Case Conference

1
Case Conference

• Toby Fugate, D.O.

2
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

5
62 year old male with history of NHL status
post Stem Cell Transplant in 1997 undergoing
repeat chemotherapy

• Admitted due to fevers and chills of three days
  duration
• Found to be neutropenic
• No focus of infection
• All cultures negative
• Started on broad spectrum antibiotics
• All radiographic studies negative
• Still febrile at 5 days despite broad antibiotic
  coverage
• Consult Question Should we add antifungal
  coverage?

6
Invasive Fungal Infections (IFI)

• Early diagnosis remains a challenge
• Low sensitivity of microbiological culture
  techniques
• Low specificity of standard radiological tools
• Infections are often advanced at the time of
  diagnostic confirmation
• Empiric antifungal therapy is considered standard
  practice in neutropenic patients with persistent
  fevers
• As many as 40-50 of high-risk neutropenic
  patients receive empiric tx
• True incidence of IFI appears to be 10-15
• Progress could come from the incorporation of
  non-culture-based tests
• Galactomannan
• High-resolution CT
• ß-D-glucan

7
Defining Opportunistic Invasive Fungal
Infections (IFI) in Immunocompromised Patients
with Cancer and Hematopoietic Stem Cell
Transplants An International Consensus

• Over the past several decades, there has been a
  steady increase in the frequency of opportunistic
  IFIs in immunocompromised patients
• Controversy concerning the optimal diagnostic
  criteria
• European Organization for Research and Treatment
  of Cancer/Invasive Fungal Infections Cooperative
  Group and the National Institute of Allergy and
  Infectious Diseases Mycoses Study Group
• formed a consensus committee to develop standard
  definitions for IFIs in CLINICAL RESEARCH
• Three levels of probability proposed
• Proven
• Probable
• Possible

Ascioglu et al. CID 2002 34 7-14
8
(No Transcript)
9
False-positive cryptococcal antigen reactions

• Trichosporon beigelii
• Stomatococcus mucilaginosis
• Circulating rheumatoid factor
• Concomitant malignancy

10
(No Transcript)
11
Galactomannan(GMN) and CT-Based Preemptive
Antifungal Therapy in Neutropenic Patients at
High Risk for Invasive fungal Infection A
Prospective Feasibility Study

• 136 treatment episodes (88 patients) for persons
  who were at risk of acquiring IFI (neutropenic
  pts) admitted
• Started on prophylaxis with fluconazole and
  levofloxacin
• Monitored for fever or the development of SS of
  IFI

Maertens et al. CID 2005 41 1242-1250
12
Maertens et al. CID 2005 41 1242-1250

• Triggers for diagnostic w/u
• Neutropenic fever refractory to 5 days of broad
  spectrum abx
• Clinic SS of IFI
• New pulmonary infiltrate
• Isolation of mold/hyphae in resp samples
• Two consecutive positive GMN assays
• Diagnostic w/u included
• HRCT
• Bronchoscopy
• Autopsy on all fatalities

13
Maertens et al. CID 2005 41
1242-1250Results

• Neutropenic fever developed in 117 episodes
• 41 episodes (35) satisfied existing criteria for
  empiric antifungal therapy
• Reduced the rate of antifungal use from 35 to
  7.7
• Led to early initiation of antifungal therapy in
  10 episodes that were not clinically suspected of
  being IFI
• No undetected cases of invasive aspergillosis
  were identified
• One case of zygomycosis was missed
• Breakthrough candidemia was diagnosed by routine
  culture techniques and treated successfully
• 12 week survival rate for pts with IFI was 63.6
• Conclusion Preemptive therapy based on EIA and
  HRCT reduced the exposure to expensive and
  potentially toxic drugs and offered effective
  antifungal control, but failed to detect
  non-Aspergillus IFI

14
(1?3) ß-D-Glucan Assay

• Can be detected by its ability to activate
  factor G of the horseshoe crab coagulation
  cascade
• Binds to the a subunit of factor G
• Causes activation of factor Gs serine protease
  zymogen ß subunit
• When this reaction is combined with the
  proclotting enzyme of the cascade and a
  chromogenic substrate, BG levels as low as 1
  pg/mL can be quantified spectrophotometrically

