scholarly journals Development of a Protocol for Predicting Bacterial Resistance to Microbicides

2015 ◽  
Vol 81 (8) ◽  
pp. 2652-2659 ◽  
Author(s):  
Laura Knapp ◽  
Alejandro Amézquita ◽  
Peter McClure ◽  
Sara Stewart ◽  
Jean-Yves Maillard
Keyword(s):  
Antibiotic Susceptibility ◽  
Burkholderia Cepacia ◽  
Bacterial Resistance ◽  
Low Cost ◽  
The United States ◽  
Cross Resistance ◽  
Early Assessment ◽  
Resistance Development ◽  
Content Type ◽  
Development Of Resistance

ABSTRACTRegulations dealing with microbicides in Europe and the United States are evolving and now require data on the risk of the development of resistance in organisms targeted by microbicidal products. There is no standard protocol to assess the risk of the development of resistance to microbicidal formulations. This study aimed to validate the use of changes in microbicide and antibiotic susceptibility as initial markers for predicting microbicide resistance and cross-resistance to antibiotics. Three industrial isolates (Pseudomonas aeruginosa,Burkholderia cepacia, andKlebsiella pneumoniae) and twoSalmonella entericaserovar Typhimurium strains (SL1344 and 14028S) were exposed to a shampoo, a mouthwash, eye makeup remover, and the microbicides contained within these formulations (chlorhexidine digluconate [CHG] and benzalkonium chloride [BZC]) under realistic, in-use conditions. Baseline and postexposure data were compared. No significant increases in the MIC or the minimum bactericidal concentration (MBC) were observed for any strain after exposure to the three formulations. Increases as high as 100-fold in the MICs and MBCs of CHG and BZC for SL1344 and 14028S were observed but were unstable. Changes in antibiotic susceptibility were not clinically significant. The use of MICs and MBCs combined with antibiotic susceptibility profiling and stability testing generated reproducible data that allowed for an initial prediction of the development of resistance to microbicides. These approaches measure characteristics that are directly relevant to the concern over resistance and cross-resistance development following the use of microbicides. These are low-cost, high-throughput techniques, allowing manufacturers to provide to regulatory bodies, promptly and efficiently, data supporting an early assessment of the risk of resistance development.

scholarly journals Characterization ofIn VitroResistance Development to the Novel Echinocandin CD101 in Candida Species

2016 ◽  
Vol 60 (10) ◽  
pp. 6100-6107 ◽  
Author(s):  
Jeffrey B. Locke ◽  
Amanda L. Almaguer ◽  
Douglas E. Zuill ◽  
Ken Bartizal
Keyword(s):  
Drug Exposure ◽  
Hot Spot ◽  
Serial Passage ◽  
Single Step ◽  
Cross Resistance ◽  
Time Curve ◽  
Resistance Development ◽  
Content Type ◽  
Development Of Resistance

ABSTRACTCD101 is a novel echinocandin with a long half-life undergoing clinical development for treatment of candidemia/invasive candidiasis and vulvovaginal candidiasis. The potential for and mechanisms underlying the development of resistance to CD101 inCandidaspecies were investigated by using spontaneous resistance and serial passage selection methodologies. FourCandidaspp. (C. albicans,C. glabrata,C. parapsilosis, andC. krusei) were chosen for resistance characterization with CD101, anidulafungin, and caspofungin. The frequency of spontaneous, single-step mutations conferring reduced susceptibility to CD101 at 1× the agar growth inhibition concentration was low across all species, with median frequencies ranging from 1.35 × 10−8to 3.86 × 10−9, similar to ranges generated for anidulafungin and caspofungin. Serial passage ofCandidaspp. on agar plates containing drug gradients demonstrated a low potential for resistance development, with passage 20 CD101-selected strains possessing increases in MICs equivalent to or lower than those for the majority of strains generated under selection with anidulafungin and caspofungin. A total of 12fks“hot spot” mutations were identified, typically in strains with the highest MIC shifts. Cross-resistance was broadly observed among the 3 echinocandins evaluated, with no CD101-selected mutants (with or withoutfkshot spot mutations) exhibiting reduced susceptibility to CD101 but not also to anidulafungin and/or caspofungin. Consistent with currently approved echinocandins, CD101 demonstrates a low potential for resistance development, which could be further enhancedin vivoby the high maximum concentration of drug in serum (Cmax)/area under the concentration-time curve (AUC) plasma drug exposure achieved with once-weekly dosing of CD101.

