Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin. Mycoplasma gallisepticum is a common etiological cause of a chronic respiratory disease in chickens; its increasing antimicrobial resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. Mutant selection window (MSW) determination was used to investigate the propensity for future resistance induction by danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. Killing of M. gallisepticum strain S6 by these antimicrobials was also studied by incubating M. gallisepticum into medium containing the compounds at the minimal concentration that inhibits colony formation by 99
Synthesis, characterization and in vitro release performance of the pegylated valnemulin prodrug Valnemulin, successfully developed by Sandoz in 1984, is a new generation derivative of pleuromutilin related to tiamulin. Valnemulin has low water-solubility, a short half-life period, low bioavailability, and instability. The application of valnemulin was restricted. Therefore, finding a more moderate delivery system is necessary to improve the shortcomings of valnemulin. The purpose of the study was to improve the strong stability and the irritation caused by of valnemulin hydrochloride power through pegylated-valnemulin prodrug mode. The prepared pegylated-valnemulin prodrug was characterized and evaluated by in vitro release performance under buffer solutions with pH levels of 7.4 and 3.6
In vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Profiles of Valnemulin in an Experimental Intratracheal Mycoplasma gallisepticum Infection Model. Valnemulin, a semisynthetic pleuromutilin antibiotic derivative, is greatly active against Mycoplasma. The objective of our study was to evaluate the effectiveness of valnemulin against Mycoplasma gallisepticum in a neutropenic intratracheal model in chickens using a pharmacokinetic/pharmacodynamic (PK-PD) method. The PK of valnemulin after intramuscular (i.m.) administration at doses of 1, 10, and 20 mg/kg of body weight in M. gallisepticum-infected neutropenic chickens was evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Real-time PCR (RT-PCR) was used for quantitative detection of M. gallisepticum. The ratio of the 24-h area
Efficacy and tolerability of early administration of valnemulin hydrochloride premix on epizootic rabbit enteropathy. A blinded, randomised, placebo-controlled clinical trial was conducted to evaluate the efficacy and safety of valnemulin hydrochloride premix during an outbreak of epizootic rabbit enteropathy (ERE) when administered in feed for 21 consecutive days after confirmation of the first ERE case. Administration of valnemulin at 20 and 35 parts per million (ppm) significantly reduced mortality by 11% and 7.6%, respectively, when compared with the non-medicated control group (23% mortality). Non-ERE related adverse events, including dysbacteriosis, enterotoxaemia and pneumonia, occurred in all groups at similar frequencies (untreated: 1.8%; 20 ppm valnemulin: 2.8%; 35 ppm valnemulin
to treat Brachyspira-associated infections, several isolates with elevated MICs (>32 μg/ml) for tiamulin, valnemulin, tylosin, tylvalosin, and lincomycin were identified. Overall, this study underscores the importance of establishing CLSI approved clinical breakpoints for Brachyspira to facilitate the interpretation of test results and support the evidence-based selection of antimicrobials in swine
that miltefosine, azithromycin, clarithromycin, josamycin, linezolid, sutezolid, retapamulin, tiamulin, and valnemulin had inhibitory and cidal activity against the pathogens at concentrations ranging from 0.25 to 64 μg/ml. Our results suggest that these antimicrobials are promising candidates for future studies on pythiosis in animals and humans.
