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
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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
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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 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
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