Given the potential risk of diabetic foot ulcers becoming infected, it is imperative to have a strong understanding of the current antibiotic options. These authors review 10 common antibiotics, discussing their efficacy, range of coverage and dosing.
Diabetic foot infections (DFIs) are a common and often severe problem for people with diabetes. Though not all diabetic foot ulcers are infected, many become infected given the patient’s compromised immune system and lack of peripheral sensation. These DFIs usually begin as small ulcerations or calluses, and frequently grow into larger ulcerations with rampant polymicrobial infections.
Those wounds that are not infected do not require the initiation of antibiotic therapy. However, for those wounds that are infected, the need for antibiotic treatment is paramount. Treatment of these DFIs will be driven by the microorganisms, the patient’s medical comorbidities and the patient’s allergies.
Accordingly, let us review the top 10 antibiotic choices for DFIs and key considerations for their selection in the management of DFIs.
In the diabetic foot, we use vancomycin (Vancocin, ViroPharma) parenterally as an empiric therapy due to its narrow spectrum, which covers aerobic Gram-positive organisms. Physicians should use vancomycin empirically in conjunction with other agents such as ceftazidime (Fortaz, GlaxoSmithKline), cefepime (Maxipime, Pfizer), piperacillin-tazobactam (Zosyn, Pfizer), aztreonam or carbapenems if they suspect a polymicrobial infection in a moderate or severe diabetic foot infection.1
With regard to resistance, vancomycin’s minimum inhibitory concentrations (MICs) for methicillin-resistant Staphylococcus aureus (MRSA) are gradually increasing, according to the Infectious Diseases Society of America (IDSA) guidelines.2 In patients with normal renal function, the IDSA recommends a vancomycin dose of 15 to 20 mg/kg every eight to 12 hours when the S. aureus MIC is equal to or less than 1 mg/L.
Vancomycin is known to be associated with a risk of nephrotoxicity, especially when one combines it with other nephrotoxic antibiotics such as an aminoglycoside. To keep serum levels within a therapeutic range and decrease the likelihood of nephrotoxicity, monitor vancomycin levels. The Society of Infectious Diseases Pharmacists and IDSA recommend a trough serum concentration of 15 to 20 mg/L.2 A trough level below 10 mg/L could promote resistant strains with vancomycin intermediate S. aureus. This is a pregnancy category C drug when one uses it as an injection.
Overall, vancomycin is a good choice for empiric therapy in the moderate to severely infected diabetic foot.
What You Should Know About Ceftazidime
Ceftazidime (Fortaz, GlaxoSmithKline) is a third-generation cephalosporin that clinicians use parenterally. This is a bactericidal antibiotic, which physicians use empirically in conjunction with vancomycin for moderate to severe diabetic foot infections.1 This combination has broad-spectrum coverage for severe diabetic foot infections. One could consider the addition of obligate anaerobe coverage as well.1 Researchers have noted ceftazidime’s bone penetration in severely ischemic limbs to be satisfactory.3
High serum concentrations of ceftazidime may result in serious adverse nervous system effects. It is of great importance to use this antibiotic cautiously in patients with penicillin allergies. A recent study showed the cross reactivity among penicillin and cephalosporins may exceed 30 percent. This occurs when the cephalosporin has an identical side chain to those of the responsible penicillin allergens.4 Use caution with this drug in patients with a history of seizure disorders as drug levels could increase significantly. This is a pregnancy category B antibiotic.
A recent study observed patients with leg ischemia who received IV ceftazidime before a podiatric surgical intervention and concluded that the delivery of the antibiotic was better to the skin than to the muscles or bone.5 The authors stated that antibiotic penetration was more of an issue with leg ischemia than diabetes.
Physicians would dose ceftazidime renally based on 1 g. For a creatinine clearance (CrCl) of 31-50 mL/min, dose 1 g q12hr. For a CrCl of 16-30 mL/min, dose 1 g q24hr. For a CrCl of 6-15 mL/min, dose 500 mg q24hr. For a CrCl <5 mL/min, dose 500 mg q48hr.
