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Hickson SM, Ledger EL, Wells TJ. Emerging antimicrobial therapies for Gram-negative infections in human clinical use. NPJ ANTIMICROBIALS AND RESISTANCE 2025; 3:16. [PMID: 40016340 PMCID: PMC11868545 DOI: 10.1038/s44259-025-00087-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/13/2025] [Indexed: 03/01/2025]
Abstract
The growing problem of multi-drug resistance (MDR) is prevalent in Gram-negative infections, and the significant decline in antibiotic development poses a critical threat to global public health. Many emerging non-antibiotic therapies have been proposed, including phage therapy, anti-virulence agents, antimicrobial peptides, plasmapheresis, and immunotherapy options. To identify the therapies most likely to be the next immediate step in treatment for MDR Gram-negative infections, this review highlights emerging therapeutics that have either been successfully used for compassionate care or are currently undergoing clinical trials.
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Affiliation(s)
- Sarah M Hickson
- Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Emma L Ledger
- Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Timothy J Wells
- Frazer Institute, The University of Queensland, Brisbane, QLD, Australia.
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Li N, Ebrahimi E, Sholeh M, Dousti R, Kouhsari E. A systematic review and meta-analysis: rising prevalence of colistin resistance in ICU-acquired Gram-negative bacteria. APMIS 2025; 133:e13508. [PMID: 39710513 DOI: 10.1111/apm.13508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Accepted: 12/03/2024] [Indexed: 12/24/2024]
Abstract
Colistin is a last-resort treatment for multidrug-resistant Gram-negative bacterial infections, particularly in critically ill patients. Nevertheless, it remains a major threat to public health. We assessed the proportion of colistin-resistant Gram-negative isolates from intensive care unit (ICU) infections in different years, areas, pathogens, and antimicrobial susceptibility tests (AST). We searched the studies in PubMed, Scopus, Embase, and Web of Science (until November 2021). Statistical analyses were conducted using STATA software (ver. 14.0). The overall rate of colistin resistance was 5.18% (95% CI 2.70%-8.22%). The proportion of colistin resistance was 4% (95% CI 2%-7%) before 2015 and 6% (95% CI 4%-9%) in 2015-2019. The rates of colistin resistance in Europe, America, Asia, and Africa were 8.24%, 3.78%, 3.60%, and 0%, respectively. The proportion of colistin-resistant non-fermenting Gram-negative bacilli isolated from the ICU was 2.25% (Acinetobacter baumannii [1.68%] and Pseudomonas aeruginosa [3.30%]). A 4-fold increase in colistin resistance was observed when comparing EUCAST and CLSI. We described the global epidemiology of colistin resistance over time and shown the distribution of colistin-resistant strains in different countries. Robust antimicrobial stewardship programs can increase the success of ICU physicians in improving patient outcomes.
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Affiliation(s)
- Na Li
- Zhejiang Provincial Headquarters Hospital of the Chinese People's Armed Police Force Zhejiang, Hangzhou, China
| | - Elaheh Ebrahimi
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Sholeh
- Department of Medical Bacteriology, Pasteur Institute of Iran, Tehran, Iran
| | - Reyhane Dousti
- Laboratory Sciences Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ebrahim Kouhsari
- Laboratory Sciences Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Laboratory Sciences, Faculty of Paramedicine, Golestan University of Medical Sciences, Gorgan, Iran
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Albac S, Anzala N, Bonnot D, Djama C, Chavanet P, Croisier D. Development of a new Acinetobacter baumannii pneumonia rabbit model for the preclinical evaluation of future anti-infective strategies. Microbiol Spectr 2024; 12:e0157024. [PMID: 39422502 PMCID: PMC11619384 DOI: 10.1128/spectrum.01570-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 08/01/2024] [Indexed: 10/19/2024] Open
Abstract
Carbapenem-resistant Acinetobacter baumannii (CRAB) is an emerging cause of hospital-acquired pneumonia (HAP). Preclinical large models are warranted to predict the efficacy and the resistance profile of anti-infectives and mimic how they will be used in the human treatment of CRAB-HAP. Here we reported on the development of an Acinetobacter baumannii experimental pneumonia model in immunocompromised rabbits, receiving a 48-h human-simulated regimen. The efficacy of meropenem (2 g/q8h i.v. over prolonged 3-h perfusion), rifampin (25 mg/kg/q8h, i.v.), or the combination of meropenem and rifampin was assessed in rabbits infected with the carbapenem-susceptible ATCC 17978 reference strain or the CRAB Turc 2 clinical strain. The emergence of rifampin mutants was also investigated. Meropenem demonstrated a strong pulmonary bacterial reduction in animals infected with the ATCC 17978 strain (unlike the CRAB strain). The high rifampin dosage was associated with a 1.3 Log10 bacterial killing on average but induced the emergence of high-level resistant mutants in 80%-100% of animals, depending on the strain. The adjunction of rifampin to meropenem did not improve the bioburden in the lungs but partially reduced the number of animals exhibiting resistant mutants, whatever the tested strain. However, this adjunctive treatment was insufficient to overcome the emergence of resistance since mutation prevention concentration-related pharmacodynamic indices were unattainable at this dose. This CRAB pneumonia rabbit model represents an innovative tool to evaluate the efficacy of new or existing therapies and will provide informative data on how they can meet the resistance pharmacodynamic targets, which now need to be investigated before deciding on clinical therapeutic regimens.IMPORTANCEWithin intensive care unit settings, carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a frequent cause of hospital-acquired pneumonia (HAP) with poor clinical outcomes. This multidrug-resistant pathogen remains very challenging to study in clinical trials, and the U.S. Food and Drug Administration highlighted the limitations of existing small animal models for evaluating antibacterial or prophylactic strategies against such critical infections. These limitations include the difficulty in anticipating the risk of the emergence of resistance during treatment. Here we developed a new Acinetobacter baumannii pneumonia rabbit model using high inoculum. We demonstrated the emergence of resistance with rifampin, an existing antibiotic debated as a rescuing option to treat CRAB infections; and even intensified rifampin doses failed to close the mutant selection window. This CRAB pneumonia rabbit model represents a valuable tool to evaluate the efficacy of new or existing therapies and provides supportive data in antimicrobial resistance pharmacodynamics.
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Affiliation(s)
| | | | | | | | - P. Chavanet
- Vivexia, Dijon, France
- Département d’Infectiologie, Centre Hospitalier Universitaire, Dijon, France
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Abichabki N, Gaspar GG, Zacharias LV, Pocente RHC, Lima DAFS, de Freitas NAB, Brancini GTP, Moreira NC, Braga GÚL, Bellissimo-Rodrigues F, Bollela VR, Darini ALC, Andrade LN. In Vitro Synergistic Activity of Rifampicin Combined with Minimal Effective Antibiotic Concentration (MEAC) of Polymyxin B Against Extensively Drug-Resistant, Carbapenem-, and Polymyxin B-Resistant Klebsiella pneumoniae Clinical Isolates. Curr Microbiol 2024; 81:371. [PMID: 39307852 DOI: 10.1007/s00284-024-03897-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 09/11/2024] [Indexed: 10/22/2024]
Abstract
We investigated the in vitro antibacterial activity of the combination rifampicin (RIF) + polymyxin B (PB) against extensively drug-resistant (XDR) Klebsiella pneumoniae isolates. We evaluated clinical isolates co-resistant to PB (non-mcr carriers; eptB, mgrB, pmr operon, and ramA mutations) and to carbapenems (KPC, CTX-M, and SHV producers; including KPC + NDM co-producer), belonging to sequence types (ST) ST16, ST11, ST258, ST340, and ST437. We used the standard broth microdilution method to determine RIF and PB minimum inhibitory concentration (MIC) and the checkerboard assay to evaluate the fractional inhibitory concentration index (FICI) of RIF + PB as well as to investigate the lowest concentrations of RIF and PB that combined (RIF + PB) had antibacterial activity. Time-kill assays were performed to evaluate the synergistic effect of the combination against selected isolates. PB MIC (32-256 µg/mL) and RIF MIC (32-1024 µg/mL) were determined. FICI (<0.5) indicated a synergistic effect for all isolates evaluated for the combination RIF + PB. Our results showed that low concentrations of PB (PB minimal effective antibiotic concentration [MEAC], ≤0.25-1 µg/mL) favor RIF (≤0.03-0.125 µg/mL) to reach the bacterial target and exert antibacterial activity against PB-resistant isolates, and the synergistic effect was also observed in time-kill results. The combination of RIF + PB showed in vitro antibacterial activity against XDR, carbapenem-, and PB-resistant K. pneumoniae and could be further studied as a potential combination therapy, with cost-effectiveness and promising efficacy.
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Affiliation(s)
- Nathália Abichabki
- School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Av. Prof. Dr. Zeferino Vaz - Vila Monte Alegre, Ribeirão Preto, SP, 14040-903, Brazil
| | - Gilberto Gambero Gaspar
- Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Av. Bandeirantes, 3900, Campus da USP - Cidade Universitária, Ribeirão Preto, SP, 14040-900, Brazil
- University Hospital of Ribeirão Preto Medical School (HCFMRP), University of São Paulo (USP), R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto, SP, 14015-010, Brazil
| | - Luísa Vieira Zacharias
- School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Av. Prof. Dr. Zeferino Vaz - Vila Monte Alegre, Ribeirão Preto, SP, 14040-903, Brazil
| | - Renata Helena Cândido Pocente
- University Hospital of Ribeirão Preto Medical School (HCFMRP), University of São Paulo (USP), R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto, SP, 14015-010, Brazil
| | - Denissani Aparecida Ferrari Santos Lima
- University Hospital of Ribeirão Preto Medical School (HCFMRP), University of São Paulo (USP), R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto, SP, 14015-010, Brazil
| | - Natália Augusta Barbosa de Freitas
- University Hospital of Ribeirão Preto Medical School (HCFMRP), University of São Paulo (USP), R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto, SP, 14015-010, Brazil
| | - Guilherme Thomaz Pereira Brancini
- School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Av. Prof. Dr. Zeferino Vaz - Vila Monte Alegre, Ribeirão Preto, SP, 14040-903, Brazil
| | - Natália Columbaro Moreira
- School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Av. Prof. Dr. Zeferino Vaz - Vila Monte Alegre, Ribeirão Preto, SP, 14040-903, Brazil
| | - Gilberto Úbida Leite Braga
- Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Av. Prof. Dr. Zeferino Vaz - Vila Monte Alegre, Ribeirão Preto, SP, 14040-903, Brazil
| | - Fernando Bellissimo-Rodrigues
- Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Av. Bandeirantes, 3900, Campus da USP - Cidade Universitária, Ribeirão Preto, SP, 14040-900, Brazil
| | - Valdes Roberto Bollela
- Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Av. Bandeirantes, 3900, Campus da USP - Cidade Universitária, Ribeirão Preto, SP, 14040-900, Brazil
- University Hospital of Ribeirão Preto Medical School (HCFMRP), University of São Paulo (USP), R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto, SP, 14015-010, Brazil
| | - Ana Lúcia Costa Darini
- Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Av. Prof. Dr. Zeferino Vaz - Vila Monte Alegre, Ribeirão Preto, SP, 14040-903, Brazil
| | - Leonardo Neves Andrade
- Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Av. Prof. Dr. Zeferino Vaz - Vila Monte Alegre, Ribeirão Preto, SP, 14040-903, Brazil.
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Zhao D, Feng W, Kang X, Li H, Liu F, Zheng W, Li G, Wang X. Dual-targeted poly(amino acid) nanoparticles deliver drug combinations on-site: an intracellular synergistic strategy to eliminate intracellular bacteria. J Mater Chem B 2023; 11:2958-2971. [PMID: 36919349 DOI: 10.1039/d3tb00125c] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
Multi-drug combinations are a common strategy for the treatment of intracellular bacterial infections. However, different internalized pathways and the accumulation of the composite drugs at different subcellular organelles very much reduce their efficacy. Herein, an intracellular synergistic strategy is proposed, which is realized by on-site delivery of a drug combination using a macrophage/intracellular bacterium-dual targeted drug delivery system (DDS). The DDS is fabricated by encapsulating vancomycin (Van) and curcumin (Cur) into poly(α-N-acryloyl-phenylalanine)-block-poly(β-N-acryloyl-D-aminoalanine-co-2-O-acetyl-α-D-mannosyloxy) nanoparticles, denoted by (Van + Cur)@F(AM) NPs. Mannose ligands on (Van + Cur)@F(AM) NPs trigger their specific internalization in macrophages, while aminoalanine moieties subsequently drive the NPs to target intracellular methicillin-resistant Staphylococcus aureus (MRSA). Thereafter, Van and Cur are durably released in a synergistic dose at the residence site of intracellular MRSA. Under this intracellular synergistic effect, (Van + Cur)@F(AM) NPs show superior elimination efficiency in vitro and in vivo compared to the control groups, including free Van, (Van + Cur), the DDS encapsulated Van and the DDSs separately-encapsulated Van and Cur. Furthermore, (Van + Cur)@F(AM) NPs significantly enhance the in vivo antibacterial capacity by modulating the immune response. Therefore, this dual-targeted DDS-assisted intracellular synergistic antibacterial strategy of drug combination is an effective therapeutic against intracellular bacteria.
