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
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
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
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
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
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
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