cefquinome and Staphylococcal-Infections

Values for pharmacokinetic variables are usually obtained in healthy animals, whereas drugs are frequently administered to diseased animals. This study investigated cefquinome pharmacokinetics in healthy goats and goats with experimentally induced mastitis. Five adult lactating goats received 75 mg of cefquinome intramammary infusion using a commercially available product into one udder half in healthy goats and goats with clinical mastitis that was induced by intracisternal infusion of 100 cfu of Staphylococcus aureus ATCC 29213 suspended in 5 ml of sterile culture broth. Cefquinome concentrations were determined in plasma and skimmed milk samples using high-performance liquid chromatography (HPLC). Pharmacodynamics was investigated using the California Mastitis Test and pH of milk. Experimentally induced mastitis significantly increased the California Mastitis Test score and pH, and decreased the maximal cefquinome concentration and shortened the half-life in milk when compared to healthy goats. In conclusion, mastitis facilitated the absorption of cefquinome from the mammary gland of lactating goats and induced marked changes in milk pH, emphasizing the importance of performing pharmacokinetic studies of antimicrobial agents in infected animals.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Female; Goat Diseases; Goats; Lactation; Mastitis; Milk; Staphylococcal Infections; Staphylococcus aureus

Clinical Staphylococcus aureus mastitis is difficult to cure. Extended antimicrobial treatment is often advocated as a practical approach to improve cure rates; however, scientific evidence of this hypothesis is lacking. A multi-centered, nonblinded, randomized, positive-controlled clinical trial was conducted in 5 European countries-France, Hungary, Italy, the Netherlands, and the United Kingdom-to study the efficacy of an extended intramammary cefquinome treatment (5 d) compared with a standard intramammary cefquinome treatment (1.5 d) of Staph. aureus clinical mastitis. Least squares means estimates of bacteriological cure during lactation were 34% [standard error (SE)=9.9%] for the standard treatment group and 27% (SE=8.4%) for the extended treatment group. In the final model, extended therapy was not significantly better. The only factor predicting bacteriological cure was pretreatment cow somatic cell count (SCC). Cows with >250,000 cells/mL in milk before treatment were less likely to cure. Least squares means of clinical cure during lactation was 60% (SE=19%) for the standard treatment group and 82% (SE=12%) for the extended treatment group. In the final model, clinical cure after extended treatment was significantly better. Pretreatment cow udder firmness predicted clinical cure. Firm udders were less likely to cure clinically. Irrespective of treatment regimen, new infection rates with pathogens other than Staph. aureus were higher (42%) after bacteriological cure than after nonbacteriological cure (22%) and cured cows had a significantly lower SCC. In conclusion, independent of the treatment protocol, cows with an SCC <250,000 cells/mL before treatment showed a higher probability of bacteriological cure. It appears that successful treatment of clinical Staph. aureus mastitis with cefquinome is associated with an increased number of new infections with coagulase-negative staphylococci. Extended treatment improved clinical, but not bacteriological, cure rates compared with the standard treatment. These results indicate that extending treatment of clinical Staph. aureus mastitis with cefquinome should not be recommended.

Topics: Animals; Anti-Bacterial Agents; Cattle; Cell Count; Cephalosporins; Female; Mammary Glands, Animal; Mastitis, Bovine; Milk; Staphylococcal Infections; Treatment Outcome

The objectives of the present study were to evaluate the efficacy of intra-mammary-administered cefquinome for the treatment of sub-clinical mastitis in lactating dairy cows and to determine if extended therapy would enhance treatment efficacy. Seventy-three Holstein dairy cows from a single farm with 150 infected quarters were enrolled in the study. Infected cows were allocated randomly to one of three treatment regimens: (1) conventional (standard) regimen: 75 mg of cefquinome administered three times at 16-h intervals (25 infected cows, 52 intra-mammary infections (IMI)), (2) extended regimen: 75 mg of cefquinome administered six times at 16-h intervals (26 infected cows, 58 IMI) and (3) negative untreated control group (22 cows, 40 IMI). Most IMI were caused by coagulase-negative staphylococci, streptococci other than Streptococcus agalactiae and coliforms. The overall bacteriological cure (BC) rates for sub-clinical IMI were 84.61%, 91.37% and 20% for the conventional, extended and the control groups, respectively, indicating a higher BC rate for the treated groups than the control group (P < 0.001). Significant differences in somatic cell count (SCC) were detected between the treated versus the control group (P < 0.001). No differences, concerning the BC rate or SCC, were observed between the extended and the conventional groups. Although fat and protein percentages increased in the treated groups, there were no significant differences in post-treatment milk production between the groups. Results of this study indicate that cefquinome therapy was effective in reducing SCC and eliminating sub-clinical IMI in lactating dairy cows, but extended therapy did not enhance treatment efficacy.

