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Review of ATB Part 1
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5/26/2018 Review of ATB Part 1
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Review of Antimicrobial Agents
Part I
Siriluck Anunnatsiri, MD, MCTM, MPH
Infectious Diseases & Tropical Medicine
Department of Medicine
Khon Kaen University
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Classif ication 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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Classif ication of Antimicrobial AgentsTetracyclines, Tigecycline
Sulfamethoxazole/Trimethoprim (SMX/TMP)
Glycopeptides: Vancomycin, Teicoplanin
Oxazolidinones: Linezolid
Fosfomycin
Fusidic acid
Polymyxins: Polymyxin B, Colistin
Metronidazole
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Classif ication of Antimicrobial AgentsLipopeptide: DaptomycinStreptogramins: Quinupristin-Dalfopristin
-lactam antibiotics
AminoglycosidesGlycopeptides
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Antimicrobial PropertiesStructure
Spectrum
Mechanisms of actionMechanism ofresistance
Pharmacokinetic
Absorption
DistributionMetabolism
Elimination
Pharmacodynamic
Drug interaction
Side effect
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Beta-lactams Antibiotic: Basic Structure
Thiazolidine ringDihydrothiazine ring
Hydroxyethyl
Aminoacyl
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Beta-lactams Antibiotic: General Properties
Inhibit cell wall synthesis
Bactericidal effect
Time-dependent bactericidal action
Inoculum effect on antimicrobial activity ismore prominent
In GNB - No or short PAE for most -lactam
Share -lactam class allergic reaction exceptmonobactams
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PD Parameters affecting Antibiotic Potency
> 40-50% of dosing interval
AUC/MIC>125 for GNB>25-50 for GPCCmax/MIC >10
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Inoculum EffectThe effect of inoculum size onantimicrobial activity
Dense population can be lesssusceptible to -lactams
Failure to express receptor (PBP)
High concentration of -lactamases
Trend to presence of resistantsubpopulation
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Postantibitic Effect
A persistent suppression of growth afterlevels have fallen below the MIC
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Bacter ial Cell Wall Synthesis
Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155
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Bacter ial Cell Wall Synthesis
Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155
(Transpeptidase)
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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 PBPtarget
Efflux of antibiotic across the outer
membrane of gram-negativeLow-affinity binding of antibiotic to PBPtarget
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Beta-lactams Antibiotic: Adverse Reactions
Hypersensitivity3 to 10 %
Irritability, jerking, confusion, seizuresespeciallywith high dose penicillins and imipenem
Leukopenia, neutropenia, thrombocytopeniatherapy > 2 weeks
Interstitial nephritis
Cephalosporin-specific: cefamandole, cefotetan,cefmetazole, cefoperazone, moxalactam
Hypoprothrombinemia - due to reduction invitamin K-producing bacteria in GI tract
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Penici l l ins: Classif ication
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 Penici l l ins: Spectrum of Activity
Gram-positive Gram-negative
S. pneumoniae Neisseriameningitidis
Streptococcussp.
Enterococcussp. Anaerobes
C. diphtheriae Above the diaphragm
B. anthracis Clostridiumperfringens
L. monocytogenes
Other
Treponema pallidum
Leptospirasp.
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Penici l l inase-Resistant Penici l l ins: Spectrum
Gram-positive
MSSA
MSSEStreptococcussp.
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Aminopenici l l ins: Spectrum of Activity
Gram-positive Gram-negative
Streptococcussp. Proteus mirabilis
Enterococcussp. Salmonella sp.L. monocytogenes Shigella
C. diphtheriae some E. coli
H. influenzae
N. meningitidisAnaerobes
Above the diaphragm
Clostridiumperfringens
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Carboxypenici l l ins: Spectrum of Activi ty
Gram-positive Gram-negative
Streptococcussp. Proteus mirabilisC. diphtheriae Salmonella sp.
ShigellaE. coli
H. influenzae
Neisseria sp.
Anaerobes Enterobacter sp.
Fairly good activity P. aeruginosa
Citrobacter sp.
Serratia sp.
