Key Considerations In Appropriate Antibiotic Selection

Dr. Armstrong: How do you rate factors such as cost, cidality, route of therapy, dosing and spectrum of activity when you are trying to choose among various antibiotics? What are some of your key considerations when treating diabetic foot infections?
Dr. Lavery: Certainly, the less frequently these drugs have to be dosed, there will be a cost savings on an institutional level and probably better patient compliance on an outpatient basis. When it comes to some mild infections, we talked about using some of the older drugs that are more focused and are often much less expensive than the newer medications. Patients may receive a 10-day course of augmentin but they often come back and say they can’t afford $125 for the antibiotic and ask for something else. It is a pivotal financial decision for many folks.
I think the shorter or once- or twice-a-day dosing certainly improves the chance of the patient getting the regimen correctly and having something that is financially affordable. It also ensures the patient is going to receive antibiotic therapy when the clinical assessment allows one to make that decision.
Dr. Lipsky: In treating patients in the VA setting, I would rate the factors in order of importance, as follows:

1. Spectrum of activity. This is first on my list. My first thought with any infection is determining the likely causative organism as this largely determines the most appropriate antibiotic agent.
2. Cost. Unfortunately, cost would probably have to come in number two simply because more expensive antibiotics are not readily available to many of us who are in the VA setting and perhaps in other clinics where cost constraints come into play.
3. Route of therapy. This usually amounts to whether oral or parenteral therapy is most appropriate and this may influence whether or not the patient would be hospitalized.
4. Frequency of dosing. We know that the less frequently any medication is dosed, the more likely the patient will adhere to the regimen. Unfortunately, this issue gets moved down the list due to other compelling issues.
5. Cidality. This is the least important factor to me as it has rarely been shown to be important and certainly is not in diabetic foot infections. This factor may have importance in cases of endocarditis and meningitis, and perhaps one should factor this in when treating immunocompromised patients with granulocytopenia. In most other situations though, I don’t worry a lot about cidal versus static agents.27

Dr. Joseph: There are at least two recent review articles that looked at this whole question of cidal versus static agents in treating complicated gram-positive skin-skin structure infections and they basically found that it does not make a difference.27,28

Addressing Cost Issues
Dr. Lavery: In a managed care, Medicare environment, I approach cases on an individual basis and let patients know the expected cost of their antibiotic. Often, when people have HMO plans, if the more expensive antibiotic is available, they will have a relatively inexpensive co-pay. However, if the prescription cost is coming out of their pocket and they don’t have a drug plan, it often becomes a serious issue for them. Otherwise, I agree with Dr. Lipsky’s order. I think cost moves up and down that scale based on some insurance issues for many of these folks.
Dr. Joseph: I agree that spectrum of activity is the most important factor. We want to know the antibiotic we are using works against the organism that we either empirically think is causing the infection or that we know (via culture reports) is causing the infection.

I am not going to put cost as high as number two in the list of factors for choosing an antibiotic agent. Working in the VA system, it is true we do not have access to some of the more expensive drugs but I think cost becomes a relatively smaller issue. I want the best antibiotic with the best coverage against the organism and the best route of therapy that I can possibly get. When we are looking at saving a limb for $120 for a 10-day course of a PO antibiotic versus a couple of thousand dollars for hospitalization or an IV antibiotic, I do not see where cost is going to be that much of an issue. Granted, we have cost containment with the VA and with HMOs. However, in the overall picture of treating a diabetic foot infection, the cost of a PO or an IV antibiotic is not going to be that big of a factor in the final end number.
I would put the frequency of dosing second. As Dr. Lipsky mentioned, if the patient is not going to take it, what good is it? I would rather prescribe a drug that has reduced dosing as this will help facilitate better compliance with the treatment regimen. From there, I agree with Dr. Lipsky’s sequence of factors.
Dr. Lipsky: A recent paper by Gillespie discussed the pharmacodynamics of antibiotic selection and dosing for severe infections.29
According to the article, “Antimicrobial resistance … is the main reason for antibiotic therapy to be deemed inappropriate and leads to unfavorable outcomes and increased costs. Knowledge of local susceptibility patterns can help clinicians empirically choose the appropriate antibiotic. In addition, the proper dosage regimen, based on pharmacodynamics, is essential to maximize the likelihood of achieving optimal therapy. ... [P]ercent susceptibility provides an accurate estimate of bactericidal exposure at standard dosage regimens for carbapenems, ceftazidime and cefepime whereas percent susceptibility overestimates actual bactericidal exposure for piperacillin/tazobactam and ciprofloxacin. The empiric use of appropriate antimicrobial therapy at the correct dosages for severe infections should improve clinical outcomes and result in economic benefit. Initial therapy should have a high likelihood of covering resistant pathogens.”29
It is an interesting point that the pharmacodynamics may be more representative of the actual clinical efficacy for some antibiotics than for others, and it may account for some of the differences we saw between ertapenem and piperacillin/tazobactam in our study.

Drug Safety: Is It An Issue With These Antibiotics?
Dr. Lipsky: I also think drug safety would rank fairly high when it comes to considerations for antibiotic selection. This is an issue with at least two agents commonly used for diabetic foot infections. Clindamycin has been associated with the potentially serious complication of antibiotic-associated diarrhea. We originally did not see much of this in our medical center and we have been using clindamycin since the first paper we published in the field 15 years ago.7 However, recently we have seen more frequent and more severe diarrhea associated with clindamycin. Accordingly, we are using less of that otherwise very good drug because of toxicity.
The second drug is linezolid, which of course has been shown to be highly active in treating diabetic foot infections and has a specific indication for this.30 However, it is potentially associated with reversible hematological toxicities and more rarely with other side effects if one uses the drug for a long duration.31
Dr. Joseph: Fortunately, we do not have nearly the safety issues or the drug-drug interaction issues with these antibiotics as we have with just about any other class of drugs.

