Simulation of vancomycin peak and trough concentrations using five dosing methods in 37 patients.

Five methods of dosing vancomycin (Matzke, Moellering, Nielsen, Lake-Peterson, and manufacturer's) were simulated in 37 patients. Ten serum samples were obtained after a 1-hour intravenous infusion of 6.2-20 mg/kg total body weight. A preinfusion serum sample was obtained from patients not studied on the first dose. Initial estimates of pharmacokinetic values were made using nonlinear iterative least squares regression and serum concentration-time data. These data were fitted to a two-compartment, open-infusion model. Simulations of the peak and trough serum concentrations at steady state for each patient were determined by multiple-dose simulated pharmacokinetics and each patient's pharmacokinetic values using the regimen suggested by each of the five methods. Steady-state serum concentrations, predicted systemic clearance by each method (except Lake-Peterson), and the daily dose for each patient recommended by each method were determined. All the methods underpredicted actual drug clearance, with the Nielsen method having the lowest prediction. The Matzke method recommended the largest dosage. Using each of the methods, only 3-16% of patients would have achieved recommended peak and trough serum concentrations. In the simulation model used, no method performed satisfactorily in attaining the desired vancomycin peak and trough concentrations. We suggest that the Lake-Peterson method could be used initially, provided that monitoring is also performed to adjust the dosage regimen further.

Vancomycin pharmacokinetics in patients with various degrees of renal function.

The influence of age, protein binding, and renal function on the pharmacokinetics of intravenous vancomycin was evaluated in 37 adult patients with various degrees of renal function. Patients were categorized into three groups based on measured creatinine clearance (CLCR): groups 1, 2, and 3 had 24-h CLCRs of greater than 70, 40 to 70, and 10 to 39 ml/min per 1.73 m2, respectively. After 1 h of intravenous infusion, concentrations of vancomycin in serum declined in a biexponential manner in all patients. Diminished renal function in groups 2 and 3 was accompanied by a lower total body vancomycin clearance (CL) (52.6 and 31.3, respectively, versus 98.4 ml/min per 1.73 m2) and a lower renal vancomycin clearance (CLR) (48.2 and 19.8, respectively, versus 88.0 ml/min per 1.73 m2) than in group 1. No significant differences in apparent distribution volume of the central compartment or apparent distribution volume at steady state were observed. Mean serum protein binding of vancomycin was 30% and was not significantly affected by renal function. Stepwise multiple linear regression analysis revealed that CLCR was the strongest predictor of vancomycin CL (r = 0.77, P less than 0.001) and vancomycin CLR (r = 0.87, P less than 0.001). Age did not significantly improve these correlations once CLCR was included. The relationship of vancomycin CL and CLCR was utilized to develop the following equation to dose vancomycin in the majority of renally impaired patients: dose (milligrams per kilogram per 24 h) = 0.227CLCR + 5.67, where CLCR is standardized to milliliters per minute per 70 kg. The practical dosing intervals that the calculated dose can be divided into and administered include 8, 12, 24, and 48 h based on the CLCR of the patient.

Pharmacokinetics and antibacterial activity of two gentamicin products given intramuscularly.

The pharmacokinetics and antibacterial activity of two injectable gentamicin products given i.m. were compared. Ten healthy men randomly received either Schering or Invenex gentamicin 1 mg/kg (as the sulfate salt) by intramuscular injection into the deltoid muscle. Four to six weeks later, subjects received the alternate preparation at the same dose in the opposite arm. Blood samples for gentamicin concentrations were obtained before drug administration and at various times for up to four hours after drug administration; urine from each subject was also collected before and after drug administration. Values for area under the curve, elimination rate constant, peak serum gentamicin concentration and time to peak concentration, clearance, half-life, and percentage of drug excreted in the urine over four hours were compared for each preparation in each subject. The serum inhibitory and bactericidal activities of each gentamicin preparation against Escherichia coli and Klebsiella pneumoniae were also evaluated. None of the pharmacokinetic values for the two preparations was significantly different. The inhibitory and bactericidal activities resulting from each product were also comparable and adequate. No clinically important differences in pharmacokinetic behavior or inhibitory or bactericidal activity were found between gentamicin products of Schering and Invenex.

Clinical and microbiological characterization of patients with nonspecific vaginosis associated with motile, curved anaerobic rods.

The vaginal secretions of 20 normal control subjects and 21 patients with motile, curved anaerobic rods were cultured for aerobic and anaerobic bacteria, Chlamydia trachomatis, herpes simplex virus, and Trichomonas vaginalis. Extensive histories and physical examinations of the patients and microscopic appearance and gas-liquid chromatography patterns of vaginal secretions were compared between the two groups. The patients who had motile rods in their vaginal secretions more frequently presented with a history of complaints about foul-smelling discharge (18 [86%] of 21); discharge noted during physical examination at their introitus (15 [71%] of 21); a vaginal pH greater than 4.5 (21 [100%] of 21); and a highly specific microscopic appearance of their secretions. The secretions were characterized by the absence of lactobacilli, the presence of highly motile, curved bacilli, and an increased number of background bacteria when compared with normal patients. Patients had more frequent anaerobic isolates than did controls (P less than .001), with increased numbers of Peptococcus, Peptostreptococcus, Propionibacterium, and Bacteroides species. All patients with motile bacteria in their secretions met the criteria of the syndrome of nonspecific vaginosis that has been previously described.

