Multiple 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.
Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we ...reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage.
Summary
Multidrug 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 D‐arabinose, 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.
Recent 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.
Multidrug 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.
The first Lactobacillus delbrueckii ssp. bulgaricus genome sequence revealed the presence of a very large inverted repeat (IR), a DNA sequence arrangement which thus far seemed inconceivable in a ...non-manipulated circular bacterial chromosome, at the replication terminus. This intriguing observation prompted us to investigate if similar IRs could be found in other bacteria. IRs with sizes varying from 38 to 76 kbp were found at the replication terminus of all 5 L. delbrueckii ssp. bulgaricus chromosomes analysed, but in none of 1373 other chromosomes. They represent the first naturally occurring very large IRs detected in circular bacterial genomes. A comparison of the L. bulgaricus replication terminus regions and the corresponding regions without IR in 5 L. delbrueckii ssp. lactis genomes leads us to propose a model for the formation and evolution of the IRs. The DNA sequence data are consistent with a novel model of chromosome rescue after premature replication termination or irreversible chromosome damage near the replication terminus, involving mechanisms analogous to those proposed in the formation of very large IRs in human cancer cells. We postulate that the L. delbrueckii ssp. bulgaricus-specific IRs in different strains derive from a single ancestral IR of at least 93 kbp.
Amikacin is an aminoglycoside commonly used in intensive care units for the treatment of patients with life-threatening Gram-negative infections. Although aminoglycosides are extensively used, the ...accurate determination of their optimal dosage is complicated by marked intra- and interindividual variability in intensive care unit patients. Amikacin pharmacokinetics have been described in numerous studies over the past 25 years.
This review presents a synthesis of the population pharmacokinetic models for amikacin described in critically ill patients. The objective was to determine whether there was a consensus on a structural model and which covariates had been identified.
A literature search was conducted from the PubMed database, from its inception up until December 2015, using the following terms: 'amikacin', 'pharmacokinetic(s)', 'population', 'model(ling)' and 'nonlinear mixed effect'. Articles were excluded if they were not pertinent. The reference lists of all selected articles were also evaluated.
Ten articles were included in this review: pharmacokinetics of amikacin were described by a one-compartment or a two-compartment model. Various covariates were tested, but only two (creatinine clearance and total body weight) were included in almost all of the described models. After inclusion of these covariates, the interindividual variability (range) in clearance and the volume of distribution were 44.4 % (28.2-69.4 %) and 31.3 % (8.1-44.7 %), respectively. The residual variability (range) was around 21.0 % (9.0-31.0 %), using a proportional model, and for a combined model (proportional/additive), the median (range) values were 0.615 mg/L (0.2-1.03 mg/L) and 29.2 % (26.8-31.6 %).
This review highlights the different population pharmacokinetic models for amikacin developed in critically ill patients over the past decades and proposes relevant information for clinicians and researchers. To optimize amikacin dosage, this review points out the relevant covariates according to the target population. In a population of critically ill patients, dose optimization mainly depends on creatinine clearance and total body weight. New pharmacokinetic population studies could be considered, with new covariates of interest to be tested in model building and to further explain variability. Another future perspective could be external evaluation of previously published models.
Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical ...applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization.
Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations.
The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance.
Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.
Repeated acute stress (RASt) is known to be associated with gastrointestinal dysfunctions. However, the mechanisms underlying these effects have not yet been fully understood. While glucocorticoids ...are clearly identified as stress hormones, their involvement in RASt-induced gut dysfunctions remains unclear, as does the function of glucocorticoid receptors (GR). The aim of our study was to evaluate the involvement of GR on RASt-induced changes in gut motility, particularly through the enteric nervous system (ENS).
Using a murine water avoidance stress (WAS) model, we characterized the impact of RASt upon the ENS phenotype and colonic motility. We then evaluated the expression of glucocorticoid receptors in the ENS and their functional impact upon RASt-induced changes in ENS phenotype and motor response.
We showed that GR were expressed in myenteric neurons in the distal colon under basal conditions, and that RASt enhanced their nuclear translocation. RASt increased the proportion of ChAT-immunoreactive neurons, the tissue concentration of acetylcholine and enhanced cholinergic neuromuscular transmission as compared to controls. Finally, we showed that a GR-specific antagonist (CORT108297) prevented the increase of acetylcholine colonic tissue level and
colonic motility.
Our study suggests that RASt-induced functional changes in motility are, at least partly, due to a GR-dependent enhanced cholinergic component in the ENS.
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.
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.
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).
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.
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