Chemotherapy of experimental streptococcal endocarditis. I. Comparison of commonly recommended prophylactic regimens.

The effectiveness of various antibiotics commonly recommended for the prophylaxis of bacterial endocarditis has been evaluated in experimental streptococcal endocarditis in rabbits. High doses of penicillin G did not prevent the development of this infection. The only consistently successful prophylactic regimens using penicillin alone were those which provided for both an early high serum level and more than 9 h of effective antimicrobial action. Vancomycin was the only other drug which proved uniformly successful when given alone, even though the duration of its antimicrobial action in the blood was only 3 h. However, combined therapy using penicillin G or ampicillin with streptomycin was always effective in prophylaxis. Treatment with single injections of ampicillin, cephaloridine, cephalexin, clindamycin, cotrimoxazole, rifampicin, streptomycin, erythromycin, and tetracycline failed to prevent infection. The findings provide information on the effect of antimicrobials in vivo and may be applicable to the chemoprophylaxis of infective endocarditis in clinical practice.

Renal excretion of cephapirin and cephaloridine: evidence for saturable tubular reabsorption.

Drug concentrations in plasma and urine were determined in 5 healthy subjects after intravenous infusion of 1 gm cephapirin and cephaloridine. Sampling of blood and urine was frequent and prolonged. Specimens were analyzed by high-pressure liquid chromatography (HPLC). Renal clearance of cephapirin decreased to less than 5% of control in all subjects when drug concentrations in plasma and urine declined. Cephaloridine clearance decreased to a lesser extent. Our findings suggest that, besides tubular secretion and glomerular filtration, a saturable and probably active tubular reabsorption is also involved in the renal handling of these two cephalosporins. The saturable reabsorption process was characterized by its Michaelis-Menten constant Km and its maximum transport capacity Tm.

Effects of furosemide on glomerular filtration rate and clearance of practolol, digoxin, cephaloridine, and gentamicin.

Furosemide was shown to decrease inulin clearance in 20 of 27 normal subjects. The depression in inulin clearance occurred in both water-loaded and non-water-loaded subjects. The renal clearance of practolol, but not digoxin, was reduced when furosemide was given. The average total plasma clearances of gentamicin and of cephaloridine over a 6-hr period were decreased after furosemide. The reduced clearances of the antibiotics were associated with higher plasma levels, the increase in antibiotic concentration being as much as 100% at 1 hr after an intravenous bolus injection.

Effects of L-carnitine on the renal tubular transport of cephaloridine.

It has been demonstrated recently that cephaloridine (Cld) inhibits the tubular reabsorption of filtered carnitine (Carn) in the rabbit kidney. This interaction has suggested that the limited net cell-to-luminal fluid movement of Cld following its secretory transport across the antiluminal membrane might result from a balance of active Cld reabsorption by a Carn carrier at the brush border approximately equal to its secretion into the tubular fluid, rather than the previously proposed luminal membrane block. Studies were done to determine the effects of L-Carn, 750 mg/kg, i.v. on the tubular secretion and cortical concentrations of Cld, infused i.v. at a dose of 28 mg/kg (Carn:Cld molar ratio = 70:1). The fractional excretions of Cld during three consecutive periods of 10 min each, one before and two following the bolus infusion of Carn, were (means +/- SEM): 1.18 +/- 0.14, 1.20 +/- 0.14, and 1.16 +/- 0.11, respectively (N = 6 each; differences NS). Cortex-to-serum concentration ratios of Cld in control and Carn-treated rabbits were 10.43 +/- 0.32 and 10.16 +/- 0.86, respectively (NS). The data provide evidence against the reabsorptive transport of Cld by a Carn carrier, and do not support a model of balanced secretion and reabsorption as the cause of limited clearance despite significant secretory transport of Cld into the tubular cell.

Absorption of antibiotics during peritoneal dialysis in patients with renal failure.

Cloxacillin, ampicillin, cephaloridine, kanamycin, and polymyxin B were administered singly in the dialysis fluid of patients having peritoneal dialysis for chronic renal failure. Therapeutic blood levels could be attained with all the drugs by the end of 12 hours of dialysis, using a concentration in the dialysis fluid which did not produce any local toxic symptoms. Absorption rates across the peritoneum were higher for cephaloridine, ampicillin, and cloxacillin than for kanamycin and polymyxin B. The serum half-lives after termination of dialysis were in excess of 11 hours, except that for cloxacillin which had a half life of about 2.5 hours.

Intra-incisional cephaloridine: a comparison of two methods of administration.

Serum cephaloridine concentrations were measured in the immediate post-operative period in 23 patients who had received a prophylactic dose of 1 g of the drug into the wound at the end of operation. Eleven patients received the antibiotic as a powder and 12 as a solution. The serum concentrations were higher, though not significantly so, in the group receiving powder, and this is thought to be due to the lesser amount of spillage and loss into dressings when the antibiotic is given in this form.

Influence of endogenous and exogenous Jaffé-reaction-positive pseudo-creatinine chromogens in determination of creatinine in blood of normal and cephaloridine-administered rats.

