A Population Pharmacokinetic Analysis of Continuous Infusion of Cloxacillin during Staphylococcus aureus Bone and Joint Infections.

Intravenous administration of antibiotics is recommended during the early phase of methicillin-susceptible S. aureus (MSSA) bone and joint infection (BJI). We sought to compare the plasma concentrations of cloxacillin administered alternately by continuous and intermittent infusion (CI and ItI) in patients with MSSA BJI. In this prospective crossover trial, patients were randomly assigned to receive either 3 days of CI (two 75-mg/kg 12-h cloxacillin infusions per day) and then 3 days of ItI (four 37.5-mg/kg 1-h cloxacillin infusions per day) or vice versa. The drug concentration measurement was performed on day 3 of each type of administration at 1, 6, and 11 h and at 1, 2, 3, 4, and 6 h after the beginning of CI and ItI, respectively. We used the nonparametric algorithm NPAG to estimate population pharmacokinetic (PK) parameters. The final model was used to perform pharmacokinetic/pharmacodynamic (PK/PD) simulations and calculate the probabilities of target attainment (PTA) for several ItI and CI dosing regimens. We considered two PK/PD targets of time spent above the MIC for free cloxacillin concentrations (fT>MIC): 50 and 100%. Eighty-four concentrations from 11 patients were analyzed. A two-compartment model adequately described the data. ItI with q6h regimens and short 1-h infusions of 2,000 or 3,000 mg were associated with low PTA, even for the low target (50% fT>MIC) while 3-h infusions and continuous infusions (6 to 12 g/day) were associated with a PTA of >90% for an MIC up to 0.5 mg/liter. These results support the use of prolonged or continuous infusion of cloxacillin in patients with BJI.

The BioFilm Ring Test: a Rapid Method for Routine Analysis of Pseudomonas aeruginosa Biofilm Formation Kinetics.

Currently, few techniques are available for the evaluation of bacterial biofilm adhesion. These detection tools generally require time for culture and/or arduous handling steps. In this work, the BioFilm Ring Test (BRT), a new technology, was used to estimate the biofilm formation kinetics of 25 strains of Pseudomonas aeruginosa, isolated from the sputum of cystic fibrosis (CF) patients. The principle of the new assay is based on the mobility measurement of magnetic microbeads mixed with a bacterial suspension in a polystyrene microplate. If free to move under the magnetic action, particles gather to a visible central spot in the well bottom. Therefore, the absence of spot formation in the plate reflects the bead immobilization by a biofilm in formation. The BRT device allowed us to classify the bacterial strains into three general adhesion profiles. Group 1 consists of bacteria, which are able to form a solid biofilm in <2 h. Group 2 comprises the strains that progressively set up a biofilm during 24 h. Lastly, group 3 includes the strains that stay in a planktonic form. The grouping of our strains did not differ according to culture conditions, i.e., the use of different sets of beads or culture media. The BRT is shown to be an informative tool for the characterization of biofilm-forming bacteria. Various application perspectives may be investigated for this device, such as the addition of antibiotics to the bacterial suspension to select which would have the ability to inhibit the biofilm formation.

Should we, and how to, optimize cefiderocol administration during severe nosocomial pneumonia due to carbapenem-resistant Acinetobacter baumanii? A viewpoint.

