5. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
ï° Mechanism of action
include:
ïź Inhibition of cell wall
synthesis
ïź Inhibition of protein
synthesis
ïź Inhibition of nucleic acid
synthesis
ïź Inhibition of metabolic
pathways
ïź Interference with cell
membrane integrity
6. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
ï° Inhibition of Cell wall synthesis
ïź Bacteria cell wall unique in
construction
ï° Contains peptidoglycan
ïź Antimicrobials that interfere with
the synthesis of cell wall do not
interfere with eukaryotic cell
ï° Due to the lack of cell wall in
animal cells and differences in cell
wall in plant cells
ïź These drugs have very high
therapeutic index
ï° Low toxicity with high effectiveness
ïź Antimicrobials of this class include
ï° ÎČ lactam drugs
ï° Vancomycin
ï° Bacitracin
7. ï° Inhibition of protein synthesis
ïź Structure of prokaryotic ribosome acts as target for
many antimicrobials of this class
ï° Differences in prokaryotic and eukaryotic ribosomes
responsible for selective toxicity
ïź Drugs of this class include
ï° Aminoglycosides
ï° Tetracyclins
ï° Macrolids
ï° Chloramphenicol
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
8. ï° Inhibition of nucleic acid synthesis
ïź These include
ï° Fluoroquinolones
ï° Rifamycins
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
9. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
ï° Inhibition of metabolic
pathways
ïź Relatively few
ïź Most useful are folate
inhibitors
ï° Mode of actions to
inhibit the production
of folic acid
ïź Antimicrobials in this
class include
ï° Sulfonamides
ï° Trimethoprim
10. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
ï° Interference with cell
membrane integrity
ïź Few damage cell
membrane
ï° Polymixn B most common
ï§ Common ingredient in
first-aid skin ointments
ïź Binds membrane of Gram
- cells
ï° Alters permeability
ï§ Leads to leakage of cell
and cell death
ï° Also bind eukaryotic cells
but to lesser extent
ï§ Limits use to topical
application
11. EFFECTS OF
COMBINATIONS OF DRUGS
ï° Sometimes the chemotherapeutic effects of
two drugs given simultaneously is greater than
the effect of either given alone.
ï° This is called synergism. For example,
penicillin and streptomycin in the treatment
of bacterial endocarditis. Damage to
bacterial cell walls by penicillin makes it
easier for streptomycin to enter.
12. EFFECTS OF
COMBINATIONS OF DRUGS
ï° Other combinations of drugs can be
antagonistic.
ï° For example, the simultaneous use of penicillin
and tetracycline is often less effective than
when wither drugs is used alone. By stopping
the growth of the bacteria, the
bacteriostatic drug tetracycline interferes
with the action of penicillin, which requires
bacterial growth.
13. EFFECTS OF
COMBINATIONS OF DRUGS
ï° Combinations of antimicrobial drugs should
be used only for:
1. To prevent or minimize the emergence of
resistant strains.
2. To take advantage of the synergistic effect.
3. To lessen the toxicity of individual drugs.
18. Concepts
Pharmacokinetics
â describe how drugs behave in the human host
Pharmacodynamics
â the relationship between drug concentration
and antimicrobial effect. âTime course of
antimicrobial activityâ
19. Minimum Inhibitory Concentration (MIC)
â The lowest concentration of an antibiotic that inhibits
bacterial growth after 16-20 hrs incubation.
Minimum Bacteriocidal Concentrations.
â The lowest concentration of an antibiotic required to
kill 99.9% bacterial growth after 16-20 hrs exposure.
C-p
â Peak antibiotic concentration
Area under the curve (AUC)
â Amount of antibiotic delivered over a specific time.
Concepts
20. Antimicrobial-micro-organism
interaction
Antibiotic must reach the binding site of
the microbe to interfere with the life cycle.
Antibiotic must occupy âsufficientâ number
of active sites.
Antibiotic must reside on the active site for
âsufficientâ time. Antibiotics are not contact
poisons.
22. Questions
Can this antibiotic inhibit/kill these bacteria?
