Differences in Potential for Selection of Clindamycin-Resistant Mutants Between Inducible erm(A) and erm(C) Staphylococcus aureus Genes

ABSTRACT The development of resistance to linezolid (LZD) in gram-positive bacteria depends on the mutation of a single 23S rRNA gene, followed by homologous recombination and gene conversion of the other alleles. We sought to inhibit this process in Staphylococcus aureus using a range of antibacterial agents, including some that suppress recombination. A model for the rapid selection of LZD resistance was developed which allowed the selection of LZD-resistant mutants with G2576T mutations in all five copies of the 23S rRNA gene following only 5 days of subculture. The emergence of LZD-resistant isolates was delayed by exposing cultures to low concentrations of various classes of antibiotics. All antibiotic classes were effective in delaying the selection of LZD-resistant mutants and, with the exception of fusidic acid (FUS) and rifampin (RIF), prolonged the selection window from 5 to ∼15 days. Inhibitors of DNA processing were no more effective than any other class of antibiotics at suppressing resistance development. However, the unrelated antimicrobials FUS and RIF were particularly effective at preventing the emergence of LZD resistance, prolonging the selection window from 5 to 25 days. The enhanced suppressive effect of FUS and RIF on the development of LZD resistance was lost in a recA-deficient host, suggesting that these drugs affect recA-dependent recombination. Furthermore, FUS and RIF were shown to be effective inhibitors of homologous recombination of a plasmid into the staphylococcal chromosome. We suggest that RIF or FUS in combination with LZD may have a role in preventing the emergence of LZD resistance.

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Linezolid and Tiamulin Cross-Resistance in Staphylococcus aureus Mediated by Point Mutations in the Peptidyl Transferase Center

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01015-07 ◽

2008 ◽

Vol 52 (5) ◽

pp. 1737-1742 ◽

Cited By ~ 50

Author(s):

Keith Miller ◽

Colin J. Dunsmore ◽

Colin W. G. Fishwick ◽

Ian Chopra

Keyword(s):

Staphylococcus Aureus ◽

Point Mutations ◽

Single Copy ◽

23S Rrna ◽

Cross Resistance ◽

Limiting Factor ◽

Peptidyl Transferase ◽

Inhibit Protein Synthesis ◽

Resistant Mutants ◽

Selection Of

ABSTRACT Oxazolidinone and pleuromutilin antibiotics are currently used in the treatment of staphylococcal infections. Although both antibiotics inhibit protein synthesis and have overlapping binding regions on 23S rRNA, the potential for cross-resistance between the two classes through target site mutations has not been thoroughly examined. Mutants of Staphylococcus aureus resistant to linezolid were selected and found to exhibit cross-resistance to tiamulin, a member of the pleuromutilin class of antibiotics. However, resistance was unidirectional because mutants of S. aureus selected for resistance to tiamulin did not exhibit cross-resistance to linezolid. This contrasts with the recently described PhLOPSA phenotype, which confers resistance to both oxazolidinones and pleuromutilins. The genotypes responsible for the phenotypes we observed were examined. Selection with tiamulin resulted in recovery of mutants with changes in the single-copy rplC gene (Gly155Arg, Ser158Leu, or Arg149Ser), whereas selection with linezolid led to recovery of mutants with changes (G2576U in 23S rRNA) in all five copies of the multicopy operon rrn. In contrast, cross-resistance to linezolid was exhibited by tiamulin-resistant mutants generated in a single-copy rrn knockout strains of Escherichia coli, illustrating that the copy number of 23S rRNA is the limiting factor in the selection of 23S rRNA tiamulin-resistant mutants. The interactions of linezolid and tiamulin with the ribosome were modeled to seek explanations for resistance to both classes in the 23S rRNA mutants and the lack of cross-resistance between tiamulin and linezolid following mutation in rplC.

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Bactericidal Activity of the Combination of Levofloxacin with Rifampin in Experimental Prosthetic Knee Infection in Rabbits Due to Methicillin-Susceptible Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01163-08 ◽

2009 ◽

Vol 53 (5) ◽

pp. 2145-2148 ◽

Cited By ~ 7

Author(s):

Claudette Muller-Serieys ◽

Azzam Saleh Mghir ◽

Laurent Massias ◽

Bruno Fantin

Keyword(s):

Staphylococcus Aureus ◽

Bactericidal Activity ◽

Rabbit Model ◽

Clinical Strain ◽

Prosthetic Infection ◽

Knee Infection ◽

Prosthetic Knee ◽

Resistant Mutants ◽

Prosthetic Knee Infection ◽

Selection Of

ABSTRACT The combination of levofloxacin and rifampin has been recommended for the treatment of staphylococcal prosthetic infection. In a rabbit model of prosthetic knee infection due to a susceptible clinical strain of Staphylococcus aureus, the combination of levofloxacin and rifampin was bactericidal, significantly reduced bacterial titers in bone compared with levels for rifampin and controls (P < 0.05), sterilized 6 of 12 animals, and prevented the selection of resistant mutants that was observed with rifampin alone, validating clinical recommendations.

