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Objectives The efficacy and quality of generic antibacterial drug formulations are often questioned by both healthcare specialists and patients. Therefore, the present study investigated the interchangeability of generic drugs with their originators by comparing bioequivalence parameters and stability data of generic cefepime, linezolid and piperacillin/tazobactam with their respective originator drugs. Methods In this open-label, randomized, crossover bioequivalence study, three groups of 12 healthy volunteers each received a single intravenous infusion of either 2 g of cefepime or 4.5 g of piperacillin/tazobactam and two generic formulations, or 600 mg of linezolid and one generic formulation. Plasma sampling was performed, with a 5 day washout period between study days. Stability was tested by storing reconstituted generic and originator products according to their own storage specifications and those of the comparator products. All concentrations were measured by LC-MS. Results Similar ratios of generic/originator (90% CI) Cmax were observed for Cefepime-MIP/Maxipime [93.7 (88.4–99.4)], Cefepime Sandoz/Maxipime [95.9 (89.1–103.2)], Linezolid Kabi/Zyvoxid [104.5 (91.1–119.9)], Piperacillin Kabi/Tazobac [95.9 (90.4–101.7)], Piperacillin Aurobindo/Tazobac [99.7 (84.9–104.7)], Tazobactam Kabi/Tazobac [93.4 (87.4–99.8)] and Tazobactam Aurobindo/Tazobac [97.4 (89.7–105.8)]. Accordingly, similar ratios of AUC0–t were observed for Cefepime-MIP/Maxipime [91.1 (87.6–94.8)], Cefepime Sandoz/Maxipime [97.9 (92.5–103.5)], Linezolid Kabi/Zyvoxid [99.7 (93.3–106.6)], Piperacillin Kabi/Tazobac [92.2 (88.3–96.3)], Piperacillin Aurobindo/Tazobac [99.9 (97.0–102.8)], Tazobactam Kabi/Tazobac [91.4 (86.4–96.7)] and Tazobactam Aurobindo/Tazobac [98.8 (94.3–103.6)]. Stable and similar concentrations were measured for all contiguous substances, regardless of storage conditions. Conclusions Compared with their respective originator drugs, generic cefepime, linezolid and piperacillin/tazobactam met the predetermined bioequivalence criteria. All formulations were stable under the storage conditions of their respective comparators.

Background Preclinical data suggested anti-inflammatory properties of tedizolid. Objectives To investigate the influence of tedizolid on the cytokine response to the human endotoxin challenge and the effect of endotoxaemia on the pharmacokinetics and protein binding of tedizolid. Methods In this cross-over trial, 14 male healthy volunteers underwent two treatment periods: (A) 200 mg of tedizolid phosphate once daily for 6 days (3 days orally and 3 days intravenously), followed by an intravenous bolus of 2 ng/kg body weight of LPS on the last treatment day; and (B) intravenous bolus of LPS (2 ng/kg body weight) without concomitant tedizolid treatment. Participants underwent first period A or B, separated by at least 6 weeks. Plasma was sampled to assess cytokines and the pharmacokinetics of tedizolid. Results Following the endotoxin challenge, the peak plasma concentration (median [IQR]; 280 [155–502] versus 287 [132–541] pg/mL; P = 0.875) and AUC0–24 (979 [676–1319] versus 1000 [647–1632] pg·h/mL; P = 0.638) of interleukin-6 remained unchanged with and without concomitant tedizolid treatment. The peak concentration and AUC0–24 of TNF-α remained also unchanged with and without tedizolid (47 [31–61] versus 54 [27–69] pg/mL; P = 0.73 and 197 [163–268] versus 234 [146–280] pg·h/mL; P = 0.875, respectively). The total maximum concentration (mean ± SD; 2.94 ± 0.69 versus 2.96 ± 0.62 mg/L), total AUC0–24 (22.3 ± 3.8 versus 21.1 ± 3.6 mg·h/L) and protein binding (21.4% ± 1.7% versus 21.6% ± 1.9%) of tedizolid were similar with and without the endotoxin challenge. Conclusions Tedizolid did not attenuate the LPS-induced cytokine response in healthy volunteers. Furthermore, endotoxaemia did not influence the plasma pharmacokinetics of tedizolid.

