Glycogenolysis during short-term fasting in malaria and healthy subjects--the potential regulatory role of glycogen content on glycogen breakdown: a hypothesis.

BACKGROUND & AIMS: During short-term starvation (< 24 h), glucose production decreases 10-20% due to a decrease in glycogenolysis. In the fed state glycogen regulates its rate of breakdown, in order to limit glycogen accumulation. Whether in the fasted state a similar mechanism exists to preserve glycogen content is not known. In malaria, the rate of glycogen breakdown after an overnight fast is considerably lower than in healthy subjects. If glycogen content regulates its rate of breakdown during fasting, we postulate that the rate of glycogenolysis should decrease faster in patients with malaria than in healthy subjects. METHODS: In six non-severe falciparum malaria patients and 6 healthy controls glucose production with [6,6-2H2]-glucose, and glycogenolysis was calculated after measuring gluconeogenesis with the 2H2O-method between 16 and 22 h of fasting. RESULTS: Glucose production after 16 h of fasting was 15% higher in the malaria patients than in controls. Glycogenolysis in the malaria patients was 2.3 +/- 0.37 and 8.4 +/- 0.93 micromol/kg/min in the controls. The absolute decrease in glycogenolysis was slower in malaria patients than in controls (P = 0.001), whereas the relative decrease in glycogenolysis from baseline was not different. CONCLUSION: During fasting the relative decrease in glycogenolysis is independent of the absolute rate of glycogenolysis. The regulation of glycogenolysis during fasting seems not preferentially dictated by glycogen content but, at least in subjects with a low (presumed) glycogen content, driven by the necessity to guarantee glucose output and maintain euglycemia.

Oral bioavailability of dihydroartemisinin in Vietnamese volunteers and in patients with falciparum malaria.

AIMS: To obtain comprehensive bioavailability data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following their separate oral administration to Vietnamese volunteers and to patients with acute, uncomplicated falciparum malaria. METHODS: Volunteers were randomized to receive either i.v. ARTS (120 mg) followed by oral ARTS (150 mg) 8 h later (Group 1, n = 10), or i.v. ARTS (120 mg) followed by oral DHA (120 mg) 8 h later. Patients, also received oral ARTS (150 mg; Group 3, n = 8) or DHA (120 mg; Group 2, n = 7), in a randomized cross-over study design. Multiple blood samples were collected after each administration and plasma ARTS and/or DHA concentrations were determined by h.p.l.c. Pharmacokinetic descriptors were obtained from noncompartmental analysis and bioavailability was calculated from AUC data. In the patients, the time to 50% parasite clearance (PCT50) and fever clearance time (FCT) also were measured. RESULTS: In Group 1 (volunteers), the mean (95% CI) absolute bioavailability of oral ARTS was 80% (62,98%), while in Group 2 (volunteers), the bioavailability of oral DHA was 45% (34,56%). In the patients (Group 3), the bioavailability of oral DHA relative to oral ARTS was 88% (49,127%). The median PCT50 and FCT were 2.3 and 28 h, respectively. CONCLUSIONS: The study shows that the absolute bioavailability of DHA was significantly lower than that for ARTS in healthy volunteers. The bioavailability of ARTS in volunteers was consistent with previous studies in patients with uncomplicated falciparum malaria. The dose-normalized Cmax and AUC(0,infinity) for DHA were significantly greater in patients with falciparum malaria than in healthy volunteers. The high relative bioavailability of DHA in the patients may have been due to lower first-pass clearance. We conclude that, for the treatment of malaria, DHA is likely to be a suitable oral substitute for ARTS. Based on our mean AUC measurements, it appears that equal doses of DHA and ARTS (mg basis) should give equivalent systemic exposure to bioactive DHA in uncomplicated falciparum malaria.

Pharmacokinetics and pharmacodynamics of intravenous artesunate in severe falciparum malaria.

To provide novel data relating to the dispositions, effects, and toxicities of the artemisinin derivatives in severe malaria, we studied 30 Vietnamese adults with slide-positive falciparum malaria treated with intravenous artesunate. Twelve patients with complications (severe; group 1) and 8 patients without complications but requiring parenteral therapy (moderately severe; group 2) received 120 mg of artesunate by injection, and 10 patients with moderately severe complications (group 3) were given 240 mg by infusion. Serial concentrations of artesunate and its active metabolite dihydroartemisinin in plasma were measured by high-performance liquid chromatography. The time to 50% parasite clearance (PCT(50)) was determined from serial parasite densities. Full clinical (including neurological) assessments were performed at least daily. In noncompartmental pharmacokinetic analyses, group mean artesunate half-lives (t(1/2)) were short (range, 2.3 to 4.3 min). The dihydroartemisinin t(1/2) (range, 40 to 64 min), clearance (range, 0.73 to 1.01 liters/h/kg), and volume of distribution (range, 0.77 to 1.01 liters/kg) were also similar both across the three patient groups (P > 0.1) and to previously reported values for patients with uncomplicated malaria. Parasite clearance was prompt (group median PCT(50) range 6 to 9 h) and clinical recovery was complete under all three regimens. These data indicate that the pharmacokinetics of artesunate and dihydroartemisinin are not influenced by the severity of malaria. Since the pharmacokinetic parameters for both artesunate and dihydroartemisinin were similar regardless of whether injection or infusion was used, artesunate can be considered a prodrug that is converted stoichiometrically to dhydroartemisinin. Conventional doses of artesunate are safe and effective when given to patients with complications of falciparum malaria.