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Efficacy of a New Fluoroquinolone, JNJ-Q2, in Murine Models of Staphylococcus aureus and Streptococcus pneumoniae Skin, Respiratory, and Systemic Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00471-11 ◽

2011 ◽

Vol 55 (12) ◽

pp. 5522-5528 ◽

Cited By ~ 11

Author(s):

Jeffrey Fernandez ◽

Jamese J. Hilliard ◽

Brian J. Morrow ◽

John L. Melton ◽

Robert K. Flamm ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Streptococcus Pneumoniae ◽

Tract Infection ◽

Lower Respiratory Tract ◽

Skin Infection ◽

Infection Model ◽

Content Type ◽

Infection Models ◽

Resistant Mutants ◽

Selection Of

ABSTRACTThein vivoefficacy of JNJ-Q2, a new broad-spectrum fluoroquinolone (FQ), was evaluated in a murine septicemia model with methicillin-susceptibleStaphylococcus aureus(MSSA) and methicillin-resistantS. aureus(MRSA) and in aStreptococcus pneumoniaelower respiratory tract infection model. JNJ-Q2 and comparators were also evaluated in an acute murine skin infection model using a community-acquired MRSA strain and in an established skin infection (ESI) model using a hospital-acquired strain, for which the selection of resistant mutants was also determined. JNJ-Q2 demonstrated activity in the MSSA septicemia model that was comparable to that moxifloxacin (JNJ-Q2 50% effective dose [ED50], 0.2 mg/kg of body weight administered subcutaneously [s.c.] and 2 mg/kg administered orally [p.o.]) and activity in the MRSA septicemia model that was superior to that of vancomycin (JNJ-Q2 ED50, 1.6 mg/kg administered s.c.). In anS. pneumoniaelower respiratory tract infection model, JNJ-Q2 displayed activity (ED50, 1.9 mg/kg administered s.c. and 7.4 mg/kg administered p.o.) that was comparable to that of gemifloxacin and superior to that of moxifloxacin. In both MRSA skin infection models, treatment with JNJ-Q2 resulted in dose-dependent reductions in bacterial titers in the skin, with the response to JNJ-Q2 at each dose exceeding the responses of the comparators ciprofloxacin, moxifloxacin, linezolid, and vancomycin. Additionally, in the ESI model, JNJ-Q2 showed a low or nondetectable propensity for ciprofloxacin resistance selection, in contrast to the selection of ciprofloxacin-resistant mutants observed for both ciprofloxacin and moxifloxacin. JNJ-Q2 demonstrated activity that was comparable or superior to the activity of fluoroquinolone or antistaphylococcal comparators in several local and systemic skin infection models performed with bothS. aureusandS. pneumoniaeand is currently being evaluated in phase II human clinical trials.

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Effect of Fluoroquinolone Concentration on Selection of Resistant Mutants of Mycobacterium bovis BCG andStaphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.7.1756 ◽

1999 ◽

Vol 43 (7) ◽

pp. 1756-1758 ◽

Cited By ~ 191

Author(s):

Yuzhi Dong ◽

Xilin Zhao ◽

John Domagala ◽

Karl Drlica

Keyword(s):

Staphylococcus Aureus ◽

Mycobacterium Bovis ◽

Methoxy Group ◽

Plateau Region ◽

Sharp Drop ◽

Mycobacterium Bovis Bcg ◽

Mutant Prevention Concentration ◽

Resistant Mutants ◽

Selection Of

ABSTRACT When Mycobacterium bovis BCG and Staphylococcus aureus were plated on agar containing increasing concentrations of fluoroquinolone, colony numbers exhibited a sharp drop, followed by a plateau and a second sharp drop. The plateau region correlated with the presence of first-step resistant mutants. Mutants were not recovered at concentrations above those required for the second sharp drop, thereby defining a mutant prevention concentration (MPC). A C-8-methoxy group lowered the MPC for anN-1-cyclopropyl fluoroquinolone.

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In Vitro Bactericidal Activities of Linezolid in Combination with Vancomycin, Gentamicin, Ciprofloxacin, Fusidic Acid, and Rifampin against Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.1.418-420.2003 ◽

2003 ◽

Vol 47 (1) ◽

pp. 418-420 ◽

Cited By ~ 66

Author(s):

Patrick Grohs ◽

Marie-Dominique Kitzis ◽

Laurent Gutmann

Keyword(s):

Staphylococcus Aureus ◽

Fusidic Acid ◽

Methicillin Resistant ◽

Bactericidal Activities ◽

Resistant Mutants ◽

Mrsa Strains ◽

Selection Of

ABSTRACT The in vitro activities of linezolid were determined alone and in combination with vancomycin, ciprofloxacin, gentamicin, fusidic acid, or rifampin against five methicillin-susceptible Staphylococcus aureus (MSSA) and five methicillin-resistant S. aureus (MRSA) strains. Similar responses were obtained against MSSA and MRSA. When combined with fusidic acid, gentamicin, or rifampin, linezolid prevented selection of resistant mutants but showed no synergy. When linezolid was combined with vancomycin and ciprofloxacin, a slight antagonism was observed. While the combination with linezolid may reduce the emergence of mutants resistant to the associated drugs, the absence of synergy, especially in the case of vancomycin and ciprofloxacin, does not argue in favor of such combinations.

