Empiric Antibiotics: A Guide To Appropriate Use

Given the challenges of selecting appropriate empiric therapy with the rise of antibiotic resistance, these authors offer a review of the literature in regard to diabetic foot infections. They offer pertinent insights on infection severity, common pathogens and other factors in choosing the right agent.

   While antibiotic therapy for infection is typically empiric at the outset, making the right call is not easy. If physicians make a too narrow selection in terms of antibiotic coverage, they may miss the offending organism. Conversely, choosing a too broad antibiotic can lead to antibiotic resistance.

   The most difficult thing about antibiotic selection is the lack of culture and sensitivity results at the time of treatment initiation. Certainly, a key to effective treatment of diabetic foot infections is obtaining good wound and tissue cultures in an expedited manner. One should obtain all cultures before initiating empiric antibiotic therapy.

   In selecting empiric antibiotic therapy, it is imperative first to consider the severity of the infection. Guidelines from the Infectious Disease Society of America (IDSA) outline the criteria for determining the severity of an infection. 1 By first establishing the severity of the infection, one can ascertain the appropriate route of antibiotic administration.

   Uninfected ulcers, ulcers that lack purulence or inflammation, do not usually require antibiotic treatment. 1,2 Antibiotic treatment of these wounds can be expensive and promote antibiotic resistance. There may be drug-related toxicity as well. 1

   Mild diabetic foot infections have at least two of the following characteristics: purulence, erythema (extending less than 2 cm around the wound), pain, tenderness, warmth or induration. There are no local complications or systemic illness. 1 One can usually treat mild infections with an antibiotic that has a narrower spectrum of activity. Generally, these are oral antibiotics. 3,4 This allows for treatment to take place on an outpatient basis. For mild soft tissue infections, treatment duration typically lasts for one to two weeks but may go up to four weeks if required. 1

   For mild infections, the IDSA recommends using dicloxacillin (Dynapen), clindamycin (Cleocin, Pfizer), cephalexin (Keflex, MiddleBrook), trimethoprim-sulfamethoxazole (TMP-SMZ) (Bactrim, Roche), amoxicillin/clavulanate (Augmentin, GlaxoSmithKline), or levofloxacin (Levaquin, Ortho-McNeil) as oral agents.

Keys To Treating Moderate DFIs

   Patients with moderately infected diabetic foot ulcers are systemically well and metabolically stable. These ulcers have at least one of the following qualities: cellulitis extending more than 2 cm from the wound, lymphangitic streaking, spread beneath the superficial fascia, deep tissue abscess, gangrene and involvement of the muscle, bone or joint. 1

   One can generally treat these infections with oral antibiotics. Alternatively, physicians may initially start patients on parenteral antibiotics and transition them to oral antibiotics. Patients can undergo therapy on either an inpatient or outpatient basis, and the treatment regimen routinely lasts two to four weeks. 1 Note that antibiotic therapy is not a substitute for surgical debridement when there is suspected abscess or bone or joint involvement. 5

   For moderate infections, oral or parental administration depends on the clinical situation and the agent one chooses. The IDSA recommends the following drugs as options for mild infections: TMP-SMZ, amoxicillin/clavulanate, levofloxacin, cefoxitin (Mefoxin, Merck), ceftriaxone (Rocephin, Hoffman-La Roche), ampicillin/sulbactam (Unasyn), linezolid (Zyvox, Pfizer) (with or without aztreonam), daptomycin (Cubicin, Cubist) (with or without aztreonam), ertapenem (Invanz, Merck), cefuroxime (Ceftin, GlaxoSmithKline) (with or without metronidazole), ticarcillin/clavulanate (Timentin, Glaxo-SmithKline), piperacillin/tazobactam (Zosyn, Wyeth), and levofloxacin or ciprofloxacin with clindamycin.

   One may use linezolid and daptomycin for patients in whom methicillin-resistant S. aureus infection is proven or likely.

Recognizing And Treating Severe DFIs

   Finally, severe diabetic foot infections are those deemed “life-threatening.” 1 These ulcers may have similar features as moderately infected ulcers but hospitalization is required as the patient presents with signs of systemic toxicity or metabolic instability. These signs and symptoms include fever, chills, tachycardia, hypotension, confusion, vomiting, acidosis, leukocytosis, severe hyperglycemia or azotemia. For these patients, medical stabilization is necessary and includes fluid and electrolyte restoration, and correction of hyperglycemia and other metabolic disturbances.

   For severe infections and for chronic, moderate infections, broad-spectrum antibiotics are the safest empiric treatment. Parenteral antibiotics are required in these patients as they need to reach therapeutic blood levels quickly. 6

   
According to the IDSA, for severe infections, one can use the following agents intravenously (at least initially): piperacillin/tazobactam, levofloxacin or ciprofloxacin with clindamycin, imipenem-cilastatin (Primaxin, Merck) or vancomycin and ceftazidime (Fortaz, GlaxoSmithKline) (with or without metronidazole). Physicians may use vancomycin for patients in whom methicillin-resistant S. aureus infection is proven or likely.

   Surgical management of the infection may be necessary and could range from a simple incision and drainage to amputation. With severe infections, patients begin therapy as inpatients and can transition to an outpatient basis when they are medically stable and have started on a definitive antibiotic regimen. Patients with severe diabetic foot infections should undergo treatment for approximately two to four weeks.

   When it comes to the most severe, life-threatening infections, empiric antibiotic therapy should include coverage for Staphylococcus aureus, streptococci, Enterobacteriaceae, and Bacteroides fragilis. 7

   In a review article, Frykberg lists potential antibiotics that one may use for these severe, life-threatening infections. This list includes ampicillin-sulbactam, piperacillin-tazobactam, imipenem-cilastatin, ertapenem, fluoroquinolones and third-generation cephalosporins. 7 In patients with penicillin allergies, one can utilize clindamycin and either ciprofloxacin and levofloxacin.

