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The 50% and 90% minimal inhibitory concentrations (MIC50 and MIC90) of polymyxin B for avian Escherichia coli and Pasteurella multocida isolates were determined by the agar plate dilution method. Polymyxin B at approximate MIC level in serum was bactericidal for E. coli in 2 to 4 hours. Aqueous polymyxin B sulfate was administered by a single bolus intravenous injection into turkeys at 10,000 IU/kg, and by a single bolus intramuscular injection at 5,000, 10,000 or 20,000 IU/kg. Effective serum drug concentrations after intramuscular injection (MIC50 levels or greater) were maintained for E. coli for 7.0 hr (10,000 IU/kg) and 11.5 hr (20,000 IU/kg), and for P. multocida for 3.0 hr (10,000 IU/kg) and 4.1 hr (20,000 IU/kg). Pharmacokinetic parameters were calculated by non-compartmental methods. Elimination time half-lives, mean residence time, clearance, and apparent volume of distribution at steady state (Vdss) were all much higher for i.m. injection of 20,000 IU/kg than for i.m. injection of 10,000 IU/kg. We postulate that there exists a minimal tissue-interaction threshold concentration (MTC) at which polymyxin B can enter previously unavailable compartments or bind to previously refractory tissue components. Bioavailability of polymyxin B injected i.m. was 0.904 for the 10,000 IU/kg dose and 0.675 for the 20,000 IU/kg dose. Dosage intervals necessary to produce minimal steady state concentrations (Cssmin) equal to the MIC were calculated. Certain aspects of the use of the parameter Vdss, and limitations on the use of dosage interval calculations for polymyxin B, are discussed. One week after i.m. injection of polymyxin B at 10,000 IU/kg, high tissue drug levels were present, especially in bound form in liver. Following single injections, no toxic effects on turkeys were observed.

The effect of continuous subcutaneous insulin infusion (c.s.i.i.) on the control of blood-glucose concentration and outcome of pregnancy was assessed in two pregnant diabetics (class B and class C White classification) who were poorly controlled with conventional insulin therapy. The insulin pump was carried in a holster and enabled the patients to ambulate freely. The patients were able to refill the syringe, to augment the infusion rate at mealtime and to change the implantation site of the needle weekly, and thus, were able to leave the hospital. Daily glucose profiles were assessed 1-3 times a week, and the infusion rate was readjusted accordingly. Twenty-four hours glucose profiles were obtained from both patients during inpatient conventional insulin regimens, and then, during c.s.i.i. which was maintained for 41 and 145 days, respectively. Mean 24 hours glucose concentrations were reduced from 156 to 113 mg/100 ml, mean fasting glucose from 152 to 106 mg/100 ml, and mean diurnal variation (maximal excursion) from 75 to 65 mg/100 ml. The favourable results achieved with the c.s.i.i. enabled both patients to reach the 18th week of gestation and to deliver healthy non-macrosomic infants, who had uneventful and morbid-free neonatal periods. Since the c.s.i.i. supplies insulin in a more physiological manner than twice daily regimens, better control of blood sugar and body fuel metabolism may be achieved. By extending the therapy to the early stages of pregnancy, or if possible to pre-conceptional period, reduced perinatal mortality and morbidity may be anticipated.