Pharmacokinetics of garenoxacin in elderly patients with respiratory tract infections

The pharmacokinetics of the new oral des-fluoroquinolone antimicrobial garenoxacin (GRNX) was investigated in elderly patients with respiratory tract infections. Patients were treated with GRNX (200 mg or 400 mg) once daily for 7 days. Plasma GRNX concentrations were determined and pharmacokinetic parameters were estimated by Bayesian predictions using reported population pharmacokinetic parameters. At each dose, the maximum plasma concentration (C_max) and the area under the concentration–time curve (AUC) were comparable with those reported in young subjects, except that the estimated C_max and AUC values in one patient receiving the 200 mg dose whose body weight and creatinine clearance rate (CL_Cr) were 38 kg and 17 mL/min, respectively, were higher than those of the other patients given 200 mg GRNX and were comparable with those of patients who received the 400 mg dose. These results suggest that the recommended dose of GRNX should be 400 mg for most elderly and young patients, but only 200 mg in patients whose body weight and CL_Cr are <40 kg and <30 mL/min, respectively.     

Determinants of early inadequate vancomycin concentrations during continuous infusion in septic patients

Vancomycin is frequently administered to critically ill patients by continuous infusion in order to optimise drug efficacy; however, there are few data available on the efficacy of this strategy in septic patients. In this retrospective analysis, 261 patients treated with continuous infusion of vancomycin in the Department of Intensive Care at Hôpital Erasme (Brussels, Belgium) were evaluated. Creatinine clearance (CL_Cr) was calculated from 24-h urine collection and normalised to body surface area. During the study period, 139 patients (53%) had insufficient vancomycin concentrations (<20 μg/mL) on Day 1 and 87 patients (33%) on Day 2. Patients who had insufficient drug concentrations on Day 1 of therapy were more likely to be men, to have a higher CL_Cr and to have received lower loading and daily vancomycin doses than other patients, who received greater vasopressor support and had higher Sepsis-related Organ Failure Assessment scores. In multivariate regression analysis, high CL_Cr and male sex independently predicted the presence of insufficient vancomycin concentrations on Days 1 and 2 of therapy. Receiver operating characteristic curve analysis for CL_Cr showed an area under the concentration–time curve of 0.75 (95% confidence interval 0.69–0.81) to predict insufficient drug concentrations on Day 1 of therapy. A CL_Cr > 120 mL/min/1.73 m² had a sensitivity of 26%, a specificity of 94% and an 84% positive predictive value of 84% for vancomycin concentrations <20 μg/mL. In conclusion, approximately one-half of the septic Intensive Care Unit patients treated with continuous infusion of vancomycin at currently recommended doses had insufficient drug concentrations in the early phase of therapy. A high CL_Cr was the variable most strongly associated with insufficient drug concentrations.     

Does consistent piperacillin dosing result in consistent therapeutic concentrations in critically ill patients? A longitudinal study over an entire antibiotic course

Piperacillin plasma concentrations are known to vary between critically ill patients. However, there are no comprehensive data on the variability of antibiotic concentrations within the same patient. The purpose of this study was to investigate the adequacy of dosing during an entire 7-day antibiotic course and to investigate the variability in antibiotic trough concentrations both between patients and within the same patient. Piperacillin trough concentrations were measured daily in critically ill patients with normal renal function. The drug assay was performed using UPLC–MS/MS. The pharmacokinetic/pharmacodynamic target was 100% fT_>MIC of the Pseudomonas aeruginosa EUCAST breakpoint. Within- and between-patient variability were calculated as percent coefficient of variation (CV). Eleven patients treated for pneumonia were included in this nested prospective observational cohort study. The median (range) age was 67 (18–79) years, weight was 75 (57–90) kg and BMI was 23.5 (22.3–26.4). The median (range) creatinine clearance on Day 1 of antibiotic treatment was 102 (62–154) mL/min. Trough concentrations were variable, ranging from 4.9 mg/L to 98.0 mg/L. A median CV of 40% for within-patient variability and 57% for between-patient variability was found. Within-patient variability was inversely correlated with SOFA score (R = 0.65, P = 0.027) and APACHE II score on admission (R = 0.73, P = 0.009). In conclusion, piperacillin concentrations varied widely both between patients and within the same patient. Within-patient variability was inversely correlated with disease severity. Consistent dosing of piperacillin/tazobactam does not result in consistent piperacillin concentrations throughout the entire treatment period.     

Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: Lessons from the DALI Study

The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10–30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2–26.0) and free 1.5 (0.7–2.5); trough, total 11.9 (10.2–22.7) and free 1.8 (0.6–2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5–15.6%) and 8.2% (5.5–16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ = 0.79, P = 0.0021) and trough (ρ = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients.     

Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration

This prospective pharmacokinetic study aimed to describe plasma and interstitial fluid (ISF) pharmacokinetics of piperacillin and tazobactam in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF). Piperacillin/tazobactam (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3–3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m². Serial blood (pre- and post-filter), filtrate/dialysate, urine and ISF concentrations were measured. Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 407 samples were collected. Median peak plasma concentrations were 210.5 (interquartile range = 161.5–229.0) and 29.4 (27.9–32.0) mg/L and median trough plasma concentrations were 64.3 (49.0–68.9) and 12.3 (7.7–13.7) mg/L for piperacillin and tazobactam, respectively. The plasma elimination half-life was 6.4 (4.6–8.7) and 7.3 (4.6–11.8) h, volume of distribution 0.42 (0.29–0.49) and 0.32 (0.24–0.36) L/kg, total clearance 5.1 (4.2–6.2) and 3.8 (3.3–4.2) L/h and CVVHDF clearance 2.5 (2.3–3.1) and 2.5 (2.3–3.2) L/h for piperacillin and tazobactam, respectively. The tissue penetration ratio or ratio of area under the concentration–time curve of the unbound drug in ISF to plasma (unbound AUC_ISF/AUC_plasma) was ca. 1 for both piperacillin and tazobactam. This is the first report of concurrent plasma and ISF concentrations of piperacillin and tazobactam during CVVHDF. For the CVVHDF settings used in this study, a dose of 4.5 g piperacillin/tazobactam administered evry 8 h resulted in piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval.     

Daily serum piperacillin monitoring is advisable in critically ill patients

The aim of the present study was to evaluate the benefit of monitoring serum piperacillin concentrations in critically ill patients. This was an 11-month, prospective, observational study in a 30-bed Intensive Care Unit in a teaching hospital, involving 24 critically ill patients with evidence of bacterial sepsis. All patients received a 66 mg/kg intravenous bolus of piperacillin in combination with tazobactam (ratio 1:0.125) followed by continuous infusion of 200 mg/kg/24 h. The dosage was adjusted when the serum piperacillin concentration either fell below 4× the drug's minimum inhibitory concentration (MIC) for the causative agent or exceeded the toxic threshold of 150 mg/L. With the initial regimen, serum piperacillin concentrations were within the therapeutic target range in only 50.0% of patients (n = 12). This proportion increased to 75.0% (18 patients) (P = 0.006) following dosage adjustment. For patients with low initial serum piperacillin concentrations (n = 8), the percentage of time during which the concentration remained above 4× MIC (%T > 4× MIC) was 7.1 ± 5.9% before dosage adjustment and 27.3 ± 8.6% afterwards. In conclusion, in critically ill patients, monitoring and adjustment of serum piperacillin levels is required to prevent overdosing and might also help to correct underdosing, an important cause of antibiotic therapy failure.     

Clinical Pharmacokinetics of Paclitaxel Liposome with a New Route of Administration in Human Based on the Analysis with Ultra Performance Liquid Chromatography

