Infectious Diseases Case Conference

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Infectious Diseases Case Conference

• Jason Kettler
• Wake Forest University
• February 10, 2003

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Case Presentation

• 68 year old BM with underlying DM/htn
• HgbA1C 13.2
• To dentist on 11/12/2 c/o tooth pain which
  resulted in an extraction, followed by a 6-day
  course of amoxicillin
• Pt. then presented to an OSH on 4 separate
  occasions w/ various c/o including facial
  swelling, h/a, ?ed facial sensation

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Case Presentation

• Hospitalized elsewhere from 12/7/2 12/12/2
  after having X-rays, CTs, bloodwork
• Apparently still symptomatic at the time of d/c
  reports he was still having h/a, facial swelling,
  ?ed visual acuity, ?ed facial sensation
• Seen by a dentist the day after d/c from the
  hospital ? full mouth extraction

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Case Presentation

• Multiple courses of antibiotics throughout the
  hospitalization
• Seen by a neurologist who ordered an MRI per the
  family but no specific dx was provided
• Also referred to an ophthalmologist but to no
  avail
• Due to persistence of h/a, worsened visual
  acuity, ?ed facial sensation, inability to
  entirely open his mouth - pt. went to DHP ?
  admitted to undergo MRI and ENT evaluation

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• Poorly-controlled diabetic man who has a symptom
  complex of facial swelling, headache, diminished
  visual acuity, diminished facial sensation,
  evidence of dental caries
• Knowing only that much, are you inclined toward a
  particular diagnosis?

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• MUCORMYCOSIS

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• MUCORMYCOSIS
• Principal other diagnosis in the differential
  would be aspergillosis
• Less likely considerations might include
  actinomycosis, botryomycosis

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Case Presentation

• PMH DM x 3-4 yrs., recently dxed htn
• Meds SSI, amiloride, amphotericin b 40 mg x 1
  dose
• All codeine, hydrocodone
• SH Remote EtOH use smoker x 30 yrs
• FH 2 daughters on dialysis 2o GN
• ROS Ff/c/wt. loss appetite good
  FN/V/D/CP/SOB/rhinorrhea/sneezing /-
  congestion h/a x 1-1/2 mos.,?ed visual acuity
  ?ed facial sensation

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Physical Exam

• tcur tmax 99.9 p89 bp143/73 r20 sat92 in
  RA
• gen pleasant, appears well
• heent perrla, eomi L eyelid swollen, eye
  closed could not appreciate light in L eye
  nares patent F obvious eschar or lesion o/p
  edentulous w/ sinus tract in mid-portion of soft
  palate, ?ed oral aperture

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Physical Exam

• neck supple, soft tissue swelling on posterior
  neck (old) FLAD
• cv regular rhythm II/VI systolic murmur
• lungs soft bibasilar crackles, F wheeze
• abd soft, nt, nd, nabs
• extrem Fc/c/e Fskin breakdown on feet
• skin hyperpigmented macules/papules on abdomen
• neuro ?ed facial sensation B, CN o/w intact
  F obvious focal weakness DTRs 2 in U/LE

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Lab data

• WBC 13.3 hgb 9.9 plt 700
• CMP entirely WNL except nf glc of 162
• CRP 4.4
• ESR 98
• Gram stain of sinuses 1 WBC, 1 GNR
• Blood cx NG

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MRI brain
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Assessment

• Elderly diabetic gentleman who now presents w/
  extensive bilateral sinusitis w/ accompanying
  tissue destruction. Statistically, the most
  likely causes would be mucormycosis,
  aspergillosis. Organisms are distinguishable
  pathologically and that specimen is pending. ENT
  feels surgery potentially not feasible, though
  therapy for invasive disease such as this is
  typically a combined medical and surgical
  approach. Cannot r/o concomitant bacterial
  sinusitis.

