Review of Antimicrobial AgentsReview of Antimicrobial AgentsPart IPart I

Siriluck Anunnatsiri, MD, MCTM, MPHInfectious Diseases & Tropical MedicineDepartment of MedicineKhon Kaen University

Classification of Antimicrobial Agents

-lactam antibiotics:

Penicillins, Cephalosporins, Carbapenems, Monobactams, -lactam/-lactamases inhibitors

Aminoglycosides

Macrolides

Ketolides: Telithromycin, Dirithromycin

Lincosamides: Lincomycin, Clindamycin

Quinolones

Chloramphenicol

Classification of Antimicrobial Agents

Tetracyclines, Tigecycline

Sulfamethoxazole/Trimethoprim (SMX/TMP)

Glycopeptides: Vancomycin, Teicoplanin

Oxazolidinones: Linezolid

Fosfomycin

Fusidic acid

Polymyxins: Polymyxin B, Colistin

Metronidazole

Classification of Antimicrobial Agents

Lipopeptide: DaptomycinStreptogramins: Quinupristin-Dalfopristin

-lactam antibiotics

Aminoglycosides

Glycopeptides

Antimicrobial Properties

StructureSpectrumMechanisms of actionMechanism of resistance

PharmacokineticAbsorptionDistributionMetabolismElimination

PharmacodynamicDrug interactionSide effect

Beta-lactams Antibiotic: Basic StructureThiazolidine ring

Dihydrothiazine ring

Hydroxyethyl

Aminoacyl

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

PD Parameters affecting Antibiotic Potency

> 40-50% of dosing interval

AUC/MIC >125 for GNB>25-50 for GPCCmax/MIC >10

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

Postantibitic Effect

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

Bacterial Cell Wall Synthesis

Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155

Bacterial Cell Wall Synthesis

Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155

(Transpeptidase)

Beta-lactams Antibiotic : Mechanism of Action

Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155

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

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

Penicillins: ClassificationNatural penicillins

Penicillin V, Penicillin G

Aminopenicillins

Ampicillin, Amoxicillin

Penicillinase-resistant penicillins

Cloxacillin, Dicloxacillin, Nafcillin, Methicillin

Carboxypenicillins

Carbenicillin, Ticarcillin

Ureidopenicillin

Piperacillin, Azlocillin, Mezlocillin

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.

Penicillinase-Resistant Penicillins: Spectrum

Gram-positive MSSAMSSE Streptococcus sp.

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

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.

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

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.

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

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

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

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.

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

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

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

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.

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

-Lactam/-Lactamase Inhibitor

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

-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.

-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

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

Aminoglycosides: Basic Chemical Structure

Aminocyclitol Ring

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

Aminoglycosides: Mechanism of Action

Aminoglycosides: Mechanism of Resistance

AcetyltransferasesAdenyltransferase

Phosphotransferases

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

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

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

Aminoglycosides: Pharmacology

99% of drug is excreted unchanged by glomerular filtration5% of excreted drug is reabsorbed at renal proximal tubule

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

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)

Glycopeptides

VancomycinTeicoplanin

Glycopeptides: Mechanism of Action

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Glycopeptides: Mechanism of Resistance in S. aureus

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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

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

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.

Glycopeptide-resistant Enterococci

VanS = Membrane-associated sensor kinaseVanR = Cytoplasmic response regulator

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

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

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

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])

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

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

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

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

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

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

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

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.