{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T04:54:28Z","timestamp":1762059268363,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,16]],"date-time":"2022-07-16T00:00:00Z","timestamp":1657929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Severe community-acquired pneumonia (CAP) is a condition that frequently requires intensive care and, eventually, can cause to death. Piperacillin\/tazobactam antibiotic therapy is employed as an empiric intravenous regimen, in many cases supplemented with intravenous bolus hydrocortisone treatment. The individual and condition-dependent pharmacokinetic properties of these drugs may lead to therapeutic failure. The impact of systemic inflammation, as well as of hydrocortisone on the altered pharmacokinetics of piperacillin is largely unknown. The protocol of a clinical study aimed at the characterization of the pharmacokinetics of piperacillin and tazobactam and its association with the concentrations of inflammatory markers and adrenal steroids during CAP therapy will be investigated in up to 40 critically ill patients. The serum concentrations of piperacillin and tazobactam, cortisol, cortisone, corticosterone and 11-deoxycortisol and interleukin-6 levels, as well as routine clinical chemistry and hematology parameters will be monitored from the beginning of treatment for up to five days. Nonparametric population pharmacokinetic modeling and Monte-Carlo simulations will be performed to make estimates of the pharmacokinetics of piperacillin and tazobactam and the probability of pharmacokinetic-pharmacodynamic target attainment. The observed individual characteristics and changes will be correlated with clinical and laboratory findings. The protocol of the observational study will be designed following the STROBE guideline.<\/jats:p>","DOI":"10.3390\/jcm11144140","type":"journal-article","created":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T22:57:06Z","timestamp":1658098626000},"page":"4140","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Assessment of Antibiotic Pharmacokinetics, Molecular Biomarkers and Clinical Status in Critically Ill Adults Diagnosed with Community-Acquired Pneumonia and Receiving Intravenous Piperacillin\/Tazobactam and Hydrocortisone over the First Five Days of Intensive Care: An Observational Study (STROBE Compliant)"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6843-7159","authenticated-orcid":false,"given":"Istv\u00e1n","family":"Vincze","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Semmelweis University, H-1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Czermann","sequence":"additional","affiliation":[{"name":"Central Department of Anaesthesiology and Intensive Care, Uzsoki Teaching Hospital, H-1145 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsuzsanna","family":"Nagy","sequence":"additional","affiliation":[{"name":"Central Department of Laboratory Diagnostics, Uzsoki Teaching Hospital, H-1145 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e1ria","family":"Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"Central Department of Laboratory Diagnostics, Uzsoki Teaching Hospital, H-1145 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Neely","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Pharmacokinetics and Bioinformatics, Children\u2019s Hospital of Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u00f3bert","family":"Farkas","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Semmelweis University, H-1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ibolya","family":"Kocsis","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Semmelweis University, H-1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gell\u00e9rt Bal\u00e1zs","family":"Karvaly","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Semmelweis University, H-1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1922-7294","authenticated-orcid":false,"given":"Csaba","family":"Kopitk\u00f3","sequence":"additional","affiliation":[{"name":"Central Department of Anaesthesiology and Intensive Care, Uzsoki Teaching Hospital, H-1145 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R209","DOI":"10.1186\/cc10444","article-title":"Community-acquired polymicrobial pneumonia in the intensive care unit: Aetiology and prognosis","volume":"15","author":"Ewig","year":"2011","journal-title":"Crit. Care."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1097\/CCM.0b013e3181eedaeb","article-title":"Age still matters prognosticating short- and long-term mortality for critically ill patients with pneumonia","volume":"38","author":"Sligl","year":"2010","journal-title":"Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1186\/cc4927","article-title":"Community-acquired pneumonia on the intensive care unit: Secondary analysis of 17,869 cases in the ICNARC Case Mix Programme Database","volume":"10","author":"Woodhead","year":"2006","journal-title":"Crit. Care."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1164\/rccm.200406-808OC","article-title":"Hydrocortisone infusion for severe community-acquired pneumonia: A preliminary randomized study","volume":"171","author":"Confalonieri","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1001\/archinte.167.15.1655","article-title":"Understanding the inflammatory cytokine response in pneumonia and sepsis: Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study","volume":"167","author":"Kellum","year":"2007","journal-title":"Arch. Intern. Med."},{"key":"ref_6","first-page":"Cd007720","article-title":"Corticosteroids for pneumonia","volume":"12","author":"Stern","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1001\/jama.288.7.862","article-title":"Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock","volume":"288","author":"Annane","year":"2002","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1097\/01.CCM.0000186370.78639.23","article-title":"Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock","volume":"33","author":"Oppert","year":"2005","journal-title":"Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1056\/NEJMoa071366","article-title":"Hydrocortisone therapy for patients with septic shock","volume":"358","author":"Sprung","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"805","DOI":"10.2165\/00003495-199957050-00017","article-title":"Piperacillin\/tazobactam: An updated review of its use in the treatment of bacterial infections","volume":"57","author":"Perry","year":"1999","journal-title":"Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1007\/BF01745246","article-title":"Pharmacokinetic characteristics of piperacillin\/tazobactam","volume":"20","author":"Kinzig","year":"1994","journal-title":"Intensive Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1093\/jac\/31.suppl_A.39","article-title":"The chemistry, pharmacokinetics and tissue distribution of piperacillin\/tazobactam","volume":"31","author":"Kinzig","year":"1993","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.4103\/2224-4018.135600","article-title":"Steroid pharmacokinetics: An \u201coverlooked\u201d issue of steroid metabolism in acute and chronic disease","volume":"2","author":"Jacobs","year":"2014","journal-title":"J. Transl. Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1183\/09031936.00154107","article-title":"Corticosteroids in severe pneumonia","volume":"32","author":"Sibila","year":"2008","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13054-015-0750-y","article-title":"Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?","volume":"19","author":"Udy","year":"2015","journal-title":"Crit. Care."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1186\/s13054-018-2155-1","article-title":"Pharmacokinetics-pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients","volume":"22","author":"Veiga","year":"2018","journal-title":"Crit. Care."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"E37","DOI":"10.1111\/j.1469-0691.2011.03752.x","article-title":"The role of pharmacokinetics\/pharmacodynamics in setting clinical MIC breakpoints: The EUCAST approach","volume":"18","author":"Mouton","year":"2012","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_18","unstructured":"EMA (2016). Guideline on the Use of Pharmacokinetics and Pharmacodynamics in the Development of Antimicrobial Medicinal Products, EMA\/CHMP\/594085\/2015."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s00134-021-06609-6","article-title":"Effect of therapeutic drug monitoring-based dose optimization of piperacillin\/tazobactam on sepsis-related organ dysfunction in patients with sepsis: A randomized controlled trial","volume":"48","author":"Hagel","year":"2022","journal-title":"Intensiv. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Vandenbroucke, J.P., von Elm, E., Altman, D.G., G\u00f8tzsche, P.C., Mulrow, C.D., Pocock, S.J., Poole, C., Schlesselman, J.J., Egger, M., and Strobe Initiative (2007). Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and elaboration. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040297"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1801261","DOI":"10.1183\/13993003.01261-2018","article-title":"What is a COPD exacerbation? Current definitions, pitfalls, challenges and opportunities for improvement","volume":"52","author":"Kim","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1086\/511159","article-title":"Infectious Diseases Society of America\/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults","volume":"44","author":"Mandell","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1016\/j.chest.2020.07.089","article-title":"International Perspective on the New 2019 American Thoracic Society\/Infectious Diseases Society of America Community-Acquired Pneumonia Guideline: A Critical Appraisal by a Global Expert Panel","volume":"158","author":"Pletz","year":"2020","journal-title":"Chest"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1701190","DOI":"10.1183\/13993003.01190-2017","article-title":"Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumonia: A multinational point prevalence study of hospitalised patients","volume":"52","author":"Restrepo","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/0732-8893(92)90095-B","article-title":"The E-Test as an epidemiologic tool","volume":"15","author":"Baquero","year":"1992","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_26","unstructured":"(2022, April 07). Chromsystems, Instruments & Chemicals GmbH. Antibiotics in Serum\/Plasma\u2014HPLC. Available online: https:\/\/chromsystems.com\/en\/antibiotics-in-serum-plasma-hplc-61000.html."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.jpba.2018.01.054","article-title":"The comprehensive characterization of adrenocortical steroidogenesis using two-dimensional ultra-performance liquid chromatography\u2014Electrospray ionization tandem mass spectrometry","volume":"153","author":"Karvaly","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1097\/00003246-198510000-00009","article-title":"APACHE II: A severity of disease classification system","volume":"13","author":"Knaus","year":"1985","journal-title":"Crit. Care Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1001\/jama.1993.03510240069035","article-title":"A new Simplified Acute Physiology Score (SAPS II) based on a European\/North American multicenter study","volume":"270","author":"Lemeshow","year":"1993","journal-title":"JAMA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/BF01709751","article-title":"The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction\/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine","volume":"22","author":"Vincent","year":"1996","journal-title":"Intensiv. Care Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1136\/thorax.58.5.377","article-title":"Defining community acquired pneumonia severity on presentation to hospital: An international derivation and validation study","volume":"58","author":"Lim","year":"2003","journal-title":"Thorax"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1056\/NEJM199701233360402","article-title":"A prediction rule to identify low-risk patients with community-acquired pneumonia","volume":"336","author":"Fine","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4097\/kja.21209","article-title":"Receiver operating characteristic curve: Overview and practical use for clinicians","volume":"75","author":"Nahm","year":"2022","journal-title":"Korean J. Anesthesiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Karvaly, G.B., Neely, M.N., Kovacs, K., Vincze, I., Vasarhelyi, B., and Jelliffe, R.W. (2020). Development of a methodology to make individual estimates of the precision of liquid chromatography-tandem mass spectrometry drug assay results for use in population pharmacokinetic modeling and the optimization of dosage regimens. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229873"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8959","DOI":"10.1021\/ac5018265","article-title":"Selecting the correct weighting factors for linear and quadratic calibration curves with least-squares regression algorithm in bioanalytical LC-MS\/MS assays and impacts of using incorrect weighting factors on curve stability, data quality, and assay performance","volume":"86","author":"Gu","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_36","unstructured":"Team, R.C. (2017). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1097\/FTD.0b013e31825c4ba6","article-title":"Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R","volume":"34","author":"Neely","year":"2012","journal-title":"Ther. Drug Monit."},{"key":"ref_38","unstructured":"Leary, R., Jelliffe, R., Schumitzky, A., and Guilder, M. (2001, January 26\u201327). An adaptive grid non-parametric approach to pharmacokinetic and dynamic (PK\/PD) population models2001. Proceedings of the 14th IEEE Symposium on Computer-Based Medical Systems, Bethesda, MD, USA."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1007\/s40262-022-01113-6","article-title":"An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients","volume":"61","author":"Wallenburg","year":"2022","journal-title":"Clin. Pharmacokinet."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/14\/4140\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:52:10Z","timestamp":1760140330000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/14\/4140"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,16]]},"references-count":39,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["jcm11144140"],"URL":"https:\/\/doi.org\/10.3390\/jcm11144140","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2022,7,16]]}}}