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Affiliation(s)
- Dongdong Zhao
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Wenli Feng
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Xiaoxu Kang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Haofei Li
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Fang Liu
- Department of Oncology of Integrative Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Weitao Zheng
- Hubei Provincial Key Laboratory of Industrial Microbiology, Sino-German Biomedical Center, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, 430068, Hubei Province, China
| | - Guofeng Li
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Xing Wang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
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Karballaei-Mirzahosseini H, Kaveh-Ahangaran R, Shahrami B, Rouini MR, Najafi A, Ahmadi A, Sadrai S, Mojtahedzadeh A, Najmeddin F, Mojtahedzadeh M. Pharmacokinetic study of high-dose oral rifampicin in critically Ill patients with multidrug-resistant Acinetobacter baumannii infection. Daru 2022; 30:311-322. [PMID: 36069988 PMCID: PMC9715901 DOI: 10.1007/s40199-022-00449-5] [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: 06/11/2022] [Accepted: 08/05/2022] [Indexed: 10/14/2022] Open
Abstract
PURPOSE Although rifampicin (RIF) is used as a synergistic agent for multidrug-resistant Acinetobacter baumannii (MDR-AB) infection, the optimal pharmacokinetic (PK) indices of this medication have not been studied in the intensive care unit (ICU) settings. This study aimed to evaluate the PK of high dose oral RIF following fasting versus fed conditions in terms of achieving the therapeutic goals in critically ill patients with MDR-AB infections. METHODS 29 critically ill patients were included in this study. Under fasting and non-fasting conditions, RIF was given at 1200 mg once daily through a nasogastric tube. Blood samples were obtained at seven time points: exactly before administration of the drug, and at 1, 2, 4, 8, 12, and 24 h after RIF ingestion. To quantify RIF in serum samples, high-performance liquid chromatography (HPLC) was used. The MONOLIX Software and the Monte Carlo simulations were employed to estimate the PK parameters and describe the population PK model. RESULTS The mean area under the curve over the last 24-h (AUC0-24) value and accuracy (mean ± standard deviation) in the fasting and fed states were 220.24 ± 119.15 and 290.55 ± 276.20 μg × h/mL, respectively. There was no significant difference among AUCs following fasting and non-fasting conditions (P > 0.05). The probability of reaching the therapeutic goals at the minimum inhibitory concentration (MIC) of 4 mg/L, was only 1.6%. CONCLUSION In critically ill patients with MDR-AB infections, neither fasting nor non-fasting administrations of high-dose oral RIF achieve the therapeutic aims. More research is needed in larger populations and with measuring the amount of protein-unbound RIF levels.
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Affiliation(s)
- Hossein Karballaei-Mirzahosseini
- Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, 16-Azar St., Enghelab Ave., Tehran, 14176-14418, Iran
| | - Romina Kaveh-Ahangaran
- Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, 16-Azar St., Enghelab Ave., Tehran, 14176-14418, Iran
| | - Bita Shahrami
- Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, 16-Azar St., Enghelab Ave., Tehran, 14176-14418, Iran
| | - Mohammad Reza Rouini
- Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Atabak Najafi
- Department of Anesthesiology and Critical Care, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arezoo Ahmadi
- Department of Anesthesiology and Critical Care, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sima Sadrai
- Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Farhad Najmeddin
- Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, 16-Azar St., Enghelab Ave., Tehran, 14176-14418, Iran.
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mojtaba Mojtahedzadeh
- Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, 16-Azar St., Enghelab Ave., Tehran, 14176-14418, Iran
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
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Wang JL, Xiang BX, Song XL, Que RM, Zuo XC, Xie YL. Prevalence of polymyxin-induced nephrotoxicity and its predictors in critically ill adult patients: A meta-analysis. World J Clin Cases 2022; 10:11466-11485. [PMID: 36387815 PMCID: PMC9649555 DOI: 10.12998/wjcc.v10.i31.11466] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/15/2022] [Accepted: 09/23/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Polymyxin-induced nephrotoxicity is a major safety concern in clinical practice due to long-term adverse outcomes and high mortality.
AIM To conducted a systematic review and meta-analysis of the prevalence and potential predictors of polymyxin-induced nephrotoxicity in adult intensive care unit (ICU) patients.
METHODS PubMed, EMBASE, the Cochrane Library and Reference Citation Analysis database were searched for relevant studies from inception through May 30, 2022. The pooled prevalence of polymyxin-induced nephrotoxicity and pooled risk ratios of associated factors were analysed using a random-effects or fixed-effects model by Stata SE ver. 12.1. Additionally, subgroup analyses and meta-regression were conducted to assess heterogeneity.
RESULTS A total of 89 studies involving 12234 critically ill adult patients were included in the meta-analysis. The overall pooled incidence of polymyxin-induced nephrotoxicity was 34.8%. The pooled prevalence of colistin-induced nephrotoxicity was not higher than that of polymyxin B (PMB)-induced nephrotoxicity. The subgroup analyses showed that nephrotoxicity was significantly associated with dosing interval, nephrotoxicity criteria, age, publication year, study quality and sample size, which were confirmed in the univariable meta-regression analysis. Nephrotoxicity was significantly increased when the total daily dose was divided into 2 doses but not 3 or 4 doses. Furthermore, older age, the presence of sepsis or septic shock, hypoalbuminemia, and concomitant vancomycin or vasopressor use were independent risk factors for polymyxin-induced nephrotoxicity, while an elevated baseline glomerular filtration rate was a protective factor against colistin-induced nephrotoxicity.
CONCLUSION Our findings indicated that the incidence of polymyxin-induced nephrotoxicity among ICU patients was high. It emphasizes the importance of additional efforts to manage ICU patients receiving polymyxins to decrease the risk of adverse outcomes.
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Affiliation(s)
- Jiang-Lin Wang
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Bi-Xiao Xiang
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Xiao-Li Song
- Department of Pharmacy, Sanya Central Hospital, Sanya 572000, Hainan Province, China
| | - Rui-Man Que
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Xiao-Cong Zuo
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Yue-Liang Xie
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
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Al-Marzooq F, Ghazawi A, Tariq S, Daoud L, Collyns T. Discerning the role of polymyxin B nonapeptide in restoring the antibacterial activity of azithromycin against antibiotic-resistant Escherichia coli. Front Microbiol 2022; 13:998671. [PMID: 36212888 PMCID: PMC9532765 DOI: 10.3389/fmicb.2022.998671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/24/2022] [Indexed: 11/24/2022] Open
Abstract
Antimicrobial resistance is a global public health threat. Antibiotic development pipeline has few new drugs; therefore, using antibiotic adjuvants has been envisioned as a successful method to preserve existing medications to fight multidrug-resistant (MDR) pathogens. In this study, we investigated the synergistic effect of a polymyxin derivative known as polymyxin B nonapeptide (PMBN) with azithromycin (AZT). A total of 54 Escherichia coli strains were first characterized for macrolide resistance genes, and susceptibility to different antibiotics, including AZT. A subset of 24 strains was then selected for synergy testing by the checkerboard assay. PMBN was able to re-sensitize the bacteria to AZT, even in strains with high minimum inhibitory concentrations (MIC: 32 to ≥128 μg/ml) for AZT, and in strains resistant to the last resort drugs such as colistin and meropenem. The fractional inhibitory concentration index was lower than 0.5, demonstrating that PMBN and AZT combinations had a synergistic effect. The combinations worked efficiently in strains carrying mphA gene encoding macrolide phosphotransferase which can cause macrolide inactivation. However, the combinations were inactive in strains having an additional ermB gene encoding macrolide methylase which causes ribosomal drug target alteration. Killing kinetics study showed a significant reduction of bacterial growth after 6 h of treatment with complete killing achieved after 24 h. Transmission electron microscopy showed morphological alterations in the bacteria treated with PMBN alone or in combination with AZT, with evidence of damage to the outer membrane. These results suggested that PMBN acted by increasing the permeability of bacterial outer membrane to AZT, which was also evident using a fluorometric assay. Using multiple antimicrobial agents could therefore be a promising strategy in the eradication of MDR bacteria. PMBN is a good candidate for use with other antibiotics to potentiate their activity, but further studies are required in vivo. This will significantly contribute to resolving antimicrobial resistance crisis.
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Affiliation(s)
- Farah Al-Marzooq
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- *Correspondence: Farah Al-Marzooq,
| | - Akela Ghazawi
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Saeed Tariq
- Department of Anatomy, College of Medicine and Health Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Lana Daoud
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Giacobbe DR, Roberts JA, Abdul-Aziz MH, de Montmollin E, Timsit JF, Bassetti M. Treatment of ventilator-associated pneumonia due to carbapenem-resistant Gram-negative bacteria with novel agents: a contemporary, multidisciplinary ESGCIP perspective. Expert Rev Anti Infect Ther 2022; 20:963-979. [PMID: 35385681 DOI: 10.1080/14787210.2022.2063838] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION : In the past 15 years, treatment of VAP caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) has represented an intricate challenge for clinicians. AREAS COVERED In this perspective article, we discuss the available clinical data about novel agents for the treatment of CR-GNB VAP, together with general PK/PD principles for the treatment of VAP, in the attempt to provide some suggestions for optimizing antimicrobial therapy of CR-GNB VAP in the daily clinical practice. EXPERT OPINION Recently, novel BL and BL/BLI combinations have become available that have shown potent in vitro activity against CR-GNB and have attracted much interest as novel, less toxic, and possibly more efficacious options for the treatment of CR-GNB VAP compared with previous standard of care. Besides randomized controlled trials, a good solution to enrich our knowledge on how to use these novel agents at best in the near future, while at the same time remaining adherent to current evidence-based guidelines, is to improve our collaboration to conduct larger multinational observational studies to collect sufficiently large populations treated in real life with those novel agents for which guidelines currently do not provide a recommendation (in favor or against) for certain causative organisms.
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Affiliation(s)
- Daniele Roberto Giacobbe
- Infectious Diseases Unit, San Martino Policlinico Hospital - IRCCS for Oncology and Neuroscience, Genoa, Italy.,Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.,Critically ill patients study group (ESGCIP) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
| | - Jason A Roberts
- Critically ill patients study group (ESGCIP) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).,University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia.,Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Australia.,Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia.,Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes France
| | - Mohd H Abdul-Aziz
- University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Etienne de Montmollin
- Medical and Infectious Diseases Intensive Care Unit, AP-HP, Bichat Claude Bernard University Hospital, Paris, France.,INSERM IAME UMR 1137, University of Paris, Sorbonne Paris Cite, Paris, France
| | - Jean-François Timsit
- Critically ill patients study group (ESGCIP) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).,Medical and Infectious Diseases Intensive Care Unit, AP-HP, Bichat Claude Bernard University Hospital, Paris, France.,INSERM IAME UMR 1137, University of Paris, Sorbonne Paris Cite, Paris, France
| | - Matteo Bassetti
- Infectious Diseases Unit, San Martino Policlinico Hospital - IRCCS for Oncology and Neuroscience, Genoa, Italy.,Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.,Critically ill patients study group (ESGCIP) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
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10
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Dobreva E, Ivanov I, Donchev D, Ivanova K, Hristova R, Dobrinov V, Dobrinov V, Sabtcheva S, Kantardjiev T. In vitro Investigation of Antibiotic Combinations against Multi- and Extensively Drug-Resistant Klebsiella pneumoniae. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.8934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Objectives: Community and hospital acquired K. pneumoniae infections have become a ubiquitous medical issue due to the limited treatment options and high mortality rate therefore the aims of this study are in vitro investigation of double antimicrobial combinations against multidrug resistant (MDR) and extensively drug resistant (XDR) isolates.
Materials and Methods: Antimicrobial susceptibility of twelve isolates from eight Bulgarian hospitals was determined to study the interaction effect of selected double combinations in accordance to fractional inhibitory concentration (FIC) method. Furthermore, the isolates were subjected to genotyping by Multilocus sequence typing (MLST) and detection of carbapenemase genes by multiplex PCR. The results were assessed by groups of strains with either NDM or KPC carbapenemase.
Results: Nine antimicrobial combinations: meropenem-colistin, meropenem-fosfomycin, meropenem-gentamicin, meropenem-rifampicin, meropenem-tigecycline, colistin-fosfomycin, colistin-gentamicin, colistin-rifampicin and colistin-tigecycline were tested for synergism on twelve K. pneumoniae, producing either KPC-2 (KPC-KP, 41.7%, 5/12) or NDM-1 (NDM-KP, 58.3%, 7/12). The isolates were distributed in three sequence types: ST11 (58.3%, 7/12), ST15 (25%, 3/12) and ST258 (16.7%, 2/12). All KPC-KP (ST258 and ST15) originated from three hospitals. The rest were NDM-1 carriers isolated from six hospitals and belonged to ST11. The highest synergistic effect was determined for MER-GEN (83.3%, 10/12) and COL-RIF (83.3%, 10/12). The MER-FOS combination was most efficient against NDM-KP, opposite to the KPC strains. Antagonism was not observed for any combinations.
Conclusions: The evaluated joint synergistic effect of the MER-GEN and COL-RIF may facilitate the treatment options for patients infected with NDM- and KPC-KP, whereas MER-FOS is highly synergetic against NDM-KP.
