Antimicrobials Making sense of them

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Antimicrobials Making sense of them

• W. Sligl
• Infectious Diseases/Critical Care

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Outline

• General considerations when prescribing
  antimicrobials
• Review of antibacterial classes
• Mechanisms of resistance

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Empiric Therapy

• Initiation of treatment for a clinical syndrome
  before the specific microbiology known
• Best guess
• Requires some understanding of infectious disease
  epidemiology

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Case Examples

• Case 1 17 yo M, previously healthy, with 2 day
  hx of fever, sore throat, cough.
• Diagnostic possibilities?
• Can he wait or should be be treated?
• What would you treat him with?
• Case 2 17 yo M with advanced HIV and 2 day hx
  of fever, sore throat, cough.
• Diagnostic possibilities?
• Can he wait or should he be treated?
• What should he be treated with?

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Factors to Consider when Prescribing
Antimicrobials

• Host Factors
• Microbial Factors
• Antimicrobial Factors

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Host Factors

• Age
• Immune adequacy
• Underlying diseases
• Renal/hepatic impairment
• Presence of prosthetic materials
• Ethnicity
• Pregnancy/nursing

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Age

• Can help to narrow the diagnosis with certain
  infections
• Examples
• Meningitis
• What bugs would you consider in a neonate? In an
  adult?
• EBV infection
• In what age group would you consider this
  diagnosis?
• UTI
• How does age affect your interpretation of
  laboratory results?

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Immune Adequacy

• Immune status important
• May be at increased risk of specific infections
• Asplenia
• Encapsulated bacterial infections
• HIV/AIDS
• Opportunistic infections
• Transplantation
• Variety of infections depending on net degree of
  immunosuppression

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Underlying Diseases

• Increased risk of infection in pts with
• Diabetes mellitus
• HIV/AIDS
• Malignancies
• Renal impairment
• Autoimmune diseases

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Renal/Hepatic Impairment

• Implications for treatment
• Dose adjustments may be needed
• Avoid concomitant nephro- or hepato-toxic drugs
• May require fluid boluses prior to administration
• E.g. amphotericin B, acyclovir
• Implications for monitoring
• Monitor renal/liver function
• Consider monitoring drug levels if available
  (i.e. therapeutic drug monitoring TDM)

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Presence of Prostheses

• Implications for diagnosis
• What bug(s) are more pathogenic in artificial
  joints/valves?
• Implications for treatment
• Infected hardware needs to be removed
  antibiotics alone dont usually work
• May add rifampin in certain situations (biofilm
  penetration)

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Ethnicity

• Consider diseases endemic in country of origin
• Examples
• TB in patients from TB endemic areas as well as
  First Nations patients
• Strongyloides in patients from tropical countries
• Also consider malaria, trypanosomiasis,
  leptospirosis, leishmaniasis, leprosy

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Geographic Factors

• Need to know common microbial causes of infection
  in your area
• Example Recent emergence of CA-MRSA in
  outpatient skin and skin structure infections
• Travel history is important
• Example Fever in traveler returning from Sudan
  vs. person who has never left Edmonton

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Pregnancy and Nursing

• Safety of antibiotic use in pregnancy and nursing
  has to be considered
• Generally SAFE
• Beta-lactams
• Macrolides
• Clindamycin
• Conventional dosing AG
• NOT SAFE
• Fluoroquinolones
• TMP/SMX
• Extended interval AG
• Tetracyclines

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Microbial Factors

• Probable microorganisms
• Microbial susceptibility patterns
• Natural history of infections
• Likelihood of obtaining microbiologic data
• Site of Infection

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Probable Microorganisms

• Have to know most likely organisms for various
  common infections
• CAP, HAP, VAP
• Intra-abdominal infections
• Catheter-related UTIs
• Line infections
• Endocarditis
• Meningitis

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Microbial Susceptibilities

• Know general microbial susceptibilities as well
  as those which are geographically specific
• S. pneumoniae
• 15 resistant to erythromycin, 3 to penicillin
• P. aeruginosa
• 30-40 resistant to ciprofloxacin
• Higher in ICU pts 50-70
• MRSA
• MRSA made up 6 of S. aureus isolates in Capital
  Health Region 2005
• Huge increase in 2007-2008 up to 50 of isolates
  in OPAT setting (CA-MRSA)
• Vs. up to 70 in some US centers
• Know your local epidemiology!
• And dont forget to ask about recent Abx use!

