Gentamicin pharmacokinetics in postpartum women with endomyometritis.

The pharmacokinetics of gentamicin in postpartum women with endomyometritis were characterized and models for predicting patient pharmacokinetic parameters were developed using multiple regression analysis. Fifty-one women 13-34 years of age received gentamicin in combination with either ampicillin or clindamycin to treat endomyometritis. Forty-three women delivered by cesarean section and 8 women had vaginal deliveries. Gentamicin serum concentrations were determined at steady-state to compute the elimination rate constant (Kc), half-life (t1/2), apparent volume of distribution (Vd), and total body clearance (Cl). Gentamicin dosages were individualized using a one-compartment intermittent infusion model to achieve steady-state peak and trough concentrations of 6.5 and less than 2 micrograms/mL, respectively. The mean gentamicin t1/2 was 2.8 +/- 0.9 h; the mean apparent Vd was 21 +/- 8 L; and the mean total body Cl was 89.5 +/- 31.7 mL/min. Multiple regression analysis revealed that total body weight (TBW) was the best predictor for the apparent Vd, described by the equation Vd = 0.146 TBW + 8.153 (r = 0.56, p = 0.00005). Total body weight and creatinine clearance (Clcr) were included as predictors for total body Cl, described by the equation Cl = 0.264 TBW + 0.337 Clcr + 3.416 (r = 0.68, p = 0.00005). Age and serum creatinine (SCr) were included in the models for the Ke, described by the equation Ke = -3.770 x 10(-3) age -0.115 SCr + 0.449 (r = 0.42, p less than 0.004). Additional patient factors need to be identified to explain the variance in these pharmacokinetic parameters.

Steady-state pharmacokinetics of intramuscular imipenem-cilastatin in elderly patients with various degrees of renal function.

We studied the concentrations in plasma and pharmacokinetics of imipenem and cilastatin in elderly patients (greater than 65 years old) who had various degrees of renal function and who were hospitalized with soft tissue infections. Three groups of patients received imipenem-cilastatin (500/500 mg) intramuscularly every 12 h: group I consisted of eight patients with a creatinine clearance (CLCR) of greater than 50 ml/min (range, 51 to 84 ml/min; mean, 65.8 ml/min); group II consisted of three patients with a CLCR of 20 to 50 ml/min; and group III consisted of two patients with a CLCR of less than 20 ml/min. Imipenem and cilastatin concentrations were measured at steady state on day 5. Mean peak and trough plasma imipenem concentrations were 5.28 +/- 1.78 and 1.43 +/- 0.76 micrograms/ml in group I, 6.25 +/- 0.78 and 2.50 +/- 0.00 micrograms/ml in group II, and 14.3 +/- 0.71 and 6.85 +/- 1.06 micrograms/ml in group III, respectively. Mean peak and trough plasma cilastatin concentrations were 11.8 +/- 2.85 and 0.31 +/- 0.43 microgram/ml in group I, 15.5 +/- 2.48 and 2.03 +/- 2.05 micrograms/ml in group II, and 24.5 +/- 6.72 and 10.7 +/- 5.94 micrograms/ml in group III, respectively. Mean imipenem AUCss (area under the concentration-time curve over a dosage interval at steady state) values were 38.7 +/- 7.9 micrograms.h/ml for group I, 52.3 +/- 7.3 micrograms.h/ml for group II, and 143.7 +/- 11.9 micrograms.h/ml for group III. Mean cilastatin AUCss values were 45.6 +/- 12.5 micrograms.h/ml for group I, 93.8 +/- 51.2 micrograms.h/ml for group II, and 217.5 +/- 57.8 micrograms.h/ml for group III. Cilastatin mean apparent body clearance values (normalized to weight) were 2.78 +/- 0.67 ml/min for group I, 1.43 +/- 0.81 ml/min for group II, and 0.71 +/- 0.24 ml/min for group III. Imipenem open-lactam metabolite levels were all below the level of detective of the assay (<3.9 micrograms/ml). There was a progressive increase in plasma imipenem and cilastatin levels and AUCss and there was a decline in body clearance as renal function declined.

