VANCOMYCIN, LINEZOLID, NITROFURANTOIN, AND METRONIDAZOLE

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VANCOMYCIN, LINEZOLID, NITROFURANTOIN, AND
METRONIDAZOLE

• Alan M. Stamm, M.D.
• astamm_at_uabmc.edu
• October 23, 2002

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Outline

• vancomycin (Vancocin)
• linezolid (Zyvox)
• quinupristin/dalfopristin (Synercid)
• nitrofurantoin (Macrodantin, Macrobid)
• metronidazole (Flagyl)
• topical antibacterials
• antiseptics

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VANCOMYCINMechanism of Action

• A glycopeptide.
• Interferes with cell wall synthesis complexes
  with D-alanine-D-alanine precursors and inhibits
  peptidoglycan polymerase.
• Bactericidal bacteriostatic versus enterococci.

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VANCOMYCINMechanism of Resistance

• Alteration of cell wall precursor decreased
  affinity, less effective competitive inhibition.
• e.g., VRE with Van A resistance
• cluster of gt7 genes encoding synthesis of
  peptidoglycan precursor
• production of pentapeptide ending with
• D-alanine-D-lactate
• No cross-resistance with beta-lactams.

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VANCOMYCINPharmacology

• Absorption poor orally usually administered
  intravenously by slow infusion.
• Half-life 6 hours.
• Serum levels desired peak at 1-2 hours
• 20-40 mcg/ml, and desired trough 5-10.
• Elimination primarily by glomerular filtration
  reduce dose and/or increase dosing interval if
  creatinine clearance lt100 ml/min not removed by
  hemodialysis.

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VANCOMYCINEfficacy

• A principal determinant is the proportion of time
  the vancomycin at the site of infection exceeds
  the minimal inhibitory concentration (MIC) of the
  pathogen, TgtMIC.
• Also has a postantibiotic effect continues to
  exert activity for 2 hours after level falls ltMIC.

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VANCOMYCINAdverse Effects

• Red-man syndrome tingling/pruritus, erythema of
  face, neck thorax hypotension too rapid
  infusion histamine release.
• Fever, chills, phlebitis at infusion site.
• Maculopapular or diffuse erythematous rash in
  4-5 hypersensitivity.
• Auditory nerve damage tinnitus, high-tone
  hearing loss, deafness dose-related.
• Selection of vancomycin resistant bacteria.

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VANCOMYCINSpectrum of Activity

• Gram-positive bacteria
• Streptococci
• including drug resistant S. pneumoniae
• Staphylococci
• including methicillin resistant S. epidermidis
  (MRSE) and S. aureus (MRSA)
• Enterococcus fecalis
• Clostridium difficile

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VANCOMYCINClinical Uses 1

• Meningitis
• ampicillin ceftriaxone vancomycin (loading
  maintenance doses) IV initially pending results
  of culture and susceptibility (C S) tests
• Nosocomial infections
• vancomycin piperacillin/tazobactam empirically
  pending results of C S

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VANCOMYCIN Clinical Uses 2

• Treatment of methicillin resistant staphylococcal
  disease
• e.g., bacteremia due to MRSE
• e.g., pneumonia due to MRSA
• Treatment of serious gram-positive disease with
  intolerance of beta-lactams.
• Prevention of surgical site infection
• e.g., 1 gm IV 1-2 hours before cardiac surgery

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LINEZOLIDMechanism of Action

• An oxazolidinone.
• Interferes with initiation of protein synthesis
  attaches to 50S ribosome.
• Bacteriostatic versus staphylococci and
  enterococci.

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LINEZOLIDMechanism of Resistance

• Mutation in the 23S rRNA gene.
• No cross-resistance with other protein synthesis
  inhibitors.

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LINEZOLID Pharmacology

• Absorption well orally available for PO and IV
  administration.
• Half-life 5 hours.
• Elimination slow nonenzymatic oxidation 30
  excreted unchanged in urine no dose adjustment
  with renal impairment.
• Postantibiotic effect 3-4 hours.

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LINEZOLIDAdverse Effects

• Diarrhea, nausea, tongue discoloration.
• Headache.
• Anemia, leukopenia, thrombocytopenia.

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LINEZOLIDSpectrum of Activity

• Gram-positive bacteria
• Streptococci
• including drug resistant S. pneumoniae
• Staphylococci
• including methicillin resistant S. epidermidis
  (MRSE) and S. aureus (MRSA)
• Enterococci
• including E. fecalis
• including vancomycin resistant E. faecium (VRE)

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LINEZOLID Clinical Uses

• Treatment of vancomycin resistant enterococcal
  (VRE) disease
• e.g., bacteremia with 600 mg IV/PO
• q 12 hours

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Quinupristin/Dalfopristin-1

• Streptogramins, derived from pristinamycins.
• Inhibit protein synthesis by irreversible binding
  to 50S ribosome resistance due to methylation of
  binding site.
• Bacteriostatic versus enterococci.
• Administered by slow infusion through central
  venous catheter.
• Eliminated by biliary excretion.

