Flucloxacillin worsens while imipenem-cilastatin protects against vancomycin-induced kidney injury in a translational rat model.
acute kidney injury
biomarkers
drug-induced kidney injury
flucloxacillin
imipenem-cilastatin
nephrotoxicity
preclinical
rodent
vancomycin
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
11 Sep 2023
11 Sep 2023
Historique:
revised:
11
08
2023
received:
16
01
2023
accepted:
28
08
2023
pubmed:
12
9
2023
medline:
12
9
2023
entrez:
11
9
2023
Statut:
aheadofprint
Résumé
Vancomycin is one of the most common clinical antibiotics, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model. Male Sprague-Dawley rats received allometrically scaled (1) vancomycin, (2) flucloxacillin, (3) vancomycin + flucloxacillin, (4) vancomycin + imipenem-cilastatin or (5) saline for 4 days. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. Urinary output increased every study day for vancomycin + flucloxacillin, but after the first dose only in the vancomycin group. In the vancomycin + flucloxacillin group, urinary KIM-1 increased on all days compared with vancomycin. In the vancomycin + imipenem-cilastatin group, urinary KIM-1 was decreased on Days 1 and 2 compared with vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin + flucloxacillin compared with vancomycin and vancomycin + imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1. Vancomycin + flucloxacillin caused more kidney injury compared with vancomycin alone and vancomycin + imipenem-cilastatin in a translational rat model. The combination of vancomycin + imipenem-cilastatin was nephroprotective.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
Vancomycin is one of the most common clinical antibiotics, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model.
EXPERIMENTAL APPROACH
METHODS
Male Sprague-Dawley rats received allometrically scaled (1) vancomycin, (2) flucloxacillin, (3) vancomycin + flucloxacillin, (4) vancomycin + imipenem-cilastatin or (5) saline for 4 days. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored.
KEY RESULTS
RESULTS
Urinary output increased every study day for vancomycin + flucloxacillin, but after the first dose only in the vancomycin group. In the vancomycin + flucloxacillin group, urinary KIM-1 increased on all days compared with vancomycin. In the vancomycin + imipenem-cilastatin group, urinary KIM-1 was decreased on Days 1 and 2 compared with vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin + flucloxacillin compared with vancomycin and vancomycin + imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1.
CONCLUSIONS AND IMPLICATIONS
CONCLUSIONS
Vancomycin + flucloxacillin caused more kidney injury compared with vancomycin alone and vancomycin + imipenem-cilastatin in a translational rat model. The combination of vancomycin + imipenem-cilastatin was nephroprotective.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R21 AI149026
Pays : United States
Informations de copyright
© 2023 British Pharmacological Society.
Références
ACCP Abstract Booklet. (2021). The combination of vancomycin & piperacillinTazobactam is protective in a rat model of vancomycin induced kidney injury. Clinical Pharmacology in Drug Development, 10(S1), 1-104. https://doi.org/10.1002/cpdd.1004
Alexander, S. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Buneman, O. P., Cidlowski, J. A., Christopoulos, A., Davenport, A. P., Fabbro, D., Spedding, M., Striessnig, J., Davies, J. A., Ahlers-Dannen, K. E., … Zolghadri, Y. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Introduction and other protein targets. British Journal of Pharmacology, 178, S1-s26. https://doi.org/10.1111/bph.15537
