antibiotic Pronunciation: "antibI'tik, "tI "antibE Function: adjective : tending to prevent, inhibit

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antibiotic Pronunciation
"an-ti-bI-'ä-tik, -"tI- "an-ti-bE-Function
adjective tending to prevent, inhibit, or
destroy lifeantibiotically /-ti-k(-)lE/
adverb Clarithromycin
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Gram-Positive Aerobes

• COCCI
• clusters - Staphylococci
• pairs - S. pneumoniae
• chains - group and viridans streptococci
• pairs and chains - Enterococcus sp.

• BACILLI
• Bacillus sp.
• Corynebacterium sp.
• Listeria monocytogenes
• Nocardia sp.

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Gram-Negative Aerobes

• COCCI
• Moraxella catarrhalis
• Neisseria gonorrhoeae
• Neisseria meningitidis
• Haemophilus influenzae

• BACILLI
• E. coli, Enterobacter sp.
• Citrobacter, Klebsiella sp.
• Proteus sp., Serratia
• Salmonella, Shigella
• Acinetobacter, Helicobacter
• Pseudomonas aeruginosa

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Anaerobes

• Above Diaphragm
• Peptococcus sp.
• Peptostreptococcus sp.
• Prevotella
• Veillonella
• Actinomyces

• Below Diaphragm
• Clostridium perfringens, tetani, and difficile
• Bacteroides fragilis, disastonis, ovatus,
  thetaiotamicron
• Fusobacterium

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Other Bacteria

• Atypical Bacteria
• Legionella pneumophila
• Mycoplasma pneumoniae or hominis
• Chlamydia pneumoniae or trachomatis
• Spirochetes
• Treponema pallidum (syphilis)
• Borrelia burgdorferi (Lyme)

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Common Bacterial Pathogens by Site of Infection

• Certain bacteria have a propensity to commonly
  cause infection in particular body sites or
  fluids
• Antibiotic may be chosen before results of the
  culture are available based on some preliminary
  information
• Site of infection and likely causative organism
• Gram-stain result (does result correlate with
  potential organism above)

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Bacteria by Site of Infection
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Macrolides

• Erythromycin is a naturally-occurring macrolide
  derived from Streptomyces erythreus problems
  with acid lability, narrow spectrum, poor GI
  intolerance, short elimination half-life
• Structural derivatives include clarithromycin and
  azithromycin
• Broader spectrum of activity
• Improved PK properties better bioavailability,
  better tissue penetration, prolonged half-lives
• Improved tolerability

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Macrolide Structure
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Macrolides

• Mechanism of Action
• Inhibits protein synthesis by reversibly binding
  to the 50S ribosomal subunit
• Suppression of RNA-dependent protein synthesis
• Macrolides typically display bacteriostatic
  activity, but may be bactericidal when present at
  high concentrations against very susceptible
  organisms
• Time-dependent activity

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Macrolides

• Mechanisms of Resistance
• Active efflux (accounts for 80 in US) mef gene
  encodes for an efflux pump which pumps the
  macrolide out of the cell away from the ribosome
  confers low level resistance to macrolides
• Altered target sites (primary resistance
  mechanism in Europe) encoded by the erm gene
  which alters the macrolide binding site on the
  ribosome confers high level resistance to all
  macrolides, clindamycin and Synercid
• Cross-resistance occurs between all macrolides

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Macrolide Spectrum of Activity

• Gram-Positive Aerobes erythromycin and
  clarithromycin display the best activity
• (ClarithrogtErythrogtAzithro)
• Methicillin-susceptible Staphylococcus aureus
• Streptococcus pneumoniae (only PSSP) resistance
  is developing
• Group and viridans streptococci
• Bacillus sp., Corynebacterium sp.

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Macrolide Spectrum of Activity

• Gram-Negative Aerobes newer macrolides with
  enhanced activity (AzithrogtClarithrogtErythro
  )
• H. influenzae (not erythro), M. catarrhalis,
  Neisseria sp.
• Do NOT have activity against any
  Enterobacteriaceae

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Macrolide Spectrum of Activity

• Anaerobes activity against upper airway
  anaerobes
• Atypical Bacteria all macrolides have excellent
  activity against atypical bacteria including
• Legionella pneumophila
• Chlamydia sp.
• Mycoplasma sp.
• Ureaplasma urealyticum
• Other Bacteria Mycobacterium avium complex (MAC
  only A and C), Treponema pallidum,
  Campylobacter, Borrelia, Bordetella, Brucella.
  Pasteurella

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MacrolidesPharmacology

• Absorption
• Erythromycin variable absorption (F 15-45)
  food may decrease the absorption
• Base destroyed by gastric acid enteric coated
• Esters and ester salts more acid stable
• Clarithromycin acid stable and well-absorbed
  (F 55) regardless of presence of food
• Azithromycin acid stable F 38 food
  decreases absorption of capsules

