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Wang H, Wang L, Li D, Fan K, Yang Y, Cao H, Sun J, Ren J, Liu Y, Xiang L, Li W, Pan M, Hu H, Chen Y, Xu Z, Huang Y, Wang W, Pan G. Uncovering the Molecular Landscape of Tetracycline Family Natural Products through Bacterial Genome Mining. J Am Chem Soc 2025; 147:15100-15114. [PMID: 40285718 DOI: 10.1021/jacs.4c17551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
Tetracycline (TC) family natural products have attracted significant attention due to their diverse chemical structures and important role in drug development. As one of the most successful classes of drugs, TC antibiotics have been used clinically for over 70 years and remain crucial in treating infections. Despite their importance, systematic exploration of novel TC natural products has been limited, leaving the molecular landscape of the TC family poorly understood and hindering further development of these compounds for therapeutic applications. Here, we developed a targeted strategy to identify TC biosynthetic gene clusters (BGCs) based on specific cyclase signatures involved in assembling the TC scaffold. This led to the discovery of 82 representative BGCs with the potential to produce structurally diverse TCs. Among them, we uncovered three groups of novel natural products─misiomycins, varsomycins, and hibarimicins J-L─and identified their biosynthetic pathways. These compounds display distinctive structural features, with misiomycin A and hibarimicin L among the most highly modified TCs identified to date. Misiomycin A biosynthesis involves extensive glycosylation, while biosynthesis of varsomycin A, featuring a unique six-membered lactone ring structure, requires the coordinated action of two TC BGCs. The biosynthesis of hibarimicins J-L, derived from TC monomer dimerization, undergoes complex oxidative modifications involving seven oxygenases. Several TCs exhibited potent activity against drug-resistant Gram-positive pathogens. Our work further expands the structural diversity within the TC family and underscores the potential of these BGCs for generating new TC structures, providing valuable insights for the discovery and development of novel TC-based therapeutics.
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Affiliation(s)
- Haiyan Wang
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Lijun Wang
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Dong Li
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Keqiang Fan
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yingzhe Yang
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Haolan Cao
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Benxi, Liaoning 117004, China
| | - Jianing Sun
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- College of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Jinwei Ren
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yao Liu
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Lijun Xiang
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Weishu Li
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Minghui Pan
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Huitao Hu
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Yihua Chen
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Zhengren Xu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Ying Huang
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Weishan Wang
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Guohui Pan
- State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101408, China
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Zhong FL, He JJ, Bai KH, Shao RN, Wu GY, Tian XP, Wang DW, Dai YJ, Chen SL. Tigecycline-induced coagulation gene prognostic prediction model and intestinal flora signature in AML. Front Immunol 2024; 15:1486592. [PMID: 39611150 PMCID: PMC11602473 DOI: 10.3389/fimmu.2024.1486592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 10/21/2024] [Indexed: 11/30/2024] Open
Abstract
Infection is among the most common causes of death in patients with acute myeloid leukemia (AML) after chemotherapy. The anti-tumor effect of the intestinal microbiota in patients with AML is increasingly being recognized. Tigecycline, a broad-spectrum antibiotics, plays a vital role in the anti-infection treatment of AML patients with neutropenia and accompanying infections. Previously, this group reported that long-term use of tigecycline caused coagulation dysfunction in patients with hematological malignancies, increasing the risk of casualties. RNA sequencing was performed on CHO cells before and after tigecycline treatment. Further, the combined analysis of AML prognostic differentially expressed genes revealed 13 genes affected by tigecycline and closely related to AML prognosis. These genes were used for modeling analysis, and the results showed that the prepared model significantly improved the prognostic prediction efficiency for AML patients. The model also explored the correlation between prognosis score and immune cells infiltrating tumors and immune therapy targets. Moreover, 16S sequencing was performed on fecal samples from AML patients before and after tigecycline treatment. The results revealed that tigecycline significantly altered the distribution of intestinal microbiota in AML patients - These changes in microbiota are related to chemotherapy resistance. This study emphasizes the importance of intestinal microbiota in AML prognosis. Thus, the findings of this study show that the long-term use of antibiotics can not only cause dysbiosis of the intestinal microbiota but also indirectly affect the sensitivity of chemotherapy drugs, affecting the prognosis of AML patients.
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Affiliation(s)
- Feng-Luan Zhong
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Jia-Jun He
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Kun-Hao Bai
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Endoscopy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ruo-Nan Shao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guo-Yan Wu
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Peng Tian
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Da-Wei Wang
- National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu-Jun Dai
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Si-Liang Chen
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
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Koch DT, Yu H, Beirith I, Schirren M, Drefs M, Liu Y, Knoblauch M, Koliogiannis D, Sheng W, De Toni EN, Bazhin AV, Renz BW, Guba MO, Werner J, Ilmer M. Tigecycline causes loss of cell viability mediated by mitochondrial OXPHOS and RAC1 in hepatocellular carcinoma cells. J Transl Med 2023; 21:876. [PMID: 38041179 PMCID: PMC10693093 DOI: 10.1186/s12967-023-04615-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 10/11/2023] [Indexed: 12/03/2023] Open
Abstract
BACKGROUND Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by the underlying liver disease and a shortage of organ donors. Especially after LR, high recurrence rates present a problem and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed to investigate the effect of tigecycline on HCC cell lines and its mechanisms of action. METHODS Huh7, HepG2, Hep3B, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot, RT-PCR and RNA sequencing. ELISA and flow cytometry were utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment and flow cytometry to detect alterations in cell cycle. Changes in mitochondrial function were detected via seahorse analysis. RNA sequencing was performed to examine involved pathways. RESULTS Tigecycline treatment resulted in a significant reduction of mitochondrial function with concomitantly preserved mitochondrial size, which preceded the observed decrease in HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes. Tigecycline inhibited both migratory and invasive properties. Tigecycline application led to an increase of detected ROS and an S-phase cell cycle arrest. Bioinformatic analysis identified RAC1 as a likely target for tigecycline and the expression of this molecule was increased in HCC cells as a result of tigecycline treatment. CONCLUSION Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced mitochondrial function, is associated with increased expression of RAC1. The reported effects of tigecycline with clinically relevant and achievable doses on HCC cells lay the groundwork for a conceivable use of this agent in cancer treatment.
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Affiliation(s)
- Dominik T Koch
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
- Transplantation Center Munich, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Liver Center Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Haochen Yu
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Iris Beirith
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Malte Schirren
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
- Transplantation Center Munich, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Liver Center Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Moritz Drefs
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
- Transplantation Center Munich, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Liver Center Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Yunfei Liu
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Mathilda Knoblauch
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Dionysios Koliogiannis
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
- Transplantation Center Munich, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Liver Center Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Weiwei Sheng
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
| | - Enrico N De Toni
- Liver Center Munich, Ludwig-Maximilians-University Munich, Munich, Germany
- Department of Internal Medicine II, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
- German Cancer Consortium (DKTK), DKTK Partner Site Munich, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - Bernhard W Renz
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
- German Cancer Consortium (DKTK), DKTK Partner Site Munich, Munich, Germany
- Transplantation Center Munich, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Liver Center Munich, Ludwig-Maximilians-University Munich, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - Markus O Guba
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
- Transplantation Center Munich, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Liver Center Munich, Ludwig-Maximilians-University Munich, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - Jens Werner
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany
- German Cancer Consortium (DKTK), DKTK Partner Site Munich, Munich, Germany
- Transplantation Center Munich, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Liver Center Munich, Ludwig-Maximilians-University Munich, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - Matthias Ilmer
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany.
- German Cancer Consortium (DKTK), DKTK Partner Site Munich, Munich, Germany.
- Transplantation Center Munich, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
- Liver Center Munich, Ludwig-Maximilians-University Munich, Munich, Germany.
- Bavarian Cancer Research Center (BZKF), Munich, Germany.
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Yang X, Jin L, Luo X, An S, Wang M, Zhu H, Zhou Y, Liu H. Pharmacokinetic/Pharmacodynamic Target Attainment of Tigecycline in Patients with Hepatic Impairment in a Real-World Setting. Ther Drug Monit 2023; 45:786-791. [PMID: 37296502 PMCID: PMC10635337 DOI: 10.1097/ftd.0000000000001115] [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: 02/20/2023] [Accepted: 04/27/2023] [Indexed: 06/12/2023]
Abstract
BACKGROUND This study aimed to investigate the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of various tigecycline dosing regimens in real-world patients with impaired liver function. METHODS The clinical data and serum concentrations of tigecycline were extracted from the patients' electronic medical records. Patients were classified into Child-Pugh A, Child-Pugh B, and Child-Pugh C groups, according to the severity of liver impairment. Furthermore, the minimum inhibition concentration (MIC) distribution and PK/PD targets of tigecycline from the literature were used to obtain a proportion of PK/PD targets attainment of various tigecycline dosing regimens at different infected sites. RESULTS The pharmacokinetic parameters revealed significantly higher values in moderate and severe liver failure (groups Child-Pugh B and Child-Pugh C) than those in mild impairment (Child-Pugh A). Considering the target area under the time-concentration curve (AUC 0-24 )/MIC ≥4.5 for patients with pulmonary infection, most patients with high-dose (100 mg, every 12 hours) or standard-dose (50 mg, every 12 hours) for tigecycline achieved the target in groups Child-Pugh A, B, and C. Considering the target AUC 0-24 /MIC ≥6.96 for patients with intra-abdominal infection, when MIC ≤1 mg/L, more than 80% of the patients achieved the target. For an MIC of 2-4 mg/L, only patients with high-dose tigecycline in groups Child-Pugh B and C attained the treatment target. Patients experienced a reduction in fibrinogen values after treatment with tigecycline. In group Child-Pugh C, all 6 patients developed hypofibrinogenemia. CONCLUSIONS Severe hepatic impairment may attain higher PK/PD targets, but carries a high risk of adverse reactions.
