Review of Antimicrobial Agents Part I

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Review of Antimicrobial AgentsPart I

• Siriluck Anunnatsiri, MD, MCTM, MPH
• Infectious Diseases Tropical Medicine
• Department of Medicine
• Khon Kaen University

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Classification of Antimicrobial Agents

• ?-lactam antibiotics
• Penicillins, Cephalosporins, Carbapenems,
  Monobactams, ?-lactam/?-lactamases inhibitors
• Aminoglycosides
• Macrolides
• Ketolides Telithromycin, Dirithromycin
• Lincosamides Lincomycin, Clindamycin
• Quinolones
• Chloramphenicol

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Classification of Antimicrobial Agents

• Tetracyclines, Tigecycline
• Sulfamethoxazole/Trimethoprim (SMX/TMP)
• Glycopeptides Vancomycin, Teicoplanin
• Oxazolidinones Linezolid
• Fosfomycin
• Fusidic acid
• Polymyxins Polymyxin B, Colistin
• Metronidazole

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Classification of Antimicrobial Agents

• Lipopeptide Daptomycin
• Streptogramins Quinupristin-Dalfopristin

?-lactam antibiotics
Aminoglycosides
Glycopeptides
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Antimicrobial Properties

• Structure
• Spectrum
• Mechanisms of action
• Mechanism of resistance

• Pharmacokinetic
• Absorption
• Distribution
• Metabolism
• Elimination
• Pharmacodynamic
• Drug interaction
• Side effect

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Beta-lactams Antibiotic Basic Structure
Aminoacyl
Thiazolidine ring
Dihydrothiazine ring
Hydroxyethyl
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Beta-lactams Antibiotic General Properties

• Inhibit cell wall synthesis
• Bactericidal effect
• Time-dependent bactericidal action
• Inoculum effect on antimicrobial activity is more
  prominent
• In GNB - No or short PAE for most ?-lactam
• Share ?-lactam class allergic reaction except
  monobactams

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PD Parameters affecting Antibiotic Potency
AUC/MIC gt125 for GNB gt25-50 for GPC Cmax/MIC gt10
gt 40-50 of dosing interval
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Inoculum Effect

• The effect of inoculum size on antimicrobial
  activity
• Dense population can be less susceptible to
  ?-lactams
• Failure to express receptor (PBP)
• High concentration of ?-lactamases
• Trend to presence of resistant subpopulation

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Postantibitic Effect

• A persistent suppression of growth after levels
  have fallen below the MIC

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Bacterial Cell Wall Synthesis
Hiramatsu K. Lancet Infect Dis 2001 1 147-155
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Bacterial Cell Wall Synthesis
(Transpeptidase)
Hiramatsu K. Lancet Infect Dis 2001 1 147-155
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Beta-lactams Antibiotic Mechanism of Action
Hiramatsu K. Lancet Infect Dis 2001 1 147-155
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Beta-lactams Antibiotic Mechanism of Resistance

• ?-lactamases destruction of antibiotic
• Failure of antibiotic to penetrate the outer
  membrane of gram-negative to reach PBP target
• Efflux of antibiotic across the outer membrane of
  gram-negative
• Low-affinity binding of antibiotic to PBP target

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Beta-lactams Antibiotic Adverse Reactions

• Hypersensitivity 3 to 10
• Irritability, jerking, confusion, seizures
  especially with high dose penicillins and
  imipenem
• Leukopenia, neutropenia, thrombocytopenia
  therapy gt 2 weeks
• Interstitial nephritis
• Cephalosporin-specific cefamandole, cefotetan,
  cefmetazole, cefoperazone, moxalactam
• Hypoprothrombinemia - due to reduction in vitamin
  K-producing bacteria in GI tract

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Penicillins Classification

• Natural penicillins
• Penicillin V, Penicillin G
• Aminopenicillins
• Ampicillin, Amoxicillin
• Penicillinase-resistant penicillins
• Cloxacillin, Dicloxacillin, Nafcillin,
  Methicillin
• Carboxypenicillins
• Carbenicillin, Ticarcillin
• Ureidopenicillin
• Piperacillin, Azlocillin, Mezlocillin

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Natural Penicillins Spectrum of Activity

• Gram-positive Gram-negative
• S. pneumoniae Neisseria meningitidis
• Streptococcus sp.
• Enterococcus sp. Anaerobes
• C. diphtheriae Above the diaphragm
• B. anthracis Clostridium perfringens
• L. monocytogenes
• Other
• Treponema pallidum
• Leptospira sp.

