Clinical Case Conference January 23, 2006

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Clinical Case ConferenceJanuary 23, 2006

• Robin Trotman, 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

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DisclosuresSection 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

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DisclosuresSection 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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Resiliency.

• A tale of two patients that exhibit the
  resiliency of the human body. Not unlike..

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Resiliency.
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Case 1 Resiliency

• Chronologic history of a female born 1921
• 1946 TB pleurisy
• 1955 Hodgkins lymphoma-IV nitrogen mustard and
  cobalt radiation
• 1959 Lymphoma Relapse
• 1962 Thyroid ablation
• 1984 and 1985 Bilateral PNA

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Case 1

• 1986 Admitted with DOE and hypoxemia, diagnosed
  with PCP. WBC 7.9K, L-9(711), and T-helper 384.
• IPPD, candida, and Trycophytin anergy.
• Family described that her allergic rhinitis
  suddenly ceased 8 years ago.
• Discharged on PCP tx and prophy.

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Case 1

• 1993 Diagnosed with granulomatous tenosynovitis
  of the right wrist, cultures grew MTB, and BAL
  grew MTB.
• Placed on 4 drug therapy
• Seen in consultation by ID.
• Immunologic w/u started

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Case 1 Immunologic workup

• IgG 460, 507
• IgG subclass
• 1. 261
• 2. 110
• 3. 10
• 4. lt1
• IgA lt7,
• IgM 14, 3.5
• IgE 3
• IgA Ab IgG lt2.0
• IgA Ab IgM lt2.0

-IPPD, candida, and Trycophytin anergy. -CD4
384 -Lymphocyte stim test responded to T cell
antigen PHA, but not responsive to Concanavalin
Acell membrane lectins -Mandell chap 11. 6th ed.
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Immunologic Workup Stopping point

• 72 yo wf with multiple infections and OIs and
  apparently low levels of immunoglobulins,
  lymphopenia, and cutaneous anergy.
• Further workup?
• Diagnosis?
• Intervention?

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Immunologic Workup Stopping point

• Would anyone treat this patient, with multiple
  infections and immunoglobulin deficiency?
• If so, How?
• Come on, somebody grab the microphone.

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Case 1 Follow-up

• Referred for outpatient immunoglobulin therapy.
  Gammimune-N 25gm infusion (400mg/kg)
• Developed elevated BP to 220/98 during infusion
• 1995 Basal cell CA of the lacrimal duct
• 1994 at age 73 Endometrial Papillary AdenoCA.
• That was chart 12, did not review charts 3-9
• This patient survived another 10 years of
  countless hospital admissions, monthly outpatient
  IVIG, subsequent infections, and generations of
  new house-staff RESILIENCY!

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CVID and immunoglobulin therapy

• 1. Diagnosis of Ig deficiency-Pathophysiology,
  SS, natural history, etc.
• 2. Workup-Anti IgA antibodies, etc..
• 3. Case definitions and different deficiency
  states.
• 4. Treatments-IVIG for CVID, other uses for IVIG,
  protocols, and monitoring therapy
• 5. Side effects/Adverse reactions BP, allergic,
  fellow night and weekend phone calls.
• 6. Should ID docs be doing this?

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CVID Ig therapy CVID

• MCC of humoral deficiencyCVID (aside from IgA
  deficiency.)
• Described in 1950s
• Defect in B cell maturation AND
• Multiple arms of the immune system-CD4, dec. in
  lympho prolif., deficiency in production of IL2.,
  etc.
• 150K persons affected
• Complicated/unknown genetics.
• Age at diagnosis-30?

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CVID Ig therapy Diagnosis

• Conjunctivitis non-encapsulated H. influenzae.
• Pneumonia Pneumococcus, Hemophilus, and
  Mycoplasma.
• Enterovirus
• OIs
• Granulomatous disease
• Bronchiectasis
• Autoimmune-Common-RA, pernicious anemia, AHA,
  ITP, anti-IgA,
• Rarely have Ig against IgA
• Diarrhea-Rarely infectious-IBD, defects in CMI.
• NHL

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CVID Ig therapy Workup

• IgG less than 2 SD below the mean for age.
• T cell subset analysis reduction of CD4/CD8 T
  cell ratio.
• Ig levels and IgG subsets
• Order IgG and IgM to IgA to predict those who are
  IgA deficient and have developed antibodies and
  are at risk for anaphylaxis.

