scholarly journals Tracing patterns of evolution and acquisition of drug resistant Aspergillus fumigatus infection from the environment using population genomics

2021 ◽  
Author(s):  
Johanna Rhodes ◽  
Alireza Abdolrasouli ◽  
Katie Dunne ◽  
Thomas R. Sewell ◽  
Yuyi Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Aspergillus Fumigatus ◽  
Population Genomics ◽  
Clinical Importance ◽  
Antifungal Drugs ◽  
Environmental Drivers ◽  
Drug Resistant ◽  
A Genome ◽  
Tract Infections ◽  
The Impact

Infections caused by opportunistic fungal pathogens are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about the extent to which susceptible patients acquire infection from drug resistant genotypes in the environment. Here, we present a population genomic analysis of the mould Aspergillus fumigatus from across the United Kingdom and Republic of Ireland. First, we show occurrences where azole resistant isolates of near identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Second, we find that the fungus is structured into two clades ('A' and 'B') with little interclade recombination and the majority of environmental azole resistance genetically clustered inside Clade A. Genome-scans show the impact of selective sweeps across multiple regions of the genome. These signatures of positive selection are seen in regions containing canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, whilst other regions under selection have no defined function. Phenotyping identified genes in these regions that could act as modifiers of resistance showing the utility of reverse genetic approaches to dissect the complex genomic architecture of fungal drug resistance. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.

scholarly journals Impact of pretreatment low-abundance HIV-1 drug-resistant variants on virological failure among HIV-1/TB-co-infected individuals

2020 ◽  
Vol 75 (11) ◽  
pp. 3319-3326
Author(s):  
Benjamin Chimukangara ◽  
Jennifer Giandhari ◽  
Richard Lessells ◽  
Nonhlanhla Yende-Zuma ◽  
Benn Sartorius ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virological Failure ◽  
Statistical Significance ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
The Impact ◽  
Hiv 1 ◽  
Control Study

Abstract Objectives To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (LA-DRVs) on virological failure (VF) among HIV-1/TB-co-infected individuals treated with NNRTI first-line ART. Methods We conducted a case–control study of 170 adults with HIV-1/TB co-infection. Cases had at least one viral load (VL) ≥1000 RNA copies/mL after ≥6 months on NNRTI-based ART, and controls had sustained VLs <1000 copies/mL. We sequenced plasma viruses by Sanger and MiSeq next-generation sequencing (NGS). We assessed drug resistance mutations (DRMs) using the Stanford drug resistance database, and analysed NGS data for DRMs at ≥20%, 10%, 5% and 2% thresholds. We assessed the effect of pretreatment drug resistance (PDR) on VF. Results We analysed sequences from 45 cases and 125 controls. Overall prevalence of PDR detected at a ≥20% threshold was 4.7% (8/170) and was higher in cases than in controls (8.9% versus 3.2%), P = 0.210. Participants with PDR at ≥20% had almost 4-fold higher odds of VF (adjusted OR 3.7, 95% CI 0.8–18.3) compared with those without, P = 0.104. PDR prevalence increased to 18.2% (31/170) when LA-DRVs at ≥2% were included. Participants with pretreatment LA-DRVs only had 1.6-fold higher odds of VF (adjusted OR 1.6, 95% CI 0.6–4.3) compared with those without, P = 0.398. Conclusions Pretreatment DRMs and LA-DRVs increased the odds of developing VF on NNRTI-based ART, although without statistical significance. NGS increased detection of DRMs but provided no additional benefit in identifying participants at risk of VF at lower thresholds. More studies assessing mutation thresholds predictive of VF are required to inform use of NGS in treatment decisions.

scholarly journals Resistance at No Cost: The Transmissibility and Potential for Disease Progression of Drug-ResistantM. Tuberculosis

2018 ◽  
Author(s):  
Mercedes C. Becerra ◽  
Chuan-Chin Huang ◽  
Leonid Lecca ◽  
Jaime Bayona ◽  
Carmen Contreras ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Pulmonary Tb ◽  
Genetic Fingerprint ◽  
Resistant Tuberculosis ◽  
Significant Difference ◽  
Mdr Tb ◽  
The Impact

