Case 2 Cellulitis

Group 2: Alison Hemy, Avril Hamilton, Gina Hummel, WaiSum Szeto, Saurabh Patel Date: June 17, 2011

Outline
Meet Christof Kottingheimer (CK) What is cellulitis?

Epidemiology Pathophysiology Risk Factors Microbiology Signs & Symptoms Complications Diagnosis Drug therapy problems and therapeutic alternatives Mild to moderate (uncomplicated) cellulitis Methicillin resistant Staphylococcus aureus (MRSA) treatments Severe (progressive/complicated) cellulitis Care plan/ monitoring/patient education Summary

Meet Christoph Kottingheimer

75 years old Visited emergency 5 days ago
diagnosed with LEFT UPPER EXTREMITY (LUE) CELLULITIS

Prescription for cephalexin 500mg po TID for 7 days, but lost it

Today:
Increased swelling and pain in left forearm Decreased range of motion and tenderness in right shoulder New onset pain in right shoulder Fever

invisibleparachute.com

Past Medical History

Left-arm cellulitis, diagnosed 5 days ago Type 2 diabetes mellitus
Recently diagnosed

Atrial fibrillation

alanderickson.com

Surgical History
1980 - motor vehicle accident and acquired large bump on forehead 1982 facial electrical burn requiring skin graft 2002- benign cyst removed from neck

Social History
Smokes 2 ppd x 20 years Occasional alcohol Denies illicit drug use
anguishedrepose.wordpress.com

Medications
Indication Cellulitis T2DM Atrial Fibrillation Medication Cephalexin 500mg po TID Metformin 500mg po BID Metoprolol 50mg BID Result to date Patient did not take Patient reports only taken a couple of doses Heart rate controlled

* No known drug allergies

leanpowerfulfitness.com

What is Cellulitis?
Type of skin and soft-tissue infection
Acute Affects epidermis, dermis and subcutaneous layers

Serious infection because possible spread through:

Lymphatic tissue Blood stream

Commonly gram positive bacteria

en.wikipedia.org

Cellulitis. PubMed Health. National Library of Medicine. 2009. Accessed June 15, 2011.

Epidemiology of Cellulitis
Not reportable in Canada
Difficult to determine incidence and prevalence

Incidence = 200 cases per 100 000 patient years More common in middle-aged and elderly Equally affects men and women

uptodate.com National Notifiable Diseases. Publich Health Agency of Canada. Accessed June 15, 2011. Baddour, LM. Cellulitis and erysipelas. UpToDate. Accessed June 15, 2011.

Pathophysiology of Cellulitis
Break to skin
Burn, trauma, ulcers, injections

Organisms from skin can enter dermis and multiply Note:

Although visible break in skin is common, can occur with microscopic breaks from dry and irritated skin
Baddour, LM. Cellulitis and erysipelas. UpToDate. Accessed June 15, 2011. Cellulitis. PubMed Health. National Library of Medicine. 2009. Accessed June 15, 2011.

Risk Factors
Co-morbidities
Diabetes (*** our patient ***) Immunodeficiency Cancer Peripheral artery disease

IV or SC drug use

invisibleparachute.com

Baddour, LM. Cellulitis and erysipelas. UpToDate. Accessed June 15, 2011.

Microbiology
80% of cases are gram positive:
-hemolytic streptococci (ex. Streptococcus pyogenes) Staphlococcus aureus.

Less common:
Streptococcus pneumoniae Haemophilus influenzae Gram-negative bacilli (pseudomonas, proteus, enterobacter) Anaerobes

Mixed aerobic-anaerbic flora also occurs in diabetes

biomarker.korea.ac.kr

equidblog.com

Baddour, LM. Cellulitis and erysipelas. UpToDate. Accessed June 15, 2011. Pendland SL, Fish DN, Danziger LH. Skin and soft tissue infections: In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York, McGraw-Hill, 2005:19771995

Signs & Symptoms of Cellulitis

Fever Chills Malaise Joint stiffness Affected area feels hot and painful Erythema of skin Edema of skin Lesions
Comes on suddenly Grows quickly in first 24 hours

Swollen lymph nodes

findmeacure.com

Cellulitis. PubMed Health. National Library of Medicine. 2009. Accessed June 15, 2011.