Can this antibiotic reach the site of bacterial replication?
What concentration of this antibiotic is needed to
inhibit/kill bacteria?
Will the antibiotic kill better or faster if we increase its
concentration?
Do we need to keep the antibiotic concentration always
high throughout the day?
23. Can this antibiotic inhibit/kill these bacteria?
In vitro susceptibility testing
Mixing bacteria with antibiotic at different
concentrations and observing for bacterial
growth.
24. 32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/ml
Sub-culture to agar medium
MIC = 8 ug/ml
MBC = 16 ug/ml
Minimal Inhibitory Concentration (MIC)
vs.
Minimal Bactericidal Concentration (MBC)
REVIEW
25. What concentration of this antibiotic is
needed to inhibit/kill bacteria?
In vitro offers some help
â Concentrations have to be above the MIC.
How much above the MIC?
How long above the MIC?
Time
Conc
MIC
26. Patterns of Microbial Killing
Concentration dependent
â Higher concentration greater killing
Aminoglycosides, Flouroquinolones, Ketolides,
metronidazole, Ampho B.
Time-dependent killing
â Minimal concentration-dependent killing (4x
MIC)
â More exposure more killing
Beta lactams, glycopeptides, clindamycin,
macrolides, tetracyclines, bactrim
27. Persistent Effects
Persistent suppression of bacterial growth
following antimicrobial exposure.
â Moderate to prolonged against all GM
positives (In vitro)
â Moderate to prolonged against GM negatives
for protein and nucleic acid synthesis
inhibitors.
â Minimal or non against GM negatives for beta
lactams (except carabapenems against P.
aeruginosa)
28. Post-antibiotic sub-MIC effect.
â Prolonged drug level at sub-MIC augment the
post-antibiotic effect.
Post-antibiotic leukocyte killing enhancement.
â Augmentation of intracellular killing by
leukocytes.
â The longest PAE with antibiotics exhibiting this
characteristic.
Persistent Effects
29. Patterns of Antimicrobial Activity
Concentration dependent with moderate to
prolonged persistent effects
â Goal of dosing
Maximize concentrations
â PK parameter determining efficacy
Peak level and AUC
â Examples
Aminoglycosides, Flouroquinolones, Ketolides,
metronidazole, Ampho B.
30. Time-dependent killing and minimal to
moderate persistent effects
â Goal of dosing
Maximize duration of exposure
â PK parameter determining efficacy
Time above the MIC
â Examples
Beta lactam, macrolides, clindamycin, flucytosine,
linezolid.
Patterns of Antimicrobial Activity
31. Patterns of Antimicrobial Activity
Time-dependent killing and prolonged
persistent effects
â Goal of dosing
Optimize amount of drug
â PK parameter determining efficacy
AUC
â Examples
Azithromycin, vancomycin, tetracyclines,
fluconazole.
33. Antibacterial spectrum â Range of activity
of an antim icrobial against bacteria. A
broad-spectrum antibacterial drug can
inhibit a wide variety of gram -positive and
gram -negative bacteria, whereas a
narrow -spectrum drug is active only
against a lim ited variety of bacteria.
Bacteriostatic activityâ -The level of
antim icro-bial activity that inhibits the
growth of an organism . This is determ ined
in vitro by testing a standardized
concentration of organism s against a
series of antim icrobial dilutions. The
lowest concentration that inhibits the
growth of the organism is referred to as
the m inim um inhibitory concentration
(M IC).
Bactericidal activityâ The level of
antim icrobial activity that kills the test
organism . This is determ ined in vitro by
exposing a standardized concentration of
organism s to a series of antim icrobial
dilutions. The lowest concentration that
kills 99.9% of the population is referred to
as the m inim um bactericidal
concentration (M BC).
Antibiotic com binationsâ Com binations of
antibiotics that m ay be used (1) to broaden
the antibacterial spectrum for em piric
therapy or the treatm ent of polym icrobial
infections, (2) to prevent the em ergence of
resistant organism s during therapy, and (3)
to achieve a synergistic killing effect.