Objectives The efficacy of an anti-infective drug is influenced by its protein binding (PB), since only the free fraction is active. We hypothesized that PB may vary in vitro and in vivo, and used clindamycin, a drug with high and concentration-dependent PB to investigate this hypothesis. Methods Six healthy volunteers received a single intravenous infusion of clindamycin 900 mg. Antibiotic plasma concentrations were obtained by blood sampling and unbound drug concentrations were determined by means of in vivo intravascular microdialysis (MD) or in vitro ultrafiltration (UF) for up to 8 h post dosing. Clindamycin was assayed in plasma and MD fluid using a validated HPLC-UV (ultraviolet) method. Non-linear mixed effects modelling in NONMEM® was used to quantify the PB in vivo and in vitro. Results C max was 14.95, 3.39 and 2.32 mg/L and AUC0–8h was 41.78, 5.80 and 6.14 mg·h/L for plasma, ultrafiltrate and microdialysate, respectively. Calculated ratio of AUCunbound/AUCtotal showed values of 13.9%±1.8% and 14.7%±3.1% for UF and microdialysate, respectively. Modelling confirmed non-linear, saturable PB for clindamycin with slightly different median (95% CI) dissociation constants (Kd) for the alpha-1 acid glycoprotein (AAG)–clindamycin complex of 1.16 mg/L (0.91–1.37) in vitro versus 0.85 mg/L (0.58–1.01) in vivo. Moreover, the estimated number of binding sites per AAG molecule was 2.07 (1.79–2.25) in vitro versus 1.66 in vivo (1.41–1.79). Conclusions Concentration-dependent PB was observed for both investigated methods with slightly lower levels of unbound drug fractions in vitro as compared with in vivo.

Background The antibiotic temocillin has recently been rediscovered as a promising therapeutic option against MDR Gram-negative bacteria. However, some aspects of the pharmacokinetic (PK) profile of the drug are still to be elucidated: subcutaneous administration of temocillin might be of interest as an alternative to the intravenous route in selected patients. Similarly, information on the penetration of temocillin into human soft tissues is lacking. Objectives To investigate the feasibility and plasma PK of subcutaneous dosing as well as soft tissue PK of temocillin after intravenous administration to healthy volunteers. Methods Eight healthy volunteers received 2 g of temocillin both as intravenous and subcutaneous infusion in a randomized two-period crossover study. Concentration–time profiles of total temocillin in plasma (after both routes) and of unbound temocillin in plasma, muscle and subcutis (only after intravenous dosing) were determined up to 12 h post-dose. Results Subcutaneous dosing caused some infusion site discomfort but resulted in sustained drug concentrations over time with only slightly decreased overall exposure compared with intravenous dosing. Plasma protein binding of temocillin showed concentration-dependent behaviour and was higher than previously reported. Still, unbound drug concentrations in muscle and subcutis determined by microdialysis markedly exceeded those in plasma, suggesting good tissue penetration of temocillin. Conclusions The subcutaneous administration of temocillin is a valid and feasible alternative to intravenous dosing. With the description of plasma protein binding and soft tissue PK of temocillin in healthy volunteers, this study provides important information that adds to the ongoing characterization of the PK profile of temocillin and might serve as input for PK/PD considerations.

