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Maraolo AE, Gatti M, Principe L, Marino A, Pipitone G, De Pascale G, Ceccarelli G. Management of methicillin-resistant Staphylococcus aureus bloodstream infections: a comprehensive narrative review of available evidence focusing on current controversies and the challenges ahead. Expert Rev Anti Infect Ther 2025:1-26. [PMID: 40165471 DOI: 10.1080/14787210.2025.2487163] [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: 01/17/2025] [Revised: 03/18/2025] [Accepted: 03/21/2025] [Indexed: 04/02/2025]
Abstract
INTRODUCTION Bloodstream infections (BSIs) caused by Staphylococcus aureus are common worldwide, representing one of the most relevant issues in clinical infectious diseases practice. In particular, BSIs by methicillin-resistant S. aureus (MRSA-BSI) are still today a challenge since mortality burden remains elevated although decades of research. AREAS COVERED The following topics regarding MRSA-BSI were reviewed and discussed by resorting to best available evidence retrieved from PubMed/MEDLINE up to October 2024: i) epidemiology; ii) microbiology; iii) classification, with a focus on complicated and not complicated forms; iv) the structured approach to the patient; v) pharmacokinetics and pharmacodynamics of the main antimicrobial options; vi) controversies regarding the best therapeutic approach. EXPERT OPINION Despite ongoing efforts to better stratify and manage MRSA-BSI, there is no universally accepted classification system accurately distinguishing between uncomplicated/low risk and complicated/high risk forms. Biomarkers such as interleukin(IL)-10 hold promise in order to enable a more precise stratification, premise for an appropriate treatment plan. There is a theoretical rationale for implementing a combination therapy including a beta-lactam agent upfront, especially for patients considered at higher risk of unfavorable outcomes, but further data are necessary, and the same applies to newer adjuvants. Novel microbiological techniques may help in guiding antimicrobial duration.
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Affiliation(s)
- Alberto Enrico Maraolo
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Milo Gatti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
- Clinical Pharmacology Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luigi Principe
- Microbiology and Virology Unit, Great Metropolitan Hospital "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy
| | - Andrea Marino
- Department of Clinical and Experimental Medicine, Infectious Diseases Unit, ARNAS Garibaldi Hospital, University of Catania, Catania, Italy
| | | | - Gennaro De Pascale
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze dell 'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, University Hospital Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
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Bassetti M, Giacobbe DR, Magnasco L, Fantin A, Vena A, Castaldo N. Antibiotic Strategies for Severe Community-Acquired Pneumonia. Semin Respir Crit Care Med 2024; 45:187-199. [PMID: 38301712 DOI: 10.1055/s-0043-1778641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Despite advancements in health systems and intensive care unit (ICU) care, along with the introduction of novel antibiotics and microbiologic techniques, mortality rates in severe community-acquired pneumonia (sCAP) patients have not shown significant improvement. Delayed admission to the ICU is a major risk factor for higher mortality. Apart from choosing the appropriate site of care, prompt and appropriate antibiotic therapy significantly affects the prognosis of sCAP. Treatment regimens involving ceftaroline or ceftobiprole are currently considered the best options for managing patients with sCAP. Additionally, several other molecules, such as delafloxacin, lefamulin, and omadacycline, hold promise as therapeutic strategies for sCAP. This review aims to provide a comprehensive summary of the key challenges in managing adults with severe CAP, focusing on essential aspects related to antibiotic treatment and investigating potential strategies to enhance clinical outcomes in sCAP patients.
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Affiliation(s)
- Matteo Bassetti
- Infectious Diseases Unit, Policlinico San Martino Hospital, IRCCS, Genoa, Italy
- Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Daniele R Giacobbe
- Infectious Diseases Unit, Policlinico San Martino Hospital, IRCCS, Genoa, Italy
- Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Laura Magnasco
- Infectious Diseases Unit, Policlinico San Martino Hospital, IRCCS, Genoa, Italy
- Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Alberto Fantin
- Department of Pulmonology, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
| | - Antonio Vena
- Infectious Diseases Unit, Policlinico San Martino Hospital, IRCCS, Genoa, Italy
- Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Nadia Castaldo
- Department of Pulmonology, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
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Cafaro A, Stella M, Mesini A, Castagnola E, Cangemi G, Mattioli F, Baiardi G. Dose optimization and target attainment of vancomycin in children. Clin Biochem 2024; 125:110728. [PMID: 38325652 DOI: 10.1016/j.clinbiochem.2024.110728] [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: 12/05/2023] [Revised: 02/01/2024] [Accepted: 02/02/2024] [Indexed: 02/09/2024]
Abstract
Vancomycin is a glycopeptide antibiotic that has been adopted in clinical practice to treat gram-positive infections for more than 70 years. Despite vancomycin's long history of therapeutic use, optimal dose adjustments and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in children are still under debate. Therapeutic drug monitoring (TDM) has been widely integrated into pediatric clinical practice to maximize efficacy and safety of vancomycin treatment. Area under the curve (AUC)-guided TDM has been recently recommended instead of trough-only TDM to ensure PK/PD target attainment of AUC0-24h/minimal inhibitory concentration (MIC) > 400 to 600 and minimize acute kidney injury risk. Bayesian forecasting in pediatric patients allows estimation of population PK to accurately predict individual vancomycin concentrations over time, and consequently total vancomycin exposure. AUC-guided TDM for vancomycin, preferably with Bayesian forecasting, is therefore suggested for all pediatric age groups and special pediatric populations. In this review we aim to analyze the current literature on the pediatric use of vancomycin and summarize the current knowledge on dosing optimization for target attainment in special patient populations.
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Affiliation(s)
- Alessia Cafaro
- Chromatography and Mass Spectrometry Section, Central Laboratory of Analysis, IRCCS Istituto Giannina, Gaslini, Genova, Italy
| | - Manuela Stella
- UOC Servizio di Sperimentazioni Cliniche Pediatriche, IRCCS Istituto Giannina Gaslini, Genova, Italy; Department of Internal Medicine, Pharmacology & Toxicology Unit, University of Genoa, Genova, Italy
| | - Alessio Mesini
- Infectious Disease Unit, Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Elio Castagnola
- Infectious Disease Unit, Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Giuliana Cangemi
- Chromatography and Mass Spectrometry Section, Central Laboratory of Analysis, IRCCS Istituto Giannina, Gaslini, Genova, Italy.
| | - Francesca Mattioli
- Department of Internal Medicine, Pharmacology & Toxicology Unit, University of Genoa, Genova, Italy; Clinical Pharmacology Unit, Ente Ospedaliero Ospedali Galliera, Genova, Italy
| | - Giammarco Baiardi
- Department of Internal Medicine, Pharmacology & Toxicology Unit, University of Genoa, Genova, Italy; Clinical Pharmacology Unit, Ente Ospedaliero Ospedali Galliera, Genova, Italy
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Yan K, Yao J, Liu L, Liang W, Cai Y. Effects of low-frequency ultrasound combined with anti-MRSA agents on the mouse model of pulmonary infection. Microbiol Spectr 2024; 12:e0101623. [PMID: 38323827 PMCID: PMC10913739 DOI: 10.1128/spectrum.01016-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 01/15/2024] [Indexed: 02/08/2024] Open
Abstract
The treatment of methicillin-resistant Staphylococcus aureus (MRSA)-induced pneumonia with antibiotics alone poses considerable challenges. To address these challenges, low-frequency ultrasound (LFU) emerges as a promising approach. In this study, a mouse pneumonia model was established through intratracheal injection of MRSA to investigate the therapeutic efficacy of LFU in combination with antibiotics. Minimal inhibitory concentration was assessed, and the distribution of antibiotics in the lung and plasma was determined using liquid chromatography coupled with mass spectrometry. Various parameters, including the survival rate, histopathology, lung bacterial clearance, and the expressions of cytokines and inflammation-related genes, were evaluated before and after treatment. Compared with the infection group, both the antibiotic-alone groups [vancomycin (VCM), linezolid, and contezolid (CZD)] and the groups in combination with LFU demonstrated an improvement in the survival status of mice. The average colony-forming units of lung tissue in the LFU combination groups were lower compared with the antibiotic-alone groups. While no significant changes in C-reactive protein and procalcitonin in plasma and bronchoalveolar lavage fluid were observed, histopathological results revealed reduced inflammatory damage in LFU combination groups. The secretion of interleukin-6 and tumor necrosis factor-alpha was decreased by the combination treatment, particularly in the VCM + LFU group. Furthermore, the expressions of MRSA virulence factors (hla and agrA) and inflammation-related genes (Saa3, Cxcl9, and Orm1) were further reduced by the combinations of LFU and antibiotics. Additionally, LFU treatment facilitated the distribution of VCM and CZD in mouse lung tissue at 30 and 45 min, respectively, after dosage.IMPORTANCETreating pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) with antibiotics alone poses significant challenges. In this in vivo study, we present compelling evidence supporting the efficacy of low-frequency ultrasound (LFU) as a promising approach to overcome these obstacles. Our findings demonstrated that LFU enhanced the effectiveness of vancomycin, linezolid, and contezolid in an MRSA pneumonia model. The combination of LFU with anti-MRSA agents markedly improved the survival rate of mice, accelerated the clearance of pulmonary bacteria, reduced inflammatory injury, inhibited the production of MRSA endotoxin, and enhanced the distribution of antibiotics in lung tissue. The application of LFU in the treatment of pulmonary infections held substantial significance. We believe that readers of your journal will find this topic of considerable interest.
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Affiliation(s)
- Kaicheng Yan
- Department of Pharmacy, Center of Medicine Clinical Research, Medical Supplies Center, Chinese PLA General Hospital, Beijing, China
- Unit 32701 of Chinese PLA, Beijing, China
| | - Jiahui Yao
- Department of Pharmacy, Center of Medicine Clinical Research, Medical Supplies Center, Chinese PLA General Hospital, Beijing, China
| | - Lingling Liu
- Department of Pharmacy, Center of Medicine Clinical Research, Medical Supplies Center, Chinese PLA General Hospital, Beijing, China
| | - Wenxin Liang
- Department of Pharmacy, Center of Medicine Clinical Research, Medical Supplies Center, Chinese PLA General Hospital, Beijing, China
| | - Yun Cai
- Department of Pharmacy, Center of Medicine Clinical Research, Medical Supplies Center, Chinese PLA General Hospital, Beijing, China
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Li XC, Sun L, Li T. Neonatal methicillin-resistant Staphylococcus aureus pneumonia-related recurrent fatal pyopneumothorax: A case report and review of literature. World J Clin Cases 2023; 11:7475-7484. [PMID: 37969452 PMCID: PMC10643081 DOI: 10.12998/wjcc.v11.i30.7475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/25/2023] [Accepted: 10/08/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND Although neonatal Staphylococcus aureus pneumonia is common and usually curable, it can also be refractory and life-threatening. Herein, we report a case of severe neonatal community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) necrotizing pneumonia with bilateral recurrent pyopneumothorax, respiratory failure, heart failure, and cardiac arrest. We hope our report will add to the understanding of this disease. CASE SUMMARY An 18-d-old boy presented with cough for five days, fever for three days, and dyspnea for two days. Preadmission chest radiograph revealed high-density shadows in both lungs. On admission, his oxygen saturation fluctuated around 90% under synchronized intermittent mandatory ventilation. He was unconscious, with dyspnea, weak heart sounds and hepatomegaly. Moist crackles were present throughout his left lung, while the breath sounds in the right lung were decreased. After high-frequency oscillatory ventilation, empiric antimicrobials (meropenem and vancomycin), improved circulation, and right pleural cavity drainage for right pneumothorax (approximately 90% compression), his oxygen saturation level stayed above 95%, and recruitment of the right lung was observed. His condition did not deteriorate until the 5th day of hospitalization (DOH 5). On the morning of DOH 5, his oxygen saturation decreased. Subsequent chest radiograph showed bilateral pneumothorax with nearly 100% compression of the left lung. Desaturation was not relieved after urgent left pleural cavity drainage, and cardiac arrest occurred soon thereafter. Although his spontaneous heartbeat returned through emergency resuscitation and salvage antibacterial therapy (linezolid and levofloxacin) was administered given the detection and antimicrobial susceptibility of MRSA, he showed no improvement, with recurrent pyopneumothorax and continued drainage of purulent fluid and necrotic lung tissue fragments from the pleural cavity. Eventually, his parents refused extracorporeal membrane oxygenation (ECMO) and gave up all the treatments, and the newborn passed away soon after withdrawal on DOH 13. CONCLUSION Neonatal MRSA pneumonia can be refractory and lethal, especially in cases where necrotizing pneumonia leads to extensive lung necrosis and recurrent pneumothorax. Despite treatment with linezolid and other medical measures, it may still be ineffective. Currently, ECMO has been a remedial therapy, but if the lung tissue is too severely eroded to be repaired, it may be useless unless the infection can be controlled and lung transplantation can be performed. Regardless of whether ECMO is initiated, the key to successful treatment is to achieve control over the pneumonia caused by MRSA as soon as possible and to reverse lung injury as much as possible.
