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Empiric Antibiotic Choices for the Infected Diabetic Foot PDF Print E-mail

Benjamin A. Lipsky, M.D., FACP, FIDSA
Medical Service, VA Puget Sound Health Care System
Department of Medicine, University of Washington, School of Medicine
Washington State, USA

Introduction
Selecting appropriate empiric antimicrobial therapy for diabetic foot infections requires knowing the likely etiologic agents, and assessing the seriousness of the infection1. Initial therapy is usually empiric, while definitive therapy is based on the results of culture and sensitivity tests, as well as the clinical response to empiric therapy.  

Microbiological Considerations
All open wounds will be colonized with microorganisms, but various skin disorders or recent antibiotic therapy can alter the colonizing flora. When a wound becomes infected, it is usually with skin organisms. Acute infections are typically caused by aerobic gram-positive cocci (often as monomicrobial infections)2, such as Staphylococcus aureus and Streptococcus pyogenes but chronic wounds develop complex flora, including aerobic gram-negative rods, anaerobes (gram-positive and negative) and enterococci. About half the patients in reported series have received antibiotic therapy for their foot lesion by the time they present, and up to a third have had their foot lesion for over a month.

Staphylococcus aureus is the most important pathogen in diabetic foot infections; even when it is not the sole isolate, it is usually a component of a mixed infection3. Coagulase-negative staphylococci and streptococci, including group A as well as groups B, C and G, are also common pathogens. Gram-negative bacilli, mainly Enterobacteriaceae, are found in many patients with chronic or previously treated infections. Pseudomonas species are associated with wounds that have been soaked or treated with wet dressings or hydrotherapy. Enterococci are commonly cultured from patients who have previously received a cephalosporin. Obligate anaerobic species are most frequent in wounds with ischemic necrosis, or that involve deep tissues. Anaerobes are rarely the sole pathogen, but most often participate in a mixed infection with aerobes.4 The prevalence of antibiotic resistant organisms, especially methicillin-resistant Staphylococcus aureus (MRSA) varies; these organisms are frequently isolated from patients who have previously received antibiotic therapy, or who have been recently hospitalized or live in a chronic care facility5. Serious (i.e., life or limb-threatening) infections are often caused by 3-5 bacterial species, including both aerobes and anaerobes.

Wound Cultures
Establishing a microbiological diagnosis for infected wounds usually assists subsequent management. A culture can identify the etiologic agent(s), if specimens are collected and processed properly, and sensitivity results generally help to tailor (and in many cases constrain) antibiotic regimens. Deep tissue specimens obtained aseptically at surgery more often contain the true pathogens (without the colonizing flora) than cultures of superficial lesions. A curettage or tissue scraping with a scalpel from the base of a debrided ulcer provides more accurate results than a wound swab2. If multiple organisms are isolated, the clinician must decide which require specifically targeted therapy. Less virulent bacteria, such as enterococci, coagulase-negative staphylococci, or corynebacteria may represent pathogens, but can sometimes be ignored. Organisms isolated from reliable specimens that are the sole or predominant pathogens on both the Gram-stained smear and culture are likely to be true pathogens.

Clinical Presentation
Assessing the severity of infection is essential to determining an appropriate antibiotic regimen. It is important to determine whether an infection affects superficial skin and skin structures, joint space or even bone. One of the first decisions is determining which patients should be hospitalized. Most patients with mild to moderate infections can be treated on an outpatient basis. Patients with a serious infection, those who need parenteral therapy, fluid resuscitation, or control of metabolic derangements, those unable or unwilling to perform proper wound care or who can or will not be able to off-load the affected area, those who are unlikely to comply with antibiotic therapy or need close monitoring of response to treatment should be admitted. Wound care and glycemic control should be optimized; antibiotics will not overcome poor foot care.

Treatment
Basic factors that should be considered in choosing an antibiotic regimen are outlined in Table 1. Indications for Therapy. Available data suggest that about 40%-60% of diabetic patients who are treated for a foot ulcer receive antibiotic therapy. Virtually all infected lesions should be treated with antibiotics. Although some practitioners believe that all foot ulcers require antibiotics, either for therapy or for prophylaxis, available studies do not generally support this view6,7. Antibiotic therapy is associated with frequent adverse effects, substantial financial costs, and potential harm to local and global microbial ecologies.

