Accepted Manuscript Review The role of the macrolide tulathromycin in veterinary medicine Nicolas Villarino, Scott Anthony Brown, Tomás Martín-Jiménez PII: DOI: Reference:
S1090-0233(13)00369-9 http://dx.doi.org/10.1016/j.tvjl.2013.07.032 YTVJL 3817
To appear in:
The Veterinary Journal
Accepted Date:
29 July 2013
Please cite this article as: Villarino, N., Brown, S.A., Martín-Jiménez, T., The role of the macrolide tulathromycin in veterinary medicine, The Veterinary Journal (2013), doi: http://dx.doi.org/10.1016/j.tvjl.2013.07.032
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Review
The role of the macrolide tulathromycin in veterinary medicine
Nicolas Villarino a, Scott Anthony Brown b, Tomás Martín-Jiménez c, *
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Department of Microbiology, University of Tennessee, Knoxville, TN37996, USA. b Pfizer Animal Health, Kalamazoo, MI49007, USA. c Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, TN37996, USA. *Corresponding author. Tel.: +1 865 974 5646 E-mail address: [email protected] (T. Martín-Jiménez)
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Abstract Tulathromycin is the first and only member of the triamilide sub-class of macrolides that is used therapeutically and has been registered in more than 30 countries across America, Europe, Oceania and Asia. The discovery of tulathromycin and its registration in multiple countries has been important for the food animal industry as it has been used successfully to treat economically important conditions such as bovine and porcine respiratory disease, infectious bovine keratoconjunctivitis and interdigital necrobacillosis. Since it was first registered about 8 years ago, considerable information has been generated to help define tulathromycin’s role in veterinary medicine as well as setting the basis for new treatment strategies and the discovery of new macrolides with further applications in veterinary and human medicine. This article reviews this information and examines more recent findings particularly the effects of tulathromycin on the immune response, its pharmacokinetics and pharmacodynamics, its pattern of susceptibility and the identification of genes that may be associated with resistance to the drug.
Keywords: Tulathromycin, Macrolides, Pneumonia, Antimicrobials, Veterinary
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Introduction Tulathromycin, an antimicrobial used in cattle and swine, was first approved in the United States of America1 and the European Union (European Medicines Agency, EMEA; 2008) for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni (Haemophilus somnus) and Mycoplasma bovis, and for the control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni (Haemophilus somnus) and Mycoplasma bovis. Infectious bovine keratoconjunctivitis associated with Moraxella bovis is included in the list of approved indications by the US Food and Drug Administration (FDA) and EMEA. In addition, tulathromycin is registered in the USA for the treatment of interdigital necrobacillosis associated with Fusobacterium necrophorum and Porphyromonas levii.
The FDA and EMEA approved label indications include only beef and non-lactating dairy cattle. In swine, tulathromycin is approved for the treatment of respiratory conditions associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, and Haemophilus parasuis (Pfizer, 2004). Of note, label indications may vary between countries and may be regionally updated.
The antimicrobial efficacy of tulathromycin has been addressed in several published studies including data on cattle, swine, horses, and goats. Studies with clinical applications are summarized in Table 1 (Appendix A: Supplementary data). Tulathromycin is safe when used according to label directions (Pfizer, 2005a) but studies of toxicity in bovine, swine and caprine 1 FDA, 2005. NADA 141-244. http://www.fda.gov/downloads/AnimalVeterinary/Products/ ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118061.pdf (Accessed 10 September 2012).
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species have revealed minor clinical and injection site histopathological changes that resolved over time (Pfizer, 2005a; Clothier et al., 2010). Hyper-salivation, head shaking, and pawing at the ground have been reported at therapeutic doses (Pfizer, 2005a). In foals, the use of tulathromycin was associated with self-limiting diarrhea, elevated temperature, and swelling at the injection site (Venner et al., 2010).
One of the benefits ascribed to tulathromycin for use in the US is that its withdrawal times in cattle and swine intended for human consumption are relatively short when compared with other approved drugs used for the treatment of similar conditions. According to the FDA, when tulathromycin is used according to manufacturer’s label indications, treated animals must not be slaughtered within 18 (cattle) and 5 (swine) days after the last treatment administration (Pfizer, 2005c). It should be noted that withdrawal times varies according to the regulations for each particular country/region (EMEA2; APVMA3; 2007). Therefore, withdrawals times should be considered within the context of the current regional regulations.
Chemical structure Tulathromycin is a semi-synthetic macrolide antimicrobial, consisting of a regioisomeric, equilibrated mixture of a 13-membered ring azalide (10%) and a 15-membered ring azalide (90%) (Norcia et al., 2004). Its chemical core is built of two sugar moieties attached to the macrolactone ring (molecular weight 806.08) (Evans, 2005). The drug molecule has three nitrogen/amine functional groups representing the first member of a novel sub–class of
2 See: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/veterinary/000077/WC500063309.pdf (Accessed 10 September 2012). 3 Australian Pesticides and Veterinary Medicines Authority. See: http://www.apvma.gov.au/registration/assessment/docs/prs_draxxin.pdf (accessed 10 September 2012)
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macrolides known as triamilides (Letavic et al., 2002). Each amino group can be positively charged at the appropriate pH.
Although all macrolides are basic molecules with a dissociation constant (pKa) higher than 7, the tulathromycin molecule is more basic than other macrolides. Depending upon the basic amino group in the molecule, pKa values can range from 8.6 to 9.6.This physicochemical feature allows the unionized fraction of the drug to easily penetrate into tissues from plasma and accumulate in compartments with acidic conditions – a phenomenon known as ion trapping. This may explain, at least in part, the large volume of distribution of the drug and the accumulation of the drug in alveolar epithelial lining fluid and bronchoalveolar lavage (BAL) cells (Bodem et al., 1983; Nielson, 1986; Nielson et al., 1981).
