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: 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: Daptomycin Streptogramins: Quinupristin-Dalfopristin -lactam antibiotics Aminoglycosides
Glycopeptides

Antimicrobial Properties
Structure Spectrum Mechanisms of action Mechanism of resistance Pharmacokinetic Absorption Distribution Metabolism Elimination Pharmacodynamic Drug interaction Side effect

Beta-lactams Antibiotic: Basic Structure

Aminoacyl
Thiazolidine ring Dihydrothiazine ring

Hydroxyethyl

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

PD Parameters affecting Antibiotic Potency

AUC/MIC >125 for GNB >25-50 for GPC Cmax/MIC >10

> 40-50% of dosing interval

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

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

(Transpeptidase)

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

Beta-lactams Antibiotic : Mechanism of Action

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

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

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: Classification
Natural 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-negative

S. pneumoniae Streptococcus sp. Enterococcus sp. C. diphtheriae B. anthracis L. monocytogenes

Neisseria meningitidis
Anaerobes Above the diaphragm

Clostridium perfringens
Other

Treponema pallidum Leptospira sp.

Penicillinase-Resistant Penicillins: Spectrum

Gram-positive MSSA MSSE Streptococcus sp.

Aminopenicillins: Spectrum of Activity

Gram-positive Gram-negative

Streptococcus sp. Enterococcus sp. L. monocytogenes C. diphtheriae

Proteus mirabilis Salmonella sp.

Shigella some E. coli

H. influenzae N. meningitidis
Anaerobes Above the diaphragm

Clostridium perfringens

Carboxypenicillins: Spectrum of Activity

Gram-positive Gram-negative

Streptococcus sp. C. diphtheriae

Anaerobes

Fairly good activity

Proteus mirabilis Salmonella sp. Shigella E. coli H. influenzae Neisseria sp. Enterobacter sp. P. aeruginosa Citrobacter sp. Serratia sp.

Ureidopenicillins: Spectrum of Activity

Gram-positive Gram-negative

Streptococcus sp. Enterococcus sp. L. monocytogenes

Anaerobes

Fairly good activity

Proteus mirabilis Salmonella sp. Shigella E. coli Klebsiella sp. H. influenzae Neisseria sp. Enterobacter sp. P. aeruginosa S. marcescens

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.

Penicillins: Pharmacology
Dose adjustment is needed when CCr < 1020 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

Cephalosporins: Classification
1st Generation 2nd Generation Cephamycins 3rd Generation 4th Generation Cefazolin Cephalothin Cephapirin Cephradine Cefadroxil Cefamandole Cefonicid Cefmetazole Cefotetan Cefoxitin Cefmetazole Cefotetan Cefoxitin Ceftriaxone Cefotaxime Ceftazidime Cefoperazone Ceftizoxime Cefepime Cefpirome

Cephalexin

Cefuroxime
Cefprozil Loracarbef Cefaclor

Cefsulodin
Moxalactam Cefdinir Cefditoren

Cefixime
Ceftibuten Cefpodoxime

1st Generation Cephalosporins: Spectrum

Best activity against gram-positive aerobes, with limited activity against a few gram-negative aerobes Gram-positive Gram-negative MSSA Enterobacteriaceae Streptococcus sp.

2nd Generation Cephalosporins/Cephamycins: Spectrum

More 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 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.

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 compounds Administration IM, IV, oral, intraperitoneum High oral bioavailability Varying protein binding 10% -> 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

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

Carbapenems: Spectrum of Activity

Most broad spectrum of activity of all antimicrobials Have activity against gram-positive and gramnegative 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.

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

-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 organisms Activity 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 absorbed Good tissue distribution Penetration into inflamed meninges
Clavulanate, Sulbactam Poor Tazobactam Good in animal model

Excretion
Clavulanate Lung, feces, urine Sulbactam, 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 crossreaction with other -Lactams Weak -Lactamase inducer

Aminoglycosides: Basic Chemical Structure

Aminocyclitol Ring

Aminoglycosides: Classification
Family Member

Streptidine aminocyclitol ring

Streptomycin Spectinomycin Kanamycin
Gentamicin

Streptomycin

2-deoxystreptamine aminocyclitol ring

Kanamycin, Amikacin, Tobramycin, Dibekacin
Gentamicin, Netilmicin, Sisomicin, Isepamicin

Neomycin

Neomycin, Paromomycin

Aminoglycosides: Mechanism of Action

Aminoglycosides: Mechanism of Resistance

Adenyltransferase

Acetyltransferases

Phosphotransferases

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

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

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

Aminoglycosides: Pharmacology
99% of drug is excreted unchanged by glomerular filtration 5% of excreted drug is reabsorbed at renal proximal tubule

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

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)

Glycopeptides
Vancomycin Teicoplanin

Glycopeptides: Mechanism of Action

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

Glycopeptides: Mechanism of Resistance in S. aureus

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

Glycopeptide-resistant S. aureus
NCCLS S Vancomycin
Teicoplanin

BSAC R >32
>32

I 8-16
16

S <4
<4

R >8
>8

<4
<8

NCCLS = The National Committee for Clinical Laboratory Studies BSAC = 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 isolates Population analysis is needed to identify heteroVRSA

Glycopeptide-resistant Enterococci
Stain Characteristics Acquired resistance level, Type

High, VanA

Variable, Moderate, VanB VanD

Low
VanG VanE

Intrinsic resistance, low level, Type VanC1, C2, C3

MIC, mg/L Vancomycin Teicoplanin Modified Target 64-100 16-512 D-AlaD-Lac 4-1000 0.5-1 D-AlaD-Lac 64-128 4-64 D-AlaD-Lac 16 0.5 D-AlaD-Ser 8-32 0.5 D-AlaD-Ser 2-32 0.5-1 D-AlaD-Ser

Courvalin P. Clin Infect Dis 2006; 42: S25-S34.

Glycopeptide-resistant Enterococci

VanS = Membrane-associated sensor kinase VanR = Cytoplasmic response regulator

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

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

Vancomycin: Pharmacology
IV administration Concentration < 5 mg/ml Rate < 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

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])

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 Trough level Average steady state 30-40 g/ml 10-15 g/ml 15 g/ml

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

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

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

Indications for Teicoplanin Dosage Monitoring

Receiving high-dose teicoplanin Rapidly changing renal function Undergoing CVVHD Suspected therapeutic failure Trough level < 20 g/ml is correlated with treatment failure. IVDU with endocarditis Burn patient

Glycopeptides: Adverse Reaction

Ototoxicity
Rare, Reversible Co-administer with AG augment this event Vertigo and tinnitus may precede hearing loss

Nephrotoxicity: Vancomycin > Teicoplanin

Rate increase when co-administer with AG Acute interstitial nephritis has been reported.

Neutropenia, Thrombocytopenia Thrombophrebitis

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

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.