A simple tool for monitoring nebulized amikacin treatments based on a single urine assay.

Aerosolized aminoglycosides have demonstrated their efficacy in the treatment of P. aeruginosa pneumonia in cystic fibrosis (CF) patients. There is wide interpatient variability in the deposited and systemic drug doses that depend on both the nebulization and inhalation conditions and result in a risk of inefficacy or toxicity. We have developed a tool to provide a simple method for individual dose monitoring by estimating the total quantity of amikacin excreted, which corresponds to the dose absorbed systemically. It is based on a single urine assay. Thirty-seven urinary pharmacokinetic time courses in healthy volunteers (groups A and B) or in CF patients (groups C and D) were used. The rules for extrapolating the total dose excreted on the basis of 6-, 8-, 10-, and 12-h urine samples, were determined from group A. The accuracy of these rules was then tested in the other three groups. The total amount excreted was poorly predictable, with a coefficient of variation (CV) of 36 and 30% in the healthy volunteers, and of 48 and 82% in the CF group, whereas the CV of the estimated amount, based on 8- to 12-h samples, was only 10-15% in the healthy volunteers and 4-8% in the CF patients. Collecting a single sample over an 8- to 12-h period requires overnight sampling. The very low circadian variations in renal function, ranging from -2% to +5%, demonstrated the absence of any significant bias resulting from overnight sampling. A single urine assay can therefore be proposed as a simple, noninvasive, low cost, and reliable method for the clinical monitoring of nebulized amikacin in CF patients. Further studies are needed before this method can be extended to aerosol treatments with other aminoglycosides.

Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. The PRIO Study Group.

BACKGROUND: Pneumocystis carinii pneumonia and toxoplasmic encephalitis are frequent life-threatening opportunistic infections in patients with human immunodeficiency virus (HIV) infection. Primary prophylaxis against P. carinii pneumonia is now common, but there are few data on regimens for primary prophylaxis against toxoplasmosis. METHODS: We conducted a randomized trial that compared two prophylactic regimens: dapsone (50 mg per day) plus pyrimethamine (50 mg per week) was compared with aerosolized pentamidine (300 mg per month). The patients had symptomatic HIV infection, no history of P. carinii pneumonia or symptomatic toxoplasmosis, and CD4+ counts below 200 per cubic millimeter (0.2 x 10(9) per liter). RESULTS: In an intention-to-treat analysis, after a median follow-up of 539 days P. carinii pneumonia developed in 10 patients in each group, whereas toxoplasmosis developed in 32 of 176 patients in the pentamidine group and 19 of 173 patients in the dapsone-pyrimethamine group. Those assigned to pentamidine had a risk of P. carinii pneumonia that was similar to the risk in those assigned to dapsone-pyrimethamine (adjusted relative risk, 1.13; 95 percent confidence interval, 0.44 to 2.92; P = 0.79), but a higher risk of toxoplasmosis (adjusted relative risk, 1.81; 95 percent confidence interval, 1.12 to 2.94; P = 0.02). Among the 262 patients with serologic evidence of past exposure to Toxoplasma gondii, the relative risk of symptomatic toxoplasmosis was 2.37 times higher in those assigned to pentamidine (95 percent confidence interval, 1.3 to 4.4; P = 0.006). More patients discontinued dapsone-pyrimethamine than pentamidine because of toxicity (42 vs. 3; P < 0.001). Survival was similar in the two groups. CONCLUSIONS: For primary prevention of P. carinii pneumonia, dapsone-pyrimethamine is as effective, though not as well tolerated, as aerosolized pentamidine. Dapsone-pyrimethamine also prevents first episodes of toxoplasmosis.

Ventilatory adaptation to metabolic alkalosis in adult awake potassium restricted rats.

The resting ventilation of awake rats, developing metabolic alkalosis as a result of sustained dietary potassium (K) restriction, was compared to that of age-matched controls. Extending the measurements over 17 weeks and using adult rats indicated, as soon as the third week, a significant progressive fall in the minute ventilation of low K rats, which previous studies limited to a single time determination did not consistently ascertain. The ventilatory adaptation observed in all groups, as well as the superimposed respiratory compensation to metabolic alkalosis in low K rats, resulted only from frequency changes. In both groups, the duration of inspiration was inversely correlated with the age of the animals. The duration of expiration was stable in controls but increased significantly with time in low K rats. According to these data, the respiratory compensation to K-depletion alkalosis in the rat is achieved only through an adjustment in the timing component of the control of breathing.

Ventilation in awake rats with permanent arterial catheters.

Respiratory frequency (f), tidal volume (VT) and minute ventilation (VE) were measured in restrained awake rats using a volumetric body plethysmograph excluding the head. An arterial catheter was then implanted and ventilatory measurements performed again two or three days later. Arterial blood gases and acid-base status were measured before entry in the plethysmograph (control values) and after, accompanying each ventilatory measurement. The pattern of ventilation (VT and VE) was significantly correlated with the respiratory status, particularly with PaCO2 (P less than 0.001). A ventilatory (VE, VT, f) and respiratory (PaO2, PaCO2, pH) steady state was obtained from the fifteenth minute to the end of the observation period. The present preparation is a stable experimental model providing respiratory and ventilatory data in the awake rat.