Cefamandole kinetics during cardiopulmonary bypass.

The kinetics of cefamandole during cardiac surgery was studied in 16 adult patients given a single intravenous infusion of 20 mg/kg at the time of anesthesia induction. Five normal volunteers who received the same dose served as controls. Cardiopulmonary bypass (CPB) was found to signficantly increase the half-life (t 1/2) of cefamandole. The mean t 1/2 during CPB (113.2 min) was longer than the terminal t 1/2 in normal volunteers (52.0 min; p less than 0.005). Throughout CPB (maximum, 3,7 hr), cefamandole plasma levels were maintained above the minimum inhibitory concentration for those organisms most likely to cause postoperative infections. We conclude that if 20 mg/kg of cefamandole is given within an hour of the beginning of cardiovascular surgery, a supplemental dose is not needed until the patient has been on CPB for at least four hours.

Cefonicid kinetics in subjects with normal and impaired renal function.

Cefonicid is a cephalosporin with a longer t1/2 than currently available cephalosporins. Cefonicid kinetics after an intravenous dose of 7.5 mg/kg were followed in four groups of subjects: group 1, four subjects with normal creatinine clearance (Clcr greater than 80 ml/min); group II, seven subjects with mild renal insufficiency (Clcr 50 to 80 ml/min); group III, five subjects with moderate to severe renal impairment (Clcr 8 to 49 ml/min); and group IV, five subjects with end-stage renal disease who were receiving maintenance hemodialysis (Clcr less than 8 ml/ml). Cefonicid volume of distribution ranged from 6.9% to 17.6% body weight but was not related to Clcr. Elimination t1/2 was 4.6 +/- 0.7 hr in group 1,6.0 +/- 2.7 hr in group II, 25.6 +/- 14.0 hr in group III, and 65.3 +/- 43.6 hr in group IV. There was a strong correlation between plasma cefonicid clearance and Clcr. Nonrenal clearance did not change with decreasing Clcr. Hemodialysis clearance calculated from plasma concentrations and recovery in dialysate was 2.5 +/- 0.9 ml/min. These kinetic parameters were used to formulate dosage regimens for patients with renal impairment.

Use and interpretation of Schlichter's test on Haemophilus influenzae: relation of in vitro to in vivo results for cefamandole.

When Haemophilus influenzae infections are treated by an antibiotic acting on the bacterial wall, the adequacy of antimicrobial therapy can be assessed by Schlichter's test. This test may be carried out using Mueller Hinton broth (or Mueller Hinton broth with 50% pooled serum and a supplement of Ca++ and Mg++) supplemented with Fildes' enrichment and an inoculum adjusted to the 0.5 McFarland turbidity standard diluted 200x. However, correct reading of end points can be obtained only by phase contrast microscopic examination, which allows the establishment of good correlation between the in vitro and in vivo findings. In patients with lung infections successfully treated with cefamandole, the presence of spheroplasts in samples derived from Schlichter's tests correlates well with clinical improvement and eradication of the pathogenic organism checked by transtracheal aspiration.

Topical versus systemic cephalosporin administration in elective biliary operations.

The role of prophylactic antibiotic lavage in elective biliary tract operations is controversial. To investigate this question, a prospective, randomized study was undertaken between 1979 and 1983. All patients more than 18 years of age who underwent elective biliary operations were included. Eighty-eight patients were enrolled in the study and were stratified into the following antibiotic groups: (1) cefamandole nafate 2 gm administered intravenously preoperatively and 6 hours postoperatively in four doses; (2) cefamandole nafate 0.4% solution: 250 ml to irrigate the abdominal wound on opening, 500 ml to irrigate the peritoneal cavity, and 250 ml to irrigate the wound on closing; and (3) systemic plus topical administrations as in Nos. 1 and 2. Age, sex, type of operation, and underlying diseases were comparable in all groups. The patients were then evaluated for postoperative infections. In the intravenous cefamandole group there was only one patient who developed a urinary tract infection after operation. In the topical cefamandole group there were four postoperative infections: wound-one, urinary tract--two, and cholangitis--one. In the intravenous plus topical cefamandole group there were four postoperative infections: wound--one, urinary tract--two, and pneumonia--one. No deaths occurred in any group. Blood, subcutaneous, and peritoneal drug levels were sampled 1 hour after opening and before closing. Therapeutic serum levels of cefamandole are 1 to 16 micrograms/ml and adequate serum levels were achieved in all groups. However, higher levels were obtained in the subcutaneous tissue and peritoneum when topical cefamandole was used. We conclude: (1) Topical cefamandole lavage alone is adequate prophylaxis in elective biliary operations and achieves comparable results as perioperative systemic administration; (2) topical cefamandole resulted in higher subcutaneous tissue and peritoneal levels than intravenous cefamandole and also achieved therapeutic serum levels; and (3) there is no advantage to the use of systemic plus topical antibiotics in elective biliary operations.

