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Wang Y, Li Y, Gao M, Zhang M, Li Y, Wang D, Li X, Zhang C, Fu Y, Li H, Zhang D. Continuous vs. intermittent meropenem infusion in critically ill patients with sepsis: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis. Front Med (Lausanne) 2025; 12:1580116. [PMID: 40557041 PMCID: PMC12185501 DOI: 10.3389/fmed.2025.1580116] [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: 02/20/2025] [Accepted: 05/05/2025] [Indexed: 06/28/2025] Open
Abstract
Background A recent large multicenter randomized controlled trial (RCT) found that continuous infusion (CI) of meropenem did not improve clinical outcomes in critically ill patients, contradicting previous meta-analysis results. Methods We conducted a search of the PubMed, EMBASE, and Cochrane databases up to March 19, 2024. Results Our study included a total of 1,075 critically ill patients with sepsis from five RCTs. The primary outcome indicated that CI of meropenem did not reduce all-cause mortality in patients (RR = 0.89; 95% CI, 0.75-1.04; P = 0.15; Chi2= 5.75; I 2 = 30%). The secondary outcomes revealed that compared to II of meropenem, patients receiving CI had shorter ICU length of stay (MD = -2.39; 95% CI, -2.98 to -1.81; P < 0.00001; Chi2= 6.63; I 2 = 40%), higher clinical cure rates (RR = 1.88; 95% CI, 1.23-2.87; P = 0.004; Chi2 = 1.87; I 2 = 0%), and shorter duration of meropenem therapy (MD = -0.86; 95% CI, -1.36 to -0.36; P = 0.0008; Chi2 = 3.65; I 2 = 45%). Conclusion In critically ill patients with sepsis, CI of meropenem did not reduce mortality but was associated with shorter ICU length of stays, higher clinical cure rates, and shorter duration of meropenem therapy. Further large-scale RCTs are needed to validate these findings. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD42024528380, identifier CRD42024528380.
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Affiliation(s)
- Youquan Wang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yanhua Li
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Meng Gao
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Mingtao Zhang
- Department of Emergency Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Yuting Li
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Dongxia Wang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Xinyu Li
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Chaoyang Zhang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yao Fu
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Hongxiang Li
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Dong Zhang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
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Baklouti S, Mané C, Bennis Y, Luyt CE, Joseph C, Ruiz S, Guilhaumou R, Concordet D, Zahr N, Gandia P. Ceftobiprole in Critically Ill Patients: Proposal for New Dosage Regimens. Ther Drug Monit 2025:00007691-990000000-00347. [PMID: 40300784 DOI: 10.1097/ftd.0000000000001338] [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: 12/31/2024] [Accepted: 03/06/2025] [Indexed: 05/01/2025]
Abstract
BACKGROUND Ceftobiprole is a broad-spectrum cephalosporin. It is currently approved for the treatment of community- and hospital-acquired pneumonia. However, the recommended dosage regimen of ceftobiprole may not be sufficient to achieve the optimal pharmacokinetic/pharmacodynamic criterion in critically ill patients. The study aimed to evaluate whether the dosage regimens proposed by the manufacturers ensure that the optimal pharmacokinetic/pharmacodynamic criterion is achieved in over 90% of critically ill patients. METHODS Ceftobiprole concentrations were measured in 27 patients admitted to intensive care unit. An external evaluation of published population pharmacokinetic models was performed using simulations. The model that best described the data was used to evaluate the dosage regimens proposed for intensive care unit patients by evaluating the probability of attaining the optimal pharmacokinetic/pharmacodynamic criterion (100% fT > 4 * minimum inhibitory concentration). In addition, the same model was used to suggest dosage regimen adjustments for these patients. RESULTS Of the 4 models evaluated, Muller's population pharmacokinetic model was selected as the best for describing the concentrations observed in 27 patients. Simulations performed with this model have shown that the manufacturer's dosing regimens do not achieve the optimal pharmacokinetic/pharmacodynamic criterion in critically ill patients. Consequently, adaptation of dosing regimens to ensure ceftobiprole effectiveness in at least 90% of the patients was proposed. CONCLUSIONS The proposed dosing regimens can be used to guide ceftobiprole administration in critically ill patients. However, measurement of ceftobiprole plasma concentration remains essential, at least once, to confirm patient exposure.
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Affiliation(s)
- Sarah Baklouti
- Pharmacokinetics and Toxicology Laboratory, Federative Institute of Biology, Toulouse University Hospital, Toulouse, France
- INTHERES, University of Toulouse, INRAE, ENVT, Toulouse, France
| | - Camille Mané
- Pharmacokinetics and Toxicology Laboratory, Federative Institute of Biology, Toulouse University Hospital, Toulouse, France
| | - Youssef Bennis
- Department of Clinical Pharmacology, University Hospital of Amiens-Picardie, Amiens, France
| | - Charles-Edouard Luyt
- Intensive Care Department, Institute of Cardiology, ICAN, Sorbonne-University, Pitié-Salpêtrière Hospital, Paris, France
| | - Cédric Joseph
- Department of Infectious Diseases, University Hospital of Amiens-Picardie, Amiens, France
| | - Stéphanie Ruiz
- Anesthesiology and Critical Care Unit, Toulouse University Hospital, Toulouse, France
| | - Romain Guilhaumou
- Institute of Systems Neuroscience, Aix Marseille University, Inserm UMR 1106, Department of Clinical Pharmacology and Pharmacosurveillance, Timone Hospital, Marseille, France; and
| | | | - Noël Zahr
- Department of Pharmacology, Pharmacokinetics and Therapeutic Drug Monitoring Unit, UMR-S 1166, Pitié-Salpêtrière Hospital, Paris, France
| | - Peggy Gandia
- Pharmacokinetics and Toxicology Laboratory, Federative Institute of Biology, Toulouse University Hospital, Toulouse, France
- INTHERES, University of Toulouse, INRAE, ENVT, Toulouse, France
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Rademacher J, Ewig S, Grabein B, Nachtigall I, Abele-Horn M, Deja M, Gaßner M, Gatermann S, Geffers C, Gerlach H, Hagel S, Heußel CP, Kluge S, Kolditz M, Kramme E, Kühl H, Panning M, Rath PM, Rohde G, Schaaf B, Salzer HJF, Schreiter D, Schweisfurth H, Unverzagt S, Weigand MA, Welte T, Pletz MW. [Epidemiology, diagnosis and treatment of adult patients with nosocomial pneumonia]. Pneumologie 2025. [PMID: 40169124 DOI: 10.1055/a-2541-9872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2025]
Abstract
BACKGROUND Nosocomial pneumonia, encompassing hospital-acquired (HAP) and ventilator-associated pneumonia (VAP), remains a major cause of morbidity and mortality in hospitalized adults. In response to evolving pathogen profiles and emerging resistance patterns, this updated S3 guideline (AWMF Register No. 020-013) provides an evidence-based framework to enhance the diagnosis, risk stratification, and treatment of nosocomial pneumonia. METHODS The guideline update was developed by a multidisciplinary panel representing key German professional societies. A systematic literature review was conducted with subsequent critical appraisal using the GRADE methodology. Structured consensus conferences and external reviews ensured that the recommendations were clinically relevant, methodologically sound, and aligned with current antimicrobial stewardship principles. RESULTS For the management of nosocomial pneumonia patients should be divided in those with and without risk factors for multidrug-resistant pathogens and/or Pseudomonas aeruginosa. Bacterial multiplex-polymerase chain reaction (PCR) should not be used routinely. Bronchoscopic diagnosis is not considered superior to non-bronchoscopic sampling in terms of main outcomes. Combination antibiotic therapy is now reserved for patients in septic shock and high risk for multidrug-resistant pathogens, while select patients may be managed with monotherapy (e. g., meropenem). In clinically stabilized patients, antibiotic therapy should be de-escalated and focused, as well as duration shortened to 7-8 days. In critically ill patients, prolonged application of suitable beta-lactam antibiotics should be preferred. Patients on the intensive care unit (ICU) are at risk for invasive pulmonary aspergillosis (IPA). Diagnostics for Aspergillus should be performed with an antigen test from bronchial lavage fluid. CONCLUSION This updated S3 guideline offers a comprehensive, multidisciplinary approach to the management of nosocomial pneumonia in adults. By integrating novel diagnostic modalities and refined therapeutic strategies, it aims to standardize care, improve patient outcomes, and enhance antimicrobial stewardship to curb the emergence of resistant pathogens.
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Affiliation(s)
- Jessica Rademacher
- Department of Respiratory Medicine and German Centre of Lung Research (DZL), Hannover Medical School, Hannover, Germany
| | - Santiago Ewig
- Thoraxzentrum Ruhrgebiet, Department of Respiratory and Infectious Diseases, EVK Herne and Augusta-Kranken-Anstalt Bochum, Bochum, Germany
| | - Béatrice Grabein
- LMU Hospital, Clinical Microbiology and Hospital Hygiene, Munich, Germany
| | - Irit Nachtigall
- Division of Infectious Diseases and Infection Prevention, Helios Hospital Emil-Von-Behring, Berlin, Germany
| | - Marianne Abele-Horn
- Institute for Hygiene and Microbiology, University of Würzburg, Würzburg, Germany
| | - Maria Deja
- Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Berlin, Lübeck, Germany
| | - Martina Gaßner
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anaesthesiology and Intensive Care Medicine, Berlin, Germany
| | - Sören Gatermann
- National Reference Centre for multidrug-resistant Gram-negative bacteria, Department of Medical Microbiology, Ruhr-University Bochum, Bochum, Germany
| | - Christine Geffers
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Herwig Gerlach
- Department for Anaesthesia, Intensive Care Medicine and Pain Management, Vivantes-Klinikum Neukoelln, Berlin, Germany
| | - Stefan Hagel
- Jena University Hospital-Friedrich Schiller University Jena, Institute for Infectious Diseases and Infection Control, Jena, Germany
| | - Claus Peter Heußel
- Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Kluge
- Department of Intensive Care, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Martin Kolditz
- Medical Department 1, Division of Pulmonology, University Hospital of TU Dresden, Dresden, Germany
| | - Evelyn Kramme
- Department of Infectious Diseases and Microbiology, University of Lübeck and University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Hilmar Kühl
- Department of Radiology, St. Bernhard-Hospital Kamp-Lintfort, Kamp-Lintfort, Germany
| | - Marcus Panning
- Institute of Virology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peter-Michael Rath
- Institute for Medical Microbiology, University Medicine Essen, Essen, Germany
| | - Gernot Rohde
- Department of Respiratory Medicine, Goethe University Frankfurt, University Hospital, Frankfurt/Main, Germany
| | - Bernhard Schaaf
- Department of Respiratory Medicine and Infectious Diseases, Klinikum Dortmund, Dortmund, Germany
| | - Helmut J F Salzer
- Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine-Pneumology, Kepler University Hospital, Medical Faculty, Johannes Kepler University, Linz, Austria
| | - Dierk Schreiter
- Helios Park Clinic, Department of Intensive Care Medicine, Leipzig, Germany
| | | | - Susanne Unverzagt
- Institute of General Practice and Family Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Markus A Weigand
- Medical Faculty Heidelberg, Department of Anesthesiology, Heidelberg University, Heidelberg, Germany
| | - Tobias Welte
- Department of Respiratory Medicine and German Centre of Lung Research (DZL), Hannover Medical School, Hannover, Germany
| | - Mathias W Pletz
- Jena University Hospital-Friedrich Schiller University Jena, Institute for Infectious Diseases and Infection Control, Jena, Germany
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Mu Z, Wang J, Mu E. Impact of prolonged versus intermittent infusion of meropenem on mortality and clinical outcomes in patients with severe infection: A systematic review and meta-analysis. J Infect Chemother 2025; 31:102634. [PMID: 39864658 DOI: 10.1016/j.jiac.2025.102634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 01/22/2025] [Accepted: 01/24/2025] [Indexed: 01/28/2025]
Abstract
OBJECTIVES To compare the clinical outcomes of patients with severe infection treated with prolonged or intermittent infusion of meropenem. METHODS PubMed, Embase, and Cochrane Central databases were searched until July 2023. Randomized controlled trials (RCTs) or observational studies comparing prolonged versus intermittent infusion of meropenem were considered eligible. The primary outcomes included all-cause mortality and clinical improvement, while secondary outcomes encompassed hospital and intensive care unit (ICU) stay duration, microbial eradication rate, and adverse events. A meta-analysis was conducted using a random-effects model. The risk of bias of included studies was assessed using the modified JADAD scale for RCTs and the Newcastle-Ottawa Scale for observational studies. RESULTS Fourteen studies were included, with a total of 1698 patients. Prolonged infusion of meropenem was associated with a significantly lower mortality rate compared to intermittent infusion (RR = 0.81, 95 % CI: 0.68-0.98). It also significantly improved clinical improvement rates (RR = 1.35, 95 % CI: 1.11-1.64) and microbial eradication rates (RR = 1.19, 95 % CI: 1.08-1.32). There were no statistically significant differences in ICU length of stay or hospital length of stay. Subgroup analyses showed that prolonged infusion was significantly associated with lower mortality and better clinical improvement rates in patients with an APACHE II score <20. CONCLUSIONS Prolonged infusion of meropenem is more effective than intermittent infusion in reducing mortality, improving clinical outcomes, and enhancing microbial eradication, without increasing adverse events. These benefits are particularly evident in patients with lower disease severity (APACHE II < 20), emphasizing the importance of patient stratification in optimizing treatment strategies. REGISTRATION This systematic review and meta-analysis is registered with PROSPERO (number: CRD42023445360).
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Affiliation(s)
- Zi Mu
- China Medical University, Shenyang City, 110001, Liaoning Province, PR China
| | - Jinli Wang
- Department of Critical Care Medicine, Baoan Central Hospital, Shenzhen City, 518102, Guangdong Province, PR China
| | - En Mu
- Department of Critical Care Medicine, Baoan Central Hospital, Shenzhen City, 518102, Guangdong Province, PR China.
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Peng Y, Liu Y, Cheng Z, Zhang Q, Xie F, Zhu S, Li S. Population Pharmacokinetics of Prolonged Infusion for Meropenem: Tailoring Dosing Recommendations for Chinese Critically Ill Patients on Continuous Renal Replacement Therapy with Consideration for Renal Function. Drug Des Devel Ther 2025; 19:1105-1117. [PMID: 39991086 PMCID: PMC11844199 DOI: 10.2147/dddt.s489603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 01/29/2025] [Indexed: 02/25/2025] Open
Abstract
Objective Extended meropenem infusion is increasingly employed to enhance clinical outcomes in critically ill patients. Nonetheless, investigations into such dosing regimens in renal-impaired patients undergoing continuous renal replacement therapy (CRRT) are scarce. This study aims to perform a population pharmacokinetic (PK) analysis of prolonged meropenem infusion in critically ill CRRT patients to inform optimal dosing regimens. Methods Ninety-four concentrations from 21 Chinese critically ill CRRT patients receiving 1 g meropenem every 8-12 hours infused over 2-3 hours were utilized to construct the population PK model. Monte Carlo simulations were employed to assess the efficacy based on PK/PD targets (100% fT>MIC or 100% fT>4×MIC) and the risk of nephrotoxicity (trough concentration ≥45 mg/L) for extended meropenem dosing regimens (0.5-2 g with a 3-hour infusion administered every 6-12 hours). Results Meropenem concentration data was adequately described by a one-compartment model with linear elimination, and creatinine clearance (CLCR) significantly influenced meropenem's endogenous clearance. 0.5 g q6h and 1 g q8h could achieve desirable attainment of 100% fT>MIC target against an MIC≤4 mg/L, with negligible risk of toxicity for CRRT patients across a CLCR range of 10-50 mL/min. 2 g q6h and 2 g q8h is required for targeting 100% fT>4×MIC for the patients, but the associated risk of toxicity is very high (>20%). Conclusion A population PK model was developed for prolonged meropenem infusion in Chinese CRRT patients, and 0.5 g q6h and 1 g q8h may be the optimal regimen for prolonged infusion.
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Affiliation(s)
- Yaru Peng
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, People’s Republic of China
- Office of Clinical Trial Institution, Department of Pharmacy, Peking University Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Yalan Liu
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Zeneng Cheng
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Qiang Zhang
- Department of Respiratory and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
| | - Feifan Xie
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Sucui Zhu
- Department of Respiratory and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Department of Nursing, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
| | - Sanwang Li
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, People’s Republic of China
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Institute of Clinical Pharmacy, Central South University, Changsha, People’s Republic of China
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Rout J, Brysiewicz P, Essack S. Antimicrobial infusion practices within intensive care units: Carbapenem infusion preparation and administration process errors. Intensive Crit Care Nurs 2025; 86:103786. [PMID: 39178524 DOI: 10.1016/j.iccn.2024.103786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 07/11/2024] [Accepted: 07/29/2024] [Indexed: 08/26/2024]
Abstract
OBJECTIVE To describe nurse preparation and administration of intermittent carbapenem infusions. RESEARCH METHODOLOGY/DESIGN This observational study documented the carbapenem infusion process to adult patients in three general intensive care units. MAIN OUTCOME MEASURES Timing and duration of infusions were observed. Volumetric analysis of infusion items was conducted to determine loss of reconstituted carbapenem during preparation and administration phases. RESULTS Carbapenem infusions (n = 223) administered to twenty adult patients were observed. Infusion duration guidance was variable, with two ICUs following current literature recommendations, and one ICU referring to medication package insert information. Within these parameters, only 60 % of infusions complied with infusion duration. Non-compliance with planned time of administration impacted on desired dosing intervals. Incomplete delivery of intended dose was found during: sub-optimal reconstitution of vials, incorrect number of vials reconstituted, failure to administer a dose (missed dose), and discarding antibiotic residue in infusion items. Volumetric analysis of infusion items showed mean dose losses of 4.9 % and 1.2 % in discarded vials and syringes. Mean drug losses of 6.3 % and 30.8 % occurred in discarded infusion bags and infusion lines respectively. No flushing guidance or practice was observed. CONCLUSION Incorrect nurse administration of antibiotics resulted in varying durations of infusions and the non-delivery of prescribed dose. Under-dosing has the potential to contribute to selection pressure for bacterial antibiotic resistance. The increasing frequency of intravenous delivery of antimicrobial agents through infusions requires an understanding of the required duration of administration and how to manage residual drug remaining in the intravenous line once the infusion is completed. IMPLICATIONS FOR CLINICAL PRACTICE Flushing of administration lines is not common practice following intermittent antimicrobial infusions. Although there are multi-factorial risk factors for antimicrobial resistance in the critical care arena, nurse infusion practice must ensure that patients receive intended antimicrobial treatment. Attention must be given to the potential for antimicrobial resistance from environmental contamination with the disposal of infusion items containing undelivered antimicrobial medication.
