G. Höffken

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.

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.

Reduced Enteral Absorption of Ciprofloxacin in the Presence of Antacids

Sir, Ciprofloxacin, a new quinoline carboxylic acid derivative, has high in vitro activity against a wide range of pathogens including members of the family Enterobacteriaeeae and Pseudomonas aeruginosa (1). The pharmacokinetics after oral administration of the drug are characterized by rapid absorption, good diffusion into the extracellular space, and elimination by biliary excretion, hepatic metabolism, glomerular filtration and tubular secretion (2). In a study in fasting volunteers the absolute bioavailability ranged from 0.63 to 0.77, and the cumulative urinary excretion of unmetabolized drug in 24-hour-urine accounted for approximately 35 % of the initial oral dose (2). To assess the effect of antacids on intestinal absorption of oraily administered ciprofloxacin, we performed a randomized study in ten healthy volunteers (5 females, 5 males, mean age 30 years, mean body weight 67.5 kg) who were given 500 mg ciprofloxacin orally either in a fasting state or 24 h after administration of the antacid 10 x8d 600 mg Mg-OH + 900 mg A1-OH (Maalox). Serum and urine concentrations were determined by a bioassay and high performance liquid chromatography. The pharmacokinetic parameters were calculated using an open two-compartment model. Administration of the antacid led to a pronounced decrease of the peak serum concentration from a mean of 1.7 mg/l (range 1.3-2.6 mg/l) after ciprofloxacin alone to a mean of 0.1 mg/1 (range 0.06-0.2 mg/1) after ciprofloxacin plus antacid (p < 0.001). The time after which the serum concentration peaked was only slightly prolonged (73 -+ 13 min versus 87 + 21 min). The cumulative urinary excretion of unmetabolized ciprofloxacin in 24-hour-urine after ciprofloxacin administered alone accounted for 24% (range 1934 %) of the administered dose as against only 2.1% (range 0.9-4.7 %) after prior administration of the antacid. A possible explanation for the reduced absorption rate of ciprofloxacin administered after the antacid is that Mg +§ or AI +++ chelates form. In fact, chelate complexes of the drug with Mg +§ have been reported to reduce bactericidal concentrations of ciprofloxacin tested in nutrient broth against Escherichia coli KL16 (3). In addition, association constants for Mg** complexes of nalidixic and oxolinic acid, analogous substances, were reported to be 3.0 and 3.3 respectively. The diminished absorption of eiprofloxacin seen in our study could be explained by a reduced rate of absorption of the Mg ++ and AI ~* ciprofloxacin chelate complexes. To date it has been difficult to assess the significance of the chelates on absorption. Nevertheless, the pronounced effect of antacids on the bioavailability of ciprofloxacin should be considered if both these drugs are administered to a patient. Furthermore, all other new quinoline derivatives should be tested for such interaction with antacid drugs.

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.

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.

Application of the polymerase chain reaction in the diagnosis of pulmonary toxoplasmosis in immunocompromised patients

Bronchoalveolar lavage (BAL) fluid from 47 immunocompromised patients (26 with AIDS and 21 patients on immunosuppressive therapy) was analysed for the presence ofToxoplasma gondii DNA by means of the polymerase chain reaction (PCR). Specific target DNA derived from the B1 and P30 gene ofToxoplasma gondii was detected in BAL fluids from three patients with AIDS (6.4%). Pneumonia as the presenting feature of disseminated toxoplasmosis was confirmed by both clinical findings and by detection ofToxoplasma gondii DNA in blood obtained from two patients. The findings indicate that PCR has potential value in the detection ofToxoplasma gondii as an etiologic agent of atypical pneumonia in immunocompromised patients.

Comparative Pharmacokinetics of New Quinolones

SummaryThe pharmacokinetic properties of the new quinolones are characterised by a high volume of distribution, long biological half-life, low serum protein binding, elimination mainly by the kidneys, high total and renal clearances, limited biotransformation and a moderate to excellent bioavailability after oral administration. However, each quinolone derivative (ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin) possesses individual pharmacokinetic characteristics, which should be considered in the treatment of patients, especially when liver and/or renal dysfunction exists.

Pharmacokinetics and serum bactericidal activity of vancomycin alone and in combination with ceftazidime in healthy volunteers.

The pharmacokinetics and serum bactericidal activity of vancomycin alone and in combination with ceftazidime were investigated in 10 healthy volunteers. The pharmacokinetic parameters showed no significant differences (P less than 0.05) between single and combined administration. No antagonistic effects were observed in serum bactericidal activity with the combination against 20 gram-positive and 20 gram-negative locally isolated bacteria. A titer of greater than or equal to 1:8 was generated by the combination against all test strains except enterococci. Seven of ten volunteers developed a typical red mans syndrome during the administration of 1.0 g of vancomycin.

Pharmacokinetic studies of amoxicillin, potassium clavulanate and their combination

Pharmacokinetic parameters after oral administration of 500 mg amoxicillin, 125 mg potassium clavulanate and 625 mg of their combination (augmentin) were determined in a randomized crossover study in ten healthy volunteers. The absolute bioavailability of amoxicillin (AUCoral/AUCi.v.) was 0.70±0.12. The mean maximum serum concentration of amoxicillin was 6.5±1.6 mg/l after administration alone and 6.5±1.4 mg/l after administration in combination. The respective values for potassium clavulanate were 3.4±1.4 mg/l and 2.8±1.1 mg/l. With both substances there was no significant difference between the pharmacokinetic parameters after administration alone and in combination. The AUC for amoxicillin was 19.5±5.4 h×mg/l after administration alone and 23.2±10.6 h×mg/l after administration in combination. The respective values for potassium clavulanate were 7.8±3.2 h×mg/l and 7.3±2.0 h×mg/l.

Pharmacokinetics of roxithromycin and influence of H2-blockers and antacids on gastrointestinal absorption

The pharmacokinetics of roxithromycin (300 mg orally) and the influence of the antacid aluminum magnesium hydroxide and the H2-blocker ranitidine on bioavailability of roxithromycin in ten healthy volunteers were studied. Pharmacokinetics after a single dose of roxithromycin were characterized by high peak serum levels (9.1 ± 2.1 mg/l) and a long elimination half-life (7.2 ± 2.5 h), resulting in a large area under the curve (116.9 ± 32.7 mg h/l). High inter- and intraindividual variations were found for both the absorption time and the elimination half-life. The bioavailability of roxithromycin was not affected by coadministration with antacids or ranitidine.