Changes in the physicochemical conditions of different body compartments as consequence of disease may affect the selectivity of a drug for a tissue, disposition of the parent compound and its residues and the efficacy of the drug. Another physicochemical feature that may dictate the movement of the drug across body compartments of tulathromycin is that the molecule is approximately 50 times more soluble in hydrophilic vs. hydrophobic media (readily soluble in water at pH 8.0 or below) (Evans, 2005).
Mechanism of action Macrolides have diverse chemical structures but are functionally similar drugs. They inhibit protein synthesis by binding reversibly to a center in the 23s ribosomal subunit of bacteria that catalyzes formation of peptide bonds during protein elongation (Nissen et al., 2000; Moore et al.,
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2002, Teson et al., 2003; Yam and Wahab 2009).
A study measuring the displacement of 14C-erythromycin from the ribosome of bacteria by tulathromycin indicated that it shares a common binding site on the ribosome with erythromycin (Pfizer, 2004). Inhibitory activity of macrolides in a transcription-translation assay using ribosomes isolated from Escherichia coli show that the potency of tulathromycin towards erythromycin-sensitive ribosomes is comparable to that of other macrolides. The drug concentration (μM) that inhibited protein synthesis by 50% was 0.39, 0.44, 0.57, 0.64, for tilmicosin, tulathromycin, erythromycin and clarithromycin, respectively (Pfizer, 2004). As shown for tilmicosin, tulathromycin is not active against erythromycin-resistant ribosomes (Pfizer, 2004).
Pharmacodynamics Both the macrolide ring and sugar moieties account for the antimicrobial activity of the drug (Pestka and Lemahieu, 1974). A remarkable feature of the chemical structure of tulathromycin is that the molecule is highly positively charged (Norcia et al., 2004). This electrostatic charge has been associated with marked enhancement of drug penetration into cells by displacing magnesium ions at the outer lipopolysaccharide layer of Gram negative bacteria (Norcia et al., 2004).
The bacteriostatic or bactericidal effect of an antimicrobial is dictated by the microorganism involved in the infection and the concentration-time profile of the drug at the site of infection (Drusano, 2005, 2007; Mouton et al., 2008). Tulathromycin concentrates markedly in some areas
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including pulmonary epithelial lining fluid, macrophages and neutrophils (Cox et al., 2010; Siegel et al., 2004; Villarino et al., 2012, 2013,a, b) but its distribution and accumulation occur at different rates and extents (Cox et al., 2010; Villarino et al., 2012, 2013,a, b).
Tulathromycin, like other macrolides, is considered a bacteriostatic agent when tested against Staphylococcus aureus and E. coli (Pfizer, 2004). However, the drug is bactericidal (at 4x and 8x the minimum inhibitory concentration [MIC]) against M. haemolytica, A. pleuropneumoniae and Pasteurella multocida (Godinho et al., 2005a; Norcia et al., 2004).
Some local conditions may impact the activity of tulathromycin. For example, according to one report, its antimicrobial activity against Histophilus somni and other fastidious microorganisms is dependent on the pH and pCO2 of the surrounding environment (Reese et al., 2004). This study reported that the MIC increased as pH decreased and pCO2 increased. Similar observations have been reported for erythromycin, azithromycin and clarithromycin (Ednie et al., 1998). However, these findings have not been observed in vivo nor have they been shown to be consistent for other microorganisms.
Local biochemical changes might be relevant in clinical situations that include abscesses and/or necrotic tissue and intracellular infections where the pH might be lower and the pCO2 higher than in plasma (Rubinstein et al., 1982a, b). Two studies involving tulathromycin and abscessation suggested that in vitro findings may not be fully correlated with all in vivo conditions and may warrant further in vivo research. Both of these studies assessed microorganisms that are intracellular pathogens and were responsible for triggering the
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formation of abscesses (Venner et al., 2007; Washburn et al., 2009). The first study reported an acceptable clinical response of goats with caseous lymphadenitis abscesses caused by Corynebacterium pseudotuberculosis when treated with tulathromycin (Washburn et al., 2009). The other study was done in foals with lung abscesses (Venner et al., 2007) which resolved after 53 days of therapy (2.5 mg/kg/once a week). The authors attributed the lung abscesses to Rhodococcus equi but the causal microorganism(s) were not identified and, interestingly, under in vitro conditions, tulathromycin showed poor activity against R. equi (Carlson et al., 2010).
Collectively, this information suggests that changes in MIC, as consequence of changes in local conditions, do not necessarily imply that the drug may became ineffective as an antimicrobial. In fact, local conditions are dynamic and may change according to the progression of the disease which may modify the inter-relationship between the drug and the target microorganism. In addition, increments in MIC may be compensated by changes in the local kinetics of the drug such as large intra-cellular drug concentrations in BAL cells or longer persistence of the drug in the epithelial lining fluid.
Tulathromycin concentrates largely in inflammatory cells, which does not imply that all drug is readily available and active (Van Bambeke et al., 2006). Some fraction of the intracellular drug content may be bound to the membrane or cellular proteins or trapped in intracellular organelles (Carlier et al., 1987; Tulkens, 1990). Macrolides and fluoroquinolones exhibit intracellular antimicrobial activity as indicated by their capacity to treat intracellular organisms located in phagosomes (Brucella spp. in macrophages) (Köhler et al., 2002), cytosol (Listeria monocytogenes in macrophages) (Portnoy et al., 2002), endosomes (Mycobacterium tuberculosis
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in macrophages) (Pieters, 2001) and phagolysosomes (Staphylococcus aureus in macrophages and neutrophils). Nevertheless, changing intracellular conditions (e.g. pH) may also render the molecule less active (Van Bambeke et al., 2006).