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Affiliation(s)
- Joan Rout
- School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
| | - Petra Brysiewicz
- School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Sabiha Essack
- Antimicrobial Research Unit, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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7
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Han J, Lin Q, Shan D. Continuous vs Intermittent β-Lactam Antibiotic Infusions for Sepsis. JAMA 2025; 333:174. [PMID: 39680400 DOI: 10.1001/jama.2024.23272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Affiliation(s)
- Jiashu Han
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Queran Lin
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dan Shan
- Clinical Science Institute, University Hospital Galway, Galway, Ireland
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Jirasomprasert T, Tian LY, You DP, Wang YK, Dong L, Zhang YH, Hao GX, van den Anker J, Wu YE, Tang BH, Zhao W, Zheng Y. Population Pharmacokinetics and Dose Optimization of Piperacillin in Infants and Children with Pneumonia. Paediatr Drugs 2025; 27:91-102. [PMID: 39602006 DOI: 10.1007/s40272-024-00664-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/20/2024] [Indexed: 11/29/2024]
Abstract
OBJECTIVE We aimed to determine the piperacillin disposition and optimize the dosing regimens for infants and children with pneumonia. METHODS An opportunistic sampling strategy was used in this pharmacokinetic study. High-performance liquid chromatography was used to measure the concentrations of piperacillin in plasma samples. A population pharmacokinetic model was conducted using NONMEM. RESULTS The pharmacokinetic data of 90 samples from 64 infants and children with pneumonia (age range: 0.09-1.72 years for infants and 2.12-11.10 years for children) were available. A two-compartment model with first-order elimination was the most suitable model to describe the population pharmacokinetics of piperacillin. A covariate analysis indicated that body weight and age were significant factors affecting clearance. Monte Carlo simulations showed that a 50-mg/kg every 8 h or every 12 h dosing regimen results in underdosing. Results both in infants and children showed that an extended infusion (3 h) of various dosing regimens (80, 100, or 130 mg/kg) three times daily or a 300-mg/kg continuous infusion can reach a therapeutic level based on the chosen target for the probability of target attainment threshold of 70%, 80%, and 90% at minimum inhibitory concentration breakpoints of 8 mg/L and 16 mg/L. CONCLUSIONS A population pharmacokinetic model was obtained to evaluate the disposition of piperacillin, and the optimal dosing regimens were provided for use in infants and children with pneumonia.
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Affiliation(s)
- Totsapol Jirasomprasert
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Li-Yuan Tian
- Department of Respiratory Care, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Dian-Ping You
- Pediatric Research Institute, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Ya-Kun Wang
- Department of Respiratory Care, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Lei Dong
- Department of Pharmacy, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Ya-Hui Zhang
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Pharmacy, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Guo-Xiang Hao
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - John van den Anker
- Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, USA
- Departments of Pediatrics, Pharmacology & Physiology, Genomics & Precision Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
- Department of Pediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland
| | - Yue-E Wu
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bo-Hao Tang
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Wei Zhao
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Yi Zheng
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
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Buyukyanbolu E, Gill CM, Genc L, Karakus M, Comert F, Otlu B, Aktas E, Nicolau DP. Dose optimization of piperacillin/tazobactam, cefepime, and ceftazidime for carbapenem-resistant Pseudomonas aeruginosa isolates in Türkiye. Eur J Clin Microbiol Infect Dis 2025; 44:159-165. [PMID: 39546100 DOI: 10.1007/s10096-024-04990-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024]
Abstract
INTRODUCTION Although CRPA may test susceptible to other β-lactams such as ceftazidime (CAZ), cefepime (FEP), and piperacillin/tazobactam (TZP), reduced potency has been observed. We assessed the adequacy of EUCAST Susceptible (S) or Susceptible Increased Exposure (SIE)/(I) doses for CAZ, FEP, and TZP against CRPA clinical isolates. METHODS CRPA isolates were collected from patients at three Turkish hospitals. CAZ, FEP, and TZP MICs were determined using broth microdilution. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for a free time above the MIC (fT > MIC) targets for various doses of each agent against isolates defined as susceptible. fT > MIC targets were 70% for CAZ or FEP and 50% for TZP. Cumulative fraction of response (CFR) was calculated. Optimal PTA and CFR was 90% target achievement. RESULTS The percentages of isolates SIE/I to CAZ, FEP, and TZP were 49,8%, 47%, and 31,8% respectively. Reduced potency was noted with 54,1% of CAZ-S isolates having MICs of 4 or 8 mg/L. Of the FEP and TZP-S isolates, MICs at the breakpoint (8 and 16 mg/L, respectively) were the mode with 45,2 and 53,9% of isolates for each, respectively. At an MIC of 8 mg/L for CAZ, the EUCAST standard dose was insufficient (CFR of 85%). 3 h infusions of EUCAST SIE doses were required for 90% PTA at MIC of 8 mg/L and an optimized CFR of 100%. For FEP, the SIE dose of 2 g q8h 0.5 h infusion of was effective (CFR 96%), utilization of an extended 3 h infusion further optimized the PTA at 8 mg/L (CFR 99%). For TZP, the standard dose of 4.5 q6h administered as a 0.5 h infusion was inadequate (CFR 86%). A standard TZP dose with an extended infusion (4.5 g q8h over 4 h) and the SIE dose 4.5 g q6h 3 h infusion resulted in CFRs > 95%. CONCLUSION These data support the EUCAST SIE breakpoints for FEP and TZP. To optimize PTA at the SIE breakpoint for CAZ, prolonged infusion is required.
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Affiliation(s)
- Ecem Buyukyanbolu
- Department of Medical Microbiology, University of Health Sciences Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey.
- Center for Anti-Infective Research & Development, Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA.
| | - Christian M Gill
- Center for Anti-Infective Research & Development, Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA
| | - Leyla Genc
- Department of Medical Microbiology, University of Health Sciences Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Mehmet Karakus
- Department of Medical Microbiology, University of Health Sciences, Istanbul, Turkey
| | - Fusun Comert
- Faculty of Medicine, Department of Medical Microbiology, Bulent Ecevit University, Zonguldak, Turkey
| | - Baris Otlu
- Faculty of Medicine, Department of Medical Microbiology, Inonu University, Malatya, Turkey
| | - Elif Aktas
- Department of Medical Microbiology, University of Health Sciences Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - David P Nicolau
- Center for Anti-Infective Research & Development, Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA
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10
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Briand A, Bernier L, Pincivy A, Roumeliotis N, Autmizguine J, Marsot A, Métras MÉ, Thibault C. Prolonged Beta-Lactam Infusions in Children: A Systematic Review and Meta-Analysis. J Pediatr 2024; 275:114220. [PMID: 39097265 DOI: 10.1016/j.jpeds.2024.114220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 07/02/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
OBJECTIVE To assess whether beta-lactam extended or continuous beta-lactam infusions (EI/CI) improve clinical outcomes in children with proven or suspected bacterial infections. STUDY DESIGN We included observational and interventional studies that compared beta-lactam EI or CI with standard infusions in children less than 18 years old, and reported on mortality, hospital or intensive care unit length of stay, microbiological cure, and/or clinical cure. Data sources included PubMed, Medline, EBM Reviews, EMBASE, and CINAHL and were searched from January 1, 1980, to November 3, 2023. Thirteen studies (2945 patients) were included: 5 randomized control trials and 8 observational studies. Indications for antimicrobial therapies and clinical severity varied, ranging from cystic fibrosis exacerbation to critically ill children with bacteriemia. RESULTS EI and CI were not associated with a reduction in mortality in randomized control trials (n = 1464; RR 0.93, 95% CI 0.71, 1.21), but were in observational studies (n = 833; RR 0.43, 95% CI 0.19, 0.96). We found no difference in hospital length of stay. Results for clinical and microbiological cures were heterogeneous and reported as narrative review. The included studies were highly heterogeneous, limiting the strength of our findings. The lack of shared definitions for clinical and microbiological cure outcomes precluded analysis. CONCLUSIONS EI and CI were not consistently associated with reduced mortality or length of stay in children. Results were conflicting regarding clinical and microbiological cures. More well-designed studies targeting high-risk populations are necessary to determine the efficacy of these alternative dosing strategies.
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Affiliation(s)
- Annabelle Briand
- Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada; Department of Pediatrics, CHU Sainte-Justine, Montreal QC, Canada
| | - Laurie Bernier
- Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada
| | - Alix Pincivy
- Library Services, CHU Sainte-Justine, Montreal, QC, Canada
| | - Nadia Roumeliotis
- Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada; Division of Critical Care Medicine, Department of Pediatrics, CHU Sainte-Justine, Montreal, QC, Canada; CHU Sainte Justine Research Center, Montreal, QC, Canada
| | - Julie Autmizguine
- Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada; CHU Sainte Justine Research Center, Montreal, QC, Canada; Department of Pharmacology and Physiology, Université de Montréal, CHU Sainte-Justine, Montreal, QC, Canada; Division of Infectious Diseases, Department of Pediatrics, CHU Sainte-Justine, Montreal, QC, Canada
| | - Amélie Marsot
- Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada; CHU Sainte Justine Research Center, Montreal, QC, Canada
| | - Marie-Élaine Métras
- Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada; Division of Critical Care Medicine, Department of Pediatrics, CHU Sainte-Justine, Montreal, QC, Canada; CHU Sainte Justine Research Center, Montreal, QC, Canada
| | - Celine Thibault
- Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada; Division of Critical Care Medicine, Department of Pediatrics, CHU Sainte-Justine, Montreal, QC, Canada; CHU Sainte Justine Research Center, Montreal, QC, Canada.
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11
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Rademacher J, Ewig S, Grabein B, Nachtigall I, Abele-Horn M, Deja M, Gaßner M, Gatermann S, Geffers C, Gerlach H, Hagel S, Heußel CP, Kluge S, Kolditz M, Kramme E, Kühl H, Panning M, Rath PM, Rohde G, Schaaf B, Salzer HJF, Schreiter D, Schweisfurth H, Unverzagt S, Weigand MA, Welte T, Pletz MW. Key summary of German national guideline for adult patients with nosocomial pneumonia- Update 2024 Funding number at the Federal Joint Committee (G-BA): 01VSF22007. Infection 2024; 52:2531-2545. [PMID: 39115698 PMCID: PMC11621171 DOI: 10.1007/s15010-024-02358-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 07/19/2024] [Indexed: 12/07/2024]
Abstract
PURPOSE This executive summary of a German national guideline aims to provide the most relevant evidence-based recommendations on the diagnosis and treatment of nosocomial pneumonia. METHODS The guideline made use of a systematic assessment and decision process using evidence to decision framework (GRADE). Recommendations were consented by an interdisciplinary panel. Evidence analysis and interpretation was supported by the German innovation fund providing extensive literature searches and (meta-) analyses by an independent methodologist. For this executive summary, selected key recommendations are presented including the quality of evidence and rationale for the level of recommendation. RESULTS The original guideline contains 26 recommendations for the diagnosis and treatment of adults with nosocomial pneumonia, thirteen of which are based on systematic review and/or meta-analysis, while the other 13 represent consensus expert opinion. For this key summary, we present 11 most relevant for everyday clinical practice key recommendations with evidence overview and rationale, of which two are expert consensus and 9 evidence-based (4 strong, 5 weak and 2 open recommendations). For the management of nosocomial pneumonia patients should be divided in those with and without risk factors for multidrug-resistant pathogens and/or Pseudomonas aeruginosa. Bacterial multiplex-polymerase chain reaction (PCR) should not be used routinely. Bronchoscopic diagnosis is not considered superior to´non-bronchoscopic sampling in terms of main outcomes. Only patients with septic shock and the presence of an additional risk factor for multidrug-resistant pathogens (MDRP) should receive empiric combination therapy. In clinically stabilized patients, antibiotic therapy should be de-escalated and focused. In critically ill patients, prolonged application of suitable beta-lactam antibiotics should be preferred. Therapy duration is suggested for 7-8 days. Procalcitonin (PCT) based algorithm might be used to shorten the duration of antibiotic treatment. Patients on the intensive care unit (ICU) are at risk for invasive pulmonary aspergillosis (IPA). Diagnostics for Aspergillus should be performed with an antigen test from bronchial lavage fluid. CONCLUSION The current guideline focuses on German epidemiology and standards of care. It should be a guide for the current treatment and management of nosocomial pneumonia in Germany.
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Affiliation(s)
- Jessica Rademacher
- Department of Respiratory Medicine and Infectious Diseases, German Centre of Lung Research (DZL), Hannover Medical School, Hannover, Germany.
| | - Santiago Ewig
- Department of Respiratory and Infectious Diseases, Thoraxzentrum Ruhrgebiet, EVK Herne and Augusta-Kranken-Anstalt Bochum, Bochum, Germany
| | - Béatrice Grabein
- LMU Hospital, Clinical Microbiology and Hospital Hygiene, Munich, Germany
| | - Irit Nachtigall
- Division of Infectious Diseases and Infection Prevention, Helios Hospital Emil-Von-Behring, Berlin, Germany
| | - Marianne Abele-Horn
- Institute for Hygiene and Microbiology, University of Würzburg, Würzburg, Germany
| | - Maria Deja
- Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Berlin, Lübeck, Germany
| | - Martina Gaßner
- Department of Anaesthesiology and Intensive Care Medicine, Charité, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Sören Gatermann
- National Reference Centre for Multidrug-Resistant Gram-Negative Bacteria, Department of Medical Microbiology, Ruhr-University Bochum, Bochum, Germany
| | - Christine Geffers
- Charité, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Herwig Gerlach
- Department for Anaesthesia, Intensive Care Medicine and Pain Management, Vivantes-Klinikum Neukoelln, Berlin, Germany
| | - Stefan Hagel
- Institute for Infectious Diseases and Infection Control, Jena University Hospital-Friedrich Schiller University Jena, Jena, Germany
| | - Claus Peter Heußel
- Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Kluge
- Department of Intensive Care, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Martin Kolditz
- Division of Pulmonology, Medical Department 1, University Hospital of TU Dresden, Dresden, Germany
| | - Evelyn Kramme
- Department of Infectious Diseases and Microbiology, University of Lübeck and University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Hilmar Kühl
- Department of Radiology, St. Bernhard-Hospital Kamp-Lintfort, Bürgermeister-Schmelzing-Str. 90, 47475, Kamp-Lintfort, Germany
| | - Marcus Panning
- Institute of Virology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peter-Michael Rath
- Institute for Medical Microbiology, University Medicine Essen, Essen, Germany
| | - Gernot Rohde
- Department of Respiratory Medicine, Goethe University Frankfurt, University Hospital, Frankfurt/Main, Germany
| | - Bernhard Schaaf
- Department of Respiratory Medicine and Infectious Diseases, Klinikum Dortmund, Dortmund, Germany
| | - Helmut J F Salzer
- Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine-Pneumology, Kepler University Hospital, Medical Faculty, Johannes Kepler University, Linz, Austria
| | - Dierk Schreiter
- Department of Intensive Care Medicine, Helios Park Clinic, Leipzig, Germany
| | | | - Susanne Unverzagt
- Institute of General Practice and Family Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Markus A Weigand
- Department of Anesthesiology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Tobias Welte
- Department of Respiratory Medicine and Infectious Diseases, German Centre of Lung Research (DZL), Hannover Medical School, Hannover, Germany
| | - Mathias W Pletz
- Institute for Infectious Diseases and Infection Control, Jena University Hospital-Friedrich Schiller University Jena, Jena, Germany
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12
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Abdul-Aziz MH, Dulhunty JM, Rajbhandari D, Roberts JA, Lipman J. Is it time to implement prolonged infusions of beta-lactam antibiotics in and beyond critical care settings? Intern Med J 2024. [PMID: 39600156 DOI: 10.1111/imj.16584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024]
Affiliation(s)
- Mohd H Abdul-Aziz
- University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Joel M Dulhunty
- Intensive Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
- Medical Administration, Redcliffe Hospital, Redcliffe, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Critical Care Program, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
| | - Dorrilyn Rajbhandari
- Critical Care Program, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
| | - Jason A Roberts
- University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Intensive Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
- Herston Infectious Diseases Institute, Metro North Health, Brisbane, Queensland, Australia
- Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
| | - Jeffrey Lipman
- University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Intensive Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
- Critical Care Program, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
- Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
- Jamieson Trauma Institute, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
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13
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Laffont-Lozes P, Naciri T, Pantel A, Martin A, Pruvot-Occean AS, Haignere V, Loubet P, Sotto A, Larcher R. First case report of a vertebral osteomyelitis caused by carbapenem-resistant Enterobacter cloacae treated with imipenem/cilastatin/relebactam prolonged infusion then meropenem/vaborbactam in continuous infusion. Front Pharmacol 2024; 15:1347306. [PMID: 39545060 PMCID: PMC11561750 DOI: 10.3389/fphar.2024.1347306] [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: 11/30/2023] [Accepted: 09/18/2024] [Indexed: 11/17/2024] Open
Abstract
Introduction Bone and joint infections (BJIs) caused by multidrug-resistant bacteria are becoming more frequent. However, data on the use of novel β-lactam/β-lactamase inhibitors, such as imipenem/cilastatin/relebactam (I-R) and meropenem/vaborbactam (MVB), to treat BJIs is lacking. Furthermore, prolonged infusions of these β-lactams should theoretically optimize pharmacokinetic/pharmacodynamics target in these indications, but there are currently no reports on this type of infusions, especially in the setting of BJI. Case Presentation We report a case of a vertebral osteomyelitis caused by carbapenem-resistant Enterobacter cloacae successfully treated with extended-infusion of I-R (1.25 g q6h over 2 h), then with continuous infusion of MVB (2 g q4h as over 4 h). Therapeutic drug monitoring confirmed that extended-infusion of I-R and continuous infusion of MVB achieved serum concentrations up to 12 mg/L of imipenem and 19 mg/L of meropenem, respectively. Conclusion The favourable outcome of this patient treated for a vertebral osteomyelitis caused by carbapenem-resistant E. cloacae suggest that extended- and continuous infusions of I-R and MVB, are promising regimens for treatment of BJIs caused by carbapenem-resistant Enterobacterales.