Background Treatment of skin and superficial soft tissue infections with topically applied antibiotics is a controversial topic, because only few clinical studies exist and target site concentrations after topical treatment are widely unknown. Objectives This study aimed to investigate the target site concentration of topically applied gentamicin as a potential cause of therapeutic failure and to explore if microporation by laser might be used to improve penetration of gentamicin through the skin barrier. Methods Six healthy volunteers were included in this cross-over Phase 1 study. On two study days, separated by a washout period, microdialysate and plasma sampling was performed for 6 h after administration of 500 mg of gentamicin cream on a predefined area. On one of the study days the skin was microporated before drug application using the P.L.E.A.S.E. Professional laser system. Results In intact skin, Cmax and AUC values were 3.3 ± 5.64 ng/mL and 5.4 ± 10.4 ng·h/mL, respectively; thereby far under the threshold needed to treat common pathogens. With a Cmax of 474.2 ± 555.3 ng/mL laser application showed a significant increase in tissue penetration and decrease in pharmacokinetic variability; however, even after microporation no therapeutically active concentrations were achieved as indicated by Cmax/epidemiological cut-off ratios of 0.237 and 0.059 for Staphylococcus aureus and Pseudomonas aeruginosa, respectively. Solely after administration on microporated skin, plasma concentrations of gentamicin were quantifiable (lower limit of quantification 10 pg/mL). Conclusions This study confirmed that after topical administration gentamicin penetration through the dermal barrier is insufficient, providing pharmacokinetic evidence that topical gentamicin in its current form might be inappropriate to treat skin infections.

Objectives Penetration of antibiotics into synovial fluid is crucial to combat septic arthritis efficiently. Since linezolid may be used for treatment of septic arthritis when methicillin-resistant bacterial strains are suspected, we investigated its target-site concentrations in synovial fluid. Patients and methods Ten patients undergoing elective knee arthroscopy were included in this study. Subjects received a single dose of 600 mg of linezolid intravenously and linezolid concentrations were measured in plasma and by using microdialysis in muscle tissue and synovial fluid. Pharmacokinetic/pharmacodynamic calculations to predict bacterial killing ability were performed using CLSI breakpoints and MIC90 for clinical isolates. Results All 10 subjects tolerated linezolid well. As indicated by AUCtissue/AUCfree plasma ratios of 0.76 ± 0.34 (synovial fluid) and 0.98 ± 0.62 (muscle tissue) linezolid penetrated well into the knee gap and tissue. In synovial fluid AUC0-24/MIC ratios for bacteria with an MIC of 1, 2 and 4 mg/L were 86.8 ± 47.0, 43.4 ± 23.5 and 21.7 ± 11.8, respectively. Conclusions Linezolid may be used to treat septic arthritis caused by bacterial strains with an MIC ≤1 mg/L. Assuming a pharmacokinetic/pharmacodynamic target of > 50 for AUC0-24/MIC, when treating strains with an MIC >1 mg/L treatment surveillance is warranted. However, pharmacokinetic/pharmacodynamic targets for tissue are poorly understood and clinical data are needed to verify our assumptions.

Background Telavancin is a novel lipoglycoprotein antibiotic with MRSA activity. To date, tissue pharmacokinetics (PK) and plasma protein binding of the drug are insufficiently described. Objectives To investigate tissue PK and plasma protein binding of telavancin in healthy volunteers. Methods Eight male healthy subjects received a single dose of 10 mg/kg of body weight of telavancin as an intravenous infusion over 1 h. At defined timepoints before and up to 24 h after treatment, total telavancin concentrations were measured in plasma. Additionally, unbound telavancin levels were determined in plasma, muscle and subcutis by means of microdialysis. Results Key PK parameters of total telavancin in plasma were in good agreement with previously described values. Mean ± SD Cmax and calculated AUC0-24 of free telavancin in plasma were 13.8 ± 7.8 mg/L and 82.9 ± 34.3 mg·h/L, respectively. Unbound drug levels in plasma ranged from 13.2% to 24.8% of corresponding total telavancin. Mean ± SD Cmax and AUC0-24 of unbound telavancin were 4.3 ± 1.5 mg/L and 61.5 ± 27.1 mg·h/L for muscle and 3.4 ± 1.8 and 50.0 ± 29.8 mg·h/L for subcutis, respectively. Relevant PK/pharmacodynamic indices were calculated for total and unbound drug. Conclusions This study provides important information on soft tissue PK and plasma protein binding of telavancin in healthy volunteers. Unbound plasma concentrations above levels assumed from previously available data and sustained free drug exposure in soft tissues support the current mode of administration.

