In vitro effect of the presence of human albumin or human serum on the bactericidal activity of daptomycin against strains with the main resistance phenotypes in Gram-positives

Cafini, Fabio; Aguilar, Lorenzo; González, Natalia; Giménez, María-José; Torrico, M.; Alou, Luís; Sevillano, David; Vallejo, P.; Prieto, J.

doi:10.1093/jac/dkm078

Cited by 35 publications

(42 citation statements)

References 8 publications

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“…Kill rates of amoxicillin were much higher in active serum, too, despite its low protein binding. This disconnect between MICs and kill rates is very well in agreement with previously published data [8,20,[40][41][42][43][44][45][46][47]. Wouldn't it be more conclusive to derive PD measures not from static but from dynamic endpoints like kill-rates [65]?…”

Section: Discussionsupporting

confidence: 89%

“…Likewise, the bactericidal activity of tigecycline was underestimated if Gram-positive and Gram-negative indicator strains were exposed to the calculated free drug level whereas the agent was three-fold more active in the presence of albumin [44]. Although high protein binding of daptomycin (>90%) caused a threeto four-fold increase in MICs and MBCs [45], total daptomycin concentrations in the presence of human albumin or serum were bactericidally active against E. faecium, whereas the calculated free fraction was not [46]. Oritavancin retained bactericidal activity against enterococci in time kill assays although MICs increased up to eightfold in the presence of albumin [47].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Impact of Protein Binding on Antibacterial Activities of Antibiotics is more than Predicted by Considering its Numerical Value Alone: Impact of Preparative and Incubation Methods on Different Pharmacodynamic Endpoints of ß-Lactams, Macrolides, or Fluoroquinolones Against Gram-positive and Gram-negative Bacteria-Part I

Dalhoff¹,

Schubert²

2016

J Clin Infect Dis Pract

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Objectives: Protein binding decreases antibacterial activities as the free fraction only crosses membranes thus reaching intracellular targets. However, serum components may also increase antibacterial activities. Therefore, the effect of serum proteins on activities of ß-lactams, macrolides, and fluoroquinolones was examined. Several preparation-and cultivation-conditions were examined as some preparative methods like freeze-thawing of sera may cause artifacts. Furthermore, previous studies have indicated that data may vary depending on the endpoints studied. Therefore, the aim of this study was to avoid an impact of methodological factors on the data generated and to analyse the activities of the study drugs by examining different static-or dynamic endpoints.Methods: Bacteria were grown in Brain Heart Infusion Broth (BHI), plus 50% of either fresh inactivated, pH 7.2, or fresh inactivated-, pH 7.2 or 8.2, frozen inactivated-serum, pH 8.2 as compared to BHI without any supplementations, pH 7.2 or 8.2, and BHI plus 45 g/L albumin. MICs of faropenem, amoxicillin, clarithromycin, azithromycin, moxifloxacin, and levofloxacin were determined and kill-kinetics were recorded following exposure to constant or fluctuating drug concentrations simulating serum pharmacokinetics of the agents. Kill-rates and areas under the bacterial kill curves were calculated.Results: Albumin and inactive serum increased MICs and reduced kill-rates of the agents studied in conformity with their protein binding, whereas active serum increased the activities of the agents. MICs and kill-rates did not change in parallel. The impact of protein binding in decreasing order was: MICs>kill-rates in time-kill experiments>kill-rates in kinetic-simulations. Macrolides and fluoroquinolones but not ß-lactams were more active at an alkaline-than neutral pH. Use of frozen sera caused alkalinization of media, thus generating artifacts. Conclusions:The impact of serum proteins on antibacterial activities is strongly dependent from three factors: the methods applied to prepare the serum pool, the incubation conditions, and the enpoints studied.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

The Impact of Protein Binding on Antibacterial Activities of Antibiotics is more than Predicted by Considering its Numerical Value Alone: Impact of Preparative and Incubation Methods on Different Pharmacodynamic Endpoints of ß-Lactams, Macrolides, or Fluoroquinolones Against Gram-positive and Gram-negative Bacteria-Part I

Dalhoff¹,

Schubert²

2016

J Clin Infect Dis Pract

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“…However, taking into consideration the rapid emergence of rifampicin resistance when used as monotherapy [23], it that the use of daptomycin in the treatment of S. epidermidis-related infections is more feasible. This is supported by other researchers who reported that, upon sometime of exposure, daptomycin was the most active agent in eradicating S. aureus [23], exhibiting very rapid bactericidal activity against this pathogen [15]. As both S. aureus and S. epidermidis are now among the major nosocomial pathogens, their similar response to these antibiotics is very favorable from the clinical point of view because it is possible to define a relatively broad spectrum therapy.…”