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11
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Alotaibi T, Abuhaimed A, Alshahrani M, Albdelhady A, Almubarak Y, Almasari O. Prevalence of multidrug-resistant Acinetobacter baumannii in a critical care setting: A tertiary teaching hospital experience. SAGE Open Med 2021; 9:20503121211001144. [PMID: 33796296 PMCID: PMC7968016 DOI: 10.1177/20503121211001144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 02/15/2021] [Indexed: 11/17/2022] Open
Abstract
Background: The management of Acinetobacter baumannii infection is considered a challenge especially in an intensive care setting. The resistance rate makes it difficult to manage and is believed to lead to higher mortality. We aim to investigate the prevalence of Acinetobacter baumannii and explore how different antibiotic regimens could impact patient outcomes as there are no available published data to reflect our population in our region. Methods: We conducted a retrospective review of all infected adult patients admitted to the intensive care unit at King Fahad University Hospital with a confirmed laboratory diagnosis of Acinetobacter baumannii from 1 January 2013 until 31 December 2017. Positive cultures were obtained from the microbiology department and those meeting the inclusive criteria were selected. Variables were analyzed using descriptive analysis and cross-tabulation. Results were further reviewed and audited by blinded co-authors. Results: A comprehensive review of data identified 198 patients with Acinetobacter baumannii. The prevalence of Acinetobacter baumannii is 3.37%, and the overall mortality rate is 40.81%. Our sample consisted mainly of male patients, that is, 68.7%, with a mean age of 49 years, and the mean age of female patients was 56 years. The mean age of survivors was less than that of non-survivors, that is, 44.95 years of age. We observed that prior antibiotic use was higher in non-survivors compared to survivors. From the review of treatment provided for patients infected with Acinetobacter baumannii, 65 were treated with colistin alone, 18 were treated with carbapenems, and 22 were treated with a combination of both carbapenems and colistin. The mean length of stay of Acinetobacter baumannii–infected patients was 20.25 days. We found that the survival rates among patients who received carbapenems were higher compared to those who received colistin.
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Affiliation(s)
- Thabit Alotaibi
- Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
| | | | | | | | | | - Osama Almasari
- Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
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12
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Russo A, Bassetti M, Bellelli V, Bianchi L, Marincola Cattaneo F, Mazzocchetti S, Paciacconi E, Cottini F, Schiattarella A, Tufaro G, Sabetta F, D'Avino A. Efficacy of a Fosfomycin-Containing Regimen for Treatment of Severe Pneumonia Caused by Multidrug-Resistant Acinetobacter baumannii: A Prospective, Observational Study. Infect Dis Ther 2021; 10:187-200. [PMID: 33068255 PMCID: PMC7568458 DOI: 10.1007/s40121-020-00357-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 10/08/2020] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION Severe pneumonia caused by multidrug-resistant Acinetobacter baumannii (MDR-AB) remains a difficult-to-treat infection. Considering the poor lung penetration of most antibiotics, the choice of the better antibiotic regimen is debated. METHODS We performed a prospective, observational, multicenter study conducted from January 2017 to June 2020. All consecutive hospitalized patients with severe pneumonia due to MDR-AB were included in the study. The primary endpoint of the study was to evaluate risk factors associated with survival or death at 30 days from pneumonia onset. A propensity score for receiving therapy with fosfomycin was added to the model. RESULTS During the study period, 180 cases of hospital-acquired pneumonia, including ventilator-associated pneumonia, caused by MDR-AB strains were observed. Cox regression analysis of factors associated with 30-day mortality, after propensity score, showed that septic shock, and secondary bacteremia were associated with death, while a fosfomycin-containing regimen was associated with 30-day survival. Antibiotic combinations with fosfomycin in definitive therapy for 44 patients were: fosfomycin + colistin in 11 (25%) patients followed by fosfomycin + carbapenem + tigecycline in 8 (18.2%), fosfomycin + colistin + tigecycline in 7 (15.9%), fosfomycin + rifampin in 7 (15.9%), fosfomycin + tigecycline in 6 (13.6%), fosfomycin + carbapenem in 3 (6.8%), and fosfomycin + aminoglycoside in 2 (4.5%). CONCLUSIONS This real-life clinical experience concerning the therapeutic approach to severe pneumonia caused by MDR-AB provides useful suggestions to clinicians, showing the use of different antibiotic regimens with a predominant role for fosfomycin. Further randomized clinical trials are necessary to confirm or exclude these observations.
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Affiliation(s)
- Alessandro Russo
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
- Internal Medicine Unit, Policlinico Casilino, Rome, Italy.
| | - Matteo Bassetti
- Department of Health Sciences, University of Genoa, Genoa, Italy
| | | | - Luigi Bianchi
- Internal Medicine Unit, Policlinico Casilino, Rome, Italy
| | | | | | - Elena Paciacconi
- Department of Intensive Care Unit, Cristo Re Hospital, Rome, Italy
| | - Fabrizio Cottini
- Intensive Care Unit, San Carlo di Nancy Hospital-GVM Care and Research, Rome, Italy
| | | | | | | | - Alessandro D'Avino
- Department of Internal Medicine and Risk Management, Cristo Re Hospital, Rome, Italy
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13
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Wagenlehner F, Lucenteforte E, Pea F, Soriano A, Tavoschi L, Steele VR, Henriksen AS, Longshaw C, Manissero D, Pecini R, Pogue JM. Systematic review on estimated rates of nephrotoxicity and neurotoxicity in patients treated with polymyxins. Clin Microbiol Infect 2021; 27:S1198-743X(20)30764-3. [PMID: 33359542 DOI: 10.1016/j.cmi.2020.12.009] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 11/03/2020] [Accepted: 12/10/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Nephrotoxicity and neurotoxicity are commonly associated with polymyxin treatment; however, the emergence of multidrug-resistant Gram-negative bacteria with limited therapeutic options has resulted in increased use of polymyxins. OBJECTIVES To determine the rates of nephrotoxicity and neurotoxicity during polymyxin treatment and whether any factors influence these. DATA SOURCES Medline, Embase and Cochrane Library databases were searched on 2 January 2020. STUDY ELIGIBILITY CRITERIA Studies reporting nephrotoxicity and/or neurotoxicity rates in patients with infections treated with polymyxins were included. Reviews, meta-analyses and reports not in English were excluded. PARTICIPANTS Patients hospitalized with infections treated with systemic or inhaled polymyxins were included. For comparative analyses, patients treated with non-polymyxin-based regimens were also included. METHODS Meta-analyses were performed using a random-effects model; subgroup meta-analyses were conducted where data permitted using a mixed-effects model. RESULTS In total, 237 reports of randomized controlled trials, cohort and case-control studies were eligible for inclusion; most were single-arm observational studies. Nephrotoxic events in 35,569 patients receiving polymyxins were analysed. Overall nephrotoxicity rate was 0.282 (95% confidence interval (CI) 0.259-0.307). When excluding studies where >50% of patients received inhaled-only polymyxin treatment or nephrotoxicity assessment was by methods other than internationally recognized criteria (RIFLE, KDIGO or AKIN), the nephrotoxicity rate was 0.391 (95% CI 0.364-0.419). The odds of nephrotoxicity were greater with polymyxin therapies compared to non-polymyxin-based regimens (odds ratio 2.23 (95% CI 1.58-3.15); p < 0.001). Meta-analyses showed a significant effect of polymyxin type, dose, patient age, number of concomitant nephrotoxins and use of diuretics, glycopeptides or vasopressors on the rate of nephrotoxicity. Polymyxin therapies were not associated with a significantly different rate of neurotoxicity than non-polymyxin-based regimens (p 0.051). The overall rate of neurotoxicity during polymyxin therapy was 0.030 (95% CI 0.020-0.043). CONCLUSIONS Polymyxins are associated with a higher risk of nephrotoxicity than non-polymyxin-based regimens.
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Affiliation(s)
- Florian Wagenlehner
- Clinic for Urology, Pediatric Urology and Andrology, Justus-Liebig-University, Giessen, Germany
| | - Ersilia Lucenteforte
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Federico Pea
- Department of Medicine, University of Udine and Institute of Clinical Pharmacology, SM Misericordia University Hospital, ASUIUD, Udine, Italy
| | - Alex Soriano
- Infectious Diseases Department, Hospital Clínic of Barcelona, University of Barcelona IDIBAPS, Barcelona, Spain
| | - Lara Tavoschi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | | | | | | | - Davide Manissero
- University College of London, Institute for Global Health, London, UK
| | | | - Jason M Pogue
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
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14
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McCarthy RR, Larrouy-Maumus GJ, Meiqi Tan MGC, Wareham DW. Antibiotic Resistance Mechanisms and Their Transmission in Acinetobacter baumannii. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1313:135-153. [PMID: 34661894 DOI: 10.1007/978-3-030-67452-6_7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The discovery of penicillin over 90 years ago and its subsequent uptake by healthcare systems around the world revolutionised global health. It marked the beginning of a golden age in antibiotic discovery with new antibiotics readily discovered from natural sources and refined into therapies that saved millions of lives. Towards the end of the last century, the rate of discovery slowed to a near standstill. The lack of discovery is compounded by the rapid emergence and spread of bacterial pathogens that exhibit resistance to multiple antibiotic therapies and threaten the sustainability of global healthcare systems. Acinetobacter baumannii is an opportunistic pathogen whose prevalence and impact has grown significantly over the last 20 years. It is recognised as a barometer of the antibiotic resistance crisis due to the diverse array of mechanisms by which it can become resistant.
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Affiliation(s)
- Ronan R McCarthy
- Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK.
| | - Gerald J Larrouy-Maumus
- MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, UK
| | - Mei Gei C Meiqi Tan
- Antimicrobial Research Group, Blizard Institute, Queen Mary University London, London, UK
| | - David W Wareham
- Antimicrobial Research Group, Blizard Institute, Queen Mary University London, London, UK
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15
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Zhao J, Han ML, Zhu Y, Lin YW, Wang YW, Lu J, Hu Y, Tony Zhou Q, Velkov T, Li J. Comparative metabolomics reveals key pathways associated with the synergistic activity of polymyxin B and rifampicin combination against multidrug-resistant Acinetobacter baumannii. Biochem Pharmacol 2020; 184:114400. [PMID: 33387481 DOI: 10.1016/j.bcp.2020.114400] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/20/2020] [Accepted: 12/28/2020] [Indexed: 01/04/2023]
Abstract
Multidrug-resistant (MDR) Acinetobacter baumannii presents a critical challenge to human health worldwide and polymyxins are increasingly used as a last-line therapy. Due to the rapid emergence of resistance during polymyxin monotherapy, synergistic combinations (e.g. with rifampicin) are recommended to treat A. baumannii infections. However, most combination therapies are empirical, owing to a dearth of understanding on the mechanism of synergistic antibacterial killing. In the present study, we employed metabolomics to investigate the synergy mechanism of polymyxin B-rifampicin against A. baumannii AB5075, an MDR clinical isolate. The metabolomes of A. baumannii AB5075 were compared at 1 and 4 h following treatments with polymyxin B alone (0.75 mg/L, i.e. 3 × MIC), rifampicin alone (1 mg/L, i.e. 0.25 × MIC) and their combination. Polymyxin B monotherapy significantly perturbed glycerophospholipid and fatty acid metabolism at 1 h, reflecting its activity on bacterial outer membrane. Rifampicin monotherapy significantly perturbed glycerophospholipid, nucleotide and amino acid metabolism, which are related to the inhibition of RNA synthesis. The combination treatment significantly perturbed the metabolism of nucleotides, amino acids, fatty acids and glycerophospholipids at 1 and 4 h. Notably, the intermediate metabolite pools from pentose phosphate pathway were exclusively enhanced by the combination, while most metabolites from the nucleotide and amino acid biosynthesis pathways were significantly decreased. Overall, the synergistic activity of the combination was initially driven by polymyxin B which impacted pathways associated with outer membrane biogenesis; and subsequent effects were mainly attributed to rifampicin via the inhibition of RNA synthesis. This study is the first to reveal the synergistic killing mechanism of polymyxin-rifampicin combination against polymyxin-susceptible MDR A. baumannii at the network level. Our findings provide new mechanistic insights for optimizing this synergistic combination in patients.
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Affiliation(s)
- Jinxin Zhao
- Infection & Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne 3800, Australia
| | - Mei-Ling Han
- Infection & Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne 3800, Australia
| | - Yan Zhu
- Infection & Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne 3800, Australia
| | - Yu-Wei Lin
- Infection & Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne 3800, Australia
| | - Yi-Wen Wang
- Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Melbourne 3010, Australia
| | - Jing Lu
- Infection & Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne 3800, Australia
| | - Yang Hu
- Infection & Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne 3800, Australia
| | - Qi Tony Zhou
- Department of Industrial and Physical Pharmacy, Purdue University, Indiana 47907, United States
| | - Tony Velkov
- Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne 3010, Australia
| | - Jian Li
- Infection & Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne 3800, Australia.
