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Assessment of incompatibilities between active pharmaceutical ingredient and pharmaceutical excipients is an important part of preformulation studies. The objective of the work was to assess the effect of moisture content of chitin calcium silicate of two size ranges (two specific surface areas) on the rate of degradation of cefotaxime sodium. The surface area of the excipient was determined using adsorption method. The effect of moisture content of a given size range on the stability of the drug was determined at 40°C in the solid state. The moisture content was determined at the beginning and the end of the kinetic study using TGA. The degradation in solution was studied for comparison. Increasing the moisture content of the excipient of size range 63-180 μm (surface area 7.2 m 2 /g) from 3.88 to 8.06% increased the rate of degradation of the drug more than two times (from 0.0317 to 0.0718 h -1 ). While an opposite trend was observed for the excipient of size range < 63 μm (surface area 55.4 m 2 /g). The rate of degradation at moisture content < 3% was 0.4547 h -1 , almost two times higher than that (0.2594 h -1 ) at moisture content of 8.54%, and the degradation in solid state at both moisture contents was higher than that in solution (0.0871 h -1 ). In conclusion, the rate of degradation in solid should be studied taking into consideration the specific surface area and moisture content of the excipient at the storage condition and it may be higher than that in solution.

Objective: To develop a pharmacostatistical model to simultaneously characterise the pharmacokinetics of cefotaxime and its main metabolite, desacetylcefotaxime, in elderly patients., Methods: Cefotaxime, 1 g, was infused three times daily to 25 elderly patients, 66-93 years old. Cefotaxime and desacetylcefotaxime plasma concentrations (289 and 304 samples, respectively), along with demographic and physiological characteristics, were analysed using a population approach., Results: Cefotaxime pharmacokinetics was best described by a two-compartment open model in which desacetylcefotaxime was produced from the central compartment. The final parameter estimates were derived from simultaneous fit of parent/metabolite data. Cefotaxime clearance, mean 5.5 l/h, was positively influenced by body weight and serum protein concentration and negatively influenced by serum creatinine and age. In contrast, desacetylcefotaxime elimination was only decreased by age. The mean terminal half-lives of cefotaxime and desacetylcefotaxime were 1.7 h and 2.6 h, respectively. The stability and predictive performance of the final population pharmacokinetic model was assessed using 200 bootstrap samples of the original data., Conclusion: Cefotaxime and desacetylcefotaxime elimination decreased with increasing age above 60 years. This decreased elimination was related to individual characteristics that are typically related to renal function.

The frequency of enterobacterial isolates with high resistance to expanded-spectrum beta-lactam antibiotics (mainly cefotaxime or ceftriaxone) has increased notoriously in Argentina, mainly because of the spread of extended-spectrum beta-lactamases. The aim of this work was the study of extended-spectrum beta-lactamases in several Morganella morganii isolates with unusually high resistance to ceftriaxone. These strains produced at least two beta-lactamases, of apparent pIs of 5.4 and 8.2, molecular weight 23 000, well inhibited by clavulanate, compatible with a broad-spectrum beta-lactamase - perhaps TEM-1 - and an extended-spectrum beta-lactamase, respectively. The extended-spectrum beta-lactamase was identified as a CTX-M-type beta-lactamase - probably CTX-M-2 - by polymerase chain reaction, restriction profile analysis and DNA-DNA hybridisation. The remaining isolates studied produced either the broad-spectrum beta-lactamase plus the ubiquitous AmpC beta-lactamase (13 strains), or the AmpC beta-lactamase only (10 strains).

The kinetics of ceftizoxime, a newly developed cephalosporin, were evaluated in 6 healthy subjects, with respect to its excretory pathways especially by the biliary route. Total, renal and biliary clearance were determined at two different steady states. Steady state was achieved by constant intravenous infusion (604.1 mg/h) over 6 h after an initial loading dose (750 mg); 1.5 h after discontinuation of that infusion, a further infusion was commenced at a lower rate (284 mg/h) over 3 h, the second steady state being reached 0.5 to 1.0 h later. The drug was mainly excreted by the kidneys (56.7 to 92.9% of the dose). Biliary excretion, measured by the duodenal perfusion and marker dilution technique, was low (0.2 to 7.8% of the dose). Urinary and biliary excretion as well as total clearance were not dose-dependent. However, there was pronounced interindividual variation in total (35.2 to 236 ml/min) and renal clearance (10.6 to 208 ml/min), which could both be explained by varying interindividual urinary flow rates (mean flow rate: 0.99 ml/min to 3.14 ml/min). Intraindividual variation in renal clearance was less pronounced, but in the same subject changes in renal clearance were correlated with changes in urinary flow rate. From the varying renal clearance, which exceeded the glomerular filtration rate at high urinary flow rates and was below it at low urinary flow rates, it can be concluded that, in addition to glomerular filtration, tubular secretion and tubular reabsorption are involved in the renal excretion of ceftizoxime.(ABSTRACT TRUNCATED AT 250 WORDS)

Excretion of an antibiotic bile may result in high intraintestinal concentrations and thus alteration in the fecal flora. We investigated the effect of ceftriaxone (45% biliary excretion) and cefotaxime (less than 5% biliary excretion) on the aerobic fecal flora. Ceftriaxone eradicated susceptible enteric organisms and resulted in overgrowth of Candida spp. and resistant enterococci. In some patients multiresistant gram negative bacteria appeared during of after therapy. Cefotaxime had a moderate effect on fecal microecology and did not promote the emergence of resistant organisms.

