review of antimicrobial agents part i
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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. Classification of Antimicrobial Agents. -lactam antibiotics: - PowerPoint PPT PresentationTRANSCRIPT
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Review of Antimicrobial AgentsReview of Antimicrobial AgentsPart IPart I
Siriluck Anunnatsiri, MD, MCTM, MPHInfectious Diseases & Tropical MedicineDepartment of MedicineKhon 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: DaptomycinStreptogramins: Quinupristin-Dalfopristin
-lactam antibiotics
Aminoglycosides
Glycopeptides
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Antimicrobial Properties
StructureSpectrumMechanisms of actionMechanism of resistance
PharmacokineticAbsorptionDistributionMetabolismElimination
PharmacodynamicDrug interactionSide effect
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Beta-lactams Antibiotic: Basic StructureThiazolidine ring
Dihydrothiazine ring
Hydroxyethyl
Aminoacyl
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Beta-lactams Antibiotic: General PropertiesInhibit cell wall synthesis
Bactericidal effect Time-dependent bactericidal actionInoculum effect on antimicrobial activity is more prominentIn GNB - No or short PAE for most -lactam Share -lactam class allergic reaction except monobactams
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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 Effect
The effect of inoculum size on antimicrobial activityDense population can be less susceptible to -lactams
Failure to express receptor (PBP)High concentration of -lactamasesTrend 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
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 antibioticFailure of antibiotic to penetrate the outer membrane of gram-negative to reach PBP targetEfflux of antibiotic across the outer membrane of gram-negativeLow-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 > 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: ClassificationNatural 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-negativeS. pneumoniae Neisseria meningitidisStreptococcus sp. Enterococcus sp. AnaerobesC. diphtheriae Above the diaphragmB. anthracis Clostridium
perfringensL. monocytogenes
OtherTreponema pallidumLeptospira sp.
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Penicillinase-Resistant Penicillins: Spectrum
Gram-positive MSSAMSSE Streptococcus sp.
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Aminopenicillins: Spectrum of Activity
Gram-positive Gram-negative
Streptococcus sp. Proteus mirabilis
Enterococcus sp. Salmonella sp.L. monocytogenes ShigellaC. diphtheriae some E. coliH. influenzae N. meningitidisAnaerobesAbove the diaphragmClostridium perfringens
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Carboxypenicillins: Spectrum of Activity
Gram-positive Gram-negative Streptococcus sp. Proteus mirabilisC. diphtheriae Salmonella sp.
ShigellaE. coliH. influenzaeNeisseria 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 mirabilisEnterococcus sp. Salmonella sp.L. monocytogenes Shigella
E. coliKlebsiella sp.H. influenzaeNeisseria sp.
Anaerobes Enterobacter sp.Fairly good activity P. aeruginosa
S. marcescens
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Penicillins: Pharmacology
Administration – Oral, IV, IMVarying oral absorption 40% for Ampicillin 75% for Amoxicillin Varying protein binding
17% for aminopenicillin 97% for dicloxacillinMore 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 < 10-20 ml/min, on hemodialysis or CVVHBiliary excretion is important only for nafcillin and antipseudomonal penicillins.Well distributed to most tissues, high concentration in urine and bileRelatively 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: Spectrum
Best activity against gram-positive aerobes, with limited activity against a few gram-negative aerobesGram-positive Gram-negativeMSSA EnterobacteriaceaeStreptococcus sp.
2nd Generation Cephalosporins/Cephamycins: SpectrumMore 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 aerobesCeftriaxone and cefotaxime have the best activity against MSSA and Streptococcus sp. Ceftazidime, moxalactam, cefixime, and ceftibuten have less activity against MSSACeftazidime, 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 compoundsAdministration – IM, IV, oral, intraperitoneumHigh oral bioavailabilityVarying protein binding – 10% -> 98%Largely confined to extracellular compartment, relatively poor intracellular concentrationGood 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
ImipenemN-formimidoyl derivative of thienamycinNeed 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 antimicrobialsHave activity against gram-positive and gram-negative aerobes, anaerobes, Nocardia sp., rapid-growing mycobacteriaBacteria not covered by carbapenems include MRSA, MRSE, E. faecium, C. difficile, S. maltophilia, B. cepaciaErtapenem not active against P. aeruginosa and Acinetobacter sp.