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16
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Zhou C, Wang Q, Jin L, Wang R, Yin Y, Sun S, Zhang J, Wang H. In vitro Synergistic Activity of Antimicrobial Combinations Against bla KPC and bla NDM-Producing Enterobacterales With bla IMP or mcr Genes. Front Microbiol 2020; 11:533209. [PMID: 33193122 PMCID: PMC7609915 DOI: 10.3389/fmicb.2020.533209] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 08/20/2020] [Indexed: 12/30/2022] Open
Abstract
Carbapenemase-producing Enterobacterales have become a severe public health concern because of their rapidly transmissible resistance elements and limited treatment options. The most effective antimicrobial combinations against carbapenemase-producing Enterobacterales are currently unclear. Here, we aimed to assess the therapeutic effects of seven antimicrobial combinations (colistin-meropenem, colistin-tigecycline, colistin-rifampicin, colistin-erythromycin, meropenem-tigecycline, meropenem-rifampicin, and meropenem-tigecycline-colistin) against twenty-four carbapenem-producing Enterobacterales (producing blaKPC, blaNDM, coexisting blaNDM and blaIMP, and coexisting mcr-1/8/9 and blaNDM genes) and one carbapenem-susceptible Enterobacterales using the checkerboard assay, time-kill curves, and scanning electron microscopy. None of the combinations were antagonistic. The combination of colistin-rifampicin showed the highest synergistic effect of 76% (19/25), followed by colistin-erythromycin at 60% (15/25), meropenem-rifampicin at 24% (6/25), colistin-meropenem at 20% (5/25), colistin-tigecycline at 20% (5/25), and meropenem-tigecycline at 4% (1/25). The triple antimicrobial combinations of meropenem-tigecycline-colistin had a synergistic effect of 100%. Most double antimicrobial combinations were ineffective on isolates with coexisting blaNDM and blaIMP genes. Meropenem with tigecycline showed no synergistic effect on isolates that produced different carbapenemase genes and were highly resistant to meropenem (92% meropenem MIC ≥ 16 mg/mL). Colistin-tigecycline showed no synergistic effect on Escherichia coli producing blaNDM–1 and Serratia marcescens. Time-kill curves showed that antimicrobial combinations achieved an eradication effect (≥ 3 log10 decreases in colony counts) within 24 h without regrowth, based on 1 × MIC of each drug. The synergistic mechanism of colistin-rifampicin may involve the colistin-mediated disruption of bacterial membranes, leading to severe alterations in their permeability, then causes more rifampicin to enter the cell and induces cell death. In conclusion, the antimicrobial combinations evaluated in this study may facilitate the successful treatment of patients infected with carbapenemase-producing pathogens.
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Affiliation(s)
- Chaoe Zhou
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Qi Wang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Longyang Jin
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Ruobing Wang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Yuyao Yin
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Shijun Sun
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Jiangang Zhang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Hui Wang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
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17
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Jangra M, Raka V, Nandanwar H. In Vitro Evaluation of Antimicrobial Peptide Tridecaptin M in Combination with Other Antibiotics against Multidrug Resistant Acinetobacter baumannii. Molecules 2020; 25:molecules25143255. [PMID: 32708842 PMCID: PMC7397017 DOI: 10.3390/molecules25143255] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/15/2020] [Accepted: 06/17/2020] [Indexed: 01/07/2023] Open
Abstract
The rapid emergence of antimicrobial resistance in Acinetobacter baumannii coupled with the dried pipeline of novel treatments has driven the search for new therapeutic modalities. Gram-negative bacteria have an extra outer membrane that serves as a permeability barrier for various hydrophobic and/or large compounds. One of the popular approaches to tackle this penetration barrier is use of potentiators or adjuvants in combination with traditional antibiotics. This study reports the in vitro potential of an antimicrobial peptide tridecaptin M in combination with other antibiotics against different strains of A. baumannii. Tridecaptin M sensitized the bacteria to rifampicin, vancomycin, and ceftazidime. Further, we observed that a tridecaptin M and rifampicin combination killed the bacteria completely in 4 h in an ex vivo blood infection model and was superior to rifampicin monotherapy. The study also found that concomitant administration of both compounds is not necessary to achieve the antimicrobial effect. Bacteria pre-treated with tridecaptin M (for 2-4 h) followed by exposure to rifampicin showed similar killing as obtained for combined treatment. Additionally, this combination hampered the survival of persister development in comparison to rifampicin alone. These findings encourage the future investigation of this combination to treat severe infections caused by extremely drug-resistant A. baumannii.
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Affiliation(s)
- Manoj Jangra
- Clinical Microbiology & Bioactive Screening Laboratory, CSIR-Institute of Microbial Technology, Chandigarh 160 036, India; (M.J.); (V.R.)
| | - Vrushali Raka
- Clinical Microbiology & Bioactive Screening Laboratory, CSIR-Institute of Microbial Technology, Chandigarh 160 036, India; (M.J.); (V.R.)
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201 002, India
| | - Hemraj Nandanwar
- Clinical Microbiology & Bioactive Screening Laboratory, CSIR-Institute of Microbial Technology, Chandigarh 160 036, India; (M.J.); (V.R.)
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201 002, India
- Correspondence:
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18
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Bayston R, Ashraf W, Pelegrin I, Fowkes K, Bienemann AS, Singleton WGB, Scott IS. An external ventricular drainage catheter impregnated with rifampicin, trimethoprim and triclosan, with extended activity against MDR Gram-negative bacteria: an in vitro and in vivo study. J Antimicrob Chemother 2020; 74:2959-2964. [PMID: 31302702 PMCID: PMC6753475 DOI: 10.1093/jac/dkz293] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 06/03/2019] [Accepted: 06/11/2019] [Indexed: 11/17/2022] Open
Abstract
Background External ventricular drainage (EVD) carries a high risk of ventriculitis, increasingly caused by MDR Gram-negative bacteria such as Escherichia coli and Acinetobacter baumannii. Existing antimicrobial EVD catheters are not effective against these, and we have developed a catheter with activity against MDR bacteria and demonstrated the safety of the new formulation for use in the brain. Objectives Our aim was to determine the ability of a newly formulated impregnated EVD catheters to withstand challenge with MDR Gram-negative bacteria and to obtain information about its safety for use in the CNS. Methods Catheters impregnated with three antimicrobials (rifampicin, trimethoprim and triclosan) were challenged in flow conditions at four weekly timepoints with high doses of MDR bacteria, including MRSA and Acinetobacter, and monitored for bacterial colonization. Catheter segments were also inserted intracerebrally into Wistar rats, which were monitored for clinical and behavioural change, and weight loss. Brains were removed after either 1 week or 4 weeks, and examined for evidence of inflammation and toxicity. Results Control catheters colonized quickly after the first challenge, while no colonization occurred in the impregnated catheters even after the 4 week challenge. Animals receiving the antimicrobial segments behaved normally and gained weight as expected. Neurohistochemistry revealed only surgical trauma and no evidence of neurotoxicity. Conclusions The antimicrobial catheter appears to withstand bacterial challenge for at least 4 weeks, suggesting that it might offer protection against infection with MDR Gram-negative bacteria in patients undergoing EVD. It also appears to be safe for use in the CNS.
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Affiliation(s)
- Roger Bayston
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Waheed Ashraf
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Ivan Pelegrin
- School of Medicine, University of Nottingham, Nottingham, UK.,Infectious Diseases Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Katherine Fowkes
- Department of Neuropathology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Alison S Bienemann
- Institute of Clinical Neurosciences, Faculty of Health Sciences, University of Bristol, Bristol, UK
| | - William G B Singleton
- Institute of Clinical Neurosciences, Faculty of Health Sciences, University of Bristol, Bristol, UK.,Department of Paediatric Neurosurgery, Bristol Royal Hospital for Children, Bristol, UK
| | - Ian S Scott
- Department of Neuropathology, Nottingham University Hospitals NHS Trust, Nottingham, UK
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19
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Vázquez-López R, Solano-Gálvez SG, Juárez Vignon-Whaley JJ, Abello Vaamonde JA, Padró Alonzo LA, Rivera Reséndiz A, Muleiro Álvarez M, Vega López EN, Franyuti-Kelly G, Álvarez-Hernández DA, Moncaleano Guzmán V, Juárez Bañuelos JE, Marcos Felix J, González Barrios JA, Barrientos Fortes T. Acinetobacter baumannii Resistance: A Real Challenge for Clinicians. Antibiotics (Basel) 2020; 9:antibiotics9040205. [PMID: 32340386 PMCID: PMC7235888 DOI: 10.3390/antibiotics9040205] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 01/29/2020] [Accepted: 02/05/2020] [Indexed: 12/21/2022] Open
Abstract
Acinetobacter baumannii (named in honor of the American bacteriologists Paul and Linda Baumann) is a Gram-negative, multidrug-resistant (MDR) pathogen that causes nosocomial infections, especially in intensive care units (ICUs) and immunocompromised patients with central venous catheters. A. baumannii has developed a broad spectrum of antimicrobial resistance, associated with a higher mortality rate among infected patients compared with other non-baumannii species. In terms of clinical impact, resistant strains are associated with increases in both in-hospital length of stay and mortality. A. baumannii can cause a variety of infections; most involve the respiratory tract, especially ventilator-associated pneumonia, but bacteremia and skin wound infections have also been reported, the latter of which has been prominently observed in the context of war-related trauma. Cases of meningitis associated with A. baumannii have been documented. The most common risk factor for the acquisition of MDR A baumannii is previous antibiotic use, following by mechanical ventilation, length of ICU/hospital stay, severity of illness, and use of medical devices. Current efforts focus on addressing all the antimicrobial resistance mechanisms described in A. baumannii, with the objective of identifying the most promising therapeutic scheme. Bacteriophage- and artilysin-based therapeutic approaches have been described as effective, but further research into their clinical use is required.
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Affiliation(s)
- Rosalino Vázquez-López
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico; (J.J.J.V.-W.); (J.A.A.V.); (L.A.P.A.); (A.R.R.); (M.M.Á.); (D.A.Á.-H.); (V.M.G.); (J.E.J.B.)
- Correspondence: or ; Tel.: +52-56-270210 (ext. 7302)
| | - Sandra Georgina Solano-Gálvez
- Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico;
| | - Juan José Juárez Vignon-Whaley
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico; (J.J.J.V.-W.); (J.A.A.V.); (L.A.P.A.); (A.R.R.); (M.M.Á.); (D.A.Á.-H.); (V.M.G.); (J.E.J.B.)
| | - Jorge Andrés Abello Vaamonde
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico; (J.J.J.V.-W.); (J.A.A.V.); (L.A.P.A.); (A.R.R.); (M.M.Á.); (D.A.Á.-H.); (V.M.G.); (J.E.J.B.)
| | - Luis Andrés Padró Alonzo
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico; (J.J.J.V.-W.); (J.A.A.V.); (L.A.P.A.); (A.R.R.); (M.M.Á.); (D.A.Á.-H.); (V.M.G.); (J.E.J.B.)
| | - Andrés Rivera Reséndiz
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico; (J.J.J.V.-W.); (J.A.A.V.); (L.A.P.A.); (A.R.R.); (M.M.Á.); (D.A.Á.-H.); (V.M.G.); (J.E.J.B.)
| | - Mauricio Muleiro Álvarez
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico; (J.J.J.V.-W.); (J.A.A.V.); (L.A.P.A.); (A.R.R.); (M.M.Á.); (D.A.Á.-H.); (V.M.G.); (J.E.J.B.)
| | - Eunice Nabil Vega López
- Medical IMPACT, Infectious Diseases Department, Mexico City 53900, Mexico; (E.N.V.L.); (G.F.-K.)
| | - Giorgio Franyuti-Kelly
- Medical IMPACT, Infectious Diseases Department, Mexico City 53900, Mexico; (E.N.V.L.); (G.F.-K.)
| | - Diego Abelardo Álvarez-Hernández
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico; (J.J.J.V.-W.); (J.A.A.V.); (L.A.P.A.); (A.R.R.); (M.M.Á.); (D.A.Á.-H.); (V.M.G.); (J.E.J.B.)
| | - Valentina Moncaleano Guzmán
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico; (J.J.J.V.-W.); (J.A.A.V.); (L.A.P.A.); (A.R.R.); (M.M.Á.); (D.A.Á.-H.); (V.M.G.); (J.E.J.B.)
| | - Jorge Ernesto Juárez Bañuelos
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico; (J.J.J.V.-W.); (J.A.A.V.); (L.A.P.A.); (A.R.R.); (M.M.Á.); (D.A.Á.-H.); (V.M.G.); (J.E.J.B.)
| | - José Marcos Felix
- Coordinación Ciclos Clínicos Medicina, FCS, Universidad Anáhuac México Norte, Huixquilucan 52786, Mexico;
| | - Juan Antonio González Barrios
- Laboratorio de Medicina Genómica, Hospital Regional “1º de Octubre”, ISSSTE, Av. Instituto Politécnico Nacional 1669, Lindavista, Gustavo A. Madero, Ciudad de Mexico 07300, Mexico;
| | - Tomás Barrientos Fortes
- Dirección Sistema Universitario de Salud de la Universidad Anáhuac México (SUSA), Huixquilucan 52786, Mexico;
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Burroughs L, Ashraf W, Singh S, Martinez-Pomares L, Bayston R, Hook AL. Development of dual anti-biofilm and anti-bacterial medical devices. Biomater Sci 2020; 8:3926-3934. [DOI: 10.1039/d0bm00709a] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Silicone catheters impregnated with antibiotics and coated with an anti-attachment polyacrylate produce a device with dual anti-biofilm and anti-bacterial properties.