The acidic environment of lysosomes and the pKa of tulathromycin (>8) suggest that the drug may tend to be trapped within lysosomes, as has been reported for other macrolides (Nyberg et al., 1992; Tulkens, 1991). The location of the intracellular unbound and the unionized fraction of tulathromycin has not been reported. Considering that the MIC of some microorganisms is inversely related to pH, it is possible to hypothesize that the intracellular antimicrobial activity of tulathromycin is limited. On the other hand, the intracellular concentrations are higher than plasma concentrations (area under the concentration time curve (AUC)0-360 cell:plasma ratio ~500) (Cox et al., 2010), which might overcome potential changes of MICs. Many unanswered questions remain and based on the evidence currently available, it is not possible to predict the intracellular antimicrobial activity of tulathromycin.
The bactericidal action of macrolides has been described as time-dependent for erythromycin and concentration dependent for clarithromycin and azithromycin (Nightingale, 1997). Studies in vitro with Haemophilus somnus indicates that tulathromycin has concentration-dependent bactericidal activity, particularly in the presence of plasma (Reese et al., 2004), with postantibiotic effect, at least for Actinobacillus pleuropneumoniae (Bair et al., 2010). The AUC/MIC ratio has been proposed as the PK/PD variable that best predicts the antimicrobial activity of tulathromycin (Evans, 2005). However, clinical PK/PD breakpoints for tulathromycin have not yet been reported. Microbiological breakpoints have been established for susceptibility testing of
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bovine and swine respiratory pathogens and defined based on bacterial isolates obtained from field studies conducted in 10 European countries and from library collections (Godinho, 2008).
Resistance of target pathogens to tulathromycin There is limited information about resistant isolates to tulathromycin. In fact, since the approval of tulathromycin in the US and Europe, only two tulathromycin-resistant Pasteurella multocida strains have been detected and reported. One isolate was from a pig in Germany in 2004 (Kaspar et al., 2007) and the other one from a case of bovine respiratory tract infection in a Nebraska feedlot in 2005 (Kadlec et al., 2011).
A study reported the MICs of tulathromycin for 1111 porcine isolates of Pasteurella multocida collected in Germany over a 2 year period from animals of different ages suffering acute respiratory disease. The MIC for tulathromycin was ≤ 4 mg/L for all isolates (n= 639) except for one resistant isolate (MIC = 64 mg/L) collected during 2004-2005. For isolates collected during the following year, the MIC for all the isolates was ≤ 2 mg/L except for one isolate (MIC = 4 mg/L) (Kaspar et al., 2007).
Another study evaluated the in vitro susceptibility tests of target bovine and porcine respiratory pathogens isolated from different European countries (Belgium, Czech Republic, Denmark, France, Germany, Italy, The Netherlands, Poland, Spain and UK) after the drug had been approved (Godinho, 2008). A total of 170 bovine and 133 porcine isolates were included in the study. The susceptibility results were compared with those using isolates obtained prior to launching the formulation in the market. The results indicated there was no shift in susceptibility
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amongst the key pathogenic target species. Additionally, findings of a recent study done with bovine isolates of Mannheimia haemolytica (n=2,977), Pasteurella multocida (n=3,291) and Histophilus somni (n=1,844), collected during 10 years revealed that the MIC50 and MIC90 values for the three microorganisms tended to decline over the years evaluated (Portis et al., 2012).
Recently, the genome of one of the resistant isolates was evaluated by whole-genome sequencing in order to identify genes associated with resistance to tulathromycin (Kadlec et al., 2011). This study detected three resistance genes, the rRNA methylase gene erm, the macrolide transporter gene msr(E), and the macrolide phosphotransferase gene mph(E) associated with a shift of the susceptibility to tulathromycin and other macrolides. Strains with and without the cloned erm gene had up to 128-fold increases in the MICs of erythromycin, tilmicosin, and clindamycin but only 8-fold increases in the MICs of tulathromycin. Clones carrying the msr(E)mph(E) amplicons exhibited up to 128-fold increases in the MICs of erythromycin, tilmicosin, and tulathromycin.
Collectively, the available information suggests that there are no relevant changes in the susceptibility to tulathromycin but monitoring of susceptibility patterns should continue.
Effects on the immune system Macrolide antibiotics affect the immune system by multiple mechanisms including recruitment of inflammatory cells (Ichikawa et al., 1992; Mikasa et al., 1992), secretion of pro-
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inflammatory cytokines (Takeshita et al., 1989) and pro-apoptotic activities (Chin et al., 1998; Lee et al., 2004; Leiva et al., 2008; Wu et al., 2009).
Tulathromycin significantly increased leukocyte apoptosis and reduced levels of proinflammatory leukotriene B4 in M. haemolytica-challenged calves (Fischer et al., 2011). In vitro, tulathromycin induces apoptosis in bovine neutrophils in a time and concentration dependent manner when evaluated at concentrations that may be attained within the cells (50 µg/mL to 2 mg/mL). It was also demonstrated in vivo that tulathromycin induces apoptosis of BAL fluid leukocytes 3 h after its administration. Tulathromycin did not significantly alter BAL neutrophil numbers at 24 h of infection. The authors also reported that tulathromycin significantly reduced levels of phosphorylated inhibitor kappa beta, nuclear factor kappa-light-chain-enhancer of activated B cells, p65, and mRNA levels of pro-inflammatory interleukin-8 in lipopolysaccharide stimulated bovine neutrophils (Fischer et al., 2011).
