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Rational antibiotic use: When to consider short antibiotic courses

By Virginia Sinnott, DVM, DACVECC
Chair of the Infection Control Committee
Angell Animal Medical Center
angell.org/emergency
emergency@angell.org
617-522-7282

 

Recently, large, multi-center randomized clinical trials and meta-analyses of several of these trials have challenged the beliefs of human physicians regarding the necessary length of antibiotic treatment.1,2 While it was repeated across the medical community to prescribe adequate lengths of antibiotics to avoid inducing resistance, as our understanding has evolved, this belief has been challenged. In humans treated with prophylactic antibiotics for viral pneumonia (similar to what is commonly done in feline URI) the risk of colonization or infection with a multi-drug resistant organism was significantly higher when longer antibiotic courses were prescribed (53% vs 21%, p=0.027).3 The prevailing theory is that the longer a patient’s normal flora is exposed to antibiotics, the higher the proportion of their flora remains resistant long-term. This theory is rooted more in evolutionary biology than clinical microbiology and paradigms are shifting to ask clinicians to consider the impact of drug use on the patient’s entire microbiome, rather than simply its effect on the bacteria causing the infection. The goal, then, would be to use just enough antibiotic to clear the infection but not enough to shift the patient’s intestinal, skin and oral flora to a more resistant population so as to avoid the patient’s next infection being multi-drug resistant. The obvious question, however, is which cases warrant a short-course of antibiotics to honor this theory, and how does one safely and effectively use short-course antibiotics?

An example of a laceration caused by sharp tearing (in this case a barbed wire fence) that result in a full thickness wound with minimal underlying tissue damage presented for repair within 6 hours of injury. In an otherwise healthy patient, this case is an excellent candidate for perioperative-only antibiotics after surgical debridement and closure.

There are two main sources of good information regarding the “what” and “how long” of treating bacterial infections. The first is the primary veterinary literature (or reviews of such literature) and the second are expert-generated, evidence-based clinical guidelines. To be informative, investigations looking at an intervention (i.e. antibiotics in this case) should always be conducted in a randomized, prospective, blinded manner. Conclusions recommending a particular treatment should ideally not be made from retrospective data due to the high potential for bias. There are few well designed studies that evaluate antibiotic treatment course lengths, but the one type of infection that has been reasonably well studied is urinary tract infection (UTI). One investigation showed that 18-20mg/kg of enrofloxacin for 3 days was not inferior to 13.75-25mg of amoxicillin-clavulanic acid for 14 days for treating uncomplicated UTI. There are some concerns with using enrofloxacin as a first-line treatment for UTI, however. Healthy animals treated with enrofloxacin have been shown to develop multi-drug resistant E. coli strains in their intestinal tract, whereas the same animals treated with amoxicillin develop resistance only to beta-lactam antibiotics.4 Should a patient treated for UTI go on to develop pneumonia, the disease is more likely to be life-threatening if the infecting bacteria is a multi-drug resistant E. coli rather than a beta-lactamase producing E. coli. Another investigation of short-course antibiotics looked at a three day course of trimethoprim sulfamethoxazole (SMZ-TMP) (15mg/kg BID) versus cephalexin 20mg/kg PO BID q 10 days and found no difference in long-term cure rates, however the overall long-term cure rate in both groups was low.5 Many clinicians are leery of potentiated sulfa drugs because of their side-effect profile, however in this study a limited number of dogs were tested for the presence of drug-specific antibodies and T-cells and none were positive, and no treated dogs had side-effects suggesting that, as is the case in women, shorter courses may not result in as much immune stimulation as longer courses of potentiated sulfas, however a larger study is needed to make definite conclusions.