AbstractBackgroundThe future trajectory of drug resistant tuberculosis strongly depends on the fitness costs of drug resistance mutations. Here, we measured the association of phenotypic drug resistance and the risk of TB infection and disease among household contacts (HHCs) of patients with pulmonary TB.MethodsWe evaluated 12767 HHCs of patients with drug sensitive and resistant pulmonary TB at baseline, two, six, and 12 months to ascertain infection status and to determine whether they developed tuberculosis disease. We also assessed the impact of drug resistance phenotype on the likelihood that a TB strain shared a genetic fingerprint with at least one other TB patient in the cohort.FindingsAmong 3339 TB patients for whom were DST available, 1274 (38%) had TB that was resistant to at least one drug and 478 (14⋅3%) had multi-drug resistant (MDR) TB, i.e. TB resistant to both INH and rifampicin. Compared to HHCs of drug sensitive TB patients, those exposed to a patient with MDR-TB had an 8% (95% CI: 4-13%) higher risk of infection by the end of follow up. We found no statistically significant difference in the relative hazard of incident TB disease among HHCs exposed to MDR-TB compared to DS-TB (Adjusted HR 1⋅28 [(95% CI: ⋅9-1⋅83]). Patients with MDR-TB were more likely to be part of a genetic cluster than were DS-TB patients.InterpretationClinical strains of MDR M. tuberculosis are neither less transmissible than drug sensitive strains nor less likely to cause disease. (ClinicalTrials.gov number,NCT00676754)FundingNational Institutes of Health: NIH/NIAID CETR U19AI109755StatementAll authors have seen the manuscript and approved the manuscript.

scholarly journals Impact of Novel Resistance Profiles in HIV-1 Reverse Transcriptase on Phenotypic Resistance to NVP

2012 ◽  
Vol 2012 ◽  
pp. 1-8
Author(s):  
Liyan Jiao ◽  
Hanping Li ◽  
Lin Li ◽  
Daomin Zhuang ◽  
Yongjian Liu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Site Directed Mutagenesis ◽  
Drug Resistant ◽  
Wild Type ◽  
Phenotypic Resistance ◽  
Drug Resistant Mutation ◽  
The Impact ◽  
Hiv 1 ◽  
Resistant Mutation ◽  
Phenotypic Drug Resistance

Objective. To clarify the impact of H221Y mutation on drug resistance to NVP.Methods. 646 bp HIV-1polgene fragments (from 592 to 1237 nucleotide) with different NNRTIs mutation profiles from AIDS patients receiving antiretroviral therapy containing NVP regimens were introduced into pNL4-3 backbone plasmid. H221Y and (or) Y181C mutations were reverted to wild type amino acids by site-directed mutagenesis, then strains containing various mutation patterns were packaged. Phenotypic drug resistance was analyzed on TZM-bl cells.Results. 12 strains containing different drug-resistant mutation profiles were constructed, including the K101Q series (K101Q/Y181C/H221Y, K101Q/Y181C, K101Q/H221Y, and K101Q), the V179D series (V179D/Y181C/H221Y, V179D/Y181C, V179D/H221Y, and V179D), and the K103N series (K103N/Y181C/H221Y, K103N/Y181C, K103N/H221Y, K103N). For strains containing the mutation profiles (K101Q/Y181C, K101Q, V179D/Y181C, V179D, K103N/Y181C, and K103N), the presence of H221Y reduced NVP susceptibility by2.1±0.5to3.6±0.5fold. To the mutation profiles K101Q/H221Y, K101Q, V179D/H221Y, V179D, K103N/H221Y, and K103N, the presence of Y181C reduced NVP susceptibility by41.9±8.4to1297.0±289.1fold. For the strains containing K101Q, V179D, and K103N, the presence of Y181C/H221Y combination decreased NVP susceptibility by100.6±32.5to3444.6±834.5fold.Conclusion. On the bases of various NNRTIs mutation profiles, Y181C remarkably improved the IC50to NVP, although H221Ymutation alone just increases 2.1 ∼ 3.6-fold resistance to NVP, the mutation could improve 100.6 ∼ 3444.6-fold resistance to NVP when it copresent with Y181C, the phenotypic drug resistance fold was improved extremely. For strains containing the mutation profiles (K101Q/Y181C, K101Q, V179D/Y181C, V179D, K103N/Y181C, and K103N), the presence of H221Y reduced NVP susceptibility by2.1±0.5to3.6±0.5fold.

scholarly journals Assessing the Impact of Drug Resistance on the Transmission Dynamics of Typhoid Fever