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Natural History of Infection

• Rapidly fatal vs. slow growing
• Meningococcemia can be rapidly fatal
• TB meningitis often more indolent course
• Know what to expect
• Pyelonephritis expect fever for up to 72 hours,
  image if still febrile after 72 hours to r/o
  perinephric abscess

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Likelihood of Obtaining Microbiologic Data

• May be difficult to get specimen(s)
• E.g. brain abscess
• If patient has been on antibiotics, will affect
  culture results
• May need to treat empirically, and follow
  clinical response/imaging

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Site of Infection

• Susceptibility testing is geared to attainable
  serum levels
• Does not account for host factors or conditions
  that alter antimicrobial access
• Diffusion into CSF is limited in many drugs
• Abscesses
• Difficult to penetrate abscess wall
• High bacterial burden
• Low pH and low oxygen tension can affect
  antimicrobial activity

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Antimicrobial Factors

• Route of Administration
• Bactericidal vs. bacteristatic
• Combination vs. monotherapy

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Route of Administration

• Many options exist
• Enteral
• Parenteral
• Nebulization
• Intrathecal
• Topical

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Enteral Administration

• Check drug oral bioavailability
• Must be resistant to breakdown by gastric acid
• Some drugs must be given with buffer
• Some require acidity for absorption
• Other drugs cannot be given in high enough doses
  orally (usually d/t side effects/intolerance)

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Bactericidal vs. Bacteristatic

• Antibiotics work by either killing (cidal) vs.
  halting growth (static) of micro-organisms
• Cidal beta-lactams, aminoglycosides,
  fluoroquinolones, glycopeptides, daptomycin,
  metronidazole
• Static tetracyclines, macrolides, clindamycin,
  linezolid

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Combination Therapy

• Three main reasons
• Broader coverage
• May be necessary for empiric treatment of certain
  infections
• E.g. intra-abdominal sepsis, VAP
• Synergistic activity
• E.g. amp gent for serious enterococcal
  infections
• Prevent resistance
• E.g. TB, pseudomonal infection
• Disadvantages
• Antagonism (e.g. linezolid and vancomycin)
• Potential for increased toxicity

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Adjunctive Approaches

• Dont forget to do all the other stuff
• Septic shock EGDT, steroids, rhAPC
• Bacterial meningitis steroids
• Benefit in S. pneumoniae in adults and H.
  influenzae in children
• Drainage and debridement of abscesses
• Removal of prosthetic materials
• Correction of malnutrition
• Assisted organ function
• Mechanical ventilation, CRRT/IHD, hemodynamic
  support with inotropes/vasopressors

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Monitoring Response to Therapy

• Monitor infectious parameters
• Fever
• WBC
• ESR etc.
• Know natural history
• Serial imaging may be useful
• Repeat cultures
• E.g. bacteremia, endocarditis

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Duration of Therapy

• Very few studies to establish minimum durations
  of therapy
• Duration usually based on anecdote
• Most uncomplicated bacterial infections should be
  treated for 714 days
• 10-14 days bacteremia
• 4-6 weeks endocarditis, empyema, septic
  arthritis, osteomyelitis
• 6-12 months mycobacterial diseases, nocardia,
  endemic mycoses
• VAP used to recommend 14-21 days! recent
  studies suggest 7-8 days is adequate but depends
  on microorganism, severity of disease, and pt
  comorbidities (e.g. may want to Rx
  immunosuppressed pts or those with Pseudomonas
  orS. aureus a little longer)

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Pharmacoeconomics

• Cost of illness includes
• Medications
• Provider visits
• Administration of medications
• Loss of productivity
• Cost is a tertiary consideration after
  effectiveness and safety

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Antibacterials
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Beta-Lactams

• Includes
• Penicillins, cephalosporins, carbapenems,
  monobactams
• Mechanism of Action
• Inhibit cell wall synthesis by binding to PBP and
  preventing formation of peptidoglycan cross
  linkage
• Toxicity
• Hypersensitivity reactions
• Cross-reactivity with penicillin allergy
• 10-20 with carbapenems (50 if skin test )
• 10 with 1st gen. cephalosporins
• 1 with 3rd gen. cephalosporins

