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.

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.

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.

Quinupristin-dalfopristin combined with beta-lactams for treatment of experimental endocarditis due to Staphylococcus aureus constitutively resistant to macrolide-lincosamide-streptogramin B antibiotics.

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

[The effect of different autotransfusion procedures on the antibiotic picture. A study on cephalosporin cefamandole]. / Der Einfluss unterschiedlicher Autotransfusionsverfahren auf Antibiotikaspiegel. Studie zum Cephalosporin Cefamandol.

Infection after open heart surgery is a serious complication since eradication of infection in these cases is difficult even with appropriate antibiotic therapy. In the attempt to avoid this problem, prophylactic administration of antibiotics is common. Their relative safety and their broad spectrum of activity make cephalosporin antibiotics popular choices for prophylaxis prior to and during operations, including cardiovascular procedures. METHODS. Preoperative antibiotic prophylaxis with 2 g cefamandole was performed in a prospective randomized study including 62 male patients divided into three groups. All patients gave informed consent, and the study was approved by the ethics committee of the hospital. Patients in group 1 (n = 21) and group 2 (n = 21) underwent aortocoronary bypass (ACVB) with extracorporeal circulation (ECC), while patients in group 3 (n = 20) had carotid surgery. Anaesthesia, coronary-bypass procedures and infusion regime were standardized. The flow rate during ECC was maintained at 2.41/min/m2 and the rectal temperature between 33 degrees and 34 degrees C. Arterial and urine specimens for the determination of plasma and urine levels of cefamandole were taken at definite times. Autologous blood salvage during operation was performed with haemofiltration techniques (HF) in group 1 (HF 80, Fresenius, Bad Homburg, Germany) and with cell separation techniques (CS) in group 2 (Hemonetics III, Hemonetics). Plasma and urine cefamandole levels were measured by high-pressure liquid chromatography (HPLC). RESULTS. After administration of 2 g cefamandole mean peak levels of 404.6 +/- 141.7 micrograms/ml were seen. Because of haemodilution at the beginning of extracorporeal circulation, group 1 and 2 showed much lower cefamandole plasma levels, 22.1 +/- 11.6 micrograms/ml and 24.3 +/- 14.4 micrograms/ml, than group 3 (after the same time course), with 47.4 +/- 19.1 micrograms/ml. For all patients in group 1 and 2 prebypass time (70.3 +/- 22.4 min) and the duration of the ECC (72.3 +/- 17.7 min) were comparable. There was a significant correlation between prebypass time and cefamandole plasma levels at the beginning of extracorporeal circulation (P < 0.001). No correlation could be seen for the plasma concentration after discontinuation of the extracorporeal circulation and the duration of extracorporeal circulation. The volume of autologous red packed cells and the enclosed amount of cefamandole showed a significant difference (P < 0.001) between group 1 (1120.0 +/- 296.8 ml, 27.5 +/- 17.1 mg) and group 2 (734.3 +/- 186.6 ml, 2.9 +/- 3.2 mg). The plasma cefamandole level after transfusion of autologous blood displayed a significant correlation (p < 0.01) with cefamandole concentration in the autologous red packed cells. Transfusion of the autologous blood produced no significant increase in plasma cefamandole levels. With an operation time of more than 2.5 h during ECC the cefamandole plasma level decreased below the necessary minimal inhibitory concentration (MIC90), particularly for gram-negative bacteria. CONCLUSION. Additional administration of 1 g cefamandole shortly before the beginning of cardiopulmonary bypass is recommended, particularly for surgical procedures with ECC of more than 2.5 h. Adjustment of drug dosage prior to or during surgery may be required to optimize therapy, but before this can be achieved precisely, more information on drug disposition during the operative procedures is needed.

Cefamandole levels during thoracoabdominal aortic aneurysm surgery.

