Antibiotics

Approach to IDHost setting + Clinical syndrome

Possible pathogens

Proper lab & investigations

Empyrical Rx

F/U clinical parameters

SPECIFIC treatment

Disease ?Disease ?

Drug?Drug?

Bug ?Bug ?

Gram-PositiveCOCCI

clusters- Staphylococcipairs and chains

- Sreptococci- Enterococcus sp.

BACILLIBacillus sp.Corynebacterium sp.Listeria

monocytogenesNocardia sp.

Gram-NegativeCOCCI

Moraxella catarrhalisNeisseria gonorrhoeaeNeisseria meningitidis

BACILLIEnterobacteriaceae (E.

coli,Enterobacter sp. Citrobacter, Klebsiella sp.Proteus sp.,

SerratiaSalmonella, Shigella)

Pseudomonas aeruginosaBurkholderia

pseudomalleiNon fermentative GNB

COCCOBACILLIH. influenzae,

Acinetobacter

AnaerobesAbove DiaphragmAbove Diaphragm

Peptococcus sp. Peptostreptococcus sp. Prevotella Veillonella Actinomyces

Below DiaphragmBelow Diaphragm Clostridium perfringens, tetani,

and difficile Bacteroides fragilis, disastonis,

ovatus, thetaiotamicron Fusobacterium

Other Pathogen Spirochete:

Leptospirosis Syphilis

Ricketsia: Scrub typhus Murine typhus

Legionella Mycoplasma Chlamydia

Higher bacteriaMycobacterium spp. TB, NTMNocardia

Bacteria by Site of InfectionMeningitis

S. pneumoniae

N. meningitidis

H. influenza

Streptococci

E. coli, listeria

Skin/Soft Tissue

S. aureus

S. pyogenes

S. epidermidis

Exposed organism

Endocarditis

Viridian strep

S.bovis

Enterococcus

Abdomen

E. coli, Proteus

Klebsiella

Enterococcus

Bacteroides sp.

Urinary Tract

E. coli, Proteus

Klebsiella

Enterococcus

Staph saprophyticus

Bone and J oint

S. aureus

S. epidermidis

Streptococci

Nram-negative rods

Upper Respiratory

S. pneumoniae

H. influenzae

M. catarrhalis

S. pyogenes

LRI Community

S. pneumoniae

H. influenzae

K. pneumoniae

Legionella,Mycoplasma,

Chlamydia, Ricketsia¤,

LRI Hospital

A. baumannii

P. aeruginosa

K. pneumoniae

Enterobacter sp.

S. aureus

Antibiotic Mechanism of action Spectrum Resistance mechanism PK/PD:

Bioavailability Absorption Distribution: Intracellular, Extracellular, Tissue penetration Elimination : Renal, Hepatic, HD, PD Killing effect ( cidal / static) Parameter correlated with efficacy

ADR Drug interaction

I. CELL WALL SYNTHESIS • Vancomycin, Fosfomycin , bacitracin • Beta-lactams

mRNA

DNA

ribosomes30

II. DNA Synthesis • Quinolones

•Metronidazole

PABA VI. CELL MEMBRANE • Polymyxin B • Colistin

IV. PROTEIN SYNTHESIS - 30S INHIBITORS

• Tetracycline

• Aminoglycoside• - 5 0 S INHIBITORS

• Macrolide

-III. DNA DEPENDENT RNA POLYMERASE • Rifampicin

V. FOLIC ACID METABOLISM • TMP/Sulfonamides

THFA

DHFA

50

ATBs: Mechanism of ATBs: Mechanism of actionaction

Terminology of PK/PD of Terminology of PK/PD of ATBATB

T>MIC-dependent bactericidal T>MIC-dependent bactericidal activityactivity Minimal or moderate Minimal or moderate

PAEPAEProlonged PAEProlonged PAE

Antimicrobials Penicillins

Cephalosporins

Carbapenems

Azithromycin Clindamycin

Cotrimoxazole Tetracycline

Vancomycin

Goal of dosing

regimen

Optimize duration of exposure

Optimize amount of drug

Parameters of efficacy

Time above MIC>40-50

Cmax/MIC>4

24-Hr AUC/MIC

Vancomycin (Cmax/MIC>10-20)

