Diabetic foot ppt

Diabetic foot Infections- An Update

‘Diabetics should treat their Feet like they do their Face’

Presentation highlights

• Introduction

• Definition

• Epidemiology

– Indian perspective

• Pathogenesis

• Microbiology

– Indian perspective

• Management

– Clindamycin in the treatment of diabetic foot infections

• Prevention

• Summary

Introduction

• Foot infections - among the most frequent and serious consequences of diabetes mellitus

• Responsible for more hospital days than any other complication of diabetes

• Dealing with this problem will require

– Greater understanding of the pathophysiology of these infections

– Better systems for implementing proven effective measures

Lipsky BA, Berendt AR. Diabetes Metab Res Rev 2004; 20(Suppl 1): S56–S64.

Definition

International Consensus on Diagnosing and Treating the Infected Diabetic Foot (2003)

Berendt T. Diabetic foot infection: what remains to be discovered?. FDA Anti-Infective Drugs Advisory Committee, October 2003. http://www.fda.gov/OHRMS/DOCKETS/ac/03/slides/3997S1_01_Berendt.ppt. Accessed on 24-7-06.

Any infection involving the foot in a person with diabetes originating in a chronic or acute injury to the soft tissues of the foot, with evidence of pre-

existing neuropathy and/or ischemia

Epidemiology

• U.S. data

– 250 million diabetics by 2025

– 2-5% of diabetics develop foot ulcer annually

– Point prevalence of ulceration estimated at 4-10%

– 40-60% of all non-traumatic lower extremity amputations are in diabetics

– 85% of these preceded by foot ulcer

Berendt T. Diabetic foot infection: what remains to be discovered?. FDA Anti-Infective Drugs Advisory Committee, October 2003. http://www.fda.gov/OHRMS/DOCKETS/ac/03/slides/3997S1_01_Berendt.ppt. Accessed on 24-7-06.

Typical Indian with diabetic foot

• First time presentation

– Male with an average age of 56 yrs

– Type 2 diabetes with average duration of 12 yrs

– Most have some degree of neuropathy and few have peripheral Vascular Disease

– Common precipitating factors

Lack of footwear

Irregular foot care

Burns

Morbach S, Viswanathan . Diabet Med. 2004 Jan;21(1):91-5.


• Patients requiring surgery

– Majority of the patients had grade II and III ulcers (50% and 26.5%, respectively)

– Grade IV was seen in another 21.9%

• After surgery

– The median healing time was 44 days

– Recurrence of infection occurred in 53%

More common in patients with neuropathy and peripheral vascular disease (PVD)

Vijay V, Narasimham DV. Diabet Med. 2000 Mar;17(3):215-8


• Diabetic subjects with foot problems incur very heavy expenditure in the treatment process

• Hospitalization costs are particularly heavy

• Total median expenditure

– Without foot complications (n=164) - Rs. 4,373

– With foot complications (n=106) - Rs. 15,450

Shobhana R, Rao PR. J Assoc Physicians India. 2000 Dec;48(12):1147-50.

Pathogenesis of Diabetic foot

• Multi-factorial, Complex and still poorly understood

– Neuropathy

– Vasculopathy

– Immune dysfunction

– Infection

• Prolonged Hyperglycemia contributes to all the above factors through different mechanisms

Lipsky BA. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S104-14.

Motor Neuropathy

Sensory Neuropathy

AutonomicNeuropathy

Vasculopathy

Immune dysfunction

Complex interplay of factors

Ulbrecht JS, Cavanagh PR. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S73-82.

