Search

In patients with renal impairment ( n = 22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher, respectively, than in patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated with linezolid concentrations ( r 2 = 0.26 for PNU-142300 and 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment.

Ceftobiprole is a fifth-generation cephalosporin approved for the treatment of pneumonia, with a broad antibacterial spectrum, including potent activity against methicillin-resistant Staphylococcus aureus. As for the other cephalosporins, high pharmacokinetic variability and concentration-dependent neurotoxicity are expected. We describe here the first simple and rapid analytical method intended for ceftobiprole serum concentration monitoring. We report the data of 5 patients treated with ceftobiprole, among who 2 developed reversible neurological disorders with high ceftobiprole serum concentration.

The aminoglycoside-modifying enzyme AAC(6′)-Ib is common among carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strains. We investigated amikacin (AMK) activity against 20 AAC(6′)-Ib-producing CR-Kp strains. MICs clustered at 16 to 32 μg/ml. By the time-kill study, AMK (1× and 4× the MIC) was bactericidal against 30% and 85% of the strains, respectively. At achievable human serum concentrations, however, the majority of strains showed regrowth, suggesting that AAC(6′)-Ib confers intermediate AMK resistance. AMK and trimethoprim-sulfamethoxazole (TMP-SMX) were synergistic against 90% of the strains, indicating that the combination may overcome resistance.

Fifty-six serum posaconazole trough levels were measured in 17 cardiothoracic transplant recipients. Initial levels were ≤0.5, 0.51 to 0.99, and ≥1 μg/ml for 47, 29, and 24% of patients, respectively. Median trough levels associated with therapeutic success were higher than those associated with failure (1.55 versus 0.34 μg/ml; P = 0.006). Patients with levels consistently >0.5 μg/ml were more likely to have successful outcome ( P = 0.055). Age ≥65 years, oral administration, and absence of proton pump inhibitors were associated with higher levels of posaconazole ( P = 0.006, 0.006, and 0.001, respectively).

We evaluated posaconazole serum concentrations and hepatotoxicity in 12 leukemia patients who transitioned from posaconazole suspension to tablets. Patients who switched to tablets had significantly increased posaconazole concentrations (median: suspension, 748 ng/ml; tablet, 1,910 ng/ml; P < 0.01) without clinically relevant hepatotoxicity.

Posaconazole (PCZ), approved for prophylaxis against invasive fungal disease in high-risk patients, is commercially available orally as a suspension formulation (PCZ-susp) and as a delayed-release tablet (PCZ-tab). We evaluated the serum steady-state concentrations ( C ss ) of PCZ stratified by the administered formulation for antifungal prophylaxis in patients with myeloid malignancies ( n = 150). The primary outcome was the attainment rate of the target C ss of ≥700 ng/ml. Secondary outcomes included toxicity assessment (hepatotoxicity and corrected QT [QTc] interval prolongation) and breakthrough fungal infections. Patients who received the PCZ-susp ( n = 118) or PCZ-tab ( n = 32) and had PCZ C ss assessment after at least 7 days of therapy were eligible. The median C ss in the PCZ-susp group was 390 ng/ml (range, 51 to 1,870 ng/ml; mean, 436 ng/ml) compared to 1,740 ng/ml (range, 662 to 3,350 ng/ml; mean, 1,781 ng/ml) in the PCZ-tab group ( P < 0.0001). The percentages of patients achieving the target goal of ≥700 ng/ml were 17% versus 97%, respectively ( P < 0.0001). Hepatotoxicity (grade 2 or higher) occurred in 1 patient in each group. QTc interval measurements were available for 32 patients in the PCZ-susp group and for 12 patients in the PCZ-tab group, and prolonged intervals of grade 2 or higher were noted in 9% ( n = 3) and 17% ( n = 2), respectively ( P = 0.6). Breakthrough fungal infections in the PCZ-susp and PCZ-tab groups were 7% ( n = 8) and 3% ( n = 1), respectively ( P = 0.68). We conclude that the use of PCZ-tab was associated with higher C ss and with the probability of achieving therapeutic goals without worsening of adverse effects.

