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Shein AMS, Hongsing P, Smith OK, Phattharapornjaroen P, Miyanaga K, Cui L, Ishikawa H, Amarasiri M, Monk PN, Kicic A, Chatsuwan T, Pletzer D, Higgins PG, Abe S, Wannigama DL. Current and novel therapies for management of Acinetobacter baumannii-associated pneumonia. Crit Rev Microbiol 2025; 51:441-462. [PMID: 38949254 DOI: 10.1080/1040841x.2024.2369948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 02/25/2024] [Accepted: 06/11/2024] [Indexed: 07/02/2024]
Abstract
Acinetobacter baumannii is a common pathogen associated with hospital-acquired pneumonia showing increased resistance to carbapenem and colistin antibiotics nowadays. Infections with A. baumannii cause high patient fatalities due to their capability to evade current antimicrobial therapies, emphasizing the urgency of developing viable therapeutics to treat A. baumannii-associated pneumonia. In this review, we explore current and novel therapeutic options for overcoming therapeutic failure when dealing with A. baumannii-associated pneumonia. Among them, antibiotic combination therapy administering several drugs simultaneously or alternately, is one promising approach for optimizing therapeutic success. However, it has been associated with inconsistent and inconclusive therapeutic outcomes across different studies. Therefore, it is critical to undertake additional clinical trials to ascertain the clinical effectiveness of different antibiotic combinations. We also discuss the prospective roles of novel antimicrobial therapies including antimicrobial peptides, bacteriophage-based therapy, repurposed drugs, naturally-occurring compounds, nanoparticle-based therapy, anti-virulence strategies, immunotherapy, photodynamic and sonodynamic therapy, for utilizing them as additional alternative therapy while tackling A. baumannii-associated pneumonia. Importantly, these innovative therapies further require pharmacokinetic and pharmacodynamic evaluation for safety, stability, immunogenicity, toxicity, and tolerability before they can be clinically approved as an alternative rescue therapy for A. baumannii-associated pulmonary infections.
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Affiliation(s)
- Aye Mya Sithu Shein
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Center of Excellence in, Antimicrobial Resistance and Stewardship Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Parichart Hongsing
- Mae Fah Luang University Hospital, Chiang Rai, Thailand
- School of Integrative Medicine, Mae Fah Luang University, Chiang Rai, Thailand
| | - O'Rorke Kevin Smith
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Phatthranit Phattharapornjaroen
- Department of Emergency Medicine, Center of Excellence, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Department of Surgery, Sahlgrenska Academy, Institute of Clinical Sciences, Gothenburg University, Gothenburg, Sweden
| | - Kazuhiko Miyanaga
- Division of Bacteriology, School of Medicine, Jichi Medical University, Tochigi, Japan
| | - Longzhu Cui
- Division of Bacteriology, School of Medicine, Jichi Medical University, Tochigi, Japan
| | - Hitoshi Ishikawa
- Yamagata Prefectural University of Health Sciences, Kamiyanagi, Japan
| | - Mohan Amarasiri
- Laboratory of Environmental Hygiene, Department of Health Science, School of Allied Health Sciences, Kitasato University, Kitasato, Sagamihara-Minami, Japan
| | - Peter N Monk
- Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield Medical School, UK
| | - Anthony Kicic
- Wal-yan Respiratory Research Centre, Telethon Kids Institute, University of Western Australia, Nedlands, Western Australia, Australia
- Centre for Cell Therapy and Regenerative Medicine, Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
- Department of Respiratory and Sleep Medicine, Perth Children's Hospital, Nedlands, Western Australia, Australia
- School of Population Health, Curtin University, Bentley, Western Australia, Australia
| | - Tanittha Chatsuwan
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Center of Excellence in, Antimicrobial Resistance and Stewardship Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Daniel Pletzer
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Paul G Higgins
- Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany
- German Centre for Infection Research, Partner site Bonn-Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Shuichi Abe
- Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Dhammika Leshan Wannigama
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Center of Excellence in, Antimicrobial Resistance and Stewardship Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan
- School of Medicine, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia
- Biofilms and Antimicrobial Resistance Consortium of ODA receiving countries, The University of Sheffield, Sheffield, UK
- Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan
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Spernovasilis N, Ishak A, Tsioutis C, Alon-Ellenbogen D, Agouridis AP, Mazonakis N. Sulbactam for carbapenem-resistant Acinetobacter baumannii infections: a literature review. JAC Antimicrob Resist 2025; 7:dlaf055. [PMID: 40224360 PMCID: PMC11992565 DOI: 10.1093/jacamr/dlaf055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025] Open
Abstract
Carbapenem-resistant Acinetobacter baumannii (CRAB) is characterized as a critical priority pathogen with restricted therapeutic options. To date, the most effective antimicrobial treatment against this difficult-to-treat bacterial strain has not been established. Sulbactam is a β-lactamase inhibitor with intrinsic activity against this pathogen, however, as a β-lactam, it can be hydrolysed by β-lactamases produced by A. baumannii. High-dose, extended-infusion treatment with sulbactam can overcome this hydrolysis by β-lactamases and is considered an effective therapeutic strategy against CRAB. The aim of this review is to analyse primary and secondary research studies that compare sulbactam-based with other regimens, such as polymyxin-containing regimens, tigecycline-containing regimens and other antimicrobial combinations against CRAB infections, especially ventilator-associated pneumonia (VAP), hospital-acquired pneumonia (HAP) and bacteraemia. Our findings suggest that results are conflicting, mostly because of high heterogeneity among studies. However, in most studies, sulbactam-based regimens have demonstrated comparable, and in several studies more favourable results in contrast to other antimicrobial treatments with respect to clinical cure and mortality in CRAB-associated pneumonia, yet without reaching statistical significance in most cases. The auspicious novel β-lactam/β-lactamase inhibitor combination sulbactam/durlobactam is also discussed, although real-world clinical data regarding its efficacy in CRAB infections are still scarce. More randomized controlled trials comparing sulbactam-based with other regimens are warranted to determine the most effective antimicrobial combination against CRAB infections. Nevertheless, current data suggest that sulbactam could play a major role in this combination treatment.
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Affiliation(s)
| | - Angela Ishak
- Department of Internal Medicine, Henry Ford Hospital, 48202 Detroit, MI, USA
| | | | - Danny Alon-Ellenbogen
- Department of Basic and Clinical Sciences, University of Nicosia, 2417 Nicosia, Cyprus
| | - Aris P Agouridis
- School of Medicine, European University Cyprus, 2404 Nicosia, Cyprus
- Department of Internal Medicine, German Medical Institute, 4108 Limassol, Cyprus
| | - Nikolaos Mazonakis
- Department of Internal Medicine, Thoracic Diseases General Hospital Sotiria, 11527 Athens, Greece
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Alwazzeh MJ, Algazaq J, Al-Salem FA, Alabkari F, Alwarthan SM, Alhajri M, AlShehail BM, Alnimr A, Alrefaai AW, Alsaihati FH, Almuhanna FA. Mortality and clinical outcomes of colistin versus colistin-based combination therapy for infections caused by Multidrug-resistant Acinetobacter baumannii in critically ill patients. BMC Infect Dis 2025; 25:416. [PMID: 40140752 PMCID: PMC11948640 DOI: 10.1186/s12879-025-10781-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/11/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Multidrug-resistant Acinetobacter baumannii emerged as a threatening "superbug" with significant morbidity and mortality and limited antimicrobial therapy options. The results of different antibiotic combination studies are heterogeneous and controversial. Further comparative studies are crucial to overcome such difficult-to-treat infections and to improve patient outcomes. This study investigates the mortality and outcomes of colistin versus colistin-based combination therapy for infections caused by Multidrug-resistant Acinetobacter baumannii in critically ill patients. METHODS A retrospective observational study was conducted at an academic tertiary hospital in Khobar City, Eastern Province, Saudi Arabia. Patients who fulfilled the inclusion criteria and were admitted from January 1, 2017, to December 31, 2022, were included. The investigated primary outcome was 30-day mortality, while secondary outcomes were one-year all-cause mortality, clinical cure, microbiologic eradication, and recurrence of Acinetobacter infections. Statistical comparisons were employed, and a P-value of ≤ .05 was considered significant. RESULTS Of the 178 patients who fulfilled the inclusion criteria, 47 received colistin only, and 131 received colistin in combinations (55 with carbapenems, 53 with tigecycline, and 23 with both). The estimated 30-day mortality rate of the study population was 22.5%, with statistically insignificant differences in 30-day mortality rates when the colistin group compared to cumulative colistin-based combination (23.4% vs. 22.1%; difference, 1.3 percentage points; 95% confidence interval [CI], 0.487-2.371; P = 0.858) or subgroups. However, colistin-based combination groups showed better secondary outcomes, with significantly less all-cause mortality and better clinical cure in colistin combination with carbapenems or tigecycline and less Acinetobacter infection recurrence in combination with carbapenems. CONCLUSIONS The study findings demonstrate the benefits of investigated colistin combination options that result in less one-year all-cause mortality, better clinical cure, higher microbiologic response, and less infection recurrence. However, no significant differences were observed regarding 30-day mortality. In addition, the study highlights the limitations of the available antimicrobial options and the crucial need for new effective antimicrobials and more successful combinations.
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Affiliation(s)
- Marwan J Alwazzeh
- Infectious Disease Division, Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, & King Fahad Hospital of the University, Al Khobar, Saudi Arabia.
| | - Jumanah Algazaq
- Infectious Disease Division, Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, & King Fahad Hospital of the University, Al Khobar, Saudi Arabia
| | - Fatimah Ali Al-Salem
- Infectious Disease Division, Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, & King Fahad Hospital of the University, Al Khobar, Saudi Arabia
| | - Fatimah Alabkari
- Infectious Disease Division, Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, & King Fahad Hospital of the University, Al Khobar, Saudi Arabia
| | - Sara M Alwarthan
- Infectious Disease Division, Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, & King Fahad Hospital of the University, Al Khobar, Saudi Arabia
| | - Mashael Alhajri
- Infectious Disease Division, Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, & King Fahad Hospital of the University, Al Khobar, Saudi Arabia
| | - Bashayer M AlShehail
- Pharmacy Practice Department, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Amani Alnimr
- Department of Microbiology, College of Medicine, King Fahad Hospital of the University, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Ahmad Wajeeh Alrefaai
- Department of Microbiology, College of Medicine, King Fahad Hospital of the University, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
- Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Fahad Hospital of the University, Dammam & King, Al Khobar, Saudi Arabia
| | - Faten Hussain Alsaihati
- Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Fahad Hospital of the University, Dammam & King, Al Khobar, Saudi Arabia
| | - Fahd Abdulaziz Almuhanna
- Nephrology Division, Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Fahad Hospital of the University, Dammam & King, Al-Khobar, Saudi Arabia
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Ungthammakhun C, Vasikasin V, Simsiriporn W, Juntanawiwat P, Changpradub D. Effect of colistin combined with sulbactam: 9 g versus 12 g per day on mortality in the treatment of carbapenems resistant Acinetobacter baumannii pneumonia: A randomized controlled trial. Int J Infect Dis 2024; 149:107267. [PMID: 39423948 DOI: 10.1016/j.ijid.2024.107267] [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: 08/13/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND The current treatment recommendation involves administering a high dose of sulbactam alongside at least one additional agent. However, there remains a lack of data regarding the optimal dosage of sulbactam. We investigated whether administering sulbactam at a dosage of 12 g/day decreases the mortality rate among patients with CRAB pneumonia compared to 9 g/day. METHODS The study was an open-label, superiority, randomized controlled trial conducted at Phramongkutklao Hospital between September 2019 and September 2023 in patients diagnosed with CRAB. Participants were randomly assigned to receive a combination of colistin with either 9 or 12 g/day of sulbactam. The primary endpoint was the all-cause mortality rate at 28 days postrandomization. RESULTS Among the 138 participants, there was a trend towards a lower mortality rate in the 12 g/day group (59.4% vs. 47.8%; P = 0.158). After adjusting for factors associated with mortality, a lower mortality was observed in the 12 g/day group (adjusted HR 0.54 [95% CI 0.33-0.87]; P = 0.0110). The microbiological cure rate at day 7 was higher in the 12 g/day group (73.2% vs. 89.4%; P = 0.02). CONCLUSIONS Colistin in combination with sulbactam at a dosage of 12 g/day may improve mortality compared to 9 g/day.
