Plasma nitriding monitoring reactor: A model reactor for studying plasma nitriding processes using an active screen.

A laboratory scale plasma nitriding monitoring reactor (PLANIMOR) has been designed to study the basics of active screen plasma nitriding (ASPN) processes. PLANIMOR consists of a tube reactor vessel, made of borosilicate glass, enabling optical emission spectroscopy (OES) and infrared absorption spectroscopy. The linear setup of the electrode system of the reactor has the advantages to apply the diagnostic approaches on each part of the plasma process, separately. Furthermore, possible changes of the electrical field and of the heat generation, as they could appear in down-scaled cylindrical ASPN reactors, are avoided. PLANIMOR has been used for the nitriding of steel samples, achieving similar results as in an industrial scale ASPN reactor. A compact spectrometer using an external cavity quantum cascade laser combined with an optical multi-pass cell has been applied for the detection of molecular reaction products. This allowed the determination of the concentrations of four stable molecular species (CH4, C2H2, HCN, and NH3). With the help of OES, the rotational temperature of the screen plasma could be determined.

Serum bactericidal activity of trovafloxacin, in combination with cefepime or amikacin, in healthy volunteers.

OBJECTIVE: To investigate the phamacokinetics and serum bactericidal activities (SBAs) of trovafloxacin, cefepime and amikacin alone and trovafloxacin in combination with cefepime or amikacin, so that the most favorable combination with trovafloxacin can be determined. METHODS: In this open, randomized, crossover study, 12 healthy volunteers (six females, six males; mean age +/- SD, 25.1 +/- 2.6 years) received an infusion of either 300 mg of alatrovafloxacin or 2000 mg of cefepime or 6 mg/kg body weight amikacin alone, or 300 mg of alatrovafloxacin plus 2000 mg of cefepime or plus 6 mg/kg body weight amikacin. The SBAs against Pseudomonas aeruginosa, Staphylococcus aureus (11 strains each), Citrobacter freundii and Acinetobacter spp. (10 strains each) 1, 10 and 24 h after drug administration were measured by a standard microdilution method. Concentrations of trovafloxacin, cefepime and amikacin in serum and urine were analyzed before and up to 10 and 12 h, respectively, after drug infusion. RESULTS: Significant synergistic effects on SBA were observed with the combination of trovafloxacin and cefepime against P. aeruginosa, S. aureus and Acinetobacter spp. 1 h after drug administration, and against Citrobacter freundii 1, 10 and 24 h after drug administration. The combination of trovafloxacin and amikacin showed significant synergistic effects against P. aeruginosa, S. aureus and C. freundii 1 h after drug administration. The combination of trovafloxacin and cefepime was, in general, more active than the combination of trovafloxacin and amikacin. No significant differences in the serum concentrations of trovafloxacin were observed between single and combined administration. However, the maximal concentration of cefepime was significantly lower when it was used in combination with trovafloxacin. CONCLUSION: Our study suggests a favorable interaction between trovafloxacin and cefepime. This combination showed more synergistic bactericidal activity against most of the test strains compared to the combination of trovafloxacin and amikacin. However, for P. aeruginosa, the bactericidal activity of cepefime alone was higher than that of the combination with trovafloxacin.

Radon concentration measurements and personnel exposure levels in Bavarian water supply facilities.

As part of a study covering the whole of Bavaria, the southern most of Germany's 16 states, water supply facilities were examined to determine the radon (222Rn) concentrations in ground water and indoor air and the radon exposure to the staff working in these buildings. Bavaria can be divided into ten geological regions of different geogenic radon potential. From each region, a number of water supply facilities proportional to the size of the region were selected for measurements. Over 500 of a total number of 2,600 water supply facilities were asked to take a 1-L groundwater sample and expose several track-etch detectors in order to obtain the mean room concentration of the main staff work places. In addition, for a period of 2 mo, the personnel had to wear a track-etch detector during the time they spent in the supply facilities. The resulting measurements were then used to estimate their individual effective dose of radon and its progenies. In the East Bavarian crystalline region, the region of the highest geogenic radon potential within Bavaria, indoor radon gas concentrations of up to 400 kBq m(-3) were observed. About 10% of the process controllers in this region are subjected to an annual effective dose of more than 20 mSv. In the other Bavarian regions, only 2% of staff exposure levels exceed this limit. The correlation between the radon concentration measurements of the indoor air, the ground water, and individual personnel exposure levels was determined. The average ratio of the radon indoor air to the processed groundwater concentration is 0.14. But due to the different types of ventilation in the various supply facilities, there can be great variations in this figure. Therefore, there is no clear relationship between the groundwater and the indoor air concentration of a supply facility. This study also reveals no clear relationship between radon indoor air concentrations and the personnel exposure levels of a supply facility.

