Impact of Beta-Lactam Target Attainment on Resistance Development in Patients with Gram-Negative Infections

Overview

Journal Antibiotics (Basel)

Specialty Pharmacology

Date 2023 Dec 23

PMID 38136730

Authors

Nicole F Maranchick

Jessica Webber

Mohammad H Alshaer

Timothy W Felton

Charles A Peloquin

Affiliations

Soon will be listed here.

Abstract

Background: The objective was to identify associations between beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) targets and Gram-negative bacteria resistance emergence in patients.

Methods: Retrospective data were collected between 2016 to 2019 at the University of Florida Health-Shands Hospital in Gainesville, FL. Adult patients with two Gram-negative isolates receiving cefepime, meropenem, or piperacillin-tazobactam and who had plasma beta-lactam concentrations were included. Beta-lactam exposures and time free drug concentrations that exceeded minimum inhibitory concentrations (ƒT > MIC), four multiples of MIC (ƒT > 4× MIC), and free area under the time concentration curve to MIC (ƒAUC/MIC) were generated. Resistance emergence was defined as any increase in MIC or two-fold increase in MIC. Multiple regression analysis assessed the PK/PD parameter impact on resistance emergence.

Results: Two hundred fifty-six patients with 628 isolates were included. The median age was 58 years, and 59% were males. Cefepime was the most common beta-lactam (65%) and the most common isolate (43%). The mean daily ƒAUC/MIC ≥ 494 was associated with any increase in MIC ( = 0.002) and two-fold increase in MIC ( = 0.004). The daily ƒAUC/MIC ≥ 494 was associated with decreased time on antibiotics ( = 0.008). was associated with any increase in MIC (OR: 6.41, 95% CI [3.34-12.28]) or 2× increase in MIC (7.08, 95% CI [3.56-14.07]).

Conclusions: ƒAUC/MIC ≥ 494 may be associated with decreased Gram-negative resistance emergence.

References

Schentag J, Nix D, ADELMAN M . Mathematical examination of dual individualization principles (I): Relationships between AUC above MIC and area under the inhibitory curve for cefmenoxime, ciprofloxacin, and tobramycin. DICP. 1991; 25(10):1050-7. DOI: 10.1177/106002809102501003. View

Alshaer M, Maranchick N, Bai C, Maguigan K, Shoulders B, Felton T . Using Machine Learning To Define the Impact of Beta-Lactam Early and Cumulative Target Attainment on Outcomes in Intensive Care Unit Patients with Hospital-Acquired and Ventilator-Associated Pneumonia. Antimicrob Agents Chemother. 2022; 66(7):e0056322. PMC: 9295596. DOI: 10.1128/aac.00563-22. View

Roberts J, Paul S, Akova M, Bassetti M, De Waele J, Dimopoulos G . DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?. Clin Infect Dis. 2014; 58(8):1072-83. DOI: 10.1093/cid/ciu027. View

. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022; 399(10325):629-655. PMC: 8841637. DOI: 10.1016/S0140-6736(21)02724-0. View

Hayakawa K, Gattu S, Marchaim D, Bhargava A, Palla M, Alshabani K . Epidemiology and risk factors for isolation of Escherichia coli producing CTX-M-type extended-spectrum β-lactamase in a large U.S. Medical Center. Antimicrob Agents Chemother. 2013; 57(8):4010-8. PMC: 3719715. DOI: 10.1128/AAC.02516-12. View

Taccone F, Laterre P, Dugernier T, Spapen H, Delattre I, Wittebole X . Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010; 14(4):R126. PMC: 2945087. DOI: 10.1186/cc9091. View

Adembri C, Novelli A, Nobili S . Some Suggestions from PK/PD Principles to Contain Resistance in the Clinical Setting-Focus on ICU Patients and Gram-Negative Strains. Antibiotics (Basel). 2020; 9(10). PMC: 7601871. DOI: 10.3390/antibiotics9100676. View

Heffernan A, Sime F, Lipman J, Roberts J . Individualising Therapy to Minimize Bacterial Multidrug Resistance. Drugs. 2018; 78(6):621-641. DOI: 10.1007/s40265-018-0891-9. View

Rybak M . Pharmacodynamics: relation to antimicrobial resistance. Am J Infect Control. 2006; 34(5 Suppl 1):S38-45. DOI: 10.1016/j.ajic.2006.05.227. View

10.