Cellulitis

Edema associated with cellulitis

Cellulitis surrounding a burn

Erythema associated with cellulitis

Medicinenet.com

Cellulitis Complications
Osteomyelitis (bone infection) Lymphangitis (inflammation of lymph vessels) Meningitis Sepsis, shock Gangrene (tissue death)

wikinfo.org

Cellulitis. PubMed Health. National Library of Medicine. 2009. Accessed June 15, 2011.

Diagnosis of Cellulitis
Must be distinguished from other infections
Herpes zoster Necrotizing fasciitis Erysipelas Impetigo

Diagnosis often based on clinical manifestations Blood cultures, needle aspirations or biopsies not useful for mild infection
Positive 5-40% of the time Should be performed with serious disease (systemic toxicity, extensive skin involvement, comorbidities (lymphedema, malignancy, neutropenia, diabetes))

Back to CK
Vitals:
BP 129/74 HR 96 RR 16 T 38.3C BMI 35

invisibleparachute.com

CV:
Irregularly irregular heart beat

CrCl= 77 mL/mins

joetri-tthardt.blogspot.com

Measurement WBC Neutrophils Bands Lymphocytes Monocytes Blood Glucose Na K CL

CO2

Value 81% 10% 7% 2%

Back to CK

Normal 3.2-9.8 x 10^3/mm3 40-70% 0-10% 22-44% 4-11% 4-7 mmol/L (FBG) 5-10 mmol/L (PPG) 136-145 mmol/L 3.5-5 mmol/L 98-106 mmol/L
21-30 mEq/L

26.3 x 10^3/mm3

14 mmol/L 134 mEg/L 3.6 mEq/L 87 mEq/L

21 mEq/L

Urea SCr Hgb Hct Platelets

23 mg/dL 118 mol/L 155 g/L 44% 329 x 10^3/mm3

10-20 mg/dL <133 mol/L 138-182 g/L 41-53% 150-350 x 10^3/mm3

Kratz A, Ferraro M, Sluss, P, Lewandrowski KB. Laboratory Reference Values. N Engl J Med. 2004. 1548 -1564. .

Brief Summary of Patient CK

75 year old male Presented to the emergency department 5 days ago
Diagnosed with left upper extremity cellulitis Given a prescription for cephalexin 500mg po TID for 7 days

Medical Conditions
Type 2 diabetes mellitus Atrial Fibrillation

Brief Summary of Patient CK

Indication Cellulitis T2DM Atrial Fibrillation Medication Cephalexin 500mg po TID Metformin 500mg po BID Metoprolol 50mg BID Result to date Patient did not take Patient reports only taken a couple of doses Heart rate controlled

CKs Drug Related Problems (DRPs)

Mr. CK has progressive left arm cellulitis and requires a drug therapy. Mr. CKs T2DM is uncontrolled secondary to nonadherence, and requires education about the consequences of diabetes.

Mr. CK is at risk of stroke due to atrial fibrillation and requires anticoagulant therapy.

Additional DRPs
Mr. CKs metoprolol may not be efficacious as his heart rate is 96bpm and irregularly irregular.
Mr. CK smokes two packs of cigarettes per day and would benefit from smoking cessation education. Mr. CK is at risk of a cardiovascular event, and may require and ACEI and statin (lipid panel unknown). Mr. CKs is at an increased risk of cardiovascular events due to BMI of 35, and requires lifestyle education.

Subjective and Objective Data Consistent with Cellulitis

Subjective:
pain in left forearm, left upper extremity tenderness/pain in right shoulder, especially when gripping or flexing

Objective:
swelling (pitting edema), warm, red left forearm decreased range of motion in right shoulder fever tachycardia increased WBCs High neutrophils count, high bands, low lymphs, low monos negative for left upper extremity (LUE) DVT

Most Common Causative Organisms of Cellulitis

Most often: S. pyogenes or S. aureus. Less common organisms include Strep. Pneumoniae, Haemophilus influenzae, Gram-negative bacilli and anaerobes Mixed aerobic-anaerbic flora also occurs in diabetes1.

