Klaus Borner

Pharmacokinetics of ciprofloxacin after oral and parenteral administration.

In 12 fasting volunteers, the pharmacokinetics of ciprofloxacin (Bay o 9867; 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carbonic acid) were determined after the administration of 50, 100, and 750 mg orally as well as 50 and 100 mg intravenously over 15 min. Serum and urine concentrations were detected with a bioassay. In addition, urine concentrations after a 50-mg dosing were measured by high-pressure liquid chromatography. The serum course of ciprofloxacin could best be described by an open three-compartment model. High volumes of distribution (exceeding 200 liters/100 kg) suggested effective diffusions in the extravascular space. The terminal half-life of ciprofloxacin ranged between 3 and 4 h. High total and renal clearances suggested additional elimination pathways, such as tubular secretion, metabolism, or biliary excretion. After oral administration, absorption was sufficient, and the absolute bioavailability varied between 0.77 and 0.63. Maximal serum concentrations were attained 0.5 to 1 h after dosing; the higher dosage tended towards a delay in absorption. The proportion of the relative amount of metabolites to the total amount of drug excreted in urine increased from 29.7% after intravenous administration to 42.7% after oral dosing, indicating a first-pass effect of the liver. Ciprofloxacin concentrations with a bioassay were 3 to 27% higher than with high-pressure liquid chromatography, which may indicate the presence of biologically active metabolites. No side effects were recorded.

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.

Comparative Pharmacokinetics of Ciprofloxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Trovafloxacin, and Moxifloxacin after Single Oral Administration in Healthy Volunteers

ABSTRACT 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 (Cmax, 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 (AUCtot, 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 highestCmaxs (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 AUCtot (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 Cmaxs than ciprofloxacin.

Pharmacokinetics of ofloxacin after parenteral and oral administration.

In 10 volunteers, the pharmacokinetics of ofloxacin [HOE 280, DL 8280; (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido-[1,2,3-de] [1,4]benzoxacine-6-carboxylic acid] was determined after administration of 25, 50, 100, and 200 mg intravenously (30-min infusion) as well as 200 and 400 mg orally. Concentrations in serum and urine were measured by high-pressure liquid chromatography. Concentrations in serum following different parenteral ofloxacin dosages demonstrated dose dependency with long biological half-lives of 231 to 267 min. Pharmacokinetic parameters were calculated on the basis of open two- and three-compartment models, which yielded nearly identical results. High volumes of distribution (1.2 to 1.4 liters/kg of body weight) suggested effective diffusion into the extravascular space. High total and renal clearances indicated primarily renal excretion with additional elimination pathways, such as tubular secretion and extrarenal elimination. After oral administration, absorption was excellent, and the absolute bioavailability following 200 mg of ofloxacin could be calculated at greater than 0.95. Maximal concentrations in serum were attained 1.2 to 1.9 h after dosing; areas under the curve increased in proportion to dose between 200 and 400 mg of oral ofloxacin. The amount of known metabolites (demethyl and N-oxide compounds) excreted in urine reached only 4.3% (intravenously) and 4.0% (orally). Transient headaches in some volunteers were the only side effects registered.

Regular Analgesic Intake and the Risk of End-Stage Renal Failure

The strength of the association between regular analgesic intake (RAI) and end-stage renal failure (EF) has been insufficiently established until now. A case-control study was conducted to estimate the relative risks (RR) of EF after RAI (defined as consumption of 15 or more analgesic doses per month for a continuous period of at least 1 year) for cumulative drug intake, single-ingredient analgesics, combinations, and specific compounds. The case group included all patients with EF undergoing renal replacement therapy in the area of West Berlin (1984-1986, n = 921). Control subjects, matched to cases by sex, age, and nationality, were selected from a group of patients in outpatient clinics. Matching was possible for 517 cases. The RR of EF after RAI of any analgesic was 2.44 (95% confidence interval: 1.77-3.39) and after RAI of combination drugs 2.65 (95% confidence interval 1.91-3.67). No significant increase was found, however, after RAI of single-ingredient analgesics. The RR after RAI of combination drugs and for the most preferred analgesic ingredients (phenacetin, paracetamol, acetylsalicylic acid, phenazones, caffeine) increased with dose. Furthermore, a dose-time-related RR after RAI of the longest used preparation was found. Thus, the results clearly show an increased RR of EF after RAI related to both dose and exposure time of mixed analgesic compounds, but not for the use of only single-ingredient analgesics.