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Penicillinase-Resistant Penicillins Spectrum

• Gram-positive
• MSSA
• MSSE
• Streptococcus sp.

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Aminopenicillins Spectrum of Activity

• Gram-positive Gram-negative
• Streptococcus sp. Proteus mirabilis
• Enterococcus sp. Salmonella sp.
• L. monocytogenes Shigella
• C. diphtheriae some E. coli
• H. influenzae
• N. meningitidis
• Anaerobes
• Above the diaphragm
• Clostridium perfringens

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Carboxypenicillins Spectrum of Activity

• Gram-positive Gram-negative
• Streptococcus sp. Proteus mirabilis
• C. diphtheriae Salmonella sp.
• Shigella
• E. coli
• H. influenzae
• Neisseria sp.
• Anaerobes Enterobacter sp.
• Fairly good activity P. aeruginosa
• Citrobacter sp.
• Serratia sp.

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Ureidopenicillins Spectrum of Activity

• Gram-positive Gram-negative
• Streptococcus sp. Proteus mirabilis
• Enterococcus sp. Salmonella sp.
• L. monocytogenes Shigella
• E. coli
• Klebsiella sp.
• H. influenzae
• Neisseria sp.
• Anaerobes Enterobacter sp.
• Fairly good activity P. aeruginosa
• S. marcescens

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Penicillins Pharmacology

• Administration Oral, IV, IM
• Varying oral absorption
• 40 for Ampicillin ? 75 for Amoxicillin
• Varying protein binding
• 17 for aminopenicillin ? 97 for dicloxacillin
• More free drugs in the presence of probenecid
• Mainly excrete via renal tubular cells, which can
  be blocked by probenecid.

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Penicillins Pharmacology

• Dose adjustment is needed when CCr lt 10-20
  ml/min, on hemodialysis or CVVH
• Biliary excretion is important only for nafcillin
  and antipseudomonal penicillins.
• Well distributed to most tissues, high
  concentration in urine and bile
• Relatively insoluble in lipid and penetrate cells
  relatively poorly

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Cephalosporins Classification
1st Generation 2nd Generation Cephamycins 3rd Generation 4th Generation
Cefazolin Cefamandole Cefmetazole Ceftriaxone Cefepime
Cephalothin Cefonicid Cefotetan Cefotaxime Cefpirome
Cephapirin Cefmetazole Cefoxitin Ceftazidime
Cephradine Cefotetan Cefoperazone
Cefadroxil Cefoxitin Ceftizoxime
Cephalexin Cefuroxime Cefsulodin
Cefprozil Moxalactam
Loracarbef Cefdinir
Cefaclor Cefditoren
Cefixime
Ceftibuten
Cefpodoxime
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1st Generation Cephalosporins SpectrumBest
activity against gram-positive aerobes, with
limited activity against a few gram-negative
aerobesGram-positive Gram-negativeMSSA
EnterobacteriaceaeStreptococcus sp.

• 2nd Generation Cephalosporins/Cephamycins
  Spectrum
• More active against gram-negative aerobes
• Cephamycin group has activity against
  gram-negative anaerobes including Bacteroides
  fragilis

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3rd Generation Cephalosporins Spectrum

• Increase potency against gram-negative aerobes
• Ceftriaxone and cefotaxime have the best activity
  against MSSA and Streptococcus sp.
• Ceftazidime, moxalactam, cefixime, and ceftibuten
  have less activity against MSSA
• Ceftazidime, cefoperazone, and cefsulodin have
  activity against P. aeruginosa.

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4th Generation Cephalosporins Spectrum

• Extended spectrum of activity
• gram-positives similar to ceftriaxone
• gram-negatives Enterobacteriaceae including
  cephalosporinase-producer, P. aeruginosa.
• Stability against ?-lactamases poor inducer of
  extended-spectrum ? -lactamases

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Cephalosporins Pharmacology

• Polar, water-soluble compounds
• Administration IM, IV, oral, intraperitoneum
• High oral bioavailability
• Varying protein binding 10 -gt 98
• Largely confined to extracellular compartment,
  relatively poor intracellular concentration
• Good CNS penetration Only 3rd 4th gen.
  cephalosporins
• Almost excrete via renal tubular secretion,
  except ceftriaxone and cefoperazone are largely
  eliminated via biliary route

