Influence of inducible cross-resistance to macrolides, lincosamides, and streptogramin B-type antibiotics in Enterococcus faecium on activity of quinupristin-dalfopristin in vitro and in rabbits with experimental endocarditis.

The influence of inducible cross-resistance to macrolides, lincosamides, and streptogramin B (MLS(B)) type antibiotics (inducible MLS(B) phenotype) on the activity of quinupristin-dalfopristin was investigated against Enterococcus faecium in vitro and in rabbits with experimental endocarditis. In vitro, quinupristin-dalfopristin displayed bacteriostatic and bactericidal activities against a MLS(B)-susceptible strain similar to those against two strains with the inducible MLS(B) phenotype. In addition, induction of the two MLS(B)-resistant strains with quinupristin (0.016 to 1 microg/ml) or quinupristin-dalfopristin (0.08 to 0.25 microg/ml) increased the MICs of quinupristin from 8 microg/ml to 32 to > 128 microg/ml, but did not modify the MIC of dalfopristin (2 microg/ml) or quinupristin-dalfopristin (0.5 microg/ml). In a rabbit endocarditis model, quinupristin-dalfopristin was as active as amoxicillin against the MLS(B)-susceptible E. faecium strain. In contrast, the activity of quinupristin-dalfopristin was significantly decreased in animals infected with either of the two inducible MLS(B)-resistant strains (P < 0.05), although no mutants resistant to quinupristin-dalfopristin were detected. Against the clinical strain with the inducible MLS(B) phenotype, quinupristin-dalfopristin was not effective and was less active than amoxicillin (P < 0.001); however, the activity of the combination of amoxicillin and dalfopristin-quinupristin was superior to that of amoxicillin (P < 0.01). The different impact of the inducible MLS(B) phenotype in E. faecium on the activity of quinupristin-dalfopristin in vitro and in experimental endocarditis may be related to the reduced diffusion of dalfopristin compared with that of quinupristin into cardiac vegetations that we previously reported. This result emphasizes the importance of the constant presence of dalfopristin at the site of infection to ensure synergism with quinupristin.

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Efficacy of colistin alone and in various combinations for the treatment of experimental osteomyelitis due to carbapenemase-producing Klebsiella pneumoniae

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz257 ◽

2019 ◽

Vol 74 (9) ◽

pp. 2666-2675 ◽

Cited By ~ 4

Author(s):

Anne-Claude Crémieux ◽

Aurélien Dinh ◽

Patrice Nordmann ◽

William Mouton ◽

Pierre Tattevin ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Experimental Model ◽

Host Defence ◽

Cross Resistance ◽

Clinical Strain ◽

Experimental Osteomyelitis ◽

Resistant Strains ◽

Time Kill

AbstractObjectivesIn a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross-resistance to host defence peptides (HDPs).MethodsKPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MIC = 4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICs = 1 mg/L) and fosfomycin (MIC = 32 mg/L). Time–kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin + fosfomycin.ResultsIn vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (P < 0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (P = 0.025). Tigecycline reduced the efficacy of colistin (P = 0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37.ConclusionsIn this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo.

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In vitro anti-mycobacterial activity of (E)-N´-(monosubstituted-benzylidene) isonicotinohydrazide derivatives against isoniazid-resistant strains

Infectious Disease Reports ◽

10.4081/idr.2012.e13 ◽

2012 ◽

Vol 4 (1) ◽

pp. 13 ◽

Cited By ~ 8

Author(s):

Tatiane S. Coelho ◽

Jessica B. Cantos ◽

Marcelle L.F. Bispo ◽

Raoni S.B. Gonçalves ◽

Camilo H.S. Lima ◽

...

Keyword(s):

Antibacterial Activity ◽

Resistant Strain ◽

Mechanisms Of Action ◽

Susceptible Strain ◽

Clinical Isolates ◽

Coding Region ◽

Resistant Strains

A series of twenty-three N-acylhydrazones derived from isoniazid (INH 1-23) have been evaluated for their in vitro antibacterial activity against INH- susceptible strain of M. tuberculosis (RG500) and three INH-resistant clinical isolates (RG102, RG103 and RG113). In general, derivatives 4, 14, 15 and 16 (MIC=1.92, 1.96, 1.96 and 1.86 mM, respectively) showed relevant activities against RG500 strain, while the derivative 13 (MIC=0.98 mM) was more active than INH (MIC=1.14 mM). However, these derivatives were inactive against RGH102, which displays a mutation in the coding region of inhA. These results suggest that the activities of these compounds depend on the inhibition of this enzyme. However, the possibility of other mechanisms of action cannot be excluded, since compounds 2, 4, 6, 7, 12-17, 19, 21 and 23 showed good activities against katG-resistant strain RGH103, being more than 10-fold more active than INH.