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CVID Ig therapy Case definitions

• DDX X linked agammaglobulinemia, SCID, Hyper IgM
  syndrome
• Secondary causes.
• Subsequent workup will determine the specific
  diagnosis.
• DXrecurrent characteristic infections with low
  levels of IgG.

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CVID Ig therapy Treatments

• Serum therapy predated Abx era-1891 Koch
  developed sheep antisera to diphtheria and saved
  a girl.
• WWII- Cohn fractionated serum with cold ethanol
  (at a local pub?) and produced fractions enriched
  with gammaglobulins. Used to prevent Hep A and
  Measles in WWII troops.
• 1951 Bruton used this preparation to treat a
  child with recurrent sepsis and
  agammaglobulinemia.
• Early uses of IVIG were limited CV collapse and
  death.
• 1960s rxns. found to be due to complement
  activation and reformulated preparations in 1970s
  and 80s to prevent comp activn.

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CVID Ig therapy Treatments

• ITP 1981
• Over time, these products have become more safe
  for IV use.-Chemical treatments, pepsin
  digestion, DEAE column chromatography,
  acidification, ultrafiltration, etc.
• Most products are purified IgG with very little M
  or A.
• From pooled human plasma donors or plasmapheresis
  patients.
• Contains large amts of Ab to various
  microorganisms

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CVID Ig therapy Treatments

• IV Preparations became available in 1980s and
  allowed patients to avoid the side effects of
  large dose SQ infusions.
• Data showing benefit of IVIG over SQ or IM. Ann
  Intern Med 1984101435-9.
• Allows increased bioavailability and higher
  doses.
• There are data supporting trough levels gt5g/L to
  further reduce infections. Ann Int Med
  2001135165-74.

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CVID Ig therapy Treatments

• IVIG sterile, processed, purified IgG from
  pooled human plasma and contain gt 95 unmodified
  IgG with intact Fc-dependent effector functions.
• IVIG has multiple immune activities and contains
  cytokines, Ab of unclear significance like Ab
  against GMCSF- occ. neutropenia following initial
  infusions.

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CVID Ig therapy Treatments

• 1/600 people are IgA deficient therefore, ideal
  preps. would have minimal IgA.
• Some preps are pure IgG with minimal IgA and no
  comp. activating properties.
• However, highly variable.
• Solvent detergent for virus inactivation
• MOA is the same as endogenous IG and specific
  activity is dependant on the donor pool.
• FDA regulates all of the different preparations
  and mandates minimal titers for certain
  infections.

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CVID Ig therapy Treatments

• Dose response for IVIG- gt600 mg IgG/kg every 4
  weeks.
• No goal trough level for IgG (Powderly and ACohen
  2nd ed.)
• T/2 approx. 2-3 weeks, unless exudative
  enteropathy.
• Not pure preparations-contain many cytokines,
  etc.
• Contains more broadly active natural antibodies
• Prevents severe and lower respiratory infections
  but not upper respiratory tract infections in
  CVID. Favre O. Allergy 2005 Mar60(3) 385-90.

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CVID Ig therapy TreatmentsGorbach S.
Infectious Diseases. 2nd ed.

• Pharmacokinetics for J,J, B
• IVIG peak serum conc. is proportional to dose
  admin.
• 200mg/kg IV lead to serum peak levels100mg/dL
• 1gm/kg IV lead to peak levels500mg/dL
• Levels drop until d3-7 where they reach 35-50
  peak levels. (Intra-extravascular, removal of
  inactivated IG, complexed)
• Levels are back to baseline at 3-4 weeks (this
  represents terminal elimination)
• IM leads to peak levels ½ those of IVIG. Same
  T/2.

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CVID Ig therapy TreatmentsGorbach S.
Infectious Diseases. 2nd ed.

• However, elimination is dependant on host.
• In BMT pts. the T/2 may be lt12h.
• Measure CMV Ab titers.
• T/26-15d for CMV titers in other transplant
  patients.
• Not clear why this occurs.
• Possibly that infections with CMV result in
  shorter T/2 and higher prevalence in this
  population.

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CVID Ig therapy Indications for replacement

• GVHD
• Unselected IM immune serum globulin for Hep A
  prophylaxis.
• Prevent or ameliorate measles in the nml. host
• Nephrotic syndrome? Burns? Everywhere else you
  can study its uses.

