Infectious Disease Case Conference

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Infectious Disease Case Conference

• Asif Zia MD, MPH
• October 11th, 2004

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Case 1

• 87 year WF with ESRD is admitted to the renal
  service with recurrent diarrhea.
• Was diagnosed with C. difficile colitis about 2
  months ago.
• Has received a 14 day course of metronidazole,
  followed by a 14 day course of PO vancomycin.
• What synergistic antibiotic combinations can be
  used in this patient?

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Case 2

• 89 year old white male recently underwent a total
  hip replacement.
• Presented one week later with infection of the
  prosthetic joint.
• Cultures are growing MRSA.
• What is an integral antibiotic in the
  combinations that can be used?

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Case 3

• 68 year old WF develops sepsis after extensive
  abdominal surgery.
• After a prolonged ICU stay, she develops
  acinetobacter sepsis with an MDR strain.
• It is resistant to all antibiotics with an MIC
  of 16 (I) to polymixin B.
• What are potential synergistic antibiotic
  combinations that can be used in this patient.

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Case 4

• A 38 year old WM is admitted with symptoms of
  meningitis.
• His cultures are positive for N. meningitidis.
• His wife asks you about prophylaxis for his 5
  year old son.
• What would you use?

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Questions?

• When was rifampin first discovered?
• 1947
• 1957
• 1967
• When was rifampin introduced to clinical use in
  the US?
• 1962
• 1968
• 1972

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Questions?

• When was rifampin first discovered?
• 1947
• 1957
• 1967
• When was rifampin introduced to clinical use in
  the US?
• 1962
• 1968
• 1972

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Rifampin

• In 1957, a new class of antibiotics called
  rifamycins was recognized at Lepetit laboratories
  in Italy.
• Isolated from Nocardia mediterranei.
• Formulations were introduced in 1963, but were
  too rapidly excreted by the liver.
• Rifampin with a longer half life was introduced
  in 1965, and in the US market in 1968.

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Mechanism of Action

• Based on inhibition of DNA-dependent RNA
  polymerase in bacteria and mycobacteria.
• RNA polymerase is the enzyme responsible for DNA
  transcription.
• Resistant strains possess an altered RNA
  polymerase.

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Mechanism of Action 2

• Mammalian cells also contain RNA polymerase.
• Mammalian polymerase is probably sensitive to
  rifampin.
• However, intact mammalian cell mitochondria are
  impermeable to rifampin.
• Thus, rifampin is selectively toxic to bacteria.

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Mechanism of Action 3

• RNA polymerase in gram negative, and gram
  positive bacteria are similarly sensitive to
  rifampin.
• However MICs for the gram negative bacteria are
  higher because of reduced penetration of rifampin
  through their outer cell membranes.
• Rifampin stops bacterial growth, and this may be
  a reason for antagonism at low concentrations
  (in-vitro) with antibiotics that act on growing
  bacteria.

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Mechanism of Action 4

• Rifampin also stops fungal RNA synthesis,
  provided the drug is used with amphotericin B.
• This is because ampho-B acts on the fungal cell
  wall and helps cell permeability of rifampin.
• The anti fungal action of rifampin may be due to
  its action of inhibition of ribosomal RNA rather
  than inhibition of fungal RNA polymerase.

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Question?

• Which of the following species are resistant to
  Rifampin.
• Clostridium spp
• Rhodococcus equi
• Nocardia brasiliensis
• Listeria monocytogenes
• Bacillus anthracis
• Pasturella multocida

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Question?

• Which of the following is sensitive to Rifampin?
• E. Coli
• Enterobacter spp
• Legionella pneumophilia
• Mycobacterium fortuitum
• Salmonella spp
• Campylobacter

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Question?

• Rifampin may be useful in the following
• Primary biliary cirrhosis.
• Henoch Schönlein purpura.
• Rheumatoid arthritis.
• Crohns disease
• AML
• Rabies
• All of the above
• None of the above

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Sensitive organisms

• Gram positive cocci
• Highly active against staph aureus, and CoNS,
  including MR strains.
• Rifampin resistance can easily arise, and it
  should only be used in combination.
• Most streptococci are also sensitive.
• Enterococcus fecalis is only moderately
  susceptible.

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Gram positive bacilli

• Listeria monocytogenes and Rhodococcus equi are
  very sensitive.
• Nocardia are nearly always resistant, and
  Nocardia brasiliensis can inactivate rifampin.
• Clostridium spp are usually sensitive.

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Gram Negative Cocci

• Meningococci are are highly sensitive to
  rifampin.
• N. gonnorrhea is highly sensitive.
• H. influenzae and H. ducrei are usually
  sensitive.
• Bordatella pertussis is usually sensitive.
• Pasturella multocida and anaerobes such as B.
  fargilis are usually sensitive.

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Gram Negative Cocci

• Enterobactericae such as E.coli, Enterobacter,
  Klebsiella, Proteus, Providencia and Citrobacter
  are resistant.
• Other sensitive spp include
• Brucella spp
• Flavobacteria spp
• Legionella (L. pneumophilia highly sensitive)
• Campylobacter, H.pylori and Francisella
  tularensis.