The pharmacokinetics of prophylactic antibodies may differ in cardiac and aortic aneurysm surgery for at least two reasons: aortic aneurysm surgery generally entails a greater blood volume loss and replacement, and aortic aneurysm surgery usually does not require extracorporeal cardiopulmonary bypass. We prospectively studied two different cefamandole dosing regimens in patients undergoing aortic aneurysm surgery (phase 1, 1 gm intravenously at the induction of anesthesia; phase 2, 2 gm intravenously at the induction of anesthesia followed by 1 gm intravenously every 2 hours during surgery). In phase 1 and 2 plasma levels were measured at the time of skin incision, aortic cross-clamping, aortic unclamping, and skin closure. In phase 2 cefamandole elimination in urine and cell-saver effluent was also determined. An adequate plasma level of 10 micrograms/ml was maintained in only 4 of 14 patients in phase 1, but in 10 of 10 patients in phase 2. Cefamandole loss in cell-saver effluent was 136 +/- 100 mg, which was 13% of the measured renally excreted amount. As has been previously shown in cardiac surgery, a cefamandole prophylactic antibiotic regimen of 2 gm intravenously at the induction of anesthesia followed by 1 gm every 2 hours during surgery provides a dependable and practical dosing regimen in patients undergoing aortic aneurysm surgery.

Simultaneous determination of cefamandole and cefamandole nafate in human plasma and urine by high-performance liquid chromatography with column switching.

A high-performance liquid chromatographic method with column switching has been developed for the simultaneous determination of cefamandole and cefamandole nafate in plasma and urine. The plasma and urine samples were injected onto a precolumn packed with Corasil RP C18 (37-50 microns) after simple dilution with an internal standard solution in 0.05 M phosphoric acid. Polar plasma and urine components were washed out using 0.05 M phosphoric acid. After valve switching, the concentrated drugs were desorbed in back-flush mode and separated by a reversed-phase C8 column with methanol-5 mM tetrabutylammonium bromide (45:55, v/v) as the mobile phase. The method showed excellent precision with good sensitivity and speed, and a detection limit of 0.5 microgram/ml. The total analysis time per sample was less than 30 min, and the mean coefficients of variation for intra- and inter-assay were both less than 4.9%. The method has been successfully applied to plasma and urine samples for human volunteers after intravenous injection of cefamandole nafate.

A comparative study of cefamandole and ceftriaxone as prophylaxis in cardiac surgery.

We compared the prophylactic use of cefamandole and ceftriaxone in 40 patients undergoing elective cardiac surgery. Postoperative wound infection occurred in one and two patients, respectively, in each group (n.s.), and bronchial superinfection in one patient in each group. In 12 additional patients drug concentrations in plasma and pericardial fluid were measured at different times following the administration of ceftriaxone. Plasma and pericardial fluid concentrations of ceftriaxone were above the minimal inhibitory concentration of susceptible microorganisms for up to 24 h after intravenous administration. We conclude, firstly, that the incidence of infection after cardiac surgery is low with both cefamandole and ceftriaxone prophylaxis. Secondly, efficient plasma and pericardial fluid levels of ceftriaxone last for up to 24 h after intravenous administration.

[A pharmacokinetic study of diffusion in adenomatous prostatic tissue of an intravenous bolus of cefamandole]. / Etude pharmacocinétique de la diffusion dans le tissu prostatique adénomateux d'un bolus intra-veineux de céfamandole.

Twenty-three patients undergoing transurethral resection of the prostate for benign prostatic hypertrophy received antibiotic prophylaxis with a second generation cephalosporin, cefamandole, administered by a single IV bolus of 2.5 g. A pharmacokinetic study was performed on blood and resection chips collected at regular intervals. Cefamandole penetrates rapidly into the prostate without any saturation threshold. It diffuses less extensively and persists for a shorter period in elderly subjects, but penetrates to an identical degree regardless of the volume of the adenoma. The prostatic concentration was always higher than the minimal inhibitory concentration for the bacteria generally encountered, except for pseudomonas. The pharmacokinetic study of cefamandole therefore demonstrated that an IV bolus of 2.5 g is perfectly suitable for antibiotic prophylaxis prior to prostatic resection.

Efficacy of prophylactic antibiotics in vascular surgery: an arterial wall microbiologic and pharmacokinetic perspective.