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Affiliation(s)
- Xing-Chao Li
- Department of Pediatrics, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
- Institute of Pediatric Research, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
- Institute of Pediatric Research, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Li Sun
- Department of Pediatrics, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Tao Li
- Department of Pediatrics, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
- Institute of Pediatric Research, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
- Institute of Pediatric Research, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
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Chang J, Tasellari A, Wagner JL, Scheetz MH. Contemporary pharmacologic treatments of MRSA for hospitalized adults: rationale for vancomycin versus non-vancomycin therapies as first line agents. Expert Rev Anti Infect Ther 2023; 21:1309-1325. [PMID: 37876291 DOI: 10.1080/14787210.2023.2275663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 10/23/2023] [Indexed: 10/26/2023]
Abstract
INTRODUCTION Methicillin-resistant Staphylococcus aureus (MRSA) remains an important pathogen in the hospital setting and causes significant morbidity and mortality each year. Since the initial discovery over 60 years ago, vancomycin has remained a first-line treatment for many different types of MRSA infections. However, significant concerns related to target attainment and nephrotoxicity have spurred efforts to develop more effective agents in the last two decades. AREAS COVERED Newer anti-MRSA antibiotics that have been approved since 2000 include linezolid, daptomycin, and ceftaroline. As clinical evidence has accumulated, these newer agents have become more frequently used, and some are now recommended as co-first-line options (along with vancomycin) in clinical practice guidelines. For this review, a scoping review of the literature was conducted to support our findings and recommendations. EXPERT OPINION Vancomycin remains an important standard of care for MRSA infections but is limited with respect to nephrotoxicity and rapid target attainment. Newer agents such as linezolid, daptomycin, and ceftaroline have specific indications for treating different types of MRSA infections; however, newer agents also have unique attributes which require consideration during therapy.
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Affiliation(s)
- Jack Chang
- Department of Pharmacy Practice, Midwestern University College of Pharmacy, Downers Grove, IL, USA
- Pharmacometrics Center of Excellence, Midwestern University College of Pharmacy, Downers Grove, IL, USA
- Northwestern Memorial Hospital, Department of Pharmacy, Chicago, IL, USA
| | - Ardita Tasellari
- Department of Pharmacy Practice, Midwestern University College of Pharmacy, Downers Grove, IL, USA
| | - Jamie L Wagner
- School of Pharmacy, University of Mississippi, Jackson, MS, USA
| | - Marc H Scheetz
- Department of Pharmacy Practice, Midwestern University College of Pharmacy, Downers Grove, IL, USA
- Pharmacometrics Center of Excellence, Midwestern University College of Pharmacy, Downers Grove, IL, USA
- Northwestern Memorial Hospital, Department of Pharmacy, Chicago, IL, USA
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Zhao D, Feng W, Kang X, Li H, Liu F, Zheng W, Li G, Wang X. Dual-targeted poly(amino acid) nanoparticles deliver drug combinations on-site: an intracellular synergistic strategy to eliminate intracellular bacteria. J Mater Chem B 2023; 11:2958-2971. [PMID: 36919349 DOI: 10.1039/d3tb00125c] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
Multi-drug combinations are a common strategy for the treatment of intracellular bacterial infections. However, different internalized pathways and the accumulation of the composite drugs at different subcellular organelles very much reduce their efficacy. Herein, an intracellular synergistic strategy is proposed, which is realized by on-site delivery of a drug combination using a macrophage/intracellular bacterium-dual targeted drug delivery system (DDS). The DDS is fabricated by encapsulating vancomycin (Van) and curcumin (Cur) into poly(α-N-acryloyl-phenylalanine)-block-poly(β-N-acryloyl-D-aminoalanine-co-2-O-acetyl-α-D-mannosyloxy) nanoparticles, denoted by (Van + Cur)@F(AM) NPs. Mannose ligands on (Van + Cur)@F(AM) NPs trigger their specific internalization in macrophages, while aminoalanine moieties subsequently drive the NPs to target intracellular methicillin-resistant Staphylococcus aureus (MRSA). Thereafter, Van and Cur are durably released in a synergistic dose at the residence site of intracellular MRSA. Under this intracellular synergistic effect, (Van + Cur)@F(AM) NPs show superior elimination efficiency in vitro and in vivo compared to the control groups, including free Van, (Van + Cur), the DDS encapsulated Van and the DDSs separately-encapsulated Van and Cur. Furthermore, (Van + Cur)@F(AM) NPs significantly enhance the in vivo antibacterial capacity by modulating the immune response. Therefore, this dual-targeted DDS-assisted intracellular synergistic antibacterial strategy of drug combination is an effective therapeutic against intracellular bacteria.
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Affiliation(s)
- Dongdong Zhao
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Wenli Feng
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Xiaoxu Kang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Haofei Li
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Fang Liu
- Department of Oncology of Integrative Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Weitao Zheng
- Hubei Provincial Key Laboratory of Industrial Microbiology, Sino-German Biomedical Center, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, 430068, Hubei Province, China
| | - Guofeng Li
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
| | - Xing Wang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
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Ravon F, Menchi E, Lambot C, Al Kattar S, Chraibi S, Remmelink M, Fontaine V, Wauthoz N. In vitro and in vivo local tolerability of a synergistic anti-tuberculosis drug combination intended for pulmonary delivery. J Appl Toxicol 2023; 43:298-311. [PMID: 35997255 DOI: 10.1002/jat.4381] [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: 06/11/2022] [Revised: 08/12/2022] [Accepted: 08/17/2022] [Indexed: 01/17/2023]
Abstract
A drug combination, vancomycin (VAN) plus tetrahydrolipstatin (THL), has demonstrated an effective synergistic action in vitro against Mycobacterium tuberculosis (Mtb). The poor oral bioavailability of VAN and THL and the predominant tropism of Mtb infection to the lungs make their pulmonary administration very attractive. To evaluate their local tolerability, bronchial cells, alveolar cells and monocytes were exposed to concentrations around and above their minimal inhibitory concentration (MIC). The VAN had no inhibitory activity on the tested human cell lines, even at a concentration 125 times higher than its MIC, whereas the THL, alone or in combination with VAN, presented a cytostatic action. Monolayer epithelium showed no significant irreversible damage at concentrations up to 100 times the combination MIC. BALB/cAnNRj mice exposed to concentration of 50 times the combination MIC delivered endotracheally 3 times a week for 3 weeks showed no clinical signs or significant weight loss. The increase of proinflammatory biomarkers (i.e., IL-1, IL-6, TNF-α and proportion of inflammatory cells) and cytotoxicity in bronchoalveolar lavage fluid (BALF) were non-significant. Lung histopathology did not show significant tissue damage. The VAN/THL combination at doses up to 50 times the combination MIC is found to be thus well tolerated by pulmonary route. This study is a promising result and encouraging further investigations of pulmonary administration of VAN/THL combination as dry powder for anti-tuberculosis treatment.
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Affiliation(s)
- Faustine Ravon
- Unit of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium.,Unit of Microbiology, Bioorganic and Macromolecular Chemistry, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Elena Menchi
- Unit of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Coralie Lambot
- Unit of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Sahar Al Kattar
- Unit of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium.,Unit of Microbiology, Bioorganic and Macromolecular Chemistry, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Selma Chraibi
- Unit of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Myriam Remmelink
- Department of Pathology, Hôpital Erasme, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Véronique Fontaine
- Unit of Microbiology, Bioorganic and Macromolecular Chemistry, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Nathalie Wauthoz
- Unit of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium
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How to Use Nebulized Antibiotics in Severe Respiratory Infections. Antibiotics (Basel) 2023; 12:antibiotics12020267. [PMID: 36830177 PMCID: PMC9952454 DOI: 10.3390/antibiotics12020267] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/31/2023] Open
Abstract
Difficult-to-treat pulmonary infections caused by multidrug-resistant (MDR) pathogens are of great concern because their incidence continues to increase worldwide and they are associated with high morbidity and mortality. Nebulized antibiotics are increasingly being used in this context. The advantages of the administration of a nebulized antibiotic in respiratory tract infections due to MDR include the potential to deliver higher drug concentrations to the site of infection, thus minimizing the systemic adverse effects observed with the use of parenteral or oral antibiotic agents. However, there is an inconsistency between the large amount of experimental evidence supporting the administration of nebulized antibiotics and the paucity of clinical studies confirming the efficacy and safety of these drugs. In this narrative review, we describe the current evidence on the use of nebulized antibiotics for the treatment of severe respiratory infections.
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Sequence Type 5 (ST5) as a Possible Predictor of Bacterial Persistence in Adult Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia Treated with Vancomycin. Microbiol Spectr 2022; 10:e0134822. [PMID: 36094217 PMCID: PMC9603198 DOI: 10.1128/spectrum.01348-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Vancomycin remains the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. This study assessed risk factors for vancomycin failure in 63 patients with MRSA pneumonia through detailed clinical, microbiological, pharmacokinetic/pharmacodynamic, and genetic analyses of prospective multicenter studies conducted from February 2012 to July 2018. Therapeutic drug monitoring was performed during vancomycin treatment, and the 24-h area under the curve (AUC0-24) was calculated. All baseline strains were collected for MIC determination, heterogeneous vancomycin-intermediate S. aureus (hVISA) screening, and biofilm determination. Whole-genome sequencing was performed on the isolates to analyze their molecular typing and virulence and adhesion genes. Clinical signs and symptoms improved in 44 patients (44/63, 69.8%), with vancomycin daily dose (P = 0.045), peak concentration (P = 0.020), and sdrC (P = 0.047) being significant factors. Isolates were eradicated in 51 patients (51/63, 81.0%), with vancomycin daily dose (P = 0.009), cardiovascular disease (P = 0.043), sequence type 5 (ST5; P = 0.017), tst (P = 0.050), and sec gene (P = 0.044) associated with bacteriological failure. Although the AUC0-24/MIC was higher in the groups with bacterial eradication, the difference was not statistically significant (P = 0.108). Multivariate analysis showed that no variables were associated with clinical efficacy; ST5 was a risk factor for bacterial persistence (adjusted odds ratio, 4.449; 95% confidence interval, 1.103 to 17.943; P = 0.036). ST5 strains had higher frequencies of the hVISA phenotype, biofilm expression, and presence of some adhesion and virulence genes such as fnbB, tst, and sec than non-ST5 strains. Our study suggests that ST5 is a possible predictor of bacterial persistence in MRSA pneumonia treated with vancomycin. IMPORTANCE Few studies have simultaneously examined the influence of clinical characteristics of patients with pneumonia, the vancomycin pharmacokinetic/pharmacodynamic (PK/PD) index, and the phenotypic and genetic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains. We assessed risk factors for vancomycin failure in patients with MRSA pneumonia by analyzing these influences in a prospective multicenter study. Sequence type 5 (ST5) was a possible predictor of bacterial persistence in adult patients with MRSA pneumonia (adjusted odds ratio, 4.449). We found that this may be related to ST5 strains having higher levels of vancomycin heterogeneous resistance, biofilms, and the presence of adhesion and virulence genes such as fnbB, tst, and sec.
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Ma A, Dong M, Cheng J, Liao X, Dong W, Liu C, Hu C, Yang J, Kang Y. Clinical efficacy and safety of linezolid in intensive care unit patients. JOURNAL OF INTENSIVE MEDICINE 2022; 3:65-72. [PMID: 36789359 PMCID: PMC9923966 DOI: 10.1016/j.jointm.2022.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/24/2022] [Accepted: 05/14/2022] [Indexed: 10/17/2022]
Abstract
Background To characterize the population of critically ill patients and infections treated with linezolid in the intensive care unit (ICU), and to evaluate the clinical efficacy and safety of linezolid therapy. Methods This multi-center, observational, real-world study was conducted across 52 hospitals between June 9, 2018, and December 28, 2019. Patients who met the following inclusion criteria were included: (1) admitted to the ICU, (2) of any age group, and (3) having a clinical or laboratory diagnosis of a Gram-positive bacterial infection. Clinical efficacy was categorized as success (cured or improved), failed, or non-evaluable. Adverse events and serious adverse events were recorded during treatment. Results A total of 366 ICU patients who met the inclusion criteria were evaluated. Linezolid was used as second- and first-line treatment in 232 (63.4%) and 134 (36.6%) patients, respectively. The most common isolated strain was Staphylococcus aureus (methicillin-resistant Staphylococcus aureus: n=37/119, 31.1%; methicillin-susceptible Staphylococcus aureus: n=15/119, 12.6%); this was followed by Enterococci (vancomycin-resistant Enterococci: n=8/119, 6.7%; vancomycin-susceptible Enterococci: n=11/119, 9.2%) and Streptococcus pneumoniae (multidrug-resistant: n=4/119, 3.4%; non-multidrug resistant: n=2/119, 1.7%). The main infection sites where pathogens were detected included the lung (n=216/366, 59.6%), skin and soft tissue (n=104/366, 28.4%), and blood (n=50/366, 13.7%). Clinical success was achieved in 301 (82.2%) patients; 34 (9.3%) were cured and 267 (73.0%) improved; treatment failure and non-evaluable outcomes were observed in 29 (7.9%) in 36 (9.8%) patients, respectively. Linezolid-related adverse events were reported in 8 (2.2%) patients. No treatment-related serious adverse events were reported. Conclusions Based on real-world results, linezolid was found to be effective and safe in the treatment of Gram-positive bacterial infections in critically ill patients.
