Pharmacokinetics and Pharmacodynamics of Antibiotics in Biofilm Infections of Pseudomonas aeruginosa In Vitro and In Vivo

Wang, Hengzhuang; Høiby, Niels; Ciofu, Oana

doi:10.1007/978-1-4939-0467-9_17

Cited by 26 publications

(22 citation statements)

References 15 publications

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“…The results of other studies of PK/PD models of P. aeruginosa biofilm treatment showed time-dependent killing for b-lactam antibiotics and concentration-dependent or dose-dependent killing for ciprofloxacin, colistin, and tobramycin, which is similar to what has been shown for planktonic growth [90][91][92]. However, the concentrations of antibiotics needed were, in all cases, very much higher, even in the case of time-dependent killing, where, on b-lactamase-overproducing biofilms, the killing pattern of ceftazidime was changed to concentration-dependent killing for biofilm cells [93].…”

Section: Micsupporting

confidence: 78%

Antimicrobial susceptibility testing in biofilm-growing bacteria

Macià

Rojo-Molinero

Oliver

2014

Clinical Microbiology and Infection

444

354

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Biofilms are organized bacterial communities embedded in an extracellular polymeric matrix attached to living or abiotic surfaces. The development of biofilms is currently recognized as one of the most relevant drivers of persistent infections. Among them, chronic respiratory infection by Pseudomonas aeruginosa in cystic fibrosis patients is probably the most intensively studied. The lack of correlation between conventional susceptibility test results and therapeutic success in chronic infections is probably a consequence of the use of planktonically growing instead of biofilm-growing bacteria. Therefore, several in vitro models to evaluate antimicrobial activity on biofilms have been implemented over the last decade. Microtitre plate-based assays, the Calgary device, substratum suspending reactors and the flow cell system are some of the most used in vitro biofilm models for susceptibility studies. Likewise, new pharmacodynamic parameters, including minimal biofilm inhibitory concentration, minimal biofilm-eradication concentration, biofilm bactericidal concentration, and biofilm-prevention concentration, have been defined in recent years to quantify antibiotic activity in biofilms. Using these parameters, several studies have shown very significant quantitative and qualitative differences for the effects of most antibiotics when acting on planktonic or biofilm bacteria. Nevertheless, standardization of the procedures, parameters and breakpoints, by official agencies, is needed before they are implemented in clinical microbiology laboratories for routine susceptibility testing. Research efforts should also be directed to obtaining a deeper understanding of biofilm resistance mechanisms, the evaluation of optimal pharmacokinetic/pharmacodynamic models for biofilm growth, and correlation with clinical outcome.

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Section: Micsupporting

confidence: 78%

Antimicrobial susceptibility testing in biofilm-growing bacteria

Macià

Rojo-Molinero

Oliver

2014

Clinical Microbiology and Infection

444

354

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“…In this model, a concentration of 2 mg/L ciprofloxacin, which correlated with the mutant prevention concentration and provided an area under the curve (DUC)/MIC ratio of 384, which should predict therapeutic success, was used, but demonstrated, nevertheless, that theoretically optimized PK/PD parameters failed to suppress resistance development on biofilms. The results of other studies of PK/PD models of P. aeruginosa biofilm treatment showed time-dependent killing for b-lactam antibiotics and concentration-dependent or dose-dependent killing for ciprofloxacin, colistin, and tobramycin, which is similar to that shown for planktonic growth (7,8,66). However, the concentrations of antibiotics needed were, in all cases, very much higher, even in the case of time-dependent killing, where, on b-lactamase-overproducing biofilms, the killing pattern of ceftazidime was changed to concentration-dependent killing for biofilm cells (8).…”

Section: Susceptibility Testing and Pk/pd In Biofilmssupporting

confidence: 71%

Antibiotic treatment of biofilm infections

Ciofu

Rojo-Molinero²,

Macià³

et al. 2017

APMIS

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335

259

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Bacterial biofilms are associated with a wide range of infections, from those related to exogenous devices, such as catheters or prosthetic joints, to chronic tissue infections such as those occurring in the lungs of cystic fibrosis patients. Biofilms are recalcitrant to antibiotic treatment due to multiple tolerance mechanisms (phenotypic resistance). This causes persistence of biofilm infections in spite of antibiotic exposure which predisposes to antibiotic resistance development (genetic resistance). Understanding the interplay between phenotypic and genetic resistance mechanisms acting on biofilms, as well as appreciating the diversity of environmental conditions of biofilm infections which influence the effect of antibiotics are required in order to optimize the antibiotic treatment of biofilm infections. Here, we review the current knowledge on phenotypic and genetic resistance in biofilms and describe the potential strategies for the antibiotic treatment of biofilm infections. Of note is the optimization of PK/PD parameters in biofilms, high-dose topical treatments, combined and sequential/alternate therapies or the use antibiotic adjuvants.

