Antimicrobial use in foals: Do we need to change how we think?

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The veterinary profession is currently under extreme pressure to re-evaluate and regulate our use of antimicrobials. This stems from a global strategy being driven by the World Health Organization to reduce the development of antimicrobial resistance [1-3]. The British Equine Veterinary Association has responded with the ‘Protect ME’ strategy to try to improve use of antimicrobials within the equine veterinary profession [4, 5].

Foals are uniquely at risk for the development of sepsis due to their reliance on the absorption of colostral antibodies for the acquisition of humoral immunity. The ‘open gut’ allows transolocation of maternal antibodies and bacteria directly into the neonatal circulation, with the potential for rapid onset of bacterial sepsis. In addition, the incidence of failure of passive transfer is relatively high, which increases the risk for the development of sepsis [6, 7]. Sepsis remains one of the primary causes of neonatal mortality, despite advances in intensive care [8]. Broad-spectrum antimicrobial coverage is indicated in foals with sepsis or suspected sepsis, and it is not feasible to wait for the results of culture and sensitivity to be available. Broad-spectrum options for antimicrobial coverage include penicillin or ampicillin with an aminoglycoside or a third- or fourth-generation cephalosporin.

As clinicians, there are many reasons why we opt to use the newer generation drugs, such as cefquinome; their effectiveness, their broad spectrum of activity, the fact that they are well tolerated with few side effects and minimal nephrotoxicity and that they can be given by both i.m. and i.v. injection. As a result of these considerations, the use of these ‘protected’ drugs is increasing, and these drugs are often given to foals that are judged to be at risk for sepsis, in addition to foals with confirmed sepsis. This coincides with increasing pressure for us to reduce and restrict the use of these drugs.

The studies by Theelen et al. in this issue of Equine Veterinary Journal raise some very important issues related to the use of antimicrobials in foals [9, 10]. The first article documents the prevalence of different bacterial isolates from foals with sepsis over the last 31 years [9]. A total of 1091 bacterial isolates were obtained from 588 foals; 70% of isolates were Gram-negative and 30% Gram-positive. Forty-seven per cent of foals in this study had a mixed infection. This highlights the importance of providing broad-spectrum antimicrobial coverage.

This study also identifies significant trends in the prevalence of bacteria isolated over the time period. An increase in the prevalence of Gram-positive infections was noted over time, with 35.9% of isolates in the most recent time period being Gram-positive, compared with only 25.9% in 1979–1990. This trend fits with that noted in human medicine, where Gram-positive infections are becoming increasingly important [11]. One of the most likely explanations for this trend in equine medicine is that the increasing use of drugs with a Gram-negative spectrum has reduced the prevalence of Gram-negative sepsis. This should highlight to us that our choice of antimicrobials has an impact on the future as well as the present.

Enterococcus spp. were also identified as increasingly important pathogens. This is a finding that has been noted previously [12]. Enterococcus spp. accounted for 5.5% of total isolates between 1979 and 1990 and 12.1% of total isolates between 1998 and 2010. This is a finding of concern for a number of reasons. Firstly, as clinicians treating individual foals, treatment of infection with Enterococcus spp. can be very challenging due to unpredictable and variable antimicrobial sensitivity patterns. Secondly, this increase in prevalence of Enterococcus infection probably represents, at least in part, an increase in hospital-acquired nosocomial infection.

Theelen et al. [9] also provide convincing evidence that our use of antimicrobials does influence antimicrobial susceptibility patterns. They demonstrate an increase in the percentage of bacteria resistant to commonly used drugs, such as gentamicin and ceftiofur, over time. They also demonstrate changes in minimal inhibitory concentration (MIC) values, which can be taken as early warning signs for the development of resistance. These findings strongly support the fact that the use of broad-spectrum antimicrobials applies strong selection pressure to bacterial isolates and encourages the development of resistance. It is interesting to note that in this study, a reverse trend also exists, with a decrease in resistance to less commonly used drugs, such as tetracyclines, over the study period. This should encourage us that it may be possible to modify the development of resistance by modification of our use of antimicrobials.

Studies from hospital-based populations are biased towards the demonstration of antimicrobial resistance. A proportion of bacterial isolates identified in the current studies [9, 10] were probably acquired during hospitalisation. Clinicians working in the hospital environment have an added responsibility to monitor and justify their use of antimicrobials and the development of resistance. Foals in the intensive care unit are frequently treated with broad-spectrum antimicrobials to combat sepsis. This greatly increases the opportunity for nosocomial infection, because alteration of the normal gastrointestinal flora and sterilisation of other bacteria allows infection with resistant organisms. Enterococcus spp. in the study by Theelen et al. showed dramatic alterations in resistance patterns over time [9]. The MIC value for ceftiofur increased and the percentage of isolates resistant to imipenem increased over time. Imipenem is a drug that is rarely used in equine medicine and is reserved for use in infections proven to be resistant to other antimicrobials. Enterococcus is known to be able to accumulate mutations and genes that confer resistance and to be able to respond rapidly to selection pressure from use of broad-spectrum antimicrobials. The fact that resistance to imipenem has increased without an increase in the use of the drug is of great concern.

As levels of intensive care continue to improve, with foals surviving from increasingly complex conditions, the prevalence of multiresistant infections is likely to increase. This encourages the use of more and more ‘reserved’ and ‘restricted’ antimicrobials to treat disease. It is essential that individual clinicians and hospitals take responsibility for the monitoring of bacterial isolates and resistance patterns to try to control the use of antimicrobials and the development of resistance.

Theelen et al. suggested that ampicillin plus amikacin is the most appropriate first-line choice for the treatment of sepsis in foals [9]. The data were collected in the USA, and this statement should be interpreted with some caution for clinicians in other areas of the world because it is known that susceptibility patterns can vary widely. It cannot be assumed that this pattern will remain true in all environments. However, the use of these drugs would be in line with the British Equine Veterinary Association Protect ME guidelines, and would reduce our usage of cephalosporins in neonatal foals. When using these drugs, we must be careful to be aware of the potential for nephrotoxicity with the use of aminoglycosides in neonates and take appropriate care to prevent this.

Also in this issue of Equine Veterinary Journal, there is a study describing the use of doxycycline at low doses to act as a disease-modifying osteoarthritic drug [13]. The authors argue that by use of the drug at such low doses, which keeps the concentration below the MIC90 for most common pathogens, there is little chance of the development of resistance. Nevertheless, this assertion should be interpreted with caution until greater evidence is available. At a time when we are striving to reduce our use of antimicrobials, we might question whether we should be encouraging long-term use antimicrobials for other purposes.

In conclusion, we should follow the lead of our American colleagues and strive to improve our recording, reporting and understanding of the development of antimicrobial resistance in neonatal foals. These studies convincingly demonstrate that our use of antimicrobials has an effect both on the prevalence of bacterial isolates identified and on susceptibility patterns. This should encourage us to think carefully about our use of antimicrobial drugs. There is also an added responsibility for clinicians working in hospital and high-selection-pressure environments to control and monitor our use of ‘protected’ antimicrobials and the development of resistance. As clinicians, our primary aim is always to save the individual animal, and for this reason, the use of broad-spectrum antimicrobial therapy to treat neonatal sepsis will remain a high priority. However, we also have an individual responsibility to regulate our use of antimicrobials, especially those that have been identified as critically important for human health. We should be avoiding the unnecessary prophylactic use of antimicrobials and reserving our use of restricted antimicrobials for foals with confirmed sepsis or high likelihood of sepsis.

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