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Quinupristin/Dalfopristin-2

• Adverse effects pain and phlebitis at the
  injection site arthralgias myalgias
  hyperbilirubinemia nausea diarrhea.
• Active in vitro against a wide variety of
  gram-positive bacteria.
• except Enterococcus fecalis
• Used for treatment of vancomycin resistant
  Enterococcus faecium (VRE) disease
• e.g., bacteremia with 7.5 mg/kg IV q 8 hours

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NITROFURANTOINMechanism of Action

• A nitrofuran.
• Inhibits intracellular metabolism mechanism is
  ill defined activity may depend on a reduced
  derivative.
• Bactericidal.

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NITROFURANTOINPharmacology

• Absorption orally 40-50, enhanced by food.
• Serum levels low-undetectable.
• Elimination predominantly by glomerular
  filtration and tubular secretion do not
  prescribe with creatinine clearance lt40 ml/min.

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NITROFURANTOINAdverse Effects

• Nausea vomiting in 17.
• Rash in 1.
• Pulmonary hypersensitivity acute fever, cough,
  dyspnea, myalgias, eosinophilia, infiltrates.
• Pulmonary fibrosis insidious onset,
  nonproductive cough, dyspnea, interstitial
  infiltrates.
• Hemolytic anemia.
• Peripheral neuropathy.

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NITROFURANTOINSpectrum of Activity

• Urinary pathogens
• Escherichia coli
• Klebsiella pneumoniae
• Staphylococcus saprophyticus
• Enterococcus fecalis

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NITROFURANTOIN Clinical Uses

• Empiric treatment of uncomplicated cystitis
• e.g., Macrobid 100 mg PO bid x 7 days
• Prevention of recurrent urinary tract infection
• e.g., nitrofurantoin 100 mg PO q hs

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METRONIDAZOLEMechanism of Action

• A nitroimidazole.
• Intracellular reduction creates short-lived
  compounds or free radicals that produce damage by
  interaction with DNA or other macromolecules.
• Bactericidal.
• Resistance rarely develops.

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METRONIDAZOLEPharmacology

• Absorption rapid and complete orally also
  administered intravenously.
• Penetration excellent into all tissues.
• Half-life 8 hours.
• Elimination metabolized reduce dose by 50 in
  patients with significant hepatic disease no
  change in dose with renal impairment.

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METRONIDAZOLEAdverse Effects

• Nausea, diarrhea, metallic taste.
• Disulfiram-like reaction with alcohol.
• Dark or red-brown urine.
• Neutropenia.
• Maculopapular rash or urticaria.

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METRONIDAZOLESpectrum of Activity

• Anaerobic bacteria
• particularly gram-negative
• Helicobacter pylori.
• Gardnerella vaginalis.
• Trichomonas vaginalis.
• Giardia lamblia.

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METRONIDAZOLE Clinical Uses 1

• Treatment of anaerobic infections or the
  anaerobic portion of mixed infections.
• e.g., 1 g loading dose 500 mg IV q 6-8 hours x
  2-4 weeks along with other agent(s)
• Treatment of Clostridium difficile colitis.
• e.g., 500 mg PO q 8 hours x 10-14 days

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METRONIDAZOLE Clinical Uses 2

• Treatment of Helicobacter pylori gastro-duodenal
  disease.
• e.g., 500 mg PO bid x 10 days in combination with
  2-3 other agents
• Treatment of Trichomonas vaginitis.
• e.g., 500 mg PO bid x 7 days
• Treatment of bacterial vaginosis.
• e.g., 5 g of 0.75 gel intravaginally bid x 5
  days (or 500 mg PO bid x 7 days)

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Topical Antibacterial Agents

• Erythromycin ophthalmic ointment to treat
  bacterial conjunctivitis.
• Mupirocin (Bactroban) ointment to eliminate nasal
  carriage of S. aureus.
• Bacitracin-neomycin-polymixin B (Neosporin)
  ointment to prevent infection of minor cuts,
  scrapes, burns.
• Silver sulfadiazine (Silvadine) or mafenide
  (Sulfamylon) cream to prevent infection of burn
  wounds.

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Antiseptics

• Agents
• Alcohol
• Chlorhexidine
• Povidone-iodine
• Uses
• Hand disinfection between patient contacts
• Preparation of operative/procedure sites
• Surgical scrub

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Summary

• Vancomycin is a very important drug in the
  initial treatment of nosocomial infections and
  for the definitive therapy of MRSA disease.
• Linezolid is the drug of choice for treatment of
  VRE disease.
• Metronidazole is a key drug in the therapy of
  anaerobic bacterial disease.
• Antibiotic use leads to resistance be judicious.