Failure of Therapy in Pseudomonas Endocarditis: Selection of Resistant Mutants

1986 ◽  
Vol 154 (1) ◽  
pp. 64-68 ◽  
Author(s):  
V. E. Jimenez-Lucho ◽  
L. D. Saravolatz ◽  
A. A. Medeiros ◽  
D. Pohlod
Keyword(s):  
Resistant Mutants ◽  
Selection Of

scholarly journals Alterations in DNA Gyrase and Topoisomerase IV in Resistant Mutants of Clostridium perfringens Found after In Vitro Treatment with Fluoroquinolones

2005 ◽  
Vol 49 (2) ◽  
pp. 488-492 ◽  
Author(s):  
Fatemeh Rafii ◽  
Miseon Park ◽  
John S. Novak
Keyword(s):  
Clostridium Perfringens ◽  
Allelic Diversity ◽  
Dna Gyrase ◽  
Serial Passage ◽  
Primary Target ◽  
Topoisomerase Iv ◽  
Resistant Mutants ◽  
In Vitro Treatment ◽  
Selection Of

ABSTRACT To compare mutations in the DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) genes of Clostridium perfringens, which are associated with in vitro exposure to fluoroquinolones, resistant mutants were selected from eight strains by serial passage in the presence of increasing concentrations of norfloxacin, ciprofloxacin, gatifloxacin, or trovafloxacin. The nucleotide sequences of the entire gyrA, gyrB, parC, and parE genes of 42 mutants were determined. DNA gyrase was the primary target for each fluoroquinolone, and topoisomerase IV was the secondary target. Most mutations appeared in the quinolone resistance-determining regions of gyrA (resulting in changes of Asp-87 to Tyr or Gly-81 to Cys) and parC (resulting in changes of Asp-93 or Asp-88 to Tyr or Ser-89 to Ile); only two mutations were found in gyrB, and only two mutations were found in parE. More mutants with multiple gyrA and parC mutations were produced with gatifloxacin than with the other fluoroquinolones tested. Allelic diversity was observed among the resistant mutants, for which the drug MICs increased 2- to 256-fold. Both the structures of the drugs and their concentrations influenced the selection of mutants.

scholarly journals Antipneumococcal Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Erythromycin, Azithromycin, Clarithromycin, Clindamycin, and Telithromycin

2004 ◽  
Vol 48 (11) ◽  
pp. 4103-4112 ◽  
Author(s):  
Vlatka Matic ◽  
Klaudia Kosowska ◽  
Bulent Bozdogan ◽  
Linda M. Kelly ◽  
Kathy Smith ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Protein Sequence ◽  
Single Step ◽  
23S Rrna ◽  
Susceptible Parent ◽  
Rrna Sequence ◽  
Resistant Strains ◽  
Resistant Mutants ◽  
Rrna Sequences ◽  
Selection Of

ABSTRACT The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with erm(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were ≥0.5 μg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No mef(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two mef(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 μg/ml. Single-step studies showed mutation frequencies <5.0 × 10−10 to 3.5 × 10−7 for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 × 10−7 to >4.3 × 10−3 for resistant strains. The postantibiotic effects of GW 773546, GW 708408, and telithromycin were 2.4 to 9.8 h.

scholarly journals Dual Targeting of DNA Gyrase and Topoisomerase IV: Target Interactions of Garenoxacin (BMS-284756, T-3811ME), a New Desfluoroquinolone

2002 ◽  
Vol 46 (11) ◽  
pp. 3370-3380 ◽  
Author(s):  
Dilek Ince ◽  
Xiamei Zhang ◽  
L. Christine Silver ◽  
David C. Hooper
Keyword(s):  
Inhibitory Concentration ◽  
Efflux Pump ◽  
Fold Increase ◽  
Single Step ◽  
The Novel ◽  
Wild Type ◽  
Topoisomerase Iv ◽  
Dual Targeting ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT We determined the target enzyme interactions of garenoxacin (BMS-284756, T-3811ME), a novel desfluoroquinolone, in Staphylococcus aureus by genetic and biochemical studies. We found garenoxacin to be four- to eightfold more active than ciprofloxacin against wild-type S. aureus. A single topoisomerase IV or gyrase mutation caused only a 2- to 4-fold increase in the MIC of garenoxacin, whereas a combination of mutations in both loci caused a substantial increase (128-fold). Overexpression of the NorA efflux pump had minimal effect on resistance to garenoxacin. With garenoxacin at twice the MIC, selection of resistant mutants (<7.4 × 10−12 to 4.0 × 10−11) was 5 to 6 log units less than that with ciprofloxacin. Mutations inside or outside the quinolone resistance-determining regions (QRDR) of either topoisomerase IV, or gyrase, or both were selected in single-step mutants, suggesting dual targeting of topoisomerase IV and gyrase. Three of the novel mutations were shown by genetic experiments to be responsible for resistance. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that garenoxacin had similar activity against topoisomerase IV and gyrase (50% inhibitory concentration, 1.25 to 2.5 and 1.25 μg/ml, respectively), and although its activity against topoisomerase IV was 2-fold greater than that of ciprofloxacin, its activity against gyrase was 10-fold greater. This study provides the first genetic and biochemical data supporting the dual targeting of topoisomerase IV and gyrase in S. aureus by a quinolone as well as providing genetic proof for the expansion of the QRDRs to include the 5′ terminus of grlB and the 3′ terminus of gyrA.

