AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.

4th Department of Internal Medicine Hematology University Hospital Hradec Kralove and Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic

Department of Clinical Microbiology University Hospital Hradec Kralove and Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic

Department of Clinical Pharmacy Hospital Pharmacy Faculty of Pharmacy in Hradec Kralove Charles University and University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Clinical Biochemistry University Hospital Hradec Kralove and Charles University Prague Faculty of Medicine in Hradec Kralove Hradec Kralove Czech Republic

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Richards DM, Brogden RN. Ceftazidime: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs. 1985;29(2):105-161. doi:10.2165/00003495-198529020-00002

Grill MF, Maganti R. Cephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring. Ann Pharmacother. 2008;42(12):1843-1850. doi:10.1345/aph.1L307

Deshayes S, Coquerel A, Verdon R. Neurological adverse effects attributable to beta-lactam antibiotics: a literature review. Drug Saf. 2017;40(12):1171-1198. doi:10.1007/s40264-017-0578-2

Collins RD, Tverdek FP, Bruno JJ, Coyle EA. Probable nonconvulsive status epilepticus with the use of high-dose continuous infusion ceftazidime. J Pharm Pract. 2016;29(6):564-568. doi:10.1177/0897190015608503

State Institute for Drug Control of Czech Republic. Summary of product characteristics (ceftazidime). Updated December 20, 2021. Accessed August 25, 2022.

Lacroix C, Kheloufi F, Montastruc F, Bennis Y, Pizzoglio V, Micallef J. Serious central nervous system side effects of cephalosporins: a national analysis of serious reports registered in the French Pharmacovigilance Database. J Neurol Sci. 2019;398:196-201. doi:10.1016/j.jns.2019.01.018

Wong G, Briscoe S, McWhinney B, et al. Therapeutic drug monitoring of beta-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures. J Antimicrob Chemother. 2018;73(11):3087-3094. doi:10.1093/jac/dky314

Scharf C, Liebchen U, Paal M, et al. The higher the better? Defining the optimal beta-lactam target for critically ill patients to reach infection resolution and improve outcome. J Intensive Care. 2020;8(1):86. doi:10.1186/s40560-020-00504-w

Goncalves-Pereira J, Povoa P. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of beta-lactams. Crit Care. 2011;15(5):R206. doi:10.1186/cc10441

Benko AS, Cappelletty DM, Kruse JA, Rybak MJ. Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected gram-negative infections. Antimicrob Agents Chemother. 1996;40(3):691-695. doi:10.1128/AAC.40.3.691

McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31(4):345-351. doi:10.1016/j.ijantimicag.2007.12.009

Mouton JW, Muller AE, Canton R, Giske CG, Kahlmeter G, Turnidge J. MIC-based dose adjustment: facts and fables. J Antimicrob Chemother. 2018;73(3):564-568. doi:10.1093/jac/dkx427

Cojutti PG, Maximova N, Schillani G, Hope W, Pea F. Population pharmacokinetics of continuous-infusion ceftazidime in febrile neutropenic children undergoing HSCT: implications for target attainment for empirical treatment against Pseudomonas aeruginosa. J Antimicrob Chemother. 2019;74(6):1648-1655. doi:10.1093/jac/dkz065

Werumeus Buning A, Hodiamont CJ, Lechner NM, et al. Population pharmacokinetics and probability of target attainment of different dosing regimens of ceftazidime in critically ill patients with a proven or suspected Pseudomonas aeruginosa infection. Antibiotics (Basel). 2021;10(6):612. doi:10.3390/antibiotics10060612

Scheich S, Weber S, Reinheimer C, et al. Bloodstream infections with Gram-negative organisms and the impact of multidrug resistance in patients with hematological malignancies. Ann Hematol. 2018;97(11):2225-2234. doi:10.1007/s00277-018-3423-5

Gudiol C, Bodro M, Simonetti A, et al. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect. 2013;19(5):474-479. doi:10.1111/j.1469-0691.2012.03879.x

Trecarichi EM, Pagano L, Candoni A, et al. Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey. Clin Microbiol Infect. 2015;21(4):337-343. doi:10.1016/j.cmi.2014.11.022

Trecarichi EM, Tumbarello M. Antimicrobial-resistant Gram-negative bacteria in febrile neutropenic patients with cancer: current epidemiology and clinical impact. Curr Opin Infect Dis. 2014;27(2):200-210. doi:10.1097/QCO.0000000000000038

Garcia-Vidal C, Cardozo-Espinola C, Puerta-Alcalde P, et al. Risk factors for mortality in patients with acute leukemia and bloodstream infections in the era of multiresistance. PLoS ONE. 2018;13(6):e0199531. doi:10.1371/journal.pone.0199531

Martinez-Nadal G, Puerta-Alcalde P, Gudiol C, et al. Inappropriate empirical antibiotic treatment in high-risk neutropenic patients with bacteremia in the era of multidrug resistance. Clin Infect Dis. 2020;70(6):1068-1074. doi:10.1093/cid/ciz319

Caselli D, Cesaro S, Ziino O, et al. Multidrug resistant Pseudomonas aeruginosa infection in children undergoing chemotherapy and hematopoietic stem cell transplantation. Haematologica. 2010;95(9):1612-1615. doi:10.3324/haematol.2009.020867

Samonis G, Vardakas KZ, Kofteridis DP, et al. Characteristics, risk factors and outcomes of adult cancer patients with extensively drug-resistant Pseudomonas aeruginosa infections. Infection. 2014;42(4):721-728. doi:10.1007/s15010-014-0635-z

Kim HS, Park BK, Kim SK, et al. Clinical characteristics and outcomes of Pseudomonas aeruginosa bacteremia in febrile neutropenic children and adolescents with the impact of antibiotic resistance: a retrospective study. BMC Infect Dis. 2017;17(1):500. doi:10.1186/s12879-017-2597-0

Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268-281. doi:10.1111/j.1469-0691.2011.03570.x

Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287

Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999;27(7):1325-1329. doi:10.1097/00003246-199907000-00022

European Committee on Antimicrobial Susceptibility Testing. Clinical breakpoints-breakpoints and guidance. Updated January 1, 2022. Accessed August 11, 2022. https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_12.0_Breakpoint_Tables.pdf

Kadri SS, Adjemian J, Lai YL, et al. Difficult-to-treat resistance in Gram-negative bacteremia at 173 US hospitals: retrospective cohort analysis of prevalence, predictors, and outcome of resistance to all first-line agents. Clin Infect Dis. 2018;67(12):1803-1814. doi:10.1093/cid/ciy378

Georges B, Conil JM, Seguin T, et al. Population pharmacokinetics of ceftazidime in intensive care unit patients: influence of glomerular filtration rate, mechanical ventilation, and reason for admission. Antimicrob Agents Chemother. 2009;53(10):4483-4489. doi:10.1128/AAC.00430-09

Moriyama B, Henning SA, Childs R, et al. High-dose continuous infusion beta-lactam antibiotics for the treatment of resistant Pseudomonas aeruginosa infections in immunocompromised patients. Ann Pharmacother. 2010;44(5):929-935. doi:10.1345/aph.1M717