Neuropathy

• Sensory

– Loss of protective sensation

– Loss of position sense

• Motor

– Muscle weakness

– Foot deformity

• Autonomic

– Poor blood flow regulation

– Dry, stiff skin

Unaware of minor cuts/bruises

Poor weight distribution

Cracked skin allows easy entry of bacteria

Clawed toes

Prominent metatarsals


Forefoot ulcer due to Neuropathy

Inappropriately high pressure distribution


• Accelerated atherosclerosis

– Diabetes

– Hypertension

– Obesity

– Age

– Dyslipidemia

Decreased local blood flow

Poor wound healing

Poor antibiotic

penetration

Heel ulcer is typical of poor blood circulation due to vasculopathy

Vasculopathy

Watkins PJ. BMJ. 2003 May 3;326(7396):977-9.

Immune dysfunction

• Impaired defenses against infection

1. Polymorphonuclear leukocyte migration

2. Phagocytosis

3. Intracellular killing

4. Chemotaxis

Geerlings SE, Hoepelman AI. FEMS Immunol Med Microbiol. 1999 Dec; 26(3-4):259-65

12

34

Infection

– Foot infections in diabetic patients usually begin in a skin ulceration

– Most infections remain superficial, but 25% will spread contiguously from the skin to deeper subcutaneous tissues and/or bone.

– An infected foot ulcer precedes 60% of amputations, making infection perhaps the most important proximate cause of this tragic outcome.

– Because all skin wounds contain microorganisms, infection must be diagnosed clinically, that is, by the presence of systemic signs (e.g., fever, chills, and leukocytosis), purulent secretions (pus), or 2 local classical signs or symptoms of inflammation (warmth, redness, pain or tenderness, and induration).

– In chronic wounds, additional signs suggesting infection may include delayed healing, abnormal coloration, friability, or foul odor.


Microbiology of Diabetic foot: U.S.

• Polymicrobial

Serious infections in hospitalized patients are often caused by 3–5 bacterial species

• Aerobes

Gram-positive cocci

S. aureus is the most important pathogen

Enterococci in patients who have previously received a cephalosporin

Gram-negative bacilli

Enterobacteriaceae in patients with chronic or previously treated infections

Pseudomonas species in patients with wounds that have been soaked or treated with wet dressings

• Anaerobes

Wounds with ischemic necrosis or that involve deep tissues


• Infection profile (n=775)

– Polymicrobial

Average of 3.07 organisms isolated per case

71.09% aerobic

28.91% anaerobic

– Related to severity of disease

Staphylococcus and Streptococcus 50% in the first two Wagner grades and were reduced to less than one-fourth of the total organisms in the last two grades

Significant increase in the Gram-negative organisms and anaerobes in the last two grades

Pathare NA, Bal A. Indian J Pathol Microbiol. 1998 Oct;41(4):437-41.

Microbiology of Diabetic foot: India

Classification

• Wagner’s Classification of diabetic ulcer

0 - Intact skin (impending ulcer)

1 - Superficial

2 - Deep to tendon bone or ligament

3 - Osteomyelitis

4 - Gangrene of toes or forefoot

5 - Gangrene of entire foot

Calhoun JH, Cantrell J. Foot Ankle. 1988 Dec;9(3):101-6.

Examples of different grades

Hall J, Preventive foot care for diabetes patients in primary care. Pfizer. Data on file.

Principles of Management

• Multidisciplinary approach

– Medical

– Surgical

– Orthopedics

• Evaluation of the patient

– Look for danger signs needing urgent intervention

• Good Blood glucose control

• Long term care after wound healing is complete

– Education and preventive foot care


Evaluation of the patient

Check posterior tibial pulse

Check Dorsalis pedis pulse Sensory

examination

X-ray of the foot

Select patients• Doppler study• Angiography


Danger signs for urgent action

• Redness and swelling of a foot that even when neuropathic causes some discomfort and pain; this often indicates a developing abscess, and urgent surgery may be needed to save the leg

• Cellulitis, discoloration, and crepitus (gas in soft tissues)

• Pink, painful, pulseless foot even without gangrene indicates critical ischaemia that needs urgent arterial investigation followed by surgical intervention whenever possible