   In regard to these severe diabetic foot infections, a single antibiotic agent usually is not sufficient. Most often, one uses these previously mentioned antibiotics in conjunction with other antibiotics such as vancomycin, linezolid and metronidazole.

Other Key Pearls In Appropriate Antibiotic Selection

   After determining the severity of infection, one should choose an antibiotic based on the suspected pathogen (see “What The IDSA Says About Common Pathogens From Diabetic Foot Infections” on page 40). Determining which ulcers are most likely to be infected with which organism is based on the severity of the ulcer.

   There are also other factors that can aid in selecting the most appropriate antibiotics. The patient history is critical as a history of prior infection, especially with resistant organisms, will play a large role in determining the most appropriate antibiotic. Physicians should also examine the results of recent cultures and account for local resistance patterns. 6



   The IDSA notes that for definitive regimens, physicians should consider results of culture and susceptibility tests as well as the clinical response to the empirical regimen. One may substitute similar agents of the same drug class. Bear in mind that some of these regimens may not have approval from the U.S Food and Drug Administration for complicated skin and skin-structure infections, and only linezolid has a specifically approved indication for diabetic foot infections.

   In treating diabetic foot infections, it is imperative to maintain close follow-up of the patients. Within 48 to 72 hours of initiating antibiotic therapy, there should be clinical signs of improvement of the infection. 7 If there are no signs of improvement, one must re-evaluate, adjust and expand the initial empiric antibiotic regimen. Also, at the 48- to 72-hour mark, results of cultures and gram stains should be available so one can initiate definitive antibiotic therapy.

What You Should Know About Chronic Wounds And Frequently Occurring Pathogens

   As wounds become more chronic in nature, the wound microenvironment changes. Chronic wounds are more likely to be polymicrobial. 6 Keep in mind that gram-negative bacteria are isolated in as many as two-thirds of infections, especially in chronic infections that have undergone previous treatment with antibiotics. Aerobic gram-negative pathogens are associated with diabetic foot infections.

   The most commonly cultured organisms include Proteus species, Escherichia coli and a variety of Enterobacteriaceae species. In one study, researchers found Enterococcus faecalis in 29 percent of infected diabetic foot wounds. 12 Corynebacterium species also often occur in diabetic foot infections and researchers suspect this is due to overgrowth of resistant bacterial strains. 7 One should ensure empiric gram-negative coverage in chronic, previously treated wounds. These antibiotics would include b-lactamase inhibitors, second- and third-generation cephalosporins, fluoroquinolones and clindamycin. 3

   To initiate empiric treatment for wounds with Pseudomonas aeruginosa, the clinician must have a high index of suspicion when wounds have blue-green drainage or those that have been exposed to hydrotherapy. 3 Pseudomonas does not occur as frequently as one would think based on the attention it receives in the literature. Researchers have noted that it is isolated in 10 to 20 percent of cultures obtained from foot wounds. 7 Antibiotic selection includes anti-pseudomonal fluoroquinolones (ciprofloxacin) and anti-pseudomonal penicillins (piperacillin/tazobactam). 6

   In regard to diabetic foot infections in ischemic limbs or those complicated by necrosis or gangrene, one is usually looking at anaerobes as the pathogens. 3,6

   Anaerobic bacteria are usually part of a polymicrobial infection and are rarely isolated as a lone pathogen. 3 A clinical sign of an anaerobic infection is a highly malodorous wound, especially in a patient with peripheral arterial disease. Bacteroides species are the major pathogen of this group of anaerobic organisms. 7 The clinician must be aware that Bacteroides fragilis pathogenicity is increased when there is a co-infection with enterococci.

   Empiric treatment of suspected anaerobic infections should include metronidazole in addition to the other broad spectrum antibiotics to cover gram-positive and gram-negative organisms. 3 Often simple debridement to expose the anaerobes to air is enough to eradicate the anaerobic component of the infection. 3

In Conclusion

   In order to determine if empiric antibiotic therapy is necessary in the treatment of diabetic foot infections, one must ascertain the classification of the wound. Based on the guidelines provided by the Infectious Diseases Society of America (IDSA), the severity of the infection dictates whether treatment is necessary as well as the route and duration of antibiotic administration.

   As most diabetic foot infections are caused by gram-positive bacteria, especially Staphylococcus aureus, empiric therapy should include the appropriate coverage. A thorough clinical exam and patient history will provide valuable clues to the presence of multi-drug resistant organisms and gram-negative organisms as well as anaerobic bacteria.

   When treating diabetic foot infections, the most important fact to keep in mind is that the use of empiric antibiotics is never a substitute for definitive, culture and sensitivity-based antibiotic therapy. 



Dr. Addis-Thomas is a first-year resident at the Yale-New Haven Hospital/ DVA CT Healthcare Podiatric Surgical Residency Program.

Dr. Key is an Assistant Clinical Professor of Orthopedics and Rehabilitation at the Yale School of Medicine in New Haven, Ct.

Dr. Blume is an Assistant Clinical Professor of Surgery, Anesthesia and Orthopedics and Rehabilitation at the Yale School of Medicine in New Haven, Ct.

For further reading, see “How To Choose Appropriate Antibiotics For Diabetic Foot Infections” in the July 2006 issue of Podiatry Today.

References:

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 2. Chantelau E, Tanudjaja T, Altenhofer F, Ersanli Z, Lacigova S, Metzger C. Antibiotic treatment for uncomplicated neuropathic forefoot ulcers in diabetes: a controlled trial. Diabet Med. 1996; 13: 156-159.
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