The clinical significance of these findings may warrant further research. An interesting hypothesis will be to test whether the dual effects (antimicrobial and anti-inflammatory) of tulathromycin are important for the treatment of disease where the inflammatory response of the host play a key role in the pathogenesis of pneumonia (e.g bovine pneumonia by Mannheimia haemolytica) (Fischer et al., 2011).
Pharmacokinetics The pharmacokinetics of tulathromycin have been studied in mice (Villarino et al., 2012), cattle (Nowakowski et al., 2004; Cox et al., 2010), pigs (Benchaoui et al., 2004; Villarino et al.,
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2013 a,b), goats (Young et al., 2010; Clothier et al., 2010) and foals (Venner et al., 2010). At label dose, tulathromycin is characterized by a rapid rate of absorption and large systemic availability (~90%) after intramuscular (IM) and subcutaneous (SC) administration. In plasma, tulathromycin has a long terminal half-life, ranging across domestic species from 60 to 140 h and a remarkable large volume of distribution (>10 L/kg) (Benchaoui et al., 2004; Nowakowski et al., 2004; Cox et al., 2010; Young et al., 2010; Clothier et al., 2010; Venner et al., 2010 Villarino et al., 2013 a,b). In pigs, most of the dose is eliminated as unchanged drug (Wang et al., 2012), by biliary and renal excretion (Pfizer, 2005a). Protein binding studies indicate that the unbound fraction of tulathromycin ranges from 0.53 to 0.68 (Pfizer, 2005b).
Lung pharmacokinetic studies in cattle, pigs and horses reveal an extraordinary capacity of tulathromycin for accumulation in lung tissue (Benchaoui et al., 2004; Cox et al., 2010; Nowakowski, 2004; Venner et al., 2010; Young et al., 2010; Villarino et al., 2013a,b). The magnitude of the local accumulation and long persistence of the drug in the target tissue (lung) results in a convenient treatment regimen (single administration) and positive clinical outcome rates for respiratory conditions (Cox et al., 2010).
Pulmonary epithelial lining fluid (PELF) is the fluid that distributes continuously throughout the respiratory tract including alveoli (Ng et al., 2004). The pharmacokinetics of tulathromycin in PELF was reported from samples from clinically healthy cattle and pigs (Cox et al., 2010; Villarino et al., 2013b).Results indicated that tulathromycin rapidly distributes into the intraairway compartment and persists there for a long time. In addition, both in cattle and pigs, the
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drug exposure in PELF was extensive (AUC0-408>60x that in plasma) (Cox et al., 2010; Villarino et al., 2013b).
Bronchial epithelial lining fluid (BELF) is the bronchial surface liquid. A pharmacokinetic study of tulathromycin in BELF in the middle lobe from clinically healthy pigs used Bronchial micro-sampling (BMS) probes guided with a fiberscope (Villarino et al., 2013b). Such BMS probes have been used experimentally in humans to harvest BELF (Kikuchi et al., 2008; Kikuchi et al., 2007; Yamazaki et al., 2003). Consistent with results reported in lung homogenate and pulmonary epithelial lining fluid, tulathromycin accumulated in BELF. The maximal concentration of tulathromycin in BELF (72 h) was observed later than plasma (0.5 h), lung homogenate (24 h for middle lobe) and PELF (6 h) (Villarino et al., 2013b). The persistence of the drug in this lung compartment was very long. This is reflected in a mean transit time longer than 10 days (Villarino et al., 2013b).
Macrolide antimicrobials accumulate to a high extent in different cell types (Baughman et al., 1994; Jacks et al., 2001; Lakritz et al., 1997; Lucchi et al., 2008; Patel et al., 1996; Portnoy et al., 2002; Togami et al., 2009, 2010; Womble et al., 2006). An in vitro study demonstrated that tulathromycin accumulates in neutrophils and blood macrophages in bovine and porcine species (Siegel et al., 2004), bronchoalveolar cells in foals (Venner et al., 2010) and pigs (Villarino et al 2013b), pulmonary epithelial lining fluid cells (majority macrophages) from clinically healthy calves (Cox et al., 2010). These studies demonstrate the remarkable capacity of tulathromycin penetrate and accumulate into cells.
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Conclusions Tulathromycin has been registered by multiple regulatory agencies as an injectable formulation and is increasingly widely included as part of the health management of swine and bovine operations. Multiple clinical studies show that tulathromycin is effective in the treatment of respiratory disease in cattle and pigs. Its efficacy and safety profiles following a single administration makes tulathromycin a valuable therapeutic option for respiratory conditions of bovine and swine species. Part of the clinical efficacy may be explained by the magnitude of drug accumulation and long persistence in lung tissue. There is evidence indicating the capacity of tulathromycin to accumulate in lung tissue based on lung homogenate samples from healthy cattle and pigs. New information indicates that tulathromycin accumulates rapidly and extensively in the intra-airway compartment in pigs, cattle and horses. This provides a step forward in knowledge about the pulmonary kinetics of tulathromycin. A full characterization of the pharmacokinetics and the mechanisms and processes involved in the accumulation of tulathromycin in the biophase (interstitial fluid and/or ELF) may help towards defining the use of this macrolide drug as a model for the design of future molecules for respiratory conditions.
Conflict of interest statement NV and TMJ have no financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper. SAB is an employee of Zoetis Animal Health.
Acknowledgements
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The authors are grateful to the Metabolism and Safety Unit and farm staff of Pfizer Animal Health, Kalamazoo, MI, USA who assisted with this manuscript. Also we want to thank Misty Bailey, Dr. Cox (University of Tennessee) and the reviewers of this manuscript for their comments on this manuscript, which improve this work.