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Affiliation(s)
| | - Tayma Naciri
- Department of Infectious and Tropical Diseases, Nimes University Hospital, Nîmes, France
| | - Alix Pantel
- Department of Microbiology and Hospital Hygiene, Nimes University Hospital, NîmesFrance
- VBIC (Bacterial Virulence and Chronic Infection), INSERM (French Institute of Health and Medical Research), Montpellier University, Montpellier, France
| | - Aurélie Martin
- Department of Infectious and Tropical Diseases, Nimes University Hospital, Nîmes, France
| | | | - Vincent Haignere
- Department of Orthopaedic Surgery and Traumatology, Nimes University Hospital, Nîmes, France
| | - Paul Loubet
- Department of Infectious and Tropical Diseases, Nimes University Hospital, Nîmes, France
- VBIC (Bacterial Virulence and Chronic Infection), INSERM (French Institute of Health and Medical Research), Montpellier University, Montpellier, France
| | - Albert Sotto
- Department of Infectious and Tropical Diseases, Nimes University Hospital, Nîmes, France
- VBIC (Bacterial Virulence and Chronic Infection), INSERM (French Institute of Health and Medical Research), Montpellier University, Montpellier, France
| | - Romaric Larcher
- Department of Infectious and Tropical Diseases, Nimes University Hospital, Nîmes, France
- PhyMedExp (Physiology and Experimental Medicine), INSERM (French Institute of Health and Medical Research), CNRS (French National Centre for Scientific Research), University of Montpellier, Montpellier, France
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14
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Metsä-Simola N, Saarenketo J, Lehtonen H, Broman N, Häggblom T, Björklöf P, Sariola S, Valta MP. Guidelines to practice in hospitals at home: safe and effective continuous infusion pumps substantially increased penicillin use in erysipelas treatment. Eur J Public Health 2024; 34:860-865. [PMID: 38996407 PMCID: PMC11430903 DOI: 10.1093/eurpub/ckae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/14/2024] Open
Abstract
Hospitals at home are increasingly offering outpatient parenteral antimicrobial therapy (OPAT) in an attempt to reduce costly inpatient care, but these settings favour broad-spectrum antibiotics that require less frequent dosing than penicillin. Benzyl penicillin could be delivered via continuous infusion pumps (eCIPs), but studies on their safety and efficacy in OPAT are scarce, and it remains unclear how much the availability of eCIPs increases penicillin use in real-life settings. We examined 462 electronic healthcare records of erysipelas patients treated between January 2018 and January 2022 in a large Finnish OPAT clinic. Average marginal effects from logistic models were estimated to assess how the introduction of eCIPs in December 2020 affected penicillin use and to compare clinical outcomes between patients with and without eCIPs. Introduction of eCIPs increased the predicted probability of penicillin treatment by 36.0 percentage points (95% confidence interval 25.5-46.5). During eCIP implementation, patients who received an eCIP had 73.1 (58.0-88.2) percentage points higher probability than patients without an eCIP to receive penicillin treatment. They also had about 20 percentage points higher probability to be cured at the time of discharge and 3 months after it. Patient and nurse satisfaction regarding eCIPs was very high. Benzyl penicillin eCIP treatment is effective and safe, and substantially increases the use of penicillin instead of broad-spectrum antibiotics. To reduce the risk of antimicrobial resistance, eCIPs could increasingly be promoted for use in OPAT clinics, and there should be adequate education and support in their implementation.
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Affiliation(s)
- Niina Metsä-Simola
- Helsinki Institute for Demography and Population Health, University of Helsinki, Helsinki, Finland
- Max Planck, University of Helsinki Center for Social Inequalities in Population Health, Helsinki, Finland
| | - Jenni Saarenketo
- Turku City Hospital OPAT Clinic, The Wellbeing Services County of Southwest Finland, Turku, Finland
| | - Henri Lehtonen
- Turku City Hospital OPAT Clinic, The Wellbeing Services County of Southwest Finland, Turku, Finland
- Department of Medicine, University of Turku, Turku, Finland
| | - Niklas Broman
- Turku City Hospital OPAT Clinic, The Wellbeing Services County of Southwest Finland, Turku, Finland
- Department of Medicine, University of Turku, Turku, Finland
| | - Tony Häggblom
- Turku City Hospital Department of Infectious Diseases, The Wellbeing Services County of Southwest Finland, Turku, Finland
| | - Pia Björklöf
- Turku City Hospital OPAT Clinic, The Wellbeing Services County of Southwest Finland, Turku, Finland
| | - Salla Sariola
- Faculty of Social Sciences, University of Helsinki, Helsinki, Finland
| | - Maija P Valta
- Turku City Hospital OPAT Clinic, The Wellbeing Services County of Southwest Finland, Turku, Finland
- Department of Medicine, University of Turku, Turku, Finland
- Department of Hematology and Stem Cell Transplantation, Turku University Hospital, The Wellbeing Services County of Southwest Finland, Turku, Finland
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15
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Rolain H, Schwartz Z, Jubrail R, Downes KJ, Hong L, FakhriRavari A, Rhodes NJ, Scheetz MH. Meta-analysis on safety of standard vs. prolonged infusion of beta-lactams. Int J Antimicrob Agents 2024; 64:107309. [PMID: 39168416 DOI: 10.1016/j.ijantimicag.2024.107309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/11/2024] [Accepted: 08/12/2024] [Indexed: 08/23/2024]
Abstract
BACKGROUND Efficacy for prolonged infusion beta-lactam dosing schemes has been previously described, but there has been less focus on the safety of standard vs. prolonged infusion protocols of beta-lactams. This study explored differences in adverse drug reactions (ADRs) reported for beta-lactams between each of these infusion protocols. METHODS A systematic review of MEDLINE literature databases via PubMed was conducted and references were reviewed. Articles were compiled and assessed with specific inclusion/exclusion criteria. We included randomised and nonrandomised, prospective, and retrospective cohort studies that reported adverse drug reactions (ADRs) due to either standard (30-60 mins) or prolonged (≥3 h) infusions of beta-lactam infusions. Total ADRs between strategies were analysed by infusion methodology. The most consistently reported ADRs were subject to meta-analysis across studies. RESULTS 12 studies met inclusion/exclusion criteria with data for 4163 patients. There was insufficient data to systematically analyse neurotoxicity or cytopenias. Seven studies reported on nephrotoxicity outcomes with no significant difference in event rates between standard (n = 434/2258,19.2%) vs. prolonged infusion (n = 266/1271, 20.9%) of beta-lactams (OR = 1.08, 95% CI [0.91, 1.29]). Six studies observed diarrhoea in a total of 759 patients with no significant difference in patients of standard (n = 18/399, 4.5%) vs. prolonged (n = 19/360, 5.3%) infusion of beta-lactams (OR = 1.14, 95% CI [0.59,2.20]). CONCLUSION Prolonged and standard infusion schemes for beta-lactams demonstrated similar adverse event rates. Future research should focus on improved standardisation of adverse effect definitions and a priori aim to study neurotoxicity and cytopenias. Consistent recording of ADRs and standardised definitions of these reactions will be paramount to further study of this subject.
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Affiliation(s)
- Hunter Rolain
- Chicago College of Osteopathic Medicine, Downers Grove Campus, Midwestern University, Downers Grove, IL, USA
| | - Zachary Schwartz
- Chicago College of Osteopathic Medicine, Downers Grove Campus, Midwestern University, Downers Grove, IL, USA
| | - Raymond Jubrail
- Department of Pharmacy Practice, Midwestern University, Downers Grove Campus, Downers Grove, IL, USA
| | - Kevin J Downes
- Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA
| | - Lisa Hong
- Department of Pharmacy Practice, Loma Linda University School of Pharmacy, Loma Linda, CA, USA
| | - Alireza FakhriRavari
- Department of Pharmacy Practice, Loma Linda University School of Pharmacy, Loma Linda, CA, USA
| | - Nathaniel J Rhodes
- Department of Pharmacy Practice, Midwestern University, Downers Grove Campus, Downers Grove, IL, USA; Pharmacometrics Center of Excellence, Midwestern University, Downers Grove Campus, Downers Grove, IL, USA; Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA
| | - Marc H Scheetz
- Department of Pharmacy Practice, Midwestern University, Downers Grove Campus, Downers Grove, IL, USA; Pharmacometrics Center of Excellence, Midwestern University, Downers Grove Campus, Downers Grove, IL, USA; Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA.
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16
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Gonçalves Pereira J, Fernandes J, Mendes T, Gonzalez FA, Fernandes SM. Artificial Intelligence to Close the Gap between Pharmacokinetic/Pharmacodynamic Targets and Clinical Outcomes in Critically Ill Patients: A Narrative Review on Beta Lactams. Antibiotics (Basel) 2024; 13:853. [PMID: 39335027 PMCID: PMC11428226 DOI: 10.3390/antibiotics13090853] [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: 07/30/2024] [Revised: 08/30/2024] [Accepted: 09/04/2024] [Indexed: 09/30/2024] Open
Abstract
Antimicrobial dosing can be a complex challenge. Although a solid rationale exists for a link between antibiotic exposure and outcome, conflicting data suggest a poor correlation between pharmacokinetic/pharmacodynamic targets and infection control. Different reasons may lead to this discrepancy: poor tissue penetration by β-lactams due to inflammation and inadequate tissue perfusion; different bacterial response to antibiotics and biofilms; heterogeneity of the host's immune response and drug metabolism; bacterial tolerance and acquisition of resistance during therapy. Consequently, either a fixed dose of antibiotics or a fixed target concentration may be doomed to fail. The role of biomarkers in understanding and monitoring host response to infection is also incompletely defined. Nowadays, with the ever-growing stream of data collected in hospitals, utilizing the most efficient analytical tools may lead to better personalization of therapy. The rise of artificial intelligence and machine learning has allowed large amounts of data to be rapidly accessed and analyzed. These unsupervised learning models can apprehend the data structure and identify homogeneous subgroups, facilitating the individualization of medical interventions. This review aims to discuss the challenges of β-lactam dosing, focusing on its pharmacodynamics and the new challenges and opportunities arising from integrating machine learning algorithms to personalize patient treatment.
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Affiliation(s)
- João Gonçalves Pereira
- Grupo de Investigação e Desenvolvimento em Infeção e Sépsis, Clínica Universitária de Medicina Intensiva, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisbon, Portugal
- Serviço de Medicina Intensiva, Hospital Vila Franca de Xira, 2600-009 Vila Franca de Xira, Portugal
| | - Joana Fernandes
- Grupo de Investigação e Desenvolvimento em Infeção e Sépsis, Serviço de Medicina Intensiva, Centro Hospitalar de Trás-os-Montes e Alto Douro, 5000-508 Vila Real, Portugal
| | - Tânia Mendes
- Serviço de Medicina Interna, Hospital Vila Franca de Xira, 2600-009 Vila Franca de Xira, Portugal
| | - Filipe André Gonzalez
- Serviço de Medicina Intensiva, Hospital Garcia De Orta, Clínica Universitária de Medicina Intensiva, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisbon, Portugal
| | - Susana M Fernandes
- Grupo de Investigação e Desenvolvimento em Infeção e Sépsis, Serviço de Medicina Intensiva, Hospital Santa Maria, Clínica Universitária de Medicina Intensiva, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisbon, Portugal
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17
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Wicha SG, Kinast C, Münchow M, Wittova S, Greppmair S, Kunzelmann AK, Zoller M, Paal M, Vogeser M, Habler K, Weig T, Terpolilli N, Heck S, Dimitriadis K, Scharf C, Liebchen U. Meropenem pharmacokinetics in cerebrospinal fluid: comparing intermittent and continuous infusion strategies in critically ill patients-a prospective cohort study. Antimicrob Agents Chemother 2024; 68:e0045124. [PMID: 39082803 PMCID: PMC11373225 DOI: 10.1128/aac.00451-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 07/08/2024] [Indexed: 09/05/2024] Open
Abstract
Meropenem penetration into the cerebrospinal fluid (CSF) is subject to high interindividual variability resulting in uncertain target attainment in CSF. Recently, several authors recommended administering meropenem as a continuous infusion (CI) to optimize CSF exposure. This study aimed to compare the concentrations and pharmacokinetics of meropenem in CSF after intermittent infusion (II) and CI. This prospective, observational study (NCT04426383) included critically ill patients with external ventricular drains who received either II or CI of meropenem. Meropenem pharmacokinetics in plasma and CSF were characterized using population pharmacokinetic modeling (NONMEM 7.5). The developed model was used to compare the concentration-time profile and probability of target attainment (PTA) between II and CI. A total of 16 patients (8 CI, 8 II; samples: nplasma = 243, nCSF = 263) were recruited, with nine patients (5 CI, 4 II) suffering from cerebral and seven patients from extracerebral infections. A one-compartment model described the plasma concentrations adequately. Meropenem penetration into the CSF (partition coefficient (KP), cCSF/cplasma) was generally low (6.0%), exhibiting substantial between-subject variability (coefficient of variation: 84.0%). There was no correlation between the infusion mode and KP, but interleukin (IL)-6 measured in CSF showed a strong positive correlation with KP (P < 0.001). Dosing simulations revealed no relevant differences in CSF concentrations and PTA in CSF between CI and II. Our study did not demonstrate increased penetration rates or higher concentrations of meropenem in the CSF with CI compared with II. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT04426383.
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Affiliation(s)
- Sebastian G. Wicha
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany
| | - Christina Kinast
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany
| | - Max Münchow
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany
| | - Sandra Wittova
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany
| | - Sebastian Greppmair
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany
| | | | - Michael Zoller
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany
| | - Michael Paal
- Institute of Laboratory Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Michael Vogeser
- Institute of Laboratory Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Katharina Habler
- Institute of Laboratory Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Thomas Weig
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany
| | - Nicole Terpolilli
- Department of Neurosurgery, LMU University Hospital, LMU Munich, Munich, Germany
| | - Suzette Heck
- Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany
| | | | - Christina Scharf
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany
| | - Uwe Liebchen
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany
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18
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Johnson EG, Maki Ortiz K, Adams DT, Kaur S, Faust AC, Yang H, Alvarez CA, Hall RG. A Retrospective Analysis of Intravenous Push versus Extended Infusion Meropenem in Critically Ill Patients. Antibiotics (Basel) 2024; 13:835. [PMID: 39335009 PMCID: PMC11429397 DOI: 10.3390/antibiotics13090835] [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: 07/23/2024] [Revised: 08/19/2024] [Accepted: 08/28/2024] [Indexed: 09/30/2024] Open
Abstract
Meropenem is a broad-spectrum antibiotic used for the treatment of multi-drug-resistant infections. Due to its pharmacokinetic profile, meropenem's activity is optimized by maintaining a specific time the serum concentration remains above the minimum inhibitory concentration (MIC) via extended infusion (EI), continuous infusion, or intermittent infusion dosing strategies. The available literature varies regarding the superiority of these dosing strategies. This study's primary objective was to determine the difference in time to clinical stabilization between intravenous push (IVP) and EI administration. We performed a retrospective pilot cohort study of 100 critically ill patients who received meropenem by IVP (n = 50) or EI (n = 50) during their intensive care unit (ICU) admission. There was no statistically significant difference in the overall achievement of clinical stabilization between IVP and EI (48% vs. 44%, p = 0.17). However, the median time to clinical stability was shorter for the EI group (20.4 vs. 66.2 h, p = 0.01). EI administration was associated with shorter hospital (13 vs. 17 days; p = 0.05) and ICU (6 vs. 9 days; p = 0.02) lengths of stay. Although we did not find a statistically significant difference in the overall time to clinical stabilization, the results of this pilot study suggest that EI administration may produce quicker clinical resolutions than IVP.
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Affiliation(s)
- Emory G. Johnson
- Texas Health Presbyterian Hospital Dallas, Dallas, TX 75231, USA (A.C.F.)