Assessing The Impact Of Potential Dosing Errors
Dr. Armstrong: However, we do have to worry about things like dosing errors. I think those are things that we don’t talk about very much. How frequently do you see dosing errors in your institution? Has that changed the way you prescribe antibiotics?

Dr. Lipsky: That is a good point. We know a good deal more about the frequency of dosing errors now because of electronic medical records. Electronic dispensing of medications in the VA and elsewhere has allowed us to track how often we have actual errors or near misses. Studies dating back 40 or 50 years have shown that for patients in the hospital, one out of four drugs administered is the wrong drug, the wrong dose or is given to the wrong patient or given at the wrong time.32,33 Accordingly, if a patient is on four or more drugs or even one drug four times a day, one is almost certain to have a dosing error every day with that patient.
With this in mind, some have made efforts to reduce the frequency of dosing errors. Sophisticated systems, like the Bar Code Medication Administration (BCMA) system used in the VA, have an electronic device that checks the identification bracelet of the patient, the identification of the unit dose medication being given to the patient and the identification of the nurse dispensing the drug.34,35 Unless all three match up with the provider’s computer-entered order for the patient, a bell will ring and the patient cannot get the medication until the error is corrected.
There are very sophisticated systems to prevent errors but one simple way of preventing errors is reducing the frequency with which one needs to dispense the drugs. I think all of us have seen nurses sometimes get quite busy and there is a delay in giving the medication to the patient. If the medication is an antibiotic that has a time-dependent mechanism of action, then it is critical that the patient gets the drug at the right time. If a clinician is giving a drug like piperacillin/tazobactam, which generally requires four times a day dosing, the chances of seeing an error are far greater than what one might see with a drug like ertapenem that can be given once a day.
Dr. Armstrong: This plays a significant role in a home health care scenario, doesn’t it?
Dr. Lavery: Certainly. The administration or the frequency of administration certainly makes some drugs impractical to administer through home IV therapy, necessitating a much more expensive course of antibiotic care or prolonged hospitalization.

What The SIDESTEP Study Reveals
Dr. Armstrong: Dr. Lipsky, please share your experience with the recent Study of Infections in Diabetic Feet Comparing Efficacy, Safety and Tolerability of Ertapenem versus Piperacillin/Tazobactam (SIDESTEP) diabetic foot study. What effect may it have on antibiotic prescribing for diabetic foot infection? What kind of interesting findings did you see in that study?
Dr. Lipsky: The SIDESTEP study is the largest study to date on diabetic foot infections.36 It was a multicenter, randomized controlled trial designed to compare ertapenem with piperacillin/tazobactam. Piperacillin/ tazobactam was selected as it is one of the most popular and appropriate broad-spectrum agents for treating moderate to severe diabetic foot infection. The trial was designed to be an optimal study both in terms of the number of patients involved and the techniques used in the study.
We used a double blinding mechanism that very few trials of diabetic foot infection have used previously. We used digital cameras, a wound scoring system and dermal thermometry.37,38 We required optimal culture techniques, obtaining specimens of tissue, as opposed to swabs, and sending them both to the local lab as well as to a special research lab in order to get optimal anaerobic cultures. (See “What Baseline Cultures From One Multicenter Trial Revealed” below.)
We enrolled a little over 600 patients and wound up with about 445 clinically evaluable patients. The outcome was similar with both drugs having an approximate 94 percent positive clinical response rate. The incidence of adverse effects and the microbial eradication rates were similar for the two drugs as well.
Several interesting points emerged from the study. In regard to patients who had Enterococcus or Pseudomonas isolated from their wounds, neither of which are generally susceptible to ertapenem, the results were just as good with ertapenem as with piperacillin/tazobactam, which covers both of those organisms.
We also used a wound scoring system which looks at the size and depth of the wound and also quantifies various parameters of inflammation to provide a total wound score. We found the wound score correlated well with the clinical outcome. Patients who had wound scores above a certain level were much less likely to respond. We think this validates the usefulness of this scoring system.21 We believe it could be used for a variety of other studies looking at wound healing agents and microbial agents.

Assessing The Diagnostic Impact Of Dermal Thermometry And Digital Photography
Dr. Armstrong: We need to evaluate several things as we wade through the data from the SIDESTEP study data. Did we capture enough sites? Did we allow the feet on both sides to equilibrate adequately and is this a valuable tool? I think that remains to be seen.
As for the short answer, we probably need to have multiple sites tested on both feet and we need to get the shoes and socks off before we actually assess these patients with thermometry to determine when the amount of inflammation has reduced. I am not sure we are going to get that information from this particular study. However, the study did raise awareness about dermal thermometry, which is a surrogate marker for inflammation.
On the issue of digital photography, there is emerging research but little published literature so far regarding the ability of clinicians to use digital photography to help assess wounds. I am excited about what we may uncover in the future on the potential use of digital photography to help diagnose and assess the severity of infection. We will see some answers on this as we conduct further investigations into this large, robust diabetic foot infection data set.