Appendix A: Supplementary material Supplementary material associated with this article can be found in the online version at doi…..setters insert doi number
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S1090-0233(13)00369-9 http://dx.doi.org/10.1016/j.tvjl.2013.07.032 YTVJL 3817
To appear in:
The Veterinary Journal
Accepted Date:
29 July 2013
Please cite this article as: Villarino, N., Brown, S.A., Martín-Jiménez, T., The role of the macrolide tulathromycin in veterinary medicine, The Veterinary Journal (2013), doi: http://dx.doi.org/10.1016/j.tvjl.2013.07.032
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Review
The role of the macrolide tulathromycin in veterinary medicine
Nicolas Villarino a, Scott Anthony Brown b, Tomás Martín-Jiménez c, *
a
Department of Microbiology, University of Tennessee, Knoxville, TN37996, USA. b Pfizer Animal Health, Kalamazoo, MI49007, USA. c Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, TN37996, USA. *Corresponding author. Tel.: +1 865 974 5646 E-mail address: [email protected] (T. Martín-Jiménez)
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Abstract Tulathromycin is the first and only member of the triamilide sub-class of macrolides that is used therapeutically and has been registered in more than 30 countries across America, Europe, Oceania and Asia. The discovery of tulathromycin and its registration in multiple countries has been important for the food animal industry as it has been used successfully to treat economically important conditions such as bovine and porcine respiratory disease, infectious bovine keratoconjunctivitis and interdigital necrobacillosis. Since it was first registered about 8 years ago, considerable information has been generated to help define tulathromycin’s role in veterinary medicine as well as setting the basis for new treatment strategies and the discovery of new macrolides with further applications in veterinary and human medicine. This article reviews this information and examines more recent findings particularly the effects of tulathromycin on the immune response, its pharmacokinetics and pharmacodynamics, its pattern of susceptibility and the identification of genes that may be associated with resistance to the drug.
Keywords: Tulathromycin, Macrolides, Pneumonia, Antimicrobials, Veterinary
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Introduction Tulathromycin, an antimicrobial used in cattle and swine, was first approved in the United States of America1 and the European Union (European Medicines Agency, EMEA; 2008) for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni (Haemophilus somnus) and Mycoplasma bovis, and for the control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni (Haemophilus somnus) and Mycoplasma bovis. Infectious bovine keratoconjunctivitis associated with Moraxella bovis is included in the list of approved indications by the US Food and Drug Administration (FDA) and EMEA. In addition, tulathromycin is registered in the USA for the treatment of interdigital necrobacillosis associated with Fusobacterium necrophorum and Porphyromonas levii.
The FDA and EMEA approved label indications include only beef and non-lactating dairy cattle. In swine, tulathromycin is approved for the treatment of respiratory conditions associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, and Haemophilus parasuis (Pfizer, 2004). Of note, label indications may vary between countries and may be regionally updated.
The antimicrobial efficacy of tulathromycin has been addressed in several published studies including data on cattle, swine, horses, and goats. Studies with clinical applications are summarized in Table 1 (Appendix A: Supplementary data). Tulathromycin is safe when used according to label directions (Pfizer, 2005a) but studies of toxicity in bovine, swine and caprine 1 FDA, 2005. NADA 141-244. http://www.fda.gov/downloads/AnimalVeterinary/Products/ ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118061.pdf (Accessed 10 September 2012).
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species have revealed minor clinical and injection site histopathological changes that resolved over time (Pfizer, 2005a; Clothier et al., 2010). Hyper-salivation, head shaking, and pawing at the ground have been reported at therapeutic doses (Pfizer, 2005a). In foals, the use of tulathromycin was associated with self-limiting diarrhea, elevated temperature, and swelling at the injection site (Venner et al., 2010).
One of the benefits ascribed to tulathromycin for use in the US is that its withdrawal times in cattle and swine intended for human consumption are relatively short when compared with other approved drugs used for the treatment of similar conditions. According to the FDA, when tulathromycin is used according to manufacturer’s label indications, treated animals must not be slaughtered within 18 (cattle) and 5 (swine) days after the last treatment administration (Pfizer, 2005c). It should be noted that withdrawal times varies according to the regulations for each particular country/region (EMEA2; APVMA3; 2007). Therefore, withdrawals times should be considered within the context of the current regional regulations.
Chemical structure Tulathromycin is a semi-synthetic macrolide antimicrobial, consisting of a regioisomeric, equilibrated mixture of a 13-membered ring azalide (10%) and a 15-membered ring azalide (90%) (Norcia et al., 2004). Its chemical core is built of two sugar moieties attached to the macrolactone ring (molecular weight 806.08) (Evans, 2005). The drug molecule has three nitrogen/amine functional groups representing the first member of a novel sub–class of
2 See: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/veterinary/000077/WC500063309.pdf (Accessed 10 September 2012). 3 Australian Pesticides and Veterinary Medicines Authority. See: http://www.apvma.gov.au/registration/assessment/docs/prs_draxxin.pdf (accessed 10 September 2012)
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macrolides known as triamilides (Letavic et al., 2002). Each amino group can be positively charged at the appropriate pH.
Although all macrolides are basic molecules with a dissociation constant (pKa) higher than 7, the tulathromycin molecule is more basic than other macrolides. Depending upon the basic amino group in the molecule, pKa values can range from 8.6 to 9.6.This physicochemical feature allows the unionized fraction of the drug to easily penetrate into tissues from plasma and accumulate in compartments with acidic conditions – a phenomenon known as ion trapping. This may explain, at least in part, the large volume of distribution of the drug and the accumulation of the drug in alveolar epithelial lining fluid and bronchoalveolar lavage (BAL) cells (Bodem et al., 1983; Nielson, 1986; Nielson et al., 1981).
