George L. Drusano

Relationship between Initial Vancomycin Concentration-Time Profile and Nephrotoxicity among Hospitalized Patients

BACKGROUND Data suggest that higher doses of vancomycin can increase the risk of nephrotoxicity. No study has been undertaken to determine the pharmacodynamic index (ie, the area under the curve [AUC] or the trough value) that best describes the relationship between vancomycin exposure and onset of nephrotoxicity. METHODS A retrospective study was conducted among patients who received vancomycin for a suspected or proven gram-positive infection during the period from 1 January 2005 through 31 December 2006 at Albany Medical Center Hospital. Patients were included in our study if they (1) were > or =18 years old, (2) had an absolute neutrophil count of > or =1000 cells/mm(3), (3) received vancomycin for >48 h, (4) had 1 vancomycin trough level collected within 96 h of vancomycin therapy, and (5) had a baseline serum creatinine level of <2.0 mg/dL. Patients were excluded if they (1) had a diagnosis of cystic fibrosis, (2) received intravenous contrast dye within 7 days of starting vancomycin or during therapy, or (3) required vasopressor support during therapy. Demographics, comorbid conditions, and treatment data were collected. The highest observed vancomycin trough value within 96 h of initiation of vancomycin therapy and the estimated vancomycin AUC were analyzed as measures of vancomycin exposure. The vancomycin AUC value from 0 to 24 h at steady state (in units of mg x h/L) for each patient was estimated by use of the maximum a posteriori probability Bayesian procedure in ADAPT II. Nephrotoxicity was defined as an increase in serum creatinine level of 0.5 mg/dL or 50%, whichever was greater, following initiation of vancomycin therapy. Logistic and Cox proportional hazards regression models identified the vancomycin pharmacodynamic index that best describes the relationship between vancomycin exposure and toxicity. RESULTS During the study period, 166 patients met the inclusion criteria. Both initial vancomycin trough values and 0-24-h at steady state AUC values were associated with nephrotoxicity in the bivariate analyses. However, the vancomycin trough value, modeled as a continuous variable, was the only vancomycin exposure variable associated with nephrotoxicity in the multivariate analyses. CONCLUSIONS The results indicate that a vancomycin exposure-toxicity response relationship exists. The vancomycin trough value is the pharmacodynamic index that best describes this association.

A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study.

BACKGROUND Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. METHODS We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. RESULTS During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. CONCLUSIONS In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects.

Role of pharmacokinetics in the outcome of infections.

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Absolute oral bioavailability of ciprofloxacin.

We evaluated the absolute bioavailability of ciprofloxacin, a new quinoline carboxylic acid, in 12 healthy male volunteers. Doses of 200 mg were given to each of the volunteers in a randomized, crossover manner 1 week apart orally and as a 10-min intravenous infusion. Half-lives (mean +/- standard deviation) for the intravenous and oral administration arms were 4.2 +/- 0.77 and 4.11 +/- 0.74 h, respectively. The serum clearance rate averaged 28.5 +/- 4.7 liters/h per 1.73 m2 for the intravenous administration arm. The renal clearance rate accounted for approximately 60% of the corresponding serum clearance rate and was 16.9 +/- 3.0 liters/h per 1.73 m2 for the intravenous arm and 17.0 +/- 2.86 liters/h per 1.73 m2 for the oral administration arm. Absorption was rapid, with peak concentrations in serum occurring at 0.71 +/- 0.15 h. Bioavailability, defined as the ratio of the area under the curve from 0 h to infinity for the oral to the intravenous dose, was 69 +/- 7%. We conclude that ciprofloxacin is rapidly absorbed and reliably bioavailable in these healthy volunteers. Further studies with ciprofloxacin should be undertaken in target patient populations under actual clinical circumstances.

Emergence of resistance to imipenem in Pseudomonas aeruginosa.

The emergence of resistance to imipenem by Pseudomonas aeruginosa was investigated with four pairs of isolates. Each pair represented pretherapy (susceptible) and posttherapy (resistant) specimens. In all cases, the imipenem-resistant isolates did not demonstrate changed susceptibilities to other beta-lactams. Agarose gel electrophoresis revealed no change in plasmid profiles between any pair of isolates. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the Sarkosyl-insoluble membrane protein revealed the loss of an outer membrane protein of apparent molecular mass 48 to 49 kilodaltons in posttherapy strains when grown with imipenem selection (5 micrograms/ml). There was no significant difference in the binding of [14C]imipenem to the penicillin-binding proteins of the pre- and posttherapy strains. Trichloroacetic acid precipitation of membranes isolated after growth in the presence of [14C]imipenem revealed that significantly less drug was bound to Sarkosyl-soluble membrane protein in three of the four posttherapy strains than the membrane proteins of the respective pretherapy strains. beta-Lactamase activity against imipenem at 100 or 3 microM was not detected in any isolate either with or without induction. These data suggest that resistance to imipenem is associated with the loss of a 48- to 49-kilodalton outer membrane protein accompanied by, in three of four cases, decreased penetration of the antibiotic across the outer membrane. Images

Commonly Used Methods of Estimating Creatinine Clearance Are Inadequate for Elderly Debilitated Nursing Home Patients

We evaluated the Jelliffe and the Cockcroft and Gault methods of estimating creatinine clearance in elderly nursing home patients (65 years) with chronic indwelling urethral catheters. Although these relationships have been prospectively validated in hospitalized and ambulatory populations previously, we found that they produced poor estimates of creatinine clearance in this patient group. For the Jelliffe method, 11 of 19 estimates were 20% or greater from the measured value; 10 of 11 poor estimates were high. The Cockcroft‐Gault method had 10 of 19 estimates 20% or greater from the measured value with 8 of 10 of the poor estimates being high. An altered relationship between body weight, muscle mass, and daily creatinine production is the most likely explanation for the bias in these creatinine‐clearance estimations. New estimates of the relationships between age, weight, serum creatinine, and creatinine clearance need to be developed for this population.