Prevention of endomyometritis using antibiotic irrigation during cesarean section.

After double-blind controlled studies demonstrated cefamandole nafate irrigation of the uterus during cesarean section to be effective in reducing the rate of endomyometritis, antibiotic irrigation was adopted as a standard procedure at Tripler Army Medical Center. The present study analyzes the outcome in patients undergoing cesarean section before (comparison group) and after (treatment group) routine use of antibiotic irrigation began. The incidence of endomyometritis in 100 patients from the comparison group was 20% and in 298 patients from the treatment group 1.7% (P less than .0001). Serum analysis for cefamandole nafate demonstrated little systemic absorption of the antibiotic. Cefamandole nafate intrauterine irrigation at cesarean section effectively prevents endomyometritis.

Comparison of intravenous administration with intrauterine irrigation with ceforanide for nonelective cesarean section.

A randomized, prospective, double-blind study was designed to compare intravenous administration with intrauterine irrigation using an extended half-life (t1/2 = three hours) cephalosporin, ceforanide. Patients included in the study had a nonelective cesarean section with rupture of membranes for three hours or longer. Sixty-four patients received a single dose of ceforanide immediately after clamping the umbilical cord. Patients were similar in both groups in age, weight, length of labor, and duration of ruptured membranes. The group receiving the intravenous ceforanide had a significantly shorter duration of surgery than the patients receiving the intrauterine ceforanide. Endometritis infection rates were similar, 11.8% (intravenous) versus 11.1% (intrauterine), P greater than .1. Serum levels were as much as tenfold higher in the intravenous group versus the intrauterine group. Intrauterine irrigation with an antimicrobial agent provided no advantage over systemic administration.

Cefamandole pharmacokinetics and dosage adjustments in relation to renal function.

The pharmacokinetic characteristics of cefamandole were determined after intravenous administration of a 1-Gm dose to 10 subjects with normal renal function, 10 patients with stabilized renal failure, and five chronic nephritic patients included in a intermittent hemodialysis program. In normal subjects, biological half-life (t1/2) averaged 0.94 hour, the overall elimination rate constant (Ke) was 0.7378 (hr-1), total clearance (Ct) was 223 ml/min/1.73 m2, renal clearance (Cr) was 164 ml/min/1.73 m2, and urine recovery of cefamandole over the 6 hours following a dose amounted to 74 per cent of the administered dose. In patients with stabilized renal failure and in patients on hemodialysis, biological half-life was markedly increased, with a theoretical value of 10.4 hours in case of a creatinine clearance of zero. The amount of antibiotic extracted over a 6-hour dialysis period accounted for 29 per cent of the cefamandole present in the vascular compartment at the beginning of the dialysis procedure. A significant correlation was established between the values of Ke and creatinine clearances, Ccr: Ke = 0.0289 + 0.0063Ccr (r = 0.937). This relationship was used to calculate the loading dose (LD), maintenance doses (D), and dosage intervals (tau) with regard to renal function. From these data recommendations regarding the adjustment of cefamandole dosage to the renal status can be made.

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.

Comparative study between two prophylactic antibiotic regimens of cefamandole during coronary artery bypass surgery.

In two groups of patients undergoing coronary artery bypass grafting (CABG), two different regimens of antibiotic prophylaxis with cefamandole nafate were compared. In Group 1, 30 mg per kilogram of body weight was administered intravenously during induction of anesthesia. In Group 2, a second dose of 15 mg/kg was administered intravenously shortly before cannulation. Serum and tissue levels in the right atrium, the pericardium, and the sternum were determined using high-pressure liquid chromatography. The results showed that in Group 2 the serum levels were significantly higher from 48 minutes onward after induction and remained at an acceptable level during CABG. The tissue levels in the sternum and pericardium were also significantly higher in Group 2 compared with Group 1. It is concluded that a second dose of cefamandole (15 mg/kg) shortly before the beginning of cardiopulmonary bypass is recommended, particularly for high-risk patients.

