Guy Humbert

Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres

Objective:To assess the clinical and economic consequences of the use of protease inhibitors in the treatment of HIV infection. Design:Multicentric, observational, retrospective cohort study. Setting:Ten AIDS reference centres in France. Patients:All patients followed in each centre from September 1995 through October 1996. Main outcome measures:AIDS-defining events, death, health-care resources use, administration of antiretroviral therapy. Results:Data from 7749 patients in 10 centres showed a drop in hospitalization days by 35%, new AIDS cases by 35%, and deaths by 46%. In the same period, the proportion of patients receiving antiretrovirals rose from 36 to 53% including highly active antiretroviral therapy (HAART), which rose from 0.3 to 18%. Overall cost evaluation showed a slight increase of monthly treatment cost of US

Is presentation of bacteremia in the elderly the same as in younger patients

12 per patient. Comparison of the three centres that used HAART earliest to the three centres that used it latest showed a clear benefit to early HAART with a drop in hospitalization days by 41%, new AIDS cases by 41% and deaths by 69%. The proportion of patients with HAART rose to 27% and monthly health-care cost decreased by US

Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment.

248 852 (i.e., by US

Ofloxacin pharmacokinetics in renal failure.

101 per patient per month). Late prescribing centres experienced a less marked effect with a drop in hospitalization days by 22%, new AIDS cases by 31%, and deaths by 32.5%. Proportion of patients with HAART rose to 12% and monthly health-care costs increased by US

Pharmacokinetics of ceftazidime in normal and uremic subjects.

113 578 (i.e., by US

Effects of amoxicillin-clavulanate combination on the motility of the small intestine in human beings.

38 per patient per month). Conclusions:This study supports the extensive use of HAART in HIV-infected patients.

Pharmacokinetics of meropenem in subjects with renal insufficiency

OBJECTIVE To compare the presentation of bacteremia in young and elderly patients. PATIENTS AND METHODS Seventy-one elderly (mean age 80.4 years) and 34 younger inpatients (mean age 45.7 years) with bacteremia were prospectively studied. These were compared with a control group of 187 geriatric patients (mean age 81.3 years) with clinical signs of bacteremia but in whom blood cultures were negative. Bacteremia was defined as one or more positive blood cultures showing a pathogenic bacteria in patients with clinical signs of bacteremia. In all 105 patients with bacteremia, 16 common clinical or biological signs of the disease were immediately investigated after blood culture. Patients were classified into three groups: elder patients and young patients with bacteremia and elderly patients without bacteremia. RESULTS Only three clinical findings of the 16 studied were found in at least 70% of the bacteremic elderly patients: fever, increased erythrocyte sedimentation rate, and a clinical indication of the source of infection. These three signs were found statistically more often in bacteremic elderly compared with nonbacteremic elderly patients (P < 0.01). Seven other signs (hypothermia, altered mental state, leukopenia, and lymphopenia) had a specificity above 80%. On a logistic regression analysis, four variables were significantly and independently associated with bacteremia in the elderly: rapid onset of infection (defined as a period < or = 48 hours between the earliest manifestation of bacteremia and the time of blood blood sample), fever, altered general state, and clinical indication of the source of infection. Younger infected patients had more chills, sweating, alter general state, altered mental state or lymphopenia than did the bacteremic elderly patients. Bacteremic elderly patients had statistically few symptoms than the young infected patients (P < 0.001). CONCLUSIONS In elderly patients with early stage bacteremia, most of the signs or symptoms that are considered typical in the literature appear irregularly. None appeared pathognomonic. Elderly patients with bacteremia had fewer signs or symptoms than younger infected patients.