There are several clinical scenarios in which knowledge of zidovudine disposition may be important. This study evaluated the clinical utility of pharmacokinetic parameters for zidovudine derived from sparse serum concentration data obtained in an outpatient setting. Twelve human immunodeficiency virus-infected participants had two serum zidovudine concentrations determinations obtained on two different clinic visits, 2 to 38 days apart. Zidovudine concentrations were measured by radioimmunoassay. A one-compartment oral absorption model was used to describe zidovudine disposition. Three different approaches were used to estimate pharmacokinetic parameters: Bayesian estimation with one or two concentrations and least squares with one concentration. The ability of these parameters to predict concentrations measured during the second clinic visit was assessed by calculation of precision and bias and compared with predictions using standard fixed or weight-adjusted parameters. Estimated pharmacokinetic parameters for zidovudine were consistent with literature values; there was no statistically significant difference among the parameters calculated with the three estimation strategies. Absorptive phase concentrations were poorly predicted by all methods (mean percent bias, 157 to 249%; mean percent precision, 389 to 537%). Predictive ability for concentrations obtained in the elimination phase was strikingly improved: mean percent bias, -17 to 70%; mean percent precision, 40 to 95%. Bayesian and least-squares estimated parameters were statistically better than fixed-parameter values for predicting concentrations in the elimination phase. These observations provide a modeling framework to determine pharmacokinetic disposition of zidovudine in an individual, screen for the existence of a drug interaction, and conduct concentration-controlled clinical trials.

Combination antibiotic therapy is often indicated for health care-associated pneumonia due to resistant pathogens and is recommended in the Infectious Diseases Society of America/American Thoracic Society guidelines on the management of community-acquired pneumonia and health care-associated

Amikacin was given to 14 noninfected men as three consecutive intramuscular injections (7.5 mg/kg) at 12-h intervals. Serum and bronchial secretion specimens were obtained at various times during flexible fiberoptic bronchoscopy after the final dose. Serum and bronchial secretion concentrations obtained between 1.5 and 2.0 h after the final dose ranged from 17 to 40 μg/ml and 2.3 to 8.4 μg/ml with a mean of 23.7 ± 2.9 and 5.23 ± 1.5 μg/ml, ±1 standard error of the mean, respectively. The highest bronchial secretion concentration in each subject correlated with the highest serum concentration ( r = 0.83, P < 0.001), and all concurrent serum and bronchial secretion concentrations demonstrated a significant correlation ( r = 0.82, P < 0.001). Clearance occurred at the same rate (half-life serum = 2.84 h; half-life of bronchial secretion = 2.60 h, P > 0.5). The mean bronchial secretion concentration of the 15 specimens obtained more than 7 h after the final dose was less than 1.0 μg/ml, with a range from 0.3 to 1.6 μg/ml. It is concluded that amikacin may achieve minimal inhibitory concentrations for many gram-negative bacteria in the bronchial secretions of noninfected patients 1 to 2 h after the final dose. However, levels fall below the reported minimal inhibitory concentrations against negative bacteria 6 to 7 h after the final dose. Furthermore, bronchial secretion levels may never reach the minimal inhibitory concentration against Pseudomonas aeruginosa .

Studies were conducted in 30 patients with neoplastic diseases. Twelve patients received sisomicin intramuscularly at doses of 20 mg/m 2 and 40 mg/m 2 . The mean peak serum concentration occurred at 1 h and was 2.5 μg/ml and 4.0 μg/ml, respectively. Ten patients received intravenous sisomicin at doses of 30 mg/m 2 during 30-min infusion. Mean peak serum level determined at 30 min was 5.1 μg/ml. The levels gradually decreased and at 6 h was 0.6 μg/ml. The serum half-life was 160 min. Serum levels determined in eight patients who received sisomicin by continuous infusion at doses of 30 mg/m 2 every 6 h were greater than 1.4 μg/ml during the 6-h period. The urinary excretion of sisomicin during the 6-h period after intramuscular administration of 20 mg/m 2 and 40 mg/m 2 was 49 and 61%, respectively. The pharmacology of sisomicin is similar to gentamicin.