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MacrolidesPharmacology

• Distribution
• Extensive tissue and cellular distribution
  clarithromycin and azithromycin with extensive
  penetration
• Minimal CSF penetration
• Elimination
• Clarithromycin is the only macrolide partially
  eliminated by the kidney (18 of parent and all
  metabolites) requires dose adjustment when CrCl
  lt 30 ml/min
• Hepatically eliminated ALL
• NONE of the macrolides are removed during
  hemodialysis!
• Variable elimination half-lives (1.4 hours for
  erythro 3 to 7 hours for clarithro 68 hours for
  azithro)

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MacrolidesAdverse Effects

• Gastrointestinal up to 33
• Nausea, vomiting, diarrhea, dyspepsia
• Most common with erythro less with new agents
• Cholestatic hepatitis - rare
• gt 1 to 2 weeks of erythromycin estolate
• Thrombophlebitis IV Erythro and Azithro
• Dilution of dose slow administration
• Other ototoxicity (high dose erythro in patients
  with RI) QTc prolongation allergy

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MacrolidesDrug Interactions

• Erythromycin and Clarithromycin ONLY are
  inhibitors of cytochrome p450 system in the
  liver may increase concentrations of
• Theophylline Digoxin, Disopyramide
• Carbamazepine Valproic acid
• Cyclosporine Terfenadine, Astemizole
• Phenytoin Cisapride
• Warfarin Ergot alkaloids

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Clinical Applications of Macrolides

• Effects on neutrophils
• Accumulation and migration, oxidative burst, and
  apoptosis
• Modification of cytokine production
• Mucoregulatory effects
• Ciliary effects
• Effects on biofilm production and bacterial
  adherence

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Applications for the Nonantibiotic Properties of
Macrolides

• Diffuse panbronchiolitis (DPB)
• Cystic fibrosis (CF)
• Acute bacterial sinusitis (ABS)
• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Bronchiectasis
• Chronic bronchitis

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Immunomodulatory effects of macrolides

• Clinical effects
• Established DPB, CF
• Probable Chronic sinusitis, asthma with
  mucus hypersecretion
• Possible Bronchiectasis
• Unknown Chronic bronchitis, primary ciliary
  dyskinesia, chronic secretory otitis media

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Macrolides and Sinus Disease

• Erythromycin reduced nasal secretion by 35 at
  rest and when stimulated by methacholine or
  histamine
• Nasal secretions were collected with or without
  nasal methacholine in healthy adults and in
  patients with purulent rhinitis
• After 2 weeks of clarithromycin 500 mg BID,
  secretion volume decreased (500.1 mg versus 28.3
  mg P.01) and mucociliary transportability
  increased 30 (P.005)

Goswami SK, et al. Am Rev Respir Dis.
199014172-78. Rubin BK, et al. Am J Respir Crit
Care Med. 19971552018-2023.
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Macrolides and Asthma

• Several studies reported that macrolides affect
  several inflammatory processes, such as migration
  of neutrophils, the oxidative burst in
  phagocytes, and production of proinflammatory
  cytokines
• Studies also have indicated that macrolides
  inhibit eosinophilic inflammation and may be
  useful in the treatment of patients with
  steroid-dependent asthma

Zalewska-Kaszubska J, et al. Pharmacol Res.
200144451-454.
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Oral Clarithromycin in the treatment of
moderate-to-severe COPD

• 57 randomized patients received clarithromycin
  (n24) or placebo (n33) for 3 months
• Examined effect on exacerbation rate, total
  number of bacterial colonies, spirometry, shuttle
  walk distance, health status, plasma viscosity,
  and fibrinogen
• No reduction in exacerbation rate, shuttle walk
  distance, spirometry, or total number of
  bacterial colonies was found with clarithromycin,
  although reductions in Streptococcus pneumoniae
  and Moraxella catarrhalis were noted
• Statistically significant improvements were seen
  in St. Georges Respiratory Questionnaire (SGRQ)
  symptom score and in the Short Form 36 (SF-36)
  physical function score

Banerjee D, et al. Eur Respir J. 20011894S,
153S, 338S.
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Effects of Long-Term Macrolide Therapy on
Bronchiectasis
Outcome
Roxithromycin Clarithromycin


(n24)
(n16)


Cough Disappeared
8/24 (33)
10/16 (63)



Sputum Disappeared 9/24
(38) 9/16 (56)



Rales Disappeared
5/17 (29) 7/12 (58)



Chest X
-
ray Disappeared 7/24 (29)
6/16 (38)


Efficacy
12/24 (50) 11/16 (69)



The antibiotic was judged effective if there was
improvement in 1 or more of the above parameters.
Shirai T, et al. Intern Med. 199534469-474.
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Characteristics of Clinical Efficacy in an
Antibiotic

• The drug must kill pathogens in vitro (minimum
  inhibitory concentrations MIC)
• The drug must penetrate infected tissues
  (pharmacodynamics)
• The drug must remain in tissues between doses
  (pharmacokinetics)
• The drug must kill the pathogen in vivo (animal
  models and invasive human sampling)
• The patient must improve (clinical trials)

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CDC Guidelines

• Empiric management of outpatient CAP using
• Macrolides
• Doxycycline
• ?-lactams with good S. pneumoniae activity
• Use fluoroquinolones only for adults
• With known treatment failures
• With allergy to other classes
• With documented high-level DRSP (penicillin MIC 4
  µg/mL)

Heffelfinger JD, et al. Arch Intern Med.
20001601399-1408.
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What Have We Learned About Resistance?

