephrotoxicity. FRONTIERS IN TOXICOLOGY 2022; 4:863643. [PMID: 35785263 PMCID: PMC9242087 DOI: 10.3389/ftox.2022.863643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/11/2022] [Indexed: 02/04/2023] Open
Abstract
In line with recent OECD activities on the use of AOPs in developing Integrated Approaches to Testing and Assessment (IATAs), it is expected that systematic mapping of AOPs leading to systemic toxicity may provide a mechanistic framework for the development and implementation of mechanism-based in vitro endpoints. These may form part of an integrated testing strategy to reduce the need for repeated dose toxicity studies. Focusing on kidney and in particular the proximal tubule epithelium as a key target site of chemical-induced injury, the overall aim of this work is to contribute to building a network of AOPs leading to nephrotoxicity. Current mechanistic understanding of kidney injury initiated by 1) inhibition of mitochondrial DNA polymerase γ (mtDNA Polγ), 2) receptor mediated endocytosis and lysosomal overload, and 3) covalent protein binding, which all present fairly well established, common mechanisms by which certain chemicals or drugs may cause nephrotoxicity, is presented and systematically captured in a formal description of AOPs in line with the OECD AOP development programme and in accordance with the harmonized terminology provided by the Collaborative Adverse Outcome Pathway Wiki. The relative level of confidence in the established AOPs is assessed based on evolved Bradford-Hill weight of evidence considerations of biological plausibility, essentiality and empirical support (temporal and dose-response concordance).
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16
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Wu XL, Long WM, Lu Q, Teng XQ, Qi TT, Qu Q, He GF, Qu J. Polymyxin B-Associated Nephrotoxicity and Its Predictors: A Retrospective Study in Carbapenem-Resistant Gram-Negative Bacterial Infections. Front Pharmacol 2022; 13:672543. [PMID: 35571125 PMCID: PMC9096016 DOI: 10.3389/fphar.2022.672543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
Polymyxin B (PMB), a kind of polymyxin, was widely used in carbapenem-resistant Gram-negative bacterial (CR-GNB) infections. However, adverse reactions such as nephrotoxicity and neurotoxicity limit its use in clinical practice. The aim of this study was to explore PMB associated with nephrotoxicity and its predictors. Patients who received PMB intravenous drip for more than 72 h were eligible for the study. Characteristics of patients, concomitant nephrotoxic agents, underlying disease, and antimicrobial susceptibility were submitted for descriptive analysis. Univariate analysis and binary logistic regression were used to assess the factors leading to acute kidney injury (AKI). AKI was assessed with serum creatinine variations according to the classification of risk (stage R), injury (stage I), failure (stage F), loss, and end-stage of kidney disease. Among 234 patients with CR-GNB infections who used PMB in our study, 67 (28.63%) patients developed AKI, including 31 (14.25%) patients in stage R, 15 (6.41%) patients in stage I, and 21 (8.97%) patients in stage F. The incident rate of PMB-related nephrotoxicity in patients with normal renal function was 32.82% (43/131). The higher risk factors of AKI include males [odds ratio (OR) = 3.237; 95% confidence interval (95%CI) = 1.426–7.350], digestive system diseases [OR = 2.481 (1.127–5.463)], using furosemide (>20 mg/day) [OR = 2.473 (1.102–5.551)], and baseline serum creatinine [OR = 0.994 (0.990–0.999)]. Nonparametric tests of K-independent samples showed that baseline serum creatinine and the PMB maintenance dose were associated with the severity of nephrotoxicity (both p < 0.05). Male, digestive system diseases, using furosemide (>20 mg/day), and high baseline serum creatinine were the independent risk factors of PMB-associated AKI development. The maintenance dose of PMB may be related to the severity of AKI. These risk factors should be taken into consideration when initiating PMB-based therapy. The serum creatinine value should be closely monitored when using PMB.