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Affiliation(s)
- Chutchawan Ungthammakhun
- Division of Infectious Disease, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand
| | - Vasin Vasikasin
- Division of Infectious Disease, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand; NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London, Hammersmith Hospital, London, United Kingdom.
| | - Waristha Simsiriporn
- Division of Microbiology, Department of Clinical Pathology, Phramongkutklao Hospital, Bangkok, Thailand
| | - Piraporn Juntanawiwat
- Division of Microbiology, Department of Clinical Pathology, Phramongkutklao Hospital, Bangkok, Thailand
| | - Dhitiwat Changpradub
- Division of Infectious Disease, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand
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Yu J, Zhang B, Yang Y, Dou W, Li Y, Yang A, Ruan X, Zuo W, Zhang B. A retrospective study of the efficacy of sulbactam in the treatment of patients with extensively drug-resistant Acinetobacter baumannii infections. Infection 2024; 52:2445-2454. [PMID: 39042327 PMCID: PMC11621167 DOI: 10.1007/s15010-024-02307-9] [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: 04/05/2024] [Accepted: 05/27/2024] [Indexed: 07/24/2024]
Abstract
PURPOSE Sulbactam (SBT) is one of the most significant treatments for patients with extensively drug-resistant Acinetobacter baumannii (XDR-AB). However, the efficacy and safety of SBT and its high dose regimen has not been well documented. This retrospective study aimed to assess the efficacy and safety of SBT-based treatment, particularly at high-dose (≥ 6 g/day), for XDR-AB infection. METHOD A total of 52 XDR-AB infected patients treated with intravenous SBT at Peking Union Medical College Hospital were included. The primary outcome was 28-day all-cause mortality, while the secondary outcome was 14-day clinical response and the time of response. The formulation of SBT in our study is 0.5 g per vial. RESULTS Among the patients, the 28-day all-cause mortality rate was 36.5% (19/52), and the favorable 14-day clinical response rate was 59.6% (31/52). The 28-day mortality was independently associated coinfection with gram-positive bacteria (GPB) and a shorter duration of therapy. Patients with intracranial infection might have a longer survival time. A favorable 14-day clinical response was associated with the dose of SBT, and a longer treatment duration. However, the higher creatinine clearance (CrCl) associated with a worse clincal response. In addition, a higher SBT dosage was significantly correlated with a shorter time to clinical response. No adverse effects related were reported. CONCLUSION The single-agent formulation of SBT emerges as a promising alternative for the treatment of XDR-AB infection, such as intracranial infection, particularly at high doses (≥ 6 g/day). Besides, longer duration of treatment correlates with higher survival rate and better favorable clinical response. Higher CrCl negatively correlates with favorable clinical response.
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Affiliation(s)
- Jiaxin Yu
- Department of pharmacy & State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China
| | - Baoshuang Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yang Yang
- Department of pharmacy & State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China
| | - Wei Dou
- Department of pharmacy & State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China
| | - Yuliu Li
- Department of pharmacy & State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China
| | - Anji Yang
- Department of pharmacy & State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiao Ruan
- Department of pharmacy & State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wei Zuo
- Department of pharmacy & State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China.
| | - Bo Zhang
- Department of pharmacy & State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China.
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Najafabadi MK, Soltani R. Carbapenem-resistant Acinetobacter baumannii and Ventilator-associated Pneumonia; Epidemiology, Risk Factors, and Current Therapeutic Approaches. J Res Pharm Pract 2024; 13:33-40. [PMID: 39830948 PMCID: PMC11737613 DOI: 10.4103/jrpp.jrpp_50_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 05/07/2024] [Accepted: 05/25/2024] [Indexed: 01/22/2025] Open
Abstract
Acinetobacter baumannii is one of the primary pathogens responsible for healthcare-associated infections. It is related to high rates of morbidity and mortality globally, mainly because of its high capacity to develop resistance to antimicrobials. Nowadays, carbapenem-resistant A. baumannii (CRAB) has increased and represents a significant concern among carbapenem-resistant organisms. It is also a key pathogen associated with ventilator-associated pneumonia. CRAB was placed on the critical group of the universal priority list of the World Health Organization for antibiotic-resistant bacteria, to mention the importance of research development and the urgency of new antibiotics. Patients with severe CRAB infections currently face significant treatment challenges. Some approaches have been taken to deal with CRAB, such as combination therapy and the synergistic effect of certain antibiotics, but the best antibiotic regimen is still unknown. In this narrative review, we attempt to clarify the issues, including epidemiology, risk factors, and current treatment options for CRAB.
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Affiliation(s)
- Malihe Kazemi Najafabadi
- Department of Clinical Pharmacy and Pharmacy Practice, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rasool Soltani
- Department of Clinical Pharmacy and Pharmacy Practice, Isfahan University of Medical Sciences, Isfahan, Iran
- Infectious Diseases and Tropical Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Rafailidis P, Panagopoulos P, Koutserimpas C, Samonis G. Current Therapeutic Approaches for Multidrug-Resistant and Extensively Drug-Resistant Acinetobacter baumannii Infections. Antibiotics (Basel) 2024; 13:261. [PMID: 38534696 DOI: 10.3390/antibiotics13030261] [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: 01/02/2024] [Revised: 02/28/2024] [Accepted: 03/06/2024] [Indexed: 03/28/2024] Open
Abstract
The treatment of Acinetobacter baumannii infections remains a challenge for physicians worldwide in the 21st century. The bacterium possesses a multitude of mechanisms to escape the human immune system. The consequences of A. baumannii infections on morbidity and mortality, as well on financial resources, remain dire. Furthermore, A. baumannii superinfections have also occurred during the COVID-19 pandemic. While prevention is important, the antibiotic armamentarium remains the most essential factor for the treatment of these infections. The main problem is the notorious resistance profile (including resistance to carbapenems and colistin) that this bacterium exhibits. While newer beta lactam/beta-lactamase inhibitors have entered clinical practice, with excellent results against various infections due to Enterobacteriaceae, their contribution against A. baumannii infections is almost absent. Hence, we have to resort to at least one of the following, sulbactam, polymyxins E or B, tigecycline or aminoglycosides, against multidrug-resistant (MDR) and extensively drug-resistant (XDR) A. baumannii infections. Furthermore, the notable addition of cefiderocol in the fight against A. baumannii infections represents a useful addition. We present herein the existing information from the last decade regarding therapeutic advances against MDR/XDR A. baumannii infections.
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Affiliation(s)
- Petros Rafailidis
- Second University Department of Internal Medicine, University General Hospital of Alexandroupolis, 681 00 Alexandroupolis, Greece
| | - Periklis Panagopoulos
- Second University Department of Internal Medicine, University General Hospital of Alexandroupolis, 681 00 Alexandroupolis, Greece
| | - Christos Koutserimpas
- Department of Orthopaedics and Traumatology, "251" Hellenic Air Force General Hospital of Athens, 115 25 Athens, Greece
| | - George Samonis
- Department of Oncology, Metropolitan Hospital, 185 47 Athens, Greece
- Department of Medicine, University of Crete, 715 00 Heraklion, Greece
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Rodjun V, Montakantikul P, Houngsaitong J, Jitaree K, Nosoongnoen W. Pharmacokinetic/pharmacodynamic (PK/PD) simulation for dosage optimization of colistin and sitafloxacin, alone and in combination, against carbapenem-, multidrug-, and colistin-resistant Acinetobacter baumannii. Front Microbiol 2023; 14:1275909. [PMID: 38098659 PMCID: PMC10720588 DOI: 10.3389/fmicb.2023.1275909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 09/15/2023] [Indexed: 12/17/2023] Open
Abstract
To the best of our knowledge, to date, no study has investigated the optimal dosage regimens of either colistin or sitafloxacin against drug-resistant Acinetobacter baumannii (A. baumannii) infections by using specific parameters. In the current study, we aimed to explore the optimal dosage regimens of colistin and sitafloxacin, either in monotherapy or in combination therapy, for the treatment of carbapenem-, multidrug-, and colistin-resistant A. baumannii infections. A Monte Carlo simulation was applied to determine the dosage regimen that could achieve the optimal probability of target attainment (PTA) and cumulative fraction of response (CFR) (≥90%) based on the specific parameters of each agent and the minimal inhibitory concentration (MIC) of the clinical isolates. This study explored the dosage regimen of 90, 50, 30, and 10 mL/min for patients with creatinine clearance (CrCL). We also explored the dosage regimen for each patient with CrCL using combination therapy because there is a higher possibility of reaching the desired PTA or CFR. Focusing on the MIC90 of each agent in combination therapy, the dosage regimen for colistin was a loading dose of 300 mg followed by a maintenance dose ranging from 50 mg every 48 h to 225 mg every 12 h and the dosage regimen for sitafloxacin was 325 mg every 48 h to 750 mg every 12 h. We concluded that a lower-than-usual dose of colistin based on specific pharmacokinetic data in combination with a higher-than-usual dose of sitafloxacin could be an option for the treatment of carbapenem-, multidrug-, and colistin-resistant. A. baumannii. The lower dose of colistin might show a low probability of adverse reaction, while the high dose of sitafloxacin should be considered. In the current study, we attempted to find if there is a strong possibility of drug selection against crucial drug-resistant pathogen infections in a situation where there is a lack of new antibiotics. However, further study is needed to confirm the results of this simulation study.
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Affiliation(s)
| | - Preecha Montakantikul
- Division of Clinical Pharmacy, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Jantana Houngsaitong
- Division of Clinical Pharmacy, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Kamonchanok Jitaree
- Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand
| | - Wichit Nosoongnoen
- Division of Clinical Pharmacy, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
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Ardebili A, Izanloo A, Rastegar M. Polymyxin combination therapy for multidrug-resistant, extensively-drug resistant, and difficult-to-treat drug-resistant gram-negative infections: is it superior to polymyxin monotherapy? Expert Rev Anti Infect Ther 2023; 21:387-429. [PMID: 36820511 DOI: 10.1080/14787210.2023.2184346] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
INTRODUCTION The increasing prevalence of infections with multidrug-resistant (MDR), extensively-drug resistant (XDR) or difficult-to-treat drug resistant (DTR) Gram-negative bacilli (GNB), including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter species, and Escherichia coli poses a severe challenge. AREAS COVERED The rapid growing of multi-resistant GNB as well as the considerable deceleration in development of new anti-infective agents have made polymyxins (e.g. polymyxin B and colistin) a mainstay in clinical practices as either monotherapy or combination therapy. However, whether the polymyxin-based combinations lead to better outcomes remains unknown. This review mainly focuses on the effect of polymyxin combination therapy versus monotherapy on treating GNB-related infections. We also provide several factors in designing studies and their impact on optimizing polymyxin combinations. EXPERT OPINION An abundance of recent in vitro and preclinical in vivo data suggest clinical benefit for polymyxin-drug combination therapies, especially colistin plus meropenem and colistin plus rifampicin, with synergistic killing against MDR, XDR, and DTR P. aeruginosa, K. pneumoniae and A. baumannii. The beneficial effects of polymyxin-drug combinations (e.g. colistin or polymyxin B + carbapenem against carbapenem-resistant K. pneumoniae and carbapenem-resistant A. baumannii, polymyxin B + carbapenem + rifampin against carbapenem-resistant K. pneumoniae, and colistin + ceftolozan/tazobactam + rifampin against PDR-P. aeruginosa) have often been shown in clinical setting by retrospective studies. However, high-certainty evidence from large randomized controlled trials is necessary. These clinical trials should incorporate careful attention to patient's sample size, characteristics of patient's groups, PK/PD relationships and dosing, rapid detection of resistance, MIC determinations, and therapeutic drug monitoring.
