Case Conference

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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
79 year old female with recurrent Clostridium
difficile diarrhea

• Diagnosed with C difficile diarrhea several
  months prior to presentation to Infectious
  disease clinic
• C difficile toxin positive on three occasions
• Complicated hospitalization due to breast cancer
  metastatic to the abdomen and pelvis
• Several subsequent hospitalizations
• Exposure to multiple antibiotic during these
  hospitalizations
• Diarrhea treated unsuccessfully with
  metronidazole on three occasions
• Oral vancomycin (without metronidazole)
  administered with some improvement

6
79 year old female with recurrent Clostridium
difficile diarrhea

• Past Medical History
• Metastatic breast cancer
• Chemotherapy
• Surgery
• Hypertension
• Atrial fibrillation with RVR.

• Past Surgical History
• Laparoscopic cholecystectomy
• Low anterior colon resection
• Lumpectomy.

7
79 year old female with recurrent Clostridium
difficile diarrhea

• Medications
• VANCOMYCIN 125 PO TID
• ACIDOPHILUS CAPS (LACTOBACILLUS)
• CALTRATE PLUS
• ATENOLOL
• CENTRUM TABS
• POTASSIUM CHLORIDE
• FERROUS SULFATE
• VITAMIN D 400 UNIT CAPS
• NEURONTIN

• Allergies
• Codeine

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Infectious Disease Clinic

• Oral vancomycin 125 mg QID x 14 days
• Rifampin 300 mg PO BID x 14 days
• Lactobacillus
• At day 7 there had been no improvement
• Scheduled for Urgent Care visit

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Infectious Disease Clinic

• Continue oral vancomycin, rifampin, and
  lactobacillus
• Add nitazoxanide (Alinia) 500 mg PO BID x 10 days
• Add Metamucil
• GI consult for other causes of diarrhea
• Malabsorption
• Short bowel
• Follow-up in two weeks

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Follow-up

• Canceled 2 week follow-up appointment
• Currently admitted for zoster
• Diarrhea completely resolved on nitazoxanide,
  oral vancomycin, and rifampin
• Actually, she now complains of constipation

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History of C difficile colitis

• First described in 1950s
• Staphylococcus aureus or Candida albicans was
  hypothesized to be the causative agent
• In 1974, a prospective study of 200 patients
  treated with clindamycin detected diarrhea in 21
  and pseudomembranous colitis in 10
• In 1977, a toxin produced by a Clostridium
  species was proposed as the cause of
  clindamycin-induced colitis in hamsters
• Later in 1977, this toxin was isolated from the
  stool of a patient with antibiotic-associated
  diarrhea
• By 1978, C difficile had been clearly identified
  as the causal agent of antibiotic-associated
  diarrhea
• Bartlett et al. Role Clostridium difficile in
  antibiotic-associated pseudomembranous colitis.
  Gastroenterology 1978 75 778-82

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Microbiology

• Gram-positive, spore-forming rod, obligate
  anaerobe, 2-17 µm in length, fast growing
• CCFA (cycloserine, cefoxitin, fructose agar in an
  egg-yolk agar base) is highly selective
• Toxin A
• fluid secretion
• intestinal inflammation
• Chemoattractant for neutrophils
• Toxin A and Toxin B
• Activate the release of cytokines from monocytes
• Binary toxin
• Role in pathogenesis unclear
• Trend toward more severe disease in patients who
  carry the strain of C difficile that produces
  binary toxin
• McEllistrem et al. A hospital outbreak of
  Clostridium difficile disease associated with
  isolates carrying binary toxin genes. Clin
  Infect Dis 2005 40 265-72

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Metronidazole

• MIC90 0.20 to 2.0 µg/mL
• One resistant isolate from Hong Kong with MIC of
  64 µg/mL
• Wong et el. Diag Microbiol Infect Dis 199934
  1-6
• 3 (6/198) of French isolates noted to have MIC
  of 8-32 µg/mL
• Barbut et al. Antimicrob Agents Chemother 1999
  43 2607-11
• 6.3 (26/415) of Spanish isolates found to have
  MIC of 32 µg/mL or more
• Pelaez et al. Antimicrob Agents Chemother 2002
  46 1647-50
• Metronidazole MICs in patients with clinical
  treatment failure was similar to those who had
  clinically responded to metronidazole therapy
• Sanchez et al. Anaerobe 19995 205-08
• Whether metronidazole resistance has an important
  role in treatment failure and recurrence is
  unclear

