[Regional lymphotropic antibiotic therapy as a part of comprehensive treatment of children with purulent-inflammatory diseases of maxillofacial region].

126 children (aged 3-14 years) with severe purulent-inflammatory maxillofacial lesions underwent complex treatment: lymhotropic method of antibiotic (cefamabol) therapy was used in 64 of them. Clinical, microbiological and pharmacokinetic investigations have shown the method of lymphotropic regional antibiotic therapy to be effective and feasible to treat purulent-inflammatory maxillofacial lesions in children.

Pharmacodynamics and pharmacokinetics of cefoperazone and cefamandole in dogs following single dose intravenous and intramuscular administration.

The pharmacokinetics and intramuscular (i.m.) bioavailability of cefoperazone and cefamandole (20mg/kg) were investigated in dogs and the findings related to minimal inhibitory concentrations (MICs) for 90 bacterial strains isolated clinically from dogs. The MICs of cefamandole for Staphylococcus intermedius (MIC(90) 0.125 microg/mL) were lower than those of cefoperazone (MIC(90) 0.5 micro/mL) although the latter was more effective against Escherichia coli strains (MIC(90) 2.0 microg/mL vs. 4.0 microg/mL). The pharmacokinetics of the drugs after intravenous administrations were similar: a rapid distribution phase was followed by a slower elimination phase (t((1/2)lambda2) 84.0+/-21.3 min for cefoperazone and 81.4+/-9.7 min for cefamandole). The apparent volume of distribution and body clearance were 0.233 L/kg and 1.96 mL/kg/min for cefoperazone, 0.190 L/kg and 1.76 mL/kg/min for cefamandole. After i.m. administration the bioavailability and peak serum concentration of cefamandole (85.1+/-13.5% and 35.9+/-5.4 microg/mL) were significantly higher than cefoperazone (41.4+/-7.1% and 24.5+/-3.0 micog/mL), but not the serum half-lives (t(1/2el) 134.3+/-12.6 min for cefoperazone and 145.4+/-12.3 min for cefamandole). The time above MIC(90) indicated that cefamandole can be administered once daily to dogs for the treatment of staphylococcal infections (T>MIC for S. intermedius 23.8+/-0.3 and for Staphylococcus aureus 21.6+/-0.6h).

Clinical pharmacokinetics of cefamandole and ceftazidime administered by continuous intravenous infusion.

In view of the results of animal studies as well as theoretical considerations, continuous administration of beta-lactam antibiotics should be superior to intermittent administration because of the close relationship between efficacy and the duration of time in which the concentration of unbound antibiotics in plasma remains above the MIC. The aim of the present study was to establish the pharmacokinetic parameters of cefamandole and ceftazidime for patients receiving these cephalosporins by continuous infusion. The interindividual differences in the concentrations in plasma at the steady state were mainly attributable to variations in renal function, as estimated by the rate of creatinine clearance. Using these results, we derived formulas for both cephalosporins that can be used to determine on an individual basis the total daily dose needed to obtain a therapeutic concentration in plasma. These formulas were tested with a group of subsequent patients and proved to be practical and fairly reliable. For some patients, a correction for a possible underestimation of the renal clearance at presentation might be required.

New polymer-antibiotic systems to inhibit bacterial biofilm formation: a suitable approach to prevent central venous catheter-associated infections.

Intravascular catheters are widely employed in medical practice. However, complications such as local or systemic infections are frequently related to their use. The significant increase in this type of nosocomial infection has prompted the search for new strategies to prevent them. This paper reports on an experimental model to prevent catheter-related infections based on the adsorption of a beta-lactam antibiotic (cefamandole nafate) on functionalized urethane polymers. The polyurethanes synthesized were used to coat a commercial central venous catheter. The influence of functional groups on the polymer-antibiotic interaction was analyzed and the kinetics of the antibiotic release from the catheters was dynamically studied. We were able to realize a polymer-antibiotic system able to inhibit bacterial growth up to 7 days. These promising results have encouraged us to extend this experimental model to other polymer-antibiotic systems in order to identify those allowing bacterial growth inhibition for longer times.

Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement.