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Affiliation(s)
- Abdollah Ardebili
- Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran.,Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ahdieh Izanloo
- Department of Biology, Faculty of Sciences, Golestan University, Gorgan, Iran
| | - Mostafa Rastegar
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, 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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Ahmadpour F, Shaseb E, Izadpanah M, Rakhshan A, Hematian F. Optimal dosing interval of intravenous Colistin monotherapy versus combination therapy: A systematic review and meta-analysis. Eur J Transl Myol 2022; 32:10833. [PMID: 36533669 PMCID: PMC9830404 DOI: 10.4081/ejtm.2022.10833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 09/09/2022] [Indexed: 01/13/2023] Open
Abstract
We aimed to maximize the clinical response and effectiveness of colistin antibiotics in patients with multi-drug (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, there is an increasing interest in colistin combination therapy with other antibiotics and extended interval dosing regimens. This systematic review and meta-analysis aim is to evaluate if the combination therapy is superior to monotherapy with colistin regarding increased survival and also which dose interval is the most effective to utilize. English language, peer-reviewed journal publications from the first date available to 25 January 2022 were identified by searching the PubMed and Web of Science databases. Forest plots for overall and subgroups and funnel plots were graphed. 42 studies were included in the study. Among them, 38 studies were on combination therapy, and four on dose interval. The overall pooled odds ratio is 0.77 (CI: 0.62; 0.95) (p value < 0.017). The I^2 value was 43% (p value < 0.01). The Begg correlation test of funnel plot asymmetry showed no significant publication bias (0.064). The overall pooled odds ratio for Carbapenem is 0.74 (CI: 0.48; 1.13). A prospective randomized controlled trials (RCT) on 40 adults intensive care unit (ICU) patients with ventilator-associated pneumonia (VAP), comparing the mortality and ICU length of stay of 8- or 24- hour intervals regimens, showed that the ICU length of stay and ICU mortality were; 31.31, 35.3 days, and 32.06, 22.2% in groups 24-h interval and 8- hour interval (p value: 0.39, 0.87), respectively. It seems that combination therapy is associated with drug synergism and increased survival. The extended interval colistin administration may result in higher peak concentration and bacterial eradication. In both cases, we face a dearth of literature.
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Affiliation(s)
- Forouzan Ahmadpour
- Department of Pharmacotherapy, School of Pharmacy, Lorestan University of Medical Sciences, Khoramabad, Iran
| | - Elnaz Shaseb
- Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mandana Izadpanah
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amin Rakhshan
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzaneh Hematian
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran,Assistant professor of clinical pharmacy, Department of Clinical Pharmacy, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. ORCID ID: 0000-0001-7062-4669
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12
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A Randomized Controlled Trial of Colistin Combined with Sulbactam: 9 g per Day versus 12 g per Day in the Treatment of Extensively Drug-Resistant Acinetobacter baumannii Pneumonia: An Interim Analysis. Antibiotics (Basel) 2022; 11:antibiotics11081112. [PMID: 36009980 PMCID: PMC9405071 DOI: 10.3390/antibiotics11081112] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
Extensively drug-resistant A. baumannii (XDRAB) pneumonia has a high mortality rate in hospitalized patients. One of the recommended treatments is colistin combined with sulbactam; however, the optimal dosage of sulbactam is unclear. In an open-label, superiority, randomized controlled trial, patients diagnosed with XDRAB pneumonia were randomly assigned (1:1) to receive colistin in combination with sulbactam at either 9 g/day or 12 g/day. The primary outcome was the 28-day mortality rate in the intention-to-treat population. A total of 88 patients received colistin in combination with sulbactam at a dosage of either 12 g/day (n = 45) or 9 g/day (n = 43). Trends toward a lower mortality rate were observed in the 12 g/day group at 7 days (11.1% vs. 23.3%), 14 days (33.3% vs. 41.9%), and 28 days (46.7% vs. 58.1%). The microbiological cure rate at day 7 was significantly higher in the 12 g/day group (90.5% vs. 58.1%; p = 0.02). Factors associated with mortality at 28 days were asthma, cirrhosis, APACHEII score ≥ 28, and a dosage of sulbactam of 9 g/day for mortality at any timepoint. Treatment with colistin combined with sulbactam at 12 g/day was not superior to the combination treatment with sulbactam at 9 g/day. However, due to being an interim analysis, this trial was underpowered to detect mortality differences.
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Paul M, Carrara E, Retamar P, Tängdén T, Bitterman R, Bonomo RA, de Waele J, Daikos GL, Akova M, Harbarth S, Pulcini C, Garnacho-Montero J, Seme K, Tumbarello M, Lindemann PC, Gandra S, Yu Y, Bassetti M, Mouton JW, Tacconelli E, Baño JR. European Society of clinical microbiology and infectious diseases (ESCMID) guidelines for the treatment of infections caused by Multidrug-resistant Gram-negative bacilli (endorsed by ESICM -European Society of intensive care Medicine). Clin Microbiol Infect 2021; 28:521-547. [PMID: 34923128 DOI: 10.1016/j.cmi.2021.11.025] [Citation(s) in RCA: 502] [Impact Index Per Article: 125.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 12/16/2022]
Abstract
SCOPE These ESCMID guidelines address the targeted antibiotic treatment of 3rd generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on the effectiveness of individual antibiotics and on combination vs. monotherapy. METHODS An expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA) and carbapenem-resistant Acinetobacter baumanni (CRAB). Treatments were classified as head-to-head comparisons between individual antibiotics and monotherapy vs. combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy vs. combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak). RECOMMENDATIONS The guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, beta-lactam beta-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low and low certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed.
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Affiliation(s)
- Mical Paul
- Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel; Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Elena Carrara
- Division of Infectious Diseases, Department of Diagnostic and Public Health, University of Verona, Verona, Italy
| | - Pilar Retamar
- Departamento de Medicina, Universidad de Sevilla, Sevilla, Spain; Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena/ Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain
| | - Thomas Tängdén
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Roni Bitterman
- Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel; Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Robert A Bonomo
- Department of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Medical Service, Research Service, and GRECC, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA;; VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, OH, USA
| | - Jan de Waele
- Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium
| | - George L Daikos
- First Department of Medicine, National and Kapodistrian University of Athens
| | - Murat Akova
- Hacettepe University School of Medicine, Department Of Infectious Diseases, Ankara, Turkey
| | - Stephan Harbarth
- Infection Control Programme, University of Geneva Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Celine Pulcini
- Université de Lorraine, APEMAC, Nancy, France; Université de Lorraine, CHRU-Nancy, Infectious Diseases Department, Nancy, France
| | | | - Katja Seme
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia
| | - Mario Tumbarello
- Department of Medical Biotechnologies, University of Siena, Italy
| | | | - Sumanth Gandra
- Division of Infectious Diseases, Washington University School of Medicine in St. Louis, Missouri, USA
| | - Yunsong Yu
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China; Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Matteo Bassetti
- Department of Health Sciences, University of Genoa, 16132 Genoa, Italy; Clinica Malattie Infettive, San Martino Policlinico Hospital, Genoa, Italy
| | - Johan W Mouton
- Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands
| | - Evelina Tacconelli
- Division of Infectious Diseases, Department of Diagnostic and Public Health, University of Verona, Verona, Italy; Division of Infectious Diseases, Department of Internal Medicine I, German Center for Infection Research, University of Tübingen, Tübingen, Germany; German Centre for Infection Research (DZIF), Clinical Research Unit for Healthcare Associated Infections, Tübingen, Germany.
| | - Jesus Rodriguez Baño
- Departamento de Medicina, Universidad de Sevilla, Sevilla, Spain; Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena/ Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain
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Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America Guidance on the Treatment of AmpC β-lactamase-Producing Enterobacterales, Carbapenem-Resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia Infections. Clin Infect Dis 2021; 74:2089-2114. [PMID: 34864936 DOI: 10.1093/cid/ciab1013] [Citation(s) in RCA: 307] [Impact Index Per Article: 76.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant infections. A previous guidance document focused on infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Here, guidance is provided for treating AmpC β-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia infections. METHODS A panel of six infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated questions about the treatment of AmpC-E, CRAB, and S. maltophilia infections. Answers are presented as suggestions and corresponding rationales. In contrast to guidance in the previous document, published data on optimal treatment of AmpC-E, CRAB, and S. maltophilia infections are limited. As such, guidance in this document is provided as "suggested approaches" based on clinical experience, expert opinion, and a review of the available literature. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States. RESULTS Preferred and alternative treatment suggestions are provided, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, duration of therapy, and other management considerations are also discussed briefly. Suggestions apply for both adult and pediatric populations. CONCLUSIONS The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of antimicrobial-resistant infections. This document is current as of September 17, 2021 and will be updated annually. The most current versions of IDSA documents, including dates of publication, are available at www.idsociety.org/practice-guideline/amr-guidance-2.0/.
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Affiliation(s)
- Pranita D Tamma
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Samuel L Aitken
- Department of Pharmacy, University of Michigan Health, Ann Arbor, Michigan, USA
| | - Robert A Bonomo
- Medical Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, University Hospitals Cleveland Medical Center and Departments of Medicine, Pharmacology, Molecular Biology, and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Amy J Mathers
- Departments of Medicine and Pathology, University of Virginia, Charlottesville, Virginia, USA
| | - David van Duin
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Cornelius J Clancy
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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O'Donnell JN, Putra V, Lodise TP. Treatment of patients with serious infections due to carbapenem-resistant Acinetobacter baumannii: How viable are the current options? Pharmacotherapy 2021; 41:762-780. [PMID: 34170571 DOI: 10.1002/phar.2607] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/14/2021] [Accepted: 06/14/2021] [Indexed: 11/07/2022]
Abstract
This review critically appraises the published microbiologic and clinical data on the treatment of patients with carbapenem-resistant Acinetobacter baumannii infections. Despite being recognized as an urgent threat pathogen by the CDC and WHO, optimal treatment of patients with serious CRAB infections remains ill-defined. Few commercially available agents exhibit reliable in vitro activity against CRAB. Historically, polymyxins have been the most active agents in vitro, though interpretations of susceptibility data are difficult given issues surrounding MIC testing methodologies and lack of correlation between MICs and clinical outcomes. Most available preclinical and clinical data involve use of polymyxins, tetracyclines, and sulbactam, alone and in combination. As the number of viable treatment options is limited, combination therapy with a polymyxin is often used for patients with CRAB infections, despite the significant risk of nephrotoxicity. However, no treatment regimen has been found to reduce mortality, which exceeds 40% across most studies, or substantially improve clinical response. While some newer agents, such as eravacycline and cefiderocol, have demonstrated in vitro activity, clinical efficacy has not been fully established. New agents with clinically relevant activity against CRAB isolates and favorable toxicity profiles are sorely needed.
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Affiliation(s)
- J Nicholas O'Donnell
- Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
| | - Vibert Putra
- Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
| | - Thomas P Lodise
- Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
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Oh S, Chau R, Nguyen AT, Lenhard JR. Losing the Battle but Winning the War: Can Defeated Antibacterials Form Alliances to Combat Drug-Resistant Pathogens? Antibiotics (Basel) 2021; 10:antibiotics10060646. [PMID: 34071451 PMCID: PMC8227011 DOI: 10.3390/antibiotics10060646] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 11/16/2022] Open
Abstract
Despite the recent development of antibacterials that are active against multidrug-resistant pathogens, drug combinations are often necessary to optimize the killing of difficult-to-treat organisms. Antimicrobial combinations typically are composed of multiple agents that are active against the target organism; however, many studies have investigated the potential utility of combinations that consist of one or more antibacterials that individually are incapable of killing the relevant pathogen. The current review summarizes in vitro, in vivo, and clinical studies that evaluate combinations that include at least one drug that is not active individually against Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, or Staphylococcus aureus. Polymyxins were often included in combinations against all three of the Gram-negative pathogens, and carbapenems were commonly incorporated into combinations against K. pneumoniae and A. baumannii. Minocycline, sulbactam, and rifampin were also frequently investigated in combinations against A. baumannii, whereas the addition of ceftaroline or another β-lactam to vancomycin or daptomycin showed promise against S. aureus with reduced susceptibility to vancomycin or daptomycin. Although additional clinical studies are needed to define the optimal combination against specific drug-resistant pathogens, the large amount of in vitro and in vivo studies available in the literature may provide some guidance on the rational design of antibacterial combinations.