Determination of linezolid in human serum and urine by high-performance liquid chromatography.

An HPLC method is described for the determination of the new oxazolidinone antibiotic linezolid (I) in human biofluids. After precipitation of serum proteins with perchloric acid the protein free supernatant was separated by isocratic reversed-phase chromatography on a Nucleosil-100 5C18 column. The mobile phase consisted of a mixture of acetonitrile: sodium acetate buffer: water (180:100:720, v/v) adjusted to pH 3.7. Urine was diluted with aqueous buffer solution. The column eluate was monitored at 250 nm. Validation of the method yielded satisfactory results for serum (and urine); detection limit 0.07 mg/l (2.4), lower limit of quantitation 0.14 mg/l (4.7), linear range 20 mg/l (500), imprecision within series (c.v.) 1.8-2.5% (0.8-1.0), imprecision between series (c.v.) 1.8-9.3 (0.4-9.3), recovery 99-102% (93-103). Comparison of HPLC results with results obtained using a quantitative microbiological assay yielded acceptable agreement both for serum and urine. The method was successfully used in a pharmacokinetic study with human volunteers.

Atovaquone nanosuspensions show excellent therapeutic effect in a new murine model of reactivated toxoplasmosis.

Immunocompromised patients are at risk of developing toxoplasma encephalitis (TE). Standard therapy regimens (including sulfadiazine plus pyrimethamine) are hampered by severe side effects. While atovaquone has potent in vitro activity against Toxoplasma gondii, it is poorly absorbed after oral administration and shows poor therapeutic efficacy against TE. To overcome the low absorption of atovaquone, we prepared atovaquone nanosuspensions (ANSs) for intravenous (i.v.) administration. At concentrations higher than 1.0 microg/ml, ANS did not exert cytotoxicity and was as effective as free atovaquone (i.e., atovaquone suspended in medium) against T. gondii in freshly isolated peritoneal macrophages. In a new murine model of TE that closely mimics reactivated toxoplasmosis in immunocompromised hosts, using mice with a targeted mutation in the gene encoding the interferon consensus sequence binding protein, i.v.-administered ANS doses of 10.0 mg/kg of body weight protected the animals against development of TE and death. Atovaquone was detectable in the sera, brains, livers, and lungs of mice by high-performance liquid chromatography. Development of TE and mortality in mice treated with 1.0- or 0.1-mg/kg i.v. doses of ANS did not differ from that in mice treated orally with 100 mg of atovaquone/kg. In conclusion, i.v. ANSs may prove to be an effective treatment alternative for patients with TE.

Ecological effects of linezolid versus amoxicillin/clavulanic acid on the normal intestinal microflora.