Ten patients received a loading dose of tobramycin of 60 mg/m2 intravenously over 0.5 h followed immediately by 60 mg/m2 over 2 h every 4 h. The highest mean serum concentration (at the end of the loading dose) was 6.0 +/- 0.3 microgram/ml (range, 3.2 to 10.9 microgram/ml). The mean serum concentration 2 h after the end of the initial 2-h infusion was 3.0 +/- 0.2 microgram/ml (range, 1.6 to 3.9 microgram/ml). This schedule of tobramycin was used to treat 117 patients with presumed or proven infection. There were no differences in the mean serum concentrations of tobramycin at comparable times on days 3 to 4 and 6 to 7. Only 60% of patients had serum levels between 3 micrograms/ml (trough) and 10 micrograms/ml (peak). This intermittent schedule of administration resulted in substantial fluctuations in serum concentrations of tobramycin and produced trough concentrations which were too low or peak concentrations which were too high in some patients.

Cefoperazone and cefoxitin concentrations were determined in serum and pelvic tissue samples obtained at various intervals after a 2-g intramuscular dose. These levels were determined in 59 women scheduled for elective abdominal hysterectomy. Concentrations were measured by a new high-pressure liquid chromatography method which correlated with the microbiological assay. The mean times (+/- standard deviation) of specimen collection were 188.5 +/- 61 and 185.5 +/- 55 min for cefoperazone and cefoxitin, respectively. The mean serum levels (+/- standard deviation) were 60.8 +/- 18.0 and 14.6 +/- 8.6 micrograms/ml, respectively. For cefoperazone, the mean pelvic tissue concentration was 19.8 micrograms/g. The mean pelvic tissue concentration for cefoxitin was 7.8 micrograms/g. The ratio of tissue concentration to serum concentration varied from 0.220 to 0.469 for cefoperazone and from 0.176 to 1.031 for cefoxitin. Although the serum and tissue concentrations of cefoperazone were much higher than those of cefoxitin, a greater portion of cefoxitin remained in the tissue. The tissue levels of both cefoperazone and cefoxitin were above the minimum inhibitory concentration of most sensitive pathogens several hours after a single prophylactic dose of either antibiotic.

Minimum inhibitory and bactericidal concentrations of four antibiotics and their combinations were determined for 38 strains of enterococci by a microtitration tube dilution technique. The drugs were ampicillin, vancomycin, gentamicin, and streptomycin; the combinations were ampicillin-gentamicin, ampicillin-streptomycin, vancomycin-gentamicin, and vancomycin-streptomycin. At achievable serum concentrations, ampicillin alone killed 60% of strains, whereas combination with streptomycin increased this to 90% and with gentamicin to 100%. Vancomycin alone showed striking inhibitory activity, but very poor bactericidal activity at achievable concentrations. Combination with one of the aminoglycosides increased the bactericidal activity substantially. When combined with ampicillin, gentamicin was both more active and showed synergistic bactericidal activity significantly more often ( P < 0.01) than streptomycin.