Bacterial flora of the lower respiratory tract in children with bronchial asthma.

The aims of this retrospective study were to (i) determine the risk of contamination of lower respiratory tract samples obtained during fiberoscopy in children; (ii) determine the incidence and profile of the bacterial flora of the lower respiratory tract in a selected group of asthmatic children at high risk for bacterial infection; and (iii) identify risk markers for such findings. In 29 asthmatic children, comparison of bacterial cultures of specimens obtained from the upper and, lower respiratory tracts showed that contamination was a possibility in only 3.4% (1/29) of cases. The results from bacterial samples obtained via flexible bronchoscopy in a further 273 consecutively investigated physician-diagnosed asthmatic children were analysed. Patients were selected for bronchoscopy if they had severe chronic asthma or in order to exclude other diseases able to provoke wheezing. Their mean (SD) and median ages were 32.2 (38.3) and 17.5 mo, respectively. The incidence of positive bacterial cultures was 12.1% (33/273 patients). Bacterial flora included H. influenzae (39.5%, 15/38), B. catarrhalis (23.7%, 9/38), Neisseria species (7.9%, 3/38), M. pneumoniae (7.9%, 3/38), P. non-aeruginosa (5.3%, 2/38) and P. aeruginosa (2.6%, 1/38). No clinical or radiological markers were significantly associated with lower respiratory tract bacterial infection. Large quantities of bacteria were present in the lower respiratory tracts of a substantial number of children (1/8) in this selected group of asthmatics. For the moment, however, the clinical implications of this finding remain unclear.

Management of acute otitis media caused by resistant pneumococci in infants.

OBJECTIVES: To assess the clinical outcome and risk of failure after oral vs. intravenous treatment in otitis media caused by penicillin-resistant pneumococci. To determine the possible correlations between pneumococcal minimal inhibitory concentration (MIC) to penicillin and clinical outcome. DESIGN: Retrospective study of 156 cases collected between 1993 and 1995. Mean follow-up: 5 months. Setting. Two tertiary academic medical centers in Paris, France. PATIENTS AND METHODS: Pneumococcus was isolated from 191 of 570 ear samples obtained from children with otitis media and shown to be penicillin-resistant in 156. Medical history, antibiotic therapy during the previous 3 months and day-care center attendance were reviewed. For the current episode microbiologic characteristics of the isolated strains, type of treatment, therapy efficacy and clinical outcome were analyzed. Patients were predominantly young (76.3% were <1 year old) and bacteriologic samples were taken mainly because of previous treatment failure. RESULTS: Among 156 children with pneumococcal penicillin-resistant otitis media, 72.2% attended day-care centers, 71.8% had been previously treated with aminopenicillin and 52.5% with cephalosporins. Failure of previous empirical oral therapy was noted in 84% (one-third of these had been receiving amoxicillin-clavulanate). Patients treated intravenously had had a more protracted otitis but no greater number of previous episodes of acute otitis media than those receiving oral therapy. Acute mastoiditis occurred in 4 infants resulting in mastoidectomy. Oral treatment (mainly with high dose amoxicillin,120 to 150 mg/kg/day) and intravenous therapy (cephalosporin or glycopeptide) had been used in 59 and 41%, respectively. Mean duration of therapy was 10.7 days. Three failures (1.9%) and 10 recurrences (6.4%, average 28 days) occurred. No statistical difference was found between intravenous and oral therapy with respect to risk of recurrence. A high penicillin MIC value was correlated with previous antibiotic treatment but not with clinical outcome. CONCLUSIONS: Oral therapy appears to be as effective as intravenous therapy for the treatment of penicillin-resistant pneumococcal otitis media. Intravenous treatment should not necessarily be dictated by the penicillin susceptibility value but should be considered in cases of failure to thrive, persistent otitis or other complications.

A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria.

AIMS: To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria. METHODS: Twenty-six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non-compartmental methods. The time to 50% parasite clearance (PCT50) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokinetic-pharmacodynamic relationships. RESULTS: Following i.v. bolus, ARTS had a peak concentration of 29.5 microM (11 mg l[-1]), elimination t1/2 = 2.7 min, CL = 2.33 l h(-1) kg(-1) and V = 0.14 l kg(-1). The Cmax for DHA was 9.3 microM (2.64 mg l[-1]), t1/2 = 40 min, CL =0.75 l h(-1) kg(-1) and V = 0.76 l kg(-1). Following oral ARTS, relative bioavailability of DHA was 82%, Cmax was 2.6 microM (0.74 mg l[-1]), t1/2 = 39 min, and MAT = 67 min. Overall, the PCT50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT50 or FCT and AUC, Cmax or MRT for DHA. CONCLUSIONS: Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.

A plasmid-mediated CMY-2 beta-lactamase from an Algerian clinical isolate of Salmonella senftenberg.

Multiresistance to antibiotics including beta-lactams, e.g. cefoxitin, was transferred by conjugation to Escherichia coli strain C1a from a clinical isolate of Salmonella senftenberg recovered from stools of an Algerian child. The susceptibility pattern to beta-lactams was similar to the profile mediated by an AmpC-type beta-lactamase. By biochemical analysis, typical AmpC-type enzyme substrate and inhibition profiles were obtained. Finally, an ampC plasmid-encoded beta-lactamase gene was cloned and sequenced. Its deduced amino acid sequence confirmed its identity as a class C beta-lactamase. It showed 99.5% sequence identity with the plasmid-mediated beta-lactamase CMY-2. The differences in the amino acid sequences of the two enzymes were located in the signal peptide.