Comparison of gentamicin immunoassays using univariate and multivariate analyses.

Gentamicin concentrations, pharmacokinetic parameters, and calculated doses from enzyme multiplied immunoassay (EMI) and fluorescence polarization immunoassay (FPIA) were compared in 79 samples from 39 patients. Associations between patient factors and the differences between assay results were also assessed. Concentrations were lower when measured by EMI than by FPIA in 71 of the 79 samples (p less than 0.001). Mean EMI values for elimination rate constant, volume of distribution, clearance, dose, and daily dose were 10-20% higher than mean FPIA values (p less than or equal to 0.01). Dosing intervals calculated from EMI and FPIA data were different in 20 pairs of intervals and varied depending on the length of calculated interval. Univariate and multivariate analyses revealed that renal function and the presence or absence of cardiovascular disease, cimetidine, or ranitidine, and heparin were related to differences between the assay results. EMI and FPIA yielded different results for gentamicin concentrations, pharmacokinetic parameters, and calculated daily doses in the clinical setting. Such differences could result in toxic or subtherapeutic doses being administered and may be related, in part, to various patient factors.

Vancomycin concentrations in infected and noninfected human bone.

Concentrations of vancomycin in bones of 14 patients undergoing total hip arthroplasty (group 1) and 5 patients with osteomyelitis (group 2) were studied. Group 1 received vancomycin, 15 mg/kg intravenously, 1 h prior to anesthesia. Group 2 received doses adjusted to achieve peak levels in serum of 20 to 30 micrograms/ml and trough levels of less than 12 micrograms/ml; bone specimens were collected during surgical debridement. The specimens were pulverized and eluted into phosphate buffer, and the supernatants were analyzed for vancomycin content by fluorescence polarization immunoassay. In group 1, vancomycin was detectable in all cancellous specimens with a mean concentration of 2.3 +/- 4.0 micrograms/g (range, 0.5 to 16 micrograms/g); 10 of 14 cortical specimens had detectable vancomycin; the mean cortical concentration was 1.1 +/- 0.8 micrograms/g (range, not detectable to 2.6 micrograms/g). In group 2, vancomycin was detectable in only two of five cortical bone specimens (mean concentration, 5.9 +/- 3.5 micrograms/g). Cancellous bone was obtained in one patient; the vancomycin concentration was 3.6 micrograms/g. In most patients the vancomycin levels in bones were higher than the MIC for susceptible staphylococci following single prophylactic doses. In the few infected patients studied, penetration was variable and deserves further study.

Ultrastructural changes in Blastomyces dermatitidis after in vitro exposure to lidocaine.

Electron microscopic examination of yeasts of Blastomyces dermatitidis, exposed in vitro to concentrations of lidocaine that occur when the drug is used for topical anesthesia, showed that lidocaine rapidly damaged intracellular structures. The extent of damage was dependent on the concentration of drug and length of exposure. The observed ultrastructural changes were very similar to those reported for other drugs that directly damage membranes. This relationship suggests that the antifungal effect of lidocaine is the result of direct membrane damage.

Inhibition of Blastomyces dermatitidis by topical lidocaine.

This study was designed to determine if lidocaine inhibited growth of Blastomyces dermatitidis and thereby reduced recovery of the fungus from bronchoscopy specimens. Case records of 36 patients with pulmonary blastomycosis showed that when the fungus was present at microscopy, whether the specimen was sputum or bronchial washings, culture of the bronchoscopic specimen was more frequently negative than the culture of the sputum specimen (p less than .05). In addition, lidocaine was shown to inhibit growth of B dermatitidis in vitro, with the inhibition depending on the concentration of the drug and the duration of exposure (p less than .01). High concentrations of lidocaine for topical anesthesia appear to adversely affect the recovery of B dermatitidis from bronchoscopic specimens.

Quality assurance program for a clinical pharmacokinetic service.