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Metronidazole

• After ingestion by HEALTHY patients (i.e., no
  diarrhea), metronidazole is absorbed from the GI
  tract and is almost undetectable in feces
• Mean concentration 1.2 µg/g
• Concentration is significantly higher when stools
  are watery (p
• Mean concentration of 9.3 µg/g
• May be due to increased GI transit time leading
  to incomplete absorption or seepage of the drug
  across the inflamed mucosa
• Concentration in semi-formed stool found to be
  lower
• Mean concentration of 3.3 µg/g
• Bolton et al. Gut 1986 27 1169-72

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Oral Vancomycin

• MIC90 0.75-2.0 µg/mL
• 3 of C difficile (Madrid) isolates had
  intermediate resistance to vancomycin (MIC 4-16
  µg/mL)
• Clinical correlation was not provided
• Pelaez et al. Reassessment of Clostridium
  difficile susceptibility to metronidazole and
  vancomycin. Antimicrob Agents Chemother 2002
  46 1647-50
• Oral vancomycin has limited absorption
• Stool concentration of up to 3100 µg/g
• Suggests that resistance in not clinically
  important

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Oral Vancomycin and Rifampin

• Seven patients with multiple bacteriologic and
  symptomatic relapses of C difficile-associated
  diarrhea treated with this combination
• Diarrhea and abdominal pain resolved within 24
  hours
• Neither C difficile nor toxin could be recovered
  initially following therapy
• Stool of all patients became culture-positive for
  C difficile within one month
• 3 of the 7 patients also had toxin detected in
  their stool
• During 12 months of follow-up, only one patient
  developed recurrent symptoms
• Whether or not the persistence of toxin is a
  cause for concern is not know
• Biotyping was performed on C difficile before and
  after treatment
• Isolates were identical
• Resistance to vancomycin and rifampin was tested
  before and after treatment
• Isolates remained susceptible
• Buggy et al. J Clin Gastroenterol 1987 9 155-59

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Probiotics

• Double-blind, randomized, placebo-controlled
  study
• Standard antibiotics (metronidazole or
  vancomycin) placebo vs standard antibiotics
  Saccharomyces boulardii for four weeks
• 124 patients (64 with an initial episode and 60
  with a history of at least one previous episode
  of C difficile)
• Patients were followed for an additional 4 weeks
  after completing therapy
• Efficacy of S boulardii was significant in
  patients with recurrent disease
• Recurrence rate was 34.6 in the S boulardii
  group vs 64.7 in the in the placebo group
  (p.04)
• Efficacy of S boulardii was not significant in
  the patients with an initial episode of C
  difficile
• Recurrence rate 19.3 compared with 24 on
  placebo (p0.86)
• McFarland et al. JAMA 1994 271 1913-18

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Nitazoxanide (Alinia)

• Approved to treat cryptosporidiosis and
  giardiasis in US in December 2003
• Blocks anaerobic metabolic pathways in
  microorganisms
• Interfers with the pyruvate ferredoxin
  oxidoreductase (PFOR) enzyme-dependent electron
  transfer reaction, which is essential to
  anaerobic energy metabolism
• Effective against C difficile in vitro
• MIC90 0.06-0.5 µg/mL

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Nitazoxanide (Alinia)

• In humans, 2/3 of the oral dose is excreted in
  the feces as an active metabolite called
  tizoxanide
• MIC90 for C difficile is 0.06 µg/mL
• Tizoxanide has been found at a concentration of
  200 µg/mL in human bile after a 1000 mg oral dose
• Thus high intraluminal concentrations can be
  achieved
• Open-label, prospective, compassionate-use study
  at VA Medical Center, Houston, Texas
• Nitazoxanide cured 75 of patients who had failed
  treatment with metronidazole
• 1/3 of these later relapsed
• Unpublished data Saima Aslam, Richard Hamill,
  and Daniel Musher, Baylor College of Medicine
• Double-blind, controlled trial comparing
  nitazoxanide and metronidazole is underway

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Bacitracin

• Two randomised clinical trials compared
  bacitracin to vancomycin
• No difference between the two drugs in terms of
  clinical response (ranged 76 to 100)
• At completion of therapy
• 55 of those who received bacitracin still had
  toxin in their stool
• 14 of those who received vancomycin still had
  toxin in their stool
• P
• Presence of toxin did not affect the number of
  clinical recurrences
• Young et al. Gastroenterology 1985 89 1038-45
• Dudley et al. Arch Intern Med 1986 146 1101-04