OBJECTIVES: Acinetobacter baumannii is classified by the centre for Disease Control and Prevention (CDC) as an "urgent threat" due to its ability to acquire and develop resistance to multiple classes of antibiotics. As a result, it is one of the most concerning pathogens in healthcare settings, with increasing incidence of infections due to carbapenem-resistant Acinetobacter baumannii (CRAB) associated with high morbidity and mortality rates. Therefore, there are ongoing efforts to find novel treatment options, one of which is cefiderocol. We aim to review available evidence on cefiderocol use for severe nosocomial pneumonia due to carbapenem-resistant Acinetobacter baumannii. METHODS: A comprehensive review was conducted from 2017 to 2023, covering articles from databases such as Pubmed, Scopus, and Embase, along with conference proceedings from ECCMID 2023. The primary focus was on severe nosocomial pneumonia due A. baumannii and cefiderocol. DISCUSSION: Cefiderocol, targeting periplasmic space Penicillin-Binding Proteins (PBPs) via siderophore transport pathways, exhibits promise against multi-drug resistant Gram-negative bacilli. Its effectiveness in treating CRAB pneumonia remains debated. The CREDIBLE trial reported higher mortality with cefiderocol compared to the best available treatment, while other cohort studies showed contrasting outcomes. Patient variations and pharmacokinetic factors may underlie these discrepancies. The recommended cefiderocol dosage regimen may fall short of desired pharmacokinetic targets, especially in critically ill patients and lung infections. Pulmonary factors hindering cefiderocol's entry into bacteria through iron transporters are overlooked in clinical breakpoints. Optimized dosing or combination regimens may enhance infection site exposure and outcomes. CONCLUSIONS: Further research is needed to determine the optimal cefiderocol dosage and administration (mono vs. dual therapy, continuous vs. intermittent infusion), in severe Acinetobacter baumannii nosocomial pneumonia.

Expert Opinion on Dose Regimen and Therapeutic Drug Monitoring for Long-Term Use of Dalbavancin: Expert Review Panel.

BACKGROUND: Dalbavancin is a lipoglycopeptide with a long elimination half-life and is currently licensed for the treatment of acute bacterial skin and skin structure infections in adults. Dalbavancin's potential in treating off-label complex Gram-positive infections is promising and real-world experience in treating such infections is growing. However, clear guidance on extended dosing regimens is lacking. OBJECTIVES: This study aimed to provide clear expert opinion based on recent pharmacokinetic literature and expert and real-world experience in infection areas that require > 2 weeks of treatment. METHODS: A single face-to-face meeting was held in September 2022 to collate expert opinion and present safety data of dalbavancin use in these clinical indications. A survey was completed by all authors on their individual experience with dalbavancin, which highlighted the heterogeneity in the regimens that were used. RESULTS: After review of the survey data and recent literature, this study presents expert panel proposals that accommodate different healthcare settings and resource availability, and centre around the length of treatment duration including up to or exceeding 6 weeks. To achieve adequate dalbavancin concentrations for up to 6 weeks, 3000 mg of dalbavancin should be given over 4 weeks for the agreed complex infections requiring > 2 weeks of treatment. Therapeutic drug monitoring (TDM) is advised for longer treatment durations and in cases of renal failure. Specific dosing recommendations for other special populations require further investigation. CONCLUSIONS: These proposals based on expert opinion have been defined to encourage best practice with dalbavancin, to optimise its administration beyond the current approved licenced dose across different healthcare settings.

Daptomycin versus vancomycin in a methicillin-resistant Staphylococcus aureus endophthalmitis rabbit model: bactericidal effect, safety, and ocular pharmacokinetics.

Staphylococcus aureus is a frequent cause of acute endophthalmitis, and infection with this virulent bacterium is often associated with a poor visual outcome. In this study, we investigated the bactericidal efficacy and the safety of intravitreal daptomycin (DAP), a lipopeptide antibiotic with broad-spectrum activity against Gram-positive bacteria, compared with those of intravitreal vancomycin (VAN) in a methicillin-resistant S. aureus endophthalmitis rabbit model. The pharmacokinetics and pharmacodynamics of daptomycin in the infected eyes were also studied. Rabbits were randomly divided into three treatment groups (n = 8) and one untreated group (n = 4), to compare the effect of single intravitreal injections of 0.2 mg and 1 mg of daptomycin (DAP 0.2 and DAP 1 groups, respectively) with that of 1 mg of intravitreal vancomycin (VAN 1 group). Vitreal aspirates were regularly collected and grading of ocular inflammation was regularly performed until euthanasia on day 7. In the DAP 0.2 group, 62.5% of the eyes were sterilized and the mean bacterial count presented a reduction of 1 log unit. In the DAP 1 and VAN 1 groups, the infection was eradicated (100% and 87.5% of eyes sterilized, respectively), with a 4-log-unit reduction of the mean bacterial count. The bactericidal efficacy in the DAP 1 group was not inferior to that in the VAN 1 group and was superior to that of the other regimens in limiting the ocular inflammation and preserving the architecture of the ocular structures (P < 0.05). The elimination half-life (t(1/2ß)) of daptomycin was independent of the administered dose (38.8 ± 16.5 h and 40.9 ± 6.7 h, respectively, for the DAP 0.2 and DAP 1 groups) and was significantly longer than the t(1/2ß) of vancomycin (20.5 ± 2.0 h for the VAN 1 group) (P < 0.05). This antibiotic could therefore be considered for the treatment of intraocular infections caused by Gram-positive bacteria.