Twelve healthy subjects (6 females, 6 males; age range 18-40 y) participated in this trial. Linezolid was given as 600 mg tablets b.i.d. for 7 d and amoxicillin/clavulanic acid as 1000 mg tablets o.d. for 7 d. The washout period between the administration of the 2 antibacterial agents was 4 weeks. Faecal samples were collected prior to administration (Days -2 and -1), during administration (Days 4 and 8) and after administration (Days 14, 21 and 35) for microbiological analyses. The samples were diluted in pre-reduced media and inoculated aerobically and anaerobically on non-selective and selective media. Different colony types were identified to genus level by morphological, biochemical and molecular analyses. During the administration of linezolid, enterococci in the intestinal aerobic microflora were markedly suppressed while Klebsiella organisms increased in number. In the anaerobic microflora, the numbers of bifidobacteria, lactobacilli, clostridia and Bacteroides decreased markedly while no impact on the other anaerobic bacteria was observed. The microflora was normalized in all volunteers after 35 d. Amoxicillin/clavulanic acid administration caused increased numbers of enterococci and Escherichia coli in the aerobic intestinal microflora while numbers of bifidobacteria, lactobacilli and clostridia decreased significantly. Clostridium difficile strains were recovered from 3 of the volunteers. At the last visit, the intestinal microflora of the volunteers had returned to normal levels. The administration of linezolid mainly had an impact on the gram-positive bacteria and linezolid thus had an ecological profile different from that of amoxicillin/clavulanic acid.

Comparative pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, trovafloxacin, and moxifloxacin after single oral administration in healthy volunteers.

In an open, randomized, six-period crossover study, the pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin were compared after a single oral dose in 12 healthy volunteers (6 men and 6 women). The volunteers received 250 mg of ciprofloxacin, 400 mg of gatifloxacin, 600 mg of grepafloxacin, 500 mg of levofloxacin, 400 mg of moxifloxacin, and 200 mg of trovafloxacin. The concentrations of the six fluoroquinolones in serum and urine were measured by a validated high-performance liquid chromatography method. Blood and urine samples were collected before and at different time points up to 48 h after medication. Levofloxacin had the highest peak concentration (C(max), in micrograms per milliliter) (6.21+/-1.34), followed by moxifloxacin (4.34+/-1.61) and gatifloxacin (3.42+/-0.74). Elimination half-lives ranged from 12.12+/-3.93 h (grepafloxacin) to 5.37+/-0.82 h (ciprofloxacin). The total areas under the curve (AUC(tot), in microgram-hours per milliliter) for levofloxacin (44.8+/-4.4), moxifloxacin (39.3+/-5.35), and gatifloxacin (30+/-3.8) were significantly higher than that for ciprofloxacin (5.75+/-1.25). Calculated from a normalized dose of 200 mg, the highest C(max)s (in micrograms per milliliter) were observed for levofloxacin (2.48 +/-0.53), followed by moxifloxacin (2.17+/-0.81) and trovafloxacin (2.09+/-0.58). The highest AUC(tot) (in microgram-hours per milliliter) for a 200-mg dose were observed for moxifloxacin (19.7+/-2.67) and trovafloxacin (19.5+/-3.1); the lowest was observed for ciprofloxacin (4.6+/-1.0). No serious adverse event was observed during the study period. The five recently developed fluoroquinolones (gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin) showed greater bioavailability, longer half-lives, and higher C(max)s than ciprofloxacin.

Metabolism of ifosfamide to chloroacetaldehyde contributes to antitumor activity in vivo.

Metabolic activation of ifosfamide (IFO) leads to the active 4-hydroxy-metabolite and to a substantial liberation of chloroacetaldehyde (CAA). CAA has been presumed responsible for side effects of IFO. We recently have shown cytotoxic effects of CAA against human tumor cells in vitro. The aim of this study was to demonstrate antitumor effects of CAA in vivo, and to compare its potency to 4-OH-IFO. Pharmacokinetics of IFO and metabolites were evaluated after infusion of 250 mg/kg IFO in mice. The area under the curve (AUC) for 4-hydroxyifosfamide (4-OH-IFO) and CAA were 138. 5 and 102.4 micromol. h/liter, respectively. To compare pharmacokinetics and antitumor effects, the mice received isolated infusion of 4-OH-IFO or CAA in equimolar doses to IFO. Administration of 4-OH-IFO yielded AUC values comparable with those obtained after administration of the parent drug. In contrast, infusion of isolated CAA via tail vein gave a low AUC value of 51.5 micromol. h/liter due to slow flow in the tail vein and rapid degradation. Administration of the parent drug gave highly cytotoxic intratumoral peak concentrations of 25 and 12 micromol/kg tumor weight for 4-OH-IFO and CAA in MX1 xenotransplanted nude mice. Both IFO and isolated 4-OH-IFO led to complete remissions. Administration of isolated CAA (75 mg/kg) delayed tumor growth significantly. The equitoxic dose of isolated 4-OH-IFO was 40 mg/kg. On a molar basis CAA was seven times less potent as 4-OH-IFO. However, on the basis of achieved AUC values, CAA seems to exhibit a similar antitumor activity to 4-OH-IFO.

Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection.

Clofazimine nanosuspensions were produced by high pressure homogenization and the formulation was optimized for lyophilization. Characterization of the product by photon correlation spectroscopy, laser diffraction and Coulter counter analysis showed that the clofazimine nanosuspensions were suitable for iv injection with a particle size permitting passive targeting to the reticuloendothelial system. Following iv administration to mice of either the nanocrystalline or a control liposomal formulation at a dose of 20 mg clofazimine/kg bodyweight, drug concentrations in livers, spleens and lungs reached comparably high concentrations, well in excess of the MIC for most Mycobacterium avium strains. When C57BL/6 mice were experimentally infected with M. avium strain TMC 724, nanocrystalline clofazimine was as effective as liposomal clofazimine in reducing bacterial loads in the liver, spleen and lungs of infected mice. Nanocrystalline suspensions of poorly soluble drugs such as riminophenazines are easy to prepare and to lyophilize for extended storage and represent a promising new drug formulation for intravenous therapy of mycobacterial infections.

Determination of trovafloxacin in human body fluids by high-performance liquid chromatography.

For the quantitative determination of trovafloxacin (a new naphthyridinone antibacterial agent) in serum and urine a simple isocratic HPLC method with fluorimetric detection is described. Serum was deproteinised with a mixture of acetonitrile and perchloric acid. The protein-free extract was separated on a reversed-phase column (Nucleosil 100-5 C18) and quantified by means of fluorescence (excitation 275 nm, emission 405 nm). The mobile phase consisted of a mixture of 250 ml acetonitrile and 750 ml distilled water containing 10 mmol/l tetrabutylammonium phosphate. Urine was diluted with 0.25 mol/l phosphoric acid 1:20 (v/v) which was adjusted to pH 3.6 with sodium hydroxide solution. Diluted urine samples were separated on a cation-exchange column (Nucleosil 100-5 SA) and also detected by means of fluorescence. Trovafloxacin was sufficiently separated from endogenous compounds. Results of validation are given. The method was applied successfully to a study of healthy volunteers.

HPLC determination of clofazimine in tissues and serum of mice after intravenous administration of nanocrystalline or liposomal formulations.

A simple HPLC method is described for the determination of clofazimine in mouse tissues and in serum. The main application of the method was the determination of the drug in mouse tissues after i.v. administration of nanocrystalline suspensions or liposomal encapsulated clofazimine. Tissues were extracted with a 10-fold (w/v) volume of an extraction solution consisting of methanol/glacial acetic acid 9:1 (v/v). Serum proteins were precipitated with a 2-fold volume of acetonitrile. Isocratic chromatography was performed using an anion exchange column (Nucleosil 100-5 SA, Macherey & Nagel) for separation. The mobile phase was a mixture of acetonitrile and 0.1 mol/l aqueous phosphoric acid (75:25, v/v), adjusted to pH 2.9 with sodium hydroxide solution. Absorption of the eluate was monitored at 495 nm. The assay was precise, simple to perform and fast. Recovery from tissues was > or = 98%, from nanoparticles > or = 98%, and from liposomes > or = 96%. No interference was observed in extracts from mouse liver, spleen, lungs and human serum.

Pharmacodynamics of fluoroquinolones.