1. Pendland SL, Fish DN, Danziger LH. Skin and soft tissue infections: In: DiPiro JT, Talbert RL,Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York, McGraw-Hill, 2005:19771995 CREST. Guidelines on the Management of Cellulitis in Adults. 2005

Goals of Therapy
Cellulitis rapid eradication of infection relief of pain and tenderness in left forearm, left upper extremity, right shoulder, and return of range of motion resolution of fever prevention of further complications prevent recurrence

Goals of Therapy
T2DM FBS 4-7mmol/L, PPBS 7-10mmol/L, HbA1c ~ 8 % Prevent complications
microvascular: neuropathy, retinopathy, nephropathy, foot ulcers/wounds, macrovascular: CV disease

Improve lifestyle factors (smoking, BMI)

Goals of Therapy
Atrial Fibrillation control atrial fibrillation
< 100 bpm

decrease risk of tachycardia induced cardiomyopathy prevent stroke

Non-drug Therapies
Local care of cellulitis: elevation and immobilization of the area involved to decrease swelling. Drainage of edema and inflammatory substances Ensure proper wound care and dressing changes Skin should be hydrated
Avoid dryness, cracking but also maceration

Management of underlying conditions Blood glucose control is important

Lowy FD, Sexton DJ, Baron EL. Up-to-date: Cellulitis and erysipelas. UpToDate INC, 2010. (Accessed June

Antimicrobial Options for the Treatment of Cellulitis

Staphylococci or unknown Gram positive: Mild:
Cloxacillin (250-500mg PO Q6h)

Moderate - Severe
administration of semisyntheitic penicillin (nafcillin or oxacillin 1-2g IV q 4-6hrs) administration of 1 st gen cephalosporin (cefazolin) clindamycin both have activity against strep and staph usual duration of therapy 5-10d

Streptococci: mild:
oral penicillin VK 0.5g q 6 hrs OR IM procaine penicillin G 600 000U q 8-12hrs

severe:
Penicillin G 1 2 million U IV q 4-6hrs OR IV ceftriaxone 50-100mg/kg as single dose

if allergic to penicillin:
oral or parenteral clindamycin OR 1st gen cephalosporin w/ caution (cefazolin 1-2g IV q 6-8hrs)
Pendland SL, Fish DN, Danziger LH. Skin and soft tissue infections: In: DiPiro JT, Talbert RL,Yee GC, et al., eds. Pharmacot herapy: A Pathophysiologic Approach, 6th ed. New York, McGraw-Hill, 2005:19771995 Kish TD, Chang MH, Fung HB. Treatment of skin and soft tissue infections in the Elderly: A review. Am J Geriatr Pharmacother. 2010 Dec;8(6):485-513.

Antimicrobial Options for the Treatment of Cellulitis

Gram negative bacilli:
mild:
cefaclor 0.5g orally q 8 hrs cefuroxime axetil 0.5g orally q 12 hrs

severe:
aminoglycoside IV cephalosporin (1st or 2nd gen depending on severity/susceptibility)

Polymicrobic (but no anaerobes)

Aminoglycosids + penicillin G or nafcillin depending on isolation of organism

Polymicrobic (w/ anaerobes)

Mild:
amoxicillin-clavulanate 0.875g po q 12hrs FQ + clindamycin OR metronidazole

Severe:
Aminoglycoside + clindamycin OR metronidazole monotherapy with 2nd or 3rd gen cephalosporin monotherpay with imipenem, meropenem, ertapenem, piperacillin/tazobactam,

tigecycline

Pendland SL, Fish DN, Danziger LH. Skin and soft tissue infections: In: DiPiro JT, Talbert RL,Yee GC, et al., eds. Pharmacot herapy: A Pathophysiologic Approach, 6th ed. New York, McGraw-Hill, 2005:19771995 Kish TD, Chang MH, Fung HB. Treatment of skin and soft tissue infections in the Elderly: A review. Am J Geriatr Pharmacother. 2010 Dec;8(6):485-513.

Antibiotics vs. Microbes

Microbes S. aureus (MSSA) Streptococci sp. Penicillin G or V (some add -hemolytic streptococci Gentamycin for serious Group B (Group A, & B common) infection & some add & S. pyogenes clindamycin for serious invasive Group A) CA-MRSA Mild to moderate Severe HA-MRSA TMP-SMX or Doxycycline or Minocycline Vancomycin Vancomycin Clindamycin, third or fourth generation Fluoroquinilones Linezolid or daptomycin TMP-SMX (some strains resistant), linezolid, daptomycin All lactams, erythromycin, clarithromycin, azithromycin (however, macrolide resistance increasing) Recommended Cephalexin, Cloxacillin Alternatives Parentral cephalosporins, Vancomycin, Clindamycin

Empiric antibiotic therapy for management of cellulitis should include activity against betahemolytic streptococci and S. aureus.

