Antibitotic Therapy: The Brave New World

Virginia Sinnott, DVM, DACVECC 

While all veterinarians were taught in veterinary school to obtain samples for culture with every infection they treat, the cost to the client of these cultures and, occasionally, the difficulty or risk in obtaining said samples forces practioners to treat in the absence of culture information a lot of the time. Additionally, even when cultures are obtained, the results are not available at best for 48-72 hours and thus antibiotic therapy is almost always commenced in the absence of culture information. In order to avoid blind guessing (and the persuasive but often biased advice of drug representatives) a rational, step-wise approach can be used. 

The goal of antibiotic susceptibility testing is to expose a pathogen isolated from a patient to several different antibiotics. A minimum inhibitory concentration (MIC) is obtained by exposing the pathogen to decreasing concentrations of a particular antibiotic. The lowest concentration that inhibits growth of the organism is the MIC. This will be expressed in micrograms per milliliter and is a good guideline for the antibiotic blood levels required produce a treatment cure. Because this testing happens in vitro, the onus is on the clinician to interpret the results with relevant physiology of the infection site in mind. Protected spaces such as the prostate, brain and eye will likely see lower concentrations of the antibiotic and thus achieving blood levels in excess of the MIC should be the goal with infection in these locations. Thus, higher doses and more frequent intervals may be required. Additionally infections in relatively avascular areas (i.e. the airway mucosal secretions as in the case of Bordatella bronchiseptica infection) may be best treated with drugs which concentrate in neutrophils and other cells of the immune system since blood flow to this mucosal barrier is minimal while diapedesis of neutrophils to site of these infections is abundant. It is likely for this reason that azithromycin and enrofloxacin appear anecdotally to result in more treatment cures for Bordatella pneumonia than penicillins such as Clavamox despite similar in vitro sensitivities. 

Once an MIC is obtained, a dose is often recommended based on that MIC by the laboratory. Because these doses do not take into account the location of the infection and the severity of the infection in that patient, it is generally recommended to use those doses as a guideline. In order to know how best to dose an antibiotic regime, it is important to know whether the killing properties of a drug are based on the maximum concentration achieved in the patient (concentration dependent antibiotics) or based on the time that the concentration of the antibiotic remains above the MIC in the patient (time-dependent). Table 1 identifies this property for commonly used drugs. For non-life-threatening infections in otherwise healthy patients (i.e. UTI, pyoderma, incisional infections), a target of 4X the MIC is adequate for concentration dependent drugs and 50% time in the dosing interval above MIC is appropriate for time-dependent drugs. For severe infections or immune-compromised patients it is important to target more aggressive goals, with the goal to be 8-10X MIC for concentration dependent drugs and >75% of the dosing interval time above MIC for time-dependent drugs.    

While discussions of time above MIC and how many multipliers above MIC a drug concentration should be seem logical in an academic discussion, applying this to a clinical case can be a bit of a burdensome leap that leaves the clinician flipping between text books, formularies and package inserts. This is not realistic for modern practice and using a single reference such as the TARGET guide can help. It is available free as an iOS application for iPhone/iPad  (search "TARGET (vet)" to avoid department store aps) and free online at  http://target.naccvp.com. Hardcopies of the book are available from your Bayer representative and are often given away at the Bayer booth at conferences. Screen shots from the iPhone/iPad application will be used throughout the following example.  

A nine-month-old female Golden Retriever puppy presents for hematuria and pollakiuria. Her vitals and PE are normal. Urine is obtained via cystocentesis and sent to the lab for a culture. In house UA reveals numerous WBCs and bacteria. You also place a drop of urine sediment on a slide and allow it to air dry and stain it with dif-quick (this is a good practice with suspected UTIs to confirm whether you're dealing with rods or cocci!). Microscopy reveals rod bacteria. What antibiotic should be chosen? 