We investigated the clinical pharmacokinetics of paclitaxel liposome with a new route of administration, which was intrapleural infusion, in nine advanced nonsmall-cell lung cancer (NSCLC) patients with malignant pleural effusions after a single administration. Paclitaxel concentrations were measured in pleural fluid and plasma using a simple and rapid ultra performance liquid chromatography (UPLC) method following intra-and inter-day validations. In subjects, AUC_0–96h values in pleural fluid and plasma were 17831 ± 6439 μgh/mL and 778 ± 328 μgh/mL, respectively, and T_max values were initial time and 6.67 h after administration and the corresponding C_max values were 558 ± 44 μg/mL and 12.89 ± 6.86 μg/mL, respectively. The T_{1/2 IP}, CL_IP and Vd_IP values in pleural fluid were 76 ± 48 h, 0.005 ± 0.002 L/hm² and 0.53 ± 0.23 L/m², respectively. The T_1/2,_pla, CL_pla, and Vd_pla values in plasma were 68.34 ± 56.74 h, 0.184 ± 0.080 L/hm², and 17.53 ± 16.57 L/m², respectively. However, some paclitaxel concentrations from several patients in plasma could not be detected at some designed time-points. Our results might offer new opportunities to design and determine individually appropriate therapeutic dosage regimens based on a pharmacokinetic profile.     

Reduced Renal Clearance of Cefotaxime in Asians with a Low-Frequency Polymorphism of OAT3 (SLC22A8)

Organic anion transporter 3 (OAT3, SLC22A8), a transporter expressed on the basolateral membrane of the proximal tubule, plays a critical role in the renal excretion of organic anions including many therapeutic drugs. The goal of this study was to evaluate the in vivo effects of the OAT3-Ile305Phe variant (rs11568482), present at 3.5% allele frequency in Asians, on drug disposition with a focus on cefotaxime, a cephalosporin antibiotic. In HEK293- Flp-In cells, the OAT3-Ile305Phe variant had a lower maximum cefotaxime transport activity, V_max, [159 ± 3 nmol*(mg protein)^- 1/min (mean ± SD)] compared with the reference OAT3 [305 ± 28 nmol*(mg protein)^? 1/min, (mean ± SD), p < 0.01], whereas the Michaelis-Menten constant values (K_m) did not differ. In healthy volunteers, we found volunteers that were heterozygous for the Ile305Phe variant and had a significantly lower cefotaxime renal clearance (CL_R; mean ± SD: 84.8 ± 32.1 mL/min, n = 5) compared with volunteers that were homozygous for the reference allele (158 ± 44.1 mL/min, n = 10; p = 0.006). Furthermore, the net secretory component of cefotaxime renal clearance (CL_sec) was reduced in volunteers heterozygous for the variant allele [33.3 ± 31.8 mL/min (mean ± SD)] compared with volunteers homozygous for the OAT3 reference allele [97.0 ± 42.2 mL/min (mean ± SD), p = 0.01]. In summary, our study suggests that a low-frequency reduced-function polymorphism of OAT3 associates with reduced cefotaxime CL_R and CL_sec .©2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3451–3457, 2013     

Novel antimicrobial lipopeptides with long in vivo half-lives

The pharmacokinetic (PK) properties of novel lipopeptides (semi-synthetic amphomycin analogues) with potent activity against Gram-positive organisms were evaluated in mice and rats following single intravenous (i.v.) and oral administration. Following oral administration at 50 mg/kg, plasma concentrations of amphomycin analogues were <0.3–0.9 μg/mL, suggesting that oral availability was low. Following i.v. administration (5–10 mg/kg), the majority of lipopeptides demonstrated a long half-life (5.2–8.0 h in mice and 4.6–7.1 h in rats), low clearance (0.005–0.016 mL/min in mice and 0.050–0.084 mL/min in rats) and a volume of distribution indicative of extracellular penetration (0.118–0.339 L/kg in mice and 0.121–0.133 L/kg in rats). The area under the plasma concentration–time curve extrapolated to infinity (AUC_0?∞) for a 10 mg/kg i.v. dose was determined to be 601.7–791.7 μg h/mL in mice and 511.1–850.2 μg h/mL in rats. The long half-life and low clearance observed with these novel lipopeptides indicate that drug serum concentrations will remain above the target minimal inhibitory concentration (MIC) levels for significant periods of time. When combined with the potent efficacy of these agents against Gram-positive organisms, the results of the present study support further development of these lipopeptide analogues towards clinical evaluation.     