This prospective study examined microbiologic features of arterial tissue and pharmacokinetics and bioactivity of cefamandole and cefazolin in patients undergoing elective primary prosthetic aortoiliofemoral/infrainguinal reconstruction. Double-blind, randomized, perioperative prophylaxis (1 gm intravenously every 6 hours for nine doses) with cefamandole or cefazolin was administered to 47 patients. Specimens of blood serum, subcutaneous fat, thrombus, atheroma, and arterial wall were obtained for culture and minimal inhibitory concentration and drug level analysis by high-pressure liquid chromatography. The serum half-life (hr +/- SEM) was 1.43 +/- 0.36 for cefamandole and 2.22 +/- 0.40 for cefazolin. Over the first 2 hours of surgery and for all time intervals combined, the serum concentration of cefazolin was significantly higher (p less than 0.025) than cefamandole. Irrespective of sampling time, the tissue concentration of cefazolin was significantly greater (p less than 0.005) than cefamandole. Positive arterial tissue cultures were obtained in 12 of 29 patients (41.4%) from 23 of 116 (19.8%) arterial tissue specimens. Coagulase-negative Staphylococcus was the predominant isolate, 64 of 93 (68.8%). Twenty-five of the 51 coagulase-negative staphylocci tested (49%) were slime-producers. During surgery, the arterial tissue concentration of cefamandole fell below the geometric mean minimal inhibitory concentration against all organisms combined, and against S. aureus (with the highest minimal inhibitory concentration of the prevalent isolates), significantly more often than the concentration of cefazolin. The data show that a significant number of primary elective aortoiliofemoral/infrainguinal reconstructions are associated with positive arterial tissue cultures, which represent a potential source of graft infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Topical and systemic antibiotics in the prevention of wound infection.

We evaluated under controlled conditions the efficacy of topical and systemic antibiotics, alone and in combination, in the prevention of wound infection and measured serum and tissue antibiotic levels in the wound and distant tissue after administration of antibiotics topically, systemically, and in combination. Adult Sprague-Dawley rats were contaminated on the dorsal paravertebral muscles with a preset standardized inoculum of Staphylococcus aureus, Escherichia coli, and Bacteroides fragilis. A second-generation cephalosporin was used; systemic administration was given intramuscularly and topically in powder form. Wound infection was confirmed by the recovery of the organism by culture. Prophylactic antibiotics were effective in preventing wound infection in all groups. Topical antibiotic and a combination (topical/systemic) antibiotic were significantly more effective than was systemic antibiotic alone in preventing wound infection. Adequate levels of antibiotic were achieved in serum and tissue with both topical and systemic antibiotics. Wound tissue concentration of antibiotic was significantly higher when topical antibiotic was used.

Effect of age and renal function on cefonicid pharmacokinetics.

Cefonicid (15 mg/kg) was administered intravenously at a constant rate of infusion over 15 min to 10 geriatric patients (mean age, 77 years) and to 4 young subjects (mean age, 35 years). Model-dependent and noncompartmental pharmacokinetic parameters were calculated and found to be congruous; noncompartmental data are reported. Significant differences in the values for area under the curve, mean residence time, total body clearance, and renal clearance were observed between the geriatric and young groups. Mean elimination half-life values were 9.59 and 4.88 h for the geriatric and young groups, respectively. Total body and renal clearances were inversely correlated to age and directly correlated to creatinine clearance. Free fraction was not correlated to albumin concentration but was correlated exponentially to total cefonicid concentration. Despite the prolonged half-life values observed in our geriatric patients, the difference in mean trough concentrations was slight. Daily administration of a 15-mg/kg dose should provide adequate concentrations in serum and should not produce appreciable accumulation in geriatric patients.

Pharmacokinetics of cefonicid in serum and its penetration into lung tissue, bronchial mucosa and pleura.

Cefonicid pharmacokinetics in serum and tissue penetration into the lung parenchyma, bronchial mucosa and pleura were studied in 39 patients undergoing lung excision for malignancy. Cefonicid concentrations in serum and tissues samples were assayed at different times after a single 1 g intramuscular administration. The concentrations observed were much higher than the reported minimal inhibitory concentrations for the microorganisms commonly responsible for bronchial and pulmonary infections and therapeutic concentrations were still detectable in the tissues 24 h after dosing. Kinetic findings demonstrated a similar half-life for cefonicid in tissues and in serum. These data provided a further kinetic explanation for the observed clinical efficacy of cefonicid with a single daily dose.

[Plasma and tissue concentrations of cefamandole during cardiac surgery]. / Concentrations sériques et tissulaires du céfamandole pendant la chirurgie cardiaque.