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

2007 ◽  
Vol 46 (2) ◽  
pp. 546-550 ◽  
Author(s):  
C. Daurel ◽  
C. Huet ◽  
A. Dhalluin ◽  
M. Bes ◽  
J. Etienne ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Resistant Mutants ◽  
Selection Of

scholarly journals Monoclonal Antibodies That Distinguish Antigenic Variants of Canine Parvovirus

2003 ◽  
Vol 10 (6) ◽  
pp. 1085-1089 ◽  
Author(s):  
Masato Nakamura ◽  
Kazuya Nakamura ◽  
Takayuki Miyazawa ◽  
Yukinobu Tohya ◽  
Masami Mochizuki ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Antigenic Site ◽  
Canine Parvovirus ◽  
The Other ◽  
Escape Mutants ◽  
Feline Parvovirus ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT Canine parvovirus (CPV) is classified as a member of the feline parvovirus (FPV) subgroup. CPV isolates are divided into three antigenic types: CPV type 2 (CPV-2), CPV-2a, and CPV-2b. Recently, new antigenic types of CPV were isolated from Vietnamese leopard cats and designated CPV-2c(a) or CPV-2c(b). CPV-2c viruses were distinguished from the other antigenic types of the FPV subgroup by the absence of reactivity with several monoclonal antibodies (MAbs). To characterize the antigenicity of CPV-2c, a panel of MAbs against CPV-2c was generated and epitopes recognized by these MAbs were examined by selection of escape mutants. Four MAbs were established and classified into three groups on the basis of their reactivities: MAbs which recognize CPV-2a, CPV-2b, and CPV-2c (MAbs 2G5 and 20G4); an MAb which reacts with only CPV-2b and CPV-2c(b) (MAb 21C3); and an MAb which recognizes all types of the FPV subgroup viruses (MAb 19D7). The reactivity of MAb 20G4 with CPV-2c was higher than its reactivities with CPV-2a and CPV-2b. These types of specificities of MAbs have not been reported previously. A mapping study by analysis of neutralization-resistant mutants showed that epitopes recognized by MAbs 21C3 and 19D7 belonged to antigenic site A. Substitution of the residues in site B and the other antigenic site influenced the epitope recognized by MAb 2G5. It was suggested that the epitope recognized by MAb 20G4 was related to antigenic site B. These MAbs are expected to be useful for the detection and classification of FPV subgroup isolates.

How effective is KRM-1648 in treatment of disseminated Mycobacterium avium complex infections in beige mice?

1996 ◽  
Vol 40 (2) ◽  
pp. 437-442 ◽  
Author(s):  
B Ji ◽  
N Lounis ◽  
C Truffot-Pernot ◽  
J Grosset
Keyword(s):  
Mycobacterium Avium ◽  
Mycobacterium Avium Complex ◽  
Antimicrobial Effect ◽  
Bacteriostatic Effect ◽  
Dose Selection ◽  
Order Of Magnitude ◽  
The Mean ◽  
Resistant Mutants ◽  
Selection Of