Fluoroquinolone antimicrobial agents are highly active against aerobic or facultative gram-negative bacilli. The fluoroquinolones have been shown to be very concentration dependent in their rates of killing and also have a postantibiotic effect against most gram-negative pathogens. These properties resemble those of aminoglycosides more than those of the beta-lactam antibiotics. In animal studies, once daily administration of a dose that produced a high peak concentration/minimal inhibitory concentration (MIC) ratio of > 10-20:1 resulted in significantly better survival than did regimens in which the same daily dose was used on a more fractionated schedule. Studies in patients, most often with ciprofloxacin, demonstrated that the area under the concentration-time curve (AUC)/MIC ratio (AUIC) is the most important predictor of both clinical and microbiological cure. These findings, when combined with microbiological and pharmacokinetic data, provide the rationale and tools needed for targeting the dosage of fluoroquinolones to individual patients on the basis of pharmacokinetics and the susceptibilities of the bacterial pathogens.

Chondrotoxicity and toxicokinetics of sparfloxacin in juvenile rats.

Sparfloxacin is a fluoroquinolone with improved antibacterial activity against gram-positive pathogens. Like other quinolones, use of this drug is contraindicated in children and adolescents because of its potential chondrotoxicity in juveniles. We performed histological and immunohistochemical studies on the knee joint cartilage in 5-week-old rats after treatment with 600 or 1,800 mg of sparfloxacin/kg of body weight. Treatment with single or multiple oral doses of 600 mg of sparfloxacin/kg was not sufficient to induce joint cartilage lesions. However, five of eight rats treated with a single oral dose of 1,800 mg of sparfloxacin/kg of body weight showed typical cartilage lesions in the femoral part of the knee joint. The concentrations of the drug in plasma measured 0.25, 0.75, 1.5, 3, 6, 12, and 24 h after the administration of an oral dose of 600 mg of sparfloxacin/kg were 6.3 +/- 1.8, 9.2 +/- 1.7, 9.6 +/- 2.7, 13.0 +/- 1.8, 12.3 +/- 1.6, 3.4 +/- 0.4, and 0.30 +/- 0.20 mg/liter, respectively (mean +/- standard deviation [SD]; n = 5 to 6 per group). The concentrations in plasma measured 0.75, 1.5, 3, 6, 24, and 48 h after the administration of an oral dose of 1,800 mg of sparfloxacin/kg were 10.9 +/- 1.5, 15.9 +/- 1.6, 19.1 +/- 1.7, 14.9 +/- 3.1, 4.1 +/- 0.6, and 0.46 +/- 0.37 mg/liter, respectively (mean +/- SD; n = 3 to 4 per group). The concentrations of sparfloxacin in joint cartilage were significantly higher at all time points studied (114.8 +/- 80, 99.4 +/- 31.5, 84.9 +/- 16.8, 44.4 +/- 13.9, and 14.2 +/- 4.8 mg of sparfloxacin/kg at 1.5, 3, 6, 24, and 48 h after the administration of 1,800 mg/kg, respectively). The range of concentrations in bone were similar to the range of concentrations in cartilage (peak, 115 +/- 12 mg/kg after 3 h). Our data indicate that chondrotoxic doses of sparfloxacin in juvenile rats are approximately 300 times higher than the doses of sparfloxacin used therapeutically (1,800 versus approximately 6 mg/kg of body weight), but due to species differences in kinetics, concentrations in plasma differ by a factor of only approximately 15. More data on quinolone concentrations in cartilage from animals and humans could provide a better basis for a reasonable risk assessment.

Surface-modified amikacin-liposomes: organ distribution and interaction with plasma proteins.

Amikacin-loaded liposomes were produced and surface-modified by adsorption of PEG 4000, Tween 80, poloxamer 407 and gelatin. The organ distribution was studied in mice by analysing the amikacin content in liver, spleen, lung, kidneys and serum. Highest serum levels were obtained with the PEG- and Tween 80 modified liposomes (at 2 hours p.inj.). Modification of the liposomes with gelatin as opsonization promoting agent distinctly increased the amikacin concentration in the liver from 36 to 66 mg/kg. Highest spleen concentrations were observed with non-modified and poloxamer 407 liposomes (242 mg/kg and 248 mg/kg, respectively). The data suggest that modification by a simple adsorption process is sufficient to effectively alter the organ distribution. The liposomes differing in organ distribution exhibited also different plasma protein adsorption patterns, up to 115 spots were detected by 2-D PAGE. Hydrophilic albumin was present in a conc. of appr. 80% on liposomes modified with ethoxylated compounds. On the gelatin liposomes, 14% of alpha-2-Macroglobulin were adsorbed which is a protein typically found on particles rapidly cleared by the RES. IgM, Apo A-I, Apo C-II and alpha-1-Antitrypsin were other detected proteins.