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Carbapenems

• Imipenem
• N-formimidoyl derivative of thienamycin
• Need to combine with cilastatin to prevent renal
  dehydropeptidase I hydrolysis and nephrotoxic
  effect
• Meropenem, Ertapenem
• ?-1-methyl, 2-thio pyrrolidinyl derivative of
  thienamycin

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Carbapenems Spectrum of Activity

• Most broad spectrum of activity of all
  antimicrobials
• Have activity against gram-positive and
  gram-negative aerobes, anaerobes, Nocardia sp.,
  rapid-growing mycobacteria
• Bacteria not covered by carbapenems include MRSA,
  MRSE, E. faecium, C. difficile, S. maltophilia,
  B. cepacia
• Ertapenem not active against P. aeruginosa and
  Acinetobacter sp.

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Carbapenems Pharmacology

• Absorbed poorly after oral ingestion
• T1/2
• Imipenem, Meropenem 1 hr
• Ertapenem 4 hr
• Well distributed to body compartment and
  penetrate well into the most tissues
• Excrete via renal, dosage adjustment is required
  in patient with impaired renal function.
• Need supplement dose in patient performing CVVH,
  hemodialysis

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?-Lactam/?-Lactamase Inhibitor

• Ampicillin/sulbactam (A/S)
• Amoxicillin/clavulanate (A/C)
• Ticarcillin/clavulanate (T/C)
• Piperacillin/tazobactam (P/T)
• Cefoperazone/sulbactam (C/S)

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?-Lactam/?-Lactamase Inhibitor Spectrum

• Maintain spectrum of ?-Lactams but enhance
  activity against ?-Lactamase (Ambler class A)
  producing organisms
• Activity against MSSA, Streptococcus sp.,
  Enterococcus sp. (Except C/S), ?-Lactamase
  producing Enterobactericeae, P. aeruginosa (Only
  P/T, C/S), Anaerobes.

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?-Lactam/?-Lactamase Inhibitor Pharmacology

• Clavulanate, Sulbactam Moderately well absorbed
• Good tissue distribution
• Penetration into inflamed meninges
• Clavulanate, Sulbactam Poor
• Tazobactam Good in animal model
• Excretion
• Clavulanate Lung, feces, urine
• Sulbactam, Tazobactam - Urine

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Monobactams

• Aztreonam
• Bind primarily to PBP 3 in Enterobacteriaceae,
  P. aeruginosa, and other gram-negative aerobes
• No activity against gram-positive or anaerobic
  bacteria
• Low incidence of drug hypersensitivity no
  cross-reaction with other ?-Lactams
• Weak ?-Lactamase inducer

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Aminoglycosides Basic Chemical Structure
Aminocyclitol Ring
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Aminoglycosides Classification
Family Member
Streptidine aminocyclitol ring Streptidine aminocyclitol ring
Streptomycin Streptomycin
Spectinomycin
2-deoxystreptamine aminocyclitol ring 2-deoxystreptamine aminocyclitol ring
Kanamycin Kanamycin, Amikacin, Tobramycin, Dibekacin
Gentamicin Gentamicin, Netilmicin, Sisomicin, Isepamicin
Neomycin Neomycin, Paromomycin
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Aminoglycosides Mechanism of Action
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Aminoglycosides Mechanism of Resistance
Adenyltransferase
Acetyltransferases
Phosphotransferases
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Aminoglycosides Spectrum of Activity

• Gram-Negative Aerobes
• Enterobacteriaceae, P. aeruginosa, Acinetobacter
  sp.- Kanamycin Gentamicin groups
• F. tularensis, Brucella sp., Y. pestis -
• Streptomycin, gentamicin
• N. gonorrhoeae - Spectinomycin
• Mycobacteria
• M. tuberculosis Streptomycin, kanamycin,
  amikacin
• Non-tuberculous Amikacin, streptomycin

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Aminoglycosides Spectrum of Activity

• Gram-Positive Aerobes (In vitro synergy)
• S. aureus, S. epidermidis, viridans
  streptococci, Enterococcus sp.
• Nocardia sp. - Amikacin
• E. histolytica, C. parvum - Paromomycin

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Aminoglycosides Pharmacology

• Bactericidal effect
• Concentration dependent killing
• Little influence by inoculum effect
• Presence of PAE effect
• Administration IV, IM, intrathecal,
  intraperitoneum, inhale, oral (neomycin,
  paromomycin), topical
• Low level of protein binding (10), high water
  solubility, lipid insolubility

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Aminoglycosides Pharmacology

