สำหรับเพื่อนแพทย์

1. Antibiotics

2. Approach to ID
Host setting + Clinical syndrome
Disease ? 
Possible pathogens
Bug ? Proper lab & investigations

Empyrical Rx
Drug?
F/U clinical parameters
SPECIFIC treatment

3. Gram-Positive Gram-Negative
COCCI COCCI
clusters- Moraxella catarrhalis
Staphylococci Neisseria gonorrhoeae
Neisseria meningitidis
pairs and chains
- Sreptococci
- Enterococcus sp. COCCOBACILLI
BACILLI H. influenzae, Acinetobacter
Bacillus sp.
BACILLI
Corynebacterium sp.
Enterobacteriaceae (E. coli,
Listeria Enterobacter sp. Citrobacter,
monocytogenes Klebsiella sp.Proteus sp., Serratia
Salmonella, Shigella)
Nocardia sp.
Pseudomonas aeruginosa
Burkholderia pseudomallei
Non fermentative GNB

4. Anaerobes Higher bacteria
Above Diaphragm Mycobacterium spp.
 Peptococcus sp. TB, NTM
 Peptostreptococcus sp.
 Prevotella
Nocardia
Veillonella
Other Pathogen

 Actinomyces
 Spirochete:
 Leptospirosis
Below Diaphragm
 Clostridium perfringens, tetani,
 Syphilis
and difficile  Ricketsia:
 Bacteroides fragilis, disastonis,  Scrub typhus
ovatus, thetaiotamicron
 Murine typhus
 Fusobacterium
 Legionella
 Mycoplasma
 Chlamydia

5. Bacteria by Site of Infection
Meningitis Skin/Soft Tissue Endocarditis
S. pneumoniae S. aureus Viridian strep
N. meningitidis S. pyogenes S.bovis
H. influenza S. epidermidis Enterococcus
Streptococci Exposed organism
E. coli, listeria
Abdomen Urinary Tract Bone and Joint
E. coli, Proteus E. coli, Proteus S. aureus
Klebsiella Klebsiella S. epidermidis
Enterococcus Enterococcus Streptococci
Bacteroides sp. Staph saprophyticus Nram-negative rods
Upper Respiratory LRI Community LRI Hospital
S. pneumoniae S. pneumoniae A. baumannii
H. influenzae H. influenzae P. aeruginosa
M. catarrhalis K. pneumoniae K. pneumoniae
S. pyogenes Legionella,Mycoplasma, Enterobacter sp.
Chlamydia, Ricketsia¤, S. aureus

6. 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

7. ATBs: Mechanism of
V. FOLIC ACID METABOLISMI. action
CELL WALL SYNTHESIS
• TMP/Sulfonamides • Vancomycin, Fosfomycin, bacitrac
• Beta-lactams
II. DNA Synthesis
• Quinolones
•Metronidazole
THFA DNA
mRNA III. DNA-DEPENDENT
DHFA RNA POLYMERASE
• Rifampicin
ribosomes
30 IV. PROTEIN
50 SYNTHESIS
- 30S INHIBITORS
• Tetracycline
•
PABA VI. CELL MEMBRANE Aminoglycoside•
• Polymyxin B - 50S INHIBITORS
• Colistin • Macrolide

8. Terminology of PK/PD of
ATB

9. T>MIC-dependent bactericidal activity
Minimal or moderate Prolonged PAE
PAE
Antimicrobials Penicillins Azithromycin
Clindamycin
Cephalosporins
Cotrimoxazole
Carbapenems Tetracycline
Vancomycin
Goal of Optimize duration of Optimize amount of
dosing exposure drug
regimen
Parameters of Time above MIC>40-50 24-Hr AUC/MIC
efficacy Cmax/MIC>4 Vancomycin
(Cmax/MIC>10-20)

10. Post-antibiotic effect (PAE)
Antibiotics Gram Gram Pseudomonas
Positive Negative aeruginosa
bacteria bacteria
Penicillins 1-2 0 0
Cephalosporins 1-2 0 0
Carbapenems 1-2 (1) 1-2
Quinolones 1-3 1-3 1-2
Protein synthesis 3-5 3-8
inhibitors
Aminoglycosides 2-4 2-3