To investigate a magnitude of analytic errors brought by certain interfering substances to the chemical method using Jaffé-reaction for determination of creatinine, two sorts of values determined by the chemical method and by the HPLC method were compared between each other, in blood samples obtained from control and cephaloridine (CER)-administered rats. The rats that received an intravenous injection of CER in dose of 1,000 mg/kg body weight, showed two peaks at the 1-hour and on the 3-day. Since the color development of CER determined in the chemical method showed that 1 g of CER corresponded to 0.0208 g of creatinine, the results of plasma CER determination proved that the first peak was ascribable to the color development of CER. As to the second peak, no significant difference was observed between the values of the two methods. This finding denoted that, when the creatinine levels were elevated, the two sorts of values due to the two methods approached to one another, and suggested that the ratio of "endogenous Jaffé-reaction-positive pseudo-creatinine chromogens" to "total Jaffé-reaction-positive chromogens" would be decreased according as the "true" creatinine was increased. In the control rats, the ratio to "total Jaffé-reaction-positive chromogens" was 60% in terms of "true" creatinine, and 40% in terms of "endogenous Jaffé-reaction-positive pseudo-creatinine chromogens."

Half-life of cephaloridine in dogs with reduced renal function.

Various degrees of renal insufficiency were produced in 9 dogs by nephrectomy, or segmental ligation of the branches of the renal artery, or both. The serum half-life of cephaloridine, measured after a single intramuscular injection, increased progressively as renal function decreased. In dogs with 85% reduction in renal mass, serum half-life was approximately 3 times that of control dogs. To prevent accumulation of cephaloridine in dogs with renal dysfunction, a modified dose schedule was established on the basis of these experimental results.

Intratracheal injection of antibiotics in the California sea lion, Zalophus californianus, and bottlenosed dolphin, Tursiops truncatus.

Gentamicin and cephaloridine were administered by intratracheal injection to the California sea lion, Zalophus californianus, and the bottlenosed dolphin, Tursiops truncatus. Uptake and clearance of these antibiotics in the blood were monitored. In all cases, absorption through the respiratory mucosa resulted in blood levels approaching therapeutic concentrations despite low dosages.

[Antibiotic therapy and renal insufficiency. Pharmacokinetics of pivampicillin, cephaloridin and streptomycin in chronic uremic patients undergoing conservative or hemodialytic treatment]. / Terapia antibiotica ed insufficienza renale. Rilievi intorno alla farmacocinetica di alcuni antibiotici (pivampicillina, cefaloridina, streptomicina) in pazienti con uremia cronica in terapia conservativa od emodialitica

The plasma kinetics of some antibiotics (pivampicillin, cephaloridine, streptomycin) has been studied in patients with chronic renal failure. The oral administration of pivampicllin promptly increases the plasma levels of the antibiotic, without any toxic side effect: this antibiotic is to be chosen in chronic uremic patients, also during regular dialytic treatment (R.D.T.). Cephaloridine has some renal toxic effects in high concentration; in the renal failure it is advisable to calculate the exact dose of the antibiotic by the use of nomograms when the creatinine clearance is known. These nomograms must absolutely be employed when administrating some toxic antibiotics, as gentamycin and streptomycin in chronic uremic patients. Some formulas have been experimentally determined, which allow a calculation of the exact dose of the antibiotic, also during R.D.T. If a kidney or urinary tract infection is present in patients with low G.F.R. (creatinine-clearance less than 30 ml/min.), it is necessary to administer only those antibiotics which can reach an active urinary concentration (i.e. penicillin and derivatives, cephaloridine).

[Pharmacokinetics of cephaloridine (author's transl)].

I studied on absorption and excretion of cephaloridine. Cephaloridine was administered intravenously to 5 healthy volunteers weighing 65 kg to 83 kg, and the blood levels were measured. A cross over test subjecting 2 grams intravenous drip infused for 1 hour against the same dose for 2 hours were performed after 1 week interval. The disposition of cephaloridine was estimated by applying one-compartment model which was scaled from YOKOKAWA & HULET PACKARD'S disc top computer. Pharmacokinetic parameters are as followings: 1 hour d.i.v.: Kel 1.410 (hr-1), Vd 9.629(L), T 1/2 30.290 (min.) 2 hours d.i.v.: Kel 0.876 (hr-1), Vd 21.106(L), T 1/2 49.372 (min.).

[Study on cephaloridine concentration in bone marrow (author's transl)].

Cephaloridine (CER) concentration in the bone marrow of tibia was examined 1, 2, and 3 hours after intramuscular injection of 1 g. CER concentration in the bone marrow of tibia 1 hour after injection was 26.0+/-8.927 microng/ml. Ratio to serum was 78.5%. CER concentration in the bone marrow of tibia 2 hours after injection was 20.6+/-5.003 microng/ml. Ratio to serum was 87.3%. CER concentration of bone marrow of tibia 3 hours after injection was 14.8+/-4.79 microng/ml. Ratio to serum was 91.9%. Difference of concentration between in bone marrow and serum was not statistically significant. Penetration capacity of CER into the bone marrow of tibia was excellent.