Antibiotic synergism â Com binations of
two antibiotics that have enhanced
bactericidal activity when tested together
com pared with the activity of each
antibiotic.
Antibiotic antagonism â Com bination of
antibiotics in which the activity of one
antibiotic interferes W ith the activity of the
other (e.g., the sum of the activity is less
than the activity of the individual drugs).
Beta-lactam aseâ An enzym e that
hydrolyzes the beta-lactam ring in the
beta-lactam class of antibiotics, thus
inactivating the antibiotic. The enzym es
specific for penicillins and cephalosporins
aret he penicillinases and
cephalosporinases, respectively.
35. Resistance
Physiological Mechanisms
4. Altered target
ïŒ RIF â altered RNA polymerase (mutants)
ïŒ NAL â altered DNA gyrase
ïŒ STR â altered ribosomal proteins
ïŒ ERY â methylation of 23S rRNA
5. Synthesis of resistant pathway
ïŒ TMPr plasmid has gene for DHF reductase;
insensitive to TMP
(contâd)
REVIEW
36. Resistance to ÎČ-Lactams â Gram pos.
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
(contâd)
REVIEW
37. Resistance to ÎČ-Lactams â Gram neg.
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
(contâd)
REVIEW
38. The Ideal Drug*
1. Selective toxicity: against target pathogen but
not against host
ïŒ LD50 (high) vs. MIC and/or MBC (low)
2. Bactericidal vs. bacteriostatic
3. Favorable pharmacokinetics: reach target site
in body with effective concentration
4. Spectrum of activity: broad vs. narrow
5. Lack of âside effectsâ
ïŒ Therapeutic index: effective to toxic dose ratio
6. Little resistance development
39. 39
Pneumonias â Classification
âą Community AcquiredCAP
âą Health Care AssociatedHCAP
âą Hospital AcquiredHAP
âą ICU AcquiredICUAP
âą VentilatorAcquiredVAP
Nosocomial Pneumonias
40. *HAP: diagnosis made > 48h after admission
*VAP: diagnosis made 48-72h after endotracheal
intubation
*HCAP: diagnosis made < 48h after admission
with any of the following risk factors:
(1) hospitalized in an acute care hospital for >
48h within 90d of the diagnosis;
(2) resided in a nursing home or long-term care
facility;
(3) received recent IV antibiotic therapy,
chemotherapy, or wound care within the 30d
preceding the current diagnosis; and
(4) attended a hospital or hemodialysis clinic
Definitions of NP
41. The American Thoracic Society suggests that the
diagnosis should be considered in any patient with new or
progressive radiological infiltrates and clinical features to
suggest infection:
âąFever (core temperature >38°C),
âą Leukocytosis (>10000mm-3) or leukopenia (<4000mm-3),
âąPurulent tracheal secretions,
âąIncreased oxygen requirements, reflecting new or
worsening hypoxaemia.
Diagnosis
47. Gram-negative bacilli, particularly enterobacteria, are
present in the oropharyngeal flora of patients with chronic
underlying illnesses, such as COPD, heart failure,
neoplasms, AIDS and chronic renal failure.
Infection by P. aeruginosa and other more resistant
Gram-negative bacilli such as Acinetobacter
baumannii and ESBL-producing enterobacteria should
be considered in patients discharged from ICUs,
submitted to wide-spectrum antibiotic treatment and in
those with severe underlying disease or prolonged
hospitalisation in areas with a high prevalence of these
microorganisms.
Risk Factors
48. An increased risk for Legionella spp. should be
considered in immunosuppressed patients (previous
treatment with high-dose steroids or chemotherapy.
Gingivitis or periodontal disease, depressed
consciousness, swallowing disorders and orotracheal
manipulation are usually recorded when anaerobes are
the causative agents of the pneumonia
Coma, head injury, diabetes, renal failure or recent
influenza infection are at risk from infection by S.
aureus.
Risk Factors
49. HAP due to fungi such as Aspergillusmay develop in
organ transplant, neutropenic or immunosuppressed
patients, especially those treated with corticoids.