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Affiliation(s)
| | | | | | | | | | | | | | - Jing Yang
- Corresponding authors: Jing Yang and Yan Kang, Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
| | - Yan Kang
- Corresponding authors: Jing Yang and Yan Kang, Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
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12
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Bian X, Qu X, Zhang J, Nang SC, Bergen PJ, Tony Zhou Q, Chan HK, Feng M, Li J. Pharmacokinetics and pharmacodynamics of peptide antibiotics. Adv Drug Deliv Rev 2022; 183:114171. [PMID: 35189264 PMCID: PMC10019944 DOI: 10.1016/j.addr.2022.114171] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 01/23/2022] [Accepted: 02/16/2022] [Indexed: 01/05/2023]
Abstract
Antimicrobial resistance is a major global health challenge. As few new efficacious antibiotics will become available in the near future, peptide antibiotics continue to be major therapeutic options for treating infections caused by multidrug-resistant pathogens. Rational use of antibiotics requires optimisation of the pharmacokinetics and pharmacodynamics for the treatment of different types of infections. Toxicodynamics must also be considered to improve the safety of antibiotic use and, where appropriate, to guide therapeutic drug monitoring. This review focuses on the pharmacokinetics/pharmacodynamics/toxicodynamics of peptide antibiotics against multidrug-resistant Gram-negative and Gram-positive pathogens. Optimising antibiotic exposure at the infection site is essential for improving their efficacy and minimising emergence of resistance.
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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; School of Pharmacy, Fudan University, Shanghai, China
| | - Xingyi Qu
- 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; School of Pharmacy, Fudan University, Shanghai, China; Phase I Unit, Huashan Hospital, Fudan University, Shanghai 200040, 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 200040, China
| | - Sue C Nang
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia
| | - Phillip J Bergen
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia
| | - Qi Tony Zhou
- Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN, USA
| | - Hak-Kim Chan
- Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Meiqing Feng
- School of Pharmacy, Fudan University, Shanghai, China
| | - Jian Li
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia.
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13
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Pickens CI, Wunderink RG. Methicillin-Resistant Staphylococcus aureus Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia. Semin Respir Crit Care Med 2022; 43:304-309. [PMID: 35170002 PMCID: PMC10623688 DOI: 10.1055/s-0041-1740583] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). MRSA pneumonia is associated with significant morbidity and mortality. Several virulence factors allow S. aureus to become an effective pathogen. The polysaccharide intracellular adhesin allows for the production of biofilms, some strains can produce capsular polysaccharides that protect against phagocytosis, microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) allow for colonization of epithelial surfaces, and S. aureus secretes several exotoxins that aid in tissue destruction. The α-hemolysin exotoxin secreted by S. aureus is one of the most important virulence factors for the bacteria. The diagnosis of MRSA pneumonia can be challenging; the infection may present as a mild respiratory infection or severe respiratory failure and septic shock. Many individuals are colonized with MRSA and thus a positive nasopharyngeal swab does not confirm infection in the lower respiratory tract. The management of MRSA pneumonia has evolved. Historically, vancomycin has been the primary antibiotic used to treat MRSA pneumonia. Over the past decade, prospective studies have shown that linezolid leads to higher rates of clinical cure. Monoclonal antibodies are being studied as potential therapeutic options. MRSA is an important cause of HAP/VAP; novel diagnostics may facilitate rapid diagnosis of this infection and the available literature should be used to make informed decisions on management.
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Affiliation(s)
- Chiagozie I. Pickens
- Division of Critical Care, Department of Medicine, Pulmonary, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Richard G. Wunderink
- Division of Critical Care, Department of Medicine, Pulmonary, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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14
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Mukai M, Uchida K, Sugo K, Nakasu M, Nakajima T, Takata K, Takaso M, Urabe K. Long-term antibacterial activity of vancomycin from calcium phosphate cement in vivo. Biomed Mater Eng 2021; 33:41-50. [PMID: 34250926 DOI: 10.3233/bme-211243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Periprosthetic joint infection is a major complication of total joint arthroplasty, with treatment requiring a two-stage exchange procedure and 6 weeks of systemic antibiotics. However, depending on the infection site, intravenous delivery of antibiotics like vancomycin (VCM) can have poor tissue transferability, thus reducing their therapeutic effect. OBJECTIVE This study demonstrates the 24-week in vivo release profile and antibacterial activity of VCM from calcium phosphate cement impregnated with VCM (CPC/VCM) and compares them with those from polymethylmethacrylate impregnated with VCM (PMMA/VCM). METHODS Rats were implanted with the test specimens between the fascia and quadriceps. After implantation for 24 weeks, the test specimens were removed and residual VCM was extracted to calculate the concentration of VCM released into rat tissues. We also examined the antibacterial activity of releasable VCM from the removed test specimens by placing them directly onto the surface of agar. RESULTS CPC/VCM released greater concentrations of VCM for a longer period of time within the 24 weeks than PMMA/VCM. Moreover, CPC/VCM released 1.4 to 26.1-fold more VCM than PMMA/VCM. Using Staphylococcus aureus, antibacterial activity was logarithmically correlated with VCM concentration across the entire concentration range tested (12.5-800 μg/mL). While the area within which inhibition was observed-the inhibition zone-for both CPC/VCM and PMMA/VCM formed and gradually shrank with time after implantation, that for CPC/VCM was significantly larger than that for PMMA/VCM in each week after implantation. CONCLUSION CPC/VCM releases greater amounts of VCM with antibacterial activity for longer periods of time than PMMA/VCM, suggesting that CPC is effective for facilitating the release of antibiotics for local action in patients with established postoperative infection.
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Affiliation(s)
- Manabu Mukai
- Department of Orthopaedic Surgery, Kitasato University School of Medicine, Minami, Sagamihara, Kanagawa, Japan
| | - Kentaro Uchida
- Department of Orthopaedic Surgery, Kitasato University School of Medicine, Minami, Sagamihara, Kanagawa, Japan.,Shonan University of Medical Sciences Research Institute, Chigasaki, Kanagawa, Japan
| | - Ken Sugo
- Research and Development Department, HOYA Technosurgical Corporation, Akishima, Tokyo, Japan
| | - Masanori Nakasu
- Research and Development Department, HOYA Technosurgical Corporation, Akishima, Tokyo, Japan
| | - Takehiko Nakajima
- Research and Development Department, HOYA Technosurgical Corporation, Akishima, Tokyo, Japan
| | - Ken Takata
- Department of Orthopaedic Surgery, Kitasato University School of Medicine, Minami, Sagamihara, Kanagawa, Japan
| | - Masashi Takaso
- Department of Orthopaedic Surgery, Kitasato University School of Medicine, Minami, Sagamihara, Kanagawa, Japan
| | - Ken Urabe
- Department of Orthopaedic Surgery, Kitasato University Medical Center, Saitama, Japan
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15
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Song X, Zeng M, Wu Y, Pan Y. Competence Mining of Vancomycin (VAN) in the Management of Infections Due to Bacterial Strains With High VAN Minimum Inhibitory Concentrations (MICs): A Novel Dosing Strategy Based on Pharmacokinetic/Pharmacodynamic Modeling. Front Microbiol 2021; 12:649757. [PMID: 33967986 PMCID: PMC8100448 DOI: 10.3389/fmicb.2021.649757] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/30/2021] [Indexed: 11/13/2022] Open
Abstract
The increasing emergence of bacterial strains with high VAN MICs (BSH–VAN–M), such as Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus bovis, results in growing concern that VAN is not effective against these isolates. Due to the limited data on VAN against BSH–VAN–M and the application limits of drugs currently considered to be effective for BSH–VAN–M, exploration of “new usages for old drugs” is reasonable to improve and maximize the efficacy of existing antibiotics. This study aimed to construct a novel dosing strategy to mine the competence of VAN in the management of BSH–VAN–M infections. Herein, we optimized the traditional intermittent i.v. infusion (TIII) method to create an optimal two-step infusion (OTSI). With pharmacokinetic (PK)/pharmacodynamic (PD) modeling at the targeted ratio of the daily area under the concentration-time curve (AUC0–24) to the minimum inhibitory concentration (MIC) (AUC0–24/MIC) of 400, we used Monte Carlo simulations to evaluate the efficacy of 25 VAN regimens (including 15 OTSI regimens and 10 TIII regimens with daily doses of up to 6 g) to treat pneumonia, meningitis, sternal osteomyelitis, mastitis, pleuritis, bacteremia, and bacterial pericarditis resulting from isolates with MICs of ≤64 mg/L and to the current E. faecalis, E. faecium, S. aureus, S. epidermidis, and S. bovis populations with a pooled MIC distribution. Our data indicated that 4 g/day VAN, with an OTSI but not a TIII, for mastitis, pleuritis, bacteremia, and bacterial pericarditis due to isolates with MICs of ≤4 mg/L or to the current E. faecalis, S. aureus, S. epidermidis, and S. bovis populations achieved the desired PK/PD exposure at the AUC0–24/MIC target of 400. This study suggests the superiority and feasibility of OTSI relative to TIII for the competence mining of VAN against BSH–VAN–M from the perspective of PK/PD and provides a new resource for understanding how PK/PD modeling shapes the performance of VAN to meet the growing challenges of BSH–VAN–M infections.
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Affiliation(s)
- Xiangqing Song
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Meizi Zeng
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yi Wu
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yong Pan
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
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16
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Evaluation of a New Culture-Based AtbFinder Test-System Employing a Novel Nutrient Medium for the Selection of Optimal Antibiotics for Critically Ill Patients with Polymicrobial Infections within 4 h. Microorganisms 2021; 9:microorganisms9050990. [PMID: 34064335 PMCID: PMC8147811 DOI: 10.3390/microorganisms9050990] [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: 04/13/2021] [Revised: 04/28/2021] [Accepted: 05/02/2021] [Indexed: 11/28/2022] Open
Abstract
Here, we describe the validation of a new phenotypic culture-based AtbFinder method for rapid selection of antibiotics in vitro using specimens with mono- and polybacterial infections. AtbFinder, which can be applied to any type of non-blood tissue, does not require isolation of pure bacterial cultures. The method uses a novel TGV medium that allows more rapid bacterial growth of Gram-positive and Gram-negative monoisolates compared with that achieved with conventional laboratory media, demonstrating overall sensitivity, specificity, PPV, NPV values of 99.6%, 98.1%, 98.5%, and 99.4%, respectively, after 4 h. For polymicrobial infections, AtbFinder utilized a novel paradigm of the population response to antibiotics, enabling bacterial growth in the form of a mixed microbial community and selecting antibiotics targeting not only the principal pathogen, but also those bacteria that support their growth. TGV medium allowed culturing of a more diverse set of bacteria from polymicrobial biospecimens, compared with that achieved with the standard media, and enabled, within 4 h, accurate selection of the antibiotics that completely eliminated all cultivatable bacteria from clinical samples. In conclusion, the AtbFinder system may be a valuable tool in improving antibiotic selection, and enabling targeted empirical therapy and accurate antibiotic replacement, which is especially important in high-risk patients.
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17
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Flannery AH, Wallace KL, Rhudy CN, Olmsted AS, Minrath RC, Pope SM, Cook AM, Burgess DS, Morris PE. Efficacy and safety of vancomycin loading doses in critically ill patients with methicillin-resistant Staphylococcus aureus infection. Ther Adv Infect Dis 2021; 8:20499361211005965. [PMID: 33854772 PMCID: PMC8013631 DOI: 10.1177/20499361211005965] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/08/2021] [Indexed: 12/11/2022] Open
Abstract
Background While vancomycin loading doses may facilitate earlier pharmacokinetic-pharmacodynamic target attainment, the impact of loading doses on clinical outcomes remains understudied. Critically ill patients are at highest risk of morbidity and mortality from methicillin resistant Staphylococcus aureus (MRSA) infection and hypothesized to most likely benefit from a loading dose. We sought to determine the association between receipt of a vancomycin loading dose and clinical outcomes in a cohort of critically ill adults. Methods Four hundred and forty-nine critically ill patients with MRSA cultures isolated from blood or respiratory specimens were eligible for the study. Cohorts were established by receipt of a loading dose (⩾20 mg/kg actual body weight) or not. The primary outcome was clinical failure, a composite outcome of death within 30 days of first MRSA culture, blood cultures positive ⩾7 days, white blood cell count up to 5 days from vancomycin initiation, temperature up to 5 days from vancomycin initiation, or substitution (or addition) of another MRSA agent. Results There was no difference in the percentage of patients experiencing clinical failure between the loading dose and no loading dose groups (74.8% versus 72.8%; p = 0.698). Secondary outcomes were also similar between groups, including mortality and acute kidney injury, as was subgroup analysis based on site of infection. Exploratory analyses, including assessment of loading dose based on quartiles and a multivariable logistic regression model showed no differences. Conclusion Use of vancomycin loading doses was not associated with improved clinical outcomes in critically ill patients with MRSA infection.