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Affiliation(s)
- Xiaoxuan Yang
- Department of Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, China;
| | - Lu Jin
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China;
- Nanjing Medical Center for Clinical Pharmacy, Nanjing, China; and
| | - Xuemei Luo
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China;
- Nanjing Medical Center for Clinical Pharmacy, Nanjing, China; and
| | - Shurun An
- Department of Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, China;
| | - Min Wang
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China;
- Nanjing Medical Center for Clinical Pharmacy, Nanjing, China; and
| | - Huaijun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China;
- Nanjing Medical Center for Clinical Pharmacy, Nanjing, China; and
| | - Yujie Zhou
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
| | - Hang Liu
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China;
- Nanjing Medical Center for Clinical Pharmacy, Nanjing, China; and
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Sung K, Park M, Chon J, Kweon O, Khan SA, Shen A, Paredes A. Concentration-Dependent Global Quantitative Proteome Response of Staphylococcus epidermidis RP62A Biofilms to Subinhibitory Tigecycline. Cells 2022; 11:3488. [PMID: 36359886 PMCID: PMC9655631 DOI: 10.3390/cells11213488] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/20/2022] [Accepted: 10/24/2022] [Indexed: 07/21/2023] Open
Abstract
Staphylococcus epidermidis is a leading cause of biofilm-associated infections on implanted medical devices. During the treatment of an infection, bacterial cells inside biofilms may be exposed to sublethal concentrations of the antimicrobial agents. In the present study, the effect of subinhibitory concentrations of tigecycline (TC) on biofilms formed by S. epidermidis strain RP62A was investigated using a quantitative global proteomic technique. Sublethal concentrations of TC [1/8 (T1) and 1/4 minimum inhibitory concentration (MIC) (T2)] promoted biofilm production in strain RP62A, but 1/2 MIC TC (T3) significantly inhibited biofilm production. Overall, 413, 429, and 518 proteins were differentially expressed in biofilms grown with 1/8 (T1), 1/4 (T2), and 1/2 (T3) MIC of TC, respectively. As the TC concentration increased, the number of induced proteins in each Cluster of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway increased. The TC concentration dependence of the proteome response highlights the diverse mechanisms of adaptive responses in strain RP62A biofilms. In both COG and KEGG functional analyses, most upregulated proteins belong to the metabolism pathway, suggesting that it may play an important role in the defense of strain RP62A biofilm cells against TC stress. Sub-MIC TC treatment of strain RP62A biofilms led to significant changes of protein expression related to biofilm formation, antimicrobial resistance, virulence, quorum sensing, ABC transporters, protein export, purine/pyrimidine biosynthesis, ribosomes, and essential proteins. Interestingly, in addition to tetracycline resistance, proteins involved in resistance of various antibiotics, including aminoglycosides, antimicrobial peptides, β-lactams, erythromycin, fluoroquinolones, fusidic acid, glycopeptides, lipopeptides, mupirocin, rifampicin and trimethoprim were differentially expressed. Our study demonstrates that global protein expression profiling of biofilm cells to antibiotic pressure may improve our understanding of the mechanisms of antibiotic resistance in biofilms.
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Affiliation(s)
- Kidon Sung
- Division of Microbiology, National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA
| | - Miseon Park
- Division of Microbiology, National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA
| | - Jungwhan Chon
- Companion Animal Health, Inje University, Gimhae 50834, Korea
| | - Ohgew Kweon
- Division of Microbiology, National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA
| | - Saeed A. Khan
- Division of Microbiology, National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA
| | - Andrew Shen
- Division of Neurotoxicology, National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA
| | - Angel Paredes
- Office of Scientific Coordination, National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA
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WANG H, WANG L, FAN K, PAN G. Tetracycline natural products: discovery, biosynthesis and engineering. Chin J Nat Med 2022; 20:773-794. [DOI: 10.1016/s1875-5364(22)60224-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Indexed: 11/03/2022]
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Serum concentration as a predictor of tigecycline-induced hypofibrinogenemia in critically ill patients: a retrospective cohort study. Int J Infect Dis 2022; 123:136-142. [PMID: 36028209 DOI: 10.1016/j.ijid.2022.08.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVES The objective of this study was to determine the thresholds of serum concentration as a predictor of tigecycline-induced hypofibrinogenemia in critically ill patients. METHODS A retrospective cohort study was conducted in ICU patients treated with tigecycline. The clinical data and serum concentration were extracted from the patients' electronic medical records. Patients were divided into hypofibrinogenemia (HF) group and normal group according to fibrinogen (FIB) value. The receiver operating characteristic (ROC) curves and logistic regression was used to derive serum concentration thresholds and quantify the association between exposure thresholds and hypofibrinogenemia while adjusting for confounders. RESULTS In total, 100 patients were included. ROC curves analyse showed that tigecycline concentration parameters were strongly predictive of hypofibrinogenemia. Adjusting for duration of tigecycline, C1/2 ≥ 0.645 mg/L, AUC0-24 ≥ 20.76 mg∙h/L and Cmin ≥ 0.455mg/L were associated with a 3- to 5-fold increased risk of tigecycline-induced hypofibrinogenemia in logistic regression. CONCLUSION The findings from this study provide evidence that tigecycline exposure is highly predictive of hypofibrinogenemia, with approximately 3- to 5-fold increased risk. C1/2 ≥ 0.645 mg/L with best area under ROC curve and NPV appears to be the most appropriate toxicity threshold.
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Yu R, Chen Z, Li D, Schwarz S, Wang X, Du XD. Studies on the Transmission of a Tigecycline Resistance-Mediating tet(A) Gene Variant from Enterobacter hormaechei via a Two-Step Recombination Process. Microbiol Spectr 2022; 10:e0049622. [PMID: 35579466 PMCID: PMC9241890 DOI: 10.1128/spectrum.00496-22] [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: 02/08/2022] [Accepted: 04/27/2022] [Indexed: 12/13/2022] Open
Abstract
To investigate the contribution of a tet(A) variant to tigecycline resistance in Enterobacter hormaechei and the recombination events that occurred during transmission of this variant. MICs were determined by broth microdilution. E. hormaechei G17 was characterized by PCR, transfer assay, S1-PFGE, Southern blot hybridization, and WGS analysis. A tet(A) variant conferring resistance to tigecycline was present in E. hormaechei G17. This strain harbored two resistance plasmids (pG17-1, 264,084 bp and pG17-2, 68,610 bp) and its E. coli transformant Tm-G17TGC one resistance plasmid (pTm-G17, 93,013 bp). The comparative analysis of pG17-1, pG17-2, and pTm-G17 showed that a tet(A) variant-carrying multiresistance gene cluster (~23 kb) originating from pG17-1 had integrated into pG17-2, forming the novel plasmid pTm-G17. In a first step, this multiresistance gene cluster was excised from pG17-1 by recombination of homologous sequences, including △TnAs1 at both termini, thereby generating an unconventional circularizable structure (UCS). In a second step, this UCS integrated into pG17-2 via recombination between homologous sequences, including IS26 present on both, the UCS and pG17-2, thereby giving rise to the new plasmid pTm-G17. In summary, a tet(A) variant conferring resistance to tigecycline was reported in E. hormaechei. Transfer of a tet(A) variant-carrying multiresistance gene cluster between plasmids occurred in a two-step recombination process, in which homologous sequences, including either △TnAs1 or IS26, were involved. IMPORTANCE Tigecycline is an important last-resort broad spectrum antimicrobial agent. This study describes the two-step recombination processes resulting in the transfer of the tet(A) variant gene between different plasmids in E. hormaechei, which depicts the role of recombination processes in the generation of UCSs and new plasmids, both carrying a tet(A) variant conferring resistance to tigecycline. Such processes enhance the dissemination of resistance genes, which is of particular relevance for resistance genes, such as the tet(A) variant. The presence and transmission of a tet(A) variant in E. hormaechei will compromise the efficacy of tigecycline treatment for E. hormaechei associated infection.