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Ureidopenici l l ins: Spectrum of Activity
Gram-positive Gram-negative
Streptococcussp. Proteus mirabilisEnterococcus sp. Salmonella sp.
L. monocytogenes ShigellaE. coli
Klebsiella sp.
H. influenzae
Neisseria sp.Anaerobes Enterobacter sp.
Fairly good activity P. aeruginosa
S. marcescens
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Penici l l ins: Pharmacology
AdministrationOral, IV, IM
Varying oral absorption
40% for Ampicillin 75% for AmoxicillinVarying protein binding
17% for aminopenicillin 97% for dicloxacillin
More free drugs in the presence of probenecid
Mainly excrete via renal tubular cells, whichcan be blocked by probenecid.
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Penici l l ins: Pharmacology
Dose adjustment is needed when CCr < 10-20 ml/min, on hemodialysis or CVVH
Biliary excretion is important only for nafcillinand antipseudomonal penicillins.Well distributed to most tissues, high
concentration in urine and bileRelatively insoluble in lipid and penetrate cellsrelatively poorly
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Cephalospor ins: Classif ication
1stGeneration 2ndGeneration Cephamycins 3rdGeneration 4thGenerationCefazolin Cefamandole Cefmetazole Ceftriaxone CefepimeCephalothin Cefonicid Cefotetan Cefotaxime CefpiromeCephapirin Cefmetazole Cefoxitin CeftazidimeCephradine Cefotetan CefoperazoneCefadroxil Cefoxitin CeftizoximeCephalexin Cefuroxime Cefsulodin
Cefprozil MoxalactamLoracarbef CefdinirCefaclor Cefditoren
CefiximeCeftibutenCefpodoxime
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1stGeneration Cephalospor ins: Spectrum
Best activity against gram-positive aerobes, withlimited activity against a few gram-negative aerobesGram-positive Gram-negativeMSSA EnterobacteriaceaeStreptococcussp.
2ndGeneration Cephalospor ins/Cephamycins:
SpectrumMore active against gram-negative aerobes
Cephamycin group has activity against gram-negative
anaerobes including Bacteroides fragilis
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3rdGeneration Cephalospor ins: Spectrum
Increase potency against gram-negativeaerobes
Ceftriaxone and cefotaxime have the bestactivity against MSSA and Streptococcus sp.
Ceftazidime, moxalactam, cefixime, andceftibuten have less activity against MSSA
Ceftazidime, cefoperazone, and cefsulodinhave activity against P. aeruginosa.
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4thGeneration Cephalospor ins: Spectrum
Extended spectrum of activity
gram-positives: similar to ceftriaxone
gram-negatives: Enterobacteriaceaeincluding cephalosporinase-producer,P. aeruginosa.
Stability against -lactamases; poor inducer
of extended-spectrum -lactamases
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Cephalospor ins: Pharmacology
Polar, water-soluble compoundsAdministrationIM, IV, oral, intraperitoneumHigh oral bioavailability
Varying protein binding10% -> 98%Largely confined to extracellularcompartment, relatively poor intracellularconcentration
Good CNS penetrationOnly 3rd
& 4th
gen.cephalosporinsAlmost excrete via renal tubular secretion,except ceftriaxone and cefoperazone arelargely eliminated via biliary route
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Carbapenems
Imipenem
N-formimidoyl derivative of thienamycin
Need to combine with cilastatin to preventrenal dehydropeptidase I hydrolysis andnephrotoxic effect
Meropenem, Ertapenem-1-methyl, 2-thio pyrrolidinyl derivative ofthienamycin
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Carbapenems: Spectrum of Activity
Most broad spectrum of activity of allantimicrobials
Have activity against gram-positive and gram-negative aerobes, anaerobes, Nocardiasp.,rapid-growing mycobacteria
Bacteria not covered by carbapenems include
MRSA, MRSE, E. faecium, C. difficile, S.maltophilia, B. cepacia
Ertapenem not active against P. aeruginosaandAcinetobactersp.