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A New Twist: The Combination of Sulbactam/Avibactam Enhances Sulbactam Activity against Carbapenem-Resistant Acinetobacter baumannii (CRAB) Isolates. Antibiotics (Basel) 2021; 10:antibiotics10050577. [PMID: 34068158 PMCID: PMC8152955 DOI: 10.3390/antibiotics10050577] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/10/2021] [Accepted: 05/11/2021] [Indexed: 01/22/2023] Open
Abstract
An increasing number of untreatable infections are recorded every year. Many studies have focused their efforts on developing new β-lactamase inhibitors to treat multi-drug resistant (MDR) isolates. In the present study, sulbactam/avibactam and sulbactam/relebactam combination were tested against 187 multi-drug resistant (MDR) Acinetobacter clinical isolates; both sulbactam/avibactam and sulbactam/relebactam restored sulbactam activity. A decrease ≥2 dilutions in sulbactam MICs was observed in 89% of the isolates when tested in combination with avibactam. Sulbactam/relebactam was able to restore sulbactam susceptibility in 40% of the isolates. In addition, the susceptibility testing using twenty-three A. baumannii AB5075 knockout strains revealed potential sulbactam and/or sulbactam/avibactam target genes. We observed that diazabicyclooctanes (DBOs) β-lactamase inhibitors combined with sulbactam restore sulbactam susceptibility against carbapenem-resistant Acinetobacter clinical isolates. However, relebactam was not as effective as avibactam when combined with sulbactam. Exploring novel combinations may offer new options to treat Acinetobacter spp. infections, especially for widespread oxacillinases and metallo-β-lactamases (MBLs) producers.
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Mohd Sazlly Lim S, Heffernan AJ, Zowawi HM, Roberts JA, Sime FB. Semi-mechanistic PK/PD modelling of meropenem and sulbactam combination against carbapenem-resistant strains of Acinetobacter baumannii. Eur J Clin Microbiol Infect Dis 2021; 40:1943-1952. [PMID: 33884516 DOI: 10.1007/s10096-021-04252-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/30/2020] [Indexed: 11/25/2022]
Abstract
Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are commonly used. In this study, we explored the potential efficacy of meropenem-sulbactam combination (MEM/SUL) against CR-AB. The checkerboard method was used to screen for synergistic activity of MEM/SUL against 50 clinical CR-AB isolates. Subsequently, time-kill studies against two CR-AB isolates were performed. Time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Subsequently, Monte Carlo simulations were performed to estimate the probability of 2-log kill, 1-log kill or stasis at 24-h following combination therapy. The MEM/SUL demonstrated synergy against 28/50 isolates. No antagonism was observed. The MIC50 and MIC90 of MEM/SUL were decreased fourfold, compared to the monotherapy MIC. In the time-kill studies, the combination displayed synergistic killing against both isolates at the highest clinically achievable concentrations. At concentrations equal to the fractional inhibitory concentration, synergism was observed against one isolate. The PK/PD model adequately delineated the data and the interaction between meropenem and sulbactam. The effect of the combination was driven by sulbactam, with meropenem acting as a potentiator. The simulations of various dosing regimens revealed no activity for the monotherapies. At best, the MEM/SUL regimen of 2 g/4 g every 8 h demonstrated a probability of target attainment of 2-log10 kill at 24 h of 34%. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that MEM/SUL may potentially be effective against some CR-AB infections.
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Affiliation(s)
- Sazlyna Mohd Sazlly Lim
- Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, Level 4, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Seri Kembangan, Malaysia
| | - Aaron J Heffernan
- Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, Level 4, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia
- School of Medicine, Griffith University, Southport, Australia
| | - Hosam M Zowawi
- UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Centre, Riyadh, Saudi Arabia
| | - Jason A Roberts
- Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, Level 4, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia
- UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia
- Royal Brisbane and Women's Hospital, Brisbane, Australia
| | - Fekade B Sime
- Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, Level 4, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia.
- UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia.
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Seok H, Choi WS, Lee S, Moon C, Park DW, Song JY, Cheong HJ, Kim J, Kim JY, Park MN, Kim YR, Lee HJ, Kim B, Pai H, Jo YM, Kim JH, Sohn JW. What is the optimal antibiotic treatment strategy for carbapenem-resistant Acinetobacter baumannii (CRAB)? A multicentre study in Korea. J Glob Antimicrob Resist 2021; 24:429-439. [PMID: 33571708 DOI: 10.1016/j.jgar.2021.01.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/13/2021] [Accepted: 01/29/2021] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVES The optimal treatment option for carbapenem-resistant Acinetobacter baumannii (CRAB) is still limited. This study investigated the efficacy of three or more antibiotic types and regimens for treatment of CRAB infection in high CRAB endemic areas. METHODS A multicentre retrospective study was conducted to evaluate the efficacy of treatment types and regimens of CRAB infections in 10 tertiary hospitals in the Republic of Korea. The outcomes comprised 7-day and 28-day mortality, and clinical and microbiological responses at 7 days, 28 days, and the end of treatment. Nephrotoxicity and hepatotoxicity were evaluated as drug adverse reactions. RESULTS A total of 282 patients were included in the study. Among the CRAB strains, the two most susceptible antibiotics were colistin (99.6%) and minocycline (80.4%). A combination of colistin and carbapenem significantly reduced 7-day mortality, and a sulbactam-containing regimen significantly reduced 28-day mortality. Colistin monotherapy was significantly associated with increased 7-day and 28-day mortality. A minocycline-containing regimen showed the best microbiological responses at 7 days, 28 days, and the end of treatment. Colistin and tigecycline were associated with increased nephrotoxicity and hepatotoxicity, respectively. Subgroup analysis of patients with pneumonia showed similar results to the overall CRAB infection. CONCLUSIONS A combination of colistin and carbapenem and sulbactam-containing regimen may contribute improved mortality in CRAB infections. Colistin monotherapy should be considered cautiously in severe CRAB infections or CRAB pneumonia. A minocycline-containing regimen showed the best microbiological responses, and further studies may be needed to evaluate improved mortality.
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Affiliation(s)
- Hyeri Seok
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Won Suk Choi
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Shinwon Lee
- Department of Internal Medicine, Pusan National University School of Medicine and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Chisook Moon
- Division of Infectious Diseases, Busan Paik Hospital, Inje University, Busan, Republic of Korea
| | - Dae Won Park
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Joon Young Song
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hee Jin Cheong
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jieun Kim
- Division of Infectious Diseases, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Jin Yong Kim
- Department of Internal Medicine, Incheon Medical Center, Incheon, Republic of Korea
| | - Mi Na Park
- Infection Control Office, Incheon Medical Center, Incheon, Republic of Korea
| | - Yang Ree Kim
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyo-Jin Lee
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bongyoung Kim
- Division of Infectious Diseases, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Hyunjoo Pai
- Division of Infectious Diseases, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Yu Mi Jo
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jong Hun Kim
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jang Wook Sohn
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
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20
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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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Samal S, Samir SB, Patra SK, Rath A, Dash A, Nayak B, Mohanty D. Polymyxin Monotherapy vs. Combination Therapy for the Treatment of Multidrug-resistant Infections: A Systematic Review and Meta-analysis. Indian J Crit Care Med 2021; 25:199-206. [PMID: 33707900 PMCID: PMC7922466 DOI: 10.5005/jp-journals-10071-23720] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objectives The objective of this review was to compare the effectiveness of Colistin monotherapy and combination therapy for the treatment of multidrug-resistant gram-negative bacterial infections. Data sources PubMed, Cochrane Library. Study eligibility interventions and exclusions In this systematic review, we included all retrospective and prospective studies and randomized controlled trials (RCTs) that compared intravenous polymyxin monotherapy and combination therapy with any other antibiotic for treating multidrug-resistant infections. Studies using inhaled polymyxins with 5 or less than 5 patients were excluded. The primary outcome was 30-day all-cause mortality and if not reported at day 30 we extracted and documented the closest time point. Both crude outcome rates and adjusted effect estimates were extracted for mortality. Study appraisal data extraction and synthesis Search string used was "(Colistin OR polymyxin) AND (Enterobacteriaceae OR Klebsiella OR Acinetobacter OR Escherichia coli OR Pseudomonas) AND (random OR prospective OR retrospective OR cohort OR observational OR blind)." Thirty-nine studies were included in our analysis; out of which 6 RCTs were included and 9 studies used carbapenem as the adjunctive antibiotic. Each study was screened and reviewed for eligibility independently by two authors and data extrapolated on an Excel sheet. Results The meta-analysis of polymyxin monotherapy vs. combination therapy in multidrug-resistant infections yielded an odds ratio (OR) of 0.81 (95% confidence interval [CI]: 0.65-1.01) with minimal heterogeneity (I 2 = 40%), whereas pooled analysis of this comparison in studies that included carbapenem as combination therapy yielded an OR of 0.64 (CI: 0.40-1.03; I 2 = 62%). Likewise, the pooled analysis of the RCTs yielded an OR of 0.82 (95% CI: 0.58-1.16, I 2 = 22%). All these showed no statistical significance. However, it was seen that polymyxin combination therapy was more effective in multidrug-resistant infections compared to polymyxin monotherapy. The effectiveness was more glaring when carbapenems were used as the combination drug instead of any other antibiotic and more so in many in vitro studies that used polymyxin combination therapy. Conclusion Although statistically insignificant, it would be prudent to use polymyxin combination therapy to treat multidrug-resistant gram-negative bacilli (GNB) infection over monotherapy with preference to use carbapenem as the adjunct alongside polymyxins. How to cite this article Samal S, Mishra SB, Patra SK, Rath A, Dash A, Nayak B, et al. Polymyxin Monotherapy vs. Combination Therapy for the Treatment of Multidrug-resistant Infections: A Systematic Review and Meta-analysis. Indian J Crit Care Med 2021;25(2):199-206.
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Affiliation(s)
- Samir Samal
- Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
| | - Shakti B Samir
- Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
| | - Shantanu K Patra
- Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
| | - Arun Rath
- Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
| | - Abhilash Dash
- Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
| | - Biswajit Nayak
- Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
| | - Diganta Mohanty
- Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
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Suphansatit R, Uitrakul S. A Pilot Study of Antibiotic Regimens for Infections Caused by Acinetobacter baumannii in a Secondary Hospital in Thailand. Infect Drug Resist 2020; 13:4495-4500. [PMID: 33364796 PMCID: PMC7751590 DOI: 10.2147/idr.s285261] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 11/30/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose This retrospective pilot study aimed to investigate the antibiotic regimens used to treat Acinetobacter baumannii infections at a secondary hospital in southern Thailand. Additionally, the clinical outcomes and mortality of each regimen are described. Patients and Methods The medical charts of all patients admitted to Phang-Nga Hospital, Thailand, between 1 January 2019 and 31 May 2020 due to Acinetobacter baumannii infection were reviewed. Data were collected on the antibiotics that patients received before and after sensitivity testing, along with the clinical cure, mortality rates, and nephrotoxicity. Results Of the 32 inpatients recruited in the study, the most prescribed antibiotic regimen for empirical therapy was beta-lactam/beta-lactamase inhibitor monotherapy (22%), and for definitive therapy was meropenem monotherapy (28%). Combination therapy with two, three, or four antibiotics was prescribed less than 50% of cases for both empirical and definitive therapy. Moreover, the results indicated that patients receiving combination therapy had a lower clinical response and higher mortality than those receiving monotherapy. Furthermore, regimens containing colistin did not provide a higher clinical cure compared to those without colistin. Conclusion The results of this pilot study support the use of monotherapy antibiotic regimens, including ceftazidime and meropenem, for the treatment of Acinetobacter baumannii infections in secondary hospitals. However, as these results are from a single hospital with limited number of patients, the application of the results should be done carefully. More patient data from other hospitals will be collected in the next phase of this study.