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Affiliation(s)
- Xiao-Li Wu
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
- Department of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wen-Ming Long
- Department of Pharmacy, Second People’s Hospital of Huaihua City, Huaihua, China
| | - Qiong Lu
- 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
| | - Ting-Ting Qi
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Qiang Qu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Ge-Fei He
- Department of Pharmacy, The First Hospital of Changsha, Changsha, China
| | - Jian Qu
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
- *Correspondence: Jian Qu,
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Locci E, Liu J, Pais GM, Chighine A, Kahnamoei DA, Xanthos T, Chalkias A, Lee A, Hauser AR, Chang J, Rhodes NJ, Aloja ED, Scheetz MH. Urinary Metabolomics from a Dose-Fractionated Polymyxin B Rat Model of Acute Kidney Injury. Int J Antimicrob Agents 2022; 60:106593. [PMID: 35460851 DOI: 10.1016/j.ijantimicag.2022.106593] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/18/2022] [Accepted: 04/11/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Polymyxin B treatment is limited by kidney injury. We sought to identify Polymyxin B related urinary metabolomic profile modifications for early detection of polymyxin-associated nephrotoxicity. METHODS Samples were obtained from a previously conducted study. Male Sprague-Dawley rats received dose-fractionated polymyxin B (12mg/kg/day) once daily (QD), twice daily (BID), and thrice daily (TID) for three days with urinary biomarkers and kidney histopathology scores determined. Daily urine was analysed for metabolites via 1H NMR. Principal Components Analyses identified spectral data trends with orthogonal Partial Least Square Discriminant Analysis applied to classify metabolic differences. Metabolomes were compared across groups (i.e., those receiving QD, BID, TID, and control) using a mixed-effects models. Spearman correlation was performed for injury biomarkers and the metabolome. RESULTS A total of 25 rats were treated with Polymyxin B, and n=2 received saline, contributing 77 urinary samples. Pre-dosing samples clustered well, characterized by higher amounts of citrate, 2-oxoglutarate, and hippurate. Day 1 samples showed higher taurine; day 3 samples had higher lactate, acetate, and creatine. Taurine was the only metabolite significantly increased in both BID and TID compared to QD group. Day 1 taurine correlated with increasing histopathology scores (rho=0.4167, P=0.038) and KIM-1 (rho =0.4052, P=0.036); whereas KIM-1 on day one and day 3 did not reach significance with histopathology (rho=0.3248, P=0.11 and rho=0.3739, P=0.066). CONCLUSIONS Polymyxin B causes increased amounts of urinary taurine on day 1 which then normalizes to baseline concentrations. Taurine may provide one of the earlier signals of acute kidney damage caused by polymyxin B.
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Affiliation(s)
- Emanuela Locci
- Department of Medical Sciences and Public Health, Section of Legal Medicine, University of Cagliari, Cagliari, Italy
| | - Jiajun Liu
- Midwestern University, Downers Grove, IL; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL; Northwestern Memorial Hospital, Chicago, IL
| | - Gwendolyn M Pais
- Midwestern University, Downers Grove, IL; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL
| | - Alberto Chighine
- Department of Medical Sciences and Public Health, Section of Legal Medicine, University of Cagliari, Cagliari, Italy
| | - Dariusc Andrea Kahnamoei
- Department of Medical Sciences and Public Health, Section of Legal Medicine, University of Cagliari, Cagliari, Italy
| | | | - Athanasios Chalkias
- University of Thessaly, Faculty of Medicine, Department of Anesthesiology, Larisa, Greece; Outcomes Research Consortium, Cleveland, OH 44195, USA
| | | | | | - Jack Chang
- Midwestern University, Downers Grove, IL; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL; Northwestern Memorial Hospital, Chicago, IL
| | - Nathaniel J Rhodes
- Midwestern University, Downers Grove, IL; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL; Northwestern Memorial Hospital, Chicago, IL
| | - Ernesto d' Aloja
- Department of Medical Sciences and Public Health, Section of Legal Medicine, University of Cagliari, Cagliari, Italy
| | - Marc H Scheetz
- Midwestern University, Downers Grove, IL; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL; Northwestern Memorial Hospital, Chicago, IL.