11. Concentration-dependent bactericidal
activity
with prolonged PAE
Goal of dosing
regimen :
Aminoglycosides Maximize concentrations
Fluoroquinolones Parameters of efficacy
Metronidazole 4. AUC/MIC > 125(-) 30(+)
5. Cmax/MIC> 8-10
6. In Vivo; T>MIC

12. Concentration-vs-time profile of once-daily
and conventional regimens (normal CCr)

14. Intracellular Pharmacokinetics
Betalactam ≤ 1X
Aminoglycosides < 1-2 X
Tetracyclines 2-4 X
Fluoroquinolones 10-20 X
Macrolides 4 - >100 X

15. β-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

16. β-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

17. Penicillinase-Resistant
Natural Penicillins Penicillins
(nafcillin, oxacillin, methicillin)
 Gram-positive
 Streptococci  Gram-positive
 DSSP  MSSA
 Gram-negative  Streptococci
 Neisseria sp.
 Anaerobes
 Above the diaphragm
 Other
 syphilis

18. Aminopenicillins Antipseudomonal
(ampicillin, amoxicillin) penicillins (piperacillin)
↑activity against gram-
negative aerobes  ↑ activity against resistant
gram-negative aerobes
 Gram-positive  Gram-positive
 streptococci
 Streptococci  some Enterococcus
 Susc.Enterococcus  Gram-negative
 Proteus mirabilis, Salmonella, Shigella
 Gram-negative  E. coli, βL- H. influenzae
 Enterobacter sp.
 Proteus mirabilis  Pseudomonas aeruginosa
 Salmonella, Shigella  Serratia marcescens
 some E. coli  some Klebsiella sp.
 βL- H. influenzae  Anaerobes Fairly good activity
 L. monocytogenes


19. BL/BI(β-lactams+ β-lactamase inhibitor)
(Unasyn, Augmentin, Tazocin, Sulperazon)
 Developed to gain or enhance activity
against β-lactamase producing organisms
 Gram-positive
 MSSA
 Gram-negative
 H. influenzae, E. coli, Proteus spp. Klebsiella spp.,
Moraxella catarrhalis
 Anaerobes
 Bacteroides sp.

20. Generation G+ G- Anaerobe
MSSA E. coli no
1 st
K. pneumoniae
DSSP
Best G +
Streptococci P. mirabilis
Less G -
less H.Influenza Only
2 nd
M.catarrhalis
Less G +
Cefoxitin
More G -
Neisseria
3 rd +DRSP no
Citrobacter sp.,
More G - (CTR/ CTX) Enterobacter sp.,
Acinetobacter sp.
Pseudomonas
less (CTZ) (CTZ/CPS)
4th no
1st + 3rd

21. 4 gen. Cephalosporins
th
 Extended spectrum of activity
 gram-positives
 gram-negatives
 Pseudomonas aeruginosa
 β-lactamase producing Enterobacter sp.
against β-lactamases
 Stability
 poor inducer of ESBLs.

22. Carbapenems
• Most broad spectrum
• Against G+/G-, aerobes/anaerobes
• Bacteria not covered by carbapenems
• MRSA, MRSE,
• Enterococci HLAR, VRE
• C. difficile
• S. maltophilia

23. β-Lactams: Adverse Effects
• Hypersensitivity – 3 to 10 %
 Cross-reactivity exists among all penicillins and other
β-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

24. β-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

25. Fluoroquinolones
 Mechanism of action:
inhibit DNA synthesis
(enz. DNA gyrase, topoisomerase IV)
 Concentration dependent
 AUC/MIC correlate with efficacy
 Bactericidal

26. FQs: Spectrum
 Gram-Negative Gram-positive levo,gati,moxi
 (cipro=levo>gati>moxi) MSSA
PRSP
• Enterobacteriaceae Enterococcus sp. – limited
• (E. coli, Klebsiella sp,
Enterobacter sp, Proteus Atypical Bacteria levo,gati,moxi
sp, Salmonella, Shigella,
Serratia marcescens, etc.) Legionella pneumophila
• H. influenzae, M. Chlamydia sp.
catarrhalis, Mycoplasma sp.
• Neisseria sp. (GC ดือ ้
60%) Others
Mycobacterium
• Pseudomonas aeruginosa Bacillus anthracis
cipro, levo

