Antimicrobial resistance in food animals-are we encountering untreatable diseases? (Proceedings)

The short answer is "no" when we look for widespread, peer-reviewed evidence of untreatable infectious disease in food animals due to a microbial pathogen. However, there are some trends which bear watching. The evaluation of "untreatable disease" involves several inputs.

Just what difference do we expect from the use of an antimicrobial?

(See the accompanying presentation on the difference antimicrobials make). For some diseases with narrow response differences due to antimicrobial treatment, it may be difficult to discern the decrease in clinical response outside of a research setting. For diseases with wider demonstrated difference due to treatment, such as bovine respiratory disease, the difference made by antimicrobials is significant enough that a lack of efficacy would be more immediately apparent in clinical practice.

How would we evaluate laboratory data to see if decreasing susceptibility is contributing to a lack of efficacy in the field?

The first thing I do is figure out if the application I am evaluating has an approved CLSI breakpoint. If it does, then I am more likely to equate resistance in the laboratory with lack of efficacy in the field. For those antimicrobial/pathogen combinations without an approved breakpoint, if the MIC is in the higher-MIC group of a biphasic distribution (a group of isolates with lower MICs and a group of isolates with higher MICs), then this is suggestive of the presence of a resistant genetic component, and I assume clinical resistance. When the population distribution is monophasic, or this information is lacking, we are left with assuming (hopefully) that "S is better than R".

The CLSI has approved the following veterinary specific breakpoints. These breakpoints are detailed in CLSI M31-A3, including the specific pathogens associated with these breakpoints.

The following breakpoints are included in CLSI M31-A3 as "generic" breakpoints, where the breakpoint was determined on the basis of published pharmacokinetic parameters in the designated species in combination with available target pathogen susceptibility data.

     • Ampicillin - Horses (respiratory disease) and Dogs (skin and soft tissue infections)

     • Gentamicin - Horses (enterobacteriaceae, Pseudomonas aeruginosa, Actinobacillus spp.)

                              Dogs (enterobacteriaceae, Pseudomonas aeruginosa)

     • Oxytetracycline – Cattle (respiratory disease) and swine (respiratory disease)

For some antimicrobials used in veterinary medicine, the CLSI/VAST Subcommittee has found it necessary to use human-derived breakpoints since no sponsor has brought the information to the subcommittee to develop approved breakpoints. The VAST Subcommittee is working on developing "generic" breakpoints for veterinary labels without approved breakpoints and for extralabel uses. The following antimicrobials have human-derived breakpoint criteria adapted by the NCCLS/VAST Subcommittee. For these antimicrobials, and for extralabel use of antimicrobials with approved veterinary breakpoints, it is necessary to evaluate the susceptibility testing results in light of the MIC breakpoint used and the pharmacokinetics/pharmacodynamics of the animal and pathogen being treated.

     • Aminoglycosides

          o amikacin, gentamicin, kanamycin

     • β-lactams

          o amoxicillin-clavulanic acid, ticarcillin-clavulanic acid

          o ampicillin, oxacillin, penicillin, ticarcillin, , imipenem, cefazolin

     • Others

          o erythromycin, chloramphenicol, trimethoprim-sulfamethoxazole

          o rifampin, sulfisoxazole, tetracyclines, vancomycin

Interpreting susceptibility testing for extralabel applications

When the disk diffusion method is used for extralabel applications, not only are the dilution MICs suspect as to clinical application, but there is also the question of if the zone diameter criteria still correlate to the MICs. The take-home message is to know what susceptibility testing situations have veterinary approved breakpoints. For unapproved breakpoints, "susceptible" is probably better than "resistant", as this may place the "S" pathogen in a defined population of zone diameters or MICs, but the "S" result does not necessarily mean that there is an increased chance for clinical success.

Is there clinical evidence of lack of efficacy?

If we mean published, peer-reviewed data of widespread problems, we are lacking. There are anecdotal reports, supported by laboratory susceptibility results, where lack of efficacy has been proposed. Here are a couple of them.

Salmonella enterica serotype newport

While Salmonella Newport is not the most common Salmonella serotype in cattle, it is very serious when it does occur. Prior to discussing susceptibility results of these isolates, it is important to note that the breakpoints used for susceptibility testing are not approved or validated for Salmonella in cattle. However, in the instance of biphasic populations, those isolates in the population on the high MIC side may be assumed to be harboring genetic resistance components.

Susceptibility results for Salmonella Newport displaying susceptibility only to ceftiofur, a enrofloxacin/danofloxacin, a potentiated sulfa, and gentamicin have been reported. In addition, isolates with ceftiofur resistance have been noted. In this case, the latter three options would pose the challenges of being illegal for extralabel use in food animals, illegal for extralabel use in lactating dairy cows, and posing an 18 month slaughter withdrawal time, respectively. Therefore, in a lactating dairy cow, a multidrug resistant S. Newport displaying ceftiofur resistance would be essentially untreatable in light of regulations and the desire to retain a reasonable slaughter withdrawal time. My definition of untreatable is that we would experience only the spontaneous cure rate in the population, which in the case of a systemic Salmonella infection may be anticipated to be fairly low.

This is an excellent example of how the realities of treatment response involve both the drug / pathogen interaction and regulatory issues.

Mannheimia haemolytica

Here we have a disease with multiple antimicrobials with CLSI-approved breakpoints, giving us more confidence in the implications of susceptibility testing.

Data to be shown in the presentation related to Mannheimia haemolytica are presented in the proceedings pending further quality assurance checks and review. It is appropriate to report that some multi-drug resistant Mannheimia haemolytica isolates are being reported form several diagnostic laboratories. The inciting factors for the presence of these isolates have not been described.

Pasteurella multocida

Three new resistance genes have been identified in a macrolides-lincosamide-triamalide resistant Pasteurella multocida isolate from a Nebraska feedlot. This suggests that some of the resistance mechanisms in this respiratory pathogen are different from those reported in other pathogens and diseases.