Route of Therapy
The key issue in antibiotic therapy is achieving adequate serum levels and delivering the drug at a therapeutic concentration to the infected site. Intravenous antibiotics are indicated for patients who are systematically ill, have a severe infection, are unable to tolerate oral agents, or are known or suspected to have pathogens that are not sensitive to available oral agents. After the patient is stabilized and the infection is clearly responding, most patients can be switched to oral therapy. Patients who require prolonged intravenous therapy, e.g., for osteomyelitis or infections resistant to oral agents, can often be treated on an outpatient basis when a programme to provide this service is available.

Table I. Factors that may influence antibiotic therapy of diabetic foot infections
(specific agents, route of administration, duration of therapy)
  • Clinical severity of the infection (mild, moderate, severe)
  • Microbiology: known or presumed (e.g., Gram-stained smear) pathogens
  • Previous (recent) antibiotic therapy
  • Osteomyelitis: present or absent
  • Vascular status: adequacy of blood flow to infected site
  • Allergies to antibiotics
  • Drug metabolism impairment (e.g., renal or hepatic insufficiency)
  • Gastrointestinal absorption impairment
  • Drug toxicity potential (direct and interactions)
  • Local antibiotic susceptibility data
  • Formulary and cost considerations
  • Patient preferences
  • Published data

Oral antibiotic therapy is less expensive, more convenient, and probably associated with fewer complications than parenteral therapy. Delivery of the first dose of antibiotic to the infected site is slower with oral therapy, but this is only an issue for critically ill patients. The main concern is the bioavailability of orally administered agents. Gastrointestinal absorption of oral antibiotics is variable, and may be decreased in diabetic patients. Fortunately, some agents, e.g., clindamycin and the fluoroquinolones, are well absorbed with oral dosing. Fluoroquinolones in particular usually achieve high tissue concentrations in diabetic foot infections (including in inflamed tissues8) when administered orally. Several newly licensed agents cover an expanded spectrum of organisms. Once-daily drugs with good bio-availability and greater activity against antibiotic-resistant gram-positive cocci are especially appealing.

With peripheral vascular disease, therapeutic antibiotic concentrations are often not achieved in the infected tissues, even when serum levels are adequate. The key hindrance to penetration of antibiotic to the infected site is the presence of ischemia, not diabetes9.

Choice of antibiotic agents
Most patients will begin antibiotic therapy with an empirical regimen that should aim to cover the most common pathogens, with some modification according to infection severity. Relatively narrow-spectrum agents may be used for minor infections, as there is likely to be time to modify treatment if there is no clinical response. Regimens for severe infection should be broader-spectrum and most often intravenously administered, because the stakes are higher. Empirical regimens must also take into consideration such factors as patient allergies, renal dysfunction, previous recent antibiotic therapy and known local antibiotic sensitivity patterns.

An antibiotic regimen should almost always include an agent active against staphylococci and streptococci. Previously treated or severe cases may need extended coverage that also includes commonly isolated gram-negative bacilli and Enterococcus species. Necrotic, gangrenous or foul-smelling wounds usually require anti-anaerobic therapy. When culture and sensitivity results are available, more specific therapy should be chosen. Narrower spectrum agents are preferred, but it is important to assess how the infection has been responding to the empirical regimen. If the lesion is healing and the patient is tolerating therapy there may be no reason to change, even if some or all of the isolated organisms are resistant to the agents being used. On the other hand, if the infection is not responding, treatment should be changed to cover all the isolated organisms. If the infection is worsening despite susceptibility of the isolated bacteria to the chosen regimen, reconsider the need for surgical intervention and the possibility that fastidious organisms were missed on culture.

While theoretical and pharmacokinetic considerations are important, the proof of an antibiotic's efficacy is the clinical trial. Agents that have demonstrated, alone or in combination, clinical effectiveness in prospective studies of diabetic foot infections include the following10:

  • Cephalosporins (cephalexin orally; cefoxitin and ceftizoxime parenterally)
  • b-lactam/b-lactamase inhibitor combinations (amoxicillin/ clavulanate orally; piperacillin/tazobactam parenterally)
  • Fluoroquinolones (ciprofloxacin orally and parenterally; levofloxacin orally and parenterally)
  • Miscellaneous agents
    - Clindamycin (orally and parenterally)
    - Imipenem/cilastatin (parenterally)

A few randomized controlled studies have compared different oral and parenteral regimens; all were powered only to demonstrate equivalence, and did. Overall, the clinical and microbiological response rates have been similar in trials with the various antibiotics and no one agent or combination has emerged as most effective11. New antibiotics are introduced and some older ones are made obsolete by emergence of resistance or newly appreciated toxicities. Understanding the principles of antibiotic therapy is therefore more important than knowing the specific agents currently in vogue.