Daptomycin Physiology-Based Pharmacokinetic Modeling to Predict Drug Exposure and Pharmacodynamics in Skin and Bone Tissues.

BACKGROUND AND OBJECTIVE: Daptomycin has been recommended in the treatment of bone and joint infection. Previous work showed that the approved dosage of daptomycin may be insufficient to achieve optimal exposure in patients with bone and joint infection. However, those studies assumed that bone exposure was similar to steady-state daptomycin-free plasma concentrations. We sought to establish a physiologically based pharmacokinetic (PBPK) model of daptomycin to describe the dynamics of daptomycin disposition in bone and skin tissue. METHODS: A PBPK model of daptomycin was built using PK-Sim®. Daptomycin concentrations in plasma and bone were obtained from three previously published studies. Physicochemical drug characteristics, mass balance, anthropometrics, and experimental data were used to build and refine the PBPK model. Internal validation of the PBPK model was performed using the usual diagnostic plots. The final PBPK model was then used to run simulations with doses of 6, 8, 10, and 12 mg/kg/24 h. Pharmacokinetic profiles were simulated in 1000 subjects and the probabilities of target attainment for the area under the concentration-time curve over the bacterial minimum inhibitory concentration were computed in blood, skin, and bone compartments. RESULTS: The final model showed a good fit of all datasets with an absolute average fold error between 0.5 and 2 for all pharmacokinetic quantities in blood, skin and bone tissues. Results of dosing simulations showed that doses ≥10 mg/kg should be used in the case of bacteremia caused by Staphylococcus aureus with a minimum inhibitory concentration >0.5 mg/L or Enterococcus faecalis with a minimum inhibitory concentration >1 mg/L, while doses ≥12 mg/kg should be used in the case of bone and joint infection or complicated skin infection. When considering a lower minimum inhibitory concentration, doses of 6-8 mg/kg would likely achieve a sufficient success rate. However, in the case of infections caused by E. faecalis with a minimum inhibitory concentration >2 mg/L, a higher dosage and combination therapy would be necessary to maximize efficacy. CONCLUSIONS: We developed the first daptomycin PBPK/pharmacodynamic model for bone and joint infection, which confirmed that a higher daptomycin dosage is needed to optimize exposure in bone tissue. However, such higher dosages raise safety concerns. In this setting, therapeutic drug monitoring and model-informed precision dosing appear necessary to ensure the right exposure on an individual basis.

Septic arthritis: monitoring with USPIO-enhanced macrophage MR imaging.

PURPOSE: To prospectively evaluate in vivo noninvasive monitoring of antibiotic therapy in experimental infectious arthritis by imaging macrophages by using magnetic resonance (MR) imaging enhanced with ultrasmall superparamagnetic iron oxide (USPIO) particles. MATERIALS AND METHODS: The institutional review committee on animal care approved the experimental protocol. Unilateral knee infection was induced by intra-articular injection of Staphylococcus aureus in 12 rabbits. Each rabbit underwent MR imaging before and after injection of USPIO particles, as well as before and after injection of gadoterate meglumine. All 12 of the animals were imaged during the acute phase of infection. Half were then sacrificed to obtain histopathologic samples, and the other half were imaged a second time after antibiotic treatment. MR imaging data were analyzed and compared with bacteriologic and histopathologic findings. RESULTS: In acute infections, intense synovitis with marked signal intensity increase of the synovium on gadoterate dimeglumine-enhanced fat-suppressed T1-weighted images was observed in all animals and was associated with areas of signal intensity loss within the infected synovium on USPIO-enhanced T2*-weighted gradient-echo images, reflecting an intense infiltration of USPIO-loaded macrophages. After antibiotic treatment and histologic evidence of healing infection, less synovial signal intensity loss was seen (P = .03). In contradistinction, the signal intensity increase on gadoterate dimeglumine-enhanced fat-suppressed T1-weighted images remained unchanged. CONCLUSION: In contrast to conventional MR imaging performed by using extracellular contrast agents, USPIO-enhanced macrophage MR imaging can demonstrate resolution of experimental bacterial joint infection.