• 99 of drug is excreted unchanged by glomerular
  filtration
• 5 of excreted drug is reabsorbed at renal
  proximal tubule

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Once-Daily Aminoglycosides

• Equal efficacy compared to multiple-dose
  administration
• May lower but not eliminate risk of drug-induced
  nephrotoxicity and ototoxicity
• Simple, less time consuming, and more cost
  effective
• Does not worsen neuromuscular function in
  critically ill ventilated patients
• Probably should not be used in enterococcal
  endocarditis
• Need further study in pregnancy, cystic fibrosis,
  GNB meningitis, endocarditis, and osteomyelitis

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Aminoglycosides Adverse Effects

• Neuromuscular blockage
• Nephrotoxicity
• Reversible if detection early
• Risk factors prolonged trough level, volume
  depletion, hypotension, underlying renal
  dysfunction, elderly, other nephrotoxins
• Ototoxicity
• Cumulative dose
• 8th cranial nerve damage - irreversible
• Vestibular toxicity dizziness, vertigo, ataxia
• Auditory toxicity tinnitus, decreased hearing
  (high frequency)

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Glycopeptides

• Vancomycin
• Teicoplanin

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Glycopeptides Mechanism of Action
Hiramatsu K. Lancet Infect Dis 2001 1 147-155
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Glycopeptides Mechanism of Resistance in S.
aureus
Hiramatsu K. Lancet Infect Dis 2001 1 147-155
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Glycopeptide-resistant S. aureus
NCCLS NCCLS NCCLS BSAC BSAC
S I R S R
Vancomycin lt4 8-16 gt32 lt4 gt8
Teicoplanin lt8 16 gt32 lt4 gt8
NCCLS The National Committee for Clinical
Laboratory Studies BSAC The British Society for
Antimicrobial Chemotherapy
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Glycopeptide-resistant S. aureus

• Recommend using MIC determination for
  confirmation of VISA, GISA, or VRSA isolates
• Heteroresistance phenomenon Hetero-VRSA
• Only a subpopulation of S. aureus can grow on
  vancomycin-containing agar (gt8 ?g/ml)
• Precursor of VISA/VRSA isolates
• Population analysis is needed to identify
  hetero-VRSA

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Glycopeptide-resistant Enterococci
Stain Characteristics Acquired resistance level, Type Acquired resistance level, Type Acquired resistance level, Type Acquired resistance level, Type Acquired resistance level, Type Intrinsic resistance, low level, Type VanC1, C2, C3
Stain Characteristics High, VanA Variable, VanB Moderate, VanD Low Low Intrinsic resistance, low level, Type VanC1, C2, C3
Stain Characteristics High, VanA Variable, VanB Moderate, VanD VanG VanE Intrinsic resistance, low level, Type VanC1, C2, C3
MIC, mg/L
Vancomycin 64-100 4-1000 64-128 16 8-32 2-32
Teicoplanin 16-512 0.5-1 4-64 0.5 0.5 0.5-1
Modified Target D-Ala-D-Lac D-Ala- D-Lac D-Ala- D-Lac D-Ala-D-Ser D-Ala-D-Ser D-Ala- D-Ser
Courvalin P. Clin Infect Dis 2006 42 S25-S34.
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Glycopeptide-resistant Enterococci
VanS Membrane-associated sensor kinase VanR
Cytoplasmic response regulator
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Glycopeptides Spectrum of Activity

• Gram-positive bacteria
• MSSA, MRSA, MSSE, MRSE
• S. pneumoniae (including PRSP)
• Streptococcus sp.
• Enterococcus sp.
• Corynebacterium, Bacillus, Listeria, Actinomyces
• Rhodococcus equi
• Clostridium sp. (including C. difficile),
  Peptococcus, Peptostreptococcus
• No activity against gram-negative aerobes or
• anaerobes

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Vancomycin Pharmacology

• Bactericidal effect except for Enterococcus spp.
• Time-dependent bactericidal action
• Short PAE effect
• Administration IV, oral (poor oral absorption),
  intraperitoneum, intrathecal, intraventricular,
  intraocular
• Protein binding 30-55
• Poor CSF/aqueous humor penetration
• Primarily excrete unchanged by glomerular
  filtration, higher clearance in burn patients

