Temocillin dosing in haemodialysis patients based on population pharmacokinetics of total and unbound concentrations and Monte Carlo simulations

Bastos, Ana C. Miranda; Vandecasteele, Stefaan; Spinewine, Anne; Tulkens, Paul M.; Bambeke, Françoise Van

doi:10.1093/jac/dky078

Cited by 4 publications

(2 citation statements)

References 39 publications

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“…As the breakpoints for temocillin against Burkholderia spp. are not well defined, previously recommended interpretative indices (Ն32 g/ml for resistant and Յ8 or 16 g/ml for susceptible) were used (39)(40)(41). The site of the infection is a critical determinant for efficacy.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, for temocillin, previously published breakpoints were used. For temocillin, resistant was an MIC of Ն32 g/ml and susceptible was an MIC of either Յ 16 g/ml (39) or Յ 8 g/ml (40,41 Table 2). To assess if susceptibility to temocillin could be restored in the resistant isolates by partnering temocillin with a ␤-lactamase inhibitor, avibactam, a diazabicyclooctane non-␤-lactam ␤-lactamase inhibitor was tested.…”

Section: Resultsmentioning

confidence: 99%

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Resurrecting Old β-Lactams: Potent Inhibitory Activity of Temocillin against Multidrug-ResistantBurkholderiaSpecies Isolates from the United States

Zeiser

Becka

Barnes

et al. 2019

Antimicrob Agents Chemother

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Burkholderia spp. are opportunistic human pathogens that infect persons with cystic fibrosis and the immunocompromised. Burkholderia spp. express class A and C ␤-lactamases, which are transcriptionally regulated by PenR A through linkage to cell wall metabolism and ␤-lactam exposure. The potency of temocillin, a 6-methoxy-␤-lactam, was tested against a panel of multidrug-resistant (MDR) Burkholderia spp. In addition, the mechanistic basis of temocillin activity was assessed and compared to that of ticarcillin. Susceptibility testing with temocillin and ticarcillin was conducted, as was biochemical analysis of the PenA1 class A ␤-lactamase and AmpC1 class C ␤-lactamase. Molecular dynamics simulations (MDS) were performed using PenA1 with temocillin and ticarcillin. The majority (86.7%) of 150 MDR Burkholderia strains were susceptible to temocillin, while only 4% of the strains were susceptible to ticarcillin. Neither temocillin nor ticarcillin induced bla expression. Ticarcillin was hydrolyzed by PenA1 (k cat /K m ϭ 1.7 Ϯ 0.2 M Ϫ1 s Ϫ1 ), while temocillin was slow to form a favorable complex (apparent K i [K i app ] ϭ ϳ2 mM). Ticarcillin and temocillin were both potent inhibitors of AmpC1, with K i app values of 4.9 Ϯ 1.0 M and 4.3 Ϯ 0.4 M, respectively. MDS of PenA revealed that ticarcillin is in an advantageous position for acylation and deacylation. Conversely, with temocillin, activesite residues K73 and S130 are rotated and the catalytic water molecule is displaced, thereby slowing acylation and allowing the 6-methoxy of temocillin to block deacylation. Temocillin is a ␤-lactam with potent activity against Burkholderia spp., as it does not induce bla expression and is poorly hydrolyzed by endogenous ␤-lactamases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Resurrecting Old β-Lactams: Potent Inhibitory Activity of Temocillin against Multidrug-ResistantBurkholderiaSpecies Isolates from the United States

Zeiser

Becka

Barnes

et al. 2019

Antimicrob Agents Chemother

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Understanding antimicrobial pharmacokinetics in critically ill patients to optimize antimicrobial therapy: A narrative review

Roger

2024

Journal of Intensive Medicine

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Population pharmacokinetics and dosing simulations of total and unbound temocillin in the plasma and CSF of neurocritically ill patients with external ventricular drain-related cerebral ventriculitis

Ngougni Pokem,

Liu,

Parker

et al. 2023

Journal of Antimicrobial Chemotherapy

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Background Cerebral ventriculitis might be caused by Gram-negative bacteria, including ESBL producers. Temocillin may be a useful treatment option in this scenario; however, no consistent data are available regarding its penetration into the CSF. Objectives To describe the population pharmacokinetics of temocillin in plasma and CSF and to determine the probability for different simulated dosing regimens to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets in the CSF. Methods Ten post-neurosurgical critically ill adult patients requiring continuous drainage of CSF were included in this monocentric, prospective, open-label, non-randomized study. They received 2 g loading dose temocillin over 30 min IV infusion, followed by a 6 g continuous infusion over 24 h. Total and unbound concentrations were measured in plasma (n = 88 and 86) and CSF (n = 88 and 88) samples and used to build a population PK model. Monte Carlo simulations were performed to estimate the PTA at 100% Css>MIC (steady state concentration above the MIC) in CSF. Results All patients were infected with Enterobacterales with temocillin MICs ≤8 mg/L. The median (min-max) temocillin penetration in CSF was 12.1% (4.3-25.5) at steady state. Temocillin unbound plasma pharmacokinetics were best described by a one-compartment model. PTA for the applied dosing regimen was >90% for bacteria with MIC ≤ 4 mg/L. Conclusions The currently approved dose of 6 g by continuous infusion may be adequate for the treatment of ventriculitis by Enterobacterales with MIC ≤ 4 mg/L if considering 100% Css>MIC as the PK/PD target to reach. Higher maintenance doses could help covering higher MICs, but their safety would need to be assessed.

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Temocillin dosing in haemodialysis patients based on population pharmacokinetics of total and unbound concentrations and Monte Carlo simulations

Cited by 4 publications

References 39 publications

Resurrecting Old β-Lactams: Potent Inhibitory Activity of Temocillin against Multidrug-ResistantBurkholderiaSpecies Isolates from the United States

Resurrecting Old β-Lactams: Potent Inhibitory Activity of Temocillin against Multidrug-ResistantBurkholderiaSpecies Isolates from the United States

Understanding antimicrobial pharmacokinetics in critically ill patients to optimize antimicrobial therapy: A narrative review

Population pharmacokinetics and dosing simulations of total and unbound temocillin in the plasma and CSF of neurocritically ill patients with external ventricular drain-related cerebral ventriculitis

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