Cornerstones of treatment

• Surgical debridement

– Drain pus and abscess cavities and to remove all necrotic and infected tissue including devitalised and infected bone resulting from osteomyelitis

• Eradication of infection

– Antibiotic choices should optimally be based on results of culture

If empirical therapy is necessary, it should cover S. aureus and anaerobes

Broader coverage should be considered based on the history & clinical judgment

• Adjuvant therapies

– Utility remains controversial

• Reduction of weight bearing forces

– Bed rest with foot raised

Lipsky BA, Berendt AR. Diab Metabol Res Rev 2004; 20: S56-S64. Ulbrecht JS, Cavanagh PR. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S73-82.

Factors affecting choice of antibiotic

Clinical severity of the infection Previous (within 2 weeks) antibiotic therapy

Bone infection (presumed or proven)Vascular status at infected site

Etiologic agent(s) (known or presumed)Local antibiotic susceptibility data

Safety profile Drug interactions potential

Frequency of dosingCost considerations

Published efficacy data

Drug-related

Allergies to antibioticsHost immunological status

Patient preferencesRenal or hepatic insufficiencyGastrointestinal absorption

Infection-related

Patient-related

Organism-related

Osteomyelitis in diabetic foot infections

• Dealing with osteomyelitis is perhaps the most difficult aspect in the management of diabetic foot infections

• Presence of osteomyelitis

– Increases the likelihood of surgical intervention, including amputation

– Impairs healing of the overlying wound

– Acts as a focus for recurrent infection

– Increases the required duration of antibiotic therapy

• ESR of >40 mm/h was associated with almost a 12-fold increased likelihood of osteomyelitis

• Larger ( ulcer area > 2 cm) and deeper (depth > 3 mm) increases the likelihood of osteomyelitis

Lipsky BA, Berendt AB. Clinical Infectious Diseases 2004; 39:885–910 Lipsky BA. Clinical Infectious Diseases 1997;25:1318–

Duration of antibiotic therapy

• The optimal duration of antibiotic therapy for diabetic foot infections is unknown.

• On the basis of available studies,

– Mild to moderate infections, 1 to 2 weeks is usually effective

– Serious infections, 2 to 4 weeks is usually sufficient

• Longer duration may be needed for

– Immunocompromised patients, poorly perfused, deep, large or necrotic wounds, osteomyelitis, patients who cannot (or will not) undergo surgical resection, or who have an implanted foreign body at the infection site

• Adequate debridement, resection, or amputation of infected tissue can shorten the necessary duration of therapy.

• Antibiotic therapy can generally be discontinued when signs and symptoms of infection have resolved, even if the wound has not completely healed.

Lipsky BA, Berendt AR. Diabetes Metab Res Rev 2004; 20(Suppl 1): S56–S64.

Adjuvant therapies are not universally accepted

• Several additional measures have been used to improve infection resolution, wound healing, and host response.

• Recombinant granulocyte-colony stimulating factor

– Larger trials are needed to define whether, and for whom, these compounds can be recommended.

• Hyperbaric oxygen

– Expensive and limited resource that should remain reserved for severe cases

• Revascularization

– An aggressive approach to revascularization in an ischemic infected foot can result in 3-year limb-salvage rates of up to 98%

• Edema control

– Simple interventions, such as leg elevation and compression stockings, are likely to be beneficial l


Suggested antibiotic regimens for treatment of diabetic foot infections*

• Mild/moderate (oral for entire course) – Clindamycin (300 mg t.i.d.) or Cephalexin (500 mg. q.i.d.) or Levofloxacin (750

mg q.d.)

• Moderate/severe (iv until stable, then switch to oral equivalent)– Clindamycin (450 mg q.i.d.) + ciprofloxacin (750 mg b.i.d.)– Clindamycin (600 t.i.d.) + ceftazidime (2 g t.i.d.)– Ampicillin/sulbactam (3.0 g q.i.d.)

