Amikacin in Critically Ill Patients: A Review of Population Pharmacokinetic Studies

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The Impact of Selection, Gene Conversion, and Biased Sampling on the Assessment of Microbial Demography

International audienceRecent studies have linked demographic changes and epidemiological patterns in bacterial populations using coalescent-based approaches. We identified 26 studies using skyline plots and found that 21 inferred overall population expansion. This surprising result led us to analyze the impact of natural selection, recombination (gene conversion), and sampling biases on demographic inference using skyline plots and site frequency spectra (SFS). Forward simulations based on biologically relevant parameters from Escherichia coli populations showed that theoretical arguments on the detrimental impact of recombination and especially natural selection on the reconstructed genealogies cannot be ignored in practice. In fact, both processes systematically lead to spurious interpretations of population expansion in skyline plots (and in SFS for selection). Weak purifying selection, and especially positive selection, had important effects on skyline plots, showing patterns akin to those of population expansions. State-of-the-art techniques to remove recombination further amplified these biases. We simulated three common sampling biases in microbiological research: uniform, clustered, and mixed sampling. Alone, or together with recombination and selection, they further mislead demographic inferences producing almost any possible skyline shape or SFS. Interestingly, sampling sub-populations also affected skyline plots and SFS, because the coalescent rates of populations and their sub-populations had different distributions. This study suggests that extreme caution is needed to infer demographic changes solely based on reconstructed genealogies. We suggest that the development of novel sampling strategies and the joint analyzes of diverse population genetic methods are strictly necessary to estimate demographic changes in populations where selection, recombination, and biased sampling are present

Prolonged continuous wound infiltration with a local anaesthetic after total mastectomy: pharmacokinetics and preliminary results on postoperative pain

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Metabolic diversity of the emerging pathogenic lineages of<i>Klebsiella pneumoniae</i>

International audienceMultidrug resistant and hypervirulent clones of Klebsiella pneumoniae are emerging pathogens. To understand the association between genotypic and phenotypic diversity in this process, we combined genomic, phylogenomic and phenotypic analysis of a diverse set of K. pneumoniae and closely related species. These species were able to use an unusually large panel of metabolic substrates for growth, many of which were shared between all strains. We analysed the substrates used by only a fraction of the strains, identified some of their genetic basis, and found that many could not be explained by the phylogeny of the strains. Puzzlingly, few traits were associated with the ecological origin of the strains. One noticeable exception was the ability to use Darabinose, which was much more frequent in hypervirulent strains. The broad carbon and nitrogen core metabolism of K. pneumoniae might contribute to its ability to thrive in diverse environments. Accordingly, even the hypervirulent and multidrug resistant clones have the metabolic signature of ubiquitous bacteria. The apparent few metabolic differences between hypervirulent, multi-resistant and environmental strains may favour the emergence of dual-risk strains that combine resistance and hypervirulence

Population pharmacokinetic model for tumescent lidocaine in women undergoing breast cancer surgery

International audiencePurposeTumescent lidocaine anesthesia (TLA) is an opportunity to perform mastectomy for breast cancer without general anesthesia in elderly women. Few reports are available on the pharmacokinetics of lidocaine in a context of TLA during a unilateral mastectomy. The aim of this study was to describe lidocaine pharmacokinetics in elderly women undergoing breast cancer surgery after TLA and to explore the risk of the toxicity of this technique.MethodsA prospective study was conducted to examine the pharmacokinetics of lidocaine in women undergoing TLA. TLA consists of an intradermal lidocaine instillation (20mL, 1% [200mg]) followed by a tumescent lidocaine infiltration (100mL of 1% lidocaine [1000mg] and 0.5mg epinephrine to 1L Ringer's lactate) via an infusion pump. A population pharmacokinetic (popPK) analysis was performed using the nonlinear mixed effects model (NONMEM).ResultsThe analysis included 116 observations from 17 women with a median (range) age of 83.4 (60.5-90.0). The median tumescent lidocaine dose was 800mg (range 375-1000mg) infused over 48.011.0min. A one-compartment disposition model with first order absorption, two input compartments, and a central elimination best described the pharmacokinetics of lidocaine. The estimates (between subject variability; relative standard error, %) of apparent volume, apparent clearance, tumescent absorption rate, and instillation absorption rate were 195.0 (46.3; 14.5%) L, 24.7 (48.9; 13.3%) Lh(-1), 0.28 (39.6; 13.8%) h(-1), and 2.56 (135.3; 44.9%) h(-1), respectively.Conclusions p id=''Par4 This is the first popPK model developed to describe kinetic profiles of TLA. These findings confirm the slow diffusion of lidocaine from the tumescent deposit