Pharmacokinetics of Ciprofloxacin in Healthy Volunteers after Oral and Intravenous Administration

The pharmacokinetics of ciprofloxacin was studied in three groups of healthy volunteers comprising a total of 16 males and 16 females (age 21–35 years; body weight 52–80 kg). Single oral doses of 50, 100, 250, 500 and 750 mg were given to fasting subjects. The 250 mg dose was repeated after a breakfast. Intravenous doses of 50, 100 and 200 mg were given by short infusion in a randomized cross-over sequence. Concentrations of the drug in serum and urine were determined by high-performance liquid chromatography and by a microbiological assay. Mean peak concentrations between 0.37±0.49 mg/l (100 mg dose) and 1.97±0.50 (750 mg dose) were measured 60–75 min after oral administration. Twelve hours after 750 mg ciprofloxacin, serum concentrations were 0.15±0.05 mg/l. Taking a breakfast reduced absorption by 15–20% compared to the fasting state, as judged by peak concentrations, AUC and renal excretion. After 200 mg i. v. (20 min infusion period), initial serum concentrations of 4.0±1.2 mg/l were observed which declined 12 h later to 0.070±0.025 mg/l. Mean cumulated recovery of ciprofloxacin from urine over 24 h varied between 25.5% and 33.6% of oral doses and between 53.2% and 57.4% of intravenous doses. Two of the three metabolites seen in the chromatograms were identified as M1 and M3 (oxo-ciprofloxacin). Cumulated renal excretion after an oral 250 mg dose was 1.2±0.4% of M1 and 5.5±1.6% of M3. Bioavailability of oral doses varied from 0.64±0.16 (100 mg) to 0.52±0.11 (500 mg). The AUC was linearly proportional to a single dose of up to 250 mg. Ciprofloxacin was rapidly absorbed and distributed. High distribution volumes were calculated (mean VDarea 186–217 1). The terminal half-life (t1/2β) was 3.1 to 5.4 h. Mean total body clearance was also high (600 to 693 ml/min · 70 kg)). Tolerance of ciprofloxacin was good for all oral doses and for intravenous administration up to 100 mg per dose. Intravenous infusion of 200 mg ciprofloxacin caused transient local irritation.

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.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.

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.

Prospective randomized controlled study of ciprofloxacin versus imipenem-cilastatin in severe clinical infections.

In a randomized prospective study, 66 patients with serious bacterial infections--mainly lower respiratory tract infections--were treated with either imipenem plus cilastatin (32 patients) or ciprofloxacin (34 patients); 30 patients in each group were evaluable for efficacy. Substantial underlying disease was present in most of the patients; pathogens isolated prior to treatment (77 isolates) consisted mainly of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and streptococci. Of the etiologic bacteria, 67% were eradicated by ciprofloxacin treatment and 79% by imipenem therapy; however, two patients (6.7%) failed in the ciprofloxacin group, and six patients (20%) did not respond to imipenem treatment (P = 0.25). All patients with therapeutic failures suffered from severe fatal underlying diseases, which had substantial impact on the outcome of treatment. Therapeutic drug monitoring in the ciprofloxacin patients revealed higher concentrations in serum at days 4 and 8 in comparison with day 1 of treatment, indicating that steady-state conditions were reached between days 1 and 4. The total number of side effects was relatively high--eight imipenem patients (25%) and six ciprofloxacin patients (18%) had reactions. Treatment had to be discontinued due to adverse reactions for three ciprofloxacin patients and two imipenem patients. Major side effects in both groups were gastrointestinal and central nervous system-related symptoms. In terms of clinical and bacteriological efficacy and safety, there was no statistical difference between the two groups, and both groups gave good to excellent results for bacterial infections that were difficult to treat.

Rationale for and Efficacy of Prolonged-Interval Treatment Using Liposome-Encapsulated Amikacin in Experimental Mycobacterium avium Infection

ABSTRACT 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.