Association between augmented renal clearance,antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of β-lactams administered by continuous infusion: a prospective observational study

This study assessed whether augmented renal clearance (ARC) impacts negatively on antibiotic concentrations and clinical outcomes in patients treated by high-dose β-lactams administered continuously. Over a 9-month period, all critically ill patients without renal impairment treated by one of the monitored β-lactams for a documented infection were eligible. During the first 3 days of antibiotic therapy, every patient underwent 24-h CL_Cr measurements and therapeutic drug monitoring. The main outcome was the rate of β-lactam underdosing, defined as a free drug concentration <4?×?MIC of the known pathogen. Secondary outcomes were rates of subexposure for β-lactams and therapeutic failure. The performance of CL_Cr in predicting underdosing was assessed by a ROC curve, and multivariable logistic regression was performed to determine risk factors for subexposure and therapeutic failure. A total of 79 patients were included and 235 samples were analysed. The rate of underdosing_<4×MIC was 12%, with a significant association with CL_Cr (P?<0.0001). A threshold of CL_Cr?≥?170?mL/min had a sensitivity and specificity of 0.93 (95% CI 0.77–0.99) and 0.65 (95% CI 0.58–0.71) for predicting β-lactam underdosing_<4×MIC. Mean CL_Cr values ≥170?mL/min were significantly associated with subexposure_<4xMIC [OR?=?10.1 (2.4–41.6); P?=?0.001]. Patients with subexposure_<4×MIC presented higher rates of therapeutic failure [OR?=?6.3 (1.2–33.2); P?=?0.03]. Mean CL_Cr values ≥170?mL/min remain a risk factor for subexposure to β-lactams despite high doses of β-lactams administered continuously. β-Lactam subexposure was associated with higher rates of therapeutic failure in septic critically ill patients.     

Ceftaroline activity tested against uncommonly isolated Gram-positive pathogens: report from the SENTRY Antimicrobial Surveillance Program (2008–2011)

Ceftaroline was tested against 1859 clinically significant Gram-positive organisms from uncommonly isolated species. The organisms (31 species/groups) were collected from 133 medical centres worldwide over a 4-year period (2008–2011). Coagulase-negative staphylococci were generally susceptible to ceftaroline, with MIC₅₀ values (minimum inhibitory concentration required to inhibit 50% of the isolates) of 0.06–0.5 mg/L. Ceftaroline was active against Micrococcus spp. [minimum inhibitory concentration required to inhibit 90% of the isolates (MIC₉₀) = 0.06 mg/L], but showed more limited potency versus some Corynebacterium spp. and Listeria monocytogenes isolates. Ceftaroline was active against all β-haemolytic streptococci and viridans group streptococcal species/groups listed, with MIC₅₀ and MIC₉₀ values ranging from ≤0.015 mg/L to 0.03 mg/L and from ≤0.015 mg/L to 0.5 mg/L, respectively. Based on these in vitro findings, ceftaroline may have a potential role in the treatment of infections caused by these rarer species as guided by reference MIC test results.     

Azole-resistance in Aspergillus: Proposed nomenclature and breakpoints

Reports of itraconazole resistance in Aspergillus fumigatus have been more frequent since the millennium. Identifying azole resistance is critically method dependent; nevertheless reproducible methods, reflective of in vivo outcome, are now in routine use. Some isolates also have elevated MICs to posaconazole and voriconazole. Multiple mechanisms of resistance are now known to be responsible, with differing degrees of azole cross-resistance, including mutations in the Cyp51A gene at G54, L98 + TR, G138, M220, G448. Establishing breakpoints for Aspergillus is probably impossible with clinical data alone for multiple reasons yet there is an urgent need to do so. We propose the following breakpoints for A. fumigatus complex using the proposed EUCAST susceptibility testing methodology: for itraconazole and voriconazole, <2 mg/L (susceptible), 2 mg/L (intermediate) and >2 mg/L (resistant); for posaconazole, <0.25, 0.5 and >0.5 mg/L respectively. We recognize that additional work will be needed to confirm these proposed breakpoints, including in vivo and clinical correlative responses. We also propose nomenclature for genotypic resistance, in the event an isolate is not cultured, typified by ITZgR, VCZgI, POSgR (G54W) indicating that the isolate has a G54W substitution with a corresponding phenotype of resistance to itraconazole and posaconazole and intermediate susceptibility to voriconazole.     