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CVID Ig therapy Indications for replacement

• Infectious Diseases
• Strep Toxic Shock Synd.
• Hyperimmune or specific IG forBotulism, CMV,
  HBV, Rabies, RSV, Tetanus, Vaccinia, VZV.
• Unselected HAV, Diphtheria, Measles.

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CVID Ig therapy Indications for replacement

• Persistent echovirus encephalitis-extremely high
  doses of IVIg
• CMV High titer specific immunoglobulin
  preparation for BMT and SOT pts.
• Anti-RSV immunoglobulin for infants
• ITP-blockade of macrophage Fc receptor
• Primary HIV Associated Thrombocytopenia
  (PHAT)-98 effective in raising PLT countgt90K.
  Single dose of 1-2g/kg IVIG Arch Intern Med
  1988148695
• Kawasaki and dermatomyositis-inhibit generation
  of MAC

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CVID Ig therapy Indications for replacement

• Indications for Ig replacement in PI.
• CVID when IgG levels fall below 250mg/dL.
• X linked hyper IgM syndrome
• IgG subclass deficiency, sometimes even in total
  IgG levels are not decreased.
• IgA and IgG deficiency, but IgA deficiency alone
  is a contraindication.
• These criteria may vary.

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IVIG therapy for CVID Procedure

• Dosage is debatable.
• Do higher doses than 200-300mg/kg Q 28d reduce
  the number and severity of infections in patients
  with hypogammaglobulinemia?
• Have demonstrated dose dependent effect. As per
  one recent well done study.

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IVIG therapy for CVID Procedure

• Eijkhout HW. Ann Intern Med 2001 135165-74
• Double blinded, randomized, multicenter,
  cross-over study in 1995-1998 eval. dosage of
  IVIG.
• 19 X-linked agammaglobulinemia or 24 CVID
• Excluded lt1 y/o, anti-IgA Ab, chronic active
  diseases, hx of anaphylactic rxn to IVIG.
• Children were lt20 y/o?

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IVIG therapy for CVID ProcedureEijkhout HW.
Ann Intern Med 2001 135165-74
Standard300/400mg/kg/4wks High600/800mg/kg/4wks
Adult/children
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IVIG therapy for CVID ProcedureEijkhout HW.
Ann Intern Med 2001 135165-74

• Intention to treat analysis.
• gt1 infection in 90 standard and 83.7 high dose
  patients.
• Mean number of infections associate with imm.
  def. were 3.5 standard and 2.5 high dose.
  P0.004. Duration of infection also
  significantly decreased in high dose group.
• Number of resp. inf. were not stat. sig.

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IVIG therapy for CVID ProcedureEijkhout HW.
Ann Intern Med 2001 135165-74

• Augment the less stringently tested older data
  from previous studies showing dose response
  curve.
• Also showed that trough IgG 9g/L resulted in
  decreased number and severity of infection
  compared to 6.5g/L and the traditional teaching
  of goal trough 5g/L
• Good database for old references on dosing and
  early trials with IVIG.

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IVIG therapy for CVID Product

• Comes as freeze dried product-made from pooled
  plasma of 1,000 voluntary donors and extracted
  with cold ethanol fractionation using that Cohn
  method, then proteolysis at pH 4. Finally freeze
  dried and at a shipped to a grocer near you.
• Once reconstituted with water, composed of 95IgG
  and .24 mol/L glucose (stabilizes IgG to prevent
  formation of aggregates).
• Can also reconstitute the lyophilized forms with
  D5W or NS at varying concentrations. Infuse are
  room temp.

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IVIG therapy for CVID Product
Journal of infusion nursing 20054265-72
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CVID Ig therapy SE-IgA def

• If a patient had CVID with complete IgA
  deficiency, they may have Ab. against IgA and
  preparations may have trace IgA and lead to
  anaphylactoid reactions.
• High levels of TNF
• Check for the presence of anti-IgA antibodies in
  the patients blood before starting IVIG.
• All products have IgA and are contraindicated for
  patients with Ab against IgA. For severe rxn, pt
  will have no IgA and IgE against IgA-this
  scenario is rare
• Ex vivo treatment of IVIgG preparations with
  autologous plasma? Tansfusion 200444509-11

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CVID Ig therapy Treatments
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CVID Ig therapy SE Adverse reactions

• Serious SE are rare. lt5 of patients
• Mild fever, HA, chills, flushing, fatigue,
  diarrhea in 1/3 to ½ of patients receiving IVIG.
• Immediate severe rxns are vanishingly rare. (even
  in 1999)
• Infuse IVIG slowly to those with high levels of
  IgG and those with immune complex disease.
• Aseptic meningitis following high dose IVIG in
  pts with migraines. IgG and pleocytosis in CSF
• ARF rarely with the sucrose stabilized form
• No HIV transmission after screening and Cohn
  fractionation. EtOH does not effect HCV-Hmmmm?

