Factors influencing antimicrobial treatment outcome

by Wouter Depondt, global product manager veterinary products, –– Concentration dependent Huvepharma. –– Time dependent

n –– T>MIC o i s pig practitioners, we constantly aim t ••• MIC a r

t – – Cmax

to improve and safeguard the health n e

status of our farms through good c n

A o management and biosecurity. Despite these C preventive measures, curative intervention with antimicrobials is still required. The educational background and professional experience of the veterinarian Time allows them to choose the right antimicrobial for the diagnosed causative pathogen. Along with the choice of Cmax: maximum concentration, MIC: Minimum inhibitory concentration treatment, a correct application is of major T>MIC: Time concentration is above MIC. importance to ensure efficacy. Prudent use of antimicrobials does not only mean Fig. 1. Two types of with an ideal Pk profile in regards to efficacy. reducing their use, but also choosing the right product and administering it in an the suspected causative pathogen is barriers anymore and consequently, the appropriate manner. sensitive. molecule is trapped. This phenomenom is Testing for sensitivity is often called ion-trapping and explains the high done by the Kirby-Bauer method, or a so- concentrations and accumulation of Making the right choice called antibiogram. With this method, small Tilmovet in phagocytes (acidic lysosomes) discs containing antibiotics are placed onto a and in tissue compartments with a low pH The choice of the right antimicrobial plate upon which bacteria are growing. If the such as the lung. depends on the known or suspected bacteria are sensitive to the antibiotic, a Other antimicrobials, such as sensitivity of the infectious agent. The clear ring, or zone of inhibition, is seen (Parofor, an suspected sensitivity can be based upon the around the disc indicating poor growth of recently registered by Huvepharma) are experience of the veterinarian, farm history the pathogen. hydrophilic, meaning they dissolve well in and surveys of the antimicrobial sensitivity Other methods to test antimicrobial water. They cannot pass lipid barriers and against pathogens in certain areas. susceptibility include, for example, MIC test consequently their uptake by the intestine is This might help to start-up an empiric strips, agar and broth dilution methods for very limited. treatment before laboratory microbiological Minimum Inhibitory Concentration (MIC) Continued on page 11 reports are available, because often determination. treatment should not be delayed due to the Crucial, but difficult for all susceptibility Antibiogram: agar plate with antibiotic seriousness of the disease and welfare testing is the isolation (sampling and discs. Bacteria are not able to grow implications. culturing) of the relevant bacteria. This around antibiotics to which they are Often, antimicrobial susceptibility testing is difficulty, and the lack of clinical breakpoints sensitive. carried out to determine to which antibiotic in animal health explain why susceptibility testing can only give an indication of what MIC value can easily be determined the clinical outcome will be. with Huvepharma’s MIC test-strips. As well as the susceptibility of the pathogen, the antimicrobial should also reach the site of infection. This is determined by the pharmacokinetic characteristics of the product. Tilmovet, for example, is lipophilic and consequently easily passes cell membranes and other lipid barriers throughout the body. Once a barrier is passed and Tilmovet enters an environment with a lower pH than its pKa value (7.4), Tilmovet is ionised. Ionised molecules cannot pass lipid

International Pig Topics — Volume 30 Number 3 9 Tilmicosin concentrations Classification Antibiotics Goal of PK/PD therapy Parameter Plasma (µg/mL) Lung (µg/g) Lung/plasma ratio

Day 5 0.077 2.302 30 Concentration (Apravet), Maximise C max/MIC Table. 1. Concentration of tilmicosin in lung and plasma after dependent Paromomycin (Parofor), concentrations Polymyxines five days of treatment with Tilmovet at 16mg/kg bodyweight (Karanikolova et al., 2014). Time (Pharmasin), Maximise T>MIC dependent Tilmicosin (Tilmovet), duration of MIC MIC Tiamulin + 4 Tiamulin (Vetmulin), exposure Tiamulin µg/ml Apramycin Penicillins, Cephalosporins No. of strains tested 30 30

MIC50 >16 0.06 Mixed (Doxx-sol), Maximise 24h-AUC/ MIC < 1 (No.) 6 15 properties Quinolones, amount MIC (Amphen) of drug MIC < 1 (%) 20 50

Table. 2. Susceptibility of Brachyspirae hyodysenteriae against Table. 3. Classification of antibiotics based upon their ideal a combination of Vetmulin (tiamulin) and Apravet (apramycin) dosing regimen. (Vyt et al., 2014).

Continued from page 9 The formulation of the veterinary medicine Most hydrophilic antimicrobials are can also influence the clinical outcome of an therefore unsuitable for systemic treatment antimicrobial treatment. Stability, solubility via oral administration. However after single and bioavailibility of the active can be oral administration of 50mg paromomycin optimised by the choice of excipients and per kg bodyweight, concentrations of the manufacturing method. For water- >5000µg/g were found in the intestinal soluble veterinary medicines for example, lumen (internal data). The fact that Parofor there may be a loss of activity and intensively concentrates in the intestinal precipitation of the active after dissolving in lumen, makes it a good option for the the drinking water. This will logically affect treatment of enteritis caused pathogens the effectiveness of the therapy. sensitive to paromomycin. Precipitation: an example of a water Loss of activity can also occur during Sometimes, the use of more than one soluble veterinary medicine unsuitable storage after opening the primary packaging, antibiotic may be justified, based upon a for use with a proportioner. because of the contact with oxygen, synergistic effect in vitro. The combination temperature and moisture. Proper storage of Vetmulin and Apravet might be justified freely available for iPhone, Android and conditions and re-closable packaging will to treat and eradicate Blackberry mobile devices. The dosage preserve the active for a longer time. hyodysenteriae. Adding 4µg/ml apramycin regimen is also of importance. The daily (Apravet) to tiamulin (Vetmulin) increased dose can be administered continuously or as the number of susceptible strains in vitro. a pulse. For concentration dependent The synergistic effect of Apravet and antibiotics, such as , a high Vetmulin has also been observed in the concentration (Cmax) several times higher field. than the MIC of the targeted pathogen at After choosing the antimicrobial, correct the site of infection, will result in a faster and administration is also of importance. Dosing better effect. The most important should be done in grams per kilogram live parameter for these antimicrobials is the body weight, independently of the Cmax/MIC. application form. Consequently pulse medication will work By doing so, underdosing will be avoided better for these types of antimicrobials. by taking account of changing ratio For time-dependent antimicrobials, such as bodyweight/water intake. This can easily be the , the efficacy depends on the done with Huvepharma’s dose calculator, period during which the bacteria are Huvepharma zipper bags are resealable exposed to the antimicrobial at a to preserve the product. Huvepharma’s dose calculator. concentration just above the MIC (T>MIC). The most important parameter is the time Huvepharma keeps investing in new and period in which the concentration is higher better formulation techniques for optimal than the MIC (T>MIC) at the site of use and results. A good example is infection. Better efficacy can be expected if Pharmasin, a stable and highly water soluble these antimicrobials are provided tylosin with a high bioavailability. continuously. In conclusion, we need a holistic approach Other antibiotics, such as tetracylines, to medicine use and by that we mean have mixed properties: they are time- responsible promotion, responsible dependent and concentration dependent. prescribing and responsible use of all The ideal dosing regimen for these medicines including antimicrobials. antibiotics maximises the amount of drug The prescribers and users of veterinary received. medicines should operate to the principle of Therefore, the 24 hour Area Under the ‘as little as possible but as much as Curve (AUC/MIC) ratio is the parameter necessary’. n that correlates with efficacy. b [email protected]

International Pig Topics — Volume 30 Number 3 11