Twelve patients undergoing total hip replacement were given 600 mg of linezolid as a 20 min iv infusion along with conventional prophylaxis of 1 g of cefamandole immediately before surgery. Routine total hip arthroplasty was carried out, and at timed intervals during surgery samples of bone, fat, muscle and blood were collected for assay by high-performance liquid chromatography analysis. Samples of the haematoma fluid that formed around the operation site and further blood samples for assay were also collected at timed intervals following the operation. The penetration of linezolid into bone was rapid, with mean concentrations of 9.1 mg/L (95% CI 7.7-10.6 mg/L) achieved at 10 min after the infusion, decreasing to 6.3 mg/L (95% CI 3.9-8.6 mg/L) at 30 min. Correction for the simultaneous blood concentrations gave mean values for bone penetration of 51% at 10 min, 60% at 20 min and 47% at 30 min. Although the penetration of linezolid into fat was also rapid, mean concentrations and degree of penetration were c. 60% of those in bone; at 10 min they were 4.5 mg/L (95% CI 3.0-6.1 mg/L; penetration 27%); at 20 min they were 5.2 mg/L (95% CI 4.0-6.4 mg/L; penetration 37%); and at 30 min, 4.1 mg/L (95% CI 3.3-4.8 mg/L; penetration 31%). For muscle the corresponding values were 10.4 mg/L (95% CI 8.1-12.7 mg/L; penetration 58%) at 10 min, 13.4 mg/L (95% CI 10.2-16.5 mg/L; penetration 94%) at 20 min and 12.0 mg/L (95% CI 9.2-14.8 mg/L; penetration 93%) at 30 min. Mean concentrations of linezolid in the haematoma fluid drained from around the operation site were 8.2 mg/L at 6-8 h and 5.6 mg/L at 10-12 h after the infusion, and 7.0 mg/L at 2-4 h following a second 600 mg infusion given 12 h post-operatively. We conclude that linezolid exhibits rapid penetration into bone, fat and muscle of patients undergoing hip arthroplasty, to achieve levels in excess of its MIC for susceptible organisms (< or=4 mg/L); therapeutic concentrations were maintained in the haematoma fluid that surrounds the operation site for >16 h.

Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques.

The pharmacokinetics of cefuroxime, cefotiam, cefamandole, and ampicillin/sulbactam were randomly measured in 40 patients undergoing major orthopedic surgery associated with high blood and volume turnover and intraoperative blood salvage. Serum and bone concentrations and the pharmacokinetics occurring in the context of these procedures were measured. No changes in elimination half-life relative to a normal population occurred with cefuroxime, cefotiam, and ampicillin. Serum and tissue concentrations were slightly lower with cefamandole and sulbactam, but reapplication of the initial dose was required with all antibiotics 4 hours after the first application.

The penetration of ceftriaxone and cefamandole into bone, fat and haematoma and relevance of serum protein binding to their penetration into bone.

Thirteen patients undergoing total hip replacement were given ceftriaxone 1 g and cefamandole 1 g simultaneously, either immediately or 8 h before surgery. For both agents the concentrations seen in the bone and fat during the operation, and for haematoma fluid

Determination of unbound cefamandole in rat blood by microdialysis and microbore liquid chromatography.

To analyze unbound cefamandole in rat blood, a method combing microdialysis with microbore liquid chromatography has been developed. A microdialysis probe was inserted into the jugular vein/right atrium of male Sprague-Dawley rats to examine the unbound cefamandole level in the rat blood following cefamandole administration (50 mg/kg, i.v.). The dialysates were directly submitted to a liquid chromatographic system. Samples were eluted with a mobile phase containing acetonitrile-methanol-100 mM monosodium phosphate (pH 5.0; 15:20:65, v/v). The UV wavelength was set at 270 nm for monitoring the analyte. Using the retrograde method, at infusion concentrations of 1 microg/mL of cefamandole, the in vivo microdialysis recoveries were 55.44% for the rat blood (n = 6). Intra- and inter-assay accuracy and precision of the analyses were < or = 10% in the range of 0.1-10 microg/mL. Pharmacokinetic parameters were calculated from the recovery-corrected dialysate concentrations of cefamandole vs time data. The elimination half-life (t1/2,beta) was 21.6 +/- 1.6 min. The results suggest that the pharmacokinetics of unbound cefamandole in blood following cefamandole administration (50 mg/kg, i.v., n = 5) fit best to the two-compartmental model.

New models for pharmacokinetic data based on a generalized Weibull distribution.