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Carbapenems: Pharmacology
Absorbed poorly after oral ingestionT1/2:
Imipenem, Meropenem 1 hrErtapenem 4 hr
Well distributed to body compartment andpenetrate well into the most tissues
Excrete via renal, dosage adjustment isrequired in patient with impaired renalfunction.Need supplement dose in patient performingCVVH, hemodialysis
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-Lactam/-Lactamase I nhibitorAmpicillin/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 I nhibitor: Spectrum
Maintain spectrum of -Lactams but enhanceactivity against -Lactamase (Ambler class A)
producing organismsActivity against MSSA, Streptococcus sp.,Enterococcus sp. (Except C/S),-Lactamaseproducing Enterobactericeae, P. aeruginosa(Only P/T, C/S), Anaerobes.
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-Lactam/-Lactamase I nhibitor: PharmacologyClavulanate, SulbactamModerately wellabsorbed
Good tissue distribution
Penetration into inflamed meninges
Clavulanate, SulbactamPoor
TazobactamGood in animal model
ExcretionClavulanateLung, 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 anaerobicbacteria
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: Classif ication
Family MemberStreptidine aminocyclitol ring
Streptomycin
Streptomycin
Spectinomycin2-deoxystreptamine aminocyclitol ring
Kanamycin Kanamycin, Amikacin,Tobramycin, Dibekacin
Gentamicin Gentamicin, Netilmicin,Sisomicin, Isepamicin
Neomycin Neomycin, Paromomycin
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Aminoglycosides: Mechanism of Action
Aminogl cosides Mechanism of Resistance
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Aminoglycosides: Mechanism of Resistance
AcetyltransferasesAdenyltransferase
Phosphotransferases
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Aminoglycosides: Spectrum of Activi ty
Gram-Negative Aerobes
Enterobacteriaceae, P. aeruginosa,Acinetobacter sp.- Kanamycin & Gentamicin
groupsF. tularensis, Brucellasp., Y. pestis -
Streptomycin, gentamicin
N. gonorrhoeae - Spectinomycin
Mycobacteria
M. tuberculosisStreptomycin, kanamycin,amikacin
Non-tuberculousAmikacin, streptomycin
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Aminoglycosides: Spectrum of Activity
Gram-Positive Aerobes(In vitro synergy)
S. aureus, S. epidermidis, viridans streptococci,
Enterococcussp.
Nocardia sp. - Amikacin
E. histolytica, C. parvum- Paromomycin
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Aminoglycosides: Pharmacology
Bactericidal effect
Concentration dependent killing
Little influence by inoculum effectPresence of PAE effect
AdministrationIV, IM, intrathecal,intraperitoneum, inhale, oral (neomycin,paromomycin), topicalLow level of protein binding (10%), highwater solubility, lipid insolubility
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Aminoglycosides: Pharmacology
99% of drug is excreted unchanged byglomerular filtration
5% of excreted drug is reabsorbed atrenal proximal tubule
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Once-Daily Aminoglycosides
Equal efficacy compared to multiple-doseadministrationMay lower but not eliminate risk of drug-induced
nephrotoxicity and ototoxicitySimple, less time consuming, and more costeffectiveDoes not worsen neuromuscular function incritically ill ventilated patientsProbably should not be used in enterococcalendocarditisNeed further study in pregnancy, cystic fibrosis,GNB meningitis, endocarditis, and osteomyelitis
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Aminoglycosides: Adverse Effects
Neuromuscular blockageNephrotoxicity
Reversible if detection early
Risk factors: prolonged trough level, volumedepletion, hypotension, underlying renaldysfunction, elderly, other nephrotoxins
Ototoxicity
Cumulative dose8th 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 BSACS I R S R
Vancomycin 32 8
Teicoplanin 32 8NCCLS = The National Committee for Clinical Laboratory StudiesBSAC = The British Society for Antimicrobial Chemotherapy
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Glycopeptide-resistant S. aureus
Recommend using MIC determination forconfirmation of VISA, GISA, or VRSA isolates
Heteroresistance phenomenon: Hetero-VRSAOnly a subpopulation of S. aureuscan grow onvancomycin-containing agar (>8 g/ml)
Precursor of VISA/VRSA isolates
Population analysis is needed to identify hetero-VRSA
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Glycopeptide-resistant Enterococci
StainCharacteristics Acquired resistance level, Type Intrinsicresistance,
low level,Type
VanC1, C2,
C3
High,VanA Variable,VanB Moderate,VanD Low
VanG VanE
MIC, mg/LVancomycin 64-100 4-1000 64-128 16 8-32 2-32Teicoplanin 16-512 0.5-1 4-64 0.5 0.5 0.5-1ModifiedTarget 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 kinaseVanR = Cytoplasmic response regulator
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Glycopeptides: Spectrum of Activity
Gram-positive bacteriaMSSA, MRSA, MSSE, MRSES. pneumoniae (including PRSP)
Streptococcussp.Enterococcussp.Corynebacterium, Bacillus, Listeria, ActinomycesRhodococcus equi
Clostridiumsp. (including C. difficile),Peptococcus,Peptostreptococcus
No activity against gram-negative aerobes oranaerobes
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Vancomycin: Pharmacology
Bactericidal effect except for Enterococcusspp.
