[Sensitivity to antibiotics of bacteria from nosocomial infections. Evolution in resuscitation services of military hospitals]. / Sensibilité aux antibiotiques des bactéries d'infections nosocomiales. Evolution dans les services de réanimation des hôpitaux des armées.

OBJECTIVE: The aim of this study, conducted in the French Military hospitals, was to monitor the course of the antimicrobial sensibility of bacteria isolated from nosocomial infection in intensive care units. PATIENTS AND METHODS: A prospective study has been conducted from January to December 1998 in all the intensive care units of the French Army. All the non-repetitive strains isolated from nosocomial infection were collected and sent to a reference centre. Antimicrobial susceptibility was determined by the agar dilution method. Beta-lactamase were identified by iso-electro-focalisation. Antibiotics choice and interpretative criteria were those of the "Comité Français de l'Antibiogramme de la Société Française de Microbiologie". RESULTS: A total of 849 strains are included in this study. Pseudomonas aeruginosa was the most frequently isolated bacterium (20%) followed by Escherichia coli (19%) Staphylococcus aureus (15%), coagulase-negative Staphylococci (CoNS) (11%) and Enterococci (7%). Imipenem was the most effective antibiotic against enterobacteriaceae (336 isolates; 100% susceptibility). Gentamicin (92%), amikacin (92%) third generation cephalosporins (83%), aztreonam (83%) and ciprofloxacin (78%) were also very effective. Resistance to III generation cephalosporins was correlated with an extended spectrum beta-lactamase (BLSE) in 36% of cases. This BLSE could be associated with an over production of the constitutive cephalosporinase. The most frequent species producing BLSE were Enterobacter aerogenes (75% of BLSE) and Klebsiella pneumoniae (17%). Among the 172 P. aeruginosa isolated, antimicrobial susceptibility were respectively: 71% for imipenem, 62%: tobramycin, 60%: amikacin 59%: ciprofloxacin 59% piperacillin + tazobactam, 55% piperacillin, 53%: ceftazidime and 44% for ticarcillin. Seventy per cent of the 96 CoNS and 50.2% of the 126 S. aureus isolated were resistant to methicillin. A strain of S. aureus and 2 CoNS strains had intermediate resistance to teicoplanin. Twenty per cent of the 59 Enterococci strains isolated were resistant to aminopenicillins (10/11 strains of E. faecium), and 9% presented a high level of resistance to gentamicine. One strain of E. faecium was resistant to vancomycin. CONCLUSION: The evolution of the susceptibility to antibiotics in intensive care units reflects the antibiotic pressure and level of cross-transmission. High rates of meticillin-resistance among staphylococci, of resistance to beta-lactams antibiotics among P. aeruginosa and of ciprofloxacin among Enterobacteriaceae are shown in this study. The implementation of appropriate strategies for surveillance and prevention is necessary.

Quinine disposition in globally malnourished children with cerebral malaria.

BACKGROUND: Both malnutrition and malaria affect drug disposition and are frequent among children in the tropics. We assessed their respective influence on quinine distribution. METHODS: Forty children were divided into 4 groups: children with normal nutritional status without (group 1) or with (group 2) cerebral malaria, and malnourished children without (group 3) or with (group 4) cerebral malaria. All children received an infusion of 8 mg/kg of a combination solution of cinchona alkaloids that contained 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (corresponding to 4.7 mg/kg quinine base). The children with malaria then received repeated infusions every 8 hours for 3 days. Pharmacokinetic profiles of plasma and erythrocyte quinine were determined during the first 8 hours, together with quinine protein binding. Additional measurements of plasma quinine concentrations were used to simulate quinine concentrations profiles in children with malaria with and without malnutrition. Clinical recovery and parasitemia clearance times were determined in the children with malaria. RESULTS: Compared with control children, malaria and malnutrition increased plasma concentrations of quinine and reduced both the volume of distribution and the total plasma clearance. Simultaneously, alglycoprotein plasma concentrations and protein-bound fraction of the drug were increased. Erythrocyte quinine concentrations correlated strongly with free plasma quinine but not with the extent of parasitemia. Similar effective and nontoxic quinine concentration profiles were obtained in malaria with and without malnutrition. CONCLUSIONS: Severe global malnutrition and cerebral malaria have a similar effect on quinine pharmacokinetics in children. Moderate malnutrition does not potentiate cerebral malaria-mediated modifications of quinine disposition. These results suggest that current parenteral quinine regimens can be used, unmodified, to treat children with both malaria and malnutrition.

Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria.

