John W. Vance

Gentamicin disposition and tissue accumulation on multiple dosing

Gentamicin pharmacokinetics was examined in a group of 47 patients with stable renal function treated an average of 10 days for severe infection. Serum concentrations rose continually during treatment, and declined in two phases after the drug was stopped, with a mean half-life of 112hr (range 27–693 hr) in the second phase. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of drug in the tissue compartment at all times during and after treatment. Predicted tissue amounts of gentamicin rose continually on multiple dosing in all patients. In six patients who died, postmortem tissues were obtained to quantitate recovery. In all cases, the predicted amount of gentamicin in tissues was in close agreement with the amount recovered at autopsy. Tissue distribution and accumulation constitute a major reason for variability in gentamicin pharmacokinetics and explain both the rising peak and trough serum concentrations and the prolonged detection of gentamicin in serum and urine after the drug is stopped.

Role for Dual Individualization with Cefmenoxime

Cefmenoxime concentration/effect relationships were retrospectively explored for gram-negative bacteria isolated from 14 critical care patients treated for nosocomial pneumonia. The effects of cefmenoxime concentrations on in vitro growth kinetics of 21 isolated pathogens were studied using the Abbott MS-2 Research System, from which a dynamic response concentration was derived. Serum pharmacokinetic profiles were obtained in each patient. These data were used to calculate the in vivo total area under the curve over dynamic response concentration and the time that cefmenoxime concentrations exceeded the dynamic response concentration for each bacteria. The same determinations were made in 18 patients prospectively treated, except that dosage was optimized on the basis of previous mathematical relations to achieve bacterial eradication in four days. This method of dosage optimization is termed dual individualization. Serial cultures of infected tissues were evaluated to determine the number of days to the eradication of bacteria, and the pharmacokinetic and pharmacodynamic variables were used to describe the bacteriologic response of the original pathogen isolated in pretreatment culture. Bacterial eradication rates could be described from cefmenoxime pharmacokinetics in the patient and from the relation between concentration and bacterial inhibition. Patients who were prospectively treated using these retrospectively derived relationships had a predictable day of bacterial eradication. This, in turn, was associated with a shorter duration of treatment (p less than 0.05). The success of prospective dual individualization is encouraging and suggests that more precise optimization of antibiotic dosage can yield a predictable rate of bacterial eradication from the infection site.

Intravenous Theophylline Therapy: Nomogram Guidelines

We evolved a nomogram for guiding and standardizing intravenous theophylline therapy in hospitalized patients. It provides rapid calculation of a loading dose based on body weight and previous therapy and a maintenance infusion rate related to three categories of expected metabolic activity. The guidelines were prospectively used in the treatment of 72 patients, mainly in a respiratory care unit. The nomogram was successfully used to attain near-steady-state serum concentrations in the therapeutic range of 8 to 20 mg/litre in 72% of patients, with only two patients outside of the range of 5 to 25 mg/litre. These guidelines facilitate initial theophylline dosage in older patients with liver and cardiac disease and provide a rational basis for interpreting serum concentration measurements and adjustment of drug therapy.

Complexation versus Hemodialysis To Reduce Elevated Aminoglycoside Serum Concentrations

Seven patients with acutely elevated aminoglycoside serum concentrations were studied comparing the effect of hemodialysis (n = 3) with removal by complexation using ticarcillin or carbenicillin (n = 4). Aminoglycoside serum half‐life before intervention averaged 96 hours for the dialysis group and 67 hours for the complexation group. Ticarcillin was used for a minimum of 48 hours, while hemodialysis removal was estimated over 48 hours, which included two 4‐hour dialysis periods. Aminoglycoside serum half‐life was reduced to an average of 11 hours with hemodialysis, while with complexation using ticarcillin, it was reduced to 12 hours.

Ciprofloxacin eradicates respiratory tract bacteria more rapidly than cephalosporins in patients with nosocomial pneumonia

Patients with nosocomial pneumonia treated with either IV ciprofloxacin or IV third generation cephalosporins (cefmenoxime or ceftazidime) were evaluated to determine the length of treatment required to sterilise their respiratory tract cultures. The time required to eradicate the respiratory pathogens was determined using daily cultures oftracheal aspirate secretions. All patients were also assessed for clinical outcomes, and all patients had measurement of the minimum inhibitory concentration (MIC) of the presenting pathogen. A clinical scoring system was employed to correlate rate of pathogen eradication with rate of clinical improvement. All patients had measurements of serum concentrations of the respective antibiotic. HPLC assays were used. Serum concentrations were analysed using the computer program ADAPT II to determine pharmacokinetic parameters (AVC, Vd and clearance) for each patient. The primary pharmacokinetic-pharmacodynamic comparison parameter was the area under the inhibitory time curve (AUIC). This measure of overall activity is calculated as (24-hour AVC + MIC). AVIC values in the patients ranged from 6.0 to over 7,212 per 24 hours. These values correlated closely with time to eradication of pathogens (p < 0.001), regardless of which of the three antibiotics the patient received. AVIC values> 125 also were predictive of clinical cures. While over 75% of patients in each of the three drug treatment regimens eventually achieved negative tracheal aspirate cultures (p, NS), there was a striking difference in the time required to sterilise these cultures. Appropriate AVIC values for ciprofloxacin sterilised cultures in an average of 1.9 days, while both cephalosporins at similar AUIC values required over five days to achieve negative cultures. The clinical symptom scoring revealed that faster clinical cures were associated with more rapid bacterial eradication for ciprofloxacin. We conclude that the more rapid in-vitro killing which is characteristic of ciprofloxacin can translate directly into more rapid clearance of bacteria in the respiratory tract of patients. Prospective studies should be designed to sample the infection site more frequently, in order to provide additional validation of these outcomes.