• Life-threatening (prolonged iv) – Clindamycin (900 mg t.i.d.) + tobramycin (5.1 mg/kg./d) + ampicillin (50

mg/kg. q.i.d.)– Imipenem/cilastin (500 mg q.i.d.)– Vancomycin (15 mg/kg b.i.d.) + aztreonam (2.0 g t.i.d.) + metronidazole (7.5

mg/kg q.i.d.)

*Based on theoretical considerations and available clinical trials.A similar agent of the same class or generation may be substituted.


BL+ - Beta-lactamase producing strains CTX – Cefotaxime CTR – Ceftriaxone CTZ - Ceftizoxime

John Hopkins antibiotic guide. http://hopkins-abxguide.org/ Accessed on 2-5-04 Mader JT, Adams K. AAC, Oct. 1989:1760-1764 EGAST study group. Hospital Today Jan-Mar 2004;Vol IX No. 1: 1-12

S. aureus S. pyogenesS. epidermidis

CLINDAMYCIN/VANCOMYCIN/TEICOPLANIN

Streptococcus spp

CTX/CTR/CTZ CTX/CTR/CTZBL+

CEFUROXIME CEFUROXIME

CEFAZOLIN CEFAZOLIN

BL+

BL+

Comparative Gram +ve coverage

Clindamycin has broad spectrum activity against gram positive aerobes

TEIC – TeicoplaninVANC – VancomycinCTX – CefotaximeCFU – CefuroximeCTZX - Ceftizoxime

B. fragilis Peptostreptococci Clostridium perfringens

DALACIN C (Clindamycin)

METRONIDAZOLE

CEFAZOLIN

CTX/CFU/CTZX

CEFTRIAXONE

TEIC/VANC

Actinomyces sp

OFLOXACIN

METRONIDAZOLE

CEFTIZOXIME

John Hopkins antibiotic guide. http://hopkins-abxguide.org/ Accessed on 2-5-04 Karchmer AW. Antibacterial therapy. In: Bennett CL, Plum F (eds). Cecil Textbook of medicine 1996 WB Saunders. 20th edition: 1559-69

Clindamycin has broad spectrum activity against anaerobes

Comparative anaerobic coverage

Clindamycin is selectively concentrated in human

PMNL lysosomes

Actively transported to site of infection in

the PMNL

PMNL – Polymorphonuclear leucocytes

Clindamycin is released at site in high concentrations for powerful anti-bacterial action

High levels in infected bones, joints, body fluids, pus and abscesses

Clindamycin achieves high concentrations in infected tissues

Mader JT, Chemotherapy 1989 Santos JI, Clinical Therapeutics 1992;

98.3

16 12.5 12.57

Clindamycin

Vancomycin

Newer quinolones

Ciprofloxacin

Cefazolin

%100

80

60

40

20

Note: in vitro susceptibility need not necessarily correlate with in vivo results

Bone/Serum Conc. Ratio

%

The degree of penetration of an antibiotic into the infected site is an important determinant of therapeutic success.

Stengel D, et al. Lancet Inf Dis. 2001;1(3): 1-12

Clindamycin has exceptional bone penetration

Clindamycin has excellent tissue concentrations near ischemic ulcers

• In patients with gangrenous peripheral arterial occlusive disease, achieving high tissue concentrations of antibiotics is important to achieve rapid suppression of local infection

Drug 1-hour (A/B) 3-hour (A/B)

Gentamicin (n=16)

4.2/9.69 2.8/6.01

Clindamycin (n=15)

19.4/12.23 11.9/6.95

Tissue (A) concentration near ischemic ulcers (mcg/g wet weight) and blood (B) concentration (mcg/mL) after intravenous administration of

clindamycin (1200 mg/day) and gentamicin (Adjusted, mean- 284 mg/day)

POOR

EXCELLENT

Comparative tissue penetration

S.E. Geerlings, A.I.M. Hoepelman. FEMS Immunology and Medical Microbiology 26 (1999) 259^265

Adequate tissue penetration of clindamycin in diabetic foot infections

• Serum and tissue samples were obtained during surgery from four diabetics with neuropathy who underwent debridement or amputation for foot infections while receiving clindamycin 600 or 900 mg iv.