21
Teicoplanin and Fusidic Acid

• Prospective study compared oral vancomycin,
  metronidazole, teicoplanin, and fusidic
• 119 patients
• 93-96 were clinically cured for all regimens
• Treatment with fusidic acid
• Associated with high recurrence rate of 28
  (p0.04)
• Associated with a higher proportion of adverse
  events
• 31 had GI discomfort, p0.001
• Neither available in US
• Wenisch et al. Clin Infect Dis 1996 22 813-18

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Administration of Donor Stool

• Retrospective review of the charts of 18 patients
  who received donor stool by NG tube
• Patients had received on average 3 courses of
  antibiotics (metronidazole, oral vancomycin, or
  both) prior to stool transplant.
• At 90 days follow-up
• 2 patients had died of unrelated illnesses
  (peritonitis and hospital acquired PNA)
• Only one patient experienced a recurrence
• No adverse effects were reported
• Aas et al. CID 2003 36 580-85

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Other Treatments

• IV immunoglobulin has been used with variable
  success
• No Prospective trials reported
• Antibodies likely neutralize toxins
• Short courses of methylprednisolone have been
  reported in a few case studies

24
Vaccine

• Strong association between serum antibody
  response to toxin A and protection against C
  difficile diarrhea
• Parenteral C difficile toxoid vaccine was used in
  30 patients
• Concentrations of anti-toxin A IgG in the sera
  exceeded the concentrations (50-fold higher) that
  were associated with protection in previous
  clinical studies
• It may be feasible to use a vaccine to protect
  high-risk patients against C difficile-associated
  diarrhea
• Aboudola et al. Infect Immun 2003 71 1608-10

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C Difficile NAP1/027 (toxinotype III)

• Epidemic strain of C difficile
• First noted in Quebec, Canada
• Reported cases in US, UK, and Netherlands as well
• Produce 16x more A toxin and 23x more B toxin
  than control strains
• Role of binary toxin unclear
• Warny et al. Lancet 2005 366 1079-84

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Case Two
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79 year old male

• 3 weeks of fevers and chills
• Night sweats
• Dry cough
• Chronic low back pain that has worsened over the
  past three months

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79 year old male

• PMHx
• HTN
• BPH
• Anxiety
• Depression
• Chronic low back pain

• PSHx
• None

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79 year old male

• Medications
• HCTZ
• Lisinopril
• Clonazepam
• Oxycodone
• Docusate
• Celexa (citalopram)

• Allergies
• ASA

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79 year old male

• Social History
• Remote hx of smoking
• No ETOH abuse
• No IVDA
• Worked as a machinist

• Family History
• No Hx of chronic illnesses

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Physical Examination

• Temp 101
• III/VI SEM with radiation to the neck
• Crackles at the right base
• Tenderness to palpation at the lumbar spine

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Labs/Radiology

• WBC7.3
• UA negative
• CXRno acute process
• CRP7.34
• ESR29
• Lumbar CT with and without contrast
• L1-L2 osteomyelitis

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Blood Cultures and FNA

• Blood cultures
• 0.11 CFU/mL GPR at 4 days on media X
• 0.20 CFU/mL GPR at 4 days on media BC
• FNA of lumbar disc
• GPR

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Any thoughts?
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Blood Cultures and FNA

• Blood cultures
• 0.11 CFU/mL GPR at 4 days on media X
• 0.20 CFU/mL GPR at 4 days on media BC
• FNA of lumbar disc
• GPR

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Microbiology and Echo

• Lactobacillus
• Special MICs
• Gatifloxacin 0.5
• Penicillin G 0.5
• Ceftriaxone 2
• Vancomycin 1
• Meropenem 0.5
• TTE
• Mild aortic stenosis
• No vegetations
• Patient refused TEE on several occasions

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Treatment

• Penicillin G 3 million units IV q 4 hours
• Gentamicin 1mg/kg IV daily

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Lactobacillus

• Gram positive rod-shaped bacterium
• Common inhabitant of the human mouth, GI tract,
  and female genital tract
• Probiotic
• Diarrhea
• Candidal vaginitis

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Lactobacillus

• What is the significance of Lactobacillus
  isolated from sterile site?