Evaluation of Rat In Vivo Fetal-to-Maternal Transfer Clearances of Various Xenobiotics by Umbilical Perfusion

It is important to address the tissue permeability of drugs, particularly in tissues that have a blood–tissue barrier, in terms of both lipophilicity and the contribution of transporters. Here, we employed umbilical perfusion in rats to evaluate in vivo fetal-to-maternal transfer clearances of various xenobiotics. We measured fetal-to-maternal clearance (CL_fm) of 23 compounds, which have a broad range of lipophilicity. Drugs for which CL_fm was more than 300 µL/(mL min) belonged exclusively to Biopharmaceutical Drug Disposition Classification System (BDDCS) class 1 (highly permeable) and those for which CL_fm was less than 50 µL/(mL min) belonged exclusively to BDDCS class 3 (poorly permeable). For most drugs, CL_fm values were broadly consistent with lipophilicity. However, CL_fm of digoxin was saturable and was inhibited by verapamil, suggesting that P-glycoprotein (P-gp)-mediated efflux has a substantially effect on measured clearance. CL_fm of mitoxantrone continued to increase slightly at high concentrations of mitoxantrone, but placental-to-maternal clearance of mitoxantrone was saturable, implying that Bcrp1 contributes to mitoxantrone efflux across the placenta. Thus, we measured CL_fm by umbilical perfusion and examined the relationship between CL_fm and lipophilicity of xenobiotics. Fetal-to-maternal transport clearances measured in this study will be helpful to understand the characteristics of the blood–placental barrier.     

In vitro and intracellular activities of fosfomycin against clinical strains of Listeria monocytogenes

This study was designed to evaluate the potential role of fosfomycin as a therapeutic agent in human listeriosis. The in vitro activity of fosfomycin against 154 Listeria monocytogenes clinical isolates under conditions that mimic the induction of prfA expression was determined and was correlated with fosfomycin intracellular antimicrobial activity. In vitro, partial induction of prfA expression is achieved through bacterial growth in brain–heart infusion agar supplemented with activated charcoal (BHIC). A fosfomycin pharmacokinetic/pharmacodynamic breakpoint of ≤64 mg/L was estimated using a Monte Carlo simulation to assess the success of an intravenous fosfomycin dose of 300 mg/kg/day over 5000 individuals. Eighty strains (51.9%) were susceptible to fosfomycin in BHIC, with minimum inhibitory concentrations (MICs) of ≤64 mg/L; 13 strains (8.4%) had the epidemic clone (EC) marker. In addition, 27 strains (17.5%) had a three doubling dilutions reduction in the MIC from ≥1024 mg/L to 128 mg/L (96–128 mg/L by Etest). The fosfomycin modal MIC is lower under prfA expression. However, this effect is smaller in terms of clinical categorisation of isolates and can be influenced by the serotype and clonal type. In A549 cells, the reductions in bacterial inocula of the two susceptible isolates studied after 1 h and 24 h of incubation with fosfomycin at 0.5× the human maximum serum concentration (C_max) were 45.8% and 46.6%, and 93.8% and 99.1%, respectively. Slightly higher reductions were found with fosfomycin at 1× C_max. The resistant strain tested showed significantly lower reductions in all assays.     

Bactericidal activity of daptomycin versus vancomycin in the presence of human albumin against vancomycin-susceptible but tolerant methicillin-resistant Staphylococcus aureus (MRSA) with daptomycin minimum inhibitory concentrations of 1–2 μg/mL