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Magalhães EP, Silva BP, Aires NL, Ribeiro LR, Ali A, Cavalcanti MM, Nunes JVS, Sampaio TL, de Menezes RRPPB, Martins AMC. (-)-α-Bisabolol as a protective agent against epithelial renal cytotoxicity induced by amphotericin B. Life Sci 2021; 291:120271. [PMID: 34974077 DOI: 10.1016/j.lfs.2021.120271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/06/2021] [Accepted: 12/22/2021] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Amphotericin B (AmB), used for systemic fungal infections, has a limited clinical application because of its high nephrotoxicity. Natural antioxidant and anti-inflammatory substances have been widely studied for protection against drug-induced nephrotoxicity. α-Bisabolol (BIS) has demonstrated a nephroprotective effect on both in vitro and in vivo models. AIMS The aim of this work was to evaluate the effect of BIS against AmB-induced nephrotoxicity in vitro. MATERIAL AND METHODS LLC-MK2 cells were pre- and post-treated with non-toxic BIS concentrations and/or AmB IC50 (13.97 μM). Cell viability was assessed by MTT [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)] assay. Flow cytometry analyses were used to assess cell death mechanism, production of reactive oxidative stress (ROS) and mitochondrial transmembrane potential. Kidney Injury Molecule-1 (KIM-1) levels were measured via ELISA. KEY FINDINGS The present work showed that BIS pretreatment (125; 62.5 and 31.25 μM) increased cell viability when compared to the group treated only with AmB IC50. AmB treatment induced both necrosis (7-AAD-labeled cells) and late apoptosis (AnxV-labeled). BIS was able to prevent the occurrence of these events. These effects were associated with a decrease of ROS accumulation, improving transmembrane mitochondrial potential and protecting against tubular cell damage, highlighted by the inhibition of KIM-1 release after BIS treatment. SIGNIFICANCE BIS presented a potential effect on model of renal cytotoxicity induced by AmB, bringing perspectives for the research of new nephroprotective agents.
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Affiliation(s)
- Emanuel Paula Magalhães
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Brenna Pinheiro Silva
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Natália Luna Aires
- Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Lyanna Rodrigues Ribeiro
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Arif Ali
- Postgraduate Program in Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | | | - João Victor Serra Nunes
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Tiago Lima Sampaio
- Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, CE, Brazil
| | | | - Alice Maria Costa Martins
- Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, CE, Brazil
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Li J, Guan D, Chen F, Shi W, Lan L, Huang W. Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure-Activity Relationship and Improve the Antibacterial Activity. J Med Chem 2021; 64:5746-5765. [PMID: 33909428 DOI: 10.1021/acs.jmedchem.0c02217] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Herein, we report the total and semisyntheses of a series of polymyxin analogues with 2-Thr and 10-Thr modifications to reveal the structure-activity relationship (SAR), which has not been fully elucidated previously. We employed two total-synthetic strategies to facilitate the diversified replacements on 2-Thr or 10-Thr, respectively. Moreover, semisynthetic approaches were utilized to achieve selective esterification of 2-Thr or dual esterification of both 2- and 10-Thr. Based on the results of in vitro antibacterial assays, SAR analysis implicated that the replacement of 2-/10-Thr with amino acids carrying hydrophobic side chains can maintain the activity against Pseudomonas aeruginosa but had varied effects on other tested Gram-negative bacteria. The aminoacetyl esterification on 2-/10-Thr achieved excellent antibacterial activity, and the compound 76 exhibited 2-8-fold higher activity against different strains and lower toxicity toward the HK-2 cell line. This work explored the SAR of polymyxin 2-/10-Thr and provided a promising strategy for the development of novel polymyxin derivatives.
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Affiliation(s)
- Jian Li
- CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.,School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Dongliang Guan
- CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China
| | - Feifei Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Weiwei Shi
- CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Lefu Lan
- School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.,State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Wei Huang
- CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.,School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
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20
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Wickremasinghe H, Yu HH, Azad MAK, Zhao J, Bergen PJ, Velkov T, Zhou QT, Zhu Y, Li J. Clinically Relevant Concentrations of Polymyxin B and Meropenem Synergistically Kill Multidrug-Resistant Pseudomonas aeruginosa and Minimize Biofilm Formation. Antibiotics (Basel) 2021; 10:405. [PMID: 33918040 PMCID: PMC8069709 DOI: 10.3390/antibiotics10040405] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/13/2022] Open
Abstract
The emergence of antibiotic resistance has severely impaired the treatment of chronic respiratory infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. Since the reintroduction of polymyxins as a last-line therapy against MDR Gram-negative bacteria, resistance to its monotherapy and recurrent infections continue to be reported and synergistic antibiotic combinations have been investigated. In this study, comprehensive in vitro microbiological evaluations including synergy panel screening, population analysis profiling, time-kill kinetics, anti-biofilm formation and membrane damage analysis studies were conducted to evaluate the combination of polymyxin B and meropenem against biofilm-producing, polymyxin-resistant MDR P. aeruginosa. Two phylogenetically unrelated MDR P. aeruginosa strains, FADDI-PA060 (MIC of polymyxin B [MICpolymyxin B], 64 mg/L; MICmeropenem, 64 mg/L) and FADDI-PA107 (MICpolymyxin B, 32 mg/L; MICmeropenem, 4 mg/L) were investigated. Genome sequencing identified 57 (FADDI-PA060) and 50 (FADDI-PA107) genes predicted to confer resistance to a variety of antimicrobials, as well as multiple virulence factors in each strain. The presence of resistance genes to a particular antibiotic class generally aligned with MIC results. For both strains, all monotherapies of polymyxin B failed with substantial regrowth and biofilm formation. The combination of polymyxin B (16 mg/L)/meropenem (16 mg/L) was most effective, enhancing initial bacterial killing of FADDI-PA060 by ~3 log10 CFU/mL, followed by a prolonged inhibition of regrowth for up to 24 h with a significant reduction in biofilm formation (* p < 0.05). Membrane integrity studies revealed a substantial increase in membrane depolarization and membrane permeability in the surviving cells. Against FADDI-PA107, planktonic and biofilm bacteria were completely eradicated. In summary, the combination of polymyxin B and meropenem demonstrated synergistic bacterial killing while reinstating the efficacy of two previously ineffective antibiotics against difficult-to-treat polymyxin-resistant MDR P. aeruginosa.