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Affiliation(s)
- Alexander H Flannery
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, 789 S. Limestone Street, TODD 251, Lexington, KY 40536, USA Department of Pharmacy Services, University of Kentucky HealthCare, Lexington, KY, USA
| | - Katie L Wallace
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA Department of Pharmacy Services, University of Kentucky HealthCare, Lexington, KY, USA
| | - Christian N Rhudy
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - Allison S Olmsted
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - Rachel C Minrath
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - Stuart M Pope
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - Aaron M Cook
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA Department of Pharmacy Services, University of Kentucky HealthCare, Lexington, KY, USA
| | - David S Burgess
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - Peter E Morris
- Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
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18
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Kato H, Hagihara M, Asai N, Shibata Y, Koizumi Y, Yamagishi Y, Mikamo H. Meta-analysis of vancomycin versus linezolid in pneumonia with proven methicillin-resistant Staphylococcus aureus. J Glob Antimicrob Resist 2021; 24:98-105. [PMID: 33401013 DOI: 10.1016/j.jgar.2020.12.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 11/26/2020] [Accepted: 12/09/2020] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines suggest that linezolid (LZD) is preferred over vancomycin (VCM) for treating methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. We conducted a systematic review and comparative meta-analysis to compare VCM and LZD efficacy against proven MRSA pneumonia. METHODS We searched EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed up to November 2019. The outcomes of the meta-analysis were mortality, clinical cure, microbiological evaluation, and adverse events. RESULTS Seven randomized controlled trials (RCTs) with a total of 1239 patients and eight retrospective cohort or case-control studies (CSs) with a total 6125 patients were identified. Clinical cure and microbiological eradication rates were significantly increased in patients treated with LZD in RCTs (clinical cure: risk ratio (RR) = 0.81, 95% confidential interval (CI) = 0.71-0.92; microbiological eradication: RR = 0.71, 95% CI = 0.62-0.81) and CSs (clinical cure: odds ratio (OR) = 0.35, 95% CI = 0.18-0.69). However, mortality was comparable between patients treated with VCM and LZD in RCTs (RR = 1.08, 95% CI = 0.88-1.32) and CSs (OR = 1.20, 95% CI = 0.94-1.53). Likewise, there was no significant difference in adverse events between VCM and LZD in CSs (thrombocytopenia: OR = 0.95, 95% CI = 0.50-1.82; nephrotoxicity: OR = 1.72, 95% CI = 0.85-3.45). CONCLUSIONS According to our meta-analysis of RCTs and CSs conducted worldwide, we found robust evidence to corroborate the IDSA guidelines for the treatment of proven MRSA pneumonia.
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Affiliation(s)
- Hideo Kato
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan.
| | - Mao Hagihara
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan; Department of Molecular Epidemiology and Biomedical Sciences, Aichi Medical University Hospital, Aichi, Japan.
| | - Nobuhiro Asai
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan.
| | - Yuichi Shibata
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan.
| | - Yusuke Koizumi
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan.
| | - Yuka Yamagishi
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan.
| | - Hiroshige Mikamo
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan.
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19
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Russo A. Spotlight on New Antibiotics for the Treatment of Pneumonia. CLINICAL MEDICINE INSIGHTS-CIRCULATORY RESPIRATORY AND PULMONARY MEDICINE 2020; 14:1179548420982786. [PMID: 33424231 PMCID: PMC7755939 DOI: 10.1177/1179548420982786] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/28/2020] [Indexed: 11/15/2022]
Abstract
In the last years, the presence of multidrug-resistant (MDR) Gram-negative (like Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) and Gram-positive bacteria (mostly methicillin-resistant Staphylococcus aureus) was worldwide reported, limiting the options for an effective antibiotic therapy. For these reasons, inappropriate antimicrobial therapy and delayed prescription can lead to an unfavorable outcome, especially in patients with pneumonia. New antibiotics approved belong to classes of antimicrobials, like beta-lactams with or without beta-lactamase inhibitors, aminoglycosides, oxazolidinones, quinolones, and tetracyclines, or based on new mechanisms of action. These new compounds show many advantages, including a broad spectrum of activity against MDR pathogens, good lung penetration, safety and tolerability, and finally the possibility of intravenous and/or oral formulations. However, the new antibiotics under development represent an important possible armamentarium against difficult-to-treat strains. The safety and clinical efficacy of these future drugs should be tested in clinical practice. In this review, there are reported characteristics of newly approved antibiotics that represent potential future options for the treatment of respiratory tract infections, including those caused by multidrug-resistant bacteria. Finally, the characteristics of the drugs under development are briefly reported.
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Affiliation(s)
- Alessandro Russo
- Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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20
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Evans SJ, Roberts AEL, Morris AC, Simpson AJ, Harris LG, Mack D, Jenkins RE, Wilkinson TS. Contrasting effects of linezolid on healthy and dysfunctional human neutrophils: reducing C5a-induced injury. Sci Rep 2020; 10:16377. [PMID: 33009444 PMCID: PMC7532177 DOI: 10.1038/s41598-020-72454-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/26/2020] [Indexed: 12/15/2022] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of ventilator-associated pneumonia (VAP). Patients with VAP have poorly functioning neutrophils, related to increased levels of the complement fragment C5a. The antibiotic linezolid has been useful in controlling MRSA-related VAP infections; however clinical benefit does not always correlate with antimicrobial effect, suggesting the possibility of immunomodulatory properties. Here the effects of linezolid on healthy and dysfunctional neutrophils (modelled by C5a-induced injury) was investigated. Functional assays (killing, phagocytosis, transmigration, and respiratory burst) were used to assess the effects of pre-, co- and post-incubating linezolid (0.4-40 mg/L) with healthy neutrophils relative to those with C5a-induced injury. C5a decreased neutrophil killing, and phagocytosis of MRSA. Furthermore, C5a significantly decreased neutrophil transmigration to IL-8, but did not affect respiratory burst. Co-incubation of linezolid significantly improved killing of MRSA by dysfunctional neutrophils, which was supported by concomitant increases in phagocytosis. Conversely linezolid impaired killing responses in healthy neutrophils. Pre- or post-incubation of linezolid prior or following C5a induced injury had no effect on neutrophil function. This study suggests that linezolid has immunomodulatory properties that protect human neutrophils from injury and provides insight into its mode of action beyond a basic antibiotic.
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Affiliation(s)
- Stephen J Evans
- Microbiology and Infectious Disease, Institute of Life Science, Swansea University Medical School, Floor 1, Room 137, Singleton Park, Swansea, SA2 8PP, UK
| | - Aled E L Roberts
- Microbiology and Infectious Disease, Institute of Life Science, Swansea University Medical School, Floor 1, Room 137, Singleton Park, Swansea, SA2 8PP, UK
| | - Andrew Conway Morris
- Division of Anaesthesia, Department of Medicine, School of Clinical Medicine, University of Cambridge, Level 4, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Box 93, Cambridge, CB2, 0QQ, UK
| | - A John Simpson
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Llinos G Harris
- Microbiology and Infectious Disease, Institute of Life Science, Swansea University Medical School, Floor 1, Room 137, Singleton Park, Swansea, SA2 8PP, UK
| | - Dietrich Mack
- Microbiology and Infectious Disease, Institute of Life Science, Swansea University Medical School, Floor 1, Room 137, Singleton Park, Swansea, SA2 8PP, UK.,Bioscientia Labor Ingelheim, Institut für Medizinische Diagnostik GmbH, Konrad-Adenauer-Str. 17, 55218, Ingelheim, Germany
| | - Rowena E Jenkins
- Microbiology and Infectious Disease, Institute of Life Science, Swansea University Medical School, Floor 1, Room 137, Singleton Park, Swansea, SA2 8PP, UK
| | - Thomas S Wilkinson
- Microbiology and Infectious Disease, Institute of Life Science, Swansea University Medical School, Floor 1, Room 137, Singleton Park, Swansea, SA2 8PP, UK.
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21
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Nebulization of Vancomycin Provides Higher Lung Tissue Concentrations than Intravenous Administration in Ventilated Female Piglets with Healthy Lungs. Anesthesiology 2020; 132:1516-1527. [PMID: 32053565 DOI: 10.1097/aln.0000000000003171] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Intravenous vancomycin is used to treat ventilator-associated pneumonia caused by methicillin-resistant Staphylococcus aureus, but achieves high rates of failure. Vancomycin nebulization may be efficient to provide high vancomycin lung tissue concentrations. The aim of this study was to compare lung tissue and serum concentrations of vancomycin administered intravenously and by aerosol in mechanically ventilated and anesthetized healthy piglets. METHODS Twelve female piglets received a single intravenous dose of vancomycin (15 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of administration. Twelve piglets received a single nebulized dose of vancomycin (37.5 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of the aerosol administration. In each group, vancomycin lung tissue concentrations were assessed on postmortem lung specimens using high-performance liquid chromatography. Blood samples were collected for serum vancomycin concentration measurement 30 min and 1, 2, 4, 6, 8, and 12 h after the end of vancomycin administration. Pharmacokinetics was analyzed by nonlinear mixed effect modeling. RESULTS One hour after vancomycin administration, lung tissue concentrations in the aerosol group were 13 times the concentrations in the intravenous group (median and interquartile range: 161 [71, 301] μg/g versus 12 [4, 42] μg/g; P < 0.0001). Twelve hours after vancomycin administration, lung tissue concentrations in the aerosol group were 63 (23, 119) μg/g and 0 (0, 19) μg/g in the intravenous group (P < 0.0001). A two-compartment weight-scaled allometric model with first-order absorption and elimination best fit serum pharmacokinetics after both routes of administration. Area under the time-concentration curve from 0 to 12 h was lower in the aerosol group in comparison to the intravenous group (56 [8, 70] mg · h · l vs. 121 [103, 149] mg · h · l, P = 0.002). Using a population model, vancomycin bioavailability was 13% (95% CI, 6 to 69; coefficient of variation = 85%) and absorption rate was slow (absorption half life = 0.3 h). CONCLUSIONS Administration of vancomycin by nebulization resulted in higher lung tissue concentrations than the intravenous route.
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Ma H, Cheng J, Peng L, Gao Y, Zhang G, Luo Z. Adjunctive rifampin for the treatment of Staphylococcus aureus bacteremia with deep infections: A meta-analysis. PLoS One 2020; 15:e0230383. [PMID: 32191760 PMCID: PMC7082046 DOI: 10.1371/journal.pone.0230383] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 02/28/2020] [Indexed: 12/13/2022] Open
Abstract
Background Staphylococcus aureus (S. aureus) bacteremia (SAB) has high morbidity and mortality, with the development of methicillin-resistant S. aureus (MRSA) and the recognized shortcomings of vancomycin, its management is becoming more complicated. Considering the capability to penetrate cells, tissues and biofilms, rifampin has been used as adjunctive agent to against staphylococcal activity. Objectives We performed this meta-analysis, aimed to explore the efficacy of adjunctive rifampin for the treatment of SAB. Methods Medical literatures were searched in the Pubmed, Medline, Embase and Cochrane databases up to October 2018. Patients with SAB received treatment with or without rifampin were included. The risk ratio (RR) and 95% confidence intervals (CI) of mortality, rate of bacteriological failure and relapse were estimated. Results Seven articles (five randomized controlled trials and two retrospective cohort studies) enrolling 979 and 636 patients of SAB treated with and without rifampin, respectively, were included. There was no difference of mortality between the adjunctive rifampin therapy and standard therapy on SAB (RR: 0.771, 95% CI: 0.442 to 1.347, I2 = 70.4%). In the subgroup analyses, the decreased mortality was observed in the adjunctive rifampin treatment for patients without MRSA infection (RR: 0.509, 95% CI: 0.372 to 0.697, I2 = 8.8%). In addition, there was no difference of the rate of bacteriologic failure (RR: 0.602, 95% CI: 0.198 to 1.825, I2 = 0.0%) or relapse (RR: 0.574, 95% CI: 0.106 to 3.112, I2 = 77.9%) between the adjunctive rifampin therapy and standard therapy on SAB. Conclusions In general, insufficient evidence supported the efficacy of adjunctive use of rifampin for treatment of SAB, adding rifampin to standard therapy didn’t decrease the incidence of death, rate of bacteriologic failure and relapse.