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Affiliation(s)
| | - Suriyon Uitrakul
- Department of Pharmaceutical Care, School of Pharmacy, Walailak University, Thasala, Nakhon Si Thammarat, Thailand
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Bian X, Liu X, Feng M, Bergen PJ, Li J, Chen Y, Zheng H, Song S, Zhang J. Enhanced bacterial killing with colistin/sulbactam combination against carbapenem-resistant Acinetobacter baumannii. Int J Antimicrob Agents 2020; 57:106271. [PMID: 33352235 DOI: 10.1016/j.ijantimicag.2020.106271] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/05/2020] [Accepted: 12/13/2020] [Indexed: 12/26/2022]
Abstract
AIMS Polymyxin-based combination therapy is often used to treat carbapenem-resistant Acinetobacter baumannii (A. baumannii) infections. Although sulbactam is intrinsically active against A. baumannii, few studies have investigated colistin/sulbactam combinations against carbapenem-resistant A. baumannii. METHODS Whole genome sequencing was undertaken on eight carbapenem-resistant (colistin-susceptible) isolates of A. baumannii from Chinese patients. Bacterial killing of colistin and sulbactam, alone and in combination, was examined with checkerboard (all isolates) and static and dynamic time-kill studies (three isolates). In the dynamic studies, antibiotics were administered in various clinically-relevant dosing regimens that mimicked patient pharmacokinetics. RESULTS The eight isolates consisted of ST195, ST191 and ST208 belonging to clonal complex 208, which is the most epidemic clonal type of A. baumannii globally. All isolates possessed Acinetobacter-derived cephalosporinase (ADC-61 or ADC-78) and seven of eight isolates contained the carbapenem-resistance gene blaOXA-23. The colistin/sulbactam combination was synergistic against two of eight isolates in checkerboard studies. In time-kill studies, rapid bacterial killing of ca. 3-6 log10 CFU/mL was observed with colistin monotherapy, followed by steady regrowth. Sulbactam monotherapy was generally ineffective. Substantially enhanced bacterial killing was observed with colistin/sulbactam combinations in both static and dynamic models, especially with the higher sulbactam concentration (2 g) and/or longer sulbactam infusion time (2 hours) in the dynamic model. CONCLUSIONS This study was the first to use a pharmacokinetics/pharmacodynamics model to investigate synergistic activity of colistin/sulbactam combinations against A. baumannii. It showed that clinically-relevant dosing regimens of colistin combined with sulbactam may substantially improve bacterial killing of multidrug-resistant and carbapenem-resistant A. baumannii.
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Affiliation(s)
- Xingchen Bian
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Xiaofen Liu
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Meiqing Feng
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Phillip J Bergen
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia
| | - Jian Li
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia
| | - Yuancheng Chen
- Phase I Unit, Huashan Hospital, Fudan University, Shanghai, China
| | - Huajun Zheng
- Chinese National Human Genome Center, Shanghai, China
| | - Sichao Song
- Chinese National Human Genome Center, Shanghai, China
| | - Jing Zhang
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Phase I Unit, Huashan Hospital, Fudan University, Shanghai, China.
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Liu J, Shu Y, Zhu F, Feng B, Zhang Z, Liu L, Wang G. Comparative efficacy and safety of combination therapy with high-dose sulbactam or colistin with additional antibacterial agents for multiple drug-resistant and extensively drug-resistant Acinetobacter baumannii infections: A systematic review and network meta-analysis. J Glob Antimicrob Resist 2020; 24:136-147. [PMID: 32889142 DOI: 10.1016/j.jgar.2020.08.021] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/20/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES This study aimed to compare the efficacy and safety of combination therapy with high-dose sulbactam or colistin with additional antibacterial agents for treating multidrug-resistant or extensively drug-resistant Acinetobacter baumannii (MDR-AB or XDR-AB) infections. METHODS We systematically searched PubMed, Embase, Cochrane, and Web of Science (through March 30, 2020) for studies that examined high-dose sulbactam or colistin with additional antibacterial agents as therapy for patients with infections with MDR-AB and XDR-AB. Through a network meta-analysis (NMA), using both direct and indirect evidence, we determined risk ratios and 95% confidence intervals. Primary outcomes included clinical improvement, clinical cure, microbiological eradication, and mortality from any cause. Secondary outcomes included nephrotoxicity. RESULTS The NMA included 18 studies and 1835 patients. We found that high-dose sulbactam (≥6 g per day), combined with another single antibacterial agent (levofloxacin or tigecycline), which were the highest ranking in clinical improvement and clinical cure. Still colistin-based combination in drug-resistant Acinetobacter baumannii therapy occupied the main position (the number of studies and patients) in most studies. Colistin combined with additional antibacterial agents was associated with a higher risk of nephrotoxicity. CONCLUSIONS Therapeutic regimens including high-dose sulbactam in combination with additional antibacterial agents (including colistin) might be one of the promising options for the treatment of MDR-AB or XDR-AB infections and high-quality study will be needed to confirm clinical efficacy.
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Affiliation(s)
- Jiating Liu
- Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, 1 Xianglin Road, Luzhou 646000, China; Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou 646000, China
| | - Yunfeng Shu
- Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, 1 Xianglin Road, Luzhou 646000, China; Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou 646000, China
| | - Feilong Zhu
- The Affiliated Xuzhou Rehabilitation Hospital of Xuzhou Medical University, Xuzhou 221009, China
| | - Bimin Feng
- Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, 1 Xianglin Road, Luzhou 646000, China
| | - Zhengjie Zhang
- Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, 1 Xianglin Road, Luzhou 646000, China; Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou 646000, China
| | - Liang Liu
- Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, 1 Xianglin Road, Luzhou 646000, China; Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou 646000, China
| | - Guojun Wang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou 646000, China.
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Abstract
PURPOSE OF REVIEW We reviewed recent data about epidemiology of Acinetobacter baumannii, resistance mechanisms, and therapeutic options for severe infections caused by multidrug-resistant strains. RECENT FINDINGS A. baumannii is a major cause of nosocomial infections affecting mainly to debilitating patients in the ICU, although the spread to regular wards and to long-term care facilities is increasing. It is characterized by its great persistence in the environment and to have an extraordinary capability to develop resistance to all antimicrobials.Carbapenems may not be considered the treatment of choice in areas with high rates of carbapenem-resistant A. baumannii. Nowadays, polymyxins are the antimicrobials with the greatest level of in-vitro activity against A. baumannii. Colistin is the most widely used in clinical practice although polymyxin B seems to be associated with less renal toxicity. Colistin is administered intravenously as its inactive prodrug colistimethate. A loading dose of 9 million IU and subsequently high, extended-interval maintenance doses (4.5 million IU/12 h) are recommended. Combination therapy instead of monotherapy increases the rates of microbiological eradication although no clinical study has demonstrated a reduction in clinical outcomes (mortality or length of stay). SUMMARY The optimal treatment for multidrug-resistant A. baumannii nosocomial infections has not been established. There are no compelling data to recommend combination therapy for severe A. baumannii infections.
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Park SY, Si HJ, Eom JS, Lee JS. Survival of carbapenem-resistant Acinetobacter baumannii bacteremia: colistin monotherapy versus colistin plus meropenem. J Int Med Res 2019; 47:5977-5985. [PMID: 31612764 PMCID: PMC7045657 DOI: 10.1177/0300060519879336] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Objective The aim of this study was to compare clinical outcomes between patients with carbapenem-resistant Acinetobacter baumannii (CRAB) bacteremia treated with colistin monotherapy and those treated with colistin plus meropenem. Methods We retrospectively evaluated data from 71 patients with CRAB bacteremia treated from November 2006 to February 2018. Predictors of 14-day mortality were determined through logistic regression analysis. Results Our study cohort included 40 bacteremia patients (44.6 %) treated with colistin monotherapy and 31 (55.4 %) treated with colistin plus meropenem. Overall 14-day mortality tended to be higher with monotherapy rather than combination therapy (47.5% vs 25.8%). The latter also showed a tendency for higher clinical success rate compared with monotherapy (61.3% vs 40.0%). Logistic regression analysis showed that Pitt bacteremia score, pneumonia, and combination therapy were significantly associated with mortality. In patients with higher Pitt bacteremia score (≥4), mortality was significantly higher with monotherapy compared with combination therapy (66.7% vs 27.8%). In patients with lower Pitt bacteremia score (≤3), mortality was similar between the two treatment groups (26.3% vs 23.1%). Conclusion Treatment with colistin plus meropenem improves survival in critically-ill patients with CRAB.
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Affiliation(s)
- So Yeon Park
- Department of Internal Medicine, Division of Infectious Disease, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
| | - Hye Jin Si
- Department of Internal Medicine, Division of Infectious Disease, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
| | - Joong Sik Eom
- Department of Internal Medicine, Division of Infectious Disease, Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea
| | - Jin Seo Lee
- Department of Internal Medicine, Division of Infectious Disease, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
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Paul M, Zusman O, Leibovici L. Meta-analysis of Polymyxin Use in Patients. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1145:143-153. [PMID: 31364077 DOI: 10.1007/978-3-030-16373-0_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
In this chapter, we systematically reviewed studies that assessed polymyxin's effectiveness and summarized results through meta-analysis. The outcomes addressed were all-cause mortality, assuming that for patients with severe multidrug-resistant infections survival is the most important outcome, and resistance development, important for future patients. Most clinical data on polymyxins in the literature are from retrospective, observational studies at high risk of bias. The majority of clinical studies were unpowered to examine mortality controlling for other risk factors. The studies had no control of dosage regimens and treatment modifications. We identified several areas of missing data, in particular randomized controlled trials (RCTs) examining treatment options for carbapenem-resistant Gram-negative bacteria, different dosage regimens, polymyxins versus alternative antibiotics (e.g. aminoglycosides, tigecycline), and monotherapy versus specific combination therapies. Ideally, mortality and development of resistance should be examined in RCTs, with further longitudinal studies required for the latter.
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Affiliation(s)
- Mical Paul
- Division of Infectious Diseases, Rambam Health Care Center and The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
| | - Oren Zusman
- Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Tel Aviv, Israel
| | - Leonard Leibovici
- Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Tel Aviv, Israel
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Ungthammakhun C, Vasikasin V, Changpradub D. Clinical Outcomes Of Colistin In Combination With Either 6-G Sulbactam Or Carbapenems For The Treatment Of Extensively Drug-Resistant Acinetobacter Baumannii Pneumonia With High MIC To Sulbactam, A Prospective Cohort Study. Infect Drug Resist 2019; 12:2899-2904. [PMID: 31571943 PMCID: PMC6750850 DOI: 10.2147/idr.s225518] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/05/2019] [Indexed: 11/23/2022] Open
Abstract
Purpose Extensively drug-resistant Acinetobacter baumannii (XDRAB) is an important cause of nosocomial pneumonia with limited therapeutic options. Colistin-based regimen is the recommended treatment. Which drugs should be combined with colistin remains uncertain. The aim of this study was to investigate the clinical outcomes of patients with XDRAB pneumonia who were treated with colistin, combined with either 6-g sulbactam or carbapenems, in the setting of high MIC to sulbactam. Patients and methods In this prospective cohort study, hospitalized patients diagnosed with XDRAB pneumonia in Phramongkutklao Hospital were enrolled. The primary outcome was 28-day mortality. Secondary outcomes were 7- and 14-day mortality, length of stay, ventilator days and factors associated with mortality. Results From 1 July 2016 to 30 September 2017, 182 patients were included; 92 received colistin plus sulbactam and 90 received colistin plus carbapenems. Most of the patients were males diagnosed with ventilator-associated pneumonia in medical intensive care unit. Overall mortality rates at 7, 14, 28 days were 24.2%, 37.4%, and 53.3%, respectively. Mortality rates did not differ between sulbactam group and carbapenem groups at 7 days (19.6% vs 28.9%, p-value 0.424, adjusted HR 1.277; 95% CI = 0.702–2.322), 14 days (34.8% vs 40%, p = 0.658, adjusted HR 1.109; 95% CI = 0.703–1.749) and 28 days (51.1% vs 55.6%, p = 0.857, adjusted HR 1.038; 95% CI = 0.690–1.562). Length of stay, ICU days and ventilator days did not differ. Complications of treatment including acute kidney injury were not statistically different. Conclusion In XDRAB pneumonia with high MIC to sulbactam, differences in mortality rates were not statistically significant between colistin plus 6-g sulbactam and colistin plus carbapenems.