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Vancomycin Pharmacology

• IV administration
• Concentration lt 5 mg/ml
• Rate lt 15 mg/min
• Dosage in normal renal function
  30 mg/kg/day divided into 2-4
  dosages
• Intraperitoneal administration
• In CAPD patient, therapeutic serum level can be
  obtained.
• Intrathecal or intraventricular administration
• Recommend for treatment of shunt
  infection/ventriculitis
• Dosage 10-20 mg/day (diluted up to 2 ml in 0.9
  NSS conc. 2.5-25 mg/ml)
• Monitor CSF trough level 10-20 ?g/ml

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Vancomycin Dosage in Renal Insufficiency

• Hemodialysis 15 mg/kg q 7-10 days
• If high-flux membrane is used, 20 mg/kg loading
  dose with 500 mg after each dialysis
• CVVH 0.5-1.5 g q 24 hours
• CVVHD 0.8-1.75 g q 24 hours
• Renal impairment
• Loading dose 15 mg/kg, followed by
• Dose (mg/day) 15.4 x CCr (mL/min)
• Loading dose 25 mg/kg, followed by 19 mg/kg at
  calculated interval
• Interval normal interval (86 0.689 x CCr
  3.66)

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Indications for Vancomycin Dosage Monitoring

• Concomitantly received another nephrotoxic agents
• Receiving high-dose vancomycin
• Rapidly changing renal function
• Undergoing hemodialysis
• Receiving vancomycin for treatment CNS infection
• Neonate
• Extremely ill patients
• Suspected therapeutic failure
• Morbid obesity
• Burn patient

Optimal Targets Peak serum concentration 30-40
?g/ml Trough level 10-15 ?g/ml Average steady
state 15 ?g/ml
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Teicoplanin Pharmacology

• Administration IV, IM, oral (poor absorption),
  intraperitoneum, intrathecal
• 90 protein binding, highly bound in tissue
• Better bone concentration compared to vancomycin
• More active against Streptococci, including
  Enterococci than vancomycin
• Eliminated by kidney

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Teicoplanin Pharmacology

• IV/IM administration
• Loading 6 mg/kg q 12 hours x 3 doses then q 24
  hours
• In S. aureus endocarditis or septic arthritis,
  and in burn pt.
• 12 mg/kg q 12 hours x 3 doses then q 24 hours
• Intraperitoneal administration
• In CAPD patient, therapeutic serum level can be
  obtained.
• 20 mg/L in each exchange (4 times daily) x 10
  days or for 5 days after bacterial clearance
• Intrathecal or intraventricular administration
• Dosage 10-20 mg/day q 24-48 hours

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Teicoplanin Dosage in Renal Insufficiency

• Hemodialysis 6-12 mg/kg q 72 hours
• CVVHD 800 mg D1, 400 mg D2 3 then 400 mg q
  48-72 hours
• Renal impairment
• CCr 40-60 mL/min 6-12 mg/kg q 48 hours
• Maintenance daily dose normal dose x pts
  CCr/normal CCr
• Extended Interval normal CCr/pts CCr

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Indications for Teicoplanin Dosage Monitoring

• Receiving high-dose teicoplanin
• Rapidly changing renal function
• Undergoing CVVHD
• Suspected therapeutic failure
• Trough level lt 20 ?g/ml is correlated with
  treatment failure.
• IVDU with endocarditis
• Burn patient

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Glycopeptides Adverse Reaction

• Ototoxicity
• Rare, Reversible
• Co-administer with AG augment this event
• Vertigo and tinnitus may precede hearing loss
• Nephrotoxicity Vancomycin gt Teicoplanin
• Rate increase when co-administer with AG
• Acute interstitial nephritis has been reported.
• Neutropenia, Thrombocytopenia
• Thrombophrebitis

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Glycopeptides Adverse Reaction

• Red neck or Red man syndrome
• Infusion-related reaction from vancomycin, rarely
  from teicoplanin
• Anaphylactoid reaction
• Rapid onset of erythematous rash and/or pruritus
  affecting head, face, neck, and upper trunk with
  or without angioedema and hypotension
• Probably related to histamine release
• Prevention by
• Decreasing infusion rate or concentration
• Using antihistamine (H1 receptor antagonist)
• Drug rash, Drug-related fever

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Glycopeptides Drug Interaction

• Drug precipitation when mixed with
• ceftazidime, heparin, chloramphenicol,
• corticosteroid, aminophylline, barbiturate,
• diphenylhydantoin, sodium bicarbonate
• Anion-exchange resins can bind vancomycin and
  decrease activity of vancomycin in the gut lumen.

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PART II
...... to be continue