Inoculum effect of high concentrations of methicillin-susceptible Staphylococcus aureus on the efficacy of cefazolin and other beta-lactams

Saeki, Masachika; Shinagawa, Morikazu; Yakuwa, Yuki; Nirasawa, Shinya; Sato, Yuki; Yanagihara, Nozomi; Takahashi, Satoshi

doi:10.1016/j.jiac.2017.10.021

Cited by 19 publications

(20 citation statements)

References 21 publications

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“…Of course, our results need to be confirmed by a larger pharmacokinetics study. Moreover, a specific clinical investigation should address whether a cefazolin-based treatment of MSSA meningitis is suitable, because the success of this approach may depend on the inoculum effect, even if cefazolin meningeal diffusion is sufficient (12). These preliminary findings show that cefazolin may be an alternative to cefotaxime, fosfomycin, or rifampin in EVD ventriculitis or meningitis.…”

mentioning

confidence: 91%

High-Dosage Cefazolin Achieves Sufficient Cerebrospinal Diffusion To Treat an External Ventricular Drainage-Related Staphylococcus aureus Ventriculitis

Grégoire

Gaborit

Deschanvres

et al. 2019

Antimicrob Agents Chemother

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A patient received continuous infusion of cefazolin 10 g then 8 g daily for an external ventricular drainage-related methicillin-susceptible Staphylococcus aureus (MSSA) ventriculitis. Median free concentrations in the cerebrospinal fluid were 11.9 and 6.1 mg/liter after 10- and 8-g doses, respectively. Free concentrations in the cerebrospinal fluid were always above the MIC usually displayed by methicillin-susceptible Staphylococcus aureus (MSSA) isolates. These results support the use of high-dose cefazolin to achieve sufficient meningeal concentrations.

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confidence: 91%

High-Dosage Cefazolin Achieves Sufficient Cerebrospinal Diffusion To Treat an External Ventricular Drainage-Related Staphylococcus aureus Ventriculitis

Grégoire

Gaborit

Deschanvres

et al. 2019

Antimicrob Agents Chemother

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“…The inoculum effect has been demonstrated experimentally for a number of bacterial strains and antimicrobials ( 13, 15, 16, 19, 20, 24, 25, 27, 28 ). In most cases the MIC ( 13, 15, 20, 24, 25, 27 ) was used to determine and quantify the inoculum effect. Udekwu et al .…”

Section: Discussionmentioning

confidence: 99%

“…In a next step, we determined the effect of enzymatic degradation in addition to the binding effects. The inoculum effect is often measured experimentally in systems with enzymes present that degrade antimicrobial molecules, for example β -lactamases ( 16, 24, 48–50 ). When allowing for enzymatic degradation in our simulations, the inoculum effect, quantified as increase in the pharmacodynamic parameters MIC PD and A 50 , was more pronounced.…”

Section: Discussionmentioning

confidence: 99%

“…The inoculum effect was first described in the early 1940s ( 18 ). Since then, the inoculum effect has been measured experimentally for a variety of combinations of bacterial species and antibiotics ( 13, 15, 20, 24–26 ). Recently, the inoculum effect became of interest in the field of antimicrobial peptides (AMPs) ( 27, 28 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the inoculum effect became of interest in the field of antimicrobial peptides (AMPs) ( 27, 28 ). It is common to determine the inoculum effect in terms of the change in the MIC with inoculum size ( 13, 15, 20, 24, 25, 27 ). To our knowledge, the inoculum effect has not yet been determined using the more comprehensive PD function approach.…”

Section: Introductionmentioning

confidence: 99%

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The pharmacodynamic inoculum effect from the perspective of bacterial population modeling

Baeder

2019

Preprint

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1Efficacy assessment of antimicrobials is essential, both to determine the best 2 clinical use of the antimicrobial and as input for predictive mathematical mod-3 eling. The pharmacodynamic (PD) function is a tool to describe antimicrobial 4 efficacy and can be seen as an extension of the commonly used MIC. While the 5 PD function describes the efficacy of a given dose of antimicrobials, it is based 6 on one bacterial inoculum size only. Therefore, the PD function does not inform 7 us about the change in efficacy due to changes in the inoculum size, also known 8 as the inoculum effect. Here, we used mathematical modeling to quantify the 9 inoculum effect in terms of PD parameters. In particular, we used the multi-hit 10 model that describes the mechanism of action of antimicrobials: When a cer-11 tain number of antimicrobial molecules have hit a bacterial cell, it dies. This 12 framework allowed us to examine the effect of reversible binding and enzymatic 13 degradation of antimicrobials on the pharmacodynamics. A change in bacte-14 rial inoculum size resulted in a change of the PD parameter A 50 , M IC P D , and 15 therefore κ due to reversible binding. We determined an extended PD function 16 that captured the inoculum effect as change in the PD parameters. When we 17 allowed for degradation of antimicrobials by bacterial enzymes, the inoculum 18 effect was intensified. The extended PD function could mimic long term pop-19 ulation dynamics based on the multi-hit model with reversible binding only, 20 1 but deviated from long-term predictions based on a multi-hit model including 21 degradation. We then used the multi-hit framework to estimate outcomes of 22 competition experiments with a sensitive and resistant strain and compared it 23 to predictions of the PD function. When we do not take the inoculum effect into 24 account, our simulations underestimated the ability of the sensitive population 25 to survive for a given PK regime and the competitiveness of the sensitive strain 26 against the resistant strain. Our work emphasizes that the PD function -and 27 in general any efficacy measure -should, at least, include information about 28 the inoculum size and, ideally, account for the inoculum effect. 29 Introduction 30 Efficacy of antimicrobials against bacteria is quantified using time-kill curves 31 and is subsequently captured in so-called pharmacodynamic (PD) functions, 32 also known as E max and Zhi models (1 -3 ). A time-kill curve captures how 33 a bacterial population changes over time in presence of a given concentration 34 of an antimicrobial (fig. 1a). During exponential growth, time-kill curves are 35 approximately linear on a logarithmic scale. Thus, the slopes of these log-linear 36 time-kill curves describe the change of the bacterial population over time and 37 are a direct measure of the bacterial net growth rate. The PD function returns 38 the net growth rate for any given antimicrobial concentration. The parameters 39 of the PD function are estimated based on several time-kill curves with the...

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Inoculum effect of methicillin-susceptible Staphylococcus aureus against broad-spectrum beta-lactam antibiotics

Song

Jung

Lee

et al. 2018

Eur J Clin Microbiol Infect Dis

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Inoculum effect of high concentrations of methicillin-susceptible Staphylococcus aureus on the efficacy of cefazolin and other beta-lactams

Cited by 19 publications

References 21 publications

High-Dosage Cefazolin Achieves Sufficient Cerebrospinal Diffusion To Treat an External Ventricular Drainage-Related Staphylococcus aureus Ventriculitis

High-Dosage Cefazolin Achieves Sufficient Cerebrospinal Diffusion To Treat an External Ventricular Drainage-Related Staphylococcus aureus Ventriculitis

The pharmacodynamic inoculum effect from the perspective of bacterial population modeling

Inoculum effect of methicillin-susceptible Staphylococcus aureus against broad-spectrum beta-lactam antibiotics

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