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Background: Life-threatening infections with multiresistant gram-positive bacteria are increasing. Treatment with quinupristin/dalfopristin (Q-D) has turned out to be effective against such resistant pathogens., Patients and Methods: We report on treatment of six patients on dialysis (four with additional liver injury) and of one renal graft recipient with normal renal function who had severe infections caused by multiresistant Staphylococus epidermidis (1/7), methicillin-resistant Staphylococcus aureus (4/7) and vancomycin-resistant Enterococcus faecium (2/7)., Results: Six out of seven patients were cured by therapy with Q-D in adjusted doses lasting for 10 to 34 days. Pharmacokinetics of Q-D and its metabolites were determined and remained within the therapeutic range, despite a modest increase of all compounds at the presumed steady state. The concentrations of the metabolites of Q-D were clearly lower than the parent drugs, including those of quinupristin-conjugated derivatives, which has not been reported previously., Conclusion: These preliminary results suggest that: a) neither quinupristin nor dalfopristin or its metabolites accumulated despite the long duration of treatment; b) no adjustment of the standard dosage regimen (three times 7.5 mg/kg/day) is necessary in end-stage renal disease.

Cefodizime (CAS 69739-16-8, HR 221) is a new third-generation cephalosporin with pharmacokinetic properties that make it suitable for once-daily administration in the treatment of lower respiratory tract infections (LRTI). Ninety-nine adult hospitalized patients (66 males, 33 females, median age 57.5 years) received a once-daily injection of 2 g cefodizime for LRTI. Median treatment duration was 8 days. Forty-two patients received cefodizime intravenously and 57 intramuscularly. Indications for treatment were as follows; primary lobar pneumonia (n = 36), bronchopneumonia (n = 14), secondary pneumonia (n = 3), aspiration pneumonia (n = 5), acute exacerbation of chronic bronchitis (n = 21), and of bronchiectasis (n = 9) and acute purulent bronchitis (n = 11). General condition was good in 29 patients and poor in 58; 12 patients were critically ill. The following pathogens were isolated at baseline (source: bronchial secretions, sputum or blood): S. pneumoniae (n = 47), Haemophilus spp. (n = 17), M. catarrhalis (n = 6), Streptococcus spp. (n = 9), Staphylococcus spp. (n = 5), Klebsiella spp. (n = 4), Pseudomonas spp. (n = 1), A. calcoaceticus (n = 1) and anaerobic organisms (n = 7). Fifty-nine patients were evaluable for bacteriological response and 82 for clinical response. Bacteriological outcome was satisfactory in 29/30 patients having LRTI with parenchymal involvement (97%) and in 29/29 patients without parenchymal involvement (100%). Clinical cure was achieved in 41/43 evaluable patients with parenchymal involvement (95%) and in 37/39 patients without parenchymal involvement (95%) in the per-protocol analysis and in 54/58 patients (93%) and 37/41 patients (93%), respectively, in the clinical intention-to-treat analysis. Three of the patients with an unsatisfactory clinical response died of infection during the study. Cefodizime was well tolerated. Adverse reactions--all of mild intensity--were tachycardia, lumbalgia and dizziness, each occurring in one patient. Cefodizime 2 g once daily either i.m. or i.v. was effective in the treatment of lower respiratory tract infections in hospitalized patients.

The safety and efficacy of two dose regimens of cefodizime (CAS 69739-16-8, HR 221) in hospitalized patients with lower respiratory tract infections were assessed in two consecutive studies. Sputum bacteriology, chest X-ray and a safety laboratory check were performed at baseline and after therapy. In order to compensate for the lack of a double-blind design the evaluation was conducted as a clinical intention-to-treat analysis. 32 patients (16 males, 16 females, mean age: 64 years) were admitted to study A and 42 subjects (30 males, 12 females, mean age: 66 years) to study B. The dosage regimens of cefodizime were 1 g b.i.d. (median 7 days) in study A and 2 g once daily (median 6 days) in study B. Parenchymal involvement was confirmed by chest X-ray in 56% of the patients in study A and 64% in study B, the remainder patients had acute exacerbations of chronic bronchitis with reasonable evidence of bacterial infection. The most frequent pathogens were Streptococcus pneumoniae and Haemophilus spp. The clinical cure rate was 97% in study A and 88% in study B. Eradication rates were 100% and 94%, respectively. No superinfection occurred. No adverse reactions were observed. In conclusion, a single daily injection of cefodizime 2 g achieved similar clinical and bacteriological cure rates to the standard dose regimen of 1 g b.i.d.