This study aimed to determine plasma (CPC) and tissue concentrations of cefamandole during cardiac surgery, so as to compare them with the minimal inhibitory concentration (MIC) for staphylococci (0.25 - 1 microgram.ml-1 for S. aureus; 2 micrograms.ml-1 for S. epidermidis). Cefamandole was given prophylactically to 8 consecutive patients as a single intravenous dose of 60 mg.kg-1. Tissue concentrations were measured in presternal subcutaneous loose tissue and sternal marrow. Average CPC was 233.75 +/- 58 micrograms.ml-1, 15 min after drug administration, 187 +/- 6.4 micrograms.ml-1 at the time of sternotomy, 57.9 +/- 36.5 micrograms.ml-1 10 min after the start of bypass and 36.4 +/- 18.4 micrograms.ml-1 at its end, and 15.5 +/- 5.9 micrograms.ml-1 at the end of the procedure. Sternal subcutaneous tissue and marrow concentrations were respectively 24.4 +/- 13.3 micrograms.g-1 and 31 +/- 5.6 micrograms.g-1 at the time of sternotomy, and 9.4 +/- 5.5 micrograms.g-1 and 9.2 +/- 3.5 micrograms.g-1 at the end of the procedure. Giving a high dose of cefamandole preoperatively appeared to have an effective prophylactic antibiotic action, as the plasma and tissue concentrations were always higher than the MIC for staphylococci.

Cost-efficiency of a long-acting cephalosporin agent.

In a prospective longitudinal study of patients in a general surgical ward, the relative cost-efficiencies of a long-acting third generation cephalosporin (ceftriaxone--mean plasma elimination t 1/2 390 min) and a short-acting second generation cephalosporin (cephamandole: mean plasma elimination t 1/2 32 min) were determined. The total cost of therapy for 24 h was +32.88 for cephamandole and +22.78 for ceftriaxone, that is, a reduction of 31%. Considerable cost containment can be achieved by using third generation cephalosporin agents that only require the administration of one intravenous injection per day.

Cefamandole pharmacokinetics during standard and pulsatile cardiopulmonary bypass.

The pharmacokinetics of cefamandole during standard or pulsatile cardiopulmonary bypass were studied in 13 adult cardiac surgery patients. All patients received 20 mg/kg of cefamandole intravenously at midnight before surgery, 6 AM on the morning of surgery and just prior to the initiation of cardiopulmonary bypass (CPB) surgery. Serum, skeletal muscle, and fat samples were taken at the beginning of CPB and at 30-minute intervals thereafter and assayed for cefamandole concentration. The average elimination rate constant and elimination half-life for cefamandole in patients undergoing standard CPB were 0.73 +/- 0.09 hour-1 and 0.94 +/- 0.11 hour, respectively. In contrast patients undergoing pulsatile CPB had significantly slower elimination rate constants (0.50 +/- 0.1 hour-1 and 1.4 +/- 0.28 hours, respectively; P less than or equal to .05). Area under the curve (AUC) values for cefamandole in fat and muscle tissue were higher in patients undergoing pulsatile CPB, but the differences were not statistically significant. Prolonged elimination from the serum, skeletal muscle, and adipose tissue, as compared with normal subjects, is seen with both pulsatile and standard CPB but is greater for the pulsatile method. Intraoperative dosing of cefamandole is required to maintain adequate serum and tissue levels for operations lasting longer than 4 or 6 hours in which standard or pulsatile CPB, respectively, are used.

Pharmacokinetics of cefonicid in patients with skin and skin structure infections.

The disposition of cefonicid (2 g intravenously every 24 h) was assessed in 15 patients with skin and skin structure infections. Trough and peak concentrations in serum were measured on two successive days to verify the attainment of steady state; and 1 trough and 12 postdose values of the concentration in serum were collected on the following day. Cefonicid concentrations in serum were determined by high-performance liquid chromatography. The cefonicid serum concentration versus time profile after intravenous infusion was clearly biexponential in all patients. The terminal elimination half-life determined by nonlinear regression analysis was 4.63 +/- 1.49 h (mean +/- standard deviation). The steady-state volume of distribution and total body clearance were 0.12 +/- 0.04 liter/kg and 0.369 +/- 0.110 ml/min per kg, respectively. These results are comparable to parameters derived from previous studies in noninfected normal volunteers. Thus, the disposition of cefonicid is not altered in patients with severe skin and skin structure infections.