Ben-Ami R, Rodriguez-Bano J, Arslan H, Pitout J, Quentin C, Calbo E . A multinational survey of risk factors for infection with extended-spectrum beta-lactamase-producing enterobacteriaceae in nonhospitalized patients. Clin Infect Dis. 2009; 49(5):682-90. DOI: 10.1086/604713. View

11.

Gatti M, Cojutti P, Pascale R, Tonetti T, Laici C, DellOlio A . Assessment of a PK/PD Target of Continuous Infusion Beta-Lactams Useful for Preventing Microbiological Failure and/or Resistance Development in Critically Ill Patients Affected by Documented Gram-Negative Infections. Antibiotics (Basel). 2021; 10(11). PMC: 8615220. DOI: 10.3390/antibiotics10111311. View

12.

Guilhaumou R, Benaboud S, Bennis Y, Dahyot-Fizelier C, Dailly E, Gandia P . Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of.... Crit Care. 2019; 23(1):104. PMC: 6441232. DOI: 10.1186/s13054-019-2378-9. View

13.

Tamma P, Aitken S, Bonomo R, Mathers A, van Duin D, Clancy C . Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. Clin Infect Dis. 2023; . DOI: 10.1093/cid/ciad428. View

14.

Felton T, Goodwin J, OConnor L, Sharp A, Gregson L, Livermore J . Impact of Bolus dosing versus continuous infusion of Piperacillin and Tazobactam on the development of antimicrobial resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2013; 57(12):5811-9. PMC: 3837869. DOI: 10.1128/AAC.00867-13. View

15.

Craig W . Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998; 26(1):1-10; quiz 11-2. DOI: 10.1086/516284. View

16.

Felton T, Roberts J, Lodise T, van Guilder M, Boselli E, Neely M . Individualization of piperacillin dosing for critically ill patients: dosing software to optimize antimicrobial therapy. Antimicrob Agents Chemother. 2014; 58(7):4094-102. PMC: 4068511. DOI: 10.1128/AAC.02664-14. View

17.

Venugopalan V, Hamza M, Santevecchi B, DeSear K, Cherabuddi K, Peloquin C . Implementation of a β-lactam therapeutic drug monitoring program: Experience from a large academic medical center. Am J Health Syst Pharm. 2022; 79(18):1586-1591. DOI: 10.1093/ajhp/zxac171. View

18.

Wang M, Wei H, Zhao Y, Shang L, Di L, Lyu C . Analysis of multidrug-resistant bacteria in 3223 patients with hospital-acquired infections (HAI) from a tertiary general hospital in China. Bosn J Basic Med Sci. 2018; 19(1):86-93. PMC: 6387671. DOI: 10.17305/bjbms.2018.3826. View

19.

Maina J, Onyambu F, Kibet P, Musyoki A . Multidrug-resistant Gram-negative bacterial infections and associated factors in a Kenyan intensive care unit: a cross-sectional study. Ann Clin Microbiol Antimicrob. 2023; 22(1):85. PMC: 10500940. DOI: 10.1186/s12941-023-00636-5. View

20.

Wong G, Briscoe S, Adnan S, McWhinney B, Ungerer J, Lipman J . Protein binding of β-lactam antibiotics in critically ill patients: can we successfully predict unbound concentrations?. Antimicrob Agents Chemother. 2013; 57(12):6165-70. PMC: 3837907. DOI: 10.1128/AAC.00951-13. View