Cultured human bronchial epithelial cells (HBEC) produce both granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 8 (IL-8). The influence of cefodizime (CAS 69739-16-8), a new broad spectrum cephalosporin with immunostimulatory effects, and ceftriaxone on the production of GM-CSF and IL-8 in HBEC primary cultures was investigated. HBEC were isolated from biopsy specimens obtained during fibreoptic bronchoscopy in 12 patients (most frequent diagnosis: chronic bronchitis). Confluent monolayers of HBEC cultured on collagen were incubated for 24 h in a medium without study drugs (spontaneous production) or containing cefodizime or ceftriaxone at the clinically relevant concentrations of 1, 10 and 100 mg/l, with or without tumor necrosis factor alpha (TNF alpha, 100 U/ml). GM-CSF and IL-8 were measured in supernatant by ELISA technique. TNF alpha alone led to a significant (p < 0.005) increase in both GM-CSF and IL-8 production. Cefodizime induced a significant (p < 0.05), dose-dependent increase in GM-CSF release. No additive effect of cefodizime with TNF alpha was observed. Cefodizime did not affect IL-8 production and ceftriaxone had no influence on cytokine production. This is the first report of a stimulatory effect of a beta-lactam antibiotic on cytokine production by epithelial cells. GM-CSF production by epithelial cells is an important immunological step for neutrophil and monocyte recruitment and cell priming during lung defence. Previous studies with cefodizime in immunodepressed subjects have shown activation of phagocytosis and phagocytosis-related functions in non-lung phagocytes. An indirect mechanism of action, similar to that indicated by our results, may have been responsible for these stimulatory effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: The concentrations of cefodizime (HR 221, CAS 69739-16-8) in bronchial secretions were measured after administration of a single intravenous bolus of 2 g in 19 patients requiring fibreoptic bronchoscopy for diagnostic purposes or as therapeutic follow-up. These concentrations, which were obtained in absence of inflammation of the mucosa, were compared to serum concentrations obtained simultaneously. The penetration into bronchial secretions was rapid, maximum levels of between 1 and 5 mg/kg being already observed 1 h after injection. Most concentrations remained about 1 mg/kg throughout the whole observation period of about 5.5 h. The percent penetration amounted to about 1.5% of the corresponding serum concentrations., Conclusion: Concentrations well above the MIC90s of the relevant respiratory pathogens--S. pneumoniae, M. catarrhalis, H. influenzae, K. pneumoniae--and Enterobacteriaceae were reached in bronchial secretions after intravenous injection of a single 2 g dose of cefodizime. Even higher levels may be expected in the usual condition of inflamed bronchial mucosa as found in respiratory infections.

Twenty-three stabilized chronic uremic patients with no active or recent infection were treated for 10 days with either cefodizime (5 x 2 g intravenously, n = 10) or cotrimoxazole (960 mg orally b.i.d., n = 8) in order to evaluate the effects on the depressed polymorphonuclear metabolic response to phagocytic challenge; a separate group of 5 patients received placebo. Ex vivo evaluation in whole blood of energy delivery to the phagocytosis-associated respiratory burst activity in response to latex and zymosan challenge was determined by measuring hexose-monophosphate shunt NAD(P)H-oxidase-related glycolytic activity. Cefodizime induced a statistically significant increase in the baseline-depressed glycolytic response for both latex and zymosan challenge, in contrast to cotrimoxazole and placebo. Depressed phagocytosis-related metabolic function in hemodialyzed patients was stimulated by cefodizime in recommended therapeutic doses but not by cotrimoxazole, the effect persisting for at least 2 weeks after the end of treatment.