Comparative studies in beagle dogs suggested that the pharmacokinetic profiles of BB-K8 and kanamycin are similar. After intravenous (iv) administration to dogs, BB-K8 and kanamycin were rapidly distributed in plasma and tissue fluids; their “apparent” volumes of distribution comprised approximately 23% of the total body volume. Like kanamycin, BB-K8 had a plasma half-life of about 0.8 h which paralleled the urinary excretion rate. Approximately 92% of the dose was excreted as unchanged drug within 6 h of dosing, and clearance appeared to be primarily by glomerular filtration. After intramuscular (im) administration to dogs, BB-K8 and kanamycin were totally and rapidly absorbed; peak concentrations in the plasma occurred 0.5 to 1.0 h after dosing. The kinetic parameters governing the distribution and elimination of BB-K8 and kanamycin after an im dose were similar to those obtained for iv dosing and indicate desirable dose-independent kinetics. A human pharmacokinetic study indicated that the kinetic profiles of BB-K8 and kanamycin are similar in man after im dosing. Like kanamycin, BB-K8 is rapidly absorbed, yielding peak serum concentrations of about 20 μg/ml at 1 h after a 500-mg im dose. The plasma half-life of these two drugs was approximately 2.3 h. Clearance in man was primarily by glomerular filtration, and the urinary excretion of BB-K8 and kanamycin accounted for 83% of the dose.

Five volunteers received intramuscular injections of 7 mg (approximately 500 mg) of cephanone, a new cephalosporin for parenteral use per kg. Peak serum concentrations averaged 36 μg/ml, about four times as high as with the same doses of cephalothin, twice as high as with cephaloridine, and slightly lower than with cefazolin. With a constant intravenous infusion of 100 mg/h, a steady-state serum concentration of 31 μg/ml was attained in four volunteers. The serum half-life was similar for the intramuscular and intravenous studies, 2.4 and 2.6 h, respectively. Over 90% of the dose administered was recovered in the urine. The factor mainly responsible for the higher and more sustained serum concentrations of cephanone was its low renal clearance of 47 ml per min per 1.73 m 2 . Cephanone has a small apparent volume of distribution, probably related to its high serum protein binding of 88%.

In infants less than 3 months of age, the serum concentration of cefamandole during therapy was higher and more prolonged than that in children older than 1 year. A dosage of 37 mg/kg administered intravenously at 6-h intervals provided a serum concentration in excess of the minimum inhibitory concentrations of common bacterial pathogens for 4 h, and in young infants for 5 h, after dosing.

Ten patients with soft-tissue infections due to Staphylococcus aureus were treated with minocycline, a semisynthetic tetracycline with potent in vitro antistaphylococcal effects. Serum concentrations averaged three to five times the concentration of minocycline required to inhibit growth of S. aureus in vitro. Clearing of the infecting organism was slow (less than 50% of lesions were sterile on day 10 of therapy), but clinical improvement was noted in 8 of 10 patients.

The absorption of orally administered nafcillin sodium monohydrate buffered with calcium carbonate was studied in 10 healthy human volunteers. Dosages of 500 mg and 1 g were studied in fasting and nonfasting states. There was considerable individual variation in the absorption of nafcillin, although measurable serum concentrations were obtained in all subjects. With few exceptions, peak serum concentrations were reached faster and were more predictable in the fasting state than in the nonfasting state. In the majority of subjects, food interfered with nafcillin absorption. Measurable serum concentrations persisted for 4 h in almost all subjects, but there were no or negligible serum concentrations at 6 h. The mean serum concentrations obtained in the present study were higher than those reported in an earlier study.

The pharmacokinetics of intravenous netilmicin was studied in cystic fibrosis (CF) and non-CF patients who were closely matched according to age. The serum concentrations showed a moderately higher variance within the CF group. The serum half-life in CF patients was 1.37 h compared with 2.29 h in the non-CF subjects (P less than 0.05). The apparent distribution coefficients were 0.306 and 0.356 liters/kg in the CF and non-CF groups, respectively. The mean body clearance was 6.6 liters/h per 1.73 m2 in the CF group compared with 5.3 liters/h per m2 in the non-CF controls, but the difference was not significant. The mean renal clearance in CF patients was 4.7 liters/h per 1.73 m2. From a pharmacokinetic point of view, the dosage of netilmicin required may be the same in CF as in non-CF patients.

