valnemulin and Swine-Diseases

Pleuromutilins (tiamulin and valnemulin) are antimicrobial agents that are used mainly in veterinary medicine, especially for swine and to a lesser extent for poultry and rabbits. In pigs, tiamulin and valnemulin are used to treat swine dysentery, spirochaete-associated diarrhoea, porcine proliferative enteropathy, enzootic pneumonia and other infections where Mycoplasma is involved. There are concerns about the reported increases in the MICs of tiamulin and valnemulin for porcine Brachyspira hyodysenteriae isolates from different European countries, as only a limited number of antimicrobials are available for the treatment of swine dysentery where resistance to these antimicrobials is already common and widespread. The loss of pleuromutilins as effective tools to treat swine dysentery because of further increases in resistance or as a consequence of restrictions would present a considerable threat to pig health, welfare and productivity. In humans, only one product containing pleuromutilins (retapamulin) is authorized currently for topical use; however, products for oral and intravenous administration to humans with serious multidrug-resistant skin infections and respiratory infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA), are being developed. The objective of this review is to summarize the current knowledge on the usage of pleuromutilins, resistance development and the potential impact of this resistance on animal and human health.

Topics: Animals; Anti-Bacterial Agents; Brachyspira hyodysenteriae; Diterpenes; Drug Resistance, Bacterial; European Union; Humans; Microbial Sensitivity Tests; Mycoplasma Infections; Pleuromutilins; Polycyclic Compounds; Poultry; Poultry Diseases; Rabbits; Swine; Swine Diseases

Production-limiting diseases in swine caused by Brachyspira are characterized by mucohemorrhagic diarrhea (B. hyodysenteriae and "B. hampsonii") or mild colitis (B. pilosicoli), while B. murdochii is often isolated from healthy pigs. Emergence of novel pathogenic Brachyspira species and strains with reduced susceptibility to commonly used antimicrobials has reinforced the need for standardized susceptibility testing. Two methods are currently used for Brachyspira susceptibility testing: agar dilution (AD) and broth microdilution (BMD). However, these tests have primarily been used for B. hyodysenteriae and rarely for B. pilosicoli. Information on the use of commercial susceptibility testing products such as antibiotic gradient strips is lacking. Our main objective was to validate and compare the susceptibility results, measured as the minimum inhibitory concentration (MIC), of 6 antimicrobials for 4 Brachyspira species (B. hyodysenteriae, "B. hampsonii", B. pilosicoli, and B. murdochii) by BMD and AD (tiamulin, valnemulin, lincomycin, tylosin, and carbadox) or antibiotic gradient strip (doxycycline) methods. In general, the results of a high percentage of all 4 Brachyspira species differed by ±1 log2 dilution or less by BMD and AD for tiamulin, valnemulin, lincomycin, and tylosin, and by BMD and antibiotic gradient strip for doxycycline. The carbadox MICs obtained by BMD were 1-5 doubling dilutions different than those obtained by AD. BMD for Brachyspira was quicker to perform with less ambiguous interpretation of results when compared with AD and antibiotic gradient strip methods, and the results confirm the utility of BMD in routine diagnostics.

Topics: Agar; Animals; Anti-Bacterial Agents; Brachyspira; Diarrhea; Diterpenes; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Microbial Sensitivity Tests; Swine; Swine Diseases

The postantibiotic effect (PAE) and postantibiotic sub-minimum inhibitory concentration (MIC) effect (PA-SME) of valnemulin against Staphylococcus aureus were investigated in vitro using a spectrophotometric technique and classic viable count method. A standard curve was constructed by regression analysis of the number of colonies and the corresponding optical density (OD) at 630 nm of the inoculum. After exposure to valnemulin at different concentrations for an hour, the antibiotic was removed by centrifuging and washing. The PA-SMEs were measured after initial exposure to valnemulin at 4 × the MIC, and then, valnemulin was added to reach corresponding desired concentrations in the resuspended culture. Samples were collected hourly until the culture became turbid. The results were calculated by converting the OD values into the counts of bacteria in accordance with the curve. The MIC of valnemulin against eight strains was identically 0.125 μg ml(-1) . The mean PAEs were 2.12 h (1 × MIC) and 5.06 h (4 × MIC), and the mean PA-SMEs were 6.85 h (0.1 × MIC), 9.12 h (0.2 × MIC) and 10.8 h (0.3 × MIC). The results showed that the strains with identical MICs exhibited different PAEs and PA-SMEs. Valnemulin produced prolonged PAE and PA-SME periods for Staph. aureus, supporting a longer dosing interval while formulating a daily administration dosage.. In this study, valnemulin demonstrated prolonged postantibiotic effects and postantibiotic sub-MIC effects on strains of Staphylococcus aureus. The strains with identical MICs of valnemulin exhibited different PAEs and PA-SMEs. Staphylococcus aureus isolated from different species has little impact on the postantibiotic effect of valnemulin. The result suggests a longer dosing interval while formulating a daily administration dosage, and it may play a valuable role of valnemulin in treating Staph. aureus infections in animals.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Chickens; Diterpenes; Microbial Sensitivity Tests; Microbial Viability; Poultry Diseases; Staphylococcal Infections; Staphylococcus aureus; Swine; Swine Diseases