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Affiliation(s)
- Huan Ma
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Cheng
- Chongqing Key Laboratory of Pediatrics, Chongqing, China
- Department of Children's Hospital of Chongqing Medical University of Education, Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Lengyue Peng
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yawen Gao
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Guangli Zhang
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Zhengxiu Luo
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Chongqing, China
- Department of Children's Hospital of Chongqing Medical University of Education, Key Laboratory of Child Development and Disorders, Chongqing, China
- * E-mail:
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Cho JY, Kim HS, Yang HJ, Lee YJ, Park JS, Yoon HI, Kim HB, Yim JJ, Lee JH, Lee CT, Cho YJ. Pilot Study of Aerosolised Plus Intravenous Vancomycin in Mechanically Ventilated Patients with Methicillin-Resistant Staphylococcus Aureus Pneumonia. J Clin Med 2020; 9:jcm9020476. [PMID: 32050447 PMCID: PMC7073531 DOI: 10.3390/jcm9020476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 01/31/2020] [Accepted: 02/06/2020] [Indexed: 11/25/2022] Open
Abstract
Treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in critically ill patients remains unsatisfactory. This pilot study aimed to evaluate the clinical outcomes of aerosolised vancomycin in addition to intravenous administration in this setting. This was a prospective, noncomparative, phase II trial. Patients receiving mechanical ventilation for >48 h in intensive care units (ICUs) were screened; those receiving intravenous vancomycin for MRSA pneumonia were enrolled. Patients received aerosolised vancomycin (250 mg every 12 h for five days) via a vibrating mesh nebuliser. The primary outcome was treatment success (clinical cure or improvement) at the conclusion of antibiotic treatment. Vancomycin concentrations were measured in bronchoalveolar lavage fluid according to administration time. Twenty patients were enrolled (median age 75 years and 13 (65%) men; 18 (90%) cases with nosocomial pneumonia). Thirteen patients (65%) showed clinical cure or improvement. Microbiological eradication of MRSA was confirmed in 14 patients (70%). ICU and hospital mortality rates were 30% and 35%, respectively. Maximum aerosolised vancomycin concentration was observed 4–5 h after nebulising (98.75 ± 21.79 mcg/mL). No additional systemic adverse effects occurred following aerosol vancomycin treatment. Aerosolised vancomycin combination therapy may be an alternative treatment for patients with severe MRSA pneumonia receiving mechanical ventilation (ClinicalTrials.gov number, NCT01925066).
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Affiliation(s)
- Jun Yeun Cho
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungbuk National University Hospital, Cheongju-si 28644, Korea;
| | - Hyung-Sook Kim
- Department of Pharmacy, Seoul National University Bundang Hospital, Seongnam-si 13620, Korea;
| | - Hye-Joo Yang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si 13620, Korea; (H.-J.Y.); (Y.J.L.); (J.S.P.); (H.I.Y.); (J.-H.L.); (C.-T.L.)
| | - Yeon Joo Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si 13620, Korea; (H.-J.Y.); (Y.J.L.); (J.S.P.); (H.I.Y.); (J.-H.L.); (C.-T.L.)
| | - Jong Sun Park
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si 13620, Korea; (H.-J.Y.); (Y.J.L.); (J.S.P.); (H.I.Y.); (J.-H.L.); (C.-T.L.)
| | - Ho Il Yoon
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si 13620, Korea; (H.-J.Y.); (Y.J.L.); (J.S.P.); (H.I.Y.); (J.-H.L.); (C.-T.L.)
| | - Hong Bin Kim
- Division of Infectious Diseases, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si 13620, Korea;
| | - Jae-Joon Yim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea;
| | - Jae-Ho Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si 13620, Korea; (H.-J.Y.); (Y.J.L.); (J.S.P.); (H.I.Y.); (J.-H.L.); (C.-T.L.)
| | - Choon-Taek Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si 13620, Korea; (H.-J.Y.); (Y.J.L.); (J.S.P.); (H.I.Y.); (J.-H.L.); (C.-T.L.)
| | - Young-Jae Cho
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si 13620, Korea; (H.-J.Y.); (Y.J.L.); (J.S.P.); (H.I.Y.); (J.-H.L.); (C.-T.L.)
- Correspondence: ; Tel.: +82-31-787-7058
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Miyazaki T, Yanagihara K, Kakeya H, Izumikawa K, Mukae H, Shindo Y, Yamamoto Y, Tateda K, Tomono K, Ishida T, Hasegawa Y, Niki Y, Watanabe A, Soma K, Kohno S. Daily practice and prognostic factors for pneumonia caused by methicillin-resistant Staphylococcus aureus in Japan: A multicenter prospective observational cohort study. J Infect Chemother 2019; 26:242-251. [PMID: 31575499 DOI: 10.1016/j.jiac.2019.08.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 08/07/2019] [Accepted: 08/29/2019] [Indexed: 11/29/2022]
Abstract
Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) is associated with poor clinical outcomes. We surveyed clinical outcomes of MRSA pneumonia in daily practice to identify risk factors for the clinical failure and mortality in patients with MRSA pneumonia. This multicenter prospective observational study was performed across 48 Japanese medical institutions. Adult patients with culture-positive MRSA pneumonia were recruited and treated with anti-MRSA antibiotics. The relationships between clinical and microbiological characteristics and clinical outcomes at test of cure (TOC) or 30-day all-cause mortality were analyzed. In total, 199 eligible patients, including nursing and healthcare-associated pneumonia (n = 95), hospital-acquired pneumonia (n = 76), and community-acquired pneumonia (n = 25), received initial treatment with anti-MRSA agents such as vancomycin (n = 135), linezolid (n = 36), or teicoplanin (n = 22). Overall clinical failure rate at TOC and the 30-day mortality rate were 51.1% (48/94 patients) and 33.7% (66/196 patients), respectively. Multivariable logistic regression analyses for vancomycin-treated populations revealed that abnormal white blood cell count (odds ratio [OR] 4.34, 95% confidence interval [CI] 1.31-14.39) was a risk factor for clinical failure and that no therapeutic drug monitoring (OR 3.10, 95% CI 1.35-7.12) and abnormally high C-reactive protein level (OR 3.54, 95% CI 1.26-9.92) were risk factors for mortality. In conclusion, this study provides evidence that majority of MRSA pneumonia patients are initially treated with vancomycin in Japan, and the absence of therapeutic drug monitoring for vancomycin is significantly associated with the mortality in patients with MRSA pneumonia.
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Affiliation(s)
- Taiga Miyazaki
- Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan; Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Katsunori Yanagihara
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hiroshi Kakeya
- Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Koichi Izumikawa
- Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hiroshi Mukae
- Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan
| | - Yuichiro Shindo
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Yoshihiro Yamamoto
- Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan
| | - Kazuhiro Tateda
- Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan
| | - Kazunori Tomono
- Division of Infection Control and Prevention, Osaka University Hospital, Osaka, Japan
| | - Tadashi Ishida
- Department of Respiratory Medicine, Kurashiki Central Hospital, Okayama, Japan
| | - Yoshinori Hasegawa
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Yoshihito Niki
- Division of Clinical Infectious Diseases, Department of Medicine, School of Medicine, Showa University, Tokyo, Japan
| | - Akira Watanabe
- Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan
| | - Kazui Soma
- Emergency Medical Center, Kitasato University Hospital, Kanagawa, Japan
| | - Shigeru Kohno
- Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan
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Esposito S, Pennoni G, Mencarini V, Palladino N, Peccini L, Principi N. Antimicrobial Treatment of Staphylococcus aureus in Patients With Cystic Fibrosis. Front Pharmacol 2019; 10:849. [PMID: 31447669 PMCID: PMC6692479 DOI: 10.3389/fphar.2019.00849] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/03/2019] [Indexed: 11/13/2022] Open
Abstract
Staphylococcus aureus is a ubiquitous human commensal pathogen. It is commonly isolated in cystic fibrosis (CF) patients and is considered one of the main causes of the recurrent acute pulmonary infections and progressive decline in lung function that characterize this inherited life-threatening multisystem disorder. However, the true role of S. aureus in CF patients is not completely understood. The main aim of this narrative review is to discuss the present knowledge of the role of S. aureus in CF patients. Literature review showed that despite the fact that the availability and use of drugs effective against S. aureus have coincided with a significant improvement in the prognosis of lung disease in CF patients, clearly evidencing the importance of S. aureus therapy, how to use old and new drugs to obtain the maximal effectiveness has not been precisely defined. The most important problem remains that the high frequency with which S. aureus is carried in healthy subjects prevents the differentiation of simple colonization from infection. Moreover, although experts recommend antibiotic administration in CF patients with symptoms and in those with persistent detection of S. aureus, the best antibiotic approach has not been defined. All these problems are complicated by the evidence that the most effective antibiotic against methicillin-resistant S. aureus (MRSA) cannot be used in patients with CF with the same schedules used in patients without CF. Further studies are needed to solve these problems and to assure CF patients the highest level of care.
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Affiliation(s)
- Susanna Esposito
- Pediatric Clinic, Cystic Fibrosis Center of Umbria Region, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Perugia, Italy
| | - Guido Pennoni
- Pediatric Unit, Cystic Fibrosis Center of Umbria Region, Branca Hospital, Branca, Italy
| | - Valeria Mencarini
- Pediatric Unit, Cystic Fibrosis Center of Umbria Region, Branca Hospital, Branca, Italy
| | - Nicola Palladino
- Pediatric Unit, Cystic Fibrosis Center of Umbria Region, Branca Hospital, Branca, Italy
| | - Laura Peccini
- Pediatric Clinic, Cystic Fibrosis Center of Umbria Region, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Perugia, Italy
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Preis E, Baghdan E, Agel MR, Anders T, Pourasghar M, Schneider M, Bakowsky U. Spray dried curcumin loaded nanoparticles for antimicrobial photodynamic therapy. Eur J Pharm Biopharm 2019; 142:531-539. [PMID: 31362056 DOI: 10.1016/j.ejpb.2019.07.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/24/2019] [Accepted: 07/26/2019] [Indexed: 01/10/2023]
Abstract
Antimicrobial resistance is one of the most serious problems that researchers of multiple disciplines are working on. The number of new antibiotics and their targeted structures have continuously decreased emphasizing the demand of alternative therapy for bacterial infections. Photodynamic therapy is such a promising strategy that has been proven to be effective against a wide range of bacterial strains. In this study, an inhalable nanoformulation for photodynamic therapy against respiratory infections was developed in the form of nano-in-microparticles consisting of curcumin nanoparticles embedded in a mannitol matrix. The produced nano-in-microparticles exhibited suitable aerodynamic properties with a mass median aerodynamic diameter of 2.88 ± 0.13 µm and a high fine particle fraction of 60.99 ± 9.50%. They could be readily redispersed in an aqueous medium producing the original nanoparticles without any substantial changes in their properties. This was confirmed using dynamic light scattering and electron microscopy. Furthermore, the redispersed nanoparticles showed an efficient antibacterial photoactivity causing 99.99992% (6.1log10) and 97.75% (1.6log10) reduction in the viability of Staphylococcus saprophyticus subsp. bovis and Escherichia coli DH5 alpha respectively. Based on these findings, it can be concluded that nano-in-microparticles represent promising drug delivery systems for antimicrobial photodynamic therapy.
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Affiliation(s)
- Eduard Preis
- Department of Pharmaceutics and Biopharmaceutics, University of Marburg, Robert-Koch-Str. 4, 35037 Marburg, Germany.
| | - Elias Baghdan
- Department of Pharmaceutics and Biopharmaceutics, University of Marburg, Robert-Koch-Str. 4, 35037 Marburg, Germany.
| | - Michael R Agel
- Department of Pharmaceutics and Biopharmaceutics, University of Marburg, Robert-Koch-Str. 4, 35037 Marburg, Germany.
| | - Thomas Anders
- Department of Pharmaceutics and Biopharmaceutics, University of Marburg, Robert-Koch-Str. 4, 35037 Marburg, Germany.
| | - Marcel Pourasghar
- Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus C4 1, 66123 Saarbrücken, Germany.
| | - Marc Schneider
- Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus C4 1, 66123 Saarbrücken, Germany.
| | - Udo Bakowsky
- Department of Pharmaceutics and Biopharmaceutics, University of Marburg, Robert-Koch-Str. 4, 35037 Marburg, Germany.
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27
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Abstract
Delayed antimicrobial prescriptions and inappropriate treatment can lead to poor outcomes in pneumonia. In nosocomial infections, especially in countries reporting high rates of antimicrobial resistance, the presence of multidrug-resistant gram-negative and gam-positive bacteria can limit options for adequate antimicrobial treatment. New antibiotics, belonging to known classes of antimicrobials or characterized by novel mechanisms of actions, have recently been approved or are under development. Advantages of the new compounds include enhanced spectrum of activity against resistant bacteria, high lung penetration, good tolerability, and possibility for intravenous to oral sequential therapy. This article reviews characteristics of newly approved and investigational compounds.
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Affiliation(s)
- Matteo Bassetti
- Infectious Diseases Clinic, Department of Medicine, University of Udine, Azienda Sanitaria Universitaria, Presidio Ospedaliero Universitario Santa Maria della Misericordia, Colugna Street, Udine 33100, Italy.
| | - Elda Righi
- Infectious Diseases Clinic, Department of Medicine, University of Udine, Azienda Sanitaria Universitaria, Presidio Ospedaliero Universitario Santa Maria della Misericordia, Colugna Street, Udine 33100, Italy
| | - Alessandro Russo
- Infectious Diseases Clinic, Department of Medicine, University of Udine, Azienda Sanitaria Universitaria, Presidio Ospedaliero Universitario Santa Maria della Misericordia, Colugna Street, Udine 33100, Italy
| | - Alessia Carnelutti
- Infectious Diseases Clinic, Department of Medicine, University of Udine, Azienda Sanitaria Universitaria, Presidio Ospedaliero Universitario Santa Maria della Misericordia, Colugna Street, Udine 33100, Italy
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28
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Abstract
Pneumonia, including community-acquired bacterial pneumonia, hospital-acquired bacterial pneumonia, and ventilator-acquired bacterial pneumonia, carries unacceptably high morbidity and mortality. Despite advances in antimicrobial therapy, emergence of multidrug resistance and high rates of treatment failure have made optimization of antibiotic efficacy a priority. This review focuses on pharmacokinetic and pharmacodynamic approaches to antibacterial optimization within the lung environment and in the setting of critical illness. Strategies for including these approaches in drug development programs as well as clinical practice are described and reviewed.
