British Poultry Science Volume 50, Number 5 (September 2009), pp.

544545

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

Downloaded By: [Eli Lilly & Company] At: 06:56 11 November 2009

Dear Editors,
We are writing to you concerning the recent
publication by Lilia et al. (2008; 49(5): 619624),
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: hunter_robert_p@lilly.com

ISSN 00071668(print)/ISSN 14661799 (online)/09/0505442 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 Tylan Soluble. The result
of such modifications could result in serious
consequences for poultry health and for food
safety.

Downloaded By: [Eli Lilly & Company] At: 06:56 11 November 2009

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