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LACTOBACILLUS

• Clinical significance of Lactobacillus isolated
  from sterile sites is subject of ongoing debate
• Should never be dismissed as a contaminate
• Sometimes a contaminate
• Despite the differing views, Lactobacillus has
  been implicated in various types of infections

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Pathogenic Relevance of Lactobacillus

• Cannon et al. Eur J Clin Microbiol Infect Dis
  (2005) 24 31-40
• Medline SearchLactobacillus
• Case reports of Lactobacillus-associated
  infections reported between 1950 and July 1,
  2005
• Cases were included if they contained at lease
  three of the following
• Patient age
• Patient gender
• Patient comorbidity
• Type of Lactobacillus infection
• Source of Lactobacillus isolate
• Species of Lactobacillus recovered
• Antimicrobial sensitivity of the isolate
• Concomitant organisms identified
• Treatment regimen/duration
• Overall mortality
• Cases were organized into three categories
• Bacteremia
• Endocarditis
• Localized infections

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Results

• 92 manuscripts reviewed
• 241 cases identified
• Bacteremia 129
• Endocarditis 73
• Localized infection 39
• Pulmonary infection
• Abscess
• Peritonitis
• Chorioamnionitis
• Intra-abdominal infection
• Endophthalmitis
• Esophageal infection
• Erysipeloid infection
• Throat infection
• Meningitis
• Wound infection
• Vascular graft infection
• Fistula
• Majority of patients were male (53.1)

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Antimicrobial Sensitivity

• Most sensitive to erythromycin (94.3) and
  clindamycin (90.9)
• Differences in antimicrobial sensitivity
  according to the site of infection
• Bacteremic infections were less sensitive to
  ciprofloxacin (P0.010)
• Endocarditis infections were less sensitive to
  gentamicin (P0.002)
• Resistance to vancomycin was high (77.5)
• Isolates sensitive to vancomycin were either
  acidophilus or not speciated

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Antibiotic Regimens

• Most common regimens
• Penicillin monotherapy (n35)
• Penicillin and aminoglycoside (n20)
• Cephalosporin monotherapy (n16)
• Average duration of therapy was 25 days

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Outcome

• Overall mortality was 29.1
• Mortality was not associated with the type of
  infection (P0.418)
• Of those who were adequately treated, 13.2 died
• Of those who were inadequately treated, 31.8
  died
• Significant association between mortality and the
  presence of a polymicrobial infection
• 43.5 of patients with polymicrobial infection
  died versus 23.0 of patients without
  polymicrobial

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Recommendations

• Most experts agree that treatment should consist
  of high-dose IV penicillin (25 million
  units/day) and an aminoglycoside for synergy
• Based on in vivo data obtained in the early 1970s
  from treating a small number of patients with
  Lactobacillus endocarditis
• Axelrod et al. Annals of Internal Medicine 78
  33-37, 1973

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Literature ReviewCannon et al. Eur J Clin
Microbiol Infect Dis (2005) 24 31-40

• Only 20 patients (8) in the literature review
  were treated with IV Penicillin and gentamicin
• Overall sensitivity data suggest that ampicillin
  plus gentamicin may be a better choice
• Disappointing sensitivity data reported for
  penicillin, ampicillin, and gentamicin
• Due to the ability of lactobacilli to lower the
  pH of their environment via lactic acid
  production
• Large quantities of lactic acid can hinder the
  activity of aminoglycoside antibiotics
• Sussman et al. Rev Infect Dis 8 771-776
• B-lactam autolytic enzyme is less active at lower
  pH
• Kim et al. Infect Immun 26 582-585

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Literature ReviewCannon et al. Eur J Clin
Microbiol Infect Dis (2005) 24 31-40

• Erythromycin and clindamycin were found to be the
  most effective agents
• Most practitioners would be hesitant in using
  these antibiotics as first-line therapy for
  serious infections
• Only bacteriostatic
• Ciprofloxacin and other new fluoroquinolones may
  offer therapeutic alternatives
• Newer antibiotics, such as linezolid or
  daptomycin, may offer alternative treatment
  options

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Plan for Patient

• Penicillin G 3 million units IV q 4 hours
• Gentamicin 1mg/kg IV daily
• Duration of 6 weeks
• Weekly CBC and CMP
• Biweekly gentamicin level
• CRP/ESR in 4 weeks
• F/U with ID in 5 weeks