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Beta-Lactams
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Natural Penicillins

• Includes
• Pen G, Pen V, benzathine penicillin
• Spectrum of activity
• Streptococci
• Viridans group strep, beta-hemolytic strep, many
  S. pneumoniae
• Most N. meningiditis
• Oral anaerobes
• Peptostreptococcus
• Other Listeria monocytogenes, Pasteurella
  multocida, Treponema pallidum, Actinomyces
  israelii

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Aminopenicillins

• Prototypes Ampicillin, Amoxicillin
• Spectrum of activity
• Streptococcus spp.
• Enterococcus faecalis (not faecium)
• Spectrum extended to include some GNB
• E. coli, Proteus mirabilis, Salmonella spp.,
  Shigella, Moraxella, Hemophilus spp.

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Penicillinase Resistant Penicillins

• Prototype Cloxacillin
• Spectrum of activity
• Staphylococci
• MSSA, 1/3 of CoNS
• Streptococcus spp.
• No enterococcal coverage
• No gram-negative or anaerobic coverage

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Carboxypenicillins

• Prototype Ticarcillin
• Broad spectrum activity including
  Stenotrophomonas and Pseudomonas
• Problems with hypernatremia, hypokalemia,
  platelet dysfunction
• If clavulanate added MSSA coverage, improved
  gram-negative and anaerobic coverage

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Ureidopenicillins

• Prototype Piperacillin
• Spectrum of activity
• Streptococcus spp. (less than earlier
  generations)
• Enterococcus faecalis (NOT faecium)
• Anaerobic organisms
• Pseudomonas
• Broad Enterobacteraciae coverage
• If tazobactam added MSSA coverage, improved
  gram-negative and anaerobic coverage

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Cephalosporins

• Divided into 4 generations
• In general ? gram-negative coverage and ?
  gram-positive coverage with ? generation
• Enterococci not covered by any generation!

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1st Generation

• Prototype Cefazolin (Ancef)
• Spectrum of activity
• MSSA
• Streptococcus spp.
• E. coli, Klebsiella, Proteus mirabilis
• No anaerobic activity

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2nd Generation

• Prototype Cefuroxime
• Spectrum of activity
• Gram positives (MSSA, Streptococcus)
• H. influenzae
• M. catarrhalis

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3rd Generation

• Divided into two main groups
• Ceftazidime
• Pseudomonal coverage
• Good gram-negative coverage
• Less gram-positive coverage
• Ceftriaxone and cefotaxime
• Less reliable MSSA coverage
• Good gram-negative coverage
• No anti-pseudomonal activity
• No anaerobic activity
• Good CSF penetration used in meningitis
• Toxicity includes biliary sludging
• Cefixime oral equivalent
• No anti-pseudomonal activity

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4th Generation

• Cefepime
• Maintains gram positive activity, better MSSA
  coverage than with 3rd generation cephalosporins
• Active against Pseudomonas
• ? Activity against SPICEM organisms
• Lower potential for resistance

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The Next GenerationFifth Generation
Extended-spectrum

• Ceftobiprole (Zeftera)
• Recently approved by Health Canada (June 2008)
• Available via special access
• First broad-spectrum anti-MRSA cephalosporin
• Broad-spectrum activity including MRSA,
  Pseudomonas, and E. faecalis
• Reduced activity against cephalosporin-resistant
  SPICEM and ESBLs organisms
• Binds to PBP2a (MRSA) and PBP2x
  (penicillin-resistant S. pneumoniae)

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The Next GenerationFifth Generation
Extended-spectrum

• Ceftobiprole (Zeftera)
• Caramel taste during infusion (diacetyl formed
  during conversion from prodrug to active
  metabolite)
• Statistically non-inferior to vancomycin and
  vancomycin/ceftazidime for the treatment of skin
  and soft tissue infections
• STRAUSS 1 and 2 trials
• Current indications complicated skin and skin
  structure infections (cSSSI), DM foot infections,
  ?nosocomial pneumonia (awaiting further trials)
• Dose 500mg IV q12h for GP, 500mg IV q8h for GN