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“…In the present study, the MBEC of colistin combined with OligoG is 4 g/ml (Tables 1 and 2), and it represents a promising combination approach to eradicate biofilm infections in CF patients at far lower concentrations of antibiotic, with the additional benefit of reducing the risk of toxicity (19). The data in the present study show that coadministration treatment of in vitro biofilms with the novel alginate oligomer OligoG CF-5/20 and colistin results in a 128-fold reduction in the MBEC value.…”

Section: Discussionmentioning

confidence: 86%

“…The lower limit of detection on plates was 10 CFU/ml. The minimal biofilm eradication concentration (MBEC) of antibiotics for biofilm alginate beads was determined as outlined previously (4,19). MBEC was defined as the concentration of antimicrobials at which no bacterial growth on the recovery plate was observed.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

OligoG CF-5/20 Disruption of Mucoid Pseudomonas aeruginosa Biofilm in a Murine Lung Infection Model

Wang

Song

Ciofu

et al. 2016

Antimicrob Agents Chemother

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Biofilm growth is a universal survival strategy for bacteria, providing an effective and resilient approach for survival in an otherwise hostile environment. In the context of an infection, a biofilm provides resistance and tolerance to host immune defenses and antibiotics, allowing the biofilm population to survive and thrive under conditions that would destroy their planktonic counterparts. Therefore, the disruption of the biofilm is a key step in eradicating persistent bacterial infections, as seen in many types of chronic disease. In these studies, we used both in vitro minimum biofilm eradication concentration (MBEC) assays and an in vivo model of chronic biofilm infection to demonstrate the biofilm-disrupting effects of an alginate oligomer, OligoG CF-5/20. Biofilm infections were established in mice by tracheal instillation of a mucoid clinical isolate of Pseudomonas aeruginosa embedded in alginate polymer beads. The disruption of the biofilm by OligoG CF-5/20 was observed in a dose-dependent manner over 24 h, with up to a 2.5-log reduction in CFU in the infected mouse lungs. Furthermore, in vitro assays showed that 5% OligoG CF-5/20 significantly reduced the MBEC for colistin from 512 g/ml to 4 g/ml after 8 h. These findings support the potential for OligoG CF-5/20 as a biofilm disruption agent which may have clinical value in reducing the microbial burden in chronic biofilm infections. It has been suggested that biofilms are present in more than 65% of all bacterial infections (1). Biofilm-associated bacteria show an innate resistance to antibiotics, disinfectants, and host defense mechanisms (2, 3) and are thought to contribute to survival in chronic lung infections. Several in vitro studies have demonstrated that bacteria growing in a biofilm can become 10 to 1,000 times more resistant to the effects of antimicrobial agents than planktonic-growing bacteria of the same strain (4, 5). Patients with cystic fibrosis (CF) are highly susceptible to lung infections. As the disease progresses their lungs become chronically infected by P. aeruginosa as a biofilm infection (6), contributing to the destructive cycle of inflammation and fibrosis (7). Clinically, the presence of mucoid variants is associated with poor prognosis, deterioration of lung function, and increased tissue damage (2, 8). Therefore, the disruption of the biofilm is a key step in eradicating persistent bacterial infections, as is seen in many types of chronic disease.The novel alginate oligomer OligoG CF-5/20 is a low-molecular-weight oligosaccharide enriched from sodium alginate polysaccharides. It is an oligomer composed of ␣-L-guluronic acid (Ͼ85%) and ␤-D-mannuronic acid (Ͻ15%) (Fig. 1). OligoG CF-5/20 is currently in phase 2b clinical trials in CF patients. Previous in vitro studies have shown the ability of OligoG CF-5/20 to perturb biofilm formation, thereby reducing tolerance to antibiotic treatment (9-12).High-molecular-weight polymeric alginate is one of the components produced by P. aeruginosa in the formation of biofilms in the a...

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Pharmacokinetics and Pharmacodynamics of Antibiotics in Biofilm Infections of Pseudomonas aeruginosa In Vitro and In Vivo

Cited by 26 publications

References 15 publications

Antimicrobial susceptibility testing in biofilm-growing bacteria

Antimicrobial susceptibility testing in biofilm-growing bacteria

Antibiotic treatment of biofilm infections

OligoG CF-5/20 Disruption of Mucoid Pseudomonas aeruginosa Biofilm in a Murine Lung Infection Model

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