We consider the development of the concentration of a drug in the blood after single oral or intravenous administration. We introduce a new nonlinear model capable of describing concentration-time curves following intravenous administration. A similar model is proposed for oral data. Both models have four parameters, of which two regulate the shape of the curve and two determine the scale of the time and concentration axes. All the parameters are closely related to geometric properties of the curve. The scale parameters determine a point in the curve, and the shape parameters can be calculated by using numerical integration. The models can be used when the object of the analysis is to quantify the shape of a concentration-time curve. We discuss the usefulness of the models in bioequivalency trials, in clinical safety and efficacy trials, and in population pharmacokinetics. The models are applied to two previously presented data sets. To reduce the number of parameters, the shape parameters are assumed common for all individuals. Encouraging results are obtained. We also present a new four-parameter Michaelis-Menten model.

Altered permeability and beta-lactam resistance in a mutant of Mycobacterium smegmatis.

Beta-lactam resistance in mycobacteria results from an interplay between the following: (i) beta-lactamase production, (ii) affinity of the penicillin-binding proteins (PBPs) for the drugs, and (iii) permeation of the drugs. A laboratory mutant of Mycobacterium smegmatis was studied in order to evaluate the roles of these factors in beta-lactam resistance. Mutant M13 was between 7- and 78-fold more resistant than the wild type to cephaloridine, cefoxitin, cefazolin, cefamandole, and cephalothin. Increased beta-lactamase activity toward these antibiotics was not observed in the mutant. The PBP profiles of the wild type and M13 were comparable. However, the affinities of PBP 1 for the beta-lactams tested were lower for the mutant than for the wild type. The permeation of the drugs measured in intact cells was lower for M13 than for the parent strain. The liposome swelling technique, which could be used for cephaloridine, also supported this view. Reduced permeation was not restricted to the beta-lactams alone. Glycine uptake was also lower in M13. Taken together, the results suggest that decreased affinities of PBP 1 for beta-lactams, combined with the decreased permeability of the cell wall of the mutant, lead to the development of high-level acquired beta-lactam resistance.

Concentration of cefamandole in plasma and tissues of patients undergoing cardiac surgery: the influence of different cefamandole dosage.

OBJECTIVE: To develop an improved regimen of antibiotic prophylaxis in cardiac surgery, three antibiotic prophylactic regimens for patients scheduled to have elective cardiothoracic surgery involving a median sternotomy were evaluated. DESIGN: A prospective, randomized, unblinded study. SETTING: A university teaching hospital. PARTICIPANTS: Sixty-nine men scheduled for elective coronary artery bypass grafting (CABG) with extracorporeal circulation (ECC) were included in the study. INTERVENTIONS: The patients were selected at random to receive 2 g of cefamandole (CM) at induction of anesthesia (group 1, n = 24), or 2 g of CM at the beginning of anesthesia followed by an additional dose (2 g) immediately after onset of cardiopulmonary bypass (CPB) (group 2, n = 22), or 4 g of CM just at the initiation of anesthesia (group 3, n = 23). Samples from the mammary artery, sternum, and plasma were obtained at various intervals after injection of the antibiotic (10 minutes intravenously) to compare antibiotic levels, assayed for CM concentrations, with high-pressure liquid chromatography (HPLC) and plasma bactericidal activity as well as infectious complications in these sites as a function of time for the three groups. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in biometric data, duration of hospitalization, or management of cardiopulmonary bypass, including urinary tract drainage and infusion volume. The mean plasma t1/2 (distributive or alpha-phase) before bypass was 51.7 +/- 16.7 minutes for group 1 and 2 patients and 54.9 +/- 15.9 minutes for group 3 patients. CM plasma values were significantly higher in group 2 (170.3 +/- 105.8 micrograms/mL) than in groups 1 and 3 (111.8 +/- 42.2 micrograms/mL, 101.2 +/- 57.2 micrograms/mL) at the end of bypass periods (p < 0.05). The antibiotic contents of mammary artery and sternum samples of group 2 (15.6 +/- 4.7 micrograms/mL, 9.5 +/- 4.7 micrograms/mL) were significantly higher after completion of CPB compared with group 1 (5.7 +/- 1.9 micrograms/mL, 3.8 +/- 2.9 micrograms/mL) and group 3 (6.3 +/- 3.5 micrograms/mL, 3.6 +/- 1.8 micrograms/mL) (p < 0.05). There were no significant differences in distribution of micro-organisms among the three groups, but two patients of groups 1 and 3 with plasma and tissue CM levels below minimal inhibitor concentration (MIC90) for Hemophilus influencea, E coli, Proteus ssp and Klebsiella ssp after completion of CPB, respectively, developed a pneumonia postoperatively caused by Hemophilus influencea (1), E coli (1) and Klebsiella ssp (2) (p < 0.05). CONCLUSIONS: It would be preferable to infuse the antibiotic shortly before the operative procedure. However, to keep tissue and plasma CM values more than MIC90 for common pathogens during the time period studied, a second infusion of 2 g of CM administered after onset of CPB suggests better protection against the risk of microbial infections. Therefore, the findings might be important for the choice of antibiotic prophylaxis, particularly for high-risk patients.