- Health Sciences Center, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas, TX 75235, USA (C.A.A.); (R.G.H.2nd)
| | - Kayla Maki Ortiz
- Texas Health Presbyterian Hospital Dallas, Dallas, TX 75231, USA (A.C.F.)
| | - David T. Adams
- Texas Health Harris Methodist Hospital Fort Worth, Fort Worth, TX 76104, USA (S.K.)
| | - Satwinder Kaur
- Texas Health Harris Methodist Hospital Fort Worth, Fort Worth, TX 76104, USA (S.K.)
| | - Andrew C. Faust
- Texas Health Presbyterian Hospital Dallas, Dallas, TX 75231, USA (A.C.F.)
| | - Hui Yang
- Health Sciences Center, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas, TX 75235, USA (C.A.A.); (R.G.H.2nd)
- Center for Real-World Evidence, Dallas, TX 75235, USA
| | - Carlos A. Alvarez
- Health Sciences Center, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas, TX 75235, USA (C.A.A.); (R.G.H.2nd)
- Center for Real-World Evidence, Dallas, TX 75235, USA
| | - Ronald G. Hall
- Health Sciences Center, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas, TX 75235, USA (C.A.A.); (R.G.H.2nd)
- Center for Real-World Evidence, Dallas, TX 75235, USA
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19
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Walker MK, Strich JR. In sepsis or septic shock, prolonged vs. intermittent infusion of β-lactam antibiotics reduces mortality at 90 d. Ann Intern Med 2024; 177:JC103. [PMID: 39222508 DOI: 10.7326/annals-24-01751-jc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Abstract
SOURCE CITATION Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs intermittent infusions of β-lactam antibiotics in adults with sepsis or septic shock: a systematic review and meta-analysis. JAMA. 12 June 2024. [Epub ahead of print.] 38864162.
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Affiliation(s)
- Morgan K Walker
- National Institutes of Health, Critical Care Medicine Department, Bethesda, Maryland, USA (M.K.W., J.R.S.)
| | - Jeffrey R Strich
- National Institutes of Health, Critical Care Medicine Department, Bethesda, Maryland, USA (M.K.W., J.R.S.)
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20
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Walker MK, Strich JR. In sepsis, continuous and intermittent infusion of β-lactam antibiotics did not differ for mortality at 90 d. Ann Intern Med 2024; 177:JC102. [PMID: 39222506 DOI: 10.7326/annals-24-01752-jc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Abstract
SOURCE CITATION Dulhunty JM, Brett SJ, De Waele JJ, et al; BLING III Study Investigators. Continuous vs intermittent β-lactam antibiotic infusions in critically ill patients with sepsis: the BLING III randomized clinical trial. JAMA. 12 June 2024. [Epub ahead of print.] 38864155.
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Affiliation(s)
- Morgan K Walker
- National Institutes of Health, Critical Care Medicine Department, Bethesda, Maryland, USA (M.K.W., J.R.S.)
| | - Jeffrey R Strich
- National Institutes of Health, Critical Care Medicine Department, Bethesda, Maryland, USA (M.K.W., J.R.S.)
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21
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Wiersinga WJ, van Agtmael MA. Resolving the Dilemma on Continuous vs Intermittent β-Lactam Antibiotics in Sepsis. JAMA 2024; 332:623-625. [PMID: 38864160 DOI: 10.1001/jama.2024.10168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/13/2024]
Affiliation(s)
- W Joost Wiersinga
- Center for Experimental and Molecular Medicine, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Department of Medicine, Division of Infectious Diseases, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Michiel A van Agtmael
- Department of Medicine, Division of Infectious Diseases, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Department of Medicine, Section Pharmacotherapy, Amsterdam University Medical Center, Amsterdam, the Netherlands
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22
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Abdul-Aziz MH, Hammond NE, Brett SJ, Cotta MO, De Waele JJ, Devaux A, Di Tanna GL, Dulhunty JM, Elkady H, Eriksson L, Hasan MS, Khan AB, Lipman J, Liu X, Monti G, Myburgh J, Novy E, Omar S, Rajbhandari D, Roger C, Sjövall F, Zaghi I, Zangrillo A, Delaney A, Roberts JA. Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis. JAMA 2024; 332:638-648. [PMID: 38864162 PMCID: PMC11170459 DOI: 10.1001/jama.2024.9803] [Citation(s) in RCA: 34] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 05/07/2024] [Indexed: 06/13/2024]
Abstract
Importance There is uncertainty about whether prolonged infusions of β-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock. Objective To determine whether prolonged β-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions. Data Sources The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024. Study Selection Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of β-lactam antibiotics in critically ill adults with sepsis or septic shock. Data Extraction and Synthesis Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach. Main Outcomes and Measures The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure. Results From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of β-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of β-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty). Conclusions and Relevance Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged β-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock. Trial Registration PROSPERO Identifier: CRD42023399434.
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Affiliation(s)
- Mohd H. Abdul-Aziz
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Naomi E. Hammond
- Critical Care Program, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Stephen J. Brett
- Department of Surgery and Cancer, Imperial College, London, United Kingdom
| | - Menino O. Cotta
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Jan J. De Waele
- Department of Intensive Care Medicine, Ghent University Hospital, Ghent, Belgium
| | - Anthony Devaux
- Statistics Division, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
| | - Gian Luca Di Tanna
- Statistics Division, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
- Department of Business Economics, Health and Social Care, University of Applied Sciences and Arts of Southern Switzerland, Manno, Switzerland
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Joel M. Dulhunty
- Critical Care Program, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
- Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- Redcliffe Hospital, Redcliffe, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Hatem Elkady
- Department of Intensive Care Medicine, Westmead Hospital, Sydney, New South Wales, Australia
| | - Lars Eriksson
- UQ Library, The University of Queensland, Brisbane, Queensland, Australia
| | - M. Shahnaz Hasan
- Department of Anesthesiology, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Ayesha Bibi Khan
- Division of Critical Care, University of Witwatersrand, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa
| | - Jeffrey Lipman
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- Jamieson Trauma Institute, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- Division of Anesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
| | - Xiaoqiu Liu
- Statistics Division, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
- School of Population Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Giacomo Monti
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - John Myburgh
- Critical Care Program, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
- Department of Intensive Care, St George Hospital, Kogarah, New South Wales, Australia
| | - Emmanuel Novy
- Service d’anesthésie-réanimation et médicine péri-opératoire Brabois adulte, CHRU de Nancy, Nancy, France
- Université de Lorraine, SIMPA, Nancy, France
| | - Shahed Omar
- Division of Critical Care, University of Witwatersrand, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa
| | - Dorrilyn Rajbhandari
- Critical Care Program, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
| | - Claire Roger
- Département d’anesthésie et réanimation, douleur et médecine d’urgence, CHU Carémeau, Nîmes, France
- UR UM 103IMAGINE, Faculté de Médecine, Montpellier Université, Nîmes, France
| | - Fredrik Sjövall
- Intensive and Perioperative Care, Skåne University Hospital, Malmö, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Irene Zaghi
- Department of Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy
| | - Alberto Zangrillo
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Anthony Delaney
- Critical Care Program, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Jason A. Roberts
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- Division of Anesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
- Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Queensland, Australia
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23
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Dulhunty JM, Brett SJ, De Waele JJ, Rajbhandari D, Billot L, Cotta MO, Davis JS, Finfer S, Hammond NE, Knowles S, Liu X, McGuinness S, Mysore J, Paterson DL, Peake S, Rhodes A, Roberts JA, Roger C, Shirwadkar C, Starr T, Taylor C, Myburgh JA, Lipman J. Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial. JAMA 2024; 332:629-637. [PMID: 38864155 PMCID: PMC11170452 DOI: 10.1001/jama.2024.9779] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/07/2024] [Indexed: 06/13/2024]
Abstract
Importance Whether β-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective To evaluate whether continuous vs intermittent infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention Eligible patients were randomized to receive an equivalent 24-hour dose of a β-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance The observed difference in 90-day mortality between continuous vs intermittent infusions of β-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration ClinicalTrials.gov Identifier: NCT03213990.
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Affiliation(s)
- Joel M. Dulhunty
- Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- Redcliffe Hospital, Brisbane, Queensland, Australia
- The University of Queensland, Brisbane, Queensland, Australia
| | - Stephen J. Brett
- Imperial College Healthcare NHS Trust, London, United Kingdom
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Jan J. De Waele
- Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium
| | - Dorrilyn Rajbhandari
- The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia
| | - Laurent Billot
- The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia
| | - Menino O. Cotta
- Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- The University of Queensland, Brisbane, Queensland, Australia
| | - Joshua S. Davis
- Infection Research Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
- Department of Infectious Diseases, John Hunter Hospital, Newcastle, New South Wales, Australia
| | - Simon Finfer
- The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia
- School of Public Health, Imperial College London, United Kingdom
| | - Naomi E. Hammond
- The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Serena Knowles
- The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia
| | - Xiaoqiu Liu
- The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia
| | - Shay McGuinness
- Auckland City Hospital, Auckland, New Zealand
- Medical Research Institute of New Zealand, Wellington, New Zealand
| | - Jayanthi Mysore
- The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia
| | - David L. Paterson
- Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- The University of Queensland, Brisbane, Queensland, Australia
- Saw Swee Hock School of Public Health and Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Sandra Peake
- The Queen Elizabeth Hospital, Adelaide, South Australia, Australia
- School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia
- School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Andrew Rhodes
- St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
- St George’s University of London, London, United Kingdom
| | - Jason A. Roberts
- Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- The University of Queensland, Brisbane, Queensland, Australia
- Herston Infectious Diseases Institute, Metro North Health, Brisbane, Queensland, Australia
- Department of Anesthesiology, Critical Care, Pain, and Emergency Medicine, University Hospital of Nîmes, Nîmes, France
| | - Claire Roger
- Department of Anesthesiology, Critical Care, Pain, and Emergency Medicine, University Hospital of Nîmes, Nîmes, France
- University of Montpellier, Montpellier, France
| | | | - Therese Starr
- Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- Metro North Health, Brisbane, Queensland, Australia
| | - Colman Taylor
- The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia
| | - John A. Myburgh
- The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia
- St George Hospital, Sydney, New South Wales, Australia
| | - Jeffrey Lipman
- Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- The University of Queensland, Brisbane, Queensland, Australia
- Department of Anesthesiology, Critical Care, Pain, and Emergency Medicine, University Hospital of Nîmes, Nîmes, France
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24
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Khilnani GC, Tiwari P, Mittal S, Kulkarni AP, Chaudhry D, Zirpe KG, Todi SK, Mohan A, Hegde A, Jagiasi BG, Krishna B, Rodrigues C, Govil D, Pal D, Divatia JV, Sengar M, Gupta M, Desai M, Rungta N, Prayag PS, Bhattacharya PK, Samavedam S, Dixit SB, Sharma S, Bandopadhyay S, Kola VR, Deswal V, Mehta Y, Singh YP, Myatra SN. Guidelines for Antibiotics Prescription in Critically Ill Patients. Indian J Crit Care Med 2024; 28:S104-S216. [PMID: 39234229 PMCID: PMC11369928 DOI: 10.5005/jp-journals-10071-24677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/20/2024] [Indexed: 09/06/2024] Open
Abstract
How to cite this article: Khilnani GC, Tiwari P, Mittal S, Kulkarni AP, Chaudhry D, Zirpe KG, et al. Guidelines for Antibiotics Prescription in Critically Ill Patients. Indian J Crit Care Med 2024;28(S2):S104-S216.
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Affiliation(s)
- Gopi C Khilnani
- Department of Pulmonary, Critical Care and Sleep Medicine, PSRI Hospital, New Delhi, India
| | - Pawan Tiwari
- Department of Pulmonary, Critical Care and Sleep Medicine, AIIMS, New Delhi, India
| | - Saurabh Mittal
- Department of Pulmonary, Critical Care and Sleep Medicine, AIIMS, New Delhi, India
| | - Atul P Kulkarni
- Division of Critical Care Medicine, Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Dhruva Chaudhry
- Department of Pulmonary and Critical Care Medicine, University of Health Sciences, Rohtak, Haryana, India
| | - Kapil G Zirpe
- Department of Neuro Trauma Unit, Grant Medical Foundation, Pune, Maharashtra, India
| | - Subhash K Todi
- Department of Critical Care, AMRI Hospital, Kolkata, West Bengal, India
| | - Anant Mohan
- Department of Pulmonary, Critical Care and Sleep Medicine, AIIMS, New Delhi, India
| | - Ashit Hegde
- Department of Medicine & Critical Care, P D Hinduja National Hospital, Mumbai, India
| | - Bharat G Jagiasi
- Department of Critical Care, Kokilaben Dhirubhai Ambani Hospital, Navi Mumbai, Maharashtra, India
| | - Bhuvana Krishna
- Department of Critical Care Medicine, St John's Medical College and Hospital, Bengaluru, India
| | - Camila Rodrigues
- Department of Microbiology, P D Hinduja National Hospital, Mumbai, India
| | - Deepak Govil
- Department of Critical Care and Anesthesia, Medanta – The Medicity, GuruGram, Haryana, India
| | - Divya Pal
- Department of Critical Care and Anesthesia, Medanta – The Medicity, GuruGram, Haryana, India
| | - Jigeeshu V Divatia
- Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Manju Sengar
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Mansi Gupta
- Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Mukesh Desai
- Department of Immunology, Pediatric Hematology and Oncology Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Narendra Rungta
- Department of Critical Care & Anaesthesiology, Rajasthan Hospital, Jaipur, India
| | - Parikshit S Prayag
- Department of Transplant Infectious Diseases, Deenanath Mangeshkar Hospital, Pune, Maharashtra, India
| | - Pradip K Bhattacharya
- Department of Critical Care Medicine, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
| | - Srinivas Samavedam
- Department of Critical Care, Ramdev Rao Hospital, Hyderabad, Telangana, India
| | - Subhal B Dixit
- Department of Critical Care, Sanjeevan and MJM Hospital, Pune, Maharashtra, India
| | - Sudivya Sharma
- Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Susruta Bandopadhyay
- Department of Critical Care, AMRI Hospitals Salt Lake, Kolkata, West Bengal, India
| | - Venkat R Kola
- Department of Critical Care Medicine, Yashoda Hospitals, Hyderabad, Telangana, India
| | - Vikas Deswal
- Consultant, Infectious Diseases, Medanta - The Medicity, Gurugram, Haryana, India
| | - Yatin Mehta
- Department of Critical Care and Anesthesia, Medanta – The Medicity, GuruGram, Haryana, India
| | - Yogendra P Singh
- Department of Critical Care, Max Super Speciality Hospital, Patparganj, New Delhi, India
| | - Sheila N Myatra
- Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
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25
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Roger C. Understanding antimicrobial pharmacokinetics in critically ill patients to optimize antimicrobial therapy: A narrative review. JOURNAL OF INTENSIVE MEDICINE 2024; 4:287-298. [PMID: 39035618 PMCID: PMC11258509 DOI: 10.1016/j.jointm.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/26/2023] [Accepted: 12/27/2023] [Indexed: 07/23/2024]
Abstract
Effective treatment of sepsis not only demands prompt administration of appropriate antimicrobials but also requires precise dosing to enhance the likelihood of patient survival. Adequate dosing refers to the administration of doses that yield therapeutic drug concentrations at the infection site. This ensures a favorable clinical and microbiological response while avoiding antibiotic-related toxicity. Therapeutic drug monitoring (TDM) is the recommended approach for attaining these goals. However, TDM is not universally available in all intensive care units (ICUs) and for all antimicrobial agents. In the absence of TDM, healthcare practitioners need to rely on several factors to make informed dosing decisions. These include the patient's clinical condition, causative pathogen, impact of organ dysfunction (requiring extracorporeal therapies), and physicochemical properties of the antimicrobials. In this context, the pharmacokinetics of antimicrobials vary considerably between different critically ill patients and within the same patient over the course of ICU stay. This variability underscores the need for individualized dosing. This review aimed to describe the main pathophysiological changes observed in critically ill patients and their impact on antimicrobial drug dosing decisions. It also aimed to provide essential practical recommendations that may aid clinicians in optimizing antimicrobial therapy among critically ill patients.
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Affiliation(s)
- Claire Roger
- Department of Anesthesiology and Intensive Care, Pain and Emergency Medicine, Nîmes-Caremeau University Hospital, Nîmes, France
- UR UM 103 IMAGINE (Initial Management and prévention of orGan failures IN critically ill patiEnts), Faculty of Medicine, Montpellier University, Montpellier, France
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Lin CC, Wu JY, Huang PY, Sung HL, Tung YC, Lai CC, Wei YF, Fu PK. Comparing prolonged infusion to intermittent infusion strategies for beta-lactam antibiotics in patients with gram-negative bacterial infections: a systematic review and meta-analysis. Expert Rev Anti Infect Ther 2024; 22:557-567. [PMID: 38441052 DOI: 10.1080/14787210.2024.2324940] [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: 12/30/2023] [Accepted: 02/20/2024] [Indexed: 03/06/2024]
Abstract
INTRODUCTION Our objective is to determine whether prolonged infusion (PI) of beta-lactam antibiotics yields superior outcomes compared to intermittent infusion (II) in patients with Gram-Negative Bacterial (GNB) infections. METHODS We systematically searched papers from PubMed, the Cochrane Library, Embase, and Clinicaltrials.gov, targeting mortality as the primary outcome and looking at the clinical cure rate, hospital and intensive care unit (ICU) stay lengths, antibiotic treatment duration, and mechanical ventilation (MV) duration as secondary outcomes. RESULTS Our meta-analysis of 18 studies, including 5 randomized control trials and 13 observational studies, with a total of 3,035 patients-1,510 in the PI group and 1,525 in the II group, revealed significant findings. PI was associated with reduced mortality (RR, 0.67; 95% CI, 0.55-0.81; p = 0.001; I2 = 4.52%) and a shorter MV duration (SMD, -0.76; 95% CI, -1.37 to -0.16; p = 0.01; I2 = 87.81%) compared to II. However, no differences were found in clinical cure rates, antibiotic treatment duration, length of hospital stay, or length of ICU stay. CONCLUSIONS The PI approach for administering beta-lactam antibiotics in patients with suspected or confirmed GNB infections may be advantageous in reducing mortality rates and the duration of MV when compared to the II strategy.
