Factors in Antimicrobial Therapy
Interaction of pharmacokinetic and pharmacodynamic parameters in antimicrobial chemotherapy, after Craig (1998).
Baytril® offers outstanding pharmacokinetic and pharmacodynamic properties under all conditions. Baytril's® intracellular activity and accumulation provides additional support for the body's defense mechanisms.
Pharmacokinetics of Baytril®
Effective antimicrobial therapy depends on a triad of the dosage regimen, bacterial susceptibility, and pharmacokinetic characteristics.
The pharmacokinetic parameters give an overview on the achievable concentrations (which depend on the systemic availability of the drug, which varies with the drug preparation, the route of administration, and the dosing rate).
The unique formulations of Baytril® provide high serum concentrations as well as excellent bioavailability and tissue penetration.
Because the efficacy of fluoroquinolones is concentration-dependent, high values for Cmax, AUC, and AUIC are important.
Cmax is defined as the maximum serum concentration obtained after application.
AUC is the area under the plasma concentration-time curve. When a comparison is made between an oral dosage form with that of an i.v. preparation of the drug, the absolute bioavailability (systemic availability) is obtained. The comparison between two AUCs for two dosage forms (test and reference) allows bioequivalence assessment. A lack of efficacy can be predicted in products that are found not to be bioequivalent to the standard formulation.
Pharmacodynamic aspects of antimicrobials describe the interaction between the drug and the microorganisms. Pharmacodynamics describe the mode of action, the in vitro activity with regard to minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC), the time-kill kinetics of an antimicrobial, and the post-antibiotic effect (PAE).
The mode of action of an antimicrobial substance influences the dosage and the dosage regimen.
Bacteriostatic Antimicrobial Action
The category of bacteriostatic drugs (e.g. tetracyclines, phenicols, sulfonamides, macrolides, lincosamides) essentially requires a dosage regimen that maintains plasma concentrations above MIC throughout the dosage interval. The success of therapy also depends strongly on the host's defense mechanisms.
Due to its rapid bactericidal action, low MIC values for the relevant pathogens and high AUIC values, Baytril® allows successful therapy in a convenient dosage regimen of a single daily dose or a simple "one shot only" treatment with Baytril® Max.
The effectiveness of therapy with these drugs (e.g. beta-lactam antibiotics) is largely influenced by the aggregate time over which effective plasma concentrations (>MIC of microorganisms involved) are maintained. The dosage regimen must be chosen in a manner that maintains plasma concentrations above the MIC for most of the dosage interval, because the effect of these drugs is a combination of bacterial killing (principal activity) and sub-MIC PAE (minor contribution) that is shown in susceptible gram-positive bacteria.
The effectiveness of drugs that produce a concentration-dependent bactericidal effect (e.g. aminoglycosides and fluoroquinolones) is influenced both by the height of the inhibitory quotient (IQ = C max :MIC ratio) and by the area under the inhibitory plasma concentration-time curve (AUIC). The latter might be of importance in gram-positive bacteria and mycoplasma, whilst the Cmax influences the activity against gram-negative bacteria. The maximum activity appears to be achieved when the IQ (C max :MIC ratio) is in the range of five to ten (Prescott et al., 2000). This was assessed and a specific product for single injection (Baytril® Max) was developed to address this principle. In addition to rapid bactericidal activity, fluoroquinolones induce a PAE that inhibits regrowth of susceptible bacteria and mycoplasma even after complete removal of the drug.
Intracellular accumulation and activity of antimicrobials is important not only for obligate or facultative intracellular bacteria (e.g. mycoplasmas, salmonellas) but also for any pathogenic bacteria to be phagocytized by polymorphonuclear leukocytes. Studies of several animal species have shown that intracellular concentrations of enrofloxacin largely exceed those of the extracellular, interstitial fluids and that such concentrations actively kill intracellular bacteria.
Intraphagocytic killing of A. pleuropneumoniae (APP) was significantly enhanced by enrofloxacin at five times the MIC in both polymorphonuclear leukocytes (PMNs) and alveolar macrophages (AMs). AMs are very susceptible to the APP cytotoxin. This suggests that in serologically naive pigs, the enhancing effect of enrofloxacin on the bactericidal action of PMNs may have clinical relevance.
(Schoevers et al. 1999. Effects of Enrofloxacin on Porcine Phagocytic Function. Antimicrob. Agents Chemother. 43: 2138–2143)
The high concentrations of enrofloxacin in polymorphonuclear leukocytes support the favorable kinetics by carrying the active ingredient to the site of infection, enhancing intracellular killing of ingested bacteria.
In addition, enrofloxacin does not impair, but rather it stimulates phagocytic activity ("respiratory burst activity") of polymorphonuclear leukocytes.
Because Baytril® shows no adverse effects on the immune system, Baytril® can be used simultaneously with vaccines or in combination with vaccination programs without adversely affecting the immune response.