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Affiliation(s)
- Chutchawan Ungthammakhun
- Division of Infectious Diseases, Department of Medicine, Phramongkutklao Hospital, Bangkok 10400, Thailand
| | - Vasin Vasikasin
- Division of Infectious Diseases, Department of Medicine, Phramongkutklao Hospital, Bangkok 10400, Thailand
| | - Dhitiwat Changpradub
- Division of Infectious Diseases, Department of Medicine, Phramongkutklao Hospital, Bangkok 10400, Thailand
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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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Mohd Sazlly Lim S, Sime FB, Roberts JA. Multidrug-resistant Acinetobacter baumannii infections: Current evidence on treatment options and the role of pharmacokinetics/pharmacodynamics in dose optimisation. Int J Antimicrob Agents 2019; 53:726-745. [DOI: 10.1016/j.ijantimicag.2019.02.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 02/11/2019] [Accepted: 02/26/2019] [Indexed: 12/22/2022]
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Hawkey PM, Warren RE, Livermore DM, McNulty CAM, Enoch DA, Otter JA, Wilson APR. Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrob Chemother 2019. [PMID: 29514274 DOI: 10.1093/jac/dky027] [Citation(s) in RCA: 208] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The Working Party makes more than 100 tabulated recommendations in antimicrobial prescribing for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) and suggest further research, and algorithms for hospital and community antimicrobial usage in urinary infection. The international definition of MDR is complex, unsatisfactory and hinders the setting and monitoring of improvement programmes. We give a new definition of multiresistance. The background information on the mechanisms, global spread and UK prevalence of antibiotic prescribing and resistance has been systematically reviewed. The treatment options available in hospitals using intravenous antibiotics and in primary care using oral agents have been reviewed, ending with a consideration of antibiotic stewardship and recommendations. The guidance has been derived from current peer-reviewed publications and expert opinion with open consultation. Methods for systematic review were NICE compliant and in accordance with the SIGN 50 Handbook; critical appraisal was applied using AGREE II. Published guidelines were used as part of the evidence base and to support expert consensus. The guidance includes recommendations for stakeholders (including prescribers) and antibiotic-specific recommendations. The clinical efficacy of different agents is critically reviewed. We found there are very few good-quality comparative randomized clinical trials to support treatment regimens, particularly for licensed older agents. Susceptibility testing of MDR GNB causing infection to guide treatment needs critical enhancements. Meropenem- or imipenem-resistant Enterobacteriaceae should have their carbapenem MICs tested urgently, and any carbapenemase class should be identified: mandatory reporting of these isolates from all anatomical sites and specimens would improve risk assessments. Broth microdilution methods should be adopted for colistin susceptibility testing. Antimicrobial stewardship programmes should be instituted in all care settings, based on resistance rates and audit of compliance with guidelines, but should be augmented by improved surveillance of outcome in Gram-negative bacteraemia, and feedback to prescribers. Local and national surveillance of antibiotic use, resistance and outcomes should be supported and antibiotic prescribing guidelines should be informed by these data. The diagnosis and treatment of both presumptive and confirmed cases of infection by GNB should be improved. This guidance, with infection control to arrest increases in MDR, should be used to improve the outcome of infections with such strains. Anticipated users include medical, scientific, nursing, antimicrobial pharmacy and paramedical staff where they can be adapted for local use.
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Affiliation(s)
- Peter M Hawkey
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK
| | | | | | - Cliodna A M McNulty
- Microbiology Department, Gloucestershire Royal Hospital, Great Western Road, Gloucester GL1 3NN, UK
| | - David A Enoch
- Public Health England, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - A Peter R Wilson
- Department of Microbiology and Virology, University College London Hospitals, London, UK
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Thwaites CL, Lundeg G, Dondorp AM, Adhikari NKJ, Nakibuuka J, Jawa R, Mer M, Murthy S, Schultz MJ, Thien BN, Kwizera A. Infection Management in Patients with Sepsis and Septic Shock in Resource-Limited Settings. SEPSIS MANAGEMENT IN RESOURCE-LIMITED SETTINGS 2019:163-184. [DOI: 10.1007/978-3-030-03143-5_8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Liu YH, Kuo SC, Yao BY, Fang ZS, Lee YT, Chang YC, Chen TL, Hu CMJ. Colistin nanoparticle assembly by coacervate complexation with polyanionic peptides for treating drug-resistant gram-negative bacteria. Acta Biomater 2018; 82:133-142. [PMID: 30316023 DOI: 10.1016/j.actbio.2018.10.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 10/09/2018] [Accepted: 10/09/2018] [Indexed: 12/11/2022]
Abstract
Amidst the ever-rising threat of antibiotics resistance, colistin, a decade-old antibiotic with lingering toxicity concern, is increasingly prescribed to treat many drug-resistant, gram-negative bacteria. With the aim of improving the safety profile while preserving the antimicrobial activity of colistin, a nanoformulation is herein developed through coacervate complexation with polyanionic peptides. Upon controlled mixing of cationic colistin with polyglutamic acids, formation of liquid coacervates was demonstrated. Subsequent stabilization by DSPE-PEG and homogenization through micro-fluidization of the liquid coacervates yielded nanoparticles 8 nm in diameter. In vitro assessment showed that the colistin antimicrobial activity against multiple drug-resistant bacterial strains was retained and, in some cases, enhanced following the nanoparticle assembly. In vivo administration in mice demonstrated improved safety of the colistin nanoparticle, which has a maximal tolerated dose of 12.5 mg/kg compared to 10 mg/kg of free colistin. Upon administration over a 7-day period, colistin nanoparticles also exhibited reduced hepatotoxicity as compared to free colistin. In mouse models of Klebsiella pneumoniae bacteremia and Acinetobacter baumannii pneumonia, treatment with colistin nanoparticles showed equivalent efficacy to free colistin. These results demonstrate coacervation-induced nanoparticle assembly as a promising approach towards improving colistin treatments against bacterial infections. STATEMENT OF SIGNIFICANCE: Improving the safety of colistin while retaining its antimicrobial activity has been a highly sought-after objective toward enhancing antibacterial treatments. Herein, we demonstrate formation of stabilized colistin nanocomplexes in the presence of anionic polypeptides and DSPE-PEG stabilizer. The nanocomplexes retain colistin's antimicrobial activity while demonstrating improved safety upon in vivo administration. The supramolecular nanoparticle assembly of colistin presents a unique approach towards designing antimicrobial nanoparticles.
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Oliota AF, Penteado ST, Tonin FS, Fernandez-Llimos F, Sanches AC. Nephrotoxicity prevalence in patients treated with polymyxins: a systematic review with meta-analysis of observational studies. Diagn Microbiol Infect Dis 2018; 94:41-49. [PMID: 30635223 DOI: 10.1016/j.diagmicrobio.2018.11.008] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 11/06/2018] [Accepted: 11/12/2018] [Indexed: 12/15/2022]
Abstract
Colistin and polymyxin B are increasingly reintroduced in clinical practice due to the absence of effective antibiotics for the treatment of emerging infections caused by gram-negative bacteria. The synthesis of current evidence on the characteristics of polymyxins, especially regarding nephrotoxicity, is necessary. This study aims to conduct a systematic review and meta-analysis of cohort-type observational studies in order to identify the prevalence of nephrotoxicity in patients treated with either colistin or polymyxin B. PubMed, Scopus, and DOAJ electronic databases were searched, and manual searches were done. Cohort studies evaluating renal damage (nephrotoxicity) in adult patients caused by colistin or polymyxin B were included. Meta-analyses of the prevalence of nephrotoxicity as well as cumulative meta-analysis and meta-regression were conducted. After the systematic searches, 95 cohorts (n = 7911 patients) were included for analysis. The nephrotoxicity prevalence was 26.7% [confidence interval (CI) 95%: 22.8-30.9%] for colistin and 29.8% (CI 23.8-36.7%) for polymyxin B (P = 0.720). The publication year of the studies, the criteria used to classify renal damage, and the nephrotoxicity as primary or secondary outcome showed a significant influence on the adverse event rates.
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Affiliation(s)
- Ana F Oliota
- Center for Medical and Pharmaceutical Sciences, Universidade Estadual do Oeste do Paraná, Cascavel, Brazil
| | - Suelem T Penteado
- Center for Medical and Pharmaceutical Sciences, Universidade Estadual do Oeste do Paraná, Cascavel, Brazil
| | - Fernanda S Tonin
- Postgraduate Program in Pharmaceutical Sciences, Universidade Federal do Paraná, Curitiba, Brazil
| | - Fernando Fernandez-Llimos
- Research Institute for Medicines (iMed.ULisboa), Departament of Social Pharmacy, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
| | - Andreia C Sanches
- Center for Medical and Pharmaceutical Sciences, Universidade Estadual do Oeste do Paraná, Cascavel, Brazil.
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Wang J, Niu H, Wang R, Cai Y. Safety and efficacy of colistin alone or in combination in adults with Acinetobacter baumannii infection: A systematic review and meta-analysis. Int J Antimicrob Agents 2018; 53:383-400. [PMID: 30447379 DOI: 10.1016/j.ijantimicag.2018.10.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/30/2018] [Accepted: 10/27/2018] [Indexed: 01/29/2023]
Abstract
This review comprehensively assessed the safety and efficacy of colistin alone or in combination in adults with Acinetobacter baumannii infection. PubMed, Embase and the Cochrane Library were searched from inception to March 2018 for studies evaluating colistin monotherapy compared with other antibiotic therapy or colistin-based combination therapy for the treatment of A. baumannii infection in adults. Efficacy outcomes were clinical response and microbiological cure. Safety outcomes were mortality and nephrotoxic adverse events. A total of 4 randomised controlled trials (RCTs) and 14 observational studies were identified, including 7 reporting colistin versus other antibiotics and 12 reporting colistin monotherapy versus colistin-based combination therapy. Overall clinical response, microbiological response and mortality did not differ significantly between colistin monotherapy versus other antibiotics. However, the incidence of nephrotoxicity was significantly higher in colistin monotherapy (OR = 2.50, 95% CI 1.05-5.98; P = 0.04). No significant differences were detected in clinical response and >28-day mortality between colistin monotherapy and combination therapy. However, colistin-based combination therapy showed an increased microbiological response (OR = 0.49, 95% CI 0.32-0.74; P = 0.0009) and decreased incidence of nephrotoxicity (OR = 1.66, 95% CI 0.99-2.78; P =0.05). In conclusion, colistin alone is as effective as other antibiotics for the treatment of A. baumannii infection but has a higher risk of nephrotoxicity. Colistin-based combination therapy demonstrated a microbiological benefit and no higher risk of nephrotoxicity compared with monotherapy. High-quality RCTs are still needed to confirm the beneficial role of colistin-based combination therapy.
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Affiliation(s)
- Jin Wang
- Center of Medicine Clinical Research, Department of Pharmacy, PLA General Hospital, 28 Fu Xing Road, Beijing 100853, P.R. China
| | - Hui Niu
- Center of Medicine Clinical Research, Department of Pharmacy, PLA General Hospital, 28 Fu Xing Road, Beijing 100853, P.R. China
| | - Rui Wang
- Center of Medicine Clinical Research, Department of Pharmacy, PLA General Hospital, 28 Fu Xing Road, Beijing 100853, P.R. China
| | - Yun Cai
- Center of Medicine Clinical Research, Department of Pharmacy, PLA General Hospital, 28 Fu Xing Road, Beijing 100853, P.R. China.
