Case Conference

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Case Conference

• Toby Fugate, D.O.

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DisclosuresSection of Infectious Diseases

• Kevin High, M.D.
• Grant/Research Support Cubist Pharmaceuticals,
  Astellas Pharma US, Inc.
• Consultant Merck Co., Inc.
• Speakers Bureau Pfizer Pharmaceuticals
• James Peacock, M.D.
• Ownership in Common Stock Pfizer
  Pharmaceuticals
• Sam Pegram, M.D.
• Grant/Research Support Roche, Bristol-Myers
  Squibb, Gilead, Schering-Plough, Tibotec
  Pharmaceuticals
• Consultant Abbott Laboratories,
  GlaxoSmithKline, Boehringer Ingelheim, Gilead,
  Roche
• Speakers Bureau Abbott Laboratories,
  GlaxoSmithKline, Boehringer Ingelheim, Merck,
  Pfizer Pharmaceuticals

3
Disclosure (continued)Section of Infectious
Diseases

• Aimee Wilkin, M.D.
• Grant/Research Support Abbott Laboratories,
  GlaxoSmithKline, Tibotec Pharmaceuticals,
  Bristol-Myers Squibb Company, Gilead
• Christopher Ohl, M.D.
• Grant/Research Support Cubist Pharmaceuticals,
  Gene-Ohm Sciences, Merck Pharmaceuticals
• Speakers Bureau/Consultant Ortho-McNeil
  Pharmaceuticals, Cubist Pharmaceuticals,
  Sanofi-Aventis Pharmaceuticals, Pfizer
  Pharmaceuticals, Bayer Pharmaceuticals

4
Disclosure (continued)Section of Infectious
Diseases

• Tobi Karchmer, M.D.
• Grant/Research Support Gene-Ohm Sciences
• Speakers Bureau Pfizer Pharmaceuticals, Cubist
  Pharmaceuticals, Cepheid,
• Gene-Ohm Sciences
• Consultant C.R. Bard
• Robin Trotman, D.O.
• Speakers Bureau Pfizer Pharmaceuticals

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90 year old female

• Pain, redness, swelling of right shin
• Developed over a period of 2 weeks following a
  fall
• No fevers or chills
• Saw PCP and started on Keflex for presumed
  cellulitis
• Symptoms worsened

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90 year old female with presumed cellulitis not
responding to Keflex

• PMHx
• Acute lymphoblastic leukemia in remission since
  1991
• Vitamin B12 deficiency
• Hypertension
• Ovarian cancer
• Gastroesophageal reflux disease
• Benign positional vertigo
• Myocardial infarction in 1994
• Ischemic cardiomyopathy with ejection fraction of
  30 to 35

• PSHx
• Total abdominal hysterectomy
• Cholecystectomy
• Left hip arthroplasty secondary to osteoporosis
  and avascular necrosis

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90 year old female with presumed cellulitis not
responding to Keflex

• Medications
• Fosamax
• Aspirin
• Eucerin Cream
• Zantac
• Lotensin
• Oxybutynin
• Keflex 500mg QID

• Allergies
• Sulfa
• Compazine
• Codeine
• Vicodin

8
90 year old female with presumed cellulitis not
responding to Keflex

• Family History
• CAD

• Social History
• Lives in Lexington, NC with her sister
• No tobacco, EtOH, IVDA

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Pertinent Findings on Physical Exam

• Afebrile
• 2/6 SEM best heard at the left 3rd ICS with
  radiation to the axilla
• Erythema and edema of right anterior tibial skin

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Pertinent Labs

• WBC 7.7
• BUN/Cr 24/1.2
• ESR 56
• CRP 4.06

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Radiological Studies

• Right tibia/fibula revealed only soft tissue
  swelling
• MRI of the right LE revealed 5.5 x 2.5-cm
  superficial abscess with underlying enhancement
  worrisome for osteomyelitis

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OR Report

• Superficial abscess
• Small area of bone softening (?bone abscess)
• Tissue was obtained for culture
• Two swabs obtained as well
• No samples for pathology were sent

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Cultures

• Grams stain was negative
• Culture of tissue grew 1 Staphylococcus
  lugdunensis
• Swabs were both negative

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Thoughts?

• Antibiotic recommendations?