Ropivacaine Wound Infiltration for Pain Management After Breast Cancer Mastectomy: A Population Pharmacokinetic Analysis

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Local Anesthetic Plasma Concentrations as a Valuable Tool to Confirm the Diagnosis of Local Anesthetic Systemic Toxicity? A Report of 10 Years of Experience

Background: Local anesthetic systemic toxicity (LAST) has been reported as a serious complication of local anesthetic (LA) peripheral injection. The signs and symptoms of LAST are highly variable, and the challenge remains to confirm its diagnosis. In this context, the determination of LA plasma concentration appears as a valuable tool to confirm LAST diagnosis. The aims of this study were to describe observed LA concentrations in patients suspected with LAST and their contribution to diagnostic confirmation. Methods: We retrospectively reported suspected LAST in patients for which at least one plasma LA concentration was determined to confirm diagnosis of LAST. Data collection came from our pharmacological laboratory&rsquo;s database. Clinical signs and symptoms of toxicity, their onset time and observed LA concentrations were used to confirm LAST diagnosis. Results: 33 patients who presented with suspected LAST after ropivacaine and/or lidocaine administration were included. Prodromal symptoms were observed in 13 patients. Isolated central nervous system (CNS) toxicity occurred in 11 patients, and combined CNS and cardiovascular toxicity occurred in 12. One, two or three venous plasma samples were performed in 11, 3 and 19 patients, respectively. Toxic plasma LA concentrations were observed in three patients, receiving peripheral LA injection using lidocaine (16.1 &micro;g/mL) and ropivacaine (4.2 and 4.8 &micro;g/mL). Conclusion: This study presents an important biological and clinical dataset of patients who presented with suspected LAST. Plasma LA concentrations could bring valuable information in the diagnosis of LAST but requires rigorous sample protocols

Local Anesthetic Plasma Concentrations as a Valuable Tool to Confirm the Diagnosis of Local Anesthetic Systemic Toxicity? A Report of 10 Years of Experience

Background: Local anesthetic systemic toxicity (LAST) has been reported as a serious complication of local anesthetic (LA) peripheral injection. The signs and symptoms of LAST are highly variable, and the challenge remains to confirm its diagnosis. In this context, the determination of LA plasma concentration appears as a valuable tool to confirm LAST diagnosis. The aims of this study were to describe observed LA concentrations in patients suspected with LAST and their contribution to diagnostic confirmation. Methods: We retrospectively reported suspected LAST in patients for which at least one plasma LA concentration was determined to confirm diagnosis of LAST. Data collection came from our pharmacological laboratory’s database. Clinical signs and symptoms of toxicity, their onset time and observed LA concentrations were used to confirm LAST diagnosis. Results: 33 patients who presented with suspected LAST after ropivacaine and/or lidocaine administration were included. Prodromal symptoms were observed in 13 patients. Isolated central nervous system (CNS) toxicity occurred in 11 patients, and combined CNS and cardiovascular toxicity occurred in 12. One, two or three venous plasma samples were performed in 11, 3 and 19 patients, respectively. Toxic plasma LA concentrations were observed in three patients, receiving peripheral LA injection using lidocaine (16.1 µg/mL) and ropivacaine (4.2 and 4.8 µg/mL). Conclusion: This study presents an important biological and clinical dataset of patients who presented with suspected LAST. Plasma LA concentrations could bring valuable information in the diagnosis of LAST but requires rigorous sample protocols

Transient Darwinian selection in Salmonella enterica serovar Paratyphi A during 450 years of global spread of enteric fever

International audienceMultiple epidemic diseases have been designated as emerging or reemerging because the numbers of clinical cases have increased. Emerging diseases are often suspected to be driven by increased virulence or fitness, possibly associated with the gain of novel genes or mutations. However, the time period over which humans have been afflicted by such diseases is only known for very few bacterial pathogens, and the evidence for recently increased virulence or fitness is scanty. Has Darwinian (diversifying) selection at the genomic level recently driven microevolution within bacterial pathogens of humans? Salmonella enterica serovar Paratyphi A is a major cause of enteric fever, with a microbiological history dating to 1898. We identified seven modern lineages among 149 genomes on the basis of 4,584 SNPs in the core genome and estimated that Paratyphi A originated 450 y ago. During that time period, the effective population size has undergone expansion, reduction, and recent expansion. Mutations, some of which inactivate genes, have occurred continuously over the history of Paratyphi A, as has the gain or loss of accessory genes. We also identified 273 mutations that were under Darwinian selection. However, most genetic changes are transient, continuously being removed by purifying selection, and the genome of Paratyphi A has not changed dramatically over centuries. We conclude that Darwinian selection is not responsible for increased frequency of enteric fever and suggest that environmental changes may be more important for the frequency of disease