scholarly journals Comparative Study of the Effect of Solvents on the Efficacy of Neonicotinoid Insecticides Against Malaria Vector Populations Across Africa

2022 ◽  
Author(s):  
Magellan Tchouakui ◽  
Tatiane Assatse ◽  
Leon M. J. Mugenzi ◽  
Benjamin D. Menze ◽  
Daniel Nguiffo-Nguete ◽  
...  
Keyword(s):  
Democratic Republic Of Congo ◽  
Natural Populations ◽  
Resistance Mechanisms ◽  
Lower Mortality ◽  
Malaria Vectors ◽  
Cross Resistance ◽  
Metabolic Resistance ◽  
Resistance Development ◽  
Development Of Resistance ◽  
Bottle Test

Abstract Background New insecticides with a novel mode of action such as neonicotinoids have recently been recommended for public health by WHO. Resistance monitoring of such novel insecticides requires a robust protocol to monitor the development of resistance in natural populations. In this study, we comparatively used three different solvents to assess the susceptibility of malaria vectors to neonicotinoids across Africa.MethodsMosquitoes were collected from May to July 2021 from three agricultural settings in Cameroon (Njombe-Penja, Nkolondom, and Mangoum), the Democratic Republic of Congo (Ndjili-Brasserie), Ghana (Obuasi), and Uganda (Mayuge). Using the CDC bottle test, we compared the effect of three different solvents (ethanol, acetone, MERO) on the efficacy of neonicotinoids against Anopheles gambiae s.l. In addition, TaqMan assays were used to genotype key pyrethroid-resistant markers in An. gambiae and to evaluate potential cross-resistance between pyrethroids and clothianidin.ResultsLower mortality were observed when using absolute ethanol or acetone alone as solvent (11.4- 51.9% mortality in Nkolondom, 31.7- 48.2% in Mangoum, 34.6- 56.1% in Mayµge, 39.4- 45.6% in Obuasi, 83.7- 89.3% in Congo and 71.05- 95.9% in Njombe pendja) compared to acetone + MERO for which 100% mortality were observed for all the populations. Synergist assays (PBO, DEM and DEF) revealed a significant increase of mortality suggesting that metabolic resistance mechanisms are contributing to the reduced susceptibility. A negative association was observed between the L1014F-kdr mutation and clothianidin resistance with a greater frequency of homozygote resistant mosquitoes among the dead than among survivors (OR=0.5; P=0.02). However, the I114T-GSTe2 was in contrast significantly associated with a greater ability to survive clothianidin with a higher frequency of homozygote resistant among survivors than other genotypes (OR=2.10; P=0.013). ConclusionsThis study revealed a contrasted susceptibility pattern depending on the solvents with ethanol/acetone resulting to lower mortality, thus possibly overestimating resistance, whereas the MERO consistently showed a greater efficacy of neonicotinoids but it could prevent to detect early resistance development. Therefore, we recommend monitoring the susceptibility using both acetone alone and acetone+MERO (8-10µg/ml for clothianidin) to capture the accurate resistance profile of the mosquito populations.

scholarly journals Evidence for the Predisposition of Fungicide-Resistant Isolates of Venturia inaequalis to a Preferential Selection for Resistance to Other Fungicides

2001 ◽  
Vol 91 (8) ◽  
pp. 776-781 ◽  
Author(s):  
Wolfram Köller ◽  
W. F. Wilcox
Keyword(s):  
Fungicide Resistance ◽  
Venturia Inaequalis ◽  
Apple Scab ◽  
The United States ◽  
Cross Resistance ◽  
Resistance Development ◽  
Flexible Response ◽  
Sterol Demethylation Inhibitors ◽  
Selection For ◽  
Selection Of