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Affiliation(s)
- Hasini Wickremasinghe
- Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (H.H.Y.); (M.A.K.A.); (J.Z.); (P.J.B.); (Y.Z.); (J.L.)
| | - Heidi H. Yu
- Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (H.H.Y.); (M.A.K.A.); (J.Z.); (P.J.B.); (Y.Z.); (J.L.)
| | - Mohammad A. K. Azad
- Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (H.H.Y.); (M.A.K.A.); (J.Z.); (P.J.B.); (Y.Z.); (J.L.)
| | - Jinxin Zhao
- Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (H.H.Y.); (M.A.K.A.); (J.Z.); (P.J.B.); (Y.Z.); (J.L.)
| | - Phillip J. Bergen
- Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (H.H.Y.); (M.A.K.A.); (J.Z.); (P.J.B.); (Y.Z.); (J.L.)
| | - Tony Velkov
- Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3053, Australia;
| | - Qi Tony Zhou
- Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN 1047907, USA;
| | - Yan Zhu
- Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (H.H.Y.); (M.A.K.A.); (J.Z.); (P.J.B.); (Y.Z.); (J.L.)
| | - Jian Li
- Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (H.H.Y.); (M.A.K.A.); (J.Z.); (P.J.B.); (Y.Z.); (J.L.)
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21
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Hua X, Li C, Pogue JM, Sharma VS, Karaiskos I, Kaye KS, Tsuji BT, Bergen PJ, Zhu Y, Song J, Li J. ColistinDose, a Mobile App for Determining Intravenous Dosage Regimens of Colistimethate in Critically Ill Adult Patients: Clinician-Centered Design and Development Study. JMIR Mhealth Uhealth 2020; 8:e20525. [PMID: 33325835 PMCID: PMC7748388 DOI: 10.2196/20525] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 09/23/2020] [Accepted: 10/28/2020] [Indexed: 01/01/2023] Open
Abstract
Background Determining a suitable dose of intravenous colistimethate is challenging because of complicated pharmacokinetics, confusing terminology, and the potential for renal toxicity. Only recently have reliable pharmacokinetic/pharmacodynamic data and dosing recommendations for intravenous colistimethate become available. Objective The aim of this work was to develop a clinician-friendly, easy-to-use mobile app incorporating up-to-date dosing recommendations for intravenous colistimethate in critically ill adult patients. Methods Swift programming language and common libraries were used for the development of an app, ColistinDose, on the iPhone operating system (iOS; Apple Inc). The compatibility among different iOS versions and mobile devices was validated. Dosing calculations were based on equations developed in our recent population pharmacokinetic study. Recommended doses generated by the app were validated by comparison against doses calculated manually using the appropriate equations. Results ColistinDose provides 3 major functionalities, namely (1) calculation of a loading dose, (2) calculation of a daily dose based on the renal function of the patient (including differing types of renal replacement therapies), and (3) retrieval of historical calculation results. It is freely available at the Apple App Store for iOS (version 9 and above). Calculated doses accurately reflected doses recommended in patients with varying degrees of renal function based on the published equations. ColistinDose performs calculations on a local mobile device (iPhone or iPad) without the need for an internet connection. Conclusions With its user-friendly interface, ColistinDose provides an accurate and easy-to-use tool for clinicians to calculate dosage regimens of intravenous colistimethate in critically ill patients with varying degrees of renal function. It has significant potential to avoid the prescribing errors and patient safety issues that currently confound the clinical use of colistimethate, thereby optimizing patient treatment.
