Administration Of Conventional Doses Research Articles

In vitro activity of rifaximin against isolates from patients with small intestinal bacterial overgrowth

Rifaximin, a non-absorbable rifamycin derivative, has published clinical efficacy in the alleviation of symptoms in patients with irritable bowel syndrome (IBS). Small intestinal bacterial overgrowth (SIBO) is associated with the pathogenesis of IBS. This study describes for the first time the antimicrobial effect of rifaximin against SIBO micro-organisms from humans. Fluid was aspirated from the third part of the duodenum from 567 consecutive patients; quantitative cultures diagnosed SIBO in 117 patients (20.6%). A total of 170 aerobic micro-organisms were isolated and the in vitro efficacy of rifaximin was studied by (i) minimum inhibitory concentration (MIC) testing by a microdilution technique and (ii) time–kill assays using bile to simulate the small intestinal environment. At a breakpoint of 32μg/mL, rifaximin inhibited in vitro 85.4% of Escherichia coli, 43.6% of Klebsiella spp., 34.8% of Enterobacter spp., 54.5% of other Enterobacteriaceae spp., 82.6% of non-Enterobacteriaceae Gram-negative spp., 100% of Enterococcus faecalis, 100% of Enterococcus faecium and 100% of Staphylococcus aureus. For the time–kill assays, 11 E. coli, 15 non-E. coli Gram-negative enterobacteria and three E. faecalis isolates were studied. Rifaximin produced a >3log10 decrease in the starting inoculum against most of the tested isolates at 500μg/mL after 24h of growth. The results indicate that rifaximin has a potent effect on specific small bowel flora associated with SIBO. This conclusion should be regarded in light of the considerable time–kill effect at concentrations lower than those achieved in the bowel lumen after administration of conventional doses in humans.

Meningeal Inflammation Increases Artemether Concentrations in Cerebrospinal Fluid in Papua New Guinean Children Treated with Intramuscular Artemether

Although the artemisinin-associated neurotoxicity identified in vitro and in animal studies has not been confirmed clinically, only one adult study has measured cerebrospinal fluid (CSF) concentrations after administration of conventional doses. Potential artemisinin neurotoxicity could be serious in children, especially those with meningitis and, consequently, a compromised blood-brain barrier. We measured CSF/plasma artemether and dihydroartemisinin (DHA) concentrations in 32 Papua New Guinean children with a mean age of 39 months with suspected or proven severe falciparum malaria who underwent a single lumbar puncture after intramuscular artemether administration. CSF artemether concentrations were 0 to 43.5 μg/liter and CSF concentration/plasma concentration ratios were 0 to 38.1%. DHA was measurable in CSF in only two children. The seven children with meningeal inflammation (CSF white cell count > 20/mm(3)) had higher CSF artemether concentration/plasma artemether concentration ratios than those without (median, 6.7% [interquartile ratio, 2.5 to 27.8%]% versus 0.0% [interquartile ratio, 0.0 to 2.5%]; P = 0.002). Meningeal inflammation was associated with a 4.6-fold increase in the CSF artemether concentration/plasma artemether concentration ratio in a population pharmacokinetic model. These data suggest that pharmacovigilance should be heightened when intramuscular artemether is given to severely ill children with evidence of meningeal inflammation.

Frequencies of CYP3A5 genotypes and haplotypes in a Korean population

CYP3A, the drug-metabolizing enzyme is an important factor in the pharmacokinetics of many drugs. Polymorphism of the CYP3A5 gene is known to influence the functionality of the CYP3A5 enzymes. The full extent of CYP3A5 genetic polymorphism was analysed in a Korean population. Specific polymerase chain reaction-restriction fragment length polymorphism tests for CYP 3AP1 through CYP3A5*7 or direct sequencing were used to identify reported CYP3A5 variant alleles, using 194 unrelated samples. The most frequent single nucleotide polymorphism (SNP) was 6986A>G (CYP3A5*3). The next most frequent SNP was 31611C>T. Haplotype analysis using detected SNPs revealed that the most frequent haplotype was *3A (frequency: 0.724), followed by *1E (frequency: 0.211), *3C (frequency: 0.034) and *1A (frequency: 0.023). We did not find CYP3AP1*3, CYP3A5*6, or *7 in this Korean sample. A large proportion of Koreans may have relatively low levels of metabolically active CYP3A5 protein and therefore may be at risk of high levels of drugs metabolized by this enzyme, after administration of conventional doses.

Activity of three β-lactams (ertapenem, meropenem and ampicillin) against intraphagocytic Listeria monocytogenes and Staphylococcus aureus

Assessment of the activity of three beta-lactams [ertapenem (a carbapenem with a prolonged half-life), meropenem and ampicillin] against intraphagocytic Listeria monocytogenes and Staphylococcus aureus. Quantitative measurements of cfu changes in broth and in THP-1 macrophages (post-phagocytosis) over time (5 and 24 h) at concentrations spanning from sub-MICs to C(max) (maximal concentration typically observed in patients' serum upon administration of conventional doses); morphological studies using an electron microscope; evaluation of drug stability (HPLC), protein binding (equilibrium dialysis) and measurement of drug cellular accumulation (microbiological assay). Ertapenem was unable to control L. monocytogenes growth in THP-1 macrophages at all concentrations and times tested, even under conditions where ampicillin and meropenem were bactericidal. This behaviour could not be ascribed to drug instability, protein binding or lack of cell accumulation in comparison with ampicillin or meropenem. Ertapenem, ampicillin and meropenem were equally effective at reducing the post-phagocytosis inoculum of S. aureus ( approximately 1 log cfu), and caused conspicuous changes in the morphology of intracellular bacteria consistent with their lysis. These effects were obtained, however, only at large multiples (100-fold or more) of the MIC maintained over 24 h. Because of the high intrinsic antimicrobial potency of the beta-lactams studied, these concentrations were below the C(max). Ertapenem will probably be ineffective against intraphagocytic forms of L. monocytogenes for reasons that remain to be discovered. Conversely, ertapenem could be an alternative to ampicillin and meropenem against intraphagocytic S. aureus since its longer half-life may allow high concentrations to be maintained for more prolonged times.