Enhanced physician adherence to antibiotic use guidelines through increased availability of guidelines at the time of drug ordering in hospital setting.

PURPOSE: Some studies have shown that making practice guidelines accessible to physicians when they are making clinical decisions could improve prescribing practices. The aim of the study was to assess the benefit of impact on physician adherence of the intervention that consisted of embedding previously paper-based antibiotic guidelines in the computerized physician drug order entry system of a teaching hospital in order to make these guidelines available to physician at the time of antibiotic ordering. Before the intervention, these guidelines were available in booklet form in all the wards of the hospital. METHODS: Adherence to guidelines was evaluated in 471 consecutive antibiotic orders for pneumonia, 104 just before and 367 just after the intervention. The evaluation criteria were: the choice of the antibiotic relative to the context of acquisition of pneumonia, the daily dose, the planned duration of treatment. Evaluation of antibiotic orders was performed at the initiation of antibiotic treatment. RESULTS: The intervention was followed by a significant decrease in the proportion of antibiotic orders containing at least one criterion of non-conformity to the guidelines, respectively, 33% after vs. 51% (p<0.001) before the intervention. Proportion of non-conform orders decreased in the post- vs. pre-intervention period for the daily dosage of antibiotics, respectively, 12.2% vs. 26.9% (p<0.001), for the planned duration of treatment, respectively, 7.3% vs. 18.3% (p<0.001), whereas for the choice of antibiotics relative to the context of acquisition of pneumonia, the improvement failed to reach statistical significance, respectively, 18.2% vs. 25% (p=0.12). CONCLUSION: In this study, the increased availability of antibiotic guidelines at the time of drug ordering, combined with a periodical reinforcement educational round, was associated with an enhanced physician adherence to these guidelines.

In vitro activity of cefiderocol and comparators against isolates of Gram-negative pathogens from a range of infection sources: SIDERO-WT-2014-2018 studies in France.

OBJECTIVES: Over recent years, France has experienced an increase of infections caused by carbapenem-resistant Gram-negative (GN) pathogens. Cefiderocol is approved in Europe for the treatment of aerobic GN infections in adults with limited treatment options. This study evaluated the in vitro activity of cefiderocol and comparators against GN clinical isolates from France. METHODS: MICs were determined by broth microdilution, according to International Organization for Standardization guidelines. Cefiderocol was tested using iron-depleted CAMHB. Susceptibility rates were based on EUCAST breakpoints. In the absence of a species-specific breakpoint, pharmacokinetic/pharmacodynamic breakpoints were used. RESULTS: Of 2027 isolates, 1344 (66.3%) were Enterobacterales and 683 (33.7%) were non-fermenters. The most common pathogen was Pseudomonas aeruginosa (16.8%), followed by Escherichia coli (16.0%), Klebsiella pneumoniae (13.1%), Acinetobacter baumannii (7.9%) and Stenotrophomonas maltophilia (5.1%). Isolates represented a range of infection sources including nosocomial pneumonia (33.6%), complicated urinary tract infection (24.3%), bloodstream infection (13.1%) and complicated intra-abdominal infection (18.0%). In total, 135/2027 (6.7%) isolates were meropenem resistant (MIC >8 mg/L); 133/135 (98.5%) were non-fermenters. Overall, 1330/1344 (99.0%) Enterobacterales and 681/683 (99.7%) non-fermenters were cefiderocol susceptible, including 100% of meropenem-resistant S. maltophilia (n = 98) and P. aeruginosa (n = 18) isolates. Susceptibility to cefiderocol was significantly higher (P < 0.01) in nosocomial pneumonia isolates (681/682 [99.9%]) than susceptibility to meropenem (586/682 [85.9%]), ceftolozane/tazobactam (593/682 [87.0%]), ceftazidime/avibactam (612/682 [89.7%]) and colistin (538/682 [78.9%]). CONCLUSIONS: Cefiderocol demonstrated high in vitro susceptibility rates against a wide range of Gram-negative pathogens, including meropenem-resistant strains, and was significantly more active than comparators against pneumonia isolates.