15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
Multicenter Clinical Evaluation of the (1?3)
ß-D-Glucan (BG) Assay as an Aid to Diagnosis of
Fungal Infections in Humans

• Subjects at 6 clinical sites enrolled as either
  fungal-negative subjects (n170) or subjects with
  proven or probable IFI based on EORTC/MSG
  criteria (n163)
• A single sample was obtained per patient and was
  evaluated using a BG Assay (Fungitell,
  Associates of Cape Cod)

Ostrosky-Zeichner et al. CID 2005 41 655-659
19
(No Transcript)
20
Multicenter Clinical Evaluation of the BG Assay
as an Aid to Diagnosis of Fungal Infections in
Humans

• Cutoff of 60 pg/mL
• Sensitivity 69.9
• Specificity 87.1
• PPV 83.8
• NPV 75.1
• Cutoff of 80 pg/mL
• Sensitivity 64.4
• Specificity 92.4
• PPV 89
• NPV 73

21
(No Transcript)
22
(No Transcript)
23
Multicenter Clinical Evaluation of the BG Assay
as an Aid to Diagnosis of Fungal Infections in
Humans

• Of the 107 patients with proven candidiasis
• 81.3 had a positive result at a cutoff of 60
  pg/mL
• 77.6 had a positive result at a cutoff 80 pg/mL
• Of the 10 patients with aspergillosis
• 80 had positive results at cutoff values of both
  60 and 80 pg/mL
• Of the 3 subjects diagnosed with Fusarium species
• 100 had a positive result at a cutoff of 60
  pg/mL

24
Multicenter Clinical Evaluation of the BG Assay
as an Aid to Diagnosis of Fungal Infections in
Humans

• Patients infected with Mucor and Rhizopus species
• Negative results at both cutoff values
• Of the 12 patients with Cryptococcus
• 25 had positive results at a cutoff value of 60
  pg/mL
• 17 had a positive result at a cutoff value of 80
  pg/mL
• Of the patients with proven positive results who
  were receiving antifungal therapy (n118)
• 72.9 had positive results at a cutoff value of
  60 pg/mL
• 69.5 had positive results at a cutoff value of
  80 pg/mL
• Interlaboratory sample test r² was 0.93

25
Medical Sources of BG/Causes of False Positive BG
Assays

• Some dialysis membranes/filters are made from
  cellulose containing BG
• Certain immunoglobulin products
• Cotton gauze and sponges used in surgery
• Some herbs/supplements
• Lentinan
• Crestin
• Scleroglucan
• Schizophyllan

26
(No Transcript)
27
Case Two
28
23 year old Male

• Admitted with recurrent right otitis media
• Cultures in the past had grown Alcaligenes
  xylosoxidans, CoNS, and Diphtheroids
• A xylosoxidans was initially sensitive amikacin,
  ceftazidime, tobramycin, meropenem and
  piperacillin
• Later isolate was found to be only sensitive to
  meropenem and piperacillin
• Treated on several occasions with Augmentin
  and/or Cipro

29
23 year old Male

• PMHx
• Mental Retardation
• Cerebral Palsy
• Seizure disorder
• Asthma
• Hx of aspiration PNA

• PSHx
• Peg Tube Placement
• Bilateral Mastoidectomy
• Bilateral Tympanostomy
• Multiple Orthopedic Procedures

30
23 year old Male

• Medications
• Ciprodex
• Prevacid
• Zyrtec
• Nasonex
• Keppra
• Phenytoin
• Ativan
• Albuterol
• Flovent
• Singulair
• Senekot

• Allergies
• Sulfa
• Thiazides

31
23 year old Male

• ID was consulted after the patient underwent
  repeat tympanostomy tube placement
• Patient would not cooperate with ENT exam
• Crusted material noted at the external ear
• Remainder of exam was unremarkable