 Penicillinase is a specific type of lactamase, which hydrolyses the -lactam ring. Pennicillinase producing bacteria are still susceptible to cloxacillin

Penicillinase Producing Bacterias Susceptibility to Cloxacillin

and methicillin, oxacillin Ortho-dimethoxyphenyl group produces steric hindrance around the amide bond.
Autiero I, Costantini S, Colonna G. Modeling of the bacterial mechanism of methicillin-resistance by a systems biology approach. PLoS One. 2009 Jul 13;4(7):e6226. Stapleton PD, Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog. 2002;85(Pt 1):57-72. Review.

Prevents penicillinase from opening the 4-membered ring

Mechanism for methicillin resistance

Methicillin Mechanism of action:
inhibits the penicillin-binding proteins (PBPs)
PBPs are involved in the cross linking and synthesis of peptidoglycans.
Peptidoglycans = essential for bacterium survival.

Will not inhibit gram negative organisms

Antibiotic use throughout the years resulted in multiresistant MRSA strains due to mutations in genes coding for target proteins (such as PBPs) and acquisition of various other resistance-coding genes S. aureus can become resistant to methicillin through expression of PBP2a
still has the same functions as PBP but is resistant to methicillin
Autiero I, Costantini S, Colonna G. Modeling of the bacterial mechanism of methicillin-resistance by a systems biology approach. PLoS One. 2009 Jul 13;4(7):e6226. Stapleton PD, Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog. 2002;85(Pt 1):57-72. Review.

Back to Patient: ER Visit 1

First diagnosis: Left upper extremity (forearm) cellulitis - Initiated on Cephalexin 500mg TID for 7 days - Appropriate option?

Evidence
- No definitive evidence in terms of which antibiotic is the best for mild-to-moderate cellulitis - Decision really depend on culture results, host factors, common organisms in the local area, resistance patterns, severity, and cost & convenience - Our recommendations are based on following resources:
- Infectious Diseases Society of America guideline(IDSA) Diagnosis and Management of Skin and Soft-tissue infections1 - Sanford Antimicrobial guideline2 - Evidence-based Infectious disease book3 - Essential Evidence Plus Cellulitis4 - Up-To-Date Cellulitis5
1. Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan EL, Montoya JG, Wade JC. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005 Nov 15;41(10):1373-406 2. Gilbert DN., Moellergin RC, Eliopoulos GM. Sandford Guideline to Antimicrobial Therapy. 40th Edition. Virginia, Sandford: Antimicrobial Therapy Inc. 2010: 1-219 3. Loeb M, Smaill Fiona, Smieja M. Cellulitis and Erysipelas. IN: Evidence-based infectious diseases. 2nd edition. NJ: John Wiley & Sons, Inc., 2009: 11-15 4. Carek PJ, Steyer TE. Essential Evidence Plus: Cellulitis. John Wiley & Sons, Inc., 2011. (Accessed June 12, 2011 at: www.essentialevidenceplus.com/content/eee/724) 5. Lowy FD, Sexton DJ, Baron EL. Up-to-date: Cellulitis and erysipelas. UpToDate INC, 2010. (Accessed June 12, 2011 at: www.uptodate.com)

Antibiotics vs. Microbes

Microbes S. aureus (MSSA) Streptococci sp. Penicillin G or V (some add -hemolytic streptococci Gentamycin for serious Group B (Group A, & B common) infection & some add & S. pyogenes clindamycin for serious invasive Group A) CA-MRSA Mild to moderate Severe HA-MRSA TMP-SMX or Doxycycline or Minocycline Vancomycin Vancomycin Clindamycin, third or fourth generation Fluoroquinilones Linezolid or daptomycin TMP-SMX (some strains resistant), linezolid, daptomycin All lactams, erythromycin, clarithromycin, azithromycin (however, macrolide resistance increasing) Recommended Cephalexin, Cloxacillin Alternatives Parentral cephalosporins, Vancomycin, Clindamycin

Empiric antibiotic therapy for management of cellulitis should include activity against betahemolytic streptococci and S. aureus.

Cellulitis Therapeutic Treatment Algorithm

Cellulitis

Mild to moderate/uncomplicated

Severe /progressive/complicated

Start Cloxacillin or Cephalexin Therapeutic Failure Obtain blood/tissue sample/pus for culture Modify based on the C&S results Start TMP-SMX or Clindamycin

Obtain blood/tissue sample/pus for culture

Start Vancomycin Modify based on the C&S results

Therapeutic failure

Daptomycin or Linezolid

Obtain blood/tissue sample/pus for culture MSSA

MRSA CA-MRSA Mild to moderate TMPSMX/Doxy/Mino/Cli nda/FQ; incision and drainage

Cloxa/Cepha lexin

HC-MRSA

TMPSMX/Clinda

Severe

Vancomycin

Daptomycin/ linezolid

Vancomycin

Answer
Yes, cephalexin was appropriate
Will see this clearer in the next few slides!