For life-threatening infections such as pneumonia or septic peritonitis, the clinician must take the opposite approach: reach for a very "big gun" if there is an expectation of resistance, and then deescalate when cultures return. However, in this case, since there is no expectation of resistance and the infection is not life threatening, a first line choice is appropriate. First line choices include penicillins and cephalosporins. Looking again at figure 1, Both cephalexin and amoxicillin would be considered first line choices but cephalexin is considered a poor choice for E. coli while Amoxicillin is fair. This is because many E. coli isolates, even in antibiotic naïve patients, are resistant to cephalexin while amoxicillin remains a good choice for E.coli in those that have very little antibiotic exposure. Notice that even for amoxicillin TARGET rates it only as "Fair". This is because the TARGET book compiles ALL cultures received by Antech, including those from animals treated with multiple antibiotics before cultures were obtained. Thus, again, the clinician needs to apply the information from this book with their patient in mind. This is a young, antibiotic naïve dog with a non-life threatening infection. Amoxicillin is a fine choice. But how do we decide the dosing interval?

Another section in the application evaluates concentration curves to help determine dosing intervals. Figure 2 is the dose curve for amoxicillin in dogs. As discussed earlier, to achieve a treatment cure in a healthy patient, dosing such that 50% of the time is above the MIC is required. Since we don't yet know the exact MIC for these bacteria, we must use the maximum sensitivity MIC of 8 mcg/mL. Evaluating the curve reveals that at the 22mg/kg dose, the drug spends about 4 hours above the MIC of 8mcg/mL. To achieve 50% time above the MIC, therefore, the dosing interval must be every 8 hours. Thus prior to cultures returning the dog must be dosed TID. When the culture returns, the actual MIC can be overlaid on this curve and another dosing plan can be created. For example, if the MIC is actually 2mcg/mL, for the 22mg/kg dose about 8 hours is spent above the MIC so the interval can be reduced to twice a day.

In addition to antibiograms such as those provided by the TARGET book, additional considerations representing a change from what was taught in veterinary schools to graduates of 2008 or earlier is the "get in quickly, hit 'em hard, get out quickly" philosophy. The concept here is to use the highest dose of effective antibiotics to quickly kill a pathogen and then stop therapy before commensal flora have endured sufficient selection pressure to either acquire resistance or to skew the population towards those bacteria with innate resistance. The idea here is that a generation of bacteria can live, breed and die in 8 hours or less under ideal conditions. Therefore antibiotic courses that last even 5-7 days may be enough to kill for tens of generations of bacterial growth. Thus, uncomplicated UTIs may be treated with a week of antibiotics and severe infections such as pneumonia or pyelonephritis may only require 12-14 days of therapy whereas in the past weeks or months of therapy may have been recommended. It also means that drugs with long half-lives such as cefovecin (Convenia) may select FOR resistance to an extreme degree since they take 4-6 hours to get to tissue concentrations above the MIC (selecting for resistance while the concentration is below MIC for almost ½ a generation of bacterial growth) and they stay in the tissues of animals below MIC for weeks after the infection is cleared while shorter half-life drugs such as Clavamox persist in the animal below MIC for only hours after the last dose. While this difference likely won't affect the current infection being treated, the NEXT infection encountered by the animal may be much more likely to be resistant in the Convenia-treated treated animal due to prolonged exposure to antibiotics by the animal's commensal flora.

When a known infection is causing morbidity in veterinary patient, antibiotics can be life saving. However, it is important to select antibiotics with care, taking into account the likelihood of resistance, the severity of the infection and co-morbidities that may impact the probability of a treatment cure. Selecting antibiotics rationally, based on what pathogens are likely to infect a particular region of infection along with obtaining cultures whenever possible will help to ensure ongoing access to and the success of antimicrobial therapy for all veterinarians.

Additional Reading and References

1) Boothe DM, Small Animal Clinical Pharmacology and Therapeutics, 2nd edition, Elsevir, St. Louis, MO, 2012. Chapter 6: Principles of Antimicrobial Therapy pp 128-188.
2) Bonagura JD, Twedt DC, Kirk's Current Veterinary Therapy XIV, Elsevir, St. Louis, MO, 2009, Chapter 266: Rational Empiric Antimicrobial Therapy, pp 1225-1229.