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Affiliation(s)
| | | | - Sonali Singh
- School of Life Sciences
- Faculty of Medicine and Health Sciences
- Queen's Medical Centre
- Nottingham NG7 2UH
- UK
| | - Luisa Martinez-Pomares
- School of Life Sciences
- Faculty of Medicine and Health Sciences
- Queen's Medical Centre
- Nottingham NG7 2UH
- UK
| | | | - Andrew L. Hook
- School of Pharmacy
- University of Nottingham
- Nottingham NG7 2RD
- UK
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21
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Nørgaard SM, Jensen CS, Aalestrup J, Vandenbroucke-Grauls CMJE, de Boer MGJ, Pedersen AB. Choice of therapeutic interventions and outcomes for the treatment of infections caused by multidrug-resistant gram-negative pathogens: a systematic review. Antimicrob Resist Infect Control 2019; 8:170. [PMID: 31709047 PMCID: PMC6830003 DOI: 10.1186/s13756-019-0624-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 10/09/2019] [Indexed: 12/24/2022] Open
Abstract
Background Antimicrobial resistance is an increasingly serious threat to public health, and the increased occurrence of multidrug-resistant (MDR) bacteria is a concern in both high-income and low- and middle-income countries. The purpose of this systematic review was to identify and critically appraise current antimicrobial treatment options for infections with MDR Gram-negative bacteria. Methods A literature search for treatment of MDR extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa was conducted in MEDLINE in January 2019. Relevant studies published in English, German, and French that evaluated clinical success, microbiological success, and 30-day mortality outcomes were included. The population of interest was adult patients. Results Of 672 studies, 43 met the inclusion criteria. Carbapenems are the most common antibiotics used for the treatment of ESBL-producing Enterobacteriaceae. The clinical and microbiological success was similar for group 1 carbapenems (imipenem, meropenem, or doripenem), group 2 carbapenems (ertapenem), and non-carbapenem antibiotics. Mortality data were contradictory for group 1 carbapenems compared to group 2 carbapenems. The most common treatment option for A. baumannii and P. aeruginosa infections was intravenous colistin, regardless of infection site. Clinical success and mortality were similar in A. baumannii infections treated with colistin combination therapy vs. colistin monotherapy, whereas heterogeneous results were found with respect to microbiological success. Monotherapy and colistin combination therapy were used against P. aeruginosa with clinical and microbiological success (70–100%) depending on the infection site and severity, and the antibiotic used. Ceftazidime-avibactam therapy for ESBL-producing Enterobacteriaceae and P. aeruginosa showed good clinical success in one study. Conclusion We did not find robust evidence for antibiotic treatment of any infection with MDR Gram-negative bacteria, including ESBL-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa, that would lead to a firm recommendation for one specific antibiotic over another or for monotherapy over combination therapy. The choice of antibiotic treatment should be based on susceptibility testing balancing the expected clinical success rate against the risk of development of antibiotic resistance and the risk of severe side effects.
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Affiliation(s)
- Sarah Melissa Nørgaard
- 1Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus, N Denmark
| | - Camilla Skaarup Jensen
- 1Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus, N Denmark
| | - Josefine Aalestrup
- 1Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus, N Denmark
| | - Christina M J E Vandenbroucke-Grauls
- 3Medical Microbiology and Infection Control, Amsterdam University Medical Centers, Vrije Universiteit, De Boelelaan 1117 Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Mark G J de Boer
- 2Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Alma Becic Pedersen
- 1Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus, N Denmark
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22
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Singh I, Priyam A, Jha D, Dhawan G, Gautam HK, Kumar P. Polydopamine -aminoglycoside nanoconjugates: Synthesis, characterization, antimicrobial evaluation and cytocompatibility. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 107:110284. [PMID: 31761233 DOI: 10.1016/j.msec.2019.110284] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 09/04/2019] [Accepted: 10/05/2019] [Indexed: 01/19/2023]
Abstract
Development of nanoparticle- and self-assembled nanomaterial-based therapeutics has become a rapidly growing area in the field of nanotechnology. One of the natural compounds, dopamine, presents as a neurotransmitter in the human brain serving as a messenger and deals with the behavioural responses, has provided an ideal platform through self-polymerization under aerobic conditions leading to the formation of a beneficial organic biopolymer, polydopamine (PDA). This polymer provides sufficient reactive functionalities, which can further be use to attach amine- or thiol-containing ligands to obtain conjugates. In the present study, self-polymerized polydopamine nanoparticles have been synthesized and tethered to aminoglycosides (AGs: Gentamicin, Kanamycin and Neomycin) through amino moieties to obtain PDA-AG nanoconjugates. These nanoconjugates are characterized by physicochemical techniques and evaluated for their antimicrobial potency against various bacterial strains including resistant ones. Simultaneously, cytocompatibility was also assessed for PDA-AG nanoconjugates. Of these three nanoconjugates (PDA-Gentamicin, PDA-Kanamycin and PDA-Neomycin), PDA-Kanamycin (PDA-K) nanoconjugate exhibited the highest activity against potent pathogens, least toxicity in human embryonic kidney (HEK 293) cells and intense toxic effects on human glioblastoma (U87) cells. Together, these results advocate the promising potential of these nanoconjugates to be used as potent antimicrobials in future applications.
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Affiliation(s)
- Indu Singh
- Microbial Biotechnology Laboratory, CSIR-Institute of Genomics and Integrative Biology, Sukhdev Vihar, New Delhi, 110025, India; Department of Biomedical Sciences, Acharya Narendra Dev College, University of Delhi, Kalkaji, New Delhi, 110019, India
| | - Ayushi Priyam
- Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India
| | - Diksha Jha
- Microbial Biotechnology Laboratory, CSIR-Institute of Genomics and Integrative Biology, Sukhdev Vihar, New Delhi, 110025, India
| | - Gagan Dhawan
- Department of Biomedical Sciences, Acharya Narendra Dev College, University of Delhi, Kalkaji, New Delhi, 110019, India.
| | - Hemant K Gautam
- Microbial Biotechnology Laboratory, CSIR-Institute of Genomics and Integrative Biology, Sukhdev Vihar, New Delhi, 110025, India.
| | - P Kumar
- Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India.
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23
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Figueiredo J, Serrano JL, Soares M, Ferreira S, Domingues FC, Almeida P, Silvestre S. 5-Hydrazinylethylidenepyrimidines effective against multidrug-resistant Acinetobacter baumannii: Synthesis and in vitro biological evaluation of antibacterial, radical scavenging and cytotoxic activities. Eur J Pharm Sci 2019; 137:104964. [PMID: 31233866 DOI: 10.1016/j.ejps.2019.104964] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 06/03/2019] [Accepted: 06/20/2019] [Indexed: 12/14/2022]
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In Vitro Anti-Biofilm Activity of Curcumin Nanoparticles in Acinetobacter baumannii: A Culture-Based and Molecular Approach. ARCHIVES OF CLINICAL INFECTIOUS DISEASES 2019. [DOI: 10.5812/archcid.83263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Namivandi-Zangeneh R, Sadrearhami Z, Dutta D, Willcox M, Wong EHH, Boyer C. Synergy between Synthetic Antimicrobial Polymer and Antibiotics: A Promising Platform To Combat Multidrug-Resistant Bacteria. ACS Infect Dis 2019; 5:1357-1365. [PMID: 30939869 DOI: 10.1021/acsinfecdis.9b00049] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The failure of many antibiotics in the treatment of chronic infections caused by multidrug-resistant (MDR) bacteria necessitates the development of effective strategies to combat this global healthcare issue. Here, we report an antimicrobial platform based on the synergistic action between commercially available antibiotics and a potent synthetic antimicrobial polymer that consists of three key functionalities: low-fouling oligoethylene glycol, hydrophobic ethylhexyl, and cationic primary amine groups. Checkerboard assays with Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli demonstrated synergy between our synthetic antimicrobial polymer and two antibiotics, doxycycline and colistin. Coadministration of these compounds significantly improved the bacteriostatic efficacy especially against MDR P. aeruginosa strains PA32 and PA37, where the minimal inhibitory concentrations (MICs) of polymer and antibiotics were reduced by at least 4-fold. A synergistic killing activity was observed when the antimicrobial polymer was used in combination with doxycycline, killing >99.999% of planktonic and biofilm P. aeruginosa PAO1 upon a 20 min treatment at a polymer concentration of 128 μg mL-1 (4.6 μM) and doxycycline concentration of 64 μg mL-1 (133.1 μM). In addition, this synergistic combination reduced the rate of resistance development in P. aeruginosa compared to individual compounds and was also capable of reviving susceptibility to treatment in the resistant strains.
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Affiliation(s)
- Rashin Namivandi-Zangeneh
- Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine (ACN), School of Chemical Engineering, University of New South Wales−Sydney, Building E8, Gate 2, High Street, Kensington, Sydney, New South Wales 2052, Australia
| | - Zahra Sadrearhami
- Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine (ACN), School of Chemical Engineering, University of New South Wales−Sydney, Building E8, Gate 2, High Street, Kensington, Sydney, New South Wales 2052, Australia
| | - Debarun Dutta
- School of Optometry and Vision Science, University of New South Wales−Sydney, Rupert Myers Building, Gate 13, High Street, Kensington, Sydney, New South Wales 2052, Australia
| | - Mark Willcox
- School of Optometry and Vision Science, University of New South Wales−Sydney, Rupert Myers Building, Gate 13, High Street, Kensington, Sydney, New South Wales 2052, Australia
| | - Edgar H. H. Wong
- Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine (ACN), School of Chemical Engineering, University of New South Wales−Sydney, Building E8, Gate 2, High Street, Kensington, Sydney, New South Wales 2052, Australia
| | - Cyrille Boyer
- Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine (ACN), School of Chemical Engineering, University of New South Wales−Sydney, Building E8, Gate 2, High Street, Kensington, Sydney, New South Wales 2052, Australia
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Carbapenem-resistant Acinetobacter baumannii: in pursuit of an effective treatment. Clin Microbiol Infect 2019; 25:951-957. [DOI: 10.1016/j.cmi.2019.03.014] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 03/11/2019] [Accepted: 03/18/2019] [Indexed: 12/27/2022]
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Peri AM, Doi Y, Potoski BA, Harris PNA, Paterson DL, Righi E. Antimicrobial treatment challenges in the era of carbapenem resistance. Diagn Microbiol Infect Dis 2019; 94:413-425. [PMID: 30905487 DOI: 10.1016/j.diagmicrobio.2019.01.020] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 01/14/2019] [Accepted: 01/28/2019] [Indexed: 12/22/2022]
Abstract
Infections due to carbapenem-resistant Gram-negative bacteria are burdened by high mortality and represent an urgent threat to address. Clinicians are currently at a dawn of a new era in which antibiotic resistance in Gram-negative bacilli is being dealt with by the availability of the first new antibiotics in this field for many years. Although new antibiotics have shown promising results in clinical trials, there is still uncertainty over whether their use will improve clinical outcomes in real world practice. Some observational studies have reported a survival benefit in carbapenem-resistant Enterobacteriaceae bloodstream infections using combination therapy, often including "old" antibiotics such as colistin, aminoglycosides, tigecycline, and carbapenems. These regimens, however, are linked to increased risk of antimicrobial resistance, and their efficacy has yet to be compared to new antimicrobial options. While awaiting more definitive evidence, antibiotic stewards need clear direction on how to optimize the use of old and novel antibiotic options. Furthermore, carbapenem-sparing regimens should be carefully considered as a potential tool to reduce selective antimicrobial pressure.
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Affiliation(s)
- Anna Maria Peri
- Infectious Diseases Unit, Department of Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy; The University of Queensland Centre for Clinical Research (UQCCR), Royal Brisbane and Women's Hospital, Herston, QLD, Australia
| | - Yohei Doi
- Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Brian A Potoski
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, PA, USA
| | - Patrick N A Harris
- The University of Queensland Centre for Clinical Research (UQCCR), Royal Brisbane and Women's Hospital, Herston, QLD, Australia
| | - David L Paterson
- The University of Queensland Centre for Clinical Research (UQCCR), Royal Brisbane and Women's Hospital, Herston, QLD, Australia
| | - Elda Righi
- The University of Queensland Centre for Clinical Research (UQCCR), Royal Brisbane and Women's Hospital, Herston, QLD, Australia; Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Italy.