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Carbapenems: Pharmacology
Absorbed poorly after oral ingestionT1/2:
Imipenem, Meropenem 1 hrErtapenem 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 organismsActivity 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 absorbedGood tissue distributionPenetration into inflamed meninges
Clavulanate, Sulbactam – Poor Tazobactam – Good in animal model
ExcretionClavulanate – Lung, feces, urineSulbactam, 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
Streptomycin Streptomycin
Spectinomycin
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
AcetyltransferasesAdenyltransferase
Phosphotransferases
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Aminoglycosides: Spectrum of Activity
Gram-Negative Aerobes Enterobacteriaceae, P. aeruginosa, Acinetobacter sp.- Kanamycin & Gentamicin groupsF. tularensis, Brucella sp., Y. pestis -Streptomycin, gentamicinN. gonorrhoeae - Spectinomycin
MycobacteriaM. tuberculosis – Streptomycin, kanamycin, amikacinNon-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. - AmikacinE. histolytica, C. parvum - Paromomycin
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Aminoglycosides: Pharmacology
Bactericidal effectConcentration dependent killingLittle influence by inoculum effectPresence of PAE effect Administration – IV, IM, intrathecal, intraperitoneum, inhale, oral (neomycin, paromomycin), topicalLow level of protein binding (10%), high water solubility, lipid insolubility
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Aminoglycosides: Pharmacology
99% of drug is excreted unchanged by glomerular filtration5% of excreted drug is reabsorbed at renal proximal tubule
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Once-Daily Aminoglycosides
Equal efficacy compared to multiple-dose administrationMay lower but not eliminate risk of drug-induced nephrotoxicity and ototoxicitySimple, less time consuming, and more cost effectiveDoes not worsen neuromuscular function in critically ill ventilated patientsProbably should not be used in enterococcal endocarditisNeed further study in pregnancy, cystic fibrosis, GNB meningitis, endocarditis, and osteomyelitis
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Aminoglycosides: Adverse EffectsNeuromuscular blockageNephrotoxicity
Reversible if detection earlyRisk factors: prolonged trough level, volume depletion, hypotension, underlying renal dysfunction, elderly, other nephrotoxins
OtotoxicityCumulative dose8th cranial nerve damage - irreversible
Vestibular toxicity: dizziness, vertigo, ataxia Auditory toxicity: tinnitus, decreased hearing (high frequency)
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Glycopeptides
VancomycinTeicoplanin
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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 BSAC
S I R S R
Vancomycin
<4 8-16 >32 <4 >8
Teicoplanin
<8 16 >32 <4 >8
NCCLS = 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 for confirmation of VISA, GISA, or VRSA isolates Heteroresistance phenomenon: Hetero-VRSA
Only a subpopulation of S. aureus can grow on vancomycin-containing agar (>8 g/ml)Precursor of VISA/VRSA isolatesPopulation analysis is needed to identify hetero-VRSA
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Glycopeptide-resistant EnterococciStain Characteristics
Acquired resistance level, Type Intrinsic resistanc
e, low level, Type
VanC1, C2, C3
High, VanA
Variable, VanB
Moderate, VanD
Low
VanG VanE
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 kinaseVanR = Cytoplasmic response regulator
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Glycopeptides: Spectrum of Activity
Gram-positive bacteriaMSSA, MRSA, MSSE, MRSES. pneumoniae (including PRSP)Streptococcus sp.Enterococcus sp.Corynebacterium, Bacillus, Listeria, ActinomycesRhodococcus equiClostridium 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 actionShort PAE effectAdministration: IV, oral (poor oral absorption), intraperitoneum, intrathecal, intraventricular, intraocularProtein binding 30-55%Poor CSF/aqueous humor penetrationPrimarily excrete unchanged by glomerular filtration, higher clearance in burn patients
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Vancomycin: PharmacologyIV administration
Concentration < 5 mg/mlRate < 15 mg/minDosage in normal renal function: 30 mg/kg/day divided into 2-4 dosages
Intraperitoneal administrationIn CAPD patient, therapeutic serum level can be obtained.
Intrathecal or intraventricular administrationRecommend 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 Insufficiency
Hemodialysis: 15 mg/kg q 7-10 daysIf high-flux membrane is used, 20 mg/kg loading dose with 500 mg after each dialysisCVVH: 0.5-1.5 g q 24 hoursCVVHD: 0.8-1.75 g q 24 hoursRenal 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 intervalInterval = normal interval (86 ÷ [0.689 x CCr + 3.66])
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Indications for Vancomycin Dosage Monitoring
Concomitantly received another nephrotoxic agentsReceiving high-dose vancomycinRapidly changing renal functionUndergoing hemodialysisReceiving vancomycin for treatment CNS infectionNeonateExtremely ill patients Suspected therapeutic failureMorbid obesityBurn patient
Optimal TargetsPeak serum concentration 30-40 g/mlTrough level 10-15 g/mlAverage steady state 15 g/ml
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Teicoplanin: Pharmacology
Administration: IV, IM, oral (poor absorption), intraperitoneum, intrathecal90% protein binding, highly bound in tissueBetter bone concentration compared to vancomycinMore active against Streptococci, including Enterococci than vancomycinEliminated by kidney
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Teicoplanin: Pharmacology
IV/IM administrationLoading 6 mg/kg q 12 hours x 3 doses then q 24 hoursIn S. aureus endocarditis or septic arthritis, and in burn pt.12 mg/kg q 12 hours x 3 doses then q 24 hours
Intraperitoneal administrationIn 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 administrationDosage: 10-20 mg/day q 24-48 hours
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Teicoplanin Dosage in Renal Insufficiency
Hemodialysis: 6-12 mg/kg q 72 hoursCVVHD: 800 mg D1, 400 mg D2 & 3 then 400 mg q 48-72 hoursRenal impairment
CCr 40-60 mL/min: 6-12 mg/kg q 48 hoursMaintenance daily dose = normal dose x [pt’s CCr/normal CCr]Extended Interval = normal CCr/pt’s CCr
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Indications for Teicoplanin Dosage Monitoring
Receiving high-dose teicoplaninRapidly changing renal functionUndergoing CVVHDSuspected therapeutic failureTrough level < 20 g/ml is correlated with treatment failure.IVDU with endocarditisBurn patient
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Glycopeptides: Adverse Reaction
OtotoxicityRare, ReversibleCo-administer with AG augment this eventVertigo and tinnitus may precede hearing loss
Nephrotoxicity: Vancomycin > TeicoplaninRate increase when co-administer with AGAcute interstitial nephritis has been reported.
Neutropenia, ThrombocytopeniaThrombophrebitis
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Glycopeptides: Adverse Reaction“Red neck” or “Red man” syndrome
Infusion-related reaction from vancomycin, rarely from teicoplaninAnaphylactoid reactionRapid onset of erythematous rash and/or pruritus affecting head, face, neck, and upper trunk with or without angioedema and hypotensionProbably related to histamine releasePrevention 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 withceftazidime, 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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