32
Infectious Disease Recommendation

• Since ENT wanted to discharge patient from Day
  Hospital the day after the procedure, we based
  our recommendations on past cultures and current
  Grams Stain (2 GPR and 1 GNR)
• Vancomycin and Meropenem for at least 3-4 weeks
• Obtain Head CT--? Longer duration of treatment
  based on the extent of the infection
• Monitor weekly CBC, CMP, and Vancomycin trough
• Follow-up with ID one week prior to
  discontinuation of IV therapy

33
Microbiology

• Alcaligenes xylosoxidans
• Sensitive
• Ceftazidime
• Meropenem
• Piperacillin
• Minocycline
• Diphtheroids

34
CT Temporal Bones without Contrast

• Pan-sinusitis
• S/P bilateral mastoidectomies with residual
  opacified mastoids
• Bilateral otitis interna and otitis externa
• Bilateral tympanostomy tubes
• Left parieto-occipital porencephalic cyst
• Right parieto-occipital periventricular
  leukomalacia

35
Achromobacter vs Alcaligenes

• Nomenclature of the genera Achromobacter and
  Alcaligenes has been confusing
• Based on molecular studies, Achromobacter has now
  been described as a separate genus
• Achromobacter xylosoxidans
• Achromobacter xylosoxidans subsp. denitrificans
• Achromobacter ruhlandii
• Achromobacter piechaudii
• Genus Alcaligenes contains one member
• Alcaligenes faecalis

36
Epidemiology of Achromobacter and Alcaligenes

• Ubiquitous in soil and water
• Well water
• Tap water
• Swimming pools
• Can be recovered from human respiratory tract and
  gastrointestinal tract in hospitalized patients
• Difficult to distinguish between colonization and
  infection

37
Alcaligenes xylosoxidans subsp xylosoxidans in
children with chronic otorrhea

• From January 1991 through December 1994, ten
  isolates (9 patients) of A xylosoxidans were
  cultured from ear fluid
• Seven of ten isolates from ear fluid cultures
  were accompanied by other known pathogens
• Pseudomonas aeruginosa and Staphylococcus aureus
• S aureus and CoNS
• Normal cutaneous flora
• S aureus and Acinetobacter haemolyticus
• P aeruginosa and Enterococcus species
• P aeruginosa
• S aureus

Wintermeyer et al. Otolaryngol Head Neck Surg
1996 114 332-4
38
(No Transcript)
39
Achromobacter xylosoxidans from Human Ear
Discharge

• Seventeen isolates from human ear discharge
  (adults and children)
• Three of seventeen isolates were from pure
  cultures
• The remaining 14 cultures contained A
  xylosoxidans among other bacteria
• Sensitivities paralleled that found in
  Wintermeyer et al.

Yabuuchi et al. Japanese J Microbio 1971 15
477-81
40
(No Transcript)
41
Achromobacter xylosoxidans Isolates in Hawaii

• Achromobacter xylosoxidans isolates were reviewed
  from August 1975 to July 1977
• Nine strains were isolated
• Majority of strains were from ear discharge in
  patients with otitis externa
• Most of the strains were sensitive to
  carbenicillin, chloramphenicol, sulfonamide, and
  TMP/SMZ

Pien et al. J Clin Microbiol 1978 7 239-41
42
(No Transcript)
43
(No Transcript)
44
Other Case Reports

• Meningitis
• Prosthetic Joint Infections
• Sternal Osteomyelitis
• Ophthalmic Infections
• Lung Infections
• Spontaneous Peritonitis
• Peritoneal Dialysis-associated Peritonitis
• Endocarditis

45
Achromobacter xylosoxidans

• Most consistently active antibiotics
• Imipenem
• Meropenem
• TMP/SMZ
• Piperacillin
• Ticarcillin/clavulanate
• Ceftazidime
• All isolates were resistant to
• Aminoglycosides
• Ampicillin
• Amoxicillin
• Aztreonam
• Most were resistant to 1st, 2nd, 3rd generation
  cephalosporins (except ceftazidime), and
  quinolones

Antimicrobial Therapy and Vaccines Pg 4
46
Plan for this patient

• Depends on how patient is doing clinically
• Continue IV tx vs transition to minocycline
• Complete four weeks therapy