Changes in the physicochemical conditions of different body compartments as consequence of disease may affect the selectivity of a drug for a tissue, disposition of the parent compound and its residues and the efficacy of the drug. Another physicochemical feature that may dictate the movement of the drug across body compartments of tulathromycin is that the molecule is approximately 50 times more soluble in hydrophilic vs. hydrophobic media (readily soluble in water at pH 8.0 or below) (Evans, 2005).
Mechanism of action Macrolides have diverse chemical structures but are functionally similar drugs. They inhibit protein synthesis by binding reversibly to a center in the 23s ribosomal subunit of bacteria that catalyzes formation of peptide bonds during protein elongation (Nissen et al., 2000; Moore et al.,
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2002, Teson et al., 2003; Yam and Wahab 2009).
A study measuring the displacement of 14C-erythromycin from the ribosome of bacteria by tulathromycin indicated that it shares a common binding site on the ribosome with erythromycin (Pfizer, 2004). Inhibitory activity of macrolides in a transcription-translation assay using ribosomes isolated from Escherichia coli show that the potency of tulathromycin towards erythromycin-sensitive ribosomes is comparable to that of other macrolides. The drug concentration (μM) that inhibited protein synthesis by 50% was 0.39, 0.44, 0.57, 0.64, for tilmicosin, tulathromycin, erythromycin and clarithromycin, respectively (Pfizer, 2004). As shown for tilmicosin, tulathromycin is not active against erythromycin-resistant ribosomes (Pfizer, 2004).
Pharmacodynamics Both the macrolide ring and sugar moieties account for the antimicrobial activity of the drug (Pestka and Lemahieu, 1974). A remarkable feature of the chemical structure of tulathromycin is that the molecule is highly positively charged (Norcia et al., 2004). This electrostatic charge has been associated with marked enhancement of drug penetration into cells by displacing magnesium ions at the outer lipopolysaccharide layer of Gram negative bacteria (Norcia et al., 2004).
The bacteriostatic or bactericidal effect of an antimicrobial is dictated by the microorganism involved in the infection and the concentration-time profile of the drug at the site of infection (Drusano, 2005, 2007; Mouton et al., 2008). Tulathromycin concentrates markedly in some areas
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including pulmonary epithelial lining fluid, macrophages and neutrophils (Cox et al., 2010; Siegel et al., 2004; Villarino et al., 2012, 2013,a, b) but its distribution and accumulation occur at different rates and extents (Cox et al., 2010; Villarino et al., 2012, 2013,a, b).
Tulathromycin, like other macrolides, is considered a bacteriostatic agent when tested against Staphylococcus aureus and E. coli (Pfizer, 2004). However, the drug is bactericidal (at 4x and 8x the minimum inhibitory concentration [MIC]) against M. haemolytica, A. pleuropneumoniae and Pasteurella multocida (Godinho et al., 2005a; Norcia et al., 2004).
Some local conditions may impact the activity of tulathromycin. For example, according to one report, its antimicrobial activity against Histophilus somni and other fastidious microorganisms is dependent on the pH and pCO2 of the surrounding environment (Reese et al., 2004). This study reported that the MIC increased as pH decreased and pCO2 increased. Similar observations have been reported for erythromycin, azithromycin and clarithromycin (Ednie et al., 1998). However, these findings have not been observed in vivo nor have they been shown to be consistent for other microorganisms.
Local biochemical changes might be relevant in clinical situations that include abscesses and/or necrotic tissue and intracellular infections where the pH might be lower and the pCO2 higher than in plasma (Rubinstein et al., 1982a, b). Two studies involving tulathromycin and abscessation suggested that in vitro findings may not be fully correlated with all in vivo conditions and may warrant further in vivo research. Both of these studies assessed microorganisms that are intracellular pathogens and were responsible for triggering the
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formation of abscesses (Venner et al., 2007; Washburn et al., 2009). The first study reported an acceptable clinical response of goats with caseous lymphadenitis abscesses caused by Corynebacterium pseudotuberculosis when treated with tulathromycin (Washburn et al., 2009). The other study was done in foals with lung abscesses (Venner et al., 2007) which resolved after 53 days of therapy (2.5 mg/kg/once a week). The authors attributed the lung abscesses to Rhodococcus equi but the causal microorganism(s) were not identified and, interestingly, under in vitro conditions, tulathromycin showed poor activity against R. equi (Carlson et al., 2010).
Collectively, this information suggests that changes in MIC, as consequence of changes in local conditions, do not necessarily imply that the drug may became ineffective as an antimicrobial. In fact, local conditions are dynamic and may change according to the progression of the disease which may modify the inter-relationship between the drug and the target microorganism. In addition, increments in MIC may be compensated by changes in the local kinetics of the drug such as large intra-cellular drug concentrations in BAL cells or longer persistence of the drug in the epithelial lining fluid.
Tulathromycin concentrates largely in inflammatory cells, which does not imply that all drug is readily available and active (Van Bambeke et al., 2006). Some fraction of the intracellular drug content may be bound to the membrane or cellular proteins or trapped in intracellular organelles (Carlier et al., 1987; Tulkens, 1990). Macrolides and fluoroquinolones exhibit intracellular antimicrobial activity as indicated by their capacity to treat intracellular organisms located in phagosomes (Brucella spp. in macrophages) (Köhler et al., 2002), cytosol (Listeria monocytogenes in macrophages) (Portnoy et al., 2002), endosomes (Mycobacterium tuberculosis
8
in macrophages) (Pieters, 2001) and phagolysosomes (Staphylococcus aureus in macrophages and neutrophils). Nevertheless, changing intracellular conditions (e.g. pH) may also render the molecule less active (Van Bambeke et al., 2006).