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Affiliation(s)
- Xueliang Hua
- Independent Researcher, Santa Clara, CA, United States
| | - Chen Li
- Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.,Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.,Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Jason M Pogue
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, United States
| | - Varun S Sharma
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Ilias Karaiskos
- 1st Internal Medicine and Infectious Diseases Department, Hygeia Hospital, Marousi, Greece
| | - Keith S Kaye
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Brian T Tsuji
- Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, United States.,School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, United States
| | - Phillip J Bergen
- Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.,Department of Microbiology, Monash University, Melbourne, Australia
| | - Yan Zhu
- Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.,Department of Microbiology, Monash University, Melbourne, Australia
| | - Jiangning Song
- Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.,Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.,Monash Centre for Data Science, Faculty of Information Technology, Monash University, Melbourne, Australia
| | - Jian Li
- Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.,Department of Microbiology, Monash University, Melbourne, Australia
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22
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Guan S, Tao S, Huang Y, Jin Y, Hu Y, Lu J. Combined toxic effects of CBNPs and Pb on rat alveolar macrophage apoptosis and autophagy flux. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 205:111062. [PMID: 32846292 DOI: 10.1016/j.ecoenv.2020.111062] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/19/2020] [Accepted: 07/20/2020] [Indexed: 06/11/2023]
Abstract
Carbon black (CB) and heavy metals are the main components of Particulate Matter (PM). Although the individual toxicities of CB and heavy metals have been extensively studied, the combined toxicity is much less understood. In this study, we choose the nano carbon black (CBNPs) and Pb2+ to simulate fine particles in the atmosphere and study the combined toxic effect on rat alveolar macrophages. The data showed that CBNPs could adsorb Pb2+ to form CBNPs-Pb2+ complex and displayed an altered physical properties by particle characterization. CBNPs-Pb2+ synergistically induced rat alveolar macrophages apoptosis and blocked autophagy flux compared with CBNPs and Pb2+ individually. Consistent with this, CBNPs-Pb2+ could impair the mitochondrial membrane potential (MMP), activate apoptotic signaling pathways, inhibit lysosomal function.
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Affiliation(s)
- Shuang Guan
- Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin, 130062, People's Republic of China; College of Food Science and Engneering, Jilin University, Changchun, Jilin, 130062, People's Republic of China
| | - SiYu Tao
- College of Basic Medical Science, Jilin University, Changchun, Jilin, 130062, People's Republic of China
| | - YiXuan Huang
- College of Food Science and Engneering, Jilin University, Changchun, Jilin, 130062, People's Republic of China
| | - YingLi Jin
- College of Basic Medical Science, Jilin University, Changchun, Jilin, 130062, People's Republic of China
| | - YuTing Hu
- College of Food Science and Engneering, Jilin University, Changchun, Jilin, 130062, People's Republic of China
| | - Jing Lu
- College of Food Science and Engneering, Jilin University, Changchun, Jilin, 130062, People's Republic of China.