Alexander, S. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Amarosi, L., Anderson, C. M. H., Beart, P. M., Broer, S., Dawson, P. A., Hagenbuch, B., Hammond, J. R., Hancox, J. C., … Verri, T. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Transporters. British Journal of Pharmacology, 178(Suppl 1), S412-s513. https://doi.org/10.1111/bph.15543
Avedissian, S. N., Pais, G. M., Liu, J., Rhodes, N. J., & Scheetz, M. H. (2019). Piperacillin-tazobactam added to vancomycin increases risk for AKI: Fact or fiction? Clinical Infectious Diseases, 71, 426-432. https://doi.org/10.1093/cid/ciz1189
Avedissian, S. N., Pais, G. M., O'Donnell, J. N., Lodise, T. P., Liu, J., Prozialeck, W. C., Joshi, M. D., Lamar, P. C., Becher, L., Gulati, A., Hope, W., & Scheetz, M. H. (2019). Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model. The Journal of Antimicrobial Chemotherapy, 74(8), 2326-2334. https://doi.org/10.1093/jac/dkz167
Baggs, J., Fridkin, S. K., Pollack, L. A., Srinivasan, A., & Jernigan, J. A. (2016). Estimating national trends in inpatient antibiotic use among US hospitals from 2006 to 2012. JAMA Internal Medicine, 176(11), 1639-1648. https://doi.org/10.1001/jamainternmed.2016.5651
Becerir, T., Tokgün, O., & Yuksel, S. (2021). The therapeutic effect of Cilastatin on drug-induced nephrotoxicity: A new perspective. European Review for Medical and Pharmacological Sciences, 25(17), 5436-5447. https://doi.org/10.26355/eurrev_202109_26651
Blair, M., Cote, J. M., Cotter, A., Lynch, B., Redahan, L., & Murray, P. T. (2021). Nephrotoxicity from vancomycin combined with piperacillin-tazobactam: A comprehensive review. American Journal of Nephrology, 52(2), 85-97. https://doi.org/10.1159/000513742
Chang, J., Pais, G. M., Valdez, K., Marianski, S., Barreto, E. F., & Scheetz, M. H. (2022). Glomerular function and urinary biomarker changes between vancomycin and vancomycin plus piperacillin-tazobactam in a translational rat model. Antimicrobial Agents and Chemotherapy, 66(3), e0213221. https://doi.org/10.1128/aac.02132-21
Christensen, E. I., Nielsen, S., Moestrup, S. K., Borre, C., Maunsbach, A. B., de Heer, E., Ronco, P., Hammond, T. G., & Verroust, P. (1995). Segmental distribution of the endocytosis receptor gp330 in renal proximal tubules. European Journal of Cell Biology, 66(4), 349-364.
Curtis, M. J., Alexander, S. P. H., Cirino, G., George, C. H., Kendall, D. A., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Patel, H. H., Sobey, C. G., Stanford, S. C., Stanley, P., Stefanska, B., Stephens, G. J., Teixeira, M. M., Vergnolle, N., & Ahluwalia, A. (2022). Planning experiments: Updated guidance on experimental design and analysis and their reporting III. British Journal of Pharmacology, 179, 3907-3913. https://doi.org/10.1111/bph.15868
Flubiclox Package insert. (2022). https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent=&id=CP-2019-PI-02254-1&d=20230513172310101. Juno 10/2022.
Guidance for Industry. (2005). Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER).
Hakeam, H. A., AlAnazi, L., Mansour, R., AlFudail, S., & AlMarzouq, F. (2019). Does nephrotoxicity develop less frequently when vancomycin is combined with imipenem-cilastatin than with meropenem? A comparative study. Infectious Diseases, 51(8), 578-584. https://doi.org/10.1080/23744235.2019.1619934
He, M., Souza, E., Matvekas, A., Crass, R. L., & Pai, M. P. (2021). Alteration in acute kidney injury potential with the combination of vancomycin and imipenem-cilastatin/relebactam or piperacillin/tazobactam in a preclinical model. Antimicrobial Agents and Chemotherapy, 65, 10-1128. https://doi.org/10.1128/AAC.02141-20
Hori, Y., Aoki, N., Kuwahara, S., Hosojima, M., Kaseda, R., Goto, S., Iida, T., de, S., Kabasawa, H., Kaneko, R., Aoki, H., Tanabe, Y., Kagamu, H., Narita, I., Kikuchi, T., & Saito, A. (2017). Megalin blockade with cilastatin suppresses drug-induced nephrotoxicity. Journal of the American Society of Nephrology: JASN, 28(6), 1783-1791. https://doi.org/10.1681/ASN.2016060606
