Antibiotics And DFIs: What The Evidence Reveals

Author(s): 
Anne Spichler, MD, PhD, and David G. Armstrong, DPM, MD, PhD

Given the prevalence of foot infections in patients with diabetes, aggressive and judicious management with antibiotics is crucial. These authors discuss the recent Infectious Diseases Society of America guideline on diabetic foot infections, emphasize the importance of a team approach in managing inpatients with diabetic foot disorders and investigate the efficacy of promising new antibiotic agents.

   Individuals with diabetes have an approximately 25 percent chance of developing a foot ulcer in their lifetime and about half of these ulcers are clinically infected at presentation.1-3 Foot wounds are now the most frequent diabetes-related cause of hospitalization and often lead to amputation.1,4 Hospitalizations are usually required for moderate or severely infected diabetic foot ulcers. When these patients are hospitalized, aggressive management is critical to increase the success of limb salvage.

   Aggressive management includes the correct identification and classification of infected and ischemic wounds, surgical intervention as appropriate, and an accurate culture specimen collection in association with the appropriate use of antibiotic therapy. Emerging publications in recent years have also emphasized an inpatient diabetic foot service to help manage hospitalized high-risk patients with diabetic foot disorders.5,6

   In order to provide curative measures for these patients and optimize the transition from inpatient to outpatient care, the members of the inpatient management team should have a number of key skills including the following that specifically pertain to diabetic foot infections:

• assessing wound infection;
• collecting appropriate wound cultures; and
• selecting antibiotic therapy for infected wounds.6

   In their guide to inpatient management, Wukich and colleagues also recommend having a pathway to address emergent treatment of diabetic foot infections and the implementation of effective hospital discharge planning to prevent the recurrence of infection.6

   A team approach to management is optimal in patients with diabetic foot infections in order to ultimately increase the likelihood of limb salvage as well as ensure the administration of appropriate antibiotics to inpatients and those who are transitioning from inpatient to outpatient.6 As a part of this team management, one should consult an infectious diseases specialist when cultures yield multiple or antibiotic-resistant organisms, the patient has substantial renal impairment, or the infection does not respond to appropriate medical or surgical therapy in a timely manner. Some goals and the success of establishing an inpatient diabetic foot service are to provide definitive treatment for soft tissue and bone infections; arrange for appropriate medical and surgical consultations when appropriate; and educate emergency department personnel on the importance of prompt consultation for patients with diabetic foot infections. Furthermore, proper antibiotic management of lower extremity infections reduces complications and length of stay.6

   Discharge planning should begin when the signs and symptoms of infection are clearly responding to treatment (resolution of the local and systemic signs of infection and improvement in white blood cell count). Clinicians can transition most patients from parenteral to oral antibiotic therapy to complete a course of therapy as outpatients. In addition, the inpatient team should aim to seamlessly perform appropriate postoperative monitoring to reduce risks of re-ulceration and infection after hospital discharge to home, a rehabilitation unit or a skilled nursing facility.6

A Closer Look At The IDSA Antibiotic Recommendations For MRSA

We usually select antibiotics based on the severity of the infection, the likely etiologic agent(s) and the previous patient history of infection.

   The Infectious Diseases Society of America (IDSA) guideline, published in 2012, explained how to clinically identify and classify diabetic foot infections.7 The guideline also described the microbiology of diabetic foot infections and suggested that the selection of antibiotic therapy depended on various parameters. One must usually select the initial antibiotic regimen empirically and may modify it later on the basis of the availability of additional clinical and microbiological information.7

   According to the IDSA, the isolation of antibiotic-resistant organisms, particularly methicillin resistant Staphylococcus aureus (MRSA), is an increasing problem with diabetic foot infections in most settings.7 Prior long-term or inappropriate use of antibiotics, previous hospitalization, long duration of the foot wound, the presence of osteomyelitis and nasal carriage of MRSA are some factors that increase the risk for diabetic foot infection with MRSA. The most common predictor for MRSA is a previous history of this infection.

   All clinically infected foot wounds require antibiotic therapy. Infection with MRSA requires specifically targeted antibiotic therapy. When it comes to patients with diabetic foot infections, the IDSA recommends empiric treatment for MRSA in patients with a history of a previous MRSA infection or colonization within the past year; when there is a high local prevalence of MRSA; and in cases of severe infection when failing to cover MRSA, while waiting for definitive cultures, would pose a risk of treatment failure. For moderate or severe MRSA infection, the recommended antibiotics are vancomycin, linezolid (Zyvox, Pfizer) or daptomycin (Cubicin, Cubist Pharmaceuticals), according to the IDSA guideline.7

   Lipsky and colleagues compared IV and oral linezolid with IV ampicillin-sulbactam and oral amoxicillin-clavulanate in 371 patients with diabetic foot infections.8 The authors note that clinical cure rates associated with linezolid and the comparators were statistically equivalent overall, but were significantly higher for linezolid-treated patients with infected foot ulcers and for patients without osteomyelitis. In the linezolid group, 13 of the 18 patients who had MRSA experienced a cure.