The pharmacokinetic parameters of total (bound and unbound) and free (unbound) ceftriaxone in six healthy volunteers after intravenous injection of 39 were compared with low-dose data from a previous study. The dose-dependent behaviour of total drug was considerably more pronounced after the 3 gram dose. In contrast, total body clearance (C1FS = 258 ml/Min), renal clearance (C1FR = 170 ml/min) and volume of distribution (VFD (beta) = 168 1) of free (unbound) drug did not differ from the data reported earlier. There was no significant change in biological half-life (t1/2 (beta) = 7.8 h) or in the fraction excreted unchanged in urine (fu = 0.67).

The kinetics of the aminothiazolyliminomethoxy cephalosporin, cefmenoxime, were determined after a 30 min intravenous infusion of 15 mg/kg body weight in 6 adult subjects undergoing continuous ambulatory peritoneal dialysis. Concentrations of cefmenoxime in serum, urine and dialysate were determined by high-pressure liquid chromatography. The mean peak serum concentration was 92.8 +/- 11.6 micrograms/ml and the harmonic mean for the elimination half-life was 5.46 h. The volume of distribution at steady-state was 14.60 +/- 3.01 l/kg. Total body clearance of the drug was 31 +/- 7.7 ml/min with 8 +/- 5% and 5.75 +/- 2.72% of the administered dose being eliminated by renal and peritoneal clearance, respectively. Peritoneal clearance for all exchanges (n = 24) was 1.93 +/- 68 ml/min. These data suggest that peritoneal losses of this drug are minimal and doses conventionally employed in advanced renal failure can be utilized in the management of systemic infections.

Guidelines presented previously for the analysis of plasma concentration versus time data for a drug exhibiting concentration-dependent plasma protein binding were successfully applied to the distributional parameters of a new cephalosporin, ceftriaxone. This approach provided several striking observations when the pharmacokinetics of ceftriaxone in a healthy and uremic population were re-examined. First, the parameter -fp converted the apparent dose-dependent distributional terms of ceftriaxone into a function of the concentration-dependent plasma protein binding. Second, a strong correlation between the term VUSS and the reciprocal of -fp was established within each of the two populations. While this -fp term accounted for the variability within the respective populations due to ceftriaxone-albumin binding differences, it did not account for all of the distributional differences between the two populations. The present analysis revealed that the altered physiologic state of uremia (larger plasma volumes and interstitial to intravascular albumin ratios), in addition to differences in plasma protein binding, dictated the distribution of ceftriaxone in healthy and uremic subjects. Furthermore, the binding-disposition model which accounts for the presence of plasma proteins outside the vascular space, was established to be appropriate in describing the distribution of ceftriaxone.

We have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, fp) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both V beta and the model-independent VSS) were inaccurate/invalid; b) V beta based on unbound drug was misleading; c) the model-independent VSS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms (-fp and V-TSS) were introduced which provide additional insight concerning the disposition of this type of drug. The -fp is the area-weighted average fraction unbound in the plasma and V-TSS is the corrected steady state distribution term for total drug levels. The present study indicates that useful distributional and clearance terms can be calculated for this type of drug, provided that the time course of unbound drug as well as total drug can be followed. Moreover, guidelines for their extrapolation to steady state conditions and their correct interpretations are discussed.

Cefodizime pharmacokinetics was investigated, evaluating drug concentrations in serum, skin suction blister fluid (SBF), saliva and urine in six healthy male subjects who were administered a 1-g dose intravenously. Serum levels in five subjects can be described according to a two-compartment open model; terminal half-life is 181 +/- 14 min. Volume of distribution (Vd beta) amounts to 15.3 +/- 1.61, serum clearance to 59 +/- 6 ml/min, renal clearance to 33 +/- 3 ml/min. Of the administered dose, 54% is renally excreted unchanged within 27 h. Unbound drug fraction in serum is 19.0% and in SBF 38.4%. Thus renal clearance of free cefodizime amounts to 172 ml/min, Vdss to 68.9 l (free drug). Whereas cefodizime has not been detected in saliva samples, SBF concentration 3-9 h post administration parallel serum levels, amounting to 40% of the respective serum concentration. At 9 h, unbound cefodizime concentrations in SBF amount to 1.4 +/- 0.4 micrograms/ml, this value being well above the MIC90% values of many clinically relevant bacteria.

Six patients, aged 52 to 71 years, with T-tube drainage of the common bile duct and a urinary catheter after cholecystectomy, were studied in order to evaluate the urinary and biliary excretion and pharmacokinetics of cefotiam in the early postoperative period. Each patient received cefotiam 1 g i.v. as a bolus injection. Cefotiam in plasma, urine, and bile were determined by HPLC. A 2-compartment open model with elimination from the central compartment satisfactorily fitted the plasma levels of the drug. The renal clearance of cefotiam (CLR = 133 ml/min) was an order of magnitude greater than its biliary clearance (CLB = 11.8 ml/min). Glomerular filtration was the main mechanism for elimination of cefotiam. The values of CLR and CLB in relation to the total plasma clearance (CL = 138. ml/min) demonstrated the negligible role of metabolism in elimination of cefotiam in these patients.

Susceptibility testing of clinical isolates of several gram-negative and gram-positive species showed LY163892 to be more active than cefaclor and cephalexin. OXA-2, TEM-1, TEM-2, PSE-1, CEP-1, CARB-3 and SHV-1 beta-lactamases showed similar activity against LY163892 and cefaclor, whereas OXA-1 hydrolyzed the latter more rapidly. Organisms producing these beta-lactamases, but not TEM-2 and CEP-1, appeared to be more susceptible to LY163892 than cephalexin, although cephalexin proved to be more resistant to beta-lactamase activity. Strains producing TEM-2 and CEP-1 were resistant to LY163892, cefaclor and cephalexin.