Humanes, B., Jado, J. C., Camaño, S., López-Parra, V., Torres, A. M., Álvarez-Sala, L. A., Cercenado, E., Tejedor, A., & Lázaro, A. (2015). Protective effects of cilastatin against vancomycin-induced nephrotoxicity. BioMed Research International, 2015, 704382. https://doi.org/10.1155/2015/704382
Im, D. S., Shin, H. J., Yang, K. J., Jung, S. Y., Song, H. Y., Hwang, H. S., & Gil, H. W. (2017). Cilastatin attenuates vancomycin-induced nephrotoxicity via P-glycoprotein. Toxicology Letters, 277, 9-17. https://doi.org/10.1016/j.toxlet.2017.05.023
Jiang, S., Li, T., Zhou, X., Qin, W., Wang, Z., & Liao, Y. (2018). Antibiotic drug piperacillin induces neuron cell death through mitochondrial dysfunction and oxidative damage. Canadian Journal of Physiology and Pharmacology, 96(6), 562-568. https://doi.org/10.1139/cjpp-2016-0679
Kahan, F. M., Kropp, H., Sundelof, J. G., & Birnbaum, J. (1983). Thienamycin: Development of imipenem-cilastatin. The Journal of Antimicrobial Chemotherapy, 12 Suppl D, 1-35. https://doi.org/10.1093/jac/12.suppl_d.1
Kusama, M., Yamamoto, K., Yamada, H., Kotaki, H., Sato, H., & Iga, T. (1998). Effect of cilastatin on renal handling of vancomycin in rats. Journal of Pharmaceutical Sciences, 87(9), 1173-1176. https://doi.org/10.1021/js9801135
Kuwahara, S., Hosojima, M., Kaneko, R., Aoki, H., Nakano, D., Sasagawa, T., Kabasawa, H., Kaseda, R., Yasukawa, R., Ishikawa, T., Suzuki, A., Sato, H., Kageyama, S., Tanaka, T., Kitamura, N., Narita, I., Komatsu, M., Nishiyama, A., & Saito, A. (2016). Megalin-mediated tubuloglomerular alterations in high-fat diet-induced kidney disease. Journal of the American Society of Nephrology: JASN, 27(7), 1996-2008. https://doi.org/10.1681/ASN.2015020190
Legg, A., Meagher, N., Johnson, S. A., Roberts, M. A., Cass, A., Scheetz, M. H., Davies, J., Roberts, J. A., Davis, J. S., & Tong, S. Y. C. (2023). Risk factors for nephrotoxicity in methicillin-resistant Staphylococcus aureus bacteraemia: A post hoc analysis of the CAMERA2 trial. Clinical Drug Investigation, 43, 23-33. https://doi.org/10.1007/s40261-022-01204-z
Lilley, E., Stanford, S. C., Kendall, D. E., Alexander, S. P., Cirino, G., Docherty, J. R., George, C. H., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Sobey, C. G., Stefanska, B., Stephens, G., Teixeira, M., & Ahluwalia, A. (2020). ARRIVE 2.0 and the British Journal of Pharmacology: Updated guidance for 2020. British Journal of Pharmacology, 177(16), 3611-3616. https://doi.org/10.1111/bph.15178
Liu, C., Bayer, A., Cosgrove, S. E., Daum, R. S., Fridkin, S. K., Gorwitz, R. J., Kaplan, S. L., Karchmer, A. W., Levine, D. P., Murray, B. E., J Rybak, M., Talan, D. A., Chambers, H. F., & Infectious Diseases Society of America. (2011). Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clinical Infectious Diseases, 52(3), e18-e55. https://doi.org/10.1093/cid/ciq146
Liu, J., Tong, S. Y. C., Davis, J. S., Rhodes, N. J., Scheetz, M. H., & Group, C. S. (2020). Vancomycin exposure and acute kidney injury outcome: A snapshot from the CAMERA2 study. Open Forum Infectious Diseases, 7(12), ofaa538. https://doi.org/10.1093/ofid/ofaa538
Lodise, T. P., Lomaestro, B., Graves, J., & Drusano, G. L. (2008). Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrobial Agents and Chemotherapy, 52(4), 1330-1336. https://doi.org/10.1128/AAC.01602-07
Lodise, T. P., Rosenkranz, S. L., Finnemeyer, M., Evans, S., Sims, M., Zervos, M. J., Creech, C. B., Patel, P. C., Keefer, M., Riska, P., Silveira, F. P., Scheetz, M., Wunderink, R. G., Rodriguez, M., Schrank, J., Bleasdale, S. C., Schultz, S., Barron, M., Stapleton, A., … Holland, T. L. (2020). The emperor's new clothes: PRospective Observational Evaluation of the Association Between Initial VancomycIn Exposure and Failure Rates Among ADult HospitalizEd Patients With Methicillin-resistant Staphylococcus aureus Bloodstream Infections (PROVIDE). Clinical Infectious Diseases, 70(8), 1536-1545. https://doi.org/10.1093/cid/ciz460
