Infectious Disease Case Conference

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Infectious Disease Case Conference

• Asif Zia, MD, MPH
• Wake Forest University
• April 19th, 2004

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Case 1

• 53 year old WM transferred from OSH for acute
  respiratory distress.
• Had been having increased dyspnea for 3-4 days
  prior to admission.
• Had been given levaquin for a pneumonia and
  depo-medorol 80 mg for COPD by his PCP 2 days
  prior to admission.

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History

• Initially started on Moxifloxacin, but continued
  to spike fevers, and became hypotensive,
  requiring Levophed.
• ID consult called on day 2 of admission.
• PMHx Morbid Obese, COPD on home O2, CHF,
  Tracheostomy, DM, Periph vasc dx with stasis
  ulcers, and s/p removal of all toes bilaterally,
  Hypothyroid, WPW, Sz d/o and chronic renal
  insufficiency.

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History 2

• Meds Tegretol, Lipitor, Toprol XL, Protonix,
  ASA, Prednisone 10mg qd.
• ALL PCN
• FHx Pos for DM and HTN
• SHx History of smoking, no ETOH use, married,
  disabled.

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Physical Exam

• Obese male, intubated
• T-102, P-121, BP 82/44 (on levophed)
• LUNGS Decreased AE, with bilateral wheezes and
  ronchi.
• CVS HS are S1, S2, RRR.
• ABD Obese, soft, NT, BS positive.
• EXT Scrotal erythema, with venous stasis ulcers
  on both feet.

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Hospital Course

• CXR showed bilateral pulmonary infiltrates
  suggestive of ARDS.
• Started aztreonam, along with clindamycin and
  vancomycin.
• Diagnosis was septic shock with concern for Toxic
  Shock Syndrome.
• Was given activated protein C.

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Hospital Course - 2

• Continued to remain critically ill and ventilator
  dependent.
• Was also started on CVVHD and required pressors.
• Initial culture of tracheal aspirate grew
  Pseudomonas aeruginosa
• sensitive to gentamicin, amikacin, meropenem
  cefepime
• Also grew MRSA from tracheal aspirate.

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Hospital Course - 3

• Aztreonam stopped, and meropenem and amikacin
  started.
• 5 days later, repeat tracheal aspirate was still
  growing Pseudomonas.
• Blood cultures and a TLC tip also grew..

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Hospital Course - 4

• Continued on the same antibiotics.
• Remained critically ill with ARDS like picture on
  CXR.
• 6 days later, repeat tracheal aspirate was still
  growing P aeruginosa, and now also the
  Acinetobacter.

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Question!

• How should this patient be treated?

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Multiresistant Acinetobacter Infections
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Acinetobacter Infections

• Microbiology.
• Epidemiology.
• Clinical features.
• Treatment strategies.

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Microbiology

• Gram negative cocci to medium rods of the
  Neisseriacae family.
• Aerobic, encapsulated and non-motile.
• Other members of this family include Neisseria,
  Moraxella, and Kingella.
• Acinetobacter has had multiple names in the past
  Micrococcus, Mimae, Anitratus and Achromobacter.

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Microbiology-2

• Acinetobacter was first used in the 1970s
  means motionless.
• In 1984, oxidase activity was used to distinguish
  Moraxella (positive) from Acinetobacter
  (negative).
• Based on DNA hybridization, there are 19
  different strains.
• A. baumanii is the most frequent clinical isolate.

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Epidemiology

• Acinetobacter can be found everywhere -
• Pasteurized milk.
• Frozen foods.
• Hospital air.
• Angiography catheters.
• Bedside urinals.
• Hospital pillows.
• Sink basins.
• Duodenoscopes.

• Differs from other Neisseriaceae by the
  simplicity of its growth requirements.
• 100 of soil and water samples.
• Up to 25 of healthy adults exhibit skin
  colonization.
• Colonize up to 45 of tracheostomy sites.

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Epidemiology - 2

• Can be grown from various human sources sputum,
  urine, feces and vaginal secretions.
• Prevalence has increased worldwide in the past
  two decades.
• In 1997, CDC reported 2 of BSI, and 6 of ICU
  pneumonias as due to Acinetobacter.

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Risk Factors

• Community Acquired
• Alcoholism.
• Smoking.
• Chronic lung dx.
• Diabetes.
• Residence in a developing country
• Koelman et al J Hosp Infec 199737113-123

• Nosocomial
• Length of hospital stay
• Surgery.
• Wounds.
• Previous infection.
• Fecal colonization.
• Broad spectrum abx.
• Parenteral nutrition.
• Burn unit/ ICU.

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Clinical Manifestations

• Limited role without disruption of normal host
  defenses.
• Can cause suppurative infection in virtually
  every organ system.
• Significance of isolates can be difficult because
  of wide prevalence in the atmosphere.
• A baumanii make up 80 of all clinical isolates.

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Clinical Manifestations - 2

• Pneumonia
• Often ICU setting, VAP, Mortality 70.
• Indicates patients poor condition.
• 10 of CAP in tropical countries (mortality
  40-60).
• Bacteremia
• Distinguish from pseudobacteremia (Improper
  tech).
• Associated with resp infections and IV catheters.
• Septic shock in 30, with mortality upto 46.
• Species other than A. baumanii less severe.
• Very rare cause of endocarditis.