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Affiliation(s)
- Chih-Chung Lin
- Department of Pharmacy, Taichung Veteran General Hospital Puli Branch, Nantou, Taiwan
| | - Jheng-Yen Wu
- Department of Nutrition, Chi Mei Medical Center, Tainan, Taiwan
| | - Po-Yu Huang
- Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Hui-Lin Sung
- Department of Pharmacy, Taichung Veteran General Hospital Puli Branch, Nantou, Taiwan
| | - Yu-Chun Tung
- Department of Pharmacy, Taichung Veteran General Hospital Puli Branch, Nantou, Taiwan
| | - Chih-Cheng Lai
- Division of Hospital Medicine, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Yu-Feng Wei
- Department of Internal Medicine, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan
- School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Pin-Kuei Fu
- Division of Clinical Research, Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- College of Medicine, National Chung Hsing University, Taichung, Taiwan
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Karaba SM, Cosgrove SE, Lee JH, Fiawoo S, Heil EL, Quartuccio KS, Shihadeh KC, Tamma PD. Extended-Infusion β-Lactam Therapy, Mortality, and Subsequent Antibiotic Resistance Among Hospitalized Adults With Gram-Negative Bloodstream Infections. JAMA Netw Open 2024; 7:e2418234. [PMID: 38954416 PMCID: PMC11220563 DOI: 10.1001/jamanetworkopen.2024.18234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 04/21/2024] [Indexed: 07/04/2024] Open
Abstract
Importance Current evidence is conflicting for associations of extended-infusion β-lactam (EI-BL) therapy with clinical outcomes. Objective To investigate the association of EI-BL therapy with survival, adverse events, and emergence of antibiotic resistance in adults with gram-negative bloodstream infections (GN-BSI). Design, Setting, and Participants This cohort study of consecutive adults with GN-BSI admitted to 24 United States hospitals between January 1, 2019, and December 31, 2019, receiving EI-BL were compared with adults with GN-BSI receiving the same agents as intermittent infusion β-lactam (II-BL; ≤1-hour infusions). Statistical analysis was performed from January to October 2023. Exposures EI-BL (ie, ≥3-hour infusion). Main Outcomes and Measures EI-BL and II-BL groups underwent 1:3 nearest-neighbor propensity score matching (PSM) without replacement. Multivariable regression was applied to the PSM cohort to investigate outcomes, all censored at day 90. The primary outcome was mortality; secondary outcomes included antibiotic adverse events and emergence of resistance (≥4-fold increase in the minimum inhibitory concentration of the β-lactam used to treat the index GN-BSI). Results Among the 4861 patients included, 2547 (52.4%) were male; and the median (IQR) age was 67 (55-77) years. There were 352 patients in the EI-BL 1:3 PSM group, and 1056 patients in the II-BL 1:3 PSM group. Among 1408 PSM patients, 373 (26.5%) died by day 90. The odds of mortality were lower in the EI-BL group (adjusted odds ratio [aOR], 0.71 [95% CI, 0.52-0.97]). In a stratified analysis, a survival benefit was only identified in patients with severe illness or elevated minimum inhibitory concentrations (ie, in the intermediate range for the antibiotic administered). There were increased odds of catheter complications (aOR, 3.14 [95% CI, 1.66-5.96]) and antibiotic discontinuation because of adverse events (eg, acute kidney injury, cytopenias, seizures) in the EI-BL group (aOR, 3.66 [95% CI, 1.68-7.95]). Emergence of resistance was similar in the EI-BL and II-BL groups at 2.9% vs 7.2%, respectively (P = .35). Conclusions and Relevance In this cohort study of patients with GN-BSI, EI-BL therapy was associated with reduced mortality for patients with severe illness or those infected with nonsusceptible organisms; potential advantages in other groups remain unclear and need to be balanced with potential adverse events. The subsequent emergence of resistance warrants investigation in a larger cohort.
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Affiliation(s)
- Sara M. Karaba
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sara E. Cosgrove
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jae Hyoung Lee
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Suiyini Fiawoo
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Emily L. Heil
- Department of Practice, Sciences, and Health-Outcomes Research, University of Maryland School of Pharmacy, Baltimore, Maryland
| | | | | | - Pranita D. Tamma
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Konkayev A, Kadralinova A, Azimova B, Tazhibayeva D, Yeltayeva A, Konkayeva M. Usage of Meropenem Continuous Infusion for Treatment of Infectious Complications in Orthopedic Elderly Patients with Anemia: A Case Series. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:929. [PMID: 38929546 PMCID: PMC11205918 DOI: 10.3390/medicina60060929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/21/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024]
Abstract
Background and Objectives: The prolonged infusion of meropenem is recommended by guidelines for the treatment of sepsis. However, studies provide controversial data on the advantages of prolonged infusions over intermittent ones. In our opinion, this can be related to age, which possibly distorts the final data, as older people have age-related characteristics. In our study, we analyzed the ventilatory status, laboratory tests and vital signs of the patient and carried out microbiological cultures. Materials and Methods: This was a prospective single-center case series investigation conducted from June 2022 to June 2023. The objective of this study was to evaluate the effectiveness of continuous infusion in elderly patients with severe infectious complications after orthopedic interventions. The primary endpoints were 28-day survival and the emergence of new multidrug-resistant strains. Secondary endpoints were long-term mortality and length of stay in the ICU. Results: Three patients (median age 65, 100% female) received a continuous infusion of meropenem. Two patients were alive at hospital discharge, and one patient died on the 105th day of hospitalization. Multi-resistant bacteria were observed in one patient. Conclusions: The use of a continuous meropenem infusion in the complex treatment of purulent-septic complications in elderly patients with periprosthetic infection and anemia probably led to clinical improvement in these case reports. However, the emergence of new pan-resistant strains and overall mortality using this infusion technique remains unclear. Further, high-quality RCTs for the elderly are needed.
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Affiliation(s)
- Aidos Konkayev
- Department of Anesthesiology and Intensive Care, National Scientific Center of Traumatology and Orthopedics Named after Academician N.D. Batpenov, Astana 010000, Kazakhstan; (A.K.); (B.A.); (A.Y.); (M.K.)
- Department of Anesthesiology and Intensive Care, Astana Medical University, Astana 010000, Kazakhstan;
| | - Assiya Kadralinova
- Department of Anesthesiology and Intensive Care, National Scientific Center of Traumatology and Orthopedics Named after Academician N.D. Batpenov, Astana 010000, Kazakhstan; (A.K.); (B.A.); (A.Y.); (M.K.)
- Department of Anesthesiology and Intensive Care, Astana Medical University, Astana 010000, Kazakhstan;
| | - Benazir Azimova
- Department of Anesthesiology and Intensive Care, National Scientific Center of Traumatology and Orthopedics Named after Academician N.D. Batpenov, Astana 010000, Kazakhstan; (A.K.); (B.A.); (A.Y.); (M.K.)
- Department of Anesthesiology and Intensive Care, Astana Medical University, Astana 010000, Kazakhstan;
| | - Damira Tazhibayeva
- Department of Anesthesiology and Intensive Care, Astana Medical University, Astana 010000, Kazakhstan;
| | - Aigerim Yeltayeva
- Department of Anesthesiology and Intensive Care, National Scientific Center of Traumatology and Orthopedics Named after Academician N.D. Batpenov, Astana 010000, Kazakhstan; (A.K.); (B.A.); (A.Y.); (M.K.)
- Department of Anesthesiology and Intensive Care, Astana Medical University, Astana 010000, Kazakhstan;
| | - Maiya Konkayeva
- Department of Anesthesiology and Intensive Care, National Scientific Center of Traumatology and Orthopedics Named after Academician N.D. Batpenov, Astana 010000, Kazakhstan; (A.K.); (B.A.); (A.Y.); (M.K.)
- Department of Anesthesiology and Intensive Care, Astana Medical University, Astana 010000, Kazakhstan;
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Dilawri A, Muir J, Brodie D, Abrams D, Agerstrand C, Madahar P, Dzierba AL. Practices surrounding antimicrobial use in patients managed with extracorporeal membrane oxygenation: An international survey. J Crit Care 2024; 81:154534. [PMID: 38367526 DOI: 10.1016/j.jcrc.2024.154534] [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: 11/14/2023] [Revised: 01/23/2024] [Accepted: 02/04/2024] [Indexed: 02/19/2024]
Abstract
PURPOSE This study aimed to survey critical care clinicians and characterize their perception of antimicrobial dosing strategies in patients receiving extracorporeal membrane oxygenation (ECMO). METHODS International, cross-sectional survey distributed to members of the Society of Critical Care Medicine in October 2022. RESULTS Respondents were primarily physicians (45%), with 92% practicing in North America. Ninety-seven percent of respondents reported antimicrobial dosing in critically ill patients to be challenging, due to physiological derangements seen in the patient population. Eighty-seven percent reported consideration of physicochemical drug properties when dosing antimicrobials in ECMO-supported patients, with lipophilicity (83%) and degree of protein binding (74%) being the two most common. Respondents' approach to antimicrobial dosing strategies did not significantly differ in critically ill ECMO-supported patients, compared to patients with equal severity of illness not receiving ECMO support. CONCLUSION Approaches to antimicrobial dosing strategies do not significantly differ among respondents between critically ill patients on ECMO support, compared to patients with equal severity of illness not receiving ECMO support. These findings were unexpected considering the added physiologic complexity of the ECMO circuit to critically ill adult patients and the need for well designed and adequately powered studies to inform empiric dosing guidance for ECMO-supported patients.
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Affiliation(s)
- Atul Dilawri
- Department of Pharmacy, NewYork-Presbyterian Hospital, New York, NY, United States of America
| | - Justin Muir
- Department of Pharmacy, NewYork-Presbyterian Hospital, New York, NY, United States of America
| | - Daniel Brodie
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Darryl Abrams
- Division of Pulmonary and Critical Care Medicine, Columbia College of Physicians and Surgeons/NewYork-Presbyterian Hospital, New York, NY, United States of America
| | - Cara Agerstrand
- Division of Pulmonary and Critical Care Medicine, Columbia College of Physicians and Surgeons/NewYork-Presbyterian Hospital, New York, NY, United States of America
| | - Purnema Madahar
- Division of Pulmonary and Critical Care Medicine, Columbia College of Physicians and Surgeons/NewYork-Presbyterian Hospital, New York, NY, United States of America
| | - Amy L Dzierba
- Department of Pharmacy, NewYork-Presbyterian Hospital, New York, NY, United States of America; Center for Acute Respiratory Failure, Columbia University College of Physicians and Surgeons and NewYork-Presbyterian Hospital, New York, NY, United States of America.
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Wang Y, Li H, Wang D, Li Y, Shen Y, Fu Y, Li Y, Gao M, Zhang D. Changes of PK/PD of Meropenem in patients with abdominal septic shock and exploration of clinical rational administration plan: a prospective exploratory study. Sci Rep 2024; 14:10173. [PMID: 38702351 PMCID: PMC11068909 DOI: 10.1038/s41598-024-60909-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 04/29/2024] [Indexed: 05/06/2024] Open
Abstract
This study aimed to explore the changes of pharmacokinetic parameters after meropenem in patients with abdominal septic shock after gastrointestinal perforation, and to simulate the probability of different dosing regimens achieving different pharmacodynamic goals. The study included 12 patients, and utilized high performance liquid chromatography-tandem mass spectrometry to monitor the plasma concentration of meropenem. The probability of target attainment (PTA) for different minimum inhibitory concentration (MIC) values and %fT > 4MIC was compared among simulated dosing regimens. The results showed that in 96 blood samples from 12 patients, the clearance (CL) of meropenem in the normal and abnormal creatinine clearance subgroups were 7.7 ± 1.8 and 4.4 ± 1.1 L/h, respectively, and the apparent volume of distribution (Vd) was 22.6 ± 5.1 and 17.2 ± 5.8 L, respectively. 2. Regardless of the subgroup, 0.5 g/q6h infusion over 6 h regimen achieved a PTA > 90% when MIC ≤ 0.5 mg/L. 1.0 g/q6h infusion regimen compared with other regimen, in most cases, the probability of making PTA > 90% is higher. For patients at low MIC, 0.5 g/q6h infusion over 6 h may be preferable. For patients at high MIC, a dose regimen of 1.0 g/q6 h infusion over 6 h may be preferable. Further research is needed to confirm this exploratory result.
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Affiliation(s)
- Youquan Wang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Chaoyang District, Changchun City, 130021, Jilin Province, China
| | - Hongxiang Li
- Department of Critical Care Medicine, The First Hospital of Jilin University, Chaoyang District, Changchun City, 130021, Jilin Province, China
| | - Dongxia Wang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Chaoyang District, Changchun City, 130021, Jilin Province, China
| | - Yuting Li
- Department of Critical Care Medicine, The First Hospital of Jilin University, Chaoyang District, Changchun City, 130021, Jilin Province, China
| | | | - Yao Fu
- Department of Critical Care Medicine, The First Hospital of Jilin University, Chaoyang District, Changchun City, 130021, Jilin Province, China
| | - Yanhua Li
- Department of Critical Care Medicine, The First Hospital of Jilin University, Chaoyang District, Changchun City, 130021, Jilin Province, China
| | - Meng Gao
- Department of Critical Care Medicine, The First Hospital of Jilin University, Chaoyang District, Changchun City, 130021, Jilin Province, China
| | - Dong Zhang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Chaoyang District, Changchun City, 130021, Jilin Province, China.
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Razazi K, Berti E, Cecchini J, Carteaux G, Habibi A, Bartolucci P, Arrestier R, Gendreau S, de Prost N, Hulin A, Dessap AM. Decreased risk of underdosing with continuous infusion versus intermittent administration of cefotaxime in patients with sickle cell disease and acute chest syndrome. PLoS One 2024; 19:e0302298. [PMID: 38635540 PMCID: PMC11025818 DOI: 10.1371/journal.pone.0302298] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 04/01/2024] [Indexed: 04/20/2024] Open
Abstract
OBJECTIVE Underdosing of antibiotics is common in patients with sickle cell disease (SCD). We hypothesized that in critically-ill patients with SCD receiving cefotaxime during acute chest syndrome, the continuous infusion may outperform the intermittent administration in achieving pharmacokinetic/pharmacodynamic targets. DESIGN Prospective before-after study. SETTINGS Intensive-care unit of a French teaching hospital and sickle cell disease referral center. PATIENTS Sixty consecutive episodes of severe acute chest syndrome in 58 adult patients with sickle cell disease. INTERVENTIONS Patients were treated with intermittent administration during the first period (April 2016 -April 2018) and with continuous infusion during the second period (May 2018 -August 2019). MEASUREMENTS AND MAIN RESULTS We included 60 episodes of acute chest syndrome in 58 patients (29 [25-34] years, 37/58 (64%) males). Daily dose of cefotaxime was similar between groups (59 [48-88] vs. 61 [57-64] mg/kg/day, p = 0.84). Most patients (>75%) presented a glomerular hyperfiltration with no difference between groups (p = 0.25). More patients had a cefotaxime trough level ≥2 mg/L with continuous infusion than intermittent administration: 28 (93%) vs. 5 (16%), p<0.001. The median residual concentration was higher in the continuous infusion than intermittent administration group: 10.5 [7.4-13.3] vs. 0 [0-0] mg/L, p<0.001. No infection relapse was observed in the entire cohort. Hospital length of stay was similar between groups. CONCLUSION As compared to intermittent administration, continuous infusion of cefotaxime maximizes the pharmacokinetic/pharmacodynamic parameters in patients with SCD. The clinical outcome did not differ between the two administration methods; however, the study was underpowered to detect such a difference.
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Affiliation(s)
- Keyvan Razazi
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Service de Médecine Intensive Réanimation, F-94010, Créteil, France
- Université Paris Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- Université Paris Est Créteil, CARMAS, Créteil, F-94010, France
| | - Enora Berti
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Service de Médecine Intensive Réanimation, F-94010, Créteil, France
- Université Paris Est Créteil, CARMAS, Créteil, F-94010, France
| | - Jerome Cecchini
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Service de Médecine Intensive Réanimation, F-94010, Créteil, France
- Université Paris Est Créteil, CARMAS, Créteil, F-94010, France
- Hôpital Intercommunal de Créteil, Service de Réanimation et Surveillance Continue Adulte, 94000, Créteil, France
| | - Guillaume Carteaux
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Service de Médecine Intensive Réanimation, F-94010, Créteil, France
- Université Paris Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- Université Paris Est Créteil, CARMAS, Créteil, F-94010, France
| | - Anoosha Habibi
- Université Paris Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Centre de Référence de la Drépanocytose, Créteil, France
| | - Pablo Bartolucci
- Université Paris Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Centre de Référence de la Drépanocytose, Créteil, France
| | - Romain Arrestier
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Service de Médecine Intensive Réanimation, F-94010, Créteil, France
- Université Paris Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- Université Paris Est Créteil, CARMAS, Créteil, F-94010, France
| | - Ségolène Gendreau
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Service de Médecine Intensive Réanimation, F-94010, Créteil, France
- Université Paris Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- Université Paris Est Créteil, CARMAS, Créteil, F-94010, France
| | - Nicolas de Prost
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Service de Médecine Intensive Réanimation, F-94010, Créteil, France
- Université Paris Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- Université Paris Est Créteil, CARMAS, Créteil, F-94010, France
| | - Anne Hulin
- AP-HP, Hôpitaux Universitaires Henri Mondor, Service de Biochimie, Créteil, 94010 France
| | - Armand Mekontso Dessap
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Service de Médecine Intensive Réanimation, F-94010, Créteil, France
- Université Paris Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- Université Paris Est Créteil, CARMAS, Créteil, F-94010, France
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Cojutti PG, Pai MP, Tonetti T, Siniscalchi A, Viale P, Pea F. Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales. Antimicrob Agents Chemother 2024; 68:e0140423. [PMID: 38411995 PMCID: PMC10994818 DOI: 10.1128/aac.01404-23] [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: 10/28/2023] [Accepted: 02/02/2024] [Indexed: 02/28/2024] Open
Abstract
Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.