Back to patient: ER Visit 2

- His car was stolen and hence he did not take the medication - He now has increase pain and swelling in the left arm, and also has new onset pain in his right shoulder and fever - Severe?

Cellulitis

Mild to moderate/uncomplicated

Severe /progressive/complicated

Start Cloxacillin or Cephalexin Therapeutic Failure Obtain blood/tissue sample/pus for culture Modify based on the C&S results Start TMP-SMX or Clindamycin

Obtain blood/tissue sample/pus for culture

Start Vancomycin Modify based on the C&S results

Therapeutic failure

Daptomycin or Linezolid

Therapeutic alternatives
Most commonly recommended
Cephalexin Cloxacillin Clindamycin Trimethoprim-Sulfamethoxazole Fluoroquinolones

ESC
Drug Product Efficacy Safety NV, C.diff colitis, headache, confusion, BUN/Scr, LFT NVD, rash NVD, headache C. diff colitis, rash, fever, neutropenia, eosinophilia, thrombocytopenia NVD, confusion, fever, rash, photosensitivity, neutropenia, eosinophilia, thrombocytopenia NVD, photosensitivity, dizziness, light headedness, tendenitis, transient increase in LFTs, intestinal nephritis, hypoglycemia Cost/Convenience Cephalexin ++++ $ 0.45/500mg tab

Cloxacillin

++++

$0.35/500mg capsule

Clindamycin

++

$0.44/300mg capsule $0.40/ (400mg & 80mg tablet) $0.55-$1.4/tab depending on tluoroquinilone you choose

TMP-SMX

++

Fluoroquinol ones

++

The 3D Dose, Dosage form, Duration of Therapy - uncomplicated

Drug Product Cephalexin Cloxacillin Clindamycin Dose/frequency 250-500mg QID 250-500mg QID 300mg QID Dosage form Tablet Capsule Capsule Duration of Therapy* 7-14 days 7-14 days 7-14 days

TMP-SMX

160/800mg (DS) Tablet once or twice daily

7-14 days

Fluoroquinolones L 500 mg daily Tablet (Levofloxacin, M- 400mg daily Moxifloxacin)

7-14 days

* Depends on the clinical response (until 3 days after the acute inflammation disappears)

Care Plan
Indication: Cellulitis Drug Product Cephalexin (Keflex) Dosage instructions Note changes 500 mg four times a Initiate day for 7 days

Non-pharmacological: Patient education

Monitoring Plan
Effectiveness Parameter Clinical symptoms: Redness, edema, tenderness, warmth, pain, range of motion in affected area Temperature (38.3 C) Pulse (96 bpm) WBC count (26.3 x 10 3/mm3 ) Bands (10%) Neutrophils (81%) Prevent complications (sepsis)
Change Timeframe

Improved

24-48 hours

Reduced to 37.5 C Return (decrease) to normal (60-80 bpm) 3.54 to 9.06 x 10 3/mm3 0-5% 40-70% None

24-48 hours 24-48 hours Improve in 3-4 days Normal in 1 week Improve in 3-4 days Normal in 1 week Improve in 3-4 days Normal in 1 week Continuously

Lowy FD, Sexton DJ, Baron EL. Cellulitis and erysipelas. Uptodate 2010. Retrieved June 15th, 2011.

Monitoring Plan
Safety Parameter GI symptoms (nausea, diarrhea, vomiting) Mild skin rash Headache/confusion Change None to minimal Timeframe 2 days and during therapy

None to minimal None to minimal

2 days and during therapy 2 days and during therapy

Rogers SH, Cavazos JE. Chapter 114 Skin and soft-tissue infections. In: Dipiro JT, Talbert TL, Yee GC, Matzke GR, Wells BG, and Posey ML. Pharmacotherapy: A pathophysiological approach, 7th edition. NY: The McGraw-Hill Companies,. 2008:1807-09

Therapeutic Failure
What is an alternative treatment if cephalexin fails?