A comparison of the penetration of cefuroxime and cephamandole into bone, fat and haematoma fluid in patients undergoing total hip replacement.

Twelve patients undergoing total hip anthroplasty received, at the induction of anaesthesia, cephamandole (1 g) and cefuroxime (1.5 g); further doses of cephamandole (1 g) and cefuroxime (750 mg) were given at 8 and 16 h after the operation. Routine total hip arthroplasty was performed and at timed intervals during operation samples of bone, fat and blood were collected for assay for HPLC analysis. Samples of the haematoma fluid that formed around the operation site and further blood samples were also collected at 7 and 15 h after the operation. Although considerable variation was observed in the bone and fat concentrations of both agents, the cefuroxime levels were substantially higher than those of cephamandole, with mean values for bone of cefuroxime 36.0 mg/L (95% CI 29.0-43.0 mg/L) and cephamandole 18.3 mg/L (95% CI 14.2-22.4 mg/L) and for fat of cefuroxime 15.0 mg/L (95% CI 11.1-18.9 mg/L) and cephamandole 11.2 mg/L (95% CI 7.2-15.2 mg/L). When corrected for blood concentrations the penetration of both agents was similar (bone, 43.6% cefuroxime and 37.8% cephamandole; fat, 16.0% cefuroxime and 19.2% cephamandole). Cefuroxime concentrations in haematoma drain fluid were higher than those of cephamandole 6-8 h after the operation (17.8 versus 8.3 mg/L) but lower at 14-16 h (7.7 versus 9.6 mg/L). We conclude that there are no significant differences between the bone, fat or haematoma penetration of cefuroxime and cephamandole and that any differences in the absolute levels of the two agents are due to differences in the total drug administered rather than their ability to penetrate into these sites. Time-kill curves for cefuroxime and cephamandole against five clinical isolates of Staphylococcus aureus failed to identify any significant differences between the rates of kill for the two agents at the concentrations seen in bone, fat or haematoma fluid. For both prophylaxis regimens antibiotic concentrations exceeded the MICs for potential pathogens for the duration of the operation and also in the haematoma which surrounds the operation site for up to 24 h after the operation.

Effect of time interval on tissue concentrations of cephalosporins after tourniquet inflation. Highest levels achieved by administration 20 minutes before inflation.

We studied the effect of different time intervals between antibiotic administration and tourniquet inflation in 62 patients undergoing reconstructive surgery in the lower extremities. The in vivo concentrations in soft tissue and bone of 3 cephalosporins (ceftazidime, ceftriaxone and ceforanide) were determined. Our findings suggest that the highest tissue concentrations were achieved by administration 20 min before tourniquet inflation.

Decreased bactericidal activity during the period of the postantibiotic effect.

Standard and clinical strains of Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae were subjected to continuous exposure to beta-lactams and aminoglycosides during the postantibiotic effect phase induced by rifampicin or erythromycin (for S. aureus). A significant inhibition of bactericidal activity by these agents during the PAE period was observed. The degree of inhibition was dependent both on the class of antimicrobial agent (beta-lactams > aminoglycosides) and the microorganism (Gram-negative bacilli > S. aureus).

[Comparative pharmacokinetics of antibiotics in blood, csf and brain]. / Pharmacocinétique comparée d'antibiotiques dans le sang, le L.C.R. et le cerveau.