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Affiliation(s)
- Runhao Yu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Zheng Chen
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Danyang Li
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Stefan Schwarz
- Institute of Microbiology and Epizootics, Centre for Infection Medicine, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany
- Veterinary Centre for Resistance Research (TZR), Freie Universität Berlin, Berlin, Germany
| | - Xinwei Wang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Xiang-Dang Du
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
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9
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Genomic and Phenotypic Evolution of Tigecycline-Resistant Acinetobacter baumannii in Critically Ill Patients. Microbiol Spectr 2022; 10:e0159321. [PMID: 35044218 PMCID: PMC8768575 DOI: 10.1128/spectrum.01593-21] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Acinetobacter baumannii is an important opportunistic pathogen of nosocomial infections. A. baumannii presently exhibits increasing antibiotic resistance, which poses great challenges to public health. The occurrence of tigecycline-resistant A. baumannii is related to tigecycline treatment and the within-host evolution of bacteria. We analyzed isogenic A. baumannii isolates from two critically ill patients who underwent tigecycline treatment. Whole-genome sequencing and comparative analyses were performed to determine the characteristics of genomic evolution. We conducted phenotypic studies, including in vitro antibiotic sensitivity tests, biofilm formation tests, growth curve determination, serum bactericidal determination, and Galleria mellonella lethality assays. In vivo emergent tigecycline resistance was observed after tigecycline treatment. After the withdrawal of tigecycline pressure, tigecycline-resistant isolates were not isolated from one patient. Four tigecycline-resistant isolates exhibited lower growth rates. The biofilm formation and virulence characteristics of tigecycline-resistant isolates were reasonably different between the two patients. A special phenotype appeared after tigecycline treatment in both patients, accompanied by reduced serum tolerance, enhanced biofilm formation ability, and reduced virulence of Galleria mellonella. Most of the genomic variation occurred after the tigecycline treatment, primarily involving transcription-, signal transduction-, translation-, ribosomal biogenesis-, and cell wall biogenesis-related genes. We determined that the genomic variations in baeR, wzc, aroQ, rluC, and adeS and acquisition of ISAba1 were associated with tigecycline resistance in vivo. Capsular polysaccharide-related genes, wzc, and itrA2, and aroQ, were the key genes related to the virulence evolution of A. baumannii within the host. IMPORTANCE Multidrug-resistant Acinetobacter baumannii poses a huge challenge to clinical treatment, and tigecycline is considered a last-line drug for the treatment of multidrug-resistant A. baumannii. However, the mechanism of tigecycline resistance in vivo has not been elucidated. This study analyzed the genomic and phenotypic evolution of tigecycline-resistant A. baumannii in two critically ill patients. In this study, after treatment with tigecycline, tigecycline-resistant A. baumannii emerged with higher fitness costs. After the withdrawal of tigecycline pressure, tigecycline-resistant isolates were not isolated from one patient. The in vivo and in vitro virulence of the isolates exhibited diametrically opposite results in the two patients. Genomic variations in baeR, wzc, aroQ, rluC, and adeS and acquisition of ISAba1 were associated with tigecycline resistance in vivo. The capsular polysaccharide-related genes, wzc, itrA2, and aroQ, were the key genes related to the virulence of A. baumannii in hosts. Our research provides a theoretical basis for elucidating the mechanism of tigecycline resistance and presents new clues for future surveillance and treatment of multidrug-resistant A. baumannii.
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10
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Hu N, Wang D, Lin Y, Zou J, Liu Y, Xiong Z, Guo J, Zeng L, Li J. Molecular Analysis and Antimicrobial Resistance Pattern of Tigecycline-Non-Susceptible K. pneumoniae Isolated from a Tertiary Care Hospital of East Asia. Infect Drug Resist 2021; 14:4147-4155. [PMID: 34675559 PMCID: PMC8504710 DOI: 10.2147/idr.s334098] [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] [Received: 08/16/2021] [Accepted: 09/23/2021] [Indexed: 11/23/2022] Open
Abstract
Introduction Tigecycline is one of the last resorts for carbapenem-resistant K. pneumoniae (CRKP) infections. Indeed, tigecycline-non-susceptible K. pneumoniae (TNSKP) strains are increasingly treated with the use of tigecycline. In this study, we attempted to better understand their epidemiological trends and characteristics. K. pneumoniae were collected from 2017 to 2020 at the First Affiliated Hospital of Nanchang University. Methods Thirty-four TNSKP strains were selected during the study period, all of which were analyzed using antimicrobial susceptibility testing, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). PCR and DNA sequencing were performed for the detection of β-lactamase genes and carbapenemase genes, and the mutation analysis of tet(A), tet(X), tet(L), tet(M), rpsJ, ramR, and oqxR, which are related to tigecycline resistance. Virulence gene and capsular genotype testing were conducted to identify whether the TNSKP strains were hypervirulent Klebsiella pneumoniae. Results An epidemiology analysis showed that Klebsiella pneumoniae carbapenemase-2 (KPC-2) was the predominant carbapenemase in tigecycline non-susceptible carbapenem-resistant K. pneumoniae (TNSCRKP) (96.7%), and the dominant clone type was ST11-K14K64 (82.4%). Among them, 55.9% (19/34) of strains were from each department of ICU, particularly EICU and neurosurgery ICU. In order to further understand the molecular mechanisms of the TNSKP, a polymerase chain reaction of the resistant determinants was carried out. The results detected many tigecycline-resistant genes, such as tet(A) (97.1%), tet(X) (17.6%), rpsJ (97.1%), and ramR (8.8%). Conclusion As the results of this study reveal, we should take effective measures to control the increase in TNSKP.
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Affiliation(s)
- Niya Hu
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Dongjiang Wang
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China
| | - Yiqing Lin
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Jun Zou
- Department of Orthopedics, Jiangxi Provincial Children's Hospital, Nanchang, People's Republic of China
| | - Yanling Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Zhigang Xiong
- Department of Orthopedics, Jiangxi Provincial Children's Hospital, Nanchang, People's Republic of China
| | - Jian Guo
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China
| | - Lingbing Zeng
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Junming Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
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11
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Barrenechea V, Vargas-Reyes M, Quiliano M, Milón P. A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines. Front Microbiol 2021; 12:682682. [PMID: 34262544 PMCID: PMC8273347 DOI: 10.3389/fmicb.2021.682682] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/10/2021] [Indexed: 11/26/2022] Open
Abstract
Tetracycline has positively impacted human health as well as the farming and animal industries. Its extensive usage and versatility led to the spread of resistance mechanisms followed by the development of new variants of the antibiotic. Tetracyclines inhibit bacterial growth by impeding the binding of elongator tRNAs to the ribosome. However, a small number of reports indicated that Tetracyclines could also inhibit translation initiation, yet the molecular mechanism remained unknown. Here, we use biochemical and computational methods to study how Oxytetracycline (Otc), Demeclocycline (Dem), and Tigecycline (Tig) affect the translation initiation phase of protein synthesis. Our results show that all three Tetracyclines induce Initiation Factor IF3 to adopt a compact conformation on the 30S ribosomal subunit, similar to that induced by Initiation Factor IF1. This compaction was faster for Tig than Dem or Otc. Furthermore, all three tested tetracyclines affected IF1-bound 30S complexes. The dissociation rate constant of IF1 in early 30S complexes was 14-fold slower for Tig than Dem or Otc. Late 30S initiation complexes (30S pre-IC or IC) exhibited greater IF1 stabilization by Tig than for Dem and Otc. Tig and Otc delayed 50S joining to 30S initiation complexes (30S ICs). Remarkably, the presence of Tig considerably slowed the progression to translation elongation and retained IF1 in the resulting 70S initiation complex (70S IC). Molecular modeling of Tetracyclines bound to the 30S pre-IC and 30S IC indicated that the antibiotics binding site topography fluctuates along the initiation pathway. Mainly, 30S complexes show potential contacts between Dem or Tig with IF1, providing a structural rationale for the enhanced affinity of the antibiotics in the presence of the factor. Altogether, our data indicate that Tetracyclines inhibit translation initiation by allosterically perturbing the IF3 layout on the 30S, retaining IF1 during 70S IC formation, and slowing the transition toward translation elongation. Thus, this study describes a new complementary mechanism by which Tetracyclines may inhibit bacterial protein synthesis.