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The Study of Bacillus Subtils Antimicrobial Activity on Some of the Pathological Isolates

International Journal of Drug Delivery Technology ◽

10.25258/ijddt.9.2.12 ◽

2019 ◽

Vol 9 (02) ◽

Author(s):

Hussein A Kadhum ◽

Thualfakar H Hasan2

Keyword(s):

Staphylococcus Aureus ◽

Pseudomonas Aeruginosa ◽

Antimicrobial Activity ◽

Bacillus Subtilis ◽

Bacterial Growth ◽

Broad Spectrum ◽

Inhibitory Activity ◽

Bacterial Pathogens ◽

Inhibitory Ability ◽

Selection Of

The study involved the selection of two isolates from Bacillus subtilis to investigate their inhibitory activity against some bacterial pathogens. B sub-bacteria were found to have a broad spectrum against test bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa. They were about 23-30 mm and less against Klebsiella sp. The sensitivity of some antibodies was tested on the test samples. The results showed that the inhibitory ability of bacterial growth in the test samples using B. subtilis extract was more effective than the antibiotics used.

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Testing the mutant selection window hypothesis in Staphylococcus aureus resistance studies with linezolid using a mixture of antibiotic-susceptible cells and resistant mutants in an in vitro dynamic model

10.26226/morressier.56d6be79d462b80296c97b28 ◽

2016 ◽

Author(s):

Kamilla Alieva

Keyword(s):

Staphylococcus Aureus ◽

Dynamic Model ◽

Mutant Selection ◽

Selection Window ◽

Resistant Mutants

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The Effects of Shock Vancomycin Concentrations on the Formation of Heteroresistance in Staphylococcus aureus

Antibiotics and Chemotherapy ◽

10.37489/0235-2990-2020-65-9-10-3-7 ◽

2020 ◽

Vol 65 (9-10) ◽

pp. 3-7

Author(s):

V. V. Gostev ◽

Yu. V. Sopova ◽

O. S. Kalinogorskaya ◽

M. E. Velizhanina ◽

I. V. Lazareva ◽

...

Keyword(s):

Staphylococcus Aureus ◽

In Vitro Selection ◽

Methicillin Resistant Staphylococcus Aureus ◽

High Concentration ◽

Short Term ◽

High Concentrations ◽

Selection Of ◽

Selection Of Resistance ◽

Test Cultures

Glycopeptides are the basis of the treatment of infections caused by MRSA (Methicillin-Resistant Staphylococcus aureus). Previously, it was demonstrated that antibiotic tolerant phenotypes are formed during selection of resistance under the influence of high concentrations of antibiotics. The present study uses a similar in vitro selection model with vancomycin. Clinical isolates of MRSA belonging to genetic lines ST8 and ST239, as well as the MSSA (ATCC29213) strain, were included in the experiment. Test isolates were incubated for five hours in a medium with a high concentration of vancomycin (50 μg/ml). Test cultures were grown on the medium without antibiotic for 18 hours after each exposure. A total of ten exposure cycles were performed. Vancomycin was characterized by bacteriostatic action; the proportion of surviving cells after exposure was 70–100%. After selection, there was a slight increase in the MIC to vancomycin (MIC 2 μg/ml), teicoplanin (MIC 1.5–3 μg/ml) and daptomycin (MIC 0.25–2 μg/ml). According to the results of PAP analysis, all strains showed an increase in the area under curve depending on the concentration of vancomycin after selection, while a heteroresistant phenotype (with PAP/AUC 0.9) was detected in three isolates. All isolates showed walK mutations (T188S, D235N, E261V, V380I, and G223D). Exposure to short-term shock concentrations of vancomycin promotes the formation of heteroresistance in both MRSA and MSSA. Formation of VISA phenotypes is possible during therapy with vancomycin.

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Characterization of sparfloxacin-resistant mutants of Staphylococcus aureus obtained in vitro

International Journal of Antimicrobial Agents ◽

10.1016/s0924-8579(01)00366-1 ◽

2001 ◽

Vol 18 (2) ◽

pp. 107-112 ◽

Cited By ~ 7

Author(s):

Joaquim Ruiz ◽

Josep M. Sierra ◽

M.Teresa Jiménez De Anta ◽

Jordi Vila

Keyword(s):

Staphylococcus Aureus ◽

Resistant Mutants

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