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23
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Polymyxin-Induced Cell Death of Human Macrophage-Like THP-1 and Neutrophil-Like HL-60 Cells Associated with the Activation of Apoptotic Pathways. Antimicrob Agents Chemother 2020; 64:AAC.00013-20. [PMID: 32660985 DOI: 10.1128/aac.00013-20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 06/26/2020] [Indexed: 12/19/2022] Open
Abstract
Innate immunity is crucial for the host to defend against infections, and understanding the effect of polymyxins on innate immunity is important for optimizing their clinical use. In this study, we investigated the potential toxicity of polymyxins on human macrophage-like THP-1 and neutrophil-like HL-60 cells. Differentiated THP-1 human macrophages (THP-1-dMs) and HL-60 human neutrophils (HL-60-dNs) were employed. Flow cytometry was used to measure the concentration-dependent effects (100 to 2,500 μM for THP-1-dMs and 5 to 2,500 μM for HL-60-dNs) and time-dependent effects (1,000 μM for THP-1-dMs and 300 μM for HL-60-dNs) of polymyxin B over 24 h. Effects of polymyxin B on mitochondrial activity, activation of caspase-3, caspase-8, and caspase-9, and Fas ligand (FasL) expression in both cell lines were examined using fluorescence imaging, colorimetric, and fluorometric assays. In both cell lines, polymyxin B induced concentration- and time-dependent loss of viability at 24 h with 50% effective concentration (EC50) values of 751.8 μM (95% confidence interval [CI], 692.1 to 816.6 μM; Hill slope, 3.09 to 5.64) for THP-1-dM cells and 175.4 μM (95% CI, 154.8 to 198.7 μM; Hill slope, 1.42 to 2.21) for HL-60-dN cells. A concentration-dependent loss of mitochondrial membrane potential and generation of mitochondrial superoxide was also observed. Polymyxin B-induced apoptosis was associated with concentration-dependent activation of all three tested caspases. The death receptor apoptotic pathway activation was demonstrated by a concentration-dependent increase of FasL expression. For the first time, our results reveal that polymyxin B induced concentration- and time-dependent cell death in human macrophage-like THP-1 and neutrophil-like HL-60 cells associated with mitochondrial and death receptor apoptotic pathways.
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24
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Jiang X, Zhang S, Azad MAK, Roberts KD, Wan L, Gong B, Yang K, Yuan B, Uddin H, Li J, Thompson PE, Velkov T, Fu J, Wang L, Li J. Structure-Interaction Relationship of Polymyxins with the Membrane of Human Kidney Proximal Tubular Cells. ACS Infect Dis 2020; 6:2110-2119. [PMID: 32619094 PMCID: PMC7485602 DOI: 10.1021/acsinfecdis.0c00190] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Multidrug-resistant Gram-negative bacteria are a serious global threat to human health. Polymyxins are increasingly used in patients as a last-line therapy to treat infections caused by these life-threatening 'superbugs'. Unfortunately, polymyxin-induced nephrotoxicity is the major dose-limiting factor and understanding its mechanism is crucial for the development of novel, safer polymyxins. Here, we undertook the first all-atom molecular dynamics simulations of the interaction between four naturally occurring polymyxins A1, B1, M1 and colistin A (representative structural variations of the polymyxin core structure) and the membrane of human kidney proximal tubular cells. All polymyxins inserted spontaneously into the hydrophobic region of the membrane where they were retained, although their insertion abilities varied. Polymyxin A1 completely penetrated into the hydrophobic region of the membrane with a unique folded conformation, whereas the other three polymyxins only inserted their fatty acyl tails into this region. Furthermore, local membrane defects and increased water penetration were induced by each polymyxin, which may represent the initial stage of cellular membrane damage. Finally, the structure-interaction relationship of polymyxins was investigated based on atomic interactions at the cell membrane level. The hydrophobicity at positions 6/7 and stereochemistry at position 3 regulated the interactions of polymyxins with the cell membrane. Collectively, our results provide new mechanistic insights into polymyxin-induced nephrotoxicity at the atomic level and will facilitate the development of new-generation polymyxins.
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Affiliation(s)
- Xukai Jiang
- Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton, Melbourne, Victoria 3800, Australia
| | - Shuo Zhang
- Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria 3800, Australia
| | - Mohammad A. K. Azad
- Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton, Melbourne, Victoria 3800, Australia
| | - Kade D. Roberts
- Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton, Melbourne, Victoria 3800, Australia
| | - Lin Wan
- School of Software, Shandong University, Jinan 250101, China
| | - Bin Gong
- School of Software, Shandong University, Jinan 250101, China
| | - Kai Yang
- Center for Soft Condensed Matter Physics and Interdisciplinary Research & School of Physical Science and Technology, Soochow University, Suzhou 215006, China
| | - Bing Yuan
- Center for Soft Condensed Matter Physics and Interdisciplinary Research & School of Physical Science and Technology, Soochow University, Suzhou 215006, China
| | - Hemayet Uddin
- Melbourne Centre for Nanofabrication, Clayton, Melbourne, Victoria 3168, Australia
| | - Jingliang Li
- Institute for Frontier Materials, Deakin University, Geelong, Victoria 3216, Australia
| | - Philip E. Thompson
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Victoria 3052, Australia
| | - Tony Velkov
- Department of Pharmacology & Therapeutics, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Jing Fu
- Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria 3800, Australia
| | - Lushan Wang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Jian Li
- Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton, Melbourne, Victoria 3800, Australia
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