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Affiliation(s)
- Victor Barrenechea
- Faculty of Health Sciences, Centre for Research and Innovation, Universidad Peruana de Ciencias Aplicadas (UPC), Lima, Peru.,Postgraduate Unit, Medicine Faculty, Universidad Nacional Mayor de San Marcos, Lima, Peru
| | - Maryhory Vargas-Reyes
- Faculty of Health Sciences, Centre for Research and Innovation, Universidad Peruana de Ciencias Aplicadas (UPC), Lima, Peru
| | - Miguel Quiliano
- Faculty of Health Sciences, Centre for Research and Innovation, Universidad Peruana de Ciencias Aplicadas (UPC), Lima, Peru
| | - Pohl Milón
- Faculty of Health Sciences, Centre for Research and Innovation, Universidad Peruana de Ciencias Aplicadas (UPC), Lima, Peru
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12
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Yang J, Wu F, Luo D, Li M, Gou X, Xi J, Zhu H. Toxic epidermal necrolysis syndrome induced by tigecycline: a case report. J Int Med Res 2021; 48:300060520922416. [PMID: 32400243 PMCID: PMC7223212 DOI: 10.1177/0300060520922416] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
A 56-year-old man diagnosed with non-Hodgkin’s lymphoma underwent autologous bone marrow transplantation. He was subsequently admitted to the hospital with fever, and his symptoms were initially controlled by multiple antibiotics, including tigecycline. He then developed a generalized body rash that improved after treatment with anti-allergy drugs and steroids. Furthermore, tigecycline treatment for a second time resulted in a severe skin reaction with systemic symptoms, suggesting toxic epidermal necrolysis syndrome (TEN). The patient was shown to have the slow-metabolizing cytochrome P450 2C19 allele, denoted CYP2C19*2. He was transferred to a laminar flow ward and given strict mucosal care, together with corticosteroids and intravenous immunoglobulin. He recovered after 3 weeks of treatment. Tigecycline-induced Stevens–Johnson syndrome (SJS)/TEN has rarely been reported in the Chinese population. However, our experience suggests that Asians are more likely to have adverse reactions to drugs metabolized by the cytochrome P450 enzyme. Early identification of drug reactions and immediate cessation of the suspected drug is essential. Additionally, a combined therapy scheme and a clean laminar flow environment may improve the cure rate of SJS/TEN.
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Affiliation(s)
- Jiahui Yang
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Fangli Wu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Dan Luo
- Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Miaojing Li
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Xinming Gou
- Department of Neurosurgery, Shaanxi Provincial Rehabilitation Hospital, Xi'an, Shaanxi, P.R. China
| | - Jieying Xi
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Huachao Zhu
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
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13
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Hassett DJ, Meyer TJ. A Novel Bactericidal Drug Effective Against Gram-Positive and Gram-Negative Pathogenic Bacteria: Easy as AB569. DNA Cell Biol 2020; 39:1473-1477. [PMID: 32721230 DOI: 10.1089/dna.2020.5824] [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] [Indexed: 11/13/2022] Open
Abstract
Global antibiotic resistance, driven by intensive antibiotic exposure/abuse, constitutes a serious challenge to all health care, particularly in an era when new antimicrobial development has slowed to a trickle. Recently, we published work demonstrating the discovery and partial mechanism of action of a novel bactericidal agent that is effective against both gram-positive and gram-negative multidrug-resistant bacteria. This drug, called AB569, consists of acidified nitrite (A-NO2-) and EDTA, of which there is no mechanism of resistance. Using both chemistry-, genetic-, and bioinformatics-based techniques, we first discovered that AB569 was able to generate bactericidal levels of nitric oxide (NO), while the EDTA component stabilized S-nitrosyl thiols, thereby furthering NO and downstream reactive nitrogen species production. This elegant chemistry triggered a paralytic downregulation of vital genes using RNA-seq involved in the synthesis of DNA, RNA, ATP, and protein in the representative ESKAPE pathogen, Pseudomonas aeruginosa.
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Affiliation(s)
- Daniel J Hassett
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Thomas J Meyer
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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14
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Sharavanan SPN, Venkatesan CS, Sathiyanarayanan S, Kabilan S. Potential Impurities of Tigecycline: Synthesis, Isolation, Characterization and In Vitro Pharmacological Evaluation. CURR PHARM ANAL 2020. [DOI: 10.2174/1573412915666190225160030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Tigecycline is a known antibiotic in the tetracycline family and a chemical
analog of minocycline. It may be used for the treatment against drug-resistant bacteria.
Methods:
HPLC method was used for related substance analysis. The degraded impurities during the
process were isolated and characterized by IR, HRMS (High Resolution Mass Spectrometry) and NMR
spectral analysis.
Results:
Four impurities of tigecycline, a broad spectrum antibacterial agent, were identified, synthesized
and characterized. The in vitro biological evaluation of the isolated compounds showed significant
antimicrobial and antioxidant properties to that of tigecycline. Apart from these, the tigecycline drug
substance showed significant degradation under oxidation conditions.
Conclusion:
The extensive investigational data confirm the structure of the four impurities. The specification
limit for these impurities is applied based on the toxicological data. The antimicrobial activity
revealed that the impurity 4 shows excellent activity towards both Gram-positive and Gram-negative
bacteria when compared with tigecycline. The results obtained for DPPH (2,2-diphenyl-1-
picrylhydrazyl) antioxidant activity concluded that the impurity 2 and the impurity 3 showed good antioxidant
properties when compared with tigecycline. There was no activity observed on fungi for both
isolated degradants as well as tigecycline.
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Affiliation(s)
| | | | | | - Senthamaraikannan Kabilan
- Department of Chemistry, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu 608002, India
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15
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Viswanathan V, Pendsey S, Radhakrishnan C, Rege TD, Ahdal J, Jain R. Methicillin-Resistant Staphylococcus aureus in Diabetic Foot Infection in India: A Growing Menace. INT J LOW EXTR WOUND 2019; 18:236-246. [DOI: 10.1177/1534734619853668] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Diabetic foot infection (DFI) is a serious and common complication of diabetes mellitus. These infections are potentially disastrous and rapidly progress to deeper spaces and tissues. If not treated promptly and appropriately, DFI can be incurable or even lead to septic gangrene, which may require foot amputation. Mostly, these infections are polymicrobial, where Gram-positive pathogens mainly Staphylococcus aureus play a dominant causative role. Methicillin-resistant Staphylococcus aureus (MRSA) is present in 10% to 32% of diabetic infections and is associated with a higher rate of treatment failure, morbidity, and hospitalization cost in patients with DFIs. The increasing resistance of bacteria and the adverse effects pertaining to the safety and tolerability towards currently available anti-MRSA agents have limited the available treatment options for patients with DFI. Infection control, antimicrobial stewardship, and rapid diagnostics based on the microbiological culture and the antimicrobial susceptibility testing results are important components in helping curb this disturbing trend. Emphasis to revisit a vigorous research effort in order to improve the therapeutic options for the increasingly resistant and highly adaptable MRSA is the need of hour. Through this review article, we have made an attempt to explore the ongoing therapeutic trends in the management of DFI and highlighted the challenges in treatment of DFI. We have also given a brief overview of a few novel drugs that are under development to treat MRSA infections.
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Affiliation(s)
| | | | | | | | | | - Rishi Jain
- Wockhardt Ltd, Bandra Kurla Complex, Mumbai, India
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16
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Elgendy SG, Abdel Hameed MR, El-Mokhtar MA. Tigecycline resistance among Klebsiella pneumoniae isolated from febrile neutropenic patients. J Med Microbiol 2018; 67:972-975. [PMID: 29799385 DOI: 10.1099/jmm.0.000770] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Febrile neutropenic patients are at a high risk of life-threatening bacterial infections. Tigecycline was developed to treat multidrug-resistant isolates, however resistance to tigecycline in Klebsiella pneumoniae has been reported. Here, we investigated tigecycline resistance among K. pneumoniae isolated from febrile neutropenic patients admitted to Hematology ICU, Egypt. Out of 75 enrolled febrile neutropenic patients, 48 cases showed bacteriologically confirmed infection. The majority of cases were infected with K. pneumoniae, of which nine were tigecycline non-susceptible. Expression levels of the efflux pump genes acrB and oqxB and their regulatory genes ramA and rarA were analysed. Six isolates had overexpression of the four efflux-related genes while one showed baseline expression. This study emphasizes the importance of growing tigecycline resistance in K. pneumoniae infecting febrile neutropenic patients. Concerning the mechanism of resistance, it was clear that the ramA gene plays the major role, although alternative resistance mechanisms may also exist.
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Affiliation(s)
- Sherein G Elgendy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Egypt
| | - Muhammad R Abdel Hameed
- Internal Medicine and Hematology Unit, Assiut University Hospitals, Assiut University, Egypt
| | - Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Egypt
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17
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Gupte V, Gogtay J, Mani RK. A Questionnaire-based Survey of Physician Perceptions of the Prevalence of Antimicrobial Resistance and Their Antibiotic Prescribing Patterns. Indian J Crit Care Med 2018; 22:491-497. [PMID: 30111923 PMCID: PMC6069314 DOI: 10.4103/ijccm.ijccm_157_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background: Antibiotic resistance is a serious problem being faced by physicians worldwide. This article was designed to study physician perceptions of antibiotic resistance and their prescribing patterns. Materials and Methods: A structured questionnaire was developed for reporting the prevalence of antibiotic resistance as perceived by physicians and recording their antibiotic preferences in specific contexts. A total of 539 intensivists across India participated in the study. Results: The prevalence of multidrug-resistant (MDR) Gram-negative pathogens was reported to be on the rise in Intensive Care Units. The prevalence rate of carbapenem-resistant Enterobacteriaceae was reported to be between 20% and 40% by 33% of the participants. Piperacillin-tazobactam was the preferred beta-lactam/beta-lactamase inhibitor antibiotic by the majority of intensivists (47%) in the treatment of infections caused by extended-spectrum beta-lactamase producers. Meropenem was recommended to be used at a higher dose (2 g t.i.d.) by 41% of intensivists for Pseudomonas/Acinetobacter infections with high minimum inhibitory concentration values for meropenem. De-escalation data revealed that 43% of intensivists “always” would like to de-escalate from carbapenems, based on the antibiotic susceptibility data. Minocycline was recommended by 33% for the treatment of ventilator-associated pneumonia (VAP) and by 21% for bloodstream infections caused by MDR Acinetobacter. Up to 83% of intensivists preferred the use of nebulized colistin for the management of VAP/hospital-acquired pneumonia. Conclusion: This study reveals that the prevalence of MDR Gram-negative pathogens is perceived to be on the rise. Prescription patterns indicate high levels of variability. Hence, antibiotic stewardship is essential to standardize antibiotic prescriptions not only for efficacy but also to reduce the burden of multiple drug resistance.