Therapeutic Failure
Cellulitis Mild to moderate/uncomplicated Severe /progressive/complicated

Start Cloxacillin or Cephalexin Therapeutic Failure Obtain blood/tissue sample/pus for culture Modify based on the C&S results Start TMP-SMX or Clindamycin

Obtain blood/tissue sample/pus for culture

Start Vancomycin Modify based on the C&S results

Therapeutic failure

Daptomycin or Linezolid

Back to patient: ER visit 3

CK took cephalexin as prescribed Comes back to ER with following:
Cellulitis progressing from left arm to right Left arm cellulitis with pain, redness, tenderness, increased edema Right shoulder pain, tenderness, with new-onset right axilla pain, and swelling; and left lower extremity pain radiating from the lower back Physical examination revealed: increase pitting edema of left arm, a right scapular fluid collection, a swollen right axilla, and adjacent lymphandopathy

ER visit 3
MRI done to rule out compartment syndrome Two blood cultures drawn Orthopedics consulted for potential incision and drainage of the left arm cellulitis Admitted for complicated/progressive cellulitis and possible MRSA Started on Cefazolin 1g IV x one dose given in ED

Questions
Severity? Appropriate drug of choice?

Background Information on MRSA

MRSA
MRSA emerged in the 1960s
Health care associated MRSA ( HA-MRSA) 1

Recently, MRSA infections without health care setting exposures is termed communityacquired MRSA (CA-MRSA) 1 CA-MRSA associated with primarily skin and soft-tissue infections 1
Sometimes associated with sepsis and necrotizing pneumonia 1
1) Rybak MJ, LaPlant KL. Community-associated methicillin-resistant Staypylococcus aureus: a review. Pharmacotherapy 2005;25:74-85

MRSA
Defined as an oxicillin minimum inhibitory concentration

(MIC) 4mcg/mL 1 If microorganism is resistant to oxicillin or methicillin, they are also resistant to beta-lactam agents such as dicloxacillin and cefazolin 1
CA-MRSA tend to be less resistant than HA-MRSA and

has different types of gene complexes known as staphylococcocal cassette chromosome mec (SCCmec) 2
1) Lowy FD, Sexton DJ, Baron EL. Treatment of skin and soft tissue infections due to methicillin-resistant Staphylococcus aureus in adults. Uptodate 2010. Retrieved June 15th, 2011. 2) Rybak MJ, LaPlant KL. Community-associated methicillin-resistant Staphylococcus aureus: a review. Pharmacotherapy 2005;25:74-85

CA-MRSA vs. HA-MRSA

The Centers for Disease Control and Prevention (CDC) has established a criteria to distinguish CAMRSA and HA-MRSA 1 CA-MRSA: 1
Outpatient setting OR culture showing MRSA within 48 hours after admission to hospital In the following year before infection
No hospitalizations; admission to nursing home, skilled nursing facility or hospice No indwelling catheters or medical devices that pass through the skin
1) Rybak MJ, LaPlant KL. Community-associated methicillin-resistant Staypylococcus aureus: a review. Pharmacotherapy 2005;25:74-85

Severity?
Cellulitis Mild to moderate/uncomplicated Severe /progressive/complicated

Start Cloxacillin or Cephalexin Therapeutic Failure Obtain blood/tissue sample/pus for culture Modify based on the C&S results Start TMP-SMX or Clindamycin

Obtain blood/tissue sample/pus for culture

Start Vancomycin Modify based on the C&S results

Therapeutic failure

Daptomycin or Linezolid

Appropriate DOC?
Cellulitis Mild to moderate/uncomplicated Severe /progressive/complicated

Start Cloxacillin or Cephalexin Therapeutic Failure Obtain blood/tissue sample/pus for culture Modify based on the C&S results Start TMP-SMX or Clindamycin

Obtain blood/tissue sample/pus for culture

Start Vancomycin Modify based on the C&S results

Therapeutic failure

Daptomycin or Linezolid

Obtain blood/tissue sample/pus for culture MSSA

MRSA CA-MRSA Mild to moderate TMPSMX/Doxy/Mino/Cli nda/FQ; incision and drainage

Cloxa/Cepha lexin

HC-MRSA

TMPSMX/Clinda

Severe

Vancomycin

Daptomycin/ linezolid

Vancomycin

Answers
Very severe Cefazolin is an inappropriate drug of choice

Therapeutic Alternatives
- Vancomycin - Linezolid - Daptomycin

Vancomycin vs. Linezolid

RCT: Non-blinded, open label, multi-centre Goal: To compare effectiveness of linezolid vs. vancomycin in complicated skin and tissue infections Patients: Infections caused by MRSA and severe enough to be hospitalized Treatment: vancomycin 1g q 12 hour vs. linezolid 600mg twice daily for 7 days Results: Clinical success rate in Vancomycin (88%) and linezolid (92%), not significant; adverse events similar in both group Limitations: unblinded, conclusion favoring linezolid based on post-hoc group analysis, some patients were started on linezolid oral versus IV based on physicians choice,

