Treating E. coli in the Era of Prudent Use

In a world where antibiotic use in livestock is increasingly under scrutiny, it is becoming vital to understand precisely the mode of action of each antibiotic. This will allow swine veterinarians to know in detail when to apply them and in which manner - making sure the best outcome is guaranteed for the pigs and their environments.

Escherichia coli is a Gram-negative bacterium which is the causative agent of pig neonatal diarrhoea and post-weaning diarrhoea. Both diseases are life-threatening and are important causes of economic losses for the pig industry due to mortality, morbidity and decreased growth rate. 

Antimicrobial therapy in cases of enteric colibacillosis infections is still based on the use of various classes of antibiotics. New regulations limit the use of different antibiotic classes for E. coli treatment. Implementation of an antibiotic categorisation system in the EU in February 2023 will restrict the use of several antibiotics that are considered critically important for human medicine; think of colistin, danofloxacin and enrofloxacin.

Zinc oxide as a therapeutic drug (2,000 - 3,000 ppm) will be banned for medical use in June 2022 and already is not marketed anymore in a range of European countries: Belgium, France, the Netherlands and Germany. Missing cross-protection and a narrow activity spectrum impede the effective use of vaccines as a preventative approach to manage colibacillosis infections. That necessitates the use of other effective colibacillosis antibiotic treatment options - ideally those which are not classed as critically important for humans.

Antibiotic stewardship and requirements

Antibiotic stewardship requires professional veterinarians to abide by certain requirements. A vet should sustain the efficacy of antibiotics and prevent resistance development. In addition, a veterinarian should optimise dosing based on improved understanding of the mode of action of antimicrobial products. Thirdly, a vet should use the most effective antibiotic for treatment purposes.

Successful treatment of E. coli infections can only be achieved by the administration of an antibiotic that reaches therapeutic concentrations at the intestinal infection site, where E. coli is present. The antimicrobial susceptibility of E. coli strains is fundamental to combat the emergence and expansion of antibacterial resistance.

When choosing antibiotics, a veterinarian should consider: 

• antibiotic therapeutic concentrations in the intestine
• the sensitivity of E. coli strains

This is why susceptibility testing is fundamental for correct therapy.

Responsible use of antibiotics in animals lowers the risk of bacteria becoming resistant. A key element in veterinary practice is prudent antibiotic use based on pharmacokinetic (PK) and pharmacodynamic (PD) data. The decision to treat and the choice of antibiotics is ideally based on PK/PD knowledge, which is in line with global treatment guidelines in place on antibiotic usage.

E. coli treatment options

Apravet (apramycin) and Parofor (paromomycin), both marketed by Huvepharma, belong to the group of aminoglycoside antibiotics. Both antibiotics are non-absorbable and concentrate in the small and large intestine of pigs after feed and water medication and, as a result, they mainly exercise their activity in the gut. In pharmacokinetic studies the concentration of both antibiotics was determined in the small and large intestine during in-feed and water administration at the registered dosage (Table 1).

Table 1. Apramycin* and paromomycin** concentrations in small and large intestine content during feed and water medication and after medication cessation

Access to recent antimicrobial susceptibility data helps guide veterinarians in selecting the most appropriate antibiotic for treatment of colibacillosis. Antimicrobial susceptibility testing on E. coli strains is conducted routinely in many countries. Those data are put in relation to minimum inhibitory concentration (MIC) data for prediction of successful treatment.

Apramycin testing results

Apramycin MIC testing results from European E. coli strains are put in relation to apramycin intestine concentrations achieved at treatment dosage after feed medication (Figure 1). 

Figure 1. Apramycin MIC ranges for E. coli strains and PK relationships following in-feed medication at therapeutic dose

The apramycin concentration in the small intestine exceeds the MIC₉₀ value of 90% of the tested EU E. coli strains. These results indicate very high sensitivity of the strains, predicting high efficacy of apramycin in the case of its metaphylatic and therapeutic use.

Paromomycin testing results

Paromomycin MIC testing results from European E. coli strains and the paromomycin concentration achieved at treatment level after water medication are related to each other and shown in Figure 2. 

Figure 2. Paromomycin MIC ranges for E. coli strains and PK relationships following water medication at therapeutic doses

The paromomycin concentration in the small intestine achieved at the lowest registered dose (25 mg/kg body weight) exceeds the MIC₉₀ value of 88% of the tested EU E. coli strains. At the highest registered dose (40 μg/kg body weight) the estimated intestinal concentration is above 1,100 mg/g, which exceeds the MIC₉₀ value of all E. coli strains tested. Those results indicate very high sensitivity of the E. coli strains, predicting high efficacy of paromomycin at the dose range registered for therapeutic use.

Susceptibility testing and prudent use

Susceptibility testing of E. coli isolates, knowledge about antibiotic pharmacokinetics and prudent use of antibiotics help to limit development of antimicrobial resistance of E. coli strains. PK/PD profiles of apramycin and paromomycin show that both antibiotics are ideal options for successful enteric colibacillosis treatment. Future dosing regimes need to consider these PK/PD concepts for provision of consistent high therapeutic effects and to prevent therapeutic failures.

This article appeared in Pig Progress, Volume 37 Number 7