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PK/PD Integration of Tiamulin by Injection against Mycoplasmal Infections of Lung and Joints

by 5m Editor
10 May 2011, at 12:00am

A report of a study into the pharmaocokinetic and pharmacodynamic integration of tiamulin (Denagard®) by injection against mycoplasmal infections of the lung and joints, presented by D.G.S. Burch (Octagon Services Ltd, UK) and U. Klein (Novartis Animal Health Inc, Switzerland) at the 5th Asian Pig Veterinary Society Congress in Pattaya, Thailand, in March 2011.

Introduction

Most of the work to develop effective dose rates of tiamulin injection (Denagard® – Novartis AH Inc.) for the treatment of enzootic pneumonia (Mycoplasma hyopneumoniae (MHP) and mycoplasmal arthritis (M. hyosynoviae (MHS) and M. hyorhinis (MHR)) were carried out before the use of integration of the pharmacokinetics (PK) of tiamulin in plasma or joint fluid with the pharmacodynamics (PD) or minimum inhibitory concentration (MIC) of the various mycoplasmas involved was established.

The purpose of this work was to review, retrospectively, the current PK /PD information and integration of tiamulin injection for these diseases.

Materials and method

Pharmacodynamics

Tiamulin’s activity against a variety of swine pathogenic mycoplasma (Hannan et al, 1997) is summarised in Table 1.

Table 1. Susceptibility of various mycoplasma strains to tiamulin (µg/ml)
Species No isolates MIC 50 MIC 90 MIC range
MHP 20 0.05 0.05 0.01-0.1
MHS 18 0.005 0.025 0.0025-0.1
MHR 20 0.1 0.25 0.025-0.5

Hannan & Windsor (1998) showed that the minimum bactericidal concentration (MBC) was approximately four times the MIC for MHP and Goodwin (1985) described it as two for MHS and one for MHR.

Pharmacokinetics

Tiamulin is co-dependent on time and concentration to exert its mycoplasmacidal effect and therefore the area under the curve over 24 hours (AUC 24h) is the most suitable PK parameter to determine the potential anti-mycoplasmal effect. McKellar et al (1993 and 2004) demonstrated that the AUC 24h for tiamulin in plasma was 8.79µg.h/ml following an injection at 15mg/kg bodyweight. Combined data from McKellar et al (1993) and Skov & Nielsen (1988) showed that there was an average joint fluid concentration at 40 per cent of the plasma concentration (range 28 to 59 per cent) giving an AUC 24h of 3.52µg.h/ml.

Results and discussion

The results are summarised in Table 2.

Table 2. PK/PD integration for tiamulin using
AUC24h / MBC (= MIC × MBC/MIC ratio)
Species AUC 24h MBC 50 MBC 90 AUC/MBC 50 AUC/MBC 90
MHP 8.79* 0.2 0.2 44 44
MHS 3.52** 0.01 0.05 352 70
MHR 3.52** 0.1 0.25 35 14
Key: * = AUC plasma; ** = AUC joint fluid

Using the =100 AUC/MIC (= MBC) ratio for bactericidal antimicrobials (Toutain, 2003) and =24 AUC/MIC ratio for bacteriostatic inhibitory antibiotics, tiamulin injection would appear to exert primarily an inhibitory effect at a dose of 15mg/kg bwt against MHP and MHR at both their MBC 50s and the former’s MBC 90, but a strong mycoplasmacidal effect against MHS’s MBC 50 and a likely mycoplasmacidal effect at its MBC 90.

This was confirmed clinically by Burch & Goodwin (1984), markedly reducing lameness caused by MHS. Burch (1984) showed an inhibitory effect against MHP reducing lung lesions by 49 per cent and Talummuk et al. (2010) demonstrated marked joint swelling reduction in nursery pigs affected by MHR polyarthritis, following treatment with Denagard Injection.

References

Burch, (1984) Proc. IPVS Congress, 117.

Burch & Goodwin, (1984) Vet. Rec., 115:594-595.

Goodwin (1985) Res. Vet. Science, 38:124-125.

Hannan et al. (1997) Antimicrob. Agents & Chemother., 41 (9):2037-2040.

Hannan & Windsor (1998) Novartis Report

McKellar et al. (1993) Leo Report

McKellar et al. (2004) Proc. IPVS Congress, 2:622.

Skov & Nielsen (1988) Leo Reports

Talummuk et al. (2010) Proc. IPVS Congress, 2:1012.

Toutain (2003) J. Vet. Pharmacol. & Therap., 26 (Supp 1): 1-7.

Further Reading

- Find out more information on enzootic pneumonia by clicking here.


Further Reading

- Find out more information on mycoplasmal arthritis by clicking here.


May 2011