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Affiliation(s)
- Ana Motos
- Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA; Division of Animal Experimentation, Department of Pulmonary and Critical Care, Hospital Clinic, 170 Villarroel Street, Barcelona 08036, Spain
| | - James M Kidd
- Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA
| | - David P Nicolau
- Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA; Division of Infectious Diseases, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
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29
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Sweet FA, Forsthoefel CW, Sweet AR, Dahlberg RK. Local Versus Systemic Antibiotics for Surgical Infection Prophylaxis in a Rat Model. J Bone Joint Surg Am 2018; 100:e120. [PMID: 30234625 DOI: 10.2106/jbjs.18.00105] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND The purpose of this study was to compare the local application of a variety of antimicrobial agents with intravenous (IV) antibiotics for infection prophylaxis in a rat model. METHODS A total of 120 adult male Sprague-Dawley rats were implanted with an expanded polytetrafluoroethylene (ePTFE) vascular graft in a submuscular position and challenged with 2 × 10 colony-forming units of methicillin-sensitive Staphylococcus aureus (MSSA). Twenty rats received pretreatment with IV cefazolin and 20 rats were pretreated with IV vancomycin. The remaining 80 rats had application of local antimicrobials in the wound at the conclusion of the procedure: 20 rats received vancomycin powder; 20 rats, cefazolin powder; and 20 rats, tobramycin powder; 20 rats underwent dilute 0.35% Betadine (povidone-iodine) lavage for 3 minutes. One week after surgery, the grafts were retrieved and cultured. RESULTS Twenty (100%) of 20 rats in each of the IV cefazolin, IV vancomycin, and dilute Betadine lavage groups had grossly positive cultures for MSSA (95% confidence interval [CI], 84% to 100%). Eighteen (90%) of 20 rats in the cefazolin local powder group demonstrated positive cultures for MSSA (95% CI, 77% to 100%). Four (20%) of 20 rats in the tobramycin local powder and vancomycin local powder groups demonstrated positive cultures for MSSA (95% CI, 3% to 38%). The infection rates for the local application of vancomycin and tobramycin powder were significantly lower compared with Betadine lavage, IV vancomycin, IV cefazolin, and local cefazolin powder (p < 0.000001). CONCLUSIONS Local antimicrobial prophylaxis with vancomycin and tobramycin powder for infections in the rat model was statistically superior to systemic prophylaxis with IV antibiotics, local cefazolin powder, and Betadine lavage. CLINICAL RELEVANCE This study supports the findings of prior clinical reports that intrawound vancomycin powder reduces the risk of surgical site infection. Local application of tobramycin powder was equivalent to vancomycin powder in this model. Additionally, the superiority of local antibiotic surgical prophylaxis suggests that clinical studies should be considered to determine the relative efficacy of local versus systemic antibiotics for surgical infection prophylaxis in humans.
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Affiliation(s)
| | - Craig W Forsthoefel
- Department of Orthopedic Surgery, University of Illinois at Chicago, Chicago, Illinois
| | - Andrea R Sweet
- University of Missouri College of Medicine, Columbia, Missouri
| | - Ryan K Dahlberg
- University of Illinois College of Medicine, Rockford, Illinois
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Booysen E, Bezuidenhout M, van Staden ADP, Dimitrov D, Deane SM, Dicks LMT. Antibacterial Activity of Vancomycin Encapsulated in Poly(DL-lactide-co-glycolide) Nanoparticles Using Electrospraying. Probiotics Antimicrob Proteins 2018; 11:310-316. [PMID: 29961212 DOI: 10.1007/s12602-018-9437-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Vancomycin is often used to treat infections caused by β-lactam-resistant bacteria. However, methicillin-resistant strains of Staphylococcus aureus (MRSA) acquired resistance to vancomycin, rendering it less effective in the treatment of serious infections. In the search for novel antibiotics, alternative delivery mechanisms have also been explored. In this study, we report on the encapsulation of vancomycin in PLGA [poly(DL-lactide-co-glycolide)] nanoparticles by electrospraying. The nanoparticles were on average 247 nm in size with small bead formations on the surface. Clusters of various sizes were visible under the SEM (scanning electron microscope). Vancomycin encapsulated in PLGA (VNP) was more effective in inhibiting the growth of S. aureus Xen 31 (MRSA) and S. aureus Xen 36 than un-encapsulated vancomycin. Encapsulated vancomycin had a minimum inhibitory concentration (MIC) of 1 μg/mL against MRSA compared to 5 μg/mL of free vancomycin. At least 70% (w/w) of the vancomycin was encapsulated. Thirty percent of the vancomycin was released within the first 144 h, followed by slow release over 10 days. Vancomycin encapsulated in PLGA nanoparticles may be used to treat serious infections.
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Affiliation(s)
- Elzaan Booysen
- Department of Microbiology, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Martin Bezuidenhout
- Department of Industrial Engineering, Faculty of Engineering, Stellenbosch University, Stellenbosch, South Africa
| | - Anton Du Preez van Staden
- Department of Physiological Science, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Dimiter Dimitrov
- Department of Industrial Engineering, Faculty of Engineering, Stellenbosch University, Stellenbosch, South Africa
| | - Shelly M Deane
- Department of Microbiology, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Leon M T Dicks
- Department of Microbiology, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South Africa.
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In Vivo Release of Vancomycin from Calcium Phosphate Cement. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4560647. [PMID: 29862270 PMCID: PMC5976990 DOI: 10.1155/2018/4560647] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/10/2018] [Accepted: 04/16/2018] [Indexed: 12/19/2022]
Abstract
Calcium phosphate cement (CPC) has good release efficiency and has therefore been used as a drug delivery system for postoperative infection. The release profile of CPC has mainly been evaluated by in vitro studies, which are carried out by immersing test specimens in a relatively large amount of solvent. However, it remains unclear whether antibiotic-impregnated CPC has sufficient clinical effects and release in vivo. We examined the in vivo release profile of CPC impregnated with vancomycin (VCM) and compared this with that of polymethylmethacrylate (PMMA) cement. To evaluate the release profile in vitro, the test specimens were immersed in 10 mL sterile phosphate-buffered saline per gram of test specimen and incubated at 37°C for 56 days in triplicate. For in vivo experiments, the test specimens were implanted between the fascia and muscle of the femur of rats. Residual VCM was extracted from the removed test specimens to determine the amount of VCM released into rat tissues. CPC released more VCM over a longer duration than PMMA in vitro. Released levels of VCM from CPC/VCM in vivo were 3.4-fold, 5.0-fold, and 8.6-fold greater on days 1, 7, and 28, respectively, than those released on the corresponding days from PMMA/VCM and were drastically greater on day 56 due to inefficient release from PMMA/VCM. The amount of VCM released from CPC and PMMA was much higher than the minimum inhibitory concentration (1.56 μg) and lower than the detection limit, respectively. Our findings suggest that CPC is a suitable material for releasing antibiotics for local action against established postoperative infection.
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Cho JY, Kim Y, Lee SH, Lee YJ, Park JS, Yoon HI, Yim JJ, Lee JH, Lee CT, Cho YJ. Bronchoscopic Improvement of Tracheobronchitis Due to Methicillin-Resistant Staphylococcus aureus After Aerosolized Vancomycin: A Case Series. J Aerosol Med Pulm Drug Deliv 2018; 31:372-375. [PMID: 29583108 DOI: 10.1089/jamp.2017.1447] [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] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Ventilator-associated tracheobronchitis (VAT) is an important risk factor for ventilator-associated pneumonia (VAP). The efficacy of aerosolized vancomycin (AV) in treating VAT has not been clearly demonstrated. METHODS Four mechanically ventilated patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia were treated with an additional AV. AV (250 mg twice per day) was administered through a vibrating mesh device for 5 days. All patients were receiving intravenous vancomycin and had severe tracheobronchitis, based on bronchoscopic findings before or soon after additional AV treatment. RESULTS After several days of AV treatment, follow-up bronchoscopies showed dramatic improvement of tracheobronchitis. All patients achieved microbiological eradication of MRSA. Finally, two of four patients survived through to hospital discharge. CONCLUSION This case series study suggests a potential role of AV in the treatment of MRSA tracheobronchitis, which were accompanied by VAP. Clinical trial addressing the efficacy of AV in MRSA VAT and/or VAP should be needed.
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Affiliation(s)
- Jun Yeun Cho
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Republic of Korea
| | - Youlim Kim
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Republic of Korea
| | - Sang Hoon Lee
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Republic of Korea
| | - Yeon Joo Lee
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Republic of Korea
| | - Jong Sun Park
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Republic of Korea
| | - Ho Il Yoon
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Republic of Korea
| | - Jae-Joon Yim
- 2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital , Seoul, Republic of Korea
| | - Jae Ho Lee
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Republic of Korea
| | - Choon-Taek Lee
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Republic of Korea
| | - Young-Jae Cho
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Republic of Korea
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Emoto C, Johnson TN, McPhail BT, Vinks AA, Fukuda T. Using a Vancomycin PBPK Model in Special Populations to Elucidate Case-Based Clinical PK Observations. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2018; 7:237-250. [PMID: 29446256 PMCID: PMC5915605 DOI: 10.1002/psp4.12279] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 11/15/2017] [Accepted: 01/03/2018] [Indexed: 12/17/2022]
Abstract
Simultaneous changes in several physiological factors may contribute to the large pharmacokinetic (PK) variability of vancomycin. This study was designed to systematically characterize the effects of multiple physiological factors to the altered PK of vancomycin observed in special populations. A vancomycin physiologically based pharmacokinetic (PBPK) model was developed as a PK simulation platform to quantitatively assess the effects of changes in physiologies to the PK profiles. The developed model predicted the concentration-time profiles in healthy adults and diseased patients. The implementation of developmental changes in both renal and non-renal elimination pathways to the pediatric model improved the predictability of vancomycin clearance. Simulated PK profiles with a 50% decrease in cardiac output (peak plasma concentration (Cmax ), 59.9 ng/mL) were similar to those observed in patients before bypass surgery (Cmax , 55.1 ng/mL). The PBPK modeling of vancomycin demonstrated its potential to provide mechanistic insights into the altered disposition observed in patients who have changes in multiple physiological factors.
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Affiliation(s)
- Chie Emoto
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | | | - Brooks T McPhail
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Alexander A Vinks
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Tsuyoshi Fukuda
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Elsebaei MM, Mohammad H, Abouf M, Abutaleb NS, Hegazy YA, Ghiaty A, Chen L, Zhang J, Malwal SR, Oldfield E, Seleem MN, Mayhoub AS. Alkynyl-containing phenylthiazoles: Systemically active antibacterial agents effective against methicillin-resistant Staphylococcus aureus (MRSA). Eur J Med Chem 2018; 148:195-209. [PMID: 29459278 DOI: 10.1016/j.ejmech.2018.02.031] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 02/09/2018] [Accepted: 02/10/2018] [Indexed: 11/29/2022]
Abstract
The promising activity of phenylthiazoles against multidrug-resistant bacterial pathogens, in particular MRSA, has been hampered by their limited systemic applicability, due to their rapid metabolism by hepatic microsomal enzymes, resulting in short half-lives. Here, we investigated a series of phenylthiazoles with alkynyl side-chains that were synthesized with the objective of improving stability to hepatic metabolism, extending the utility of phenylthiazoles from topical applications to treatment of a more invasive, systemic MRSA infections. The most promising compounds inhibited the growth of clinically-relevant isolates of MRSA in vitro at concentrations as low as 0.5 μg/mL, and exerted their antibacterial effect by interfering with bacterial cell wall synthesis via inhibition of undecaprenyl diphosphate synthase and undecaprenyl diphosphate phosphatase. We also identified two phenylthiazoles that successfully eradicated MRSA inside infected macrophages. In vivo PK analysis of compound 9 revealed promising stability to hepatic metabolism with a biological half-life of ∼4.5 h. In mice, compound 9 demonstrated comparable potency to vancomycin, and at a lower dose (20 mg/kg versus 50 mg/kg), in reducing the burden of MRSA in a systemic, deep-tissue infection, using the neutropenic mouse thigh-infection model. Compound 9 thus represents a new phenylthiazole lead for the treatment of MRSA infections that warrants further development.