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Our Suggestions

• Abelcet 10mg/kg/d
• Cefepime 2 g IV q12
• Await further culture / pathologic data

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Path Specimen
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Hospital Course

• Initially treated with 10/kg Abelcet but dose
  diminished 2o renal insufficiency
• Ultimately infusion extended over 11 hours

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Hospital Course

• Initially treated with 10/kg Abelcet but dose
  diminished 2o renal insufficiency
• Ultimately infusion extended over 11 hours
• Rifampin 600 mg BID
• Briefly treated w/ Cefepime
• S/P B max antrotomies, B ethmoidectomies,
  septectomy, inf. middle turbinate resections
  AND 2 subsequent debridements

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MUCORMYCOSIS

• Salient points of interest and management issues

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Classification

• Mucormycosis refers to a group of mycoses caused
  by one of the ubiquitous, saprophytic fungi of
  the ORDER Mucorales
• The names of the fungi have changed over the
  years
• The term Zygomycosis refers to the class
  Zygomycetes, which contains the Mucorales as well
  as the Entomophthorales, agents that cause
  completely different diseases than the Mucorcales
• Rhizopus, Rhizomucor, Absidia are most commonly
  isolated pathogens but diseases are virtually
  identical

• I. Zygomycotina
• A. Zygomycetes
• a. Mucorales
• 1. Mucoraceae
• i. Absidia
• (a) A. corymbifera
• (b) A. ramosa
• ii. Mucor
• (a) M. circinelloides
• iii. Rhizomucor
• (a) R. pusillus
• iv. Rhizopus
• (a) R. oryzae ( R. arrhizus)
• (c) R. rhizopodiformis
• 2. Cunninghamellacaeae
• i. Cunninghamella
• (a) C. bertholletiae
• 3. Mortierellaceae
• i. Mortierella

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Characteristics of Mucorales

• NOT fastidious organisms and grow at a range of
  temperatures
• The organisms are aerobic and typically grow
  within 2-5 days of incubation
• Ubiquitous organisms which initiate and
  facilitate decay of organic material
• Exposure to spores of these fungi is unavoidable
  and hence the rarity of infections caused by
  Mucorales is indicative of their relative
  avirulence
• Infection caused by one of these organisms
  suggests a serious underlying predisposition
• Can colonize the respiratory and GI tracts of
  healthy humans

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Pathogenesis

• Infection occurs after inhalation of spores into
  the respiratory tract
• Spores may be deposited into the nasal turbinates
  or may pass through to the pulmonary alveoli
• It is thought that impaired function of
  macrophages in diabetic pts. predisposes them to
  invasive disease (CID 1992)
• Most characteristic feature of mucormycosis is
  hyphal invasion of blood vessels, leading to
  hemorrhage, thrombosis, infarction necrosis
• This can lead to cavernous sinus and internal
  carotid artery thrombosis

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Clinical Manifestations

• Six separate syndromes rhinocerebral,
  pulmonary, cutaneous, GI, CNS, disseminated
• Most common is rhinocerebral
• Most common complaints are facial pain, h/a,
  fever can extend to orbit via the nasal
  turbinates and cause visual disturbances can
  also extend to the brain, esp. the frontal lobes
• When the disease invades into the mouth, a black
  necrotic eschar can be seen on the palate, a
  finding which is highly suggestive of invasive
  mucormycosis (though perhaps overemphasized,
  occurring 19-40 of the time in one case series)

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At-risk populations

• Diabetics, especially with poor glycemic control,
  /or who are in ketoacidosis
• Other immunocompromised individuals, especially
  organ transplant pts., hematologic malignancies,
  severe burns, ESRD
• These pts. are more likely to present with
  pulmonary or disseminated disease
• Rarely reported in pts. w/ AIDS
• Pts. receiving deferoxamine as a chelating agent

