Dr. Frykberg's 3rd Instalment on Diabetic Foot Infections

Robert Frykberg, DPM, MPH PRESENT Editor, Diabetic Limb Salvage

The Challenges of Diabetic Foot Infections (Part 3):
A Brief Primer on Antibiotics
In the last couple of issues of Footnotes, we have been discussing the assessment and non-pharmacologic management of diabetic foot infections. Certainly, infection is that complication that so often leads to tissue loss – and in the presence of ischemia, directly contributes to limb loss. Antimicrobial therapy is the third element of care for diabetic foot infections (DFI) – third because antibiotics should be considered adjunctive to surgical management, although this 3rd rail is crucial to effective eradication of bacterial pathogens in this difficult setting.
I am a clinician, not an infectious disease specialist. But having been in the trenches with such patients for a good many years, I’ve learned a little about antimicrobial management for DFIs. Granted, I’ve made many mistakes to go along with the successes. Hopefully, those experiences have made me somewhat wiser in my approach to such patients. Relatively mild or non-limb threatening infections are generally straightforward to manage with oral agents. For the purposes of this Foot Notes, however, we will concentrate on the more serious DFIs requiring hospitalization (IDSA Grade 3-4).
Simplification, while appreciating the magnitude of the problem at hand, is always best. Many years ago, the standard “cocktail” for hospitalized patients with DFI consisted of triple therapy with Gentamicin, Ampicillin, and Clindamycin (or cephalothin). This regimen would cover most Gram negative rods (GNR), Gram positive cocci (GPC), as well as anaerobes. MRSA was not the problem that it is today.  As you have surmised, we must have done a lot of harm to the diabetic kidneys with the aminoglycosides.  In the mid-seventies, we didn’t have carbapenems or extended spectrum penicillins (with or without beta-lactamase inhibiting agent combinations). With the advent of Imipenem, Ticarcillin, amoxicillin-clavulanate, and then piperacillin, and piperacillin/tazobactam, our options expanded dramatically. Soon, we were able to treat even the most severe of infections with a single empirical agent in many cases. Of course, then as now, penicillin (PCN) allergic patients presented a little more difficulty. Clindamycin even today remains a mainstay of treatment for such patients, although the options are quite a bit more numerous than before.  Hence, we can discuss antimicrobial management in terms of severity of infection, as well as in the setting of PCN-allergic patients. This is obviously a simplistic approach, but in most cases, this approach will be sufficient for the average clinician to provide for reasonable initial empirical therapy. As always, antibiotic regimens need to be fine tuned and adjusted, based on culture and sensitivity (C&S) results, patient response, and renal function.
Only three currently marketed antibiotics have a specific indication for diabetic foot infections: piperacillin/tazobactam, linezolid, and ertapenem. These are great agents, and found to be superior to their various comparators in clinical trials (see references). Nonetheless, these agents are not always effective for all patients or pathogens (or combinations of pathogens). Hence, we usually provide parenteral empirical therapy with combinations of agents, until our C&S results have been returned.

Common antibiotics used for the management of diabetic foot infections

Aside from the need to empirically cover GNRs, GPC (especially Staph aureus and Group B Streptococci), and anaerobes, we must now be vigilant for the predominance of MRSA in the United States. Since more than 50% of our staphylococcal isolates in my facility are MRSA, we always empirically cover for this organism. For this, we add Vancomycin to our broad spectrum agent, Piperacillin/Tazobactam. One could just as easily prescribe Vancomycin plus ertapenem to achieve very broad coverage (even in PCN allergic patients). Whereas amoxicillin/clavulanate previously was my combination agent of choice, it no longer has the Gram positive and Gram negative spectrum that it once enjoyed.  I do not really like vancomycin, due to rising minimum inhibitory concentrations (MIC) required, as well as its nephrotoxicity in diabetic patients with acute renal failure. Linezolid is a far more effective drug (that can also be given orally), but with a rising number of patients on SSRI agents for depression – especially in the Veteran population- we must be cognizant of Serotonin syndrome. Therefore, we use this agent primarily for documented MRSA infections in patients  who have failed or responded poorly to vancomycin. I suppose daptomycin would be an equally good choice in this regard. Again, once our initial cultures have been returned with sensitivities, we narrow our coverage accordingly- to the simplest effective agent. Nafcillin or cefazolin are the single agents most often used for methicillin-sensitive staph aureus (MSSA) or streptococcal infections. For purely streptococcal infections, (excluding enterococcus) we prefer intravenous Penicillin G until we can safely switch to the oral formulation. For Enterococcus faecalis, we prefer ampicillin in some format (or vancomycin if being used for MRSA).
For the PCN allergic patient, we rely very much on Clindamycin, Ciprofloxacin, and vancomycin (or linezolid). While Ciprofloxacin will provide coverage for most GNRs, clindamycin will cover MSSA, streptococci (not enterococcus), and even anaerobes. Occasionally, it will even cover MRSA.  Furthermore, it can be safely used in patients with impaired renal function. Vancomycin is a more certain coverage for MRSA (as well as MSSA) and enterococcus. We will generally start those with moderately severe infections on a combination of Vancomycin and oral Ciprofloxacin for fairly broad coverage (but not good anaerobic coverage). Hence, for severe infections and necrotizing infections, it makes sense to add clindamycin to this regimen or at least metronidazole. Linezolid can also be considered for excellent GPC coverage – MSSA, MRSA, streptococcal, and enterococcus (including VRE). Again, tailoring coverage to isolated pathogens once sensitivities are known will make your patients and pharmacists very happy.
I have left many possible agents or combinations out of this discussion for the sake of simplicity. In managing your patients, however, you must always consider the severity of the infection, prior cultures, local antibiogram profiles, renal function, concurrent medications, and general allergy profiles. It is also wise to be familiar with the profiles of your favorite antimicrobial agents – know the pathogen coverage they provide as well as the gaps in coverage. Remember that if the patient dos not respond within 24 to 48 hours, you have missed something. This could be an undrained abscess, ischemia, or a resistant or untreated pathogen. For particularly difficult patients, infections, or pathogens, I will consult my infectious disease specialist for help. Things can go downhill awfully quickly in this patient population.
Nothing says it better than this quote from Louis Pasteur in 1880:

“The germ is nothing.  It is the terrain in which it is found that is everything”

References are provided below that can expand upon many of the points made above. We welcome your opinions, concerns, and suggestions.  If you have an interesting case or a troubling circumstance that you would like to share with fellow PRESENT Diabetes members,  please feel free to comment on eTalk.
Best regards,

Robert Frykberg, DPM, MPH
PRESENT Editor,
Diabetic Limb Salvage

REFERENCES