Bottom-line: Linezolid does not provide any significant advantages in terms of effectiveness over vancomycin. The unblinded nature of this study, post hoc subgroup analyses, and failure to describe criteria for initiating oral versus intravenous therapy are serious limitations. Any trends toward an advantage for linezolid should be interpreted very cautiously.
Weigelt J, Itani K, Stevens D, et al, for the Linezolid CSSTI Study Group. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005; 49:2260-66.

Vancomycin vs. Daptomycin

RCT : A prospective, double-blinded, multi-centre trial Goal: To evaluate whether Daptomycin treatment for cellulitis or erysipelas would result in faster resolution compared to vancomycin. Population: Patients with cellulitis or erysipelas requiring hospitalization or IV therapy. Treatments: Daptomycin 4 mg/kg once daily or vancomycin according to standard of care for 714 days Result: Clinical success in Daptomycin (94%) vs Vancomycin (90%). There were no statistically significant differences between treatment arms in the time to resolution or improvement in any of the predefined clinical end-points. Both daptomycin and vancomycin were well tolerated.

Bottom-line: There was no difference in the rate of resolution of cellulitis or erysipelas among patients treated with daptomycin or vancomycin. Daptomycin 4 mg/kg once daily appeared to be effective and safe for treating cellulitis or erysipelas.
Pertel et al. The efficacy and safety of daptomycin vs. vancomycin for the treatment of cellulitis and erysipelas. Int J Clin Prcact 2009; 3: 368-375

Vancomycin vs. Linezolid vs. Daptomycin

Study: A Systematic Review Clinical Question: what is the most effective therapy in the treatment of complicated skin and skin-structure infections (cSSI), including surgical site infection? Recommendations (Evidence GRADE A-D) 1) Vancomycin should be considered a standard of care in patients with cSSI due to MRSA (Grade A). 2) Linezolid appears to be more effective (Grade C). Linezolid could be an alternative treatment to vancomycin despite the low to medium methodological quality of trials (Grade D). 3) Daptomycin are as effective as vancomycin (Grade C). 4) When choosing the therapeutic strategy, the pharmacoeconomic issue should be considered, i.e., cost of the drug, duration of intravenous therapy, length of hospital stay, and early discharge; a switch to the oral drug should be made whenever possible (grade C).
Pan et al. for the GISIG group. Consensus document on controversial issues in the treatment of complicated skin and skin-structure infections. Int J of Infect Dis; 2010: S39-S53

ESC
Drug Product Efficacy Safety Cost/Convenience

Vancomycin

+++++

Nausea, vomiting, nephrotoxicity(rare), neutropenia, C. Diff., red man syndrome, Ototoxicity Nausea, vomiting, diarrhea, vision disturbances, headache, body aches, fever, rash Vomiting, diarrhea, edema, numbness, tingling, headache, pneumonia, pain in throat, renal failure

$$$ IV

Linezolid

++++

$$$$ IV PO

Daptomycin

++++

$$$$ IV

Note: Local antibiotic resistance patterns and culture susceptibility results are absolutely critical in tailoring the treatment. This table is a tool in selecting therapy when local resistance data and culture susceptibility are not available.

Care Plan
Drug Product Cefazolin Vancomycin Dosage instructions 1g IV daily 1g every 12 hour, infused over two hours for 10 days Note changes Discontinue Initiate

Monitoring Plan
Effectiveness Parameter Clinical symptoms

Change

Timeframe

Left arm -pain, redness, tenderness, increased swelling Right shoulder pain, tenderness, right axilla pain, and swelling; and swollen lymph nodes
Pain radiating to lower extremities Pain, redness, tenderness, swelling
Shoulder motions

Improvement in pain; decrease swelling Improvement in pain; decrease swelling

24-48 hours

24-48 hours

Decrease in severity of pain and radiation of pain subsides to the lower extremities Complete resolution
Improve and normal