The aim of study was to determine the influence of zinc chelate, valnemulin and it's combination on Brachyspira hyodysenteriae shedding and morphological changes of colonic mucosa in an experimental model of swine dysentery (SD). The study was performed on pigs coming from a dysentery-free herd. Animals were inoculated by B. hyodysenteriae strain B204. When the clinical signs of SD and B. hyodysenteriae shedding developed, the pigs were divided into four treatment groups. The first group was treated with zinc chelate (250 ml/1000 L in water), second group was given valnemulin in feed at 75 ppm; the third group was given a combination of both and the fourth group was control. The results demonstrated therapeutic effect of valnemulin in pigs with serious SD and did not show therapeutic effect of chelated zinc.

Topics: Animals; Brachyspira hyodysenteriae; Colon; Diterpenes; Drug Therapy, Combination; Dysentery; Gram-Negative Bacterial Infections; Immunohistochemistry; Intestinal Mucosa; Sepharose; Swine; Swine Diseases

A novel ABC transporter gene, vga(C), was identified on the 14,365-bp multiresistance plasmid pKKS825 in a porcine methicillin (meticillin)-resistant Staphylococcus aureus isolate of sequence type 398. The vga(C) gene encodes a 523-amino-acid protein which confers resistance not only to streptogramin A antibiotics but also to lincosamides and pleuromutilins. Plasmid pKKS825 also carries the resistance genes aadD, tet(L), and dfrK, which may enable the coselection of vga(C) under selective pressure by kanamycin/neomycin, tetracyclines, and trimethoprim.

Topics: Animals; Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Diterpenes; Drug Resistance, Multiple, Bacterial; Kanamycin; Lincosamides; Methicillin-Resistant Staphylococcus aureus; Molecular Sequence Data; Neomycin; Plasmids; Pleuromutilins; Polycyclic Compounds; Staphylococcal Infections; Streptogramin A; Swine; Swine Diseases; Tetracyclines; Trimethoprim

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 and valnemulin demonstrated in this study reflect the intensity of pleuromutilin use in the treatment of swine dysentery in the Czech Republic.

Topics: Animals; Anti-Bacterial Agents; Brachyspira hyodysenteriae; Czech Republic; Diterpenes; Drug Resistance, Bacterial; Dysentery; Microbial Sensitivity Tests; Spirochaetales Infections; Swine; Swine Diseases

In Germany treatment of swine dysentery is hampered by Brachyspira hyodysenteriae strains showing elevated MIC values to the few antibiotics licensed. Therefore, susceptibility testing of clinical isolates is an important service to the swine practitioner. This study compares the established agar dilution procedure for antimicrobial susceptibility testing of this fastidious anaerobe to the broth microdilution test newly developed [Anim. Health Res. 2 (2001) 59; Vet. Microbiol. 84 (2002) 123; J. Clin. Microbiol. 41 (2003) 2596]. A total of 221 isolates were examined twice with either test procedure using tiamulin and valnemulin as antibiotics. Both methods gave reproducible results, and the MIC values for the reference strains B. hyodysenteriae B204 and Staphylococcus aureus ATCC 29213 corresponded to previously published data. However, the results for individual strains differed significantly for both tests (P < 0.001) with MIC values being on average one dilution step lower in the broth dilution method. The 221 strains used for comparing test procedures were isolated between 1989 and 2001. An additional 102 strains isolated in 2002 were tested only with the broth dilution procedure. A significant rise in the average MIC value for both pleuromutilins could be demonstrated when comparing earlier isolates to those from 2000 to 2001 (P < 0.05), while in 2002 the average MIC significantly decreased when compared to the value in 2000 (P < 0.05). However, strains with MIC values for tiamulin as high as 8 microg/ml (broth dilution) could still be isolated.