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Affiliation(s)
- Vaishali Gupte
- Director Medical Affairs, Cipla Ltd., Mumbai, Maharashtra, India
| | - Jaideep Gogtay
- Senior Vice President, Global Chief Medical Head, Cipla Ltd, Mumbai, Maharashtra, India
| | - Raj Kumar Mani
- Department of Critical Care, Pulmonology and Sleep Medicine, Nayati Medicity, Nayati Mod, Mathura, Uttar Pradesh, India
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18
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Galichanin K. Exposure to subthreshold dose of UVR-B induces apoptosis in the lens epithelial cells and does not in the lens cortical fibre cells. Acta Ophthalmol 2017; 95:834-838. [PMID: 28083904 DOI: 10.1111/aos.13370] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 11/19/2016] [Indexed: 01/20/2023]
Abstract
PURPOSE The aim of this study was to investigate in which part of the lens in vivo exposure to subthreshold dose of UVR-B radiation induces apoptosis. METHODS Twenty 6-week-old female albino Sprague-Dawley rats were exposed to subthreshold dose (1 kJ/m2 ) of UVR-B unilaterally and killed at 120 hr after exposure. Lenses were enucleated and dissected on three regions: the lens epithelium, the cortex and the nucleus. The lens nucleus then was removed. Apoptosis markers p53 and caspase 3 were used to study apoptosis in the lens regions. qRT-PCR and Western blot were utilized to analyse the lenses. RESULTS TP53 and CASP3 mRNA expressions are increased in exposed lenses, both in the lens epithelium and in the cortex regions, in relation to non-exposed lenses. Expression of p53 protein is increased in exposed lens epithelium in relation to non-exposed lens epithelium. Caspase 3 protein is expressed in exposed lens epithelial cells, while it is not expressed in non-exposed lens epithelial cells. p53 and caspase 3 proteins are not expressed in either exposed nor non-exposed lens fibre cells. CONCLUSION Exposure to UVR-B increases mRNA transcription of apoptosis marker p53 in vivo in both regions of the lens and of apoptosis marker caspase 3 in the lens cortex. Exposure to UVR-B increases p53 and caspase 3 proteins expression just in the lens epithelium. In vivo exposure to subthreshold dose of UVR-B induces apoptosis in the lens epithelial cells and does not in the lens fibre cells.
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Affiliation(s)
- Konstantin Galichanin
- Gullstrand lab; Section of Ophthalmology; Department of Neuroscience; Uppsala University; Uppsala Sweden
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19
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Sakarya Y, Sakarya R, Ozcimen M, Goktas S, Ozcimen S, Alpfidan I, Ivacık IS, Erdogan E, Cetinkaya S, Bukus A. Ocular penetration of topically applied 1% tigecycline in a rabbit model. Int J Ophthalmol 2017; 10:679-683. [PMID: 28546920 DOI: 10.18240/ijo.2017.05.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 08/11/2016] [Indexed: 11/23/2022] Open
Abstract
AIM To evaluate ocular penetration of topically applied 1% tigecycline. METHODS Forty-two New Zealand White rabbits were divided into 3 groups. A 50 µL drop of 1% tigecycline was administered in group 1. In groups 2 and 3, the drop was administered every 15min for 60min (keratitis protocol). Aqueous humor samples in groups 1 and 2 were collected under general anesthesia at 15, 30, 45, 60, 120, and 180min after the last drop. All animals in group 3 were euthanatized. Cornea, vitreous and blood samples were collected 60 and 120min after the last drop. Tigecycline concentrations were measured using high performance liquid chromatography-mass spectrometry (LC-MS/MS). RESULTS The peak aqueous humor tigecycline concentration [mean 0.73±0.14 mg/L (SD) and 2.41±0.14 mg/L, respectively] occurred 45min after topical drug application in groups 1 and 2. Group 3 mean values in the cornea, and vitreous, were 3.27±0.50 µg/g, and 0.17±0.10 mg/L at 60min and 3.17±0.77 µg/g and 0.20±0.07 mg/L at 120min, respectively. Tigecycline serum concentrations were negligible. CONCLUSION Tigecycline levels in the aqueous humor in groups 1 and 2, and in the cornea in group 3 exceeded the minimum inhibitory concentrations of most gram-positive organisms that cause bacterial keratitis and endophthalmitis.
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Affiliation(s)
- Yasar Sakarya
- Department of Ophthalmology, Konya Training and Research Hospital, Konya 42090, Turkey
| | - Rabia Sakarya
- Department of Ophthalmology, Konya Training and Research Hospital, Konya 42090, Turkey
| | - Muammer Ozcimen
- Department of Ophthalmology, Konya Training and Research Hospital, Konya 42090, Turkey
| | - Sertan Goktas
- Department of Ophthalmology, Konya Training and Research Hospital, Konya 42090, Turkey
| | - Serap Ozcimen
- Department of Infectious Diseases and Clinical Microbiology, Konya State Hospital, Konya 42060, Turkey
| | - Ismail Alpfidan
- Department of Ophthalmology, Konya Training and Research Hospital, Konya 42090, Turkey
| | - Ismail Senol Ivacık
- Department of Ophthalmology, Konya Training and Research Hospital, Konya 42090, Turkey
| | - Erkan Erdogan
- Department of Ophthalmology, Konya Training and Research Hospital, Konya 42090, Turkey
| | - Servet Cetinkaya
- Department of Ophthalmology, Konya Kizilay Hospital, Konya 42200, Turkey
| | - Abdulkadir Bukus
- Department of Ophthalmology, Konya Training and Research Hospital, Konya 42090, Turkey
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20
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Jones RA, Robinson TJ, Liu JC, Shrestha M, Voisin V, Ju Y, Chung PED, Pellecchia G, Fell VL, Bae S, Muthuswamy L, Datti A, Egan SE, Jiang Z, Leone G, Bader GD, Schimmer A, Zacksenhaus E. RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation. J Clin Invest 2016; 126:3739-3757. [PMID: 27571409 DOI: 10.1172/jci81568] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 07/12/2016] [Indexed: 01/03/2023] Open
Abstract
Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low-like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration-approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC.
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Analysis of tigecycline resistance development in clinical Acinetobacter baumannii isolates through a combined genomic and transcriptomic approach. Sci Rep 2016; 6:26930. [PMID: 27240484 PMCID: PMC4886253 DOI: 10.1038/srep26930] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 05/10/2016] [Indexed: 12/30/2022] Open
Abstract
Tigecycline (Tgc) is considered a last-resort antibiotic for the treatment of multi-drug resistant bacteria. To study Tgc resistance development in the important nosocomial pathogen Acinetobacter baumannii, we adopted six clinical isolates from three patients undergoing antibiotic treatment, and bacterial genomic sequences and seven strand-specific transcriptomes were studied. Interestingly, the Tgc-intermediate 2015ZJAB1 only differed from Tgc-resistant 2015ZJAB2 in an SNP-clustered region including OprD, a sugar-type MFS permease, and a LuxR-type transcriptional regulator. Surprisingly, an almost identical region was found in 2015ZJAB3, which supports the possibility of a homologous recombination event that increased Tgc resistance. Furthermore, comparative transcriptomic analysis identified significantly regulated genes associated with Tgc resistance, which was verified using qRT-PCR. Three enriched COG categories included amino acid transport and metabolism, transcription, and inorganic ion transport and metabolism. KEGG analysis revealed common features under Tgc conditions, including up regulated benzoate degradation and a less active TCA cycle. This may be related to selective antimicrobial pressure in the environment and adaptation by lowering metabolism. This study provides the first report of an in vivo evolutionary process that included a putative homologous recombination event conferring Tgc resistance in clinical A. baumannii isolates in which transcriptome analysis revealed resistance-conferring genes and related metabolism characteristics.