• Clindamycin was detected in all (11/11 - 100%) serum and tissue samples

– Tissues: 0.04-2.8 mg/kg

– Serum: 1.1-11.1 mg/L .

• In 82% samples (9/11), clindamycin concentration exceeded the MICs reported for many pathogens commonly involved in such infections.

Duckworth C, Fisher JF. J Antimicrob Chemother. 1993 Apr;31(4):581-4.

Clindamycin is effective inpatients with osteomyelitis

• Retrospective review of 22 patients with diabetic foot and associated osteomyelitis treated conservatively with antibiotics only

• The total duration of antibiotic treatment was 12 weeks (5-72)– Clindamycin was the most commonly used oral agent.

• Results:– 17 patients had resolution of osteomyelitis over a median period of

follow-up of 27 (range 5-73) months. – 1 patient responded clinically but had a recurrence of osteomyelitis at the

same site 6 years later. – 4 patients did not respond to initial conservative therapy and proceeded

to amputation

“The success of conservative therapy with prolonged courses of oral antibiotics challenges conventional advice that excision of infected bone is essential in the management of osteomyelitis affecting the foot in diabetes”

Venkatesan P, Lawn S. Diabet Med. 1997 Jun;14(6):487-90.

Immunocompromised patients Impaired chemotaxis

e.g., diabetes Activity against resistant S. aureus

These effects are seen at a drug concentration of just 2 mcg/ml

Clindamycin is selectively concentrated in human

PMNL lysosomes

Santos JI, Clinical Therapeutics 1992;

Clindamycin has added benefit in diabetic patients

*Needed if drug given q6h or more frequently

System impairment Mild Moderate Severe

Renal X X X

Hepatic X X X*

Clindamycin dosage modification may not be necessary in most patients with renal disease or liver disease

No need for dosage adjustment in elderly patients

Dalacin C. Local prescribing information.

X - No need

Clindamycin requires no dosage adjustment in patients with hepatic or renal impairment

Clinical response (n=56)

Clindamycin* (n=27)

Cephalexin (n=29)

Cured

Improved

Failed

21(78)

5(19)

1(4)

21(72)

4(14)

4(14)

Lipsky BA, Pecoraro RE. Arch Intern Med. 1990 Apr;150(4):790-7.

Outcome of 2-week Out-patient treatment with oral Clindamycin and oral Cephalexin in Uncomplicated

lower-extremity Infection in diabetic patients

Clindamycin in patients with uncomplicated diabetic foot infections

*Differences are not statistically significant because of the small sample size

1990

Clindamycin in patients with Severe Diabetic Foot infections

In a recent prospective study involving 84 hospitalized diabetics with severe lower limb infections. (largest patient population in any such study), a single combination was evaluated:

Recommended regimen:

IV Ciprofloxacin 300mg BID

IV Clindamycin 600mg TID

Response after 5 days of therapy: 95.4%

Cure Improvement Failure

46 (54.7%) 20 (23.8%) 18 (21.4%)

Diamantopoulos EJ, Exp Clin Endocrinol Diabetes. 1998

Response at 3 weeks post Rx

→ Polymicrobial (2.8 species per specimen) in 83% of the cases

→ Osteomyelitis in 58 % of the patients

1998

The side effects of the combination of ciprofloxacin/clindamycin were mild and there were no cases of pseudomembranous enterocolitis.