BL-P1654 is a new α-substituted ureido penicillin which has broad-spectrum activity. Doses of 0.5 and 1.0 g administered by rapid intravenous injection produce mean peak serum concentrations of 40.7 and 80.8 μg/ml, respectively. The same doses administered by 1-h intravenous infusions produce mean peak serum concentrations of 22.6 and 47 μg/ml, respectively. The mean serum concentrations from 1 to 6 h after onset of administration of the drug are the same for both schedules. The mean serum concentration at 6 h after the rapid intravenous injection of 0.5- and 1.0-g doses of BL-P1654 are 3.4 and 5.4 μg/ml, respectively. A dose of 1.0 g every 4 h maintains a serum concentration of about 15 μg/ml. About 50 to 65% of the BL-P1654 is excreted in the urine during the first 6 h.

Sisomicin in doses of 1 mg/kg was administered intramuscularly to 10 healthy volunteers, and 1 week later the same volunteers received sisomicin at the same dose intravenously. A peak serum concentration of sisomicin of 3.08 μg/ml was obtained 1 h after intramuscular injection, and a peak serum concentration of 7.12 μg/ml was achieved 30 min after a 30-min intravenous infusion. The sisomicin elimination data were analyzed according to a two-compartment model. Pharmacokinetic parameters derived from the intramuscular and intravenous studies were quite similar.

We measured the serum concentrations of moxalactam in 10 children receiving antibiotic prophylaxis for surgery and in 18 children treated for documented or suspected infections. Moxalactam was administered intravenously at a dose of 50 mg/kg every 8 h. After the first dose in 28 patients, mean moxalactam concentrations 5 min, 30 min, 2 h, and 8 h after infusion were 257, 177, 82.2, and 17.5 micrograms/ml, respectively. The mean half-life (T 1/2) was 2.44 h (range: 0.55 to 7.96 h). The mean distribution volume (VD) was 0.30 liters per kg. No significant accumulation was observed with multiple doses. Prophylactic and therapeutic groups had similar serum levels, T 1/2, and VD. The five infants less than 1 year of age had a lower mean 30-min level (P less than 0.01), larger VD (P less than 0.001) and longer T 1/2 (P less than 0.025) than the children older than 1 year. A dose of 50 mg/kg produced 30-min levels in excess of 64 microgram/ml in all patients studied, but 8-h trough levels were below the minimal inhibitory concentrations breakpoint of 17 mg/ml in 32% of patients.

Large doses of cephapirin (50 mg/kg) administered during the first and last half hours of routine hemodialysis produced effective antimicrobial serum concentrations for 48 h. Repetitive administration during five successive hemodialysis sessions did not result in accumulation or accelerated metabolism of cephapirin. Ten infectious episodes in nine patients were treated in this manner with good clinical results and no toxicity.

A new immunofluorescent method (FIAX) was compared with a radioimmunoassay procedure for the determination of tobramycin serum concentrations. When assaying three tobramycin control sera repeatedly, within-run and run-to-run variations by the FIAX method were all within acceptable limits, and no statistically significant differences were found. Results of 155 sera from patients who had been treated with tobramycin showed a correlation coefficient of 0.93 between the two methods. The FIAX method represents another practical alternative for determining tobramycin serum levels.

Pharmacokinetic parameters of cefaclor were studied in eight patients after an oral dose of 250 mg. Serum samples were obtained before and on 19 occasions after oral administration. Cefaclor serum concentrations were determined by a new high-performance liquid chromatographic technique.