The acidic environment of lysosomes and the pKa of tulathromycin (>8) suggest that the drug may tend to be trapped within lysosomes, as has been reported for other macrolides (Nyberg et al., 1992; Tulkens, 1991). The location of the intracellular unbound and the unionized fraction of tulathromycin has not been reported. Considering that the MIC of some microorganisms is inversely related to pH, it is possible to hypothesize that the intracellular antimicrobial activity of tulathromycin is limited. On the other hand, the intracellular concentrations are higher than plasma concentrations (area under the concentration time curve (AUC)0-360 cell:plasma ratio ~500) (Cox et al., 2010), which might overcome potential changes of MICs. Many unanswered questions remain and based on the evidence currently available, it is not possible to predict the intracellular antimicrobial activity of tulathromycin.
The bactericidal action of macrolides has been described as time-dependent for erythromycin and concentration dependent for clarithromycin and azithromycin (Nightingale, 1997). Studies in vitro with Haemophilus somnus indicates that tulathromycin has concentration-dependent bactericidal activity, particularly in the presence of plasma (Reese et al., 2004), with postantibiotic effect, at least for Actinobacillus pleuropneumoniae (Bair et al., 2010). The AUC/MIC ratio has been proposed as the PK/PD variable that best predicts the antimicrobial activity of tulathromycin (Evans, 2005). However, clinical PK/PD breakpoints for tulathromycin have not yet been reported. Microbiological breakpoints have been established for susceptibility testing of
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bovine and swine respiratory pathogens and defined based on bacterial isolates obtained from field studies conducted in 10 European countries and from library collections (Godinho, 2008).
Resistance of target pathogens to tulathromycin There is limited information about resistant isolates to tulathromycin. In fact, since the approval of tulathromycin in the US and Europe, only two tulathromycin-resistant Pasteurella multocida strains have been detected and reported. One isolate was from a pig in Germany in 2004 (Kaspar et al., 2007) and the other one from a case of bovine respiratory tract infection in a Nebraska feedlot in 2005 (Kadlec et al., 2011).
A study reported the MICs of tulathromycin for 1111 porcine isolates of Pasteurella multocida collected in Germany over a 2 year period from animals of different ages suffering acute respiratory disease. The MIC for tulathromycin was ≤ 4 mg/L for all isolates (n= 639) except for one resistant isolate (MIC = 64 mg/L) collected during 2004-2005. For isolates collected during the following year, the MIC for all the isolates was ≤ 2 mg/L except for one isolate (MIC = 4 mg/L) (Kaspar et al., 2007).
Another study evaluated the in vitro susceptibility tests of target bovine and porcine respiratory pathogens isolated from different European countries (Belgium, Czech Republic, Denmark, France, Germany, Italy, The Netherlands, Poland, Spain and UK) after the drug had been approved (Godinho, 2008). A total of 170 bovine and 133 porcine isolates were included in the study. The susceptibility results were compared with those using isolates obtained prior to launching the formulation in the market. The results indicated there was no shift in susceptibility
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amongst the key pathogenic target species. Additionally, findings of a recent study done with bovine isolates of Mannheimia haemolytica (n=2,977), Pasteurella multocida (n=3,291) and Histophilus somni (n=1,844), collected during 10 years revealed that the MIC50 and MIC90 values for the three microorganisms tended to decline over the years evaluated (Portis et al., 2012).
Recently, the genome of one of the resistant isolates was evaluated by whole-genome sequencing in order to identify genes associated with resistance to tulathromycin (Kadlec et al., 2011). This study detected three resistance genes, the rRNA methylase gene erm, the macrolide transporter gene msr(E), and the macrolide phosphotransferase gene mph(E) associated with a shift of the susceptibility to tulathromycin and other macrolides. Strains with and without the cloned erm gene had up to 128-fold increases in the MICs of erythromycin, tilmicosin, and clindamycin but only 8-fold increases in the MICs of tulathromycin. Clones carrying the msr(E)mph(E) amplicons exhibited up to 128-fold increases in the MICs of erythromycin, tilmicosin, and tulathromycin.
Collectively, the available information suggests that there are no relevant changes in the susceptibility to tulathromycin but monitoring of susceptibility patterns should continue.
Effects on the immune system Macrolide antibiotics affect the immune system by multiple mechanisms including recruitment of inflammatory cells (Ichikawa et al., 1992; Mikasa et al., 1992), secretion of pro-
11
inflammatory cytokines (Takeshita et al., 1989) and pro-apoptotic activities (Chin et al., 1998; Lee et al., 2004; Leiva et al., 2008; Wu et al., 2009).
Tulathromycin significantly increased leukocyte apoptosis and reduced levels of proinflammatory leukotriene B4 in M. haemolytica-challenged calves (Fischer et al., 2011). In vitro, tulathromycin induces apoptosis in bovine neutrophils in a time and concentration dependent manner when evaluated at concentrations that may be attained within the cells (50 µg/mL to 2 mg/mL). It was also demonstrated in vivo that tulathromycin induces apoptosis of BAL fluid leukocytes 3 h after its administration. Tulathromycin did not significantly alter BAL neutrophil numbers at 24 h of infection. The authors also reported that tulathromycin significantly reduced levels of phosphorylated inhibitor kappa beta, nuclear factor kappa-light-chain-enhancer of activated B cells, p65, and mRNA levels of pro-inflammatory interleukin-8 in lipopolysaccharide stimulated bovine neutrophils (Fischer et al., 2011).