Comparative aminoglycoside inactivation by beta-lactam antibiotics. Effects of a cephalosporin and six penicillins on five aminoglycosides.

Gentamicin, tobramycin, netilmicin, kanamycin and amikacin were evaluated over time for biologic activity in human serum, in combination with 6 beta-lactams. Simple addition of aminoglycoside and 250 micrograms/ml penicillin produced aminoglycoside inactivation at 8 approximately 48 hours. However, all beta-lactam antibiotics exhibited decay in human serum at 37 degrees C, even when present as a single component. All aminoglycosides could be inactivated by penicillins but differed markedly in their susceptibility. Amikacin, at 20 micrograms/ml, was the least inactivated by any penicillin; netilmicin, at 10 micrograms/ml, was the next least inactivated. Tobramycin had pronounced loss of biological activity exceeding that of any aminoglycoside, appearing as early as 8 hours. The ability of the various penicillins to produce aminoglycoside inactivation, in approximate descending order, was; carbenicillin, ticarcillin, penicillin G, oxacillin, methicillin, ampicillin. Cephalothin produced minimal inactivation. Aminoglycoside inactivation also occurred at 25 degrees C, and with many samples stored at 4 degrees C, although at proportionately slower rates. For samples stored at -20 degrees C, only tobramycin had substantial loss of activity. These data indicate that adequate handling and prompt assay of the specimen are important.

Netilmicin use in pediatric patients.

40 newborn infants and children were treated with netilmicin. With a 2-mg/kg dose, the average peak serum concentration was 4.4 microgram/ml. Serum concentrations resulting from the first dose were markedly lower than subsequent doses and therapeutically inadequate. Significant drug accumulation did not occur: peak and trough concentrations on days 2 and 7 were the same in patients with normal renal function. The half-life of netilmicin in infants less than 1 week old was 3.8 h in infants older than 1 week. Infants less than 7 days old require a prolonged dose interval (12 h) to adequately clear the administered dose. Recovery of netilmicin in urine ranged from 50 to 100% and correlated with age and duration of treatment. Elimination of netilmicin was prolonged in newborn infants with renal failure and requires dosage adjustment. Transient change in creatinine clearance occurred in 2 patients (4.6%) and ototoxicity was observed on 2 other patients.

Netilmicin and gentamicin: comparative pharmacology in humans.

Thirteen male subjects received 1 mg of either gentamicin or netilmicin per kg, first intramuscularly and then intravenously. After the intramuscular dose, concentrations of gentamicin in the serum were more variable than those of netilmicin. After the intravenous dose, the distribution phase of netilmicin was twice as rapid as gentamicin. The average half-times of the elimination phase were similar, but there was marked variability among the subjects receiving gentamicin. Serum clearance of netilmicin was more rapid than that of gentamicin and could not be attributed to renal elimination. The data indicate that, after intramuscular administration, netilmicin may produce more predictable blood levels than gentamicin and suggest that the body distribution of netilmicin may differ from that of gentamicin.

Double-blind comparison of cephacetrile with cephalothin-cephaloridine.

Under double-blind protocol, a controlled comparison was made between a new cephalosporin, cephacetrile, and cephalothin or cephaloridine. The patient's primary physician determined the indications for treatment, and the dosage was uniform for each route of administration. Infecting strains of staphylococci and Proteus mirabilis had a lower median inhibitory concentration for cephalothin than cephacetrile; the opposite was true for Escherichia coli and Klebsiella species. The average peak serum level 1 h after a dose of 2 g intravenously was 74.9 +/- 21 and 21.5 +/- 8.7 mug/ml for cephacetrile and cephalothin, respectively; 6 h after the dose, the respective levels were 12.4 +/- 4.3 and 3.7 +/- 0.9 mug/ml. Renal clearances were similar and the plasma clearance was proportional to the serum levels. In the urine, the concentration of cephacetrile was three times higher than that of cephalothin. Based on a percentage of therapeutic potential, success in the treatment of infections with susceptible organisms was 42 and 44% for the two different drug regimens. Initial bacterial resistance was found in about one-fifth of infections, and concomitant therapy with other drugs was practiced in one-half of the treatment courses. Intravenous use of cephacetrile was discontinued prematurely more often than was use of cephalothin, suggesting less tolerance. Although there was no overt toxicity, more than 75% of patients on either regimen had some form of unwanted response to treatment, the most common being superinfection. From this limited but controlled experience, cephacetrile can be considered comparable to cephalothin in antimicrobial treatment and overall side reactions.