Erratum to: In vitro activity of cefiderocol and comparators against isolates of Gram-negative pathogens from a range of infection sources: SIDERO-WT-2014-2018 studies in France.

[This corrects the article DOI: 10.1093/jacamr/dlab081.].

MRI of macrophages in infectious knee synovitis.

OBJECTIVE: The objective of our study was to prospectively evaluate macrophage imaging using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI to depict bacterial knee infection in an experimental rabbit model. SUBJECTS AND METHODS: Unilateral knee infection was induced by intraarticular injection of Staphylococcus aureus in eight rabbits. The contralateral knees were used as internal controls. After a mean interval of 3 days, two MRI sessions (3-T MRI) were performed before and 24 hours after IV administration of USPIO. The protocol included T1-weighted spin-echo, T2-weighted spin-echo, and T2*-weighted gradient-echo images. A gadolinium-enhanced T1-weighted sequence was also performed in the first session to optimize detection of synovial hyperplasia. MR data were analyzed qualitatively and quantitatively and compared with histopathologic findings (H and E stain and Perls Prussian blue stain). Signal-to-noise ratio changes after USPIO administration were compared using Wilcoxon's signed rank test. RESULTS: All inoculated knees presented infectious synovitis with intense infiltration of iron-loaded macrophages. In these infected knees, signal loss was determined visually and quantitatively on T1-weighted (p < 0.01), T2-weighted (p < 0.01), and T2*-weighted images (p < 0.01) 24 hours after USPIO administration, reflecting the presence of USPIO-loaded macrophages in the synovium. In contrast, no significant MR signal changes were observed in the control knees (p = 0.07-0.48), which presented a normal synovium without infiltration of iron-loaded macrophages. CONCLUSION: Macrophage imaging using USPIO-enhanced MRI can depict infectious knee synovitis.

Macrophage imaging by USPIO-enhanced MR for the differentiation of infectious osteomyelitis and aseptic vertebral inflammation.

The purpose of this study was to prospectively evaluate USPIO-enhanced MR imaging for the differentiation of vertebral infectious osteomyelitis and sterile inflammation. Vertebral osteomyelitis and sterile vertebral inflammation were induced in two groups of six rabbits each. MRI examinations were performed including unenhanced and gadolinium-enhanced fat-saturated SE T1w sequences. Once endplate enhancement was observed on the T1 gadolinium-enhanced MR sequence, a second MRI examination (SE T1w sequence) was performed 24 h after USPIO administration (45 micromol Fe/kg). MR imaging was correlated with histopathological findings (macrophage immunostaining and Perls Prussian blue staining). On gadolinium-enhanced T1 sequences, a significant SNR increase in vertebral endplates was present in both groups without significant difference between the two groups (P = 0.26). On USPIO-enhanced T1 sequences, a significant SNR increase was only observed in the infection group (P = 0.03) with a significant difference in SNR between the infection and the sterile-inflammation groups (P = 0.002). Infected areas presented replacement of bone marrow by an intense macrophage infiltration, some being iron-loaded. Sterile inflammation showed a replacement of bone marrow by inflammatory tissue with only rare macrophages without any Perls blue staining. USPIO-enhanced MR imaging can distinguish infectious osteomyelitis from sterile vertebral inflammation due to different macrophage distributions in the two lesions.

Breakpoint to MIC quotient: A parameter to rapidly evaluate the in vitro bactericidal activity of ß-lactams on Enterobacteriaceae.

Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) do not completely predict the bactericidal nature of the antimicrobial agent. Patients with pathogens having MICs near the clinical breakpoint experience a higher risk of clinical failure. This study defined an indicator, breakpoint to MIC quotient (BMQ), that incorporates MIC and the European Committee on Antimicrobial Susceptibility Testing breakpoint. The BMQ was inversely correlated with MBC in antibiotic combinations against Enterobacteriaceae strains (Spearman coefficient ≤ -0.96). This new parameter may provide timely additional insight for choosing an antibiotic for a severe bacterial infection.