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Carbapenems

• Imipenem/Meropenem
• MSSA, Streptococcus
• Broad-spectrum gram-negative coverage including
  SPICEM organisms
• Pseudomonas
• Enterococcus faecalis but NOT faecium
• Anaerobic activity
• Ertapenem
• Allows once a day dosing
• Does not cover Pseudomonas or Enterococcus

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Monobactam

• Prototype Aztreonam
• Aerobic GNB
• Including Pseudomonas
• No gram-positive or anaerobic coverage
• Similar spectrum to aminoglycosides without renal
  toxicity
• Cross reactivity to penicillin rare (may use in
  pen-allergic pts)
• Some cross-reactivity with ceftazidime (same
  side-chains)

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Aminoglycosides

• Includes
• Gentamicin
• Tobramycin
• Amikacin
• Streptomycin
• Mechanism of action
• Bind to 30S/50S ribosomal subunit
• Inhibit protein synthesis
• Toxicity
• CN VIII - irreversible
• Renal toxicity reversible
• Rarely hypersensitivity reactions

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Aminoglycosides

• Spectrum of activity
• Aerobic GNB including Pseudomonas
• Mycobacteria (mainly streptomycin)
• Brucella, Fransicella (tularemia)
• Nocardia
• Synergistic with beta-lactams (Enterococci,
  Staphylococci)

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Fluoroquinolones

• Includes
• Ciprofloxacin
• Ofloxacin
• Levofloxacin
• Gatifloxicin
• Moxifloxacin
• Mechanism of Action
• DNA gyrase inhibitors
• Toxicity
• GI symptoms, QTc prolongation

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Fluoroquinolones

• All cover
• Atypicals Mycoplasma, Legionella, Chlamydia
• Fransicella, Rickettsia, Bartonella
• Atypical mycobacteria
• Ciprofloxacin
• Good gram-negative coverage
• N. gonorrhea, H. influenzae
• Good for UTI, infectious diarrhea
• May be used in combination for Pseudomonas

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Fluoroquinolones

• Levofloxacin
• L-enantomer of ofloxacin
• Better gram-positive coverage (mainly
  Streptococcus) than ciprofloxacin
• Used for LRTI
• Moxifloxacin
• Quite broad-spectrum
• Activity against Strep/Staph plus gram-negatives
• Anaerobic coverage
• Minimal to no anti-pseudomonal activity

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Macrolides

• Includes
• Erythromycin
• Clarithromycin
• Azithromycin
• Mechanism of Action
• Bind to ribosomal subunit
• Block protein synthesis
• Static, not cidal
• Toxicity
• GI upset (especially with erythromycin)

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Erythromycin

• Active against Streptococcal spp.
• Also effective against
• Legionella
• Mycoplasma
• Campylobacter
• Chlamydia
• Neisseria gonorrheae
• Poor for H. influenzae
• Used infrequently due to GI upset
• Lots of safety data in children/pregnancy

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Clarithromycin

• Spectrum of activity
• Streptococci including S. pneumoniae
• Moraxella, Legionella, Chlamydia
• Atypical mycobacteria
• More active against H. influenzae
• Used in combination against H. pylori
• Less GI side effects

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Azithromycin

• Spectrum of activity
• Mycoplasma, Legionella, Chlamydia
• H. influenzae
• Streptococcus spp.
• Long half-life
• 5 day course is adequate
• Less GI side effects
• Anti-inflammatory properties in addition to
  antimicrobial action?
• Some evidence of improved outcomes when added to
  beta-lactam in bacteremic pneumococcal CAP

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Telithromycin

• Ketolide, similar to macrolides
• Macrolide resistant S. pneumoniae usually the
  result of a point mutation altering ribosomal
  target site binding
• Telithromycin binds to two independent sites on
  50S and is a poor substrate for efflux potent
  against macrolide-R pneumococcus
• Bewrare serious side effects hepatic necrosis,
  GI upset, arrhythmias, rash
• P450 inhibitor multiple drug interactions
• Used only for mild-moderate CAP due to multi-drug
  resistant S. pneumoniae

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Clindamycin

• Mechanism of Action
• Blocks protein synthesis by binding to ribosomal
  subunits
• Static, not cidal
• Toxicity
• Rash
• GI symptoms
• C. difficile colitis in 1-10
• Covers MSSA, Streptococcus, and anaerobes
• No gram-negative or Enterococcal coverage

