British Poultry Science Volume 50, Number 5 (September 2009), pp. 544—545
Letter to the Editor ROBERT P. HUNTER, THOMAS J. BURNETT
AND
SHABBIR A. SIMJEE
Elanco Animal Health, A Division of Eli Lilly and Company, PO Box 708, 2001 W. Main Street, Greenfield, IN 46140, USA
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Dear Editors, We are writing to you concerning the recent publication by Lilia et al. (2008; 49(5): 619—624), entitled ‘‘Circadian serum concentrations of tylosin in broilers after feed or water medication’’, in which we believe there are serious flaws concerning the interpretation of the results and the conclusions drawn from the data. As we will explain in this letter, the conclusion reached by the authors that ‘‘. . . it appears necessary to design a strategy to achieve adequate night serum concentrations of tylosin’’, challenges the efficacy of currently approved treatment regimens for tylosin in chickens. This conclusion is not supported by years of clinical and field efficacy of this product, the data provided in Lilia et al. nor is it consistent with the current understanding of the pharmacology of macrolides in veterinary or human medicine. We are especially concerned that poultry veterinarians may not recognize the deficiencies in the publication and mistakenly make poor dosing decisions when using tylosin for treating poultry, which could have serious consequences for poultry health and food safety. Firstly, the authors accurately identify tylosin as a time-dependent drug, but immediately contradict themselves by stating that the serum concentrations must remain above the MIC, which describes a concentration-dependent drug. All macrolides are time dependent (Craig, 1998). For many of the macrolides, azalides, and ketolides, the AUC/MIC ratio has been reported to be the best correlate (Cazzola et al., 2002; Nicolau, 2002; McKellar et al., 2004). Thus, the use of ‘‘therapeutic serum concentrations’’ is not relevant to macrolides in general or to tylosin specifically since plasma or serum concentrations, individually, do not predict the efficacy of tylosin. Predicting clinical efficacy is not a simple matter: (1) macrolides with higher
intrapulmonary concentrations appear to have greater clinical efficacy in respiratory disease than those with lower lung concentrations (Carbon, 1998; Cazzola et al., 2002); (2) in vivo, bacteria are not exposed to a constant concentration, but to a gradient of macrolide concentrations, based on the pharmacokinetics of an individual agent (Cazzola et al., 2002); (3) macrolide penetration into phagocytic cells and their presence in these cells at the time of phagocytosis has also been reported to contribute to their efficacy (Gladue et al., 1989; McKellar et al., 2004); (4) uptake into these cells is pH dependent — it has been suggested that the release of macrolides from their intracellular sites subjects the pathogen to prolonged exposure (McKellar et al., 2004); and (5) this class has an extended postantimicrobial effect (PAE; Diarra et al., 1999) — macrolides with long PAEs do not need to be administered as frequently as those with short or non-existent PAE (Van Bambeke and Tulkens, 2001). To this end, the PK/PD parameter often associated with macrolides is the AUC/MIC (Nicolau, 2002). However, this ratio is not directly related across species, indications, or pathogen, nor has it been determined for macrolides (Toutain and Lees, 2004). Until the PK/PD relationship of tylosin in chickens is better defined, clinical efficacy from well controlled and clinical designed studies should be used to establish the dose (Wigle, 2000; Lo ¨ hren et al., 2008). Secondly, we believe that the decrease in plasma concentrations shown in Figure 1 of the paper is due to feeding behavior, not an inherent, physiologically dependent circadian rhythm. In practice, an 11-h dark cycle is not used in most modern poultry operations, nor is the withdrawal of food and water during a dark period. Typical dark cycles range from 0 h to approximately 5 h per night, dependent on the age of the birds. Thus the observation is not circadian, nor representative of field use.
Correspondence to: Dr R.P. Hunter, Elanco Animal Health, A Division of Eli Lilly and Company, PO Box 708, 2001 W. Main Street, Greenfield, IN 46140, USA. E-mail:
[email protected]
ISSN 0007–1668(print)/ISSN 1466–1799 (online)/09/050544—2 ß 2009 British Poultry Science Ltd DOI: 10.1080/00071660903346703
LETTER TO THE EDITOR
We strongly recommend that the conclusions of this paper should not be used by veterinarians to modify dosing regimens provided on the label of TylanÕ Soluble. The result of such modifications could result in serious consequences for poultry health and for food safety.
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(CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrobial Agents and Chemotherapy, 33: 277–282. LILIA, G., AGUILERA, R., CORTE´S-CUEVAS, A., ROSARIO, C. & SUMANO, H. (2008) Circadian serum concentrations of tylosin in broilers after feed or water medication. British Poultry Science, 49: 619–624. LO¨HREN, U., RICCI, A. & CUMMINGS, T.A. (2008) Guidelines for antimicrobial use in poultry, in: GUARDABASSI, L., JENSEN, L.B. & KRUSE, H. (Eds) Guide to Antimicrobial Use in Animals, pp. 126—142 (Oxford, UK, Blackwell Publishing). MCKELLAR, Q.A., SANCHEZ BRUNI, S.F. & JONES, D.G. (2004) Pharmacokinetic/pharmacodynamics relationships of antimicrobial drugs used in veterinary medicine. Journal of Veterinary Pharmacology and Therapeutics, 27: 503–514. NICOLAU, D.P. (2002) Pharmacodynamic rationale for shortduration antibacterial therapy. Journal of Infection, 44(Suppl A): 17–23. TOUTAIN, P.L. & LEES, P. (2004) Integration and modeling of pharmacokinetic and pharmacodynamics data to optimize dosage regimens in veterinary medicine. Journal of Veterinary Pharmacology and Therapeutics, 27: 467–477. VAN BAMBEKE, F. & TULKENS, P.M. (2001) Macrolides: pharmacokinetics and pharmacodynamics. International Journal of Antimicrobial Agents, 18: S17–S23. WIGLE, W.L. (2000) Respiratory diseases of gallinaceous birds. Veterinary Clinics of North America: rxotic Animal Practice, 3: 403–421.