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Arias K, Robinson SG, Lyngaas SS, Cherala SS, Hartzell M, Mei S, Vilic A, Girel JK, Kuemmell A, Vrettos JS, Zielinski J, Liechti K, Jin L. Minocycline and tigecycline form higher-order Ca2+ complexes of stronger affinity than tetracycline. Inorganica Chim Acta 2016. [DOI: 10.1016/j.ica.2015.10.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Hu H, Dong Z, Tan P, Zhang Y, Liu L, Yang L, Liu Y, Cui H. Antibiotic drug tigecycline inhibits melanoma progression and metastasis in a p21CIP1/Waf1-dependent manner. Oncotarget 2016; 7:3171-85. [PMID: 26621850 PMCID: PMC4823098 DOI: 10.18632/oncotarget.6419] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 11/16/2015] [Indexed: 02/06/2023] Open
Abstract
Antibiotics are common drugs with low toxicity but high effectiveness. They have been suggested to be drug candidates for cancer therapy in recent years. Here, we tried to investigate the antitumour effect of tigecycline on malignant melanoma. We showed that tigecycline dramatically inhibited cell proliferation and induced cell cycle arrest at G0/G1 phase. At the same time, tigecycline suppressed cell invasion and migration through preventing epithelial-mesenchymal transition (EMT) process. In addition, tigecycline also significantly blocked tumor growth in vivo. Expression of cell cycle-related proteins were investigated and resulted in downregulation of G1/S checkpoint proteins, such as CDK2 and Cyclin E. However, cyclin-dependent kinase inhibitor 1 (CDKN1A, p21(CIP1/Waf1)) was downregulated after tigecycline treatment, which was not conformed to its conventional function. To explain this, we overexpressed p21 in melanoma cells. We found that p21 overexpression significantly rescued tigecycline-induced cell proliferation inhibition as well as migration and invasion suppression. Taken together, our results revealed that the essential role of p21 in the inhibitory effect of tigecycline on proliferation, migration and invasion of melanoma. Tigecycline might act as a candidate therapeutic drug for treatment of patients suffering from malignant melanoma.
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Affiliation(s)
- Huanrong Hu
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, P.R. China
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, P.R. China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, P.R. China
| | - Peng Tan
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, P.R. China
| | - Yanli Zhang
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, P.R. China
| | - Lichao Liu
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, P.R. China
| | - Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, P.R. China
| | - Yaling Liu
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, P.R. China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, P.R. China
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Morales-Cartagena A, Lalueza A, López-Medrano F, Juan RS, Aguado JM. Treatment of methicillin-resistant Staphylococcus aureus infections: Importance of high vancomycin minumum inhibitory concentrations. World J Clin Infect Dis 2015; 5:14-29. [DOI: 10.5495/wjcid.v5.i2.14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 10/30/2014] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
Staphylococcus aureus (SA) infections remain a major cause of morbidity and mortality despite the availability of numerous effective anti-staphylococcal antibiotics. This organism is responsible for both nosocomial and community-acquired infections ranging from relatively minor skin and soft tissue infections to life-threatening systemic infections. The increasing incidence of methicillin-resistant strains has granted an increasing use of vancomycin causing a covert progressive increase of its minimum inhibitory concentration (MIC) (dubbed the MIC “creep”). In this way, the emergence of vancomycin-intermediate SA (VISA) strains and heteroresistant-VISA has raised concern for the scarcity of alternative treatment options. Equally alarming, though fortunately less frequent, is the emergence of vancomycin-resistant SA. These strains show different mechanisms of resistance but have similar problems in terms of therapeutic approach. Ultimately, various debate issues have arisen regarding the emergence of SA strains with a minimum inhibitory concentration sitting on the superior limit of the sensitivity range (i.e., MIC = 2 μg/mL). These strains have shown certain resilience to vancomycin and a different clinical behaviour regardless of vancomycin use, both in methicillin-resistant SA and in methicillin-sensitive SA. The aim of this text is to revise the clinical impact and consequences of the emergence of reduced vancomycin susceptibility SA strains, and the different optimal treatment options known.
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Fusco NM, Toussaint KA, Prescott WA. Antibiotic Management of Methicillin-Resistant Staphylococcus aureus–Associated Acute Pulmonary Exacerbations in Cystic Fibrosis. Ann Pharmacother 2015; 49:458-68. [DOI: 10.1177/1060028014567526] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Objective: To review the treatment of methicillin-resistant Staphylococcus aureus (MRSA)–associated acute pulmonary exacerbations (APEs) in cystic fibrosis (CF). Data Sources: A search of PubMed, MEDLINE, Cochrane Library and Clinicaltrials.gov databases through November 2014 was conducted using the search terms Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, pulmonary exacerbations, and cystic fibrosis. Study Selection and Data Extraction: All English-language research articles, case reports, and case series were evaluated. A total of 185 articles were identified related to MRSA and CF; 30 articles that studied treatments of MRSA APE in CF were included. Data Synthesis: The persistent presence of MRSA in the respiratory tract of patients with CF has been associated with higher morbidity and an increased risk of death. Limited clinical data exist supporting the efficacy of any specific antimicrobial currently available for the treatment of APE secondary to MRSA. Conclusions: Data extrapolated from other populations suggest that vancomycin and linezolid are appropriate first-line treatment options for the treatment of APE secondary to MRSA. Second-line options include doxycycline or minocycline and trimethoprim/sulfamethoxazole, each of which may be useful in patients coinfected with other respiratory pathogens, for which they may provide overlapping coverage. Ceftaroline and ceftobiprole are newer antibiotics that appear to have a potential role in the treatment of APE in CF, but the latter is not currently available to the US market. Although potentially useful, clindamycin is limited by high rates of resistance, telavancin is limited by its toxicity profile, and tigecycline is limited by a lack of demonstrated efficacy for infections that are similar to that seen in the CF population. Studies investigating the clinical utility of the above-cited antibiotics for APE in CF secondary to MRSA are desperately needed to broaden the treatment armamentarium for this medical condition.
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Affiliation(s)
- Nicholas M. Fusco
- University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA
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Jha BK, Seo I, Kong HH, Suh SI, Suh MH, Baek WK. Tigecycline inhibits proliferation of Acanthamoeba castellanii. Parasitol Res 2015; 114:1189-95. [DOI: 10.1007/s00436-014-4302-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 12/23/2014] [Indexed: 10/24/2022]
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CIEF separation, UV detection, and quantification of ampholytic antibiotics and bacteria from different matrices. Anal Bioanal Chem 2014; 406:6285-96. [DOI: 10.1007/s00216-014-8053-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/25/2014] [Accepted: 07/18/2014] [Indexed: 01/24/2023]
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Loffler CA, MacDougall C. Update on prevalence and treatment of methicillin-resistantStaphylococcus aureusinfections. Expert Rev Anti Infect Ther 2014; 5:961-81. [DOI: 10.1586/14787210.5.6.961] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Tsutsumi LS, Owusu YB, Hurdle JG, Sun D. Progress in the discovery of treatments for C. difficile infection: A clinical and medicinal chemistry review. Curr Top Med Chem 2014; 14:152-75. [PMID: 24236721 PMCID: PMC3921470 DOI: 10.2174/1568026613666131113154753] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Revised: 09/06/2013] [Accepted: 09/15/2013] [Indexed: 02/07/2023]
Abstract
Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality. The incidence of C. difficile infection in developed countries has become increasingly high due to the emergence of newer epidemic strains, a growing elderly population, extensive use of broad spectrum antibiotics, and limited therapies for this diarrheal disease. Because treatment options currently available for C. difficile infection have some drawbacks, including cost, promotion of resistance, and selectivity problems, new agents are urgently needed to address these challenges. This review article focuses on two parts: the first part summarizes current clinical treatment strategies and agents under clinical development for C. difficile infection; the second part reviews newly reported anti-difficile agents that have been evaluated or reevaluated in the last five years and are in the early stages of drug discovery and development. Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments. This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance.
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Affiliation(s)
| | | | | | - Dianqing Sun
- Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA.
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Rodvold KA, McConeghy KW. Methicillin-Resistant Staphylococcus aureus Therapy: Past, Present, and Future. Clin Infect Dis 2013; 58 Suppl 1:S20-7. [DOI: 10.1093/cid/cit614] [Citation(s) in RCA: 233] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Garazzino S, Lutsar I, Bertaina C, Tovo PA, Sharland M. New antibiotics for paediatric use: A review of a decade of regulatory trials submitted to the European Medicines Agency from 2000—Why aren’t we doing better? Int J Antimicrob Agents 2013; 42:99-118. [DOI: 10.1016/j.ijantimicag.2013.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 05/04/2013] [Indexed: 10/26/2022]
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Boyd N, Nailor MD. Combination antibiotic therapy for empiric and definitive treatment of gram-negative infections: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2012; 31:1073-84. [PMID: 22026395 DOI: 10.1592/phco.31.11.1073] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The widespread emergence of antibiotic-resistant gram-negative organisms has compromised the utility of current treatment options for severe infections caused by these pathogens. The rate of gram-negative multidrug resistance is worsening, threatening the effectiveness of newer broad-spectrum antibiotic agents. Infections associated with multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae are having a substantial impact on hospital costs and mortality rates. The potential for these resistant gram-negative nosocomial pathogens must always be a primary consideration when selecting antibiotic therapy for critically ill patients. Empiric combination therapy directed at gram-negative pathogens is a logical approach for patients with suspected health care-associated infections, particularly those with risk factors for infections caused by multidrug-resistant pathogens. Although in vitro synergy tests have shown potential benefits of continued combination therapy, convincing clinical data that demonstrate a need for combination therapy once susceptibilities are known are lacking. Thus, deescalation to a single agent once susceptibilities are known is recommended for most patients and pathogens. Use of polymyxins, often in combination with other antimicrobials, may be necessary for salvage therapy.