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Tetracyclines

• Includes
• Tetracycline
• Doxycycline
• Minocycline
• Tigecycline (glycylcycline)
• Mechanism of Action
• Bind to 30S ribosomal subunit
• Block protein synthesis
• Static, not cidal
• Toxicity
• Rash, photosensitivity, impairs bone growth and
  stains teeth of children, increased uremia

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Tetracyclines

• Spectrum includes unusual organisms
• Rickettsia
• Chlamydia
• Mycoplasma
• Vibrio cholera
• Brucella
• Borreila burgdorferii (Lyme disease)
• Minocycline
• Active against Stenotrophomonas and P. acnes
• May be active against MRSA
• Doxycycline
• Used in uncomplicated CAP and for prophylaxis
  against malaria

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Tigecycline

• Tygacil
• Novel broad-spectrum
• Glycylcyline
• Biliary/fecal excretion
• Active against gram-positives including MSSA and
  MRSA (not VRE), Enterobacteraciae including
  ESBLs, MDR-Acinetobacter, and anerobes
• No anti-pseudomonal activity
• For complicated intra-abdominal and skin/soft
  tissue infections
• Not approved for bacteremia or pneumonia

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Glycopeptides

• Prototype Vancomycin
• Mechanism of Action
• Inhibits cell wall synthesis
• Toxicity
• Ototoxicity rare
• Can induce histamine release red man syndrome
• Usually with rapid infusion

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Glycopeptides

• Spectrum of activity
• Gram-positives S. aureus (incl. MRSA), CoNS,
  Streptococcus, Enterococcus
• Gram-positive anaerobes
• Exceptions VRE, Leuconostoc, Lactobacillis
• Inferior to beta-lactams in terms of cure rates
  for beta-lactam sensitive organisms
• Big, bulky molecule poor CSF penetration in the
  absence of meningeal inflammation (including
  those treated with corticosteroids)

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Lipopeptides

• Daptomycin or Cubicin
• Bactericidal
• Disrupts bacterial membrane function
• Binds to cell membrane, forms ion channel, K
  efflux, depolarization, cell death
• In vitro activity against gram-positive organisms
  including MSSA, MRSA, VRSA, VRE, PRSP

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Daptomycin

• Approved for use in MSSA/MRSA and other selected
  gram-positives (not VRE, yet)
• Complicated skin and soft tissue infections
• S. aureus bacteremia/R. IE
• Cannot be used to treat pneumonia
• Does not achieve sufficiently high concentrations
  in the respiratory tract
• Inactivated by surfactant
• Side effects myopathy monitor CK

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Metronidazole

• Mechanism not well understood
• Interferes with DNA synthesis via toxic
  intermediates
• Spectrum of activity
• Most anaerobes except Peptostreptococcus,
  Actinomyces, Propionibacterium acnes
• Parasites Giardia lamblia, Entamoeba histolytica
• Toxicity
• Disulfuram reaction
• Neuropathy
• Potentiation of warfarin

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Sulfa drugs

• Includes TMP/SMX
• Mechanism of Action
• Folate reductase inhibitor
• Toxicity
• Hypersensitivity reactions
• Thrombocytopenia
• Rash
• Hyperkalemia

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Sulfa drugs

• Broad-spectrum coverage
• Streptococcus, Staphylococcus
• H. influenza
• L. monocytogenes
• Many Enterobacteraciae (E. coli, Klebsiella)
• Stenotrophomonas maltophila
• PJP
• Nocardia
• Isospora belli
• Frequent allergic rxns
• Used in special circumstances (e.g. PJP,
  nocardia, Stenotrophomonas)

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Chloramphenicol

• Broad-spectrum activity
• GPC, GNB
• Meningitis organisms
• Rickettsia spp.
• No activity against Klebsiella, Enterobacter,
  Serratia, Proteus, Pseudomonas
• Toxicity
• Dose related marrow toxicity
• Idiosyncratic aplastic anemia
• Gray baby syndrome

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Linezolid

• Oxazolidinone
• Binds to ribosomal subunit inhibiting protein
  synthesis
• Static, not cidal
• Excellent oral bioavailability
• Active against
• MSSA, MRSA, enterococci including VRE, S.
  pneumoniae
• No activity against gram-negatives