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Mycobacteria

• Highly active against M. tuberculosis.
• Rate of development of resistance is low.
• Usually due to rpo B gene which alters the RNA
  polymerase.
• M. leprae is also very sensitive to rifampin.
• Many atypical mycobacterium are sensitive.
• Resistant are M. fortuitum, M. chelonae, M.
  simiae, and M. ulcerans (however combinations
  have been used in buruli ulcer with mixed
  results).

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Other Agents

• Active against
• Chlamydia.
• Rickettsiae.
• Ehrlichia.
• Naegleria.
• Leishmania.
• Malaria (some activity against P. vivax, but not
  enough for cure).
• One mouse study showed improved survival in
  rabies (83.4 Vs 25) Anne B. Morris et al
  Antimicrob agents and Chemo Jan 193, 1-7

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Non-Infectious Disease

• Thought to have an immuno-modulatory effect. Has
  been used in
• Reducing itching in primary biliary cirrhosis.
• Henoch-schönlein purpura.
• Improvement noticed in Rheumatoid arthritis.
• Ocular manifestations of Crohns disease found to
  be improved in one study.
• One study showed a delay in relapse of AML in
  patients who received rifampin.
• Anne B. Morris et al Antimicrob agents and Chemo
  Jan 193, 1-7

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Side Effects

• Usually well tolerated. Side effects can occur
  with continuous or intermittent therapy.
• Hypersensitivity reaction
• Early in treatment, flushing and itching of the
  skin with or without a rash.
• Symptoms 2 3 hours after a dose. Self limiting,
  and only symptomatic treatment.
• GI side effects such as nausea, vomiting,
  abdominal pain and diarrhea can occur. Improved
  by taking it with a meal.

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Side Effects

• Hepatotoxicity
• Hepatitis can occur in up to 1 of patients.
  Stopping the drug usually helps. Can be
  re-started after the liver recovers.
• Thrombocytopenia
• With purpura can occur with intermittent therapy.
  Stopping rifampin allows the counts to return to
  normal in 36 hours.

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Side Effects

• Renal Failure
• Sudden onset of fever and lumbar pain, followed
  by oliguria, then anuria has been described. Most
  of these patients had discontinued therapy, and
  then re-started. This damage is reversible.
• Influenza syndrome
• A flu like illness can occur with intermittent
  therapy. Does not happen in continuous therapy,
  so patients should be switched to daily therapy.

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Topics of Discussion

• Use of rifampin in biofilms and prosthetic
  devices.
• Synergistic combinations with rifampin.

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Prosthetic Devices

• Rifampin has become an indispensable part of
  regimens to treat staphylococcal infections with
  prosthetic devices.
• Zimmerli et al demonstrated the ability of cipro
  rifampin combination to actually cure early
  prosthetic joint infections.
• JAMA, May 20, 998-Vol 279, No 19

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Biofilms (Slime)

• Biofilms are sessile microbial communities
  embedded in a self produced extracellular
  polymeric matrix.
• Biofilm associated bacteria show an innate
  resistance to antibiotics, disinfectants and
  clearance by host defenses.
• There are two stages to its development.

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Biofilms

• 1st stage
• Attachment of cells to a surface. Mediated by
  cell wall associated adhesins.
• 2nd stage
• Cell multiplication and formation of a mature
  structure consisting of many cell layers. This
  stage is also associated with the production of
  polysaccharide intercellular adhesin component of
  the extra cellular matrix.

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Quorum Sensing

• Bacteria can produce and sense molecules that
  signal a whole population to a concerted action.
• This intercellular signaling is often referred to
  as quorum sensing.
• Shown to be involved in the development of
  biofilms by several bacteria.
• Different bacteria have different quorum sensing
  mechanisms.
• S. aureus quorum sensing is encoded by the
  accessory gene regulator (agr) locus.
• Yarwood et al J of Bacteriology Mar 2004,
  p1838-50

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Biofilms
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Biofilms
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Kombucha Tea
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Rifampin and Slime

• Maria Souli and Helen Giamarellou did an in-vitro
  study to see the effects of CoNS slime on
  different antibiotics.
• Slime containing bacteria were incubated with
  different antibiotics.
• Rifampin was the only drug whose actions were not
  inhibited by slime.
• Antimicrob agents and chemo, Apr 1998, p 939-941

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Rifampin and Slime

• There is no clear explanation as to this effect
  of rifampin.
• There is no correlation with molecular weights or
  the hydrophobicities or the charges of the
  antibiotic molecules.
• Slime also had only minimal influence on the
  activity of macrolides and clindamycin.
• Antimicrob agents and chemo, Apr 1998, p 939-941

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Rifampin and Slime

• Zimmerli and Blaser did a similar study in 1998
  on S. epidermidis.
• Compared 2 strains with different adherence
  capabilities in-vitro and in animals.
• Compared amikacin, levofloxacin, rifampin and
  teicoplanin.
• Rifampin was more effective than the others in
  the adherent strain.
• Antimicrob agents and chemo, Apr 1998, p 895-898