The development and implementation of a quality assurance program for a clinical pharmacokinetic service is described. The goal of the pharmacokinetic use review program is to assure the quality and consistency of pharmacokinetic monitoring by all pharmacists within the institution. Criteria were formulated as specific indications for pharmacokinetic monitoring of four drugs. The review process consists of: (1) an initial screen of a randomly selected sample of patient charts to determine if patients meeting predetermined criteria were actually pharmacokinetically monitored; (2) a peer review committee review to specify the appropriateness of monitoring; and (3) a reporting process to the pharmacists responsible for the service regarding their performance. The quality assurance program allows documentation and improvement of the quality of a clinical pharmacokinetic service and assures a consistent level of service.

Cunninghamella bertholletiae wound infection of probable nosocomial origin.

After closed reduction and casting of a tibial fracture in a 69-year-old diabetic man, a gangrenous lesion developed under the cast. Cultures of debrided tissue revealed multiple bacteria, including Bacillus sp, plus two fungi, Fusarium sp and a zygomycete identified as Cunninghamella bertholletiae. Large nonseptate hyphae in thrombosed blood vessels suggested that C bertholletiae played a major role in the development of the infection. Recovery of organisms from our patient's wound and from the cast padding suggests that the wound infection was acquired from nonsterile dressings.

Phenytoin-dexamethasone interaction: a previously unreported observation.

A possible drug interaction between phenytoin and dexamethasone was evaluated by comparing serum phenytoin concentrations in 23 patients receiving both drugs with those of a control group of 15 patients receiving phenytoin only. Serum phenytoin concentrations obtained 24 hours after a loading dose of 11 mg per kilogram body weight administered intravenously and 13 mg/kg given intramuscularly were examined. The total amounts of dexamethasone administered during the 24-hour period ranged from 16 to 150 mg. The average serum phenytoin concentration was 17.28 +/- 3.49 micrograms/ml in patients receiving both drugs, as compared to 12.48 +/- 3.52 micrograms/ml in patients receiving only phenytoin (p less than 0.001). Our results suggest that serum phenytoin concentrations should be monitored in patients receiving concurrent dexamethasone therapy.

Studies on the susceptibility of 150 consecutive clinical isolates of Pseudomonas aeruginosa to tobramycin, gentamicin, colistin, carbenicillin, and five other antimicrobials.

The in vitro susceptibilities of 150 clinical isolates of Pseudomonas aeruginosa to the aminoglycoside tobramycin and eight other antimicrobials were evaluated. The Food and Drug Administration standardized disk diffusion method showed that tobramycin inhibited 100% of the 150 isolates with gentamicin inhibiting only 90.7%. The difference between colistin (97.3%) and tobramycin was less marked. Carbenicillin (87.3%) was found to be slightly less active than gentamicin. Only a small percentage of the isolates were inhibited by the other drugs used. By using a minimal inhibitory concentration of 4 mug/ml in brain heart infusion broth as the level of susceptibility, it was found that only three of the isolates showed resistance to tobramycin, whereas 20 of the isolates were resistant to gentamicin. Approximately half of the isolates were inhibited by 0.5 mug/ml or less of tobramycin, whereas 1.5 mug of gentamicin per ml was required to inhibit 50% of susceptible strains.

Morphology and entry of enveloped and deenveloped equine abortion (herpes) virus.

Selective removal of the envelope of equine abortion (herpes) virus was accomplished by utilizing the nonionic detergent Nonidet P-40 followed by sonic treatment. The deenveloped particles differ significantly in size and buoyant density from the enveloped form. The cellular entry of purified enveloped and purified deenveloped virus was examined by electron microscopy during critical time periods. Both forms appeared to enter cells by a viropexis mechanism in which particles were engulfed by pseudopodia which either surround the virus and fuse with the cell membrane or to other pseudopodia, forming fusion vacuoles containing from one to numerous viral particles. This mode of entry was noted extensively at 5 min postinoculation. Deenveloped particles were apparently infectious only for hamsters, with a large inoculum being required. Contamination by enveloped forms was not noted after exhaustive search by electron microscopy.