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Russo A, Bassetti M, Ceccarelli G, Carannante N, Losito AR, Bartoletti M, Corcione S, Granata G, Santoro A, Giacobbe DR, Peghin M, Vena A, Amadori F, Segala FV, Giannella M, Di Caprio G, Menichetti F, Del Bono V, Mussini C, Petrosillo N, De Rosa FG, Viale P, Tumbarello M, Tascini C, Viscoli C, Venditti M. Bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii: Clinical features, therapy and outcome from a multicenter study. J Infect 2019; 79:130-138. [PMID: 31145911 DOI: 10.1016/j.jinf.2019.05.017] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 05/23/2019] [Accepted: 05/24/2019] [Indexed: 11/18/2022]
Abstract
OBJECTIVES bloodstream infections (BSI) due to multidrug-resistant (MDR) Acinetobacter baumannii (AB) have been increasingly observed among hospitalized patients. METHODS prospective, observational study conducted among 12 large tertiary-care hospitals, across 7 Italian regions. From June 2017 to June 2018 all consecutive hospitalized patients with bacteremia due to MDR-AB were included and analyzed in the study. RESULTS During the study period 281 episodes of BSI due to MDR-AB were observed: 98 (34.8%) episodes were classified as primary bacteremias, and 183 (65.2%) as secondary bacteremias; 177 (62.9%) of them were associated with septic shock. Overall, 14-day mortality was observed in 172 (61.2%) patients, while 30-day mortality in 207 (73.6%) patients. On multivariate analysis, previous surgery, continuous renal replacement therapy, inadequate source control of infection, and pneumonia were independently associated with higher risk of septic shock. Instead, septic shock and Charlson Comorbidity Index >3 were associated with 14-day mortality, while adequate source control of infection and combination therapy with survival. Finally, septic shock, previous surgery, and aminoglycoside-containing regimen were associated with 30-day mortality, while colistin-containing regimen with survival. CONCLUSIONS BSI caused by MDR-AB represents a difficult challenge for physicians, considering the high rates of septic shock and mortality associated with this infection.
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Affiliation(s)
- Alessandro Russo
- Infectious Diseases Clinic, Department of Medicine, University of Udine and Azienda Sanitaria Universitaria Integrata Presidio Ospedaliero Universitario Santa Maria della Misericordia, Udine, Italy
| | - Matteo Bassetti
- Infectious Diseases Clinic, Department of Medicine, University of Udine and Azienda Sanitaria Universitaria Integrata Presidio Ospedaliero Universitario Santa Maria della Misericordia, Udine, Italy
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Policlinico Umberto I, Viale dell'Università 37, 00161 Rome, Italy
| | - Novella Carannante
- First division of Infectious Diseases, Cotugno Hospital, AORN dei Colli, Naples, Italy
| | - Angela Raffaella Losito
- Institute of Infectious Diseases, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Michele Bartoletti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Silvia Corcione
- Department of Medical Sciences, University of Turin, Infectious Diseases, City of Health and Sciences, Turin, Italy
| | - Guido Granata
- Clinical and Research Department for Infectious Diseases, Unit Systemic and Immunedepression-Associated Infections, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy
| | | | - Daniele Roberto Giacobbe
- Infectious Diseases Unit, Ospedale Policlinico San Martino - IRCCS per l'Oncologia, Italy; Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Maddalena Peghin
- Infectious Diseases Clinic, Department of Medicine, University of Udine and Azienda Sanitaria Universitaria Integrata Presidio Ospedaliero Universitario Santa Maria della Misericordia, Udine, Italy
| | - Antonio Vena
- Infectious Diseases Clinic, Department of Medicine, University of Udine and Azienda Sanitaria Universitaria Integrata Presidio Ospedaliero Universitario Santa Maria della Misericordia, Udine, Italy
| | - Francesco Amadori
- Infectious Diseases Clinic, Nuovo Santa Chiara University Hospital, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Francesco Vladimiro Segala
- Department of Medical Sciences, University of Turin, Infectious Diseases, City of Health and Sciences, Turin, Italy
| | - Maddalena Giannella
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Di Caprio
- First division of Infectious Diseases, Cotugno Hospital, AORN dei Colli, Naples, Italy
| | - Francesco Menichetti
- Infectious Diseases Clinic, Nuovo Santa Chiara University Hospital, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Valerio Del Bono
- Infectious Diseases Unit, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | - Cristina Mussini
- Clinic of Infectious Disease, University Hospital, Modena, Italy
| | - Nicola Petrosillo
- Clinical and Research Department for Infectious Diseases, Unit Systemic and Immunedepression-Associated Infections, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy
| | - Francesco Giuseppe De Rosa
- Department of Medical Sciences, University of Turin, Infectious Diseases, City of Health and Sciences, Turin, Italy
| | - Pierluigi Viale
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Mario Tumbarello
- Institute of Infectious Diseases, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Carlo Tascini
- First division of Infectious Diseases, Cotugno Hospital, AORN dei Colli, Naples, Italy
| | - Claudio Viscoli
- Infectious Diseases Unit, Ospedale Policlinico San Martino - IRCCS per l'Oncologia, Italy; Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Mario Venditti
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Policlinico Umberto I, Viale dell'Università 37, 00161 Rome, Italy.
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Synergistic Antimicrobial Activity of Colistin in Combination with Rifampin and Azithromycin against Escherichia coli Producing MCR-1. Antimicrob Agents Chemother 2018; 62:AAC.01631-18. [PMID: 30224527 DOI: 10.1128/aac.01631-18] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 09/10/2018] [Indexed: 11/20/2022] Open
Abstract
The lack of available antibiotics is a global public health problem due to the emergence of antimicrobial resistance. Effective therapeutic regimens are urgently needed against Escherichia coli strains that produce the colistin resistance gene mcr-1 and to inhibit the emergence of resistance. In this study, we assessed the antimicrobial activity of a series of concentrations of colistin-based combinations with rifampin and/or azithromycin against three strains of Escherichia coli, including colistin-resistant isolate MZ1501R, isolate HE1704R that produces MCR-1, and colistin-susceptible isolate MZ1509S Experiments were conducted with a medium inoculum of ∼107 CFU/ml over 48 h. Subsequently, the in vivo therapeutic effect was investigated using a neutropenic mouse thigh infection model. Almost all monotherapies showed unsatisfactory antibacterial activity against E. coli isolates producing MCR-1. In contrast, colistin in combination with rifampin or azithromycin resulted in an obvious decrease in the bacterial burden albeit with regrowth. More obviously, synergistic antimicrobial activity of colistin-based triple-combination therapy with rifampin and azithromycin was observed, resulting in a rapid and exhaustive antibacterial effect. In vivo treatments confirmed these findings, where mean decreases of 0.38 to 0.90 log10 CFU and 1.27 to 1.78 log10 CFU were noted after 24 h and 48 h of treatment, respectively, against colistin-resistant E. coli strains when 5 mg/kg of body weight of colistin was combined with rifampin and azithromycin. Colistin-based combinations with rifampin and azithromycin provide a more active therapeutic regimen than monotherapy or colistin-based double combinations against E. coli producing MCR-1.
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Wang JL, Kuo CF, Yeh CM, Chen JR, Cheng MF, Hung CH. Efficacy of φkm18p phage therapy in a murine model of extensively drug-resistant Acinetobacter baumannii infection. Infect Drug Resist 2018; 11:2301-2310. [PMID: 30532563 PMCID: PMC6245353 DOI: 10.2147/idr.s179701] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Purpose Few effective antibiotics are available for treating extensively drug-resistant Acinetobacter baumannii (XDRAB) sepsis. Phage therapy may show potential in treating XDRAB infections. Materials and methods We studied φkm18p phage therapy in BALB/c and C57BL/6 mice models of XDRAB bacteremia. Results We observed survival rates of nearly 100% in groups given phage therapy concurrent with XDRAB at different multiplicities of infection. In mice that received phage therapy after a 1-hour delay, the survival rate decreased to about 50%. The bacterial load in the blood decreased from 108 to 102 and 103 colony-forming units (CFU)/mL in the concurrent treatment group. In the phage therapy group, the levels of the cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), were low at 3 hours after infection. Although some phage-resistant mutants were isolated after phage therapy, a cytotoxicity study showed that they had reduced fitness. Conclusion Phage therapy in XDRAB bacteremia increased the animal survival rates, decreased the bacteremia loads, and decreased the levels of inflammatory markers TNF-α and IL-6. However, the reduced therapeutic effect with delayed administrations may be a concern in developing a successful phage therapy for treating acute infections of multidrug-resistant pathogens.
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Affiliation(s)
- Jiun-Ling Wang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Chih-Feng Kuo
- Department of Nursing, I-Shou University, Kaohsiung, Taiwan, ROC
| | - Che-Ming Yeh
- Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, Taiwan, ROC,
| | - Jung-Ren Chen
- Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan, ROC
| | - Ming-Fang Cheng
- Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC.,School of Medicine, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.,Department of Nursing, Fooyin University, Kaohsiung, Taiwan, ROC
| | - Chih-Hsin Hung
- Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, Taiwan, ROC,
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Choi SH, Cho EB, Chung JW, Lee MK. Changes in the early mortality of adult patients with carbapenem-resistant Acinetobacter baumannii bacteremia during 11 years at an academic medical center. J Infect Chemother 2018; 25:6-11. [PMID: 30342838 DOI: 10.1016/j.jiac.2018.09.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/13/2018] [Accepted: 09/23/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND In the past decade, carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major pathogen of serious infections in critically ill adult patients. Despite very limited antimicrobial options, clinicians have sought to reduce the mortality of patients with serious CRAB infections. To determine whether these long-term efforts effectively lessened the mortality of such patients, we investigated changes in the early mortality of adult patients with CRAB bacteremia and related clinical factors. METHODS We reviewed clinical data from 111 adult patients with monomicrobial CRAB bacteremia admitted to an academic medical center between 2006 and 2016. RESULTS The 14-day mortality rate from 2013 to 2016 was lower than that from 2009 to 2012 (43.4% vs. 71.1%, p = 0.01). When the clinical characteristics of adult patients with CRAB bacteremia from 2013 to 2016 were compared to those of the patients from 2009 to 2012, chronic lung disease (6.7% vs. 24.4%, p = 0.01), a recent history of mechanical ventilation (38.3% vs. 57.8%, p = 0.048), and pneumonia (48.3% vs. 68.9%, p = 0.04) were less frequent in 2013-2016, while neurological disease (43.3% vs. 22.2%, p = 0.02), central venous catheter infection (20.0% vs. 6.7%, p = 0.05), and early appropriate antimicrobial therapy (46.7% vs. 24.4%, p = 0.01) were more frequent. CONCLUSION The 14-day mortality rate of adult patients with CRAB bacteremia was reduced during 2013-2016. This decrease was associated with early appropriate antimicrobial therapy and a lower proportion of patients with bacteremic pneumonia, which seemed to result from improved hospital infection control during that time period.
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Affiliation(s)
- Seong-Ho Choi
- Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Eun Been Cho
- Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Jin-Won Chung
- Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
| | - Mi-Kyung Lee
- Department of Laboratory Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
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Asif M, Alvi IA, Rehman SU. Insight into Acinetobacter baumannii: pathogenesis, global resistance, mechanisms of resistance, treatment options, and alternative modalities. Infect Drug Resist 2018; 11:1249-1260. [PMID: 30174448 PMCID: PMC6110297 DOI: 10.2147/idr.s166750] [Citation(s) in RCA: 183] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Acinetobacter baumannii, once considered a low-category pathogen, has emerged as an obstinate infectious agent. The scientific community is paying more attention to this pathogen due to its stubbornness to last resort antimicrobials, including carbapenems, colistin, and tigecycline, its high prevalence of infections in the hospital setting, and significantly increased rate of community-acquired infections by this organism over the past decade. It has given the fear of pre-antibiotic era to the world. To further enhance our understanding about this pathogen, in this review, we discuss its taxonomy, pathogenesis, current treatment options, global resistance rates, mechanisms of its resistance against various groups of antimicrobials, and future therapeutics.
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Affiliation(s)
- Muhammad Asif
- Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan,
- Department of Pathology, King Edward Medical University, Lahore, Pakistan
| | - Iqbal Ahmad Alvi
- Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan,
- Department of Microbiology, Hazara University, Mansehra, Pakistan
| | - Shafiq Ur Rehman
- Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan,
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Abstract
With the increasing incidence of multi-drug resistant strains, especially carbapenem resistant strains, polymyxsins (mainly colistin and polymyxin B) based regimens seem to be a revival as an effective treatment of last resort in these infections. Evidence from 47 clinical trials or case series we reviewed showed that polymyxins based regimens are effective and have less toxicity compared with previous trials. When used alone, the mortality of intravenous polymyxsins ranged from 0% to 74.3%, clinical response (cure and improvement) rate was 7-82.1%, and microbiological eradication was 27.3-73.9%. The main reasons for the combination therapy are to get potential synergistic effects and to prevent the selection of heteroresistant strains. Several studies showed combination therapy seemed to be more effective than monotherapy, though a few doubts remain. Clinically, polymyxsins can be used in combination with several antibiotics, such as carberpenem, sulbactam, tigecycline, fosfomycin, glycopeptide, rifampicin and so on, but the optimal combination regimen is yet to be confirmed. The optimal dose of polymyxins is also controversial. With the limited clinical evidence, it's suggested loading dose regimens may be more effective, but more attention should be paid to adverse effects. Although recommended in some studies, high dose polymxins regimens with inconsistent clinical evidence need more trials to confirm. It is important to note that concerning dosing regimens, colistin and polymyxin B are not quite the same. In renal impaired patients polymyxin B should be prescribed without dosing adjustment. Risk of renal failure may increase in the following situations, such as the combination of intravenous colistin plus intravenous vancomycin, higher doses-colistin, and intravenous colistin combined with inhalational colistin. In conclusion, there're still controversies in combination regimens, dosing strategies and so on. Prospective trials of lager sample size are needed.
