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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
TYGACIL® (tigecycline) Mechanism - inhibiting protein synthesis Board spectrum, (ไม่� cover Pseudomonas) limit used only to treat infections proven or strongly
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
Dose - 46 กรั�ม่ต่�อวั�น อาจจะเพิ่�ม่ได้�ถึ�ง - 48 กรั�ม่ต่�อครั��ง วั�นละ 3 ครั��ง
สำ�าหรั�บการัรั�กษาบรั�เวัณที่$ยาที่�วัไปเข้�าถึ�งยาก หรั�อ เป(นเชื้��อที่$ม่$ค�า MIC สำ*ง
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