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SENSITIVITY
MSCAN MICAMOX/CLAVULANIC lt4/2
SUSCEPTIBLEAMPICILLIN lt0.25 SUSCEPTIBLE
AMPICILLIN/SULBACTAM lt8/4 SUSCEPTIBLE
CEFAZOLIN lt2 SUSCEPTIBLE
CEFTRIAXONE lt4 SUSCEPTIBLE
CIPROFLOXACIN lt1 SUSCEPTIBLE
CLINDAMYCIN lt0.25 SUSCEPTIBLE ERYTHROMYCIN
lt0.5 SUSCEPTIBLE GATIFLOXACIN
lt2 SUSCEPTIBLE GENTAMICIN lt1
SUSCEPTIBLE LINEZOLID 1
SUSCEPTIBLE OXACILLIN 0.5 SUSCEPTIBLE.
PENICILLIN G lt0.03 SUSCEPTIBLE
QUINUPRISTIN/DALFOPRISTIN lt0.25
SUSCEPTIBLE TETRACYCLINE lt4
SUSCEPTIBLE TMP/SMX lt2/38 SUSCEPTIBLE
VANCOMYCIN lt2 SUSCEPTIBLE
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Plan for this patient

• Rocephin 2 grams IV q 24 hours for 6 weeks

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Discovery of Staphylococcus lugdunensis

• First described by Freney et al in 1988
• Named after Lyon (Latin adjective of Lugdunum),
  the French city where the organism was first
  isolated

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Staphylococcus lugdunensis

• Readily differentiated from other
  coagulase-negative staphylococci by the
  production of ornithine decarboxylase and
  pyrrolidonyl arylamidase
• Some strains may test positive for SLIDE
  coagulase and be mistaken for Staphylococcus
  aureus
• However, TUBE coagulase will be negative

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Infections associated with Staphylococcus
lugdunensis (SL)

• Soft tissue infections
• Breast abscess
• Peritonitis
• Infected joint prostheses
• Osteomyelitis
• Discitis
• Septic arthritis
• Pacemaker infections
• Ventriculoperitoneal shunt infections
• Endocarditis

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Most infections involve sites below the waist

• Overall, 73 of infections involved sites below
  the waist
• Infections that occur above the waist are often
  associated with skin breaks in the lower
  abdomen/inguinal area
• Vasectomy
• Scrotal wounds
• Renal transplantation
• Peritoneal dialysis
• Femoral artery catheterization
• Prostatic cancer
• Inguinal furuncle

Vandenesch et al. Skin and post-surgical wound
infection due to SL. Clin Microbiol Infect,
1995 Herchine et al. Occurrence of SL in
consecutive clinical cultures and relationship of
isolation to infection. J Clin Microbiol, 1991
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Inguinal Carriage

• Evaluated the prevalence of SL carriage in the
  inguinal area of 140 incoming patients (swabs of
  left and right inguinal folds)
• 22 carried SL in this area
• Highest frequency of carriage over-all (51) was
  observed in women aged 65yrs and older
• Highest frequency of carriage in men (41) was
  found in younger men (age less than 65)
• Obesity did not seem to play a role, regardless
  of age

van der Mee-Marquet et al. SL Infections High
Frequency of Inguinal Area Carriage. Journal of
Clinical Microbiology, 2003.
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Endocarditis Looks like Staph epi, but behaves
like Staph aureus

• 2/3 of patients have symptoms less than 3 weeks
• Native valve involvement
• Gross valvular destruction, often with abscess
  formation
• High mortality (70 in some reports)
• Need for valve replacement

Vandenesch et al. Endocarditis Due to SL
Report of 11 Cases and Review. Clinical
Infectious Diseases, 1993.
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Seenivasan et al. SL Endocarditis-The Hidden
Peril of Coagulase-Negative Staphylococcus in
Blood Cultures
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Jones et al. Endocarditis Caused By SL.
Pediatric Infectious Disease Journal, 2002
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Antibiotic Selection

• Prevalence of beta-lactamase-producing SL
• 25 in North America
• 5 in Europe
• Generally, SL is described as being susceptible
  to beta-lactam agents
• Only 6 of 48 previously reported cases of SL
  endocarditis were reported resistant to
  penicillin
• Adequate therapy of invasive infections consist
  of a beta-lactam plus rifampin or gentamicin
• Of note, MICs of penicillin were at least two
  dilutions lower than those of oxacillin
• Penicillin IV may be the drug of choice
• Sanford guide suggests oxacillin/nafcillin or
  penicillin G (alternative choices are parenteral
  1st generation cephalosporin, vancomycin, or
  teicoplanin)

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Virulence Factors

• Glycocalyx
• Interfere with host antimicrobial actions of the
  immune system
• SL synergistic hemolytic activity (SLUSH)
• Phenotypically similar to delta-hemolysin of S
  aureus
• Invasion factors
• Esterase
• FAME (fatty acid methyl esters?)
• Proteases
• Lipase

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Nilsson et al. A fibrinogen-binding protein of
SL. Federation of European Microbiological
Societies Letters, 2004