Objectives: The use of efflux pump inhibitors may be a powerful strategy to overcome transporter-mediated bacterial multidrug resistance. In the present study, we set out to investigate the potency of tariquidar, a third-generation P-glycoprotein inhibitor in clinical development, for overcoming bacterial resistance towards ciprofloxacin. Methods: Staphylococcus aureus 29213 (SA29213) and S. aureus 1199B (SA1199B), which overexpresses the multidrug transporter NorA, as well as Pseudomonas aeruginosa 27853 and Stenotrophomonas maltophilia BAA-85, which expresses SmeDEF, were exposed to ciprofloxacin in the presence and absence of tariquidar or, for comparative reasons, elacridar. Activity of both P-glycoprotein inhibitors was evaluated by determination of MICs and time-kill curves, and by quantification of uptake of ciprofloxacin into bacterial cells. Results: Activity of tariquidar and elacridar was comparable for S. aureus strains, and both dose-dependently increased susceptibility towards ciprofloxacin. Highest effects were observed for SA1199B, where the addition of tariquidar resulted in a 10-fold reduction of the ciprofloxacin MIC, while no effect was observed for P. aeruginosa. For S. maltophilia, elacridar but not tariquidar improved susceptibility. Uptake of [ 14 C]ciprofloxacin and modification of susceptibility showed significant correlations (r=0.89, P

OBJECTIVES although plasma protein binding (PPB) is accepted to be an essential factor in reducing antimicrobial activity, little is known about the underlying mechanisms. One possibility includes impaired penetration of an antimicrobial into bacterial cells in the presence of PPB. As a prerequisite for testing this hypothesis an optimized medium displaying high protein binding without impairing bacterial growth had to be identified for our model compound clindamycin. METHODS determination of PPB, bacterial growth and antimicrobial killing was performed in Mueller-Hinton broth (MHB) containing various amounts of human albumin or serum. [(3)H]clindamycin was used to investigate clindamycin penetration into Staphylococcus aureus. RESULTS of all investigated media only MHB(50%serum) and MHB(70%serum) achieved protein binding comparable to pure serum. In contrast, MHB(20%serum) and most media containing only albumin demonstrated considerably lower protein binding. Pure serum resulted in bacterial growth inhibition compared with MHB while MHB(16%albumin) and MHB(50%serum) did not result in significant differences in bacterial count after 24 h. However, in both MHB(16%albumin) and MHB(50%serum) the antimicrobial activity of clindamycin was reduced by >2 log(10) cfu/mL compared with pure MHB. The radioactive signal after administration of [(3)H]clindamycin to S. aureus was significantly decreased in pure serum as well as in MHB(16%albumin) and MHB(50%serum), while no significant difference was observed for MHB(4%albumin) and MHB(20%serum). CONCLUSIONS reduction of the intracellular radioactive signal in the presence of serum proteins correlated both with the degree of protein binding and reduction of antimicrobial activity supporting the hypothesis of impairment of activity by PPB by reducing intra-bacterial antimicrobial concentrations.