This study explored the influence of vancomycin tolerance and protein binding on the bactericidal activity of vancomycin versus daptomycin (protein binding 36.9% vs. 91.7%, respectively) against four vancomycin-tolerant methicillin-resistant Staphylococcus aureus (MRSA) [minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) = 0.5/16, 1/32, 2/32 and 1/32 μg/mL for vancomycin and 1/1, 1/2, 2/2 and 2/4 μg/mL for daptomycin]. Killing curves were performed with vancomycin/daptomycin concentrations equal to serum peak concentrations (C_max) (65.70/98.60 μg/mL) and trough concentrations (C_min) (7.90/9.13 μg/mL) in the presence and absence of a physiological human albumin concentration (4 g/dL), controlled with curves with the theoretical free drug fraction of vancomycin/daptomycin C_max (41.45/8.18 μg/mL) and C_min (4.98/0.76 μg/mL). Vancomycin C_max and C_min concentrations, regardless of the media, showed a bacteriostatic profile not reaching a reduction of 99% or 99.9% of the initial inocula during the 24-h experimental time period. Daptomycin antibacterial profiles significantly differed when testing C_max and C_min. C_max was rapidly bactericidal (≤4 h) with >5 log₁₀ reduction in the initial inocula for all strains, regardless of the presence or not of albumin or the use of concentrations similar to free C_max. C_min exhibited similar final colony counts at 0 h and 24 h in curves with albumin, but with >3 log colony-forming units (CFU)/mL reduction at ≤4 h for strains with an MIC of 1 μg/mL and ca. 2 log CFU/mL reduction at ≤6 h for strains with an MIC of 2 μg/mL. This activity was significantly higher than the activity of the free C_min fraction. The results of this study reinforce the idea that pharmacodynamics using concentrations calculated using reported protein binding are unreliable. Daptomycin exhibited rapid antibacterial activity against vancomycin-tolerant MRSA isolates even against those with high daptomycin MICs in the presence of physiological albumin concentrations.     

Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012)

During 2012, a total of 2968 isolates were consecutively collected from 59 medical centres in the USA and 15 European countries from hospitalised patients with pneumonia. Ceftolozane/tazobactam (tazobactam at a fixed concentration of 4 mg/L) and comparator agents were tested by reference methods, and MIC endpoints were interpreted by CLSI (2013) and EUCAST (2013) breakpoint criteria. Pseudomonas aeruginosa was the most common isolated pathogen (1019 strains; 34.3%), and ceftolozane/tazobactam was the most active β-lactam tested against P. aeruginosa (MIC_50/90, 0.5/4 mg/L; 94.1% inhibited at ≤8 mg/L). P. aeruginosa exhibited moderate susceptibility to meropenem (MIC_50/90, 0.5/>8 mg/L; 73.7% susceptible), ceftazidime (MIC_50/90, 2/>32 mg/L; 73.6% susceptible), cefepime (MIC_50/90, 4/>16 mg/L; 76.5% susceptible), piperacillin/tazobactam (MIC_50/90, 8/>64 mg/L; 69.5% susceptible), levofloxacin [MIC_50/90, 0.5/>4 mg/L; 69.9/61.0% susceptible (CLSI/EUCAST criteria)] and gentamicin (MIC_50/90, 2/>8 mg/L; 80.7% susceptible). Ceftolozane/tazobactam exhibited activity against many ceftazidime-non-susceptible, meropenem-non-susceptible and piperacillin/tazobactam-non-susceptible, multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa isolates. Ceftolozane/tazobactam was active (MIC_50/90, 0.25/4 mg/L; 94.6% inhibited at ≤8 mg/L) against 1530 Enterobacteriaceae, including activity against many MDR and XDR strains. MDR and XDR prevalence varied widely between countries both for P. aeruginosa (24.1% MDR and 17.1% XDR overall) and Enterobacteriaceae (15.4% MDR and 2.7% XDR overall). All β-lactams had limited activity against Acinetobacter spp. and Stenotrophomonas maltophilia. Ceftolozane/tazobactam demonstrated greater in vitro activity than currently available cephalosporins, carbapenems and piperacillin/tazobactam when tested against P. aeruginosa. In addition, ceftolozane/tazobactam demonstrated greater activity than contemporary cephalosporins and piperacillin/tazobactam when tested against most Enterobacteriaceae.     

