diabetic foot ppt
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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.
Typical Indian with diabetic foot
• 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
Typical Indian with diabetic foot
• 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
Ulbrecht JS, Cavanagh PR. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S73-82.
Forefoot ulcer due to Neuropathy
Inappropriately high pressure distribution
Ulbrecht JS, Cavanagh PR. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S73-82.
• 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.
Lipsky BA. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S104-14.
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
Lipsky BA. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S104-14.
• 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
Watkins PJ. BMJ. 2003 May 3;326(7396):977-9.
Evaluation of the patient
Check posterior tibial pulse
Check Dorsalis pedis pulse Sensory
examination
X-ray of the foot
Select patients• Doppler study• Angiography
Watkins PJ. BMJ. 2003 May 3;326(7396):977-9.
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
Watkins PJ. BMJ. 2003 May 3;326(7396):977-9.
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
Lipsky BA. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S104-14.
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.
Lipsky BA. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S104-14.
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:
Cure Improvement Failure
0/40 (0%) 21/40 (52.5%) 19/40 (47.5%)
Response after 9 weeks of therapy:
Cure Improvement Failure
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
Ulbrecht JS, Cavanagh PR. Clin Infect Dis. 2004 Aug 1;39 Suppl 2:S73-82.
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