Cost of therapy is also an important factor in selecting a regimen. For deep foot infections, antibiotics account for only 3%-5% of the total costs for treatment; costs for topical wound treatments are considerably higher. One study demonstrated that therapy with ampicillin/sulbactam was significantly less expensive than with imipenem/cilastatin for limb-threatening diabetic foot infections, primarily because of the lower drug and hospitalization costs and less severe side effects associated with the former12. More comparative trials and economic analyses are needed. Published suggestions on specific antibiotic regimens for diabetic foot infections vary, but are more alike than different. Table 2 highlights some empirical recommendations by type of infection. A more extensive list may be found elsewhere11,13.

Table 2. Suggested empiric antibiotic regimens for treating diabetic foot infections 1
Severity of Infection Recommended 2 Alternative3
Mild/Moderate (oral for entire course)
  • Cephalexin (500mg q6h)
  • Amoxicillin/clavulanate (500/125mg q8h)
  • Clindamycin (300 mg q6h)
  • Ciprofloxacin (500 mg or 750 mg bid)
  • Clindamycin (300mg q6h)
  • TMP/SMX (1ds bid) + clindamycin (300 mg q6h)
Moderate/Severe
(Intravenous until stable, then switch to oral equivalent)
  • Piperacillin/ tazobactam (3.375g q6h)
  • Clindamycin (600 mg q8h) + Ciprofloxacin (400 mg ivq12h or 750 mg po q12 h)
  • Piperacillin/tazobactam (3.374 g q6h)
  • Clindamycin (600 mg q6h) + 3rd generation cefalosporin4
Life Threatening (Prolonged Intravenous)
  • Imipenem/cilastin (500mg q6h)
  • Clindamycin (900mg tid) + Tobramycin5 (5.1mg/kg.ld) + Ampicillin (50mg/kg. qid)
  • Meropenem 1 g q8h
  • Vancomycin (1g q12h) + Aminoglycocide5 + Metronidazole (500 mg po or iv q 8 h)
  1. The usual recommended doses are shown in the table. A modification must be made for renal impairment/hemodialysis, hepatic impairment and allergies in certain cases. Please check with the pharmacy staff or a consultant knowledgeable with the use of these agents if necessary.
  2. Based upon theoretical considerations and available clinical trials.
  3. Prescribed in special circumstances, e.g., patient allergies, recent treatment with recommended agent, cost considerations.
  4. A similar agent of the same class or generation may be substituted, e.g., Ceftriaxone 1 g q 24h; Cefotaxime 1 g q 8h
  5. Aminoglycosides should be used with caution in persons with diabetes. Prior to the use of an aminoglycoside it would be prudent to contact a consultant knowledgeable with the use of these agents.
    * A high local prevalence of methicillin-resistance among staphylococci may require using vancomycin or other appropriate agents active against these organisms. Use of drugs in combination may be more effective and help prevent emergence of resistance.

Duration of therapy
The necessary duration of antibiotic therapy for diabetic foot infections has not been well studied. For mild to moderate infections, a 1-2 week course has been found to be effective2, while for more serious infections, treatment has usually been given for about two weeks, sometimes longer. Adequate debridement, resection, or amputation of infected tissue can shorten the necessary duration of therapy. In those few patients with diabetic foot infection who develop bacteremia, therapy for at least two weeks seems prudent. Antibiotic therapy can generally be discontinued when all signs and symptoms of infection have resolved, even if the wound has not completely healed. In some instances of extensive infection, large areas of gangrene or necrotic tissue, or poor vascular supply, more prolonged therapy may be needed. Some patients who cannot, or will not, undergo surgical resection, or who have surgical metalwork at the site of infection, may require prolonged suppressive antibiotic therapy.