Comparative efficacy of novobiocin and amoxicillin in experimental sepsis caused by β-lactam-susceptible and highly resistant pneumococci

Therapeutic alternatives are needed against infections caused by highly multidrug-resistant Streptococcus pneumoniae. Novobiocin, an old antibiotic, was tested in vitro and in a murine sepsis model against one amoxicillin-susceptible and three amoxicillin-resistant strains [minimum inhibitory concentrations (MICs) 8–64 mg/L]. Novobiocin MICs for all strains were 0.25–0.5 mg/L. In sepsis, novobiocin and amoxicillin were evaluated at 25, 50, 100 and 200 mg/kg given at 1, 5, 24 and 48 h post bacterial challenge. The most effective regimens in animals infected with the amoxicillin-susceptible strain were 200 mg/kg novobiocin and 25 mg/kg amoxicillin, achieving 100% survival and undetectable organisms in the peritoneum. Among mice infected with amoxicillin-resistant S. pneumoniae, 200 mg/kg novobiocin gave the highest protection (90–100% survivors), followed by 200 mg/kg amoxicillin (60–100%), 100 mg/kg novobiocin (50–87.5%) and 50 mg/kg amoxicillin (14.3–25%). The killing effect of antibiotics in the peritoneum (mean Δlog₁₀ colony-forming units/mL between treated and control mice) was as follows: 200 mg/kg novobiocin (?6.6) > 200 mg/kg amoxicillin (?5.6) > 100 mg/kg novobiocin (?3.7) > 50 mg/kg amoxicillin (?0.7). Total plasma and ultrafiltrate pharmacokinetics of novobiocin (200 mg/kg, single dose) in non-infected mice showed, respectively, half-lives of 151 min and 215 min, area under the concentration–time curves (AUCs) of 945.0 mg h/L and 136.6 mg h/L and maximal concentrations of 147 mg/L and 18 mg/L. Novobiocin may be a promising agent for therapy of highly β-lactam-resistant pneumococcal infections.     

Determination of repaglinide in human plasma by high-performance liquid chromatography–tandem mass spectrometry

A rapid and sensitive method based on high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) has been developed for the determination of repaglinide in human plasma. The analyte and internal standard (I.S.), diazepam, were extracted from plasma (25 μL) by liquid–liquid extraction with diethyl ether–dichloromethane (60:40, v/v) and separated on a XDB-C₁₈ column using acetonitrile–ammonium acetate buffer (pH 6.8, 0.01 mol/L) as mobile phase. The retention times of repaglinide and I.S. were 1.95 and 2.35 min, respectively. Detection was carried out using API 4000 mass spectrometer with an ESI interface operating in the multiple reaction monitoring (MRM) mode. The assay was linear over the concentration range 0.050–50 ng/mL with a limit of detection (LOD) of 0.010 ng/mL. Intra- and inter-day precisions (as relative standard deviation, R.S.D.) were ≤5.07% and ≤11.2%, respectively, and accuracy (as relative error, R.E.) was from ?0.593% to ?1.26%. The assay was successfully applied to a pharmacokinetic study involving a single oral administration of a tablet containing 2 mg repaglinide to each of 10 healthy volunteers.     

Significance of individual adjustment of initial loading dosage of teicoplanin based on population pharmacokinetics

An initial loading dose of teicoplanin is required to reach the optimal trough concentration (≥10 μg/mL) rapidly. To attain the optimal teicoplanin concentration efficiently, an individual loading dose regimen based on population pharmacokinetics, in which the target trough concentration was set to 15 μg/mL, was defined. Among 70 patients, 33 patients received the individual loading dose regimen, 33 patients received the conventional loading dose regimen (200 mg or 400 mg every 12 h on Day 1 followed by 200 mg once daily) and 4 patients received no loading dose. The proportion of patients showing an optimal plasma concentration was 88% in the individual loading dose regimen but only 33% in the conventional loading dose regimen. No patient without a loading dose showed the optimal concentration. Both total loading dose and plasma concentration were significantly (P < 0.001) higher in the individual loading dose group than in the conventional loading dose group. Notably, the trough concentration was almost constant in patients with individual loading doses ranging from 800 mg to 1800 mg. These findings suggest that individual adjustment of the initial loading dose of teicoplanin is potentially useful to attain the optimal concentration rapidly.