Where Metronidazole Is Effective In DFIs
Metronidazole (Flagyl, Pfizer) is useful once one obtains cultures in the diabetic foot against facultative and obligate anaerobes. It is effective against Clostridium, Eubacterium, Peptococcus, Peptostreptococcus, Bacteroides fragilis and Fusobacterium species. Anaerobic bacteria are commonly present in deep infections but are also in many chronic superficial wounds. They can cause severe tissue destruction as well as gas gangrene, more associated with C. perfringens.5 Surveys show that more than 95 percent of anaerobes are susceptible to metronidazole.6 Despite worldwide use of this antibiotic for various conditions, resistance is rare among anaerobes.
Caution patients not to drink alcohol while taking this oral medication. This can result in a disulfiram-like reaction, which is characterized by flushing, tachycardia, palpitations, nausea and vomiting. This is a pregnancy category B antibiotic, which pregnant women should avoid, especially in the first trimester. There is a black box warning that animal data has shown a possible carcinogenic effect. Metronidazole is effective in the infected diabetic foot for coverage of anaerobic bacterium.
How Effective Is Piperacillin/Tazobactam In Treating Infection?
Piperacillin/tazobactam (Zosyn, Pfizer) is a bactericidal parenteral antibiotic clinicians use in the diabetic foot for broad spectrum coverage. Zosyn is a combination of an aminopenicillin and beta-lactamase inhibitor.7 The Food and Drug Administration (FDA) has approved Zosyn for the treatment of complicated skin and skin structure infections including diabetic foot infections but not for any accompanying osteomyelitis.1
According to the IDSA guidelines, Zosyn is useful as an empiric therapy as it provides broad spectrum coverage for moderate to severe diabetic foot infections, especially those with suspected Pseudomonas.1 It may be useful against bacterium with extended spectrum beta-lactamases.8 Use combined vancomycin and piperacillin/tazobactam therapy in severe diabetic foot infections to cover MRSA, Enterobacteriaceae, Pseudomonas and obligate anaerobes. Researchers believe prolonged infusions of Zosyn maximize the time that serum concentrations are above the MIC of the bacteria in the infected wound.9
An advantage to using Zosyn is it has minimal nephrotoxicity.10 The main side effect is diarrhea (10 percent of patients). This is a pregnancy category B antibiotic. Zosyn provides a safe and effective empiric treatment for moderate to severe diabetic foot infections, and has the advantage of covering Pseudomonas aeruginosa.11
When it comes to Zosyn renal dosing for CrCl >40 mL/min, dose adjustment is not necessary. For CrCl 20-40 mL/min, dose at 2.25 g IV q6hr. For CrCl <20 mL/min, dose at 2.25 g IV q8hr.
Key Insights On Prescribing Amoxicillin-Clavulanate
In general, amoxicillin-clavulanate (Augmentin, GlaxoSmithKline) is a relatively broad spectrum oral antibiotic with Gram positive, Gram negative and anaerobic coverage. It is effective for mild to moderate diabetic foot infections as well as localized cellulitis. The drug does not provide any coverage for bone infections.
Regarding bacteria common to DFIs, the drug covers Streptococcus species, Staph aureus, Enterococcus species, Proteus mirabilis, Bacteroides species and some strains of E. coli. Augmentin has minimal activity against MRSA and Pseudomonas. According to the IDSA, clinical trials have demonstrated success with the appropriate use of amoxicillin-clavulanate in treating diabetic foot infections.12
Augmentin is an FDA pregnancy category B drug and is not expected to be harmful to a fetus. Common side effects of the drug are relatively mild and mainly include mild diarrhea, gas, vomiting, stomach pain, headaches, itching and vaginal yeast infections.
The dosage for mild to moderate skin and soft tissue infections is 500 to 875 mg/125 mg BID for seven to 14 days.
Renal dosing is necessary for patients with a glomerular filtration rate of < 30 mL/min. Do not use the 875 mg tablet in these patients.13
A Guide To The Use Of Clindamycin
Clindamycin covers Gram positive and anaerobic infections involving the diabetic foot. It does not have activity against Gram negative bacteria. The FDA guidance states the drug is effective against skin and soft tissue infections caused by Streptococci and Staphylococci as well as anaerobes. It is active against most Gram-positive cocci, except Enterococcus and hospital-acquired MRSA. With regard to bacteria involved in polymicrobial diabetic foot infections, clindamycin is effective against Corynebacterium diphtheriae, Clostridium species and Bacteroides species. However, recently, Pham and Bartlett documented an increase in Bacteroides fragilis resistance.14
Non-FDA approved uses of the drug include community-acquired MRSA skin and soft tissue infections as well as osteomyelitis. If one is using the drug to treat culture-documented community-acquired-MRSA, which is resistant to erythromycin, it is important to have a D-test performed to ensure clindamycin sensitivity.