In the United States, populations of the apple scab pathogen Venturia inaequalis have progressed through three consecutive rounds of fungicide resistance development, first to dodine, then to the benzimidazoles, and most recently to the sterol demethylation inhibitors (DMIs). Analysis of extensive monitoring data have to date provided no indication of detectable cross-resistance or partial cross-resistance of V. inaequalis populations to the three unrelated classes of fungicides prior to the selection of resistant subpopulations. However, in this study, resistance to both benomyl and DMIs developed to significantly higher frequencies within the previously established dodine-resistant population than in the population sensitive to dodine. Accelerated selection of phenotypes double resistant to dodine and the DMI fenarimol was apparent over the course of distinct seasons of apple scab management with either dodine or fenarimol. The data provide evidence for an accelerated speed of resistance development among phenotypes of V. inaequalis already resistant to an unrelated fungicide. This finding represents a departure from the previous model, which assumed entirely independent rounds of resistance developments. The data indicate that phenotypes of V. inaequalis might not only be selected for the trait of fungicide resistance but also for traits allowing a more flexible response to changes in the environment where they compete.

scholarly journals Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms

2016 ◽  
Vol 60 (10) ◽  
pp. 6067-6075 ◽  
Author(s):  
Jun Hong ◽  
Jianye Hu ◽  
Fei Ke
Keyword(s):  
Antimicrobial Peptide ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
Antibacterial Drug ◽  
Cationic Antimicrobial Peptide ◽  
Content Type ◽  
Tachyplesin I

ABSTRACTTachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel β-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms.Aeromonas hydrophilaXS91-4-1,Pseudomonas aeruginosaCGMCC1.2620, andEscherichia coliATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition,P. aeruginosaandE. coliexhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism ofP. aeruginosawas not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity inP. aeruginosa. Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I.

scholarly journals Evaluation of Portability and Cost of a Fluorescent PCR Ribotyping Protocol for Clostridium difficile Epidemiology

2015 ◽  
Vol 53 (4) ◽  
pp. 1192-1197 ◽  
Author(s):  
Jonathan N. V. Martinson ◽  
Susan Broadaway ◽  
Egan Lohman ◽  
Christina Johnson ◽  
M. Jahangir Alam ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Low Cost ◽  
Cost Effective ◽  
Pcr Primers ◽  
The United States ◽  
Content Type ◽  
Fluorescent Pcr ◽  
Address Data ◽  
Pcr Ribotyping ◽  
Data Portability

Clostridium difficileis the most commonly identified pathogen among health care-associated infections in the United States. There is a need for accurate and low-cost typing tools that produce comparable data across studies (i.e., portable data) to help characterize isolates during epidemiologic investigations ofC. difficileoutbreaks and sporadic cases of disease. The most popularC. difficile-typing technique is PCR ribotyping, and we previously developed methods using fluorescent PCR primers and amplicon sizing on a Sanger-style sequencer to generate fluorescent PCR ribotyping data. This technique has been used to characterize tens of thousands ofC. difficileisolates from cases of disease. Here, we present validation of a protocol for the cost-effective generation of fluorescent PCR ribotyping data. A key component of this protocol is the ability to accurately identify PCR ribotypes against an online database (http://walklab.rcg.montana.edu) at no cost. We present results from a blinded multicenter study to address data portability across four different laboratories and three different sequencing centers. Our standardized protocol and centralized database for typing ofC. difficilepathogens will increase comparability between studies so that important epidemiologic linkages between cases of disease and patterns of emergence can be rapidly identified.

scholarly journals Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections

2014 ◽  
Vol 59 (1) ◽  
pp. 289-298 ◽  
Author(s):  
Karen O'Dwyer ◽  
Aaron T. Spivak ◽  
Karen Ingraham ◽  
Sharon Min ◽  
David J. Holmes ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract ◽  
Urinary Tract Infections ◽  
Bacterial Resistance ◽  
Multidrug Resistant ◽  
Trna Synthetase ◽  
Content Type ◽  
Development Of Resistance ◽  
Tract Infections ◽  
Abdominal Infections

ABSTRACTGSK2251052, a novel leucyl-tRNA synthetase (LeuRS) inhibitor, was in development for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. In a phase II study (study LRS114688) evaluating the efficacy of GSK2251052 in complicated urinary tract infections, resistance developed very rapidly in 3 of 14 subjects enrolled, with ≥32-fold increases in the GSK2251052 MIC of the infecting pathogen being detected. A fourth subject did not exhibit the development of resistance in the baseline pathogen but posttherapy did present with a different pathogen resistant to GSK2251052. Whole-genome DNA sequencing ofEscherichia coliisolates collected longitudinally from two study LRS114688 subjects confirmed that GSK2251052 resistance was due to specific mutations, selected on the first day of therapy, in the LeuRS editing domain. Phylogenetic analysis strongly suggested that resistantEscherichia coliisolates resulted from clonal expansion of baseline susceptible strains. This resistance development likely resulted from the confluence of multiple factors, of which only some can be assessed preclinically. Our study shows the challenges of developing antibiotics and the importance of clinical studies to evaluate their effect on disease pathogenesis. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01381549 for the study of complicated urinary tract infections and registration no. NCT01381562 for the study of complicated intra-abdominal infections.)