[Experimental studies on the passage of antibiotics into cerebrospinal fluid in staphylococcal meningitis in rabbits. II. Cephaloridine, cephalothin and cefazolin (author's transl)].

Passage of cephaloridine, cephalothin and cefazolin into cerebrospinal fluid (CSF) was evaluated in Staphylococcus aureus meningitis in rabbits and the following results were obtained. 1. Concentration in CSF (microgram/ml) [CSF/serum ratio (%)] was determined 1/2, 1 and 2 hours after a single intravenous injection of 100 mg/kg of each antibiotic, respectively; cephaloridine-7.5 [8.9], 9.7 [13.8], 9.1 [22.6]; cephalothin-0.42 [3.6], 0.23 [6.4], not detectable [0]; cefazolin-7.5 [11.8], 5.2 [19.3], 2.0 [17.5]. 2. When results with cefazolin after an intravenous injection 100 mg/kg and 200 mg/kg were compared, a definite dose response was noted in blood concentration but not in CSF concentration. 3. A standard error of CSF concentrations of each antibiotic was larger than that of penicillins, and "Unpredictability" of their passage into CSF was considered to be one of the characteristics common to these three drugs in respect of their passage into CSF. 4. There was no significant difference noted in antibiotic passage into CSF between cephaloridine of low protein binding rate and cefazolin of very high binding rate. Cephalothin, of which binding rate was intermediate, showed a remarkably lower passage into CSF. These results indicate that a correlation does not always exist between protein binding rate of the antibiotics and their passage into CSF. 5. Based on the above results, a review of the literature was made on clinical applicability of these three antibiotics in the treatment of bacterial meningitis. Low transport rate of cephalothin into CSF and nephrotoxicity of cephaloridine make them to be unsuitable for bacterial meningitis. Cefazolin is considered to be suitable in the treatment of ampicillin-resistant Escherichia coli meningitis and Gram-positive coccal meningitis in which penicillins are not applicable.

[Penetration of cephaloridine and cephalothin into the cerebrospinal fluid-clinical study (author's transl)].

There were 35 cases, treated with Cephaloridine or Cephalothin after neurosurgical operation. Neurological surgeon always troubled with passage of blood-brain barrier when drug was given. Antibiotics was not exceptionally, therefore we, neurological surgeon, must select the effective drug to bacterium, that which penetrated enough to the intracranial organ through the blood-brain barrier. In this paper, we measured the concentration of Cephaloridine and Cephalothin into cerebrospinal fluid in the cases with non inflammatory meninges. We collected the cerebrospinal fluid from continued ventricle tap and serum, then measured the concentration of the drug with bioassay. Cephaloridie treated cases. 22 cases. 1) 1 g intramuscular injection. 4 cases. Serum level got to highest value, 64 mug/ml (mean value) 1 hour after injection. CSF level got to maximum concentration 46.8 mug/ml. (mean value) serum mean level 21.5 mug/ml. CSF mean level 0.73 mug/ml. 2) 1 g 3 minutes-intravenous injection 5 cases. Serum level got to highest value 67.5 mug/ml. CSF maximum level was 5.25 mug/ml. Serum mean level 19.74 mug/ml. CSF mean level 0.61 mug/ml. 3) 1 g 1 hour-intravenous drip. 9 cases. Serum maximum level 121.0 mug/ml. CSF maximum level 2.30 mug/ml. Serum mean level 20.08 mug/ml. CSF mean level 0.67 mug/ml. 4) 1 g 8 hours-intravenous drip. 3 cases. Serum maximum level 61.0 mug/ml. CSF maximum level 1.36 mug/ml. Serum mean level 14.78 mug/ml. CSF mean level 0.47 mug/ml. Cephalothin treated cases, 12 cases. 1) 1 g 8 hours-intravenous drip, 4 cases. In fact we could detect the drug only in one case, in CSF, and we could not in other three cases. In KF - 4 case, serum maximum concentration was 26.0 mug/ml, CSF maximum concentration was 0.07 mug/ml. Serum mean level 16.97 mug/ml. CSF mean level 0.01 mug/ml 2) 2 g 1 hour-intravenous drip, 9 cases. Serum maximum level 690.0 mug/ml. CSF maximum level 2.03 mug/ml. Serum mean level 29.59 mug/ml. CSF mean level 0.06 mug/ml. In cephaloridine cases, the tendency was observed, that which, as concentration of the drug in CSF increased, cell count and protein decreased, and, as concentration of the drug decreased, cell count and protein increased. CSF/serum concentration ratio of Cephaloridine increased, when time passed, in intramuscular, 3 minutes intravenous, and 1 hour-intravenous drip group. Then only in 8-hours-intravenous prip group. Then only in 8-hours-intravenous drip group, concentration ratio decreased. In Cephaloridine group, mean value of CSF/serum ratio showed. 1 g i.m. 0.084 1 g 3 minutes-i.v. 0.098 1 g 1 hour-i.v. 0.194 1 g 8 hours-i.v. 0.044.