CTX-M beta-lactamase-producing Escherichia coli in French hospitals: prevalence, molecular epidemiology, and risk factors

In 2004, 65 CTX-M-producing Escherichia coli isolates were collected from infected patients in four French hospitals. The blaCTX-M-15 genes were predominant. Pulsed-field gel electrophoresis highlighted a clonal propagation of CTX-M-15-producing strains belonging to phylogenetic group B2, notably in the community. The main risk factors for acquiring these isolates were urinary tract infections or the presence of a urinary catheter in diabetic or renal failure patients.     

The influence of food on the pharmacokinetics of CGP 6140 (amocarzine) after oral administration of a 1200 mg single dose to patients with onchocerciasis.

Eleven male patients from Mali with Onchocerca volvulus infections received in random order a 1200 mg single oral dose of CGP 6140 after an overnight fast and after food intake. The concentrations of CGP 6140 and of its N-oxide metabolite, CGP 13231, were measured in plasma and urine. Mean (+/- s.d.) AUC CGP 6140 values were 67.0 +/- 10.8 mumol l-1 h in fed and 22.0 +/- 17.2 mumol l-1 h in fasting patients. The mean maximum concentrations (Cmax) in plasma +/- s.d. were 12.7 +/- 2.8 mumol l-1 in fed and 4.7 +/- 4.1 mumol l-1 in fasting patients. The median time to Cmax was 3 h in fed and 2 h in fasting patients. Mean (+/- s.d.) AUC of the N-oxide metabolite was 59.9 +/- 10.7 mumol l-1 h in fed and 23.4 +/- 16.2 mumol l-1 h in fasting patients. The urinary recovery was less than 0.5% of dose for CGP 6140 in both fed and fasting conditions. It was 30.1 +/- 11.5 and 11.4 +/- 8.0% of the dose for the N-oxide metabolite in fed and fasting conditions, respectively. Variability in plasma concentrations and urinary recovery of CGP 6140 and of the N-oxide metabolite was greater in fasted patients. The low solubility of CGP 6140 in aqueous solutions at neutral pH and its higher solubility at acidic pH might explain the increase in bioavailability after food intake. The administration of CGP 6140 after food intake is therefore recommended for an optimal systemic effect.     

Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder Inhalation via aerolizerTM

Objective: The pharmacokinetics of the long-acting β₂-agonist formoterol fumarate, which is a racemate of the (S,S)- and (R,R)-enantiomers were evaluated in 12 healthy (eight male, four female) volunteers after a single inhaled high dose of 120 μg of formoterol fumarate. The tolerability and safety were also assessed. Methods: Each volunteer inhaled the single 120-μg dose through the Aerolizer device within 2–5 min, using ten 12-μg dry powder capsules for inhalation. Formoterol, i.e., the sum of both enantiomers, was determined in plasma over 24 h, whereas the separate enantiomers were determined in urine over 48 h. Incidence, seriousness and severity of adverse experiences, electrocardiogram (ECG), including the corrected QT interval (QTc) calculation, systolic blood pressure, heart rate, and plasma potassium levels were recorded. Results: In nine of the 12 volunteers, the peak plasma concentration of formoterol was observed already at 5 min after inhalation. The absorption kinetics were complex, as depicted by multiple peaks or shoulders within 0.5–6 h after inhalation. Mean with (SD; n = 12) of maximum concentration (C_max) and area under the curve (AUC) of formoterol in plasma were 266 (108) pmol · l⁻¹ and 1330 (398) pmol · h · l⁻¹, respectively. The moderate inter-individual variability in systemic exposure of formoterol reflects the homogeneous pharmacokinetics of the drug. A predominant slow elimination of formoterol from plasma with a mean half-life (t_1/2) of 10 h was demonstrated. Assuming linear kinetics in plasma suggested by urinary data, the steady-state trough plasma levels of formoterol for a b.i.d. dosing regimen are predicted to amount to 20% of C_max. In urine, mean with (SD; n = 10) of the amount excreted over 48 h was 3.61 (0.89)% of dose for the pharmacologically active (R,R)-enantiomer and 4.80 (1.33)% of dose for the (S,S)-enantiomer. The terminal half-lives calculated from the excretion rate-time curves, i.e., 13.9 h and 12.3 h for the (R,R)- and (S,S)-enantiomer, respectively, confirm the slow elimination of formoterol from plasma. The dose inhaled was 10 times the most frequently recommended dose (12 μg) and 5 times the highest recommended dose (24 μg). Ten of 12 subjects experienced mild and transient nervousness. Pulse readings demonstrated the maximum mean increase of 25.8 beats · min⁻¹ at 6 h. The mean maximum QTc increase was 25 msec at 6 h. Pulse and QTc values returned to baseline or close to baseline values at 24 h or before. Potassium levels in plasma decreased in eight out of 12 subjects; the lowest mean value was 3.53 mmol · l⁻¹ at 2 h post-dose. The lowest individual potassium measurement was 2.95 mmol · l⁻¹ between 15 min and 6 h. By 8 h post-dose all values had returned to within the normal ranges. Conclusions: The extremely fast appearance of formoterol in plasma shows the predominance of airways absorption shortly after inhalation. Due to a terminal elimination half-life of about 10 h, sustained systemic concentrations of formoterol are predicted for a twice daily treatment regimen without noteworthy accumulation. The excreted amounts in percent of dose of the enantiomers in urine and the enantiomer ratio are similar to data reported previously after lower doses and suggest linear kinetics for doses between 12 μg and 120 μg of formoterol fumarate. The expected side effects on heart rate, QTc interval, and plasma potassium were small and had no clinical consequences in spite of the very high dose of 120 μg (5 to 10 times the recommended therapeutic dose of Foradil). It should be noted that the impact of high doses may be greater in patients. Nevertheless these findings provide reassurance on the safety margin of formoterol after accidental and intentional overdosing. Received: 22 June 1998 / Accepted in revised form: 2 December 1998     