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Affiliation(s)
- Pier Giorgio Cojutti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
- Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Bologna, Italy
| | - Manjunath P. Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Tommaso Tonetti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
- Anesthesiology and Intensive Care Medicine, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Bologna, Italy
| | - Antonio Siniscalchi
- Division of Anesthesiology, Department of Anesthesia and Intensive Care, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Bologna, Italy
| | - Pierluigi Viale
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
- Infectious Diseases Unit, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Bologna, Italy
| | - Federico Pea
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
- Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Bologna, Italy
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Wenker SAM, Alabdulkarim N, Readman JB, Slob EMA, Satta G, Ali S, Gadher N, Shulman R, Standing JF. Defining the pharmacokinetic/pharmacodynamic index of piperacillin/tazobactam within a hollow-fibre infection model to determine target attainment in intensive care patients. JAC Antimicrob Resist 2024; 6:dlae036. [PMID: 38476774 PMCID: PMC10928666 DOI: 10.1093/jacamr/dlae036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/10/2024] [Indexed: 03/14/2024] Open
Abstract
Background It is important to optimize dosing schemes of antibiotics to maximize the probability of therapeutic success. The recommended pharmacokinetic/pharmacodynamic (PK/PD) index for piperacillin/tazobactam therapy in clinical studies ranges widely (50%-100% fT>1-4×MIC). Dosing schemes failing to achieve PK/PD targets may lead to negative treatment outcomes. Objectives The first aim of this study was to define the optimal PK/PD index of piperacillin/tazobactam with a hollow-fibre infection model (HFIM). The second aim was to predict whether these PK/PD targets are currently achieved in critically ill patients through PK/PD model simulation. Patients and methods A dose-fractionation study comprising 21 HFIM experiments was performed against a range of Gram-negative bacterial pathogens, doses and infusion times. Clinical data and dose histories from a case series of nine patients with a known bacterial infection treated with piperacillin/tazobactam in the ICU were collected. The PK/PD index and predicted plasma concentrations and therefore target attainment of the patients were simulated using R version 4.2.1. Results fT >MIC was found to be the best-fitting PK/PD index for piperacillin/tazobactam. Bactericidal activity with 2 log10 cfu reduction was associated with 77% fT>MIC. Piperacillin/tazobactam therapy was defined as clinically 'ineffective' in ∼78% (7/9) patients. Around seventy-one percent (5/7) of these patients had a probability of >10% that 2 log10 cfu reduction was not attained. Conclusions Our dose-fractionation study indicates an optimal PK/PD target in piperacillin/tazobactam therapies should be 77% fT>MIC for 2 log10 kill. Doses to achieve this target should be considered when treating patients in ICU.
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Affiliation(s)
- Suzanne A M Wenker
- Infection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Najla Alabdulkarim
- Infection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK
- Department of Clinical Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - John B Readman
- Infection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Elise M A Slob
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
- Department of Clinical Pharmacy, Haaglanden Medical Center, The Hague, The Netherlands
| | - Giovanni Satta
- Department of Infection, University College London Hospitals NHS Foundation Trust, London, UK
| | - Shanom Ali
- Environmental Research Laboratory, University College London Hospitals NHS Foundation Trust, London, UK
| | - Nishma Gadher
- Pharmacy Department, CMORE, University College London Hospitals NHS Foundation Trust, London, UK
| | - Rob Shulman
- Pharmacy Department, CMORE, University College London Hospitals NHS Foundation Trust, London, UK
| | - Joseph F Standing
- Infection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK
- Department of Pharmacy, Great Ormond Street Hospital for Children, London, UK
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Lai J, Liang J, Chen K, Guan B, Chen Z, Chen L, Fan J, Zhang Y, Li Q, Su J, Chen Q, Lin J. Carrimycin ameliorates lipopolysaccharide and cecal ligation and puncture-induced sepsis in mice. Chin J Nat Med 2024; 22:235-248. [PMID: 38553191 DOI: 10.1016/s1875-5364(24)60600-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Indexed: 04/02/2024]
Abstract
Carrimycin (CA), sanctioned by China's National Medical Products Administration (NMPA) in 2019 for treating acute bronchitis and sinusitis, has recently been observed to exhibit multifaceted biological activities, encompassing anti-inflammatory, antiviral, and anti-tumor properties. Despite these applications, its efficacy in sepsis treatment remains unexplored. This study introduces a novel function of CA, demonstrating its capacity to mitigate sepsis induced by lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) in mice models. Our research employed in vitro assays, real-time quantitative polymerase chain reaction (RT-qPCR), and RNA-seq analysis to establish that CA significantly reduces the levels of pro-inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6), in response to LPS stimulation. Additionally, Western blotting and immunofluorescence assays revealed that CA impedes Nuclear Factor Kappa B (NF-κB) activation in LPS-stimulated RAW264.7 cells. Complementing these findings, in vivo experiments demonstrated that CA effectively alleviates LPS- and CLP-triggered organ inflammation in C57BL/6 mice. Further insights were gained through 16S sequencing, highlighting CA's pivotal role in enhancing gut microbiota diversity and modulating metabolic pathways, particularly by augmenting the production of short-chain fatty acids in mice subjected to CLP. Notably, a comparative analysis revealed that CA's anti-inflammatory efficacy surpasses that of equivalent doses of aspirin (ASP) and TIENAM. Collectively, these findings suggest that CA exhibits significant therapeutic potential in sepsis treatment. This discovery provides a foundational theoretical basis for the clinical application of CA in sepsis management.
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Affiliation(s)
- Junzhong Lai
- The Cancer Center, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Jiadi Liang
- The Cancer Center, Fujian Medical University Union Hospital, Fuzhou 350001, China; Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Kunsen Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Biyun Guan
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Zhirong Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Linqin Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Jiqiang Fan
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Yong Zhang
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Qiumei Li
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Jingqian Su
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Qi Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China.
| | - Jizhen Lin
- The Cancer Center, Fujian Medical University Union Hospital, Fuzhou 350001, China; The Department of Otolaryngology, Head & Neck Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
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Zhao Y, Zang B, Wang Q. Prolonged versus intermittent β-lactam infusion in sepsis: a systematic review and meta-analysis of randomized controlled trials. Ann Intensive Care 2024; 14:30. [PMID: 38368588 PMCID: PMC10874917 DOI: 10.1186/s13613-024-01263-9] [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: 11/14/2023] [Accepted: 02/13/2024] [Indexed: 02/19/2024] Open
Abstract
BACKGROUND The two latest studies on prolonged versus intermittent use of β-lactam antibiotics in patients with sepsis did not reach consistent conclusions, further contributing to the controversy surrounding the effectiveness of the prolonged β-lactam antibiotics infusion strategy. We conducted a systemic review and meta-analysis to evaluate the efficacy and safety of prolonged and intermittent β-lactam infusion in adult patients with sepsis. METHODS We systematically searched PubMed, EMBASE, and Cochrane Library databases for original randomized controlled trials comparing prolonged and intermittent β-lactam infusion in sepsis patients. A random-effects model was used to evaluate mortality, clinical success, microbiological success, and adverse events. We also conducted subgroup analyses to explore the impact of various factors on the mortality rates. Relative risk (RR) and corresponding 95% confidence intervals (CIs) were used to calculate the overall effect sizes for dichotomous outcomes. This meta-analysis was registered in PROSPERO (CRD42023463905). RESULTS We assessed 15 studies involving 2130 patients. In our comprehensive assessment, we found a significant reduction in all-cause mortality (RR, 0.83; 95% CI 0.72-0.97; P = 0.02) and a notable improvement in clinical success (RR, 1.16; 95% CI 1.03-1.31; P = 0.02) in the prolonged infusion group compared to the intermittent infusion group, whereas microbiological success did not yield statistically significant results (RR, 1.10; 95% CI 0.98-1.23; P = 0.11). No significant differences in adverse events were observed between the two groups (RR, 0.91; 95% CI 0.64-1.29; P = 0.60). Additionally, remarkable conclusions were drawn from subgroup analyses including studies with sample sizes exceeding 20 individuals per group (RR, 0.84; 95%CI 0.72-0.98; P = 0.03), research conducted post-2010 (RR, 0.84; 95%CI 0.72-0.98; P = 0.03), cases involving infections predominantly caused by Gram-negative bacteria (RR, 0.81; 95%CI 0.68-0.96; P = 0.02), as well as the administration of a loading dose (RR, 0.84; 95% CI 0.72-0.97; P = 0.02) and the use of penicillin (RR, 0.61; 95% CI 0.38-0.98; P = 0.04). CONCLUSIONS Compared to intermittent infusion, prolonged infusion of β-lactam antibiotics significantly decreases all-cause mortality among patients with sepsis and enhances clinical success without increasing adverse events.
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Affiliation(s)
- Yang Zhao
- Department of Critical Care Medicine, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110000, China
| | - Bin Zang
- Department of Critical Care Medicine, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110000, China.
| | - Qian Wang
- Department of Emergency, The Fourth Affiliated Hospital of China Medical University, 4 Chongshan East Road, Shenyang, 110000, China.
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Cusack R, Little E, Martin-Loeches I. Practical Lessons on Antimicrobial Therapy for Critically Ill Patients. Antibiotics (Basel) 2024; 13:162. [PMID: 38391547 PMCID: PMC10886263 DOI: 10.3390/antibiotics13020162] [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: 12/19/2023] [Revised: 01/30/2024] [Accepted: 02/02/2024] [Indexed: 02/24/2024] Open
Abstract
Sepsis stands as a formidable global health challenge, with persistently elevated mortality rates in recent decades. Each year, sepsis not only contributes to heightened morbidity but also imposes substantial healthcare costs on survivors. This narrative review aims to highlight the targeted measures that can be instituted to alleviate the incidence and impact of sepsis in intensive care. Here we discuss measures to reduce nosocomial infections and the prevention of equipment and patient colonisation by resilient pathogens. The overarching global crisis of bacterial resistance to newly developed antimicrobial agents intensifies the imperative for antimicrobial stewardship and de-escalation. This urgency has been accentuated in recent years, notably during the COVID-19 pandemic, as high-dose steroids and opportunistic infections presented escalating challenges. Ongoing research into airway colonisation's role in influencing disease outcomes among critically ill patients underscores the importance of tailoring treatments to disease endotypes within heterogeneous populations, which are important lessons for intensivists in training. Looking ahead, the significance of novel antimicrobial delivery systems and drug monitoring is poised to increase. This narrative review delves into the multifaceted barriers and facilitators inherent in effectively treating critically ill patients vulnerable to nosocomial infections. The future trajectory of intensive care medicine hinges on the meticulous implementation of vigilant stewardship programs, robust infection control measures, and the continued exploration of innovative and efficient technological solutions within this demanding healthcare landscape.
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Affiliation(s)
- Rachael Cusack
- Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St James' Hospital, D08 NHY1 Dublin, Ireland
| | - Elizabeth Little
- Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St James' Hospital, D08 NHY1 Dublin, Ireland
| | - Ignacio Martin-Loeches
- Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St James' Hospital, D08 NHY1 Dublin, Ireland
- Hospital Clinic, Universitat de Barcelona, IDIBAPS, CIBERES, 08180 Barcelona, Spain
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Jenkins A, Jamieson C, Santillo M. Systematic review of room temperature stability of key beta-lactam antibiotics for extended infusions in inpatient settings. Eur J Hosp Pharm 2023; 31:2-9. [PMID: 37848286 PMCID: PMC11148869 DOI: 10.1136/ejhpharm-2023-003855] [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: 05/24/2023] [Accepted: 09/26/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND Extended infusion (EI) of beta-lactam antibiotics may offer clinical benefits aligned with improved probability of target attainment for critical pharmacokinetic/pharmacodynamic parameters that correlate with efficacy. There is much research interest in prolonged and continuous infusions (collectively, extended infusions) of beta-lactams to improve patient outcomes, particularly in critically ill patients in intensive care. While definitive clinical trial data demonstrating beneficial outcomes is awaited, there has been limited focus on the stability of the agents given by EI, which may be an equally critical parameter. EI may allow for savings in nursing time due to reduced need for drug reconstitution. We set out to examine the data for stability for EI at room temperature, consistent with the requirements of 'A Standard Protocol for Deriving and Assessment of Stability- Part 1 Aseptic Preparation (Small Molecules)', which allows a 5% loss of active pharmaceutical ingredient (API) applicable for those territories that use the British Pharmacopoeia also for a 10% loss applicable in much of rest of the world. METHODS Searches using preferred reporting items for systematic reviews and meta-analyses (PRISMA) principles for stability data on freshly prepared beta-lactam antimicrobials for extended administration at room temperature (at or above 23°C) were conducted in November 2021 and updated in December 2022. RESULTS We found data to support the extension of the shelf life of 12 key beta-lactam antibiotics once reconstituted (aztreonam, amoxicillin, benzylpenicillin, flucloxacillin, piperacillin/tazobactam, cefazolin, cefmetazole, ceftaroline, ceftazidime, ceftriaxone, imipenem and meropenem) compliant with the NHS protocol, and data for five other agents (ticarcillin, cefepime, cefiderocol, cefoxitin and doripenem) which would be acceptable in regions outside the UK beyond that listed in the Summary of Product Characteristics.This review has not been registered under PROSPERO.
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Affiliation(s)
- Abi Jenkins
- Pharmacy, University Hospitals Birmingham, Birmingham, UK
| | | | - Mark Santillo
- UK and University Hospitals Bristol and Weston NHS Trust, Plymouth Bristol, UK
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Cojutti PG, Giuliano S, Pascale R, Angelini J, Tascini C, Viale P, Pea F. Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections. Microorganisms 2023; 11:2964. [PMID: 38138108 PMCID: PMC10745581 DOI: 10.3390/microorganisms11122964] [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: 11/02/2023] [Revised: 12/05/2023] [Accepted: 12/10/2023] [Indexed: 12/24/2023] Open
Abstract
Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fCtrough/MIC or fCss/MIC) ≥ 1 or ≥4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fCtrough/MIC or fCss/MIC ≥ 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE.
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Affiliation(s)
- Pier Giorgio Cojutti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy; (R.P.); (P.V.); (F.P.)
- Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Simone Giuliano
- Infectious Diseases Clinic, Santa Maria della Misericordia University Hospital of Udine, ASUFC, 33100 Udine, Italy; (S.G.); (C.T.)
| | - Renato Pascale
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy; (R.P.); (P.V.); (F.P.)
- Infectious Diseases Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Jacopo Angelini
- Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, ASUFC, 33100 Udine, Italy;
| | - Carlo Tascini
- Infectious Diseases Clinic, Santa Maria della Misericordia University Hospital of Udine, ASUFC, 33100 Udine, Italy; (S.G.); (C.T.)
| | - Pierluigi Viale
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy; (R.P.); (P.V.); (F.P.)
- Infectious Diseases Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Federico Pea
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy; (R.P.); (P.V.); (F.P.)
- Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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Li X, Long Y, Wu G, Li R, Zhou M, He A, Jiang Z. Prolonged vs intermittent intravenous infusion of β-lactam antibiotics for patients with sepsis: a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis. Ann Intensive Care 2023; 13:121. [PMID: 38051467 DOI: 10.1186/s13613-023-01222-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/26/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND The prolonged β-lactam antibiotics infusion has been an attractive strategy in severe infections, because it provides a more stable free drug concentration and a longer duration of free drug concentration above the minimum inhibitory concentration (MIC). We conducted this systematic review of randomized clinical trials (RCTs) with meta-analysis and trial sequential analysis (TSA) to compare the effects of prolonged vs intermittent intravenous infusion of β-lactam antibiotics for patients with sepsis. METHODS This study was prospectively registered on PROSPERO database (CRD42023447692). We searched EMBASE, PubMed, and Cochrane Library to identify eligible studies (up to July 6, 2023). Any study meeting the inclusion and exclusion criteria would be included. The primary outcome was all-cause mortality within 30 days. Two authors independently screened studies and extracted data. When the I2 values < 50%, we used fixed-effect mode. Otherwise, the random effects model was used. TSA was also performed to search for the possibility of false-positive (type I error) or false-negative (type II error) results. RESULTS A total of 4355 studies were identified in our search, and nine studies with 1762 patients were finally included. The pooled results showed that, compared with intermittent intravenous infusion, prolonged intravenous infusion of beta-lactam antibiotics resulted in a significant reduction in all-cause mortality within 30 days in patients with sepsis (RR 0.82; 95%CI 0.70-0.96; P = 0.01; TSA-adjusted CI 0.62-1.07). However, the certainty of the evidence was rated as low, and the TSA results suggested that more studies were needed to further confirm our conclusion. In addition, it is associated with lower hospital mortality, ICU mortality, and higher clinical cure. No significant reduction in 90-day mortality or the emergence of resistance bacteria was detected between the two groups. CONCLUSIONS Prolonged intravenous infusion of beta-lactam antibiotics in patients with sepsis was associated with short-term survival benefits and higher clinical cure. However, the TSA results suggested that more studies are needed to reach a definitive conclusion. In terms of long-term survival benefits, we could not show an improvement.