Post-antibiotic effect Post-antibiotic effect (PAE)(PAE)

AntibioticsAntibiotics Gram Gram Positive Positive bacteriabacteria

Gram Gram Negative Negative bacteriabacteria

Pseudomonas Pseudomonas aeruginosaaeruginosa

Penicillins 1-2 0 0Cephalosporins 1-2 0 0Carbapenems 1-2 (1) 1-2Quinolones 1-3 1-3 1-2Protein synthesis inhibitors

3-5 3-8

Aminoglycosides 2-4 2-3

Aminoglycosides

Fluoroquinolones

Metronidazole

Concentration-dependent bactericidal Concentration-dependent bactericidal activityactivity

with prolonged PAE with prolonged PAE Goal of dosing Goal of dosing

regimen :regimen :

Maximize concentrationsMaximize concentrations

Parameters of Parameters of efficacyefficacy

1.1. AUC/MIC > 125(-) AUC/MIC > 125(-) 30(+)30(+)

2.2. Cmax/MIC> 8-10Cmax/MIC> 8-10

3.3. In Vivo; T>MICIn Vivo; T>MIC

Concentration-vs-time profile of once-Concentration-vs-time profile of once-daily and conventional regimens daily and conventional regimens

(normal CCr)(normal CCr)

Intracellular PharmacokineticsIntracellular Pharmacokinetics

Betalactam

Aminoglycosides

Tetracyclines

Fluoroquinolones

Macrolides

1 X

< 1-2 X

2-4 X

10-20 X

4 - >100 X

-Lactam

Mechanism of action Inhibit cell wall synthesis by binding to

penicillin-binding proteins (PBPs) Bactericidal (except against Enterococci)

PK/PD Time-dependent killers Time above MIC correlates with efficacy

Cross-allergenicity : except aztreonam

-lactams

• Mechanisms of Resistance production of beta-lactamase enzymes

most important and most common hydrolyzes beta-lactam ring causing

inactivation Alteration in PBPs binding affinity Alteration of outer membrane

penetration

Natural Penicillins

Gram-positive Streptococci DSSP

Gram-negative Neisseria sp.

Anaerobes Above the diaphragm

Other syphilis

Penicillinase-Resistant Penicillins(nafcillin, oxacillin, methicillin) Gram-positive

MSSA Streptococci

Aminopenicillins(ampicillin, amoxicillin)activity against gram-negative

aerobes

Gram-positive Streptococci Susc.Enterococcus

Gram-negative Proteus mirabilis Salmonella, Shigella some E. coli L- H. influenzae L. monocytogenes

Antipseudomonal penicillins (piperacillin)

activity against resistant gram-negative aerobes

Gram-positive streptococci some Enterococcus Gram-negative Proteus mirabilis, Salmonella, Shigella E. coli, L- H. influenzae

Enterobacter sp. Pseudomonas aeruginosa Serratia marcescens some Klebsiella sp. Anaerobes Fairly good activity

BL/BI(-lactams+ -lactamase inhibitor)(Unasyn, Augmentin, Tazocin, Sulperazon) Developed to gain or enhance activity

against -lactamase producing organisms Gram-positive

MSSA

Gram-negative H. influenzae, E. coli, Proteus spp. Klebsiella spp.,

Moraxella catarrhalis Anaerobes

Bacteroides sp.

Generation G + G - Anaerobe

1st

Best G +

Less G -

MSSA

DSSP

Streptococci

E. coli

K. pneumoniae

P. mirabilis

no

2nd

Less G +

More G -

less H.Influenza

M.catarrhalisOnly Cefoxitin

3rd

More G -

+DRSP

(CTR/ CTX)

less (CTZ)

Neisseria

Citrobacter sp., Enterobacter sp., Acinetobacter sp.

Pseudomonas

(CTZ/CPS)

no

4th

1st + 3rd

no

4th gen. Cephalosporins

Extended spectrum of activity gram-positives gram-negatives

Pseudomonas aeruginosa -lactamase producing Enterobacter sp.

Stability against -lactamases poor inducer of ESBLs.