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Clinical Manifestations - 3

• Genitourinary
• Rarely invasive, cystitis and pyelonephritis have
  been documented.
• Intracranial Infection
• Meningitis can occur.
• Can be morphologically confused with N.
  meningitidis (on gram stain).
• Soft Tissue
• Can cause cellulitis in association with trauma
  and IV catheters.
• Most common gram negative bacilli in traumatic
  wounds in Vietnam.

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Treatment Strategies

• A. baumanii has a propensity for rapidly
  developing resistance.
• Mechanisms for resistance are
• Production of extended spectrum beta lactamase.
• Aminoglycoside modifying enzymes.
• Changes in outer membrane porins (permeability is
  3 of E.coli).
• Alterations in protein binding proteins (PBP).
• Resistance is growing. In 1991 in Spain, 100
  susceptible to imipenem. In 2000 only 50 were
  susceptible.
• 
  Cisneros et al, clin micro and inf
  811 Nov 2002

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Treatment Strategies - 2

• Role of sulbactam combinations.
• Role of IV colistimethate.
• Role of synergistic rifampin.

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Sulbactam Combination

• Production of ESBL is one mechanism of
  resistance.
• ß-lactamase inhibitors can help in overcoming
  this resistance.
• Sulbactam also has direct antimicrobial activity
  against A. baumanii.
• Animal models have shown it to be as efficacious
  as imipenem.
• Rodriguez-Hernandez et al, J antimicrob chemother
  2001, Apr, 47(4) 479-82

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Sulbactam Combinations - 2

• Excellent review by A.S Levin in Clin Microbiol
  Infect 2002 8 144-153.
• Reviewed different studies that looked at
  ampicillin-sulbactam, and cefoperazone-sulbactam
  combinations.
• ampicillin-sulbactam appears to be more effective
  than other combinations.

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Sulbactam Combinations - 3

• Several studies have demonstrated excellent
  efficacy in treating MDR strains with sulbactam
  combinations.
• Corbella et al in J Antimicrob Chemother 1998
  42 793-802 compared sulbactam alone with
  amp-sulb in treatment on non life threatening
  MDRAB.

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Sulbactam Combinations - 4

• Similar cure or improved rates in the two groups.
• Killing curves showed sulbactam to be
  bacteriostatic.
• Demonstrates activity of sulbactam alone.
• Would amp-sulbactam, or sulbactam alone, be
  effective in combination with another drug even
  if the strain was resistant to it?

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Colistimethate Sodium

• Colistimethate (polymixin E) was discovered in
  1947.
• Structurally similar to polymixin B.
• Produced by Aerobacillus colistinus a spore
  forming bacteria.
• Use of this agent had been abandoned until
  recently because of its toxicity.

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Colistimethate Sodium - 2

• Mechanism of action is not clear.
• Appears to have a detergent effect on the cell
  membrane, causing disruption and lysis of the
  bacteria.
• Excellent in vitro activity against a variety of
  gram negative rods E. Coli, Klebsiella,
  Salmonella, Pasturella, Bordatella, Shigella, and
  Pseudomonas.

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Colistimethate Sodium - 3

• Not effective against Serratia, Proteus
  Providencia or Neisseria.
• Study done by Levin, A.S. et al in CID 1999
  281008-11.
• Looked at 60 ICU patients with MDR P
  aeruginosa and A baumanii, and treated with
  colistimethate.

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Colistimethate Sodium - 4
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Colistimethate Sodium - 5

• The worst outcomes were in the pneumonia patients
  (25 improved).
• Not clear why, although there may be binding with
  surfactant.
• CNS infections had a good outcome (80) despite
  poor penetrability of the blood brain barrier.
• Overall, 58 had a good outcome.

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Colistimethate Sodium - 6

• Toxicity is important, particularly
  nephrotoxicity renal tubular necrosis.
• More severe in patients with pre-existing renal
  insufficiency.
• Neurotoxicity and neuromuscular blockade have
  also been reported.
• Not noticed in this study because many patients
  were intubated.

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Colistimethate Sodium - 7

• Other side effects include
• Paresthesias.
• Numbness.
• Pruritus.
• Vertigo.
• Dizziness.
• Apnea.
• Fever.
• Slurred speech.

• In the Levin study, no patient needed
  discontinuation due to side effects.
• Elimination is primarily renal. Not known if it
  can be removed by hemodialysis.

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Colistimethate Sodium - 8

• Dosing is as follows
• 2.5 5 mg/kg/day in 2 4 divided doses.
• In impaired renal function.

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Colistimethate Sodium - 9

• In summary, colistimethate should be reserved for
  patients with serious infections caused by MDR
  gram negatives
• Monitor closely for neurotoxicity and
  nephrotoxicity.
• Pneumonia patients have the poorest response.

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Synergistic Rifampin

• Giamarellos-Bourboulis et al in Diagnostic
  Microbiol and Infect Dis 40 (2001) 117-120.
• In vitro study whereby MICs to colistin,
  rifampin and combination of the two were tested.

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Synergistic Rifampin -2
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Synergistic Rifampin - 3

• However this is an in-vitro situation, and this
  may be different in-vivo.
• In-vivo study on mice pneumonia done by Wolff et
  al in Antimicrob Agents Chemoth 199, Jun 43(6)
  1406-11.
• Rifampin is synergistic with Imipenem and
  Amp-Sulbactam

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Conclusion

• MDR Acinetobacter infections becoming an
  increasing problem.
• Often an indication of poor condition of patient.
• Strategies include use of colistimethate.
• amp-sulbactam combination often effective.
• Can also use rifampin for synergy.