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CVID Ig therapy SE Adverse reactions

• If patients have predictable side effects, they
  can be premedicated with antihistamines and iv
  hydrocortisone.
• Use IgA depleted IVIG in patients with anti-IgA
  antibodies.
• Hyperviscosity and pseudohyponatremia
• Invariably patients develop fibrosis at the SQ
  infusion site.

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CVID Ig therapy SE Adverse reactions

• Subcutaneous dosing-off lablel?
• 100mg/kg/SQ/wk started 2 weeks after loading dose
  IV.

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CVID Ig therapy Treatments

• 1/11/2006 FDA approved ZLB Behrings Vivaglobin
• First FDA approved SQ IG for PI patients and can
  be given at home.
• Approval based on 1 US study of 65 ped and adult
  pts with primary Immune deficiencies over 12 mos.
• Weekly injections of 158mg/kg136 of their
  previous IVIG dose. No difference in infections
  or SE.
• Safety study in Europe and Brazil in healthy
  volunteers.
• http//www.pharmalive.com/News
• http//www.vivaglobin.com,

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CVID Ig therapy Costs

• In 1999 IVIG _at_ 400mg/kg/mo 8600 wholesale per
  year.

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CVID Ig therapy Monitoring therapy

• Measure IgA in saliva or tears.
• Measure trough levels?

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CVID Ig therapy Adjunctive therapy

• Counsel that mucosal immunity is impaired despite
  IVIG.-more susceptible to enteric pathogens (Cl-)
• Avoid live vaccines (Counsel, dont just avoid)

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CVID Ig therapy Summary

• CVID and X-linked agammaglobulinemia are often
  managed by ID specialist.
• CVID therapy is traditionally monthly IVIG, after
  extensive immunologic workup.400-600mg/kg
• Familiarity with the uses and consequences of
  serum therapy are part of ID repertoire.
• Monitoring therapy with trough levels is
  questionable and likely the best monitoring is
  clinical correlation with subsequent trough
  levels if needed.
• Recently approved SQ product Vivaglobin may prove
  to be safe alternative to IVIG

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Case 2

• 71yo wm with ICM, CKD, PVD, COPD, and other
  comorbidities was admitted to FMC 11/11/05 for
  dyspnea and edema.
• Initial complaints were c/w decompensated CHF.
• He also described a fall 10 weeks ago and left
  elbow swelling.

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Case 2

• At an outside clinic he underwent aspiration of
  his Olecranon bursa and was given a script for
  prednisone.
• He was admitted several days later via the ED
  with c/o dyspnea, increased abdominal girth, left
  elbow pain, and back pain.

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Case 2

• We was admitted for diuresis and pain control.
• T12 compression frx. was seen on plain film.
• On further questioning on HD2, he described
  intermittent fevers.
• Of note, right IJ Hickman catheter was placed
  5/23/05. He had no complaints regarding the
  catheter.

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Case 2

• ROS As above, otherwise negative. He denied any
  redness or drainage from his left elbow.
• PMH Need an entire slide for this!!!
• Again, Resiliency!!!!

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Case 2

• RAS-s/p renal a. stent in 1985 with
  intraoperative cardiac arrest
• PVD-s/p R axillo-bifemoral graft, with subsequent
  thrombosis in 2001 and R to L femoral graft.
  Multiple subsequent thromboses.
• COPD- FEV1lt1L on home O2
• DM2
• CAD-s/p CABG 11/2002 with PTCI X2
• GI hemorrhage
• BiV PM/AICD placed in 4/2004
• Hickman catheter place 5/05 for Natrecor
  infusions
• TIA with 95 L ICA and 75 R ICA stenosis
• On 9/30/05 he was admitted for GI hemorrhage,
  vasc surg recommended leaving the HC in place.