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Linezolid

• No cross-resistance with other drugs
• Approved for use in nosocomial pneumonia and
  skin/soft tissue infections
• Major side effect
• Reversible myelosuppression
• Monitor CBCD
• Resistance reported, but rare
• Very expensive (140/day) and currently not
  covered (used mainly in WCB cases)

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Quinupristin/dalfopristin

• Synercid
• Combined stretogramin A and B
• Bactericidal
• Approved for use in skin and soft tissue
  infections only
• Active against a wide variety of gram-positive
  bacteria
• MSSA, MRSA, CoNS, Streptococci, VRE (E. faecium
  not E. faecalis)
• Major side effect phlebitis, hyperbilirubinemia
• Resistance, although rare, has been reported

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Colistin

• Polymyxin E
• Older drug, recently has come into re-use
• Binds to phospholipids in cell membrane causing
  disruption
• Most commonly used in salvage Rx in
  MDR-Pseudomonas or Acinetobacter infections
• Bactericidal
• Nephrotoxic, neurotoxic
• Needs to be renally adjusted

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Nitrofurantoin

• Synthetic nitrofuran
• Inhibits bacterial acetylcoenzyme A disrupts
  carbohydrate metabolism
• Cidal at high concentrations, static at lower
• Concentrated in urine with normal renal function
• Contraindicated in renal insufficiency

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Nitrofurantoin

• Effective against
• E. coli, Enterococcus, S. aureus, some strains
  Klebsiella and Enterobacter
• Proteus, Serratia, and Pseudomonas are resistant!
• Only indication is Rx or prophylaxis of lower
  UTIs
• Should not be used for systemic infection
• Adverse effects n/v, hypersensitivity
  pneumonitis, pulmonary fibrosis, hemolytic anemia
  in G6PD deficiency, hepatitis

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Mechanisms of Action Summary I
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Mechanisms of Action Summary II
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Mechanisms of Resistance
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Mechanisms of Resistance

• Enzymatic inactivation of antimicrobial
• Target site binding
• Efflux
• Decreased permeability
• Others

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Enzymatic Inactivation

• Beta-lactamases
• Penicillinases, ampCs, ESBLs, metallo-beta-lactama
  ses
• Seen in S. aureus, H. influenzae, N.
  meningitidis, SPICEM, E. coli, Klebsiella spp.,
  P. aeruginosa

80
Enzymatic Inactivation

• AG-modifying enzymes
• n-acetylation, o-nucleotidylation,
  o-phosphorylation
• Seen in Enterobacteriaceae, Pseudomonas, and
  Enterococci
• Macrolide, lincosamide, and streptogramin
  inactivating enzymes (esterases)
• Uncommon

81
Altered Target Site Binding

• Cell wall precursor targets
• D-ala-D-ala changed to D-ala-D-lac in VRE
• Target enzymes
• PBP2a in MRSA low affinity for beta-lactams
• Ribosomal target sites
• Methylase enzymes
• Seen in tetracyclines, macrolides, lincosamides,
  aminoglycosides
• erm gene confers MLSB phenotype in S. aureus
  which may be constitutive or inducible

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Efflux

• Seen with tetracyclines, macrolides,
  streptogramins, beta-lactams, fluoroquinolones,
  and carbapenems
• Macrolide resistance in
• S. pneumoniae (mef)
• Staphylococci (msr)
• Beta-lactam resistance in Pseudomonas
• Fluoroquinolone resistance in Enterobacteriaceae

83
Clindamycin Resistance
ERYTHRO
CLINDA
84
Decreased Permeability

• Porin channels determine rate of diffusion of Abx
  mainly a problem in GN organisms
• Causes
• Fluoroquinolones resistance in
• P. aeruginosa and S. marsecans
• Aminoglycoside resistance in
• E. coli, S. aureus, and Salmonella spp.

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Others

• Target site protection
• DNA gyrase protection and fluoroquinolone-R
• Ribosomal protection and tetracycline-R
• Overproduction of target
• Sulfonamides compete with enzyme DHFR and halt
  nucleic acid production
• Overproduction of DHFR may overwhelm sulfa
  inhibition
• Bypass of antimicrobial inhibition
• Development of different growth factor
  requirements and subsequent evasion of inhibition
• E.g. trimethoprim/sulfamethoxazole

86
Questions?