Risk Factors
50. Risk for ventilator-associated pneumonia
due to multidrug-resistant pathogens
Hospitalisation
Especially if intubated and in the ICU for â„5â days (late-onset
infection)
Prior antibiotic therapy
Particularly in the prior 2â weeks
Recent hospitalisation in the preceding 90â days
Other HCAP risk factors
From a nursing home
Haemodialysis
Home-infusion therapy
Poor functional status
Risk factors for specific pathogens
Pseudomonas aeruginosa
Prolonged ICU stay
Corticosteroids
Structural lung disease
Methicillin-resistant Staphylococcus aureus
Coma
Head trauma
Diabetes
Renal failure
Prolonged ICU stay
Recent antibiotic therapy
51. The optimal empiric monotherapy for nosocomial
pneumonia consists of ceftriaxone, ertapenem,
levofloxacin, or moxifloxacin. Monotherapy may be
acceptable in patients with early onset hospital-
acquired pneumonia.
Avoid monotherapy with ciprofloxacin,
ceftazidime, or imipenem, as they are likely to
induce resistance potential.
Empiric monotherapy versus
combination therapy
52. Late-onset hospital-acquired pneumonia,
ventilator-associated pneumonia, and health
careâassociated pneumonia require
combination therapy using an antipseudomonal
cephalosporin, beta lactam, or carbapenem
plus an antipseudomonal fluoroquinolone or
aminoglycoside plus an agent such as linezolid
or vancomycin to cover MRSA
Empiric monotherapy versus
combination therapy
53. Optimal combination regimens for proven P
aeruginosa nosocomial pneumonia include (1)
piperacillin/tazobactam plus amikacin or (2) meropenem
plus levofloxacin, aztreonam, or amikacin.[12]
Avoid using ciprofloxacin, ceftazidime, gentamicin, or
imipenem in combination regimens, as combination
therapy does not eliminate the resistance potential of
these antibiotics.
Empiric monotherapy versus
combination therapy
54. When selecting an aminoglycoside for a combination
therapy regimen, amikacin once daily is preferred to
gentamicin or tobramycin to avoid resistance problems.
When selecting a quinolone in a combination therapy
regimen, use levofloxacin, which has very good antiâ P
aeruginosa activity (equal or better than ciprofloxacin at
a dose of 750 mg).
Empiric monotherapy versus
combination therapy
55. Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Pseudomonas aeruginosa
*Piperacillin-tazobactam 4.5 g IV q6h plus amikacin 20 mg/kg/day
IV plus levofloxacin 750 mg IV q24h or
*Cefepime 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin
750 mg IV q24h or
*Imipenem 1 g q6-8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750
mg IV q24h or
*Meropenem 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin
750 mg IV q24h or
*Aztreonam 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin
750 mg IV q24h
Duration of therapy: 10-14d
56. Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Klebsiella pneumoniae
Cefepime 2 g IV q8h or
Ceftazidime 2 g IV q8h or
Imipenem 500 mg IV q6h or
Meropenem 1 g IV q8h or
Piperacillin-tazobactam 4.5 g IV q6h
Extended-spectrum beta-lactamase (ESBL)strain
Imipenem 500 mg IV q6h or
Meropenem 1 g IV q8h
K pneumoniae carbapenemase (KPC) strain
Colistin 5 mg/kg/day divided q12h or
Tigecycline 100 mg IV, then 50 mg IV q12h
Duration of therapy: 8-14d
57. Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
MRSA
Vancomycin 15 mg/kg IV q12h for 7-14 d or
Linezolid 600mg IV or PO q12h for 7-14 d
Targocid 400mg IV once daily for 7-14 d
58. Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
MSSA
Oxacillin 1g IV q4-6h for 7-14 d or
Nafcillin 1-2 g IV q6h for 7-14 d
59. Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Legionella pneumophila
Levofloxacin 750 mg IV q24h, then 750 mg/day PO for 7-
14d or
Moxifloxacin 400 mg IV or PO q24h for 7-14d or
Azithromycin 500 mg IV q24h for 7-10d
60. Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Acinetobacter baumannii
Imipenem 1 g IV q6h or
Meropenem 1 g IV q8h or
Doripenem 500 mg IV q8h or
Ampicillin-sulbactam 3 g IV q6h or
Tigecycline 100 mg IV in a single dose, then 50 mg IV
q12h or
Colistin 5 mg/kg/day IV divided q12h
Duration of therapy: 14-21d
61. Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Stenotrophomonas maltophilia
Trimethoprim-sulfamethoxazole 15-20 mg/kg/day of TMP
IV or PO divided q8h or
Ticarcillin-clavulanate 3 g IV q4h or
Ciprofloxacin 750 mg PO or 400 mg IV q12h or
Moxifloxacin 400 mg PO or IV q24h
Duration of therapy: 8-14d
62. Category Circumstances Treatment
Severe HAP# Severity criteria
Cefepime 2â g every 8â h + aminoglycoside (Amikacin
20â mg·kgâ1·dayâ1) or quinolone (Levofloxacin 750 mg i.v.