   Arbeit and colleagues compared daptomycin with conventional antibiotics (cloxacillin, nafcillin, oxacillin, or flucloxacillin or vancomycin) in two trials involving a total of 1,092 patients ages 18 to 85.9 The primary inclusion criterion was a complicated skin and skin structure infection that was due, at least in part, to Gram-positive organisms and that required hospitalization and parenteral antimicrobial therapy for 96 hours or more. More than 80 percent of the patients had an infecting organism identified and the distribution of infecting organisms was similar in both groups. The authors noted that the safety and efficacy of daptomycin were comparable with the comparator groups in the study.

What You Should Know About New Antibiotic Agents

However, new antibiotics and new combinations of antibiotics are always welcome for the physician. Ceftaroline (Teflaro, Forest Laboratories) is a new parenteral cephalosporin with antimicrobial activity for multidrug-resistant Gram-positive bacteria, including S. aureus strains with reduced susceptibility to methicillin and vancomycin.

   The antibacterial activity of ceftaroline is similar to that of other ß-lactams and occurs by binding to penicillin-binding proteins (PBP) and accordingly interfering with cell wall synthesis. Ceftaroline binds to PBP 1–4 and has an especially high affinity for PBP2a (mecA), which is associated with methicillin resistance. This unique affinity for PBP2a distinguishes ceftaroline from other cephalosporins. Ceftaroline is a broad-spectrum cephalosporin with bactericidal activity against Gram-positive bacteria, including MRSA and MRSA strains such as Panton Valentine-leukocidin-producing strains.

   Ceftaroline also has bactericidal activity against strains that are resistant to other classes of antimicrobial agents such as glycopeptides, daptomycin, clindamycin, sulfamethoxazole-trimethoprim (Bactrim, Roche) and linezolid.10 Patients tolerate ceftaroline well and the agent has an adverse effect profile similar to that of other cephalosporins. Furthermore, it has excellent bioavailability via intramuscular administration.

   A randomized study compared ceftaroline with other antibiotics such as vancomycin in adults with complicated skin and skin structure infections.11 However, the study authors excluded diabetic foot ulcers from this study. The results showed that ceftaroline had similar efficacy to the comparator group in treating overall infections including a MRSA subset.

   This antibiotic is approved for the treatment of acute bacterial skin and skin structure infections.10 Perhaps a future study will assess the use of ceftaroline as empiric therapy for diabetic foot infections with MRSA and when there is a noted resistance to vancomycin.

Investigating The Potential Of A Ceftaroline/Avibactam Combination

With the increased incidence of MRSA and extended-spectrum ß-lactamase (ESBL) producing Enterobacteriaceae in diabetic foot infections, there is probably a need for the use of two antimicrobials, one for the usual mixed aerobic (including extended-spectrum ß-lactamase producers) and anaerobic pathogens, and a second agent to ensure MRSA activity.12,13 Ceftaroline has excellent in vitro activity against staphylococci and MRSA, but limited activity against extended-spectrum ß-lactamase producing organisms.

   Avibactam is a non–ß-lactam, ß-lactamase inhibitor, which shows little or no activity against anaerobes. However, it confers activity against resistant aerobic Gram-negative bacteria, including those that produce carbapenemases. These factors make a ceftaroline/avibactam combination potentially well suited for use in diabetic foot infections.

   Accordingly, Goldstein and colleagues evaluated the potential of this antibiotic combination against the full range of culture isolates clinicians encounter in moderate to severe diabetic foot infections.12 Researchers tested 316 aerobic pathogens and 154 anaerobic pathogens recovered from patients with moderate to severe diabetic foot infections. All of the Staphylococcus spp., Enterobacteriaceae, B. fragilis and group species tested positive for ß-lactamase production. The study results showed markedly improved activity against anaerobic Gram-positive cocci, including Finegoldia magna, a common diabetic foot pathogen, clostridia, anaerobic Gram-positive rods, the beta-lactamase producing Prevotella, Porphyromonas species, Bacteroides fragilis and B. caccae.

   While ceftaroline alone has excellent activity against most of the aerobic component of pathogens in moderate to severe diabetic foot infections, this study shows that the addition of avibactam results in a broader spectrum of antibiotic coverage. Ceftaroline/avibactam is a promising agent for monotherapy against the wide spectrum of diabetic foot infection isolates.