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Lead Optimization of Dehydroemetine for Repositioned Use in Malaria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01444-19 ◽

2020 ◽

Vol 64 (4) ◽

Author(s):

Priyanka Panwar ◽

Kepa K. Burusco ◽

Muna Abubaker ◽

Holly Matthews ◽

Andrey Gutnov ◽

...

Keyword(s):

De Novo ◽

Antimalarial Activity ◽

Drug Repositioning ◽

Multidrug Resistant ◽

Cross Resistance ◽

Synthetic Analogue ◽

80S Ribosome ◽

Content Type ◽

Resistant Strains

ABSTRACT Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM ± 2.1 nM [mean ± standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have less-cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (P. falciparum 80S ribosome in complex with emetine), and it was found that (−)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than did (−)-S,S-dehydroisoemetine. (−)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (−)-S,S-dehydroisoemetine (IC50, 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (−)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (−)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.

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Effects of the probiotic Enterococcus faecium NCIMB 10415 on selected lactic acid bacteria and enterobacteria in co-culture

Beneficial Microbes ◽

10.3920/bm2014.0052 ◽

2015 ◽

Vol 6 (3) ◽

pp. 345-352 ◽

Cited By ~ 9

Author(s):

I.C. Starke ◽

J. Zentek ◽

W. Vahjen

Keyword(s):

Intestinal Microbiota ◽

Enterococcus Faecium ◽

Lactobacillus Reuteri ◽

Specific Growth ◽

Probiotic Strain ◽

Lactobacillus Mucosae ◽

Vitro Effect ◽

Reference Strains ◽

Faecium Strain

Enterococcus faecium NCIMB 10415 is used as a probiotic for piglets and has been shown to modify the porcine intestinal microbiota. However, the mode of action of this probiotic modification is still unclear. One possible explanation is the direct growth inhibiting or stimulating effect of the probiotic on other indigenous bacteria. Therefore, the aim of the present study was to examine the growth interactions of the probiotic with different indigenous porcine bacteria in vitro. Reference strains were cultivated with the probiotic E. faecium strain NCIMB10415 (SF68) in a checkerboard assay with 102 to 105 cells/ml inoculum per strain. Growth kinetics were recorded for 8 h and used to determine specific growth of the co-cultures. Additionally, total DNA was extracted from the co-cultures at the end of the incubation to verify which strain in the co-culture was affected. Co-cultivation with eight Enterococcus spp. tester strains showed strain-specific growth differences. Three of four E. faecium strains were not influenced by the probiotic strain. PCR results showed reduced growth of the probiotic strain in co-culture with E. faecium DSM 6177. Three of four Enterococcus faecalis strains showed reduced specific growth in co-culture with the probiotic strain. However, E. faecalis DSM 20478 impaired growth of the probiotic E. faecium strain. The growth of Lactobacillus johnsonii DSM 10533 and Lactobacillus reuteri DSM 20016 was enhanced in co-culture with the probiotic strain, but co-cultivations with Lactobacillus mucosae DSM13345 or Lactobacillus amylovorus DSM10533 showed no differences. Co-cultures with the probiotic E. faecium showed no impact on the growth rate of four different enterobacterial reference strains (2 strains of Salmonella enterica and 2 strains of Escherichia coli), but PCR results showed reduced cell numbers for a pathogenic E. coli isolate at higher concentration of the probiotic strain. As the in vitro effect of the probiotic E. faecium on enterococci was strain specific and the growth of certain Lactobacillus spp. was enhanced by the probiotic, these results indicate a direct effect of the probiotic on certain members of the porcine gastro intestinal microbiota.

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Susceptibility of Candida spp. clinical isolates to antimycotics and disinfectants

Open Life Sciences ◽

10.2478/s11535-010-0068-3 ◽

2010 ◽

Vol 5 (6) ◽

pp. 821-826

Author(s):

Monika Staniszewska ◽

Beata Rozbicka ◽

Aleksandra Rajnisz ◽

Ewa Bocian ◽

Ewa Wasińska ◽

...