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Affiliation(s)
- Yun Yu
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine
| | - Aihua Fei
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine
| | - Zengbin Wu
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine
| | - Chengjin Gao
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine
| | - Shuming Pan
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine
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Lee CY, Huang CH, Lu PL, Ko WC, Chen YH, Hsueh PR. Role of rifampin for the treatment of bacterial infections other than mycobacteriosis. J Infect 2017; 75:395-408. [PMID: 28870736 DOI: 10.1016/j.jinf.2017.08.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 06/06/2017] [Accepted: 08/25/2017] [Indexed: 01/14/2023]
Abstract
OBJECTIVES Rifampin was initially approved for the treatment of tuberculosis. Because of its low toxicity, broad-spectrum activity, and good bioavailability, rifampin is now commonly administered as combination antimicrobial therapy for the treatment of various infections caused by organisms other than mycobacteria. This review summarizes the most recent clinical studies on the use of rifampin combinations for treating four common non-mycobacterial infections: acute bacterial meningitis, infective endocarditis and bacteraemia, pneumonia, and biofilm-related infections. METHODS We performed a literature search of clinical studies published in English from January 2005 to June 2016 using the PubMed database with the search terms "rifampin" with "meningitis" or "infective endocarditis and bacteraemia" or "pneumonia" or "prosthetic joint infections. RESULTS Current evidence to support a rifampin combination therapy as a treatment for non-mycobacterial infections was largely based on in vitro/in vivo studies and non-comparable retrospective case series. Additionally, controlled clinical trials that directly compared outcomes resulting from rifampin treatment versus treatment without rifampin were limited. CONCLUSIONS Rifampin combination therapy appears promising for the treatment of non-mycobacterial infections. However, further definitive clinical trials are necessary to validate its use because the risk of adverse drug-drug interactions and of the emergence of rifampin resistance during treatment may outweigh the potential benefits.
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Affiliation(s)
- Chun-Yuan Lee
- Kaohsiung Medical University, Kaohsiung Medical University Hospital, Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung, Taiwan; Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Hao Huang
- Kaohsiung Medical University, Kaohsiung Medical University Hospital, Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung, Taiwan; Sepsis Research Center, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Graduate Institute of Medicine, Kaohsiung, Taiwan
| | - Po-Liang Lu
- Kaohsiung Medical University, Kaohsiung Medical University Hospital, Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Wen-Chien Ko
- Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan; Centre of Infection Control, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan
| | - Yen-Hsu Chen
- Kaohsiung Medical University, Kaohsiung Medical University Hospital, Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung, Taiwan; Sepsis Research Center, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Graduate Institute of Medicine, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsin Chu, Taiwan.
| | - Po-Ren Hsueh
- Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
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Rabanal F, Cajal Y. Recent advances and perspectives in the design and development of polymyxins. Nat Prod Rep 2017. [PMID: 28628170 DOI: 10.1039/c7np00023e] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Covering: 1947-early 2017, particularly from 2005-early 2017The rise of bacterial pathogens with acquired resistance to almost all available antibiotics is becoming a serious public health issue. Polymyxins, antibiotics that were mostly abandoned a few decades ago because of toxicity concerns, are ultimately considered as a last-line therapy to treat infections caused by multi-drug resistant Gram-negative bacteria. This review surveys the progress in understanding polymyxin structure, and their chemistry, mechanisms of antibacterial activity and nephrotoxicity, biomarkers, synergy and combination with other antimicrobial agents and antibiofilm properties. An update of recent efforts in the design and development of a new generation of polymyxin drugs is also discussed. A novel approach considering the modification of the scaffold of polymyxins to integrate metabolism and detoxification issues into the drug design process is a promising new line to potentially prevent accumulation in the kidneys and reduce nephrotoxicity.
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Affiliation(s)
- Francesc Rabanal
- Organic Chemistry Section, Department of Inorganic and Organic Chemistry, Faculty of Chemistry, University of Barcelona, Spain.
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Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplant Rev (Orlando) 2017; 32:36-57. [PMID: 28811074 DOI: 10.1016/j.trre.2017.07.001] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 07/02/2017] [Indexed: 12/17/2022]
Abstract
Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate's phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection.
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Cooper TW, Pass SE, Brouse SD, Hall RG. Can Pharmacokinetic and Pharmacodynamic Principles Be Applied to the Treatment of Multidrug-Resistant Acinetobacter? Ann Pharmacother 2017; 45:229-40. [DOI: 10.1345/aph.1p187] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE: To discuss treatment options that can be used for treatment of Acinetobacter infections. DATA SOURCES: A MEDLINE search (1966-November 2010) was conducted to identify English-language literature on pharmacotherapy of Acinetobacter and the bibliographies of pertinent articles. Programs and abstracts from infectious diseases meetings were also searched. Search terms included Acinetobacter, multidrug resistance, pharmacokinetics, pharmacodynamics, Monte Carlo simulation, nosocomial pneumonia, carbapenems, polymyxins, sulbactam, aminoglycosides, tetracyclines, tigecycline, rifampin, and fluoroquinolones. DATA SELECTION AND DATA EXTRACTION: All articles were critically evaluated and all pertinent information was included in this review. DATA SYNTHESIS: Multidrug resistant (MDR) Acinetobacter, defined as resistance to 3 or more antimicrobial classes, has increased over the past decade. The incidence of carbapenem-resistant Acinetobacter is also increasing, leading to an increased use of dose optimization techniques and/or alternative antimicrobials, which is driven by local susceptibility patterns. However, Acinetobacter infections that are resistant to all commercially available antibiotics have been reported. General principles are available to guide dose optimization of aminoglycosides, β-lactams, fluoroquinolones, and tigecycline for infections due to gram-negative pathogens. Unfortunately, data specific to patients with Acinetobacter infections are limited. Recent pharmacokinetic-pharmacodynamic information has shed light on colistin dosing. The dilemma with colistin is its concentration-dependent killing, which makes once-daily dosing seem like an attractive option, but its short postantibiotic effect limits a clinician's ability to extend the dosing interval. Localized delivery of antimicrobials is also an attractive option due to the ability to increase drug concentration at the infection site while minimizing systemic adverse events, but more data are needed regarding this approach. CONCLUSIONS: Increased reliance on dosage optimization, combination therapy, and localized delivery of antimicrobials are methods to pursue positive clinical outcomes in MDR Acinetobacter infections since novel antimicrobials will not be available for several years. Well-designed clinical trials with MDR Acinetobacter are needed to define the best treatment options for these patients.
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Lee CR, Lee JH, Park M, Park KS, Bae IK, Kim YB, Cha CJ, Jeong BC, Lee SH. Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options. Front Cell Infect Microbiol 2017; 7:55. [PMID: 28348979 PMCID: PMC5346588 DOI: 10.3389/fcimb.2017.00055] [Citation(s) in RCA: 549] [Impact Index Per Article: 68.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 02/13/2017] [Indexed: 12/27/2022] Open
Abstract
Acinetobacter baumannii is undoubtedly one of the most successful pathogens responsible for hospital-acquired nosocomial infections in the modern healthcare system. Due to the prevalence of infections and outbreaks caused by multi-drug resistant A. baumannii, few antibiotics are effective for treating infections caused by this pathogen. To overcome this problem, knowledge of the pathogenesis and antibiotic resistance mechanisms of A. baumannii is important. In this review, we summarize current studies on the virulence factors that contribute to A. baumannii pathogenesis, including porins, capsular polysaccharides, lipopolysaccharides, phospholipases, outer membrane vesicles, metal acquisition systems, and protein secretion systems. Mechanisms of antibiotic resistance of this organism, including acquirement of β-lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites, are also discussed. Lastly, novel prospective treatment options for infections caused by multi-drug resistant A. baumannii are summarized.
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Affiliation(s)
- Chang-Ro Lee
- National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University Yongin, South Korea
| | - Jung Hun Lee
- National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University Yongin, South Korea
| | - Moonhee Park
- National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji UniversityYongin, South Korea; DNA Analysis Division, Seoul Institute, National Forensic ServiceSeoul, South Korea
| | - Kwang Seung Park
- National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University Yongin, South Korea
| | - Il Kwon Bae
- Department of Dental Hygiene, College of Health and Welfare, Silla University Busan, South Korea
| | - Young Bae Kim
- Biotechnology Program, North Shore Community College Danvers, MA, USA
| | - Chang-Jun Cha
- Department of Systems Biotechnology, College of Biotechnology and Natural Resources, Chung-Ang University Anseong, South Korea
| | - Byeong Chul Jeong
- National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University Yongin, South Korea
| | - Sang Hee Lee
- National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University Yongin, South Korea
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Zhang X, Guo F, Shao H, Zheng X. Clinical translation of polymyxin-based combination therapy: Facts, challenges and future opportunities. J Infect 2016; 74:118-130. [PMID: 27998750 DOI: 10.1016/j.jinf.2016.11.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 11/18/2016] [Accepted: 11/27/2016] [Indexed: 10/20/2022]
Abstract
The emergence and spread of multidrug resistant Gram-negative bacteria has led to a resurgence in the clinical use of polymyxin antibiotics. However, the prevalence of polymyxin resistance is on the rise at an alarming rate, motivating the idea of combination therapy to sustain the revival of these "old" antibiotics. Although ample evidence in favor of combination therapy has emerged, it seems impracticable and confusing to find a promising combination from the diverse reports or gain adequate information on the efficacy and safety profile. With a stagnating discovery pipeline of novel antimicrobials, there is a clear need to fill the knowledge gaps in translating these basic research data to beneficial clinical practice. In this review, we examined the factors and ambiguities that stand as major hurdles in bringing polymyxin combination therapy to bedside care, highlighting the importance and urgency of incorporating translational research insights into areas of difficulty. We also discussed future research priorities that are essential to gather the necessary evidence and insights for promoting the best possible use of polymyxins in combination therapy.
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Affiliation(s)
- Xueli Zhang
- Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Fengmei Guo
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Hua Shao
- Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
| | - Xiao Zheng
- State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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Florescu DF, Mindru C, Keck MA, Qiu F, Kalil AC. Colistin, an Old Drug in a New Territory, Solid Organ Transplantation. Transplant Proc 2016; 48:152-7. [PMID: 26915861 DOI: 10.1016/j.transproceed.2016.01.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 01/05/2016] [Indexed: 10/22/2022]
Abstract
BACKGROUND The clinical experience with colistin therapy for multidrug-resistant Gram-negative pathogens in solid organ transplantation is limited. METHODS Patients transplanted from January 2003 to July 2011 and treated with intravenous or nebulized colistin were included. Descriptive statistics were used to summarize patients' characteristics and Kaplan-Meier curves for survival analysis. RESULTS Fifteen patients were included: 10 adults (median age, 54.6 y; range, 32.2-79.6 y) and 5 children (median age, 3.3 y; range, 1.1-10.4 y). Eight patients had intra-abdominal infections, 3 had pneumonia, and 4 had bacteremia. The infections were diagnosed at a median of 5.9 months (range, 0.8-49.8 mo) after transplantation. Eight patients had coinfections, mainly with enteric pathogens. Pseudomonas aeruginosa was isolated in 13 cases and ESBL Klebsiella oxytoca and ESBL Escherichia coli were isolated in 1 case each. Thirteen patients received concomitant antibiotics with colistin. The median dose of intravenous colistin (13 patients) was 2.7 mg/kg/d (range, 1-4.9 mg/kg/d) and nebulized colistin (2 patients) was 241.7 mg/d (range, 150-333.3 mg/d). Clinical cure was achieved in 9 patients (60%). Four-week survival rate after infection was 86.7% (95% confidence interval, 56.4%-96.5%). There was no difference in the median creatinine clearance in adults (P = .38) or children (P = .88) before and after colistin. One patient had both neurotoxicity and nephrotoxicity, and 1 patient had neurotoxicity only. CONCLUSIONS Colistin might be used as an alternate therapy for transplant patients with multidrug-resistant Gram-negative pathogens.
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Affiliation(s)
- D F Florescu
- Infectious Diseases Division, University of Nebraska Medical Center, Omaha, Nebraska; Transplant Surgery Division, University of Nebraska Medical Center, Omaha, Nebraska.
| | - C Mindru
- Infectious Diseases Division, University of Nebraska Medical Center, Omaha, Nebraska
| | - M A Keck
- Department of Pharmaceutical and Nutrition Care, Nebraska Medical Center, Omaha, Nebraska
| | - F Qiu
- Biostatistics Department, University of Nebraska Medical Center, Omaha, Nebraska
| | - A C Kalil
- Infectious Diseases Division, University of Nebraska Medical Center, Omaha, Nebraska
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Correlation between the number of Pro-Ala repeats in the EmrA homologue of Acinetobacter baumannii and resistance to netilmicin, tobramycin, imipenem and ceftazidime. J Glob Antimicrob Resist 2016; 7:145-149. [PMID: 27835840 DOI: 10.1016/j.jgar.2016.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/30/2016] [Accepted: 09/12/2016] [Indexed: 11/20/2022] Open
Abstract
Acinetobacter baumannii coccobacilli are dangerous to patients in intensive care units because of their multidrug resistance to antibiotics, developed mainly in the past decade. This study aimed to examine whether there is a significant correlation between the number of Pro-Ala repeats in the CAP01997 protein, the EmrA homologue of A. baumannii, and resistance to antibiotics. A total of 79 multidrug-resistant A. baumannii strains isolated from patients were analysed. Resistance to antibiotics was determined on Mueller-Hinton agar plates using the Kirby-Bauer disk diffusion method. The number of CCTGCA repeats encoding Pro-Ala repeats in CAP01997 was determined by PCR and capillary electrophoresis. The 3D models of CAP01997 containing Pro-Ala repeats were initially generated using RaptorX Structure Prediction server and were assembled with EasyModeller 4.0. The models were embedded in a model bacterial membrane based on structural information from homologous proteins and were refined using 100-ns molecular dynamics simulations. The results of this research show significant correlation between susceptibility to netilmicin, tobramycin and imipenem and the number of repeated Pro-Ala sequences in the CAP01997 protein, a homologue of the Escherichia coli transporter EmrA. Predicted structures suggest potential mechanisms that confer drug resistance by reshaping the cytoplasmic interface between CAP01997 protein and the critical component of the multidrug efflux pump homologous to EmrB. Based on these results, we can conclude that the CAP01997 protein, an EmrA homologue of A. baumannii, confers resistance to netilmicin, tobramycin and imipenem, depending on the number of Pro-Ala repeats.