24-48 hours

10-14 days
Improve within 48 hours and normal within a week

BP/HR/temperature WBC/Neutrophils

Improvement or stabilization Improvement and normalization

24-48 hours and on going Improvement 24-48 hours; normalization 10 to 14 days

Monitoring Plan
Safety Parameter GI symptoms (nausea, diarrhea, vomiting)
Mild skin rash Change Timeframe

None to minimal
None to minimal

24-48 hours
24-48 hours

Muscle pain or tightness Hearing C. Difficile infection (severe diarrhea, abdominal cramp, and fever) SCr Serum trough concentration of vancomycin time dependent

None to minimal none None

Throughout the therapy Ongoing Ongoing (patient to c

Normal to prevent renal failure Ongoing Therapeutic range At least 10mcg/mL 15mcg/mL 30 mins before 3rd or 4th dose Every 3 days once concentration is therapeutic

Rogers SH, Cavazos JE. Chapter 114 Skin and soft-tissue infections. In: Dipiro JT, Talbert TL, Yee GC, Matzke GR, Wells BG, and Posey ML. Pharmacotherapy: A pathophysiological approach, 7th edition. NY: The McGraw-Hill Companies,. 2008:1807-09

Therapeutic Failure
What to do if vancomycin does not work (improvement within 48 hour of effectiveness parameters) or the patient experiences serious side effects?

Cellulitis Mild to moderate/uncomplicated Severe /progressive/complicated

Start Cloxacillin or Cephalexin Therapeutic Failure Obtain blood/tissue sample/pus for culture Modify based on the C&S results Daptomycin or Linezolid Start TMP-SMX or Clindamycin

Obtain blood/tissue sample/pus for culture

Start Vancomycin

Modify based on the C&S results

Therapeutic failure

Therapeutic failure
Cellulitis Mild to moderate/uncomplicated Severe /progressive/complicated

Start Cloxacillin or Cephalexin Therapeutic Failure Obtain blood/tissue sample/pus for culture Modify based on the C&S results Start TMP-SMX or Clindamycin

Obtain blood/tissue sample/pus for culture

Start Vancomycin Modify based on the C&S results

Therapeutic failure

Daptomycin or Linezolid

Therapeutic failure
Drug Product Vancomycin Dose/frequency 1g twice q 12 hour 600 mg q 12 hour 4mg/kg IV Tablet/oral suspension/IV injection IV Dosage form Duration of Therapy* 7-14 days 7-14 days

Linezolid

Daptomycin

7-14 days

Consider either linezolid or daptomycin if vancomycin does not improve symptoms within 2 days or severe side effects occur

Follow-up regarding other DTPs

Follow up with his family physician regarding additional therapy for CV prevention secondary to diabetes and stroke prevention secondary to his atrial fibrillation CVD risk reduction strategy statin and ACE inhibitor therapy Assess patients desire for smoking cessation

Patient Education
Elevation of affected area
Improves draining of edema and inflammatory substances

Keep affected area clean and dry

Avoid antibacterial creams and ointments

Keep skin hydrated to prevent cracks

Patience
Takes time to heal
Lowy FD, Sexton DJ, Baron EL. Cellulitis and erysipelas. Uptodate 2010. Retrieved June 15th, 2011.

Patient Education
Adherence to antibiotics in the future
Explain importance of full duration of treatment
Effectiveness and resistance

Explain side effects

Adherence to his other medications ( i.e. Meformin,

consequence of diabetes, diet restrictions etc)

Prevention
Proper skin wound care Proper nutrition
Lowy FD, Sexton DJ, Baron EL. Cellulitis and erysipelas. Uptodate 2010. Retrieved June 15th, 2011.

Summary
Cellulitis is a type of skin and soft tissue infection, affecting epidermis, dermis, and subcutaneous layers CK diagnosed with LUE cellulitis, but lost prescription for cephalexin,
returned 5 days later with progressing cellulitis
given cephalexin

CK took cephalexin as prescribed, but came back to ER again with progressing cellulitis (severe)
admitted for complicated/progressive cellulitis and possible MRSA
given vancomycin

CK also had multiple other drug therapy problems needing to be addressed at a later date
education regarding his conditions and medications CV disease prevention

Cellulitis Mild to moderate/uncomplicated Severe /progressive/complicated

Start Cloxacillin or Cephalexin Therapeutic Failure Obtain blood/tissue sample/pus for culture Modify based on the C&S results Start TMP-SMX or Clindamycin

Obtain blood/tissue sample/pus for culture

Start Vancomycin Modify based on the C&S results

Therapeutic failure

Daptomycin or Linezolid

QUESTIONS?