Keyword(s):

Clinical Isolates ◽

Cross Resistance ◽

Biocidal Activity ◽

Candida Spp ◽

In Vitro Susceptibility ◽

Minimal Inhibitory Concentrations ◽

Antiseptic Agent ◽

Resistant Strains ◽

Candida Infections

AbstractThe incidence of candidiasis among immunocompromised patients and emergence of antimycotics resistant strains has increased significantly. The aims of this study were: to examine the in vitro activity of antimycotics and biocides against Candida clinical isolates; to detect cross-resistance of fungi to these preparations and to estimate whether disinfectants applied in hospital areas are active against clinical Candida isolates. In vitro susceptibility of 102 Candida isolates to eight antimycotics was examined by Etest and ATB Fungus. Sensitivity of these strains to four disinfectants and an antiseptic agent was tested according to EN 1275:2005. Amphotericin B, caspofungin and 5-fluorocytosine were the most effective antimycotics against all Candida isolates. Resistance to itraconazole and fluconazole was observed among C. krusei and C. glabrata. The MICs (Minimal Inhibitory Concentrations) for ketoconazole, voriconazole and posaconazole against Candida albicans ranged: 0.003 - >32 μg/ml and one strain was resistant to three agents tested. All analysed Candida strains were sensitive to biocides containing either chlorine, aldehyde, alcohol mixtures, glucoprotamin or chlorhexidine gluconate with isopropanol. Sensitivity to these agents was observed at concentrations lower than those concentrations recommended by manufacturers to achieve proper biocidal activity to those preparations. Our data suggest that these disinfectants can be effectively applied in clinical wards to prevent nosocomial Candida infections.

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In Vitro Activity of Sanfetrinem and Affinity for the Penicillin-Binding Proteins of Streptococcus pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.1.173 ◽

1998 ◽

Vol 42 (1) ◽

pp. 173-175 ◽

Cited By ~ 6

Author(s):

Farid Sifaoui ◽

Emmanuelle Varon ◽

Marie-Dominique Kitzis ◽

Laurent Gutmann

Keyword(s):

Streptococcus Pneumoniae ◽

Binding Proteins ◽

Susceptible Strain ◽

Vitro Activity ◽

In Vitro Activity ◽

Penicillin Binding Proteins ◽

Resistant Strains

ABSTRACT Against penicillin-susceptible pneumococci, the activity of sanfetrinem was similar to those of penicillin, amoxicillin, cefotaxime, imipenem, and meropenem, while against penicillin-resistant strains, sanfetrinem and the carbapenems exhibited superior activity (MICs at which 90% of strains are inhibited, ≤1 μg/ml). PBP 1a in the penicillin-susceptible strain and PBP 1a and PBP 2b in the more resistant isolates seemed to be the essential penicillin-binding proteins for imipenem and sanfetrinem.

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New insecticide screening platforms indicate that Mitochondrial Complex I inhibitors are susceptible to cross-resistance by mosquito P450s that metabolise pyrethroids

Scientific Reports ◽

10.1038/s41598-020-73267-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rosemary S. Lees ◽

Hanafy M. Ismail ◽

Rhiannon A. E. Logan ◽

David Malone ◽

Rachel Davies ◽

...

Keyword(s):

Vector Control ◽

Complex I ◽

Pyrethroid Resistance ◽

In Vitro Assays ◽

Cross Resistance ◽

Malaria Vector Control ◽

Resistant Strains ◽

Extended Exposure

Abstract Fenazaquin, pyridaben, tolfenpyrad and fenpyroximate are Complex I inhibitors offering a new mode of action for insecticidal malaria vector control. However, extended exposure to pyrethroid based products such as long-lasting insecticidal nets (LLINs) has created mosquito populations that are largely pyrethroid-resistant, often with elevated levels of P450s that can metabolise and neutralise diverse substrates. To assess cross-resistance liabilities of the Complex I inhibitors, we profiled their susceptibility to metabolism by P450s associated with pyrethroid resistance in Anopheles gambiae (CYPs 6M2, 6P3, 6P4, 6P5, 9J5, 9K1, 6Z2) and An. funestus (CYP6P9a). All compounds were highly susceptible. Transgenic An. gambiae overexpressing CYP6M2 or CYP6P3 showed reduced mortality when exposed to fenpyroximate and tolfenpyrad. Mortality from fenpyroximate was also reduced in pyrethroid-resistant strains of An. gambiae (VK7 2014 and Tiassalé 13) and An. funestus (FUMOZ-R). P450 inhibitor piperonyl butoxide (PBO) significantly enhanced the efficacy of fenpyroximate and tolfenpyrad, fully restoring mortality in fenpyroximate-exposed FUMOZ-R. Overall, results suggest that in vivo and in vitro assays are a useful guide in the development of new vector control products, and that the Complex I inhibitors tested are susceptible to metabolic cross-resistance and may lack efficacy in controlling pyrethroid resistant mosquitoes.