Topics: Animals; Anti-Bacterial Agents; Asymptomatic Infections; Cattle; Cell Count; Cephalosporins; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Injections, Intradermal; Iran; Mammary Glands, Animal; Mastitis, Bovine; Staphylococcal Infections; Staphylococcus; Streptococcal Infections; Streptococcus; Time Factors

The emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains of animal origin that are resistant to several antibiotics is of great concern. Cefquinome is a fourth-generation cephalosporin developed specifically for veterinary use. The mechanism of MRSA resistance to cefquinome is still not established. Therefore, we designed this study to evaluate the effect of cefquinome on the transcriptome of MRSA1679a, a strain that was isolated from a chicken. The transcriptome analysis indicated that multiple efflux pumps (QacA, NorB, Bcr, and ABCb) were upregulated in MRSA1679a as a resistance mechanism to expel cefquinome. Additionally, penicillin-binding protein 1A was overexpressed, which conferred resistance to cefquinome, a β-lactam antibiotic. Adhesion and the biofilm-forming capacity of the MRSA strain was also enhanced in addition to overexpression of many stress-related genes. Genes related to carbohydrate metabolism, secretion systems, and transport activity were also significantly upregulated in MRSA1679a. In conclusion, global transcription was triggered to overcome the stress induced by cefquinome, and the MRSA1679a showed a great genetic potential to survive in this challenging environment. This study provides a profound understanding of MRSA1679a as a potentially important pathogen and identifies key resistance characteristics of MRSA against cefquinome. Studies should be aimed to demonstrate multidrug resistance mechanisms of virulent strains by exposing to different antibiotic combinations.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Cephalosporins; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; RNA-Seq; Staphylococcal Infections

The main objectives of this study were to quantify the consumption of antimicrobials on a convenience sample of dairy herds and to determine the association between herd-level antimicrobial consumption and inhibition zone diameters (IZD) of non-aureus staphylococci and Staphylococcus aureus isolates from subclinical mastitis cases. Also, the association between the IZD of non-aureus staphylococci and Staph. aureus isolates within a herd was studied. Antimicrobial consumption data on 56 Flemish dairy farms were obtained between 2013 and 2014 by so-called garbage can audits and expressed as antimicrobial treatment incidence (ATI), with the unit of ATI being the number of defined daily doses animal (DDDA) used per 1,000 cow-days. The average total ATI in adult dairy cattle for all active substances was 18.73 DDDA per 1,000 cow-days and ranged from 6.28 to 42.13 DDDA between herds. The ATI of critically important (for human health) antimicrobials was 6.91 DDDA per 1,000 cow-days; that is, 37% of total antimicrobial consumption. The average ATI for intramammary therapy of (sub)clinical mastitis, intramammary dry-cow therapy, and systemically administered therapy was 5.20, 6.70, and 6.73 DDDA, respectively. The IZD of 239 non-aureus staphylococci and 88 Staph. aureus isolates originating from milk samples from cows with subclinical mastitis collected on selected dairy herds were determined using Kirby-Bauer disk diffusion and ranged between 6 and 42 mm. Because only a limited number of clinical breakpoints (Clinical and Laboratory Standards Institute) and epidemiological cut-off values (European Committee on Antimicrobial Susceptibility Testing) are available for mastitis-causing bacteria in bovine, IZD were used as a proxy for antimicrobial resistance. Inhibition zone diameters of non-aureus staphylococci for cefquinome, a critically important β-lactam antibiotic, were negatively associated with the ATI of critically important β-lactam for systemically administered therapy and positively with the ATI for intramammary therapy of (sub)clinical mastitis of critically important β-lactam antimicrobials. Only for neomycin was a positive association between the IZD of non-aureus staphylococci and Staph. aureus isolates within the same herd observed.