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Affiliation(s)
- Xiaoming Li
- Department of Critical Care Medicine, Chongqing University Cancer Hospital, 181 Han-Yu Road, Chongqing, 400030, China
| | - Yi Long
- Department of Critical Care Medicine, Chongqing University Cancer Hospital, 181 Han-Yu Road, Chongqing, 400030, China
| | - Guixin Wu
- Department of Critical Care Medicine, Chongqing University Cancer Hospital, 181 Han-Yu Road, Chongqing, 400030, China
| | - Rui Li
- Department of Critical Care Medicine, Chongqing University Cancer Hospital, 181 Han-Yu Road, Chongqing, 400030, China
| | - Mingming Zhou
- Department of Critical Care Medicine, Chongqing University Cancer Hospital, 181 Han-Yu Road, Chongqing, 400030, China
| | - Aiting He
- Department of Critical Care Medicine, Chongqing University Cancer Hospital, 181 Han-Yu Road, Chongqing, 400030, China
| | - Zhengying Jiang
- Department of Critical Care Medicine, Chongqing University Cancer Hospital, 181 Han-Yu Road, Chongqing, 400030, China.
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Fresán D, Luque S, Benítez-Cano A, Sorlí L, Montero MM, De-Antonio M, Vega V, Roberts JA, Horcajada JP, Grau S. Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria. J Antimicrob Chemother 2023; 78:2810-2815. [PMID: 37823445 DOI: 10.1093/jac/dkad296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 09/14/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For β-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD). OBJECTIVES To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections. METHODS Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT>4×MIC was the pre-specified PK/PD target and 100%fT>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient's clinical condition. RESULTS Twelve patients [83.3% male, median age of 73 (38-83) years] were included. Nine patients (75%) achieved 100%fT>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one. CONCLUSIONS The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.
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Affiliation(s)
- Daniel Fresán
- Pharmacy Department, Hospital Universitario de Navarra, Pamplona, Spain
| | - Sonia Luque
- Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
- Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
- CIBERINFEC, ISCIII-CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, Madrid 28029, Spain
| | - Adela Benítez-Cano
- Department of Anaesthesiology and Surgical Intensive Care, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Luisa Sorlí
- Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
- CIBERINFEC, ISCIII-CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, Madrid 28029, Spain
- Infectious Diseases Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
- Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
| | - María Milagro Montero
- Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
- CIBERINFEC, ISCIII-CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, Madrid 28029, Spain
- Infectious Diseases Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
- Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
| | - Marta De-Antonio
- Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Victoria Vega
- Analytical Department, Laboratori de Referència de Catalunya, Barcelona, Spain
| | - Jason A Roberts
- University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Australia
- Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia
- Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
| | - Juan P Horcajada
- Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
- CIBERINFEC, ISCIII-CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, Madrid 28029, Spain
- Infectious Diseases Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
- Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
| | - Santiago Grau
- Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
- Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
- CIBERINFEC, ISCIII-CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, Madrid 28029, Spain
- Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
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Larcher R, Laffont-Lozes P, Naciri T, Bourgeois PM, Gandon C, Magnan C, Pantel A, Sotto A. Continuous infusion of meropenem-vaborbactam for a KPC-3-producing Klebsiella pneumoniae bloodstream infection in a critically ill patient with augmented renal clearance. Infection 2023; 51:1835-1840. [PMID: 37277691 PMCID: PMC10665223 DOI: 10.1007/s15010-023-02055-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/23/2023] [Indexed: 06/07/2023]
Abstract
PURPOSE To demonstrate the feasibility of continuous infusion of meropenem-vaborbactam to optimize the treatment of carbapenem-resistant Enterobacterales. METHODS Report of a case of a Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae bloodstream infection comfirmed by whole genome sequencing and therapeutic drug monitoring (TDM) of meropenem. RESULTS A patient with augmented renal clearance (ARC) went into septic shock caused by an ST11 KPC-3-producing K. pneumoniae bloodstream infection that was successfully treated with a continuous infusion of meropenem-vaborbactam at a dosage of 1 g/1 g q4h as a 4-h infusion. TDM confirmed sustained concentrations of meropenem ranging from 8 to 16 mg/L throughout the dosing interval. CONCLUSION Continuous infusion of meropenem-vaborbactam was feasible. It could be appropriate for optimizing the management of critically ill patients with ARC, as it resulted in antibiotic concentrations above the minimum inhibitory concentration for susceptible carbapenem-resistant Enterobacterales (up to 8 mg/L) throughout the dosing interval.
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Affiliation(s)
- Romaric Larcher
- Department of Infectious and Tropical Diseases, PhyMedExp (Physiology and Experimental Medicine), INSERM (French Institute of Health and Medical Research), CNRS (French National Centre for Scientific Research), University of Montpellier, Nimes University Hospital, Nimes, France.
- Service Des Maladies Infectieuses Et Tropicales, Hôpital Caremeau-Centre Hospitalo-Universitaire de Nîmes, 1 Place Robert Debre, 30000, Nîmes, France.
| | - Paul Laffont-Lozes
- Department of Infectious and Tropical Diseases, Nimes University Hospital, Nimes, France
- Department of Pharmacy, Nimes University Hospital, Nimes, France
| | - Tayma Naciri
- Department of Infectious and Tropical Diseases, Nimes University Hospital, Nimes, France
| | - Pierre-Marie Bourgeois
- Department of Infectious and Tropical Diseases, Nimes University Hospital, Nimes, France
| | - Cléa Gandon
- Department of Anesthesiology and Critical Care Medicine, Nimes University Hospital, Nimes, France
| | - Chloé Magnan
- Department of Microbiology and Hospital Hygiene, VBIC (Bacterial Virulence and Chronic Infection), INSERM (French Institute of Health and Medical Research), Montpellier University, Nimes University Hospital, Nimes, France
| | - Alix Pantel
- Department of Microbiology and Hospital Hygiene, VBIC (Bacterial Virulence and Chronic Infection), INSERM (French Institute of Health and Medical Research), Montpellier University, Nimes University Hospital, Nimes, France
| | - Albert Sotto
- Department of Infectious and Tropical Diseases, VBIC (Bacterial Virulence and Chronic Infection), INSERM (French Institute of Health and Medical Research), Montpellier University, Nimes University Hospital, Nimes, France
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Yassin A, Huralska M, Pogue JM, Dixit D, Sawyer RG, Kaye KS. State of the Management of Infections Caused by Multidrug-Resistant Gram-Negative Organisms. Clin Infect Dis 2023; 77:e46-e56. [PMID: 37738671 DOI: 10.1093/cid/ciad499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Indexed: 09/24/2023] Open
Abstract
In the past decade, the prevalence of multidrug-resistant gram-negative (MDR-GN) bacterial infections has increased significantly, leading to higher rates of morbidity and mortality. Treating these infections poses numerous challenges, particularly when selecting appropriate empiric therapy for critically ill patients for whom the margin for error is low. Fortunately, the availability of new therapies has improved the treatment landscape, offering safer and more effective options. However, there remains a need to establish and implement optimal clinical and therapeutic approaches for managing these infections. Here, we review strategies for identifying patients at risk for MDR-GN infections, propose a framework for the choice of empiric and definitive treatment, and explore effective multidisciplinary approaches to managing patients in the hospital while ensuring a safe transition to outpatient settings.
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Affiliation(s)
- Arsheena Yassin
- Department of Pharmacy, Robert Wood Johnson University Hospital, New Brunswick, New Jersey, USA
| | - Mariya Huralska
- Division of Allergy, Immunology and Infectious Diseases, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
| | - Jason M Pogue
- Department of Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA
- Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Deepali Dixit
- Department of Pharmacy, Robert Wood Johnson University Hospital, New Brunswick, New Jersey, USA
- Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, New Jersey, USA
| | - Robert G Sawyer
- Department of Surgery, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, Michigan, USA
| | - Keith S Kaye
- Division of Allergy, Immunology and Infectious Diseases, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
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43
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Budai KA, Tímár ÁE, Obeidat M, Máté V, Nagy R, Harnos A, Kiss-Dala S, Hegyi P, Garami M, Hankó B, Lódi C. Extended infusion of β-lactams significantly reduces mortality and enhances microbiological eradication in paediatric patients: a systematic review and meta-analysis. EClinicalMedicine 2023; 65:102293. [PMID: 38021371 PMCID: PMC10651452 DOI: 10.1016/j.eclinm.2023.102293] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/09/2023] [Accepted: 10/12/2023] [Indexed: 12/01/2023] Open
Abstract
Background Paediatric patients are often exposed to subtherapeutic levels or treatment failure of β-lactams, and prolonged infusion may be beneficial. We aimed to investigate the efficacy and safety of extended infusion (EI; defined as ≥3 h) or continuous infusion vs. short, intermittent infusion (SI; defined as ≤60 min) of β-lactams in patients <21 years of age. Methods A systematic review and meta-analysis was conducted to compare EI and continuous infusion with SI of β-lactams in children. A systematic search was performed in MEDLINE (via PubMed), Embase, CENTRAL, and Scopus databases for randomised controlled trials (RCTs) and observational studies published from database inception up to August 22, 2023. Any comparative study concerned with mortality, clinical efficacy, adverse events, or plasma concentrations of β-lactams for any infection was eligible. Case reports, case series, and patients aged >21 years were excluded. Odds ratios (OR) and median differences with 95% confidence intervals (CI) were calculated using a random-effects model. Risk of bias (ROB) was assessed using ROB2 and ROBINS-I tools. The protocol was registered with PROSPERO, CRD42022375397. Findings In total, 19,980 articles were screened, out of which 19 studies (4195 patients) were included in the meta-analysis. EI administration was associated with a significantly lower all-cause mortality in both RCTs and non-RCTs [OR 0.74; CI 0.55-0.99; I2 = 0%; CI 0-58%]. Early microbiological eradication was higher with EI [OR 3.18; CI 2.24-4.51; I2 = 0%; CI 0-90%], but the clinical cure did not differ significantly between the two groups [OR 1.20; CI 0.17-8.71; I2 = 79%; CI 32-93%]. Achieving the optimal plasma level (50-100% fT > MIC) appeared favourable in the EI group compared to the SI. No significant differences were observed in the adverse events. The overall ROB was high because of the small sample sizes and clinically heterogeneous populations. Interpretation Our findings suggest that extended infusion of β-lactams was associated with lower mortality and increased microbiological eradication and was considered safe compared to short-term infusion. Funding None.
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Affiliation(s)
- Kinga Anna Budai
- University Pharmacy, Department of Pharmacy Administration, Semmelweis University, Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Ágnes Eszter Tímár
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Heim Pál National Pediatric Institute, Budapest, Hungary
| | - Mahmoud Obeidat
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Vanda Máté
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Pediatric Center, MTA Center of Excellence, Semmelweis University, Budapest, Hungary
| | - Rita Nagy
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Heim Pál National Pediatric Institute, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Andrea Harnos
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Biostatistics at the University of Veterinary Medicine, Budapest, Hungary
| | - Szilvia Kiss-Dala
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Péter Hegyi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
| | - Miklós Garami
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Pediatric Center, MTA Center of Excellence, Semmelweis University, Budapest, Hungary
| | - Balázs Hankó
- University Pharmacy, Department of Pharmacy Administration, Semmelweis University, Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Csaba Lódi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Pediatric Center, MTA Center of Excellence, Semmelweis University, Budapest, Hungary
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Williams P, Cotta MO, Abdul‐Aziz MH, Wilks K, Farkas A, Roberts JA. In silico evaluation of a beta-lactam dosing guideline among adults with serious infections. Pharmacotherapy 2023; 43:1121-1130. [PMID: 36567467 PMCID: PMC10946580 DOI: 10.1002/phar.2753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 12/27/2022]
Abstract
STUDY OBJECTIVE The aim of this study was to compare the achievement of therapeutic pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for beta-lactam antibiotics using product information dosing or guideline-based dosing for the treatment of serious infections. DESIGN In silico study. DATA SOURCE ID-ODSTM (Individually Designed Optimum Dosing Strategies). PATIENTS AND INTERVENTION None. MEASUREMENTS AND MAIN RESULTS In silico product information and guideline-based dosing simulations for cefepime, ceftazidime, flucloxacillin, meropenem, and piperacillin/tazobactam were performed using pharmacokinetic models from seriously ill patient populations. The median simulated concentration at 48 and 96 h was used to measure the probability of target attainment (PTA) to achieve predefined therapeutic and toxicity PK-PD targets. A multiple linear regression model was constructed to identify the effect of guideline-based dosing covariates on achieving pre-defined therapeutic targets. In total, 480 dosing simulations were performed. The PTA percentage with guideline-based dosing at 48 and 96 h was 80% and 68%, respectively, yielding significantly higher results when compared to product information dosing (48.45% and 49%, respectively), p < 0.001 at both time points. At 48 h, predefined toxicity thresholds were exceeded in 4.7% and 0% of simulations for guideline-based and product information-based dosing, respectively (p = 0.002). eGFR was significantly associated with the % PTA by guideline-based dosing, with eGFR values of 20 and 50 ml/min both statistically significant in leading to an increase in PTA. CONCLUSIONS Our study demonstrated that achievement of PK-PD exposures associated with an increased likelihood of effectiveness was more likely to occur with guideline-based dosing; especially at 48 h.
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Affiliation(s)
- Paul Williams
- University of Queensland Centre for Clinical Research (UQCCR), The University of QueenslandBrisbaneQueenslandAustralia
- Pharmacy DepartmentSunshine Coast University HospitalBirtinyaQueenslandAustralia
| | - Menino Osbert Cotta
- University of Queensland Centre for Clinical Research (UQCCR), The University of QueenslandBrisbaneQueenslandAustralia
| | - Mohd H. Abdul‐Aziz
- University of Queensland Centre for Clinical Research (UQCCR), The University of QueenslandBrisbaneQueenslandAustralia
| | - Kathryn Wilks
- Infectious Diseases DepartmentSunshine Coast University HospitalBirtinyaQueenslandAustralia
- School of Public HealthThe University of QueenslandBrisbaneQueenslandAustralia
| | - Andras Farkas
- Department of PharmacyMount Sinai WestNew YorkNew YorkUSA
- Optimum Dosing StrategiesBloomingdaleNew JerseyUSA
| | - Jason A. Roberts
- University of Queensland Centre for Clinical Research (UQCCR), The University of QueenslandBrisbaneQueenslandAustralia
- Department of Intensive Care MedicineRoyal Brisbane and Women's HospitalBrisbaneQueenslandAustralia
- Pharmacy DepartmentRoyal Brisbane and Women's HospitalBrisbaneQueenslandAustralia
- Division of Anaesthesiology Critical Care Emergency and Pain MedicineNîmes University Hospital, University of MontpellierNîmesFrance
- Herston Infectious Diseases Institute (HeIDI)BrisbaneQueenslandAustralia
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Kalın G, Alp E, Chouaikhi A, Roger C. Antimicrobial Multidrug Resistance: Clinical Implications for Infection Management in Critically Ill Patients. Microorganisms 2023; 11:2575. [PMID: 37894233 PMCID: PMC10609422 DOI: 10.3390/microorganisms11102575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/05/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
The increasing incidence of antimicrobial resistance (AMR) worldwide represents a serious threat in the management of sepsis. Due to resistance to the most common antimicrobials prescribed, multidrug-resistant (MDR) pathogens have been associated with delays in adequate antimicrobial therapy leading to significant increases in mortality, along with prolonged hospital length of stay (LOS) and increases in healthcare costs. In response to MDR infections and the delay of microbiological results, broad-spectrum antibiotics are frequently used in empirical antimicrobial therapy. This can contribute to the overuse and misuse of antibiotics, further promoting the development of resistance. Multiple measures have been suggested to combat AMR. This review will focus on describing the epidemiology and trends concerning MDR pathogens. Additionally, it will explore the crucial aspects of identifying patients susceptible to MDR infections and optimizing antimicrobial drug dosing, which are both pivotal considerations in the fight against AMR. Expert commentary: The increasing AMR in ICUs worldwide makes the empirical antibiotic therapy challenging in septic patients. An AMR surveillance program together with improvements in MDR identification based on patient risk stratification and molecular rapid diagnostic tools may further help tailoring antimicrobial therapies and avoid unnecessary broad-spectrum antibiotics. Continuous infusions of antibiotics, therapeutic drug monitoring (TDM)-based dosing regimens and combination therapy may contribute to optimizing antimicrobial therapy and limiting the emergence of resistance.
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Affiliation(s)
- Gamze Kalın
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Erciyes University, Kayseri 38280, Türkiye
| | - Emine Alp
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara 06760, Türkiye;
| | - Arthur Chouaikhi
- Department of Anesthesiology and Intensive Care, Pain and Emergency Medicine, Nîmes-Caremeau University Hospital, Place du Professeur Robert Debré, CEDEX 9, 30029 Nîmes, France;
| | - Claire Roger
- Department of Anesthesiology and Intensive Care, Pain and Emergency Medicine, Nîmes-Caremeau University Hospital, Place du Professeur Robert Debré, CEDEX 9, 30029 Nîmes, France;
- UR UM 103 IMAGINE, Faculty of Medicine, Montpellier University, Chemin du Carreau de Lanes, 30029 Nîmes, France
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46
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Brasier N, Ates HC, Sempionatto JR, Cotta MO, Widmer AF, Eckstein J, Goldhahn J, Roberts JA, Gao W, Dincer C. A three-level model for therapeutic drug monitoring of antimicrobials at the site of infection. THE LANCET. INFECTIOUS DISEASES 2023; 23:e445-e453. [PMID: 37348517 DOI: 10.1016/s1473-3099(23)00215-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 06/24/2023]
Abstract
The silent pandemic of bacterial antimicrobial resistance is a leading cause of death worldwide, prolonging hospital stays and raising health-care costs. Poor incentives to develop novel pharmacological compounds and the misuse of antibiotics contribute to the bacterial antimicrobial resistance crisis. Therapeutic drug monitoring (TDM) based on blood analysis can help alleviate the emergence of bacterial antimicrobial resistance and effectively decreases the risk of toxic drug concentrations in patients' blood. Antibiotic tissue penetration can vary in patients who are critically or chronically ill and can potentially lead to treatment failure. Antibiotics such as β-lactams and glycopeptides are detectable in non-invasively collectable biofluids, such as sweat and exhaled breath. The emergence of wearable sensors enables easy access to these non-invasive biofluids, and thus a laboratory-independent analysis of various disease-associated biomarkers and drugs. In this Personal View, we introduce a three-level model for TDM of antibiotics to describe concentrations at the site of infection (SOI) by use of wearable sensors. Our model links blood-based drug measurement with the analysis of drug concentrations in non-invasively collectable biofluids stemming from the SOI to characterise drug concentrations at the SOI. Finally, we outline the necessary clinical and technical steps for the development of wearable sensing platforms for SOI applications.