Clindamycin has excellent oral bioavailability as well as bone penetration. It is also a very useful drug in patients sensitive to penicillin and vancomycin. Combining clindamycin and ciprofloxacin can be effective for severe and life-threatening diabetic foot infections. Clindamycin is an FDA pregnancy category B drug and is not expected to be harmful to a fetus. Common side effects of the drug include diarrhea (not caused by C. difficile) and gastrointestinal upset. C. difficile infections are considered rare and occur in approximately 6 percent of patients taking the drug.14
For osteomyelitis, dose at 600mg IV q8h/300-450 mg PO four times daily, usually for six to eight weeks. Then reassess the patient’s wound.
In addition, clindamycin is a good choice in DFIs due to the fact that it does not require renal dosing.14
When To Use Ampicillin-Sulbactam
Ampicillin-sulbactam (Unasyn, Pfizer) is a broad-spectrum antibiotic used in many empiric therapies for moderate to severe diabetic foot infections. Regarding coverage, it is effective against many Staph and Strep species, E. coli, Proteus species, Morganella, Clostridium and Bacteroides species. It does not provide coverage for MRSA or Pseudomonas.
Unasyn is only available for parenteral treatment and the closest oral equivalent of Unasyn is Augmentin. Unasyn is a good choice when the risk factors for a polymicrobial infection are present. These risk factors include a severe infection, a chronic infection or a previously treated infection.15 Unasyn is a pregnancy category B drug. In general, patients tolerate the drug well but some common side effects include mild gastrointestinal upset as well as skin hypersensitivity.
One should dose Unasyn at 1.5-3.0 g q6h. Renal dosing for CrCl 15-30 is at 1.5-3.0 g q12h. For CrCl <15, the dosing is 1.5-3.0 g q24h.16
What Does Ciprofloxacin Cover?
Ciprofloxacin is a fluoroquinolone antibiotic with good Gram-negative bacterial coverage and moderate Gram positive coverage. According to the FDA, it is effective for skin and soft tissue infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, and Streptococcus pyogenes. In addition, it is indicated for osteomyelitis caused by Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa. The drug does not provide MRSA coverage.
Ciprofloxacin has excellent bone penetration and oral bioavailability.17 As we stated previously, combining ciprofloxacin with clindamycin has proven effective for severe and life-threatening diabetic foot infections.14 It is important to note the black box warning when using ciprofloxacin and other fluoroquinolones regarding the possibility of tendinitis and tendon ruptures. Ciprofloxacin is a pregnancy category C drug and pregnant women should not use it unless the risks outweigh the benefits to both the mother and baby.
Dose ciprofloxacin at 500-750 mg po q12h or 500-750 mg IV q12h. Renal dosing is 500 mg q24h or 250 mg q12h.17
A Closer Look At Doxycycline
Doxycycline is a tetracycline antibiotic that has broad indications for DFIs. It covers a wide range of microorganisms, both Gram positive (good coverage for MRSA infections) and Gram negative including Klebsiella species, Vibrio, E. coli, and Enterobacter species, and some anaerobic coverage including Clostridial species.18 Doxycycline is most commonly an oral prescription and there is almost complete penetration of the drug. This antibiotic is bacteriostatic and thus doesn’t kill any living bacteria. However, it prevents any further growth of the susceptible microorganisms.
The advantage to using this medication is that it doesn’t cause the adverse reactions associated with many antibiotics, namely lower gastrointestinal side effects (diarrhea). Furthermore, this drug does not need renal dosing as there have been very few instances of renal complications with the use of doxycycline.19 Additionally, doxycycline is not accepted for use in pediatric patients under 8 years of age and is a pregnancy class D drug.
The usual dosing guidelines for doxycycline are a 200 mg loading dose followed by a maintenance dose of 100 mg/day.