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Case 2

• MEDS Vancomycin, etc.., etc..,
• ALL Only antibiotics are included here PCN,
  doxycycline, tetracycline, erythromycin,
  macrodantin, sulfa, prednisone?, antihistamine,
  and many more!!
• SOC HX previous smoker, no pets, lives in WS
  with his wife, disabled

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Case 2

• P/E Initially, T 98, 154/71 _at_ 86, 20, SpO2 88
  on 2L NC.
• Chronically ill appearing, appears dyspneic
• Decreased BS in b/l bases with rales, JVD, edema.
• Ascites
• Fluid _at_ L olecranon bursa without erythema or
  induration. Point tenderness at T spine.
• Otherwise, nonfocal exam.
• Very pleasant, cantankerous, ready to go home.
  Today!!!

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Case 2

• Initial labs
• WBC 12.6, 80 PMN, Hgb 10, PLTs 328K
• BUN/Cr 52/2.9, BNP 2,5000
• CXR showed signs of CHF

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Case 2 Hospital course

• On HD2, temp 100.3 and BCX from admit were
  resulted as 2/2 with MSCoNS and third BCX
  obtained was also positive.
• Vanco started, vasc surg consult with the
  impressions that the pos. BCX were false BCX.
  Leave Hickman Cath in and consult ID.
• ID consult 11/14-cath needs to come out and
  repeat BCX, rx vanco, echo

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Case 2 Hospital course

• CoNS was susceptible to erythro, clinda,
  cefazolin, gent, naf, PCN, rif, tetracycline,
  vanco2.0, and res to TMP/SMX.
• 11/21 TEE

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Case 2 Hospital course

• Echo findings
• Moderate size cyst like structure attached by a
  stalk to the TV. The coronary sinus wire has
  solid lesion with central lucency c/w a
  vegetation.
• Too large to remove percutaneously.

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Case 2 Hospital course

• Would need thoracotomy to remove wires.
• 11/22 Hickman removed and f/u Bcx negative. PICC
  placed.
• 11/22 BUN/Cr 79/2.4
• New ID consultant on service the weekend of Nov.
  11/26
• Current Mgt was vancomycin, retention of PM/AICD,
  and d/c to home.

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Case 2 Questions

• What do you think that the new ID consultant
  said?
• Medical mgt. of MSCoNS IE with retained AICD?
  Can the lead be safely removed percutaneously?
  And does it matter what the ID doc thinks about
  this question?
• Abx. and duration recs.?
• Any need to use vancomycin instead of nafcillin?
• What do you tell the patient, his family, and the
  PCP for his chance of cure?

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Case 2 Hospital course

• Any credence to the concept of heterogenous
  populations of MSCoNS and the emergence of
  resistance? Small Colony Variants?
• My rationale was that the infection will not be
  cured with med. mgt. alone, if he fails due to
  the emergence of resistance, then switch. In the
  meantime, give him the best opportunity at cure
  with the most cidal drug.

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PM I.E. with MS CoNS

• 1. Microbiology of CoNS resistance
• 2. Concept of heterogenous populations of CoNS
  and emergence of methicillin resistance. Small
  Colony Variants?
• 3. Pacemaker/AICD I.E. and medical mgt. alone.
  Brief review of the numbers-percent chance of
  cure with med. mgt. vs surgical vs perc. removal
  (how big of a veggie can be removed
  percutaneously?)
• Does everyone know how a BiV PM/AICD in placed?

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Coagulase-Negative Staphylococci

• 32 Species of CoNS
• Most commonly recovered
• S. epidermidis, S. hominis
• Most commonly encountered human pathogens
• S. epidermidis, S. saprophyticus, S.
  haemolyticus, S. lugdunensis, S. schleiferi
• S. saccharolyticus the only ob. Anaerobe

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PM/AICD I.E. with MSCoNSResistance

• CoNS methicillin resistance is conferred through
  SCCmec.
• MecA and PBP2a -same as MRSA
• This inefficient PBP confers resistance to all
  beta lactams.
• SCCmec is transferable in vivo
• The level of PBP2a expression determines
  phenotype.

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PM/AICD I.E. with MSCoNSResistance

• S. aureus has a bimodal distribution of oxacillin
  susc. (either lt 0.5 or gt8mg/dL).
• S. epidermidis, the natural breakpoint for
  resistance appears to be lower than S. aureus.
• More CoNS than S. aureus with MICs showing meth
  susc. yet are mecA positive.
• Antimicrob Agents Chemother 199539982-4.

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PM/AICD I.E. with MSCoNSResistance Antimicrob
Agents Chemother 199539982-4.