Pharmacokinetics of Aztreonam in Patients with Chronic Renal Failure

The pharmacokinetics of meropenem (ICI 194,660) and its open-ring metabolite (ICI 213,689) were studied in 6 healthy volunteers and 16 patients with moderate to severe renal impairment after a single intravenous dose of 500 mg given as a 30-min infusion. Concentrations of unchanged meropenem in plasma and urine were measured by both microbiological and high-pressure liquid chromatographic (HPLC) assays. A good correlation was found between the two techniques. Pharmacokinetic parameters of unchanged meropenem were determined by using the HPLC data. The terminal half-life of unchanged meropenem increased in relation to the degree of renal impairment, being 1.2 h in subjects with normal renal function and 10 h in patients with end-stage renal failure. Total body clearance and renal clearance of unchanged meropenem are linearly related to creatinine clearance. The concentrations of the metabolite in plasma, which are very low in healthy subjects, significantly increased in uremic patients. The apparent half-life of ICI 213,689 increased in uremic patients and was about 35 h in patients with severe renal insufficiency. Meropenem and its metabolite are effectively removed by hemodialysis. The dialysis clearance of the unchanged drug was 81 +/- 22 ml/min. Dosage adjustments of meropenem will be necessary in patients with severe renal impairment.

Lomefloxacin pharmacokinetics in subjects with normal and impaired renal function.

The pharmacokinetics of ofloxacin were investigated in 12 normal subjects and 21 uremic patients after the administration of a single oral 200-mg dose. An open three-compartment body model was used to calculate ofloxacin pharmacokinetic parameters. In healthy subjects, the peak plasma level averaged 2.24 +/- 0.90 micrograms/ml and was obtained at 0.83 +/- 0.31 h. The absorption rate constant was 4.22 +/- 1.64 h-1. The terminal half-life was 7.86 +/- 1.81 h. The apparent volume of distribution was 2.53 +/- 0.78 liters/kg. Total body and renal clearances were 241.4 +/- 53.8 and 196.5 +/- 42.9 ml/min per 1.73 m2, respectively. A total of 68.4 +/- 11.9% of the dose was recovered unchanged in 24-h urine. In uremic patients, the terminal half-life increased in relation to the degree of renal failure: from 8 h in normal subjects to 37 h in severely uremic patients. Renal insufficiency did not significantly modify the peak plasma level, the apparent volume of distribution, the fractional clearance, or the nonrenal clearance of ofloxacin. However, the time to peak level was delayed in patients with creatinine clearance of less than 30 ml/min. Linear relationships were found between ofloxacin pharmacokinetic parameters and glomerular filtration rate data. Ofloxacin is only very slightly removed by hemodialysis. Dosage adjustments of ofloxacin in uremic patients are proposed.

Pharmacokinetics of Netilmicin in the Presence of Normal or Impaired Renal Function

The pharmacokinetics of ceftazidime, administered as a single intravenous dose of 15 mg/kg given in a bolus injection over 3 min, were investigated in 5 normal subjects and in 19 uremic patients. The subjects studied were divided into five groups according to values for endogenous creatinine clearance (CLCR): group I, five subjects with CLCR greater than 80 ml/min; group II, five patients with CLCR = 30 to 80 ml/min; group III, six patients with CLCR = 10 to 30 ml/min; group IV, four patients with CLCR = 2 to 10 ml/min; and group V, four anuric patients on hemodialysis. A two-compartment open model was used to calculate the pharmacokinetic parameters. In normal subjects, the mean apparent elimination half-life was 1.57 +/- 0.13 h. The central distribution volume and the apparent volume of distribution were 0.127 +/- 0.023 and 0.230 +/- 0.015 liter/kg, respectively. Of the injected dose, 83.6 +/- 3.6% was eliminated in the urine as parent drug within 24 h. The terminal half-life increased with impairment of renal function to about 25 h in severely uremic patients. Impairment of function did not significantly modify the half-life at alpha phase, central distribution volume, or apparent distribution volume. A 6- to 8-h hemodialysis procedure reduced concentrations of ceftazidime in plasma by approximately 88%, and the elimination half-life was 2.8 +/- 0.2 h. There was no evidence of accumulation of ceftazidime in four patients with severe and chronic impairment of function who received doses of 0.5 to 1.0 g every 24 h for 10 days.