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Synergistic Combinations

• Jensen in 1968 first used fusidic acid and
  novobiocin with rifampin to treat 38 patients
  with staphylococcal infection.
• It was recognized early on that rifampin used
  alone risked development of resistance.
• Early studies showed synergy with novobiocin,
  TMP-SMX and tetracycline in gram negative
  organisms.
• J of antimicrob chemo (1977)3, 19-114

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Synergistic Combinations

• Staphylococcal Infections
• Rifampin has been shown to be synergistic with
  minocycline.
• Also synergistic with oxacillin.
• Zimmerli et al have reported use with quinolones
  such as cipro.
• Vancomycin along with rifampin is a common
  regimen, particularly in the presence of
  prosthetic devices.

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Synergistic Combinations

• Staphylococcal Infections - 2
• Studies in Greece have also shown synergy of
  rifampin with quinopristin-dalfopristin.
• These are also in-vitro studies.
• J Antimicrob Chemother. 1998 Mar41(3)349-55.
• A rabbit model for endocarditis was used to look
  at linezolid synergy with rifampin.
• No synergy was observed.
• Antimicrob Agents Chemother. 2003
  Aug47(8)2655-8.

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Synergistic Combinations

• Enterococci
• In-vitro studies were done with daptomycin and
  rifampin against VRE.
• Synergy was observed in this study.
• Journal of Antimicrobial Chemotherapy (2004) 53,
  530532
• Pseudomonas and Stenotrophomonas
• Synergy of colistin has been observed with
  rifampin in in-vitro studies in Greece.
• J Chemother. 2003 Jun15(3)235-8.
• Diagn Microbiol Infect Dis. 2002
  Nov44(3)259-63.

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Synergistic Combinations

• Acinetobacter
• Synergy has been demonstrated in-vitro with
  polymixin B and rifampin.
• Antimicrob Agents Chemother. 2004
  Mar48(3)753-7.
• In mouse studies, synergy has also been
  demonstrated with colistin and rifampin.
• Antimicrob Agents Chemother. 2002
  Jun46(6)1946-52.

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Synergistic Combinations

• Brucellosis
• Rifampin has been found to be synergistic with
  aminoglycosides and TMP-SMX. Also synergistic
  with tetracycline, but not doxycycline.
• Meningococcal Infections
• Not of any value in treatment, but has been used
  as chemoprophylaxis. One place where it can be
  used on its own.

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Synergistic Combinations

• Rhodococcus Equi
• Erythromycin has been used in combination with
  rifampin.
• Naegleria Fowleri
• Rifampin in various combinations with
  amphotericin B, miconazole and tetracycline have
  been used.

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Synergistic Combinations

• Fungi
• Synergy has been described in-vitro between
  ampho- B and rifampin in Saccharomyces cerevisae,
  Histoplasma capsulatum and Aspergillus spp.
• Medoff, G. 1983 Rev Infect. Dis 5S614-S619
• Mouse studies have indicated synergy with ampho-B
  in Candida and Blastomyces dermatidis.

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Synergistic Combinations

• Fungi-2
• Case reports have suggested synergy of
  fluocytosine with rifampin in aspergillus.
• Anne B. Morris et al Antimicrob agents and Chemo
  Jan 1993, 1-7
• More recently an in-vitro study indicated synergy
  or an additive effect of ampho-B and rifampin in
  zygomycosis.
• Eric Dannaoui et al Antimicrob agents and
  Chemo Aug 2002, p 2708-2711

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Synergistic Combinations

• Zygomycetes
• These are very aggressive infections with very
  high mortality.
• Eric Dannoui et al did an in-vitro study from the
  Netherlands looking at flucytosine, amphotericin
  B and Rifampin.
• There was a synergistic or additive effect
  between amphotericin B and rifampin, but not with
  flucytosine.
• Eric Dannaoui et al Antimicrob agents and Chemo
  Aug 2002, p 2708-2711

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Synergistic Combinations

• Mycobacterium Ulcerans
• Cause of Buruli ulcer, also known as tropical
  ulcer.
• Usually in Africa (Buruli district in Uganda).
• Debridement is the mainstay of therapy.
• This is usually resistant.
• However synergy was shown of a fluoroquinolone
  (sitafloxacin) with rifampin in the post surgical
  treatment of this debilitating disease.
• Dhople and Namba J of antimicrob chemo (2002)50,
  77-729

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Synergistic Combinations

• Pneumococci
• Rifampin has actually been found to be
  antagonistic in combinations with levofloxacin
  and ceftriaxone.
• Studies done in South Africa and Texas in 1995
  1996 reported these findings.
• Thus rifampin is not indicated in the treatment
  of resistant pneumococci

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Conclusion

• Rifampin is a drug with a unique mechanism of
  action, and a broad spectrum of activity.
• It is bacteriostatic and should usually be used
  in combination with other drugs.
• It has demonstrated synergy with a wide variety
  of antibiotics in different clinical situations.