Time-dependent bactericidal action
Short PAE effectAdministration: 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 administrationConcentration < 5 mg/ml
Rate < 15 mg/min
Dosage in normal renal function:
30 mg/kg/day divided into 2-4 dosagesIntraperitoneal administration
In CAPD patient, therapeutic serum level can be obtained.
Intrathecal or intraventricular administration
Recommend for treatment of shunt infection/ventriculitisDosage: 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 I nsuf f iciency
Hemodialysis: 15 mg/kg q 7-10 daysIf high-flux membrane is used, 20 mg/kg loadingdose with 500 mg after each dialysis
CVVH: 0.5-1.5 g q 24 hoursCVVHD: 0.8-1.75 g q 24 hours
Renal impairmentLoading dose 15 mg/kg, followed by
Dose (mg/day) = 15.4 x CCr (mL/min)Loading dose 25 mg/kg, followed by19 mg/kg atcalculated interval
Interval = normal interval (86 [0.689 x CCr + 3.66])
I di ti f V i D M i t i
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I ndications for Vancomycin Dosage Moni tor ing
Concomitantly received another nephrotoxic agents
Receiving high-dose vancomycinRapidly changing renal function
Undergoing hemodialysis
Receiving vancomycin for treatment CNS infection
NeonateExtremely ill patients
Suspected therapeutic failure
Morbid obesity
Burn patientOptimal TargetsPeak serum concentration 30-40 g/mlTrough 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 tissueBetter bone concentration compared tovancomycin
More active against Streptococci, includingEnterococci 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. aureusendocarditis 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 clearanceIntrathecal or intraventricular administration
Dosage: 10-20 mg/day q 24-48 hours
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Teicoplanin Dosage in Renal I nsuf f iciency
Hemodialysis: 6-12 mg/kg q 72 hours
CVVHD: 800 mg D1, 400 mg D2 & 3 then400 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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I ndications for Teicoplanin Dosage Moni tor ing
Receiving high-dose teicoplanin
Rapidly changing renal function
Undergoing CVVHDSuspected therapeutic failure
Trough level < 20 g/ml is correlated withtreatment failure.
IVDU with endocarditis
Burn patient
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Glycopeptides: Adverse Reaction
OtotoxicityRare, Reversible
Co-administer with AG augment this eventVertigo and tinnitus may precede hearing loss
Nephrotoxicity: Vancomycin > TeicoplaninRate 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 syndromeInfusion-related reaction from vancomycin, rarelyfrom teicoplanin
Anaphylactoid reactionRapid onset of erythematous rash and/or pruritusaffecting head, face, neck, and upper trunk withor 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 I nteraction
Drug precipitation when mixed with
ceftazidime, heparin, chloramphenicol,
corticosteroid, aminophylline, barbiturate,
diphenylhydantoin, sodium bicarbonate
Anion-exchange resins can bind
vancomycin and decrease activity ofvancomycin in the gut lumen.
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