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
S. Mushayabasa ◽  
C. P. Bhunu ◽  
E. T. Ngarakana-Gwasira
Keyword(s):  
Public Health ◽  
Mathematical Model ◽  
Drug Resistance ◽  
Typhoid Fever ◽  
Public Health Problem ◽  
Transmission Dynamics ◽  
Reproductive Number ◽  
Major Public Health Problem ◽  
Drug Resistant ◽  
The Impact

Typhoid fever continues to be a major public health problem in the developing world. Antibiotic therapy has been the main stay of treating typhoid fever for decades. The emergence of drug-resistant typhoid strain in the last two decades has been a major problem in tackling this scourge. A mathematical model for investigating the impact of drug resistance on the transmission dynamics of typhoid fever is developed. The reproductive number for the model has been computed. Numerical results in this study suggest that when a typhoid outbreak occurs with more drug-sensitive cases than drug-resistant cases, then it may take 10–15 months for symptomatic drug-resistant cases to outnumber all typhoid cases, and it may take an average of 15–20 months for nonsymptomatic drug-resistant cases to outnumber all drug-sensitive cases.

scholarly journals Increase of Virulence and Its Phenotypic Traits in Drug-Resistant Strains of Candida albicans

2008 ◽  
Vol 52 (3) ◽  
pp. 927-936 ◽  
Author(s):  
Letizia Angiolella ◽  
Anna Rita Stringaro ◽  
Flavia De Bernardis ◽  
Brunella Posteraro ◽  
Mariantonietta Bonito ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Biological Properties ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Phenotypic Traits ◽  
Homozygous Mutation ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT There is concern about the rise of antifungal drug resistance, but little is known about comparative biological properties and pathogenicity of drug-resistant strains. We generated fluconazole (FLC; CO23RFLC)- or micafungin (FK; CO23RFK)-resistant strains of Candida albicans by treating a FLC- and FK-susceptible strain of this fungus (CO23S) with stepwise-increasing concentrations of either drug. Molecular analyses showed that CO23RFLC had acquired markedly increased expression of the drug-resistance efflux pump encoded by the MDR1 gene, whereas CO23RFK had a homozygous mutation in the FSK1 gene. These genetic modifications did not alter to any extent the growth capacity of the drug-resistant strains in vitro, either at 28°C or at 37°C, but markedly increased their experimental pathogenicity in a systemic mouse infection model, as assessed by the overall mortality and target organ invasion. Interestingly, no apparent increase in the vaginopathic potential of the strains was observed with an estrogen-dependent rat vaginal infection. The increased pathogenicity of drug-resistant strains for systemic infection was associated with a number of biochemical and physiological changes, including (i) marked cellular alterations associated with a different expression and content of major cell wall polysaccharides, (ii) more rapid and extensive hypha formation in both liquid and solid media, and (iii) increased adherence to plastic and a propensity for biofilm formation. Overall, our data demonstrate that experimentally induced resistance to antifungal drugs, irrespective of drug family, can substantially divert C. albicans biology, affecting in particular biological properties of potential relevance for deep-seated candidiasis.

scholarly journals COVID-19 and Environmental factors. A PRISMA-compliant systematic review

2020 ◽  
Author(s):  
Apostolos Vantarakis ◽  
Ioanna Chatziprodromidou ◽  
Thomas Apostolou
Keyword(s):  
Environmental Factors ◽  
Respiratory Tract Infections ◽  
Meteorological Factors ◽  
Health Concern ◽  
Environmental Drivers ◽  
Show Evidence ◽  
Human Coronaviruses ◽  
Tract Infections ◽  
Available Information ◽  
The Impact

The emergence of a novel human coronavirus, SARS-CoV-2, has become a global health concern causing severe respiratory tract infections in humans. Human-to-human transmissions have been described with incubation times between 2-10 days, facilitating its airborne spread via droplets. The impact of environmental factors on the coronavirus disease 2019 (COVID-19) outbreak is under consideration. We therefore reviewed the literature on all available information about the impact of environmental factors on human coronaviruses. Temperature, humidity and other environmental factors have been recorded as environmental drivers of the COVID-19 outbreak in China and in other countries. Higher temperatures might be positive to decrease the COVID-19 incidence. In our review, the analysis of 23 studies show evidence that high temperature and high humidity reduce the COVID-19 transmission. However, further studies concerning other environmental (namely meteorological) factors role should be conducted in order to further prove this correlation. As no specific therapies are available for SARS-CoV-2, early containment and prevention of further spread will be crucial to stop the ongoing outbreak and to control this novel infectious thread.