Clinical Impact of Antibiotics for the Treatment of Pseudomonas aeruginosa Biofilm Infections.

Bacterial biofilms are highly recalcitrant to antibiotic therapies due to multiple tolerance mechanisms. The involvement of Pseudomonas aeruginosa in a wide range of biofilm-related infections often leads to treatment failures. Indeed, few current antimicrobial molecules are still effective on tolerant sessile cells. In contrast, studies increasingly showed that conventional antibiotics can, at low concentrations, induce a phenotype change in bacteria and consequently, the biofilm formation. Understanding the clinical effects of antimicrobials on biofilm establishment is essential to avoid the use of inappropriate treatments in the case of biofilm infections. This article reviews the current knowledge about bacterial growth within a biofilm and the preventive or inducer impact of standard antimicrobials on its formation by P. aeruginosa. The effect of antibiotics used to treat biofilms of other bacterial species, as Staphylococcus aureus or Escherichia coli, was also briefly mentioned. Finally, it describes two in vitro devices which could potentially be used as antibiotic susceptibility testing for adherent bacteria.

Bone penetration of daptomycin in diabetic patients with bacterial foot infections.

OBJECTIVES: Daptomycin has shown clinical efficacy in diabetic foot infections (DFI). However, only limited data are available on its bone penetration in this particular population. The aim of this study was to determine daptomycin bone concentrations in patients with DFI undergoing surgery after multiple daptomycin infusions and to determine bone daptomycin inhibitory quotients (IQs) for the predominant gram-positive species involved in DFI. METHODS: Fourteen adult patients hospitalized with DFI treated with daptomycin and requiring surgical bone debridement and amputation were included in this single-centre prospective study. Daptomycin concentrations in serum and bone were determined by HPLC at steady state. Bone IQs were then calculated according to different minimum inhibitory concentrations (MICs; range 0.25-4mg/l) that are representative of the main MICs for Staphylococcus aureus, coagulase-negative staphylococci (CoNS), and Enterococcus sp populations. RESULTS: Residual and peak concentrations varied from 4.5mg/l to 39.9mg/l and from 31.8mg/l to 110.9mg/l, respectively. Bone daptomycin concentrations at the moment of surgery varied from 1.2mg/l to 17mg/l. Up to a MIC of 1mg/l, which is the epidemiological cut-off value (ECOFF) and breakpoint value for S. aureus and CoNS, all bone daptomycin IQs were positive. The highest bone IQs were observed with Staphylococcus species. Calculated bone IQs for Enterococcus species were often weak at MIC values near the ECOFF. CONCLUSIONS: Daptomycin penetrates bone well in patients treated for DFI. At an initially recommended dosage of 6mg/kg, bone concentrations are likely to be effective against staphylococcal infections and infections due to low-MIC Enterococcus.

Macrophage activity in infected areas of an experimental vertebral osteomyelitis model: USPIO-enhanced MR imaging--feasibility study.

PURPOSE: To prospectively evaluate ultrasmall superparamagnetic iron oxide (USPIO) magnetic resonance (MR) imaging for the depiction of macrophages in infected areas of an experimental rabbit vertebral osteomyelitis model. MATERIALS AND METHODS: Lumbar vertebral osteomyelitis was induced in 10 rabbits with intradiscal injection of bacteria in a vertebral disk (test level) versus saline injection in another disk (control level). After a mean interval of 12 days, rabbits were imaged prior to and 24 hours after administration of USPIO. The MR imaging protocol included T1-weighted spin-echo, T2-weighted fast spin-echo, and T2*-weighted gradient-echo sequences. MR findings were compared with histologic findings (macrophage immunostaining and Perls Prussian blue staining). A Wilcoxon signed rank test was used to compare signal-to-noise ratio (SNR) results before and after USPIO administration. RESULTS: T1-weighted MR images of infected vertebral test levels obtained 24 hours after USPIO administration showed a significant increase in SNR (P = .005), whereas T2- and T2*-weighted images showed no significant changes in SNR (P = .14 and P = .87, respectively). Histologic examination results of infected areas demonstrated complete replacement of hematopoietic bone marrow by macrophage infiltration. Perls Prussian blue staining showed that some macrophages were iron loaded. T1- (P = .02), T2- (P = .04), and T2*-weighted (P = .04) images of control vertebrae showed a significant decrease in SNR. Histologic examination results confirmed the persistence of normal hematopoietic bone marrow without macrophage infiltration, which was reflected by more intensive Perls Prussian blue staining compared with that in infected areas. CONCLUSION: MR imaging can depict USPIO-loaded macrophage infiltration present in infected areas in an experimental rabbit model of vertebral osteomyelitis.