Reemergence of gentamicin-susceptible strains of methicillin-resistant Staphylococcus aureus in France: a phylogenetic approach

The reemergence of gentamicin-susceptible (Gen(s)) methicillin-resistant Staphylococcus aureus (MRSA) isolates in France between 1992 and 1996 was investigated using a phylogenetic approach (multiprimer randomly amplified polymorphic DNA typing). Eighty-six percent (65 of 85) of the French strains were grouped into one phylogenetic cluster within which all but one Gen(s) strain were grouped into a subcluster. Thus, the reemergence of Gen(s) MRSA strains in France was likely due to the spread of one specific clone which belonged to a cluster comprising most French gentamicin-resistant (Gen(r)) strains. This suggests that the Gen(s) clone has emerged from a Gen(r) strain of this cluster.     

Endemic heteroresistant glycopeptide intermediate Staphylcoccus aureus (hGISA) comprising unrelated clonal types and not associated with vancomycin therapy

The detection of methicillin-resistant S. aureus (SA) (MRSA) refractory to glycopeptides is a serious clinical issue. The prevalence of hetero-resistant GISA (hGISA) strains at H. Maréchal Joffre, France is reported.858 non-repeat SA were isolated during 1999. 367 (43%) of these, from 257 patients, were MRSA (mean incidence 11.9/1000 admissions). All MSRA detected during 1999 were screened for vancomycin (VAN) resistance (BHI+4 mg/l VAN). Isolates recovered were retested using Etest strips (2 McFarland inoculum on BHI) and population analysis profile/area under the curve (PAP-AUC) analysis with hGISA SA Mu3 as a comparator. 58 selected strains were screened for teicoplanin resistance(TEI) using SFM recommended screen (2 McFarland inoculum on MH+5 mg/L TEI) and MIC (0.5 MF inoculum swabbed on MH agar) methods. 188 (51.3%) grew on VAN screen agar (6.1/1000 admissions). 58 strains (7.6%) possessed Etest VAN MIC > 8 mg/l all others being VAN < 8 mg/l. Of these 58 isolates, 10 were stably heterogeneously resistant to both VAN and teicoplanin (MIC > 8 mg/l). PAP-AUC showed 12 strains to have PAP-AUC ratios > 0.95 but < 1.5 (ie. hGISA, not GISA). All 7 isolates defined as hGISA by both Etest and PAP-AUC comprised 1 PFGE clone (< 3 bands difference).Additionally 2 distinct PFGE types were detected among the other 5 hGISA identified PAP-AUC. The 12 hGISAs, were derived from 12 patients with severe underlying disease. None were on glycopeptide therapy prior to hGISA isolation.This is the first report of endemic hGISA, comprising 3 clonal types. The isolation of hVISA seems not to be associated with patient-specific glycopeptide therapies.     