, including mono-, di-, and trihydroxylation, and demethylation. Like tiamulin and valnemulin, the major metabolic routes of retapamulin were hydroxylation at the 2β and 8α positions of the mutilin moiety. Moreover, metabolism concurred with the results of the assays. Additionally, we observed significant interspecies differences in the metabolism of retapamulin. Until now, modifying the side chain
), pleuromutilins (with MIC values of 0.078 μg/ml and ≤0.039 μg/ml for tiamulin and valnemulin) and the combination of lincomycin and spectinomycin (MIC 1 μg/ml (0.333/0.667 μg/ml)) were found to be the most effective antibiotic agents against M. synoviae in vitro. High MIC values were detected in numerous strains for fluoroquinolones (with MIC values of 1.25 μg/ml and 2.5 μg/ml for enrofloxacin and difloxacin
of drugs, and development of antibiotic resistance. Pleuromutilins have a potential to be developed as a new class of antibiotics for systemic use in humans. In the current study, we investigated the relationship between pleuromutilins, including valnemulin, tiamulin, and retapamulin, and 13 other antibiotics representing different mechanisms of action, against methicillin-susceptible and -resistant
Pleuromutilins: Potent Drugs for Resistant Bugs-Mode of Action and Resistance. Pleuromutilins are antibiotics that selectively inhibit bacterial translation and are semisynthetic derivatives of the naturally occurring tricyclic diterpenoid pleuromutilin, which received its name from the pleuromutilin-producing fungus Pleurotus mutilus Tiamulin and valnemulin are two established derivatives
origins of the isolates. We evaluated the susceptibility of B. hyodysenteriae, B. hampsonii, Brachyspira pilosicoli, and Brachyspira murdochii to tiamulin, valnemulin, doxycycline, lincomycin, and tylosin by broth microdilution and that to carbadox by agar dilution. In general, Brachyspira species showed high susceptibility to tiamulin, valnemulin, and carbadox, heterogeneous susceptibility
values with spectinomycin, tylosin and florfenicol (8 μg/ml), while enrofloxacin (MIC50 5 μg/ml), doxycycline (MIC50 5 μg/ml), lincomycin (MIC50 4 μg/ml) and lincomycin-spectinomycin (1:2) combination (MIC50 4 μg/ml) inhibited the growth of the bacteria with lower concentrations. Tylvalosin (MIC50 0.5 μg/ml) and two pleuromutilins (tiamulin MIC50 0.625 μg/ml; valnemulin MIC50 ≤ 0.039 μg/ml) were found to be the most effective drugs against M. sp. 1220. However, strains with elevated MIC values were detected for all applied antibiotics. Valnemulin, tiamulin and tylvalosin were found to be the most effective antibiotics in the study. Increasing resistance was observed in the cases of several antibiotics. The results highlight the importance of testing Mycoplasma species for antibiotic susceptibility before
to currently known species. No isolates related to human strains were found. None of the tested strains showed decreased susceptibility to tiamulin, valnemulin, doxycycline, tylvalosin, lincomycin, or tylosin. This is the first report of intestinal spirochaetes from this region. Despite limitations of current diagnostic methods, our results, together with earlier studies, show that Brachyspira spp
MRSA isolates, which exhibited high MICs of tiamulin, valnemulin and retapamulin, were investigated for pleuromutilin resistance genes and mutations. They were characterized by staphylococcal cassette chromosome mec (SCCmec) typing, spa typing and multilocus sequence typing (MLST). Plasmid DNA was extracted from the lsa(E)-positive strains and transferred to S. aureus RN4220 for selection
of rRNA mutations at the PTC are organism dependent. Moreover, the data show a nonpredictable cross-resistance pattern between linezolid, chloramphenicol, clindamycin, and valnemulin. The data underscore the significance of mutations at distal nucleotides, either alone or in combination with other mutated nucleotides, in contributing to linezolid resistance.
Use of valnemulin in the control of Mycoplasma bovis infection under field conditions. In a blind trial, alternate calves in six consecutive production batches of calves (total 70), on a farm with a high incidence of respiratory and reproductive disease, were allocated to treatment with either valnemulin or a placebo premix added to the milk from four days of age. The calves were weighed at the beginning and end of a 21-day period of medication. Blood samples and nasal swabs were taken and examined for the presence of Mycoplasma and Pasteurella species, and antibodies to viral agents. Clinical condition, rectal temperature, respiratory and other signs and refusals of milk were recorded daily. Dead calves were examined postmortem. The calves medicated with valnemulin gained weight more quickly
Decreased susceptibility to tiamulin and valnemulin among Czech isolates of Brachyspira hyodysenteriae. The agar dilution method was used to investigate the sensitivity to pleuromutilins of 100 isolates of Brachyspira hyodysenteriae isolated from 63 pig farms between 1997 and 2001. In the period under investigation, MICs to both tiamulin and valnemulin increased, with differences between the periods 1997-98 and 1999-2001 being statistically significant (P < 0.001 for tiamulin and P < 0.0001 for valnemulin). Between 1997 and 2001, the MIC50 and MIC90 of tiamulin increased from 0.062 and 0.25 microg ml, respectively, to 1.0 and 4.0 microg ml. Valnemulin MIC50 and MIC90 were < or = 0.031 microg ml in 1997 and by 2001 were respectively, 2.0 and 8.0 microg ml. The increase in MICs of tiamulin
effects are observed at U2584 and U2585, indicating that the side chain extensions adopt distinct conformations within the cavity and thereby affect the rRNA conformation differently. An Escherichia coli L3 mutant strain is resistant to tiamulin and pleuromutilin, but not valnemulin, implying that valnemulin is better able to withstand an altered rRNA binding surface around the mutilin core . This is likely due to additional interactions made between the valnemulin side chain extension and the rRNA binding site. The data suggest that pleuromutilin drugs with enhanced antimicrobial activity may be obtained by maximizing the number of interactions between the side chain moiety and the peptidyl transferase cavity.