Multiple-dose pharmacokinetics of imipenem-cilastatin.

We characterized the pharmacokinetic profile of imipenem-cilastatin administered intravenously to six normal volunteers in a dose of 1,000 mg of each drug every 6 h for 40 doses. The plasma concentrations of imipenem and cilastatin 1 h after the end of a 30-min infusion were 18.7 (+/- 2.1) and 19.1 (+/- 4.6), 20.0 (+/- 3.2) and 17.8 (+/- 4.8), and 23.4 (+/- 2.3) and 19.1 (+/- 3.5) micrograms/ml in the 1st, 17th, and 37th dosing intervals, respectively. The central compartment volumes of distribution for imipenem and cilastatin were 0.16 (+/- 0.05) and 0.14 (+/- 0.03) liter/kg, respectively. Elimination half-lives were short: 0.93 (+/- 0.09) h for imipenem and 0.84 (+/- 0.11) h for cilastatin. Plasma clearances were 12.1 (+/- 0.06) liters/h per 1.73 m2 for imipenem and 12.4 (+/- 1.1) liters/h per 1.73 m2 for cilastatin. Renal clearance accounted for 54% of the plasma clearance of imipenem and 69% of the plasma clearance of cilastatin. The concentrations of imipenem in plasma and urine remained above the MICs of the vast majority of pathogens throughout the dosing interval.

Multiple-dose pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers.

We administered multiple doses of ciprofloxacin intravenously over 30 min every 12 h for 1 week to nine healthy volunteers. Three volunteers received a placebo (vehicle) intravenously. Doses of 100, 150, and 200 mg were evaluated with a 1-week wash-out period intervening between each dose level. Terminal excretion half-lives averaged 3.67 +/- 0.65, 3.60 +/- 0.26, and 4.00 +/- 0.69 h for the 100-, 150-, and 200-mg doses, respectively. Serum clearances were 30.1 +/- 3.4, 29.8 +/- 4.0, and 26.9 +/- 4.1 liters/h per 1.73 m2 for these doses. Urine concentrations remained in excess of the MIC for 90% of the relevant urinary tract pathogens for the full 12-h dosing interval at each dose. Renal clearance accounted for 56 to 71% of the serum clearance. However, because a microbiologic assay was used and biologically active, renally excreted metabolites were identified, the renal clearance determinations are likely to be in excess of the true values. The doses of ciprofloxacin administered intravenously were well tolerated, and the drug concentrations appeared adequate for the treatment of the vast majority of cases of nosocomially acquired sepsis and urinary tract infections. For patients with serious Pseudomonas infections and perhaps staphylococcal infections, either an 8-h dosing schedule or larger doses on a 12-h schedule should be considered.

An evaluation of optimal sampling strategy and adaptive study design

We have evaluated the utility of optimal sampling strategy coupled with adaptive study design in the determination of individual patient and population pharmacokinetic parameter values. In 9 patients with cystic fibrosis receiving a short (1 minute) infusion of ceftazidime pharmacokinetic parameter values were determined with a nonlinear least‐squares estimator analyzing a traditional, geometrically spaced set of 12 postinfusion serum samples drawn over 8 hours. These values were compared with values generated from four sample subsets of the 12 obtained at optimal times and analyzed by nonlinear least‐squares estimator, as well as a maximum a posteriori probability Bayesian estimator with prior distributions placed on β and clearance. The four sampling times were determined according to an adaptive design optimization technique that employs sequential updating of population prior distributions on parameter values. Compared with the 12‐point determination, the four optimal points analyzed with the maximum a posteriori probability Bayesian estimator faithfully reproduced both microscopic and hybrid pharmacokinetic parameter values for individual patients and, consequently, also produced accurate measures of population central tendency and dispersion. This has important implications in being able to more efficiently derive target patient population pharmacokinetic information for new drugs. This should also allow generation of better concentration‐effect relationships in populations of interest.

Dose ranging study and constant infusion evaluation of ciprofloxacin.

We evaluated the pharmacokinetics of 100- and 200-mg doses of ciprofloxacin, with the 200-mg dose administered either as a 30-min infusion or as a 100-mg loading dose followed by a 4-h constant infusion of 25 mg/h in six normal volunteers. No significant differences were seen in the dose-normalized area under the curve when the 100- and 200-mg 30-min administrations were compared. Differences that approached statistical significance were seen when data from either of these trials were compared with data from the constant-infusion arm. Serum clearances averaged 23.0 +/- 9.1 liters/h per 1.73 m2 for the 100-mg dose and 23.7 +/- 5.1 liters/h per 1.73 m2 for the 200-mg dose. Renal clearance accounted for approximately two-thirds of the serum clearance in each instance. Half-lives were slightly longer than 4 h. For the constant-infusion arm, serum clearance was 28.9 +/- 2.7 liters/h per 1.73 m2, with renal clearance accounting for 58% of serum clearance. Although no nonlinearities were apparent in the 100- to 200-mg dose range, larger doses, particularly in the multiple-dosing situation, may uncover nonlinearity in the disposition of ciprofloxacin.