• Gene called fbl encodes a SL fibrinogen-binding
  protein (Fbl)
• The Fbl fibrinogen binding domain showed 62
  identity to the corresponding region in clumping
  factor (ClfA) from S aureus
• Clumping factor is a fibrinogen-binding protein
  that mediates adherence of S aureus to
  fibrinogen, an important first step in infection

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Nilsson et al. A von Willebrand factor-binding
protein from SL. Federation of European
Microbiological Societies, 2004

• SL posses a gene, vwbl, coding for a vWf-binding
  protein
• Distribution of this gene is widespread among
  clinical strains
• Importance of the protein vWbl in the context of
  infections remain to be elucidated
• vWf is the bridging molecule required for
  platelet adherence to exposed subendothelium and
  platelet aggregation
• The vWbl and its interaction with vWf might serve
  a critical role in the bacterial attachment to
  minor vascular lesion

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Follow-up

• She followed-up with PCP
• She completed 6 weeks treatment
• There was no transition to oral antibiotics
• Based on clinic notes she seems to be doing well

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Case Two
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47 year old male with skin lesions

• Blister-like lesions on hands and nape of his
  neck
• Lesions develop and resolve throughout the year
• Lesions more troublesome in the spring and summer
• Urine dark in color
• Generalized joint pains

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47 year old male with skin lesions

• PMHx
• Depression
• Anxiety
• Alcohol dependence
• Tobacco abuse
• Chronic low back pain

• PSHx
• None

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47 year old male with skin lesions

• Medications
• Bupropion
• Ibuprofen

• Allergies
• NKDA

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47 year old male with skin lesions

• Social Hx
• Has smoked 1ppd for at least 25 years
• Drank heavy in the past now drinks only on
  special occasions
• IVDA in the 1970s
• Currently unemployed
• No significant travel hx

• Family Hx
• Depression
• DM

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Pertinent Physical Findings

• Blister-like lesions on the hands, forearms,
  legs, and nape of the neck
• Crusted lesions in the above mentioned
  distribution

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Any thoughts?
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Hepatitis C and Porphyria Cutanea Tarda (PCT)

• Hepatitis C serology POSITIVE
• Genotype 1a
• HCV PCR1,560,000
• Liver biopsy revealed Grade 4 inflammation and
  Stage 3 cirrhosis
• Uroporphyrin level 1500 micrograms/day (normal
  lt20)

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Plan for this Patient

• Combination treatment with peginterferon and
  ribavirin

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Porphyria Cutanea Tarda

• First recognized by Waldenstrom in the 1930s
• Identified a group of patients with excessive
  porphyrins in the urine, skin lesions in light
  exposed areas and a late (tarda) onset in
  adulthood
• Most common of the hepatic porphyrias
• Due to reduced activity of the enzyme
  uroporphyrinogen decarboxylase (UROD)
• Subsequent build-up of uroporphyrinogen in the
  blood and urine
• Both sporadic and inherited (autosomal dominant)
  forms
• Hepatic UROD enzyme activity is diminished in
  both disorders
• Erythrocyte UROD activity levels are reduced only
  in the inherited form

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Clinical Manifestations

• Skin and the liver are the two main sites
  affected
• Classic presentation consists of photosensitivity
  and uroporphyrinuria in the setting of chronic
  liver disease
• Hypertrichosis occurs in 2/3 of patients
• Skin
• Exposure to the sun and/or minor trauma can lead
  to skin erythema and the development of vesicles
  and bullae
• Hyperpigmentation, hypopigmentation, hirsutism,
  and sclerodermatoid changes may develop
• Liver
• Liver biopsy shows a wide range of changes,
  including steatosis, mild to severe inflammation,
  hepatic fibrosis, and cirrhosis
• Hepatocellular carcinoma
• liver involvement appears to be infrequent in
  inherited PCT

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Relationship To Hepatitis C Virus

• Strong association between the sporadic form of
  PCT and HCV infection
• Gisbert et al. Journal of Hepatology, 2003
• Systematic review and meta-analysis on the
  prevalence of HCV infection in PCT
• 50 studies that included a total of 2167 patients
  with PCT
• Overall prevalence of HCV of 50 percent
• Marked geographic variability
• Lowest prevalence rates (20 to 30 percent)
• Australia, Czech Republic and France
• Highest rates (71 to 85 percent)
• Japan, Italy and Spain
• Prevalence in North America was 66 percent
• Central factor in the geographic variability
  appeared to be the baseline rates of HCV
  infection in the general population.