A positive effect of cefodizime (CAS 69739-16-8), a new aminothiazolyl cephalosporin, on a number of immunological variables, and in particular phagocytosis, was demonstrated in several test systems. The aim of the present investigation was to establish whether clinically relevant concentrations of cefodizime affect cell-mediated immune variables. Peripheral lymphocytes from healthy subjects were isolated and incubated with cefodizime in increasing concentrations from 0 to 200 mg/l. The effects of cefodizime on membrane-bound antigenic determinants of the lymphocytes were determined in the rosette inhibition test, and its effects on the proliferative capacity of lymphocytes after stimulation with phytohaemagglutinin, concanavalin A and pokeweed mitogen were determined in the lymphocyte transformation test. Cefodizime inhibited rosette formation in a concentration dependent manner. A direct inhibitory effect on proliferation was not, however, demonstrated in the lymphocyte transformation test. Indeed, stimulation of mitogen-induced lymphocyte transformation, particularly of concanavalin A-sensitive cells was observed at concentrations higher than 100 mg/l. The findings in healthy volunteers were reproduced in samples from three female patients with impaired host-defence. These results may suggest a positive effect of cefodizime on the proliferative capacity of the cellular immune system. However, no conclusions can be drawn on the clinical relevance of these findings until the results of in vivo investigations are available.

In this randomized dose range study conducted in Bangkok, 326 patients with presumed acute uncomplicated gonorrhoea were treated with a single intramuscular dose of either 0.25 g, 0.5 g, or 1.0 g of a new aminothiazole cephalosporin, cefodizime. One hundred and eighty men and 110 women were evaluable for efficacy. Pathogens were eliminated in all but 4 of these patients resulting in a cure rate of 99%, irrespective of dose, sex, or multiplicity of infected sites. A high percentage of the 290 strains of Neisseria gonorrhoeae isolated from the evaluable patients showed resistance to penicillin, and 40% were penicillinase producing (PPNG). The minimum inhibitory concentration of cefodizime for 90% of the PPNG strains was less than 0.04 mg/l. No clinically relevant adverse drug reactions were reported. This study demonstrates that a single 0.25 g dose of cefodizime is effective against both PPNG and non-PPNG strains in a geographic region characterized by high endemic antibiotic resistance.

The pharmacokinetics of cefodizime (CDZ) were determined after i.v. and i.m. administration of single doses of up to 2 g and after i.v. administration of 2 g b.i.d. for six days. Serum concentrations were adequately described by three exponential functions, with a terminal half-life of about 4 h. Serum and urine levels and amounts excreted were dose-proportional, and derived pharmacokinetic characteristics were dose-independent. Steady state was established after the second dose (b.i.d.). CDZ is 100% bioavailable after i.m. administration. Concomitant administration of lidocaine did not alter either bioavailability or pharmacokinetic characteristics. Following administration of 1 and 2 g i.m., Cmax was reached after 1.2 h and amounted to 60 and 140 mg/l, respectively. CDZ is 88% bound to plasma proteins. CDZ was predominantly eliminated by the kidneys (80% of dose), a further 20% being excreted in the bile. Metabolites were not detectable in serum or urine. Dose adjustment does not seem warranted in the elderly. For renally impaired patients with CLcr between 30 and 10 ml/min, the daily dose should not exceed 2 g. For patients with CLcr below 10 ml/min, individual adjustment is suggested. CDZ showed good penetration into tissues and biological fluids (lung, bronchial secretions, pleural fluid, kidney, prostate, urine, bone, muscle, skin, Fallopian tube) with long-lasting concentrations. In urine, therapeutic concentrations were present for more than 24 h after administration of 1 and 2 g. Thus, on the basis of its pharmacokinetic profile, cefodizime is appropriate for effective treatment with once-daily administration.