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Diagnosis

• Since invasion of blood vessels is a major
  manifestation of mucor, areas of vasculitis w/
  thrombosis, hemorrhage, etc. are important clues
• Aggressive progression (hours to days) w/ assoc.
  tissue damage esp. in the resp. tree CNS is
  characteristic
• Pts. w/ aspergillosis can present w/ cutaneous
  and respiratory findings that are similar to mucor

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Diagnosis

• Culture of, and pathologic examination of bx
  specimens is, thus, the only way to definitively
  dx mucormycosis
• Mucorales appear in tissue as irregularly shaped,
  broad, nonseptate hyphae with right-angle
  branching
• Cultures are infrequently positive
• CT/MR may reveal orbital involvement, extent of
  soft tissue/vascular invasion by fungi
• In pts. w/ intracranial involvement, CSF sampling
  is nonspecific and unhelpful

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Treatment

• Historically has involved three fundamental
  components 1) systemic antifungal treatment
  with amphotericin B, 2) debridement and excision
  of all necrotic tissue, 3) reversal of underlying
  predispositions
• With the combined approach, mortality rates have
  fallen below 20
• Mortality higher in pts. w/o DM, but with other
  predisposing risk factors or underlying diseases

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Amphotericin B

• No definitive recommended dosing of amphotericin
  therapy usually has required the maximum
  recommended dosage of 1.5 mg/kg/d
• The lipid formulations offer an attractive
  treatment option
• substantially reduced renal toxicity
• the lethal dose of lipid-based AmB is approx.
  10-15x higher than conventional ampho
• may exhibit better diffusion into the CNS

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• Mondy, K, B Haughey et al. Rhinocerebral
  Mucormycosis in the Era of Lipid-Based
  Amphotericin B Case Report and Literature
  Review. Pharmacotherapy 200222519-26.
• Lipid formulations of AmB are ideally suited for
  therapy against infections such as RCM, which
  require large doses of drug given for long
  periods of time (CID 1998)
• Of 24 immunocompromised pts. w/ various forms of
  mucor prior nephrotoxicity or therapeutic
  failure while on conventional AmB, 17 (71) were
  cured or improved after switching to ABLC

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Mondy et al

• A study of AmB lipid complex administered to pts.
  w/ DM revealed that of four patients treated for
  RCM, all were either cured or improved w/ this
  drug, despite prior nephrotoxicity or poor
  response to conventional AmB (Infect Dis in Clin
  Practice 1997)

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Medical therapy only?

• 3 case reports in the literature of pts. cured w/
  medical therapy alone
• 2 are similar diabetic, advanced rhinoorbital
  involvement w/ intracranial extension cavernous
  sinus involvement both treated w/ ABLC
• 1 an IVDA w/ a basal ganglia abscess received
  conventional AmB only but had no rhinoorbital
  involvement that could serve as a persistent
  source for spread of infection no underlying
  illness

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Other experimental therapies

• Hyperbaric oxygen
• Nebulized or local irrigation w/ AmB
• Topical H2O2
• Combo of AmB w/ either flucytosine, rifampin, or
  fluconazole
• None of these agents has shown consistent in vivo
  or in vitro activity

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Prolonging ABLC infusion

• Eriksson U et al. Comparison of effects of
  amphotericin B deoxycholate infused over 4 or 24
  hours randomised controlled trial. BMJ 2001.
• Continuous infusions of AmB reduce nephrotoxicity
  and SEs related to infusion w/o increasing
  mortality
• At WFUBMC, we have extrapolated these findings to
  pts. being treated with ABLC therapy with
  favorable results
• Not yet reported
• At least 3 clinical observations of success
• We, the ID people of Wake Forest, are pioneers!

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Take-home points regarding therapy

• Best outcomes are achievable with combined
  surgical medical approaches, w/ reversal of
  underlying illness if possible
• Lipid-based ampho appears to be the best medical
  option considering length of therapy and need for
  very high doses
• Other adjunctive therapies, e.g. rifampin, may or
  may not be of benefit