Prospects for the global economy in 2018

2017 ◽  
Keyword(s):  
United States ◽  
Global Economy ◽  
Low Cost ◽  
Commodity Prices ◽  
Balance Of Power ◽  
The United States ◽  
Industrial Growth ◽  
Content Type ◽  
The Us ◽  
Open Markets

Subject PROSPECTS 2018: Global economy Significance Global GDP growth is likely to edge higher in 2018 as trade, investment and employment expand. However, monetary policy is gradually tightening, fiscal expansion is limited and there is little chance of a repeat of the surprise boost from trade seen in 2017 or a recovery in productivity. Inflation may remain obdurately low in the United States, Japan and the euro-area but not sufficiently to deter the US Federal Reserve (Fed) and the ECB from gently reeling in their bond-buying programmes. Modestly higher commodity prices should support economic recovery in resource producers. Impacts The timing of elections in the United States, Canada and Mexico may prolong the NAFTA trade talks into 2019 or beyond. China will battle any US attempts to constrain its innovation and access to technology, which it sees as key to its rebalancing. Technological progress and more open markets exacerbate the unpredictability of jobs and wages, but policy will increasingly address this. Automation means the job intensive low-cost industrial growth engine is now less effective; developing countries must consider new models. A better balance of power between multinationals, international organisations and governments will be key to global tax cooperation.

scholarly journals Key Role for Efflux in the Preservative Susceptibility and Adaptive Resistance of Burkholderia cepacia Complex Bacteria

2013 ◽  
Vol 57 (7) ◽  
pp. 2972-2980 ◽  
Author(s):  
Laura Rushton ◽  
Andrea Sass ◽  
Adam Baldwin ◽  
Christopher G. Dowson ◽  
Denise Donoghue ◽  
...  
Keyword(s):  
Burkholderia Cepacia ◽  
Burkholderia Cepacia Complex ◽  
Fluoroquinolone Resistance ◽  
Cross Resistance ◽  
Natural Environments ◽  
Content Type ◽  
Adaptive Resistance ◽  
Benzethonium Chloride ◽  
Industrial Strains

ABSTRACTBacteria from theBurkholderia cepaciacomplex (Bcc) are encountered as industrial contaminants, and little is known about the species involved or their mechanisms of preservative resistance. Multilocus sequence typing (MLST) revealed that multiple Bcc species may cause contamination, withB. lata(n= 17) andB. cenocepacia(n= 11) dominant within the collection examined. At the strain level, 11 of the 31 industrial sequence types identified had also been recovered from either natural environments or clinical infections. Minimal inhibitory (MIC) and minimum bactericidal (MBC) preservative concentrations varied across 83 selected Bcc strains, with industrial strains demonstrating increased tolerance for dimethylol dimethyl hydantoin (DMDMH). Benzisothiazolinone (BIT), DMDMH, methylisothiazolinone (MIT), a blend of 3:1 methylisothiazolinone-chloromethylisothiazolinone (M-CMIT), methyl paraben (MP), and phenoxyethanol (PH), were all effective anti-Bcc preservatives; benzethonium chloride (BC) and sodium benzoate (SB) were least effective. SinceB. latawas the dominant industrial Bcc species, the type strain, 383T(LMG 22485T), was used to study preservative tolerance. Strain 383 developed stable preservative tolerance for M-CMIT, MIT, BIT, and BC, which resulted in preservative cross-resistance and altered antibiotic susceptibility, motility, and biofilm formation. Transcriptomic analysis of theB. lata383 M-CMIT-adapted strain demonstrated that efflux played a key role in its M-CMIT tolerance and elevated fluoroquinolone resistance. The role of efflux was corroborated using the inhibitorl-Phe-Arg-β-napthylamide, which reduced the MICs of M-CMIT and ciprofloxacin. In summary, intrinsic preservative tolerance and stable adaptive changes, such as enhanced efflux, play a role in the ability of Bcc bacteria to cause industrial contamination.