Outcome of Treatment
A good clinical response for mild to moderate infections can be expected in 80%-90% of appropriately treated patients, and in 50%-60% of deeper or more extensive infections14. When infection involves deep soft tissue structures or bone, more thorough debridement is usually needed. Most amputations can be foot-sparing and long-term control of infection is achieved in over 80% of cases. Infection recurs in 20%-30% of patients, many of whom have underlying osteomyelitis. The presence of edema or atherosclerotic cardiovascular disease increases the likelihood of an amputation. Patients with combined soft tissue and bone infection may require amputation more often than either type of infection alone.

Conclusion
Although there are seemingly countless antibiotic choices for the management of the infected diabetic foot, it is reasonable to initiate broad-spectrum empiric antimicrobial therapy pending culture results. The decision of oral versus parenteral antimicrobial therapy is based upon the extent of the infection and the patient's overall clinical status. The duration of therapy is based upon the tissues involved. Skin and skin structure infections can usually be treated for 1-2 weeks while osteomyelitis will require weeks to months of therapy. Cost considerations and antimicrobial resistance issues should be considered in making empiric antimicrobial choices. Although it is appropriate to initiate broad-spectrum antimicrobial therapy pending final cultures, once the results become available, streamlining antimicrobial therapy to the narrowest spectrum agents is most appropriate to prevent the emergence of antimicrobial resistance. If doubts exist as to the clinical and pathologic significance of some of the recovered agents, it would be reasonable to seek assistance in guiding antimicrobial therapy.

References
  1. Lipsky B.A.: Infectious problems of the foot in diabetic patients. The Diabetic Foot, 6th edition. 2001, J.H. Bowker, M.A. Pfeifer, eds, pages 467-480.

  2. Lipsky B.A., Pecoraro R.E., Larson S.A., Ahroni, J.H.: Outpatient management of uncomplicated lower-extremity infections in diabetic patients. Arch Intern Med150:790-797, 1990.

  3. Breen J.D., Karchmer A.W.: Staphylococcus aureus infections in diabetic patients. Infect Dis Clin North Am 9 :11-24, 1995.

  4. Gerding D.N.: Foot infections in diabetic patients: The role of anaerobes. Clin Infect Dis 20(Suppl 2):S283-288, 1995.

  5. Tentolouris N., Jude E.H., Smirnof I., Knowles E.A., Boulton A.J.M.: Methicillin-resistant Staphylococcus aureus: an increasing problem in a diabetic foot clinic. Diabetic Med 16:767-771, 1999.

  6. O'Meara S.M., Cullum N.A., Majid M., Sheldon T.A.: Systemic review of antimicrobial agents used for chronic wounds. Br J Surg 88 :4-21, 2001.

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

  8. Kuck E.M., Houter K.P., Hoekstra J.B.L., Conemans J.M.H., Diepersloot R.J.A.: Tissue concentrations after a single-dose, orally administered ofloxacin in patients with diabetic foot infections. Foot Ankle Int 19:38-40, 1998.

  9. Raymakers J.T., Houben A.J., vd Heyden J.J., Tordoir J.H., Kitslaar P.J., Schaper N.C.: The effect of diabetes and severe ischaemia on the penetration of ceftazidime into tissues of the limb. Diabetic Med18:229-234, 2001.

  10. Lipsky B.A.: Evidence-based antibiotic therapy of diabetic foot infections. FEMS Immunol Med Microbiol 26: 267- 276, 1999.

  11. Cunha H.A. Antibiotic selection for diabetic foot infections: a review. J Foot Ankle 39:253-257, 2000.

  12. McKinnon P.S., Paladino J.A., Grayson M.L., Gibbons G.W., Karchmer A.W.: Cost effectiveness of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis 24:57- 63, 1997.

  13. Embil J.M., Choudhri S.H., Germaine G., Imlah T., Duerksen F., Darcel M., Fong H., Koulack J., Gin A., Stern S., Simonsen J.N., Harding G.K.M., Nicolle L.E.: Community Intravenous Therapy Program and a treatment Plan for Foot Infections for Persons Diabetes: A Clinical Perspective. Can J Infect Dis 11(Suppl A): 49A-56A, 2000.

  14. Eneroth M., Apelqvist J., Stenstrom A.: Clinical characteristics and outcome in 223 diabetic patients with deep foot infections. Foot Ankle Int 18(11):716-722, 1997.