Section: Resultsmentioning

confidence: 53%

“…Cells were harvested by centrifugation (for 10 min at 9,5009g and 4°C), resuspended in TSB, and the suspension was adjusted to an optical density (640 nm) equivalent to 1 9 10 9 cells ml -1 before being used in the subsequent assays. Each stock solution of daptomycin (with calcium supplementation at 50 mg l -1 ) [15,16] and rifampicin was prepared in methanol. It was confirmed that methanol, at the concentration used, had no effect on the growth of the S. epidermidis strains studied.…”

Section: Bacterial Strains and Growth Conditionsmentioning

confidence: 99%

In vitro Activity of Daptomycin, Linezolid and Rifampicin on Staphylococcus epidermidis Biofilms

et al. 2011

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Owing to their massive use, Staphylococcus epidermidis has recently developed significant resistance to several antibiotics, and became one of the leading causes of hospital-acquired infections. Current antibiotics are typically ineffective in the eradication of bacteria in biofilmassociated persistent infections. Accordingly, the paucity of effective treatment against cells in this mode of growth is a key factor that potentiates the need for new agents active in the prevention or eradication of biofilms. Daptomycin and linezolid belong to the novel antibiotic therapies that are active against gram-positive cocci. On the other hand, rifampicin has been shown to be one of the most potent, prevalent antibiotics against S. epidermidis biofilms. Therefore, the main aim of this study was to study the susceptibility of S. epidermidis biofilm cells to the two newer antimicrobial agents previously mentioned, and compare the results obtained with the antimicrobial effect of rifampicin, widely used in the prevention/treatment of indwelling medical device infections. To this end the in vitro activities of daptomycin, linezolid, and rifampicin on S. epidermidis biofilms were accessed, using these antibiotics at MIC and peak serum concentrations. The results demonstrated that at MIC concentration, rifampicin was the most effective antibiotic tested. At peak serum concentration, both strains demonstrated similar susceptibility to rifampicin and daptomycin, with colony-forming units (CFUs) reductions of approximately 3-4 log 10 , with a slightly lower response to linezolid, which was also more strain dependent. However, considering all the parameters studied, daptomycin was considered the most effective antibiotic tested, demonstrating an excellent in vitro activity against S. epidermidis biofilm cells. In conclusion, this antibiotic can be strongly considered as an acceptable therapeutic option for S. epidermidis biofilm-associated infections and can represent a potential alternative to rifampicin in serious infections where rifampicin resistance becomes prevalent.

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“…PB is one of several factors which can substantially influence the PDs of an antibiotic (9,(46)(47)(48). Similar extents of PB have been shown to differentially affect the antimicrobial activity of highly protein-bound antibiotics (7,9,49,50) and impairment of antimicrobial activity in protein-rich medium may differ between gram-positive and gram-negative pathogens (9). Therefore, the effect of PB on individual pathogens has to be investigated for antibiotics on a case by case base.…”

Section: Protein Binding In In Vitro Studies Of Antimicrobial Activitymentioning

confidence: 99%

Protein Binding of Antimicrobials: Methods for Quantification and for Investigation of its Impact on Bacterial Killing

Beer

Wagner

Zeitlinger

2009

AAPS J

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Abstract. Plasma protein binding of antimicrobial agents is considered to be a key characteristic of antibiotics as it affects both their pharmacokinetics and pharmacodynamics. However, up to the present, no standard methods for measuring protein binding or for quantification of the influence of protein binding on antimicrobial activity exist. This short-coming has previously led to conflicting results on antibacterial activity of highly protein-bound antibiotics. The present review, therefore, set out to summarize (1) methods for quantification of protein binding, (2) microbiological growth media used for determination of the impact of protein binding on antimicrobial activity of antibiotics, and (3) different pharmacodynamic in vitro studies that are used in this context. The advantages and disadvantages of a wide range of different approaches are discussed and compared. The urgent call for international standardization by microbiological societies and laboratories may be considered as a logical consequence of the presented data.

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In vitro effect of the presence of human albumin or human serum on the bactericidal activity of daptomycin against strains with the main resistance phenotypes in Gram-positives

Abstract: Daptomycin exhibited rapid bactericidal activity against the strains of the three Gram-positive species tested, regardless of resistance phenotype or the presence of physiological concentrations of albumin.

Cited by 35 publications

References 8 publications

In vitro Activity of Daptomycin, Linezolid and Rifampicin on Staphylococcus epidermidis Biofilms

Protein Binding of Antimicrobials: Methods for Quantification and for Investigation of its Impact on Bacterial Killing

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