The clinical significance of these findings may warrant further research. An interesting hypothesis will be to test whether the dual effects (antimicrobial and anti-inflammatory) of tulathromycin are important for the treatment of disease where the inflammatory response of the host play a key role in the pathogenesis of pneumonia (e.g bovine pneumonia by Mannheimia haemolytica) (Fischer et al., 2011).
Pharmacokinetics The pharmacokinetics of tulathromycin have been studied in mice (Villarino et al., 2012), cattle (Nowakowski et al., 2004; Cox et al., 2010), pigs (Benchaoui et al., 2004; Villarino et al.,
12
2013 a,b), goats (Young et al., 2010; Clothier et al., 2010) and foals (Venner et al., 2010). At label dose, tulathromycin is characterized by a rapid rate of absorption and large systemic availability (~90%) after intramuscular (IM) and subcutaneous (SC) administration. In plasma, tulathromycin has a long terminal half-life, ranging across domestic species from 60 to 140 h and a remarkable large volume of distribution (>10 L/kg) (Benchaoui et al., 2004; Nowakowski et al., 2004; Cox et al., 2010; Young et al., 2010; Clothier et al., 2010; Venner et al., 2010 Villarino et al., 2013 a,b). In pigs, most of the dose is eliminated as unchanged drug (Wang et al., 2012), by biliary and renal excretion (Pfizer, 2005a). Protein binding studies indicate that the unbound fraction of tulathromycin ranges from 0.53 to 0.68 (Pfizer, 2005b).
Lung pharmacokinetic studies in cattle, pigs and horses reveal an extraordinary capacity of tulathromycin for accumulation in lung tissue (Benchaoui et al., 2004; Cox et al., 2010; Nowakowski, 2004; Venner et al., 2010; Young et al., 2010; Villarino et al., 2013a,b). The magnitude of the local accumulation and long persistence of the drug in the target tissue (lung) results in a convenient treatment regimen (single administration) and positive clinical outcome rates for respiratory conditions (Cox et al., 2010).
Pulmonary epithelial lining fluid (PELF) is the fluid that distributes continuously throughout the respiratory tract including alveoli (Ng et al., 2004). The pharmacokinetics of tulathromycin in PELF was reported from samples from clinically healthy cattle and pigs (Cox et al., 2010; Villarino et al., 2013b).Results indicated that tulathromycin rapidly distributes into the intraairway compartment and persists there for a long time. In addition, both in cattle and pigs, the
13
drug exposure in PELF was extensive (AUC0-408>60x that in plasma) (Cox et al., 2010; Villarino et al., 2013b).
Bronchial epithelial lining fluid (BELF) is the bronchial surface liquid. A pharmacokinetic study of tulathromycin in BELF in the middle lobe from clinically healthy pigs used Bronchial micro-sampling (BMS) probes guided with a fiberscope (Villarino et al., 2013b). Such BMS probes have been used experimentally in humans to harvest BELF (Kikuchi et al., 2008; Kikuchi et al., 2007; Yamazaki et al., 2003). Consistent with results reported in lung homogenate and pulmonary epithelial lining fluid, tulathromycin accumulated in BELF. The maximal concentration of tulathromycin in BELF (72 h) was observed later than plasma (0.5 h), lung homogenate (24 h for middle lobe) and PELF (6 h) (Villarino et al., 2013b). The persistence of the drug in this lung compartment was very long. This is reflected in a mean transit time longer than 10 days (Villarino et al., 2013b).
Macrolide antimicrobials accumulate to a high extent in different cell types (Baughman et al., 1994; Jacks et al., 2001; Lakritz et al., 1997; Lucchi et al., 2008; Patel et al., 1996; Portnoy et al., 2002; Togami et al., 2009, 2010; Womble et al., 2006). An in vitro study demonstrated that tulathromycin accumulates in neutrophils and blood macrophages in bovine and porcine species (Siegel et al., 2004), bronchoalveolar cells in foals (Venner et al., 2010) and pigs (Villarino et al 2013b), pulmonary epithelial lining fluid cells (majority macrophages) from clinically healthy calves (Cox et al., 2010). These studies demonstrate the remarkable capacity of tulathromycin penetrate and accumulate into cells.
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Conclusions Tulathromycin has been registered by multiple regulatory agencies as an injectable formulation and is increasingly widely included as part of the health management of swine and bovine operations. Multiple clinical studies show that tulathromycin is effective in the treatment of respiratory disease in cattle and pigs. Its efficacy and safety profiles following a single administration makes tulathromycin a valuable therapeutic option for respiratory conditions of bovine and swine species. Part of the clinical efficacy may be explained by the magnitude of drug accumulation and long persistence in lung tissue. There is evidence indicating the capacity of tulathromycin to accumulate in lung tissue based on lung homogenate samples from healthy cattle and pigs. New information indicates that tulathromycin accumulates rapidly and extensively in the intra-airway compartment in pigs, cattle and horses. This provides a step forward in knowledge about the pulmonary kinetics of tulathromycin. A full characterization of the pharmacokinetics and the mechanisms and processes involved in the accumulation of tulathromycin in the biophase (interstitial fluid and/or ELF) may help towards defining the use of this macrolide drug as a model for the design of future molecules for respiratory conditions.
Conflict of interest statement NV and TMJ have no financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper. SAB is an employee of Zoetis Animal Health.
Acknowledgements
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The authors are grateful to the Metabolism and Safety Unit and farm staff of Pfizer Animal Health, Kalamazoo, MI, USA who assisted with this manuscript. Also we want to thank Misty Bailey, Dr. Cox (University of Tennessee) and the reviewers of this manuscript for their comments on this manuscript, which improve this work.
Appendix A: Supplementary material Supplementary material associated with this article can be found in the online version at doi…..setters insert doi number
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