Rationale for and efficacy of prolonged-interval treatment using liposome-encapsulated amikacin in experimental Mycobacterium avium infection.

The potential of liposome-encapsulated antibiotics for prolonging drug application intervals was investigated by using a murine model of chronic lethal Mycobacterium avium infection. Liposomal encapsulation of amikacin, but not of ciprofloxacin, resulted in high and sustained drug levels in infected tissues, exceeding the minimal inhibitory concentration for M. avium for at least 28 days. As a consequence, once-weekly and even once-monthly treatments with liposomal amikacin significantly reduced bacterial replication in infected tissues and extended the survival time of infected mice.

Pharmacokinetics of sparfloxacin and interaction with cisapride and sucralfate.

In an open, randomized, triple crossover study, the effects of cisapride and sucralfate on the pharmacokinetics of sparfloxacin were assessed. Fifteen healthy volunteers received 400 mg of sparfloxacin as a single oral dose on day 0. In a random order, concomitant doses of 10 mg of cisapride three times daily from day -2 to day 2 and 1 g of sucralfate four times daily from day -2 to day 0 were administered. Sparfloxacin concentrations were measured by bioassay and high-performance liquid chromatography. Pharmacokinetic parameters for sparfloxacin alone were as follows (mean +/- standard deviation): maximum concentration of drug in serum (C(max)), 1.27 +/- 0.39 microg/ml; time to C(max) (T(max)), 4.1 +/- 1.9 h; area under the concentration-time curve (AUC), 35.0 +/- 9.7 microg x h/ml; mean residence time, 28.5 +/- 5.7 h; half-life (t1/2), 20 +/- 4 h; urinary recovery (UR x f), 11.0% +/- 2.7%; and metabolite-sparfloxacin ratio in urine, 2.6. For the cisapride group there was a significant decrease in the sparfloxacin T(max) (1.9 +/- 2.1 h) and a significant increase in C(max) (1.74 +/- 0.73 microg/ml). The QTc interval for patients receiving sparfloxacin and cisapride was prolonged by 7.7% compared to the QTc interval during medication-free periods. Significant differences in the values for the group receiving sucralfate compared to the values for the group receiving sparfloxacin alone were found: C(max), 0.77 +/- 0.31 microg/ml; AUC, 18.6 +/- 5.8 microg x h/ml; t1/2, 26 +/- 10 h; and UR x f, 5.8 +/- 1.8%. Concomitant adminstration of cisapride accelerates the absorption and increases the peak concentration of sparfloxacin without having a significant effect on the extent of bioavailability. Coadministration of sucralfate leads to a 44% decrease in the bioavailability of sparfloxacin.

Penetration of sparfloxacin and ciprofloxacin into alveolar macrophages, epithelial lining fluid, and polymorphonuclear leucocytes.