A comparison of the safety, efficacy, and distribution of ceforanide and cephalothin in coronary artery bypass graft surgery.

Antibiotic prophylaxis in open-heart operations is a widely accepted practice. Introduction of new antibiotics with differences in tissue distribution, spectrum of activity and therapeutic index prompts their evaluation as possible effective prophylactic agents. We compared the distribution, clinical efficacy, and safety of ceforanide with cephalothin as a prophylactic agent in coronary artery bypass graft (CABG) procedures. The results indicated that the intravenous administration of ceforanide at the dose of 1 gm every 12 hours for 2.5 days was equivalent to cephalothin 1 gm every 6 hours for 2.5 days. Serum, muscle, and bone concentrations of ceforanide were significantly greater than those of cephalothin. These concentrations consistently exceeded the minimal inhibitory concentration for Staphylococcus aureus, the major pathogen implicated in wound infections. No toxicty was observed with either antibiotic. Ceforanide merits consideration as a prophylactic antibiotic in CABG operations.

Penetration characteristics of cefamandole into the right atrial appendage and pericardial fluid in patients undergoing open-heart surgery.

In 24 patients undergoing open-heart operation, 2 gm of cefamandole was administered intravenously by bolus technique at various time intervals prior to operation. Samples of pericardial fluid, atrial appendage tissue, and serum were obtained simultaneously in order to compare antibiotic levels in these sites as a function of time. All samples were microbiologically assayed by disc diffusion. Using linear regression analysis, the atrial appendage and serum half-lives for cefamandole were 36 and 38 minutes, respectively. At 40 minutes, peak levels of cefamandole were observed both in pericardial fluid and in atrial appendage tissue. The peak concentrations of cefamandole were 50 micrograms/gm in atrial appendage and 25 micrograms/ml for free drug content in pericardial fluid. These amounts were appreciably above the mean minimum inhibitory concentration of cefamandole for penicillin-resistant staphylococci, the usual pathogens grown in infections following implant operation.

Human vitreous levels of cefamandole and moxalactam.

We gave 2-g intravenous doses of either cefamandole or moxalactam to 22 patients before vitrectomy. At 1 1/2 to 2 1/2 hours after administration, cefamandole vitreous concentrations varied from 0.36 to 2.05 micrograms/ml (mean, 0.94 micrograms/ml). Individual levels above the minimum inhibitory concentration of cefamandole for 90% (MIC90) of Staphylococcus aureus were found in five of 11 patients. Levels above the MIC90 for S. epidermidis were found in only two of 11 samples. Vitreous concentrations above the MIC90 of cefamandole for common gram-negative pathogens were found in only two patients. Moxalactam concentrations in the vitreous varied from 1.1 to 4 micrograms/ml 30 minutes to six hours after administration. These levels were not above moxalactam's MIC90 for S. aureus or S. epidermidis but were many times higher than the MIC90 of moxalactam for Enterobacteriaceae excluding Pseudomonas.

Evaluation of tissue levels of cefamandole in severely ischaemic lower limbs using two regimens of dosage.

Cefamandole levels were measured in peripheral blood, and in skeletal muscle and subcutaneous fat samples taken from 20 patients during amputation of the leg for severe ischemia. Tissue samples were taken from both proximal and distal levels in the amputated limb. Cefamandole was administered as either a 2 g intravenous bolus given with induction of anaesthesia, or a combination of 1 g intramuscularly with the premedication plus 1 g intravenously with anaesthetic induction. Levels of cefamandole in serum and proximal muscle and fat samples were well above the minimum inhibitory concentrations required for most Gram-positive and Gram-negative organisms. Cefamandole levels in more distal samples were somewhat lower but still achieved therapeutic levels in most cases. Higher tissue levels of cefamandole were achieved when 2 g were given intravenously as a bolus.

Blood-pancreatic juice barrier to antibiotic excretion.

Antibiotics were given intravenously to dogs with chronic pancreatic fistulas, and serum and pancreatic juice levels were measured. Despite adequate serum values, gentamicin, tetracycline, clindamycin, and moxalactam did not appear in the pancreatic juice, which suggested a barrier to their excretion. In contrast, chloramphenicol reached a peak concentration in the pancreatic juice that amounted to 36 percent of the peak serum value. In the pancreatic juice, ampicillin, cefoxitin, and cefamandole reached only 5 percent of the peak serum values but were still within the therapeutic range. We have concluded that there is a blood-pancreatic juice barrier to some antibiotics, which leads to selective excretion.