• To prevent the emergence of resistance, therapy
  must be
• Potent (throw your best pitch first)
• Focused (no innocent bystanders)
• Short (courses to encourage compliance)
• Appropriate (follow guidelines)

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Conclusions

• In vitro resistance Does not equal clinical
  failure
• Clinical failures To be expected
• Appropriate use Macrolides and doxycycline are
  consistently endorsed
• Focused therapy Macrolides and doxycycline
• Best in class Clarithromycingterythromycingt
  azithromycin

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Klacid 500mg BD Serum
MIC of 0.5 mg/l 100 of TgtMIC
Clarithromycin Extended-Release Tablet A Review
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Klacid 500mg BD Serum
MIC of 1 mg/l 100 of TgtMIC
Clarithromycin Extended-Release Tablet A Review
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Klacid 500mg BD Serum
MIC of 2 mg/l 38 of TgtMIC
Clarithromycin Extended-Release Tablet A Review
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Klacid 1g XL OD Serum
MIC of 0.5 mg/l 100 of TgtMIC
Clarithromycin Extended-Release Tablet A Review
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Klacid 1g XL OD Serum
MIC of 1 mg/l 100 of TgtMIC
Clarithromycin Extended-Release Tablet A Review
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Klacid 1g XL OD Serum
MIC of 2 mg/l 52 of TgtMIC
Clarithromycin Extended-Release Tablet A Review
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Klacid 500mg ELFBD (9 doses) Measured After
Last Dose
MIC of 15 mg/l 50 of TgtMIC
Intrapulmonary Concentrations of Clarithromycin
Gotfried et al.Abstract, 3rd ICMAS, Lisbon 1996
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Pharmacodynamic Profilingat Site of Infection

• Derived using serum data not wholly predictive of
  bactericidal effects in pneumonia model
• Intrapulmonary disposition of clarithromycin used
  in subsequent pharmacodynamic assessments
• Epithelial lining fluid (ELF) concentrations used
  as a surrogate marker for drug concentrations at
  the site (interstitial or extracellular space) of
  bronchopulmonary infection

Tessier PR, et al. Anitmicrob Agents Chemother.
200246(5)1425-1434.
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Klacid 500mg ELFBD (9 doses) Measured After
Last Dose
MIC of 20 mg/l 40 of TgtMIC
Intrapulmonary Concentrations of Clarithromycin
Gotfried et al.Abstract, 3rd ICMAS, Lisbon 1996
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Klacid 1g XL vs BD

• Side Effect Profile
• Klacid 1g XL offers a significantly improved side
  effect profile compared to BD.
• Dieter et al. Clin Ther 200123585-595
• Compliance
• Studies show this to be a significant indicator
  of efficacy in the treatment of infection.
• Once daily regimes have a non-compliance of 1.7
  versus 25 for a BD regime
• Cockburn et al. BMJ 1987295814-818

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ADVANTAGES Klacid 1g XL vs Klacid BD

• Klacid 1g XL has a better serum and ELF
  (anticipated) pharmacodynamic profile
• Klacid 1g XL has an improved side effect profile
• Klacid 1g XL offers improved compliance

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Atypical Bacteria Are Important Causes of CAP
Mycoplasma pneumoniae
Legionella pneumophila
Chlamydia (Chlamydophila) pneumoniae
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Antimicrobial Pharmacodynamics of ?-Lactams and
Macrolides

• Time-dependent bactericidal activity
• Rate and extent of bacterial killing does not
  increase with increasing drug concentration
• Clinical goal Maximize drug exposure (ie, time
  serum level remains above the MIC timegtMIC)

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Serum Concentrations of Macrolides
Clarithromycin Erythromycin Azithromycin
3.0
Serum Concentrations, ?g/mL
2.0
1.0
1 2 3 4 5 6 7 8
9 10 11 12 Time, hours
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Clinical Efficacy of Clarithromycin
Clarithromycin Clinical Success
Competitor Clinical Success
Clarithromycin Bacteriologic Eradication
Competitor Bacteriologic Eradication
CAP 1997 (competitor grepafloxacin) values not
available. CAP, community-acquired pneumonia
AECB, acute exacerbation of chronic bronchitis.
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Clinical Efficacy of Clarithromycin (cont.)
Clarithromycin Clinical Success
Competitor Clinical Success
Clarithromycin Bacteriologic Eradication
Competitor Bacteriologic Eradication
AMS 1999 (competitor gatifloxacin), AMS 1998
(competitor levofloxacin), and AMS 1997
(competitor trovafloxacin) values not
available. AECB, acute exacerbation of chronic
bronchitis.
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• Complete eradication of bacteria suppresses the
  emergence of resistant organisms
• Bacterial eradication is related to the
  concentration of drug to which the bacteria is
  exposed and the duration of exposure
• Suppression of the emergence of resistant
  bacteria involves the same principles as
  bacterial eradication
• _at_

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