Although the MICs of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin, or KRM-1648 (KRM), for Mycobacterium avium complex (MAC) were significantly lower than those of other drugs, its in vivo activity was very weak. Beginning 28 days after inoculation, beige mice that had been infected intravenously with 1.87 x 10(7) CFU of MAC 101 were administered KRM alone, clarithromycin (CLARI) alone, or CLARI plus KRM six times weekly for 16 weeks. In contrast to the mice treated with CLARI-containing regimens, the mortality and the mean spleen weights of mice treated with KRM alone (either 10 or 20 mg/kg of body weight per dose) did not differ significantly from those of untreated mice, their numbers of CFU were very much greater than pretreatment values, and multiplication of MAC was only slightly inhibited. Although monotherapy by KRM selected KRM-resistant mutants, the selection was very weak; the mean number of CFU and the frequency of KRM-resistant mutants increased by no more than 1 order of magnitude after 16 weeks of treatment with KRM at 20 mg/kg per dose. Selection of CLARI-resistant mutants was inhibited but not completely prevented by treatment of the mice with CLARI plus KRM. These results indicate that KRM displayed only a weak bacteriostatic effect against the isolate tested in the beige mouse model; its ability to enhance the antimicrobial effect of CLARI or to prevent emergence of CLARI-resistant mutants was very limited.

scholarly journals Select β-Lactam Combinations Exhibit Synergy againstMycobacterium abscessus In Vitro

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Elizabeth Story-Roller ◽  
Emily C. Maggioncalda ◽  
Gyanu Lamichhane
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Mycobacterium Abscessus ◽  
Nontuberculous Mycobacterium ◽  
Pulmonary Infections ◽  
Content Type ◽  
Resistant Mutants ◽  
Lactamase Inhibitor ◽  
Selection Of

ABSTRACTMycobacterium abscessusis a nontuberculous mycobacterium that causes invasive pulmonary infections in patients with structural lung disease.M. abscessusis intrinsically resistant to several classes of antibiotics, and an increasing number of strains isolated from patients exhibit resistance to most antibiotics considered for treatment of infections by this mycobacterium. Therefore, there is an unmet need for new regimens with improved efficacy to treat this disease. Synthesis of the essential cell wall peptidoglycan inM. abscessusis achieved via two enzyme classes,l,d- andd,d-transpeptidases, with each class preferentially inhibited by different subclasses of β-lactam antibiotics. We hypothesized that a combination of two β-lactams that comprehensively inhibit the two enzyme classes will exhibit synergy in killingM. abscessus. Paired combinations of antibiotics tested forin vitrosynergy againstM. abscessusincluded dual β-lactams, a β-lactam and a β-lactamase inhibitor, and a β-lactam and a rifamycin. Of the initial 206 combinations screened, 24 pairs exhibited synergy. A total of 13/24 pairs were combinations of two β-lactams, and 12/24 pairs brought the MICs of both drugs to within the therapeutic range. Additionally, synergistic drug pairs significantly reduced the frequency of selection of spontaneous resistant mutants. These novel combinations of currently available antibiotics may offer viable immediate treatment options against highly-resistantM. abscessusinfections.

scholarly journals Contribution of Pretomanid to Novel Regimens Containing Bedaquiline with either Linezolid or Moxifloxacin and Pyrazinamide in Murine Models of Tuberculosis

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Jian Xu ◽  
Si-Yang Li ◽  
Deepak V. Almeida ◽  
Rokeya Tasneen ◽  
Kala Barnes-Boyle ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mouse Models ◽  
Treatment Duration ◽  
Resistant Mutant ◽  
Murine Models ◽  
First Line ◽  
Independent Contribution ◽  
Resistant Mutants ◽  
Treatment Of Infection ◽  
Selection Of

ABSTRACT Novel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure tuberculosis (TB) in BALB/c mice compared to that of the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not been examined, and its contribution to BPaL has been examined only over the first 2 months of treatment. In the present study, the addition of pretomanid to BL increased bactericidal activity, prevented emergence of bedaquiline resistance, and shortened the duration needed to prevent relapse with drug-susceptible isolates by at least 2 months in BALB/c mice. Addition of pretomanid to bedaquiline, moxifloxacin, and pyrazinamide (BMZ) resulted in a 1-log10 greater CFU reduction after 1 month of treatment and/or reduced the number of mice relapsing in each of 2 experiments in BALB/c mice and in immunocompromised nude mice. Bedaquiline-resistant isolates were found at relapse in only one BMZ-treated nude mouse. Treatment of infection with a pyrazinamide-resistant mutant in BALB/c mice with BPaMZ prevented selection of bedaquiline-resistant mutants and reduced the proportion of mice relapsing compared to that for BMZ treatment alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 versus 21 days) and reduced median lung CFU by 2.4 log10 at 1 month compared to the level for BMZ. In conclusion, in 3 different mouse models, pretomanid contributed significantly to the efficacy of the BPaMZ and BPaL regimens, including restricting the selection of bedaquiline-resistant mutants.

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