Objectives: Dosage recommendations for fosfomycin are available for haemodialysed patients but there are no data for patients undergoing continuous renal replacement therapy. Therefore, the present study was designed to determine the concentration-versus-time profile of fosfomycin in continuous venovenous haemofiltration (CVVH). Patients and methods: A total of 12 anuric intensive care patients (10 males and 2 females) with suspected or proven infection requiring parenteral antibiotic therapy were included in the study. All patients underwent CVVH. Blood samples were drawn from the arterial (input) and venous (output) line of the extracorporeal circuit after application of a single dose of 8 g of fosfomycin. Ultrafiltration samples were collected from the outlet of the ultrafiltrate compartment of the haemofilter. Fosfomycin in the samples was quantified by gas chromatography. Results: The peak serum concentration was 442.7 ± 124 mg/L at the arterial port. The trough serum level was 103.1 ± 36.6 mg/L at the arterial port after 720 min. The mean value of the area under the concentration-versus-time curve from 0 to 12 h (AUC 0-12 ) was 2159.4 ± 609.8 mg·h/L. Mean total removal of the drug was 76.7 ± 6.2%. The mean calculated clearance was 1.1 ± 0.2 L/h for CL HF . Mean CL tot was 6.4 ± 7.7 L/h. Conclusions: A regimen of 8.0 g of fosfomycin every 12 h, which is usually used in patients with intact renal function, should be an appropriate antimicrobial treatment for patients undergoing CVVH.

Plasma protein binding (PPB) is known to impair the antimicrobial activity of beta-lactams, but its impact on the activity of other classes of antimicrobials such as fluoroquinolones is controversial. This study was undertaken to investigate the effect of PPB on bacterial killing by selected antibiotics and moxifloxacin, which served as a model compound for the class of fluoroquinolones.Bacterial time-killing curves were employed in the absence and presence of physiological albumin concentrations (40 g/L). Moxifloxacin, ampicillin and oxacillin were investigated. Fosfomycin, a non-protein bound antibiotic was used for comparison. Simulations were carried out by employing concentrations of antibiotics of one-fourth of the minimal inhibitory concentration (MIC), equal to the MIC and four-fold the MIC of one select bacterial strain (Staphylococcus aureus ATCC 29213). To correlate bacterial killing to the extent of PPB, bacterial time-killing curves were plotted using the calculated free and the total drug concentration.Bacterial killing by fosfomycin was not affected by the addition of albumin. The antimicrobial activity of oxacillin and ampicillin was reduced in the presence of albumin as expected by the calculation of the free fraction of these antibiotics. Adding albumin to moxifloxacin resulted in a significant decrease in bacterial killing of more than 1 log10 cfu/mL after a period of 8 h when the moxifloxacin concentration was equal to the respective MIC.Our data confirm the view that albumin substantially impairs the antimicrobial activity of antibiotics including moxifloxacin, a member of the class of fluoroquinolones.

The present study was performed to test the ability of fosfomycin to penetrate into the CSF of neurointensive care patients with ventriculostomy-associated ventriculitis.Six patients requiring neurointensive care monitoring, including extraventricular drainage due to secondary obstructive hydrocephalus, were enrolled into the study. All patients received 8 g of fosfomycin intravenously three times a day over a period of at least 5 days. Concentrations of fosfomycin in the CSF and plasma were measured after single-dose administration and at steady state.Mean values of the fosfomycin area under the time-concentration curves for the dosing interval of 8 h (AUC(8)) were 929 +/- 280 and 225 +/- 131 mg.h/L for plasma and CSF after single-dose administration, respectively (P0.03). The ratios of the AUC(8) for CSF to the AUC(8) for plasma were 0.23 +/- 0.07 after a single dose and 0.27 +/- 0.08 following multiple doses (P0.05, not significant). Additional in vitro experiments have shown that fosfomycin exerts non-concentration-dependent microbial growth inhibition. At steady state, the time above MIC (tMIC) values were 98%, 92% and 61% for pathogens with MIC values of 8, 16 and 32 mg/L, respectively.The present pharmacokinetic study indicates that 8 g of fosfomycin three times per day should provide sufficient antimicrobial concentrations in the CSF for the overall treatment period. Thus, the co-administration of fosfomycin could be useful for the treatment of ventriculitis caused by susceptible pathogens.