What You Should Know About Ertapenem
Ertapenem (Invanz, Merck) is a carbapenem antibiotic clinicians give parenterally for severe DFIs. Ertapenem demonstrates broad-spectrum antimicrobial activity against a wide spectrum of Gram-positive and Gram-negative aerobes and anaerobes, and is effective against nearly all beta-lactamase producing bacteria, including extended-spectrum beta-lactamases and AmpC-producing bacteria. However, it differs from both imipenem and meropenem in demonstrating limited activity against Enterococcus species, Pseudomonas aeruginosa and other non-fermentative Gram-negative bacteria commonly associated with nosocomial infections.20
Avoid the use of this antibiotic only in patients with previous anaphylactic reactions. Keep in mind though that side effects do include the occasional bout of C. difficile colitis and, less commonly, confusion and/or seizures. For life-/limb-threatening DFIs, clinicians may consider ertapenem, given its broad spectrum coverage.
With its extensive protein binding, ertapenem has an extended half-life, which allows for once-daily dosing.21 One may give this antibiotic 1g IV/IM QD in the setting of a resistant DFI (vancomycin-resistant Enterococcus infection) or when patient allergies severely limit the antibiotic choices available. The kidneys excrete this drug. Ertapenem has a renal dosing guideline of 500 mg/day IV for patients with a CrCl <30 mL/min/1.73 m² and end-stage renal disease (ESRD). In addition, one may dose patients on dialysis at 500 mg/day IV but if patients take the medication six or fewer hours before dialysis, they may have a supplemental dose of 150 mg afterward.22
Antibiotics are a necessary starting point for the treatment of DFIs. The appropriate antibiotic coverage, based on the patient’s medical history and the infecting microorganisms for each DFI, is paramount to treat these infections adequately and prevent further complications. The aforementioned antibiotic choices are not the only management options for DFIs. However, they provide strong initial treatment regimens for most DFIs. In conclusion, these 10 antibiotics will, in most instances, be the cornerstone of antibiotic treatment for diabetic foot infections.
Dr. Blume is an Assistant Clinical Professor of Surgery in the Department of Surgery and an Assistant Clinical Professor of Orthopaedics and Rehabilitation in the Department of Orthopaedics, Section of Podiatric Surgery at the Yale University School of Medicine in New Haven, Ct. He is a Fellow of the American College of Foot and Ankle Surgeons.
Dr. Ciaramello is a second-year resident with the Yale New Haven Medical Center Foot and Ankle Residency.
Dr. Kaufman is a second-year resident with the Yale New Haven Medical Center Foot and Ankle Residency.
Dr. Reynolds is a third-year resident with the Yale New Haven Medical Center Foot and Ankle Residency.
- Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections. Clin Infect Dis. 2012; 54(12):e132–72.
- Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2004; 39(7):885-910.
- Raymakers JT, Houben AJ, van der Heyden JJ, et al. The effect of diabetes and severe ischaemia on the penetration of ceftazidime into tissues of the limb. Diabet Med. 2001;18(3):229–234.
- Romano A, Gaeta F, Arribas Poves MF, Valluzzi RL. Cross-reactivity among beta-lactams. Current Allergy Asthma Rep. 2016; 16(3):24.
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- Lipsky BA, Armstrong DG, Citron DM, et al. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomized, controlled, double-blinded, multicentre trial. Lancet. 2005; 366(9498):1695–703.
- Harkless L, Boghossian J, Pollak R, et al. An open-label, randomized study comparing efficacy and safety of intravenous piperacillin/ tazobactam and ampicillin/sulbactam for infected diabetic foot ulcers. Surg Infect (Larchmt). 2005;6(1):27–40.
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- Zeillemaker AM, Veldkamp KE, Van Kraaij MGJ, et al. Piperacillin/tazobactam therapy for diabetic foot infection. Foot Ankle Int. 1998; 19(3):169-72.
- Harkless L, Boghossian J, Pollak R, et al. An open-label, randomized study comparing efficacy and safety of intravenous piperacillin/tazobactam and ampicillin/sulbactam for infected diabetic foot ulcers. Surgical Infect. 2005; 6(1):27-40.
- Holten KB, Onusko EM. Appropriate prescribing of oral beta-lactam antibiotics. Am Fam Physician. 2000; 63(3):611–20.
- Pham P, Bartlett J. Amoxicillin + clavulanate. Johns Hopkins Guides. Available at www.hopkinsguides.com/hopkins/search?st=OSS&q=.+Amoxicillin+%2B+clavulanate .
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