“The combination of ciprofloxacin/clindamycin was found to

provide an excellent empirical as well as definitive treatment of severe diabetic foot

infections”

40 diabetic patients with severe, limb-threatening foot infection were included in a clinical study of recombinant human granulocyte colony-stimulating factor (G-CSF). All displayed evidence of osteomyelitis and long-standing ulcer infection. Empiric antibiotic therapy was based on the consensus standard

Selected empiric regimen:

IV Ciprofloxacin 400 mg BID

IV Clindamycin 900 mg TID

Oral Ciprofloxacin 750 mg BID

Oral Clindamycin 300 mg QID

Response after 3 weeks of therapy:


0/40 (0%) 21/40 (52.5%) 19/40 (47.5%)

Response after 9 weeks of therapy:


14/40 (35%) 12/40 (30%) 14/40 (35%)

Febrile disease, extended cellulitis with lymphangitis, incomplete debridement of necrotic tissues, or extensive bone involvement had been observed

Less critical patients and switch from initial intravenous therapy

2001

Clindamycin based regimes are preferred in patients with severe diabetic foot infections

Lalla FD, Pellizzer G. Antimicrob Ag Chemother 2001;45:1094-98.

37 subjects with infected diabetic foot ulcers were studied to evaluate the use of G-CSF#. All subjects received a combination antibiotic regimen intravenously until the inflammation had subsided.

Preferred regimen:

IV Ciprofloxacin + IV Clindamycin

Diamantopoulos EJ, Haritos D Exp Clin Endocrinol Diabetes. 1998;106(4):346-52.

“Antibiotics and bed rest accelerated the resolution of cellulitis in infected foot

ulcers. Additional treatment with G-CSF had no further beneficial effect”

2003

Clindamycin based regimes are preferred in patients with severe diabetic foot infections

Infection score Pre-Rx Post Rx

G-CSF* arm (n=20) 29.5 6.7 (p<0.001)

Placebo (n=20) 24.2 8.9 (p<0.001)

The ulcer volume also reduced by 59% (G-CSF arm) and 35% (placebo arm).*

*Differences between G-CSF and placebo were not statistically significant.

Outcomes:

#Granulocyte colony-stimulating factor

Safety profile of clindamycin

• The most common adverse effect of clindamycin is diarrhea

– 2% to 20% of patients

– In most cases, the diarrhea is not clinically important and subsides when the drug is discontinued.

– However, in a small percentage of patients (<1%), intestinal overgrowth of C difficile, an anaerobe that is not sensitive to clindamycin, leads to toxin production that causes pseudomembranous colitis.

– Systemic toxicity including toxic megacolon have been reported with severe colitis.

• Hypersensitivity reactions are the next most common adverse effect of clindamycin

– Usually presenting as a morbilliform rash

– More severe reactions have been reported but are rare.

• Less common adverse effects include liver toxicity, bone marrow suppression, and muscle weakness, all of which are reversible when the drug is discontinued.

Weingarten-Arams J. Pediatrics in Review 2002; Volume 23. Number 4:1-3

Prevention

• Regular foot exams and patient education can prevent 85% of amputations

• Four basic steps for preventive foot care

– Early identification of the high risk diabetic foot

– Early diagnosis of foot problems

– Early intervention to prevent further deterioration that may lead to amputation

– Patient education for proper care of the the feet and footwear


Summary

• Foot ulceration, sepsis, and amputation are known and feared by almost every person who has diabetes

• Potentially, they are the most preventable of all diabetic complications by the simplest techniques of education and care

• The majority can also be cured by immediate and energetic treatment which includes appropriate antibiotic selection

– Clindamycin (Dalacin C) is safe and effective as monotherapy or in a combination regime and offers many advantages over alternative agents e.g., in patients with osteomyelitis

Watkins PJ, BMJ. 2003 May 3;326(7396):977-9. Klainer AS. Clindamycin in the treatment of diabetic foot infections. In: Zambrano D ed. Clindamycin in the treatment of human infections. Ch 11. Sec.11.1- 11.16.Diamantopoulos EJ ; Haritos D. Exp Clin Endocrinol Diabetes. 1998; 106(4):346-52

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Diabetic foot ppt