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Liang CA, Lin YC, Lu PL, Chen HC, Chang HL, Sheu CC. Antibiotic strategies and clinical outcomes in critically ill patients with pneumonia caused by carbapenem-resistant Acinetobacter baumannii. Clin Microbiol Infect 2018; 24:908.e1-908.e7. [DOI: 10.1016/j.cmi.2017.10.033] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/29/2017] [Accepted: 10/31/2017] [Indexed: 01/27/2023]
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Kengkla K, Kongpakwattana K, Saokaew S, Apisarnthanarak A, Chaiyakunapruk N. Comparative efficacy and safety of treatment options for MDR and XDR Acinetobacter baumannii infections: a systematic review and network meta-analysis. J Antimicrob Chemother 2018; 73:22-32. [PMID: 29069421 DOI: 10.1093/jac/dkx368] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 09/08/2017] [Indexed: 12/11/2022] Open
Abstract
Objectives To comprehensively compare and rank the efficacy and safety of available treatment options for patients with MDR and XDR Acinetobacter baumannii (AB) infection. Methods We searched PubMed, Embase and the Cochrane register of trials systematically for studies that examined treatment options for patients with MDR- and XDR-AB infections until April 2016. Network meta-analysis (NMA) was performed to estimate the risk ratio (RR) and 95% CI from both direct and indirect evidence. Primary outcomes were clinical cure and microbiological cure. Secondary outcomes were all-cause mortality and nephrotoxic and non-nephrotoxic adverse events. Results A total of 29 studies with 2529 patients (median age 60 years; 65% male; median APACHE II score 19.0) were included. Although there were no statistically significant differences between treatment options, triple therapy with colistin, sulbactam and tigecycline had the highest clinical cure rate. Colistin in combination with sulbactam was associated with a significantly higher microbiological cure rate compared with colistin in combination with tigecycline (RR 1.23; 95% CI 1.03-1.47) and colistin monotherapy (RR 1.21; 95% CI 1.06-1.38). No significant differences in all-cause mortality were noted between treatment options. Tigecycline-based therapy also appeared less effective for achieving a microbiological cure and is not appropriate for treating bloodstream MDR- and XDR-AB infections. Conclusions Combination therapy of colistin with sulbactam demonstrates superiority in terms of microbiological cure with a safety profile similar to that of colistin monotherapy. Thus, our findings support the use of this combination as a treatment for MDR- and XDR-AB infections.
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Affiliation(s)
- Kirati Kengkla
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | | | - Surasak Saokaew
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.,Center of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.,Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
| | - Anucha Apisarnthanarak
- Division of Infectious Diseases, Faculty of Medicine, Thammasat University Hospital, Pratumthani, Thailand
| | - Nathorn Chaiyakunapruk
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.,Center of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.,School of Pharmacy, University of Wisconsin, Madison, USA.,Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
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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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Ju M, Hou D, Chen S, Wang Y, Tang X, Liu J, Chen C, Song Y, Li H. Risk factors for mortality in ICU patients with Acinetobacter baumannii ventilator-associated pneumonia: impact of bacterial cytotoxicity. J Thorac Dis 2018; 10:2608-2617. [PMID: 29997922 DOI: 10.21037/jtd.2018.04.86] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Background Acinetobacter baumannii (A. baumannii) ventilator-associated pneumonia (VAP) in intensive care unit (ICU) is associated with high morbidity and mortality in patients with critical illness. However, the literatures that focused on the short-term prognosis and the risk factors for mortality are limited. The aim of this study was to evaluate the risk factors for mortality in ICU patients with A. baumannii VAP. Methods A retrospective cohort study was conducted in the medical/surgical ICU at Zhongshan Hospital in Shanghai, China. Adult patients meeting the criteria of A. baumannii VAP from January 2012 to October 2015 were enrolled. Apart from collecting clinical and microbiologic data, we performed biofilm-formation and cytotoxicity testing using A. baumannii strains which are isolated from patients. Multivariate logistic regression analysis was used to determine the independent risk factors for 30-day mortality in ICU. Results Seventy-eight patients were included in this study. The 30-day mortality rate in ICU for the patients was 37.2%. Multivariate analysis revealed that short-term mortality was significantly associated with prior surgery [OR, 0.277; 95% confidence interval (CI), 0.089-0.866; P=0.027], higher APACHEII score (OR, 1.140; 95% CI, 1.007-1.291; P=0.038) and an increased bacterial cytotoxicity (OR, 1.029 ; 95% CI, 1.001-1.058; P=0.047). Conclusions The main finding of our study was that increased bacterial cytotoxicity might be a risk factor for short-term mortality in ICU patients with A. baumannii VAP.
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Affiliation(s)
- Mohan Ju
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Dongni Hou
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shu Chen
- Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Ying Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xinjun Tang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jie Liu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Cuicui Chen
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yuanlin Song
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Huayin Li
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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New Shuttle Vectors for Gene Cloning and Expression in Multidrug-Resistant Acinetobacter Species. Antimicrob Agents Chemother 2018; 62:AAC.02480-17. [PMID: 29339383 DOI: 10.1128/aac.02480-17] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 01/02/2018] [Indexed: 12/28/2022] Open
Abstract
Understanding bacterial pathogenesis requires adequate genetic tools to assess the role of individual virulence determinants by mutagenesis and complementation assays, as well as for homologous and heterologous expression of cloned genes. Our knowledge of Acinetobacter baumannii pathogenesis has so far been limited by the scarcity of genetic tools to manipulate multidrug-resistant (MDR) epidemic strains, which are responsible for most infections. Here, we report on the construction of new multipurpose shuttle plasmids, namely, pVRL1 and pVRL2, which can efficiently replicate in Acinetobacter spp. and in Escherichia coli The pVRL1 plasmid has been constructed by combining (i) the cryptic plasmid pWH1277 from Acinetobacter calcoaceticus, which provides an origin of replication for Acinetobacter spp.; (ii) a ColE1-like origin of replication; (iii) the gentamicin or zeocin resistance cassette for antibiotic selection; and (iv) a multilinker containing several unique restriction sites. Modification of pVRL1 led to the generation of the pVRL2 plasmid, which allows arabinose-inducible gene transcription with an undetectable basal expression level of cloned genes under uninduced conditions and a high dynamic range of responsiveness to the inducer. Both pVRL1 and pVRL2 can easily be selected in MDR A. baumannii, have a narrow host range and a high copy number, are stably maintained in Acinetobacter spp., and appear to be compatible with indigenous plasmids carried by epidemic strains. Plasmid maintenance is guaranteed by the presence of a toxin-antitoxin system, providing more insights into the mechanism of plasmid stability in Acinetobacter spp.
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Makris D, Petinaki E, Tsolaki V, Manoulakas E, Mantzarlis K, Apostolopoulou O, Sfyras D, Zakynthinos E. Colistin versus Colistin Combined with Ampicillin-Sulbactam for Multiresistant Acinetobacter baumannii Ventilator-associated Pneumonia Treatment: An Open-label Prospective Study. Indian J Crit Care Med 2018. [PMID: 29531445 PMCID: PMC5842460 DOI: 10.4103/ijccm.ijccm_302_17] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Background: Retrospective studies have reported good clinical success rates using colistin as monotherapy to treat Acinetobacter baumannii ventilator-associated pneumonia (VAP), comparable to that obtained with colistin combined with other antibiotics. However, inadequate penetration into the pulmonary parenchyma for colistin has been shown in animal models. Aim: The aim of the study was to study prospectively the outcome, measured as clinical response and survival, of intravenously administered colistin versus colistin combined with high-dose ampicillin-sulbactam in Intensive Care Unit (ICU) patients with multiresistant A. baumannii VAP. Methods and Subjects: This prospective, open-label, randomized study included consecutive patients who developed microbiologically documented VAP due to A. baumannii with carbapenem-resistant strains but susceptible to colistin and ampicillin-sulbactam. Seventy-four patients were screened, but finally, 39 participants were enrolled and finished the study Patients received colistin (Group A – 19 patients) or colistin and ampicillin/sulbactam (Group B – 20 patients). The clinical response of VAP was assessed on day 4th to 5th of treatment (early response). If therapy was considered unsuccessful after this period, ampicillin/sulbactam was added in Group A or changed therapy in B. Results: Early cure rates in Group A and B were 15.8% and 70%, respectively (P = 0.001). Multiple regression analysis revealed that combination treatment (odds ratio [OR]: 43.6, 95% confidence interval [CI]: 3.594–530.9) and Sequential Organ Failure Assessment score <8 (OR: 0.022, 95% CI: 0.001–0.43) were independently associated with favorable clinical response. APACHE II score ≤15 (OR: 0.049, 95% CI: 0.003–0.0942) and an early favorable response to treatment (OR: 244.4, 95% CI: 2.151–27850.9) were associated with survival and discharge from ICU. Conclusion: Combination therapy with colistin and a high dose of ampicillin/sulbactam was associated with a more favorable clinical response to VAP due to carbapenem-resistant A. baumannii than colistin monotherapy.
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Affiliation(s)
- Demosthenes Makris
- Department of Critical Care, University Hospital of Larissa, Larissa, Greece
| | - Efi Petinaki
- Department of Microbiology, University Hospital of Larissa, Larissa, Greece
| | - Vasssiliki Tsolaki
- Department of Critical Care, University Hospital of Larissa, Larissa, Greece
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Karaiskos I, Antoniadou A, Giamarellou H. Combination therapy for extensively-drug resistant gram-negative bacteria. Expert Rev Anti Infect Ther 2017; 15:1123-1140. [DOI: 10.1080/14787210.2017.1410434] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Ilias Karaiskos
- 6th Department of Internal Medicine, Hygeia General hospital, Athens, Greece
| | - Anastasia Antoniadou
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens School of Medicine, University General Hospital ATTIKON, Athens, Greece
| | - Helen Giamarellou
- 6th Department of Internal Medicine, Hygeia General hospital, Athens, Greece
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Chen H, Liu Q, Chen Z, Li C. Efficacy of sulbactam for the treatment of Acinetobacter baumannii complex infection: A systematic review and meta-analysis. J Infect Chemother 2017; 23:278-285. [DOI: 10.1016/j.jiac.2017.01.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 12/24/2016] [Accepted: 01/20/2017] [Indexed: 12/22/2022]
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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: 578] [Impact Index Per Article: 72.3] [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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Classical β-Lactamase Inhibitors Potentiate the Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus and Colistin against Acinetobacter baumannii. Antimicrob Agents Chemother 2017; 61:AAC.01745-16. [PMID: 27872080 PMCID: PMC5278754 DOI: 10.1128/aac.01745-16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 11/14/2016] [Indexed: 01/01/2023] Open
Abstract
We asked whether beta-lactamase inhibitors (BLIs) increased the activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA), the peptide antibiotic colistin (COL) against the emerging Gram-negative nosocomial pathogen Acinetobacter baumannii, and the human host defense peptide cathelicidin LL37 against either pathogen. DAP and LL37 kill curves were performed with or without BLIs against MRSA, vancomycin-intermediate S. aureus (VISA), and heterogeneous VISA (hVISA). COL and LL37 kill curves were performed against A. baumannii. Boron-dipyrromethene (BODIPY)-labeled DAP binding to MRSA grown with the BLI tazobactam (TAZ) was assessed microscopically. The combination of COL plus TAZ was studied in a murine model of A. baumannii pneumonia. TAZ alone lacked in vitro activity against MRSA or A. baumannii. The addition of TAZ to DAP resulted in a 2- to 5-log10 reduction in recoverable MRSA CFU at 24 h compared to the recoverable CFU with DAP alone. TAZ plus COL showed synergy by kill curves for 4 of 5 strains of A. baumannii tested. Growth with 20 mg/liter TAZ resulted in 2- to 2.5-fold increases in the intensity of BODIPY-DAP binding to MRSA and hVISA strains. TAZ significantly increased the killing of MRSA and A. baumannii by LL37 in vitro. TAZ increased the activity of COL in a murine model of A. baumannii pneumonia. Classical BLIs demonstrate synergy with peptide antibiotics. Since BLIs have scant antimicrobial activity on their own and are thus not expected to increase selective pressure toward antibiotic resistance, their use in combination with peptide antibiotics warrants further study.