Moestrup, S. K., Cui, S., Vorum, H., Bregengård, C., Bjørn, S. E., Norris, K., Gliemann, J., & Christensen, E. I. (1995). Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. The Journal of Clinical Investigation, 96(3), 1404-1413. https://doi.org/10.1172/jci118176
Nakamura, T., Kokuryo, T., Hashimoto, Y., & Inui, K. I. (1999). Effects of fosfomycin and imipenem-cilastatin on the nephrotoxicity of vancomycin and cisplatin in rats. The Journal of Pharmacy and Pharmacology, 51(2), 227-232. https://doi.org/10.1211/0022357991772187
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. (2011). Guide for the care and use of laboratory animals (8th ed.). National Academies Press (US). https://doi.org/10.17226/12910
O'Donnell, J. N., Rhodes, N. J., Lodise, T. P., Prozialeck, W. C., Miglis, C. M., Joshi, M. D., Venkatesan, N., Pais, G., Cluff, C., Lamar, P. C., Briyal, S., Day, J. Z., Gulati, A., & Scheetz, M. H. (2017). 24-hour pharmacokinetic relationships for vancomycin and novel urinary biomarkers of acute kidney injury. Antimicrobial Agents and Chemotherapy, 61(11), e00416-17. https://doi.org/10.1128/AAC.00416-17
Ohnishi, A., Bryant, T. D., Branch, K. R., Sabra, R., & Branch, R. A. (1989). Role of sodium in the protective effect of ticarcillin on gentamicin nephrotoxicity in rats. Antimicrobial Agents and Chemotherapy, 33(6), 928-932. https://doi.org/10.1128/aac.33.6.928
Pais, G. M., Avedissian, S. N., O'Donnell, J. N., Rhodes, N. J., Lodise, T. P., Prozialeck, W. C., Lamar, P. C., Cluff, C., Gulati, A., Fitzgerald, J. C., Downes, K. J., Zuppa, A. F., & Scheetz, M. H. (2019). Comparative performance of urinary biomarkers for vancomycin-induced kidney injury according to timeline of injury. Antimicrobial Agents and Chemotherapy, 63(7), e00079-e00019. https://doi.org/10.1128/AAC.00079-19
Pais, G. M., Chang, J., Liu, J., & Scheetz, M. H. (2022). A translational rat model to assess glomerular function changes with vancomycin. International Journal of Antimicrobial Agents, 59(5), 106583. https://doi.org/10.1016/j.ijantimicag.2022.106583
Pais, G. M., Liu, J., Avedissian, S. N., Hiner, D., Xanthos, T., Chalkias, A., d'Aloja, E., Locci, E., Gilchrist, A., Prozialeck, W. C., Rhodes, N. J., Lodise, T. P., Fitzgerald, J. C., Downes, K. J., Zuppa, A. F., & Scheetz, M. H. (2020). Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model. The Journal of Antimicrobial Chemotherapy, 75(5), 1228-1236. https://doi.org/10.1093/jac/dkz563
Pais, G. M., Liu, J., Zepcan, S., Avedissian, S. N., Rhodes, N. J., Downes, K. J., Moorthy, G. S., & Scheetz, M. H. (2020). Vancomycin-induced kidney injury: Animal models of toxicodynamics, mechanisms of injury, human translation, and potential strategies for prevention. Pharmacotherapy, 40(5), 438-454. https://doi.org/10.1002/phar.2388
Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., Emerson, M., Garner, P., Holgate, S. T., Howells, D. W., Karp, N. A., Lazic, S. E., Lidster, K., MacCallum, C. J., Macleod, M., … Würbel, H. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biology, 18(7), e3000410. https://doi.org/10.1371/journal.pbio.3000410
Persy, V. P., Verstrepen, W. A., Ysebaert, D. K., De Greef, K. E., & De Broe, M. E. (1999). Differences in osteopontin up-regulation between proximal and distal tubules after renal ischemia/reperfusion. Kidney International, 56(2), 601-611. https://doi.org/10.1046/j.1523-1755.1999.00581.x
Primaxin Package insert. (2016). https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050587s074lbl.pdf. Merck 12/2016.