scholarly journals The Impact of Alcohol Drinking And Tobacco Smoking On The Drug-Resistance of Newly Diagnosed Tuberculosis

2021 ◽  
Author(s):  
Wan-mei Song ◽  
Jing-yue Liu ◽  
Qi Fu ◽  
Ting-ting Xu ◽  
Shi-jin Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tobacco Smoking ◽  
Alcohol Drinking ◽  
Joint Effect ◽  
Independent Effect ◽  
Drug Resistant ◽  
Newly Diagnosed ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
The Impact

Abstract Background: Finding out more predictors of drug-resistant tuberculosis (DR-TB) helps to facilitate TB prevention and control. Previous study had revealed that tobacco smoking and alcohol drinking might be a risk factor for developing drug-resistant tuberculosis. However, few discussed their joint impact on resistance among newly diagnosed TB cases. This study aimed to assess and compare the joint and independent effect of smoking and drinking on TB resistance.Methods: This was a retrospective study of 7996 newly diagnosed TB patients who were collected from Shandong, China from Jan 1, 2004, to Dec 31, 2020, and all had drug susceptibility results, information about smoking and alcohol consumption. Patients were classified into four groups including smoker only(G1), drinker only(G2), smoker+drinker(G3), non-smoker+non-drinker group(G0). We described the drug-resistant profiles, clinical factors and also calculated the ORs of different drug-resistance among G1, G2, G3, compared to G0.Results:Of 7996 TB cases enrolled, the proportions of G1, G2, G3, and G0 were 8.25%, 3.89%, 16.46%, 71.40%, respectively. The rates of DR-TB, mono-resistant (MR)-TB, multidrug resistant (MDR)-TB, polydrug resistant (PDR)-TB in G1, G2, G3 and G0 were 19.24%/16.4%/17.33%/19.08%, 11.52%/8.68%/10.94%/11.63%, 3.03%/2.57%/2.96%/3.66%, 4.7%/4.82%/3.34%/4.08%, respectively. G3 had a higher risk of MDR1: isoniazid+rifampin (adjusted odds ratio (aOR)=1.913, 95% confidence interval(CI): 1.036-3.532), but had a lower risk of DR-TB (aOR=0.839, 95%CI: 0.712-0.988), rifampin-related resistance (aOR=0.675, 95%CI: 0.492-0.925), streptomycin-related resistance (aOR=0.819, 95%CI: 0.675-0.993), EMB-related resistance (aOR=0.571, 95%CI: 0.342-0.954), MDR3: isoniazid+rifampin+streptomycin (aOR=0.406, 95%CI: 0.194-0.851, any isoniazid+streptomycin resistance (aOR=0.845, 95%CI: 0.714-1). However, there were no significant differences between G1 and G0, G2 and G0 in all drug-resistant sub-types. Those who with cavity had a higher risk of DR-TB among G3 (OR=1.354, 95%CI:1.011-1.814).Conclusions: Although we did not found a independent impact of alcohol drinking or tobacco smoking on TB drug-resistance respectively, these two habits had a joint effect on TB drug-resistance. We should be alert for the emergence of isoniazid+rifampin resistance among populations with both smoking and drinking habits.

scholarly journals Combined Antifungal Resistance and Biofilm Tolerance: the Global Threat of Candida auris

mSphere ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Ryan Kean ◽  
Gordon Ramage
Keyword(s):  
Clinical Importance ◽  
Multidrug Resistant ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Medical Mycology ◽  
Candida Auris ◽  
Content Type ◽  
Echinocandin Resistance ◽  
Global Threat ◽  
The Impact

ABSTRACT The enigmatic yeast Candida auris has emerged over the last decade and rapidly penetrated our consciousness. The global threat from this multidrug-resistant yeast has generated a call to arms from within the medical mycology community. Over the past decade, our understanding of how this yeast has spread globally, its clinical importance, and how it tolerates and resists antifungal agents has expanded. This review highlights the clinical importance of antifungal resistance in C. auris and explores our current understanding of the mechanisms associated with azole, polyene, and echinocandin resistance. We also discuss the impact of phenotypic tolerance, with particular emphasis on biofilm-mediated resistance, and present new pipelines of antifungal drugs that promise new hope in the management of C. auris infection.

Sign in / Sign up

Export Citation Format

Share Document