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Affiliation(s)
- Natalie Boyd
- Parkland Health and Hospital System, Dallas, Texas, USA
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34
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Chen LY, Chen TC, Chen YH, Lin CY, Lin WR, Lu PL. Microbial isolation and emergence of antimicrobial resistance associated with tigecycline usage. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2011; 44:352-7. [DOI: 10.1016/j.jmii.2011.01.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2010] [Revised: 06/30/2010] [Accepted: 08/16/2010] [Indexed: 11/24/2022]
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Mishra BB, Tiwari VK. Natural products: An evolving role in future drug discovery. Eur J Med Chem 2011; 46:4769-807. [DOI: 10.1016/j.ejmech.2011.07.057] [Citation(s) in RCA: 565] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 07/29/2011] [Accepted: 07/30/2011] [Indexed: 11/16/2022]
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Bounthavong M, Zargarzadeh A, Hsu DI, Vanness DJ. Cost-effectiveness analysis of linezolid, daptomycin, and vancomycin in methicillin-resistant Staphylococcus aureus: complicated skin and skin structure infection using Bayesian methods for evidence synthesis. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2011; 14:631-639. [PMID: 21839399 DOI: 10.1016/j.jval.2010.12.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Revised: 11/18/2010] [Accepted: 12/12/2010] [Indexed: 05/31/2023]
Abstract
BACKGROUND Methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and skin structure infection (cSSSI) is a prominent infection encountered in hospital and outpatient settings that is associated with high resource use for the health-care system. OBJECTIVE A decision analytic (DA) model was developed to evaluate the cost-effectiveness analysis (CEA) of linezolid, daptomycin, and vancomycin in MRSA cSSSI. METHODS Bayesian methods for evidence synthesis were used to generate efficacy and safety parameters for a DA model using published clinical trials. CEA was done from the US health-care perspective. Efficacy was defined as a successfully treated patient at the test of cure without any adverse reaction. Primary outcome was the incremental cost-effectiveness ratio between linezolid and vancomycin, daptomycin and vancomycin, and linezolid and daptomycin in MRSA cSSSI. Univariate and probabilistic sensitivity analyses were performed to test the robustness of the model. RESULTS The total direct costs of linezolid, daptomycin, and vancomycin were $18,057, $20,698, and $23,671, respectively. The cost-effectiveness ratios for linezolid, daptomycin, and vancomycin were $37,604, $44,086, and $52,663 per successfully treated patient, respectively. Linezolid and daptomycin were dominant strategies compared to vancomycin. However, linezolid was dominant when compared to daptomycin. The model was sensitive to the duration of daptomycin and linezolid treatment. CONCLUSION Linezolid and daptomycin are potentially cost-effective based on the assumptions of the DA model; however, linezolid appears to be more cost-effective compared to daptomycin and vancomycin for MRSA cSSSIs.
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Affiliation(s)
- Mark Bounthavong
- Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
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37
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Zuckerman JM, Qamar F, Bono BR. Review of macrolides (azithromycin, clarithromycin), ketolids (telithromycin) and glycylcyclines (tigecycline). Med Clin North Am 2011; 95:761-91, viii. [PMID: 21679791 DOI: 10.1016/j.mcna.2011.03.012] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The advanced macrolides, azithromycin and clarithromycin, and the ketolide, telithromycin, are structural analogs of erythromycin. They have several distinct advantages when compared with erythromycin, including enhanced spectrum of activity, more favorable pharmacokinetics and pharmacodynamics, once-daily administration, and improved tolerability. Clarithromycin and azithromycin are used extensively for the treatment of respiratory tract infections, sexually transmitted diseases, and Helicobacter pylori-associated peptic ulcer disease. Telithromycin is approved for the treatment of community-acquired pneumonia. Severe hepatotoxicity has been reported with the use of telithromycin.
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Affiliation(s)
- Jerry M Zuckerman
- Jefferson Medical College, 1025 Walnut Street, Philadelphia, PA 19107, USA.
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38
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Sapi E, Kaur N, Anyanwu S, Luecke DF, Datar A, Patel S, Rossi M, Stricker RB. Evaluation of in-vitro antibiotic susceptibility of different morphological forms of Borrelia burgdorferi. Infect Drug Resist 2011; 4:97-113. [PMID: 21753890 PMCID: PMC3132871 DOI: 10.2147/idr.s19201] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi. Although antibiotic therapy is usually effective early in the disease, relapse may occur when administration of antibiotics is discontinued. Studies have suggested that resistance and recurrence of Lyme disease might be due to formation of different morphological forms of B. burgdorferi, namely round bodies (cysts) and biofilm-like colonies. Better understanding of the effect of antibiotics on all morphological forms of B. burgdorferi is therefore crucial to provide effective therapy for Lyme disease. METHODS Three morphological forms of B. burgdorferi (spirochetes, round bodies, and biofilm-like colonies) were generated using novel culture methods. Minimum inhibitory concentration and minimum bactericidal concentration of five antimicrobial agents (doxycycline, amoxicillin, tigecycline, metronidazole, and tinidazole) against spirochetal forms of B. burgdorferi were evaluated using the standard published microdilution technique. The susceptibility of spirochetal and round body forms to the antibiotics was then tested using fluorescent microscopy (BacLight™ viability staining) and dark field microscopy (direct cell counting), and these results were compared with the microdilution technique. Qualitative and quantitative effects of the antibiotics against biofilm-like colonies were assessed using fluorescent microscopy and dark field microscopy, respectively. RESULTS Doxycycline reduced spirochetal structures ∼90% but increased the number of round body forms about twofold. Amoxicillin reduced spirochetal forms by ∼85%-90% and round body forms by ∼68%, while treatment with metronidazole led to reduction of spirochetal structures by ∼90% and round body forms by ∼80%. Tigecycline and tinidazole treatment reduced both spirochetal and round body forms by ∼80%-90%. When quantitative effects on biofilm-like colonies were evaluated, the five antibiotics reduced formation of these colonies by only 30%-55%. In terms of qualitative effects, only tinidazole reduced viable organisms by ∼90%. Following treatment with the other antibiotics, viable organisms were detected in 70%-85% of the biofilm-like colonies. CONCLUSION Antibiotics have varying effects on the different morphological forms of B. burgdorferi. Persistence of viable organisms in round body forms and biofilm-like colonies may explain treatment failure and persistent symptoms following antibiotic therapy of Lyme disease.
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Affiliation(s)
- Eva Sapi
- Lyme Disease Research Group, Department of Biology and Environmental Sciences, University of New Haven, New Haven, CT, USA
| | - Navroop Kaur
- Lyme Disease Research Group, Department of Biology and Environmental Sciences, University of New Haven, New Haven, CT, USA
| | - Samuel Anyanwu
- Lyme Disease Research Group, Department of Biology and Environmental Sciences, University of New Haven, New Haven, CT, USA
| | - David F Luecke
- Lyme Disease Research Group, Department of Biology and Environmental Sciences, University of New Haven, New Haven, CT, USA
| | - Akshita Datar
- Lyme Disease Research Group, Department of Biology and Environmental Sciences, University of New Haven, New Haven, CT, USA
| | - Seema Patel
- Lyme Disease Research Group, Department of Biology and Environmental Sciences, University of New Haven, New Haven, CT, USA
| | - Michael Rossi
- Lyme Disease Research Group, Department of Biology and Environmental Sciences, University of New Haven, New Haven, CT, USA
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Arias CA, Contreras GA, Murray BE. Management of multidrug-resistant enterococcal infections. Clin Microbiol Infect 2011; 16:555-62. [PMID: 20569266 DOI: 10.1111/j.1469-0691.2010.03214.x] [Citation(s) in RCA: 268] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Enterococci are organisms with a remarkable ability to adapt to the environment and acquire antibiotic resistance determinants. The evolution of antimicrobial resistance in these organisms poses enormous challenges for clinicians when faced with patients affected with severe infections. The increased prevalence and dissemination of multidrug-resistant Enterococcus faecium worldwide has resulted in a major decrease in therapeutic options because the majority of E. faecium isolates are now resistant to ampicillin and vancomycin, and exhibit high-level resistance to aminoglycosides, which are three of the traditionally most useful anti-enterococcal antibiotics. Newer antibiotics such as linezolid, daptomycin and tigecycline have good in vitro activity against enterococcal isolates, although their clinical use may be limited in certain clinical scenarios as a result of reduced rates of success, possible underdosing for enterococci and low serum levels, respectively, and also by the emergence of resistance. The experimental agent oritavancin may offer some hope for the treatment of vancomycin-resistant enterococci but clinical data are still lacking. Thus, optimal therapies for the treatment of multidrug-resistant enterococcal infections continue to be based on empirical observations and extrapolations from in vitro and animal data. Clinical studies evaluating new strategies, including combination therapies, to treat severe vancomycin-resistant E. faecium infections are urgently needed.