Rhodes, N. J., Prozialeck, W. C., Lodise, T. P., Venkatesan, N., O'Donnell, J. N., Pais, G., Cluff, C., Lamar, P. C., Neely, M. N., Gulati, A., & Scheetz, M. H. (2016). Evaluation of vancomycin exposures associated with elevations in novel urinary biomarkers of acute kidney injury in vancomycin-treated rats. Antimicrobial Agents and Chemotherapy, 60(10), 5742-5751. https://doi.org/10.1128/AAC.00591-16
Rybak, M. J., le, J., Lodise, T. P., Levine, D. P., Bradley, J. S., Liu, C., Mueller, B. A., Pai, M. P., Wong-Beringer, A., Rotschafer, J. C., Rodvold, K. A., Maples, H. D., & Lomaestro, B. M. (2020). Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. American Journal of Health-System Pharmacy, 77(11), 835-864. https://doi.org/10.1093/ajhp/zxaa036
Sabra, R., & Branch, R. A. (1990). Role of sodium in protection by extended-spectrum penicillins against tobramycin-induced nephrotoxicity. Antimicrobial Agents and Chemotherapy, 34(6), 1020-1025. https://doi.org/10.1128/aac.34.6.1020
Scheetz, M. H., Pais, G. M., Lodise, T. P., Tong, S. Y. C., Davis, J. S., O'Donnell, J. N., Liu, J., Neely, M., Prozialeck, W. C., Lamar, P. C., Rhodes, N. J., Holland, T., & Avedissian, S. N. (2021). Of rats and men: A translational model to understand vancomycin pharmacokinetic/toxicodynamic relationships. Antimicrobial Agents and Chemotherapy, 65(10), e0106021. https://doi.org/10.1128/aac.01060-21
Suzuki, T., Yamaguchi, H., Ogura, J., Kobayashi, M., Yamada, T., & Iseki, K. (2013). Megalin contributes to kidney accumulation and nephrotoxicity of colistin. Antimicrobial Agents and Chemotherapy, 57(12), 6319-6324. https://doi.org/10.1128/aac.00254-13
Tong, S. Y. C., Lye, D. C., Yahav, D., Sud, A., Robinson, J. O., Nelson, J., Archuleta, S., Roberts, M. A., Cass, A., Paterson, D. L., Foo, H., Paul, M., Guy, S. D., Tramontana, A. R., Walls, G. B., McBride, S., Bak, N., Ghosh, N., Rogers, B. A., … for the Australasian Society for Infectious Diseases Clinical Research Network. (2020). Effect of vancomycin or daptomycin with vs without an antistaphylococcal β-lactam on mortality, bacteremia, relapse, or treatment failure in patients with MRSA bacteremia: A randomized clinical trial. Jama, 323(6), 527-537. https://doi.org/10.1001/jama.2020.0103
Toyoguchi, T., Takahashi, S., Hosoya, J., Nakagawa, Y., & Watanabe, H. (1997). Nephrotoxicity of vancomycin and drug interaction study with cilastatin in rabbits. Antimicrobial Agents and Chemotherapy, 41(9), 1985-1990. https://doi.org/10.1128/AAC.41.9.1985
Tune, B. M. (1997). Nephrotoxicity of beta-lactam antibiotics: Mechanisms and strategies for prevention. Pediatric Nephrology, 11(6), 768-772. https://doi.org/10.1007/s004670050386
Tune, B. M., & Fravert, D. (1980). Mechanisms of cephalosporin nephrotoxicity: A comparison of cephaloridine and cephaloglycin. Kidney International, 18(5), 591-600. https://doi.org/10.1038/ki.1980.177
van Hal, S. J., Paterson, D. L., & Lodise, T. P. (2013). Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrobial Agents and Chemotherapy, 57(2), 734-744. https://doi.org/10.1128/AAC.01568-12
Wickham, H. (2016). ggplot2: Elegant graphics for data analysis. Springer-Verlag. https://doi.org/10.1007/978-3-319-24277-4
Wolman, A. T., Gionfriddo, M. R., Heindel, G. A., Mukhija, P., Witkowski, S., Bommareddy, A., & Vanwert, A. L. (2013). Organic anion transporter 3 interacts selectively with lipophilic beta-lactam antibiotics. Drug Metabolism and Disposition, 41(4), 791-800. https://doi.org/10.1124/dmd.112.049569
Wunderink, R. G., Niederman, M. S., Kollef, M. H., Shorr, A. F., Kunkel, M. J., Baruch, A., McGee, W. T., Reisman, A., & Chastre, J. (2012). Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: A randomized, controlled study. Clinical Infectious Diseases, 54(5), 621-629. https://doi.org/10.1093/cid/cir895
Zosyn Package insert. (2019). https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/050684s094lbl.pdf. Pfizer 5/2019.