Three doses (3 mg, 6 mg and 12 mg) of piretanide, a new high ceiling diuretic, and placebo were given to 8 volunteers to investigate the relationship between the pharmacodynamic parameters, the dose and its urinary excretion. Intake of food and fluid were standardized from 48 h before until 24 h after drug administration. Urinary output, excretion of unchanged drug, and the excretion and clearance of Na+ and K+ were measured hourly for 7 h after treatment. A clear dose-response relationship was found for cumulative urinary output, cumulative excretion of Na+ and K+, clearance of Na+ and K+ and the urinary sodium/potassium ratio. A significant correlation was found between the net urine volume and the excretion of piretanide per time interval. The clearances of Na+ and K+ were significantly correlated with the excretion of piretanide. Clearance values correlated well with corresponding urine volumes.

Ofloxacin (HOE 280, DL 8280, OFX) is a new broad-spectrum chemotherapeutic agent belonging to the group of the gyrase inhibitors. The tolerability and pharmacokinetics have been investigated for the dose range from 100 mg to 2 X 600 mg. The substance has proved to be well tolerated; investigation of the effects on renal enzymes after multiple dosing with 300 mg b.i.d. showed that the risk of nephrotoxicity is negligible. Ofloxacin is rapidly and almost completely absorbed. Cmax and AUC are dose-dependent. The favourable half-life--between 6 and 7 h, irrespective of the dose--results in prolonged serum concentrations. Food interaction is slight and of no clinical relevance. The penetration into tissue and body secretions is rapid, and high levels are reached. The main route of elimination is the kidneys. The urinary concentrations are dose-dependent; but the proportion of the dose excreted via the kidneys remains approximately constant, 80% or more of the dose being recovered as unchanged ofloxacin. The degree of metabolisation in humans is small and of no clinical relevance. The glucuronide of ofloxacin found in the bile together with the two metabolites detected in the urine account for at most 5% of the dose given. The favourable kinetic profile of ofloxacin means that the daily regimen required is two doses at most. This is confirmed by clinical findings to date.

The influence of experimental rhinitis on the absorption of buserelin, measured as the serum luteinizing hormone (LH) response, has been investigated. A single dose of 200 micrograms buserelin was given to 24 healthy male volunteers after induction of experimental rhinitis with histamine and after use of a saline spray (placebo control). Except on one occasion, when the pump-spray apparently was incorrectly operated, serum LH concentration rose after buserelin. There was no difference in the LH response between histamine-induced rhinitis and saline controls. It was concluded that intranasal application of buserelin represents a reliable mode of application and that modification of the administration route or a change in the dosage schedule during naturally-occurring nasal inflammations, such as the common cold and allergic rhinitis, is unnecessary in patients undergoing chronic treatment with intranasal buserelin, e.g. for prostatic cancer, endometriosis, precocious puberty, and contraception.

Twelve healthy male volunteers received 14 oral doses of ofloxacin (300 mg each), and the concentrations of the unchanged drug were measured at various times in serum and urine over a period of 15 days. Serum and urine ofloxacin concentrations were determined in specific assays using high-pressure liquid chromatography (HPLC); urine levels were also determined by means of a microbiological assay. A washout period of 72 hours followed the first and 14th doses, allowing comparison of serum pharmacokinetics at the beginning and end of the multiple-dose regimen. Doses 2 to 14 were administered at 12-hour intervals. Maximum serum concentration (Cmax), concentration at 12 hours after dosing (C12), and area under the serum concentration-time curve (0 to 72 hours) were all 1.3 to 1.7 times greater after the 14th dose than after the initial dose. A 1.6-fold increase in C12 was already evident after the third dose; C12 remained more or less constant thereafter. Thus it is concluded that ofloxacin rapidly attained steady-state serum levels under a multiple-dose regimen, at levels only slightly above those following a single dose. High serum Cmax levels (4.6 and 5.9 micrograms/ml after the first and 14th doses, respectively) and long serum half-lives (6.0 and 7.3 hours after the first and last doses, respectively) indicated long-lasting, clinically relevant serum ofloxacin concentrations after oral administration. Serum ofloxacin levels 24 hours after the last dose were in the range of 0.3 to 0.7 microgram/ml, above the minimal inhibitory concentration (MIC90) for most bacterial strains. Cumulative urinary recovery remained high throughout the study. After 14 doses of ofloxacin (total, 4.2 gm), 88% of the unchanged drug was recovered in the urine; urinary concentrations remained above 1 microgram/ml, far above the MIC90 for most bacterial strains, for at least 108 hours after the final dose. High renal clearance values relative to total clearance (98%) confirmed the importance of the renal elimination route. Determinations of ofloxacin in urine using a microbiological assay were in close agreement with the HPLC determinations for all samples obtained throughout the study. Thus no detectable appearance of active metabolites occurred under the multiple-dose regimen. Ofloxacin was well tolerated; mild, probably drug-induced side effects were reported by three subjects, but they did not require any countermeasures.

