Improving the Outcome of Antimicrobial Treatment

The most common and important enteric infections in the ileum and colon are the following: 

• Porcine Proliferative Enteropathy (PPE, ileitis), caused by Lawsonia intracellularis. This is a common and widespread infection in the small intestine and also occurs infrequently in the large intestine of pigs. Often the disease progresses subclinically, causing poor pig performance. Acute and chronic forms of ileitis are treated by antibiotics of several drug groups (pleuromutilins, macrolides, lincosamides, tetracyclines). 
• Swine Dysentary (SD), caused by Brachyspira hyodysenteriae, is a serious diarrhoeal disease in the colon of grower-finisher pigs with re-emerging character in many countries (US/Canada/Brazil/Spain). 
• Porcine Colonic Spirochaetosis (PCS, colitis), caused by Brachyspira pilosicoli, is a mild to moderate non-fatal infection mainly in young weaned animals (20-40kg). Economic losses are due to reduced growth and the associated impact on pig flows and market uniformity.

When pigs are challenged by PPE, SD or PCS the most important consideration must be to quickly control the disease with an appropriate treatment. Different antibiotics are licensed for therapeutic use against Lawsonia and Brachyspira infections in pigs.

No suitable protective vaccines against B. hyodysenteriae and B. pilosicoli are available commercially. In the case of L. intracellularis, currently an inactivated Lawsonia vaccine and a live attenuated vaccine can be used for PPE prevention. 

Responsible use of antibiotics and AMR

Sustaining antibiotic efficacy in the long term is critical and demands the responsible use of antibiotic therapies. The targeted use of antibiotics aims to limit the development and the expansion of antimicrobial resistance (AMR). 

The animal health and production industries play a significant role in minimising AMR risk. Following internationally endorsed recommendations summarised in the '5Ds' of antibiotic stewardship is the basis for AMR minimisation. 

• Diagnosis - does the condition require antibiotic therapy? 
• Drug - are the bacteria susceptible?
• Dose - what is the recommended dose?
• Duration - what is the recommended duration?
• De-escalation - what is the appropriate treatment and route of administration?

Considerations when using antibiotics

Selecting the best antibiotic depends on the therapeutically effective concentrations that the antibiotic achieves at the gut infection site and the susceptibility of L. intracellularis / B. hyodysenteriae / B. pilosicoli strains to the antibiotics registered. Use of a drug with broader spectrum can be beneficial based on different bacteria organisms possibly present in the ileum and colon based on polymicrobial infections. 

When selecting the appropriate type of antibiotics for PPE, SD or PCS treatment, it is vital to look at two different antibiotic characteristics, both of which are essential for treatment justification. They must have:

1. A favourable pharmacodynamic (PD) activity measured as minimum inhibitory concentrations (MICs)
2. Specific pharmacokinetic (PK) behaviour
   • Distribution to the entire gastrointestinal tract
   • Intracellular absorption/high concentration in crypts and epithelial cells of the large intestine
   • A sustained activity at the site of infection

Favourable MICs

Lawsonia intracellularis susceptibility testing

Limited data on the in vitro sensitivity of L. intracellularis strains to antibiotics are available. This is due to the difficulty of isolating and maintaining L. intracellularis from faecal or intestine samples and the need to use complicated cell culture systems to evaluate antimicrobial activity in vitro. The in vitro sensitivities of L. intracellularis strains from important pig production countries are shown in Table 1. 

Table 1. Intracellular MIC endpoints (in μg/ml) for different antimicrobials against L. intracellularis strains from USA, Denmark, UK, Brazil, Thailand and Korea. The bacteria were tested twice.

The MICs evaluate the L. intracellularis antimicrobial susceptibility in four different important pig production regions worldwide. The intracellular MICs were determined to measure the effect of the antibiotics on L. intracellularis when the intracellular organisms were inside the enterocytes. The intracellular MIC results show that tiamulin is the most active compound against the tested L. intracellularis isolates. Tylosin shows intermediate activity and lincomycin is the least active compound with high MICs. High MIC variation was determined for chlortetacycline. 

Brachyspira hyodysenteriae susceptibility testing

Sensitivity tests with B. hyodysenteriae strains are conducted routinely worldwide in several institutes with experience in Brachyspira culturing, isolation and MIC testing. In Table 2, results of MIC investigations on the use of broth microdilution method (one study use of agar dilution) are summarised. In the majority of the countries, low MIC values and high susceptibility to tiamulin was found. In contrast, most Brachyspira isolates show low susceptibility to lincomycin and tylosin with constantly high MICs. B. hyodysenteriae isolates displayed heterogeneous susceptibility to tylvalosin with moderately high MICs. 

Table 2. Country-specific MIC results (μg/ml) for B. hyodysenteriae isolates for commonly used antimicrobial agents. AST: Antimicrobial susceptibility testing, BD: broth microdilution method, AD: agar dilution method.

Pharmacokinetics

Once the MIC against L. intracellularis and B. hyodysenteriae strains is determined, it is necessary to relate the MIC data to the PK characteristic of the antibiotics. The relation allows vets to assess if effective therapeutic concentrations can be achieved at the ileum and colon infection site. In Table 3, the colon content concentration (CCC) and ileum content concentration (ICC) of different antibiotics achieved after in-feed treatment at registered dose levels is summarised.

Table 3. Colon and ileum concentration (μg/g) of different antibiotics used for enteric infection treatment (oral application). E = estimate

The published data show a rather linear relationship between the in-feed concentration and found CCC and ICC of the antibiotics. Tiamulin achieves relatively low concentrations in the colon and ileum in comparison with lincomycin and tylosin. Concentrations of tylvalosin in the colon and ileum are in between after in-feed medication.

PK/PD profiles for Lawsonia intracellularis

PK/PD analysis demonstrates differences between the three drugs and their likely potential to inhibit ileitis infections. A strong treatment effect against ileitis can be expected at ICC of the drug after oral administration at or above the intracellular MICs. This is the case for tiamulin (tiamulin ICC 2-18 times above the MIC) and for tylosin (tylosin ICC 1-125 times above the MIC). In the case of lincomycin, a prediction of the treatment effect cannot be given after oral administration based on much lower lincomycin ICC versus the determined lincomycin MICs.

PK/PD profiles for Brachyspira hyodysenteriae

PK/PD differences of the four drugs are important to consider for the decision on what antibiotic to select for SD treatment. For prediction of successful treatment against SD, the CCC of the drug needs to be at or above the MIC₅₀ and MIC₉₀ values. This is the case for tiamulin at both dosage levels tested. High lincomycin MIC₅₀ and MIC₉₀ values predict a therapeutic effect only at the higher tested dose. A treatment effect of tylosin is unlikely based on tylosin MICs greatly in excess of tylosin CCCs achieved. Tylvalosin CCCs at two treatment levels are in between MIC₅₀ and MIC₉₀ values. A therapeutic effect is likely to be achieved at lower MICs.

Conclusions

Susceptibility testing, knowledge of antibiotic pharmcokinetics and targeted use of antibiotics are effective tools to limit development and expansion of AMR. Antibiotic drug PK/PD profiles help to identify the best dosing regimes for enteric infection treatments. These PK/PD concepts are the basis for therapeutic success, for distinct reduction of B. hydysenteriae and L. intracellularis levels to avoid SD/PPE reinfections in the next production phases and for dose optimisation which helps to prevent therapeutic failures.

References are available on request.

This article originally appeared in Pig Progress Vol 36 No 3.