Effect of food on the bioavailability of triclabendazole in patients with fascioliasis

Aims Preliminary results indicate higher absorption of triclabendazole (TCBZ) administered postprandially. Therefore, the influence of food on the pharmacokinetics of TCBZ and its active sulphoxide (TCBZ-SO) and sulphone (TCBZ-SO2) metabolites was investigated.
Methods Two single doses (10  mg  kg⁻¹ ) of TCBZ were administered to 20 patients with fascioliasis. Ten patients were first given the drug after a high energy breakfast and then, 48  h later, after an overnight fast. The other 10 patients first received the drug in fasting state and then, 48  h later, after breakfast. A low energy breakfast was served 2  h after drug administration for fasting state.
Results Compared with the fasting state, an increased AUC and C _max after food intake (significant, P <0.0001) was shown from the values of TCBZ, TCBZ-SO and TCBZ-SO2. The mean AUC for TCBZ (fasting: 1.55, fed: 5.72  μmol  l⁻¹ h), TCBZ-SO (fasting: 177, fed: 386  μmol  l⁻¹ h) and TCBZ-SO2 (fasting: 13.9, fed: 30.5  μmol  l⁻¹ h) indicated a large availability increase with food and the strong systemic predominance of the active sulphoxide metabolite over the unchanged drug. (All patients were cured at the end of the trial except one who required a second course of two postprandial doses of triclabendazole (10  mg  kg⁻¹ each). Tolerability to the treatment among the patients was good.
Conclusions The administration of triclabendazole with food is recommended for improved systemic availability in patients with fascioliasis or paragonimiasis.     

The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated.The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2–2.5-times higher in patients with severe renal impairment (CL_CR<10 ml·min^–1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects.The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance.The maximum target dose in patients with slight renal impairment (CL_CR>30 ml·min^–1) should not be changed. In patients with moderate renal impairment (CL_CR10–30 ml·min^–1) it should be reduced by 50%. In patients with severe renal impairment (CL_CR<10 ml·min^–1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.     

Évolution de la résistance des entérobactéries aux céphalosporines de troisième génération de 2000 à 2008 au centre hospitalier de Perpignan

The aim of this work was to evaluate the evolution of Enterobacteriaceae resistance to third generation cephalosporin (3CG) from 2000 to 2008 at Perpignan hospital. Were observed: the percentage of strains isolated from short stay wards, intensive care unit and medium and long-term care facility. The percentage of strains isolated from: urine, suppuration, tracheal aspiration, and blood have been evaluated. The proportion of Escherichia coli (E. coli) strains among the Enterobacteriaceae strains intermediate (I) or resistant (R) to 3GC was also evaluated.The number of Enterobacteriaceae intermediated (I) or resistant (R) to 3GC increased (402 %).The distribution of species I or R to 3GC has changed, decrease of Klebsielle pneumoniae and Enterobacter aeorogenes species, Escherichia.coli and Enterobacter cloacae became dominant in 2008. We noted the change of isolated species distribution, urines represent the main source of multiresistant Enterobacteriaceae (MRE), 72 % of strains. The profile of patients colonised or infected by MRE has changed. Patients mainly infected with hospital acquirred MRE changed to MRE colonised patients carrying the strain into the hospital. The association of fluorinated quinolone resistance and Extended-Spectrum Beta-Lactamase Enterobacteriaceae represented 51 % in 2000, became stable at 73 % from 2002. The association of fluorinated quinolone resistance and high-level Enterobacteriaceae cephalosporinase has increased from 21 % in 2000 to be stable at 50 % since 2006. The mesures to contain the spread of MRE strains remained inefficient because of outpatients circulation, multiresistant E. coli being community species.