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Affiliation(s)
- C A Arias
- Department of Internal Medicine, Division of Infectious Diseases and Center for the Study of Emerging and Reemerging Pathogens, University of Texas Medical School at Houston, Houston, TX, USA
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Synergy testing by Etest, microdilution checkerboard, and time-kill methods for pan-drug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2010; 54:4678-83. [PMID: 20713678 DOI: 10.1128/aac.00497-10] [Citation(s) in RCA: 203] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Pan-drug-resistant (PDR) Acinetobacter baumannii is an important nosocomial pathogen that poses therapeutic challenges. Tigecycline alone or in combination with agents such as colestimethate, imipenem, and/or amikacin is being used clinically to treat PDR A. baumannii infections. The purpose of this study was to compare in vitro susceptibility testing by epsilometric (Etest) methods and the checkerboard (CB) method with testing by time-kill analysis. PDR A. baumannii clinical strains representing eight unique pulsed-field gel electrophoresis clones selected from a total of 32 isolates were tested in vitro with tigecycline, colestimethate, imipenem, and amikacin in single- and two-drug combinations by using two different methods of Etest (with a fixed ratio method [method 1] and with the incorporation of the active drug in medium [method 2]) and by using CB. The three-drug combination of imipenem, tigecycline, and amikacin was also tested by CB. These results were compared to time-kill results. Synergy was consistently detected with the imipenem plus colestimethate and tigecycline plus imipenem combinations. The Etest method with active drug incorporated into the agar allowed us to detect synergy even in the presence of the active drug and was more comparable to CB and time-kill tests. Synergy was detected with the three-drug combination of imipenem, tigecycline, and amikacin by both CB and time-kill methods among several tested clones. These findings indicate the utility of synergy testing to predict activity of specific antibiotic combinations against PDR A. baumannii.
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Successful Tigecycline Combination Therapy for Mycobacterium abscessus Infection of a Total Hip Arthroplasty. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2010. [DOI: 10.1097/ipc.0b013e3181d04a09] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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43
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Woodford Guegan EM. Development of new antimicrobials. J Infect Prev 2010. [DOI: 10.1177/1757177410366326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
This paper describes the need for developing new antimicrobial drugs and outlines techniques used in the developmental process for new drugs. The second section details some of the newer antimicrobial agents that have been launched recently and those that are currently under development.
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Affiliation(s)
- EM Woodford Guegan
- Senior Research Fellow, European HTA, NETSCC, University of Southampton, Southampton, SO16 7NS, UK,
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44
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Zuckerman JM, Qamar F, Bono BR. Macrolides, ketolides, and glycylcyclines: azithromycin, clarithromycin, telithromycin, tigecycline. Infect Dis Clin North Am 2010; 23:997-1026, ix-x. [PMID: 19909895 DOI: 10.1016/j.idc.2009.06.013] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The advanced macrolides, azithromycin and clarithromycin, and the ketolide, telithromycin, are structural analogs of erythromycin. They have several distinct advantages when compared with erythromycin, including enhanced spectrum of activity, more favorable pharmacokinetics and pharmacodynamics, once-daily administration, and improved tolerability. Clarithromycin and azithromycin are used extensively for the treatment of respiratory tract infections, sexually transmitted diseases, and Helicobacter pylori-associated peptic ulcer disease. Telithromycin is approved for the treatment of community-acquired pneumonia. Severe hepatotoxicity has been reported with the use of telithromycin.
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Affiliation(s)
- Jerry M Zuckerman
- Jefferson Medical College, 1025 Walnut Street, Philadelphia, PA 19107, USA.
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45
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Skibeli V, Aaløkken I, Lingaas E, Midtvedt T, Solberg C, Melby K. Tigesyklin – et nytt antibiotikum. TIDSSKRIFT FOR DEN NORSKE LEGEFORENING 2010; 130:1624-6. [DOI: 10.4045/tidsskr.09.0722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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46
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Nicolau DP. Management of complicated infections in the era of antimicrobial resistance: the role of tigecycline. Expert Opin Pharmacother 2009; 10:1213-22. [PMID: 19405794 DOI: 10.1517/14656560902900853] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Increasing antimicrobial resistance and infection complications pose challenges to optimal antibiotic therapy. Paucity of new antibiotics (and the eventual bacterial resistance they face) highlights the critical need for more appropriate use of broadly effective agents, which may help to thwart the dramatic rise in global resistance. Single agents that can be combined effectively with others, if needed, promise the simplest overall utility. Approved in 2005 to treat complicated skin and intra-abdominal infections, tigecycline is a novel extended-spectrum minocycline derivative that circumvents bacterial resistance, as it is unaffected by efflux pumps and ribosomal protection. However, tigecycline should not be used as empiric monotherapy for treatment of health-care associated infections known or suspected to be owing to Pseudomonas aeruginosa or Proteus spp. OBJECTIVE This article summarizes the demonstrated clinical utility of tigecycline so far. METHODS A MEDLINE search examined authoritative published clinical studies, reviews and case reports detailing the clinical record of tigecycline since 2004. RESULTS/CONCLUSION Tigecycline continues to maintain satisfactory profiles of safety, efficacy and antimicrobial resistance avoidance. Regardless, continued surveillance is needed to detect reduced susceptibility and resistance against both community and nosocomial pathogens. Judicious use of agents reserved for multidrug resistant pathogens is vital to preserve their effectiveness.
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Affiliation(s)
- David P Nicolau
- Center for Anti-Infective Research & Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102-5037, USA.
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47
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Cunha BA. Pharmacokinetic considerations regarding tigecycline for multidrug-resistant (MDR) Klebsiella pneumoniae or MDR Acinetobacter baumannii urosepsis. J Clin Microbiol 2009; 47:1613. [PMID: 19403778 PMCID: PMC2681882 DOI: 10.1128/jcm.00404-09] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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48
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High concentrations of manganese in Mueller-Hinton agar increase MICs of tigecycline determined by Etest. J Clin Microbiol 2009; 47:827-9. [PMID: 19144806 DOI: 10.1128/jcm.02464-08] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
MICs of tigecycline determined by Etest were 4 to 12 times (three ATCC strains) and 2 to 8 times (50 clinical isolates) higher in Mueller-Hinton agar from Merck than in Mueller-Hinton agar from either Oxoid or Difco. This was related to a much higher concentration of manganese in the medium from Merck.
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49
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Wargo KA, Eiland EH, Eiland LS. Management and Treatment Considerations for Infections Caused by Methicillin-Resistant Staphylococcus aureus. J Pharm Pract 2008. [DOI: 10.1177/0897190008318501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Infections caused by methicillin-resistant Staphylococcus aureus have been documented since the 1960s. Four decades later, this microorganism has evolved from a pathogen found primarily in the health care environment to a major pathogen of community-acquired infections. Interestingly, the community-acquired methicillin-resistant Staphylococcus aureus isolates tend to be genetically distinct from their health-care–acquired relatives, have a propensity to be more virulent, yet be susceptible to more antibiotics. Furthermore, infections caused in the pediatric population have a susceptibility pattern that differs from those found in adults. With an increase in infections caused by methicillin-resistant Staphylococcus aureus, empiric therapy should contain an agent with activity against this microorganism. Currently several options exist for the treatment of skin and skin structure infections, yet very few options are available for the treatment of more invasive diseases caused by methicillin-resistant Staphylococcus aureus. This article will review the history of methicillin-resistant Staphylococcus aureus, Staphylococcus aureus economic considerations, and the current plus future treatment options for these infections.
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Affiliation(s)
- Kurt A. Wargo
- Auburn University Harrison School of Pharmacy, UAB School of Medicine Huntsville Regional Medical Campus-Division of Internal Medicine, Huntsville, Alabama,
| | | | - Lea S. Eiland
- Auburn University Harrison School of Pharmacy, Auburn, Alabama
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50
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Abstract
The emergence and spread of multidrug resistance in many pathogenic bacterial species is increasing at an alarming rate, especially with hospital-acquired infections in the critical care setting. Deaths associated with hospital-acquired infections have exceeded the number attributable to several of the top 10 leading causes of death reported in the United States. The emerging resistance limits the use of older antibiotics. Tigecycline is a new agent, and this article explores its role in the treatment of adults in the critical care setting.
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Affiliation(s)
- Praveen K Mullangi
- Department of Infectious Diseases, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA
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