Carbapenems

• Most broad spectrum • Against G+/G-, aerobes/anaerobes• Bacteria not covered by carbapenems

• MRSA, MRSE, • Enterococci HLAR, VRE• C. difficile• S. maltophilia

-Lactams: Adverse Effects

• Hypersensitivity – 3 to 10 % Cross-reactivity exists among all penicillins and other

-lactams Desensitization is possible

• Hematologic Leukopenia, neutropenia, thrombocytopenia –

prolonged therapy (> 2 weeks)

• Neurologic – esp. penicillins, carbapenems, Cefipime, Especially in patients receiving high doses in the presence of renal insufficiency Irritability, jerking, confusion, seizures

-Lactams:Adverse Effects

• Gastrointestinal Increased LFTs, n/v, diarrhea, AAC

Interstitial Nephritis Cellular infiltration in renal tubules Especially with methicillin or nafcillin

• Cephalosporin with MTT side chain (cefamandole, cefoperazone) • Hypoprothrombinemia due to reduction in vitamin K-

producing bacteria in GI tract • Ethanol intolerance

Fluoroquinolones

Mechanism of action:inhibit DNA synthesis

(enz. DNA gyrase, topoisomerase IV) Concentration dependent AUC/MIC correlate with efficacy Bactericidal

FQs: Spectrum Gram-Negative (cipro=levo>gati>moxi)

• Enterobacteriaceae • (E. coli, Klebsiella sp,

Enterobacter sp, Proteus sp, Salmonella, Shigella, Serratia marcescens, etc.)

• H. influenzae, M. catarrhalis, • Neisseria sp. (GC ดื้��อ 6

0 %)

• Pseudomonas aeruginosa cipro, levo

Gram-positive levo,gati,moxiMSSAPRSP Enterococcus sp. – limited

Atypical Bacteria levo,gati,moxiLegionella pneumophila Chlamydia sp.Mycoplasma sp.

OthersMycobacteriumBacillus anthracis

Fluoroquinolones: Pharmacology

Absorption Most FQs have good bioavailability

Distribution Extensive tissue distribution – prostate, liver,

lung, S/ST and bone; urinary tract Minimal CSF penetration

Dose Ciproflox 400 mg I.V. q 8 h Levoflox 750 mg IV OD

Fluoroquinolones:Adverse Effects

• Gastrointestinal – 5 % Nausea, vomiting, diarrhea, dyspepsia

• Central Nervous System Headache, agitation, insomnia, dizziness, rarely,

hallucinations and seizures (elderly)• Hepatotoxicity

LFT elevation (led to withdrawal of trovafloxacin) • Cardiac

Variable prolongation in QTc interval Led to withdrawal of grepafloxacin, sparfloxacin

Fluoroquinolones Adverse Effects

• Articular Damage Arthopathy including articular cartilage damage,

arthralgias, and joint swelling Led to contraindication in pediatric patients and

pregnant or breastfeeding women Risk versus benefit

• Other adverse reactions: tendon rupture, dysglycemias, hypersensitivity

FluoroquinolonesDrug Interactions

• Divalent and trivalent cations – ALL FQs Zinc, Iron, Calcium, Aluminum, Magnesium Antacids, Sucralfate, ddI, enteral feedings Impair oral absorption of orally-administered FQs

– may lead to CLINICAL FAILURE Administer doses 2 to 4 hours apart; FQ first

• Theophylline and Cyclosporine - ciproflox inhibition of metabolism, levels, toxicity

• Warfarin – idiosyncratic, all FQs

Macrolides • Erythromycin is a naturally-occurring

macrolide • Structural derivatives: clarithromycin and

azithromycin: Broader spectrum of activity Improved PK properties – better

bioavailability, better tissue penetration, prolonged half-lives

Improved tolerability

Macrolides• Mechanism of Action

Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit Suppression of RNA-dependent protein synthesis

Macrolides typically display bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms

Time-dependent activity Prolonged PAE

Macrolide: Spectrum Gram-Positive Aerobes (C>E>A)

MSSA Streptococcus pneumoniae (only PSSP) streptococci Bacillus sp., Corynebacterium sp.

Gram-Negative Aerobes – newer macrolides (A>C>E) H. influenzae, M. catarrhalis, Neisseria sp.• Do NOT have activity against any Enterobacteriaceae

• Atypical Bacteria • Legionella, Chlamydia, Mycoplasma• Ricketsia- Azithromycin

• Anaerobes – activity against upper airway anaerobes• Other Bacteria – Mycobacterium avium complex (MAC – only A and C),

Treponema pallidum, Campylobacter, Borrelia, Bordetella, Brucella.