HAP with risk factors for
Gram-negative bacilli Chronic underlying disease Antipseudomonal ÎČ-lactam± aminoglycoside or quinolone
Cefepime 1â2â g every 8â12â h i.v.
Carbapenems¶: imipenem 500â mg every 6â h or 1â g every
8â h i.v.; or meropenem 1â g every 8â h i.v.; or
ertapenem+ 1â g·dayâ1i.v.
P. aeruginosaand multi-
resistant Gram-negative
bacilli
Wide-spectrum antibiotics, severe
underlying disease, ICU stay
Antipseudomonal ÎČ-lactam±aminoglycoside or quinolone
Cefepime 1â2â g every 8â12â h i.v.
ÎČ-lactamic/ÎČ-lactamase inhibitor: piperacillin-tazobactam
4.5â g every 6â hi.v.
Carbapenems¶: imipenem 500â mg every 6â h or 1â g every
8â h i.v.; or meropenem 1â g every 8â h i.v.
Legionella#
Hospital potable water colonisation and/or
previous nosocomial Legionellosis
Levofloxacin 500â mg every 12â24â h i.v.or 750§ mg every
24â h i.v. or azitromycin 500â mg·dayâ1 i.v.
Anaerobes
Gingivitis or periodontal disease,
depressed consciousness, swallowing
disorders and orotracheal manipulation
Carbapenems¶: imipenem 500â mg every 6â h or 1â g every
8â h i.v.; or meropenem 1â g every 8â h i.v.; or
ertapenem+ 1â g·dayâ1i.v.
ÎČ-lactam/ÎČ-lactamase inhibitor amoxicillin/clavulanate 2â g
every 8â hi.v.¶; piperacillin-tazobactam 4.5â g every 6â h i.v.
MRSA
Risk factors for MRSA or high prevalence
of MRSA
Vancomycin 15â mg·kgâ1 every 12â h i.v.Linezolid 600â mg
every 12â h i.v.
Aspergillus
Corticotherapy, neutropenia or
transplantation
Amphotericyn B desoxicolate 1â mg·kgâ1·dayâ1 i.v. or
amphotericyn liposomal 3â5â mg·kgâ1·dayâ1 i.v.Voriconazol
6â mg·kgâ1 every 12â h i.v.(day 1) and 4â mg·kgâ1 every
12â h i.v.(following days)
Early-onset HAP <5â days Without risk factors and non-severe
ÎČ-lactam/ÎČ-lactamase inhibitor: amoxicillin/clavulanate 1â2â g
every 8â hi.v.
Third generation non-pseudomonal cephalosporin:
ceftriaxone 2â g·dayâ1i.v./i.m. or cefotaxime 2â g every 6â8â hi.v.
Fluoroquinolones: levofloxacin 500â mg every 12â24â h i.v. or
750§ mg·dayâ1 i.v.
Late-onset HAP â„ 5â days Without risk factors and non-severe
Antipseudomonal cephalosporin (including pneumococcus):
cefepime 2â g every 8â h i.v.
Fluoroquinolones: levofloxacin 500â mg every 12â24â h i.v. or
750§ mg·dayâ1 i.v.