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Affiliation(s)
- Noé Brasier
- Institute for Translational Medicine, ETH Zurich, Zurich, Switzerland; Department of Digitalization & ICT, University Hospital Basel, Basel, Switzerland.
| | - H Ceren Ates
- FIT Freiburg Centre for Interactive Materials and Bioinspired Technology, University of Freiburg, Freiburg, Germany; Department of Microsystems Engineering, IMTEK, University of Freiburg, Freiburg, Germany
| | - Juliane R Sempionatto
- Andrew and Peggy Cherng Department of Medical Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Menino O Cotta
- Faculty of Medicine, University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia
| | - Andreas F Widmer
- Department of Infectious Disease and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
| | - Jens Eckstein
- Department of Digitalization & ICT, University Hospital Basel, Basel, Switzerland; Division for Internal Medicine, University Hospital Basel, Basel, Switzerland
| | - Jörg Goldhahn
- Institute for Translational Medicine, ETH Zurich, Zurich, Switzerland
| | - Jason A Roberts
- Faculty of Medicine, University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia; Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, QLD, Australia; Department of Pharmacy and Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Division of Anaesthesiology, Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
| | - Wei Gao
- Andrew and Peggy Cherng Department of Medical Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Can Dincer
- FIT Freiburg Centre for Interactive Materials and Bioinspired Technology, University of Freiburg, Freiburg, Germany; Department of Microsystems Engineering, IMTEK, University of Freiburg, Freiburg, Germany.
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Barker CIS, Kipper K, Lonsdale DO, Wright K, Thompson G, Kim M, Turner MA, Johnston A, Sharland M, Standing JF. The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence. J Antimicrob Chemother 2023; 78:2148-2161. [PMID: 37531085 PMCID: PMC10477139 DOI: 10.1093/jac/dkad196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 06/09/2023] [Indexed: 08/03/2023] Open
Abstract
BACKGROUND Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care. OBJECTIVES The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing. METHODS NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (n = 10 000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval. RESULTS For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT>MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h-1 and 1.3 h-1) and bioavailability terms (62.7% and 58.7%, respectively). CONCLUSIONS NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin.
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Affiliation(s)
- Charlotte I S Barker
- Centre for Neonatal and Paediatric Infection, Level 2 Jenner Wing, Institute for Infection and Immunity, St George’s, University of London SW17 0RE, London, UK
- Paediatric Infectious Diseases Department, St George’s University Hospitals NHS Foundation Trust, London, UK
- Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Department of Medical & Molecular Genetics, King’s College London, London, UK
| | - Karin Kipper
- Centre for Neonatal and Paediatric Infection, Level 2 Jenner Wing, Institute for Infection and Immunity, St George’s, University of London SW17 0RE, London, UK
- Analytical Services International, St George’s, University of London, London, UK
- Analytical Chemistry Department, Epilepsy Society, Chesham Lane, Chalfont St Peter, Buckinghamshire, UK
- Institute of Chemistry, University of Tartu, Tartu, Estonia
| | - Dagan O Lonsdale
- Centre for Neonatal and Paediatric Infection, Level 2 Jenner Wing, Institute for Infection and Immunity, St George’s, University of London SW17 0RE, London, UK
- Paediatric Infectious Diseases Department, St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Kirstie Wright
- Centre for Neonatal and Paediatric Infection, Level 2 Jenner Wing, Institute for Infection and Immunity, St George’s, University of London SW17 0RE, London, UK
| | - Georgina Thompson
- Centre for Neonatal and Paediatric Infection, Level 2 Jenner Wing, Institute for Infection and Immunity, St George’s, University of London SW17 0RE, London, UK
| | - Min Kim
- Centre for Neonatal and Paediatric Infection, Level 2 Jenner Wing, Institute for Infection and Immunity, St George’s, University of London SW17 0RE, London, UK
- Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Mark A Turner
- Department of Women’s and Children’s Health, University of Liverpool, Liverpool Health Partners, Liverpool, UK
| | - Atholl Johnston
- Analytical Services International, St George’s, University of London, London, UK
- Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Mike Sharland
- Centre for Neonatal and Paediatric Infection, Level 2 Jenner Wing, Institute for Infection and Immunity, St George’s, University of London SW17 0RE, London, UK
- Paediatric Infectious Diseases Department, St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Joseph F Standing
- Centre for Neonatal and Paediatric Infection, Level 2 Jenner Wing, Institute for Infection and Immunity, St George’s, University of London SW17 0RE, London, UK
- Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Pharmacy Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
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48
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Shields AD, Plante LA, Pacheco LD, Louis JM. Society for Maternal-Fetal Medicine Consult Series #67: Maternal sepsis. Am J Obstet Gynecol 2023; 229:B2-B19. [PMID: 37236495 DOI: 10.1016/j.ajog.2023.05.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Maternal sepsis is a significant cause of maternal morbidity and mortality, and is a potentially preventable cause of maternal death. This Consult aims to summarize what is known about sepsis and provide guidance for the management of sepsis during pregnancy and the postpartum period. Most studies cited are from the nonpregnant population, but where available, pregnancy data are included. The following are the Society for Maternal-Fetal Medicine recommendations: (1) we recommend that clinicians consider the diagnosis of sepsis in pregnant or postpartum patients with otherwise unexplained end-organ damage in the presence of a suspected or confirmed infectious process, regardless of the presence of fever (GRADE 1C); (2) we recommend that sepsis and septic shock in pregnancy be considered medical emergencies and that treatment and resuscitation begin immediately (Best Practice); (3) we recommend that hospitals and health systems use a performance improvement program for sepsis in pregnancy with sepsis screening tools and metrics (GRADE 1B); (4) we recommend that institutions develop their own procedures and protocols for the detection of maternal sepsis, avoiding the use of a single screening tool alone (GRADE 1B); (5) we recommend obtaining tests to evaluate for infectious and noninfectious causes of life-threatening organ dysfunction in pregnant and postpartum patients with possible sepsis (Best Practice); (6) we recommend that an evaluation for infectious causes in pregnant or postpartum patients in whom sepsis is suspected or identified includes appropriate microbiologic cultures, including blood, before starting antimicrobial therapy, as long as there are no substantial delays in timely administration of antibiotics (Best Practice); (7) we recommend obtaining a serum lactate level in pregnant or postpartum patients in whom sepsis is suspected or identified (GRADE 1B); (8) in pregnant or postpartum patients with septic shock or a high likelihood of sepsis, we recommend administration of empiric broad-spectrum antimicrobial therapy, ideally within 1 hour of recognition (GRADE 1C); (9) after a diagnosis of sepsis in pregnancy is made, we recommend rapid identification or exclusion of an anatomic source of infection and emergency source control when indicated (Best Practice); (10) we recommend early intravenous administration (within the first 3 hours) of 1 to 2 L of balanced crystalloid solutions in sepsis complicated by hypotension or suspected organ hypoperfusion (GRADE 1C); (11) we recommend the use of a balanced crystalloid solution as a first-line fluid for resuscitation in pregnant and postpartum patients with sepsis or septic shock (GRADE 1B); (12) we recommend against the use of starches or gelatin for resuscitation in pregnant and postpartum patients with sepsis or septic shock (GRADE 1A); (13) we recommend ongoing, detailed evaluation of the patient's response to fluid resuscitation guided by dynamic measures of preload (GRADE 1B); (14) we recommend the use of norepinephrine as the first-line vasopressor during pregnancy and the postpartum period with septic shock (GRADE 1C); (15) we suggest using intravenous corticosteroids in pregnant or postpartum patients with septic shock who continue to require vasopressor therapy (GRADE 2B); (16) because of an increased risk of venous thromboembolism in sepsis and septic shock, we recommend the use of pharmacologic venous thromboembolism prophylaxis in pregnant and postpartum patients in septic shock (GRADE 1B); (17) we suggest initiating insulin therapy at a glucose level >180 mg/dL in critically ill pregnant patients with sepsis (GRADE 2C); (18) if a uterine source for sepsis is suspected or confirmed, we recommend prompt delivery or evacuation of uterine contents to achieve source control, regardless of gestational age (GRADE 1C); and (19) because of an increased risk of physical, cognitive, and emotional problems in survivors of sepsis and septic shock, we recommend ongoing comprehensive support for pregnant and postpartum sepsis survivors and their families (Best Practice).
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Berrino PM, Gatti M, Rinaldi M, Brunocilla E, Viale P, Pea F. Pharmacokinetic/Pharmacodynamic Target Attainment of Continuous Infusion Piperacillin-Tazobactam or Meropenem and Microbiological Outcome among Urologic Patients with Documented Gram-Negative Infections. Antibiotics (Basel) 2023; 12:1388. [PMID: 37760685 PMCID: PMC10525318 DOI: 10.3390/antibiotics12091388] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
(1) Objectives: To describe the relationship between pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) piperacillin-tazobactam or meropenem monotherapy and microbiological outcome in a case series of urological patients with documented Gram-negative infections. (2) Methods: Patients admitted to the urology ward who were treated with CI piperacillin-tazobactam or meropenem monotherapy for documented Gram-negative infections and underwent real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program from June 2021 to May 2023 were retrospectively retrieved. Average steady-state (Css) piperacillin-tazobactam and meropenem concentrations were determined, and the free fractions (fCss) were calculated. Optimal PK/PD target attainments were defined as an fCss/MIC ratio >4 for CI meropenem and an fCss/MIC ratio of piperacillin >4 coupled with an fCss/CT ratio for tazobactam >1 for piperacillin-tazobactam (joint PK/PD target). The relationship between beta-lactam PK/PD targets and microbiological outcome was explored. (3) Results: Sixteen urologic patients with documented Gram-negative infections (62.5% complicated urinary tract infections (cUTI)) had 30 TDM-guided ECPAs. At first TDM assessment, beta-lactam dosing adjustments were recommended in 11 out of 16 cases (68.75%, of which 62.5% decreases and 6.25% increases). Overall, beta-lactam dosing adjustments were recommended in 14 out of 30 ECPAs (46.6%). Beta-lactam PK/PD target attainments were optimal in 100.0% of cases. Microbiological failure occurred in two patients, both developing beta-lactam resistance. (4) Conclusion: A TDM-guided ECPA program may allow for optimizing beta-lactam treatment in urologic patients with documented Gram-negative infections, ensuring microbiological eradication in most cases.
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Affiliation(s)
- Pasquale Maria Berrino
- Division of Urology, IRCCS Azienda Ospedaliero-Universitaria of Bologna, 40138 Bologna, Italy; (P.M.B.); (E.B.)
| | - Milo Gatti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (M.R.); (P.V.); (F.P.)
- Clinical Pharmacology Unit, Department for integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria of Bologna, 40138 Bologna, Italy
| | - Matteo Rinaldi
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (M.R.); (P.V.); (F.P.)
- Infectious Disease Unit, Department for integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria of Bologna, 40138 Bologna, Italy
| | - Eugenio Brunocilla
- Division of Urology, IRCCS Azienda Ospedaliero-Universitaria of Bologna, 40138 Bologna, Italy; (P.M.B.); (E.B.)
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (M.R.); (P.V.); (F.P.)
| | - Pierluigi Viale
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (M.R.); (P.V.); (F.P.)
- Infectious Disease Unit, Department for integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria of Bologna, 40138 Bologna, Italy
| | - Federico Pea
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (M.R.); (P.V.); (F.P.)
- Clinical Pharmacology Unit, Department for integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria of Bologna, 40138 Bologna, Italy
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Guilhaumou R, Chevrier C, Setti JL, Jouve E, Marsot A, Julian N, Blin O, Simeone P, Lagier D, Mokart D, Bruder N, Garnier M, Velly L. β-Lactam Pharmacokinetic/Pharmacodynamic Target Attainment in Intensive Care Unit Patients: A Prospective, Observational, Cohort Study. Antibiotics (Basel) 2023; 12:1289. [PMID: 37627709 PMCID: PMC10451857 DOI: 10.3390/antibiotics12081289] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND The aims of this study were to describe pharmacokinetic/pharmacodynamic target attainment in intensive care unit (ICU) patients treated with continuously infused ß-lactam antibiotics, their associated covariates, and the impact of dosage adjustment. METHODS This prospective, observational, cohort study was performed in three ICUs. Four ß-lactams were continuously infused, and therapeutic drug monitoring (TDM) was performed at days 1, 4, and 7. The primary pharmacokinetic/pharmacodynamic target was an unbound ß-lactam plasma concentration four times above the bacteria's minimal inhibitory concentration during the whole dosing interval. The demographic and clinical covariates associated with target attainment were evaluated. RESULTS A total of 170 patients were included (426 blood samples). The percentages of empirical ß-lactam underdosing at D1 were 66% for cefepime, 43% for cefotaxime, 47% for ceftazidime, and 14% for meropenem. Indexed creatinine clearance was independently associated with treatment underdose if increased (adjusted odds ratio per unit, 1.01; 95% CI, 1.00 to 1.01; p = 0.014) or overdose if decreased (adjusted odds ratio per unit, 0.95; 95% CI, 0.94 to 0.97; p < 0.001). Pharmacokinetic/pharmacodynamic target attainment was significantly increased after ß-lactam dosage adjustment between day 1 and day 4 vs. no adjustment (53.1% vs. 26.2%; p = 0.018). CONCLUSIONS This study increases our knowledge on the optimization of ß-lactam therapy in ICU patients. A large inter- and intra-patient variability in plasmatic concentrations was observed, leading to inadequate exposure. A combined indexed creatinine clearance and TDM approach enables adequate dosing for better pharmacokinetic/pharmacodynamic target attainment.
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Affiliation(s)
- Romain Guilhaumou
- Department of Clinical Pharmacology and Pharmacosurveillance, La Timone University Hospital; 13005 Marseille, France
- Institut de Neurosciences des Systèmes, Aix Marseille University, INSERM UMR 1106, 13005 Marseille, France
| | - Constance Chevrier
- Department of Clinical Pharmacology and Pharmacosurveillance, La Timone University Hospital; 13005 Marseille, France
- Institut de Neurosciences des Systèmes, Aix Marseille University, INSERM UMR 1106, 13005 Marseille, France
| | - Jean Loup Setti
- University Hospital Timone, Department of Anaesthesiology and Critical Care Medicine, APHM, Aix Marseille University, 13005 Marseille, France; (J.L.S.); (P.S.); (D.L.)
| | - Elisabeth Jouve
- Department of Clinical Pharmacology and Pharmacosurveillance, La Timone University Hospital; 13005 Marseille, France
- Institut de Neurosciences des Systèmes, Aix Marseille University, INSERM UMR 1106, 13005 Marseille, France
| | - Amélie Marsot
- Faculté de Pharmacie, Université de Montréal, Montreal, QC H3T 1J4, Canada;
| | - Nathan Julian
- University Hospital Timone, Department of Anaesthesiology and Critical Care Medicine, APHM, Aix Marseille University, 13005 Marseille, France; (J.L.S.); (P.S.); (D.L.)
| | - Olivier Blin
- Department of Clinical Pharmacology and Pharmacosurveillance, La Timone University Hospital; 13005 Marseille, France
- Institut de Neurosciences des Systèmes, Aix Marseille University, INSERM UMR 1106, 13005 Marseille, France
| | - Pierre Simeone
- University Hospital Timone, Department of Anaesthesiology and Critical Care Medicine, APHM, Aix Marseille University, 13005 Marseille, France; (J.L.S.); (P.S.); (D.L.)
- Inst Neurosci Timone, INT, CNRS, Aix Marseille University, UMR7289, 13005 Marseille, France
| | - David Lagier
- University Hospital Timone, Department of Anaesthesiology and Critical Care Medicine, APHM, Aix Marseille University, 13005 Marseille, France; (J.L.S.); (P.S.); (D.L.)
- C2VN, Inserm 1263, Inra 1260, Aix Marseille Université, 13005 Marseille, France
| | - Djamel Mokart
- Department of Anaesthesiology and Critical Care Medicine, Institut Paoli-Calmette, 13009 Marseille, France
| | - Nicolas Bruder
- University Hospital Timone, Department of Anaesthesiology and Critical Care Medicine, APHM, Aix Marseille University, 13005 Marseille, France; (J.L.S.); (P.S.); (D.L.)
| | - Marc Garnier
- Sorbonne University, GRC29, APHP, DMU DREAM, Rive Droite, Site Tenon, 75020 Paris, France
- Département d’Anesthésie-Réanimation et Médecine Périopératoire, CHU de Clermont-Ferrand, University Clermont Auvergne, 63000 Clermont-Ferrand, France
| | - Lionel Velly
- University Hospital Timone, Department of Anaesthesiology and Critical Care Medicine, APHM, Aix Marseille University, 13005 Marseille, France; (J.L.S.); (P.S.); (D.L.)
- Inst Neurosci Timone, INT, CNRS, Aix Marseille University, UMR7289, 13005 Marseille, France
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