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Lead optimisation of dehydroemetine for repositioned use in malaria

10.1101/538413 ◽

2019 ◽

Author(s):

Priyanka Panwar ◽

Kepa K. Burusco ◽

Muna Abubaker ◽

Holly Matthews ◽

Andrey Gutnov ◽

...

Keyword(s):

De Novo ◽

Antimalarial Activity ◽

Drug Repositioning ◽

Cross Resistance ◽

Synthetic Analogue ◽

Drug Resistant ◽

Lead Optimisation ◽

Resistant Strains ◽

Drug Resistant Strains

AbstractDrug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM + 2.1 nM). 2,3-dehydroemetine, a synthetic analogue of emetine dihydrochloride has been claimed to have less cardiotoxic effects than emetine. The structures of two diastereoisomers of 2,3-dehydroemetine were modelled on the reported emetine binding site on cryo-EM structure 3J7A and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine, which loses its potency due to the change of configuration at C-1’. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed atovoquone-like activity on the mitochondrial membrane potential.

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Toxicity evaluation for an Enterococcus faecium strain TM39 in vitro and in vivo

Food and Chemical Toxicology ◽

10.1016/j.fct.2004.05.005 ◽

2004 ◽

Vol 42 (10) ◽

pp. 1601-1609 ◽

Cited By ~ 12

Author(s):

Cheng-Chih Tsai ◽

Tseng-Huang Liu ◽

Ming-Hui Chen ◽

Chin-Chuan Tsai ◽

Hau-Yang Tsen

Keyword(s):

Enterococcus Faecium ◽

Toxicity Evaluation ◽

Faecium Strain

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In vitro activities of eight macrolide antibiotics and RP-59500 (quinupristin-dalfopristin) against viridans group streptococci isolated from blood of neutropenic cancer patients.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.9.2117 ◽

1996 ◽

Vol 40 (9) ◽

pp. 2117-2120 ◽

Cited By ~ 26

Author(s):

F Alcaide ◽

J Carratala ◽

J Liñares ◽

F Gudiol ◽

R Martin

Keyword(s):

Cancer Patients ◽

High Rate ◽

Cross Resistance ◽

Macrolide Antibiotics ◽

Dilution Method ◽

Agar Dilution Method ◽

Agar Dilution ◽

Resistant Strains ◽

Viridans Group Streptococci

From January 1988 to December 1994, 66 consecutive blood culture isolates of viridans group streptococci collected from febrile neutropenic cancer patients were tested for antimicrobial susceptibilities by the agar dilution method. The antibiotics studied were erythromycin, clarithromycin, roxithromycin, dirithromycin, azithromycin, josamycin, diacetyl-midecamycin, spiramycin, and quinupristin-dalfopristin. A total of 26 (39.4%) strains were resistant to erythromycin with an MIC range of 0.5 to > 128 micrograms/ml. The strains were classified into three groups according to their penicillin susceptibility: 42 (63.6%) were susceptible, 8 (12.1%) were intermediately resistant, and 16 (24.3%) were highly resistant. The percentages of erythromycin-resistant strains in each group were 23.8, 62.5, and 68.8%, respectively. Streptococcus mitis was the species most frequently isolated (83.3%) and showed the highest rates of penicillin (40%) and erythromycin (43.6%) resistance. MICs of all macrolide antibiotics tested and of quinupristin-dalfopristin were higher for penicillin-resistant strains than for penicillin-susceptible strains. All macrolide antibiotics tested had cross-resistance to erythromycin, which was not observed with quinupristin-dalfopristin. Our study shows a high rate of macrolide resistance among viridans group streptococci isolated from blood samples of neutropenic cancer patients, especially those infected with penicillin-resistant strains. These findings make macrolides unsuitable prophylactic agents against viridans group streptococcal bacteremia in this patient population.

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