Sparfloxacin (SPX), a novel fluoroquinolone with a broad spectrum of antibacterial activity, has been shown, in vitro, to be more effective against common pulmonary pathogens, particularly Streptococcus pneumoniae, Mycoplasma pneumoniae and some intracellular organisms, than ciprofloxacin (CPX). The objective of this open, comparative, randomized study in two parallel groups was to assess the serum concentrations and penetration of SPX and CPX into alveolar macrophages (AMs), epithelial lining fluid (ELF), and peripheral polymorphonuclear leucocytes (PMNs). Patients received either a single oral dose of SPX, 400 mg (16 patients), or CPX, 500 mg (15 patients), at various times before a routine diagnostic bronchoscopy was performed. Antibiotic concentrations were determined by using a microbiological assay. The median serum elimination half-lives were 17.3 h for SPX and 5.3 h for CPX. Peak levels (median+/-68% confidence range) of CPX were attained in AMs (7.6+/-1.7 mg x L(-1)) at 5 h after admission, and in both ELF (2.13+/-0.91 mg x L(-1)) and PMNs (9.1+/-6.2 mg x L(-1)) at 2.5 h after administration. SPX achieved comparable peak levels in PMNs (median+/-68% range, 9.4+/-1.1 mg x L(-1) at 5 h), but peak concentrations attained in AMs and ELF (35.1+/-15.4 and 32.2+/-28.2 mg x L(-1), respectively, at 24 h) were several times higher than those of CPX. SPX demonstrated substantially greater accumulation in all three sites than did CPX (peak site to serum ratios of 11.0+/-4.3, 65.5+/-28.4 and 63.0+/-66 versus 4.94+/-0.64, 10.6+/-3.7 and 10.6+/-3.7 for PMNs, AMs and ELF, respectively). The results indicate, that sparfloxacin has a long elimination half-life and that it achieves higher concentrations in alveolar macrophages and epithelial lining fluid than ciprofloxacin. Site concentrations of sparfloxacin greatly exceeded the minimal inhibitory concentrations of common respiratory pathogens.

Dosage adjustment of antiinfective therapy in patients with renal impairment.

Schematic dosage adjustments for aminoglycosides, vancomycin, and ciprofloxacin were derived from published data on the prolongation of elimination half-lives in patients with renal impairment. Therapeutic drug monitoring was retrospectively evaluated with 84 severely ill patients, 29 of whom needed renal replacement therapy (35%). Mortality (n = 27) and antiinfective failures were high (n = 23). Toxicity was suspected in 5 patients, though it was demonstrated only in 1 case. As compared to the patients with normal renal function, patients with renal impairment exhibited peak levels that tended to be lower, although their trough levels tended to be higher; the aminoglycoside troughs even were significantly elevated in renal replacement patients (1.0 mg/l (0.6-1.4) versus 0.6 mg/l (0.3-0.8)). Seen in relation to toxicity, antiinfective failure was by far the greater problem even with dosage adjustments at high trough levels. Multivariate analysis showed antiinfective failure to be significantly correlated to 10 canonical variables (age, weight, leucocyte count, peak level, trough level, initial creatinine, increase in creatinine, fever, change of dosage, and renal replacement therapy). Among these variables, it were neither drug levels nor renal replacement, but only persistent fever and deteriorating renal function that independently contributed to antiinfective failure. For adjustment of antiinfective therapy, paradoxically we conclude that trough concentrations higher than normal must be allowed for to avoid underdosage in renal replacement patients.

Comparative pharmacokinetics of dirithromycin and erythromycin in normal volunteers with special regard to accumulation in polymorphonuclear leukocytes and in saliva.

OBJECTIVE: In a randomized cross-over study, we assessed pharmacokinetics and intracellular concentrations in polymorphonuclear leukocytes (PMN) and saliva of erythromycin and erythromycylamine, the active metabolite of dirithromycin. METHODS: Ten healthy volunteers received 1 g erythromycin b.i.d. or 500 mg dirithromycin qd for 5 days (wash out period, 35 days). Concentrations of erythromycin and erythromycylamine were measured in serum, urine, saliva, and granulocytes by bioassay and high-performance liquid chromatography (HPLC) on days 1, 3, and 5 of each study period, respectively. RESULTS: While maximal serum concentrations (Cmax) and the area under the data (AUDtot) of erythromycin were significantly higher (Cmax 1.44 mg.l-1, AUDtot 5.66 mg.h.l-1) than those of erythromycylamine (Cmax 0.29 mg.l-1, AUDtot 1.96 mg.h.l-1), erythromycylamine had a significantly higher mean residence time (21 h) than erythromycin (5.5 h). Erythromycylamine accumulated significantly more in PMN than erythromycin; the accumulation factor of erythromycylamine was 100 with a maximal intracellular concentration of 13.4 mg.l-1, whereas the maximal accumulation factor of erythromycin was 4 with a maximal intracellular concentration of 6.1 mg.l-1. There were no significant differences in maximal saliva concentrations (erythromycin 0.35 mg.l-1, erythromycylamine 0.31 mg.l-1).