review of atb part 1

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


(Transpeptidase)


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Beta-lactams Antibiotic : Mechanism of Action



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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


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


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


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



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Glycopeptides: Mechanism of Resistance in S. aureus



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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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review of atb part 1

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