Pasteurella

Macrolides:Adverse Effects• Gastrointestinal – up to 33 %

Nausea, vomiting, diarrhea, dyspepsia Most common with erythro; less with new agents

• Cholestatic hepatitis - rare > 1 to 2 weeks of erythromycin estolate

• Thrombophlebitis – IV Erythro and Azithro Dilution of dose; slow administration

• Other: ototoxicity (high dose erythro in patients with RI); QTc prolongation; allergy

Aminoglycosides• Irreversibly bind to 30S ribosomes• Bactericidal• Distribution

primarily in extracellular fluid volume; are widely distributed into body fluids but NOT the CSF

• Elimination eliminated unchanged by the kidney via

glomerular filtration; 85-95% of dose elimination half-life dependent on renal function

normal renal function - 2.5 to 4 hours impaired renal function - prolonged

Aminoglycosides: Spectrum Gram-Positive Aerobes

Synergistic for Enterococcus sp.

Gram-Negative Aerobes E. coli, K. pneumoniae, Proteus sp. Acinetobacter, Citrobacter, Enterobacter sp. Morganella, Providencia, Serratia, Salmonella,

Shigella Pseudomonas aeruginosa

Mycobacteria tuberculosis NTM

Aminoglycosides Adverse Effects

• Nephrotoxicity Non-oliguric azotemia due to proximal tubule

damage; risk factors: prolonged high troughs, long

duration of therapy (> 2 weeks), underlying renal dysfunction, elderly, other nephrotoxins

• Ototoxicity vestibular and auditory toxicity irreversible risk factors: same as for nephrotoxicity

Vancomycin• Inhibits bacterial cell wall synthesis (at a site

different than beta-lactams)• Bactericidal (except for Enterococcus)• Distribution

widely distributed into body tissues and fluids inconsistent penetration into CSF, even with inflamed

meninges

• Elimination primarily eliminated unchanged by the kidney via

glomerular filtration elimination half-life depends on renal function

Vancomycin:Spectrum Gram-positive bacteria

Methicillin-Susceptible AND Methicillin-Resistant S. aureus and coagulase-negative staphylococci

Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus

Enterococcus sp. Corynebacterium, Bacillus. Listeria, Actinomyces Clostridium sp. (including C. difficile), Peptococcus,

Peptostreptococcus

No activity against gram-negative aerobes or anaerobes

Vancomycin Clinical Uses

• Infections due to MRSA • Serious gram-positive infections in

-lactam allergic patients

• Oral vancomycin for refractory C. difficile colitis

Vancomycin: Adverse Effects

• Red-Man Syndrome flushing, pruritus, erythematous rash on face and upper torso related to RATE of intravenous infusion; should be infused over at

least 60 minutes resolves spontaneously after discontinuation may lengthen infusion (over 2 to 3 hours) or pretreat with

antihistamines in some cases• Nephrotoxicity and Ototoxicity

rare with monotherapy, more common when administered with other nephro- or ototoxins

risk factors include renal impairment, prolonged therapy, high doses, ? high serum concentrations, other toxic meds

• Dermatologic - rash• Hematologic - neutropenia and thrombocytopenia with prolonged

therapy• Thrombophlebitis

Clindamycin

• Inhibits protein synthesis by binding exclusively to the 50S ribosomal subunit

• bacteriostatic activity, but may be bactericidal at high concentrations against very susceptible organisms

Dosing IV 600 - 900 mg q 8 h Oral 300 – 450 mg q 6 h

Clindamycin: Spectrum

Gram-Positive Aerobes • Methicillin-susceptible Staphylococcus aureus

(MSSA only)• Streptococcus pneumoniae (only PSSP) –

resistance is developing• Group and viridans streptococci

• Anaerobes • Other Bacteria – Pneumocystis carinii,

Toxoplasmosis gondii, Malaria

Clindamycin: Pharmacology

• Absorption • Rapidly and completely absorbed (F =

90%); food with minimal effect on absorption

• Distribution• Good serum concentrations with PO or IV• Good tissue penetration including bone• minimal CSF penetration