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Affiliation(s)
- Mohamed M Elsebaei
- Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Haroon Mohammad
- Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, United States
| | - Mohamed Abouf
- Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Nader S Abutaleb
- Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, United States
| | - Youssef A Hegazy
- Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, United States
| | - Adel Ghiaty
- Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Lu Chen
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
| | - Jianan Zhang
- School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
| | - Satish R Malwal
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
| | - Eric Oldfield
- Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
| | - Mohamed N Seleem
- Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, United States; Purdue Institute for Inflammation, Immunology, and Infectious Diseases, West Lafayette, IN 479067, United States.
| | - Abdelrahman S Mayhoub
- Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt; University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt.
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Suwantarat N, Rubin M, Bryan L, Tekle T, Boyle MP, Carroll KC, Jennings MT. Frequency of small-colony variants and antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus in cystic fibrosis patients. Diagn Microbiol Infect Dis 2017; 90:296-299. [PMID: 29343421 DOI: 10.1016/j.diagmicrobio.2017.11.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 11/09/2017] [Accepted: 11/19/2017] [Indexed: 01/15/2023]
Abstract
BACKGROUND Small-colony variants (SCVs) are a distinct phenotype of Staphylococcus aureus, known for their role in chronic, difficult to treat infections, including cystic fibrosis (CF) lung disease. The goal of this study was to characterize SCV MRSA infection in an adult and pediatric CF population and to identify antibiotic susceptibility patterns unique to SCV MRSA. METHODS We recovered methicillin-resistant S. aureus (MRSA) from respiratory culture samples from CF patients at the Johns Hopkins Hospital during a 6month study period. RESULTS Of 1161 samples, 200 isolates (17%) were identified as MRSA, and 37 isolates from 28 patients were identified as SCV MRSA. A higher proportion of MRSA was found among SCV isolates (37/66, 56%) compared to normal colony variant (NCV) isolates (163/417, 39%), p=0.02. All SCV MRSA isolates from individual patients were susceptible to vancomycin and ceftaroline, but they demonstrated higher rates of antibiotic resistance to trimethoprim/sulfamethoxazole, moxifloxacin, and erythromycin, compared to NCV MRSA isolates. Additionally, individuals with SCV MRSA had lower lung function, higher rates of persistent MRSA infection, and higher rates of previous antibiotic use, compared to individuals with NCV MRSA. CONCLUSIONS A significant proportion of MRSA isolates recovered from patients with CF have the SCV morphology. Compared to individuals with NCV MRSA, those with SCV MRSA have higher rates of persistent MRSA infection and lower lung function. SCV MRSA isolates were more resistant than NCV, but they are highly susceptible to vancomycin, linezolid and ceftaroline.
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Affiliation(s)
- Nuntra Suwantarat
- Division of Medical Microbiology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Chulabhorn International College of Medicine, Thammasat University, PathumThani, Thailand
| | - Mayer Rubin
- Division of Medical Microbiology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Latetia Bryan
- Division of Medical Microbiology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tsigereda Tekle
- Division of Medical Microbiology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael P Boyle
- The Cystic Fibrosis Foundation, Bethesda, MD, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Karen C Carroll
- Division of Medical Microbiology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mark T Jennings
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Eliakim-Raz N, Hellerman M, Yahav D, Cohen J, Margalit I, Fisher S, Zusman O, Shaked H, Bishara J. Trimethoprim/sulfamethoxazole versus vancomycin in the treatment of healthcare/ventilator-associated MRSA pneumonia: a case-control study. J Antimicrob Chemother 2017; 72:882-887. [PMID: 27999052 DOI: 10.1093/jac/dkw510] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 10/26/2016] [Indexed: 02/06/2023] Open
Abstract
Objectives Therapeutic options available to treat MRSA pneumonia are limited. Trimethoprim/sulfamethoxazole is an attractive treatment because of its bactericidal anti-MRSA activity, oral and parenteral formulations and good penetration to the lung tissue. We aimed to compare the efficacy and safety of trimethoprim/sulfamethoxazole with vancomycin in the treatment of healthcare/ventilator-associated MRSA pneumonia. Methods We carried out a retrospective case-control study of all consecutive hospitalized adult patients diagnosed with MRSA pneumonia at Beilinson Hospital during 2010-15 and treated with either vancomycin or trimethoprim/sulfamethoxazole. The primary outcomes were all-cause mortality at 30 days and clinical failure at the end of treatment. In order to reduce bias affecting the decision to use a specific antibiotic and as a sensitivity analysis, a propensity-score model for choosing between vancomycin and trimethoprim/sulfamethoxazole was used. Results We identified 42 patients with MRSA pneumonia treated with trimethoprim/sulfamethoxazole and 39 treated with vancomycin. There were no significant differences in the baseline characteristics between the groups. Vancomycin-treated patients showed significantly higher 30 day mortality on both multivariate analysis (HR = 5.28; 95% CI = 1.50-18.60; P < 0.05) and sensitivity analysis with propensity score [vancomycin 13/24 (54.1%) versus trimethoprim/sulfamethoxazole 4/24 (16.7%); P < 0.05], and higher clinical failure rates [vancomycin 23/39 (59%) versus trimethoprim/sulfamethoxazole 15/42 (35.7%); P < 0.05], also in the sensitivity analysis with propensity score [vancomycin 14/24 (58.3%) versus trimethoprim/sulfamethoxazole 6/24 (25%); P < 0.05]. The rates of side effects in both arms were comparable. Conclusions Trimethoprim/sulfamethoxazole appears to be superior to vancomycin in the treatment of MRSA pneumonia. A large-scale randomized controlled trial is needed to evaluate these findings.
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Affiliation(s)
- Noa Eliakim-Raz
- Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel.,Department of Internal Medicine E, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Moran Hellerman
- Department of Internal Medicine F, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel
| | - Dafna Yahav
- Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Jonathan Cohen
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.,Intensive Care Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel
| | - Ili Margalit
- Department of Internal Medicine F, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel
| | - Sharon Fisher
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Oren Zusman
- Department of Internal Medicine E, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Hila Shaked
- Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Jihad Bishara
- Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
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Pei Y, Mohamed MF, Seleem MN, Yeo Y. Particle engineering for intracellular delivery of vancomycin to methicillin-resistant Staphylococcus aureus (MRSA)-infected macrophages. J Control Release 2017; 267:133-143. [PMID: 28797580 DOI: 10.1016/j.jconrel.2017.08.007] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 07/30/2017] [Accepted: 08/05/2017] [Indexed: 12/25/2022]
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) infection is a serious threat to the public health. MRSA is particularly difficult to treat when it invades host cells and survive inside the cells. Although vancomycin is active against MRSA, it does not effectively kill intracellular MRSA due to the molecular size and polarity that limit its cellular uptake. To overcome poor intracellular delivery of vancomycin, we developed a particle formulation (PpZEV) based on a blend of polymers with distinct functions: (i) poly(lactic-co-glycolic acid) (PLGA, P) serving as the main delivery platform, (ii) polyethylene glycol-PLGA conjugate (PEG-PLGA, p) to help maintain an appropriate level of polarity for timely release of vancomycin, (iii) Eudragit E100 (a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, E) to enhance vancomycin encapsulation, and (iv) a chitosan derivative called ZWC (Z) to trigger pH-sensitive drug release. PpZEV NPs were preferentially taken up by the macrophages due to its size (500-1000nm) and facilitated vancomycin delivery to the intracellular pathogens. Accordingly, PpZEV NPs showed better antimicrobial activity than free vancomycin against intracellular MRSA and other intracellular pathogens. When administered intravenously, PpZEV NPs rapidly accumulated in the liver and spleen, the target organs of intracellular infection. Therefore, PpZEV NPs is a promising carrier of vancomycin for the treatment of intracellular MRSA infection.
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Affiliation(s)
- Yihua Pei
- Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
| | - Mohamed F Mohamed
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA
| | - Mohamed N Seleem
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Inflammation, Immunology, and Infectious Diseases, West Lafayette, IN 47907, USA
| | - Yoon Yeo
- Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
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Burnham JP, Kollef MH. Prevention of Staphylococcus aureus Ventilator-Associated Pneumonia: Conventional Antibiotics Won't Cut It. Clin Infect Dis 2017; 64:1089-1091. [PMID: 28158521 PMCID: PMC5850453 DOI: 10.1093/cid/cix060] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 01/21/2017] [Indexed: 12/15/2022] Open
Affiliation(s)
- Jason P Burnham
- Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Marin H Kollef
- Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, Missouri, USA
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Eissa IH, Mohammad H, Qassem OA, Younis W, Abdelghany TM, Elshafeey A, Abd Rabo Moustafa MM, Seleem MN, Mayhoub AS. Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus. Eur J Med Chem 2017; 130:73-85. [PMID: 28249208 DOI: 10.1016/j.ejmech.2017.02.044] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/13/2017] [Accepted: 02/17/2017] [Indexed: 10/20/2022]
Abstract
A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.
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Affiliation(s)
- Ibrahim H Eissa
- Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Haroon Mohammad
- Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, USA
| | - Omar A Qassem
- Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Waleed Younis
- Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, USA
| | - Tamer M Abdelghany
- Department of Pharmacology, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Ahmed Elshafeey
- Department of Pharmaceutics, College of Pharmacy, Cairo University, Cairo 11777, Egypt; Bioequivalence Section, Genuine Research Center, Heliopolis, Cairo 11757, Egypt
| | - Mahmoud M Abd Rabo Moustafa
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, University of Dammam, Eastern Province, P.O. Box 1982, Dammam 31441, Kingdom of Saudi Arabia
| | - Mohamed N Seleem
- Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, USA; Purdue Institute for Inflammation, Immunology, and Infectious Diseases, West Lafayette, IN 479067, USA.
| | - Abdelrahman S Mayhoub
- Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt; Biomedical Sciences, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt.
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Maclayton DO, Hall RG. Infectious Diseases: Pharmacologic Treatment Options for Nosocomial Pneumonia Involving Methicillin-Resistant Staphylococcus aureus. Ann Pharmacother 2016; 41:235-44. [PMID: 17299012 DOI: 10.1345/aph.1h414] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Objective: To discuss current and potential treatment options for nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). Data Sources: A MEDLINE search (1966–January 2007) was conducted to identify English-language literature on pharmacotherapy of nosocomial pneumonia and the bibliographies of pertinent articles. Programs and abstracts from infectious disease meetings were also searched. Search terms included MRSA, nosocomial pneumonia, pulmonary infections, vancomycin, quinupristin/dalfopristin, linezolid, daptomycin, tigecycline, dalbavancin, oritavancin, and ceftobiprole. Data Selection and Data Extraction: All articles were critically evaluated and all pertinent information was included in this review. Data Synthesis: Vancomycin has been the drug of choice for MRSA infections for many years. Recent data suggest that linezolid may be superior to vancomycin in the treatment of MRSA nosocomial pneumonia. However, there are limitations to the available data. Therefore, prospective, randomized studies are needed before linezolid is recommended as the preferred first-line therapy. Other approved agents for nosocomial MRSA infections, such as quinupristin/dalfopristin and daptomycin, should not be used in the treatment of MRSA pneumonia, as they were inferior in clinical trials. Tigecycline has excellent activity against MRSA in vitro, but should not be routinely used for the treatment of MRSA pneumonia, as clinical data are lacking. In a Phase III clinical trial, an anti-MRSA cephalosporin, ceftobiprole, is being evaluated for effectiveness against nosocomial pneumonia. Investigational glycopeptides may eventually have a role in the treatment of nosocomial pneumonia, but data are currently lacking. Conclusions: Vancomycin is still the drug of choice for treatment of MRSA pneumonia, and linezolid should be used as an alternative agent. Linezolid should carry strong consideration for patients with vancomycin-induced nephrotoxicity or a documented lack of response to vancomycin. Tigecycline and investigational agents with activity against MRSA may be future options for nosocomial pneumonia due to MRSA.
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Affiliation(s)
- Darego O Maclayton
- Texas Southern University College of Pharmacy & Health Sciences, Michael E DeBakey Veterans Affairs Medical Center, Houston, TX 77004, USA.
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Abstract
PURPOSE OF REVIEW The progressive increase of respiratory tract infections caused by multidrug-resistant organisms (MDROs) has been associated with delays in the prescription of an adequate antibiotic treatment and increased mortality, representing a major concern in both community and hospital settings. When infections because of methicillin-resistant Staphylococcus aureus (MRSA) are suspected, vancomycin still represents the first choice, although its efficacy has been recently questioned in favor of new drugs, reported to provide better clinical outcomes. Moreover, few therapeutic options are currently available for the treatment of severe infections caused by Multidrug-resistant (MDR) Gram-negative pathogens, which are frequently resistant to all the available β-lactams, including carbapenems. We have reviewed the therapeutic options for the treatment of respiratory tract infections that have recently become available with promising implications for clinical practice, including ceftaroline, ceftrobiprole, tedizolid, telavancin, delafloxacin, eravacycline, and new β-lactams/β-lactamase inhibitors. RECENT FINDINGS A number of new antimicrobials with activity against MDROs have been recently approved for the treatment of respiratory tract infections, and other agents are under investigation. Recent developments, with a specific focus on the possible advantages of new drugs for the management of respiratory tract infections caused by MDROs in everyday clinical practice are discussed. SUMMARY Newly approved and investigational drugs for the treatment of respiratory tract infections are expected to offer many advantages for the management of patients with suspected or confirmed infections caused by MDROs. Most promising features among new compounds include the broad spectrum of activity against both MRSA and MDR Gram-negative bacteria, a limited risk of antimicrobial resistance, the availability of oral formulations, and a promising safety profile.