1. Three groups of seven children aged 2-14 years with acute uncomplicated Plasmodium falciparum malaria received 12.8 mg kg-1 quinine gluconate by the intrarectal route (new cream formulation) or 8 mg kg-1 Quinimax (a Cinchona alkaloid alkaloid combination) by the intramuscular or intravenous (4 h infusion) route every 8 h for 3 days. Clinical and parasitological status was similar in the three groups at enrolment. 2. At 36 h, body temperature of all children of the three groups was returned to normal and remained so until day 7. 3. The decrease in parasitaemia did not differ between the three groups and the time required for a 50% fall in parasitaemia relative to baseline was 12.3 +/- 5.4, 18.2 +/- 6.1 and 14.5 +/- 4.2 h in the intrarectal, intramuscular and intravenous treatment groups, respectively. Parasitaemia expressed as a percentage of initial values was not significantly different in the three groups after 48 h of treatment (7.4 +/- 16.0, 4.1 +/- 4.2 and 2.2 +/- 3.8% in the intrarectal, intramuscular and intravenous treatment groups, respectively). All the patients were aparasitaemic by day 7. 4. The tolerability of the three treatments was good; in particular, no rectal irritation was reported with the cream formulation. 5. The tmax occurred later after intrarectal (4.1 +/- 2.4 h) and intravenous infusion (3.8 +/- 0.5 h) than after intramuscular injection (1.6 +/- 1.3 h) (P = 0.02). Cmax was lower with the intrarectal (3.0 +/- 1.0 mg 1(-1)) and intramuscular routes (3.2 +/- 0.7 mg 1(-1)) than with the intravenous route (5.1 +/- 1.4 mg 1(-1)) (P = 0.003). Areas under the curve (AUC(0, 8 h)) were smaller with intrarectal (17.0 +/- 7 mg 1(-1) h) and intramuscular routes (19.4 +/- 4.8 mg 1(-1)) than with the intravenous route (27.8 +/- 8.2 mg 1(-1) h) (P = 0.02). The approximate bioavailability of intrarectal quinine from 0 to 8 h was 36% vs intravenous quinine and 51% vs intramuscular quinine. 6. The good tolerability and efficacy of this new intrarectal quinine formulation outweigh its low approximate bioavailability. This new approach might thus be a safe and effective alternative to intramuscular quinine injection for the treatment of children with acute uncomplicated Plasmodium falciparum malaria in the field.

[Rectal quinine, an alternative to parenteral injections for the treatment of childhood malaria. Clinical, parasitological and pharmacological study]. / La quinine intrarectale, une alternative aux injections parentérales pour le traitement du paludisme du jeune enfant. Etude clinique, parasitologique et pharmacologique.

In order to avoid the frequent side effects with injections of quinine in african children, empirical intrarectal administration of quinine (Quinimax, Sanofi Winthrop) has already been used successfully in Madagascar and Niger. In an attempt to optimise its use, a pharmacokinetic study was carried out with 66 children, 2 to 15 years old, admitted in pediatric unit for acute uncomplicated Plasmodium falciparum malaria, but warranting parenteral therapy. Children received Quinimax intrarectally (20 mg/kg/12h), intravenously (12,5 mg/kg in a slow infusion over 4 hours/12h) or intramusculary (12,5 mg/kg/12h). Plasma quinine concentrations were determined by HPLC. In this study, temperature and parasite clearance were similar in the 3 groups. A second randomized study was performed with 3 different dosages of intrarectal Quinimax: 8 and 13 mg/kg/8h and 20 mg/kg/12h. Temperature fell stably to normal at 36 hours with all regimens. Total clearance of parasitaemia was only obtained at 48 h with 30 mg/kg/12h regimen. Pharmacokinetic stimulation allowed to propose that intrarectal administration of Quinimax 20 mg/kg/8h would be a safe and effective regimen. A third approach studied the efficacy and pharmacokinetics of a new rectal quinine formulation (12,8 mg/kg/8h quinine gluconate) compared to IM and IV (8 mg/kg/8h) : at 36h, body temperature of all children was returned to normal and remained so until day 7. Parasitaemia expressed as a percentage of initial values was not different in the 3 groups after 48 h. At day 7, all the patients were aparasitaemics. The good tolerability and efficacy of this new intrarectal quinine formulation might allow to propose this route as an alternative to intramuscular route for the treatment of childhood malaria in Africa.

Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients.

Sensitive immunoenzymatic assays were used to study the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 beta in sera from dengue-infected patients obtained during the 1989-1990 outbreak of dengue-3 in Tahiti, French Polynesia. The patients, both children (n = 47) and adults (n = 18), were clinically classified as having dengue hemorrhagic fever (DHF) and graded according to the severity of illness (grade I = fever, grade II = fever with spontaneous hemorrhagic manifestations, grade III = circulatory failure, grade IV = deep shock). The serum samples were obtained from day 1 to day 10 after the onset of the disease. High levels of TNF-alpha were observed in dengue-infected children of all severity grades. The highest values of TNF-alpha were found before day 6 after the onset of the infection, these values decreased from day 6 to day 10. The highest values were observed in sera from grade III and IV patients. High values of IL-6 were observed in serum samples of grade I and II patients on day 1, which decreased on day 4, and by day 5 were similar to those obtained from 25 control children. In grade III and IV patients, the highest values of IL-6 were observed from day 3 to day 5 after the onset of infection; after day 5, these values were very low.(ABSTRACT TRUNCATED AT 250 WORDS)