Clindamycin: Adverse Effects

• Gastrointestinal – 3 to 4 % Nausea, vomiting, diarrhea, dyspepsia

• C. difficile colitis – one of worst offenders Mild to severe diarrhea Requires treatment with metronidazole

• Hepatotoxicity - rare Elevated transaminases

• Allergy - rare

Metronidazole• Mechanism of Action

Ultimately inhibits DNA synthesis concentration-dependent bactericidal

activity

Metronidazole: Adverse Effects

• Gastrointestinal Nausea, vomiting, stomatitis, metallic taste

• CNS – most serious Peripheral neuropathy, seizures, encephalopathy Use with caution in pts with CNS disorders

• Mutagenicity, carcinogenicity Avoid during pregnancy and breastfeeding

Metronidazole -Drug Interactions Drug Interaction

Warfarin* anticoagulant effect Alcohol* Disulfuram reaction Phenytoin phenytoin concentrations Lithium lithium concentrations Phenobarbital metronidazole concentrations Rifampin metronidazole concentrations

Colistin Nephrotoxic :

Toxic ATN Correlate with accumalative dose Onset at first 4 days Process will go on until 1-2 wks Recover within 3-9 wks Neuromuscular blockade, CNS SE

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suspected to be caused by susceptible bacteria.

SE เหม่�อน tetracycline อ�น Anaphylaxis/anaphylactoid reactions Fetal harm, tooth discoloration hepatic dysfunction and hepatic failure have been

reported Acute pancreatitis have been reported

Teicoplanin, Targocid

Glycopeptide antibiotics ADR – same as vancomycin in lower incidience alternative agent in subjects experiencing

severe RMS due to vancomycin Dosing

Loading 400 mg i.v. injection q 12 hrs *3 doses Maintenance dose: 400 mg IV or IM OD

Fosfomycin - phosphonic acid cell-wall inhibitor , Bactericidal little cross-resistance, cross SE Spectrum

MRSA Enterobacteriaceae Enterococci ? A.baumannii MDR

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Mechanisms of antibiotic resistance1. Enzymatic inhibition

2. Target alteration or overproduction

3. Decreased uptake

4. Bypass pathway(s): sulfa, trimethoprim

1.1 Inactivation: b-lactams (b-lactamases)1.2 Modification: aminoglycosides (AG-modifyingenz)

2.1 Alteration• Ribosome: macrolides, lincosamides• Enzymes: b-lactams (PRSP, MRSA),quinolones,

rifampin, sulfa, TMP2.2 Overproduction: sulfa, TMP; glycopeptides (VISA)

3.1 Impermeability: imipenem (Opr-D def.)3.2 Active efflux pump: tetracycline, b-lactams,

quinolones

= antibiotic2. Target alteration

1.1 Enzymatic inactivation

1.2 Enzymatic modification

3.1 Impermeability

D B

A B C

4. Bypass pathway

3.2 Efflux pump

Types of antibiotic resistanceI. Intrinsic (primary) resistance

II. Extrinsic (secondary, acquired) resistance

• Chromosomal change•Micro-evolutionary change (antigenic drift): point mutation•Macro-evolutionary change (antigenic shift): inversions, duplications etc

• Plasmids: transformation (Tf), transduction (Td), conjugation (Cj)• Transposons/integrons: Tf, Td or Cj• Bacteriophages: Td• Genomic islands: Td• Naked foreign DNA: Tf

Gram-positive

PRSP MRSA VISA, VRSA VRE MLS-R-GAS

• Target• Chr

• Target• Tn/Pl

• Target (VISA)• Target (VRSA)• Pl/Tn

• Target• Plasmid/Tn

• Target• Efflux• Chr/Tn/Pl• Enz. Inacti- vation• Chr. or PlGram-negative

b-lactamase- producing organisms

Quinolone-R Efflux-mediated

• ESBL• AmpC• Carbapenemases

• Target (Chr)• Efflux (Chr >Pl)

• Chr > Pl

Transduction

ChromosomePlasmid

Nucleus

Naked foreign DNA

Transformation

Bacterial cell (+)

Bacterial cell (-)Conjugation

BacteriaNucleus

Chromosome

1. Plasmid

2. Transposon

mutation, inversion

3. Integronint I

att I

gene cassette

4. GI