What About The Potential Of Moxifloxacin And Piperacillin/Tazobactam For Diabetic Foot Infections?

For the empirical treatment of diabetic foot infections, some antibiotics such as moxifloxacin (Avelox, Bayer) offer an advantage of being available intravenously (IV) or orally. Moxifloxacin has a broad spectrum of activity and the switch between the two formulations is simple as they have similar pharmacokinetics.

   Schaper and coworkers conducted a randomized controlled trial in 2013 involving a total of 206 patients.14 The authors focused on patients with diabetic foot infections of mild to severe intensity and a diagnosis of complicated bacterial skin and skin structure infection that required hospitalization and initial parenteral antibiotic treatment for 48 hours or more. Researchers compared moxifloxacin IV followed by oral moxifloxacin with piperacillin/tazobactam (Zosyn, Pfizer) IV and subsequent oral amoxicillin/clavulanic acid. The study parameters included clinical cure rates and bacteriology eradication among others.

   The results revealed that intravenous and oral moxifloxacin and the combination of IV piperacillin/tazobactam and oral amoxicillin/clavulanic acid had similar clinical efficacy rates in patients with moderate to severe diabetic foot infections.14 In addition, the study showed bacteriological eradication was higher for moxifloxacin versus piperacillin/tazobactam and amoxicillin/clavulanic acid in polymicrobial infections. There was no significant difference between the two treatment arms regarding the length of either oral or intravenous treatments as both durations of therapy in either groups were approximately eight days each. Therefore, IV/oral moxifloxacin monotherapy could be an alternative option for patients with moderate to severe diabetic foot infections.

In Summary

It would be ideal to follow the aforementioned inpatient management proposed by Wukich and colleagues in all hospitals that admit patients with diabetic foot ulcers and diabetic foot infections.6 In addition, clinicians who are part of a multidisciplinary team that treats diabetic foot infections should be alert for an increase in MRSA prevalence in this population with foot infections and follow the IDSA specific recommendations when empirically treating a patient with diabetic foot infections and MRSA.7

   Ceftaroline is a new cephalosporin with activity against MRSA and is a possible candidate for therapy when one detects or empirically suspects this microorganism. If broad spectrum coverage is necessary, a combination of ceftaroline-avibactam would be another possibility. A transition from an intravenous to oral route of administration with the same class of antibiotics (e.g., moxifloxacin), while patients start therapy during hospitalization, can be an alternative option.

   Dr. Spichler is a researcher in the Department of Surgery, Division of Vascular and Endovascular Surgery at the Southern Arizona Limb Salvage Alliance (SALSA) at the University of Arizona Health Sciences Center in Tucson, Ariz.

   Dr. Armstrong is a Professor of Surgery and the Director of the Southern Arizona Limb Salvage Alliance (SALSA) at the University of Arizona Health Sciences Center in Tucson, Ariz.

References

1. Lavery LA, Armstrong DG, Wunderlich RP, et al. Risk factors for foot infections in individuals with diabetes. Diabetes Care. 2006; 29(6):1288-93.
2. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005; 293(2):217- 228.
3. Prompers L, Schaper N, Apelqvist J, et al. Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study. Diabetologia. 2008; 51:747–755.
4. Fisher TK, Wolcott R, Wolk DM, et al. Diabetic foot infections: A need for innovative assessments. Int J Low Extrem Wounds. 2010; 9(1):31-36.
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7. 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):e132-73.
8. Lipsky BA, Itani K, Norden C. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Infect Dis. 2004; 38(1):17-24.
9. Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004; 38(12):1673-81.
10. Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2011; 52(9):1156-63.
11. Corey GR, Wilcox MH, Talbot GH, et al; CANVAS 1 investigators. CANVAS 1: the first Phase III, randomized, double blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother. 2010; 65 Suppl 4:iv41-51.
12. Goldstein EJ, Citron DM, Merriam CV, et al. Comparative in vitro activity of ceftaroline, ceftaroline-avibactam, and other antimicrobial agents against aerobic and anaerobic bacteria cultured from infected diabetic foot wounds. Diagn Microbiol Infect Dis. 2013; 76(3):347-51.
13. Uçkay I, Gariani K, Pataky Z, Lipsky BA. Diabetic foot infections: state-of-the-art. Diabetes Obes Metab. 2013; epub Aug 2.
14. Schaper NC, Dryden M, Kujath P, et al. Efficacy and safety of IV/PO moxifloxacin and IV piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid in the treatment of diabetic foot infections: results of the RELIEF study. Infection. 2013; 41(1):175-86.

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