Molecular pharmacokinetics of catharanthus (vinca) alkaloids.

This review focuses on the published data regarding the molecular determinants (enzymes, transporters, orphan nuclear receptors) of Catharanthus (vinca) alkaloids pharmacokinetics in humans. The clinical impact of these determinants (drug disposition, drug-drug interactions) is also discussed.

Tobramycin and Amikacin Delay Adhesion and Microcolony Formation in Pseudomonas aeruginosa Cystic Fibrosis Isolates.

Cystic fibrosis (CF) patients are predisposed to chronic colonization of the major airways by Pseudomonas aeruginosa biofilms. Pulmonary infections, involving sessile bacteria, are the main cause of morbidity and mortality. As the eradication of antibiotic-resistant biofilms remains impossible, one key objective for the treatment of lung infections is to delay the switch of P. aeruginosa to a sessile phenotype. Few tools are currently available in hospital laboratories to evaluate the susceptibility of adherent microorganisms to antimicrobials. In this study, we used the Biofilm Ring Test®, for the achievement of Antibiofilmograms® on CF clinical isolates. In comparison to standard antibiograms, these procedures allow the investigation of antibiotic effects on the biofilm formation by bacteria. To confirm the inter-assay reproducibility, conventional Crystal Violet assays were performed. To mimic the pathologic reality of CF, we also used a model allowing the biofilm growth on CF-derived cells. Results obtained from these three different assays showed that amikacin and tobramycin, the two favored aminoglycosides in CF therapies, were able to prevent the early adhesion of P. aeruginosa isolates. This promising inhibitory effect of antimicrobials confirm that biofilm setting up is governed by adaptive responses and depends on environmental conditions, as opposite processes of biofilm induction by aminoglycosides were previously described in literature. Finally, Antibiofilmograms®, whose given results are in concordance with other in vitro antibiotic susceptibility testing, appear to be useful for the optimisation of CF therapies by the selection of antimicrobials able to delay chronic infection establishment.

Kinetics of biofilm formation by Staphylococcus lugdunensis strains in bone and joint infections.

OBJECTIVE: To describe the clinical presentation and 1-year follow-up of patients with bone and joint infections (BJIs) caused by Staphylococcus lugdunensis and evaluate its biofilm-forming capacities. PATIENTS AND METHODS: Overall, 28 patients with BJIs from VISLISI clinical trials were included. We evaluated 1-year clinical follow-up and analyzed biofilm production kinetics of the 28 strains using the BioFilm Ring Test®. RESULTS: Of all patients, 12 had osteoarticular infections without material and 16 had prosthetic joint infections, of which 9 underwent a 1-stage revision procedure. At the 1-year follow-up, all patients were cured but needed a surgical intervention. Diabetes affected 46.4% of all patients. Of all, 20 strains (71.4%) started biofilm formation within 2 h, but all strains started the formation after 4 h experiment, and 25 strains (89.3%) reached a maximum after 6 h. CONCLUSIONS: This study describes the clinical and surgical management of BJIs caused by S. lugdunensis and shows that 1-stage prosthesis exchange procedures may be efficient. Further, It shows that biofilm production by this strain was not marginal and directly impacted clinical and surgical management.

Clinical pharmacokinetics of voriconazole.

This review presents the published clinical pharmacokinetic data for the antifungal agent voriconazole. Aspects regarding absorption, tissue distribution, elimination and kinetic interactions are also discussed.