• NCCLS breakpoint for CoNS to oxacillin lt
  0.25mg/dL. Previously it was same as for S.
  aureus
• 3/5 isolates with MIC 0.5 were mecA pos.
• On disk diffusion, these 3 isolates also had
  large zones of inhibition but also had colonies
  within the diameter representing sensitivity.
• Of the 14 isolates with MIC1mg/dL, 8 showed
  heteroresistance and all had mecA. No isolates
  with ox MIClt0.25 had mecA

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PM/AICD I.E. with MSCoNSHeterogenicity of drug
resistance.

• 80 of nosocomial CoNS is meth res.(mecA)
• CoNS heterotypy of meth res. gtgt S. aureus.
• Can show low oxacillin MIC, lt to the accepted
  breakpoint for S. aureus.
• BUT contain mecA gene and are fully resistant to
  methicillin in animal models.
• Therefore, the breakpoints for detecting ox res.
  in CoNS are lower than in S. aureus.(0.25 vs 2)

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PM/AICD I.E. with MSCoNSHeterogenicity of drug
resistance.

• However, this has not been validated in humans.
• The clinical significance of this heterogeneity
  is not known.
• Can detect PBP2A with latex agglutination or MecA
  with PCR in these CoNS, and if co-colonized with
  MSSA, could get false positive MRSA result in
  nasal surveillance culture. pseudo-MRSA

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PM/AICD I.E. with MSCoNSHeterogenicity of drug
resistance.

• J Clin Microbiol 200644229-31.
• 235 nasal swabs in Germany and looked at
  co-colonization of MSSA and MRCoNS.
• Used culture and molecular diagnostics.
• With parallel SCCmec and nuc gene molecular
  diagnostics, high false positive.
• PPV 40, 100 sens, 100 specific.
• Only 5 MRSA of 235 swabs-Prevelance?

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PM/AICD I.E. with MSCoNSMicrobiology-Small
colony variants?

• Pin point colonies, weakly coagulase positive (S
  aureus) 4-5 days after innoculation
• Misdiagnose as MSCoNS
• Contain Mec A, express, PBP2, and may or may not
  be in vitro resistant to methicillin, otherwise
  they are often very drug resistant
• Can cause latent infection/failed seemingly
  appropriate therapy. Can invade eukaryotic cells
  and persist despite cell wall active abx.

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PM/AICD I.E. with MSCoNSHeterogenicity of drug
resistance.

• With MRSA, methicillin resistance is
  heterogenous. (more so with CoNS)
• Can incorporate NaCl into medium and lower the
  temperature to increase the expression of
  resistance.
• Archives of Microbiology 2002178165-71

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PM/AICD I.E. with MSCoNSTreatment

• Refer to recent supplement in CID on vancomycin.
• CID 200642(Suppl 1)S51 PK and PD Esp. for
  J,J,B
• Older studies showed vanco was more rapidly
  bactericidal than were beta lactams and better in
  animal model if IE.
• All clinical data show that beta lactam is better
  and there are more recent in vitro data to the
  contrary.
• Shorter duration of bacteremia and fewer
  relapses.
• For references
• CID 200642(Suppl 1)S51
• Antimicrob Agents Chemother 1990341227-31.

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PM/AICD I.E. with MSCoNSHeterogeneous
population.

• Summary
• If CoNS Ox MIClt0.25, no mec A, no expression of
  MR phenotype.
• May be able to be transformed in vivo, but
  inherent resistance genes are not present.
• No clinical failures in humans with beta-lactam
  treatment of MSCoNS due to emergence of meth
  resistance.

76
PM/AICD I.E. with MSCoNSPM I.E.

• Infection of the device pouch and wire occurs at
  1-7 (0.5-12) Infectious Disease Clinics. June
  200216477-505.
• PM and AICD (Cardiac Devices CDs) Transvenous
  only.
• TEE required to evaluate the entire system (SVC
  to RV). Increase in sensitivity from 25 to 95,
  except in TV IE.
• BCX are in gt80 of CD IE and cx of the wires
  reveals the causative agent.

77
PM/AICD I.E. with MSCoNSPM I.E.

• CD IE occurs in 3 scenarios with equal frequency
  gt50 of cases of IE in PM recipients involved a
  valve regardless of lead involvement. (CID
  20043968-74)
• 1. IE exclusively on leads
• 2. Combo of lead and valve IE
• 3. Isolated valve inf. independent of leads
• Incidence 400 cases of IE per million CD
  recipients. (.04)(French CID 20043968-74)
  Midway between native valve and prosthetic valve
  IE incidence in the general population.