Human pharmacokinetics of a new braod-spectrum parenteral cephalosporin antibiotic, ceforanide.

The pharmacokinetics of the l-lysine salt of ceforanide were studied after intravenous administration of 1132 and 2264 mg as 30-min constant-rate infusions and after intramuscular administration of 556 and 1132 mg. The peak intravenous plasma concentrations were 136 and 222 microgram/ml at termination of infusion, and 12-hr trough concentrations were 5.9 and 9.0 microgram/ml, respectively. The peak intramuscular plasma concentrations were 38 and 74 microgram/ml at 1.0-1.3 hr after dosing, and 12-hr trough concentrations were 3.9 and 6.7 microgram/ml, respectively. When 19 successive intravenous and intramuscular doses at these levels were administered at 12-hr intervals, there was no tendency toward drug accumulation. The major drug elimination route was urinary excretion; 85% of the dose was excreted unchanged in the urine within 12 hr, and no metabolites with antibiotic activity were observed in urine. The mean terminal plasma half-life was 2.98 hr, the mean plasma protein binding was 80.6%, the steady-state volume of distribution was 12 liters, the plasma clearance was 45.9 ml/min/1.73 m2, and the renal clearance was 34.9 ml/min/1.73 m2. The pharmacokinetic properties and antibacterial activity spectrum indicate that this antibiotic should be effective in treating human bacterial infections when administered at 12-hr intervals. It is presently under clinical investigation.

Pharmacokinetics of cefamandole in rabbits with experimentally induced renal impairment.

The pharmacokinetics of cefamandole have been studied in rabbits with normal renal function and varying degrees of renal impairment caused experimentally, by uranyl nitrate, after i.v. administration of a single dose of 30 mg/kg of the antibiotic. The plasma concentrations of cefamandole 80 minutes after administration were 3 micrograms/ml in normal rabbits reaching 90 micrograms/ml at 9 hours in the case of terminal renal impairment. With respect to the pharmacokinetic parameters established in rabbits with normal renal function, the following modifications may be observed in the case of rabbits with renal impairment: alpha, beta, K12, K21, K13, Vc and Vp are decreased, while there is an increase in t 1/2 alpha, t 1/2 beta and (AUC)infinity 0. Linear relationships have been established between log alpha and log beta, respectively, and serum creatinine. Biliary excretion of cefamandole is increased parallel to the increase in the degree of renal impairment, there being a linear relationship between the percentage excreted of the antibiotic and serum creatinine. The values of KB fall from 0.57 h-1 in rabbits with normal renal function, to 0.26 h-1 in rabbits with severe renal impairment.

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.

Penetration of cefonicid in skin suction blister fluid in healthy volunteers.

A new cephalosporin, cefonicid (1 g) was given intramuscularly to six healthy volunteers 12 h after induction of skin suction blister. Serum and blister fluid were collected during a 24 h period. Antibiotic assay was made by a microbiological method. The data were analysed by a one-compartment kinetic model. Despite the high protein binding, cefonicid penetrated in microbiologically effective concentration into blister fluid. Blister fluid concentrations were higher than the serum concentrations at 24 h.

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.

Serum bactericidal activity against Klebsiella pneumoniae in volunteers receiving increasing doses of tobramycin with or without cefamandole.

Ten volunteers received intravenously in a randomly allocated order and on separate days the following regimens: cefamandole (15 mg/kg); tobramycin (1.5 mg/kg); tobramycin (3 mg/kg); cefamandole (15 mg/kg) + tobramycin (1.5 mg/kg); cefamandole (15 mg/kg) + tobramycin (3 mg-kg). Tobramycin serum levels were 3.7 +/- 0.7 micrograms/ml one hour after infusion of the 1.5-mg/kg and 7.8 +/- 1.6 micrograms/ml after the higher dose. Cefamandole serum levels were 26.0 +/- 5.2 micrograms/ml at the same time. Serum bactericidal activity and killing-rate studies were performed on a collection of 18 strains of Klebsiella pneumoniae. Against cefamandole-sensitive strains, all regimens were satisfactory (median serum bactericidal activity 1:16 to 1:64). Tobramycin (3 mg/kg) and both combinations were slightly more active on cefamandole-resistant strains (1:16 to 1:32) than cefamandole (1:2) and tobramycin low dose (1:8). Except for cefamandole alone, all regimens were equivalent in killing studies.