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Dysentery; Germany; Microbial Sensitivity Tests; Retrospective Studies; Spirochaetales; Spirochaetales Infections; Swine; Swine Diseases

The pleuromutilins are the only antimicrobial agents with sufficient minimum inhibitory concentration (MIC) values left to treat swine dysentery in Sweden. Other antimicrobials are either not approved for use against swine dysentery or only partly active against Brachyspira hyodysenteriae. To date, in Sweden two pleuromutilins, tiamulin and valnemulin, are authorized for use in pigs. This study includes a comparison between MICs of tiamulin and valnemulin for Swedish field isolates of B. hyodysenteriae, as determined by broth dilution. For different isolates the MIC of tiamulin was between 0 and 8 times higher than that of valnemulin. No resistance to pleuromutilins was recorded (tiamulin MIC range 0.031-2 microg/ml, valnemulin MIC range < or =0.016-1 microg/ml). In vitro development of tiamulin resistance was also studied. Two B. hyodysenteriae and two B. pilosicoli strains became resistant to tiamulin following reiterated passages on agar containing tiamulin in increasing concentrations. The resistance emerged slowly and three of the strains that went through more than 60 passages increased their tiamulin MICs from 0.031-0.25 to more than 128 microg/ml. The tiamulin MIC for one B. hyodysenteriae strain that went through 29 passages increased from 0.0125 to 4 microg/ml. One B. pilosicoli strain developed cross-resistance to valnemulin; the MIC increased from 0.25 to more than 64 microg/ml. The valnemulin MIC for one B. hyodysenteriae strain increased from 0.031 microg/ml to 32 microg/ml. Valnemulin MIC was not determined for the B. hyodysenteriae strain that only went through 29 passages. The valnemulin MIC of the other B. pilosicoli strain increased from 0.031 to 4 microg/ml.

Topics: Animals; Anti-Bacterial Agents; Brachyspira hyodysenteriae; Diterpenes; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Dysentery; Microbial Sensitivity Tests; Pleuromutilins; Polycyclic Compounds; Spirochaetales Infections; Sweden; Swine; Swine Diseases

The authors have performed a comparative study of the efficacy of various in-feed medications for the treatment of 5- to 6-week-old specific pathogen-free (SPF) piglets experimentally infected on day 1 with Mycoplasma hyopneumoniae, on day 8 with Pasteurella multocida (serotype A), and on day 15 with Actinobacillus pleuropneumoniae (serotype 2). The treatment started on day 9 and continued for 12 consecutive days, then the piglets were euthanized for examination of macroscopic, histologic, and pathologic lesions and for the presence of mycoplasmas and bacteria in the lungs. Based on the results of clinical observations (respiratory signs, rectal temperature, body weight gain, and feed conversion efficiency), macroscopic and histologic lesions of the lungs, and microbiologic findings, the best results were obtained by treatment of pigs with Econor + chlortetracycline, followed by Tetramutin, Pulmotil, Cyfac, and lincomycin + chlortetracycline.

Topics: Actinobacillus Infections; Actinobacillus pleuropneumoniae; Animal Feed; Animals; Anti-Bacterial Agents; Chlortetracycline; Diterpenes; Drug Therapy, Combination; Mycoplasma; Mycoplasma Infections; Pasteurella Infections; Pasteurella multocida; Specific Pathogen-Free Organisms; Swine; Swine Diseases; Treatment Outcome; Weight Gain

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Drug Hypersensitivity; Swine; Swine Diseases

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Europe; Product Surveillance, Postmarketing; Swine; Swine Diseases; Veterinary Drugs

Topics: Actinobacillus pleuropneumoniae; Animals; Anti-Bacterial Agents; Bacteria; Brachyspira hyodysenteriae; Diterpenes; Microbial Sensitivity Tests; Mycoplasma; Streptococcus suis; Swine; Swine Diseases