 

Again, when it comes to UTI, there is a relative wealth of expert-derived guidelines. The international society of companion animal infectious disease (ISCAID) has released guidelines for the management of UTI. For simple, uncomplicated urinary tract infections, after complete urinalysis and ideally, culture submission, Amoxicillin 11-15mg/kg PO q 8 or SMZ-TMP (15mg/kg PO q 12) are recommended for empiric treatment. Amoxicillin/clavulanic acid is an acceptable option but not recommended due to the desire to keep the spectrum narrow and the lack of significant increase in coverage.6 As for duration, the working group recommends 7 days of therapy, however this guideline was published prior to the study looking at 3 days of therapy for SMZ-TMP. Thus, synthesizing the two sources, it seems reasonable to treat with amoxicillin for 7 days and SMZ-TMP for three days. Further bolstering the clinicians’ confidence that short courses would be supported by expert colleagues, the American College of Veterinary Internal Medicine’s guidelines for antimicrobial use specifically point out that there is “little justification for longer therapy in animals” as compared to the much more thoroughly investigated human antibiotic regimens.7 In other words, “what we have always done” is not based on evidence; it is based on tradition.

 

For complicated urinary tract infections, the literature is quite sparse. These infections are defined in the ISCAID guidelines as an infection occurring in the presence of an anatomic or functional abnormality or a comorbidity that predisposes the patient to infection, or a recurrent infection. A recurrent infection is defined as 3 or more episodes of UTI in a year.6 If an infection is defined as complicated, considering a short-course option is likely unwise, however the ISCAID recognizes that there is no evidence supporting the current recommendation of 4 weeks of therapy and suggests considering shorter courses on a case-by-case basis, specifically in cases of first-time UTI in a patient whose co-morbidity (i.e. diabetes or Cushing’s disease) makes their UTI “complicated”.

 

Outside of UTI, there are very few studies which address the length of antibiotic therapy for a specific disease. One area where antibiotic use may be surprisingly controversial however is minor bite wounds. A recent study found that despite seven of the dogs being on an antibiotic to which the cultured organisms were resistant, none developed an infection associated with their bite wound.8 In fact, a systematic review of bite wounds to humans revealed that there is no evidence for prophylactic antibiotic use (i.e. a fresh bite with no signs of infection) for dog and cat bite wounds to humans.9 Thus it would be prudent to consider either not using antibiotics or using a short (3-5 days) course of antibiotics in minor bite wounds with a low risk of infection. A wound could reasonably be considered low risk if it is less than six hours old, minor in nature (little evidence of underlying tissue damage or pocketing), the patient is otherwise healthy without significant co-morbid diseases and the wound is addressed either medically (clipped and cleaned) or surgically debrided. There is no evidence to support a course that covers the time to full healing (10-14 days) and this may increase the likelihood of selecting for resistant organisms in the patient’s skin and intestinal flora.4 Injections of long-acting antibiotics are likely not indicated for such fresh, minor wounds using similar rationale. An even stronger case can be made for solely using perioperative antibiotics for lacerations that a surgeon feels comfortable closing primarily (i.e. skin ripped on a fence, cuts from glass) as surgical debridement and lavage should reduce contamination to levels the immune system can overcome (Figure 1).  Although not common in Massachusetts, it should bring some comfort to those seeking to reduce antibiotic use and thus resistance that it has been shown prospectively that the deep puncture from rattlesnake bites in dogs do not require antibiotics to avoid infection.10 It stands to reason that other such small wounds (i.e. torn toenails, partial thickness lacerations, grazing or minor bite wounds) would likely not require anything more than topical therapy to have a successful outcome. It is also a good idea to confirm good health in cases where antibiotics are to be avoided by taking a good history (including ascertaining the level of force/violence associated with a bite incident) and performing a biochemical analysis as diseases like diabetes and hyperadrenocorticism can have subtle signs in the early stages of the disease but may affect healing and immune function.