Topics: Animals; Anti-Infective Agents; Cattle; Cephalosporins; Female; Humans; Mastitis, Bovine; Milk; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus

Staphylococcus aureus remains the major cause of morbidity of bovine mastitis worldwide leading to massive economic losses. Cefquinome is a fourth generation cephalosporin, which preserves susceptibility and antibacterial activity against S. aureus. This work aims to study the pharmacokinetic (PK) and pharmacodynamic (PD) modeling following intramammary administration of cefquinome against S. aureus mastitis. The mouse model of S. aureus mastitis was developed for the PK/PD experiments. The plasma PK characteristics after intramammary injection of cefquinome at various single doses of 25, 50, 100, 200, 400 μg per gland (both fourth pairs of glands: L4 and R4) were calculated using one-compartment and first-order absorption model. PD study was investigated based on twenty-one intermittent dosing regimens, of which total daily dose ranged from 25 to 4800 μg per mouse and dosage intervals included 8, 12 or 24 h. The sigmoid Emax model of inhibitory effect was employed for PK/PD modeling. The results of PK/PD integration of cefquinome against S. aureus suggested that the percentage of duration that drug concentration exceeded the minimal inhibitory concentration (%T>MIC) and the ratio of area under time-concentration curve over MIC (AUC/MIC) are important indexes to evaluate the antibacterial activity. The PK/PD parameters of %T>MIC and AUC0-24/MIC were 35.98% and 137.43 h to obtain a 1.8 logCFU/gland reduction of bacterial colony counts in vivo, against S. aureus strains with cefquinome MIC of 0.5μg/ml.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Cattle; Cephalosporins; Disease Models, Animal; Female; Injections; Mastitis; Mice; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against Staphylococcus aureus. The objective of our study was to examine the in vivo activity of cefquinome against S. aureus strains by using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo postantibiotic effects (PAEs) were determined after a dose of 100 mg/kg of body weight in mice infected with S. aureus strain ATCC 29213. The animals were treated by subcutaneous injection of cefquinome at doses of 2.5 to 320 mg/kg of body weight per day divided into 1, 2, 3, 6, or 12 doses over 24 h. Cefquinome exhibited time-dependent killing and produced in vivo PAEs at 2.9 h. The percentage of time that serum concentrations were above the MIC (%T>MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best described the efficacy of cefquinome. Subsequently, we employed a similar dosing strategy by using increasing total cefquinome doses that increased 4-fold and were administered every 4 h to treat animals infected with six additional S. aureus isolates. A sigmoid maximum effect (Emax) model was used to estimate the magnitudes of the ratios of the %T that the free-drug serum concentration exceeded the MIC (%T>fMIC) associated with net bacterial stasis, a 0.5-log10 CFU reduction from baseline, and a 1-log10 CFU reduction from baseline; the respective values were 30.28 to 36.84%, 34.38 to 46.70%, and 43.50 to 54.01%. The clear PAEs and potent bactericidal activity make cefquinome an attractive option for the treatment of infections caused by S. aureus.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Cephalosporins; Disease Models, Animal; Female; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Specific Pathogen-Free Organisms; Staphylococcal Infections; Staphylococcus aureus; Tandem Mass Spectrometry; Thigh

Maintenance of adequate drug concentration at the site of infection is an important problem in mastitis antibiotic therapy, and the efficacy of intramammary β-lactams can be optimized by maintaining the drug concentration at the site of infection above the minimum inhibitory concentration (MIC) as long as possible. The most important pharmacokinetic and pharmacodynamic parameter for efficacy evaluation is time during which drug concentrations exceed the MIC (t>MIC). In this study, we assessed the pharmacokinetic profile of cefquinome (CFQ) after repeated intramammary administration in healthy cows and cows subclinically infected with Staphylococcus aureus as well as the MIC of Staph. aureus field strains. In addition, the degree of drug passage was investigated from udder to bloodstream by measuring systemic drug absorption in healthy and infected animals. Cefquinome concentrations were quantified by HPLC (UV-visible detection) in milk samples collected from quarters and from blood serum samples. The systemic drug absorption was negligible in healthy and subclinically infected animals (maximum concentration 0.09±0.02 and 0.1±0.01 μg/mL in healthy and subclinically infected animals, respectively). The MIC(90) value for CFQ in Staph. aureus field strains (n=20) was 0.24 μg/mL. The pharmacokinetic and pharmacodynamic evaluation, determined by t>MIC, showed an equal persistence of CFQ in all quarters, indicating an equivalent activity of the drug regardless of the pathological status of the udder. Moreover, with literature data regarding CFQ MIC, the t>MIC has been calculated for other bacterial species.

Topics: Animals; Anti-Bacterial Agents; Cattle; Cephalosporins; Drug Administration Routes; Female; Lactation; Mammary Glands, Animal; Mastitis, Bovine; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) have emerged in animals. Testing 98 mecA negative and 71 mecA positive S. aureus we compared the usefulness of ceftiofur and cefquinome to cefoxitin, for detection of MRSA and found that these cephalosporins are not as efficient as cefoxitin.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Disk Diffusion Antimicrobial Tests; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Phenotype; Sensitivity and Specificity; Staphylococcal Infections; Swine; Swine Diseases