78
PM/AICD I.E. with MSCoNSPM I.E.

• Early lt1 month S. aureus EtiologySQ site of
  implantation. Infectious Disease Clinics NA. June
  200216477-505.
• LateCoNS (1-12mo late, gt12mo delayed)-25,
  33, 48 of cases
• Both are from local contamination during
  implantation.
• Hematogenous seeding of CD conducting system
  during the course of bacteremia is
  rare-neoendothelium and fibrous coating. Chest
  20031241451-9, IDCNA 200216477.
• Exception is S aureus. 29 chance of CD infxn
  following S aureus BSI _at_ gt1 yr. Circulation
  20011041029-33.

79
PM/AICD I.E. with MSCoNSChest 20031241451-9

• 31 cases of PM IE. 4,228 devices implanted.
• Prospectively identified all cases of CD
  infection over 10 years.
• 0.6 incidence of IE on CDs.
• 7/31 patients with medical mgt alone. All
  relapsed and one died. 1.6 relapses per pt.
  before surgery
• 24 underwent surgical removal (5 sternotomy/19
  perc) 1 relapse, 3 died after surgery, 20 were
  cured at 389 months.
• Only prognostic factor for treatment was absence
  of surgery (Plt0.0001).

80
PM/AICD I.E. with MSCoNSAnn Int Med
2000133604-8

• 123 CD infections and 117 underwent complete
  device removal with only one relapse (varying
  methods of abx therapy)
• Of the 6 with incomplete removal, 3 had relapse.

81
PM/AICD I.E. with MSCoNSAm J Cardiol
199882480-4

• 190 pts with PM IE
• Med Mgt alone-41 mortality rate
• Removal of entire apparatus-19 Mor Rate.
• All cause MR. That associated with thoracotomy
  was also included.

82
PM/AICD I.E. with MSCoNSPercutaneous Removal

• Percutaneous removal has been performed on leads
  with veggies up to 23mm and 100 months following
  implantation. Chest 20031241451-9.
• Within 12 mos, perc. traction can be done. Chest
  20031241451-9.
• Data showing that wires not amenable to traction
  are often able to be removed with laser sheath.
  IDCNA 200216477.

83
PM/AICD I.E. with MSCoNSPercutaneous Removal

• Leads with vegetations gt10mm can be safely
  removed without PE complications. Circulation
  1997952095-2107.
• Transvenous removal of leads with vegetations
  from 10-38mm. Am Heart J 2003146339-44
• Dilator sheaths, transfemoral snares, retrieval
  baskets, needles eye snare, laser assisted
  All with some rate of major complication.
• Less-invasive surgical approach to percutaneous
  lead removal. Chang el al Ann Thorac Surg
  2005791250-4.

84
PM/AICD I.E. with MSCoNSPercutaneous Removal

• PE may occur following lead extraction in the
  presence of infected vegetations, but their
  sequelae have not been severe and mortality does
  not change.
• AICD leads are harder to remove, especially at
  longer times from implantation to diagnosis.
• However, vegetations seem to remain adherent to
  the endocardial surface of the heart after
  removal.
• Perc removal unless the PE would be
  catastrophic
• Complication rate2-2.5, major0.5 no data on
  coronary sinus lead extraction-BUT seem easier to
  dc.
• Current opinions in cardiology 20041919-22

85
PM/AICD I.E. with MSCoNSAnn Int Med
2000133604-8

• Medical Mgt See Karchmers chapter in Infectious
  Disease Clinics of North America. June
  200216477-505.
• Anecdotes
• Extensive ID with local instillation of abx
• Indefinite systemic abx.

86
PM/AICD I.E. with MSCoNS

• Difficulty of medical mgt is the fibrous matrix
  of dense layers of endotheliazed fibrous tissue
  surrounding the generator and leads.
• Poor antibiotic penetration.
• Proven higher mortality.

87
PM/AICD I.E. MGT Summary

• Complete percutaneous explantation-percutaneously
  at expert center, modified perc approach in
  China, open if needed (rarely).
• Partial removal (only if infection is clearly
  limited to the removed component)
• Optimize/prolong abx. regimen if medical mgt. is
  the only course. Cure rate is intolerably low.
• If MSSA, beta-lactam is drug of choice with
  consideration for hetergenous population if
  clinical failure.