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Pathogenesis

• Mechanism by which HCV infection might trigger
  PCT in predisposed subjects is not known
• HCV (cyptopathic virus) causes the release of
  free iron
• Iron may uncouple the cytochrome P450
  reductase/cytochrome P450 system
• Resulting in the release of activated oxygen
  which may decrease UROD activity and provoke an
  attack
• Chronic HCV infection may impair porphyrin
  metabolism by reducing the glutathione
  concentration in hepatic cells
• Lack of glutathione may decrease the ability to
  reduce oxidized uroporphyrins
• Accumulation of these compounds may exert an
  inhibitory effect on UROD

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Triggers

• Several observations support the hypothesis that
  environmental triggers are necessary to provoke
  an attack of PCT
• When families of patients with inherited PCT have
  been studied
• First-degree relatives often have decreased UROD
  activity despite having no symptoms of PCT
• Patients with sporadic PCT
• May have normal UROD activity in between attacks
• Possible triggers of PCT
• polyhalogenated hydrocarbons (such as
  hexachlorobenzene)
• Alcohol
• Estrogens
• Iron overload (Hemochromatosis)

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Diagnosis

• Typically suspected on clinical grounds
• Markedly elevated urine uroporphyrin levels
  (normal 10 to 50 µg/day)
• Values above 800 µg/day are often seen when
  photosensitivity is present

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Treatment

• Phlebotomy
• Removal of iron
• Chloroquine
• Used successfully in cases of PCT refractory or
  intolerant to phlebotomy
• Forms a water-soluble complex with uroporphyrin
• Removes excess uroporphyrins from the tissue and
  allows urinary excretion
• Low-dose therapy (125 to 250 mg, two times weekly
  or less) recommended

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What effect does treatment of Hepatits C have on
the PCT?
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Furuta et al. Journal of Gastroenterology, 2000

• 66 year old male with positive HCV serology and
  PCT
• HCV Genotype 1b
• HCV VL 120,000
• Hepatitis B studies were negative
• Heavy EtOH
• Liver biopsy showed chronic active hepatitis 2A
  with abundant iron deposits in hepatocytes and
  Kupffer cells
• Urinary coproporphyrin elevated at 120
  micrograms/liter (normal lt 100)
• Uroporphyrin elevated at 706 micrograms/day
  (normal lt20)

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Treatment and Outcome

• Treated with 9 million IU of natural IFN-alpha
  daily for two weeks and subsequently three times
  a week for 22 weeks (total 24 weeks)
• HCV RNA levels transiently decreased
• Serum transaminases, ferritin, urine porphyrin,
  and skin pigmentation remained unchanged

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Okano et al. Hepato-Gastroenterology, 1997

• 61 year old male with hepatitis C and PCT
• Heavy EtOH for 40 year
• HCV RNA (PCR) 104 copy/ml
• AST 207 and ALT 126
• Urine uroporphyrin (UP) elevated at 4564
  mircograms/L (normal 14.4/-8.4)
• Heptacarboxylic porphyrin elevated at 1210.6
  micrograms/L (normal 5.3/-4.3)
• Stool iso-coproporphyrin (ISO-CP) elevated at
  0.48 microgram/g (normally undetectable)

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Treatment and Outcome

• After 5 months of EtOH abstinence
• Treated with INF-beta 600 MU/day for 6 weeks
• During treatment, urinary excretion of UP, AST,
  and ALT increased
• One week after treatment
• AST 33 and ALT 17
• UP decreased to 479
• Skin lesions had resolved as well

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Thevenot et al. Journal of Hepatology, 2005 (Two
Case Reports)

• First Case
• 34 year old male with hx of ETOH abuse
• Hepatitis C and NO signs/symptoms of PCT
• Genotype 1a
• Liver biopsy showed METAVIR score A2F2
• AST 82, ALT 104, ferritin 2408
• Tests for hemochromotosis (C282Y and H63D)
  negative
• Hepatitis B and HIV studies negative

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Treatment and Outcome

• Treated with peginterferon-alpha2b (1.5
  micrograms/kg/wk) plus ribavirin 1000 mg/day
• From July 2003 until July 2004
• Viral clearance at the end of treatment
• August 2003, pt presents with SS of PCT
• Biopsy c/w PCT
• Urinary uroporphyrin elevated at 343 g/day

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Thevenot et al. Journal of Hepatology, 2005 (Two
Case Reports)

• Case Two
• 47 year old male with ETOH abuse
• Hepatitis C and NO SS of PCT
• Genotype 1b
• METAVIR A2F3
• AST and ALT were both 2-3 times the upper limit
  of normal
• Ferritin 800 ng/ml
• Hemochromatosis and autoimmune liver disease were
  excluded

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Treatment and Outcome

• Treated with peginterferon-alpha2b (1.5
  micrograms/kg/wk) plus ribavirin 1200 mg/day
• September 2003 until January 2004
• No early virological response
• November 2003, PCT developed
• Urinary uroporphyrin level elevated at 2728
  nmol/L (normal lt50)

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