Pharmacological studies of moxalactam were conducted with 37 cancer patients. Intramuscular administration of 500 mg of moxalactam to 10 patients produced a mean peak serum concentration of 12.4 micrograms/ml. The serum terminal-phase half-life was 3.9 h. Intravenous administration of 500 mg of moxalactam over 5 min to the same 10 patients produced a mean serum concentration of 42.0 micrograms/ml at 15 min, which decreased to 3.3 micrograms/ml at 6 h. A dose of 1 g of moxalactam was given in an identical manner to the same 10 patients. The mean serum concentration was 69.7 micrograms/ml at 15 min and 7.4 micrograms/ml at 6 h. The mean proportions of a drug recovered in the urine by 12 h after administration were 59% after the intramuscular dose and 61 and 55% after the single intravenous doses. Multiple-dose intravenous studies were also conducted. The serum terminal-phase half-life varied from 2.0 to 3.2 h. Continuous infusion studies were performed by up to 9 days by using a loading dose of 1 g over 0.5 h, followed by 2 g every 6 h. Serum concentrations were maintained at about 30.0 micrograms/ml during the study period.

Fourteen hydrocephalic pediatric patients with suspected shunt infections were studied for penetrance of nafcillin into the ventricular fluid after intravenous administration. In seven patients with bacterial ventriculitis, the concentration of nafcillin in ventricular fluid was 0.8 to 20.4% of the peak concentration in serum. In the remaining seven patients without bacterial ventriculitis, ventricular fluid levels ranged between less than or equal to 0.02 to 4% of peak serum concentrations. Although the degree of pleocytosis correlated poorly with penetrance, ventricular fluid glucose levels correlated inversely with penetrance of nafcillin (r = -0.7275, P less than 0.001).

Serum and urine concentrations were measured after administration of 0.5-and 1-g doses of cefamandole intramuscularly and intravenously to healthy volunteers. Intramuscular doses of 0.5 and 1 g yielded serum concentrations at 1 h of 14.7 and 35.6 μg/ml, respectively. Significant antibacterial concentrations persisted through h 8. Intravenous doses of 0.5 and 1 g resulted in respective peak serum levels of 21 μg/ml at 45 min and 103 μg/ml at 15 min; these serum levels rapidly declined. Very high urine concentrations were achieved during the first 8 h after injection.

The entry of amoxicillin and ampicillin into cerebrospinal fluid (CSF) of humans was studied in the absence of meningeal inflammation. Twelve volunteers received 33 mg of amoxicillin per kg intravenously over 30 min and nine volunteers received 33 mg of ampicillin per kg. The CSF specimens were sampled at 1, 2, and 4 h after the beginning of the infusion. Blood samples were obtained at the end of the infusion and at 45, 60, 90, 120, 180, and 240 min after the beginning of the infusion. Amoxicillin and ampicillin were both detected in the CSF. Ampicillin tended to give higher CSF levels than amoxicillin, although the difference was small. Serum concentrations of ampicillin equaled those of amoxicillin.

The effectiveness of gentamicin administered by the intranasal route in healthy human volunteers was studied. Thirty minutes after gentamicin in a solution of 1% sodium glycocholate was administered at 2 mg/kg of body weight, gentamicin concentrations of 2.48 +/- 0.42 mg/ml were present in the sera. Serum concentrations decreased to 0.94 +/- 0.13 mg/ml at 180 min. No serious side effects were observed. There was slight local irritation after a single dose. When administered intranasally without glycocholate, gentamicin was not present in the sera in detectable amounts.

The pharmacokinetics of cefotaxime were determined in newborn infants who were 1 to 7 days of age. Mean peak serum concentrations of 116 and 132 micrograms/ml were observed at completion of a 10-min intravenous infusion of 50 mg of cefotaxime per kg in low and average birth weight infants, respectively. The mean elimination half-lives were 4.6 and 3.4 h and rates of clearance from serum were 23 and 44 ml/min per 1.73 m2, respectively. A dosage schedule for cefotaxime in newborn infants is presented.

Hepatic function failed to influence serum concentrations of the antifungal agent 5-fluorocytosine when the drug was given intravenously to rabbits with CCl 4 -induced hepatic insufficiency or orally to a patient with postnecrotic cirrhosis.