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Zusman O, Altunin S, Koppel F, Dishon Benattar Y, Gedik H, Paul M. Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis. J Antimicrob Chemother 2016; 72:29-39. [PMID: 27624572 DOI: 10.1093/jac/dkw377] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 08/01/2016] [Accepted: 08/10/2016] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVES The objective of this study was to summarize available data on polymyxin-based combination therapy or monotherapy for carbapenem-resistant Gram-negative bacteria. METHODS This is a systematic review. We included observational studies and randomized controlled trials (RCTs) comparing polymyxin monotherapy versus polymyxin-based combination therapy in adult patients with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. Only named antibiotic regimens were included. The primary outcome was 30 day mortality. Unadjusted OR (uOR) and adjusted OR where available with 95% CI were pooled in random-effects meta-analyses. RESULTS Twenty-two studies including 28 comparisons were included. Polymyxin monotherapy was associated with a uOR of 1.58 (95% CI = 1.03-2.42) for mortality compared with polymyxin/carbapenem combination therapy (seven observational studies, 537 patients), without heterogeneity. Subgrouping studies to serious and critical risk of bias resulted in uORs of 0.94 (95% CI = 0.42-2.09) and 1.94 (95% CI = 1.17-3.23), respectively. Mortality was significantly higher with polymyxin monotherapy compared with combination therapy with tigecycline, aminoglycosides or fosfomycin (potentially double-coverage regimens): uOR of 1.57 (95% CI = 1.06-2.32) overall (10 observational studies and 1 RCT, 585 patients, no heterogeneity) and uOR of 2.09 (95% CI = 1.21-3.6) for Klebsiella pneumoniae bacteraemia (7 observational studies, 285 patients, no heterogeneity); very low quality evidence. Two RCTs and one observational study assessing rifampicin/colistin combination therapy for Acinetobacter baumannii infections showed no difference in mortality compared with colistin monotherapy; moderate quality evidence. CONCLUSIONS The significant association observed in observational studies between polymyxin monotherapy and mortality cannot be taken as proof of combination therapy effects due to the low quality of the evidence. The only three RCTs to date show no effect of rifampicin/colistin or fosfomycin/colistin on mortality for Acinetobacter infections.
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Affiliation(s)
- Oren Zusman
- Department of Medicine E, Rabin Medical Center, Petah-Tiqva, Israel
| | - Sergey Altunin
- Infectious Diseases Unit, Rambam Medical Center, Haifa, Israel.,The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
| | - Fidi Koppel
- Infectious Diseases Unit, Rambam Medical Center, Haifa, Israel
| | - Yael Dishon Benattar
- Infectious Diseases Unit, Rambam Medical Center, Haifa, Israel.,The Cheryl Spencer Department of Nursing, University of Haifa, Haifa, Israel
| | - Habip Gedik
- Department of Infectious Diseases and Clinical Microbiology, MoH Bakirkoy Sadi Konuk Training and Research Hospital, Istanbul, Turkey
| | - Mical Paul
- Infectious Diseases Unit, Rambam Medical Center, Haifa, Israel.,The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
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Abstract
Septic shock is still a lethal disease in intensive care units (ICU). The mortality can exceed 40% even with therapeutic management. The high mortality is clearly associated with the delay of appropriate antimicrobial therapy. Early diagnosis and identification of infectious source is the mainstay of optimal therapeutic management. On the other hand, source control and optimize antibiotic dosing according to pharmacokinetics (PK)/pharmacodynamics (PD) properties of antibiotics and organ dysfunction of patients are required to get the best clinical outcome.
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Affiliation(s)
- Emine Alp
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
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Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O'Grady NP, Bartlett JG, Carratalà J, El Solh AA, Ewig S, Fey PD, File TM, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016; 63:e61-e111. [PMID: 27418577 PMCID: PMC4981759 DOI: 10.1093/cid/ciw353] [Citation(s) in RCA: 2201] [Impact Index Per Article: 244.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 05/18/2016] [Indexed: 02/06/2023] Open
Abstract
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.
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Affiliation(s)
- Andre C. Kalil
- Departmentof Internal Medicine, Division of Infectious Diseases,
University of Nebraska Medical Center,
Omaha
| | - Mark L. Metersky
- Division of Pulmonary and Critical Care Medicine,
University of Connecticut School of Medicine,
Farmington
| | - Michael Klompas
- Brigham and Women's Hospital and Harvard Medical School
- Harvard Pilgrim Health Care Institute, Boston,
Massachusetts
| | - John Muscedere
- Department of Medicine, Critical Care Program,Queens University, Kingston, Ontario,
Canada
| | - Daniel A. Sweeney
- Division of Pulmonary, Critical Care and Sleep Medicine,
University of California, San
Diego
| | - Lucy B. Palmer
- Department of Medicine, Division of Pulmonary Critical Care and Sleep
Medicine, State University of New York at Stony
Brook
| | - Lena M. Napolitano
- Department of Surgery, Division of Trauma, Critical Care and Emergency
Surgery, University of Michigan, Ann
Arbor
| | - Naomi P. O'Grady
- Department of Critical Care Medicine, National
Institutes of Health, Bethesda
| | - John G. Bartlett
- Johns Hopkins University School of Medicine,
Baltimore, Maryland
| | - Jordi Carratalà
- Department of Infectious Diseases, Hospital Universitari
de Bellvitge, Bellvitge Biomedical Research Institute, Spanish Network for Research in
Infectious Diseases, University of Barcelona,
Spain
| | - Ali A. El Solh
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep
Medicine, University at Buffalo, Veterans Affairs Western New
York Healthcare System, New York
| | - Santiago Ewig
- Thoraxzentrum Ruhrgebiet, Department of Respiratory and Infectious
Diseases, EVK Herne and Augusta-Kranken-Anstalt
Bochum, Germany
| | - Paul D. Fey
- Department of Pathology and Microbiology, University of
Nebraska Medical Center, Omaha
| | | | - Marcos I. Restrepo
- Department of Medicine, Division of Pulmonary and Critical Care
Medicine, South Texas Veterans Health Care System and University
of Texas Health Science Center at San Antonio
| | - Jason A. Roberts
- Burns, Trauma and Critical Care Research Centre, The
University of Queensland
- Royal Brisbane and Women's Hospital,
Queensland
| | - Grant W. Waterer
- School of Medicine and Pharmacology, University of
Western Australia, Perth,
Australia
| | - Peggy Cruse
- Library and Knowledge Services, National Jewish
Health, Denver, Colorado
| | - Shandra L. Knight
- Library and Knowledge Services, National Jewish
Health, Denver, Colorado
| | - Jan L. Brozek
- Department of Clinical Epidemiology and Biostatistics and Department of
Medicine, McMaster University, Hamilton,
Ontario, Canada
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Buppajarntham A, Apisarnthanarak A, Khawcharoenporn T, Rutjanawech S, Singh N. National Survey of Thai Infectious Disease Physicians on Treatment of Carbapenem-Resistant Acinetobacter baumannii Ventilator-Associated Pneumonia: The Role of Infection Control Awareness. Infect Control Hosp Epidemiol 2016; 37:61-9. [PMID: 26510383 DOI: 10.1017/ice.2015.240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To evaluate the expected and treatment outcomes of Thai infectious disease physicians (IDPs) regarding carbapenem-resistant Acinetobacter baumannii (CRAB) ventilator-associated pneumonia (VAP) METHODS From June 1, 2014, to March 1, 2015, survey data regarding the expected and clinical success rates of CRAB VAP treatment were collected from all Thai IDPs. The expected success rate was defined as the expectation of clinical response after CRAB VAP treatment for the given case scenario. Clinical success rate was defined as the overall reported success rate of CRAB VAP treatment based on the clinical practice of each IDP. The expected and clinical success rates were divided into low (80%) categories and were then compared with standard clinical response rates archived in the existing literature. RESULTS Of 183 total Thai IDPs, 111 (60%) were enrolled in this study. The median expected and clinical success rates were 68% and 58%, respectively. Using multivariate analysis, we determined that working in a hospital that implemented the standard intervention combined with an intensified infection control (IC) intervention for CRAB (adjusted odds ratio [aOR], 3.01; 95% confidence interval [CI], 1.17-7.73; P=.02) was associated with standard and high expected rates (>60%). Being a board-certified IDP (aOR, 5.76; 95% CI, 2.16-15.37; P60%). We identified a significant correlation between expected and clinical success rates (r=0.58; P<.001). CONCLUSIONS Awareness of IC among IDPs can improve physicians' expected and clinical success rates for CRAB VAP treatment, and treatment experience impacts overall treatment success. Infect. Control Hosp. Epidemiol. 2015;37(1):61-69.
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Affiliation(s)
- Aubonphan Buppajarntham
- 1Division of Infectious Diseases, Faculty of Medicine,Thammasat University,Pathumthani,Thailand
| | - Anucha Apisarnthanarak
- 1Division of Infectious Diseases, Faculty of Medicine,Thammasat University,Pathumthani,Thailand
| | - Thana Khawcharoenporn
- 1Division of Infectious Diseases, Faculty of Medicine,Thammasat University,Pathumthani,Thailand
| | - Sasinuch Rutjanawech
- 1Division of Infectious Diseases, Faculty of Medicine,Thammasat University,Pathumthani,Thailand
| | - Nalini Singh
- 2Division of Infectious Diseases,Children's National Medical Center,Department of Pediatrics,Epidemiology and Global Health,George Washington University,School of Medicine and Health Sciences,School of Public Health,Washington DC,United States
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50
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Özvatan T, Akalın H, Sınırtaş M, Ocakoğlu G, Yılmaz E, Heper Y, Kelebek N, İşçimen R, Kahveci F. Nosocomial Acinetobacter pneumonia: Treatment and prognostic factors in 356 cases. Respirology 2015; 21:363-9. [PMID: 26635315 DOI: 10.1111/resp.12698] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 07/13/2015] [Accepted: 08/31/2015] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND OBJECTIVE Acinetobacter baumannii and A. baumannii/calcoaceticus complex are commonly encountered pathogens in nosocomial infections. This study aimed to evaluate the treatment and prognostic risk factors in nosocomial pneumonia caused by these microorganisms. METHODS The study was conducted retrospectively in Uludag University Hospital and included 356 adult non-neutropenic patients with nosocomial pneumonia. RESULTS Of the subjects, 94.9% (n = 338) had ventilator-associated pneumonia. The clinical response rate was 57.2%, the 14-day mortality 39.6% and the 30-day mortality 53.1%. The significant independent risk factors for the 30-day mortality were severe sepsis (OR, 2.60; 95% CI: 1.49-4.56; P = 0.001), septic shock (OR, 6.12; 95% CI: 2.75-13.64; P < 0.001), APACHE II score ≥ 20 (OR, 2.12; 95% CI: 1.28-3.50; P = 0.003) and empiric monotherapy (OR, 1.63; 95% CI: 1.00-2.64; P = 0.048). Multi-trauma (OR, 2.50; 95% CI: 1.11-5.68; P = 0.028) was found to be a protective factor. In patients with a clinical pulmonary infection score (CPIS) > 6 on the third day of treatment, both the 14- and 30-day mortality rates were high (P < 0.001, P < 0.001). Also, the 14- and 30-day mortality rates were significantly higher in the patients treated with empiric monotherapy compared with combination therapy (48/93 (51.6%)-46/123 (37.4%), P = 0.037 and 62/93 (66.7%)-65/123 (52.8%), P = 0.041, respectively) in pneumonia caused by imipenem-resistant strains. CONCLUSION Mortality rates were high in pneumonia caused by imipenem-resistant A. baumannii or A. baumannii/calcoaceticus complex. In the units with a high level of carbapenem resistance, antibiotic combinations should be considered for empiric therapy.
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Affiliation(s)
- Tülay Özvatan
- Department of Infectious Diseases and Clinical Microbiology, Uludag University, Bursa, Turkey
| | - Halis Akalın
- Department of Infectious Diseases and Clinical Microbiology, Uludag University, Bursa, Turkey
| | - Melda Sınırtaş
- Department of Microbiology and Clinical Microbiology, Uludag University, Bursa, Turkey
| | - Gökhan Ocakoğlu
- Department of Biostatistics, Uludag University, Bursa, Turkey
| | - Emel Yılmaz
- Department of Infectious Diseases and Clinical Microbiology, Uludag University, Bursa, Turkey
| | - Yasemin Heper
- Department of Infectious Diseases and Clinical Microbiology, Uludag University, Bursa, Turkey
| | - Nermin Kelebek
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Remzi İşçimen
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Ferda Kahveci
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Uludag University, Bursa, Turkey
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