The Knowledge of the antibiotic's cerebral diffusion is essential to define a of neurosurgical antibioprophylaxis' strategy. Without references in the medical world-literature, we've decided to compare the pharmacological kinetics in the blood, the cerebrospinal fluid and the sound cerebral tissue of common used molecules in neurosurgery that is to say: amoxicillin, cefamandole, metronidazole and pefloxacin. The results show that the cerebral levels of metronidazole and pefloxacine are rapidly high with an extended duration (> 10 times the M.I.C. of the sensitive bacteriae), but the tissue penetration of amoxicillin is hazardous and shot-duration for cefamandole (undosable after 3 hours).

Comparative study of cefazolin, cefamandole, and vancomycin for surgical prophylaxis in cardiac and vascular operations. A double-blind randomized trial.

Three-hundred twenty-one adults undergoing cardiac or major vascular operations were randomized to receive intravenous cefazolin, cefamandole, or vancomycin for prophylaxis against surgical infection in a double-blind trial. All three regimens provided therapeutic blood levels throughout operation in patients studied undergoing cardiopulmonary bypass. The prevalence of surgical wound infection was lowest with vancomycin (4 infections [3.7%] versus 14 [12.3%] and 13 [11.5%] in the cefazolin and cefamandole groups, respectively; p = 0.05); there were no thoracic wound infections in cardiac operations in the vancomycin group (p = 0.04). The mean duration of postoperative hospitalization was lowest in the vancomycin group (10.1 days; p < 0.01) and highest in the cefazolin group (12.9 days). Prophylaxis with vancomycin or cefamandole, compared with cefazolin, did not prevent nosocomial cutaneous colonization by methicillin-resistant coagulase-negative staphylococci; colonization or infection with vancomycin-resistant staphylococci or enterococci was not detected. Adverse effects attributable to the prophylactic regimen were infrequent in all three groups. Eight patients given vancomycin became hypotensive during administration of a dose, despite infusion during a 1-hour period; however, slowing the rate of administration and pretreating with diphenhydramine allowed vancomycin to be resumed and prophylaxis completed uneventfully in five of the patients. We conclude that administration of vancomycin (approximately 15 mg/kg), immediately preoperatively, provides therapeutic blood levels for surgical prophylaxis throughout most cardiac and vascular operations, resulting in protection against postoperative infection superior to that obtained with cefazolin or cefamandole. Vancomycin deserves consideration for inclusion in the prophylactic regimen (1) for prosthetic valve replacement and prosthetic vascular graft implantation, to reduce the risk of implant infection by methicillin-resistant coagulase-negative staphylococci and enterococci; (2) for any cardiovascular operation if the patient has recently received broad-spectrum antimicrobial therapy; and (3) for all cardiovascular operations in centers with a high prevalence of surgical infection with methicillin-resistant staphylococci or enterococci. Guidelines for dosing and administration of vancomycin for cardiovascular surgical prophylaxis are provided.

Comparison of three methods of antibiotic prophylaxis in knee arthroplasty.

Prophylactic intravenous cefamandole nafate was administered by the systemic, systemic with probenecid (causing renal tubular blockade of antibiotic excretion), and intravenous regional routes. Bone antibiotic levels were assayed 15 minutes and 12 hours after administration, and hematoma concentrations after 8 hours. Bone concentrations after intravenous regional administration were significantly greater than systemic after 15 minutes, but were not detectable after 12 hours. Probenecid produced inhibitory concentrations in bone after 12 hours and also increased hematoma antibiotic concentrations to three times those achieved by systemic administration. Adequate prophylaxis may be possible with two rather than three doses of cefamandole if probenecid is used.

Determination of bone and fat concentrations following systemic cefamandole and regional cefuroxime administration in patients undergoing knee arthroplasty.

Five patients undergoing routine total knee replacement received standard antibiotic prophylaxis of 1000 mg of iv cefamandole and also regional administration of 750 mg of cefuroxime. Regional dosing was carried out at the start of the operation, following the application of a mid-thigh tourniquet, by administration into a foot vein. Samples of bone and fat were collected during the operation and assayed for cefuroxime and cefamandole by HPLC analysis. The mean cefuroxime bone (133.1 mg/l) and fat (88.4 mg/l) levels following regional administration were significantly higher (P less than 0.001) than the mean cefamandole bone (9.1 mg/l) and fat (9.8 mg/l) levels following systemic dosing. The possibility of administration of prophylaxis by the regional route is suggested.