Thin-layer chromatographic methods were up-dated for pharmacokinetic studies of imipramine in plasma and urine. The free parent compound and its free desmethyl metabolite desipramine are determined in plasma. Conjugates of both compounds in urine are cleaved on treatment with glucuronidase/arylsulfatase. Following chromatography, intense yellow derivatives are obtained overnight on standing or by exposure to nitrous gases. Detection is performed in the visible range at 405 nm (plasma) or 460 nm (urine). The methods are selective, accurate and sensitive, with detection limits for plasma of 2 ng/ml imipramine--HCl and 2 ng/ml desipramine--HCl, and 0.06 micrograms/ml total imipramine--HCl and 0.126 micrograms/ml total desipramine--HCl for urine. Pharmacokinetic data from plasma and urine results following single oral doses of 50 mg imipramine--HCl to eight volunteers were computed using one-compartment open models.

Pharmacokinetics of cefodizime, a broad-spectrum cephalosporin antibiotic, were determined after intravenous (IV) administration of single doses of 1.0, 1.5, and 2.0 gm to 12 healthy male volunteers in an open study. In a separate pilot study, data were obtained after IV administration of 0.5 gm of cefodizime to six healthy male volunteers. Determinations of cefodizime in serum and urine using a microbiological assay agreed with determinations using high-pressure liquid chromatography (HPLC), which specifically measures the unchanged drug. Active metabolites of cefodizime were not detected. After IV administration of 1.0, 1.5, and 2.0 gm of cefodizime, initial mean serum concentrations were 215, 322, and 394 mg/L, respectively (HPLC determinations). A linear response to dosage was shown (coefficient of correlation r = .89), as was the case for area under the serum concentration-time curve to infinity, AUC infinity (r = .82), and 48-hour urinary recovery of cefodizime (r = .94). In all cases, the corresponding values obtained after the 0.5-gm dose showed that the linearity extended to this dose. The kinetics of single-dose administration of cefodizime corresponded to a two-compartment open model with an apparent steady-state volume of distribution of about 40 L. Volume of distribution, terminal elimination half-life, serum and renal clearance, and percent urinary recovery were not dose dependent. Cefodizime combined a long terminal elimination half-life (mean, 2.5 hours) with a high urinary recovery (80%). After IV administration of cefodizime, urinary concentrations of the unchanged drug remained above 5 micrograms/ml for at least 24 hours after drug administration and were dose dependent. Mean values for the 1.0-gm and 2.0-gm doses were, respectively, approximately 12 mg/L and 30 mg/L, several times the minimal inhibitory concentrations (MIC90) for most clinically relevant bacteria. These results suggest that once- or twice-daily IV dosing with cefodizime (depending on the dose regimen) would be suitable for clinical use. The drug was safe and well tolerated.

An open study was carried out in 12 male, healthy volunteers to investigate the renal tolerance of ofloxacin, a new, broad-spectrum oral antibacterial agent. Subjects received single doses of 300 mg and then repeated doses of 300 mg ofloxacin twice daily for 7 days. Urine was collected in several fractions during the study and the excretion of creatinine, alanine-aminopeptidase (AAP), gamma-glutamyl transferase (GGT) and n-acetyl-beta-glucose aminidase (NAG) was calculated in 12-hour fractions. Serum creatinine, beta 2-microglobulin concentrations and creatinine clearance were also determined. Based on the findings for the kidney enzymes AAP, GGT and NAG, renal tolerance was good. This was confirmed by creatinine clearance and serum beta 2-microglobulin values. Ofloxacin showed no nephrotoxic potential in this study.