27. 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

28. 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

29. 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

30. Fluoroquinolones
Drug 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. Vancomycin Clinical Uses
• Infections due to MRSA
• Serious gram-positive infections in
β-lactam allergic patients
• Oral vancomycin for refractory C.
difficile colitis

41. 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

42. 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

43. 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

44. 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

45. 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

46. Metronidazole
• Mechanism of Action
 Ultimately inhibits DNA synthesis
 concentration-dependent bactericidal
activity

47. 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

48. Metronidazole -Drug Interactions
 Drug Interaction
 Warfarin* ↑ anticoagulant effect
 Alcohol* Disulfuram reaction
 Phenytoin ↑ phenytoin concentrations
 Lithium ↑ lithium concentrations
 Phenobarbital ↓ metronidazole concentrations
 Rifampin ↓ metronidazole concentrations

49. 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

50. 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
 เหมือน tetracycline อื่น
 Anaphylaxis/anaphylactoid reactions
 Fetal harm, tooth discoloration
 hepatic dysfunction and hepatic failure have been
reported
 Acute pancreatitis have been reported

51. 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

52. Fosfomycin - phosphonic acid
 cell-wall inhibitor , Bactericidal
 little cross-resistance, cross SE
 Spectrum
 MRSA
 Enterobacteriaceae
 Enterococci
 ? A.baumannii MDR
 Dose
 4-6 กรัมต่อวัน อาจจะเพิ่มได้ถง 4-8 กรัมต่อครั้ง วัน
ึ
ละ 3 ครั้ง สำาหรับการรักษาบริเวณที่ยาทั่วไปเข้าถึง
ยาก หรือ เป็นเชือที่มีค่า MIC สูง
้

53. Mechanisms of antibiotic resistance
1. Enzymatic inhibition
1.1 Inactivation: b-lactams (b-lactamases)
1.2 Modification: aminoglycosides (AG-modifying enz)
2. Target alteration or overproduction
2.1 Alteration
• Ribosome: macrolides, lincosamides
• Enzymes: b-lactams (PRSP, MRSA),quinolones,
rifampin, sulfa, TMP
2.2 Overproduction: sulfa, TMP; glycopeptides (VISA)
3. Decreased uptake
3.1 Impermeability: imipenem (Opr-D def.)
3.2 Active efflux pump: tetracycline, b-lactams,
quinolones
4. Bypass pathway(s): sulfa, trimethoprim

54. = antibiotic
2. Target alteration
3.1 Impermeability
1.1 Enzymatic inactivation
D B
3.2 Efflux
.2 Enzymatic modification
A B C pump
4. Bypass pathway

55. Types of antibiotic resistance
I. Intrinsic (primary) resistance
• Chromosomal change
•Micro-evolutionary change (antigenic drift): point mutation
•Macro-evolutionary change (antigenic shift): inversions,
duplications etc
II. Extrinsic (secondary, acquired) resistance
• Plasmids: transformation (Tf), transduction (Td),
conjugation (Cj)
• Transposons/integrons: Tf, Td or Cj
• Bacteriophages: Td
• Genomic islands: Td
• Naked foreign DNA: Tf

56. Gram-positive
PRSP MRSA VISA, VRSA VRE MLS-R-GAS
• Target • Target • Target • Target • Target
• Chr • Tn/Pl (VISA) • Plasmid/Tn • Efflux
• Target (VRSA) • Chr/Tn/Pl
• Pl/Tn • Enz. Inacti-
vation
Gram-negative • Chr. or Pl
b-lactamase- Quinolone-R Efflux-mediated
producing
organisms • Target (Chr) • Chr > Pl
• ESBL • Efflux (Chr >Pl)
• AmpC
• Carbapenemases

57. Naked foreign DNA
Nucleus Transformation
Trans Chromosome
duction Plasmid
Bacterial cell (+)
Conjugation
Bacterial cell (-)

58. Chromosome
1. Plasmid
mutation,
inversion
4. GI
att I
2. Transposon
int I gene cassette
3. Integron
Nucleus
Bacteria