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Garnacho-Montero J, Dimopoulos G, Poulakou G, Akova M, Cisneros JM, De Waele J, Petrosillo N, Seifert H, Timsit JF, Vila J, Zahar JR, Bassetti M. Task force on management and prevention of Acinetobacter baumannii infections in the ICU. Intensive Care Med 2015; 41:2057-75. [PMID: 26438224 DOI: 10.1007/s00134-015-4079-4] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 09/22/2015] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Acinetobacter baumannii constitutes a dreadful problem in many ICUs worldwide. The very limited therapeutic options available for these organisms are a matter of great concern. No specific guidelines exist addressing the prevention and management of A. baumannii infections in the critical care setting. METHODS Clinical microbiologists, infectious disease specialists and intensive care physicians were invited by the Chair of the Infection Section of the ESICM to participate in a multidisciplinary expert panel. After the selection of clinically relevant questions, this document provides recommendations about the use of microbiological techniques for identification of A. baumannii in clinical laboratories, antibiotic therapy for severe infections and recommendations to control this pathogen in outbreaks and endemic situations. Evidence supporting each statement was graded according to the European Society of Clinical Microbiology and Infection Diseases (ESCMID) grading system. RESULTS Empirical coverage of A. baumannii is recommended in severe infections (severe sepsis or septic shock) occurring during an A. baumannii outbreak, in an endemic setting, or in a previously colonized patient. For these cases, a polymyxin is suggested as part of the empirical treatment in cases of a high suspicion of a carbapenem-resistant (CR) A. baumannii strain. An institutional program including staff education, promotion of hand hygiene, strict contact and isolation precautions, environmental cleaning, targeted active surveillance, and antimicrobial stewardship should be instituted and maintained to combat outbreaks and endemic situations. CONCLUSIONS Specific recommendations about prevention and management of A. baumannii infections in the ICU were elaborated by this multidisciplinary panel. The paucity of randomized controlled trials is noteworthy, so these recommendations are mainly based on observational studies and pharmacodynamics modeling.
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Affiliation(s)
- José Garnacho-Montero
- Unidad Clínica de Cuidados Intensivos, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Seville, Spain.
| | - George Dimopoulos
- Department of Critical Care, University Hospital ATTIKON, Medical School, University of Athens, Athens, Greece
| | - Garyphallia Poulakou
- 4th Department of Internal Medicine, Athens University School of Medicine, Attikon University General Hospital, Athens, Greece
| | - Murat Akova
- Department of Infectious Diseases, Hacettepe University School of Medicine, Ankara, Turkey
| | - José Miguel Cisneros
- Unidad Clínicia de Enfermedades Infecciosas, Microbiología y Preventiva, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Jan De Waele
- Department of Critical Care Medicine, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium
| | - Nicola Petrosillo
- 2nd Infectious Disease Division, National Institute for Infectious Diseases 'L. Spallanzani', Rome, Italy
| | - Harald Seifert
- Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany
- German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany
| | - Jean François Timsit
- Medical and Infectious Diseases ICU, Bichat Hospital, 75018, Paris, France
- University Paris-Diderot - Inserm U1137 - IAME, 75018, Paris, France
| | - Jordi Vila
- Department of Clinical Microbiology, CDB, Hospital Clínic, School of Medicine, University of Barcelona, Centre for International Health Research, (CRESIB-Hospital Clínic), Barcelona, Spain
| | - Jean-Ralph Zahar
- Unité de Prévention et de Lutte Contre les Infections Nosocomiales, Université d'Angers, Centre Hospitalo-universitaire d'Angers, Angers, France
| | - Matteo Bassetti
- Infectious Diseases Clinic, Santa Maria Misericordia University Hospital, Udine, Italy
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Chen Z, Chen Y, Fang Y, Wang X, Chen Y, Qi Q, Huang F, Xiao X. Meta-analysis of colistin for the treatment of Acinetobacter baumannii infection. Sci Rep 2015; 5:17091. [PMID: 26597507 PMCID: PMC4657015 DOI: 10.1038/srep17091] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 07/13/2015] [Indexed: 01/24/2023] Open
Abstract
Multidrug resistant among Acinetobacter baumannii infection is associated with a high mortality rate and limits the therapeutic options. The aim of this study was to assess the safety and efficacy of colistin monotherapy vs. other single antibiotic therapy AND colistin-based combination therapy (with other antibiotics) vs. colistin alone for the treatment of Acinetobacter baumannii infection. Online electronic database were searched for studies evaluating colistin with or without other antibiotics in treatment of patients with drug-resistant Acinetobacter baumannii infection. Totally, twelve studies met the inclusion criteria. For colistin-based combination therapy, six articles including 668 patients were included. Our results showed that the overall clinical response did not differ significantly between colistin-based combination therapy and monotherapy (OR = 1.37, 95% CI = 0.86-2.19, P = 0.18). This insignificance was also detected in ICU mortality, length of stay and nephrotoxicity (P > 0.05). However, the colistin-based combination therapy was shown increasing the microbiological response (OR = 2.14, 95% CI = 1.48-3.07, P < 0.0001). For colistin monotherapy, six studies involving 491 patients were analyzed. The results were in concordance with the findings of the colistin-based combination therapy group. Our results suggest that colistin may be a promising therapy as safe and efficacious as standard antibiotics for the treatment of drug-resistant Acinetobacter baumannii infection.
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Affiliation(s)
- Zhijin Chen
- Department of Hospital Infection-Control, Affiliated Houjie Hospital, Guangdong Medical College, Dongguan, Guangdong 523945, China
| | - Yu Chen
- Department of Urology, Affiliated Hospital of Huzhou Teachers' College, The First People's Hospital of Hu zhou, Hu zhou, 313000, P.R. China
| | - Yaogao Fang
- Department of Hospital Infection-Control, Affiliated Houjie Hospital, Guangdong Medical College, Dongguan, Guangdong 523945, China
| | - Xiaotian Wang
- Department of Hospital Infection-Control, Affiliated Houjie Hospital, Guangdong Medical College, Dongguan, Guangdong 523945, China
| | - Yanqing Chen
- Department of Hospital Infection-Control, Affiliated Houjie Hospital, Guangdong Medical College, Dongguan, Guangdong 523945, China
| | - Qingsong Qi
- Department of Hospital Infection-Control, Affiliated Houjie Hospital, Guangdong Medical College, Dongguan, Guangdong 523945, China
| | - Fang Huang
- Department of Hospital Infection-Control, Affiliated Houjie Hospital, Guangdong Medical College, Dongguan, Guangdong 523945, China
| | - Xungang Xiao
- Department of Joint Surgery, Chenzhou NO.1 People's Hospital, Hunan Province, 423000 P.R. China
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Combined therapy for multi-drug-resistant Acinetobacter baumannii infection – is there evidence outside the laboratory? J Med Microbiol 2015. [DOI: 10.1099/jmm.0.000144] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
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Izadpanah M, Khalili H. Antibiotic regimens for treatment of infections due to multidrug-resistant Gram-negative pathogens: An evidence-based literature review. J Res Pharm Pract 2015; 4:105-14. [PMID: 26312249 PMCID: PMC4548428 DOI: 10.4103/2279-042x.162360] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Evidences regarding the efficacy of different antibiotic regimens proposed for treatment of multidrug-resistant (MDR) Gram-negative pathogens have been reviewed. Available data in Scopus, Medline, EMBASE, the Cochrane central register of controlled trials, and Cochrane database of systematic reviews have been collected. Several antibiotic regimens are proposed for treatment of MDR Gram-negative infections (defined as nonsusceptibility to at least one agent in three or more antimicrobial categories). The most challenging issue is the treatment of carbapenem-resistant (CR) Gram-negative pathogens. A carbapenem plus either colistin or tigecycline was the most effective regimen for treatment of CR Gram-negative pathogens with low-level resistance (minimal inhibitory concentration [MIC] ≤ 8 mg/L). However, in high-level resistance (MIC > 8 mg/L), combination of colistin and tigecycline showed promising effect.
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Affiliation(s)
- Mandana Izadpanah
- Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Khalili
- Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Bailey KL, Kalil AC. Ventilator-Associated Pneumonia (VAP) with Multidrug-Resistant (MDR) Pathogens: Optimal Treatment? Curr Infect Dis Rep 2015; 17:494. [PMID: 26092246 DOI: 10.1007/s11908-015-0494-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Ventilator-associated pneumonia (VAP) due to multidrug-resistant bacteria (MDR) is an emerging problem worldwide. Both gram-negative and gram-positive microorganisms are associated with VAP. We first describe the magnitude of the problem of MDR VAP followed by its clinical impact on survival outcomes, with the primary aim to review the optimal antibiotic choices to treat patients with MDR VAP. We discuss the challenges of intravenous and inhaled antibiotic treatments, as well as of monotherapy and combination antimicrobial therapies.
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Affiliation(s)
- Kristina L Bailey
- Pulmonary, Critical Care Allergy and Sleep Medicine Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
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Shahbazi F, Dashti-Khavidaki S. Colistin: efficacy and safety in different populations. Expert Rev Clin Pharmacol 2015; 8:423-48. [DOI: 10.1586/17512433.2015.1053390] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Molloy L, Arora H, Gupta S, Sutton J, Abdel-Haq N. Multidrug-Resistant Organisms: Considerations in Antibiotic Selection and Administration. J Pediatr Intensive Care 2015; 4:87-96. [PMID: 31110857 PMCID: PMC6513150 DOI: 10.1055/s-0035-1556751] [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: 09/23/2014] [Accepted: 12/02/2014] [Indexed: 10/23/2022] Open
Abstract
Managing infections caused by multidrug-resistant organisms is a significant clinical challenge. Multidrug-resistant organisms' treatment is complicated in the pediatric population because of the lack of primary data, treatment guidelines, rapidly changing pharmacokinetic/pharmacodynamic parameters, and fewer approved antibiotic indications and dosing guidance. Treatment decisions must incorporate available pediatric data, clinical experience, and careful extrapolation from adult data while considering the unique challenges faced by children with complicated infections.
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Affiliation(s)
- Leah Molloy
- Department of Pharmacy, Children's Hospital of Michigan, Detroit, Michigan, United States
| | - Harbir Arora
- Division of Infectious Diseases, Children's Hospital of Michigan, Detroit, Michigan, United States
| | - Shipra Gupta
- Division of Infectious Diseases, Children's Hospital of Michigan, Detroit, Michigan, United States
| | - Jesse Sutton
- Department of Pharmacy, Baptist Health Louisville, Louisville, Kentucky, United States
| | - Nahed Abdel-Haq
- Division of Infectious Diseases, Children's Hospital of Michigan, Detroit, Michigan, United States
- Carman and Ann Adams Department of Pediatrics, Wayne State University, Detroit, Michigan, United States
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Viehman JA, Nguyen MH, Doi Y. Treatment options for carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii infections. Drugs 2015; 74:1315-33. [PMID: 25091170 DOI: 10.1007/s40265-014-0267-8] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Acinetobacter baumannii is a leading cause of healthcare-associated infections worldwide. Because of various intrinsic and acquired mechanisms of resistance, most β-lactam agents are not effective against many strains, and carbapenems have played an important role in therapy. Recent trends show many infections are caused by carbapenem-resistant or even extensively drug-resistant (XDR) strains, for which effective therapy is not well established. Evidence to date suggests that colistin constitutes the backbone of therapy, but the unique pharmacokinetic properties of colistin have led many to suggest the use of combination antimicrobial therapy. However, the combination of agents and dosing regimens that delivers the best clinical efficacy while minimizing toxicity is yet to be defined. Carbapenems, sulbactam, rifampin and tigecycline have been the most studied in the context of combination therapy. Most data regarding therapy for invasive, resistant A. baumannii infections come from uncontrolled case series and retrospective analyses, though some clinical trials have been completed and others are underway. Early institution of appropriate antimicrobial therapy is shown to consistently improve survival of patients with carbapenem-resistant and XDR A. baumannii infection, but the choice of empiric therapy in these infections remains an open question. This review summarizes the most current knowledge regarding the epidemiology, mechanisms of resistance, and treatment considerations of carbapenem-resistant and XDR A. baumannii.
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Affiliation(s)
- J Alexander Viehman
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, S319 Falk Medical Building, 3601 Fifth Avenue, Pittsburgh, PA, 15213, USA
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