scholarly journals In VitroAntifungal Activity of Naftifine Hydrochloride against Dermatophytes

2013 ◽  
Vol 57 (9) ◽  
pp. 4369-4372 ◽  
Author(s):  
M. Ghannoum ◽  
N. Isham ◽  
A. Verma ◽  
S. Plaum ◽  
A. Fleischer ◽  
...  
Keyword(s):  
Developed Countries ◽  
Microsporum Canis ◽  
Test Panel ◽  
Resistance Development ◽  
Epidermophyton Floccosum ◽  
Content Type ◽  
Development Of Resistance ◽  
Time Kill ◽  
Dose Dependent

ABSTRACTThe incidence of superficial dermatophytoses is high in developed countries, and there remains a need for effective topical antifungals. In this study, we evaluated thein vitroantifungal activity of naftifine hydrochloride, the active ingredient in naftifine hydrochloride cream and gel 1% and 2%, against dermatophytes. The MICs and minimum fungicidal concentrations (MFCs) of naftifine hydrochloride against 350 clinical strains, includingTrichophyton rubrum,T. mentagrophytes,T. tonsurans,Epidermophyton floccosum, andMicrosporum canis, were determined using the CLSI methodology. Subsets from this test panel were subsequently tested in a time-kill assay at 0.125×, 0.25×, 0.5×, and 1× the MFC for each isolate. CFU counts were performed over a period of 48 h of incubation. Additionally, in order to determine the potential for resistance development, six strains were subjected to 15 serial passages in concentrations higher than the MIC for each strain. MICs were determined following each passage. The MIC range against the dermatophyte isolates tested was 0.015 to 1.0 μg/ml, with naftifine hydrochloride being fungicidal against 85% of theTrichophytonspecies. The time-kill assay showed dose-dependent activity, with the greatest reduction in the numbers of CFU corresponding to the highest drug concentration. There was no increase in MIC for any strains following repeated exposure to naftifine hydrochloride. Naftifine hydrochloride demonstrated potent activity against all dermatophytes tested, and none of the isolates within this test panel demonstrated the potential for the development of resistance. Thus, future clinical studies of naftifine hydrochloride against dermatophytes may be warranted for the treatment of superficial dermatophytoses.

scholarly journals Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

2013 ◽  
Vol 58 (2) ◽  
pp. 901-908 ◽  
Author(s):  
Hans H. Locher ◽  
Patrick Caspers ◽  
Thierry Bruyère ◽  
Susanne Schroeder ◽  
Philippe Pfaff ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Clostridium Difficile ◽  
Dna Synthesis ◽  
Mode Of Action ◽  
Cross Resistance ◽  
Resistance Development ◽  
Content Type ◽  
Inhibition Of Protein Synthesis ◽  
Inhibitor Of Protein Synthesis ◽  
Inhibition Of Dna Synthesis

ABSTRACTCadazolid is a new oxazolidinone-type antibiotic currently in clinical development for the treatment ofClostridium difficile-associated diarrhea. Here, we report investigations on the mode of action and the propensity for spontaneous resistance development inC. difficilestrains. Macromolecular labeling experiments indicated that cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA synthesis was also observed, albeit only at substantially higher concentrations of the drug. Strong inhibition of protein synthesis was also obtained in strains resistant to linezolid, in agreement with low MICs against such strains. Inhibition of protein synthesis was confirmed in coupled transcription/translation assays using extracts from differentC. difficilestrains, including strains resistant to linezolid, while inhibitory effects in DNA topoisomerase assays were weak or not detectable under the assay conditions. Spontaneous resistance frequencies of cadazolid were low in all strains tested (generally <10−10at 2× to 4× the MIC), and in multiple-passage experiments (up to 13 passages) MICs did not significantly increase. Furthermore, no cross-resistance was observed, as cadazolid retained potent activity against strains resistant or nonsusceptible to linezolid, fluoroquinolones, and the new antibiotic fidaxomicin. In conclusion, the data presented here indicate that cadazolid acts primarily by inhibition of protein synthesis, with weak inhibition of DNA synthesis as a potential second mode of action, and suggest a low potential for spontaneous resistance development.

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