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Abushahba MF, Mohammad H, Seleem MN. Targeting Multidrug-resistant Staphylococci with an anti-rpoA Peptide Nucleic Acid Conjugated to the HIV-1 TAT Cell Penetrating Peptide. MOLECULAR THERAPY-NUCLEIC ACIDS 2016; 5:e339. [PMID: 27434684 PMCID: PMC5330942 DOI: 10.1038/mtna.2016.53] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 06/13/2016] [Indexed: 01/22/2023]
Abstract
Staphylococcus aureus infections present a serious challenge to healthcare practitioners due to the emergence of resistance to numerous conventional antibiotics. Due to their unique mode of action, peptide nucleic acids are novel alternatives to traditional antibiotics to tackle the issue of bacterial multidrug resistance. In this study, we designed a peptide nucleic acid covalently conjugated to the HIV-TAT cell penetrating peptide (GRKKKRRQRRRYK) in order to target the RNA polymerase α subunit gene (rpoA) required for bacterial genes transcription. We explored the antimicrobial activity of the anti-rpoA construct (peptide nucleic acid-TAT) against methicillin-resistant S. aureus, vancomycin-intermediate S. aureus, vancomycin-resistant S. aureus, linezolid-resistant S. aureus, and methicillin-resistant S. epidermidis in pure culture, infected mammalian cell culture, and in an in vivo Caenorhabditis elegans infection model. The anti-rpoA construct led to a concentration-dependent inhibition of bacterial growth (at micromolar concentrations) in vitro and in both infected cell culture and in vivo in C. elegans. Moreover, rpoA gene silencing resulted in suppression of its message as well as reduced expression of two important methicillin-resistant S. aureus USA300 toxins (α-hemolysin and Panton-Valentine leukocidin). This study confirms that rpoA gene is a potential target for development of novel antisense therapeutics to treat infections caused by methicillin-resistant S. aureus.
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Affiliation(s)
- Mostafa Fn Abushahba
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
| | - Haroon Mohammad
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
| | - Mohamed N Seleem
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.,Purdue Institute for Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, Indiana, USA
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Mohamed MF, Abdelkhalek A, Seleem MN. Evaluation of short synthetic antimicrobial peptides for treatment of drug-resistant and intracellular Staphylococcus aureus. Sci Rep 2016; 6:29707. [PMID: 27405275 PMCID: PMC4942614 DOI: 10.1038/srep29707] [Citation(s) in RCA: 199] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 06/21/2016] [Indexed: 02/07/2023] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) infections present a serious challenge because of the emergence of resistance to numerous conventional antibiotics. Due to their unique mode of action, antimicrobial peptides are novel alternatives to traditional antibiotics for tackling the issue of bacterial multidrug resistance. Herein, we investigated the antibacterial activity of two short novel peptides (WR12, a 12 residue peptide composed exclusively of arginine and tryptophan, and D-IK8, an eight residue β-sheet peptide) against multidrug resistant staphylococci. In vitro, both peptides exhibited good antibacterial activity against MRSA, vancomycin-resistant S. aureus, linezolid-resistant S. aureus, and methicillin-resistant S. epidermidis. WR12 and D-IK8 were able to eradicate persisters, MRSA in stationary growth phase, and showed significant clearance of intracellular MRSA in comparison to both vancomycin and linezolid. In vivo, topical WR12 and D-IK8 significantly reduced both the bacterial load and the levels of the pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in MRSA-infected skin lesions. Moreover, both peptides disrupted established in vitro biofilms of S. aureus and S. epidermidis significantly more so than traditional antimicrobials tested. Taken together, these results support the potential of WR12 and D-IK8 to be used as a topical antimicrobial agent for the treatment of staphylococcal skin infections.
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Affiliation(s)
- Mohamed F. Mohamed
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA
| | - Ahmed Abdelkhalek
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA
| | - Mohamed N. Seleem
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA
- Purdue Institute for Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA
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Baughman RP, Kerr MA. Ventilator-Associated Pneumonia Patients who Do Not Reduce Bacteria from the Lungs have a Worse Prognosis. J Intensive Care Med 2016; 18:269-74. [PMID: 15035762 DOI: 10.1177/0885066603256012] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The authors determined the significance of serial semi-quantitative bronchoalveolar lavage (BAL) culture results in patients undergoing therapy for ventilator-associated pneumonia. A total of 32 patients underwent at least 2 nonbronchoscopic BAL studies. Fourteen patients had methicillin-resistant Staphylococcus aureus(MRSA). Of these, 11 had more than 100 colony-forming units (cfu) of MRSA/mL of BAL from the follow-up BAL. Eighteen patients had an organism other than MRSA, and 7 of these patients had > 100 cfu of bacteria/mL of BAL from the follow-up BAL. Of the 18 patients with > 100 cfu of bacteria/mL of BAL at follow-up, 14 (79%) died, whereas only 5 of 14 (36%) patients who cleared their bacteria at follow-up died within 28 days. The inability to reduce the bacterial burden from the lower respiratory tract within the first few days of therapy for ventilator-associated pneumonia was associated with increased mortality.
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MESH Headings
- Anti-Bacterial Agents/adverse effects
- Anti-Bacterial Agents/therapeutic use
- Bronchoalveolar Lavage Fluid/microbiology
- Colony Count, Microbial
- Cross Infection/etiology
- Cross Infection/mortality
- Cross Infection/therapy
- Hospital Mortality
- Humans
- Likelihood Functions
- Methicillin Resistance
- Monitoring, Physiologic/methods
- Monitoring, Physiologic/standards
- Mucociliary Clearance
- Pneumonia, Bacterial/etiology
- Pneumonia, Bacterial/mortality
- Pneumonia, Bacterial/therapy
- Pneumonia, Pneumococcal/etiology
- Pneumonia, Pneumococcal/mortality
- Pneumonia, Pneumococcal/therapy
- Pneumonia, Staphylococcal/etiology
- Pneumonia, Staphylococcal/mortality
- Pneumonia, Staphylococcal/therapy
- Prognosis
- Respiration, Artificial/adverse effects
- Retrospective Studies
- Sensitivity and Specificity
- Serratia Infections/etiology
- Serratia Infections/mortality
- Serratia Infections/therapy
- Sputum/microbiology
- Staphylococcus aureus
- Survival Analysis
- Time Factors
- Vancomycin/adverse effects
- Vancomycin/therapeutic use
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Affiliation(s)
- Robert P Baughman
- University of Cincinnati Medical Center, Cincinnati, OH 45267-0565, USA.
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Soon RL, Lenhard JR, Reilly I, Brown T, Forrest A, Tsuji BT. Impact of Staphylococcus aureus accessory gene regulator (agr) system on linezolid efficacy by profiling pharmacodynamics and RNAIII expression. J Antibiot (Tokyo) 2016; 70:98-101. [DOI: 10.1038/ja.2016.59] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 04/16/2016] [Accepted: 04/25/2016] [Indexed: 12/21/2022]
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McDade EJ, Hewlett JL, Moonnumakal SP, Baker CJ. Evaluation of Vancomycin Dosing in Pediatric Cystic Fibrosis Patients. J Pediatr Pharmacol Ther 2016; 21:155-61. [PMID: 27199623 DOI: 10.5863/1551-6776-21.2.155] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVES The presence of methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis (CF) patients' sputa is associated with a decline in pulmonary function and increased mortality. Vancomycin is the preferred treatment for MRSA pneumonia in children. No published studies have evaluated the vancomycin dose needed to achieve goal vancomycin trough concentrations (VTCs; 15-20 mg/L) in pediatric patients with CF. The primary objective is to determine whether a vancomycin dosage of 60 mg/kg/day achieves a goal VTC in pediatric CF patients. Secondary objectives include determining the average dosage required to reach a goal VTC and the impact of achieving a goal VTC on estimated glomerular filtration rate (eGFR) and pulmonary function. METHODS A retrospective review of pediatric patients with CF who received vancomycin was conducted. RESULTS A total of 90 vancomycin treatment courses were analyzed. Standard vancomycin dosing (60 mg/kg/day) achieved goal VTC in 11 courses (12.2%). The mean dosage required to achieve a goal VTC for all courses was 70.6 ± 16.7 mg/kg/day. Patients who achieved goal VTCs were more often older, weighed more, and had higher serum creatinine concentrations at therapy initiation. On average, a dosage of 70.6 mg/kg/day was required to achieve a goal VTC. Despite dosages up to 120 mg/kg/day, no significant changes in renal function occurred. Achieving a goal VTC had no significant impact on eGFR or pulmonary function during therapy. CONCLUSIONS Vancomycin dosing of 60 mg/kg/day does not reliably achieve a VTC of 15 to 20 mg/L in pediatric CF patients. Younger CF patients may require higher vancomycin doses.
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Affiliation(s)
- Erin J McDade
- Department of Pharmacy, Texas Children's Hospital, Houston, Texas ; Section of Pulmonary Medicine, Department of Pediatrics
| | - Jennifer L Hewlett
- Department of Pharmacy, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | | | - Carol J Baker
- Section of Infectious Diseases, Departments of Pediatrics and of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
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Bassetti M, Luyt CE, Nicolau DP, Pugin J. Characteristics of an ideal nebulized antibiotic for the treatment of pneumonia in the intubated patient. Ann Intensive Care 2016; 6:35. [PMID: 27090532 PMCID: PMC4835402 DOI: 10.1186/s13613-016-0140-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 04/06/2016] [Indexed: 02/06/2023] Open
Abstract
Gram-negative pneumonia in patients who are intubated and mechanically ventilated is associated with increased morbidity and mortality as well as higher healthcare costs compared with those who do not have the disease. Intravenous antibiotics are currently the standard of care for pneumonia; however, increasing rates of multidrug resistance and limited penetration of some classes of antimicrobials into the lungs reduce the effectiveness of this treatment option, and current clinical cure rates are variable, while recurrence rates remain high. Inhaled antibiotics may have the potential to improve outcomes in this patient population, but their use is currently restricted by a lack of specifically formulated solutions for inhalation and a limited number of devices designed for the nebulization of antibiotics. In this article, we review the challenges clinicians face in the treatment of pneumonia and discuss the characteristics that would constitute an ideal inhaled drug/device combination. We also review inhaled antibiotic options currently in development for the treatment of pneumonia in patients who are intubated and mechanically ventilated.
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Affiliation(s)
- Matteo Bassetti
- Infectious Diseases Clinic, Santa Maria Misericordia University Hospital, Udine, Italy.
| | - Charles-Edouard Luyt
- Service de Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, INSERM, UMRS_1166-ICAN Institute of Cardiometabolism and Nutrition, Paris, France
| | - David P Nicolau
- Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, USA
| | - Jérôme Pugin
- Service des Soins Intensifs, University Hospitals of Geneva and Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Enterococcus faecium Mediastinitis Complicated by Disseminated Candida parapsilosis Infection after Congenital Heart Surgery in a 4-Week-Old Baby. Case Rep Infect Dis 2015; 2015:543685. [PMID: 26605096 PMCID: PMC4641177 DOI: 10.1155/2015/543685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 09/29/2015] [Indexed: 12/02/2022] Open
Abstract
Background. Cardiac surgery offers multiple treatment options for children with congenital heart defects. However, infectious complications still remain a major cause of morbidity and mortality in these patients. Mediastinitis is a detrimental complication in children undergoing cardiac surgery. The risk of mediastinitis after delayed sternal closure is up to 10%. Case Presentation. We report a case of Enterococcus faecium mediastinitis in a 4-week-old female baby on extracorporeal membrane oxygenation after Norwood procedure. Although repeated antibiotic irrigation, debridement, and aggressive antibiotic treatment were started early, the pulmonary situation deteriorated. Candida parapsilosis was isolated from bronchoalveolar lavage after pulmonary hemorrhage. Disseminated C. parapsilosis infection with pulmonary involvement was treated with liposomal amphotericin B. Subsequently, inflammatory markers increased again and eventually C. parapsilosis was isolated from the central venous catheter. Conclusion. Children undergoing delayed sternal closure have a higher risk of mediastinitis. Therefore, antibiotic prophylaxis, for example, for soft tissue infection seems justified. However, long-term antibiotic treatment is a risk factor for fungal superinfection. Antifungal treatment of disseminated C. parapsilosis infection may fail in PICU patients with nonbiological material in place due to capacity of this species to form biofilms on medical devices. Immediate removal of central venous catheters and other nonbiological material is life-saving in these patients.
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50
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Bue M, Birke-Sørensen H, Thillemann TM, Hardlei TF, Søballe K, Tøttrup M. Single-dose pharmacokinetics of vancomycin in porcine cancellous and cortical bone determined by microdialysis. Int J Antimicrob Agents 2015; 46:434-8. [DOI: 10.1016/j.ijantimicag.2015.06.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 06/03/2015] [Accepted: 06/13/2015] [Indexed: 11/30/2022]
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