 

Finally, not all cases of pneumonia may require the traditionally recommended but not evidence based “continue antibiotics for 1-2 weeks past radiographic resolution of pneumonia”. A pilot study performed at Angell and currently accepted but awaiting publication in the Canadian Journal of Veterinary Medicine found no difference in recurrence rates in animals treated with antibiotics for less than 14 days or greater than 14 days and we often recommend 10 days of therapy for uncomplicated pneumonia in which the patient didn’t require oxygen therapy, especially if the disease was mild enough to be treated on an outpatient basis or with less than 24h of therapy in hospital.

 

It is important for clinicians to remember that recommended antibiotic treatment courses for most of the diseases we treat are based on clinical experience and expert opinion, rather than evidence. While this has worked to cure a specific disease, veterinarians will be challenged in the decades ahead, as less and less pharmaceutical dollars are going into antibiotic research, to help avoid resistance by treating not only the infection at hand but considering the effect their therapy has on the patient’s next infection and the other beings in the household (including pets, children and adults who may have disease of their own). For non-life threatening infections in healthy individuals there is little defense to use long courses of antibiotics and more and more veterinary evidence is being published that suggests short-courses (or no antibiotics) may be a better or equivalent option.

For more information, contact Dr. Sinnott at 617-522-7282 or emergency@angell.org.

 

References

  1. Sawyer RG, Claridge JA, Nathens AB, Rotstein OD, Duane TM, Evans HL, et al. Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection. N Engl J Med. 2015 May 21;372(21):1996–2005.
  2. Li JZ, Winston LG, Moore DH, Bent S. Efficacy of Short-Course Antibiotic Regimens for Community-Acquired Pneumonia: A Meta-analysis. Am J Med. 2007 Sep;120(9):783–90.
  3. Crotty MP, Meyers S, Hampton N, Bledsoe S, Ritchie DJ, Buller RS, et al. Impact of antibacterials on subsequent resistance and clinical outcomes in adult patients with viral pneumonia: an opportunity for stewardship. Crit Care [Internet]. 2015 Dec [cited 2016 Dec 21];19(1). Available from: http://ccforum.com/content/19/1/404
  4. Aly SA, Debavalya N, Suh S-J, Oryazabal OA, Boothe DM. Molecular mechanisms of antimicrobial resistance in fecal Escherichia coli of healthy dogs after enrofloxacin or amoxicillin administration. Can J Microbiol. 2012 Nov;58(11):1288–94.
  5. Clare S, Hartmann FA, Jooss M, Bachar E, Wong YY, Trepanier LA, et al. Short- and Long-Term Cure Rates of Short-Duration Trimethoprim-Sulfamethoxazole Treatment in Female Dogs with Uncomplicated Bacterial Cystitis. J Vet Intern Med. 2014 May;28(3):818–26.
  6. Weese JS, Blondeau JM, Boothe D, Breitschwerdt EB, Guardabassi L, Hillier A, et al. Antimicrobial Use Guidelines for Treatment of Urinary Tract Disease in Dogs and Cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases. Vet Med Int. 2011;2011:1–9.
  7. Weese JS, Giguère S, Guardabassi L, Morley PS, Papich M, Ricciuto DR, et al. ACVIM Consensus Statement on Therapeutic Antimicrobial Use in Animals and Antimicrobial Resistance. J Vet Intern Med. 2015 Mar;29(2):487–98.
  8. Indrawirawan Y, Lam I, McAlees T. Characteristics of dog bite wounds in Melbourne, Australia: Is prophylactic antibiotic use justified? Aust Vet Pract. 2014;44(3):654–9.
  9. Medeiros IM, Saconato H. Antibiotic prophylaxis for mammalian bites. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2001 [cited 2017 Jan 3]. Available from: http://doi.wiley.com/10.1002/14651858.CD001738
  10. Carr A, Schultz J. Prospective evaluation of the incidence of wound infection in rattlesnake envenomation in dogs: Wound infection in rattlesnake envenomation in dogs. J Vet Emerg Crit Care. 2015 Jul;25(4):546–51.

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